NEUROMUSCULAR DISORDERS:

Disorders of Peripheral Nerve, Neuromuscular Junction, and Muscle

Abridged from the Neurology Clerkship handout by Stephen E. Nadeau and Edward Valenstein

SUMMARY
Neuropathy can be divided into five categories based upon clinical localization. (1) Mononeuropathies are usually traumatic or due to entrapments, such as the carpal tunnel syndrome. You should be familiar with median, ulnar, radial, peroneal and lateral femoral cutaneous nerve syndromes. Multiple mononeuropathy (mononeuritis multiplex) should first suggest systemic vasculitis, requiring urgent evaluation for diagnosis and treatment to avoid serious disability or death. (2) Polyneuropathy affects the longest nerves first, with symptoms therefore beginning in the feet. Signs are atrophy of intrinsic foot muscles, reduced or absent ankle jerk, and distal ( Astocking @) sensory loss. Etiologies are usually metabolic or toxic. (3) Radiculopathy, with pain radiating from the neck or low back to one extremity, usually has subtle if any findings on neurological exam. Herniated disk, spondylosis and Herpes zoster are the common causes. (4) Polyradiculoneuropathies are usually bilateral, but differ from polyneuropathies in that symptoms and signs are as likely to be proximal as distal. The differential diagnosis includes Guillain-Barr syndrome when acute or subacute, and when chronic, CIDP (chronic inflammatory demyelinating polyradiculoneuropathy) and a variety of neuropathies associated with paraproteinemias. (5) Finally, plexopathies affect usually one limb, are painful, and are associated with considerable neurological deficit. Trauma, neoplasm, and radiation are in the differential diagnosis, but when pain and weakness occur subacutely (days to weeks) without trauma or tumor, the diagnosis is most commonly idiopathic when the brachial plexus is involved, and diabetic amyotrophy when the lumbosacral plexus is involved. Disorders of Neuromuscular Transmission: Myasthenia gravis, an autoimmune disorder with antibodies directed against the acetyl choline receptor, typically presents with ocular (ptosis, diplopia) and bulbar (dysarthria, dysphagia, neck weakness) symptoms and signs and proximal weakness, with preserved tendon reflexes and no sensory disturbances. The Tensilon test and antibodies to acetyl choline receptor are helpful diagnostically. Treatment with anticholinesterases, thymectomy, and immunosuppressants of various kinds is usually effective. The Lambert-Eaton myasthenic syndrome results from antibodies to calcium channels in the nerve endings, reducing the release of acetyl choline. Proximal weakness, autonomic disturbances, and decreased reflexes are common, and electrophysiological studies are often diagnostic. In many patients there is an associated neoplasm (most often small cell cancer of the lung). Disorders of Muscle usually present with symmetrical proximal weakness without sensory loss. Tendon reflexes may be normal or reduced. There are many inherited disorders of muscle that for the most part are the purview of specialists. You should be aware of the muscular dystrophies, particularly myotonic dystrophy, which is a multisystem disease that often presents with symptoms other than weakness. Acquired myopathies are often treatable. All patients should get thyroid functions studies. Cushing =s syndrome and other endocrinopathies should be considered. Inflammatory myopathies include two autoimmune disorders, polymyositis and dermatomyositis, that usually respond to appropriate treatment. Adults with dermatomyositis have a high incidence of cancer. Finally, medication-induced myopathy and myopathy associated with HIV infection should be considered.

You should be familiar with the principles that help to distinguish central nervous system (CNS) disorders from neurological disoders outside the CNS. Muscle atrophy, fasciculations, diminished tendon reflexes, and peripheral patterns of sensory loss suggest peripheral disorders, whereas little or no atrophy, increased tone, slowness of initiating movement, posturing, brisk reflexes, Babinski responses, and central patterns of sensory loss (hemisensory loss, or a level on the trunk) indicate CNS lesions.

Remember that CNS lesions in the brainstem and spinal cord can damage lower motor neurons, incoming sensory nerves or roots, and the reflex arc (segmental signs). Only associated long tract findings will distinguish these segmental signs of CNS lesions from lesions affecting the nerve roots.

