Current Medical Diagnosis & Treatment 2015

24

Nervous System Disorders

Michael J. Aminoff, MD, DSc, FRCP
Geoffrey A. Kerchner, MD, PhD

HEADACHE

Headache is such a common complaint and can occur for so many different reasons that its proper evaluation may be difficult. New, severe, or acute headaches are more likely than chronic headaches to relate to an intracranial disorder; the approach to such headaches is discussed in Chapter 2Chronic headaches may be primary or secondary to another disorder. Common primary headache syndromes include migraine, tension-type headache, and cluster headache. Important secondary causes to consider include intracranial lesions, head injury, cervical spondylosis, dental or ocular disease, temporomandibular joint dysfunction, sinusitis, hypertension, depression, and a wide variety of general medical disorders. Although underlying structural lesions are not present in most patients presenting with headache, it is nevertheless important to bear this possibility in mind. About one-third of patients with brain tumors, for example, present with a primary complaint of headache.

  1. Migraine

 ESSENTIALS OF DIAGNOSIS

 Headache, usually pulsatile.

 Pain is typically, but not always, unilateral.

 Nausea, vomiting, photophobia, and phonophobia are common accompaniments.

 An aura of transient neurologic symptoms (commonly visual) may precede head pain.

 Commonly, head pain occurs with no aura.

 General Considerations

The pathophysiology of migraine probably relates to neurovascular dysfunction. Headache results from the dilatation of blood vessels innervated by the trigeminal nerve caused by release of neuropeptides from parasympathetic nerve fibers approximating these vessels. Migraine often exhibits a complex, polygenic pattern of inheritance. Sometimes, an autosomal dominant inheritance pattern is apparent, as infamilial hemiplegic migraine (FHM), in which attacks of lateralized weakness represent the aura. Mutations in three associated genes—ATP1A2,CACNA1A, and SCN1A—account for about three-quarters of cases.

 Clinical Findings

Classic migrainous headache is a lateralized throbbing headache that occurs episodically following its onset in adolescence or early adult life. In many cases, however, the headaches do not conform to this pattern, although their associated features and response to antimigrainous preparations nevertheless suggest that they have a similar basis. In this broader sense, migrainous headaches may be lateralized or generalized, may be dull or throbbing, and are sometimes associated with anorexia, nausea, vomiting, photophobia, phonophobia, osmophobia, cognitive impairment, and blurring of vision. They usually build up gradually and may last for several hours or longer. Focal disturbances of neurologic function may precede or accompany the headaches and have been attributed to constriction of branches of the internal carotid artery. Visual disturbances occur commonly and may consist of field defects; of luminous visual hallucinations such as stars, sparks, unformed light flashes (photopsia), geometric patterns, or zigzags of light; or of some combination of field defects and luminous hallucinations (scintillating scotomas). Other focal disturbances such as aphasia or numbness, paresthesias, clumsiness, dysarthria, dysequilibrium, or weakness in a circumscribed distribution may alsooccur.

In rare instances, the neurologic or somatic disturbance accompanying typical migrainous headaches becomes the sole manifestation of an attack (“migraine equivalent”). Very rarely, the patient may be left with a permanent neurologic deficit following a migrainous attack, and migraine with aura may be a risk factor for stroke.

Patients often give a family history of migraine. Attacks may be triggered by emotional or physical stress, lack or excess of sleep, missed meals, specific foods (eg, chocolate), alcoholic beverages, bright lights, loud noise, menstruation, or use of oral contraceptives.

An uncommon variant isbasilar artery migraine, in which blindness or visual disturbances throughout both visual fields are initially accompanied or followed by dysarthria, dysequilibrium, tinnitus, and perioral and distal paresthesias and are sometimes followed by transient loss or impairment of consciousness or by a confusional state. This, in turn, is followed by a throbbing (usually occipital) headache, often with nausea and vomiting.

Inophthalmoplegic migraine, lateralized pain—often about the eye—is accompanied by nausea, vomiting, and diplopia due to transient external ophthalmoplegia. The ophthalmoplegia is due to third nerve palsy, sometimes with accompanying sixth nerve involvement, and may outlast the orbital pain by several days or even weeks. The ophthalmic division of the fifth nerve has also been affected in some patients. Ophthalmoplegic migraine is rare; more common causes of a painful ophthalmoplegia are internal carotid artery aneurysms and diabetes.

 Treatment

Management of migraine consists of avoidance of any precipitating factors, together with prophylactic or symptomatic pharmacologic treatment if necessary.

  1. Symptomatic Therapy

During acute attacks, rest in a quiet, darkened room may be helpful until symptoms subside. A simple analgesic (eg, aspirin, acetaminophen, ibuprofen, or naproxen) taken right away often provides relief, but treatment with prescription therapy is sometimes necessary. To prevent medication overuse, use of simple analgesics should be limited to 15 days or less per month, and combination analgesics should be limited to no more than 10 dayspermonth.

  1. Ergotamines—Cafergot, a combination of ergotamine tartrate (1 mg) and caffeine (100 mg), is often particularly helpful; one or two tablets are taken at the onset of headache or warning symptoms, followed by one tablet every 30 minutes, if necessary, up to six tablets per attack and no more than 10 days per month. Because of impaired absorption or vomiting during acute attacks, oral medication sometimes fails to help. Cafergot given rectally as suppositories (one-half to one suppository containing 2 mg of ergotamine) or dihydroergotamine mesylate (0.5–1 mg intravenously or 1–2 mg subcutaneously or intramuscularly) may be useful in such cases. Ergotamine-containing preparations should be avoided in pregnancy and when cardiovascular disease or risk factors are present.
  2. Triptans—Sumatriptan, which has a high affinity for 5-HT1receptors, is a rapidly effective agent for aborting attacks when given subcutaneously by an autoinjection device (4–6 mg once subcutaneously, may repeat once after 2 hours if needed; maximum dose 12 mg/24 h). Nasal and oral preparations are available but may be less effective due to slower absorption. Zolmitriptan, another selective 5-HT1receptor agonist, has high bioavailability after oral administration and is also effective for the immediate treatment of migraine. The optimal initial oral dose is 5 mg, and relief usually occurs within 1 hour; may repeat once after 2 hours. It is also available in a nasal formulation, which has a rapid onset of action; the dose is 5 mg in one nostril once and it may be repeated once after 2 hours. The maximum dose for both formulations is 10 mg/24 h. Other available triptans are available, including rizatriptan (5–10 mg orally at onset, may repeat every 2 hours twice [maximum dose 30 mg/24 h]); naratriptan (1–2.5 mg orally at onset, may repeat once after 4 hours [maximum dose 5 mg/24 h]); almotriptan (6.25–12.5 mg orally at onset, may repeat dose once after 2 hours [maximum dose 25 mg/24 h]); frovatriptan (2.5 mg orally at onset, may repeat after 2 hours once [maximum dose 7.5 mg/24]); and eletriptan (20–40 mg orally at onset; may repeat after 2 hours once [maximum dose 80 mg/24 h]). Eletriptan is useful for immediate therapy and frovatriptan, which has a longer half-life, may be worthwhile for patients with prolonged attacks or attacks provoked by menstrual periods.

Triptans may cause nausea and vomiting. They should probably be avoided in women who are pregnant, in patients with hemiplegic or basilar migraine, and in patients with risk factors for stroke (such as hypertension, prior stroke or transient ischemic attack, diabetes mellitus, hypercholesterolemia, obesity). Triptans are contraindicated in patients with coronary or peripheral vascular disease. Patients often experience greater benefit when the triptan is combined with naproxen (500 mg).

  1. Other agents—Prochlorperazine is effective and may be administered rectally (25 mg suppository), intravenously or intramuscularly (5–10 mg), or orally (5–10 mg). The neuroleptic droperidol is also helpful in aborting acute attacks, particularly in an emergency setting in opioid-tolerant patients. Intravenous metoclopramide (10–20 mg) and various butalbital-containing combination analgesics are effective. Opioid analgesics are sometimes required when other therapies fail. Intravenous propofol in subanesthetic doses may help in intractable cases.
  2. Preventive Therapy

Preventive treatment may be necessary if migraine headaches occur more frequently than two or three times a month or significant disability is associated with attacks. Some of the more common drugs used for this purpose are listed in Table 24–1. Their mode of action is unclear but may involve alteration of central neurotransmission. Several drugs may have to be tried in turn before the headaches are brought under control. Once a drug has been found to help, it should be continued for several months. If the patient remains headache-free, the dose may be tapered and the drug eventually withdrawn. Botulinum toxin type A is approved by the US Food and Drug Administration (FDA) for migraine prevention. A randomized controlled trial failed to show any difference between acupuncture and sham acupuncture in prophylaxis of migraine. Some neurostimulation techniques look promising, including occipital nerve stimulation, but critical appraisal is necessary.

Table 24–1. Prophylactic treatment of migraine.

  1. Tension-type Headache

This is the most common type of primary headache disorder. Patients frequently complain of pericranial tenderness, poor concentration, and other nonspecific symptoms, in addition to constant daily headaches that are often vise-like or tight in quality but are not pulsatile. Headaches may be exacerbated by emotional stress, fatigue, noise, or glare. The headaches are usually generalized, may be most intense about the neck or back of the head, and are not associated with focal neurologic symptoms. There is diagnostic overlap with migraine.

The therapeutic approach is similar to that in migraine, except that triptan drugs are not indicated. Treatment of comorbid anxiety or depression is important. Techniques to induce relaxation are sometimes useful and include massage, hot baths, and biofeedback.

  1. Cluster Headache

Cluster headache affects predominantly middle-aged men. The pathophysiology is unclear but may relate to activation of cells in the ipsilateral hypothalamus, triggering the trigeminal autonomic vascular system. There is often no family history of headache or migraine. Episodes of severe unilateral periorbital pain occur daily for several weeks and are often accompanied by one or more of the following: ipsilateral nasal congestion, rhinorrhea, lacrimation, redness of the eye, and Horner syndrome (ptosis of the eyelid, meiosis or constriction of the pupil, and anhidrosis or reduced sweat secretion). During attacks, patients are often restless and agitated. Episodes typically occur at night, awaken the patient, and last for between 15 minutes and 3 hours. Spontaneous remission then occurs, and the patient remains well for weeks or months before another bout of closely spaced attacks. Bouts may last for 4 to 8 weeks and may occur up to several times per year. During a bout, many patients report that alcohol triggers an attack; others report that stress, glare, or ingestion of specific foods occasionally precipitates attacks. In occasional patients, remission does not occur. This variant has been referred to as chronic cluster headache.Hemicrania continua is a separate primary headache syndrome with unilateral head pain and associated autonomic symptoms; unlike cluster headache, the pain is continuous without pain-free periods, and it completely resolves with indomethacin.

Examination reveals no abnormality apart from Horner syndrome that either occurs transiently during an attack or, in longstanding cases, remains as a residual deficit between attacks.

Treatment of an individual attack with oral drugs is generally unsatisfactory, but subcutaneous (6 mg dose) or intranasal (20-mg/spray) sumatriptan or inhalation of 100% oxygen (12–15 L/min for 15 minutes via a non-rebreather mask) may be effective. Zolmitriptan (5- and 10-mg nasal spray) is also effective. Dihydroergotamine (0.5–1 mg intramuscularly or intravenously) is sometimes used. Viscous lidocaine (1 mg of 4–6% solution) intranasally is sometimes effective.

Various prophylactic agents include oral medications such as, lithium carbonate (start at 300 mg daily, titrating according to serum levels and treatment response up to a typical total daily dose of 900–1200 mg, divided three or four times), verapamil (240–960 mg daily), topiramate (100–400 mg daily), valproate (750–1500 mg daily), civamide (not available in the United States); and suboccipital corticosteroid injection about the greater occipital nerve. As there is often a delay before these medications are effective, transitional therapy is often used. Ergotamine tartrate is effective and can be given as rectal suppositories (0.5–1 mg at night or twice daily), by mouth (2 mg daily), or by subcutaneous injection (0.25 mg three times daily for 5 days per week). Other options include prednisone (60 mg daily for 5 days followed by gradual withdrawal), or dihydroergotamine (9.25 mg intravenously over several days or 0.5 mg intramuscularly twice daily). Stimulation of the occipital nerve may be helpful.

  1. Posttraumatic Headache

A variety of nonspecific symptoms may follow closed head injury, regardless of whether consciousness is lost. Headache is often a conspicuous feature.

The headache itself usually appears within a day or so following injury, may worsen over the ensuing weeks, and then gradually subsides. It is usually a constant dull ache, with superimposed throbbing that may be localized, lateralized, or generalized. It is sometimes accompanied by nausea, vomiting, or scintillating scotomas. Headaches occurring more than 1–2 weeks after the inciting event are probably not directly attributable to the head injury.

Dysequilibrium, sometimes with a rotatory component, may also occur and is often enhanced by postural change or head movement. Impaired memory, poor concentration, emotional instability, and increased irritability are other common complaints and occasionally are the sole manifestations of the syndrome. The duration of symptoms relates in part to the severity of the original injury, but even trivial injuries are sometimes followed by symptoms that persist for months.

Special investigations are usually not helpful. The electroencephalogram may show minor nonspecific changes, while the electronystagmogram sometimes suggests either peripheral or central vestibulopathy. CT scans or MRI of the head usually are normal.

Treatment is difficult, but optimistic encouragement and graduated rehabilitation, depending on the occupational circumstances, are advised as symptoms often resolve spontaneously within several months. Headaches often respond to simple analgesics, but severe headaches may necessitate preventive treatment as outlined for migraine.

  1. Primary Cough Headache

Severe head pain may be produced by coughing (and by straining, sneezing, and laughing) but, fortunately, usually lasts for only a few minutes or less. The pathophysiologic basis of the complaint is not known, and often there is no underlying structural lesion. However, intracranial lesions, usually in the posterior fossa (eg, Arnold-Chiari malformation), are present in about 10% of cases, and brain tumors or other space-occupying lesions may present in this way. Accordingly, CT scanning or MRI should be undertaken in all patients and repeated annually for several years, since a small structural lesion may not show up initially.

The disorder is usually self-limited, although it may persist for several years. For unknown reasons, symptoms sometimes clear completely after lumbar puncture. Indomethacin (75–150 mg daily orally) may provide relief. Similar activity-triggered headache syndromes include primary exertional headache and primary headache associated with sexual activity.

  1. Headache Due to Giant Cell (Temporal or Cranial) Arteritis

This topic is discussed in Chapter 20.

  1. Headache Due to Intracranial Mass Lesions

Intracranial mass lesions of all types may cause headache owing to displacement of vascular structures and other pain-sensitive tissues. Posterior fossa tumors often cause occipital pain, and supratentorial lesions lead to bifrontal headache, but such findings are too inconsistent to be of value in attempts at localizing a pathologic process. The headaches are nonspecific in character and may vary in severity from mild to severe. They may be worsened by exertion or postural change (standing may relieve pain) and may be associated with nausea and vomiting, but this is true of migraine also. Headaches are also a feature of pseudotumor cerebri (idiopathic intracranial hypertension) (see below). Signs of focal or diffuse cerebral dysfunction or of increased intracranial pressure will indicate the need for further investigation. Similarly, a progressive headache disorder or the new onset of headaches in middle or later life merits investigation if no cause is apparent.

  1. Medication Overuse (Analgesic Rebound) Headache

In approximately half of all patients with chronic daily headaches, medication overuse is responsible. Patients have chronic pain or severe headache unresponsive to medication. Early initiation of a migraine preventive therapy (see above) permits withdrawal of analgesics and eventual relief of headache.

  1. Headache Due to Other Neurologic Causes

Cerebrovascular disease may be associated with headache, but the mechanism is unclear. Headache may occur with internal carotid artery occlusion or carotid dissection and after carotid endarterectomy. Acute severe headache accompanies subarachnoid hemorrhage and meningeal infections; accompanying signs of impairment of consciousness and sign of meningeal irritation indicate the need for further investigations.

Dull or throbbing headache is a frequent sequela of lumbar puncture and may last for several days. It is aggravated by the erect posture and alleviated by recumbency. The mechanism is unclear, but the headache is commonly attributed to leakage of cerebrospinal fluid through the dural puncture site. Its incidence may be reduced if an atraumatic needle is used for the lumbar puncture.

 When to Refer

  • Acute onset of “worst headache in my life.”
  • Increasing headache unresponsive to simple measures.
  • History of trauma, hypertension, fever, visual changes.
  • Presence of neurologic signs or of scalp tenderness.

 When to Admit

Suspected subarachnoid hemorrhage or structural intracranial lesion.

Ashkenazi A et al. Cluster headache: acute and prophylactic therapy. Headache. 2011 Feb;51(2):272–86. [PMID: 21284609]

Furman JM et al. Vestibular migraine: clinical aspects and pathophysiology. Lancet Neurol. 2013 Jul;12(7):706–15. [PMID: 23769597]

Jackson JL et al. Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA. 2012 Apr 25;307(16):1736–45. [PMID: 22535858]

Kaniecki RG. Tension-type headache. Continuum (Minneap Minn). 2012 Aug;18(4):823–34. [PMID: 22868544]

Magis D et al. Treatment of migraine: update on new therapies. Curr Opin Neurol. 2011 Jun;24(3):203–10. [PMID: 21464715]

Silberstein SD et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012 Apr 24;78(17):1337–45. [PMID: 22529202]

Tepper SJ. Medication-overuse headache. Continuum (Minneap Minn). 2012 Aug;18(4):807–22. [PMID: 22868543]

FACIAL PAIN

  1. Trigeminal Neuralgia

 ESSENTIALS OF DIAGNOSIS

 Brief episodes of stabbing facial pain.

 Pain is in the territory of the second and third division of the trigeminal nerve.

 Pain exacerbated by touch.

 General Considerations

Trigeminal neuralgia (“tic douloureux”) is most common in middle and later life. It affects women more frequently than men. Pain may be due to an anomalous artery or vein impinging on the trigeminal nerve.

 Clinical Findings

Momentary episodes of sudden lancinating facial pain occur and commonly arise near one side of the mouth and shoot toward the ear, eye, or nostril on that side. The pain may be triggered or precipitated by such factors as touch, movement, drafts, and eating. Indeed, in order to lessen the likelihood of triggering further attacks, many patients try to hold the face still while talking. Spontaneous remissions for several months or longer may occur. As the disorder progresses, however, the episodes of pain become more frequent, remissions become shorter and less common, and a dull ache may persist between the episodes of stabbing pain. Symptoms remain confined to the distribution of the trigeminal nerve (usually the second or third division) on one side only.

 Differential Diagnosis

The characteristic features of the pain in trigeminal neuralgia usually distinguish it from other causes of facial pain. Neurologic examination shows no abnormality except in a few patients in whom trigeminal neuralgia is symptomatic of some underlying lesion, such as multiple sclerosis or a brainstem neoplasm, in which case the finding will depend on the nature and site of the lesion. Similarly, CT scans and radiologic contrast studies are often normal in patients with classic trigeminal neuralgia.

In a young patient presenting with trigeminal neuralgia, multiple sclerosis must be suspected even if there are no other neurologic signs. In such circumstances, findings on evoked potential testing and examination of cerebrospinal fluid may be corroborative. When the facial pain is due to a posterior fossa tumor, CT scanning and MRI generally reveal the lesion.

 Treatment

The drugs most helpful for treatment are oxcarbazepine (although not approved by the FDA for this indication) or carbamazepine, with monitoring by serial blood counts and liver function tests. If these medications are ineffective or cannot be tolerated, phenytoin should be tried. (Doses and side effects of these drugs are shown in Table 24–3). Baclofen (10–20 mg orally three or four times daily), topiramate (50 mg orally twice daily), or lamotrigine (400 mg orally daily) may also be helpful, either alone or in combination with one of these other agents. Gabapentin may also relieve pain, especially in patients who do not respond to conventional medical therapy and those with multiple sclerosis. Depending on response and tolerance, up to 2400 mg daily orally is given in divided doses.

For neuralgia due to vascular impingement on the trigeminal nerve (despite normal findings on CT scans, MRI, or arteriograms), microvascular surgical decompression and separation of the anomalous vessel from the nerve root produce lasting relief of symptoms. In elderly patients with a limited life expectancy, radiofrequency rhizotomy is sometimes preferred because it is easy to perform, has few complications, and provides symptomatic relief for a period of time. Gamma radiosurgery to the trigeminal root is another noninvasive approach that appears to be successful in most patients, with essentially no side effects other than facial paresthesias in a few instances; up to one-third of patients achieved a pain-free state without need for medication after the procedure. Surgical exploration is inappropriate in patients with trigeminal neuralgia due to multiple sclerosis.

Pollock BE. Surgical management of medically refractory trigeminal neuralgia. Curr Neurol Neurosci Rep. 2012 Apr;12(2):125–31. [PMID: 22183181]

Torpy JM et al. JAMA patient page: Trigeminal neuralgia. JAMA. 2013 Mar 13;309(10):1058. [PMID: 23483182]

Zakrzewska JM. Medical management of trigeminal neuropathic pains. Expert Opin Pharmacother. 2010 Jun;11(8):1239–54. [PMID: 20426709]

  1. Atypical Facial Pain

Facial pain without the typical features of trigeminal neuralgia is generally a constant, often burning pain that may have a restricted distribution at its onset but soon spreads to the rest of the face on the affected side and sometimes involves the other side, the neck, or the back of the head as well. The disorder is especially common in middle-aged women, many of them depressed, but it is not clear whether depression is the cause of or a reaction to the pain. Simple analgesics should be given a trial, as should tricyclic antidepressants, carbamazepine, oxcarbazepine, and phenytoin; the response is often disappointing. Opioid analgesics pose a danger of addiction in patients with this disorder. Attempts at surgical treatment are not indicated.

  1. Glossopharyngeal Neuralgia

Glossopharyngeal neuralgia is an uncommon disorder in which pain similar in quality to that in trigeminal neuralgia occurs in the throat, about the tonsillar fossa, and sometimes deep in the ear and at the back of the tongue. The pain may be precipitated by swallowing, chewing, talking, or yawning and is sometimes accompanied by syncope. In most instances, no underlying structural abnormality is present; multiple sclerosis is sometimes responsible. Oxcarbazepine and carbamazepine (see Table 24–3) are the treatments of choice and should be tried before any surgical procedures are considered. Microvascular decompression is generally preferred over destructive surgical procedures such as partial rhizotomy in medically refractory cases and is often effective without causing severe complications.

Kandan SR et al. Neuralgia of the glossopharyngeal and vagal nerves: long-term outcome following surgical treatment and literature review. Br J Neurosurg. 2010 Aug;24(4):441–6. [PMID: 20726751]

  1. Postherpetic Neuralgia

Postherpetic neuralgia develops in about 15% of patients who have herpes zoster (shingles). This complication seems especially likely to occur in elderly or immunocompromised persons, when the rash is severe, and when the first division of the trigeminal nerve is affected. It also relates to the duration of the rash before medical consultation. A history of shingles and the presence of cutaneous scarring resulting from shingles aid in the diagnosis. Severe pain with shingles correlates with the intensity of postherpetic symptoms.

The incidence of postherpetic neuralgia may be reduced by the treatment of shingles with oral acyclovir or famciclovir, but this is disputed; systemic corticosteroids do not help (see Chapter 6). Management of the established complication is essentially medical. If simple analgesics fail to help, a trial of a tricyclic antidepressant (eg, amitriptyline or nortriptyline, up to 100–150 mg daily orally) is often effective. Other patients respond to carbamazepine (up to 1200 mg daily orally), phenytoin (300 mg daily orally), gabapentin (up to 3600 mg daily orally), or pregabalin (up to 600 mg/daily orally). A combination of gabapentin and morphine taken orally may provide better analgesia at lower doses of each agent than either taken alone. Topical application of capsaicin cream (eg, Zostrix, 0.025%) may be helpful, but a transdermal patch (8%) had no effect. Topical lidocaine (5%) is also worthy of trial. The administration of live-attenuated zoster vaccine to patients over the age of 60 years is important in reducing the likelihood of herpes zoster and reducing the severity of postherpetic neuralgia should a reactivation occur.

Chen N et al. Vaccination for preventing postherpetic neuralgia. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD007795. [PMID: 21412911]

Edelsberg JS et al. Systematic review and meta-analysis of efficacy, safety, and tolerability data from randomized controlled trials of drugs used to treat postherpetic neuralgia. Ann Pharmacother. 2011 Dec;45(12):1483–90. [PMID: 22085778]

  1. Facial Pain Due to Other Causes

Facial pain may be caused by temporomandibular joint dysfunction in patients with malocclusion, abnormal bite, or faulty dentures. There may be tenderness of the masticatory muscles, and sometimes pain begins at the onset of chewing. This pattern differs from that of jaw (masticatory) claudication, a symptom of giant cell arteritis, in which pain develops progressively with mastication. Treatment of the underlying joint dysfunction relieves symptoms.

A relationship of facial pain to chewing or temperature changes may suggest a dental disturbance. The cause is sometimes not obvious, and diagnosis requires careful dental examination and radiographs. Sinusitis and ear infections causing facial pain are usually recognized by the history of respiratory tract infection, fever and, in some instances, nasal or aural discharge. There may be localized tenderness. Radiologic evidence of sinus infection or mastoiditis is confirmatory.

Glaucoma is an important ocular cause of facial pain, usually localized to the periorbital region.

On occasion, pain in the jaw may be the principal manifestation of angina pectoris. Precipitation by exertion and radiation to more typical areas suggests the cardiac origin.

 When to Refer

  • Worsening pain unresponsive to simple measures.
  • Continuing pain of uncertain cause.
  • For consideration of surgical treatment (trigeminal or glossopharyngeal neuralgia).

EPILEPSY

 ESSENTIALS OF DIAGNOSIS

 Recurrent seizures.

 Characteristic electroencephalographic changes accompany seizures.

 Mental status abnormalities or focal neurologic symptoms may persist for hours postictally.

 General Considerations

The term “epilepsy” denotes any disorder characterized by recurrent unprovoked seizures. A seizure is a transient disturbance of cerebral function due to an abnormal paroxysmal neuronal discharge in the brain. Epilepsy is common, affecting approximately 0.5% of the population in the United States.

 Etiology

According to the International League Against Epilepsy classification system, the many etiologies of seizures can be grouped into three categories.

  1. Genetic Epilepsy

This category encompasses a broad range of disorders, for which the age at onset ranges from the neonatal period to adolescence or even later in life. Monogenic disorders tend to exhibit an autosomal dominant pattern of inheritance, and where the mutation is known, the responsible gene often encodes a neuronal ion channel.

  1. Structural/Metabolic Epilepsy

There are many causes for recurrent seizures.

  1. Pediatric age groups—Congenital abnormalities and perinatal injuries may result in seizures presenting in infancy or childhood.
  2. Metabolic disorders—Withdrawal from alcohol or drugs is a common cause of recurrent seizures, and other metabolic disorders (such as uremia and hypoglycemia or hyperglycemia) may also be responsible. Since these seizures are provoked by a readily reversible cause, this would not be considered epilepsy.
  3. Trauma—Trauma is an important cause of seizures at any age, but especially in young adults. Posttraumatic epilepsy is more likely to develop if the dura mater was penetrated and generally becomes manifest within 2 years following the injury. However, seizures developing in the first week after head injury do not necessarily imply that future attacks will occur. There is no clear evidence that prophylactic anticonvulsant drug treatment reduces the incidence of posttraumatic epilepsy.
  4. Tumors and other space-occupying lesions—Neoplasms may lead to seizures at any age, but they are an especially important cause of seizures in middle and later life, when the incidence of neoplastic disease increases. The seizures are commonly the initial symptoms of the tumor and often are focal in character. They are most likely to occur with structural lesions involving the frontal, parietal, or temporal regions. Tumors must be excluded by imaging studies (MRI preferred over CT) in all patients with onset of seizures after 30 years of age, focal seizures or signs, or a progressive seizure disorder.
  5. Vascular diseases—Vascular diseases become increasingly frequent causes of seizures with advancing age and are the most common cause of seizures with onset at age 60 years or older.
  6. Degenerative disorders—Alzheimer disease and other degenerative disorders are a cause of seizures in later life.
  7. Infectious diseases—Infectious diseases must be considered in all age groups as potentially reversible causes of seizures. Seizures may occur with an acute infective or inflammatory illness, such as bacterial meningitis or herpes encephalitis, or in patients with more longstanding or chronic disorders, such as neurosyphilis or cerebral cysticercosis. In patients with AIDS, they may result from central nervous system toxoplasmosis, cryptococcal meningitis, secondary viral encephalitis, or other infective complications. Seizures are a common sequela of supratentorial brain abscess, developing most frequently in the first year after treatment.
  8. Unknown

In many cases, the cause of epilepsy cannot be determined.

 Classification of Seizures

The International League Against Epilepsy distinguishes seizures affecting only part of the brain (focal seizures) from those that are generalized (Table 24–2).

Table 24–2. Seizure classification.

  1. Focal Seizures

The initial clinical and electroencephalographic manifestations of partial seizures indicate that only a restricted part of one cerebral hemisphere has been activated. The ictal manifestations depend on the area of the brain involved. Focal seizures sometimes involve impairment of consciousness and may evolve to convulsive seizures, in a process previously called secondary generalization.

  1. Without impairment of consciousness—Seizures may be manifested by focal motor symptoms (convulsive jerking) or somatosensory symptoms (eg, paresthesias or tingling) that spread (or “march”) to different parts of the limb or body depending on their cortical representation;such seizures were previously described as “simple partial” seizures. In other instances, special sensory symptoms (eg, light flashes or buzzing) indicate involvement of visual, auditory, olfactory, or gustatory regions of the brain, or there may be autonomic symptoms or signs (eg, abnormal epigastric sensations, sweating, flushing, pupillary dilation). The sole manifestations of some seizures are phenomena such as dysphasia, dysmnesic symptoms (eg, déjà; vu, jamais vu), affective disturbances, illusions, or structured hallucinations, but such symptoms are usually accompanied by impairment of consciousness.
  2. With impairment of consciousness—Impaired consciousness or responsiveness may be preceded, accompanied, or followed by the various symptoms mentioned above, and automatisms may occur. Such dyscognitive seizures were previously called “complex partial” seizures.
  3. Generalized Seizures

There are several different varieties of generalized seizures, as outlined below. In some circumstances, seizures cannot be classified because of incomplete information or because they do not fit into any category.

  1. Absence seizures—These are characterized by impairment of consciousness, sometimes with mild clonic, tonic, or atonic components (ie, reduction or loss of postural tone), autonomic components (eg, enuresis), or accompanying automatisms. Onset and termination of attacks are abrupt. If attacks occur during conversation, the patient may miss a few words or may break off in midsentence for a few seconds. The impairment of external awareness is so brief that the patient is unaware of it. Absence (“petit mal”) seizures almost always begin in childhood and frequently cease by the age of 20 years or are then replaced by other forms of generalized seizure. Electroencephalographically, such attacks are associated with bursts of bilaterally synchronous and symmetric 3-Hz spike-and-wave activity. A normal background in the electroencephalogram and normal or above-normal intelligence imply a good prognosis for the ultimate cessation of these seizures.
  2. Atypical absence seizures—There may be more marked changes in tone, or attacks may have a more gradual onset and termination than in typical absence seizures. They commonly occur in patients with multiple seizure types, may be accompanied by developmental delay or mental retardation, and are associated with slower spike-wave discharges than those in typical absence attacks.
  3. Myoclonic seizures—Myoclonic seizures consist of single or multiple myoclonic jerks.
  4. Tonic-clonic (“grand mal”) seizures—In these seizures, which are characterized by sudden loss of consciousness, the patient becomes rigid and falls to the ground, and respiration is arrested. This tonic phase, which usually lasts for < 1 minute, is followed by a clonic phase in which there is jerking of the body musculature that may last for 2 or 3 minutes and is then followed by a stage of flaccid coma. During the seizure, the tongue or lips may be bitten,urinary or fecal incontinence may occur, and the patient may be injured. Immediately after the seizure, the patient may recover consciousness, drift into sleep, have a further convulsion without recovery of consciousness between the attacks(status epilepticus), or after recovering consciousness have a further convulsion(serial seizures). In other cases, patients will behave in an abnormal fashion in the immediate postictal period, without subsequent awareness or memory of events(postepileptic automatism). Headache, disorientation, confusion, drowsiness, nausea, soreness of the muscles, or some combination of these symptoms commonly occurs postictally.
  5. Tonic, clonic, or atonic seizures—Loss of consciousness may occur with either the tonic or clonic accompaniments described above, especially in children. Atonic seizures(epileptic drop attacks)have also been described.

 Clinical Findings

  1. Symptoms and Signs

Nonspecific changes such as headache, mood alterations, lethargy, and myoclonic jerking alert some patients to an impending seizure hours before it occurs. These prodromal symptoms are distinct from the aura; the aura that may precede a generalized seizure by a few seconds or minutes is itself a part of the attack and it arises locally from a restricted part of the brain.

In most patients, seizures occur unpredictably at any time and without any relationship to posture or ongoing activities. Occasionally, however, they occur at a particular time (eg, during sleep) or in relation to external precipitants such as lack of sleep, missed meals, emotional stress, menstruation, alcohol ingestion (or alcohol withdrawal; see below), or use of certain drugs. Fever and nonspecific infections may also precipitate seizures in epileptic patients. In a few patients, seizures are provoked by specific stimuli such as flashing lights or a flickering television set(photosensitive epilepsy), music, or reading.

Clinical examination between seizures shows no abnormality in patients with idiopathic epilepsy, but in the immediate postictal period, extensor plantar responses may be seen. The presence of lateralized or focal signs postictally suggests that seizures may have a focal origin. In patients with symptomatic epilepsy, the findings on examination will reflect the underlying cause.

  1. Imaging

MRI is indicated for patients with focal neurologic symptoms or signs, focal seizures, or electroencephalographic findings of a focal disturbance; some clinicians routinely order MRI for all patients with new-onset seizure disorders. CT is generally less sensitive than MRI to small structural brain abnormalities but may be used when MRI is contraindicated (eg, in a patient with a metallic implant). Such studies should be performed in patients with clinical evidence of a progressive disorder and in those with new onset of seizures after the age of 20 years because of the possibility of an underlying neoplasm.

  1. Laboratory and Other Studies

Initial investigations should include complete blood count, serum glucose, electrolytes, creatinine, calcium, magnesium, and liver function tests to exclude various causes of seizures and to provide a baseline for subsequent monitoring of long-term effects of treatment. A lumbar puncture may be necessary when any sign of infection is present or in the evaluation of new-onset seizures in the acute setting.

Electroencephalography may support the clinical diagnosis of epilepsy (by demonstrating paroxysmal abnormalities containing spikes or sharp waves), provide a guide to prognosis, and help classify the seizure disorder. Classification of the disorder is important for determining the most appropriate anticonvulsant drug with which to start treatment. For example, absence and focal seizures with impairment of consciousness may be difficult to distinguish clinically, but the electroencephalographic findings and treatment of choice differ in these two conditions. Finally, by localizing the epileptogenic source, the electroencephalographic findings are important in evaluating candidates for surgical treatment.

 Differential Diagnosis

The distinction between the various disorders likely to be confused with generalized seizures is usually made on the basis of the history. The importance of obtaining an eyewitness account of the attacks cannot be overemphasized.

  1. Differential Diagnosis of Focal Seizures
  2. Transient ischemic attacks—These attacks are distinguished from seizures by their longer duration, lack of spread, and symptoms. Level of consciousness, which is unaltered, does not distinguish them. There is a loss of motor or sensory function (eg, weakness or numbness) with transient ischemic attacks, whereas positive symptoms (eg, convulsive jerking or paresthesias) characterize seizures.
  3. Rage attacks—Rage attacks are usually situational and lead to goal-directed aggressive behavior.
  4. Panic attacks—These may be hard to distinguish from focal seizures unless there is evidence of an anxiety disorder between attacks and the attacks have a clear relationship to external circumstances.
  5. Differential Diagnosis of Generalized Seizures
  6. Syncope—Syncopal episodes usually occur in relation to postural change, emotional stress, instrumentation, pain, or straining. They are typically preceded by pallor, sweating, nausea, and malaise and lead to loss of consciousness accompanied by flaccidity; recovery occurs rapidly with recumbency, and there is no postictal headache or confusion. In some instances, however, motor accompaniments and urinary incontinence may simulate a seizure.
  7. Cardiac disease—Cerebral hypoperfusion due to a disturbance of cardiac rhythm should be suspected in patients with known cardiac or vascular disease or in elderlypatients who present with episodic loss of consciousness. Prodromal symptoms are typically absent. Repeated Holter monitoring may be necessary to establish the diagnosis; monitoring initiated by the patient (“event monitor”) may be valuable if the disturbances of consciousness are rare. A relationship of attacks to physical activity and the finding of a systolic murmur are suggestive of aortic stenosis.
  8. Brainstem ischemia—Loss of consciousness is preceded or accompanied by other brainstem signs. Basilar artery migraine and vertebrobasilar vascular disease are discussed elsewhere in this chapter.
  9. Psychogenic nonepileptic seizure (PNES)—Simulating an epileptic seizure, a PNES may occur due to a conversion disorder or malingering. Many patients also have true seizures or a family history of epilepsy. Although a PNES tends to occur at times of emotional stress, this may also be the case with true seizures.

Clinically, the attacks superficially resemble tonic-clonic seizures, but there may be obvious preparation before a PNES. Moreover, there is usually no tonic phase; instead, there may be an asynchronous thrashing of the limbs, which increases if restraints are imposed and rarely leads to injury. Consciousness may be normal or “lost,” but in the latter context the occurrence of goal-directed behavior or of shouting, swearing, etc, indicates that it is feigned. Postictally, there are no changes in behavior or neurologic findings.

