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InternalMed_Harrison. associated conditions (see “Monoclonal Gammopathy of Undetermined Significance,” below). In all patients with presumptive CIDP, it is also reasonable to exclude vasculitis, collagen vascular disease (especially SLE), chronic hepatitis, HIV infection, amyloidosis, and diabetes mellitus. Other associated conditions include inflammatory bowel disease and lymphoma.


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InternalMed_Harrison. Pathogenesis Although there is evidence of immune activation in CIDP, the precise mechanisms of pathogenesis are unknown. Biopsy typically reveals little inflammation and onion-bulb changes (imbricated layers of attenuated Schwann cell processes surrounding an axon) that result from recurrent demyelination and remyelination (Fig. 460-1). The response to therapy suggests that CIDP is immune-mediated; CIDP responds to glucocorticoids, whereas GBS does not. Passive transfer of demyelination into experimental animals has been accomplished using IgG purified from the serum of some patients with CIDP, lending support for a humoral autoimmune pathogenesis. A minority of patients have serum antibodies against P0, myelin P2 protein, PMP22, or neurofascin. It is also of interest that a CIDP-like illness developed spontaneously in the nonobese diabetic (NOD) mouse when the immune co-stimulatory molecule B7-2 (CD86) was genetically deleted; this suggests that CIDP can result from altered


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InternalMed_Harrison. illness developed spontaneously in the nonobese diabetic (NOD) mouse when the immune co-stimulatory molecule B7-2 (CD86) was genetically deleted; this suggests that CIDP can result from altered triggering of T cells by antigen-presenting cells.


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InternalMed_Harrison. Approximately 25% of patients with clinical features of CIDP also have a monoclonal gammopathy of undetermined significance (MGUS). Cases associated with monoclonal IgA or IgG kappa usually respond to treatment as favorably as cases without a monoclonal gammopathy. Patients with IgM monoclonal gammopathy and antibodies directed against myelin-associated glycoprotein (MAG) have a distinct polyneuropathy, tend to have more sensory findings and a more protracted course, and usually have a less satisfactory response to treatment.


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InternalMed_Harrison. Most authorities initiate treatment for CIDP when progression is rapid or walking is compromised. If the disorder is mild, management can be expectant, awaiting spontaneous remission. Controlled studies have shown that high-dose IVIg, PE, and glucocorticoids are all more effective than placebo. Initial therapy is usually with IVIg, administered as 2.0 g/kg body weight given in divided doses over 2–5 days; three monthly courses are generally recommended before concluding a patient is a treatment failure. If the patient responds, the infusion intervals can be gradually increased or the dosage decreased (e.g., 1 g/kg per month). PE, which appears to be as effective as IVIg, is initiated at two to three treatments per week for 6 weeks; periodic re-treatment may also be required. Treatment with glucocorticoids is another option (60–80 mg prednisone PO daily for 1–2 months, followed by a gradual dose reduction of 10 mg per month as tolerated), but long-term adverse effects including bone


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InternalMed_Harrison. glucocorticoids is another option (60–80 mg prednisone PO daily for 1–2 months, followed by a gradual dose reduction of 10 mg per month as tolerated), but long-term adverse effects including bone demineralization, gastrointestinal bleeding, and cushingoid changes are problematic. As many as one-third of patients with CIDP fail to respond adequately to the initial therapy chosen; a different treatment should then be tried. Patients who fail therapy with IVIg, PE, and glucocorticoids may benefit from treatment with immunosuppressive agents such as azathioprine, methotrexate, cyclosporine, and cyclophosphamide, either alone or as adjunctive therapy. Early experience with anti-CD20 (rituximab) has also shown promise. Use of these therapies requires periodic reassessment of their risks and benefits. In patients with a CIDP-like neuropathy who fail to respond to treatment, it is important to evaluate for POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy,


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InternalMed_Harrison. In patients with a CIDP-like neuropathy who fail to respond to treatment, it is important to evaluate for POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes; see below).


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InternalMed_Harrison. Multifocal motor neuropathy (MMN) is a distinctive but uncommon neuropathy that presents as slowly progressive motor weakness and atrophy evolving over years in the distribution of selected nerve trunks, associated with sites of persistent focal motor conduction block in the same nerve trunks. Sensory fibers are relatively spared. The arms are affected more frequently than the legs, and >75% of all patients are male. Some cases have been confused with lower motor neuron forms of amyotrophic lateral sclerosis (Chap. 452). Less than 50% of patients present with high titers of polyclonal IgM antibody to the ganglioside GM1. It is uncertain how this finding relates to the discrete foci of persistent motor conduction block, but high concentrations of GM1 gangliosides are normal constituents of nodes of Ranvier in peripheral nerve fibers. Pathology reveals demyelination and mild inflammatory changes at the sites of conduction block.


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InternalMed_Harrison. Most patients with MMN respond to high-dose IVIg (dosages as for CIDP, above); periodic re-treatment is required (usually at least monthly) to maintain the benefit. Some refractory patients have responded to rituximab or cyclophosphamide. Glucocorticoids and PE are not effective. Clinically overt polyneuropathy occurs in ~5% of patients with the commonly encountered type of multiple myeloma, which exhibits either lytic or diffuse osteoporotic bone lesions. These neuropathies are sensorimotor, are usually mild and slowly progressive but may be severe, and generally do not reverse with successful suppression of the myeloma. In most cases, Edx and pathologic features are consistent with a process of axonal degeneration.


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InternalMed_Harrison. In contrast, myeloma with osteosclerotic features, although representing only 3% of all myelomas, is associated with polyneuropathy in one-half of cases. These neuropathies, which may also occur with solitary plasmacytoma, are distinct because they (1) are usually 2700 demyelinating in nature and resemble CIDP; (2) often respond to radiation therapy or removal of the primary lesion; (3) are associated with different monoclonal proteins and light chains (almost always lambda as opposed to primarily kappa in the lytic type of multiple myeloma); (4) are typically refractory to standard treatments of CIDP; and (5) may occur in association with other systemic findings including thickening of the skin, hyperpigmentation, hypertrichosis, organomegaly, endocrinopathy, anasarca, and clubbing of fingers. These are features of the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes). Levels of vascular endothelial growth factor (VEGF) are


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InternalMed_Harrison. of fingers. These are features of the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes). Levels of vascular endothelial growth factor (VEGF) are increased in the serum, and this factor is felt to somehow play a pathogenic role in this syndrome. Treatment of the neuropathy is best directed at the osteosclerotic myeloma using surgery, radiotherapy, chemotherapy, or autologous peripheral blood stem cell transplantation. Neuropathies are also encountered in other systemic conditions with gammopathy, including Waldenström’s macroglobulinemia, primary systemic amyloidosis, and cryoglobulinemic states (mixed essential cryoglobulinemia, some cases of hepatitis C).


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InternalMed_Harrison. Chronic polyneuropathies occurring in association with MGUS are usually associated with the immunoglobulin isotypes IgG, IgA, and IgM. Most patients present with isolated sensory symptoms in their distal extremities and have Edx features of an axonal sensory or sensorimotor polyneuropathy. These patients otherwise resemble idiopathic sensory polyneuropathy, and the MGUS might just be coincidental. They usually do not respond to immunotherapies designed to reduce the concentration of the monoclonal protein. Some patients, however, present with generalized weakness and sensory loss and Edx studies indistinguishable from CIDP without monoclonal gammopathy (see “Chronic Inflammatory Demyelinating Polyneuropathy,” above), and their response to immunosuppressive agents is also similar. An exception is the syndrome of IgM kappa monoclonal gammopathy associated with an indolent, longstanding, sometimes static sensory neuropathy, frequently with tremor and sensory ataxia. Most patients are


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InternalMed_Harrison. is the syndrome of IgM kappa monoclonal gammopathy associated with an indolent, longstanding, sometimes static sensory neuropathy, frequently with tremor and sensory ataxia. Most patients are male and older than age 50 years. In the majority, the monoclonal IgM immunoglobulin binds to a normal peripheral nerve constituent, MAG, found in the paranodal regions of Schwann cells. Binding appears to be specific for a polysaccharide epitope that is also found in other normal peripheral nerve myelin glycoproteins, P0 and PMP22, and also in other normal nerve-related glycosphingolipids (Fig. 460-1). In the MAG-positive cases, IgM paraprotein is incorporated into the myelin sheaths of affected patients and widens the spacing of the myelin lamellae, thus producing a distinctive ultrastructural pattern. Demyelination and remyelination are the hallmarks of the lesions, but axonal loss develops over time. These anti-MAG polyneuropathies are typical refractory to immunotherapy. In a small


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InternalMed_Harrison. pattern. Demyelination and remyelination are the hallmarks of the lesions, but axonal loss develops over time. These anti-MAG polyneuropathies are typical refractory to immunotherapy. In a small proportion of patients (30% at 10 years), MGUS will in time evolve into frankly malignant conditions such as multiple myeloma or lymphoma.


