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

10. Proximal and generalized weakness

Weakness and its mimics

Weakness is both a sign and symptom of motor dysfunction characterized by the failure of a movement to generate an appropriate force. Careful questioning of many patients referred for weakness reveals that the problem is not actually weakness, but rather a condition that mimics it:

• Fatigue is the common sensation of tiredness or physical exhaustion that accompanies medical conditions such as hypothyroidism and anemia, sleep disorders, and depression. Although fatigued patients often describe themselves as weak, formal motor testing shows that they actually possess full strength.

• Bradykinesia is slowness of movement. It is a core feature of parkinsonism, and is discussed in greater detail in Chapter 13.

• Musculoskeletal system dysfunction may reduce the range of motion of a joint but does not produce actual weakness.

• Pain from any source may restrict movement and be erroneously interpreted as weakness.

• Sensory loss that impairs joint position sensation may lead to the impression of weakness. The telltale sign that sensory loss is the cause of impaired movement is that the joint moves normally when the patient looks directly at it, but fails to move appropriately when they look away.

The evaluation of weakness

The key step in diagnosing the weak patient is to define the distribution and speed of onset of weakness by history and physical examination. The most common gradual-onset patterns of weakness are:

• proximal (this chapter)

• distal (Chapter 15)

• extraocular muscle (Chapter 6)

• focal limb (Chapter 11)

• bulbar (Chapter 8)

• facial (Chapter 8)

• myelopathic (Chapter 17)

Rapidly developing weakness is discussed further in Chapters 12 and 21.

Even if the history strongly suggests one of these patterns, it is imperative to perform a comprehensive neurological examination. Patients are frequently unaware of or adapt to minor weakness, and you will miss subtle signs of more widespread motor system dysfunction if you focus only on the weakness that the patient describes. This is often true for patients with amyotrophic lateral sclerosis, in whom the diagnosis is routinely overlooked for several months due to exclusive focus on a single weak muscle group.

While it is tempting to proceed directly to power testing when evaluating a weak patient, you will miss important diagnostic clues if you fail to examine muscle bulk. Look for muscle atrophy in both proximal and distal muscles, around the temples, and in the tongue. Muscles in which atrophy is obvious include the deltoid, periscapular muscles, abductor pollicis brevis, first dorsal interosseous, quadriceps, and extensor digitorum brevis.

After examining muscle bulk, examine muscle tone in the upper and lower extremities. Instruct the patient to lie still and relax. Move the arms at the elbows and wrists, looking for an increase in resistance. Check tone in the legs while the patient lies flat. Grasp the thigh and lower leg from above and shake the leg, looking for movement at the foot: normally, the foot moves back and forth loosely, but in patients with hypertonicity, the foot remains stiff at the ankle. Abnormalities of tone include:

• Flaccidity: a floppy decrease in tone, which points to a peripheral nervous system lesion or to a hyperacute CNS lesion (e.g. acute stroke or spinal shock).

• Spasticity: the form of hypertonicity caused by disease of the pyramidal system. The initial limb movement is met with the greatest amount of resistance, which then dissipates as joint displacement increases. Spasticity is most obvious when attempting to extend the flexed arm or wrist, or attempting to flex the extended leg.

• Rigidity: the increase in tone caused by extrapyramidal disease. It is independent of the velocity and direction of movement.

• Paratonia: caused by frontal lobe degeneration and characterized by an increase in tone that varies with the amount of resistance applied by the examiner.

When examining power, oppose the muscle being tested with a muscle of approximately equal strength. Use extra effort for large, physically fit patients. You will often need to exercise a mechanical advantage to find subtle weakness in muscles such as the quadriceps, tibialis anterior, and gastrocnemius, as these muscles tend to be strong when using conventional muscle strength testing techniques. Subtle weakness of the gastrocnemius, in fact, may be detected only by an inability of the patient to stand on their toes. The genioglossus, abductor digiti minimi, and iliopsoas lie at the other extreme, and you should give these muscles a mechanical advantage to avoid incorrectly labeling them as weak. Be aware of “giveway” weakness caused by pain or poor effort: encourage the patient to push as hard as they can for even as little as 1 second if it appears that they are not giving maximal effort.

While there is no substitute for detailed knowledge of the nerve roots, nerves, and muscles that control joint movement, relearning all the details of first-year medical school anatomy is often not necessary to localize the source of weakness in a given patient. Table 10.1 distills this information to a high-yield format of the 20 most commonly tested movements for use on the ward and in the clinic. The muscles are organized into proximal and distal groups, whether they are weak in pyramidal (corticospinal) lesions, and by the nerve root and nerves that innervate them. Aids to the Examination of the Peripheral Nervous System1 is an additional, invaluable guide to the sensorimotor examination.

