Neurology: A Clinician's Approach (Cambridge Medicine (Paperback)), 1st Ed.

1. Confusion

History

Confusion is a cognitive disorder characterized by loss of the normal coherent stream of thought or action.1 Up to 50% of older hospitalized patients will develop an acute confusional state, and those who become confused are at greater risk for prolonged hospitalization and death.2 Unfortunately, the confused patient cannot provide a reasonable account of the problem, and detailed narrative histories from family members, nurses, and primary physicians are often similarly unhelpful. The history may consist only of a single phrase such as “He’s agitated,” “He’s not waking up,” or “He’s confused.” Sometimes the history is comprised of examples of abnormal behavior. In many cases, especially when the physician requesting the consult does not know the patient very well, the history is summarized as nothing more than the ambiguous catch-all term “change in mental status.”

The three variations of confusion are agitated delirium, somnolence, and incoherence. Despite their strikingly different phenotypes, these three states are all caused by a fundamental disturbance in the attentional matrix and a group of responsible medical conditions.

Agitated delirium

Agitated delirium is characterized by hyperactivity and aggressiveness, and is the most disruptive form of confusion. Patients with agitated delirium scream, yell, rip out intravenous catheters, and sometimes assault hospital staff or even other patients. They are often physically and chemically restrained or undergoing psychiatric evaluation by the time a neurologist is consulted.

Somnolence

Somnolent patients are sleepy and difficult to arouse. While this variant is less disruptive to the hospital staff than agitated delirium, somnolence is often serious, sometimes heralding the onset of coma. These patients, therefore, require immediate medical and neurological attention.

Incoherence

Incoherence lies between agitated delirium and somnolent confusion on the arousal spectrum. These patients are neither aggressive nor sleepy, but lack the ability to think, speak, or act in a lucid, goal-directed manner.1 Incoherent patients misidentify people and misinterpret situations, especially the circumstances of their hospitalization. They are easily distracted by novel but trivial stimuli and are inattentive to important ones.

Examination

Inattention

The signature mental status abnormality of the confused patient is inattention. This may become quite obvious with simple observation or when listening to the patient attempt to relate their history. Several bedside tests may help to establish inattention for patients with more subtle deficits:

Months of the year backwards

This is perhaps the best test of attention, as it allows both description and quantification of deficits. Normal people should be able to recite the months of the year backwards in 10–15 seconds. When asked to recite the months of the year backwards, the confused patient may respond in one of several ways. Agitated patients may erupt in anger at the request to perform such a silly task. Somnolent patients will give no response and quickly fall asleep. Incoherent patients may begin by starting with December, reciting November and October in the correct sequence, and then lose track of the task. Some may stop completely, while others may resume by reciting the months in calendar order. Still others may start with December, and when they reach November, start to talk about the fall or Thanksgiving. Patients with only subtle inattention may make no mistake other than transposing the months in the May–April–March transition.

Reverse digit span

Digit span is another useful, quantifiable test of attention. To perform this test, first recite a list of random numbers at a rate of one digit per second, and then ask the patient to repeat the list to you in sequence. After establishing the forward digit span, ask the patient to recite a different number sequence backwards. Most people have digit spans of at least seven forwards and five backwards.

Serial sevens

Test serial sevens by asking the patient to subtract seven from 100 and then seven from that result and so on until they can subtract no more. This test of attention is somewhat dependent on the patient’s mathematical abilities and education level, and is therefore less useful or quantifiable than testing the months of the year backwards or the reverse digit span.

Spelling “world” backwards

Spelling “world” backwards is generally not very useful, as the only common mistake is transposing the letters “l” and the “r,” an error that is due to chance as often as it is to inattention.

Other changes in mental status

In addition to the primary disturbance in attention, confused patients often demonstrate a variety of other mental status examination abnormalities including problems with language, memory, and praxis (Chapters 3 and 4). Careful testing, however, shows that the main problem is inattention.

Asterixis

Asterixis accompanies most metabolic and some structural encephalopathies, and is not, as many believe, pathognomonic for hepatic encephalopathy. To test for asterixis, ask the patient to elevate their pronated arms and extend their wrists in front of them as if they are making stop signs. After a latent period of up to 30 seconds, both hands will drop forward slightly and then jerk backwards several times, quickly and asynchronously.3 These movements are accompanied by tiny oscillations of the fingers. After several jerks, the movements disappear, only to reappear a few seconds later.