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InternalMed_Harrison. Peripheral nerve involvement is common in polyarteritis nodosa (PAN), appearing in half of all cases clinically and in 100% of cases at postmortem studies (Chap. 385). The most common pattern is multifocal (asymmetric) motor-sensory neuropathy (mononeuropathy multiplex) due to ischemic lesions of nerve trunks and roots; however, some cases of vasculitic neuropathy present as a distal, symmetric sensorimotor polyneuropathy. Symptoms of neuropathy are a common presenting complaint in patients with PAN. The Edx findings are those of an axonal process. Smallto medium-sized arteries of the vasa nervorum, particularly the epineural vessels, are affected in PAN, resulting in a widespread ischemic neuropathy. A high frequency of neuropathy occurs in allergic angiitis and granulomatosis (Churg-Strauss syndrome [CSS]).


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InternalMed_Harrison. Systemic vasculitis should always be considered when a subacute or chronically evolving mononeuropathy multiplex occurs in conjunction with constitutional symptoms (fever, anorexia, weight loss, loss of energy, malaise, and nonspecific pains). Diagnosis of suspected vasculitic neuropathy is made by a combined nerve and muscle biopsy, with serial section or skip-serial techniques. Approximately one-third of biopsy-proven cases of vasculitic neuropathy are “nonsystemic” in that the vasculitis appears to affect only peripheral nerves. Constitutional symptoms are absent, and the course is more indolent than that of PAN. The erythrocyte sedimentation rate may be elevated, but other tests for systemic disease are negative. Nevertheless, clinically silent involvement of other organs is likely, and vasculitis is frequently found in muscle biopsied at the same time as nerve.


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InternalMed_Harrison. Vasculitic neuropathy may also be seen as part of the vasculitis syndrome occurring in the course of other connective tissue disorders (Chap. 385). The most frequent is rheumatoid arthritis, but ischemic neuropathy due to involvement of vasa nervorum may also occur in mixed cryoglobulinemia, Sjögren’s syndrome, granulomatosis with polyangiitis (Wegener’s), hypersensitivity angiitis, systemic lupus erythematosus, and progressive systemic sclerosis. Some vasculitides are associated with antineutrophil cytoplasmic antibodies (ANCAs), which in turn, are subclassified as cytoplasmic (cANCA) or perinuclear (pANCA). cANCAs are directed against proteinase 3 (PR3), whereas pANCAs target myeloperoxidase (MPO). PR3/cANCAs are associated with granulomatosis with polyangiitis (Wegener’s), whereas MPO/pANCAs are typically associated with microscopic polyangiitis, CSS, and less commonly PAN. Of note, MPO/pANCA has also been seen in minocycline-induced vasculitis.


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InternalMed_Harrison. Management of these neuropathies, including the “nonsystemic” vasculitic neuropathy, consists of treatment of the underlying condition as well as the aggressive use of glucocorticoids and cyclophosphamide. Use of these immunosuppressive agents has resulted in dramatic improvements in outcome, with 5-year survival rates now greater than 80%. Recent clinical trials found that the combination of rituximab and glucocorticoids is not inferior to cyclophosphamide and glucocorticoids. Thus, combination therapy with glucocorticoids and rituximab is increasingly recommended as the standard initial treatment, particularly for ANCA-associated vasculitis. ANTI-Hu PARANEOPLASTIC NEUROPATHY (CHAP. 122)


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InternalMed_Harrison. This uncommon immune-mediated disorder manifests as a sensory neuronopathy (i.e., selective damage to sensory nerve bodies in dorsal root ganglia). The onset is often asymmetric with dysesthesias and sensory loss in the limbs that soon progress to affect all limbs, the torso, and the face. Marked sensory ataxia, pseudoathetosis, and inability to walk, stand, or even sit unsupported are frequent features and are secondary to the extensive deafferentation. Subacute sensory neuronopathy may be idiopathic, but more than half of cases are paraneoplastic, primarily related to lung cancer, and most of those are small-cell lung cancer (SCLC). Diagnosis of the underlying SCLC requires awareness of the association, testing for the paraneoplastic antibody, and often positron emission tomography (PET) scanning for the tumor. The target antigens are a family of RNA-binding proteins (HuD, HuC, and Hel-N1) that in normal tissues are only expressed by neurons. The same proteins are usually expressed


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InternalMed_Harrison. scanning for the tumor. The target antigens are a family of RNA-binding proteins (HuD, HuC, and Hel-N1) that in normal tissues are only expressed by neurons. The same proteins are usually expressed by SCLC, triggering in some patients an immune response characterized by antibodies and cytotoxic T cells that cross-react with the Hu proteins of the dorsal root ganglion neurons, resulting in immune-mediated neuronal destruction. An encephalomyelitis may accompany the sensory neuronopathy and presumably has the same pathogenesis. Neurologic symptoms usually precede, by ≤6 months, the identification of SCLC. The sensory neuronopathy runs its course in a few weeks or months and stabilizes, leaving the patient disabled. Most cases are unresponsive to treatment with glucocorticoids, IVIg, PE, or immunosuppressant drugs.


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InternalMed_Harrison. myasthenia Gravis and other Diseases of the Neuromuscular junction Daniel B. Drachman, Anthony A. Amato Myasthenia gravis (MG) is a neuromuscular disorder characterized by 461 weakness and fatigability of skeletal muscles. The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at neuromuscular junctions due to an antibody-mediated autoimmune attack. Treatment now available for MG is highly effective, although a specific cure has remained elusive.


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InternalMed_Harrison. At the neuromuscular junction (Fig. 461-1, Video 461-1), acetylcholine (ACh) is synthesized in the motor nerve terminal and stored in vesicles (quanta). When an action potential travels down a motor nerve and reaches the nerve terminal, ACh from 150 to 200 vesicles is released and combines with AChRs that are densely packed at the peaks of postsynaptic folds. The AChR consists of five subunits (2α, 1β, 1δ, and 1γ or ε) arranged around a central pore. When ACh combines with the binding sites on the α subunits of the AChR, the channel in the AChR opens, permitting the rapid entry of cations, chiefly sodium, which produces depolarization at the end-plate region of the muscle fiber. If the depolarization is sufficiently large, it initiates an action potential that is propagated along the muscle fiber, triggering muscle contraction. This process is rapidly terminated by hydrolysis of ACh by acetylcholinesterase (AChE), which is present within the synaptic folds, and by diffusion of ACh


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InternalMed_Harrison. fiber, triggering muscle contraction. This process is rapidly terminated by hydrolysis of ACh by acetylcholinesterase (AChE), which is present within the synaptic folds, and by diffusion of ACh away from the receptor.


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InternalMed_Harrison. In MG, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane. In addition, the postsynaptic folds are flattened, or “simplified.” These changes result in decreased efficiency of neuromuscular transmission. Therefore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger muscle action potentials. Failure of transmission at many neuromuscular junctions results in weakness of muscle contraction. The amount of ACh released per impulse normally declines on repeated activity (termed presynaptic rundown). In the myasthenic patient, the decreased efficiency of neuromuscular transmission com-2701 bined with the normal rundown results in the activation of fewer and


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InternalMed_Harrison. Axon Release site Small electrical response AChR A Normal Vesicle Nerve terminal Strong electrical response Mitochondria AChE Nerve impulse MuscleMuscle B MG End plate potential End plate potential FIGURE 461-1 Diagrams of (A) normal and (B) myasthenic neuromuscular junctions. AChE, acetylcholinesterase. See text for description of normal neuromuscular transmission. The myasthenia gravis (MG) junction demonstrates a normal nerve terminal; a reduced num-ber of acetylcholine receptors (AChRs) (stippling); flattened, simplified postsynaptic folds; and a widened synaptic space. See Video 461-1 also. (Modified from DB Drachman: N Engl J Med 330:1797, 1994; with permission.) fewer muscle fibers by successive nerve impulses and hence increasing weakness, or myasthenic fatigue. This mechanism also accounts for the decremental response to repetitive nerve stimulation seen on electro-diagnostic testing.