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NEUROMUSCULAR DISORDERS

NEUROPATHY

Here we include disorders of the roots, plexus and peripheral nerves. The same principles of diagnosis apply as in disorders of the central nervous system; namely, that localization of the lesion(s) precedes consideration of a differential diagnosis. In most cases, your clinical examination will enable localization to one of five broad categories: (1) Mononeuropathy or multiple mononeuropathy: the deficits are in the distribution of one or more individual peripheral nerves, for example, the right median nerve. (2) Polyneuropathy: the deficits affect nerves in proportion to their length, with the longest nerves Table I Localization Mononeuropathy Multiple mononeuropathy (mononeuritis multiplex, multifocal neuropathy) Polyneuropathy Radiculopathy Polyradiculoneuropathy Plexopathy Pattern Single named nerve

affected first. Therefore, symptoms and signs appear first in the feet, and are in a stocking and (then) glove distribution. (3) Nerve root: the deficits localize to one or more nerve roots, for example, a C6 radiculopathy. (4) Plexus: localization is to the brachial or lumbosacral plexus on one or both sides. (5) Polyradiculoneuropathy: deficits are widespread, but do not conform to the distribution of a polyneuropathy, in that proximal limb weakness and/or sensory loss can be present. Each localization has a distinct differential diagnosis (Table I).

Most likely diagnoses Entrapment, trauma Vasculitis, multiple entrapments

Several named nerves

Longest nerves first (distal, stocking-glove pattern) One or more nerve roots Proximal and distal weakness, sometimes asymmetrical Brachial Lumbosacral

Metabolic/toxic, hereditary Herniated disc, spondylosis, herpes zoster Guillain-Barr syndrome, CIDP, paraproteinemias Trauma, idiopathic, neoplasm, radiation Diabetes, neoplasm, idiopathic, radiation

Mononeuropathy Carpal tunnel entrapment Typically symptoms are brought on by prolonged wrist flexion or extension, most often during sleep or while driving a car. Numbness is in the median distribution (see figure 1), but often patients report that the entire hand is numb. Pain can involve the palm, wrist, forearm, and sometimes even the arm or shoulder. At first symptoms abate with a change in wrist position, but with increasing nerve damage they become constant. The neurological examination is normal until late, when median sensory loss, weakness of thumb opposition, and thenar atrophy can be present. Tinel =s sign, paresthesias in the hand with tapping over the median nerve at the wrist, is of little help since it can be present in normals. Prolonged wrist flexion may reproduce symptoms (Phalen=s sign). The carpal tunnel may be small congenitally, or it may be narrowed by rheumatoid arthritis, myxedema, acromegaly, and during pregnancy (from fluid accumulation). If there is no underlying cause to be treated, patients with early carpal tunnel entrapment are advised to avoid wrist flexion. Splints are useful. Surgical decompression is usually successful in patients who do not respond to splinting.

Mononeuropathy most commonly results from entrapment of nerves at specific sites. Susceptibility to entrapment depends upon several factors: (1) Anatomical: for example, the carpal tunnel may be small because of normal anatomic variation, or it may be compromised by arthritis or the accumulation of fluid. (2) Occupational: recurrent wrist movements or maintenance of wrist flexion will predispose to carpal tunnel entrapment; leaning on the elbows or maximum flexion of the elbows to ulnar palsy. (3) Other conditions affecting nerves: sick nerves will be more easily damaged at sites of entrapment; for example, entrapment neuropathies are more common among patients with diabetic polyneuropathy. (4) Sedation: a sedated person, either intoxicated, using sleeping pills, or under anesthesia, will not be aroused by the tingling discomfort that signals nerve ischemia from compression, and will therefore allow the compression to progress to damage first myelin, and then axons.