Differential diagnosis

The four conditions that are most often “confused with confusion” are aphasia, neglect, transient global amnesia, and psychosis.

Aphasia

Aphasia is an acquired disorder of language resulting from brain damage (Chapter 3). It may be difficult to distinguish some patients with aphasia, particularly those with fluent varieties, from patients with acute confusional states. A patient with Wernicke’s aphasia, for example, may appear confused because they produce a copious verbal output that makes little sense and because they do not appear to understand simple instructions. Confusion is best distinguished from aphasia by a more widespread pattern of cognitive dysfunction.

Neglect and the right hemispheric syndrome

Neglect4 is a multidomain disorder of focused rather than global attention. This syndrome is seen most often in patients with right middle cerebral artery infarction, and when fully formed is almost always accompanied by left hemiparesis or hemiplegia. Many of the behaviors of a patient with neglect described here are quite unusual, and it is easy to see why a physician unfamiliar with the condition would mislabel the patient as being confused.

Visual neglect

Visual neglect is usually the most striking behavioral feature of the right hemispheric syndrome. The patient with severe neglect looks exclusively to the right side of space and may not respond to the examiner if approached from the left. Specific testing may be required to elicit neglect in patients with more subtle deficits. For example, the patient with neglect will describe fewer details of a complex visual scene. They will also have difficulty with line bisection. To perform this test, place an 8 ½ × 11 piece of blank paper in

Figure 1.1

Figure 1.1 Line bisection test in a patient with neglect. Note that the line is bisected well to the right of the midline.

Figure 1.2

Figure 1.2 Template for the “A” cancellation task. The patient is instructed to circle the target letter “A.” Patients with neglect will begin on the right side of the page and may completely ignore the left side.

landscape orientation before the patient. Draw a line across the page from left to right and instruct the patient to bisect the line. Normal subjects will come within a few millimeters of the center of the line, but the patient with neglect will bisect it to the right of the midline, sometimes within a few centimeters of the line’s right side (Figure 1.1). Target cancellation is another useful test of hemineglect. Write the letter “A” in a random distribution approximately 15–20 times on a blank sheet of paper in landscape orientation (Figure 1.2). Make sure to distribute the target letter evenly on the left, right, center, top, and bottom. Next, surround the target with randomly chosen letters of the alphabet and instruct the patient to circle only the letter “A.” The patient with neglect will circle the targets predominantly or even exclusively on the right side of the page.

Somatosensory neglect

To test for somatosensory neglect, first make sure that gross touch perception is preserved on both the left and right sides of the body, as somatosensory neglect cannot be diagnosed if basic sensation is impaired. Instruct the patient to close their eyes and gently stroke the dorsal surfaces of both hands. Patients with neglect will acknowledge only the sensation of being touched on the right hand, a phenomenon known as double simultaneous extinction.

Other elements of the right hemispheric syndrome

Patients with the right hemispheric syndrome are usually not aware of their deficits or deny them explicitly, a phenomenon known as anosognosia. When asked why they are in the hospital, a patient with the right hemispheric syndrome may tell you that they should not be there because they feel well. They may tell you that they are at home rather than in the hospital. Even when confronted with incontrovertible evidence that they are sick and in the hospital, the patient may continue to deny their illness or express a lack of concern about the problem (anosodiaphoria). Because prosody, the rhythmic and melodic elements of speech, is largely a function of the right hemisphere, patients with the right hemisphere syndrome tend to speak in monotone.

Transient global amnesia

Transient global amnesia (TGA) is a sudden-onset, temporary disorder of memory encoding that often prompts consultation for confusion. Without warning, the patient starts to ask questions such as, “How did I get here?”, “What happened?”, and “Where am I?” After being provided with an apparently satisfactory explanation, the patient repeats the same questions a few minutes later. The typical patient is otherwise attentive and comports himself normally. They are capable of the entire spectrum of complex behaviors, including the ability to drive themselves home during an episode. Transient global amnesia typically lasts for several hours and then resolves. The precise etiology of TGA is unclear, with seizure, migraine, and stroke being implicated as possible etiologies.5 Because TGA resolves on its own, it requires no specific treatment other than reassurance.