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InternalMed_Harrison. The neuromuscular abnormalities in MG are caused by an autoimmune response mediated by specific anti-AChR antibodies. The anti-AChR antibodies reduce the number of available AChRs at neuromuscular junctions by three distinct mechanisms: (1) accelerated turnover of AChRs by a mechanism involving cross-linking and rapid endocytosis of the receptors; (2) damage to the postsynaptic muscle membrane by the antibody in collaboration with complement; and (3) blockade of the active site of the AChR, i.e., the site that normally binds ACh. An immune response to muscle-specific kinase (MuSK), a protein involved in AChR clustering at neuromuscular junctions, can also result in MG, with reduction of AChRs demonstrated experimentally. Anti-MuSK antibody occurs in about 40% of patients without AChR antibody. A small proportion of patients whose sera are negative for both AChR and MuSK antibodies have antibodies to another protein at the neuromuscular junction—low-density lipoprotein receptor-related


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InternalMed_Harrison. A small proportion of patients whose sera are negative for both AChR and MuSK antibodies have antibodies to another protein at the neuromuscular junction—low-density lipoprotein receptor-related protein 4 (lrp4)—that is important for clustering of AChRs. The pathogenic antibodies are IgG and are T cell dependent. Thus, immunotherapeutic strategies directed against either the antibody-producing B cells or helper T cells are effective in this antibody-mediated disease.


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InternalMed_Harrison. How the autoimmune response is initiated and maintained in MG is not completely understood, but the thymus appears to play a role in this process. The thymus is abnormal in ~75% of patients with AChR antibody–positive MG; in ~65% the thymus is “hyperplastic,” with the presence of active germinal centers detected histologically, although the hyperplastic thymus is not necessarily enlarged. An additional 10% of patients have thymic tumors (thymomas). Muscle-like cells within the thymus (myoid cells), which express AChRs on their surface, may serve as a source of autoantigen and trigger the autoimmune reaction within the thymus gland. MG is not rare, having a prevalence as high as 2–7 in 10,000. It affects individuals in all age groups, but peaks of incidence occur in women in their twenties and thirties and in men in their fifties and sixties. Overall, women are affected more frequently than men, in a ratio of ~3:2. The cardinal features are weakness and fatigability of muscles.


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InternalMed_Harrison. The weakness increases during repeated use (fatigue) or late in the day and may improve following rest or sleep. The course of MG is often variable. Exacerbations and remissions may occur, particularly during the first few years after the onset of the disease. Remissions are rarely complete or permanent. Unrelated infections or systemic disorders can lead to increased myasthenic weakness and may precipitate “crisis” (see below).


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InternalMed_Harrison. The distribution of muscle weakness often has a characteristic pattern. The cranial muscles, particularly the lids and extraocular muscles, are typically involved early in the course of MG; diplopia and ptosis are common initial complaints. Facial weakness produces a “snarling” expression when the patient attempts to smile. Weakness in chewing is most noticeable after prolonged effort, as in chewing meat. Speech may have a nasal timbre caused by weakness of the palate or a dysarthric “mushy” quality due to tongue weakness. Difficulty in swallowing may occur as a result of weakness of the palate, tongue, or pharynx, giving rise to nasal regurgitation or aspiration of liquids or food. Bulbar weakness is especially prominent in MuSK antibody–positive MG. In ~85% of Myasthenia Gravis and Other Diseases of the Neuromuscular Junction DiaGNosis of myastheNia Gravis (mG) Diplopia, ptosis, dysarthria, dysphagia, dyspnea


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InternalMed_Harrison. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction DiaGNosis of myastheNia Gravis (mG) Diplopia, ptosis, dysarthria, dysphagia, dyspnea Weakness in characteristic distribution: proximal limbs, neck extensors, generalized Fluctuation and fatigue: worse with repeated activity, improved by rest Effects of previous treatments Ptosis, diplopia Motor power survey: quantitative testing of muscle strength Absence of other neurologic signs Anti-AChR radioimmunoassay: ~85% positive in generalized MG; 50% in ocular MG; definite diagnosis if positive; negative result does not exclude MG; ~40% of AChR antibody–negative patients with generalized MG have anti-MuSK antibodies Repetitive nerve stimulation: decrement of >15% at 3 Hz: highly probable Single-fiber electromyography: blocking and jitter, with normal fiber density; confirmatory, but not specific For ocular or cranial MG: exclude intracranial lesions by CT or MRI


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InternalMed_Harrison. Single-fiber electromyography: blocking and jitter, with normal fiber density; confirmatory, but not specific For ocular or cranial MG: exclude intracranial lesions by CT or MRI Abbreviations: AChR, acetylcholine receptor; CT, computed tomography; MRI, magnetic resonance imaging; MuSK, muscle-specific tyrosine kinase. patients, the weakness becomes generalized, affecting the limb muscles as well. If weakness remains restricted to the extraocular muscles for 3 years, it is likely that it will not become generalized, and these patients are said to have ocular MG. The limb weakness in MG is often proximal and may be asymmetric. Despite the muscle weakness, deep tendon reflexes are preserved. If weakness of respiration becomes so severe as to require respiratory assistance, the patient is said to be in crisis.


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InternalMed_Harrison. (Table 461-1) The diagnosis is suspected on the basis of weakness and fatigability in the typical distribution described above, without loss of reflexes or impairment of sensation or other neurologic function. The suspected diagnosis should always be confirmed definitively before treatment is undertaken; this is essential because (1) other treatable conditions may closely resemble MG and (2) the treatment of MG may involve surgery and the prolonged use of drugs with potentially adverse side effects.


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InternalMed_Harrison. Antibodies to AChR, MuSK, or lpr4 As noted above, anti-AChR antibodies are detectable in the serum of ~85% of all myasthenic patients but in only about 50% of patients with weakness confined to the ocular muscles. The presence of anti-AChR antibodies is virtually diagnostic of MG, but a negative test does not exclude the disease. The measured level of anti-AChR antibody does not correspond well with the severity of MG in different patients. However, in an individual patient, a treatment-induced fall in the antibody level often correlates with clinical improvement, whereas a rise in the level may occur with exacerbations. Antibodies to MuSK have been found to be present in ~40% of AChR antibody–negative patients with generalized MG, and their presence is a useful diagnostic test in these patients. MuSK antibodies are rarely present in AChR antibody–positive patients or in patients with MG limited to ocular muscles. These antibodies may interfere with clustering of AChRs at


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InternalMed_Harrison. in these patients. MuSK antibodies are rarely present in AChR antibody–positive patients or in patients with MG limited to ocular muscles. These antibodies may interfere with clustering of AChRs at neuromuscular junctions, as MuSK is known to do during early development. A small proportion of MG patients without antibodies to AChR or MuSK may have antibodies to lrp4, although a test for lrp4 antibodies is not yet commercially available. Finally, antibodies against agrin have recently been found in some patients with MG. Agrin is a protein derived from motor nerves that normally binds to lrp4 and thus may also interfere with clustering of AChRs at neuromuscular junctions. There may well be other—as yet undefined—antibodies that impair neuromuscular transmission.


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InternalMed_Harrison. Electrodiagnostic Testing Repetitive nerve stimulation may provide helpful diagnostic evidence of MG. Anti-AChE medication is stopped 6–24 h before testing. It is best to test weak muscles or proximal muscle groups. Electric shocks are delivered at a rate of two or three per second to the appropriate nerves, and action potentials are recorded from the muscles. In normal individuals, the amplitude of the evoked muscle action potentials does not change at these rates of stimulation. However, in myasthenic patients, there is a rapid reduction of >10–15% in the amplitude of the evoked responses.


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InternalMed_Harrison. Anticholinesterase Test Drugs that inhibit the enzyme AChE allow ACh to interact repeatedly with the limited number of AChRs in MG, producing improvement in muscle strength. Edrophonium is used most commonly for diagnostic testing because of the rapid onset (30 s) and short duration (~5 min) of its effect. An objective end point must be selected to evaluate the effect of edrophonium, such as weakness of extraocular muscles, impairment of speech, or the length of time that the patient can maintain the arms in forward abduction. An initial IV dose of 2 mg of edrophonium is given. If definite improvement occurs, the test is considered positive and is terminated. If there is no change, the patient is given an additional 8 mg IV. The dose is administered in two parts because some patients react to edrophonium with side effects such as nausea, diarrhea, salivation, fasciculations, and rarely with severe symptoms of syncope or bradycardia. Atropine (0.6 mg) should be drawn up in a syringe


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InternalMed_Harrison. to edrophonium with side effects such as nausea, diarrhea, salivation, fasciculations, and rarely with severe symptoms of syncope or bradycardia. Atropine (0.6 mg) should be drawn up in a syringe and ready for IV administration if these symptoms become troublesome. The edrophonium test is now reserved for patients with clinical findings that are suggestive of MG but who have negative antibody and electrodiagnostic test results. False-positive tests occur in occasional patients with other neurologic disorders, such as amyotrophic lateral sclerosis, and in placebo-reactors. False-negative or equivocal tests may also occur. In some cases, it is helpful to use a longer-acting drug such as neostigmine (15 mg PO), because this permits more time for detailed evaluation of strength.