Often, clinical observation is insufficient to discriminate epileptic from nonepileptic seizures. Video electroencephalographic monitoring may be helpful: epileptic seizures, especially those involving altered consciousness, commonly involve scalp electroencephalographic signs that coincide with a behavioral spell, whereas a PNES does not. The serum level of prolactin has been found to increase dramatically between 15 and 30 minutes after a tonic-clonic convulsion in most patients, whereas it is unchanged after a PNES. Serum creatine kinase levels also increase after a convulsion but not a PNES.

 Treatment

  1. General Measures

For patients with epilepsy, drug treatment is prescribed with the goal of preventing further attacks and is usually continued until there have been no seizures for at least 2 years. Epileptic patients should be advised to avoid situations that could be dangerous or life-threatening if further seizures should occur. Legislation may require clinicians to report to the state authorities any patients with seizures or other episodic disturbances of consciousness; driving cessation for 6 months or as legislated is appropriate following an unprovoked seizure.

  1. Choice of medication—Drug selection depends on seizure type (Table 24–3). The dose of the selected drug is gradually increased until seizures are controlled or side effects prevent further increases. If seizures continue despite treatment at the maximal tolerated dose, a second drug is added and the dose increased depending on tolerance; the first drug is then gradually withdrawn. In treatment of focal seizures, the success rate is higher with carbamazepine, phenytoin, or valproic acid than with phenobarbital or primidone. Gabapentin, topiramate, lamotrigine, oxcarbazepine, levetiracetam, zonisamide, lacosamide, ezogabine, vigabatrin, and tiagabine are newer antiepileptic drugs used to treat focal seizures. Felbamate is also effective for such seizures but, because it may cause aplastic anemia or fulminant hepatic failure, should be used only in selected patients unresponsive to other measures. Rufinamide is currently approved only for seizures in patients with Lennox-Gastaut syndrome, but it may be effective against seizures in a broader range of refractory patients. For generalized or unclassified seizures, valproate is better tolerated than topiramate and more efficacious than lamotrigine and is thus preferred for many patients; however, the teratogenic potential of valproate makes its use undesirable in women of childbearing age. All antiepileptics are potentially teratogenic, although the teratogenicity of the newer antiseizure medications is less clear. Nevertheless, antiepileptic medication must be given to pregnant women with epilepsy to prevent seizures, which can pose serious risk to the fetus from trauma, hypoxia, or other factors. In most patients with seizures of a single type, satisfactory control can be achieved with a single anticonvulsant drug. Treatment with two drugs may further reduce seizure frequency or severity but usually only at the cost of greater toxicity. Treatment with more than two drugs is almost always unhelpful unless the patient is having seizures of different types.

Table 24–3. Drug treatment for seizures in adults.

  1. Monitoring—Monitoring serum drug levels has led to major advances in the management of seizure disorders. Individual differences in drug metabolism cause a given dose of a drug to produce different blood concentrations in different patients, and this will affect the therapeutic response. In general, the dose of an antiepileptic agent is increased depending on the clinical response regardless of the serum drug level. When a dose is achieved that either controls seizures or is the maximum tolerated, then a steady-state trough drug level may be obtained for future reference; rechecking this level may be appropriate if a breakthrough seizure occurs, a dose change occurs, or another (potentially interacting) drug is added to the regimen. A laboratory’s therapeutic range for a drug is only a guide; many patients achieve good seizure control with no adverse effect at serum levels that exceed the stipulated range, and in these cases no dose adjustment is needed. The most common cause of a lower concentration of drug than expected for the prescribed dose is poor patient compliance. Compliance can be improved by limiting to a minimum the number of daily doses. Recurrent seizures or status epilepticus may result if drugs are taken erratically, and in some circumstances noncompliant patients may be better off without any medication.

All anticonvulsant drugs have side effects, and some of these are shown in Table 24–3.

Treatment with certain drugs may require regular laboratory monitoring. For example, periodic tests of hepatic function are necessary if valproic acid, carbamazepine, or felbamate is used, and serial blood counts are important with carbamazepine, ethosuximide, or felbamate. Detailed medication-specific recommendations should be sought from a drug reference source before prescribing, since baseline studies are often necessary.

  1. Discontinuance of medication—Only when adult patients have been seizure-free for 2 years should withdrawal of medication be considered. Unfortunately, there is no way of predicting which patients can be managed successfully without treatment, although seizure recurrence is more likely in patients who initially did not respond to therapy, those with seizures having focal features or of multiple types, and those with continuing electroencephalographic abnormalities. Dose reduction should be gradual (over weeks or months), and drugs should be withdrawn one at a time. If seizures recur, treatment is reinstituted with the previously effective drug regimen.
  2. Surgical treatment—Patients with seizures refractory to pharmacologic management may be candidates for operative treatment. Surgical resection is most efficacious when there is a single well-defined seizure focus, particularly in the temporal lobe. Among well-chosen patients, up to 70% remain seizure-free after extended follow-up. Bilateral deep brain stimulation of the anterior thalamus for medically refractory focal-onset seizures may be of benefit.
  3. Vagal nerve stimulation—Treatment by chronic vagal nerve stimulation for adults and adolescents with medically refractory focal seizures is approved in the United States and provides an alternative approach for patients who are not optimal candidates for surgical treatment. The mechanism of therapeutic action is unknown. Adverse effects consist mainly of transient hoarseness during stimulus delivery.
  4. Special Circumstances
  5. Solitary seizures—In patients who have had only one seizure or a flurry of seizures over a brief period of several hours, investigation as outlined earlier should exclude an underlying cause requiring specific treatment. An electroencephalogram should be obtained, preferably within 24 hours after the seizure, because the findings may influence management—especially when focal abnormalities are present. Prophylactic anticonvulsant drug treatment is generally not required unless further attacks occur or investigations reveal some underlying pathology. The risk of seizure recurrence varies in different series between about 30% and 70%. Epilepsy should not be diagnosed on the basis of a solitary seizure. If seizures occur in the context of transient, nonrecurrent systemic disorders such as acute cerebral anoxia, the diagnosis of epilepsy is inaccurate, and long-term prophylactic anticonvulsant drug treatment is unnecessary.
  6. Alcohol withdrawal seizures—The characteristic alcohol withdrawal seizure pattern is one or more generalized tonic-clonic seizures that may occur within 48 hours or so of withdrawal from alcohol after a period of high or prolonged intake. If the seizures have consistently focal features, the possibility of an associated structural abnormality, often traumatic in origin, must be considered. Head CT scan or MRI should be performed in patients with new onset of generalized seizures and whenever there arefocal features. Treatment with anticonvulsant drugs is generally not required for alcohol withdrawal seizures, since they are self-limited. Benzodiazepines (diazepam or lorazepam, dosed as needed to reduce withdrawal symptoms and to avoid oversedation) are effective and safe for preventing further seizures. Status epilepticus may rarely follow alcohol withdrawal and is managed along conventional lines (see below). Further attacks will not occur if the patient abstains from alcohol.
  7. Tonic-clonic status epilepticus—Poor compliance with the anticonvulsant drug regimen is the most common cause; other causes include alcohol withdrawal, intracranial infection or neoplasms, metabolic disorders, and drug overdose. The mortality rate may be as high as 20%, and among survivors the incidence of neurologic and cognitive sequelae is high. The prognosis relates to the length of time between onset of status epilepticus and the start of effective treatment.

Status epilepticus is a medical emergency. Initial management includes maintenance of the airway and 50% dextrose (25–50 mL) intravenously in case hypoglycemia is responsible. If seizures continue, an intravenous bolus of lorazepam, 4 mg, is given at a rate of 2 mg/min and repeated once after 10 minutes if necessary; alternatively, 10 mg of diazepam is given intravenously over the course of 2 minutes, and again after 10 minutes if necessary. Diazepam can also be given rectally as a gel (0.2 mg/kg). These measures are usually effective in halting seizures for a brief period. Respiratory depression and hypotension may complicate the treatment and are treated as in other circumstances; this treatment may include intubation and mechanical ventilation and admission to an intensive care unit.

Regardless of the response to lorazepam or diazepam, phenytoin (18–20 mg/kg) is given intravenously at a rate of 50 mg/min; this provides initiation of long-term seizure control. The drug is best injected directly but can also be given in saline; it precipitates, however, if injected into glucose-containing solutions. Because arrhythmias may develop during rapid administration of phenytoin, electrocardiographic monitoring is prudent. Hypotension may complicate phenytoin administration, especially if diazepam has also been given. In many countries, injectable phenytoin has been replaced by fosphenytoin, which is rapidly and completely converted to phenytoin following intravenous administration. No dosing adjustments are necessary because fosphenytoin is expressed in terms of phenytoin equivalents (PE); fosphenytoin is less likely to cause reactions at the infusion site, can be given with all common intravenous solutions, and may be administered at a faster rate (150 mg PE/min).

If seizures continue, phenobarbital is then given in a loading dose of 10–20 mg/kg intravenously by slow or intermittent injection (50 mg/min). Respiratory depression and hypotension are especially common with this therapy. Alternatively or additionally, intravenous valproate is used for status epilepticus (loading dose 25–30 mg/kg over 15 min; then 100 mg/h); although valproate has not yet been approved by the FDA for this indication, it has been used with success.

If these measures fail, general anesthesia with ventilatory assistance may be required. Intravenous midazolam may provide control of refractory status epilepticus; the suggested loading dose is 0.2 mg/kg, followed by 0.05–0.2 mg/kg/h. Propofol (1–2 mg/kg as an intravenous bolus, followed by infusion at 2–15 mg/kg/h depending on response) may also be used, as may pentobarbital (15 mg/kg intravenously, followed by 0.5–4 mg/kg/h).

After status epilepticus is controlled, an oral drug program for the long-term management of seizures is started, and investigations into the cause of the disorder are pursued.

  1. Nonconvulsive status epilepticus—In some cases, status epilepticus presents not with convulsions, but with a fluctuating abnormal mental status, confusion, impaired responsiveness, and automatism. Electroencephalography is helpful in establishing the diagnosis. The treatment approach outlined above applies to any type of status epilepticus, although intravenous anesthesia is usually not necessary. The prognosis is a reflection of the underlying cause rather than of continuing seizures.

 When to Refer

  • Behavioral episodes of uncertain nature.
  • Seizures are difficult to control or have focal features.
  • There is a progressive neurologic disorder.
  • Status epilepticus.

 When to Admit

  • Status epilepticus.
  • For monitoring, or when PNES are suspected.
  • If surgery is contemplated.

Anderson J et al. Anti-epileptic drugs: a guide for the non- neurologist. Clin Med. 2010 Feb;10(1):54–8. [PMID: 20408309]

Berg AT et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010 Apr;51(4):676–85. [PMID: 20196795]

Englot DJ et al. Rates and predictors of long-term seizure freedom after frontal lobe epilepsy surgery: a systematic review and meta-analysis. J Neurosurg. 2012 May;116(5):1042–8. [PMID: 22304450]

Glauser Tet al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013 Mar;54(3):551–63. [PMID: 23350722]

Johnston A et al. Epilepsy in the elderly. Expert Rev Neurother. 2010 Dec;10(12):1899–910. [PMID: 21384700]

Perucca E et al. The pharmacological treatment of epilepsy in adults. Lancet Neurol. 2011 May;10(5):446–56. [PMID: 21511198]

Riviello JJ Jret al; Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Treatment of status epilepticus: an international survey of experts. Neurocrit Care. 2013 Apr;18(2):193–200. [PMID: 23097138]

DYSAUTONOMIA

 ESSENTIALS OF DIAGNOSIS

 Abnormalities of blood pressure or heart rate regulation, sweating, intestinal motility, sphincter control, sexual function, respiration, or ocular function.

 Symptoms occur in isolation or any combination.

 General Considerations

Dysautonomia may occur as a result of central or peripheral pathologic processes. It is manifested by a variety of symptoms that may occur in isolation or in various combinations and relate to abnormalities of blood pressure regulation, thermoregulatory sweating, gastrointestinal function, sphincter control, sexual function, respiration, and ocular function. Syncope, a symptom of dysautonomia, is characterized by a transient loss of consciousness, usually accompanied by hypotension and bradycardia. It may occur in response to emotional stress, postural hypotension, vigorous exercise in a hot environment, obstructed venous return to the heart, acute pain or its anticipation, fluid loss, and a variety of other circumstances.

  1. Central Neurologic Causes

Disease at certain sites in the central nervous system, regardless of its nature, may lead to dysautonomic symptoms. Postural hypotension, which is usually the most troublesome and disabling symptom, may result from spinal cord transection and other myelopathies (eg, due to tumor or syringomyelia) above the T6 level or from brainstem lesions such as syringobulbia and posterior fossa tumors. Sphincter or sexual disturbances may result from cord lesions below T6. Certain primary degenerative disorders are responsible for dysautonomia occurring in isolation(pure autonomic failure) or in association with more widespread abnormalities(multisystem atrophy orShy-Drager syndrome) that may include parkinsonian, pyramidal symptoms, and cerebellar deficits.

  1. Peripheral Neurologic Causes

A pure autonomic neuropathy may occur acutely or subacutely after a viral infection or as a paraneoplastic disorder related usually to small cell lung cancer, particularly in association with certain antibodies, such as anti-Hu or those directed at neuronal nicotinic acetylcholine receptors. Dysautonomia is often conspicuous in patients with Guillain-Barré syndrome, manifesting with marked hypotension or hypertension or cardiac arrhythmias that may have a fatal outcome. It may also occur with diabetic, uremic, amyloidotic, and various other metabolic or toxic neuropathies; in association with leprosy or Chagas disease; and as a feature of certain hereditary neuropathies with autosomal dominant or recessive inheritance or an X-linked pattern. Autonomic symptoms are prominent in the crises of hepatic porphyria. Patients with botulism or the Lambert-Eaton myasthenic syndrome may have constipation, urinary retention, and a sicca syndrome as a result of impaired cholinergic function.

 Clinical Findings

  1. Symptoms and Signs

Dysautonomic symptoms include syncope, postural hypotension, paroxysmal hypertension, persistent tachycardia without other cause, facial flushing, hypohidrosis or hyperhidrosis, vomiting, constipation, diarrhea, dysphagia, abdominal distention, disturbances of micturition or defecation, erectile dysfunction, apneic episodes, and declining night vision. In syncope, prodromal malaise, nausea, headache, diaphoresis, pallor, visual disturbance, loss of postural tone, and a sense of weakness and impending loss of consciousness are followed by actual loss of consciousness. Although the patient is usually flaccid, some motor activity is not uncommon, and urinary (and rarely fecal) incontinence may also occur, thereby simulating a seizure. Recovery is rapid once the patient becomes recumbent, but headache, nausea, and fatigue are common postictally.

  1. Evaluation of the Patient

Testing of autonomic function includes evaluating the cardiovascular response to the Valsalva maneuver, startle, mental stress, postural change, and deep respiration, and the sudomotor (sweating) responses to warming or a deep inspiratory gasp. Tilt-table testing may reproduce syncopal or presyncopal symptoms. Pharmacologic studies to evaluate the pupillary responses, radiologic studies of the bladder or gastrointestinal tract, uroflowmetry and urethral pressure profiles, and recording of nocturnal penile tumescence may also be necessary in selected cases. Further investigation depends on the presence of other associated neurologic abnormalities. In patients with a peripheral cause, work-up for peripheral neuropathy may be required and should include testing for ganglionic acetylcholine receptor antibody. For those with evidence of a central lesion, imaging studies will exclude a treatable structural cause. Reversible, nonneurologic causes of symptoms must be considered. Postural hypotension and syncope may relate to a reduced cardiac output, paroxysmal cardiac dysrhythmias, volume depletion, various medications, and endocrine and metabolic disorders such as Addison disease, hypothyroidism or hyperthyroidism, pheochromocytoma, and carcinoid syndrome.

 Treatment

The most disabling symptom is usually postural hypotension and syncope. Abrupt postural change, prolonged recumbency, and other precipitants should be avoided. Medications associated with postural hypotension should be discontinued or reduced in dose. Treatment may include wearing waist-high elastic hosiery, salt supplementation, sleeping in a semierect position (which minimizes the natriuresis and diuresis that occur during recumbency), and fludrocortisone (0.1–0.2 mg daily). Vasoconstrictor agents may be helpful and include midodrine (2.5–10 mg orally three times daily) and ephedrine (15–30 mg orally three times daily). Other agents that have been used occasionally or experimentally are dihydroergotamine, yohimbine, pyridostigmine, and clonidine; refractory cases may respond to erythropoietin (epoetin alfa) or desmopressin. Patients must be monitored for recumbent hypertension. Postprandial hypotension is helped by caffeine. There is no satisfactory treatment for disturbances of sweating, but an air-conditioned environment is helpful in avoiding extreme swings in body temperature.

 When to Refer

  • When the diagnosis is uncertain.
  • When symptoms persist despite conventional treatment.

Lanier JB et al. Evaluation and management of orthostatic hypotension. Am Fam Physician. 2011 Sep 1;84(5):527–36. [PMID: 21888303]

Mathias CJ et al. Autonomic dysfunction: recognition, diagnosis, investigation, management, and autonomic neurorehabilitation. Handb Clin Neurol. 2013;110:239–53. [PMID: 23312645]

TRANSIENT ISCHEMIC ATTACKS

 ESSENTIALS OF DIAGNOSIS

 Focal neurologic deficit of acute onset.

 Clinical deficit resolves completely within 24 hours.

 Risk factors for vascular disease often present.

 General Considerations

Transient ischemic attacks are characterized by focal ischemic cerebral neurologic deficits that last for < 24 hours (usually < 1–2 hours). About 30% of patients with stroke have a history of transient ischemic attacks, and proper treatment of the attacks is an important means of prevention.

 Etiology

An important cause of transient cerebral ischemia is embolization. In many patients with these attacks, a source is readily apparent in the heart or a major extracranial artery to the head, and emboli sometimes are visible in the retinal arteries. Moreover, an embolic phenomenon explains why separate attacks may affect different parts of the territory supplied by the same major vessel. Cardiac causes of embolic ischemic attacks include atrial fibrillation, rheumatic heart disease, mitral valve disease, infective endocarditis, atrial myxoma, and mural thrombi complicating myocardial infarction. Atrial septal defects and patent foramen ovale may permit emboli from the veins to reach the brain (“paradoxical emboli”). An ulcerated plaque on a major artery to the brain may serve as a source of emboli. In the anterior circulation, atherosclerotic changes occur most commonly in the region of the carotid bifurcation extracranially, and these changes may cause a bruit. In some patients with transient ischemic attacks or strokes, an acute or recent hemorrhage is found to have occurred into this atherosclerotic plaque, and this finding may have pathologic significance. Patients with AIDS have an increased risk of developing transient ischemic deficits or strokes.

Less common abnormalities of blood vessels that may cause transient ischemic attacks include fibromuscular dysplasia, which affects particularly the cervical internal carotid artery; atherosclerosis of the aortic arch; inflammatory arterial disorders such as giant cell arteritis, systemic lupus erythematosus, polyarteritis, and granulomatous angiitis; and meningovascular syphilis. Hypotension may cause a reduction of cerebral blood flow if a major extracranial artery to the brain is markedly stenosed, but this is a rare cause of transient ischemic attack.

Hematologic causes of ischemic attacks include polycythemia, sickle cell disease, and hyperviscosity syndromes. Severe anemia may also lead to transient focal neurologic deficits in patients with preexisting cerebral arterial disease.

The subclavian steal syndrome may lead to transient vertebrobasilar ischemia. Symptoms develop when there is localized stenosis or occlusion of one subclavian artery proximal to the source of the vertebral artery, so that blood is “stolen” from this artery. A bruit in the supraclavicular fossa, unequal radial pulses, and a difference of 20 mm Hg or more between the systolic blood pressures in the arms should suggest the diagnosis in patients with vertebrobasilar transient ischemic attacks.

 Clinical Findings

  1. Symptoms and Signs

The symptoms of transient ischemic attacks vary markedly among patients; however, the symptoms in a given individual tend to be constant in type. Onset is abrupt and without warning, and recovery usually occurs rapidly, often within a few minutes. The specific symptoms depend on the arterial distribution affected, as outlined in the subsequent section on stroke. Of note, transient ischemic attack is a rare cause of loss of consciousness or acute confusion but is often erroneously blamed for such symptoms.

The natural history of attacks is variable. Some patients will have a major stroke after only a few attacks, whereas others may have frequent attacks for weeks or months without having a stroke. The risk of stroke is high in the first 3 months after an attack, particularly in the first month and especially within the first 48 hours. Attacks may occur intermittently over a long period of time, or they may stop spontaneously. In general, carotid ischemic attacks are more liable than vertebrobasilar ischemic attacks to be followed by stroke. The stroke risk is greater in patients older than 60 years, in patients with diabetes, or after transient ischemic attacks that last longer than 10 minutes and with symptoms or signs of weakness, speech impairment, or gait disturbance.

  1. Imaging

CT or MRI scan is indicated within 24 hours of symptom onset, in part to exclude the possibility of a small cerebral hemorrhage or a cerebral tumor masquerading as a transient ischemic attack; MRI with diffusion-weighted sequences is particularly sensitive for revealing acute or subacute infarction. Noninvasive imaging of the cervical vasculature should also be performed. Carotid duplex ultrasonography is useful for detecting significant stenosis of the internal carotid artery, and MR or CT angiography permits broader visualization of cervical and intracranial vasculature. When noninvasive studies fail to reveal an etiology for transient ischemic attacks, conventional cerebral arteriography may be indicated. This technique is the gold standard for investigating the integrity of the cervical and cerebral vasculature, and allows for angioplasty or other interventions, if necessary.

  1. Laboratory and Other Studies

Clinical and laboratory evaluation must include assessment for hypertension, heart disease, hematologic disorders, diabetes mellitus, hyperlipidemia, and peripheral vascular disease. It should include complete blood count, fasting blood glucose and serum cholesterol and homocysteine determinations, serologic tests for syphilis, and an ECG and chest radiograph. Echocardiography with bubble contrast is performed if a cardiac source is likely, and blood cultures are obtained if endocarditis is suspected. Holter monitoring is indicated if a transient, paroxysmal disturbance of cardiac rhythm is suspected.

 Differential Diagnosis

Focal seizures usually cause abnormal motor or sensory phenomena such as clonic limb movements, paresthesias, or tingling, rather than weakness or loss of feeling. Symptoms generally spread (“march”) up the limb and may lead to a generalized tonic-clonic seizure.

Classic migraine is easily recognized by the visual premonitory symptoms, followed by nausea, headache, and photophobia, but less typical cases may be hard to distinguish. The patient’s age and medical history (including family history) may be helpful in this regard. Patients with migraine commonly have a history of episodes since adolescence and report that other family members have a similar disorder.

Focal neurologic deficits may occur during periods of hypoglycemia in diabetic patients receiving insulin or oral hypoglycemic agent therapy.

 Treatment

  1. Medical Measures

Hospitalization should be considered for patients seen within 72 hours of the attack, when they are at increased risk for early recurrence. One commonly used method to assess recurrence risk is the ABCD 2score; points are assigned for each of the following criteria: age 60 years or older (1 point), blood pressure ≥ 140/90 mm Hg (1 point), clinical symptoms of focal weakness (2 points) or speech impairment without weakness (1 point), duration ≥ 60 minutes (2 points) or 10–59 minutes (1 point), or diabetes mellitus (1 point). An ABCD2 score of 3 or more points has been suggested as a threshold for hospital admission. Admission is also advisable for patients with crescendo attacks, symptomatic carotid stenosis, or known cardiac source of emboli or hypercoagulable state; such hospitalization facilitates early intervention for any recurrence and rapid institution of secondary prevention measures.

Medical treatment is aimed at preventing further attacks and stroke. Treat diabetes mellitus; hematologic disorders; and hypertension, preferably with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Consider starting a statin medication regardless of the current low-density lipoprotein level; in addition to reducing stroke risk, antecedent statin use may improve the outcome if an ischemic stroke does occur. Cigarette smoking should be stopped, and cardiac sources of embolization should be treated appropriately. Weight reduction and regular physical activity should be encouraged when appropriate.

In patients with carotid ischemic attacks who are poor operative candidates (and thus have not undergone arteriography) or who are found to have extensive vascular disease, medical treatment should be instituted. Similarly, patients with vertebrobasilar ischemic attacks are treated medically and are not subjected to arteriography unless there is clinical evidence of stenosis or occlusion in the carotid or subclavian arteries.

  1. Embolization from the heart—Cardioembolism, especially in the setting of atrial fibrillation, is an indication for anticoagulation as a preventive treatment for stroke. If anticoagulants are indicated for the treatment of embolism from the heart, they should be started immediately, provided that the area of cerebral infarct is small and there is no contraindication to their use. There is no advantage in delay, and the common fear of causing hemorrhage into a previously infarcted area is misplaced, since there is a far greater risk of further embolism to the cerebral circulation if treatment is withheld (see Treatment of Atrial Fibrillation,Chapter 10).
  2. Noncardioembolic attacks—In a patient naïve to antiplatelet therapy, low-dose aspirin (81 mg daily orally) should be initiated to reduce the frequency of transient ischemic attacks and the incidence of stroke. For patients already taking aspirin who continue to experience transient ischemic attacks, adding sustained-release dipyridamole (200 mg twice daily orally) to the regimen provides additional protection against stroke compared to aspirin alone. Clopidogrel (75 mg daily orally) alone is marginally more efficacious than aspirin alone; combining clopidogrel with aspirin is not clearly better than clopidogrel alone but does increase the risk of bleeding complications. Cilostazol, another antiplatelet medication, appears to offer similar efficacy at strokeprevention as aspirin, and possibly less risk of hemorrhage. Anticoagulant drugs are not recommended, as they offer no benefit over antiplatelet therapy, and the risk of serious hemorrhagic adverse effects is greater.
  3. Surgical or Endovascular Measures

When arteriography reveals a surgically accessible high-grade stenosis (70–99% in luminal diameter) on the side appropriate to carotid ischemic attacks and there is relatively little atherosclerosis elsewhere in the cerebrovascular system, operative treatment (carotid endarterectomy) or endovascular intervention reduces the risk of ipsilateral carotid stroke, especially when transient ischemic attacks are of recent onset (< 1 month). Some evidence suggests that transluminal angioplasty and stenting is inferior to aggressive medical management alone. There is a more moderate benefit for patients with 50–69% stenosis, and surgery is not indicated for mild stenosis (< 50%); its benefits are unclear with severe stenosis plus diffuse intracranial atherosclerotic disease.

 When to Refer

All patients should be referred for urgent investigation and treatment to prevent stroke.

 When to Admit

If seen within 72 hours of a transient ischemic attack, patients should be considered for admission when they have an ABCD2 score of 3 points or more, when outpatient evaluation is impractical, or when there are crescendo attacks or other concern for early recurrence or stroke.

Chimowitz MI et al; SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011 Sep 15;365(11):993–1003. [PMID: 21899409]

Geeganage CM et al; Acute Antiplatelet Stroke Trialists Collaboration. Dual or mono antiplatelet therapy for patients with acute ischemic stroke or transient ischemic attack: systematic review and meta-analysis of randomized controlled trials. Stroke. 2012 Apr;43(4):1058–66. [PMID: 22282894]

Merwick À et al. Reduction in early stroke risk in carotid stenosis with transient ischemic attack associated with statin treatment. Stroke. 2013 Oct;44(10):2814–20. [PMID: 23908061]

Tsivgoulis G et al. Multicenter external validation of the ABCD2 score in triaging TIA patients. Neurology. 2010 Apr 27;74(17):1351–7. [PMID: 20421579]

STROKE

 ESSENTIALS OF DIAGNOSIS

 Sudden onset of characteristic neurologic deficit.

 Patient often has history of hypertension, diabetes mellitus, valvular heart disease, or atherosclerosis.

 Distinctive neurologic signs reflect the region of the brain involved.

 General Considerations

In the United States, stroke remains the third leading cause of death, despite a general decline in the incidence of stroke in the last 30 years. The precise reasons for this decline are uncertain, but increased awareness of risk factors (hypertension, diabetes mellitus, hyperlipidemia, cigarette smoking, cardiac disease, AIDS, recreational drug abuse, heavy alcohol consumption, family history of stroke) and improved prophylactic measures and surveillance of those at increased risk have been contributory. Elevation of the blood homocysteine level is also a risk factor for stroke, but it is unclear whether this risk is reduced by treatment to lower the level. A previous stroke makes individual patients more susceptible to additional strokes.

For years, strokes have been subdivided pathologically into infarcts (thrombotic or embolic) and hemorrhages, and clinical criteria for distinguishing between these possibilities have been emphasized. However, it is often difficult to determine on clinical grounds the pathologic basis for stroke (Table 24–4).

Table 24–4. Features of the major stroke subtypes.

  1. Lacunar Infarction

Lacunar infarcts are small lesions (usually < 5 mm in diameter) that occur in the distribution of short penetrating arterioles in the basal ganglia, pons, cerebellum, internal capsule, thalamus and, less commonly, the deep cerebral white matter (Table 24–4). Lacunar infarcts are associated with poorly controlled hypertension or diabetes and have been found in several clinical syndromes, including contralateral pure motor or pure sensory deficit, ipsilateral ataxia with crural paresis, and dysarthria with clumsiness of the hand. The neurologic deficit may progress over 24–36 hours before stabilizing.

Early mortality and risk of stroke recurrence is higher for patients with nonlacunar than lacunar infarcts. The prognosis for recovery from the deficit produced by a lacunar infarct is usually good, with partial or complete resolution occurring over the following 4–6 weeks in many instances. Treatment is as described for transient ischemic attack and cerebral infarction.

  1. Cerebral Infarction

Thrombotic or embolic occlusion of a major vessel leads to cerebral infarction. Causes include the disorders predisposing to transient ischemic attacks (see above) and atherosclerosis of cerebral arteries. The resulting deficit depends on the particular vessel involved and the extent of any collateral circulation. Cerebral ischemia leads to release of excitatory and other neuropeptides that may augment calcium flux into neurons, thereby leading to cell death and increasing the neurologic deficit.

 Clinical Findings

  1. Symptoms and Signs

Onset is usually abrupt, and there may then be very little progression except that due to brain swelling. Clinical evaluation should always include examination of the heart and auscultation over the subclavian and carotid vessels to determine whether there are any bruits.

  1. Obstruction of carotid circulation—Occlusion of the ophthalmic artery is probably symptomless in most cases because of the rich orbital collaterals, but its transient embolic obstruction can lead to amaurosis fugax—sudden and brief loss of vision in one eye.

Occlusion of the anterior cerebral artery distal to its junction with the anterior communicating artery causes weakness and cortical sensory loss in the contralateral leg and sometimes mild weakness of the arm, especially proximally. There may be a contralateral grasp reflex, paratonic rigidity, and abulia (lack of initiative) or frank confusion. Urinary incontinence is not uncommon, particularly if behavioral disturbances are conspicuous. Bilateral anterior cerebral infarction is especially likely to cause marked behavioral changes and memory disturbances. Unilateral anterior cerebral artery occlusion proximal to the junction with the anterior communicating artery is generally well tolerated because of the collateral supply from the other side.

Middle cerebral artery occlusion leads to contralateral hemiplegia, hemisensory loss, and homonymous hemianopia (ie, bilaterally symmetric loss of vision in half of the visual fields), with the eyes deviated to the side of the lesion. If the dominant hemisphere is involved, global aphasia is also present. It may be impossible to distinguish this clinically from occlusion of the internal carotid artery. With occlusion of either of these arteries, there may also be considerable swelling of the hemisphere, leading to drowsiness, stupor, and coma in extreme cases. Occlusions of different branches of the middle cerebral artery cause more limited findings. For example, involvement of the anterior main division leads to a predominantly expressive dysphasia and to contralateral paralysis and loss of sensations in the arm, the face and, to a lesser extent, the leg. Posterior branch occlusion produces a receptive (Wernicke) aphasia and a homonymous visual field defect. With involvement of the nondominant hemisphere, speech and comprehension are preserved, but there may be a left hemispatial neglect syndrome or constructional and visuospatial deficits.

  1. Obstruction of vertebrobasilar circulation—Occlusion of theposterior cerebral arterymay lead to a thalamic syndrome in which contralateral hemisensory disturbance occurs, followed by the development of spontaneous pain and hyperpathia. There is often a macular-sparing homonymous hemianopia and sometimes a mild, usually temporary, hemiparesis. Depending on the site of the lesion and the collateral circulation, the severity of these deficits varies and other deficits may also occur, including involuntary movements and alexia. Occlusion of the main artery beyond the origin of its penetrating branches may lead solely to a macular-sparing hemianopia.

Vertebral artery occlusion distally, below the origin of the anterior spinal and posterior inferior cerebellar arteries, may be clinically silent because the circulation is maintained by the other vertebral artery. If the remaining vertebral artery is congenitally small or severely atherosclerotic, however, a deficit similar to that of basilar artery occlusion is seen unless there is good collateral circulation from the anterior circulation through the circle of Willis. When the small paramedian arteries arising from the vertebral artery are occluded, contralateral hemiplegia and sensory deficit occur in association with an ipsilateral cranial nerve palsy at the level of the lesion. An obstruction of the posterior inferior cerebellar artery or an obstruction of the vertebral artery just before it branches to this vessel leads to ipsilateral spinothalamic sensory loss involving the face, ninth and tenth cranial nerve lesions, limb ataxia and numbness, and Horner syndrome, combined with contralateral spinothalamic sensory loss involving the limbs.

Occlusion of both vertebral arteries or the basilar artery leads to coma with pinpoint pupils, flaccid quadriplegia and sensory loss, and variable cranial nerve abnormalities. With partial basilar artery occlusion, there may be diplopia, visual loss, vertigo, dysarthria, ataxia, weakness or sensory disturbances in some or all of the limbs, and discrete cranial nerve palsies. In patients with hemiplegia of pontine origin, the eyes are often deviated to the paralyzed side, whereas in patients with a hemispheric lesion, the eyes commonly deviate from the hemiplegic side.

Occlusion of any of the major cerebellar arteries produces vertigo, nausea, vomiting, nystagmus, ipsilateral limb ataxia, and contralateral spinothalamic sensory loss in the limbs. If the superior cerebellar artery is involved, the contralateral spinothalamic loss also involves the face; with occlusion of the anterior inferior cerebellar artery, there is ipsilateral spinothalamic sensory loss involving the face, usually in conjunction with ipsilateral facial weakness and deafness. Massive cerebellar infarction may lead to coma, tonsillar herniation, and death.

  1. Coma—Infarction in either the carotid or vertebrobasilar territory may lead to loss of consciousness. For example, an infarct involving one cerebral hemisphere may lead to such swelling that the function of the other hemisphere or the rostral brainstem is disturbed and coma results. Similarly, coma occurs with bilateral brainstem infarction when this involves the reticular formation, and it occurs with brainstem compression after cerebellar infarction.
  2. Imaging

A CT scan of the head (without contrast) should be performed immediately, before the administration of aspirin or other antithrombotic agents, to exclude cerebral hemorrhage (Table 24–4). CT is relatively insensitive to acute ischemic stroke, and subsequent MRI with diffusion-weighted sequences helps define the distribution and extent of infarction as well as to exclude tumor or other differential considerations. Perfusion-weighted MRI sequences can be useful for outlining any additional areas at risk for infarction, thus guiding treatment decisions; specific guidelines are still being determined. Imaging of the cervical vasculature, by CT angiography, MR angiography, or conventional catheter angiography, is indicated as part of a search to identify the source of the stroke.

  1. Laboratory and Other Studies

Investigations should include a complete blood count, erythrocyte sedimentation rate, blood glucose determination, and serologic tests for syphilis. Screening for antiphospholipid antibodies (lupus anticoagulants and anticardiolipin antibodies); the factor V Leiden mutation; abnormalities of protein C, protein S, or antithrombin; or a prothrombin gene mutation is indicated if a hypercoagulable disorder is suspected (eg, a young patient without apparent risk factors for stroke). Similarly, elevated serum cholesterol and lipids and serum homocysteine may indicate an increased risk of thrombotic stroke. Electrocardiography or continuous cardiac monitoring for at least 24 hours will help exclude a recent myocardial infarction or a cardiac arrhythmia that might be serving as a source of embolization. Blood cultures should be performed if endocarditis is suspected, echocardiography (bubble contrast study) if heart disease—especially valvular disease, left-to-right shunting, or cardiac thrombus—is a concern, and Holter monitoring if paroxysmal cardiac arrhythmia requires exclusion. Examination of the cerebrospinal fluid is not always necessary but may be helpful if cerebral vasculitis or another inflammatory or infectious cause of stroke is suspected, but it should be delayed until after CT or MRI to exclude any risk for herniation due to mass effect.

 Treatment

Prophylactic measures were discussed earlier under Transient Ischemic Attacks. The management of acute stroke should be in a stroke care unit, when feasible. Intravenous thrombolytic therapy with recombinant tissue plasminogen activator (rtPA; 0.9 mg/kg to a maximum of 90 mg, with 10% given as a bolus over 1 minute and the remainder over 1 hour) is effective in reducing the neurologic deficit in selected patients without CT evidence of intracranial hemorrhage. Patients should receive tPA within 1 hour after arriving to the hospital but not more than 4.5 hours after the onset of ischemic symptoms. Data for treatment with tPA up to 4.5 hours after the onset of symptoms show reduced disability at 90 days.

Recent hemorrhage, increased risk of hemorrhage (eg, treatment with anticoagulants), arterial puncture at a noncompressible site, and systolic pressure > 185 mm Hg or diastolic pressure > 110 mm Hg are among the contraindications to this treatment. In selected patients with thrombotic stroke, percutaneous procedures, including endovascular intra-arterial rtPA administration or mechanical removal of an embolus or clot from an occluded cerebral artery using an intra-arterial mechanical thrombolytic device, are also effective relative to non-thrombolytic medical treatment, despite an increased risk of intracranial hemorrhage; it is not clear how these invasive approaches compare to intravenous thrombolytic therapy.