Psychosis

Psychosis may closely resemble an acute confusional state. Factors that help to differentiate between psychosis and confusion include the better organization and greater consistency of psychotic hallucinations and delusions, and the overall preserved level of consciousness and orientation in psychosis.6 A normal electroencephalogram helps to exclude encephalopathy in cases that are difficult to distinguish on clinical grounds alone. Formal psychiatric assessment may help to differentiate between the two if any doubt remains.

Diagnostic testing

A complete medical history, medication list review, and chart review often disclose the source of confusion. Table 1.1 contains a basic guide to testing for some of the more common disorders that produce confusion. Many of these tests are ordered routinely in all hospitalized patients, and there are just a few additions specifically for the confused patient. EEG may help to confirm that a patient is encephalopathic (see Figures 1.3 and 1.4) if any doubt remains after the history and physical examination. EEG is also useful for determining whether a patient is in nonconvulsive status epilepticus. Almost all confused patients should undergo a neuroimaging study, generally a noncontrast head CT to exclude the possibility of a structural lesion, particularly subdural hematoma. MRI may be needed when acute stroke or inflammatory lesions are suspected. Finally, a lumbar puncture may be indicated when an infectious, inflammatory, or neoplastic process is suspected.

Etiologies

Toxic and metabolic encephalopathies

Medical diseases and intoxications are the most common causes of the acute confusional state. While essentially any medical disturbance may lead to confusion, commonly identified precipitants include pneumonia, urinary tract infections, hyponatremia, uremia, hepatic dysfunction, hypoxia, and hypercarbia (Table 1.1). In many elderly patients, subtle rather than overt metabolic derangements are often responsible for the problem. Among the medications that lead to confusion, the most common culprits are opioids, benzodiazepines, sleeping aids, and anticonvulsants. Intoxication with drugs of abuse

Table 1.1 Diagnostic testing for confusion

Table 1.1

is another important cause of confusion. While the various toxic and metabolic encephalopathies are quite similar in their presentations, those related to ethanol consumption and hepatic failure present in distinctly different fashions and I will therefore discuss them in more detail here.

Ethanol and confusion

Ethanol intoxication

The signs of ethanol intoxication are easily identifiable and include slurred speech, incoherence, and ataxia. If there is any doubt about the diagnosis, it may be confirmed by finding an elevated serum ethanol level.

Figure 1.4

Figure 1.4 EEG in a patient with severe encephalopathy. Posterior dominant rhythm (thin arrow) is approximately 2–3 Hz. Additional slowing is noted throughout the record (thick arrow). There is no reactivity of the EEG to a request for movement. Image courtesy of Dr. Julie Roth.

Figure 1.3

Figure 1.3 EEG in patient with moderate encephalopathy. The posterior dominant rhythm (thin arrow) is slow at approximately 5–6 Hz. There is also superimposed generalized slowing (thick arrow). Image courtesy of Dr. Julie Roth.

Ethanol withdrawal

Withdrawal symptoms may develop as early as 6 hours after stopping heavy alcohol intake. The most common manifestation of ethanol withdrawal is tremulousness. When ethanol withdrawal causes a confusional state, it most frequently takes the form of agitated delirium, including auditory and visual hallucinations. These typically peak between 24 and 36 hours of ethanol withdrawal.7 Delirium tremens is characterized by autonomic instability including diaphoresis, hypertension, and tachycardia, and develops between 2 and 4 days after ethanol discontinuation. If not treated properly, delirium tremens may be fatal. Benzodiazepines, administered on a standing basis or as needed for signs of severe withdrawal (Table 1.2) are the agents of choice in reducing morbidity from ethanol withdrawal.8

Wernicke’s encephalopathy

Chronic alcoholism and malnutrition may lead to thiamine deficiency and the clinical syndrome of Wernicke’s encephalopathy. The classic clinical triad of Wernicke’s encephalopathy is confusion, ophthalmoplegia, and ataxia. Because the triad is complete in only a minority of patients with Wernicke’s encephalopathy, it is good practice to administer thiamine 100 mg intravenously for 5 days unless another source of confusion