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InternalMed_Harrison. Inherited Myasthenic Syndromes The congenital myasthenic syndromes (CMS) comprise a heterogeneous group of disorders of the neuromuscular junction that are not autoimmune but rather are due to genetic mutations in which virtually any component of the neuromuscular junction may be affected. Alterations in function of the presynaptic nerve terminal, in the various subunits of the AChR, AChE, or the other molecules involved in end-plate development or maintenance, have been identified in the different forms of CMS. These disorders share many of the clinical features of autoimmune MG, including weakness and fatigability of skeletal muscles, in some cases involving extraocular muscles (EOMs), lids, and proximal muscles, similar to the distribution in autoimmune MG. CMS should be suspected when symptoms of myasthenia have begun in infancy or childhood and AChR antibody tests are consistently negative. By far the most common genetic defects occur in the AChR or other postsynaptic molecules


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InternalMed_Harrison. symptoms of myasthenia have begun in infancy or childhood and AChR antibody tests are consistently negative. By far the most common genetic defects occur in the AChR or other postsynaptic molecules (67% in the Mayo Clinic series of 350 CMS patients), with about equal frequencies of abnormalities in AChE (13%) and the various maintenance molecules (DOK7, GFPT, etc.; ~14%). In the forms that involve the AChR, a wide variety of mutations have been identified in each of the subunits, but the ε subunit is affected in ~75% of these cases. In most of the recessively inherited forms of CMS, the mutations are heteroallelic; that is, different mutations affecting each of the two alleles are present. Features of the four most common forms of CMS are summarized in Table 461-2. Although clinical features and electrodiagnostic and pharmacologic tests may suggest the correct diagnosis, molecular analysis is required for precise elucidation of the defect; this may lead to helpful treatment as well as


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InternalMed_Harrison. and electrodiagnostic and pharmacologic tests may suggest the correct diagnosis, molecular analysis is required for precise elucidation of the defect; this may lead to helpful treatment as well as genetic counseling.


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InternalMed_Harrison. Differential Diagnosis Other conditions that cause weakness of the cranial and/or somatic musculature include the nonautoimmune CMS discussed above, drug-induced myasthenia, Lambert-Eaton myasthenic syndrome (LEMS), neurasthenia, hyperthyroidism (Graves’ disease), botulism, intracranial mass lesions, oculopharyngeal dystrophy, and mitochondrial myopathy (Kearns-Sayre syndrome, progressive external ophthalmoplegia). Treatment with penicillamine (used for scleroderma or rheumatoid arthritis) may result in true autoimmune Abbreviations: AChE, acetylcholinesterase; AChR, acetylcholine receptor; EOM, extraocular muscles; MEPP, miniature end-plate potentials; MG, myasthenia gravis; 3,4-DAP, 3,4-diaminopyridine.


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InternalMed_Harrison. Abbreviations: AChE, acetylcholinesterase; AChR, acetylcholine receptor; EOM, extraocular muscles; MEPP, miniature end-plate potentials; MG, myasthenia gravis; 3,4-DAP, 3,4-diaminopyridine. MG, but the weakness is usually mild, and recovery occurs within weeks or months after discontinuing its use. Aminoglycoside antibiotics or procainamide can cause exacerbation of weakness in myasthenic patients; very large doses can cause neuromuscular weakness in normal individuals.


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InternalMed_Harrison. LEMS is a presynaptic disorder of the neuromuscular junction that can cause weakness similar to that of MG. The proximal muscles of the lower limbs are most commonly affected, but other muscles may be involved as well. Cranial nerve findings, including ptosis of the eyelids and diplopia, occur in up to 70% of patients and resemble features of MG. However, the two conditions are usually readily distinguished, because patients with LEMS have depressed or absent reflexes and experience autonomic changes such as dry mouth and impotence. Nerve stimulation produces an initial low-amplitude response and, at low rates of repetitive stimulation (2–3 Hz), decremental responses like those of MG; however, at high rates (50 Hz), or following exercise, incremental responses occur. LEMS is caused by autoantibodies directed against P/Q-type calcium channels at the motor nerve terminals, which can be detected in ~85% of LEMS patients by radioimmunoassay. These autoantibodies result in impaired release


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InternalMed_Harrison. directed against P/Q-type calcium channels at the motor nerve terminals, which can be detected in ~85% of LEMS patients by radioimmunoassay. These autoantibodies result in impaired release of ACh from nerve terminals. Many patients with LEMS have an associated malignancy, most commonly small-cell carcinoma of the lung, which may express calcium channels that stimulate the autoimmune response. The diagnosis of LEMS may signal the presence of a tumor long before it would otherwise be detected, permitting early removal. Treatment of LEMS involves plasmapheresis and immunosuppression, as for MG. 3,4-Diaminopyridine (3,4-DAP) and pyridostigmine may also be symptomatically helpful. 3,4-DAP acts by blocking potassium channels, which results in prolonged depolarization of the motor nerve terminals and thus enhances ACh release. Pyridostigmine prolongs the action of ACh, allowing repeated interactions with AChRs.


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InternalMed_Harrison. Botulism (Chap. 178) is due to potent bacterial toxins produced by any of eight different strains of Clostridium botulinum. The toxins enzymatically cleave specific proteins essential for the release of ACh from the motor nerve terminal, thereby interfering with neuromuscular transmission. Most commonly, botulism is caused by ingestion of improperly prepared food containing toxin. Rarely, the nearly ubiquitous spores of C. botulinum may germinate in wounds. In infants, the spores may germinate in the gastrointestinal (GI) tract and release toxin, causing muscle weakness. Patients present with myasthenia-like bulbar weakness (e.g., diplopia, dysarthria, dysphagia) and lack sensory symptoms and signs. Weakness may generalize to the limbs and may result in respiratory failure. Reflexes are present early, but they may be diminished as the disease progresses. Mentation is normal. Autonomic findings include paralytic ileus, constipation, urinary retention, dilated or poorly reactive pupils,


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InternalMed_Harrison. early, but they may be diminished as the disease progresses. Mentation is normal. Autonomic findings include paralytic ileus, constipation, urinary retention, dilated or poorly reactive pupils, and dry mouth. The demonstration of toxin in serum by bioassay is definitive, but the results usually take a relatively long time to be completed and may be negative. Nerve stimulation studies reveal findings of presynaptic neuromuscular blockade with reduced compound muscle action potentials (CMAPs) that increase in amplitude following high-frequency repetitive stimulation. Treatment includes ventilatory support and aggressive inpatient supportive care (e.g., nutrition, deep vein thrombosis prophylaxis) as needed. Antitoxin should be given as early as possible to be effective and can be obtained through the Centers for Disease Control and Prevention. A preventive vaccine is available for laboratory workers or other highly exposed individuals.


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InternalMed_Harrison. Neurasthenia is the historic term for a myasthenia-like fatigue syndrome without an organic basis. These patients may present with subjective symptoms of weakness and fatigue, but muscle testing usually reveals the “give-away weakness” characteristic of nonorganic disorders; the complaint of fatigue in these patients means tiredness or apathy rather than decreasing muscle power on repeated effort. Hyperthyroidism is readily diagnosed or excluded by tests of thyroid function, which should be carried out routinely in patients with suspected MG. Abnormalities of thyroid function (hyperor hypothyroidism) may increase myasthenic weakness. Diplopia resembling that in MG may occasionally be due to an intracranial mass lesion that compresses nerves to the EOMs (e.g., sphenoid ridge meningioma), but magnetic resonance imaging (MRI) of the head and orbits usually reveals the lesion.


InternalMed_Harrison

InternalMed_Harrison. Progressive external ophthalmoplegia is a rare condition resulting in weakness of the EOMs, which may be accompanied by weakness of the proximal muscles of the limbs and other systemic features. Most patients with this condition have mitochondrial disorders that can be detected on muscle biopsy (Chap. 462e).


InternalMed_Harrison

InternalMed_Harrison. Search for Associated Conditions (Table 461-3) Myasthenic patients have an increased incidence of several associated disorders. Thymic abnormalities occur in ~75% of AChR antibody–positive patients, as noted above. Neoplastic change (thymoma) may produce enlargement of the thymus, which is detected by computed tomography (CT) scanning of the anterior mediastinum. A thymic shadow on CT scan may normally be present through young adulthood, but enlargement of the thymus in a patient age >40 years is highly suspicious of thymoma. Hyperthyroidism occurs in 3–8% of patients and may aggravate the myasthenic weakness. Thyroid function tests should be obtained in all patients with suspected MG. Because of the association of MG with other autoimmune disorders, blood tests for rheumatoid factor and antinuclear antibodies should also be carried out. Chronic infection of any kind can exacerbate MG and should be sought carefully. Finally, measurements of ventilatory function are valuable because of


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InternalMed_Harrison. antibodies should also be carried out. Chronic infection of any kind can exacerbate MG and should be sought carefully. Finally, measurements of ventilatory function are valuable because of the frequency and seriousness of respiratory impairment in myasthenic patients.