Figure 1: Median sensory distribution

Ulnar neuropathy: cubital tunnel syndrome and tardy ulnar palsy Ulnar neuropathy is commonly caused either by compression of the nerve just distal to the elbow as it passes throught the cubital tunnel (the Acubital tunnel syndrome@), or by repeated compression or stretching of the nerve as it passes across the elbow in the ulnar groove ( Atardy ulnar palsy @). The ulnar nerve is particularly vulnerable to compression during anesthesia, in which case the nerve can be inadvertently compressed against the rail of the operating table. Clinical manifestations including wasting and weakness of ulnar-innervated intrinsic hand musculature, and numbness and paresthesias confined to the ulnar (medial) aspect of the hand, the fifth finger, and the medial aspect of the fourth finger (figure 2

Figure 3: Peroneal sensory distribution

Peroneal neuropathy Peroneal neuropathy typically develops with repeated compression of the nerve at the point where it passes in a relatively superficial location immediately behind the head of the fibula. This may occur with repeated or prolonged leg crossing, at times during a period of unaccustomed and enforced immobility because of other illness. Examination demonstrates weakness of dorsiflexion and eversion, and sensory loss in the lateral aspect of the leg and the dorsum of the foot (see figure 3). Reflexes are normal, since the knee jerk is mediated by the femoral nerve, and the ankle jerk by the posterior tibial nerve. Treatment consists of avoiding or eliminating recurrent compression, and the prognosis is good. Radial neuropathy Radial neuropathy, so-called Saturday-night palsy, is caused by prolonged compression of the radial nerve in the spiral groove of the humerus as the arm hangs over the back of a chair or beneath someone's head. Often the patient is inebriated. There is wrist drop and weakness in finger extensors; the brachioradialis is weak, but the triceps is usually strong. Sensory loss is often absent; when present, it affects the lateral aspect of the dorsum of the hand (Figure 4). The prognosis for eventual recovery of function is good.

Figure 2: Ulnar sensory distribution

Figure 4: Radial sensory distribution

Meralgia paresthetica Numbness and/or burning paresthesias of the anterolateral aspect of the thigh often raises concern about disease affecting the lumbar roots, plexus, or femoral nerve; however, the commonest cause of such sensory changes is lateral femoral cutaneous nerve entrapment. This is called meralgia paresthetica, and is easily differentiated from more serious causes of thigh numbness by the absence of associated weakness or reflex change, and in particular by an intact knee jerk. The typical distribution of sensory loss is indicated in figure 5. It is fundamentally benign, but tends to be very persistent and may be very uncomfortable. Multiple mononeuropathy (mononeuritis multiplex) The development of sequential multiple mononeuropathies should always suggest a systemic necrotizing vasculitis, such as polyarteritis nodosa. The involvement of each nerve, in effect neural infarction, is Figure 5: Lateral typically marked by severe femoral cutaneous sharp pain and the nerve distribution development of focal numbness and weakness. The acute onset and the involvement of nerves at sites where entrapment or compression are unusual distinguishes vasculitic multiple mononeuropathies from multiple entrapment or compressive neuropathies. Polyarteritis nodosa and Wegener's granulomatosis are malignant systemic diseases with high case fatality: early recognition and vigorous treatment with immunosuppresive drugs, particularly corticosteroids and cyclophosphamide, may prevent serious complications or death. Polyneuropathy

Many metabolic and toxic disorders result in polyneuropathy. These disorders may interfere with nerve metabolism. They affect the longest neurons first, since long neurons have greater metabolic demands than short ones. Symptoms therefore begin in the feet, progress up the legs, and then affect the hands. Tingling or burning are common complaints. The earliest physical findings are loss of vibratory sensation in the toes, atrophy of intrinsic foot mus cles, and reduced or absent ankle jerks. AStocking@ and Aglove@ sensory loss may be demonstrable with touch or pin: the deficits taper off proximally without any sharp demarcation, and the sensory loss does not conform to the distribution of any one peripheral nerve or root (Figures 6-8). We will merely list a number of important causes of polyneuropathy; you will learn more about individual disorders next year. $ $ Endocrine & Metabolic disorders -Diabetic polyneuropathy -Uremic polyneuropathy Toxic and drug-related neuropathies -Alcohol -Heavy metals -organophosphates -nitrous oxide -Drug-induced polyneuropathies (cancer therapies, AZT, DDI, phenytoin, colchicine, and others) Nutritional neuropathies -thiamine -B12 -pyridoxine toxicity Autoimmune, inflammatory and paraneoplastic neuropathies: -collagen vascular diseases -paraproteinemias

Figure 6: Mild polyneuropathy

Figure 7: Moderate Polyneuropathy

Figure 8: Severe polyneuropathy

Inherited (Charcot-Marie-Tooth, etc.)