Early management of a completed stroke otherwise requires general supportive measures. During the acute stage, there may be marked brain swelling and edema, with symptoms and signs of increasing intracranial pressure, an increasing neurologic deficit, or herniation syndrome. Elevated intracranial pressure is managed by head elevation and osmotic agents such as mannitol. Maintenance of an adequate cerebral perfusion pressure helps prevent further ischemia. Decompressive hemicraniectomy for malignant middle cerebral artery infarctions may reduce mortality and improve functional outcome in some instances. Attempts to lower the blood pressure of hypertensive patients during the acute phase (ie, within 2 weeks) of a stroke should generally be avoided, as there is loss of cerebral autoregulation, and lowering the blood pressure may further compromise ischemic areas. However, if the systolic pressure exceeds 220 mm Hg, it can be lowered using intravenous labetalol or nicardipine with continuous monitoring to 170–200 mm Hg and then, after 2 weeks, it can be reduced further to < 140/90 mm Hg.

In patients not eligible for thrombolytic therapy, and in whom hemorrhage has been excluded by CT, the immediate administration of aspirin 325 mg orally daily is indicated. Anticoagulant drugs should also be started without delay in the setting of atrial fibrillation or other source of cardioembolism when hemorrhage has been excluded by CT. Treatment is with warfarin (target INR 2.0–3.0) or dabigatran (150 mg twice daily); bridging warfarin with heparin is not necessary, but some experts advocate treatment with aspirin until the INR becomes therapeutic.

Physical therapy has an important role in the management of patients with impaired motor function. Passive movements at an early stage will help prevent contractures. As cooperation increases and some recovery begins, active movements will improve strength and coordination. In all cases, early mobilization and active rehabilitation are important. Occupational therapy may improve morale and motor skills, while speech therapy may help expressive dysphasia or dysarthria. Because of the risk for dysphagia following stroke, access to food and drink is typically restricted until an appropriate swallowing evaluation. When there is a severe and persisting motor deficit, a device such as a leg brace, toe spring, frame, or cane may help the patient move about, and the provision of other aids to daily living may improve the quality of life.

 Prognosis

The prognosis for survival after cerebral infarction is better than after cerebral or subarachnoid hemorrhage. The only proved effective therapy for acute stroke requires initiation within 3–4.5 hours after stroke onset, and the prognosis therefore depends on the time that elapses before arrival at the hospital. Patients receiving such treatment with rtPA are at least 30% more likely to have minimal or no disability at 3 months than those not treated by this means. Loss of consciousness after a cerebral infarct implies a poorer prognosis than otherwise. The extent of the infarct governs the potential for rehabilitation. Patients who have had a cerebral infarct are at risk for additional strokes and for myocardial infarcts. Statin therapy to lower serum lipid levels may reduce this risk. Antiplatelet therapy (same treatment guidelines as for transient ischemic attack; see above) reduces the recurrence rate by 30% among patients without a cardiac cause for the stroke who are not candidates for carotid endarterectomy. Nevertheless, the cumulative risk of recurrence of noncardioembolic stroke is still 3–7% annually.

Patients with massive strokes from which meaningful recovery is unlikely should receive palliative care (see Chapter 5).

 When to Refer

All patients should be referred.

 When to Admit

All patients should be hospitalized, preferably in a stroke care unit.

Biffi A et al. Statin treatment and functional outcome after ischemic stroke: case-control and meta-analysis. Stroke. 2011 May;42(5):1314–9. [PMID: 21415396]

Grise EM et al. Blood pressure control for acute ischemic and hemorrhagic stroke. Curr Opin Crit Care. 2012 Apr;18(2):132–8. [PMID: 22322257]

Jauch EC et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013 Mar;44(3):870–947. [PMID: 23370205]

Lansberg MG et al. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a meta-analysis. Stroke. 2009 Jul;40(7):2438–41. [PMID: 19478213]

Micheli S et al. Lacunar versus non-lacunar syndromes. Front Neurol Neurosci. 2012;30:94–8. [PMID: 22377873]

O’Donnell MJ et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet. 2010 Jul 10;376(9735):112–23. [PMID: 20561675]

O’Rourke K et al. Percutaneous vascular interventions for acute ischaemic stroke. Cochrane Database Syst Rev. 2010 Oct 6;(10):CD007574. [PMID: 20927761]

  1. Intracerebral Hemorrhage

Spontaneous, nontraumatic intracerebral hemorrhage in patients with no angiographic evidence of an associated vascular anomaly (eg, aneurysm or angioma) is usually due to hypertension. The pathologic basis for hemorrhage is probably the presence of microaneurysms that develop on perforating vessels in hypertensive patients. Hypertensive intracerebral hemorrhage occurs most frequently in the basal ganglia and less commonly in the pons, thalamus, cerebellum, and cerebral white matter. Hemorrhage may extend into the ventricular system or subarachnoid space, and signs of meningeal irritation are then found. Hemorrhages usually occur suddenly and without warning, often during activity. In the elderly, cerebral amyloid angiopathy is another important and frequent cause of hemorrhage, which is usually lobar in distribution, sometimes recurrent, and associated with a better prognosis than hypertensive hemorrhage.

Other causes of nontraumatic intracerebral hemorrhage include hematologic and bleeding disorders (eg, leukemia, thrombocytopenia, hemophilia, or disseminated intravascular coagulation), anticoagulant therapy, liver disease, high alcohol intake, and primary or secondary brain tumors. There is also an association with advancing age and male sex. Bleeding is primarily into the subarachnoid space when it occurs from an intracranial aneurysm or arteriovenous malformation (see below), but it may be partly intraparenchymal as well. In some cases, no specific cause for cerebral hemorrhage can be identified.

 Clinical Findings

  1. Symptoms and Signs

With hemorrhage into the cerebral hemisphere, consciousness is initially lost or impaired in about one-half of patients. Vomiting occurs very frequently at the onset of bleeding, and headache is sometimes present. Focal symptoms and signs then develop, depending on the site of the hemorrhage. With hypertensive hemorrhage, there is generally a rapidly evolving neurologic deficit with hemiplegia or hemiparesis. A hemisensory disturbance is also present with more deeply placed lesions. With lesions of the putamen, loss of conjugate lateral gaze may be conspicuous. With thalamic hemorrhage, there may be a loss of upward gaze, downward or skew deviation of the eyes, lateral gaze palsies, and pupillary inequalities.

Cerebellar hemorrhage may present with sudden onset of nausea and vomiting, dysequilibrium, headache, and loss of consciousness that may terminate fatally within 48 hours. Less commonly, the onset is gradual and the course episodic or slowly progressive—clinical features suggesting an expanding cerebellar lesion. In yet other cases, however, the onset and course are intermediate, and examination shows lateral conjugate gaze palsies to the side of the lesion; small reactive pupils; contralateral hemiplegia; peripheral facial weakness; ataxia of gait, limbs, or trunk; periodic respiration; or some combination of these findings.

  1. Imaging

CT scanning (without contrast) is important not only in confirming that hemorrhage has occurred but also in determining the size and site of the hematoma. It is superior to MRI for detecting intracranial hemorrhage of < 48 hours duration. If the patient’s condition permits further intervention, CT angiography, MR angiography, or cerebral angiography may be undertaken thereafter to determine whether an aneurysm or arteriovenous malformation is present (see below). Follow-up imaging during the hospitalization may reveal hematoma expansion, a predictor of poor outcome.

  1. Laboratory and Other Studies

A complete blood count, platelet count, bleeding time, prothrombin and partial thromboplastin times, and liver and kidney function tests may reveal a predisposing cause for the hemorrhage. Lumbar puncture is contraindicated because it may precipitate a herniation syndrome in patients with a large hematoma, and CT scanning is superior in detecting intracerebral hemorrhage.

 Treatment

Neurologic management is generally conservative and supportive, regardless of whether the patient has a profound deficit with associated brainstem compression, in which case the prognosis is grim, or a more localized deficit not causing increased intracranial pressure or brainstem involvement. Such therapy may include ventilatory support, blood pressure regulation, seizure prophylaxis, control of fever, osmotherapy, and nutritional supplementation. Intracranial pressure may require monitoring. Ventricular drainage may be required in patients with intraventricular hemorrhage and acute hydrocephalus. Decompression may be helpful when a superficial hematoma in cerebral white matter is exerting a mass effect and causing incipient herniation. In patients with cerebellar hemorrhage, prompt surgical evacuation of the hematoma is appropriate, because spontaneous unpredictable deterioration may otherwise lead to a fatal outcome and because operative treatment may lead to complete resolution of the clinical deficit. The treatment of underlying structural lesions or bleeding disorders depends on their nature. Hemostatic therapy with recombinant activated factor VII has not improved survival or functional outcome. There is no specific treatment for cerebral amyloid angiopathy.

 When to Refer

All patients should be referred.

 When to Admit

All patients should be hospitalized.

Biffi A et al. Statin use and outcome after intracerebral hemorrhage: case-control study and meta-analysis. Neurology. 2011 May 3;76(18):1581–8. [PMID: 21451150]

Dowlatshahi D et al. Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes. Neurology. 2011 Apr 5;76(14):1238–44. [PMID: 21346218]

Wang X et al. Cholesterol levels and risk of hemorrhagic stroke: a systematic review and meta-analysis. Stroke. 2013 Jul;44(7):1833–9. [PMID: 23704101]

  1. Spontaneous Subarachnoid Hemorrhage

 ESSENTIALS OF DIAGNOSIS

 Sudden severe headache.

 Signs of meningeal irritation usually present.

 Obtundation is common.

 Focal deficits frequently absent.

 General Considerations

Between 5% and 10% of strokes are due to subarachnoid hemorrhage. Trauma is the most common cause of sub-arachnoid hemorrhage, the prognosis of which depends on the severity of the head injury. Spontaneous (nontraumatic) subarachnoid hemorrhage frequently results from the rupture of an arterial saccular (“berry”) aneurysm or from an arteriovenous malformation. Occasional patients with aneurysms have headaches, sometimes accompanied by nausea and neck stiffness, a few hours or days before massive subarachnoid hemorrhage occurs. This has been attributed to “warning leaks” of a small amount of blood from the aneurysm.

 Clinical Findings

  1. Symptoms and Signs

Subarachnoid hemorrhage has a characteristic clinical picture. Its onset is with sudden headache of a severity never experienced previously by the patient. This may be followed by nausea and vomiting and by a loss or impairment of consciousness that can either be transient or progress inexorably to deepening coma and death. If consciousness is regained, the patient is often confused and irritable and may show other symptoms of an altered mental status. Neurologic examination generally reveals nuchal rigidity and other signs of meningeal irritation, except in deeply comatose patients.

Aneurysms may cause a focal neurologic deficit by compressing adjacent structures. However, most are asymptomatic or produce only nonspecific symptoms until they rupture, at which time subarachnoid hemorrhage results. A higher risk of subarachnoid hemorrhage is associated with older age, female sex, “nonwhite” ethnicity, hypertension, tobacco smoking, high alcohol consumption (exceeding 150 g per week), previous symptoms, posterior circulation aneurysms, and larger aneurysms. Focal neurologic signs are usually absent but, when present, may relate either to a focal intracerebral hematoma (from arteriovenous malformations) or to ischemia in the territory of the vessel with a ruptured aneurysm.

  1. Imaging

A CT scan (preferably with CT angiography) should be performed immediately to confirm that hemorrhage has occurred and to search for clues regarding its source. It is preferable to MRI because it is faster and more sensitive in detecting hemorrhage in the first 24 hours. CT findings sometimes are normal in patients with suspected hemorrhage, and the cerebrospinal fluid must then be examined for the presence of blood or xanthochromia before the possibility of subarachnoid hemorrhage is discounted.

Cerebral arteriography is undertaken to determine the source of bleeding. In general, bilateral carotid and vertebral arteriography are necessary because aneurysms are often multiple, while arteriovenous malformations may be supplied from several sources. The procedure allows an interventional radiologist to treat an underlying aneurysm or arteriovenous malformation by various techniques. If arteriograms show no abnormality, the examination should be repeated after 2 weeks because vasospasm or thrombus may have prevented detection of an aneurysm or other vascular anomaly during the initial study. CT or MR angiography may also be revealing but is less sensitive than conventional arteriography.

  1. Laboratory and Other Studies

The cerebrospinal fluid is bloodstained. Electro-cardiographic evidence of arrhythmias or myocardial ischemia has been well described and probably relates to excessive sympathetic activity. Peripheral leukocytosis and transient glycosuria are also common findings.

 Treatment

All patients should be admitted to hospital and seen by a neurologist. The measures outlined below in the section on stupor and coma are applied to comatose patients. Conscious patients are confined to bed, advised against any exertion or straining, treated symptomatically for headache and anxiety, and given laxatives or stool softeners. If there is severe hypertension, the blood pressure can be lowered gradually, but not below a diastolic level of 100 mm Hg (see treatment of stroke, earlier). Phenytoin is generally prescribed routinely to prevent seizures. If no cause for the hemorrhage can be identified, medical management is continued for about 6 weeks and is followed by gradual mobilization.

The major aim of treatment is to prevent further hemorrhage. The risk of further hemorrhage from a ruptured aneurysm is greatest within a few days of the first hemorrhage; approximately 20% of patients will have further bleeding within 2 weeks and 40% within 6 months. Definitive treatment, ideally within 2 days of the hemorrhage, requires surgical clipping of the aneurysm base or endovascular treatment by interventional radiologists; the latter is sometimes feasible even for inoperable aneurysms and has a lower morbidity than surgery.

 Complications

Spontaneous subarachnoid hemorrhage may result in severe complications, so monitoring is necessary, usually in an intensive care unit. Intrathecal thrombolytic therapy, presumably by speeding clearance of extravasated blood, appears to reduce the rate of these complications. Hemiplegia or other focal deficit sometimes may follow aneurysmal bleeding after a delay of 2–14 days due to focal arterial spasm. The etiology of vasospasm is uncertain and likely multifactorial, and it sometimes leads to significant cerebral ischemia or infarction and may further aggravate any existing increase in intracranial pressure. Transcranial Doppler ultrasound may be used to screen noninvasively for vasospasm, but conventional arteriography is required to document and treat vasospasm when the clinical suspicion is high. Nimodipine has been shown to reduce, in neurologically normal patients, the incidence of ischemic deficits from arterial spasm without producing any side effects. The dose of nimodipine is 60 mg every 4 hours orally for 21 days. After surgical obliteration of all aneurysms, symptomatic vasospasm may also be treated by intravascular volume expansion and induced hypertension; transluminal balloon angioplasty of involved intracranial vessels is also helpful. Aspirin provides no benefit. Results from a randomized trial suggest that the prophylactic administration of intravenous magnesium sulfate, sufficient to achieve serum levels of 4.9–6.1 mg/dL (2–2.5 mmol/L), reduced the risk of transcranial ultrasound-detectable vasospasm and of vasospasm-induced cerebral infarction but did not change overall clinical outcomes.

Acute hydrocephalus, which sometimes occurs due to cerebrospinal fluid outflow disruption by the subar achnoid blood, should be suspected if the patient deteriorates clinically and a repeat CT scan should be done. Acute hydrocephalus frequently causes intracranial hypertension severe enough to require temporary, and less commonly prolonged or permanent, intraventricular cerebrospinal fluid shunting. Renal salt-wasting is another complication of subarachnoid hemorrhage that may develop abruptly during the first several days of hospitalization. The resulting hyponatremia and cerebral edema may exacerbate intracranial hypertension and may require carefully titrated treatment with oral sodium chloride or intravenous hyperosmotic sodium solution. Daily measurement of the serum sodium level allows for the early detection of this complication. Hypopituitarism may occur as a late complication of subarachnoid hemorrhage.

Kramer AH et al. Locally administered intrathecal thromboly-tics following aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Neurocrit Care. 2011 Jun;14(3):489–99. [PMID: 20740327]

Mahaney KB et al. Variation of patient characteristics, management, and outcome with timing of surgery for aneurysmal subarachnoid hemorrhage. J Neurosurg. 2011 Apr;114(4): 1045–53. [PMID: 21250801]

Schmutzhard E et al. Spontaneous subarachnoid hemorrhage and glucose management. Neurocrit Care. 2011 Sep;15(2): 281–6. [PMID: 21850563]

  1. Intracranial Aneurysm

 ESSENTIALS OF DIAGNOSIS

 Subarachnoid hemorrhage or focal deficit.

 Abnormal imaging studies.

 General Considerations

Saccular aneurysms (“berry” aneurysms) tend to occur at arterial bifurcations, are frequently multiple (20% of cases), and are usually asymptomatic. They may be associated with polycystic kidney disease and coarctation of the aorta. Risk factors for aneurysm formation include smoking, hypertension, and hypercholesterolemia. Most aneurysms are located on the anterior part of the circle of Willis—particularly on the anterior or posterior communicating arteries, at the bifurcation of the middle cerebral artery, and at the bifurcation of the internal carotid artery. Mycotic aneurysms resulting from septic embolism occur in more distal vessels and often at the cortical surface. The most significant complication of intracranial aneurysms is a subarachnoid hemorrhage, which is discussed in the preceding section. A higher risk of subarachnoid hemorrhage is associated with older age, female sex, “non-white” ethnicity, hypertension, tobacco smoking, high alcohol consumption (exceeding 150 g per week), previous symptoms, posterior circulation aneurysms, and larger aneurysms.

 Clinical Findings

  1. Symptoms and Signs

Aneurysms may cause a focal neurologic deficit by compressing adjacent structures. However, most are asymptomatic or produce only nonspecific symptoms until they rupture, at which time subarachnoid hemorrhage results. Its manifestations, complications, and management were outlined in the preceding section.

  1. Imaging

Definitive evaluation is by angiography (bilateral carotid and vertebral studies), which generally indicates the size and site of the lesion, sometimes reveals multiple aneurysms, and may show arterial spasm if rupture has occurred. Visualization by CT or MR angiography is not usually adequate if operative treatment is under consideration because lesions may be multiple and small lesions are sometimes missed.

 Treatment

The major aim of treatment is to prevent hemorrhages. Management of ruptured aneurysms was described in the section on subarachnoid hemorrhage. Symptomatic but unruptured aneurysms merit prompt treatment, either surgically or by endovascular techniques, whereas small asymptomatic ones discovered incidentally are often monitored arteriographically and corrected only if they increase in size to over 10 mm.

 When to Refer

All patients should be referred.

 When to Admit

  • All patients with a subarachnoid hemorrhage.
  • All patients for detailed imaging.
  • All patients undergoing surgical or endovascular treatment.

Connolly ES Jret al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012 Jun;43(6):1711–37. [PMID: 22556195]

Ferns SP et al. De novo aneurysm formation and growth of untreated aneurysms: a 5-year MRA follow-up in a large cohort of patients with coiled aneurysms and review of the literature. Stroke. 2011 Feb;42(2):313–8. [PMID: 21164110]

  1. Arteriovenous Malformations

 ESSENTIALS OF DIAGNOSIS

 Sudden onset of subarachnoid and intracerebral hemorrhage.

 Distinctive neurologic signs reflect the region of the brain involved.

 Signs of meningeal irritation in patients presenting with subarachnoid hemorrhage.

 Seizures or focal deficits may occur.

 General Considerations

Arteriovenous malformations are congenital vascular malformations that result from a localized maldevelopment of part of the primitive vascular plexus and consist of abnormal arteriovenous communications without intervening capillaries. They vary in size, ranging from massive lesions that are fed by multiple vessels and involve a large part of the brain to lesions so small that they are hard to identify at arteriography, surgery, or autopsy. In approximately 10% of cases, there is an associated arterial aneurysm, while 1–2% of patients presenting with aneurysms have associated arteriovenous malformations. Clinical presentation may relate to hemorrhage from the malformation or an associated aneurysm or may relate to cerebral ischemia due to diversion of blood by the anomalous arteriovenous shunt or due to venous stagnation. Regional maldevelopment of the brain, compression or distortion of adjacent cerebral tissue by enlarged anomalous vessels, and progressive gliosis due to mechanical and ischemic factors may also be contributory. In addition, communicating or obstructive hydrocephalus may occur and lead to symptoms.

 Clinical Findings

  1. Symptoms and Signs
  2. Supratentorial lesions—Most cerebral arteriovenous malformations are supratentorial, usually lying in the territory of the middle cerebral artery. Initial symptoms consist of hemorrhage in 30–60% of cases, recurrent seizures in 20–40%, headache in 5–25%, and miscellaneous complaints (including focal deficits) in 10–15%. Up to 70% of arteriovenous malformations bleed at some point in their natural history, most commonly before the patient reaches the age of 40 years. This tendency to bleed is unrelated to the lesion site or to the patient’s sex, but small arteriovenous malformations are more likely to bleed than large ones. Arteriovenous malformations that have bled once are more likely to bleed again. Hemorrhage is commonly intracerebral as well as into the subarachnoid space, and it has a fatal outcome in about 10% of cases. Focal or generalized seizures may accompany or follow hemorrhage, or they may be the initial presentation, especially with frontal or parietal arteriovenous malformations. Headaches areespecially likely when the external carotid arteries are involved in the malformation. These sometimes simulate migraine but more commonly are nonspecific in character, with nothing about them to suggest an underlying structural lesion.

In patients presenting with subarachnoid hemorrhage, examination may reveal an abnormal mental status and signs of meningeal irritation. Additional findings may help localize the lesion and sometimes indicate that intracranial pressure is increased. A cranial bruit always suggests the possibility of a cerebral arteriovenous malformation, but bruits may also be found with aneurysms, meningiomas, acquired arteriovenous fistulas, and arteriovenous malformations involving the scalp, calvarium, or orbit. Bruits are best heard over the ipsilateral eye or mastoid region and are of some help in lateralization but of no help in localization. Absence of a bruit in no way excludes the possibility of arteriovenous malformation.

  1. Infratentorial lesions—Brainstem arteriovenous malformations are often clinically silent, but they may hemorrhage, cause obstructive hydrocephalus, or lead to progressive or relapsing brainstem deficits. Cerebellar arteriovenous malformations may also be clinically inconspicuous but sometimes lead to cerebellar hemorrhage.
  2. Imaging

In patients presenting with suspected hemorrhage, CT scanning indicates whether subarachnoid or intracerebral bleeding has recently occurred, helps localize its source, and may reveal the arteriovenous malformation. If the CT scan shows no evidence of bleeding but subarachnoid hemorrhage is diagnosed clinically, a lumbar puncture should be performed to examine the cerebrospinal fluid for blood.

When intracranial hemorrhage is confirmed but the source of hemorrhage is not evident on the CT scan, arteriography is necessary to exclude aneurysm or arteriovenous malformation. MR and CT angiography are not sensitive enough for this purpose. Even if the findings on CT scan suggest arteriovenous malformation, arteriography is required to establish the nature of the lesion with certainty and to determine its anatomic features so that treatment can be planned. The examination must generally include bilateral opacification of the internal and external carotid arteries and the vertebral arteries. Arteriovenous malformations typically appear as a tangled vascular mass with distended tortuous afferent and efferent vessels, a rapid circulation time, and arteriovenous shunting.

In patients presenting without hemorrhage, CT scan or MRI usually reveals the underlying abnormality, and MRI frequently also shows evidence of old or recent hemorrhage that may have been asymptomatic. The nature and detailed anatomy of any focal lesion identified by these means are delineated by angiography, especially if operative treatment is under consideration.

  1. Laboratory and Other Studies

Electroencephalography is usually indicated in patients presenting with seizures and may show consistently focal or lateralized abnormalities resulting from the underlying cerebral arteriovenous malformation. This should be followed by CT scanning.

 Treatment

Surgical treatment to prevent further hemorrhage is justified in patients with arteriovenous malformations that have bled, provided that the lesion is accessible and the patient has a reasonable life expectancy. Surgical treatment is also appropriate if intracranial pressure is increased and to prevent further progression of a focal neurologic deficit. In patients presenting solely with seizures, anticonvulsant drug treatment is usually sufficient, and operative treatment is unnecessary unless there are further developments.

Definitive operative treatment consists of excision of the arteriovenous malformation if it is surgically accessible. Arteriovenous malformations that are inoperable because of their location are sometimes treated solely by embolization; although the risk of hemorrhage is not reduced, neurologic deficits may be stabilized or even reversed by this procedure. Two other techniques for the treatment of intracerebral arteriovenous malformations are injection of a vascular occlusive polymer through a flow-guided microcatheter and permanent occlusion of feeding vessels by positioning detachable balloon catheters in the desired sites and then inflating them with quickly solidifying contrast material. Stereotactic radiosurgery with the gamma knife or related approaches is also useful in the management of inoperable cerebral arteriovenous malformations.

 When to Refer

All patients should be referred.

 When to Admit

  • All patients with a subarachnoid or cerebral hemorrhage.
  • All patients for detailed imaging.
  • All patients undergoing surgical or endovascular treatment.

Sandalcioglu IE et al. The management of arteriovenous malformations. J Neurosurg Sci. 2011 Mar;55(1):57–69. [PMID: 21464810]

Starke RM et al. A practical grading scale for predicting outcome after radiosurgery for arteriovenous malformations: analysis of 1012 treated patients. J Neurosurg. 2013 Oct;119(4):981–7. [PMID: 23829820]

  1. Intracranial Venous Thrombosis

Intracranial venous thrombosis may occur in association with intracranial or maxillofacial infections, hypercoagulable states, polycythemia, sickle cell disease, and cyanotic congenital heart disease and in pregnancy or during the puerperium. Genetic factors are also important. The disorder is characterized by headache, focal or generalized convulsions, drowsiness, confusion, increased intracranial pressure, and focal neurologic deficits—and sometimes by evidence of meningeal irritation. The diagnosis is confirmed by CT scanning, MRI, MR venography, or angiography.

Treatment includes anticonvulsant drugs if seizures have occurred and antiedema agents (eg, dexamethasone, 4 mg four times daily intravenously or intramuscularly and continued as necessary) or other measures to reduce intracranial pressure. Anticoagulation with dose-adjusted intravenous heparin or weight-adjusted subcutaneous low-molecular-weight heparin, followed by oral warfarin anticoagulation for 6 months reduces morbidity and mortality of venous sinus thrombosis. Concomitant intracranial hemorrhage related to the venous thrombosis does not contraindicate heparin therapy. In cases refractory to heparin, endovascular techniques including catheter-directed thrombolytic therapy (urokinase) and thrombectomy, are sometimes helpful but may increase risk for major hemorrhage.

 When to Refer

All patients should be referred.

 When to Admit

All patients should be hospitalized.

Saposnik G et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011 Apr;42(4):1158–92. [PMID: 21293023]

  1. Spinal Cord Vascular Diseases

 ESSENTIALS OF DIAGNOSIS

 Sudden onset of back or limb pain and neurologic deficit in limbs.

 Motor, sensory, or reflex changes in limbs depending on level of lesion.

 Imaging studies distinguish between infarct and hematoma.

 Infarction of the Spinal Cord

Infarction of the spinal cord is rare. It typically occurs in the territory of the anterior spinal artery because this vessel, which supplies the anterior two-thirds of the cord, is itself supplied by only a limited number of feeders. Infarction usually results from interrupted flow in one or more of these feeders, eg, with aortic dissection, aortography, polyarteritis, or severe hypotension, or after surgical resection of the thoracic aorta. The paired posterior spinal arteries, by contrast, are supplied by numerous arteries at different levels of the cord. Spinal cord hypoperfusion may lead to a central cord syndrome with distal weakness of lower motor neuron type and loss of pain and temperature appreciation, with preserved posterior column function.

Since the anterior spinal artery receives numerous feeders in the cervical region, infarcts almost always occur caudally. Clinical presentation is characterized by acute onset of flaccid, areflexive paraplegia that evolves after a few days or weeks into a spastic paraplegia with extensor plantar responses. There is an accompanying dissociated sensory loss, with impairment of appreciation of pain and temperature but preservation of sensations of vibration and position. Treatment is symptomatic.

Tubbs RS et al. Spinal cord ischemia and atherosclerosis: a review of the literature. Br J Neurosurg. 2011 Dec;25(6):666–70. [PMID: 21707414]

 Epidural or Subdural Hemorrhage

Epidural or subdural hemorrhage may lead to sudden severe back pain followed by an acute compressive myelopathy necessitating urgent spinal MRI or myelography and surgical evacuation. It may occur in patients with bleeding disorders or those who are taking anticoagulant drugs, sometimes following trauma or lumbar puncture. Epidural hemorrhage may also be related to a vascular malformation or tumor deposit.

Hussenbocus SM et al. Spontaneous spinal epidural hematoma: a case report and literature review. J Emerg Med. 2012 Feb;42(2):e31–4. [PMID: 19128914]

 Spinal Dural Arteriovenous Fistulae

Spinal dural arteriovenous fistulae are congenital lesions that present with spinal subarachnoid hemorrhage or myeloradiculopathy. Since most of these malformations are located in the thoracolumbar region, they lead to motor and sensory disturbances in the legs and to sphincter disorders. Pain in the legs or back is often severe. Examination reveals an upper, lower, or mixed motor deficit in the legs; sensory deficits are also present and are usually extensive, although occasionally they are confined to radicular distribution. Cervical spinal dural arteriovenous fistulae lead also to symptoms and signs in the arms. Spinal MRI may not detect the spinal dural arteriovenous fistulae, and negative findings do not exclude the diagnosis. Myelography (performed with the patient prone and supine) detects serpiginous filling defects due to enlarged vessels. Selective spinal arteriography confirms the diagnosis. Most lesions are extramedullary, are posterior to the cord (lying either intradurally or extradurally), and can easily be treated by ligation of feeding vessels and excision of the fistulous anomaly or by embolization procedures. Delay in treatment may lead to increased and irreversible disability or to death from recurrent subarachnoid hemorrhage.

 When to Refer

All patients should be referred.

 When to Admit

All patients should be hospitalized.

Rubin MN et al. Vascular diseases of the spinal cord. Neurol Clin. 2013 Feb;31(1):153–81. [PMID: 23186899]

INTRACRANIAL & SPINAL MASS LESIONS

  1. Primary Intracranial Tumors

 ESSENTIALS OF DIAGNOSIS

 Generalized or focal disturbance of cerebral function, or both.

 Increased intracranial pressure in some patients.

 Neuroradiologic evidence of space-occupying lesion.

 General Considerations

Half of all primary intracranial neoplasms (Table 24–5) are gliomas and the remainder are meningiomas, pituitary adenomas (see Chapter 26), neurofibromas, and other tumors. Certain tumors, especially neurofibromas, hemangioblastomas, and retinoblastomas, may have a familial basis, and congenital factors bear on the development of craniopharyngiomas. Tumors may occur at any age, but certain gliomas show particular age predilections.

Table 24–5. Primary intracranial tumors.

 Clinical Findings

  1. Symptoms and Signs

Intracranial tumors may lead to a generalized disturbance of cerebral function and to symptoms and signs of increased intracranial pressure. In consequence, there may be personality changes, intellectual decline, emotional lability, seizures, headaches, nausea, and malaise. If the pressure is increased in a particular cranial compartment, brain tissue may herniate into a compartment with lower pressure. The most familiar syndrome is herniation of the temporal lobe uncus through the tentorial hiatus, which causes compression of the third cranial nerve, midbrain, and posterior cerebral artery. The earliest sign of this is ipsilateral pupillary dilation, followed by stupor, coma, decerebrate posturing, and respiratory arrest. Another important herniation syndrome consists of displacement of the cerebellar tonsils through the foramen magnum, which causes medullary compression leading to apnea, circulatory collapse, and death. Other herniation syndromes are less common and of less clear clinical importance.

Intracranial tumors also lead to focal deficits depending on their location.

  1. Frontal lobe lesions—Tumors of the frontal lobe often lead to progressive intellectual decline, slowing of mental activity, personality changes, and contralateral grasp reflexes. They may lead to expressive aphasia if the posterior part of the left inferior frontal gyrus is involved. Anosmia may also occur as a consequence of pressure on the olfactory nerve. Precentral lesions may cause focal motor seizures or contralateral pyramidal deficits.
  2. Temporal lobe lesions—Tumors of the uncinate region may be manifested by seizures with olfactory or gustatory hallucinations, motor phenomena such as licking or smacking of the lips, and some impairment of external awareness without actual loss of consciousness. Temporal lobe lesions also lead to depersonalization, emotional changes, behavioral disturbances, sensations of déjà; vu or jamais vu, micropsia or macropsia (objects appear smaller or larger than they are), visual field defects (crossed upper quadrantanopia), and auditory illusions or hallucinations. Left-sided lesions may lead to dysnomia and receptive aphasia, while right-sided involvement sometimes disturbs the perception of musical notes and melodies.
  3. Parietal lobe lesions—Tumors in this location characteristically cause contralateral disturbances of sensation and may cause sensory seizures, sensory loss or inattention, or some combination of these symptoms. The sensory loss is cortical in type and involves postural sensibility and tactile discrimination, so that the appreciation of shape, size, weight, and texture is impaired. Objects placed in the hand may not be recognized (astereognosis). Extensive parietal lobe lesions may produce contralateral hyperpathia and spontaneous pain (thalamic syndrome). Involvement of the optic radiation leads to a contralateral homonymous field defect that sometimes consists solely of lower quadrantanopia. Lesions of the left angular gyrus cause Gerstmann syndrome (a combination of alexia, agraphia, acalculia, right-left confusion, and finger agnosia), whereas involvement of the left submarginal gyrus causes ideational apraxia. Anosognosia (the denial, neglect, or rejection of a paralyzed limb) is seen in patients with lesions of the nondominant (right) hemisphere. Constructional apraxia and dressing apraxia may also occur with right-sided lesions.
  4. Occipital lobe lesions—Tumors of the occipital lobe characteristically produce crossed homonymous hemianopia or a partial field defect. With left-sided or bilateral lesions, there may be visual agnosia both for objects and for colors, while irritative lesions on either side can cause unformed visual hallucinations. Bilateral occipital lobe involvement causes cortical blindness in which there is preservation of pupillary responses to light and lack of awareness of the defect by the patient. There may also be loss of color perception, prosopagnosia (inability to identify a familiar face), simultagnosia (inability to integrate and interpret a composite scene as opposed to its individual elements), and Balint syndrome (failure to turn the eyes to a particular point in space, despite preservation of spontaneous and reflex eye movements). The denial of blindness or a field defect constitutes Anton syndrome.
  5. Brainstem and cerebellar lesions—Brainstem lesions lead to cranial nerve palsies, ataxia, incoordination, nystagmus, and pyramidal and sensory deficits in the limbs on one or both sides. Intrinsic brainstem tumors, such as gliomas, tend to produce an increase in intracranial pressure only late in their course. Cerebellar tumors produce marked ataxia of the trunk if the vermis cerebelli is involved and ipsilateral appendicular deficits (ataxia, incoordination and hypotonia of the limbs) if the cerebellar hemispheres are affected.
  6. False localizing signs—Tumors may lead to neurologic signs other than by direct compression or infiltration, thereby leading to errors of clinical localization. These false localizing signs include third or sixth nerve palsy and bilateral extensor plantar responses produced by herniation syndromes, and an extensor plantar response occurring ipsilateral to a hemispheric tumor as a result of compression of the opposite cerebral peduncle against the tentorium.
  7. Imaging

MRI with gadolinium enhancement is the preferred method to detect the lesion and to define its location, shape, and size; the extent to which normal anatomy is distorted; and the degree of any associated cerebral edema or mass effect. CT scanning with radiocontrast enhancement could be performed; however, it is less helpful than MRI for small lesions or tumors in the posterior fossa. Newer neuroimaging techniques may help identify brain tumors by increased blood perfusion (perfusion-weighted MRI, single photon-emission computed tomography, positron-emission tomography) and high metabolism or cell turnover (magnetic resonance spectroscopy, positron-emission tomography), but non-neoplastic diseases, such as stroke and inflammatory or infectious diseases, are sometimes associated with hyperperfusion and hypermetabolism. Diffusion-weighted MRI may also be helpful. Arteriography may show stretching or displacement of normal cerebral vessels by the tumor and the presence of tumor vascularity. The presence of an avascular mass is a nonspecific finding that could be due to tumor, hematoma, abscess, or any space-occupying lesion. In patients with normal hormone levels and an intrasellar mass, angiography is necessary to distinguish with confidence between a pituitary adenoma and an arterial aneurysm.

  1. Laboratory and Other Studies

The electroencephalogram provides supporting information concerning cerebral function and may show either a focal disturbance due to the neoplasm or a more diffuse change reflecting altered mental status. Lumbar puncture is rarely necessary; the findings are seldom diagnostic, and the procedure carries the risk of causing a herniation syndrome.

 Treatment

Treatment depends on the type and site of the tumor (Table 24–5) and the condition of the patient. Some benign tumors, especially meningiomas discovered incidentally during brain imaging for another purpose, may be monitored with serial annual imaging. For symptomatic tumors, complete surgical removal may be possible if the tumor is extra-axial (eg, meningioma, acoustic neuroma) or is not in a critical or inaccessible region of the brain (eg, cerebellar hemangioblastoma). Surgery also permits the diagnosis to be verified and may be beneficial in reducing intracranial pressure and relieving symptoms even if the neoplasm cannot be completely removed. Clinical deficits are sometimes due in part to obstructive hydrocephalus, in which case simple surgical shunting procedures often produce dramatic benefit. In patients with malignant gliomas, radiation therapy increases median survival rates regardless of any preceding surgery, and its combination with chemotherapy provides additional benefit. Indications for irradiation in the treatment of patients with other primary intracranial neoplasms depend on tumor type and accessibility and the feasibility of complete surgical removal. Temozolomide is a commonly used oral and intravenous chemotherapeutic for gliomas, and there is an increasing trend to use monoclonal antibodies as a component of therapy. Corticosteroids help reduce cerebral edema and are usually started before surgery. Herniation is treated with intravenous dexamethasone (10–20 mg as a bolus, followed by 4 mg every 6 hours) and intravenous mannitol (20% solution given in a dose of 1.5 g/kg over about 30 minutes). Anticonvulsants are also commonly administered in standard doses (see Table 24–3) but are not indicated for prophylaxis in patients who have no history of seizures. Long-term neurocognitive deficits may complicate radiation therapy. For those patients whose disease deteriorates despite treatment, palliative care is important (see Chapter 5).