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InternalMed_Harrison. Because of the side effects of glucocorticoids and other immunosuppressive agents used in the treatment of MG, a thorough medical Myasthenia Gravis and Other Diseases of the Neuromuscular Junction Associated disorders Disorders of the thymus: thymoma, hyperplasia Other autoimmune disorders: Hashimoto’s thyroiditis, Graves’ disease, rheu matoid arthritis, lupus erythematosus, skin disorders, family history of autoimmune disorder Disorders or circumstances that may exacerbate myasthenia gravis: hyperthyroidism or hypothyroidism, occult infection, medical treatment for other conditions (see Table 461-4) Disorders that may interfere with therapy: tuberculosis, diabetes, peptic ulcer, gastrointestinal bleeding, renal disease, hypertension, asthma, osteoporosis, obesity


InternalMed_Harrison

InternalMed_Harrison. Disorders that may interfere with therapy: tuberculosis, diabetes, peptic ulcer, gastrointestinal bleeding, renal disease, hypertension, asthma, osteoporosis, obesity Recommended laboratory tests or procedures CT or MRI of chest Tests for lupus erythematosus, antinuclear antibody, rheumatoid factor, antithyroid antibodies Thyroid function tests PPD skin test Fasting blood glucose, hemoglobin A1c Pulmonary function tests Bone densitometry Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PPD, purified protein derivative. investigation should be undertaken, searching specifically for evidence of chronic or latent infection (such as tuberculosis or hepatitis), hypertension, diabetes, renal disease, and glaucoma.


InternalMed_Harrison

InternalMed_Harrison. investigation should be undertaken, searching specifically for evidence of chronic or latent infection (such as tuberculosis or hepatitis), hypertension, diabetes, renal disease, and glaucoma. The prognosis has improved strikingly as a result of advances in treatment. Nearly all myasthenic patients can be returned to full productive lives with proper therapy. The most useful treatments for MG include anticholinesterase medications, immunosuppressive agents, thymectomy, and plasmapheresis or intravenous immunoglobulin (IVIg) (Fig. 461-2).


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InternalMed_Harrison. Anticholinesterase medication produces at least partial improvement in most myasthenic patients, although improvement is complete in only a few. Patients with anti-MuSK MG generally obtain less benefit from anticholinesterase agents than those with AChR antibodies. Pyridostigmine is the most widely used anticholinesterase drug. The beneficial action of oral pyridostigmine begins within 15–30 min and lasts for 3–4 h, but individual responses vary. Treatment is begun with a moderate dose, e.g., 30–60 mg three to four times daily. The frequency and amount of the dose should be tailored to the patient’s individual requirements throughout the day. For example, patients with weakness in chewing and swallowing may benefit by taking the medication before meals so that peak strength coincides with mealtimes. Long-acting pyridostigmine may occasionally be useful to get the patient through the night but should not be used for daytime medication because of variable absorption. The maximum useful


InternalMed_Harrison

InternalMed_Harrison. mealtimes. Long-acting pyridostigmine may occasionally be useful to get the patient through the night but should not be used for daytime medication because of variable absorption. The maximum useful dose of pyridostigmine rarely exceeds 120 mg every 4–6 h during daytime. Overdosage with anticholinesterase medication may cause increased weakness and other side effects. In some patients, muscarinic side effects of the anticholinesterase medication (diarrhea, abdominal cramps, salivation, nausea) may limit the dose tolerated. Atropine/diphenoxylate or loperamide is useful for the treatment of GI symptoms.


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InternalMed_Harrison. Two separate issues should be distinguished: (1) surgical removal of thymoma, and (2) thymectomy as a treatment for MG. Surgical removal of a thymoma is necessary because of the possibility of local tumor spread, although most thymomas are histologically benign. Establish diagnosis unequivocally (see Table 461-1) Search for associated conditions (see Table 461-3) Ocular only MRI of brain (if positive, reassess) Anticholinesterase (pyridostigmine) Anticholinesterase (pyridostigmine) Evaluate for thymectomy (indications: thymoma or generalized MG); evaluate surgical risk, FVC Crisis Intensive care (tx respiratory infection; fluids) Generalized If unsatisfactory Thymectomy Good risk (good FVC) Poor risk (low FVC) If not improved Immunosuppression Evaluate clinical status; if indicated, go to immunosuppression Improved See text for short-term, intermediate, and long-term treatments Plasmapheresis or intravenous Ig then


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InternalMed_Harrison. FIGURE 461-2 Algorithm for the management of myasthenia gravis. FVC, forced vital capacity; MRI, magnetic resonance imaging.


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InternalMed_Harrison. In the absence of a tumor, the available evidence suggests that up to 85% of patients experience improvement after thymectomy; of these, ~35% achieve drug-free remission. However, the improvement is typically delayed for months to years. The advantage of thymectomy is that it offers the possibility of long-term benefit, in some cases diminishing or eliminating the need for continuing medical treatment. Review of the published studies showed that following thymectomy, MG patients were 1.7 times as likely to improve and twice as likely to attain remission as those who did not have surgical thymectomy. In view of these potential benefits and of the negligible risk in skilled hands, thymectomy has gained widespread acceptance in the treatment of MG. It is the consensus that thymectomy should be carried out in all patients with generalized MG who are between the ages of puberty and at least 55 years. Whether thymectomy should be recommended in children, in adults >55 years of age, and in


InternalMed_Harrison

InternalMed_Harrison. be carried out in all patients with generalized MG who are between the ages of puberty and at least 55 years. Whether thymectomy should be recommended in children, in adults >55 years of age, and in patients with weakness limited to the ocular muscles is still a matter of debate. There is also evidence that patients with MuSK antibody–positive MG respond less well to thymectomy than those with AChR antibody. Thymectomy must be carried out in a hospital where it is performed regularly and where the staff is experienced in the preand postoperative management, anesthesia, and surgical techniques of total thymectomy. Thymectomy should never be carried out as an emergency procedure, but only when the patient is adequately prepared. If necessary, treatment with IVIg or plasmapheresis may be used before surgery, but it is helpful to try to avoid immunosuppressive agents because of the risk of infection.


InternalMed_Harrison

InternalMed_Harrison. Immunosuppression using one or more of the available agents is effective in nearly all patients with MG. The choice of drugs or other immunomodulatory treatments should be guided by the relative benefits and risks for the individual patient and the urgency of treatment. It is helpful to develop a treatment plan based on short-term, intermediate-term, and long-term objectives. For example, if immediate improvement is essential either because of the severity of weakness or because of the patient’s need to return to activity as soon as possible, IVIg should be administered or plasmapheresis should be undertaken. For the intermediate term, glucocorticoids and cyclosporine or tacrolimus generally produce clinical improvement within a period of 1–3 months. The beneficial effects of azathioprine and mycophenolate mofetil usually begin after many months (as long as a year), but these drugs have advantages for the long-term treatment of patients with MG. There is a growing body of evidence


InternalMed_Harrison

InternalMed_Harrison. and mycophenolate mofetil usually begin after many months (as long as a year), but these drugs have advantages for the long-term treatment of patients with MG. There is a growing body of evidence that rituximab is effective in many MG patients, especially those with MuSK antibody.


InternalMed_Harrison

InternalMed_Harrison. Glucocorticoid Therapy Glucocorticoids, when used properly, produce improvement in myasthenic weakness in the great majority of patients. To minimize adverse side effects, prednisone should be given in a single dose rather than in divided doses throughout the day. The initial dose should be relatively low (15–25 mg/d) to avoid the early weakening that occurs in up to one-third of patients treated initially with a high-dose regimen. The dose is increased stepwise, as tolerated by the patient (usually by 5 mg/d at 2to 3-day intervals), until there is marked clinical improvement or a dose of 50–60 mg/d is reached. This dose is maintained for 1–3 months and then is gradually modified to an alternate-day regimen over the course of an additional 1–3 months; the goal is to reduce the dose on the “off day” to zero or to a minimal level. Generally, patients begin to improve within a few weeks after reaching the maximum dose, and improvement continues to progress for months or years. The


InternalMed_Harrison

InternalMed_Harrison. on the “off day” to zero or to a minimal level. Generally, patients begin to improve within a few weeks after reaching the maximum dose, and improvement continues to progress for months or years. The prednisone dosage may gradually be reduced, but usually months or years may be needed to determine the minimum effective dose, and close monitoring is required. Few patients are able to do without immunosuppressive agents entirely. Patients on longterm glucocorticoid therapy must be followed carefully to prevent or treat adverse side effects. The most common errors in glucocorticoid treatment of myasthenic patients include (1) insufficient persistence—improvement may be delayed and gradual; (2) tapering the dosage too early, too rapidly, or excessively; and (3) lack of attention to prevention and treatment of side effects.