Radiculopathy Radiculopathy is suggested by pain that radiates from the neck to the arm, or from the low back to the leg. Often pain is precipitated by movement of the spine, and sometimes by maneuvers that affect intraspinal pressure, such as coughing or straining. Focal neurological deficits, when present, are in a radicular distribution. Although pain is often widespread in the back and limb, sensory loss is usually confined to a small portion of the sensory dermatome, because there is some overlap from adjacent dermatomes. The most common etiology is probably root compression from herniated disc or spondylosis. Neoplasms such as schwannomas, meningiomas, or metastatic tumors can also present with radicular pain. Painful radiculopathy or polyradiculopathy is the most common neurological manifestation of Lyme disease. Diabetics can have radiculopathy affecting several adjacent thoracic dermatomes, resulting in an area of burning dysesthesia, sometimes with numbness, over the chest or abdomen on one side. Herpes zoster (shingles) is a common cause of radiculopathy in elderly or immunosuppressed patients. In most cases it is readily recognized on the basis of burning pain and hyperpathia in conjunction with the characteristic vescicular rash occurring in the distribution of one or more nerve roots, most commonly in the thorax, less often in the face (usually in the V1 distribution) or the extremities. Polyradiculoneuropathy Weakness in polyradiculoneuropathy is just as likely to be proximal as distal, distinguishing it from polyneuropathy, in which weakness and sensory loss are predominately distal. Although polyradiculoneuropathy may appear multifocal at onset, it is unusual for the focal deficits to conform to single nerves, thus helping to distinguish it from mononeuritis multiplex (see above). The Guillain-Barr syndrome (GBS) is the most common example of a polyradiculoneuropathy. It is classically characterized by the rapid development of generalized weakness, often sufficiently severe to compromise respiration, in association with loss of deep tendon reflexes and modest sensory symptoms, usually in the distal extremities. In over half of cases, a preceding infection may be identified. Campylobacter and cytomegalovirus have been most commonly implicated, but Ebstein Barr virus, unspecified viral infections, and other stressors such as trauma or surgery have the potential for precipitating the disorder. Many patients with GBS have other prominent clinical features, including facial diplegia and autonomic instability (labile hypertension, tach- and bradyarrhythmias, urinary retention). Some patients have prominent sensory loss. The so-called Miller-Fisher variant is characterized

by disproportionate involvement of cranial nerves and the presence of cerebellar signs. The GuillainBarr syndrome is autoimmune, with serum antibodies to nerve components being demonstrable in some cases. The presentation of GBS may be extremely protean, and respiratory insufficiency may develop unexpectedly. Therefore, early neurological consultation is prudent. Nerve conduction studies may be very helpful in making the diagnosis during early stages of the disease. At some point in the course, a rise of CSF protein without a CSF pleocytosis is characteristic. Unfortunately, GBS today represents one of the more common neuropathies affecting patients with AIDS (usually in early, minimally symptomatic phases of the disease), and in AIDS patients with GBS, there is commonly a CSF pleocytosis. Patients with classical GBS reach their nadir in one to four weeks. However, there exists a chronic form of this disease, known as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), that may run a progressive or relapsing course over months or years. Polyradiculoneuropathy may also be associated with multiple myeloma and Waldenstrom =s macroglobulinemia. The neuropathy may antedate the diagnosis of the underlying paraproteinemia by months or even years. It is therefore important to test patients with chronic polyradiculoneuropathy for evidence of a paraproteinemia. Plexopathy Differentiating plexopathy from radiculopathy can be difficult, since both usually present with pain and weakness confined to one limb. In general, weakness is usually more profound and widespread in plexopathy. Brachial plexus: The common causes are: $ trauma $ neoplasm (metastatic, usually lung, breast) $ radiation $ idiopathic Idiopathic brachial plexus neuropathy begins with pain in the neck and shoulder, followed usually within days by weakness that can be very focal or can involve most of the arm. The disease is self-limited, but recovery takes many months. The pathogenesis is unknown; it is presumed to be autoimmune. Lumbosacral plexus: The lumbosacral plexus is less susceptible to trauma than the brachial plexus. It may also be affected by metastatic neoplasm in the retroperitoneal space and by radiation. Spontaneous lumbosacral plexopathy