 When to Refer

All patients should be referred.

 When to Admit

  • All patients with increased intracranial pressure.
  • All patients requiring biopsy, surgical treatment, or shunting procedures.

Ricard D et al. Primary brain tumours in adults. Lancet. 2012 May 26;379(9830):1984–96. [PMID: 22510398]

  1. Metastatic Intracranial Tumors

Cerebral Metastases

Metastatic brain tumors present in the same way as other cerebral neoplasms, ie, with increased intracranial pressure, with focal or diffuse disturbance of cerebral function, or with both of these manifestations. Indeed, in patients with a single cerebral lesion, the metastatic nature of the lesion may only become evident on histopathologic examination. In other patients, there is evidence of widespread metastatic disease, or an isolated cerebral metastasis develops during treatment of the primary neoplasm.

The most common source of intracranial metastasis is carcinoma of the lung; other primary sites are the breast, kidney, skin (melanoma), and gastrointestinal tract. Most cerebral metastases are located supratentorially. Laboratory and radiologic studies used to evaluate patients with metastases are those described for primary neoplasms. They include MRI and CT scanning performed both with and without contrast material. Lumbar puncture is necessary only in patients with suspected carcinomatous meningitis (see later). In patients with verified cerebral metastasis from an unknown primary, investigation is guided by symptoms and signs. In women, mammography is indicated; in men under 50, germ cell origin is sought since both have therapeutic implications.

In patients with only a single, surgically accessible cerebral metastasis who are otherwise well (ie, a high level of functioning and little or no evidence of extracranial disease), it may be possible to remove the lesion and then treat with irradiation; the latter may also be selected as the sole treatment. In patients with multiple metastases or widespread systemic disease, the prognosis is poor; stereotactic radiosurgery, whole-brain radiotherapy, or both, may help in some instances, but in others treatment is palliative only.

Tsao MN et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012 Apr 18;4:CD003869. [PMID: 22513917]

Leptomeningeal Metastases (Carcinomatous Meningitis)

The neoplasms metastasizing most commonly to the leptomeninges are carcinoma of the breast, lymphomas, and leukemia. Leptomeningeal metastases lead to multifocal neurologic deficits, which may be associated with infiltration of cranial and spinal nerve roots, direct invasion of the brain or spinal cord, obstructive hydrocephalus, or some combination of these factors.

The diagnosis is confirmed by examination of the cerebrospinal fluid. Findings may include elevated cerebrospinal fluid pressure, pleocytosis, increased protein concentration, and decreased glucose concentration. Cytologic studies may indicate that malignant cells are present; if not, lumbar puncture should be repeated at least twice to obtain further samples for analysis.

CT scans showing contrast enhancement in the basal cisterns or showing hydrocephalus without any evidence of a mass lesion support the diagnosis. Gadolinium-enhanced MRI frequently shows enhancing foci in the leptomeninges. Myelography may show deposits on multiple nerve roots.

Treatment is by irradiation to symptomatic areas, combined with intrathecal methotrexate. The long-term prognosis is poor—only about 10% of patients survive for 1 year—and palliative care is therefore important (see Chapter 5).

Clarke JL. Leptomeningeal metastasis from systemic cancer. Continuum (Minneap Minn). 2012 Apr;18(2):328–42. [PMID: 22810130]

Grewal J et al. Novel approaches to treating leptomeningeal metastases. J Neurooncol. 2012 Jan;106(2):225–34. [PMID: 21874597]

  1. Intracranial Mass Lesions in AIDS Patients

Primary cerebral lymphoma is a common complication in patients with AIDS. This leads to disturbances in cognition or consciousness, focal motor or sensory deficits, aphasia, seizures, and cranial neuropathies. Similar clinical disturbances may result from cerebral toxoplasmosis, which is also a common complication in patients with AIDS (see Chapters 31 and 35).

Cryptococcal meningitis is a common opportunistic infection in AIDS patients. Clinically, it may resemble cerebral toxoplasmosis or lymphoma, but cranial CT scans are usually normal (see Chapter 36).

  1. Primary & Metastatic Spinal Tumors

Approximately 10% of spinal tumors are intramedullary. Ependymoma is the most common type of intramedullary tumor; the remainder are other types of glioma. Extramedullary tumors may be extradural or intradural in location. Among the primary extramedullary tumors, neurofibromas and meningiomas are relatively common, are benign, and may be intradural or extradural. Carcinomatous metastases, lymphomatous or leukemic deposits, and myeloma are usually extradural; in the case of metastases, the prostate, breast, lung, and kidney are common primary sites.

Tumors may lead to spinal cord dysfunction by direct compression, by ischemia secondary to arterial or venous obstruction and, in the case of intramedullary lesions, by invasive infiltration.

 Clinical Findings

  1. Symptoms and Signs

Symptoms usually develop insidiously. Pain is often conspicuous with extradural lesions; is characteristically aggravated by coughing or straining; may be radicular, localized to the back, or felt diffusely in an extremity; and may be accompanied by motor deficits, paresthesias, or numbness, especially in the legs. Bladder, bowel, and sexual dysfunction may occur. When sphincter disturbances occur, they are usually particularly disabling. Pain, however, often precedes specific neurologic symptoms from epidural metastases.

Examination may reveal localized spinal tenderness. A segmental lower motor neuron deficit or dermatomal sensory changes (or both) are sometimes found at the level of the lesion, while an upper motor neuron deficit and sensory disturbance are found below it.

  1. Imaging

CT myelography or, preferably, MRI with contrast is used to identify and localize the lesion. The combination of known tumor elsewhere in the body, back pain, and either abnormal plain films of the spine or neurologic signs of cord compression is an indication to perform these studies on an urgent basis.

  1. Laboratory Findings

The cerebrospinal fluid is often xanthochromic and contains a greatly increased protein concentration with normal cell content and glucose concentration.

 Treatment

Intramedullary tumors are treated by decompression and surgical excision (when feasible) and by irradiation. The prognosis depends on the cause and severity of cord compression before it is relieved.

Treatment of epidural spinal metastases consists of irradiation, irrespective of cell type. Dexamethasone is also given in a high dosage (eg, 25 mg four times daily for 3 days orally or intravenously, followed by rapid tapering of the dosage, depending on response) to reduce cord swelling and relieve pain. Surgical decompression is reserved for patients with tumors that are unresponsive to irradiation or have previously been irradiated and for cases in which there is some uncertainty about the diagnosis. The long-term outlook is poor, but radiation treatment may at least delay the onset of major disability.

Mechtler LL et al. Spinal cord tumors: new views and future directions. Neurol Clin. 2013 Feb;31(1):241–68. [PMID: 23186903]

  1. Brain Abscess

 ESSENTIALS OF DIAGNOSIS

 Symptoms and signs of expanding intracranial mass.

 Signs of primary infection or congenital heart disease are sometimes present.

 Fever may be absent.

 General Considerations

Brain abscess presents as an intracranial space-occupying lesion and arises as a sequela of disease of the ear or nose, may be a complication of infection elsewhere in the body, or may result from infection introduced intracranially by trauma or surgical procedures. The most common infective organisms are streptococci, staphylococci, and anaerobes; mixed infections are not uncommon.

 Clinical Findings

  1. Symptoms and Signs

Headache, drowsiness, inattention, confusion, and seizures are early symptoms, followed by signs of increasing intracranial pressure and then a focal neurologic deficit. There may be little or no systemic evidence of infection.

  1. Imaging and Other Investigations

A CT scan of the head characteristically shows an area of contrast enhancement surrounding a low-density core. Similar abnormalities may be found in patients with metastatic neoplasms. MRI findings often permit earlier recognition of focal cerebritis or an abscess. Arteriography indicates the presence of a space-occupying lesion, which appears as an avascular mass with displacement of normal cerebral vessels. Stereotactic needle aspiration may enable a specific etiologic organism to be identified. Examination of the cerebrospinal fluid does not help in diagnosis and may precipitate a herniation syndrome. Peripheral leukocytosis is sometimes present.

 Treatment

Treatment consists of intravenous antibiotics, combined with surgical drainage (aspiration or excision) if necessary to reduce the mass effect, or sometimes to establish the diagnosis. Abscesses smaller than 2 cm can often be cured medically. Broad-spectrum antibiotics, selected based on risk factors and likely organisms, are used if the infecting organism is unknown (see Chapter 33). Initial empiric antibiotic regimens typically include ceftriaxone (2 g intravenously every 12 hours), metronidazole (15 mg/kg intravenous loading dose, followed by 7.5 mg/kg intravenously every 6 hours), and vancomycin (1 g intravenously every 12 hours). The regimen is altered once culture and sensitivity data are available. Antimicrobial treatment is usually continued parenterally for 6–8 weeks, followed by orally for 2–3 months. The patient should be monitored by serial CT scans or MRI every 2 weeks and at deterioration. Dexamethasone (4–25 mg four times daily intravenously or orally, depending on severity, followed by tapering of dose, depending on response) may reduce any associated edema, but intravenous mannitol is sometimes required.

Helweg-Larsen J et al. Pyogenic brain abscess, a 15 year survey. BMC Infect Dis. 2012 Nov 30;12:332. [PMID: 23193986]

NONMETASTATIC NEUROLOGIC COMPLICATIONS OF MALIGNANT DISEASE

A variety of nonmetastatic neurologic complications of malignant disease (see Table 39–2) can be recognized. Metabolic encephalopathy due to electrolyte abnormalities, infections, drug overdose, or the failure of some vital organ may be reflected by drowsiness, lethargy, restlessness, insomnia, agitation, confusion, stupor, or coma. The mental changes are usually associated with tremor, asterixis, and multifocal myoclonus. The electroencephalogram is generally diffusely slowed. Laboratory studies are necessary to detect the cause of the encephalopathy, which must then be treated appropriately.

Immune suppression resulting from either the malignant disease or its treatment (eg, by chemotherapy) predisposes patients to brain abscess, progressive multifocal leukoencephalopathy, meningitis, herpes zoster infection, and other opportunistic infectious diseases. Moreover, an overt or occult cerebrospinal fluid fistula, as occurs with some tumors, may also increase the risk of infection. MRI or CT scanning aids in the early recognition of a brain abscess, but metastatic brain tumors may have a similar appearance. Examination of the cerebrospinal fluid is essential in the evaluation of patients with meningitis but is of no help in the diagnosis of brain abscess.

Cerebrovascular disorders that cause neurologic complications in patients with systemic cancer include nonbacterial thrombotic endocarditis and septic embolization. Cerebral, subarachnoid, or subdural hemorrhages may occur in patients with myelogenous leukemia and may be found in association with metastatic tumors, especially malignant melanoma. Spinal subdural hemorrhage sometimes occurs after lumbar puncture in patients with marked thrombocytopenia.

Disseminated intravascular coagulation occurs most commonly in patients with acute promyelocytic leukemia or with some adenocarcinomas and is characterized by a fluctuating encephalopathy, often with associated seizures, that frequently progresses to coma or death. There may be few accompanying neurologic signs. Venous sinus thrombosis, which usually presents with convulsions and headaches, may also occur in patients with leukemia or lymphoma. Examination commonly reveals papilledema and focal or diffuse neurologic signs. Anticonvulsants, anticoagulants, and drugs to lower the intracranial pressure may be of value.

Autoimmune paraneoplastic disorders occur when the immune system reacts against neuronal antigens expressed by tumor cells. The clinical manifestations depend on the autoantibody. Symptoms may precede those due to the neoplasm itself. Several distinct syndromes are common, including paraneoplastic cerebellar degeneration, limbic encephalitis, encephalomyelitis, anti-NMDA receptor-associated encephalitis, opsoclonus/myoclonus, sensory neuronopathy, and dermatomyositis.

Paraneoplastic cerebellar degeneration occurs most commonly in association with carcinoma of the lung, but also in breast and gynecologic cancers and Hodgkin lymphoma. Typically, there is a pancerebellar syndrome causing dysarthria, nystagmus, and ataxia of the trunk and limbs. The disorder is associated with anti-Yo, -Tr, -voltage-gated calcium channel (VGCC), and -Zic antibodies. Treatment is of the underlying malignant disease. Limbic encephalitis, characterized by impaired recent memory, disturbed affect, hallucinations, and seizures, occurs in some patients with tumors of the lungs, breast, thymus, and germ cells. Associated antibodies include anti-Hu, -Ma2, -CV2/CRMP5, voltage-gated potassium channel (VGKC), -AMPA receptor, and -GABA B receptor. A more generalizedencephalomyelitis occurs with anti-Hu, -CV2/CRMP5, -Ma2, and -amphiphysin antibodies in the context of a similar spectrum of tumors. Anti-NMDA receptor-associated encephalitis causes a characteristic syndrome of severe psychiatric symptoms, dyskinesias, dysautonomia, and hypoventilation, and is frequently associated with ovarian teratoma. Opsoclonus/myoclonus, a syndrome of involuntary, erratic, and conjugate saccadic eye movements and myoclonic movements of the limbs, occurs in patients with lung, breast, and gynecologic tumors, often without an identifiable antibody.Sensory neuronopathy, typically caused by anti-Hu antibodies in small cell lung cancer or other carcinomas, manifests itself with asymmetric, multifocal sensory nerve root deficits leading to pain, numbness, sensory ataxia, and sometimes hearing loss. Dermatomyositis (see Chapter 20) or the Lambert-Eaton myasthenic syndrome (discussed below) may be seen in patients with underlying carcinoma. Identification of an antibody is not always possible in a suspected autoimmune paraneoplastic condition, and a search for anunderlying neoplasm should not be deterred. Treatment of the neoplasm takes priority and offers the best hope for stabilization or improvement of the neurologic symptoms, which often are not completely reversible. Specific treatment of the antibody-mediated symptoms by intravenous immunoglobulin (IVIG) administration, plasmapheresis, corticosteroids, or other immunosuppressive regimens, is frequently attempted despite limited efficacy. Encephalitides involving antibodies directed against neuronal cell surface antigens, such as VGKC or AMPA, NMDA, or GABAB receptors, can occur either as paraneoplastic phenomena or in isolation, and typically respond well to immunotherapy.

Graus F et al. Paraneoplastic neurological syndromes. Curr Opin Neurol. 2012 Dec;25(6):795–801. [PMID: 23041955]

McKeon A. Paraneoplastic and other autoimmune disorders of the central nervous system. Neurohospitalist. 2013 Apr;3(2):53–64. [PMID: 23983888]

PSEUDOTUMOR CEREBRI (Benign Intracranial Hypertension)

 ESSENTIALS OF DIAGNOSIS

 Headache, worse on straining.

 Visual obscurations or diplopia may occur.

 Examination reveals papilledema.

 Abducens palsy is commonly present.

 General Considerations

There are many causes of pseudotumor cerebri. Thrombosis of the transverse venous sinus as a noninfectious complication of otitis media or chronic mastoiditis is one cause, and sagittal sinus thrombosis may lead to a clinically similar picture. Other causes include chronic pulmonary disease, systemic lupus erythematosus, uremia, endocrine disturbances such as hypoparathyroidism, hypothyroidism, or Addison disease, vitamin A toxicity, and the use of tetracycline or oral contraceptives. Cases have also followed withdrawal of corticosteroids after long-term use. In most instances, however, no specific cause can be found, and the disorder remits spontaneously after several months. This idiopathic variety—known as idiopathic intracranial hypertension—occurs most commonly among overweight women aged 20–44. In all cases, screening for a space-occupying lesion of the brain is important.

 Clinical Findings

  1. Symptoms and Signs

Symptoms consist of headache, diplopia, and other visual disturbances due to papilledema and abducens nerve dysfunction. Pulse-synchronous tinnitus may also occur. Examination reveals the papilledema and some enlargement of the blind spots, but patients otherwise look well.

  1. Imaging

Investigations reveal no evidence of a space-occupying lesion. CT scan shows small or normal ventricles. MR venography is helpful in screening for thrombosis of the intracranial venous sinuses.

  1. Laboratory Findings

Lumbar puncture confirms the presence of intracranial hypertension, but the cerebrospinal fluid is normal. Laboratory studies help exclude some of the other causes mentioned earlier.

 Treatment

Untreated intracranial hypertension sometimes leads to secondary optic atrophy and permanent visual loss. Acetazolamide (250–500 mg orally three times daily, increasing slowly to a maintenance dose of 1000–2000 mg daily, divided two to four times daily) reduces formation of cerebrospinal fluid and can be used to start treatment. Like acetazolamide, the antiepileptic drug topiramate (Table 24–3) is a carbonic anhydrase inhibitor and was shown to be similarly effective in an open label study; topiramate has the added benefit of causing weight loss. Corticosteroids (eg, prednisone, 60–80 mg daily) may also be necessary. Obese patients should be advised to lose weight. Repeated lumbar puncture to lower the intracranial pressure by removal of cerebrospinal fluid is effective as a temporizing measure, but pharmacologic approaches to treatment provide better long-term relief. Treatment is monitored by checking visual acuity and visual fields, funduscopic appearance, and pressure of the cerebrospinal fluid. The disorder may worsen after a period of stability, indicating the need for long-term follow-up.

If medical treatment fails to control the intracranial pressure, surgical placement of a lumboperitoneal or ventriculoperitoneal shunt or optic nerve sheath fenestration should be undertaken to preserve vision.

In addition to the above measures, any specific cause of intracranial hypertension requires appropriate treatment. Thus, hormone therapy should be initiated if there is an underlying endocrine disturbance. Discontinuing the use of tetracycline, oral contraceptives, or vitamin A will allow for resolution of intracranial hypertension due to these agents. If corticosteroid withdrawal is responsible, the medication should be reintroduced and then tapered more gradually.

 When to Refer

All patients should be referred.

 When to Admit

All patients requiring shunt placement or optic nerve sheath fenestration should be hospitalized.

Peng KP et al. High-pressure headaches: idiopathic intracranial hypertension and its mimics. Nat Rev Neurol. 2012 Dec;8(12):700–10. [PMID: 23165338]

SELECTED NEUROCUTANEOUS DISEASES

Because the nervous system develops from the epithelial layer of the embryo, a number of congenital diseases include both neurologic and cutaneous manifestations. Among these disorders, three are discussed below, and von Hippel–Lindau disease is discussed in Chapter 26.

  1. Tuberous Sclerosis

Tuberous sclerosis may occur sporadically or on a familial basis with autosomal dominant inheritance. Neurologic presentation is with seizures and progressive psychomotor retardation beginning in early childhood. The cutaneous abnormality, adenoma sebaceum, becomes manifest usually between 5 and 10 years of age and typically consists of reddened nodules on the face (cheeks, nasolabial folds, sides of the nose, and chin) and sometimes on the forehead and neck. Other typical cutaneous lesions include subungual fibromas, shagreen patches (leathery plaques of subepidermal fibrosis, situated usually on the trunk), and leaf-shaped hypopigmented spots. Associated abnormalities include retinal lesions and tumors, benign rhabdomyomas of the heart, lung cysts, benign tumors in the viscera, and bone cysts.

The disease is slowly progressive and leads to increasing mental deterioration. There is no specific treatment, but anticonvulsant drugs may help in controlling seizures.

Kohrman MH. Emerging treatments in the management of tuberous sclerosis complex. Pediatr Neurol. 2012 May;46(5):267–75. [PMID: 22520346]

  1. Neurofibromatosis

Neurofibromatosis may occur either sporadically or on a familial basis with autosomal dominant inheritance. Two distinct forms are recognized: Type 1 (Recklinghausen disease) is characterized by multiple hyperpigmented macules and neurofibromas, and results from mutations in the NF1 gene on chromosome 17.Type 2 is characterized by eighth nerve tumors, often accompanied by other intracranial or intraspinal tumors, and is associated with mutations in the NF2 (merlin) gene on chromosome 22.

Neurologic presentation is usually with symptoms and signs of tumor. Multiple neurofibromas characteristically are present and may involve spinal or cranial nerves, especially the eighth nerve (Figure 24–1). Examination of the superficial cutaneous nerves usually reveals palpable mobile nodules. In some cases, there is an associated marked overgrowth of subcutaneous tissues (plexiform neuromas), sometimes with an underlying bony abnormality. Associated cutaneous lesions include axillary freckling and patches of cutaneous pigmentation (café au lait spots). Malignant degeneration of neurofibromas occasionally occurs and may lead to peripheral sarcomas. Meningiomas, gliomas (especially optic nerve gliomas), bone cysts, pheochromocytomas, scoliosis, and obstructive hydrocephalus may also occur.

 Figure 24–1. Neurofibromatosis. (From Jack Resnick, Sr, MD; reproduced with permission from Usatine RP, Smith MA, Mayeaux EJ, Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)

Lin AL et al. Advances in the treatment of neurofibromatosis-associated tumours. Nat Rev Clin Oncol. 2013 Nov;10(11):616–24. [PMID: 23939548]

Uhlmann EJ et al. Neurofibromatoses. Adv Exp Med Biol. 2012;724:266–77. [PMID: 22411249]

  1. Sturge-Weber Syndrome

Sturge-Weber syndrome consists of a congenital, usually unilateral, cutaneous capillary angioma involving the upper face, leptomeningeal angiomatosis and, in many patients, choroidal angioma. It has no sex predilection and usually occurs sporadically. The cutaneous angioma sometimes has a more extensive distribution over the head and neck and is often quite disfiguring, especially if there is associated overgrowth of connective tissue. Focal or generalized seizures are the usual neurologic presentation and may commence at any age. There may be contralateral homonymous hemianopia, hemiparesis and hemisensory disturbance, ipsilateral glaucoma, and mental subnormality. Skull radiographs taken after the first 2 years of life usually reveal gyriform (“tramline”) intracranial calcification, especially in the parieto-occipital region, due to mineral deposition in the cortex beneath the intracranial angioma.

Treatment is aimed at controlling seizures pharmacologically, but surgical treatment may be necessary. Ophthalmologic advice should be sought concerning the management of choroidal angioma and of increased intraocular pressure.

Lo W et al; Brain Vascular Malformation Consortium National Sturge-Weber Syndrome Workgroup. Updates and future horizons on the understanding, diagnosis, and treatment of Sturge-Weber syndrome brain involvement. Dev Med Child Neurol. 2012 Mar;54(3):214–23. [PMID: 22191476]

MOVEMENT DISORDERS

  1. Benign Essential (Familial) Tremor

 ESSENTIALS OF DIAGNOSIS

 Postural tremor of hands, head, or voice.

 Family history common.

 May improve temporarily with alcohol.

 No abnormal findings other than tremor.

 General Considerations

The cause of benign essential tremor is uncertain, but it is sometimes inherited in an autosomal dominant manner. Responsible genes have been identified at 3q13, 2p22-p25, and 6p23.

 Clinical Findings

Tremor may begin at any age and is enhanced by emotional stress. The tremor usually involves one or both hands, the head, or the hands and head, while the legs tend to be spared. Examination reveals no other abnormalities. Ingestion of a small quantity of alcohol commonly provides remarkable but short-lived relief by an unknown mechanism.

Although the tremor may become more conspicuous with time, it generally leads to little disability. Occasionally, it interferes with manual skills and leads to impairment of handwriting. Speech may also be affected if the laryngeal muscles are involved.

 Treatment

Treatment is often unnecessary. When it is required because of disability, propranolol (60–240 mg daily orally) may be helpful. Long-term therapy is typical; however, intermittent therapy is sometimes useful in patients whose tremor becomes exacerbated in specific predictable situations. Primidone may be helpful when propranolol is ineffective, but patients with essential tremor are often very sensitive to it. Therefore, the starting dose is 50 mg daily orally, and the daily dose is increased by 50 mg every 2 weeks depending on the patient’s response; a maintenance dose of 125 mg three times daily orally is commonly effective. Occasional patients do not respond to these measures but are helped by alprazolam (up to 3 mg daily orally in divided doses), topiramate (titrated up to a dose of 400 mg daily orally in divided doses over about 8 weeks), or gabapentin (1800 mg daily orally in divided doses). Botulinum toxin A may reduce tremor, but adverse effects include dose-dependent weakness of the injected muscles. Levetiracetam, flunarizine, and 3,4-diaminopyridine are probably ineffective, and there is insufficient evidence to support the use of pregabalin, zonisamide, and clozapine.

Disabling tremor unresponsive to medical treatment may be helped by high-frequency thalamic stimulation on one or both sides, according to the laterality of symptoms. Subdural motor cortex stimulation has also been effective in a small trial.

 When to Refer

All patients should be referred.

 When to Admit

Patients requiring surgical treatment (deep brain stimulator placement) should be hospitalized.

Moro E et al. Unilateral subdural motor cortex stimulation improves essential tremor but not Parkinson’s disease. Brain. 2011 Jul;134(Pt 7):2096–105. [PMID: 21646329]

Zesiewicz TA et al. Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology. Neurology. 2011 Nov 8;77(19):1752–5. [PMID: 22013182]

  1. Parkinsonism

 ESSENTIALS OF DIAGNOSIS

 Any combination of tremor, rigidity, bradykinesia, and progressive postural instability.

 Cognitive impairment is sometimes prominent.

 General Considerations

Parkinsonism is a relatively common disorder that occurs in all ethnic groups, with an approximately equal sex distribution. The most common variety, idiopathic Parkinson disease, begins most often between 45 and 65 years of age and is a progressive disease.

 Etiology

Parkinsonism may rarely occur on a familial basis, and the parkinsonian phenotype may result from mutations of several different genes (alpha-synuclein, parkin, LRRK2DJ1, and PINK1). Mutations inLRRK2 also account for some cases of apparently sporadic Parkinson disease. Postencephalitic parkinsonism is becoming increasingly rare. Exposure to certain toxins (eg, manganese dust, carbon disulfide) and severe carbon monoxide poisoning may lead to parkinsonism. Reversible parkinsonism may develop in patients receiving neuroleptic drugs (see Chapter 25), reserpine, or metoclopramide. Only rarely is hemiparkinsonism the presenting feature of a progressive space-occupying lesion.

In idiopathic Parkinson disease, dopamine depletion due to degeneration of the dopaminergic nigrostriatal system leads to an imbalance of dopamine and acetylcholine, which are neurotransmitters normally present in the corpus striatum. Treatment is directed at redressing this imbalance by blocking the effect of acetylcholine with anticholinergic drugs or by the administration of levodopa, the precursor of dopamine. Prior use of ibuprofen is associated with a decreased risk of developing Parkinson disease; age, family history, male sex, ongoing herbicide/pesticide exposure, and significant prior head trauma are risk factors.

 Clinical Findings

Tremor, rigidity, bradykinesia, and postural instability are the cardinal features of parkinsonism and may be present in any combination. There may also be a mild decline in intellectual function. The tremor of about four to six cycles per second is most conspicuous at rest, is enhanced by emotional stress, and is often less severe during voluntary activity. Although it may ultimately be present in all limbs, the tremor is commonly confined to one limb or to the limbs on one side for months or years before it becomes more generalized. In some patients, tremor is absent.

Rigidity (an increase in resistance to passive movement) is responsible for the characteristically flexed posture seen in many patients, but the most disabling symptoms of parkinsonism are due to bradykinesia, manifested as a slowness of voluntary movement and a reduction in automatic movements such as swinging of the arms while walking. Curiously, however, effective voluntary activity may briefly be regained during an emergency (eg, the patient is able to leap aside to avoid an oncoming motor vehicle).

Clinical diagnosis of the well-developed syndrome is usually simple. The patient has a relatively immobile face with widened palpebral fissures, infrequent blinking, and a fixity of facial expression. Seborrhea of the scalp and face is common. There is often mild blepharoclonus, and a tremor may be present about the mouth and lips. Repetitive tapping (about twice per second) over the bridge of the nose produces a sustained blink response (Myerson sign). Other findings may include saliva drooling from the mouth, perhaps due to impairment of swallowing; soft and poorly modulated voice; a variable rest tremor and rigidity in some or all of the limbs; slowness of voluntary movements; impairment of fine or rapidly alternating movements; and micrographia. There is typically no muscle weakness (provided that sufficient time is allowed for power to be developed) and no alteration in the tendon reflexes or plantar responses. It is difficult for the patient to arise from a sitting position and begin walking. The gait itself is characterized by small shuffling steps and a loss of the normal automatic arm swing; there may be unsteadiness on turning, difficulty in stopping, and a tendency to fall.

 Differential Diagnosis

Diagnostic problems may occur in mild cases, especially if tremor is minimal or absent. For example, mild hypokinesia or slight tremor is commonly attributed to old age. Depression, with its associated expressionless face, poorly modulated voice, and reduction in voluntary activity, can be difficult to distinguish from mild parkinsonism, especially since the two disorders may coexist; in some cases, a trial of antidepressant drug therapy is necessary. The family history, the character of the tremor, and lack of other neurologic signs should distinguish essential tremor from parkinsonism. Wilson disease can be distinguished by its early age at onset, the presence of other abnormal movements, Kayser-Fleischer rings, and chronic hepatitis, and by increased concentrations of copper in the tissues. Huntington disease presenting with rigidity and bradykinesia may be mistaken for parkinsonism unless the family history and accompanying dementia are recognized. In multisystem atrophy (previously called theShy-Drager syndrome), autonomic insufficiency (leading to postural hypotension, anhidrosis, disturbances of sphincter control, erectile dysfunction, etc) may be accompanied by parkinsonism, pyramidal deficits, lower motor neuron signs, or cerebellar dysfunction. In progressive supranuclear palsy, bradykinesia and rigidity are accompanied by a supranuclear disorder of eye movements, pseudobulbar palsy, pseudo-emotional lability (pseudobulbar affect), and axial dystonia. Jakob-Creutzfeldt disease may be accompanied by features of parkinsonism, but dementia is usual, myoclonic jerking is common, ataxia and pyramidal signs may be conspicuous, and the MRI and electroencephalographic findings are usually characteristic. In corticobasal degeneration, asymmetric parkinsonism is accompanied by conspicuous signs of cortical dysfunction (eg, apraxia, sensory inattention, dementia, aphasia).

 Treatment

Treatment is symptomatic. There is great interest in developing disease-modifying therapies, and trials of several putative neuroprotective agents are in progress. Trials of various gene therapies have shown limited or no benefit.

  1. Medical Measures

Drug treatment is not required early in the course of Parkinson disease, but the nature of the disorder and the availability of medical treatment for use when necessary should be discussed with the patient.

  1. Amantadine—Patients with mild symptoms but no disability may be helped by amantadine. This drug improves all of the clinical features of parkinsonism, but its mode of action is unclear. Side effects include restlessness, confusion, depression, skin rashes, edema, nausea, constipation, anorexia, postural hypotension, and disturbances of cardiac rhythm. However, these are relatively uncommon with the usual dose (100 mg twice daily orally). It also ameliorates dyskinesias resulting from chronic levodopa therapy.
  2. Levodopa—Levodopa, which is converted in the body to dopamine, improves all of the major features of parkinsonism, including bradykinesia, but does not stop progression of the disorder. The most common early side effects of levodopa are nausea, vomiting, and hypotension, but cardiac arrhythmias may also occur. Dyskinesias, restlessness, confusion, and other behavioral changes tend to occur somewhat later and become more common with time. Levodopa-induced dyskinesias may take any conceivable form, including chorea, athetosis, dystonia, tremor, tics, and myoclonus. An even later complication is the “on-off phenomenon,” in which abrupt but transient fluctuations in the severity of parkinsonism occur unpredictably but frequently during the day. The “off” period of marked bradykinesia has been shown to relate in some instances to falling plasma levels of levodopa. During the “on” phase, dyskinesias are often conspicuous but mobility is increased.

Carbidopa, which inhibits the enzyme responsible for the breakdown of levodopa to dopamine, does not cross the blood-brain barrier. When levodopa is given in combination with carbidopa, the extracerebral breakdown of levodopa is diminished. This reduces the amount of levodopa required daily for beneficial effects, and it lowers the incidence of nausea, vomiting, hypotension, and cardiac irregularities. Such a combination does not prevent the development of the “on-off phenomenon,” and the incidence of other side effects (dyskinesias or psychiatric complications) may actually be increased.

Sinemet, a commercially available preparation that contains carbidopa and levodopa in a fixed ratio (1:10 or 1:4), is generally used. Treatment is started with a small dose—eg, one tablet of Sinemet 25/100 (containing 25 mg of carbidopa and 100 mg of levodopa) three times daily—and gradually increased depending on the response. Sinemet CR is a controlled-release formulation (containing 25 or 50 mg of carbidopa and 100 or 200 mg of levodopa). It is sometimes helpful in reducing fluctuations in clinical response to treatment and in reducing the frequency with which medication must be taken. The commercially available combination of levodopa with both carbidopa and entacapone (Stalevo) may also be helpful in this context and is discussed in the following section on COMT inhibitors. Response fluctuations are also reduced by keeping the daily intake of protein at the recommended minimum and taking the main protein meal as the last meal of the day.

The dyskinesias and behavioral side effects of levodopa are dose-related, but reduction in dose may eliminate any therapeutic benefit. Levodopa-induced dyskinesias may also respond to amantadine or possibly levetiracetam.

Levodopa therapy is contraindicated in patients with psychotic illness or narrow-angle glaucoma. It should not be given to patients taking monoamine oxidase A inhibitors or within 2 weeks of their withdrawal, because hypertensive crises may result. Levodopa should be used with care in patients with suspected malignant melanomas or with active peptic ulcers because of concerns that it may exacerbate these disorders.

  1. Dopamine agonists—Dopamine agonists, such as pramipexole and ropinirole, act directly on dopamine receptors, and their use in parkinsonism is associated with a lower incidence of the response fluctuations and dyskinesias that occur with long-term levodopa therapy. They were previously reserved for patients who had either become refractory to levodopa or developed the “on-off phenomenon.” However, they are now best given either before the introduction of levodopa or with a low dose of Sinemet 25/100 (carbidopa 25 mg and levodopa 100 mg), one tablet three times daily when dopaminergic therapy is first introduced; the dose of Sinemet is kept constant, while the dose of the agonist is gradually increased.

Pramipexole and ropinirole are effective in both early and advanced stages of Parkinson disease. In each case, the daily dose is built up gradually. Pramipexole is started at a dosage of 0.125 mg three times daily orally, and the dose is doubled after 1 week and again after another week; the daily dose is then increased by 0.75 mg at weekly intervals depending on response and tolerance. Most patients require between 0.5 and 1.5 mg three times daily orally. Ropinirole is begun in a dosage of 0.25 mg three times daily orally, and the total daily dose is increased at weekly intervals by 0.75 mg until the fourth week and by 1.5 mg thereafter. Most patients require between 2 and 8 mg three times daily for benefit. Adverse effects include fatigue, somnolence, nausea, peripheral edema, dyskinesias, confusion, and postural hypotension. Less commonly, an irresistible urge to sleep may occur, sometimes in inappropriate and hazardous circumstances. Impulse control disorders involving gambling, shopping, or sexual activity have also been related to use of dopamine agonists. Extended-release, once-daily formulations of pramipexole and ropinirole are available with similar efficacy and tolerability as the immediate release versions. Bromocriptine is not widely used in the United States because of side effects, including anorexia; nausea; vomiting; constipation; postural hypotension; digital vasospasm; cardiac arrhythmias; various dyskinesias and mental disturbances; headache; nasal congestion; erythromelalgia; pulmonary infiltrates; and pericardial, pleural, or pulmonary fibrosis.

  1. Selective monoamine oxidase inhibitors—Rasagiline, a selective monoamine oxidase B inhibitor, has a clear symptomatic benefit in a daily oral dose of 1 mg, taken in the morning; it may also be used for adjunctive therapy in patients with response fluctuations to levodopa. Selegiline (5 mg orally with breakfast and lunch) is another monoamine oxidase B inhibitor that is sometimes used as adjunctive treatment for parkinsonism. By inhibiting the metabolic breakdown of dopamine, these drugs may improve fluctuations or declining response to levodopa. Although it is sometimes advised that tyramine-rich foods be avoided when either rasagiline or selegiline is taken because of the theoretical possibility of a hypertensive (“cheese”) effect, there is no clinical evidence to support the need for such dietary precautions when they are taken at the recommended dosage.

Studies have suggested (but failed to show conclusively) that rasagiline may slow the progression of Parkinson disease, and it appears to delay the need for other symptomatic therapies. For these reasons, rasagiline is often started early, particularly for patients who are young or have mild disease. However, the FDA has rejected an expansion of rasagiline’s indication to include disease modification.

  1. COMT inhibitors—Catecholamine-O-methyltransferase inhibitors reduce the metabolism of levodopa to 3- O-methyldopa and thereby alter the plasma pharmacokinetics of levodopa, leading to more sustained plasma levels and more constant dopaminergic stimulation of the brain. Two such agents, tolcapone and entacapone, are currently available and may be used as an adjunct to levodopa-carbidopa in patients with response fluctuations or an otherwise inadequate response. Treatment results in reduced response fluctuations, with a greater period of responsiveness to administered levodopa; however, the use of these agents does not delay the eventual development of levodopa-induced dyskinesias. Tolcapone is given in a dosage of 100 mg or 200 mg three times daily orally, and entacapone is given as 200 mg with each dose of Sinemet (levodopa-carbidopa). With either preparation, the dose of Sinemet taken concurrently may have to be reduced by up to one-third to avoid side effects such as dyskinesias, confusion, hypotension, and syncope. Diarrhea is sometimes troublesome. Because rare cases of fulminant hepatic failure have followed its use, tolcapone should be avoided in patients with preexisting liver disease. Serial liver function tests should be performed at 2-week intervals for the first year and at longer intervals thereafter in patients receiving the drug—as recommended by the manufacturer. Hepatotoxicity has not been reported with entacapone, which is therefore the preferred agent, and serial liver function tests are not required.