InternalMed_Harrison

InternalMed_Harrison. The management of patients treated with glucocorticoids is discussed in Chap. 406. Other Immunosuppressive Drugs Mycophenolate mofetil, azathioprine, cyclosporine, tacrolimus, rituximab, and occasionally cyclophosphamide are effective in many patients, either alone or in various combinations.


InternalMed_Harrison

InternalMed_Harrison. Mycophenolate mofetil has become one of the most widely used drugs in the treatment of MG because of its effectiveness and relative lack of side effects. A dose of 1–1.5 g bid is recommended. Its mechanism of action involves inhibition of purine synthesis by the de novo pathway. Since lymphocytes have only the de novo pathway, but lack the alternative salvage pathway that is present in all other cells, mycophenolate inhibits proliferation of lymphocytes but not proliferation of other cells. It does not kill or eliminate preexisting autoreactive lymphocytes, and therefore clinical improvement may be delayed for many months to a year, until the preexisting autoreactive lymphocytes die spontaneously. The advantage of mycophenolate lies in its relative lack of adverse side effects, with only occasional production of GI symptoms, rare development of leukopenia, and very small risks of malignancy or progressive multifocal leukoencephalopathy inherent in nearly all immunosuppressive


InternalMed_Harrison

InternalMed_Harrison. only occasional production of GI symptoms, rare development of leukopenia, and very small risks of malignancy or progressive multifocal leukoencephalopathy inherent in nearly all immunosuppressive treatments. Although two published studies did not show positive outcomes, most experts attribute the negative results to flaws in the trial designs, and mycophenolate is widely used for long-term treatment of myasthenic patients.


InternalMed_Harrison

InternalMed_Harrison. Until recently, azathioprine has been the most commonly used 2705 immunosuppressive agent for MG because of its relative safety in most patients and long track record. Its therapeutic effect may add to that of glucocorticoids and/or allow the glucocorticoid dose to be reduced. However, up to 10% of patients are unable to tolerate azathioprine because of idiosyncratic reactions consisting of flu-like symptoms of fever and malaise, bone marrow suppression, or abnormalities of liver function. An initial dose of 50 mg/d should be used for several days to test for these side effects. If this dose is tolerated, it is increased gradually to about 2–3 mg/kg of total body weight, or until the white blood count falls to 3000–4000/μL. The beneficial effect of azathioprine takes 3–6 months to begin and even longer to peak. In patients taking azathioprine, allopurinol should never be used to treat hyperuricemia. Because the two drugs share a common degradation pathway; the result may be severe


InternalMed_Harrison

InternalMed_Harrison. and even longer to peak. In patients taking azathioprine, allopurinol should never be used to treat hyperuricemia. Because the two drugs share a common degradation pathway; the result may be severe bone marrow suppression due to increased effects of the azathioprine.


InternalMed_Harrison

InternalMed_Harrison. The calcineurin inhibitors cyclosporine and tacrolimus (FK506) are approximately as effective as azathioprine and are being used increasingly in the management of MG. Their beneficial effect appears more rapidly than that of azathioprine. Either drug may be used alone, but they are usually used as an adjunct to glucocorticoids to permit reduction of the glucocorticoid dose. The usual dose of cyclosporine is 4–5 mg/kg per day, and the average dose of tacrolimus is 0.07–0.1 mg/kg per day, given in two equally divided doses (to minimize side effects). Side effects of these drugs include hypertension and nephrotoxicity, which must be closely monitored. “Trough” blood levels are measured 12 h after the evening dose. The therapeutic range for the trough level of cyclosporine is 150–200 ng/L, and for tacrolimus, it is 5–15 ng/L.


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InternalMed_Harrison. Rituximab (Rituxan) is a monoclonal antibody that binds to the CD20 molecule on B lymphocytes. It has been widely used for the treatment of B cell lymphomas and has also proven successful in the treatment of several autoimmune diseases including rheumatoid arthritis, pemphigus, and some IgM-related neuropathies. There is now an extensive literature on the benefit of rituximab in MG. It is particularly effective in MuSK antibody–positive MG, although some patients with AChR antibody MG respond to it as well. The usual dose is 375 mg/m2, given IV in 4 weekly infusions, or 1 g, given IV on two occasions 2 weeks apart.


InternalMed_Harrison

InternalMed_Harrison. For the occasional patient with MG that is genuinely refractory to optimal treatment with conventional immunosuppressive agents, a course of high-dose cyclophosphamide may induce long-lasting benefit by “rebooting” the immune system. At high doses, cyclophosphamide eliminates mature lymphocytes but spares hematopoietic precursors (stem cells), because they express the enzyme aldehyde dehydrogenase, which hydrolyzes cyclophosphamide. At present, this procedure is reserved for refractory patients and should be administered only in a facility fully familiar with this approach. Maintenance immunotherapy after rebooting is usually required to sustain the beneficial effect.


InternalMed_Harrison

InternalMed_Harrison. Plasmapheresis has been used therapeutically in MG. Plasma, which contains the pathogenic antibodies, is mechanically separated from the blood cells, which are returned to the patient. A course of five exchanges (3–4 L per exchange) is generally administered over a 10to 14-day period. Plasmapheresis produces a short-term reduction in anti-AChR antibodies, with clinical improvement in many patients. It is useful as a temporary expedient in seriously affected patients or to improve the patient’s condition prior to surgery (e.g., thymectomy).


InternalMed_Harrison

InternalMed_Harrison. The indications for the use of IVIg are the same as those for plasma exchange: to produce rapid improvement to help the patient through a difficult period of myasthenic weakness or prior to surgery. This treatment has the advantages of not requiring special equipment or large-bore venous access. The usual dose is 2 g/ kg, which is typically administered over 5 days (400 mg/kg per day). If tolerated, the total dose of IVIg can be given over a 3to 4-day period. Improvement occurs in ~70% of patients, beginning during


InternalMed_Harrison

InternalMed_Harrison. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction 2706 treatment, or within a week, and continuing for weeks to months. The mechanism of action of IVIg is not known; the treatment has no consistent effect on the measurable amount of circulating AChR antibody. Adverse reactions are generally not serious but may include headache, fluid overload, and rarely aseptic meningitis or renal failure. IVIg should rarely be used as a long-term treatment in place of rationally managed immunosuppressive therapy. Unfortunately, there is a tendency for physicians unfamiliar with immunosuppressive treatments to rely on repeated IVIg infusions, which usually produce only intermittent benefit, do not reduce the underlying autoimmune response, and are very costly. The intermediate and long-term treatment of myasthenic patients requires other methods of therapy outlined earlier in this chapter.


InternalMed_Harrison

InternalMed_Harrison. Myasthenic crisis is defined as an exacerbation of weakness sufficient to endanger life; it usually consists of respiratory failure caused by diaphragmatic and intercostal muscle weakness. Crisis rarely occurs in properly managed patients. Treatment should be carried out in intensive care units staffed with teams experienced in the management of MG, respiratory insufficiency, infectious disease, and fluid and electrolyte therapy. The possibility that deterioration could be due to excessive anticholinesterase medication (“cholinergic crisis”) is best excluded by temporarily stopping anticholinesterase drugs. The most common cause of crisis is intercurrent infection. This should be treated immediately, because the mechanical and immunologic defenses of the patient can be assumed to be compromised. The myasthenic patient with fever and early infection should be treated like other immunocompromised patients. Early and effective antibiotic therapy, respiratory assistance (preferably


InternalMed_Harrison

InternalMed_Harrison. compromised. The myasthenic patient with fever and early infection should be treated like other immunocompromised patients. Early and effective antibiotic therapy, respiratory assistance (preferably noninvasive, using bilevel positive airway pressure), and pulmonary physiotherapy are essentials of the treatment program. As discussed above, plasmapheresis or IVIg is frequently helpful in hastening recovery.