Proximal weakness

History

The proximal muscles are those that are close to the trunk. Complaints of proximal muscle weakness include difficulty when reaching overhead, combing or brushing the hair, rising from a seated position, or ascending stairs. The patient may describe themself as “walking like a cowboy” with bowed legs and side-to-side waddling. Contrary to popular belief, proximal weakness is not pathognomonic for myopathic disease. Other localizations that commonly produce proximal weakness include the motor neuron, nerve root, nerve plexus, neuromuscular junction, and, in some cases, the peripheral nerves.

Associated features

Although mild muscle tenderness is a feature of many myopathic disorders, severe pain is uncommon in myopathy. In the absence of trauma, rhabdomyolysis and myoglobinuria suggest the possibility of a metabolic myopathy. Rash points to dermatomyositis or to an overlap myopathy. Diplopia, ptosis, and dysphagia are seen in patients with myasthenia gravis or oculopharyngeal muscular dystrophy. Dry eyes and dry mouth often accompany Lambert–Eaton myasthenic syndrome (LEMS). Cramps, fasciculations, and muscle atrophy are features of amyotrophic lateral sclerosis.

Examination

Muscle bulk

Proximal weakness with prominent muscle atrophy suggests muscular dystrophy, a cachectic myopathy, or motor neuron disease. Most patients with inflammatory myopathies do not have muscle wasting in the early stages. Neuromuscular junction disorders do not affect muscle bulk.

Muscle strength

Muscle strength testing should always begin with an examination of neck flexion and extension, especially for patients with proximal muscle weakness. In most patients, neck flexors become weak before neck extensors. The proximal muscles of the arms include the deltoids, biceps, and triceps. In the legs, the proximal muscles are the iliopsoas, quadriceps, gluteal muscles, and hip adductors.

Exercise testing

Muscle fatigability is the defining feature of myasthenia gravis. This is most easily assessed at the deltoid. First, test the maximal strength of shoulder abduction. Next, instruct the patient to abduct the arm 20–30 times in succession at a frequency of approximately twice per

Table 10.1 Commonly tested movements in localizing weakness

Table 10.1

DIP = distal interphalangeal, FCR = flexor carpi radialis, FCU = flexor carpi ulnaris, MCP = metacarpophalangeal, PIP = proximal interphalangeal.

second. Observe for either a failure to complete the series of contractions or a decrease in strength when testing the patient after the final contraction. If necessary, use contralateral shoulder abduction as a control for patients with subtle weakness.

All patients with proximal weakness should also undergo testing for postexercise facilitation, the characteristic finding of the presynaptic neuromuscular junction LEMS. To test for postexercise facilitation, instruct the patient to contract a weak muscle maximally against resistance for 10 seconds. Postexercise facilitation is present if there is a clear improvement in muscle strength after brief exercise.

Reflexes

Patients with myopathies usually have normal deep tendon reflexes unless there is substantial weakness or muscle atrophy. Lambert–Eaton myasthenic syndrome classically causes diminished or absent reflexes that reappear when the reflex is checked after 10 seconds of sustained exercise. Neuropathic and radiculopathic conditions should produce hyporeflexia or areflexia. Upper motor neuron dysfunction in amyotrophic lateral sclerosis (ALS) may produce hyperreflexia, but because ALS is a disease of both the upper and lower motor neurons, it may cause either an increase or decrease in reflexes.

Sensation

Sensory examination is usually normal in patients with proximal weakness. Exceptions include LEMS and neuropathic conditions such as chronic inflammatory demyelinating polyneuropathy. Do not assign too much weight to mild distal pinprick loss, as this is often secondary to a preexisting but trivial polyneuropathy.

Gait

Patients with proximal muscle weakness waddle from side to side, the so-called Trendelenburg gait (Chapter 18). To elicit Trendelenburg’s sign, observe the patient from behind and instruct them to stand on one foot. The sign is present when the trunk droops towards the side of the elevated leg. Patients with proximal muscle weakness require several attempts to rise from a seated position, and may be unable to do it at all. This test is even more difficult if the patient attempts to do it when their arms are folded across their chest.