Table 1.2 Benzodiazepine regimens for ethanol withdrawal

Table 1.2

is identified.9 Thiamine is a benign intervention, and if Wernicke’s encephalopathy is not treated quickly, it may be irreversible. Intravenous thiamine leads to improvement in ocular symptoms in hours to days and ataxia and confusion in days to weeks.7

Hepatic encephalopathy

Both acute and chronic liver failure produce neurological dysfunction. In its mildest form, hepatic encephalopathy is characterized by inattention and psychomotor slowing. Deficits may not be detected at this stage unless they are sought specifically. Moderate hepatic encephalopathy produces more prominent inattention and somnolence. Asterixis, the most well-known sign of hepatic encephalopathy, is usually present at this stage. Other features of moderate hepatic encephalopathy include pyramidal and extrapyramidal signs including dysarthria, tremor, rigidity, and bradykinesia. EEG recordings may show triphasic waves, although this finding is not pathognomonic for hepatic encephalopathy. Advanced hepatic encephalopathy is characterized by seizures and more severe cognitive dysfunction, which may progress to coma and death. While a high serum ammonia level may suggest the diagnosis of hepatic encephalopathy, the substantial overlap between venous ammonia levels and the degree of hepatic encephalopathy makes following ammonia levels unhelpful for monitoring disease progression.10 Treatment of hepatic encephalopathy includes reducing enteric bacterial ammonia production with the nonabsorbable disaccharide lactulose (30–60 mg tid) and short-term treatment with the antibiotics rifaximin (400 mg tid) or neomycin (1000–3000 mg qid). Although symptoms may be temporarily reversible, hepatic encephalopathy has a poor long-term prognosis.

Spinal fluid pleocytosis

Abnormal cells in the spinal fluid, whether they are neutrophils in bacterial meningitis, lymphocytes in viral meningitis, tumor cells in neoplastic meningitis, or red blood cells in subarachnoid hemorrhage (Chapter 19), may produce an acute confusional state.

Bacterial meningitis

The typical presentation of bacterial meningitis is fever, headache, and stiff neck. It is often accompanied by a confusional state that is otherwise indistinguishable from other toxic or metabolic encephalopathies. If you do not have a high index of suspicion for bacterial meningitis from the outset, you will miss the diagnosis, potentially leading to irreversible neurological damage and even death. Several findings may assist in making the diagnosis. Nuchal rigidity may be present in approximately 30% of patients with meningitis.11 Kernig’s sign is elicited by instructing the patient to lie flat with the hip flexed to 90° and looking for resistance or pain with attempted knee extension. Brudzinski’s sign is elicited in a supine patient by observing spontaneous hip flexion when the neck is flexed. Unfortunately, Kernig’s and Brudzinski’s signs are unreliable, as they accompany meningitis in only 5% of cases.11 If you suspect bacterial meningitis, then you must perform a lumbar puncture. The technique and safety of lumbar punctures is discussed in Box 1.1. The most important findings in the cerebrospinal fluid of a patient with bacterial meningitis are neutrophilic pleocytosis, elevated protein, and low glucose. Even if all three of these parameters are normal, however, until the Gram stain and cultures return, treat patients with suspected bacterial meningitis empirically with antibiotics covering the commonly responsible pathogens Streptococcus pneumoniaeNeisseria meningitidisHaemophilus influenzae, and Listeria monocytogenes:12,13

• ceftriaxone 2 g IV q12h (substitute cefepime 2 g q8h in immunocompromised patients)

• vancomycin 1 g IV q12h

• ampicillin 2 g IV q4h

• dexamethasone 10 mg q6h for the first 2–4 days

Continue treatment until bacterial cultures are negative for 48 hours or a specific organism is isolated. Further tailoring and duration of antibiotic therapy depends on the organism cultured and its antibiotic sensitivity, and should be determined in consultation with an infectious disease specialist.

Box 1.1 Lumbar puncture

Many of the causes of confusion require CSF analysis. Although time is of the essence in performing a lumbar puncture, it is first necessary to exclude space-occupying intracranial lesions, as such lesions increase the risk of cerebral herniation. Not every patient, however, requires a CT scan before lumbar puncture. Risk factors for space-occupying lesions, and therefore indications for performing a head CT prior to lumbar puncture include age > 60 years, an immunocompromised state, a history of seizures within 1 week prior to presentation, papilledema, or an abnormal neurological examination.14 In addition to cerebral herniation, the risks of the procedure include headache (30%), bleeding at the site of the puncture, and infection.