resembles idiopathic brachial plexus neuropathy, with unilateral pain and weakness evolving over days to weeks. However, whereas brahcial plexus Diagnostic approach. Mild polyneuropathy Mild polyneuropathies, so long as they don =t cause pain, are often asymptomatic, and are discovered incidentally on examination. The major concern in the diagnostic evaluation of mild polyneuropathy is the identification of an underlying disease that may warrant treatment, such as diabetes mellitus, collagen vascular disease, an underlying malignancy, or B12 deficiency, The diagnostic evaluation can be confined to blood studies, and should include a CBC, sedimentation rate, two-hour post-prandial glucose, thyroid function studies, B 12 and folate levels, and a serum protein electrophoresis. You should also be sure the patient is not taking a potentially neurotoxic medication. Severe neuropathy By severe, we mean a neuropathy that threatens disability from weakness, sensory loss or autonomic dysfunction. In general, a neurological consultation is warranted. Because the causes of neuropathy are myriad, one attempts to reduce the differential diagnosis by defining the characteristics of the neuropathy in the individual case. Important considerations include localization (as discussed above), whether or not the neuropathy is predominately demyelinating (see Table II), as defined by clinical and especially electrophysiologic criteria, and whether or not it is inherited.

neuropathy is idiopathic, most cases lumbosacral plexopathy are related to diabetes.

of

DISORDERS OF THE NEUROMUSCULAR JUNCTION

Disorders of neuromuscular transmission include myasthenia gravis, the Lambert Eaton myasthenic syndrome, disorders caused by several drugs, and botulism. Although they are uncommon disorders, they are important because they can be lifethreatening, and because in many instances effective therapy is available. Myasthenia gravis This is an autoimmune disease in which antibodies are directed against the acetylcholine receptor on the muscle end-plate of the neuromuscular junction. These antibodies block or degrade the receptor, resulting in failure of neuromuscular transmission and weakness. For reasons not known, the muscles most often involved are the extraocular muscles, levator palpebrae, bulbar and respiratory muscles, and proximal limb muscles. The most frequent presenting symptoms are ptosis, diplopia, dysphagia, dysarthria, dyspnea and symptoms of proximal weakness (difficuty climbing stairs, rising from a chair, reaching above the head). Fatigue is common in any disorder causing weakness, so it is not a distinguishing feature of myasthenia; however, myasthenics generally experience greater fluctuations in strength than other patients with weakness. When weakness is present, the diagnosis can be made by injecting intravenously the short acting anticholinesterase drug, edrophonium (Tensilon J), which decreases the rate at which acetyl choline is degraded at the neuromuscular junction. Myasthenic patients can demonstrate dramatic improvement in strength lasting a minute or two. The diagnosis should be confirmed by electrodiagnostic testing and a serum assay for acetylcholine receptor antibody. The latter test may be the only means of documenting the illness in patients whose symptoms suggest myasthenia but who are not weak on presentation; however, 10-15% have antibodies that are not detected by the currently available laboratory assay. Myasthenia is highly associated with other autoimmune disorders, particularly of the thyroid, and with thymoma, which is occasionally malignant. Treatment entails thymectomy (except in elderly myasthenics), longer acting anticholinesterase medications, such as pyridostigmine (Mestinon J), and immunosuppressant medication, including glucocorticosteroids, azathioprine (Imuran J) and sometimes cyclosporine A. Plasmapheresis or intravenous immunoglobulin treatment can provide temporary relief lasting up to several weeks or months.