Other signs and symptoms

Bulbar weakness accompanies amyotrophic lateral sclerosis and myasthenia gravis but is not universal in either condition, especially in their early stages. Dysphagia is prominent in oculopharyngeal muscular dystrophy and may also occur in patients with advanced inflammatory myopathies. Diplopia and ptosis in patients with proximal weakness strongly suggest myasthenia gravis, a mitochondrial myopathy, or oculopharyngeal muscular dystrophy, and essentially exclude the possibility of amyotrophic lateral sclerosis. Myotonia is impaired relaxation of a muscle, and is the characteristic finding of myotonic dystrophy and myotonia congenita. If myotonia is not immediately obvious when the patient fails to loosen their grip after shaking your hand, test for percussion myotonia by briskly tapping the tongue, deltoid, or thenar eminence with a reflex hammer (Chapter 14). Myoedema is a mounding of the muscles upon percussion, seen in patients with hypothyroidism.

Laboratory testing in the patient with proximal weakness

Creatine kinase

Creatine kinase (CK) catalyzes the conversion of creatine and ATP to phosphocreatine and ADP. Phosphocreatine is the largest phosphate reserve for regenerating ATP during active muscle contraction. When muscle cells are damaged by a myopathic process, the serum CK level increases. Although CK is the most sensitive and specific laboratory marker for myopathy, as many as one-third of otherwise normal subjects have CK levels greater than the upper limit of normal of approximately 150 U/liter.2 This leads to a large number of referrals for patients with asymptomatic or minimally symptomatic hyperCKemia (see Box 10.1). The CK level should be elevated in patients with inflammatory myopathy, dystrophinopathy, limb-girdle dystrophy, and hypothyroidism – question these diagnoses if CK is normal. The CK level may be normal in patients with cachectic myopathy, steroid myopathy, and hyperthyroidism. While an elevated CK level is considered synonymous with myopathy, neuromuscular diseases including ALS, Guillain–Barré syndrome, and even benign cramps may all cause modest CK elevations. Heavy exercise, large muscle bulk, and African ancestry may also increase the CK level in the absence of muscle disease.

Box 10.1 HyperCKemia

The CK level is often checked by primary care physicians in patients with nonspecific complaints including myalgias and fatigue. This is especially true in patients who take statins. Because most patients with mildly elevated CK levels do not actually have a myopathic disorder, this finding must be interpreted cautiously. The largest study of patients with so-called “idiopathic hyperCKemia” found relevant neuromuscular disorders in only 18% of 114 patients with persistently elevated CK levels.3 Careful reading of this study shows, however, that none of these patients had a treatable neuromuscular disorder. Although there are no firm guidelines, it is difficult to rationalize further evaluation of otherwise strong, minimally symptomatic patients with hyperCKemia of <1000 U/liter.

Aldolase

Aldolase is an important glycolytic enzyme found in muscle and the liver. It may be elevated in patients with muscle disease, but usually adds little to the diagnostic evaluation of a patient with suspected myopathy.

Nerve conduction studies and electromyography

Nerve conduction studies (NCS) and electromyography (EMG) are often helpful diagnostic studies for patients with weakness secondary to peripheral nervous system dysfunction (Figure 10.1).4 In brief, for patients with proximal and generalized weakness, nerve conduction studies are useful in pinpointing sites of focal nerve compression and differentiating between axonal and demyelinating polyneuropathies. Needle EMG helps to localize radiculopathy, detect myopathic processes, and confirm the diagnosis of motor neuron disease. Repetitive nerve stimulation and single-fiber EMG establish the presence of neuromuscular junction disorders. It is important to recognize the limitations of neurophysiological testing: as Preston and Shapiro note in their essential textbook on electrodiagnosis, EMG is an extension of the clinical examination, and is

Figure 10.1

Figure 10.1 Motor nerve conduction study (NCS) of the left median nerve recording from the abductor pollicis brevis (APB). The median nerve is stimulated at the wrist (top trace) and at the elbow (bottom trace). Parameters of interest are the distal latency (the time elapsed between stimulation and the onset of the first motor response at point 1, the response amplitude (the difference in heights between points 1 and 2), and the conduction velocity (obtained by subtracting the time elapsed between points 3 and 1 and dividing by the distance between the stimulation sites). Axonal neuropathies are characterized by low amplitudes and mildly reduced conduction velocities. Demyelinating neuropathies are characterized by mildly reduced amplitudes and markedly reduced conduction velocities.

unlikely to establish a specific diagnosis if the diagnosis is not considered prior to performing the test.5

Muscle biopsy

Muscle biopsy is routinely performed when a myopathic process is suspected. While a muscle biopsy may help to diagnose many exotic varieties of muscle and nerve disease, it is most important for patients with inflammatory, toxic, or endocrine myopathies, because these are potentially treatable conditions. Special histochemical stains and electron microscopy may aid in diagnosis, but rarely do these studies increase the likelihood of finding a treatable condition.