The main reason that a lumbar puncture is unsuccessful is that the patient is positioned improperly. Almost all textbooks instruct that the lumbar puncture should be performed in the lateral decubitus position. This position is ideal to obtain an accurate measurement of the cerebrospinal fluid pressure, but is also associated with a greater failure rate due to spine rotation and incomplete opening of the intervertebral space. The subarachnoid space is easier to access if the patient sits up and leans forward (Figure 1.7).

Identify the L2–3 or L3–4 interspace by drawing an imaginary line between the iliac crests as a marker of the L4 interspace. Next, sterilize the area with iodine or other sterilizing agent and place a drape over the planned lumbar puncture site. Infiltrate the target interspace with a small amount of lidocaine. Place the lumbar puncture needle into the space and advance slightly until you feel a slight decrease in resistance or “pop.” Opening pressure may be measured by rotating the patient into the lateral decubitus position, withdrawing the stylet, and connecting the manometer. Be sure to collect enough spinal fluid to perform all necessary studies and to use an appropriate fixative solution when performing cytological examination to look for neoplastic cells. After all of the fluid is collected, replace the stylet and withdraw the needle. I instruct the patient to remain flat for 1 hour after the procedure to decrease the risk for headache.

Viral meningitis and encephalitis

Because they present so similarly, it may be difficult to distinguish between bacterial and viral meningitis on clinical grounds alone. Lumbar puncture is also often unhelpful in the acute setting, as viral meningitis may also cause a neutrophilic pleocytosis in the first 24 hours of infection. While waiting to repeat lumbar puncture in 24–48 hours (by which time the shift to lymphocytic pleocytosis should have occurred), check the Gram stain and bacterial cultures, and treat patients with empiric therapy for bacterial meningitis.

Viral encephalitis is characterized by viral invasion of the brain parenchyma, and therefore a greater likelihood of confusion, seizures, and serious neurological morbidity than viral meningitis. The most important causes of viral meningitis and encephalitis are:

• Enteroviruses. Most viral meningitis is due to enteroviral (e.g. coxsackievirus and echovirus) infection and does not require treatment beyond supportive care.

• Herpes simplex virus type 1 (HSV-1). HSV-1 produces encephalitis that preferentially (but not exclusively) affects the temporal lobes. The only way to make the diagnosis is by finding a positive HSV polymerase chain reaction (PCR) result in the cerebrospinal fluid. The classic findings of HSV encephalitis including T2-weighted MRI hyperintensities in the temporal lobes (Figure 1.5), periodic lateralizing epileptiform discharges on EEG, and red blood cells in the CSF are not universal, especially in the early stages. Because the HSV PCR usually requires several days to process during which time neurological deterioration may occur, treat all patients with suspected HSV encephalitis with acyclovir 10 mg/kg tid until the HSV PCR results return. Monitor kidney function while treating with acyclovir. Continue treatment for confirmed HSV infection with acyclovir for 21 days.

• Herpes simplex virus type 2 (HSV-2). Most patients with HSV-2 meningitis have genital herpes at the time of presentation. In the absence of herpetic lesions, the diagnosis is made by finding a positive HSV PCR in the CSF. Treat patients with HSV-2 meningitis with intravenous acyclovir, as described for patients with HSV-1 encephalitis.

• Human immunodeficiency virus (HIV). It may be difficult to distinguish HIV seroconversion from other causes of viral meningitis. While patients with a meningitic presentation of HIV seroconversion usually improve with little more than supportive care, it is important to recognize the pathogen for counseling purposes and for planning further treatment.

Figure 1.5

Figure 1.5 Fluid attenuation inversion recovery (FLAIR) MRI of a patient with hyperintensity in the left temporal lobe.

Figure 1.6

Figure 1.6 Fluid attenuation inversion recovery (FLAIR) MRI of a patient with posterior reversible encephalopathy syndrome showing the characteristic occipital lobe hyperintensities.