Stalevo is the commercial preparation of levodopa combined with both carbidopa and entacapone. It is best used in patients already stabilized on equivalent doses of carbidopa/levodopa and entacapone. It is priced at or below the price of the individual ingredients (ie, carbidopa/levodopa and entacapone) and has the added convenience of requiring fewer tablets to be taken daily. It is available in three strengths: Stalevo 50 (12.5 mg of carbidopa, 50 mg of levodopa, and 200 mg of entacapone), Stalevo 100 (25 mg of carbidopa, 100 mg of levodopa, and 200 mg of entacapone), and Stalevo 150 (37.5 mg of carbidopa, 150 mg of levodopa, and 200 mg of entacapone).

  1. Anticholinergic drugs—Anticholinergics are more helpful in alleviating tremor and rigidity than bradykinesia. Treatment is started with a small dose and gradually increased until benefit occurs or side effects limit further increments. If treatment is ineffective, the drug is gradually withdrawn and another preparation then tried.

Side effects limit the routine use of these drugs, and include dryness of the mouth, nausea, constipation, palpitations, cardiac arrhythmias, urinary retention, confusion, agitation, restlessness, drowsiness, mydriasis, increased intraocular pressure, and defective accommodation. Anticholinergic drugs are contraindicated in patients with prostatic hyperplasia, narrow-angle glaucoma, or obstructive gastrointestinal disease and are often tolerated poorly by the elderly. They are best avoided whenever cognitive impairment or a predisposition to delirium exists.

  1. Atypical antipsychotics—Confusion and psychotic symptoms may occur as a side effect of dopaminergic therapy or as a part of the underlying illness. They often respond to atypical antipsychotic agents, which have few extrapyramidal side effects and do not block the effects of dopaminergic medication. Olanzapine, quetiapine, and risperidone may be tried, but the most effective of these agents is clozapine, a dibenzodiazepine derivative. Clozapine may rarely cause marrow suppression, and weekly blood counts are therefore necessary for patients taking it. The patient is started on 6.25 mg at bedtime and the dosage increased to 25–100 mg/d as needed. In low doses, it may also improve iatrogenic dyskinesias.
  2. General Measures

Physical therapy or speech therapy helps many patients. Cognitive impairment and psychiatric symptoms may be helped by a cholinesterase inhibitor, such as rivastigmine (3–12 mg orally daily or 4.6 or 9.5 mg/24 hours transdermally daily). The quality of life can often be improved by the provision of simple aids to daily living, eg, rails or banisters placed strategically about the home, special table cutlery with large handles, nonslip rubber table mats, and devices to amplify the voice.

  1. Surgical Measures

Thalamotomy or pallidotomy may help patients who become unresponsive to medical treatment or have intolerable side effects from antiparkinsonian agents, especially if they have no evidence of diffuse vascular disease or significant cognitive decline. Ablative surgery should generally be confined to one side because the morbidity is considerably greater after bilateral procedures. Because of their morbidity, ablative procedures have generally been supplanted by deep brain stimulation.

  1. Brain Stimulation

High-frequency stimulation of the subthalamic nuclei or globus pallidus internus may benefit all the major features of the disease. Electrical stimulation of the brain has the advantage over ablative procedures of being reversible and of causing minimal or no damage to the brain, and is therefore the preferred surgical approach to treatment. There is no evidence that the natural history of Parkinson disease is affected. Deep brain stimulation is reserved for patients without cognitive impairment or psychiatric disorder who have a good response to levodopa but in whom dyskinesias or response fluctuations are problematic. It frequently takes 3–6 months after surgery to adjust stimulator programming and to achieve optimal results. Side effects include depression, apathy, impulsivity, executive dysfunction, and decreased verbal fluency in a subset of patients.

  1. Gene Therapy

Injections of adeno-associated viruses encoding various human genes have been made into the subthalamic nucleus or putamen in various phase I and phase II trials. These trials are currently continuing, but the procedure appears to be safe. The results have been disappointing except that transfer of the gene for glutamic acid decarboxylase (the enzyme that produces the inhibitory neurotransmitter GABA) into the subthalamic nucleus seems to improve motor function in patients with Parkinson disease. It is unclear whether this provides any greater benefit than subthalamic deep-brain stimulation.

 When to Refer

All patients should be referred.

 When to Admit

Patients requiring surgical treatment should be admitted.

Devos D et al. New pharmacological options for treating advanced Parkinson’s disease. Clin Ther. 2013 Oct;35(10):1640–52. [PMID: 24011636]

Gao X et al. Use of ibuprofen and risk of Parkinson disease. Neurology. 2011 Mar 8;76(10):863–9. [PMID: 21368281]

Gottwald MD, Aminoff MJ. Therapies for dopaminergic-induced dyskinesias in Parkinson disease. Ann Neurol. 2011 Jun;69(6):919–27. [PMID: 21681795]

LeWitt PA et al. AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 2011 Apr;10(4):309–19. [PMID: 21419704]

Rascol O et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol. 2011 May;10(5):415–23. [PMID: 21482191]

Williams DR et al. Parkinsonian syndromes. Continuum (Minneap Minn). 2013 Oct;19(5):1189–212. [PMID: 24092286]

  1. Huntington Disease

 ESSENTIALS OF DIAGNOSIS

 Gradual onset and progression of chorea and dementia or behavioral change.

 Family history of the disorder.

 Responsible gene identified on chromosome 4.

 General Considerations

Huntington disease is characterized by chorea and dementia. It is inherited in an autosomal dominant manner and occurs throughout the world, in all ethnic groups, with a prevalence rate of about 5 per 100,000. There is an expanded and unstable CAG trinucleotide repeat in the huntingtin gene at 4p16.3; longer repeat lengths correspond to an earlier age of onset and faster disease progression.

 Clinical Findings

  1. Symptoms and Signs

Clinical onset is usually between 30 and 50 years of age. The disease is progressive and usually leads to a fatal outcome within 15–20 years. The initial symptoms may consist of either abnormal movements or intellectual changes, but ultimately both occur. The earliest mental changes are often behavioral, with irritability, moodiness, antisocial behavior, or a psychiatric disturbance, but a more obvious dementia subsequently develops. The dyskinesia may initially be no more than an apparent fidgetiness or restlessness, but eventually choreiform movements and some dystonic posturing occur. Progressive rigidity and akinesia (rather than chorea) sometimes occur in association with dementia, especially in cases with childhood onset.

  1. Imaging

CT scanning or MRI usually demonstrates cerebral atrophy and atrophy of the caudate nucleus in established cases. Positron emission tomography (PET) has shown reduced striatal metabolic rate.

 Differential Diagnosis

The diagnosis is established with a widely available genetic test, although such testing should be pursued under the guidance of a licensed genetic counselor. Chorea developing with no family history of choreoathetosis should not be attributed to Huntington disease, at least not until other causes of chorea have been excluded clinically and by appropriate laboratory studies. Nongenetic causes of chorea include stroke, systemic lupus erythematosus and related disorders, paraneoplastic syndromes, infection with HIV, and various medications. In younger patients, self-limiting Sydenham chorea develops after group A streptococcal infections on rare occasions. If a patient presents solely with progressive intellectual failure, it may not be possible to distinguish Huntington disease from other causes of dementia unless there is a characteristic family history or a dyskinesia develops.

Huntington disease–like (HDL) disorders resemble Huntington disease but the CAG trinucleotide repeat number of the huntingtin gene is normal. There are autosomal dominant (HDL1, a familial prion disease involving a mutation in the PRNP gene on chromosome 20; and HDL2, a triplet repeat disease involving the gene for junctophilin-3 on chromosome 16) and recessive forms (HDL3, 4p15.3).

A clinically similar autosomal dominant disorder (dentatorubral-pallidoluysian atrophy), manifested by chorea, dementia, ataxia, and myoclonic epilepsy, is uncommon except in persons of Japanese ancestry. It is due to a mutation in the ATN1 gene mapping to 12p13.31. Treatment is as for Huntington disease.

 Treatment

There is no cure for Huntington disease; progression cannot be halted; and treatment is purely symptomatic. The reported biochemical changes suggest a relative underactivity of neurons containing gamma-aminobutyric acid (GABA) and acetylcholine or a relative overactivity of dopaminergic neurons. Tetrabenazine, a drug that interferes with the vesicular storage of biogenic amines, is widely used to treat the dyskinesia. The starting dose is 12.5 mg twice or three times daily orally, increasing by 12.5 mg every 5 days depending on response and tolerance; the usual maintenance dose is 25 mg three times daily. Side effects include depression, postural hypotension, drowsiness, and parkinsonian features; tetrabenazine should not be given within 14 days of taking monoamine oxidase inhibitors and is not indicated for the treatment of levodopa-induced dyskinesias. Reserpine is similar in depleting central monoamines but has more peripheral effects and a worse side-effect profile, making its use problematic in Huntington disease; if utilized, the dose is built up gradually to between 2 mg and 5 mg orally daily, depending on the response. Treatment with drugs blocking dopamine receptors, such as phenothiazines or haloperidol, may control the dyskinesia and any behavioral disturbances. Haloperidol treatment is usually begun with a dose of 1 mg once or twice daily orally, which is then increased every 3 or 4 days depending on the response; alternatively, atypical antipsychotic agents such as quetiapine (increasing from 25 mg daily orally up to 100 mg twice daily orally as tolerated) may be tried. Amantadine in a dose of 200 mg to 400 mg daily orally is sometimes helpful for chorea. Behavioral disturbances may respond to clozapine. Attempts to compensate for the relative GABA deficiency by enhancing central GABA activity or to compensate for the relative cholinergic underactivity by giving choline chloride have not been therapeutically helpful. Neuroprotective strategies are being explored.

Offspring should be offered genetic counseling. Genetic testing permits presymptomatic detection and definitive diagnosis of the disease.

 When to Refer

All patients should be referred.

Biglan KM et al. Refining the diagnosis of Huntington disease: the PREDICT-HD study. Front Aging Neurosci. 2013 Apr 2;5:12. [PMID: 23565093]

Videnovic A. Treatment of Huntington disease. Curr Treat Options Neurol. 2013 Aug;15(4):424–38. [PMID: 23417276]

  1. Idiopathic Torsion Dystonia

 ESSENTIALS OF DIAGNOSIS

 Dystonic movements and postures.

 Normal birth and developmental history. No other neurologic signs.

 Investigations (including CT scan or MRI) reveal no cause of dystonia.

 General Considerations

Idiopathic torsion dystonia may occur sporadically or on a hereditary basis, with autosomal dominant, autosomal recessive, and X-linked recessive modes of transmission. Symptoms may begin in childhood or later and persist throughout life.

 Clinical Findings

The disorder is characterized by the onset of abnormal movements and postures in a patient with a normal birth and developmental history, no relevant past medical illness, and no other neurologic signs. Investigations (including CT scan) reveal no cause for the abnormal movements. Dystonic movements of the head and neck may take the form of torticollis, blepharospasm, facial grimacing, or forced opening or closing of the mouth. The limbs may also adopt abnormal but characteristic postures. The age at onset influences both the clinical findings and the prognosis. With onset in childhood, there is usually a family history of the disorder, symptoms commonly commence in the legs, and progression is likely until there is severe disability from generalized dystonia. In contrast, when onset is later, a positive family history is unlikely, initial symptoms are often in the arms or axial structures, and severe disability does not usually occur, although generalized dystonia may ultimately develop in some patients. If all cases are considered together, about one-third of patients eventually become so severely disabled that they are confined to chair or bed, while another one-third are affected only mildly.

 Differential Diagnosis

Perinatal anoxia, birth trauma, and kernicterus are common causes of dystonia, but abnormal movements usually then develop before the age of 5, the early development of the patient is usually abnormal, and a history of seizures is not unusual. Moreover, examination may reveal signs of mental retardation or pyramidal deficit in addition to the movement disorder. Dystonic posturing may also occur in Wilson disease, Huntington disease, or parkinsonism; as a sequela of encephalitis lethargica or previous neuroleptic drug therapy; and in certain other disorders. In these cases, diagnosis is based on the history and accompanying clinical manifestations.

 Treatment

Idiopathic torsion dystonia usually responds poorly to drugs. Levodopa, diazepam, baclofen, carbamazepine, amantadine, or anticholinergic medication (in high dosage) is occasionally helpful; if not, a trial of treatment with tetrabenazine, phenothiazines, or haloperidol may be worthwhile. In each case, the dose has to be individualized, depending on response and tolerance. However, the doses of these latter drugs that are required for benefit lead usually to mild parkinsonism. Pallidal deep brain stimulation is helpful for medically refractory dystonia and has a lower morbidity than stereotactic thalamotomy, which is sometimes helpful in patients with predominantly unilateral limb dystonia. Potential adverse events of deep brain stimulation include cerebral infection or hemorrhage, broken leads, affective changes, and dysarthria.

A distinct variety of dominantly inherited dystonia, caused by a mutation in the gene for GTP cyclohydrolase I on chromosome 14q, is remarkably responsive to levodopa.

 When to Refer

All patients should be referred.

 When to Admit

Patients requiring surgical treatment should be admitted.

Morgante F et al. Dystonia. Continuum (Minneap Minn). 2013 Oct;19(5):1225–41. [PMID: 24092288]

Petrucci S et al. Genetic issues in the diagnosis of dystonias. Front Neurol. 2013 Apr 10;4:34. [PMID: 23596437]

  1. Focal Torsion Dystonia

A number of the dystonic manifestations that occur in idiopathic torsion dystonia may also occur as isolated phenomena. They are best regarded as focal dystonias that either occur as formes frustes of idiopathic torsion dystonia in patients with a positive family history or represent a focal manifestation of the adult-onset form of that disorder when there is no family history. Mapping of responsible genes to chromosome 8 (DYT6) and chromosome 18 (DYT7) has been reported in some instances of cervical or cranial dystonia. Medical treatment is generally unsatisfactory. A trial of the drugs used in idiopathic torsion dystonia is worthwhile, however, since a few patients do show some response. In addition, with restricted dystonias such as blepharospasm or torticollis, local injection of botulinum A toxin into the overactive muscles may produce worthwhile benefit for several weeks or months and can be repeated as needed.

Both blepharospasm and oromandibular dystonia may occur as an isolated focal dystonia. The former is characterized by spontaneous involuntary forced closure of the eyelids for a variable interval. Oromandibular dystonia is manifested by involuntary contraction of the muscles about the mouth causing, for example, involuntary opening or closing of the mouth, roving or protruding tongue movements, and retraction of the platysma.

Spasmodic torticollis, usually with onset between 25 and 50 years of age, is characterized by a tendency for the neck to twist to one side. This initially occurs episodically, but eventually the neck is held to the side. Spontaneous resolution may occur in the first year or so. The disorder is otherwise usually lifelong. Selective section of the spinal accessory nerve and the upper cervical nerve roots is sometimes helpful if medical treatment is unsuccessful. Local injection of botulinum A toxin provides benefit in most cases.

Writer’s cramp is characterized by dystonic posturing of the hand and forearm when the hand is used for writing and sometimes when it is used for other tasks, eg, playing the piano or using a screwdriver or eating utensils. Drug treatment is usually unrewarding, and patients are often best advised to learn to use the other hand for activities requiring manual dexterity. Injections of botulinum A toxin are helpful in some instances.

Jinnah HA et al; Dystonia Coalition Investigators. The focal dystonias: current views and challenges for future research. Mov Disord. 2013 Jun 15;28(7):926–43. [PMID: 23893450]

  1. Myoclonus

Occasional myoclonic jerks may occur in anyone, especially when drifting into sleep. General or multifocal myoclonus is common in patients with idiopathic epilepsy and is especially prominent in certain hereditary disorders characterized by seizures and progressive intellectual decline, such as the lipid storage diseases. It is also a feature of various rare degenerative disorders, notably Ramsay Hunt syndrome, and is common in subacute sclerosing panencephalitis and Jakob-Creutzfeldt disease. Generalized myoclonic jerking may accompany uremic and other metabolic encephalopathies, result from therapy with levodopa or cyclic antidepressants, occur in alcohol or drug withdrawal states, or follow anoxic brain damage. It also occurs on a hereditary or sporadic basis as an isolated phenomenon in otherwise healthy subjects.

Segmental myoclonus is a rare manifestation of a focal spinal cord lesion. It may also be the clinical expression of epilepsia partialis continua, a disorder in which a repetitive focal epileptic discharge arises in the contralateral sensorimotor cortex, sometimes from an underlying structural lesion. An electroencephalogram is often helpful in clarifying the epileptic nature of the disorder, and CT or MRI scan may reveal the causal lesion.

Myoclonus may respond to certain anticonvulsant drugs, especially valproic acid, or to one of the benzodiazepines, particularly clonazepam (see Table 24–3). It may also respond to piracetam (up to 16.8 g daily). Myoclonus following anoxic brain damage is often responsive to oxitriptan (5-hydroxytryptophan), an investigational agent that is the precursor of serotonin, and sometimes to clonazepam. Oxitriptan is given in gradually increasing doses up to 1–1.5 mg daily. In patients with segmental myoclonus, a localized lesion should be searched for and treated appropriately.

Espay AJ et al. Myoclonus. Continuum (Minneap Minn). 2013 Oct;19(5):1264–86. [PMID: 24092290]

  1. Wilson Disease

In this metabolic disorder, abnormal movement and posture may occur with or without coexisting signs of liver involvement. Psychiatric and neuropsychological manifestations are common. Wilson disease is discussed in Chapter 16.

Weiss KH et al. Evolving perspectives in Wilson disease: diagnosis, treatment and monitoring. Curr Gastroenterol Rep. 2012 Feb;14(1):1–7. [PMID: 22083169]

  1. Drug-Induced Abnormal Movements

Phenothiazines, butyrophenones, and metoclopramide may produce a wide variety of abnormal movements, including parkinsonism, akathisia (ie, motor restlessness), acute dystonia, chorea, and tardive dyskinesias or dystonia; several of these are also produced by aripiprazole. These complications are discussed in Chapter 25. Chorea may also develop in patients receiving levodopa, bromocriptine, anticholinergic drugs, phenytoin, carbamazepine, lithium, amphetamines, or oral contraceptives, and it resolves with withdrawal of the offending substance. Similarly, dystonia may be produced by levodopa, bromocriptine, lithium, or carbamazepine; and parkinsonism by reserpine and tetrabenazine. Postural tremor may occur with a variety of drugs, including epinephrine, isoproterenol, theophylline, caffeine, lithium, thyroid hormone, tricyclic antidepressants, and valproic acid.

Robottom BJ et al. Drug-induced movement disorders: emergencies and management. Neurol Clin. 2012 Feb;30(1):309–20. [PMID: 22284065]

  1. Restless Legs Syndrome

This disorder may occur as a primary (idiopathic) disorder or in relation to Parkinson disease, pregnancy, iron deficiency anemia, peripheral neuropathy (especially uremic or diabetic), or periodic leg movements of sleep. It may have a hereditary basis, and several genetic loci have been associated with the disorder (12q12-q21, 14q13-q21, 9p24-p22, 2q33, 20p13, 6p21, and 2p14-p13). Restlessness and curious sensory disturbances lead to an irresistible urge to move the limbs, especially during periods of relaxation. Disturbed nocturnal sleep and excessive daytime somnolence may result. Therapy is with nonergot dopamine agonists, such as pramipexole (0.125–0.5 mg orally once daily or ropinirole (0.25–4 mg orally once daily) 2 to 3 hours before bedtime, or with benzodiazepines, such as clonazepam. Gabapentin (starting with 300 mg orally daily, increasing to approximately 1800 mg daily depending on response and tolerance), pregabalin (150–300 mg orally divided twice to three times daily), or gabapentin enacarbil (600 mg extended release daily) are related drugs that improve symptoms. Levodopa is helpful but may lead to an augmentation of symptoms, so that its use is generally reserved for those who do not respond to other measures. In some instances, opioids are required to control symptoms.

Dauvilliers Y et al. Restless legs syndrome: update on pathogenesis. Curr Opin Pulm Med. 2013 Nov;19(6):594–600. [PMID: 24048084]

Hornyak M et al. What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications. Sleep Med Rev. 2014 Apr;18(2):153–64. [PMID: 23746768]

  1. Gilles de la Tourette Syndrome

 ESSENTIALS OF DIAGNOSIS

 Multiple motor and phonic tics.

 Symptoms begin before age 21 years.

 Tics occur frequently for at least 1 year.

 Tics vary in number, frequency, and nature over time.

 Clinical Findings

Motor tics are the initial manifestation in 80% of cases and most commonly involve the face, whereas in the remaining 20%, the initial symptoms are phonic tics; ultimately a combination of different motor and phonic tics develop in all patients. These are noted first in childhood, generally between the ages of 2 and 15. Motor tics occur especially about the face, head, and shoulders (eg, sniffing, blinking, frowning, shoulder shrugging, head thrusting, etc). Phonic tics commonly consist of grunts, barks, hisses, throat-clearing, coughs, etc, but sometimes also of verbal utterances including coprolalia (obscene speech). There may also be echolalia (repetition of the speech of others), echopraxia (imitation of others’ movements), and palilalia (repetition of words or phrases). Some tics may be self-mutilating in nature, such as nail-biting, hair-pulling, or biting of the lips or tongue. The disorder is chronic, but the course may be punctuated by relapses and remissions. Obsessive-compulsive behaviors are commonly associated and may be more disabling than the tics themselves. A family history is sometimes obtained.

Examination usually reveals no abnormalities other than the tics. In addition to obsessive-compulsive behavior disorders, psychiatric disturbances may occur because of the associated cosmetic and social embarrassment. The diagnosis of the disorder is often delayed for years, the tics being interpreted as psychiatric illness or some other form of abnormal movement. Patients are thus often subjected to unnecessary treatment before the disorder is recognized. The tic-like character of the abnormal movements and the absence of other neurologic signs should differentiate this disorder from other movement disorders presenting in childhood. Wilson disease, however, can simulate the condition and should be excluded.

 Treatment

Treatment is symptomatic and may need to be continued indefinitely. Cognitive behavioral therapy or other forms of behavioral intervention can be effective alone or in combination with pharmacotherapy. Alpha-adrenergic agonists, such as clonidine (start 0.05 mg orally at bedtime, titrating to 0.3–0.4 mg orally daily, divided three to four times per day) or guanfacine (start 0.5 mg orally at bedtime, titrating to a maximum of 3–4 mg orally daily, divided twice daily) are first-line therapies because of a favorable side-effect profile compared with typical antipsychotics, which are the only FDA-approved therapies for the disorder. Topiramate has yielded mixed results in several studies, and the use of tetrabenazine has been described but not rigorously tested. Atypical antipsychotics, including risperidone and aripiprazole, have shown possible efficacy and may be tried before the typical antipsychotic agents. When a typical antipsychotic is required in cases of severe tics, haloperidol is generally regarded as the drug of choice. It is started in a low dose (0.25 mg daily orally) that is gradually increased (by 0.25 mg every 4 or 5 days) until there is maximum benefit with a minimum of side effects or until side effects limit further increments. A total daily oral dose of between 2 mg and 8 mg is usually optimal, but higher doses are sometimes necessary. Fluphenazine (2–15 mg orally daily) or pimozide (1–10 mg orally daily) are alternatives. Typical antipsychotics can cause significant weight gain and carry a risk of tardive dyskinesias and other long-term, potentially irreversible motor side effects.

Injection of botulinum toxin type A at the site of the most distressing tics is sometimes worthwhile. Bilateral high-frequency deep brain stimulation at various sites has been helpful in some, otherwise intractable, cases.

 When to Refer

All patients with Gilles de la Tourette syndrome should be referred.

 When to Admit

Patients undergoing surgical (deep brain stimulation) treatment should be admitted.

Sassi M et al. Deep brain stimulation therapy for treatment-refractory Tourette’s syndrome: a review. Acta Neurochir (Wien). 2011 Mar;153(3):639–45. [PMID: 20853121]

Thomas R et al. The pharmacology of Tourette syndrome. J Neural Transm. 2013 Apr;120(4):689–94. [PMID: 23361655]

Wile DJ et al. Behavior therapy for Tourette syndrome: a systematic review and meta-analysis. Curr Treat Options Neurol. 2013 Aug;15(4):385–95. [PMID: 23645295]

DEMENTIA

 ESSENTIALS OF DIAGNOSIS

 Progressive intellectual decline.

 Not due to delirium or psychiatric disease.

 Age is the main risk factor, followed by family history and vascular disease risk factors.

 General Considerations

Dementia is a progressive decline in intellectual function that is severe enough to compromise social or occupational functioning. “Mild cognitive impairment” describes a decline that has not resulted in a change in the level of function. Although a few patients identify a precipitating event, most experience an insidious onset and gradual progression of symptoms.

Dementia typically begins after age 60, and the prevalence doubles approximately every 5 years thereafter; in persons aged 85 and older, around half have dementia. In most, the cause of dementia is acquired, either as a sporadic primary neurodegenerative disease or as the result of another disorder, such as stroke. Other risk factors for dementia include family history, diabetes mellitus and other vascular disease risk factors, and a history of significant head injury. Dementia is more prevalent among women, but this is accounted for by their longer life expectancy. Education and ongoing intellectual stimulation may be protective, perhaps by promoting a “cognitive reserve,” an improved capacity to compensate for insidious neurodegeneration.

Dementia is distinct from delirium and psychiatric disease. Delirium is an acute confusional state that often occurs in response to an identifiable trigger, such as drug or alcohol intoxication or withdrawal (eg, Wernicke encephalopathy, described below); medication side effects (especially drugs with anticholinergic properties, antihistamines, benzodiazepines, sleeping aids, opioids, neuroleptics, corticosteroids, and other sedative or psychotropic agents), infection (consider occult urinary tract infection or pneumonia in elderly patients), metabolic disturbance (including an electrolyte abnormality; hypoglycemia or hyperglycemia; or a nutritional, endocrine, renal, or hepatic disorder), sleep deprivation, or other neurologic disease (seizure, including a postictal state, or stroke). A delirium typically involves fluctuating level of arousal, including drowsiness or agitation, and it improves after removal or treatment of the precipitating factor. Patients with dementia are especially susceptible to episodes of delirium, but recognition of the dementia is not possible until the delirium lifts. For this reason, dementia is typically diagnosed in outpatients who are otherwise medically stable, rather than in acutely ill patients in the hospital.

Psychiatric disease sometimes leads to complaints of impaired cognition. Impaired attention is usually to blame, and in some patients with depression or anxiety, poor focus and concentration may even be a primary complaint. The symptoms should improve with appropriate psychiatric treatment. Mood disorders are commonly seen in patients with neurodegenerative disease and in some cases are an early symptom. There is some evidence that a persistent, untreated mood disorder may predispose to the development of an age-related dementia, and psychiatric symptoms can clearly exacerbate cognitive impairment in patients who already have dementia; therefore, suspicion of dementia should not distract from appropriate screening for and treatment of depression or anxiety.

 Clinical Findings

  1. Symptoms and Signs

Clinicians should be aware that a patient’s insight into a cognitive change may be vague or absent, and collateral history is essential to a proper evaluation. As patients age, primary care clinicians should inquire periodically about the presence of any cognitive symptoms.

Symptoms depend on the area of the brain affected. Short-term memory loss, involving the repeating of questions or stories and a diminished ability to recall the details of recent conversations or events, frequently results from pathologic changes in the hippocampus. Word-finding difficulty often involves difficulty recalling the names of people, places, or objects, with low-frequency words affected first, eventually resulting in speech laden with pronouns and circumlocutions. This problem is thought to arise from pathology at the temporoparietal junction of the left hemisphere. Problems with articulation, fluency, comprehension, or word meaning are anatomically distinct and less common. Visuospatial dysfunction may result in poor navigation and getting lost in familiar places, impaired recognition of previously familiar faces and buildings, or trouble discerning an object against a background. The right parietal lobe is one of the brain areas implicated in such symptoms. Executive dysfunction may manifest by easy distractibility, impulsivity, mental inflexibility, concrete thought, slowed processing speed, poor planning and organization, or impaired judgment. Localization may vary and could include the frontal lobes or subcortical areas like the basal ganglia or cerebral white matter. Apathy or indifference, separate from depression, is common and may have a similar anatomy as executive dysfunction. Apraxia, or the loss of learned motor behaviors, may result from dysfunction of the frontal or parietal lobes, especially the left parietal lobe.

The time of symptom onset must be established, but subtle, early symptoms are often apparent only in retrospect. Another event, such as an illness or hospitalization, may lead to a new recognition of existing symptoms. Symptoms often accumulate over time, and the nature of the earliest symptom is most helpful in forming the differential diagnosis. The history should establish risk factors for dementia, including family history, other chronic illnesses, and vascular disease risk factors. Finally, it is important to document the patient’s current capacity to perform basic and instrumental activities of daily living (see Chapter 4) and to note the extent of decline from the premorbid level of function. Indeed, it is this functional assessment that defines the presence and severity of a dementia.

The physical examination is important to identify any occult medical illness. In addition, eye movement abnormalities, parkinsonism (see above), or other motor abnormalities may help identify an underlying neurologic condition. The workup should prioritize the exclusion of conditions that are reversible or require separate therapy. Screening for depression is necessary, along with imaging and laboratory workup, as indicated below.

  1. Neuropsychological Assessment

Brief quantification of cognitive impairment is indicated in a patient complaining of cognitive symptoms. The Folstein Mini Mental State Exam (MMSE) is commonly used, and can be administered in approximately 5 minutes. The Montreal Cognitive Assessment takes slightly longer and may be slightly more sensitive. These tests are useful because they are objective and widely used, but both have important limitations: they are insensitive to mild cognitive impairment, they may be biased negatively by the presence of language or attention problems, and they do not correlate with functional capacity.

An evaluation by a trained neuropsychologist or psychometrician may be appropriate. The goal of such testing is to enhance localization by defining the cognitive domains that are impaired as well as to quantify the degree of impairment. There is no standard battery of tests, but a variety of metrics are commonly used to assess all of the symptom types highlighted above. Assessments are most accurate when a patient is well-rested, comfortable, and otherwise medically stable.

In an asymptomatic patient, there is no screening guideline. Because occult cognitive impairment can lead to morbidity through isolation and poor attentiveness to basic needs (for instance, in an elderly individual living alone), periodic screening is prudent for patients in their 70s and older: Ask the patient to repeat three simple nouns (not referring to objects in the room), then to draw a clock face with numbers in the correct place and the hands indicating a time of 11:10, and finally to recall the three nouns; recall of fewer than three words or any abnormality in the clock drawing may signify the need to continue with the full MMSE and to pursue further questioning and workup.

  1. Imaging

Brain imaging is indicated in any patient with a new, progressive cognitive complaint. The goal is to exclude occult cerebrovascular disease, tumor, or other identifiable structural abnormality, rather than to provide positive evidence of a neurodegenerative disease. Global or focal brain atrophy may be worse than expected for age and could suggest a particular neurodegenerative process, but such findings are rarely specific. MRI is preferred, but CT scan will suffice; no contrast is necessary. If MRI is obtained, then diffusion-weighted sequences may be helpful if acute stroke or prion disease is a consideration.

Positron-emission tomography (PET) with fluorodeoxyglucose (FDG) may identify particular brain structures that are hypometabolic and thus likely to harbor pathology. PET imaging does not confirm or exclude any specific cause of dementia but may be useful as an element of the workup in specific clinical circumstances, such as discriminating between Alzheimer disease and frontotemporal dementia in a patient with some symptoms of each. PET imaging with a radiolabeled ligand for beta-amyloid, one of the pathologic proteins in Alzheimer disease, is highly sensitive to amyloid pathology and may help provide positive evidence for Alzheimer disease in a patient with cognitive decline. However, after age 60 or 70, amyloid plaques can accumulate in the absence of cognitive impairment; thus, the specificity of a positive amyloid scan diminishes with age. Single photon-emission computed tomography offers similar information as FDG-PET but is less sensitive. PET imaging with radiolabeled ligands for tau, a pathogenic protein in Alzheimer disease, progressive supranuclear palsy, and some forms of frontotemporal dementia, has entered clinical trials and may help refine premortem diagnostic accuracy.

  1. Laboratory Findings

Serum levels of vitamin B12, free T4, and thyroid-stimulating hormone should be measured for any patient with cognitive symptoms. A serum rapid plasma regain (RPR) used to be obtained routinely, but now is done only if there is a risk factor or suspicion for a remote, untreated syphilis infection. Other testing should be driven by clinical suspicion, and often includes a complete blood count, serum electrolytes, glucose, and lipid profile. Also prudent is age-appropriate cancer screening.

Other tests are available if Alzheimer disease is a consideration: ApoE genotyping is clinically available, and the presence of one or two ApoE epsilon-4 alleles indicates an increased risk of Alzheimer disease. Importantly, the gene does not cause Alzheimer disease; familial Alzheimer disease is rare and is caused by mutations in the amyloid precursor protein or presenilin genes. Finding an ApoE epsilon-4 allele in a young patient with dementia might raise the index of suspicion for Alzheimer disease. Obtaining a genotype in an elderly patient is unlikely to be helpful, and doing so in an asymptomatic patient as a marker of risk for Alzheimer disease is inappropriate until a preventive therapy becomes available. Spinal fluid protein measurements are also available; levels of beta-amyloid decrease and tau protein increase in Alzheimer disease, but this testing shares some of the same concerns as amyloid PET imaging.

 Differential Diagnosis

In elderly patients with gradually progressive cognitive symptoms and no other complaint or sign, a neurodegenerative disease is likely (Table 24–6). Decline beginning before age 60, rapid progression, fluctuating course, unintended weight loss, systemic complaints, or other unexplained symptoms or signs raise suspicion for another process. In this case, the differential is broad and includes infection or inflammatory disease (consider a lumbar puncture to screen for cells or antibodies in the spinal fluid), neoplasm or a paraneoplastic condition, endocrine or metabolic disease, drugs or toxins, or other conditions. Normal pressure hydrocephalus is a difficult diagnosis to establish. Symptoms include gait apraxia (sometimes described as a “magnetic” gait, as if the feet are stuck to the floor), urinary incontinence, and dementia. CT scanning or MRI of the brain reveals ventricles that are enlarged in obvious disproportion to sulcal widening and overall brain atrophy.

Table 24–6. Common causes of age-related dementia.

 Treatment

  1. Nonpharmacologic Approaches

Aerobic exercise (45 minutes most days of the week) and frequent mental stimulation may reduce the rate of functional decline and decrease the demented patient’s caregiving needs, and these interventions may reduce the risk of dementia in normal individuals. The most efficacious manner of mental stimulation is a matter of debate: maintaining as active a role in the family and community as practically possible is most likely to be of benefit, emphasizing activities at which the patient feels confident. Patients with neurodegenerative diseases have a limited capacity to regain lost skills; for instance, memory drills in a patient with Alzheimer disease are more likely to lead to frustration than benefit and studies show that computerized cognitive training does not improve cognition or function in demented patients.

  1. Cognitive Symptoms

Cholinesterase inhibitors are first-line therapy for Alzheimer disease and dementia with Lewy bodies. They provide modest, symptomatic treatment for cognitive dysfunction and may prolong the capacity for independence. However, they do not prevent disease progression. Commonly used medications include donepezil (start at 5 mg orally daily for 4 weeks, then increase to 10 mg daily; a 23 mg daily dose is newly approved for moderate to severe Alzheimer disease, although its very modest additional efficacy over the 10-mg dose is overshadowed by an increased risk of side effects); rivastigmine (start at 1.5 mg orally twice daily, then increasing every 2 weeks by 1.5 mg twice daily to a goal of 3–6 mg twice daily; or 4.6, 9.5, or 13.3 mg/24 hours transdermally daily); and galantamine (start at 4 mg orally twice daily, then increasing every 4 weeks by 4 mg twice daily to a goal of 8–12 mg twice daily; a once-daily extended-release formulation is also available). Cholinesterase inhibitors are not given for frontotemporal dementia because they may worsen behavioral symptoms. Nausea and diarrhea are common side effects; syncope and cardiac dysrhythmia are uncommon but more serious. An ECG is often obtained before and after starting therapy, particularly in a patient with cardiac disease or a history of syncope.

Memantine (start at 5 mg orally daily, then increase by 5 mg per week up to a target of 10 mg twice daily) is approved for the treatment of moderate to severe Alzheimer disease. In frontotemporal dementia, memantine is ineffective and may worsen cognition. There is some evidence that memantine may improve cognition and behavior among patients with dementia with Lewy bodies.

Disease-modifying drugs are not yet available for Alzheimer disease. Immunotherapy directed against beta-amyloid has not shown promise in phase III trials.

  1. Mood and Behavioral Disturbances

Selective serotonin reuptake inhibitors are generally safe and well-tolerated in elderly, cognitively impaired patients, and they may be efficacious for the treatment of depression, anxiety, or agitation. However, paroxetine should be avoided because it has anticholinergic effects. Other antidepressant agents, such as buproprion or venlafaxine, may also be tried. Studies on the efficacy of antidepressant therapy in this population are conflicting, but these medications are better tolerated than some alternatives (discussed here).