Forearm exercise testing

The basis of the forearm exercise test is that muscle contraction leads to increases in the metabolic by-products lactate and ammonia. To perform forearm exercise testing, draw lactate and ammonia levels from the antecubital vein. Next, have the patient contract the forearm and hand muscles for 1 minute using a dynamometer. Draw lactate and ammonia levels at 1, 3, and 5 minutes following exercise. In normal subjects, there is a rise in both lactate and ammonia after exercise, usually to at least twice the resting value. In patients with myopathies due to glycolytic enzyme deficiencies, lactate does not rise but ammonia does. In patients with myoadenylate deaminase deficiency, ammonia rises but lactate does not. A frustratingly common finding in forearm exercise testing is that both the ammonia and lactate fail to rise sufficiently, suggesting inadequate exercise quality. Because forearm exercise testing is rarely helpful in establishing a diagnosis in adult patients and never uncovers a treatable condition, I rarely perform it.

Causes of proximal weakness

Inflammatory myopathies

The shared features of the inflammatory myopathies are proximal muscle weakness, CK elevation, myopathic EMG changes, and inflammatory infiltrates on muscle biopsy. Severe cases are associated with dysarthria, dysphagia, and diaphragmatic weakness. Muscle aches and pains, if present, are not prominent. In adults, inflammatory myopathies are among the most important causes of proximal weakness, as they are often treatable. The four common inflammatory myopathies may be distinguished on clinical as well as pathological grounds.

Polymyositis

Polymyositis is the least common of the three primary inflammatory myopathies. Patients with polymyositis have proximal muscle weakness and elevated CK levels. Muscle biopsy shows endomysial lymphocytic infiltrates that invade nonnecrotic muscle fibers. Corticosteroids are the first-line treatment for polymyositis. Prednisone should be initiated at 60–80 mg qd for 2–3 months. The daily dose is tapered subsequently by 5–10 mg each week. A steroid-sparing agent should be added for patients who respond incompletely. Methotrexate is usually the agent of first choice. This should be started at 2.5 mg qwk and increased by 2.5 mg qwk to reach a goal of 15–20 mg qwk. Obtain a chest X-ray and pulmonary function tests before starting methotrexate and at least every 6 months to screen for pulmonary fibrosis. Because methotrexate may also be hepatotoxic, check liver function tests at least every 2 months. Persistently elevated liver function tests should prompt referral for liver biopsy. For patients who do not respond to methotrexate, azathioprine is usually the next choice among the steroid-sparing agents. Start azathioprine at 50 mg/day and titrate up by 50 mg each week to a dose of 1–2 mg/kg over 2–3 weeks. Monitor complete blood counts weekly for the first month, then biweekly for the next month, then every month for the entire course of therapy. Check liver function tests every 3 months in patients who take azathioprine.

Dermatomyositis

Dermatomyositis is the most common of the idiopathic inflammatory myopathies. In addition to proximal muscle weakness, patients with dermatomyositis have several characteristic skin changes.6 The heliotrope rash is a symmetric violaceous mask around the upper and lower borders of the eyes. Gottron’s papules are elevated violaceous plaques that involve bony prominences, most typically the metacarpophalangeal and interphalangeal joints. Two other typical skin changes are the V sign (erythema over the anterior neck and chest) and the shawl sign (erythema over the posterior neck and shoulders). Unlike polymyositis and inclusion body myositis, dermatomyositis is a multisystem disorder that often involves the gastrointestinal and pulmonary systems in addition to the skin and skeletal muscle. The CK level is elevated in the overwhelming majority of patients with dermatomyositis. Muscle biopsy shows perimysial inflammation of lymphocytes and perifascicular atrophy. Approximately 25% of patients with dermatomyositis have an underlying malignancy and are at greater risk of developing a malignancy both before and after the diagnosis.6 Patients with dermatomyositis should therefore undergo annual screening for age- and gender-appropriate cancers. When the diagnosis of dermatomyositis is established, it is important to test for antibodies to Jo-1, a tRNA synthetase (also seen in patients with polymyositis, but less frequently), which is associated with a greater likelihood of pulmonary disease, and therefore warrants more caution when considering treatment with methotrexate. Treat dermatomyositis using an approach similar to that described for polymyositis.

Inclusion body myositis

Inclusion body myositis (IBM) is distinguished from the other inflammatory myopathies by early involvement of wrist flexors and finger flexors in addition to proximal muscles. The CK level may be elevated more modestly in IBM than in the other inflammatory myopathies. Diagnostic muscle biopsy abnormalities include inflammatory infiltrates and inclusions within muscle fibers. Unfortunately, IBM does not respond to treatment with corticosteroids or other immunosuppressants.