MOTOR NEURON DISORDERS

There are a group of disorders that quite selectively affect motor neurons, and present with weakness unassociated with sensory loss or autonomic dysfunction. They are classified according to whether they affect the upper motor neuron, lower motor neuron or both. Disorders confined to upper or lower motor neuron are rare and difficult to diagnose, and will not be considered here. The most common motor neuron disorder is amyotrophic lateral sclerosis (ALS) which affects both upper and lower motor neuron. Patients present with weakness that progresses inexorably over 1 to 5 years. Death occurs from respiratory weakness. Although life could be preserved with artificial respiration, most patients are rendered so helpless by weakness that they prefer not to have their lives prolonged. The characteristic clinical appearance of ALS is the combination of lower motor neuron signs (weakness, atrophy and fasciculations) with upper motor neuron findings (weakness, brisk reflexes, and Babinski responses), in the absence of sensory symptoms. Bladder function and extraocular movements are invariably preserved. There is no effective treatment. Because of the dire prognosis, diagnosis must be confirmed by a physician with experience in this area.

TABLE II Some demyelinating neuropathies Guillain-Barr syndrome (some forms) CIDP Multifocal motor neuropathy Neuropathy associated with paraproteinemias (some) Diabetic polyneuropathy (in part demyelinating) Some inherited neuropathies (Charcot-Marie-Tooth type I, Djerine-Sottas)

Other disorders of the neuromuscular junction The Lambert-Eaton myasthenic syndrome (LEMS) is another autoimmune disease, but in this disorder the antibodies block calcium channels on motor nerve terminals, impairing release of acetylcholine. In more than half the cases, a malignant neoplasm is found, most often a small cell carcinoma of the lung. Aminoglycoside antibiotics, quinidine, procainamide, and a few other drugs have neuromuscular blocking effects that cause weakness when administered to a patient with myasthenia or when combined with some anesthetic agents.

Botulinum toxin is a potent neuromuscular blocking agent that binds irreversibly and causes weakness lasting months. Natural exposure stems from eating food contaminated with the toxin, or harboring the organism in a wound or in the GI tract (the source of neonatal botulism). Botulinum toxin is now used therapeutically to treat disorders in which muscle contraction at a specific site is causing the patient=s problem. Intramuscular injections relieve hemifacial spasm, blepharospasm, torticollis, spasmodic dysphonia, and certain other focal dystonias. Injections into the lower esophageal sphincter provide relief from achalasia. Although such treatment is far from ideal, it is currently the most effective therapy for these disorders.

manifestations, so it is important that nonneurologists recognize the disorder. Treatment is entirely symptomatic. Acquired disorders of muscle These present with symmetrical proximal weakness. You should think of three categories: inflammatory myopathies, iatrogenic (drug-induced) myopathies, and endocrine myopathies. Inflammatory myopathies Two autoimmune disorders affect muscle, and are treatable with steroids, IVIG, or other immunomodulatory therapies. Polymyositis results from a Tcell mediated attack on muscle fibers. Symmetrical proximal weakness, a high serum CK, an abnormal EMG and a muscle biopsy that demonstrates intrafascicular inflammation associated with necrosis of muscle fibers, form the basis of the diagnosis. Polymyositis may be the sole disease, or it may accompany one of the collagen vascular diseases. Dermatomyositis results from an immune-mediated attack on muscle microvasculature, with resulting ischemic atrophy of muscle fibers. Symmetrical proximal weakness, high serum CK levels, and an abnormal EMG are seen, as in polymyositis. In addition, however, there is a characteristic rash, involving the skin around the eyes ( Aheliotrope@ rash) and on the dorsal surface of the digits. Subcutaneous calcification is usually a late complication. The disease is more common in childhood. When it appears in adults, an undiagnosed malignancy should be sought. Although the muscle biopsy findings in dermatomyositis are diagnostic, a biopsy is not necessary in the patient with the characteristic rash, weakness and EMG findings. Sarcoidosis should be mentioned as a treatable cause of inflammatory myopathy, although more often than not the muscle involvement is clinically silent. Viral myositis, and bacterial infection of muscle occur, and trichinosis is an important parasitic disease of muscle. Inclusion body myositis has only recently been distinguished from polymyositis: weakness is often distal as well as proximal, the course is chronic, the biopsy demonstrates inclusion bodies and amyloid deposits, and the disease usually does not respond to immunomodulatory treatment. Finally, patients with HIV may develop several kinds of myopathy, including an inflammatory myopathy similar to polymyositis. A myopathy may also underlie in part the profound wasting syndrome seen in these patients. Finally, prolonged treatment with AZT is associated with a mitochondrial myopathy. Drug-induced (iatrogenic) myopathies These are uncommon but should be recognized because withdrawal of the drug is usually curative. Offending agents include corticosteroids (see below), AZT, lovostatin (Mevacor) and colchicine (which produces a neuropathy as well). Endocrine myopathies