InternalMed_Harrison

InternalMed_Harrison. Many drugs have been reported to exacerbate weakness in patients with MG (Table 461-4), but not all patients react adversely to all of Aminoglycosides: e.g., streptomycin, tobramycin, kanamycin Quinolones: e.g., ciprofloxacin, levofloxacin, ofloxacin, gatifloxacin Macrolides: e.g., erythromycin, azithromycin D-Tubocurarine (curare), pancuronium, vecuronium, atracurium Propranolol, atenolol, metoprolol Procaine, Xylocaine in large amounts Procainamide (for arrhythmias) Quinine, quinidine, chloroquine, mefloquine (Lariam) Drugs with Important Interactions in MG Broad range of drug interactions, which may raise or lower cyclosporine levels. Avoid allopurinol—combination may result in myelosuppression. FIGURE 461-3 Abbreviated interval assessment form for use in evaluating treatment for myasthenia gravis.


InternalMed_Harrison

InternalMed_Harrison. Avoid allopurinol—combination may result in myelosuppression. FIGURE 461-3 Abbreviated interval assessment form for use in evaluating treatment for myasthenia gravis. these. Conversely, not all “safe” drugs can be used with impunity in patients with MG. As a rule, the listed drugs should be avoided whenever possible, and myasthenic patients should be followed closely when any new drug is introduced.


InternalMed_Harrison

InternalMed_Harrison. To evaluate the effectiveness of treatment as well as drug-induced side effects, it is important to assess the patient’s clinical status systematically at baseline and on repeated interval examinations. Because of the variability of symptoms of MG, the interval history and physical findings on examination must be taken into account. The most useful clinical tests include forward arm abduction time (up to a full 5 min), spirometry with determination of forced vital capacity, range of eye movements, and time to development of ptosis on upward gaze. Manual muscle testing or, preferably, quantitative dynamometry of limb muscles, especially proximal muscles, is also important. An interval form can provide a succinct summary of the patient’s status and a guide to treatment results; an abbreviated form is shown in Fig. 461-3. A progressive reduction in the patient’s AChR antibody level also provides clinically valuable confirmation of the effectiveness of treatment; conversely, a rise in


InternalMed_Harrison

InternalMed_Harrison. form is shown in Fig. 461-3. A progressive reduction in the patient’s AChR antibody level also provides clinically valuable confirmation of the effectiveness of treatment; conversely, a rise in AChR antibody levels during tapering of immunosuppressive medication may predict clinical exacerbation. For reliable quantitative measurement of AChR antibody levels, it is best to compare antibody levels from prior frozen serum aliquots with current serum samples in simultaneously run assays.


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InternalMed_Harrison. Muscular Dystrophies and Other Muscle Diseases Anthony A. Amato, Robert H. Brown, Jr. Skeletal muscle diseases, or myopathies, are disorders with structural changes or functional impairment of muscle. These conditions can be 462e


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InternalMed_Harrison. Variable weakness includes EOMs, ptosis, bulbar and limb muscles Yes No Exam normal between attacks Proximal > distal weakness during attacks Exam usually normal between attacks Proximal > distal weakness during attacks Forearm exercise DNA test confirms diagnosis Low potassium level Normal or elevated potassium level Hypokalemic PP Hyperkalemic PP Paramyotonia congenita Muscle biopsy defines specific defect Reduced lactic acid rise Consider glycolytic defect Normal lactic acid rise Consider CPT deficiency or other fatty acid metabolism disorders No Yes AChR or Musk AB positive Acquired seropositive MG Check chest CT for thymoma Lambert-Eaton myasthenic syndrome Check: Voltage gated Ca channel Abs Chest CT for lung Ca Yes No Yes No Decrement on 2–3 Hz repetitive nerve stimulation (RNS) or increased jitter on single fiber EMG (SFEMG) Consider: Seronegative MG Congenital MG* Psychosomatic weakness** *Genetic testing (Chap. 461) **If Abs, RNS, SFEMG are all normal or negative EKG


InternalMed_Harrison

InternalMed_Harrison. or increased jitter on single fiber EMG (SFEMG) Consider: Seronegative MG Congenital MG* Psychosomatic weakness** *Genetic testing (Chap. 461) **If Abs, RNS, SFEMG are all normal or negative EKG Abnormal Check for dysmorphic features Genetic testing for Anderson-Tawil syndrome Normal Myotonia on exam FIgURE 462e-1 Diagnostic evaluation of intermittent weakness. AChR AB, acetylcholine receptor antibody; CPT, carnitine palmitoyltransfer-ase; EOMs, extraocular muscles; MG, myasthenia gravis; PP, periodic paralysis.


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InternalMed_Harrison. differentiated from other diseases of the motor unit (e.g., lower motor neuron or neuromuscular junction pathologies) by characteristic clinical and laboratory findings. Myasthenia gravis and related disorders are discussed in Chap. 461; dermatomyositis, polymyositis, and inclusion body myositis are discussed in Chap. 388. Most myopathies present with proximal, symmetric limb weakness (arms or legs) with preserved reflexes and sensation. However, asymmetric and predominantly distal weakness can be seen in some myopathies. An associated sensory loss suggests injury to a peripheral nerve or the central nervous system (CNS) rather than myopathy. On occasion, disorders affecting the motor nerve cell bodies in the spinal cord (anterior horn cell disease), the neuromuscular junction, or peripheral nerves can mimic findings of myopathy.


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InternalMed_Harrison. Muscle Weakness Symptoms of muscle weakness can be either intermittent or persistent. Disorders causing intermittent weakness (Fig. 462e-1) include myasthenia gravis, periodic paralyses (hypokalemic, hyperkalemic, and paramyotonia congenita), and metabolic energy deficiencies of glycolysis (especially myophosphorylase deficiency), fatty acid utilization (carnitine palmitoyltransferase deficiency), and some mitochondrial myopathies. The states of energy deficiency cause activity-related muscle breakdown accompanied by myoglobinuria, appearing as light-brownto dark-brown-colored urine.


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InternalMed_Harrison. Most muscle disorders cause persistent weakness (Fig. 462e-2). In the majority of these, including most types of muscular dystrophy, polymyositis, and dermatomyositis, the proximal muscles are weaker than the distal and are symmetrically affected, and the facial muscles are spared, a pattern referred to as limb-girdle. The differential diagnosis is more restricted for other patterns of weakness. Facial weakness (difficulty with eye closure and impaired smile) and scapular winging (Fig. 462e-3) are characteristic of facioscapulohumeral dystrophy 462e-1 (FSHD). Facial and distal limb weakness associated with hand grip myotonia is virtually diagnostic of myotonic dystrophy type 1. When other cranial nerve muscles are weak, causing ptosis or extraocular muscle weakness, the most important disorders to consider include neuromuscular junction disorders, oculopharyngeal muscular dystrophy, mitochondrial myopathies, or some of the congenital myopathies (Table 462e-1). A pathognomonic pattern


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InternalMed_Harrison. to consider include neuromuscular junction disorders, oculopharyngeal muscular dystrophy, mitochondrial myopathies, or some of the congenital myopathies (Table 462e-1). A pathognomonic pattern characteristic of inclusion body myositis is atrophy and weakness of the flexor forearm (e.g., wrist and finger flexors) and quadriceps muscles that is often asymmetric. Less frequently, but important diagnostically, is the presence of a dropped head syndrome indicative of selective neck extensor muscle weakness. The most important neuromuscular diseases associated with this pattern of weakness include myasthenia gravis, amyotrophic lateral sclerosis, late-onset nemaline myopathy, hyperparathyroidism, focal myositis, and some forms of inclusion body myopathy. A final pattern, recognized because of preferential distal extremity weakness, is typical of a unique category of muscular dystrophy, the distal myopathies.


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InternalMed_Harrison. It is important to examine functional capabilities to help disclose certain patterns of weakness (Table 462e-2). The Gowers’ sign (Fig. 462e-4) is particularly useful. Observing the gait of an individual may disclose a lordotic posture caused by combined trunk and hip weakness, frequently exaggerated by toe walking (Fig. 462e-5). A waddling gait is caused by the inability of weak hip muscles to prevent hip drop or hip dip. Hyperextension of the knee (genu recurvatum or back-kneeing) is characteristic of quadriceps muscle weakness; and a steppage gait, due to footdrop, accompanies distal weakness.