Figure 1.7

Figure 1.7 Technique for performing lumbar puncture. Identify the L3–4 interspace as the interspace superior to a line connecting the iliac crests (A). Prepare the area with iodine or another sterilizing agent (B) and a sterile drape (C). After anesthetizing the area with lidocaine or another anesthetic, place the lumbar puncture needle into the L2–3 or L3–4 interspace, advancing slowly until a sudden decrease in resistance or “pop” is heard (D). If an opening pressure needs to be measured, then rotate the patient into the lateral decubitus position, withdraw the stylet and attach the manometer (E). Collect the fluid and send to the laboratory for studies.

Neoplastic meningitis

Tumor cells that invade the CSF and leptomeninges have the potential to cause multifocal dysfunction of the CNS, cranial nerves, and nerve roots. The constellation of symptoms may include encephalopathy, headaches, seizures, increased intracranial pressure, diplopia, dysarthria, radicular pain, and weakness. The most common tumors that produce neoplastic meningitis are primary CNS tumors, carcinomas of the lung and breast, melanoma, lymphoma, and leukemia.15 Although neoplastic meningitis usually accompanies advanced cancer, it may be the first sign of disease in some cases. Routine CSF examination shows a high cell count with lymphocytic predominance and a high protein level. A positive cytological examination of the CSF establishes the diagnosis. Malignant cells are found after a single lumbar puncture in approximately 55% and after a second lumbar puncture in 85%.16 Three or more lumbar punctures should therefore be performed before declaring the evaluation negative. Contrast-enhanced MRI serves an adjunctive role in diagnosis, showing leptomeningeal enhancement and focal nodular tumor deposits in about half of high-risk patients with initially normal cytological examinations.17 If possible, perform MRI prior to lumbar puncture, as lumbar puncture itself may lead to artifactual leptomeningeal enhancement. Neoplastic meningitis is a poor prognostic sign, associated with a median survival of <6 months.15 In most cases, therapy is supportive. Steroids, local radiation, and intrathecal or systemic methotrexate or cytarabine may be used for palliative purposes.15

Lyme meningitis

Infection with the tick-borne spirochete Borrelia burgdorferi produces Lyme disease, a disorder with protean neurological and systemic manifestations. Symptoms of early disseminated Lyme disease occur several weeks to months after tick bite and may include radiculopathy, Bell’s palsy, or lymphocytic meningitis. There is often no history of the classical erythema chronicum migrans rash. The diagnosis is established by finding Borrelia antibodies in the CSF. In many patients, however, antibodies are not present and the diagnosis is made only from the relevant clinical and exposure history. Treat Lyme meningitis with ceftriaxone (2 g IV qd for 28 days).

Tuberculous meningitis

Tuberculous meningitis produces a monocytic pleocytosis with high protein and very low glucose levels. The diagnosis is made by finding acid-fast bacilli (AFB) in the CSF. This test is of low diagnostic yield, and multiple lumbar punctures may be required before finding a positive AFB stain. Treat tuberculous meningitis with a four-drug regimen (most regimens include a combination of isoniazid, pyrazinamide, rifampin, and either ethambutol or streptomycin) in consultation with an infectious disease specialist.

Fungal meningitis

Coccidioides immitis produces a lymphocytic meningitis endemic to the American Southwest. The diagnosis is made by culturing the organisms or by finding coccidioidal antibodies in the CSF. Treat patients with coccidioidal meningitis with oral fluconazole (400 mg qd).

Cryptococcus neoformans may produce a life-threatening meningitis that is mostly seen in immunocompromised patients. The CSF shows a monocytic pleocytosis, which is often modest in patients who cannot mount a robust immune response. Cryptocci stain positively with India ink. Treat cryptococcal meningitis with a combination of amphotericin B IV 0.7 mg/kg qd and flucytosine PO 25 mg/kg qid for 2 weeks followed by fluconazole 400 mg PO qd for 8 weeks.18 Additional treatment should be determined in conjunction with an infectious disease specialist.

Drug-induced meningitis

The most common causes of drug-induced meningitis are nonsteroidal anti-inflammatory drugs, trimethoprim-sulfamethoxazole, and intravenous immunoglobulin. These agents usually produce a neutrophilic pleocytosis in the acute setting. Drug-induced meningitis resolves when the offending agent is withdrawn.