Overlap myopathies

Overlap myopathies are inflammatory myopathies that occur in the context of a rheumatological disorder such as systemic lupus erythematosus, scleroderma, or rheumatoid arthritis. Like polymyositis and dermatomyositis, overlap myopathies are usually steroid responsive.

Muscular dystrophies

Dystrophinopathies

Duchenne’s muscular dystrophy is an X-linked disorder produced by an out-of-frame shift in the gene that encodes the muscle membrane protein dystrophin. Duchenne’s muscular dystrophy is always diagnosed in childhood, and survival past early adulthood is not typical. Milder dystrophinopathies, however, may present for the first time in one of several ways in adulthood. Becker’s muscular dystrophy is produced by an in-frame shift in the dystrophin gene, and leads to proximal weakness, sometimes affecting the quadriceps in isolation.7 Female carriers of the dystrophin mutation may also present with proximal weakness in adulthood.8 Molecular diagnosis is available for patients with suspected dystrophinopathies. Treatment of dystrophinopathies in adults is generally supportive.

Limb-girdle muscular dystrophies

The limb-girdle muscular dystrophies are a heterogeneous group of disorders that produce hip and shoulder muscle weakness. They may be inherited in any fashion, and may not become clinically obvious until adulthood. Although many patients choose to pursue genetic testing for the peace of mind of having a diagnosis, there are no medications that reverse limb-girdle muscular dystrophy symptoms.

Thyroid myopathies

Both hypothyroidism and hyperthyroidism may result in myopathy. While thyroid myopathies are among the more common of the endocrine myopathies, they are often recognized and treated by primary care physicians or endocrinologists without coming to the attention of neurologists. Levels of CK are usually elevated in patients with hypothyroid myopathy and normal or mildly elevated in patients with hyperthyroid myopathy. In patients with no other explanation, checking thyroid function studies may help to establish the diagnosis in a patient who presents with a suspected myopathy.

Toxic and iatrogenic myopathies

The most important medications and toxins that lead to myopathy are statins, ethanol, and corticosteroids. Other important causes are chloroquine, colchicine, hydroxychloroquine, penicillamine, and zidovudine.

Statin-induced myopathy

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are commonly prescribed cholesterol-lowering agents that produce a wide variety of muscle pathology ranging from asymptomatic CK elevation, to mild muscle aches and cramps, to frank myopathy, to rhabdomyolysis.9 Despite popular opinion that suggests otherwise, atorvastatin, fluvastatin, pravastatin, and simvastatin are all equally likely to lead to myopathy.10 It should not be assumed that a statin is the cause of proximal weakness in a patient who happens to be taking one of these medications: thorough evaluation for other causes of proximal weakness should be conducted before assigning responsibility to the statin. The best treatment for muscle problems in patients taking statins is not entirely clear. For patients with tolerable muscle aches or asymptomatic CK elevations, it is usually safe to continue the statin. For patients with rhabdomyolysis or frank myopathy, discontinue the statin immediately and avoid prescribing statins in the future. Alternative lipid-lowering agents including ezetimibe, gemfibrozil, or niacin may also produce myopathic side effects similar to those produced by the statins. Among the lipid-lowering agents, cholestyramine is likely associated with the smallest risk for muscle pathology.

Alcohol-related myopathies

Excessive alcohol use causes two types of myopathy. The first type is an acute-onset necrotizing myopathy with severe muscle weakness, cramps, and myalgias. More commonly, many years of heavy alcohol use leads to a painless proximal myopathy that develops over weeks to months. The exact lifetime dose of alcohol necessary to produce this myopathy and the role of nutritional deficiencies are unclear. Moderate alcohol use (one or two drinks per day) is likely not sufficient to cause a myopathy. Discontinuing alcohol use may improve symptoms.

Steroid myopathy

Chronic corticosteroid use may lead to a myopathy. Although the exact duration of therapy required before the myopathy develops is not clear, 4 weeks is a probable minimum. The typical clinical picture is painless proximal muscle weakness greater in the legs than in the arms, mild or no CK elevation, and normal EMG. Other features of chronic steroid use are usually present. In most patients, the chronology of steroid administration and symptom development makes diagnosis straightforward. For patients who receive steroids for inflammatory myopathy or myasthenia gravis, establishing whether the problem is steroid myopathy or the condition for which the steroids are being prescribed may be more challenging. In these cases, muscle biopsy demonstrating type II muscle fiber atrophy may be necessary to make the diagnosis. Symptoms usually improve several weeks to months after steroid discontinuation. Physical activity may help to prevent steroid myopathy.