DISORDERS OF MUSCLE
Disorders of muscle can be divided into inherited and acquired. The inherited disorders are legion. Most are not treatable, many are rare, and students need only be aware that they exist. In contrast, acquired disorders of muscle are relatively few, and most are treatable. The student should know when to suspect such illness, so that they can initiate appropriate diagnostic procedures and direct the patient to the appropriate specialist for treatment. Inherited diseases of muscle Inherited disorders of muscle include the muscular dystrophies, the congenital myopathies, the glycogen storage diseases and certain other inborn errors of metabolism, the mitochondrial myopathies, and the periodic paralyses. Many of these disorders manifest themselves in childhood or young adult life, and are of interest to pediatricians. The muscular dystrophies are a group of disparate inherited myopathies that until recently were linked only by similarities in pathology. Recently, it has been discovered that molecules that link the contractile apparatus to the muscle membrane are altered in several of the muscular dystrophies. You should be aware of the two commonest kinds of muscular dystrophy. Duchenne=s muscular dystrophy is inherited as an X-linked recessive disorder, and manifests in early childhood with calf hypertrophy, a waddling gait because of proximal weakness, and very high serum CK levels. It results from absence of a protein called dystrophin, part of the molecular apparatus mentioned above that links the contractile apparatus to muscle membrane. Myotonic muscular dystrophy is a dominantly inherited trinucleotide repeat disorder, that can manifest in many systems. Ptosis, temporalis and sternocleidomastoid weakness and atrophy, and distal upper extremity weakness are characteristic. Myotonia, a failure of relaxation of muscle due to continued discharge of muscle membrane after the initial muscle twitch, is manifested by prolonged muscle twitch to percussion, and by failure to relax after a forceful grip. Other manifestations include cataracts, frontal baldness, testicular atrophy, glucose intolerance, cardiac arrhythmias, central hypoventilation, excessive sleeping, and dementia. Patients may present with cardiac or central nervous system

Steroid myopathy can be seen in association with Cushing=s disease or with exogenous corticosteroid administration. In either case, patients are usually cushingoid. Serum cortisol levels should be obtained if other studies have failed to suggest a diagnosis in a patient with proximal muscle weakness. Both hypothyroidism and hyperthyroidism are associated with myopathy manifested by symmetric proximal weakness. Thyroid hormone affects the metabolism of serum CK: it is decreased (leading to elevation of CK) in hypothyroidism and increased (leading to low CK values) in hyperthyroidism irrespective of the presence of myopathy. Muscle weakness is detectable in many hyperthyroid patients, and may be the most prominent clinical feature. The EMG may be Amyopathic @ or normal. Thyroid function studies should be obtained in every patient with proximal weakness. Treatment of the endocrine disorder usually results in improvement in strength. Rarely, weakness in a patient with thyroid disorder will represent associated myasthenia gravis and not myopathy. Treatment of the thyroid disorder will not affect the course of myasthenia. Myopathy can also been seen in acromegaly, and possibly in parathyroid disorders. Myopathy is not a feature of diabetes. Diagnostic evaluation Progressive proximal weakness in a patient with normal sensation and normal or reduced reflexes should suggest myopathy. A careful history of prior athletic or other physical abilities and the ability to examine first degree relatives can sometimes distinguish a chronic familial muscular disorder from a potentially treatable acquired myopathy. The patient=s medications should be examined for drugs that may cause myopathy. CK elevations to more than 10 times the upper limits of normal are indicative of myopathy. Lesser degrees of elevation may indicate myopathy, but can also be seen with neurogenic atrophy, or as a normal variant. Normal CK levels do not exclude myopathy. CBC, ESR, and thyroid function studies should be obtained in every case. EMG studies may be helpful in distinguishing neurogenic causes of proximal weakness, such as spinal muscular atrophy. EMG in inflammatory myopathies is usually abnormal, and while not absolutely characteristic, may suggest this type of disorder. Proximal weakness with a typical rash is sufficient to diagnose dermatomyositis. Confirmation with EMG and serum CK is usually helpful, but muscle biopsy is not necessary. When endocrine studies are negative and a diagnosis is still in doubt, a muscle biopsy should be obtained. This should be obtained from a muscle that is moderately weak. Minimally weak muscles may not have diagnostic pathology, and very weak muscles may yield insufficient muscle tissue for diagnosis. Finally, patients with dermatomyositis should undergo a thorough evaluation for an occult malignancy.