Insomnia is common, and trazodone (25–50 mg orally at bedtime as needed) can be safe and effective. Over-the-counter antihistamine hypnotics must be avoided, along with benzodiazepines, because of their tendency to worsen cognition and precipitate delirium. Other prescription hypnotics such as zolpidem may result in similar adverse reactions.

For agitation, impulsivity, and other behaviors that interfere with safe caregiving, causes of delirium (detailed above) should first be considered. When no reversible trigger is identified, treatment should be approached in a staged manner. Behavioral interventions, such as reorientation and distraction from anxiety-provoking stimuli, are first-line. Ensure that the patient is kept active during the day with both physical exercise and mentally stimulating activities, and that there is adequate sleep at night. Reassess the level of caregiving, and consider increasing the time spent directly with an attendant. Next, ensure that appropriate pharmacologic treatment of cognition and mood is maximized. Finally, as a last resort, when other measures prove insufficient and the patient’s behaviors raise safety concerns, consider low doses of an atypical antipsychotic medication, such as quetiapine (start 25 mg orally daily as needed, increasing to two to three times daily as needed); even though atypical agents cause extrapyramidal side effects less frequently than typical antipsychotics, they should be used with particular caution in a patient at risk for falls, especially if parkinsonian signs are already present. Regularly scheduled dosing is not recommended, and if implemented should be reassessed on a frequent basis (eg, weekly), with attempts to taper off as tolerated. There is an FDA black box warning against the use of all antipsychotic medications in demented patients because of an increased risk of death. Benzodiazepines, such as lorazepam (0.5 mg as needed, up to one to two times daily) may be used as an alternative, but they may sometimes worsen rather than ameliorate agitation.

Finally, psychostimulants like methylphenidate have been studied as a means to treat apathy in dementia. While such treatment may be of benefit to selected patients, the possibility of causing agitation or cardiovascular strain limits routine use.

 Special Circumstances

  1. Rapidly Progressive Dementia

When dementia develops quickly, with obvious decline over a few weeks to a few months, the syndrome may be classified as a rapidly progressive dementia. The differential diagnosis for typical dementias is still relevant, but additional etiologies must be considered, including prion disease; infections; toxins; neoplasms; and autoimmune and inflammatory diseases, including corticosteroid-responsive (Hashimoto) encephalopathy and antibody-mediated paraneoplastic syndromes. Workup should begin with brain MRI with contrast and diffusion-weighted imaging, routine laboratory studies (serum vitamin B 12, free T4, and thyroid-stimulating hormone levels), serum RPR, HIV antibody, Lyme serology, rheumatologic tests (erythrocyte sedimentation rate, C-reactive protein, and antinuclear antibody), anti-thyroglobulin and anti-thyroperoxidase antibody levels, paraneoplastic autoimmune antibodies, and cerebrospinal fluid studies (cell count and differential; protein and glucose levels; protein electrophoresis for oligoclonal bands; IgG index [spinal-fluid-to-serum gamma-globulin level] ratio; and VDRL). Depending on the clinical context, it may be necessary to exclude Wilson disease (24-hour urine copper level), heavy metal intoxication (24-hour urine heavy metal panel), and infectious encephalitis (cerebrospinal fluid polymerase chain reaction for Whipple disease, herpes simplex virus, cytomegalovirus, varicella-zoster virus, and other viruses).

Jakob-Creutzfeldt disease is a relatively common cause of rapidly progressive dementia (see Chapter 32). Family history is important since mutations in PRNP, the gene for the prion protein, account for around 15% of cases. Diffusion-weighted MRI is the most helpful diagnostic tool, classically revealing cortical ribboning (a gyral pattern of hyperintensity) as well as restricted diffusion in the caudate and anterior putamen. Reflecting the high rate of neuronal death, cerebrospinal fluid levels of the intraneuronal proteins tau, 14-3-3, and neuron-specific enolase are often elevated, although this finding is neither sensitive nor specific. An electroencephalogram often shows periodic complexes.

  1. Driving and Dementia

It is recommended that any patient with mild dementia or worse should discontinue driving. Most states have laws regulating driving among cognitively impaired individuals, and many require the clinician to report the patient’s diagnosis to the public health department or department of motor vehicles. There is no evidence that driving classes help patients with neurodegenerative diseases.

 When to Refer

All patients with new, unexplained cognitive decline should be referred.

 When to Admit

Dementia alone is not an indication for admission, but admission is sometimes necessary when a superimposed delirium poses safety risks at home.

Ahlskog JE et al. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011 Sep;86(9):876–84. [PMID: 21878600]

Galasko D. The diagnostic evaluation of a patient with dementia. Continuum (Minneap Minn). 2013 Apr;19(2):397–410. [PMID: 23558485]

McKhann GM et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 May;7(3):263–9. [PMID: 21514250]

Paterson RW et al. Diagnosis and treatment of rapidly progressive dementias. Neurol Clin Pract. 2012 Sep;2(3):187–200. [PMID: 23634367]

Schwarz S et al. Pharmacological treatment of dementia. Curr Opin Psychiatry. 2012 Nov;25(6):542–50. [PMID: 22992546]

Seitz DP et al. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD008191. [PMID: 21328305]

MULTIPLE SCLEROSIS

 ESSENTIALS OF DIAGNOSIS

 Episodic neurologic symptoms.

 Patient usually under 55 years of age at onset.

 Single pathologic lesion cannot explain clinical findings.

 Multiple foci best visualized by MRI.

 General Considerations

This common neurologic disorder, which probably has an autoimmune basis, has its greatest incidence in young adults. Epidemiologic studies indicate that multiple sclerosis is much more common in persons of western European lineage who live in temperate zones. No population with a high risk for multiple sclerosis exists between latitudes 40° N and 40° S. A genetic susceptibility to the disease is present, based on twin studies, familial cases, and an association with specific HLA antigens (HLA-DR2) and alleles of IL2RA (the interleukin-2 receptor alpha gene) and IL7RA (the interleukin-7 receptor alpha gene). Pathologically, focal—often perivenular—areas of demyelination with reactive gliosis are found scattered in the white matter of brain and spinal cord and in the optic nerves. Axonal damage also occurs.

 Clinical Findings

  1. Symptoms and Signs

The common initial presentation is weakness, numbness, tingling, or unsteadiness in a limb; spastic paraparesis; retrobulbar optic neuritis; diplopia; dysequilibrium; or a sphincter disturbance such as urinary urgency or hesitancy. Symptoms may disappear after a few days or weeks, although examination often reveals a residual deficit.

Several forms of the disease are recognized. In most patients, there is an interval of months or years after the initial episode before new symptoms develop or the original ones recur (relapsing-remitting disease). Eventually, however, relapses and usually incomplete remissions lead to increasing disability, with weakness, spasticity, and ataxia of the limbs, impaired vision, and urinary incontinence. The findings on examination at this stage commonly include optic atrophy; nystagmus; dysarthria; and pyramidal, sensory, or cerebellar deficits in some or all of the limbs. In some of these patients, the clinical course changes so that a steady deterioration occurs, unrelated to acute relapses (secondary progressive disease). Less commonly, symptoms are steadily progressive from their onset, and disability develops at a relatively early stage (primary progressive disease). The diagnosis cannot be made with confidence unless the total clinical picture indicates involvement of different parts of the central nervous system at different times. Fatigue is common in all forms of the disease.

A number of factors (eg, infection) may precipitate or trigger exacerbations. Relapses are reduced in pregnancy but are more likely during the 2 or 3 months following pregnancy, possibly because of the increased demands and stresses that occur in the postpartum period.

  1. Imaging

MRI of the brain or cervical cord has a major role in demonstrating the presence of multiple lesions. In T1-weighted images, hypointense “black holes” probably represent areas of permanent axonal damage; hyperintense lesions are also found. Gadolinium-enhanced T1-weighted images may highlight areas of inflammation with breakdown of the blood-brain barrier, which helps identify newer lesions. T2-weighted images provide information about disease burden or total number of lesions, which typically appear as areas of high signal intensity. CT scans are less helpful than MRI.

In patients with myelopathy alone and in whom there is no clinical or laboratory evidence of more widespread disease, MRI or myelography may be necessary to exclude a congenital or acquired surgically treatable lesion. The foramen magnum region must be visualized to exclude the possibility of Arnold-Chiari malformation, in which parts of the cerebellum and the lower brainstem are displaced into the cervical canal and produce mixed pyramidal and cerebellar deficits in the limbs.

  1. Laboratory and Other Studies

A definitive diagnosis can never be based solely on the laboratory findings. If there is clinical evidence of only a single lesion in the central nervous system, multiple sclerosis cannot properly be diagnosed unless it can be shown that other regions are affected subclinically. The electrocerebral responses evoked by monocular visual stimulation with a checkerboard pattern stimulus, by monaural click stimulation, and by electrical stimulation of a sensory or mixed peripheral nerve have been used to detect subclinical involvement of the visual, brainstem auditory, and somatosensory pathways, respectively. Other disorders may also be characterized by multifocal electrophysiologic abnormalities.

There may be mild lymphocytosis or a slightly increased protein concentration in the cerebrospinal fluid, especially soon after an acute relapse. Elevated IgG in cerebrospinal fluid and discrete bands of IgG (oligoclonal bands) are present in many patients. The presence of such bands is not specific, however, since they have been found in a variety of inflammatory neurologic disorders and occasionally in patients with vascular or neoplastic disorders of the nervous system.

  1. Diagnosis

Multiple sclerosis should not be diagnosed unless there is evidence that two or more different regions of the central white matter (dissemination in space) have been affected at different times (dissemination in time). The diagnosis may be made in a patient with two or more typical attacks and two or more MRI lesions. To fulfill the criterion of dissemination in space in a patient with only one lesion, repeat imaging in a few months should demonstrate at least one lesion in at least two of four typical sites (periventricular, juxtacortical, infratentorial, or spinal); alternatively, an additional attack localized to a different site suffices. To fulfill the criterion of dissemination in time in a patient with only one attack, the simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time (including at initial examination) suffices; alternatively, await a new lesion on follow-up MRI or a second attack. Primary progressive disease requires at least a year of progressive disease, plus two of three of the following: at least one typical brain lesion, at least two spinal lesions, or oligoclonal banding in the cerebrospinal fluid.

In patients with a single clinical event who do not satisfy criteria for multiple sclerosis, a diagnosis of a clinically isolated syndrome (CIS) is made. Such patients are at risk for developing multiple sclerosis and are sometimes offered beta-interferon or glatiramer acetate therapy, which may delay progression to clinically definite disease. Follow-up MRI should be considered 6–12 months later to assess for the presence of any new lesion.

 Treatment

At least partial recovery from acute exacerbations can reasonably be expected, but further relapses may occur without warning, and there is no means of preventing progression of the disorder. Some disability is likely to result eventually, but about half of all patients are without significant disability even 10 years after onset of symptoms.

Recovery from acute relapses may be hastened by treatment with corticosteroids, but the extent of recovery is unchanged. Intravenous therapy is given first—typically methylprednisolone 1 g daily for 3 days—followed by oral prednisone at 60–80 mg daily for 1 week with a taper over the ensuing 2–3 weeks. Long-term treatment with corticosteroids provides no benefit and does not prevent further relapses.

In patients with relapsing disease, numerous injectable medications have well-established efficacy at reducing the frequency of attacks, including beta-interferon (interferon beta-1a 30 mcg intramuscularly once weekly, or 44 mcg subcutaneously three times per week; or interferon beta-1b 0.25 mg subcutaneously every other day) and glatiramer acetate (20 mg subcutaneously daily). Natalizumab reduces the relapse rate when given intravenously once monthly but increases risk of developing progressive multifocal leukoencephalopathy; its use is therefore restricted to monotherapy (not combined with other immune-modulating therapy) in patients with relapsing-remitting disease who have not responded to other therapies or who have a particularly aggressive initial disease course. Alemtuzumab, a lymphocyte inhibitor that similarly raises the risk of opportunistic infection, is approved in Europe but not the United States.

Oral therapies are less well-established, but offer excellent efficacy (at reducing the relapse rate), convenience, and tolerability; these include dimethyl fumarate (120–240 mg twice daily) and fingolimod (0.5 mg orally daily). Teriflunomide (7–14 mg once daily) is another effective oral therapy, limited by liver toxicity in some patients.

For patients with severe or progressive disease, limited evidence supports immunosuppressive therapy with rituximab, cyclophosphamide, azathioprine, methotrexate, or mitoxantrone. Plasmapheresis is sometimes helpful in patients with severe relapses unresponsive to corticosteroids. Intravenous immunoglobulins (IVIGs) may reduce the clinical attack rate in relapsing-remitting disease, but the available studies are inadequate to permit treatment recommendations. Statins may have immunomodulatory effects, and their possible role in the treatment of multiple sclerosis is being studied, but most studies have failed to show any benefit.

Symptomatic therapy for spasticity (see below), neurogenic bladder, or fatigue may be required. Fatigue is especially common in multiple sclerosis, and modafinil (200 mg orally every morning) is an effective and FDA-approved therapy for this indication. Dalfampridine (an extended-release formulation of 4-aminopyridine administered as 10 mg orally twice daily) is efficacious at improving timed gait in multiple sclerosis. Depression and even suicidality can occur in multiple sclerosis and may worsen with interferon beta-1a therapy; screening and conventional treatment of such symptoms are appropriate.

 When to Refer

All patients, but especially those with progressive disease despite standard therapy, should be referred.

 When to Admit

  • Patients requiring plasma exchange.
  • During severe relapses.
  • Patient unable to manage at home.

Coles AJ et al. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011 Apr;10(4):338–48. [PMID: 21397567]

Filippini G et al. Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2013 Jun 6;6:CD008933. [PMID: 23744561]

Khatri B et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol. 2011 Jun;10(6):520–9. [PMID: 21571593]

Oh J et al. Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs. 2013 Aug;27(8):591–609. [PMID: 23801528]

Polman CH et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb;69(2):292–302. [PMID: 21387374]

NEUROMYELITIS OPTICA

This disorder is characterized by optic neuritis and acute myelitis with MRI changes that extend over at least three segments of the spinal cord. An isolated myelitis or optic neuritis may also occur. Previously known as Devic disease and once regarded as a variant of multiple sclerosis, neuromyelitis optica is associated with a specific antibody marker (NMO-IgG) targeting the water channel aquaporin-4. MRI of the brain typically does not show widespread white matter involvement, but such changes do not exclude the diagnosis. Treatment is by long-term immunosuppression. First-line therapy is with rituximab (two 1 g intravenous infusions spaced by 2 weeks, or four weekly infusions of 375 mg/m2; re-dosing may occur every 6 months or when CD19/20-positive or CD27-positive lymphocytes become detectable) or with azathioprine (2.5–3 mg/kg orally); intravenous immunoglobulin may be used if immunosuppressive therapy is contraindicated.

Jacob A et al. Current concept of neuromyelitis optica (NMO) and NMO spectrum disorders. J Neurol Neurosurg Psychiatry. 2013 Aug;84(8):922–30. [PMID: 23142960]

Trebst C et al. Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. 2014 Jan;261(1):1–16. [PMID: 24272588]

VITAMIN E DEFICIENCY

Vitamin E deficiency may produce a disorder somewhat similar to Friedreich ataxia (see below). There is spinocerebellar degeneration involving particularly the posterior columns of the spinal cord and leading to limb ataxia, sensory loss, absent tendon reflexes, slurring of speech and, in some cases, pigmentary retinal degeneration. The disorder may occur as a consequence of malabsorption or on a hereditary basis (eg, abetalipoproteinemia). Treatment is with alpha-tocopheryl acetate as discussed in Chapter 29.

SPASTICITY

The term “spasticity” is commonly used for an upper motor neuron deficit, but it properly refers to a velocity-dependent increase in resistance to passive movement that affects different muscles to a different extent, is not uniform in degree throughout the range of a particular movement, and is commonly associated with other features of pyramidal deficit. It is often a major complication of stroke, cerebral or spinal injury, static perinatal encephalopathy, and multiple sclerosis.

Physical therapy with appropriate stretching programs is important during rehabilitation after the development of an upper motor neuron lesion and in subsequent management of the patient. The aim is to prevent joint and muscle contractures and perhaps to modulate spasticity.

Drug management is important also, but treatment may increase functional disability when increased extensor tone is providing additional support for patients with weak legs. Dantrolene weakens muscle contraction by interfering with the role of calcium. It is best avoided in patients with poor respiratory function or severe myocardial disease. Treatment is begun with 25 mg once daily, increased by 25 mg every 3 days, depending on tolerance, to a maximum of 100 mg four times daily. Side effects include diarrhea, nausea, weakness, hepatic dysfunction (that may rarely be fatal, especially in women older than 35), drowsiness, light-headedness, and hallucinations.

Baclofen is an effective drug for treating spasticity of spinal origin and painful flexor (or extensor) spasms. The maximum recommended daily oral dose is 80 mg; treatment is started with a dose of 5 or 10 mg twice daily orally and then built up gradually. Side effects include gastrointestinal disturbances, lassitude, fatigue, sedation, unsteadiness, confusion, and hallucinations. Diazepam may modify spasticity by its action on spinal interneurons and perhaps also by influencing supraspinal centers, but effective doses often cause intolerable drowsiness and vary with different patients. Tizanidine, a centrally acting alpha-2-adrenergic agonist, is as effective as these other agents and is probably better tolerated. The daily dose is built up gradually, usually to 8 mg taken three times daily. Side effects include sedation, lassitude, hypotension, and dryness of the mouth.

Intramuscular injection of botulinum toxin has been used to relax targeted muscles.

In patients with severe spasticity that is unresponsive to other therapies and is associated with marked disability, intrathecal injection of phenol or alcohol may be helpful. Surgical options include implantation of an intrathecal baclofen pump, rhizotomy, or neurectomy. Severe contractures may be treated by surgical tendon release.

Spasticity may be exacerbated by decubitus ulcers, urinary or other infections, and nociceptive stimuli.

Maanum G et al. Effects of botulinum toxin A in ambulant adults with spastic cerebral palsy: a randomized double-blind placebo controlled-trial. J Rehabil Med. 2011 Mar;43(4):338–47. [PMID: 21305227]

MYELOPATHIES IN AIDS

A variety of myelopathies may occur in patients with AIDS. These are discussed in Chapter 31.

MYELOPATHY OF HUMAN T CELL LEUKEMIA VIRUS INFECTION

Human T cell leukemia virus (HTLV-1), a human retrovirus, is transmitted by breast-feeding, sexual contact, blood transfusion, and contaminated needles. Most patients are asymptomatic, but after a variable latent period (which may be as long as several years) a myelopathy develops in some instances. The MRI, electrophysiologic, and cerebrospinal fluid findings are similar to those of multiple sclerosis, but HTLV-1 antibodies are present in serum and spinal fluid. There is no specific treatment, but intravenous or oral corticosteroids may help in the initial inflammatory phase of the disease. Prophylactic measures are important. Needles or syringes should not be shared; infected patients should not breastfeed their infants or donate blood, semen, or other tissue. Infected patients should use condoms to prevent sexual transmission.

Yamano Y et al. Clinical pathophysiology of human T-lymphotropic virus-type 1-associated myelopathy/tropical spastic paraparesis. Front Microbiol. 2012 Nov 9;3:389. [PMID: 23162542]

SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD

Subacute combined degeneration of the spinal cord is due to vitamin B 12 deficiency, such as occurs in pernicious anemia. It is characterized by myelopathy with spasticity, weakness, proprioceptive loss, and numbness, sometimes in association with polyneuropathy, mental changes, or optic neuropathy. Megaloblastic anemia may also occur, but this does not parallel the neurologic disorder, and the former may be obscured if folic acid supplements have been taken. Treatment is with vitamin B12. For pernicious anemia, a convenient therapeutic regimen is 100 mg cyanocobalamin intramuscularly daily for 1 week, then weekly for 1 month, and then monthly for the remainder of the patient’s life. Oral cyanocobalamin replacement is not advised for pernicious anemia when neurologic symptoms are present.

WERNICKE ENCEPHALOPATHY & KORSAKOFF SYNDROME

Wernicke encephalopathy is characterized by confusion, ataxia, and nystagmus leading to ophthalmoplegia (lateral rectus muscle weakness, conjugate gaze palsies); peripheral neuropathy may also be present. It is due to thiamine deficiency and in the United States occurs most commonly in patients with alcoholism. It may also occur in patients with AIDS or hyperemesis gravidarum, and after surgery for obesity. In suspected cases, thiamine (100 mg) is given intravenously immediately and then intramuscularly on a daily basis until a satisfactory diet can be ensured. Intravenous glucose given before thiamine may precipitate the syndrome or worsen the symptoms. The diagnosis is confirmed by the response in 1 or 2 days to treatment, which must not be delayed while awaiting laboratory confirmation of thiamine deficiency from a blood sample obtained prior to thiamine administration. Korsakoff syndrome occurs in more severe cases; it includes anterograde and retrograde amnesia and sometimes confabulation, and may not be recognized until after the initial delirium has lifted.

Zahr NM et al. Clinical and pathological features of alcohol-related brain damage. Nat Rev Neurol. 2011 May;7(5):284–94. [PMID: 21487421]

STUPOR & COMA

 ESSENTIALS OF DIAGNOSIS

 Level of consciousness is depressed.

 Stuporous patients respond only to repeated vigorous stimuli.

 Comatose patients are unarousable and unresponsive.

 General Considerations

The patient who is stuporous is unresponsive except when subjected to repeated vigorous stimuli, while the comatose patient is unarousable and unable to respond to external events or inner needs, although reflex movements and posturing may be present.

Coma is a major complication of serious central nervous system disorders. It can result from seizures, hypothermia, metabolic disturbances, or structural lesions causing bilateral cerebral hemispheric dysfunction or a disturbance of the brainstem reticular activating system. A mass lesion involving one cerebral hemisphere may cause coma by compression of the brainstem. All comatose patients should be admitted to hospital and referred to a neurologist or neurosurgeon.

 Assessment & Emergency Measures

The diagnostic workup of the comatose patient must proceed concomitantly with management. Supportive therapy for respiration or blood pressure is initiated; in hypothermia, all vital signs may be absent and all such patients should be rewarmed before the prognosis is assessed.

The patient can be positioned on one side with the neck partly extended, dentures removed, and secretions cleared by suction; if necessary, the patency of the airways is maintained with an oropharyngeal airway. Blood is drawn for serum glucose, electrolyte, and calcium levels; arterial blood gases; liver and kidney function tests; and toxicologic studies as indicated. Dextrose 50% (25 g), naloxone (0.4–1.2 mg), and thiamine (100 mg) are given intravenously without delay.

Further details are then obtained from attendants of the patient’s medical history, the circumstances surrounding the onset of coma, and the time course of subsequent events. Abrupt onset of coma suggests subarachnoid hemorrhage, brainstem stroke, or intracerebral hemorrhage, whereas a slower onset and progression occur with other structural or mass lesions. Urgent noncontrast CT scanning of the head is appropriate if it can be obtained directly from the emergency department, in order to identify intracranial hemorrhage, brain herniation, or other structural lesion that may require immediate neurosurgical intervention. A metabolic cause is likely with a preceding intoxicated state or agitated delirium. On examination, attention is paid to the behavioral response to painful stimuli, the pupils and their response to light, the position of the eyes and their movement in response to passive movement of the head and ice-water caloric stimulation, and the respiratory pattern.

  1. Response to Painful Stimuli

Purposive limb withdrawal from painful stimuli implies that sensory pathways from and motor pathways to the stimulated limb are functionally intact. Unilateral absence of responses despite application of stimuli to both sides of the body in turn implies a corticospinal lesion; bilateral absence of responsiveness suggests brainstem involvement, bilateral pyramidal tract lesions, or psychogenic unresponsiveness. Inappropriate responses may also occur. Decorticate posturing may occur with lesions of the internal capsule and rostral cerebral peduncle, decerebrate posturing with dysfunction or destruction of the midbrain and rostral pons, and decerebrate posturing in the arms accompanied by flaccidity or slight flexor responses in the legs in patients with extensive brainstem damage extending down to the pons at the trigeminal level.

  1. Ocular Findings
  2. Pupils—Hypothalamic disease processes may lead to unilateral Horner syndrome, while bilateral diencephalic involvement or destructive pontine lesions may lead to small but reactive pupils. Ipsilateral pupillary dilation with no direct or consensual response to light occurs with compression of the third cranial nerve, eg, with uncal herniation. The pupils are slightly smaller than normal but responsive to light in many metabolic encephalopathies; however, they may be fixed and dilated following overdosage with atropine or scopolamine, and pinpoint (but responsive) with opioids. Pupillary dilation for several hours following cardiopulmonary arrest implies a poor prognosis.
  3. Eye movements—Conjugate deviation of the eyes to the side suggests the presence of an ipsilateral hemispheric lesion or a contralateral pontine lesion. A mesencephalic lesion leads to downward conjugate deviation. Dysconjugate ocular deviation in coma implies a structural brainstem lesion unless there was preexisting strabismus.

The oculomotor responses to passive head turning and to caloric stimulation relate to each other and provide complementary information. In response to brisk rotation of the head from side to side and to flexion and extension of the head, normally conscious patients with open eyes do not exhibit contraversive conjugate eye deviation (doll’s-head eye response) unless there is voluntary visual fixation or bilateral frontal pathology. With cortical depression in lightly comatose patients, a brisk doll’s-head eye response is seen. With brainstem lesions, this oculocephalic reflex becomes impaired or lost, depending on the site of the lesion.

The oculovestibular reflex is tested by caloric stimulation using irrigation with ice water. In normal subjects, jerk nystagmus is elicited for about 2 or 3 minutes, with the slow component toward the irrigated ear. In unconscious patients with an intact brainstem, the fast component of the nystagmus disappears, so that the eyes tonically deviate toward the irrigated side for 2–3 minutes before returning to their original position. With impairment of brainstem function, the response becomes perverted and finally disappears. In metabolic coma, oculocephalic and oculovestibular reflex responses are preserved, at least initially.

  1. Respiratory Patterns

Diseases causing coma may lead to respiratory abnormalities. Cheyne-Stokes respiration (in which episodes of deep breathing alternate with periods of apnea) may occur with bihemispheric or diencephalic disease or in metabolic disorders. Central neurogenic hyperventilation occurs with lesions of the brainstem tegmentum; apneustic breathing (in which there are prominent end-inspiratory pauses) suggests damage at the pontine level (eg, due to basilar artery occlusion); and atactic breathing (a completely irregular pattern of breathing with deep and shallow breaths occurring randomly) is associated with lesions of the lower pontine tegmentum and medulla.

  1. Stupor & Coma Due to Structural Lesions

Supratentorial mass lesions tend to affect brain function in an orderly way. There may initially be signs of hemispheric dysfunction, such as hemiparesis. As coma develops and deepens, cerebral function becomes progressively disturbed, producing a predictable progression of neurologic signs that suggest rostrocaudal deterioration.

Thus, as a supratentorial mass lesion begins to impair the diencephalon, the patient becomes drowsy, then stuporous, and finally comatose. There may be Cheyne-Stokes respiration; small but reactive pupils; doll’s-head eye responses with side-to-side head movements but sometimes an impairment of reflex upward gaze with brisk flexion of the head; tonic ipsilateral deviation of the eyes in response to vestibular stimulation with cold water; and initially a positive response to pain but subsequently only decorticate posturing. With further progression, midbrain failure occurs. Motor dysfunction progresses from decorticate to bilateral decerebrate posturing in response to painful stimuli; Cheyne-Stokes respiration is gradually replaced by sustained central hyperventilation; the pupils become middle-sized and fixed; and the oculocephalic and oculovestibular reflex responses become impaired, perverted, or lost. As the pons and then the medulla fail, the pupils remain unresponsive; oculovestibular responses are unobtainable; respiration is rapid and shallow; and painful stimuli may lead only to flexor responses in the legs. Finally, respiration becomes irregular and stops, the pupils often then dilating widely.

In contrast, a subtentorial (ie, brainstem) lesion may lead to an early, sometimes abrupt disturbance of consciousness without any orderly rostrocaudal progression of neurologic signs. Compressive lesions of the brainstem, especially cerebellar hemorrhage, may be clinically indistinguishable from intraparenchymal processes.

A structural lesion is suspected if the findings suggest focality. In such circumstances, a CT scan should be performed before, or instead of, a lumbar puncture in order to avoid any risk of cerebral herniation. Further management is of the causal lesion and is considered separately under the individual disorders.

In some cases of traumatic brain injury, swelling may be diffuse rather than focal. Decompressive craniectomy may reduce otherwise refractory intracranial hypertension but does not improve neurologic outcome. Hypothermic therapy is controversial.

Clifton GL et al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurol. 2011 Feb;10(2):131–9. [PMID: 21169065]

Cooper DJ et al. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. 2011 Apr 21;364(16):1493–502. [PMID: 21434843]

Moore SA et al. The acutely comatose patient: clinical approach and diagnosis. Semin Neurol. 2013 Apr;33(2):110–20. [PMID: 23888395]

  1. Stupor & Coma Due to Metabolic Disturbances

Patients with a metabolic cause of coma generally have signs of patchy, diffuse, and symmetric neurologic involvement that cannot be explained by loss of function at any single level or in a sequential manner, although focal or lateralized deficits may occur in hypoglycemia. Moreover, pupillary reactivity is usually preserved, while other brainstem functions are often grossly impaired. Comatose patients with meningitis, encephalitis, or subarachnoid hemorrhage may also exhibit little in the way of focal neurologic signs, however, and clinical evidence of meningeal irritation is sometimes very subtle in comatose patients. Examination of the cerebrospinal fluid in such patients is essential to establish the correct diagnosis.

In patients with coma due to cerebral ischemia and hypoxia, the absence of pupillary light reflexes at the time of initial examination indicates that there is little chance of regaining independence; by contrast, preserved pupillary light responses, the development of spontaneous eye movements (roving, conjugate, or better), and extensor, flexor, or withdrawal responses to pain at this early stage imply a relatively good prognosis.

Treatment of metabolic encephalopathy is of the underlying disturbance and is considered in other chapters. If the cause of the encephalopathy is obscure, all drugs except essential ones may have to be withdrawn in case they are responsible for the altered mental status.

Bouwes A et al. Prognosis of coma after therapeutic hypothermia: a prospective cohort study. Ann Neurol. 2012 Feb;71(2):206–12. [PMID: 22367993]

Chiota NA et al. Hypoxic-ischemic brain injury and prognosis after cardiac arrest. Continuum (Minneap Minn). 2011 Oct;17(5):1094–118. [PMID: 22809984]

  1. Brain Death

The definition of brain death is controversial, and diagnostic criteria have been published by many different professional organizations. In order to establish brain death, the irreversibly comatose patient must be shown to have lost all brainstem reflex responses, including the pupillary, corneal, oculovestibular, oculocephalic, oropharyngeal, and respiratory reflexes, and should have been in this condition for at least 6 hours. Spinal reflex movements do not exclude the diagnosis, but ongoing seizure activity or decerebrate or decorticate posturing is not consistent with brain death. The apnea test (presence or absence of spontaneous respiratory activity at a Paco2 of at least 60 mm Hg) serves to determine whether the patient is capable of respiratory activity.

Reversible coma simulating brain death may be seen with hypothermia (temperature < 32°C) and overdosage with central nervous system depressant drugs, and these conditions must be excluded. Certain ancillary tests may assist the determination of brain death but are not essential. An isoelectric electroencephalogram, when the recording is made according to the recommendations of the American Electroencephalographic Society, may help in confirming the diagnosis. Alternatively, the demonstration of an absent cerebral circulation by intravenous radioisotope cerebral angiography or by four-vessel contrast cerebral angiography is confirmatory.

Wijdicks EF. The case against confirmatory tests for determining brain death in adults. Neurology. 2010 Jul 6;75(1):77–83. [PMID: 20603486]

  1. Persistent Vegetative State

Patients with severe bilateral hemispheric disease may show some improvement from an initially comatose state, so that, after a variable interval, they appear to be awake but lie motionless and without evidence of awareness or higher mental activity. This persistent vegetative state has been variously referred to as akinetic mutism, apallic state, or coma vigil. Most patients in this persistent vegetative state will die in months or years, but partial recovery has occasionally occurred and in rare instances has been sufficient to permit communication or even independent living.

Hirschberg R et al. The vegetative and minimally conscious states: diagnosis, prognosis and treatment. Neurol Clin. 2011 Nov;29(4):773–86. [PMID: 22032660]

  1. Minimally Conscious State

In this state, patients exhibit inconsistent evidence of consciousness. There is some degree of functional recovery of behaviors suggesting self- or environmental awareness, such as basic verbalization or context-appropriate gestures, emotional responses (eg, smiling) to emotional but not neutral stimuli, or purposive responses to environmental stimuli (eg, a finger movement or eye blink apparently to command). Further improvement is manifest by the restoration of communication with the patient. The minimally conscious state may be temporary or permanent. Little information is available about its natural history or long-term outlook, which reflect the underlying cause. The likelihood of useful functional recovery diminishes with time; after 12 months, patients are likely to remain severely disabled and without a reliable means of communication. Prognostication is difficult.

  1. Locked-In Syndrome (De-efferented State)

Acute destructive lesions (eg, infarction, hemorrhage, demyelination, encephalitis) involving the ventral pons and sparing the tegmentum may lead to a mute, quadriparetic but conscious state in which the patient is capable of blinking and of voluntary eye movement in the vertical plane, with preserved pupillary responses to light. Such a patient can mistakenly be regarded as comatose. Clinicians should recognize that “locked-in” individuals are fully aware of their surroundings. The prognosis is usually poor, but recovery has occasionally been reported in some cases, including resumption of independent daily life.

Barbic D et al. Locked-in syndrome: a critical and time-dependent diagnosis. CJEM. 2012 Sep;14(5):317–20. [PMID: 22967701]

Stoll J et al. Pupil responses allow communication in locked-in syndrome patients. Curr Biol. 2013 Aug 5;23(15):R647–8. [PMID: 23928079]

HEAD INJURY

Trauma is the most common cause of death in young people, and head injury accounts for almost half of these trauma-related deaths. The incidence of head injury can be reduced by, for example, using bicycle helmets and protective equipment in sports.

The prognosis following head injury depends on the site and severity of brain damage. Some guide to prognosis is provided by the mental status, since loss of consciousness implies a worse prognosis than otherwise. Similarly, the degree of retrograde and posttraumatic amnesia provides an indication of the severity of injury and thus of the prognosis. Absence of skull fracture does not exclude the possibility of severe head injury. During the physical examination, special attention should be given to the level of consciousness and extent of any brainstem dysfunction.

Note: Patients (especially elderly, > 65 years) who are intoxicated with drugs or alcohol or have evidence of soft-tissue injury above the clavicles following head injury should be admitted to the hospital for observation, as should patients with recurrent vomiting, persistent anterograde amnesia, retrograde amnesia for more than 30 minutes, focal neurologic deficits, lethargy, or skull fractures. If admission is declined, responsible family members should be given clear instructions about the need for, and manner of, checking on them at regular (hourly) intervals and for obtaining additional medical help if necessary.

Skull radiographs or CT scans may provide evidence of fractures. Because injury to the spine may have accompanied head trauma, cervical spine radiographs (especially in the lateral projection) should always be obtained in comatose patients and in patients with severe neck pain or a deficit possibly related to cord compression.

CT scanning has an important role in demonstrating intracranial hemorrhage and may also provide evidence of cerebral edema and displacement of midline structures.

  1. Cerebral Injuries

These are summarized in Table 24–7. Increased intracranial pressure may result from ventilatory obstruction, abnormal neck position, seizures, dilutional hyponatremia, or cerebral edema; an intracranial hematoma requiring surgical evacuation may also be responsible. Other measures that may be necessary to reduce intracranial pressure include induced hyperventilation, intravenous mannitol infusion, and intravenous furosemide; corticosteroids provide no benefit in this context. Overall, treatment is mainly supportive. The role of induced hypothermia in reducing long-term neurologic deficits is currently under investigation.

Table 24–7. Acute cerebral sequelae of head injury.

  1. Scalp Injuries & Skull Fractures

Scalp lacerations and depressed or compound depressed skull fractures should be treated surgically as appropriate. Simple skull fractures require no specific treatment.

The clinical signs of basilar skull fracture include bruising about the orbit (raccoon sign), blood in the external auditory meatus (Battle sign), and leakage of cerebrospinal fluid (which can be identified by its glucose content) from the ear or nose. Cranial nerve palsies (involving especially the first, second, third, fourth, fifth, seventh, and eighth nerves in any combination) may also occur. If there is any leakage of cerebrospinal fluid, conservative treatment, with elevation of the head, restriction of fluids, and administration of acetazolamide (250 mg orally four times daily), is often helpful; but if the leak continues for more than a few days, lumbar subarachnoid drainage may be necessary. Antibiotics are given if infection occurs, based on culture and sensitivity studies. Only very occasional patients require intracranial repair of the dural defect because of persistence of the leak or recurrent meningitis.

  1. Late Complications of Head Injury

The relationship of chronic subdural hemorrhage to head injury is not always clear. In many elderly persons there is no history of trauma, but in other cases a head injury, often trivial, precedes the onset of symptoms by several weeks. The clinical presentation is usually with mental changes such as slowness, drowsiness, headache, confusion, memory disturbances, personality change, or even dementia. Focal neurologic deficits such as hemiparesis or hemisensory disturbance may also occur but are less common. CT scan is an important means of detecting the hematoma, which is sometimes bilateral. Treatment is by surgical evacuation to prevent cerebral compression and tentorial herniation. There is no clear evidence that prophylactic anticonvulsant therapy reduces the incidence of posttraumatic seizures.