Other myopathies

Almost all treatable myopathies are due to inflammatory, iatrogenic, toxic, or endocrine processes. Two uncommon myopathies deserve mention because they may be treatable. Acid maltase deficiency is a metabolic myopathy characterized by proximal weakness and respiratory failure due to diaphragmatic dysfunction, which may respond to weekly infusions of α-glucosidase.11 Mitochondrial myopathy is often part of a multisystem disorder, and is usually treated with a cocktail containing vitamin E, creatine monohydrate, and coenzyme Q10 with variable results. Other dystrophic and metabolic myopathies are usually not treatable, and the length to which a diagnosis is pursued is largely determined by the patient’s curiosity and interest in genetic counselling.

Generalized myasthenia gravis

Myasthenia gravis is an autoimmune disease produced by antibodies that disrupt the function of the postsynaptic neuromuscular junction. Although many patients develop fixed weakness, fatigability with exercise is the distinguishing feature of myasthenia gravis. Other common forms of myasthenia gravis include ocular myasthenia (Chapter 6), myasthenic crisis (Chapter 12), and bulbar myasthenia (Chapter 8). Patients with generalized myasthenia usually, but not always, have preceding or accompanying ocular signs and symptoms. In their absence, the diagnosis may be challenging.

The two bedside tests that may be used to confirm a diagnosis of myasthenia gravis are the ice test and the edrophonium or tensilon test, both of which are described in more detail in Chapter 6, as they are more reliable in patients with ocular symptoms than in patients with isolated proximal weakness.

Beyond history and physical examination, a wide variety of diagnostic tests is available for patients with suspected myasthenia gravis. The diagnosis is most often established by finding acetylcholine receptor (AChR)-binding antibodies in the blood. A very small minority of patients without AChR-binding antibodies have blocking or modulating antibodies. Of the 20% of myasthenics without AChR antibodies, half possess antibodies to muscle-specific tyrosine kinase (MuSK). Patients with no detectable AChR or MuSK antibodies are called seronegative myasthenics, and require electrophysiological testing to establish the diagnosis. The characteristic finding is the electrodecremental response to 3 Hz repetitive nerve stimulation (Figure 10.2). If repetitive nerve stimulation is normal, single-fiber EMG showing abnormal jitter and blocking may help to reach a diagnosis. All patients with myasthenia gravis should undergo a CT scan of the chest to look for thymoma or thymic hyperplasia.

Figure 10.2

Figure 10.2 Slow (3 Hz) repetitive nerve stimulation of the left facial nerve recording the nasalis. Six recordings are present in each of the five traces. Note the electrodecremental response suggestive of a disorder of neuromuscular transmission.

While symptomatic treatment with the acetylcholinesterase inhibitor pyridostigmine may improve symptoms of ocular myasthenia, it is not an effective treatment strategy for generalized myasthenia gravis. Almost all patients require immunosuppression with corticosteroids. Rapid steroid initiation, however, is often harmful to myasthenics, exacerbating their symptoms and sometimes leading to myasthenic crisis. A safer approach for patients with generalized myasthenia is to start prednisone at a dose of 10 mg/day and to titrate upwards to a goal of 60–80 mg/day over 4–6 weeks. The daily dose can be tapered by 5–10 mg each week after 6–8 weeks of high-dose treatment. Benefit from starting or increasing steroids in myasthenia is typically first seen at 2 weeks and becomes maximal at 1 or 2 months. In many cases, steroids by themselves are inadequate for the treatment of myasthenia gravis, and additional immunosuppressive agents such as mycophenolate mofetil (500 mg bid, titrated up to 1500 mg bid as needed) or azathioprine (50 mg qd, titrated up by 50 mg qd/week to a goal dose of 1–2 mg/kg qd) are needed. Mycophenolate mofetil and azathioprine may not produce any benefit until 3–6 months (or longer) after initiation.

Approximately 10% of patients with myasthenia gravis have thymoma, and those with thymoma should undergo thymectomy, usually within several weeks to months after detection, and sooner if there is evidence of malignant invasion. Patients with nonthymomatous myasthenia gravis may benefit from thymectomy, but the literature guiding this decision is murky at best.12 I generally offer thymectomy to younger patients, as it may be curative and allow steroids to be discontinued. In order to optimize the perioperative course, thymectomy should be performed when symptoms are relatively stable and the daily dose of prednisone is 20 mg or less. I pretreat patients with severe myasthenia or history of myasthenic crisis with five plasma exchanges ending approximately 1 week before anticipated thymectomy.