conduction studies, studies of neuromuscular transmission, and electromyography (EMG) are very important adjuncts for the diagnosis of neuromuscular problems. Their value depends upon the questions asked, and the knowledge and skill of the person performing the test. Some questions that these studies can help answer include: $ Is there peripheral nerve involvement? If the clinical evaluation has already answered this question, there is no need to perform electrophysiologic studies; however, studies may help if symptoms and signs are minimal or ambiguous. For example, a patient presenting with rapidly progressive quadriparesis, areflexia, and urinary incontinence could have a disorder of the spinal cord (transverse myelopathy, compressive myelopathy) with areflexia from spinal shock or acute inflammatory demyelinating polyradiculoneuropathy (AIDP, better known as the GuillainBarr syndrome). Nerve conduction studies are normal in myelopathy, but abnormal in the Guillain-Barr syndrome. $ Is a neuropathy demyelinating? The differential diagnosis of demyelinating neuropathy is much smaller than neuropathy in general, so this information is diagnostically (and therapeutically) important. Nerve conduction studies can identify some patients with primary demyelinating neuropathies. $ Is there nerve entrapment? Nerve conduction studies are a useful adjunct in the diagnosis of carpal tunnel entrapment, and certain other entrapment neuropathies. Studies are helpful when the history and physical are not diagnostic, and several alternatives exist (e.g., between nerve entrapment and nerve root disorders), or before surgical correction. Nerve conduction studies also help assess the severity of nerve damage. $ Is weakness due to a disorder of nerve, neuromuscular junction, or muscle? Repetitive stimulation studies and EMG can often help in this determination. For example, in an ICU patient who cannot be weaned off the respirator, the differential diagnosis includes amyotrophic lateral sclerosis (denervation without nerve conduction slowing), Guillain-Barr (denervation with nerve conduction slowing), neuromuscular blockade from drugs or myasthenia (abnormal repetitive stimulation), critical illness neuropathy (abnormal nerve conductions without demyelination), or myopathy (abnormal EMG). It is not necessary for non-specialists to understand much about electrophysiologic testing, but a little background my be helpful. Motor nerve conduction studies: The nerve is stimulated with surface electrodes at 2 or more sites, and a response for each stimulation is recorded by surface electrodes over a muscle. The time from stimulation to response (latency) is determined. Conduction velocity is calculated by dividing the difference between two latencies obtained by stimulation at two sites along the nerve by the distance between these two sites of stimulation. Sensory nerve conduction studies: The skin is stimulated and a response recorded from surface

Electrophysiologic testing
Clinical electrophysiology, including nerve

electrodes placed over the nerve, or vice versa. Neuromuscular junction testing: The set-up is the same as motor nerve conductions, but the stimulus is repeated at different rates. Decremental responses (loss of amplitude over the first 5 stimuli) at 3Hz stimulation is seen in myasthenia; Incremental responses (increase in amplitude over many responses) is seen in Lambert-Eaton and botulism. EMG: A needle is inserted in the muscle. The pattern of response helps distinguish denervation from other causes of muscle dysfunction.