After major head injury causing severe, acute mental status changes, cognitive deficits may persist indefinitely. Memory training may be a helpful component of rehabilitation. In addition, there is an association between head trauma and the later development of a neurodegenerative disease, such as Alzheimer or Parkinson disease and amyotrophic lateral sclerosis. Chronic traumatic encephalopathy, characterized by mood and cognitive changes after repetitive, mild head injury, as may occur in athletes or military personnel, is due to the abnormal aggregation of tau or other proteins either focally or globally in the cerebral cortex.

Normal-pressure hydrocephalus may follow head injury, subarachnoid hemorrhage, or meningoencephalitis. Other late complications of head injury include posttraumatic seizure disorder, headache, vertigo, and hyposmia.

 When to Refer

  • Patients with focal neurologic deficits, altered consciousness, or skull fracture.
  • Patients with late complications of head injury, eg, posttraumatic seizure disorder or normal pressure hydrocephalus.

 When to Admit

  • Patients (especially elderly, > 65 years) who are intoxicated with drugs or alcohol or have evidence of soft-tissue injury above the clavicles should be admitted for observation.
  • Patients with recurrent vomiting, focal neurologic deficits, persistent anterograde amnesia, retrograde amnesia for more than 30 minutes, altered consciousness, or skull fracture.
  • Patients with acute epidural, subdural, or cerebral hematoma.
  • Patients requiring shunt placement for normal pressure hydrocephalus.

McKee AC et al. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013 Jan;136(Pt 1):43–64. [PMID: 23208308]

Roberts DJ et al. Sedation for critically ill adults with severe traumatic brain injury: a systematic review of randomized controlled trials. Crit Care Med. 2011 Dec;39(12):2743–51. [PMID: 22094498]

Shum D et al. A randomized controlled trial of prospective memory rehabilitation in adults with traumatic brain injury. J Rehabil Med. 2011 Feb;43(3):216–23. [PMID: 21305237]

SPINAL TRAUMA

 ESSENTIALS OF DIAGNOSIS

 History of preceding trauma.

 Development of acute neurologic deficit.

 Signs of myelopathy on examination.

 General Considerations

While spinal cord damage may result from whiplash injury, severe injury usually relates to fracture-dislocation causing compression or angular deformity of the cord either cervically or in the lower thoracic and upper lumbar regions. Extreme hypotension following injury may also lead to cord infarction.

 Clinical Findings

Total cord transection results in immediate flaccid paralysis and loss of sensation below the level of the lesion. Reflex activity is lost for a variable period, and there is urinary and fecal retention. As reflex function returns over the following days and weeks, spastic paraplegia or quadriplegia develops, with hyperreflexia and extensor plantar responses, but a flaccid atrophic (lower motor neuron) paralysis may be found depending on the segments of the cord that are affected. The bladder and bowels also regain some reflex function, permitting urine and feces to be expelled at intervals. As spasticity increases, flexor or extensor spasms (or both) of the legs become troublesome, especially if the patient develops bed sores or a urinary tract infection. Paraplegia with the legs in flexion or extension may eventually result.

With lesser degrees of injury, patients may be left with mild limb weakness, distal sensory disturbance, or both. Sphincter function may also be impaired, urinary urgency and urgency incontinence being especially common. More particularly, a unilateral cord lesion leads to an ipsilateral motor disturbance with accompanying impairment of proprioception and contralateral loss of pain and temperature appreciation below the lesion (Brown-Séquard syndrome). A central cord syndrome may lead to a lower motor neuron deficit and loss of pain and temperature appreciation, with sparing of posterior column functions. A radicular deficit may occur at the level of the injury—or, if the cauda equina is involved, there may be evidence of disturbed function in several lumbosacral roots.

 Treatment

Treatment of the injury consists of immobilization and—if there is cord compression—early decompressive laminectomy and fusion (within 24 hours). Early treatment with high doses of corticosteroids (eg, methylprednisolone, 30 mg/kg by intravenous bolus, followed by 5.4 mg/kg/h for 23 hours) may improve neurologic recovery if commenced within 8 hours after injury; the findings from various studies are conflicting, however, and evaluation of the published evidence suggest that significant benefit is unlikely. Anatomic realignment of the spinal cord by traction and other orthopedic procedures is important. Subsequent care of the residual neurologic deficit—paraplegia or quadriplegia—requires treatment of spasticity and care of the skin, bladder, and bowels.

 When to Refer

All patients with focal neurologic deficits should be referred.

 When to Admit

  • Patients with neurologic deficits.
  • Patients with spinal cord injury, compression, or acute epidural or subdural hematoma.
  • Patients with vertebral fracture-dislocation likely to compress the cord.

Evans LT et al. Management of acute spinal cord injury in the neurocritical care unit. Neurosurg Clin N Am. 2013 Jul;24(3):339–47. [PMID: 23809029]

Zhang S et al. Spine and spinal cord trauma: diagnosis and management. Neurol Clin. 2013 Feb;31(1):183–206. [PMID: 23186900]

SYRINGOMYELIA

Destruction or degeneration of gray and white matter adjacent to the central canal of the cervical spinal cord leads to cavitation and accumulation of fluid within the spinal cord. The precise pathogenesis is unclear, but many cases are associated with Arnold-Chiari malformation, in which there is displacement of the cerebellar tonsils, medulla, and fourth ventricle into the spinal canal, sometimes with accompanying meningomyelocele. In such circumstances, the cord cavity connects with and may merely represent a dilated central canal. In other cases, the cause of cavitation is less clear. There is a characteristic clinical picture, with segmental atrophy, areflexia and loss of pain and temperature appreciation in a “cape” distribution, owing to the destruction of fibers crossing in front of the central canal in the mid-cervical spinal cord. Thoracic kyphoscoliosis is usually present. With progression, involvement of the long motor and sensory tracts occurs as well, so that a pyramidal and sensory deficit develops in the legs. Upward extension of the cavitation (syringobulbia) leads to dysfunction of the lower brainstem and thus to bulbar palsy, nystagmus, and sensory impairment over one or both sides of the face.

Syringomyelia, ie, cord cavitation, may also occur in association with an intramedullary tumor or following severe cord injury, and the cavity then does not communicate with the central canal.

In patients with Arnold-Chiari malformation, CT scans reveal a small posterior fossa and enlargement of the foramen magnum, along with other associated skeletal abnormalities at the base of the skull and upper cervical spine. MRI reveals the syrinx as well as the characteristic findings of the Arnold-Chiari malformation, including the caudal displacement of the fourth ventricle and herniation of the cerebellar tonsils through the foramen magnum. Focal cord enlargement is found at myelography or by MRI in patients with cavitation related to past injury or intramedullary neoplasms.

Treatment of Arnold-Chiari malformation with associated syringomyelia is by suboccipital craniectomy and upper cervical laminectomy, with the aim of decompressing the malformation at the foramen magnum. The cord cavity should be drained, and if necessary an outlet for the fourth ventricle can be made. In cavitation associated with intra-medullary tumor, treatment is surgical, but radiation therapy may be necessary if complete removal is not possible. Posttraumatic syringomyelia is also treated surgically if it leads to increasing neurologic deficits or to intolerable pain.

Roy AK et al. Idiopathic syringomyelia: retrospective case series, comprehensive review, and update on management. Neurosurg Focus. 2011 Dec;31(6):E15. [PMID: 22133183]

DEGENERATIVE MOTOR NEURON DISEASES

 ESSENTIALS OF DIAGNOSIS

 Weakness.

 No sensory loss or sphincter disturbance.

 Progressive course.

 No identifiable underlying cause other than genetic basis in familial cases.

 General Considerations

This group of degenerative disorders is characterized clinically by weakness and variable wasting of affected muscles, without accompanying sensory changes.

Motor neuron disease in adults generally commences between 30 and 60 years of age. There is degeneration of the anterior horn cells in the spinal cord, the motor nuclei of the lower cranial nerves, and the corticospinal and corticobulbar pathways. The disorder is usually sporadic, but familial cases may occur and several genetic mutations or loci have been identified. Cigarette smoking may be one risk factor.

 Classification

Five varieties have been distinguished on clinical grounds.

  1. Progressive Bulbar Palsy

Bulbar involvement predominates owing to disease processes affecting primarily the motor nuclei of the cranial nerves.

  1. Pseudobulbar Palsy

Bulbar involvement predominates in this variety also, but it is due to bilateral corticobulbar disease and thus reflects upper motor neuron dysfunction. There may be a “pseudobulbar affect,” with uncontrollable episodes of laughing or crying to stimuli that would not normally have elicited such marked reactions.

  1. Progressive Spinal Muscular Atrophy

This is characterized primarily by a lower motor neuron deficit in the limbs due to degeneration of the anterior horn cells in the spinal cord.

  1. Primary Lateral Sclerosis

There is a purely upper motor neuron deficit in the limbs.

  1. Amyotrophic Lateral Sclerosis

A mixed upper and lower motor neuron deficit is found in the limbs. This disorder is sometimes associated with cognitive decline (in a pattern consistent with frontotemporal dementia), a pseudobulbar affect, or parkinsonism. Approximately 10% of cases of amyotrophic lateral sclerosis are familial and have been associated with mutations at several different genetic loci, including a hexanucleotide repeat on chromosome 9 that also associates with frontotemporal dementia.

 Differential Diagnosis

The spinal muscular atrophies (SMAs) are inherited syndromes caused most often by mutations of the survival motor neuron (SMN) gene on chromosome 5. Different mutations result in more or less severe disruptions of the protein, resulting in an age of onset that ranges from infancy (SMA type I; Werdnig-Hoffmann disease), to early (type II) or late childhood (type III; Kugelberg-Welander syndrome), to adulthood (type IV). X-linked bulbospinal neuronopathy (Kennedy syndrome) is associated with an expanded trinucleotide repeat sequence on the androgen receptor gene and carries a more benign prognosis than other forms of motor neuron disease.

There are reports of juvenile SMA due to hexosaminidase deficiency. Pure motor syndromes resembling motor neuron disease may also occur in association with monoclonal gammopathy or multifocal motor neuropathies with conduction block. A motor neuronopathy may also develop in Hodgkin disease and has a relatively benign prognosis. Infective anterior horn cell diseases (polio virus or West Nile virus infection) can generally be distinguished by the acute onset and monophasic course of the illness, as discussed in Chapter 32.

 Clinical Findings

  1. Symptoms and Signs

Difficulty in swallowing, chewing, coughing, breathing, and talking (dysarthria) occur with bulbar involvement. In progressive bulbar palsy, there is drooping of the palate; a depressed gag reflex; pooling of saliva in the pharynx; a weak cough; and a wasted, fasciculating tongue. In pseudobulbar palsy, the tongue is contracted and spastic and cannot be moved rapidly from side to side. Limb involvement is characterized by motor disturbances (weakness, stiffness, wasting, fasciculations) reflecting lower or upper motor neuron dysfunction; there are no objective changes on sensory examination, although there may be vague sensory complaints. The sphincters are generally spared. Cognitive changes or pseudobulbar affect may be present. The disorder is progressive, and amyotrophic lateral sclerosis is usually fatal within 3–5 years; death usually results from pulmonary infections. Patients with bulbar involvement generally have the poorest prognosis, while patients with primary lateral sclerosis often have a longer survival despite profound quadriparesis and spasticity.

  1. Laboratory and Other Studies

Electromyography may show changes of chronic partial denervation, with abnormal spontaneous activity in the resting muscle and a reduction in the number of motor units under voluntary control. In patients with suspected SMA or amyotrophic lateral sclerosis, the diagnosis should not be made with confidence unless such changes are found in at least three spinal regions (cervical, thoracic, lumbosacral) or two spinal regions and the bulbar musculature. Motor conduction velocity is usually normal but may be slightly reduced, and sensory conduction studies are also normal. Biopsy of a wasted muscle shows the histologic changes of denervation. The serum creatine kinase may be slightly elevated but never reaches the extremely high values seen in some of the muscular dystrophies. The cerebrospinal fluid is normal. There are abnormal findings on rectal biopsy and reduced hexosaminidase A in serum and leukocytes in patients with juvenile SMA due to hexosaminidase deficiency.

 Treatment

Riluzole, 50 mg orally twice daily, which reduces the presynaptic release of glutamate, may slow progression of amyotrophic lateral sclerosis. There is otherwise no specific treatment except in patients with gammopathy, in whom plasmapheresis and immunosuppression may lead to improvement. Therapeutic trials of various neurotrophic factors and other agents to slow disease progression have yielded generally disappointing results. Symptomatic and supportive measures may include prescription of anticholinergic drugs (such as trihexyphenidyl, amitriptyline, or atropine) or use of a portable suction machine if drooling is troublesome, braces or a walker to improve mobility, and physical therapy to prevent contractures. Behavioral modification (eg, exercising facial muscles and encouraging frequent swallowing) or over-the-counter decongestants may also help mild drooling. Spasticity may be helped by baclofen or diazepam. A semiliquid diet or nasogastric tube feeding may be needed if dysphagia is severe. Gastrostomy or cricopharyngomyotomy is sometimes resorted to in extreme cases of predominant bulbar involvement, and tracheostomy may be necessary if respiratory muscles are severely affected; however, in the terminal stages of these disorders, the aim of treatment should be to keep patients as comfortable as possible. Information on palliative care is provided in Chapter 5.

 When to Refer

All patients (to exclude other treatable causes of symptoms and signs) should be referred.

 When to Admit

Patients may need to be admitted during the terminal stages of the disorders for palliative care.

Chen S et al. Genetics of amyotrophic lateral sclerosis: an update. Mol Neurodegener. 2013 Aug 13;8(1):28. [PMID: 23941283]

Robberecht W et al. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci. 2013 Apr;14(4):248–64. [PMID: 23463272]

PERIPHERAL NEUROPATHIES

Peripheral neuropathies can be categorized on the basis of the structure primarily affected. The predominant pathologic feature may be axonal degeneration (axonal or neuronal neuropathies) or paranodal or segmental demyelination. The distinction may be possible on the basis of neurophysiologic findings. Motor and sensory conduction velocity can be measured in accessible segments of peripheral nerves. In axonal neuropathies, conduction velocity is normal or reduced only mildly and needle electromyography provides evidence of denervation in affected muscles. In demyelinating neuropathies, conduction may be slowed considerably in affected fibers, and in more severe cases, conduction is blocked completely, without accompanying electromyographic signs of denervation.

POLYNEUROPATHIES & MONONEURITIS MULTIPLEX

 ESSENTIALS OF DIAGNOSIS

 Weakness, sensory disturbances, or both in the extremities.

 Pain sometimes common.

 Depressed or absent tendon reflexes.

 May be family history of neuropathy.

 May be history of systemic illness or toxic exposure.

 General Considerations

Diffuse polyneuropathies lead to a symmetric sensory, motor, or mixed deficit, often most marked distally. They include the hereditary, metabolic, and toxic disorders; idiopathic inflammatory polyneuropathy (Guillain-Barré syndrome); and the peripheral neuropathies that may occur as a nonmetastatic complication of malignant diseases. Involvement of motor fibers leads to flaccid weakness that is most marked distally; dysfunction of sensory fibers causes impaired sensory perception. Tendon reflexes are depressed or absent. Paresthesias, pain, and muscle tenderness may also occur. Multiplemononeuropathies suggest a patchy multifocal disease process such as vasculopathy (eg, diabetes, arteritis), an infiltrative process (eg, leprosy, sarcoidosis), radiation damage, or an immunologic disorder (eg, brachial plexopathy).

 Clinical Findings

The cause of polyneuropathy or mononeuritis multiplex is suggested by the history, mode of onset, and predominant clinical manifestations. Laboratory workup includes a complete blood count and erythrocyte sedimentation rate, serum protein electrophoresis, and immunophoresis, determination of plasma urea and electrolytes, liver and thyroid function tests, tests for rheumatoid factor and antinuclear antibody, HBsAg determination, a serologic test for syphilis, fasting blood glucose level, urinary heavy metal levels, cerebrospinal fluid examination, and chest radiography. These tests should be ordered selectively, as guided by symptoms and signs. Measurement of nerve conduction velocity is important in confirming the peripheral nerve origin of symptoms and providing a means of following clinical changes, as well as indicating the likely disease process (ie, axonal or demyelinating neuropathy). Cutaneous nerve biopsy may help establish a precise diagnosis (eg, polyarteritis, amyloidosis). In about half of cases, no specific cause can be established; of these, slightly less than half are subsequently found to be familial.

 Treatment

Treatment is of the underlying cause, when feasible, and is discussed below under the individual disorders. Physical therapy helps prevent contractures, and splints can maintain a weak extremity in a position of useful function. Anesthetic extremities must be protected from injury. To guard against burns, patients should check the temperature of water and hot surfaces with a portion of skin having normal sensation, measure water temperature with a thermometer, and use cold water for washing or lower the temperature setting of their hot-water heaters. Shoes should be examined frequently during the day for grit or foreign objects in order to prevent pressure lesions.

Patients with polyneuropathies or mononeuritis multiplex are subject to additional nerve injury at pressure points and should therefore avoid such behavior as leaning on elbows or sitting with crossed legs for lengthy periods.

Neuropathic, burning pain may respond to simple analgesics, such as aspirin or nonsteroidal anti-inflammatory agents, and to gabapentin (300 mg orally three times daily, titrated up to a maximum of 1200 mg orally three times daily as necessary). Duloxetine (60 mg orally daily) or venlafaxine (start 37.5 mg orally twice daily, and titrate up to 75 mg orally two to three times daily) may be helpful, especially in painful diabetic neuropathy. Opioids may be necessary for severe hyperpathia or pain induced by minimal stimuli, but their use should be avoided as much as possible. The use of a frame or cradle to reduce contact with bedclothes may be helpful. Many patients experience episodic stabbing pains, which may respond to gabapentin, pregabalin (100 mg orally three times daily), carbamazepine (start 100 mg orally twice daily, and titrate up to 400 mg orally twice daily), or tricyclic antidepressants (eg, amitriptyline 10–150 mg orally at bedtime daily).

Symptoms of autonomic dysfunction are occasionally troublesome. Postural hypotension is often helped by wearing waist-high elastic stockings and sleeping in a semierect position at night. Fludrocortisone reduces postural hypotension, but doses as high as 1 mg/d are sometimes necessary for patients with diabetes and may lead to recumbent hypertension. Midodrine, an alpha-agonist, is sometimes helpful in a dose of 2.5–10 mg three times daily. Erectile dysfunction and diarrhea are difficult to treat; a flaccid neuropathic bladder may respond to parasympathomimetic drugs such as bethanechol chloride, 10–50 mg three or four times daily.

Alport AR et al. Clinical approach to peripheral neuropathy: anatomic localization and diagnostic testing. Continuum (Minneap Minn). 2012 Feb;18(1):13–38. [PMID: 22810068]

Chaparro LE et al. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev. 2012 Jul 11;7:CD008943. [PMID: 22786518]

  1. Inherited Neuropathies
  2. Charcot-Marie-Tooth Disease (HMSN Type I, II)

Several distinct varieties of Charcot-Marie-Tooth disease can be recognized. There is usually an autosomal dominant mode of inheritance, but occasional cases occur on a sporadic, recessive, or X-linked basis. The responsible gene is commonly located on the short arm of chromosome 17 and less often shows linkage to chromosome 1 or the X chromosome. It has also been linked to several other chromosomes, emphasizing the genetic heterogeneity of the disorder. Clinical presentation may be with foot deformities or gait disturbances in childhood or early adult life. Slow progression leads to the typical features of polyneuropathy, with distal weakness and wasting that begin in the legs, a variable amount of distal sensory loss, and depressed or absent tendon reflexes. Tremor is a conspicuous feature in some instances. Electrodiagnostic studies show a marked reduction in motor and sensory conduction velocity (hereditary motor and sensory neuropathy [HMSN] type I). In other instances (HMSN type II), motor conduction velocity is normal or only slightly reduced, sensory nerve action potentials may be absent, and signs of chronic partial denervation are found in affected muscles electromyographically. The predominant pathologic change is axonal loss rather than segmental demyelination.

A similar disorder may occur in patients with progressive distal SMA, but there is no sensory loss; electrophysiologic investigation reveals that motor conduction velocity is normal or only slightly reduced, and nerve action potentials are normal.

Rossor AM et al. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol. 2013 Oct;9(10):562–71. [PMID: 24018473]

  1. Dejerine-Sottas Disease (HMSN Type III)

The disorder may occur on a sporadic, autosomal dominant or, less commonly, autosomal recessive basis. Onset in infancy or childhood leads to a progressive motor and sensory polyneuropathy with weakness, ataxia, sensory loss, and depressed or absent tendon reflexes. The peripheral nerves may be palpably enlarged and are characterized pathologically by segmental demyelination, Schwann cell hyperplasia, and thin myelin sheaths. Electrophysiologically, there is slowing of conduction, and sensory action potentials may be unrecordable.

  1. Friedreich Ataxia

This disorder, the only known autosomal recessive trinucleotide repeat disease, is caused by expansion of a poly-GAA locus in the gene for frataxin on chromosome 9, leading to symptoms in childhood or early adult life. The gait becomes ataxic, the hands become clumsy, and other signs of cerebellar dysfunction develop accompanied by weakness of the legs and extensor plantar responses. Involvement of peripheral sensory fibers leads to sensory disturbances in the limbs and depressed tendon reflexes. There is bilateral pes cavus. Pathologically, there is a marked loss of cells in the posterior root ganglia and degeneration of peripheral sensory fibers. In the central nervous system, changes are conspicuous in the posterior and lateral columns of the cord. Electrophysiologically, conduction velocity in motor fibers is normal or only mildly reduced, but sensory action potentials are small or absent. Cardiac disease is the most common cause of death.

In the differential diagnosis for Friedreich ataxia are other spinocerebellar ataxias, a growing group of at least 29 inherited disorders, each involving a different identified gene. These heterogeneous disorders, which frequently (but not exclusively) exhibit an autosomal dominant inheritance pattern and poly-CAG expansion of the affected gene, typically cause cerebellar ataxia and varying combinations of other symptoms (such as peripheral neuropathy, ophthalmoparesis, dysarthria, and pyramidal and extrapyramidal signs).

Parkinson MH et al. Clinical features of Friedreich’s ataxia: classical and atypical phenotypes. J Neurochem. 2013 Aug;126 (Suppl 1):103–17. [PMID: 23859346]

  1. Refsum Disease (HMSN Type IV)

This autosomal recessive disorder is due to a disturbance in phytanic acid metabolism. Clinically, pigmentary retinal degeneration is accompanied by progressive sensorimotor polyneuropathy and cerebellar signs. Auditory dysfunction, cardiomyopathy, and cutaneous manifestations may also occur. Motor and sensory conduction velocity are reduced, often markedly, and there may be electromyographic evidence of denervation in affected muscles. Dietary restriction of phytanic acid and its precursors may be helpful therapeutically. Plasmapheresis to reduce stored phytanic acid may help at the initiation of treatment.

Zolotov D et al. Long-term strategies for the treatment of Refsum’s disease using therapeutic apheresis. J Clin Apher. 2012;27(2):99–105. [PMID: 22267052]

  1. Porphyria

Peripheral nerve involvement may occur during acute attacks in both variegate porphyria and acute intermittent porphyria. Motor symptoms usually occur first, and weakness is often most marked proximally and in the upper limbs rather than the lower. Sensory symptoms and signs may be proximal or distal in distribution. Autonomic involvement is sometimes pronounced. The electrophysiologic findings are in keeping with the results of neuropathologic studies suggesting that the neuropathy is axonal in type. Hematin (4 mg/kg intravenously over 15 minutes once or twice daily) may lead to rapid improvement. A high-carbohydrate diet and, in severe cases, intravenous glucose or levulose may also be helpful. Propranolol (up to 100 mg orally every 4 hours) may control tachycardia and hypertension in acute attacks.

  1. Neuropathies Associated with Systemic & Metabolic Disorders
  2. Diabetes Mellitus

In this disorder, involvement of the peripheral nervous system may lead to symmetric sensory or mixed polyneuropathy, asymmetric motor radiculoneuropathy or plexopathy (diabetic amyotrophy), thoracoabdominal radiculopathy, autonomic neuropathy, or isolated lesions of individual nerves. These may occur singly or in any combination and are discussed in Chapter 27.

Smith AG et al. Diabetic neuropathy. Continuum (Minneap Minn). 2012 Feb;18(1):60–84. [PMID: 22810070]

Snedecor SJ et al. Systematic review and meta-analysis of pharmacological therapies for painful diabetic peripheral neuropathy. Pain Pract. 2014 Feb;14(2):167–84. [PMID: 23534696]

  1. Uremia

Uremia may lead to a symmetric sensorimotor polyneuropathy that tends to affect the lower limbs more than the upper limbs and is more marked distally than proximally (see Chapter 22). The diagnosis can be confirmed electrophysiologically, for motor and sensory conduction velocity is moderately reduced. The neuropathy improves both clinically and electrophysiologically with kidney transplantation and to a lesser extent with chronic dialysis.

Said G. Uremic neuropathy. Handb Clin Neurol. 2013;115:607–12. [PMID: 23931805]

  1. Alcoholism and Nutritional Deficiency

Many patients with alcoholism have an axonal distal sensorimotor polyneuropathy that is frequently accompanied by painful cramps, muscle tenderness, and painful paresthesias and is often more marked in the legs than in the arms. Symptoms of autonomic dysfunction may also be conspicuous. Motor and sensory conduction velocity may be slightly reduced, even in subclinical cases, but gross slowing of conduction is uncommon. A similar distal sensorimotor polyneuropathy is a well-recognized feature of beriberi (thiamine deficiency). In vitamin B12 deficiency, distal sensory polyneuropathy may develop but is usually overshadowed by central nervous system manifestations (eg, myelopathy, optic neuropathy, or intellectual changes).

  1. Paraproteinemias

A symmetric sensorimotor polyneuropathy that is gradual in onset, progressive in course, and often accompanied by pain and dysesthesias in the limbs may occur in patients (especially men) with multiple myeloma. The neuropathy is of the axonal type in classic lytic myeloma, but segmental demyelination (primary or secondary) and axonal loss may occur in sclerotic myeloma and lead to predominantly motor clinical manifestations. Both demyelinating and axonal neuropathies are also observed in patients with paraproteinemias without myeloma. A small fraction will develop myeloma if serially followed. The demyelinating neuropathy in these patients may be due to the monoclonal protein’s reacting to a component of the nerve myelin. The neuropathy of classic multiple myeloma is poorly responsive to therapy. The polyneuropathy of benign monoclonal gammopathy may respond to immunosuppressant drugs and plasmapheresis.

Polyneuropathy may also occur in association with macroglobulinemia and cryoglobulinemia and sometimes responds to plasmapheresis. Entrapment neuropathy, such as carpal tunnel syndrome, is more common than polyneuropathy in patients with (nonhereditary) generalized amyloidosis. With polyneuropathy due to amyloidosis, sensory and autonomic symptoms are especially conspicuous, whereas distal wasting and weakness occur later; there is no specific treatment.

  1. Neuropathies Associated with Infectious & Inflammatory Diseases
  2. Leprosy

Leprosy is an important cause of peripheral neuropathy in certain parts of the world. Sensory disturbances are mainly due to involvement of intracutaneous nerves. In tuberculoid leprosy, they develop at the same time and in the same distribution as the skin lesion but may be more extensive if nerve trunks lying beneath the lesion are also involved. In lepromatous leprosy, there is more extensive sensory loss, and this develops earlier and to a greater extent in the coolest regions of the body, such as the dorsal surfaces of the hands and feet, where the bacilli proliferate most actively. Motor deficits result from involvement of superficial nerves where their temperature is lowest, eg, the ulnar nerve in the region proximal to the olecranon groove, the median nerve as it emerges from beneath the forearm flexor muscle to run toward the carpal tunnel, the peroneal nerve at the head of the fibula, and the posterior tibial nerve in the lower part of the leg; patchy facial muscular weakness may also occur owing to involvement of the superficial branches of the seventh cranial nerve.

Motor disturbances in leprosy are suggestive of multiple mononeuropathy, whereas sensory changes resemble those of distal polyneuropathy. Examination, however, relates the distribution of sensory deficits to the temperature of the tissues; in the legs, for example, sparing frequently occurs between the toes and in the popliteal fossae, where the temperature is higher. Treatment is with antileprotic agents (see Chapter 33).

  1. AIDS

A variety of neuropathies occur in HIV-infected patients (see Chapter 31).

  1. Lyme Borreliosis

The neurologic manifestations of Lyme disease include meningitis, meningoencephalitis, polyradiculoneuropathy, mononeuropathy multiplex, and cranial neuropathy. Serologic tests establish the underlying disorder. Lyme disease and its treatment are discussed in depth in Chapter 34.

  1. Sarcoidosis

Cranial nerve palsies (especially facial palsy), multiple mononeuropathy and, less commonly, symmetric polyneuropathy may all occur, the latter sometimes preferentially affecting either motor or sensory fibers. Improvement may occur with use of corticosteroids.

  1. Polyarteritis

Involvement of the vasa nervorum by the vasculitic process may result in infarction of the nerve. Clinically, one encounters an asymmetric sensorimotor polyneuropathy (mononeuritis multiplex) that pursues a waxing and waning course. Corticosteroids and cytotoxic agents—especially cyclophosphamide—may be of benefit in severe cases.

  1. Rheumatoid Arthritis

Compressive or entrapment neuropathies, ischemic neuropathies, mild distal sensory polyneuropathy, and severe progressive sensorimotor polyneuropathy can occur in rheumatoid arthritis.

  1. Neuropathy Associated with Critical Illness

Patients in intensive care units with sepsis and multiorgan failure sometimes develop polyneuropathies. This may be manifested initially by unexpected difficulty in weaning patients from a mechanical ventilator and in more advanced cases by wasting and weakness of the extremities and loss of tendon reflexes. Sensory abnormalities are relatively inconspicuous. The neuropathy is axonal in type. Its pathogenesis is obscure, and treatment is supportive. The prognosis is good provided patients recover from the underlying critical illness.

  1. Toxic Neuropathies

Axonal polyneuropathy may follow exposure to industrial agents or pesticides such as acrylamide, organophosphorus compounds, hexacarbon solvents, methyl bromide, and carbon disulfide; metals such as arsenic, thallium, mercury, and lead; and drugs such as phenytoin, perhexiline, isoniazid, nitrofurantoin, vincristine, and pyridoxine in high doses. Detailed occupational, environmental, and medical histories and recognition of clusters of cases are important in suggesting the diagnosis. Treatment is by preventing further exposure to the causal agent. Isoniazid neuropathy is prevented by pyridoxine supplementation.

Diphtheritic neuropathy results from a neurotoxin released by the causative organism and is common in many areas. Palatal weakness may develop 2–4 weeks after infection of the throat, and infection of the skin may similarly be followed by focal weakness of neighboring muscles. Disturbances of accommodation may occur about 4–5 weeks after infection and distal sensorimotor demyelinating polyneuropathy after 1–3 months.

  1. Neuropathies Associated with Malignant Diseases

Both a sensorimotor and a purely sensory polyneuropathy may occur as a nonmetastatic complication of malignant diseases, and have been associated with circulating anti-MAG or anti-Hu antibodies that can be detected by a paraneoplastic antibody panel that is available commercially. The sensorimotor polyneuropathy may be mild and occur in the course of known malignant disease, or it may have an acute or subacute onset, lead to severe disability, and occur before there is any clinical evidence of the cancer, occasionally following a remitting course. An autonomic neuropathy may also occur as a paraneoplastic disorder related to the presence of anti-Hu antibodies or to an antibody against ganglionic acetylcholine receptors (anti-nAChR).

  1. Acute Idiopathic Polyneuropathy (Guillain-Barré Syndrome)

 ESSENTIALS OF DIAGNOSIS

 Acute or subacute progressive polyradiculoneuro-pathy.

 Weakness is more severe than sensory disturbances.

 Acute dysautonomia may be life-threatening.

 General Considerations

This acute or subacute polyradiculoneuropathy sometimes follows infective illness, inoculations, or surgical procedures. There is an association with preceding Campylobacter jejuni enteritis. The disorder probably has an immunologic basis, but the precise mechanism is unclear.

 Clinical Findings

  1. Symptoms and Signs

The main complaint is of weakness that varies widely in severity in different patients and often has a proximal emphasis and symmetric distribution. It usually begins in the legs, spreading to a variable extent but frequently involving the arms and often one or both sides of the face. The muscles of respiration or deglutition may also be affected. Sensory symptoms are usually less conspicuous than motor ones, but distal paresthesias and dysesthesias are common, and neuropathic or radicular pain is present in many patients. Autonomic disturbances are also common, may be severe, and are sometimes life-threatening; they include tachycardia, cardiac irregularities, hypotension or hypertension, facial flushing, abnormalities of sweating, pulmonary dysfunction, and impaired sphincter control. The axonal subtypes of the syndrome (acute motor axonal neuropathy [AMAN] and acute motor and sensory axonal neuropathy [AMSAN]) are caused by antibodies to gangliosides on the axon membrane, including anti-GM1, anti-GM1b, anti-GD1a, anti-GD1b, and (in AMAN) anti-GalNAC-GD1a antibodies. The Miller Fisher syndrome, another subtype, is characterized by the clinical triad of ophthalmoplegia, ataxia, and areflexia, and is associated with anti-GQ1b antibodies.

  1. Laboratory Findings

The cerebrospinal fluid characteristically contains a high protein concentration with a normal cell content, but these changes may take 2 or 3 weeks to develop. Electrophysiologic studies may reveal marked abnormalities, which do not necessarily parallel the clinical disorder in their temporal course. Pathologic examination shows primary demyelination or, less commonly, axonal degeneration.

 Differential Diagnosis

When the diagnosis is made, the history and appropriate laboratory studies should exclude the possibility of porphyric, diphtheritic, or toxic (heavy metal, hexacarbon, organophosphate) neuropathies. The temporal course excludes other peripheral neuropathies. Poliomyelitis, botulism, and tick paralysis must also be considered as they cause weakness of acute onset. The presence of pyramidal signs, a markedly asymmetric motor deficit, a sharp sensory level, or early sphincter involvement should suggest a focal cord lesion.

 Treatment

Treatment with prednisone is ineffective and may prolong recovery time. Plasmapheresis is of value; it is best performed within the first few days of illness and is particularly useful for clinically severe or rapidly progressive cases or those with ventilatory impairment. IVIG (400 mg/kg/d for 5 days) is equally helpful and imposes less stress on the cardiovascular system than plasmapheresis. Patients should be admitted to intensive care units if their forced vital capacity is declining, and intubation is considered if the forced vital capacity reaches 15 mL/kg, the mean inspiratory force reaches –40 mm Hg, dyspnea becomes evident, or the oxygen saturation declines. Respiratory toilet and chest physical therapy help prevent atelectasis. Marked hypotension may respond to volume replacement or pressor agents. Low-dose heparin to prevent pulmonary embolism should be considered.

Approximately 3% of patients with acute idiopathic polyneuropathy have one or more clinically similar relapses, sometimes several years after the initial illness. Plasma exchange therapy may produce improvement in chronic and relapsing inflammatory polyneuropathy.

 Prognosis

Most patients eventually make a good recovery, but this may take many months, and about 20% of patients are left with persisting disability.

 When to Refer

All patients should be referred.

 When to Admit

All patients should be hospitalized until their condition is stable and there is no respiratory compromise.

Arcila-Londono X et al. Guillain-Barré syndrome. Semin Neurol. 2012 Jul;32(3):179–86. [PMID: 23117942]

Hughes RA et al. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2012 Aug 15;8:CD001446. [PMID: 22895921]

Hughes RA et al. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2012 Jul 11;7:CD002063. [PMID: 22786476]

Raphaël JC et al. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2012 Jul 11;7:CD001798. [PMID: 22786475]

  1. Chronic Inflammatory Polyneuropathy

Chronic inflammatory demyelinating polyneuropathy, an acquired immunologically mediated disorder, is clinically similar to Guillain-Barré syndrome except that it has a relapsing or steadily progressive course over months or years and that autonomic dysfunction is generally less common. It may present as an exclusively motor disorder or with a mixed sensorimotor disturbance. In the relapsing form, partial recovery may occur after some relapses, but in other instances there is no recovery between exacerbations. Although remission may occur spontaneously with time, the disorder frequently follows a progressive downhill course leading to severe functional disability.

Electrodiagnostic studies show marked slowing of motor and sensory conduction, and focal conduction block. Signs of partial denervation may also be present owing to secondary axonal degeneration. Nerve biopsy may show chronic perivascular inflammatory infiltrates in the endoneurium and epineurium, without accompanying evidence of vasculitis. However, a normal nerve biopsy result or the presence of nonspecific abnormalities does not exclude the diagnosis.

Corticosteroids may arrest or reverse the downhill course. Treatment is usually begun with prednisone, 60–80 mg orally daily, continued for 2–3 months or until a definite response has occurred. If no response has occurred despite 3 months of treatment, a higher dose may be tried. In responsive cases, the dose is gradually tapered, but most patients become corticosteroid-dependent, often requiring prednisone, 20 mg daily on alternate days, on a long-term basis. IVIG can be used in place of, or in addition to corticosteroids and is best used as the initial treatment in pure motor syndromes. When both IVIG and corticosteroids are ineffective, plasma exchange may be worthwhile. Consistent with the notion that the condition is antibody mediated, rituximab has shown promise. Immunosuppressant or immunomodulatory drugs (such as azathioprine) may be added when the response to other measures is unsatisfactory or to enable maintenance doses of corticosteroids to be lowered. Symptomatic treatment is also important.

Benedetti L et al. Rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a report of 13 cases and review of the literature. J Neurol Neurosurg Psychiatry. 2011 Mar;82(3):306–8. [PMID: 20639381]

Dimachkie MM et al. Chronic inflammatory demyelinating polyneuropathy. Curr Treat Options Neurol. 2013 Jun;15(3):350–66. [PMID: 23564314]

MONONEUROPATHIES

 ESSENTIALS OF DIAGNOSIS

 Focal motor or sensory deficit.