Lambert–Eaton myasthenic syndrome

This disorder of neuromuscular transmission is produced by antibodies to presynaptic voltage-gated calcium channels. It usually occurs in middle-aged people with underlying neoplasms, most commonly small-cell lung cancer. Less frequently, LEMS is secondary to nonneoplastic autoimmune disorders such as rheumatoid arthritis, pernicious anemia, or hypothyroidism. The typical presentation of LEMS is subacute-to-chronic proximal weakness that is greater in the legs than in the arms. It may be associated with fatigability, but in many cases resembles a myopathy in that the symptoms do not fluctuate. Some patients have bulbar and extraocular muscle weakness, but if these are the most prominent or sole clinical features, consider an alternative diagnosis. Because voltage-gated calcium channels are also present on sensory and autonomic nerve terminals, patients with LEMS may also have mild sensory symptoms and autonomic dysfunction including dry mouth, constipation, and orthostatic hypotension. The cardinal examination finding in patients with LEMS is postexercise facilitation of strength and reflexes.

Confirm the diagnosis of LEMS by checking the blood for antibodies to voltage-gated calcium channels. For patients who require more rapid diagnosis (the antibodies usually require up to 2 weeks to return), the characteristic electrophysiological finding is a reduced compound muscle action potential amplitude that increases after 10 seconds of sustained exercise (Figure 10.3). Because small-cell lung cancer and LEMS coexist so commonly, order a CT scan of the chest for all patients with this disorder. Screen for other cancers as indicated by risk factors and physical examination. If you do not find a tumor or autoimmune disorder, repeat the surveillance scans every 3–6 months, as LEMS may predate cancer diagnosis by several years.

Figure 10.3

Figure 10.3 Motor nerve conduction study obtained by stimulating the left median nerve and recording the left abductor pollicis brevis (APB) in a patient with Lambert–Eaton myasthenic syndrome at rest (top trace). Ten seconds of sustained exercise followed by another stimulation produces an incremental response using the same recording parameters (bottom trace).

Treating LEMS is usually challenging. Obviously, addressing the underlying cancer or autoimmune disease is the first step. Most patients show an incomplete response to the acetylcholinesterase inhibitor pyridostigmine at a dose of 60 mg qid. The potassium channel blocker 3,4-diaminopyridine (which is available at a limited number of centers in the USA on a compassionate basis through Jacobus Pharmaceuticals) is also modestly effective. Patients with longer life expectancies require steroids, intravenous immunoglobulin, or other immunosuppressants.

Chronic inflammatory demyelinating polyradiculoneuropathy

As its name indicates, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated polyradiculoneuropathy that develops over several months. Although the association of neuropathy with distal weakness is widely known, most patients with CIDP present with simultaneous proximal and distal weakness. Weakness in CIDP is symmetric and, as a rule, accompanied by hyporeflexia or areflexia: increased reflexes should prompt investigation for alternative sources of weakness. Sensory deficits are usually present, but overshadowed by motor abnormalities. Nerve conduction studies demonstrate

Figure 10.4

Figure 10.4 Motor nerve conduction study (NCS) of the left ulnar nerve recording abductor digiti minimi (ADM). Note the drop in amplitude (measured from the baseline to the peak) with stimulation of the nerve above and below the elbow compared with the amplitude obtained by stimulating at the wrist. This is conduction block, a pathognomonic finding of inherited demyelinating neuropathies such as Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

changes consistent with demyelination including slow nerve conduction velocities, abnormal temporal dispersion, and conduction block (Figure 10.4). Similar to Guillain–Barré syndrome (Chapter 12), the CSF in CIDP shows albuminocytological dissociation in which the white blood cell count is low and the protein level is high. HIV, Lyme disease, sarcoidosis, and lymphoma or leukemia should be considered for patients with a CIDP-type presentation and >10 cells/mm3. While CIDP is usually idiopathic, it may be associated with systemic diseases, the most widely known of which are HIV infection and osteosclerotic myeloma. Patients with osteosclerotic myeloma develop the POEMS syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. This syndrome is often incomplete. The first steps in evaluating for the possibility of myeloma include serum protein electrophoresis, urine protein electrophoresis, immunofixation, calcium levels, and a skeletal survey to evaluate for a possible myeloma. Corticosteroids and intravenous immunoglobulin (IVIg) are the two agents that are most commonly employed for patients with CIDP. Because IVIg causes fewer side effects, it is usually the treatment of first choice. Initiate IVIg at 2 mg/kg over 5 days, and follow with monthly supplemental doses of 0.4–1 mg/kg. For patients who do not respond to IVIg, start prednisone at a dose of 60 mg and taper by 5–10 mg per dose per week. Although most patients will benefit from either of these treatments, CIDP is a relapsing disease that gets worse when treatment is withdrawn. Plasmapheresis and other immunosuppressants may be used for patients with refractory CIDP.