Limbic encephalitis

Limbic encephalitis is an immune-mediated neurological syndrome characterized by confusion, memory loss, and seizures. It generally occurs in patients with cancer (sometimes as the first sign), but in others, it is secondary to a nonneoplastic, autoimmune process. Common antibodies associated with limbic encephalitis include:

• anti-Hu (ANNA-1) associated with small-cell lung cancer19

• anti-Ma2 associated with testicular cancer in young men19

• anti-CV2/CRMP5 associated with small-cell lung cancer20

• voltage-gated potassium channel antibodies20

• N-methyl-D-aspartate (NMDA) receptor antibodies associated with ovarian teratoma20,21

Limbic encephalitis may improve with successful treatment of the underlying cancer. Intravenous immunoglobulin is often a useful adjunctive treatment.

Nonconvulsive status epilepticus

Nonconvulsive status epilepticus (NCSE) is defined as uninterrupted complex partial or absence seizures that last for at least 30 minutes. The behavior of a patient in NCSE differs little from that of a patient with any of the more common toxic or metabolic sources of confusion. Because of its obvious treatability, maintaining a high index of suspicion for NCSE when evaluating any confused patient is important. The best way to confirm the diagnosis is by finding ongoing seizures on EEG. There are many times, however, when EEG is not readily available, in which case empiric treatment with 2 mg of intravenous lorazepam may disrupt NCSE and improve the confusional state. Unlike convulsive status epilepticus, NCSE may not necessarily pose a substantial risk for brain damage or death. It is not clear, therefore, how aggressively NCSE should be treated. While small doses of benzodiazepines and initiating or augmenting maintenance doses of anticonvulsants are obviously warranted, it is less clear whether patients in NCSE require drastic measures such as propofol, midazolam, or pentobarbital infusions. The decision to proceed with aggressive pharmacological treatment of NCSE should be decided on a case-by-case basis, bearing in mind that the ultimate prognosis of NCSE is related to the process responsible for the seizures and not to the seizures themselves.

Structural lesions responsible for confusion

Because of their rarity, it is easy to become cavalier and dismiss the possibility of focal structural lesions as a source of confusion. Subdural hematoma is the diagnosis that is most often missed. Usually caused by traumatic tearing of the bridging subdural veins, subdural hematoma may result in a wide variety of neurological presentations including hemiparesis, seizures, headaches, and confusion. The head trauma that produces a subdural hematoma is often trivial and sometimes not remembered by the patient. Thus, it is almost mandatory to obtain a noncontrast head CT in every confused patient (see Chapter 21Figure 23.3). Most subdural hematomas reabsorb without intervention, but progressive neurological deficits or radiographic evidence of hematoma expansion require surgical intervention. Although stroke is not a common cause of confusion, left posterior cerebral22 and right middle cerebral artery23infarctions may rarely produce a confusional state.

Posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy syndrome (PRES) is a severe encephalopathy produced by vasogenic edema.24 The clinical syndrome may be quite variable, but usually takes the form of a rapidly developing encephalopathy accompanied by visual disturbances and sometimes by seizures. The most commonly identified precipitants are hypertensive emergency, eclampsia, and calcineurin inhibitors used as immunosuppressants after organ transplantation (most commonly tacrolimus and cyclosporine). Characteristic imaging findings of PRES are T2 hyperintensities (best visualized using fluid-attenuated inversion recovery sequences) with a predilection for the subcortical white matter of the parietal and occipital lobes (Figure 1.6). Despite its name, PRES is not necessarily restricted to the posterior part of the brain and may not be reversible: the frontal lobes, thalamus, and basal ganglia may be involved, and PRES may be associated with poor neurological outcome and death. Blood pressure correction (most commonly with a regimen including verapamil or other calcium-channel blockers), delivery of the baby for women with eclampsia, and discontinuation of calcineurin inhibitors may lead to resolution of PRES.

General approach to treatment

Most acute confusional states have an identifiable and often a reversible cause. It is essential to ensure that no more harm comes to the patient while the responsible abnormality is being corrected. This is best accomplished by providing the patient with a room of their own, soft lighting, and the company of a family member or friend. Many patients, particularly elderly ones, will require chemical or physical restraints, which must be administered judiciously. Quetiapine (25 mg prn) is the most popular agent for sedating combative patients. Haloperidol (0.5–1 mg IV) may be used for patients who refuse or cannot take oral medications. Security sitters and physical restraints may be necessary in extreme cases.

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