 Deficit is in territory of an individual peripheral nerve.

An individual nerve may be injured along its course or may be compressed, angulated, or stretched by neighboring anatomic structures, especially at a point where it passes through a narrow space (entrapment neuropathy). The relative contributions of mechanical factors and ischemia to the local damage are not clear. With involvement of a sensory or mixed nerve, pain is commonly felt distal to the lesion. Symptoms never develop with some entrapment neuropathies, resolve rapidly and spontaneously in others, and become progressively more disabling and distressing in yet other cases. The precise neurologic deficit depends on the nerve involved. Percussion of the nerve at the site of the lesion may lead to paresthesias in its distal distribution.

Entrapment neuropathy may be the sole manifestation of subclinical polyneuropathy, and this must be borne in mind and excluded by nerve conduction studies. Such studies are also indispensable for the accurate localization of the focal lesion.

In patients with acute compression neuropathy such as may occur in intoxicated individuals (“Saturday night palsy”), no treatment is necessary. Complete recovery generally occurs, usually within 2 months, presumably because the underlying pathology is demyelination. However, axonal degeneration can occur in severe cases, and recovery then takes longer and may never be complete.

In chronic compressive or entrapment neuropathies, avoidance of aggravating factors and correction of any underlying systemic conditions are important. Local infiltration of the region about the nerve with corticosteroids may be of value; in addition, surgical decompression may help if there is a progressively increasing neurologic deficit or if electrodiagnostic studies show evidence of partial denervation in weak muscles.

Peripheral nerve tumors are uncommon, except in neurofibromatosis type 1, but also give rise to mononeuropathy. This may be distinguishable from entrapment neuropathy only by noting the presence of a mass along the course of the nerve and by demonstrating the precise site of the lesion with appropriate electrophysiologic studies. Treatment of symptomatic lesions is by surgical removal if possible.

  1. Carpal Tunnel Syndrome

See Chapter 20.

  1. Pronator Teres or Anterior Interosseous Syndrome

The median nerve gives off its motor branch, the anterior interosseous nerve, below the elbow as it descends between the two heads of the pronator teres muscle. A lesion of either nerve may occur in this region, sometimes after trauma or owing to compression from, for example, a fibrous band. With anterior interosseous nerve involvement, there is no sensory loss, and weakness is confined to the pronator quadratus, flexor pollicis longus, and the flexor digitorum profundus to the second and third digits. Weakness is more widespread and sensory changes occur in an appropriate distribution when the median nerve itself is affected. The prognosis is variable. If improvement does not occur spontaneously, decompressive surgery may be helpful.

Rodner CM et al. Pronator syndrome and anterior interosseous nerve syndrome. J Am Acad Orthop Surg. 2013 May;21(5):268–75. [PMID: 23637145]

  1. Ulnar Nerve Lesions

Ulnar nerve lesions are likely to occur in the elbow region as the nerve runs behind the medial epicondyle and descends into the cubital tunnel. In the condylar groove, the ulnar nerve is exposed to pressure or trauma. Moreover, any increase in the carrying angle of the elbow, whether congenital, degenerative, or traumatic, may cause excessive stretching of the nerve when the elbow is flexed. Ulnar nerve lesions may also result from thickening or distortion of the anatomic structures forming the cubital tunnel, and the resulting symptoms may also be aggravated by flexion of the elbow, because the tunnel is then narrowed by tightening of its roof or inward bulging of its floor. A severe lesion at either site causes sensory changes in the fifth and medial half of the fourth digits and along the medial border of the hand. There is weakness of the ulnar-innervated muscles in the forearm and hand. With a cubital tunnel lesion, however, there may be relative sparing of the flexor carpi ulnaris muscle. Electrophysiologic evaluation using nerve stimulation techniques allows more precise localization of the lesion.

If conservative measures are unsuccessful in relieving symptoms and preventing further progression, surgical treatment may be necessary. This consists of nerve transposition if the lesion is in the condylar groove, or a release procedure if it is in the cubital tunnel.

Ulnar nerve lesions may also develop at the wrist or in the palm of the hand, usually owing to repetitive trauma or to compression from ganglia or benign tumors. They can be subdivided depending on their presumed site. Compressive lesions are treated surgically. If repetitive mechanical trauma is responsible, this is avoided by occupational adjustment or job retraining.

Caliandro P et al. Treatment for ulnar neuropathy at the elbow. Cochrane Database Syst Rev. 2012 Jul 11;7:CD006839. [PMID: 22786500]

  1. Radial Nerve Lesions

The radial nerve is particularly liable to compression or injury in the axilla (eg, by crutches or by pressure when the arm hangs over the back of a chair). This leads to weakness or paralysis of all the muscles supplied by the nerve, including the triceps. Sensory changes may also occur but are often surprisingly inconspicuous, being marked only in a small area on the back of the hand between the thumb and index finger. Injuries to the radial nerve in the spiral groove occur characteristically during deep sleep, as in intoxicated individuals (Saturday night palsy), and there is then sparing of the triceps muscle, which is supplied more proximally. The nerve may also be injured at or above the elbow; its purely motor posterior interosseous branch, supplying the extensors of the wrist and fingers, may be involved immediately below the elbow, but then there is sparing of the extensor carpi radialis longus, so that the wrist can still be extended. The superficial radial nerve may be compressed by handcuffs or a tight watch strap.

Naam NH et al. Radial tunnel syndrome. Orthop Clin North Am. 2012 Oct;43(4):529–36. [PMID: 23026469]

  1. Femoral Neuropathy

The clinical features of femoral nerve palsy consist of weakness and wasting of the quadriceps muscle, with sensory impairment over the anteromedian aspect of the thigh and sometimes also of the leg to the medial malleolus, and a depressed or absent knee jerk. Isolated femoral neuropathy may occur in patients with diabetes or from compression by retroperitoneal neoplasms or hematomas (eg, expanding aortic aneurysm). Femoral neuropathy may also result from pressure from the inguinal ligament when the thighs are markedly flexed and abducted, as in the lithotomy position.

  1. Meralgia Paresthetica

The lateral femoral cutaneous nerve, a sensory nerve arising from the L2 and L3 roots, may be compressed or stretched in obese or diabetic patients and during pregnancy. The nerve usually runs under the outer portion of the inguinal ligament to reach the thigh, but the ligament sometimes splits to enclose it. Hyperextension of the hip or increased lumbar lordosis—such as occurs during pregnancy—leads to nerve compression by the posterior fascicle of the ligament. However, entrapment of the nerve at any point along its course may cause similar symptoms, and several other anatomic variations predispose the nerve to damage when it is stretched. Pain, paresthesia, or numbness occurs about the outer aspect of the thigh, usually unilaterally, and is sometimes relieved by sitting. The pain stops at the knee, unlike the pain from lower lumbar sciatica that radiates to the foot. Examination shows no abnormalities except in severe cases when cutaneous sensation is impaired in the affected area. Symptoms are usually mild and commonly settle spontaneously. Hydrocortisone injections medial to the anterosuperior iliac spine often relieve symptoms temporarily, while nerve decompression by transposition may provide more lasting relief.

Khalil N et al. Treatment for meralgia paraesthetica. Cochrane Database Syst Rev. 2012 Dec 12;12:CD004159. [PMID: 23235604]

Parisi TJ et al. Meralgia paresthetica: relation to obesity, advanced age, and diabetes mellitus. Neurology. 2011 Oct 18;77(16):1538–42. [PMID: 21975198]

  1. Sciatic & Common Peroneal (Fibular) Nerve Palsies

Misplaced deep intramuscular injections are probably still the most common cause of sciatic nerve palsy. Trauma to the buttock, hip, or thigh may also be responsible. The resulting clinical deficit depends on whether the whole nerve has been affected or only certain fibers. In general, the peroneal (fibular) fibers of the sciatic nerve are more susceptible to damage than those destined for the tibial nerve. A sciatic nerve lesion may therefore be difficult to distinguish from peroneal (fibular) neuropathy unless there is electromyographic evidence of involvement of the short head of the biceps femoris muscle. The common peroneal (fibular) nerve itself may be compressed or injured in the region of the head and neck of the fibula, eg, by sitting with crossed legs or wearing high boots. There is weakness of dorsiflexion and eversion of the foot, accompanied by numbness or blunted sensation of the anterolateral aspect of the calf and dorsum of the foot.

  1. Tarsal Tunnel Syndrome

The tibial nerve, the other branch of the sciatic, supplies several muscles in the lower extremity, gives origin to the sural nerve, and then continues as the posterior tibial nerve to supply the plantar flexors of the foot and toes. It passes through the tarsal tunnel behind and below the medial malleolus, giving off calcaneal branches and the medial and lateral plantar nerves that supply small muscles of the foot and the skin on the plantar aspect of the foot and toes. Compression of the posterior tibial nerve or its branches between the bony floor and ligamentous roof of the tarsal tunnel leads to pain, paresthesias, and numbness over the bottom of the foot, especially at night, with sparing of the heel. Muscle weakness may be hard to recognize clinically. Compressive lesions of the individual plantar nerves may also occur more distally, with clinical features similar to those of the tarsal tunnel syndrome. Treatment is surgical decompression.

  1. Facial Neuropathy

An isolated facial palsy is most often idiopathic (Bell palsy, see later) but may occur in patients with HIV seropositivity, sarcoidosis, Lyme disease (Figure 24–2; also see Chapter 34) or with any process causing an inflammatory reaction in the subarachnoid space, such as meningitis. Whenever facial palsies occur bilaterally, or a facial palsy occurs in conjunction with other neurologic deficits, MRI brain imaging should be undertaken and other investigations considered.

 When to Refer

  • If there is uncertainty about the diagnosis.
  • Symptoms or signs are progressing despite treatment.

 When to Admit

When a patient should be hospitalized depends on the cause and treatment.

BELL PALSY

 ESSENTIALS OF DIAGNOSIS

 Sudden onset of lower motor neuron facial palsy.

 Hyperacusis or impaired taste may occur.

 No other neurologic abnormalities.

 General Considerations

Bell palsy is an idiopathic facial paresis of lower motor neuron type that has been attributed to an inflammatory reaction involving the facial nerve near the stylomastoid foramen or in the bony facial canal. Increasing evidence incriminates reactivation of herpes simplex or varicella zoster virus infection in the geniculate ganglion at least in some instances. The disorder is more common in pregnant women or in persons with diabetes mellitus.

 Clinical Findings

The facial paresis (Figure 24–2) generally comes on abruptly, but it may worsen over the following day or so. Pain about the ear precedes or accompanies the weakness in many cases but usually lasts for only a few days. The face itself feels stiff and pulled to one side. There may be ipsilateral restriction of eye closure and difficulty with eating and fine facial movements. A disturbance of taste is common, owing to involvement of chorda tympani fibers, and hyperacusis due to involvement of fibers to the stapedius occurs occasionally.

 Figure 24–2. Facial palsy caused by an infection with Borrelia burgdorferi (Lyme disease). (Public Health Image Library, CDC.)

 Treatment

Other disorders that can produce a facial palsy and require specific treatment, such as tumors, Lyme disease, AIDS, sarcoidosis, and herpes zoster infection of the geniculate ganglion, must be excluded. The management of Bell palsy is controversial. Approximately 60% of cases recover completely without treatment, presumably because the lesion is so mild that it leads merely to conduction block. Considerable improvement occurs in most other cases, and only about 10% of all patients have permanent disfigurement or other long-term sequelae. Treatment is unnecessary in most cases but is indicated for patients in whom an unsatisfactory outcome can be predicted. The best clinical guide to progress is the severity of the palsy during the first few days after presentation. Patients with clinically complete palsy when first seen are less likely to make a full recovery than those with an incomplete one. A poor prognosis for recovery is also associated with advanced age, hyperacusis, and severe initial pain. Electromyography and nerve excitability or conduction studies provide a guide to prognosis but not early enough to aid in the selection of patients for treatment.

The only medical treatment that may influence the outcome is administration of corticosteroids, but this must be commenced within 5 days of onset. Treatment with prednisone, 60–80 mg orally daily for 4 or 5 days, followed by tapering of the dose over the next 7–10 days, is a satisfactory regimen; prednisolone (50 mg daily orally) for 10 days is another acceptable alternative. It is helpful to protect the eye with lubricating drops (or lubricating ointment at night) and a patch if eye closure is not possible. Acyclovir does not confer any additional benefit. There is no evidence that surgical procedures to decompress the facial nerve are of benefit. Physical therapy may improve facial function.

Gronseth GS et al. Evidence-based guideline update: steroids and antivirals for Bell palsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2012 Nov 27;79(22):2209–13. [PMID: 23136264]

Teixeira LJ et al. Physical therapy for Bell’s palsy (idiopathic facial paralysis). Cochrane Database Syst Rev. 2011 Dec 7;(12):CD006283. [PMID: 22161401]

DISCOGENIC NECK PAIN

 ESSENTIALS OF DIAGNOSIS

 Neck pain, sometimes radiating to arms.

 Restricted neck movements.

 Motor, sensory, or reflex changes in arms with root involvement.

 Neurologic deficit in legs, gait disorder, or sphincter disturbance with cord involvement.

 General Considerations

A variety of congenital abnormalities may involve the cervical spine and lead to neck pain; these include hemivertebrae, fused vertebrae, basilar impression, and instability of the atlantoaxial joint. Traumatic, degenerative, infective, and neoplastic disorders may also lead to pain in the neck. When rheumatoid arthritis involves the spine, it tends to affect especially the cervical region, leading to pain, stiffness, and reduced mobility; displacement of vertebrae or atlantoaxial subluxation may lead to cord compression that can be life-threatening if not treated by fixation. Further details are given in Chapter 20 (including a discussion on low back pain), and discussion here is restricted to disk disease.

  1. Acute Cervical Disk Protrusion

Acute cervical disk protrusion leads to pain in the neck and radicular pain in the arm, exacerbated by head movement. With lateral herniation of the disk, motor, sensory, or reflex changes may be found in a radicular (usually C6 or C7) distribution on the affected side (Figure 24–3); with more centrally directed herniations, the spinal cord may also be involved, leading to spastic paraparesis and sensory disturbances in the legs, sometimes accompanied by impaired sphincter function. The diagnosis is confirmed by MRI or CT myelography. In mild cases, bed rest or intermittent neck traction may help, followed by immobilization of the neck in a collar for several weeks. If these measures are unsuccessful or the patient has a significant neurologic deficit, surgical removal of the protruding disk may be necessary.

Figure 24–3. Cutaneous innervation. The segmental or radicular (root) distribution is shown on the left side of the body and the peripheral nerve distribution on the right side. Above: anterior view; facing page: posterior view. (Reproduced, with permission, from Haymaker W, Woodhall B. Peripheral Nerve Injuries, 2nd ed. Philadelphia, Saunders, 1953.)

  1. Cervical Spondylosis

Cervical spondylosis results from chronic cervical disk degeneration, with herniation of disk material, secondary calcification, and associated osteophytic outgrowths. One or more of the cervical nerve roots may be compressed, stretched, or angulated; and myelopathy may also develop as a result of compression, vascular insufficiency, or recurrent minor trauma to the cord. Patients present with neck pain and restricted head movement, occipital headaches, radicular pain and other sensory disturbances in the arms, weakness of the arms or legs, or some combination of these symptoms. Examination generally reveals that lateral flexion and rotation of the neck are limited. A segmental pattern of weakness or dermatomal sensory loss (or both) may be found unilaterally or bilaterally in the upper limbs, and tendon reflexes mediated by the affected root or roots are depressed. The C5 and C6 nerve roots are most commonly involved, and examination frequently then reveals weakness of muscles supplied by these roots (eg, deltoids, supraspinatus and infraspinatus, biceps, brachioradialis), pain or sensory loss about the shoulder and outer border of the arm and forearm, and depressed biceps and brachioradialis reflexes. Spastic paraparesis may also be present if there is an associated myelopathy, sometimes accompanied by posterior column or spinothalamic sensory deficits in the legs.

Plain radiographs of the cervical spine show osteophyte formation, narrowing of disk spaces, and encroachment on the intervertebral foramina, but such changes are common in middle-aged persons and may be unrelated to the presenting complaint. CT or MRI helps confirm the diagnosis and exclude other structural causes of the myelopathy.

Restriction of neck movements by a cervical collar may relieve pain. Local injection of local anesthetics or corticosteroids, for instance by a pain management specialist, may be of benefit. Operative treatment may be necessary to prevent further progression if there is a significant neurologic deficit or if root pain is severe, persistent, and unresponsive to conservative measures.

 When to Refer

  • Pain unresponsive to simple measures.
  • Patients with neurologic deficits.
  • Patients in whom surgical treatment is under consideration.

 When to Admit

  • Patients with progressive or significant neurologic deficit.
  • Patients with sphincter involvement (from cord compression).
  • Patients requiring surgical treatment.

Diwan S et al. Effectiveness of cervical epidural injections in the management of chronic neck and upper extremity pain. Pain Physician. 2012 Jul–Aug;15(4):E405–34. [PMID: 22828692]

BRACHIAL & LUMBAR PLEXUS LESIONS

  1. Brachial Plexus Neuropathy

Brachial plexus neuropathy may be idiopathic, sometimes occurring in relationship to a number of different nonspecific illnesses or factors. In other instances, brachial plexus lesions follow trauma or result from congenital anomalies, neoplastic involvement, or injury by various physical agents. In rare instances, the disorder occurs on a familial basis.

Idiopathic brachial plexus neuropathy (neuralgic amyotrophy) characteristically begins with severe pain about the shoulder, followed within a few days by weakness, reflex changes, and sensory disturbances involving especially the C5 and C6 segments but affecting any nerve in the brachial plexus. Symptoms and signs are usually unilateral but may be bilateral. Wasting of affected muscles is sometimes profound. The disorder relates to disturbed function of cervical roots or part of the brachial plexus, but its precise cause is unknown. Recovery occurs over the ensuing months but may be incomplete. Treatment is purely symptomatic.

  1. Cervical Rib Syndrome

Compression of the C8 and T1 roots or the lower trunk of the brachial plexus by a cervical rib or band arising from the seventh cervical vertebra leads to weakness and wasting of intrinsic hand muscles, especially those in the thenar eminence, accompanied by pain and numbness in the medial two fingers and the ulnar border of the hand and forearm. The subclavian artery may also be compressed, and this forms the basis of Adson test for diagnosing the disorder; the radial pulse is diminished or obliterated on the affected side when the seated patient inhales deeply and turns the head to one side or the other. Electromyography, nerve conduction studies, and somatosensory evoked potential studies may help confirm the diagnosis. MRI may be especially helpful in revealing the underlying compressive structure. Plain radiographs or CT scanning sometimes shows the cervical rib or a large transverse process of the seventh cervical vertebra, but normal findings do not exclude the possibility of a cervical band. Treatment of the disorder is by surgical excision of the rib or band.

  1. Lumbosacral Plexus Lesions

A lumbosacral plexus lesion may develop in association with diseases such as diabetes, cancer, or bleeding disorders or in relation to injury. It occasionally occurs as an isolated phenomenon similar to idiopathic brachial plexopathy, and pain and weakness then tend to be more conspicuous than sensory symptoms. The distribution of symptoms and signs depends on the level and pattern of neurologic involvement.

Van Alfen N et al. Diagnosis of brachial and lumbosacral plexus lesions. Handb Clin Neurol. 2013;115:293–310. [PMID: 23931788]

DISORDERS OF NEUROMUSCULAR TRANSMISSION

  1. Myasthenia Gravis

 ESSENTIALS OF DIAGNOSIS

 Fluctuating weakness of commonly used voluntary muscles, producing symptoms such as diplopia, ptosis, and difficulty in swallowing.

 Activity increases weakness of affected muscles.

 Short-acting anticholinesterases transiently improve the weakness.

 General Considerations

Myasthenia gravis occurs at all ages, sometimes in association with a thymic tumor or thyrotoxicosis, as well as in rheumatoid arthritis and lupus erythematosus. It is most common in young women with HLA-DR3; if thymoma is associated, older men are more commonly affected. Onset is usually insidious, but the disorder is sometimes unmasked by a coincidental infection that leads to exacerbation of symptoms. Exacerbations may also occur before the menstrual period and during or shortly after pregnancy. Symptoms are due to a variable degree of block of neuromuscular transmission caused by autoantibodies binding to acetylcholine receptors; these are found in most patients with the disease and have a primary role in reducing the number of functioning acetylcholine receptors. Additionally, cellular immune activity against the receptor is found.

 Clinical Findings

  1. Symptoms and Signs

Patients present with ptosis, diplopia, difficulty in chewing or swallowing, respiratory difficulties, limb weakness, or some combination of these problems. Weakness may remain localized to a few muscle groups or may become generalized. The external ocular muscles and certain other cranial muscles, including the masticatory, facial, and pharyngeal muscles, are especially likely to be affected, and the respiratory and limb muscles may also be involved. Symptoms often fluctuate in intensity during the day, and this diurnal variation is superimposed on a tendency to longer-term spontaneous relapses and remissions that may last for weeks. Nevertheless, the disorder follows a slowly progressive course and may have a fatal outcome owing to respiratory complications such as aspiration pneumonia.

Clinical examination confirms the weakness and fatigability of affected muscles. In most cases, the extraocular muscles are involved, and this leads to ocular palsies and ptosis, which are commonly asymmetric. Pupillary responses are normal. The bulbar and limb muscles are often weak, but the pattern of involvement is variable. Sustained activity of affected muscles increases the weakness, which improves after a brief rest. Sensation is normal, and there are usually no reflex changes.

Life-threatening exacerbations of myasthenia (so-called myasthenic crisis) may lead to respiratory weakness requiring immediate admission to the intensive care unit, where respiratory function can be monitored and ventilator support is readily available.

  1. Imaging

A CT scan of the chest with and without contrast should be obtained to demonstrate a coexisting thymoma, but a normal study does not exclude this possibility.

  1. Laboratory and Other Studies

Electrophysiologic demonstration of a decrementing muscle response to repetitive 2- or 3-Hz stimulation of motor nerves indicates a disturbance of neuromuscular transmission. Such an abnormality may even be detected in clinically strong muscles with certain provocative procedures. Needle electromyography of affected muscles shows a marked variation in configuration and size of individual motor unit potentials, and single-fiber electromyography reveals an increased jitter, or variability, in the time interval between two muscle fiber action potentials from the same motor unit.

Assay of serum for elevated levels of circulating acetylcholine receptor antibodies is useful because it has a sensitivity of 80–90% for the diagnosis of myasthenia gravis. Certain patients without antibodies to acetylcholine receptors have serum antibodies to muscle-specific tyrosine kinase (MuSK), which should therefore be determined; these patients are more likely to have facial, respiratory, and proximal muscle weakness than those with antibodies to acetylcholine receptors.

 Treatment

Medication such as aminoglycosides that may exacerbate myasthenia gravis should be avoided. Anticholinesterase drugs provide symptomatic benefit without influencing the course of the disease. Neostigmine, pyridostigmine, or both can be used, the dose being determined on an individual basis. The usual dose of neostigmine is 7.5–30 mg (average, 15 mg) orally taken four times daily; of pyridostigmine, 30–180 mg (average, 60 mg) orally four times daily. Overmedication may temporarily increase weakness.

Thymectomy usually leads to symptomatic benefit or remission and should be considered in all patients younger than age 60, unless weakness is restricted to the extraocular muscles. If the disease is of recent onset and only slowly progressive, operation is sometimes delayed for a year or so, in the hope that spontaneous remission will occur.

Treatment with corticosteroids is indicated for patients who have responded poorly to anticholinesterase drugs and have already undergone thymectomy. It is often introduced with the patient in the hospital, since weakness may initially be aggravated. Once weakness has stabilized after 2–3 weeks or any improvement is sustained, further management can be on an outpatient basis. Alternate-day treatment is usually well tolerated, but if weakness is enhanced on the nontreatment day it may be necessary for medication to be taken daily. The dose of corticosteroids is determined on an individual basis, but an initial high daily dose (eg, prednisone, 60–100 mg orally daily) can gradually be tapered to a relatively low maintenance level as improvement occurs; total withdrawal is difficult, however. Treatment with azathioprine may also be effective. The usual dose is 2–3 mg/kg orally daily after a lower initial dose. Mycophenolate mofetil or cyclosporine is typically reserved for more refractory cases or as a strategy to reduce the corticosteroid dose.

In patients with major disability, plasmapheresis or IVIG therapy may be beneficial and have similar efficacy. It is also useful for stabilizing patients before thymectomy and for managing acute crisis.

 When to Refer

All patients should be referred.

 When to Admit

  • Patients with acute exacerbation or respiratory involvement.
  • Patients requiring plasmapheresis.
  • Patients who are starting corticosteroid therapy.
  • For thymectomy.

Barth D et al. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology. 2011 Jun 7;76(23):2017–23. [PMID: 21562253]

Díaz-Manera J et al. Treatment strategies for myasthenia gravis: an update. Expert Opin Pharmacother. 2012 Sep;13(13):1873–83. [PMID: 22775575]

  1. Myasthenic Syndrome (Lambert-Eaton Syndrome)

 ESSENTIALS OF DIAGNOSIS

 Variable weakness, typically improving with activity.

 Dysautonomic symptoms may also be present.

 A history of malignant disease may be obtained.

 General Considerations

Myasthenic syndrome may be associated with small-cell carcinoma, sometimes developing before the tumor is diagnosed, and occasionally occurs with certain autoimmune diseases. There is defective release of acetylcholine in response to a nerve impulse, caused by P/Q-type voltage-gated calcium-channel antibody, and this leads to weakness, especially of the proximal muscles of the limbs. Unlike myasthenia gravis, however, power steadily increases with sustained contraction. The diagnosis can be confirmed electrophysiologically, because the muscle response to stimulation of its motor nerve increases remarkably if the nerve is stimulated repetitively at high rates, even in muscles that are not clinically weak.

Treatment with plasmapheresis and immunosuppressive drug therapy (prednisone and azathioprine) may lead to clinical and electrophysiologic improvement, in addition to therapy aimed at tumor when present. Prednisone is usually initiated in a daily dose of 60–80 mg orally and azathioprine in a daily dose of 2 mg/kg orally. Symptomatic therapy includes the use of potassium channel antagonists; of these, 3,4-diaminopyridine (60–80 mg/d orally in three divided doses) has been best studied and appears efficacious. Guanidine hydrochloride (25–50 mg/kg/d orally in divided doses) is an alternative and is occasionally helpful in seriously disabled patients, but adverse effects of the drug include marrow suppression. The response to treatment with anticholinesterase drugs such as pyridostigmine or neostigmine is usually disappointing.

Keogh M et al. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD003279. [PMID: 21328260]

Titulaer MJ et al. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011 Dec;10(12):1098–107. [PMID: 22094130]

  1. Botulism

The toxin of Clostridium botulinum prevents the release of acetylcholine at neuromuscular junctions and autonomic synapses. Botulism occurs most commonly following the ingestion of contaminated home-canned food and should be suggested by the development of sudden, fluctuating, severe weakness in a previously healthy person. Symptoms begin within 72 hours following ingestion of the toxin and may progress for several days. Typically, there is diplopia, ptosis, facial weakness, dysphagia, and nasal speech, followed by respiratory difficulty and finally by weakness that appears last in the limbs. Blurring of vision (with unreactive dilated pupils) is characteristic, and there may be dryness of the mouth, constipation (paralytic ileus), and postural hypotension. Sensation is preserved, and the tendon reflexes are not affected unless the involved muscles are very weak. If the diagnosis is suspected, the local health authority should be notified and a sample of serum and contaminated food (if available) sent to be assayed for toxin. Support for the diagnosis may be obtained by electrophysiologic studies; with repetitive stimulation of motor nerves at fast rates, the muscle response increases in size progressively.

Patients should be hospitalized in case respiratory assistance becomes necessary. Treatment is with trivalent antitoxin, once it is established that the patient is not allergic to horse serum. Potassium channel antagonists may provide symptomatic relief as they do in Lambert-Eaton myasthenic syndrome (see above). Anticholinesterase drugs are of no value. Respiratory assistance and other supportive measures should be provided as necessary. Further details are provided in Chapter 33.

Chalk C et al. Medical treatment for botulism. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD008123. [PMID: 21412916]

  1. Disorders Associated with Use of Aminoglycosides

Aminoglycoside antibiotics, eg, gentamicin, may produce a clinical disturbance similar to botulism by preventing the release of acetylcholine from nerve endings, but symptoms subside rapidly as the responsible drug is eliminated from the body. These antibiotics are particularly dangerous in patients with preexisting disturbances of neuromuscular transmission and are therefore best avoided in patients with myasthenia gravis.

MYOPATHIC DISORDERS

  1. Muscular Dystrophies

 ESSENTIALS OF DIAGNOSIS

 Muscle weakness, often in a characteristic distribution.

 Age at onset and inheritance pattern depend on the specific dystrophy.

 General Considerations

These inherited myopathic disorders are characterized by progressive muscle weakness and wasting. They are subdivided by mode of inheritance, age at onset, and clinical features, as shown in Table 24–8. In the Duchenne type, pseudohypertrophy of muscles frequently occurs at some stage; intellectual retardation is common; and there may be skeletal deformities, muscle contractures, and cardiac involvement. The serum creatine kinase level is increased, especially in the Duchenne and Becker varieties, and mildly increased also in limb-girdle dystrophy. Electromyography may help confirm that weakness is myopathic rather than neurogenic. Similarly, histopathologic examination of a muscle biopsy specimen may help confirm that weakness is due to a primary disorder of muscle and to distinguish between various muscle diseases.

Table 24–8. The muscular dystrophies.1

A genetic defect on the short arm of the X chromosome has been identified in Duchenne dystrophy. The affected gene codes for the protein dystrophin, which is markedly reduced or absent from the muscle of patients with the disease. Dystrophin levels are generally normal in the Becker variety, but the protein is qualitatively altered. Duchenne muscular dystrophy can be recognized early in pregnancy in about 95% of women by genetic studies; in late pregnancy, DNA probes can be used on fetal tissue obtained for this purpose by amniocentesis. The genes causing some of the other muscular dystrophies are listed in Table 24–8.

There is no specific treatment for the muscular dystrophies, but it is important to encourage patients to lead as normal lives as possible. Prednisone (0.75 mg/kg orally daily) improves muscle strength and function in boys with Duchenne dystrophy, but side effects need to be monitored. Prolonged bed rest must be avoided, as inactivity often leads to worsening of the underlying muscle disease. Physical therapy and orthopedic procedures may help counteract deformities or contractures.

Flanigan KM. The muscular dystrophies. Semin Neurol. 2012 Jul;32(3):255–63. [PMID: 23117950]

Leung DG et al. Therapeutic advances in muscular dystrophy. Ann Neurol. 2013 Sep;74(3):404–11. [PMID: 23939629]

  1. Myotonic Dystrophy

Myotonic dystrophy, a slowly progressive, dominantly inherited disorder, usually manifests itself in the third or fourth decade but occasionally appears early in childhood. Two types, with a different genetic basis, have been recognized. Myotonia leads to complaints of muscle stiffness and is evidenced by the marked delay that occurs before affected muscles can relax after a contraction. This can often be demonstrated clinically by delayed relaxation of the hand after sustained grip or by percussion of the belly of a muscle. In addition, there is weakness and wasting of the facial, sternocleidomastoid, and distal limb muscles. Associated clinical features include cataracts, frontal baldness, testicular atrophy, diabetes mellitus, cardiac abnormalities, and intellectual changes. Electromyographic sampling of affected muscles reveals myotonic discharges in addition to changes suggestive of myopathy.

It is difficult to determine whether drug therapy for myotonia is safe or effective. When myotonia is disabling, treatment with a sodium channel blocker—such as phenytoin (100 mg orally three times daily), procainamide (0.5–1 gorally four times daily), or mexiletine (150–200 mg orally three times daily)—may be helpful, but the associated side effects, particularly for antiarrhythmic drugs, are often limiting. Neither the weakness nor the course of the disorder is influenced by treatment.

Heatwole CR et al. The diagnosis and treatment of myotonic disorders. Muscle Nerve. 2013 May;47(5):632–48. [PMID: 23536309]

  1. Myotonia Congenita

Myotonia congenita is commonly inherited as a dominant trait. The responsible gene on chromosome 7 encodes a voltage-gated chloride channel. Generalized myotonia without weakness is usually present from birth, but symptoms may not appear until early childhood. Patients complain of muscle stiffness that is enhanced by cold and inactivity and relieved by exercise. Muscle hypertrophy, at times pronounced, is also a feature. A recessive form with later onset is associated with slight weakness and atrophy of distal muscles. Treatment with procainamide, tocainide, mexiletine, or phenytoin may help the myotonia, as in myotonic dystrophy.

  1. Polymyositis & Dermatomyositis

See Chapter 20.

  1. Inclusion Body Myositis

This disorder, of unknown cause, begins insidiously, usually after middle age, with progressive proximal weakness of first the lower and then the upper extremities, and affecting facial and pharyngeal muscles. Weakness often begins in the quadriceps femoris in the lower limbs and the forearm flexors in the upper limbs. Distal weakness is usually mild. Serum creatine kinase levels may be normal or increased. The diagnosis is confirmed by muscle biopsy. Corticosteroid and immunosuppressive therapy is usually ineffective, but IVIG therapy is occasionally of mild benefit.

Dimachkie MM et al. Inclusion body myositis. Curr Neurol Neurosci Rep. 2013 Jan;13(1):321. [PMID: 23250766]

  1. Mitochondrial Myopathies

The mitochondrial myopathies are a clinically diverse group of disorders that on pathologic examination of skeletal muscle with the modified Gomori stain show characteristic “ragged red fibers” containing accumulations of abnormal mitochondria. Patients may present with progressive external ophthalmoplegia or with limb weakness that is exacerbated or induced by activity. Other patients present with central neurologic dysfunction, eg, myoclonic epilepsy (myoclonic epilepsy, ragged red fiber syndrome, or MERRF), or the combination of myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). These disorders result from separate abnormalities of mitochondrial DNA. (See also Chapter 20.) Treatment is symptomatic and palliative, but various experimental approaches are being explored.

A mitochondrial myopathy may develop in patients receiving zidovudine for treatment of AIDS, and patients receiving highly active antiretroviral therapy (HAART) for HIV-1 infection may develop a lipodystrophy, with fat accumulating in muscle.

Milone M et al. Diagnosis of mitochondrial myopathies. Mol Genet Metab. 2013 Sep–Oct;110(1–2):35–41. [PMID: 23911206]

  1. Myopathies Associated with Other Disorders

Myopathy may occur in association with chronic hypokalemia, any endocrinopathy, and in patients taking corticosteroids, chloroquine, colchicine, clofibrate, emetine, aminocaproic acid, statin drugs, or bretylium tosylate. Weakness is mainly proximal, and serum creatine kinase is typically normal, except in hypothyroidism and some of the toxic myopathies. Treatment is of the underlying cause. Myopathy also occurs with chronic alcoholism, whereas acute reversible muscle necrosis may occur shortly after acute alcohol intoxication. Inflammatory myopathy may occur in patients taking penicillamine; myotonia may be induced by clofibrate, and preexisting myotonia may be exacerbated or unmasked by depolarizing muscle relaxants (eg, suxamethonium), beta-blockers (eg, propranolol), fenoterol, ritodrine and, possibly, certain diuretics.

 When to Refer

All patients should be referred to establish the diagnosis and underlying cause.

 When to Admit

  • For respiratory assistance.
  • For rhabdomyolysis.

PERIODIC PARALYSIS SYNDROMES

Periodic paralysis may have a familial (dominant inheritance) basis. The syndromes to be described are channelopathies that manifest as abnormal, often potassium-sensitive, muscle-membrane excitability and lead clinically to episodes of flaccid weakness or paralysis, sometimes in association with abnormalities of the plasma potassium level. Strength is normal between attacks. Mutations in genes encoding three ion channels [CACNA1S (1q32), SCN4A (17q23.1-q25.3), and KCNJ2 (17q23.1-q24.2)] account for most cases. Hypokalemic periodic paralysis has been related to mutations in the CACNL1A3, SCN4A, or KCNE3 (11q13-q14) gene and is characterized by attacks that tend to occur on awakening, after exercise, or after a heavy meal and may last for several days. Patients should avoid excessive exertion. A low-carbohydrate and low-salt diet may help prevent attacks, as may acetazolamide, 250–750 mg orally daily. Nonselective beta-adrenergic blockers may also prevent recurrent paralytic attacks. An ongoing attack may be aborted by potassium chloride given orally or by intravenous drip, provided the ECG can be monitored and kidney function is satisfactory. In young Asian men, it is commonly associated with hyperthyroidism and has been related to polymorphism in the CACNA1S gene; treatment of the endocrine disorder prevents recurrences. In hyperkalemic periodic paralysis, which is mostly associated with mutations in the SCN4A gene, attacks also tend to occur after exercise but usually last for < 1 hour. They may be terminated by intravenous calcium gluconate (1–2 g) or by intravenous diuretics (furosemide, 20–40 mg), glucose, or glucose and insulin; daily acetazolamide or chlorothiazide may prevent recurrences. Normokalemic periodic paralysis is similar clinically to the hyperkalemic variety, but the plasma potassium level remains normal during attacks; treatment is with acetazolamide.

 When to Refer

All patients should be referred.

Burge JA et al. Novel insights into the pathomechanisms of skeletal muscle channelopathies. Curr Neurol Neurosci Rep. 2012 Feb;12(1):62–9. [PMID: 22083238]

Cope TE et al. Thyrotoxic periodic paralysis: correct hypokalemia with caution. J Emerg Med. 2013 Sep;45(3):338–40. [PMID: 23849367]