Central nervous system dysfunction

Peripheral nervous system disease accounts for most cases of proximal muscle weakness. The classic example of CNS dysfunction that breaks this rule is infarction in the border zone or watershed between the anterior and middle cerebral arteries (Chapter 21). Cervical spine disease (Chapter 17) may also lead to predominantly proximal weakness of both arms and legs, sometimes without much sensory dysfunction.

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons characterized by progressive muscle wasting and weakness. Although people of any age may develop ALS, the typical patient is in their 50s or 60s and presents initially with hand clumsiness, gait difficulty, or dysphagia. Patients may not complain specifically of weakness. In the earliest stages, symptoms are quite subtle, and may be overlooked or assigned to more common conditions such as radiculopathy, compression mononeuropathies, or musculoskeletal disorders. Because essentially any subacute-to-chronic- onset focal-or-generalized pattern of weakness described in this or the next chapter may be secondary to ALS, it is important always to consider the diagnosis in patients with painless muscle weakness.

The findings in ALS are best explained with reference to the motor neuron pool. The upper motor neurons begin in the cerebral cortex and descend through the corticospinal tract, while the lower motor neurons begin in the anterior horn cell in the spinal cord. Amyotrophic lateral sclerosis causes degeneration of both upper and lower motor neurons, although lower motor neuron symptoms including multifocal weakness, wasting, and fasciculations often predominate in the initial stages of the disease. While fasciculations are often present, they are not pathognomonic for the diagnosis, nor does their absence exclude ALS. Upper motor neuron findings include dysarthria, spasticity, and hyperreflexia. Sphincter function and extraocular movements are unimpaired. On the surface, cognition is preserved, but most patients eventually show signs of frontal dysfunction if they are tested carefully enough. Sensation should be preserved. Variations of ALS include progressive muscular atrophy in which exclusively lower motor neuron findings are present and primary lateral sclerosis in which exclusively upper motor neuron findings are present. These variants are associated with better long-term prognoses than ALS, although both still lead to disability.

Patients with suspected ALS should undergo EMG: fibrillations, positive sharp waves, and large motor units establish more widespread lower motor neuron involvement than may be evident from bedside examination. The use of EMG also helps to distinguish ALS from multifocal motor neuropathy with conduction block, the condition that most frequently mimics it (Chapter 11). MRI of the brain and spine should be performed to exclude structural processes that may lead to weakness and wasting.

Unfortunately, ALS is a relentlessly progressive condition that leaves patients paralyzed, unable to speak, eat, or breathe, and confined to bed requiring 24-hour care. Patients ultimately die of respiratory failure unless they choose long-term mechanical ventilation. The one medication that is approved for the treatment of ALS, the glutamate antagonist riluzole (50 mg bid), is only marginally effective at prolonging lifespan, and has an unclear benefit on delaying functional decline.13 Care, therefore, is largely supportive and involves a multidisciplinary team of physical and occupational therapists, speech and swallowing specialists, social workers, and nutritionists.

References

1. Aids to the Examination of the Peripheral Nervous System. Edinburgh: WB Saunders; 2000.

2. Brewster LMMairuhu GSturk Avan Montfrans GA. Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J 2007;154:655–661.

3. Prelle ATancredi LSciacco M, et al. Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels. J Neurol 2002;249:305–311.

4. Nardin RARutkove SBRaynor EM. Diagnostic accuracy of electrodiagnostic testing in the evaluation of weakness. Muscle Nerve 2002;26:201–205.

5. Preston DCShapiro BEElectromyography and Neuromuscular Disorders: Clinical–Electrophysiologic Correlations. Boston: Butterworth-Heineman; 1998.

6. Callen JP. Dermatomyositis. Lancet 2000;355:53–57.

7. Wada YItoh YFurukawa TTsukagoshi HArahata K. Quadriceps myopathy: a clinical variant form of Becker muscular dystrophy. J Neurol 1990;237: 310–312.

8. Hoffman EPArahata KMinetti CBonilla ERowland LP. Dystrophinopathy in isolated cases of myopathy in females. Neurology 1992;42:967–975.

9. Thompson PDClarkson PKaras RH. Statin-associated myopathy. JAMA 2003;289:1681–1690.

10. Evans MRees A. Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same? Drug Saf 2002;25:649–663.

11. Winkel LPFVan den Hout JMPKamphoven JHJ, et al. Enzyme replacement therapy in late-onset Pompe’s disease: a three-year follow-up. Ann Neurol 2004;55:495–502.

12. Gronseth GSBarohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review). Neurology 2000;55:7–15.

13. Bensimon GLacomblez LMeininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994;330:585–591.