InternalMed_Harrison

InternalMed_Harrison. Any disorder causing muscle weakness may be accompanied by fatigue, referring to an inability to maintain or sustain a force (pathologic fatigability). This condition must be differentiated from asthenia, a type of fatigue caused by excess tiredness or lack of energy. Associated symptoms may help differentiate asthenia and pathologic fatigability. Asthenia is often accompanied by a tendency to avoid physical activities, complaints of daytime sleepiness, necessity for frequent naps, and difficulty concentrating on activities such as reading. There may be feelings of overwhelming stress and depression. Thus, asthenia is not a myopathy. In contrast, pathologic fatigability occurs in disorders of neuromuscular transmission and in disorders altering energy production, including defects in glycolysis, lipid metabolism, or mitochondrial energy production. Pathologic fatigability also occurs in chronic myopathies because of difficulty accomplishing a task with less


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InternalMed_Harrison. FIgURE 462e-2 Diagnostic evaluation of persistent weakness. Examination reveals one of seven patterns of weakness. The pattern of weakness in combination with the laboratory evaluation leads to a diagnosis. ALS, amyotrophic lateral sclerosis; CK, creatine kinase; DM, dermatomyositis; EMG, electromyography; EOMs, extraocular muscles; FSHD, facioscapulohumeral dystrophy; IBM, inclusion body myositis; MG, myasthenia gravis; OPMD, oculopharyngeal muscular dystrophy; PM, polymyositis. muscle. Pathologic fatigability is accompanied by abnormal clinical or laboratory findings. Fatigue without those supportive features almost never indicates a primary muscle disease.


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InternalMed_Harrison. muscle. Pathologic fatigability is accompanied by abnormal clinical or laboratory findings. Fatigue without those supportive features almost never indicates a primary muscle disease. Muscle Pain (Myalgias), Cramps, and Stiffness Muscle pain can be associated with cramps, spasms, contractures, and stiff or rigid muscles. In distinction, true myalgia (muscle aching), which can be localized or generalized, may be accompanied by weakness, tenderness to palpation, or swelling. Certain drugs cause true myalgia (Table 462e-3).


InternalMed_Harrison

InternalMed_Harrison. There are two painful muscle conditions of particular importance, neither of which is associated with muscle weakness. Fibromyalgia is a common, yet poorly understood, type of myofascial pain syndrome. Patients complain of severe muscle pain and tenderness and have specific painful trigger points, sleep disturbances, and easy fatigability. Serum creatine kinase (CK), erythrocyte sedimentation rate (ESR), electromyography (EMG), and muscle biopsy are normal (Chap. 396). Polymyalgia rheumatica occurs mainly in patients >50 years and is characterized by stiffness and pain in the shoulders, lower back, hips, and thighs (Chap. 385). The ESR is elevated, while serum CK, EMG, and muscle biopsy are normal. Temporal arteritis, an inflammatory FIgURE 462e-3 Facioscapulohumeral dystrophy with prominent scapular winging.


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InternalMed_Harrison. FIgURE 462e-3 Facioscapulohumeral dystrophy with prominent scapular winging. disorder of mediumand large-sized arteries, usually involving one or more branches of the carotid artery, may accompany polymyalgia rheumatica. Vision is threatened by ischemic optic neuritis. Glucocorticoids can relieve the myalgias and protect against visual loss. Localized muscle pain is most often traumatic. A common cause of sudden abrupt-onset pain is a ruptured tendon, which leaves the muscle belly appearing rounded and shorter in appearance compared to the normal side. The biceps brachii and Achilles tendons are particularly vulnerable to rupture. Infection or neoplastic infiltration of the muscle is a rare cause of localized muscle pain.


InternalMed_Harrison

InternalMed_Harrison. A muscle cramp or spasm is a painful, involuntary, localized, muscle contraction with a visible or palpable hardening of the muscle. Cramps are abrupt in onset, short in duration, and may cause abnormal posturing of the joint. The EMG shows firing of motor units, reflecting an origin from spontaneous neural discharge. Muscle cramps often occur Inability to forcibly close eyes Upper facial muscles Inability to raise head from prone Neck extensor muscles position Inability to raise head from supine Neck flexor muscles position Inability to raise arms above head Proximal arm muscles (may be only scapular stabilizing muscles) Inability to walk without hyperex-Knee extensor muscles tending knee (back-kneeing or genu recurvatum) Inability to walk with heels touching Shortening of the Achilles tendon the floor (toe walking) Inability to lift foot while walking Anterior compartment of leg (steppage gait or footdrop) Inability to walk without a waddling Hip muscles gait


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InternalMed_Harrison. Inability to lift foot while walking Anterior compartment of leg (steppage gait or footdrop) Inability to walk without a waddling Hip muscles gait Inability to get up from the floor Hip, thigh, and trunk muscles without climbing up the extremities (Gowers’ sign) Inability to get up from a chair Hip muscles without using arms in neurogenic disorders, especially motor neuron disease (Chap. 452), radiculopathies, and polyneuropathies (Chap. 459), but are not a feature of most primary muscle diseases. Duchenne muscular dystrophy is an exception because calf muscle complaints are a common complaint. Muscle cramps are also common during pregnancy.


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InternalMed_Harrison. A muscle contracture is different from a muscle cramp. In both conditions, the muscle becomes hard, but a contracture is associated with energy failure in glycolytic disorders. The muscle is unable to relax after an active muscle contraction. The EMG shows electrical silence. Confusion is created because contracture also refers to a muscle that cannot be passively stretched to its proper length (fixed contracture) because of fibrosis. In some muscle disorders, especially in Emery-Dreifuss muscular dystrophy and Bethlem myopathy, fixed contractures occur early and represent distinctive features of the disease.


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InternalMed_Harrison. Muscle stiffness can refer to different phenomena. Some patients with inflammation of joints and periarticular surfaces feel stiff. This condition is different from the disorders of hyperexcitable motor nerves causing stiff or rigid muscles. In stiff-person syndrome, spontaneous discharges of the motor neurons of the spinal cord cause involuntary muscle contractions mainly involving the axial (trunk) and proximal lower extremity muscles. The gait becomes stiff and labored, with hyperlordosis of the lumbar spine. Superimposed episodic muscle spasms are precipitated by sudden movements, unexpected noises, and emotional upset. The muscles relax during sleep. Serum antibodies against glutamic acid decarboxylase are present in approximately two-thirds of cases. In neuromyotonia (Isaacs’ syndrome), there is hyper-excitability of the peripheral nerves manifesting as continuous muscle fiber activity. Myokymia (groups of fasciculations associated with continuous undulations of muscle) and


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InternalMed_Harrison. there is hyper-excitability of the peripheral nerves manifesting as continuous muscle fiber activity. Myokymia (groups of fasciculations associated with continuous undulations of muscle) and impaired muscle relaxation are the result. Muscles of the leg are stiff, and the constant contractions of the muscle cause increased sweating of the extremities. This peripheral nerve hyperexcitability is mediated by antibodies that target voltage-gated potassium channels. The site of origin of the spontaneous nerve discharges is principally in the distal portion of the motor nerves.


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InternalMed_Harrison. Myotonia is a condition of prolonged muscle contraction followed by slow muscle relaxation. It always follows muscle activation (action myotonia), usually voluntary, but may be elicited by mechanical stimulation (percussion myotonia) of the muscle. Myotonia typically causes difficulty in releasing objects after a firm grasp. In myotonic muscular dystrophy type 1 (DM1), distal weakness usually accompanies myotonia, whereas in DM2, proximal muscles are more affected; thus FIgURE 462e-4 Gowers’ sign showing a patient using his arms to climb up the legs in attempting to get up from the floor.


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InternalMed_Harrison. FIgURE 462e-4 Gowers’ sign showing a patient using his arms to climb up the legs in attempting to get up from the floor. the related term proximal myotonic myopathy (PROMM) is used to describe this condition. Myotonia also occurs with myotonia congenita (a chloride channel disorder), but in this condition muscle weakness is not prominent. Myotonia may also be seen in individuals with sodium channel mutations (hyperkalemic periodic paralysis or potassium-sensitive myotonia). Another sodium channelopathy, paramyotonia congenita, also is associated with muscle stiffness. In contrast to other disorders associated with myotonia in which the myotonia is eased by repetitive activity, paramyotonia congenita is named for a paradoxical phenomenon whereby the myotonia worsens with repetitive activity.


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InternalMed_Harrison. Muscle Enlargement and Atrophy In most myopathies muscle tissue is replaced by fat and connective tissue, but the size of the muscle is usually not affected. However, in many limb-girdle muscular dystrophies (and particularly the dystrophinopathies), enlarged calf muscles are typical. The enlargement represents true muscle hypertrophy; thus the term pseudohypertrophy should be avoided when referring to these patients. The calf muscles remain very strong even late in the course of these disorders. Muscle enlargement can also result from infiltration by sarcoid granulomas, amyloid deposits, bacterial and parasitic infections, and focal myositis. In contrast, muscle atrophy is characteristic of other myopathies. In dysferlinopathies (LGMD2B) FIgURE 462e-5 Lordotic posture, exaggerated by standing on toes, associated with trunk and hip weakness.


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InternalMed_Harrison. FIgURE 462e-5 Lordotic posture, exaggerated by standing on toes, associated with trunk and hip weakness. and anoctaminopathies (LGMD2L), there is a predilection for early atrophy of the gastrocnemius muscles, particularly the medial aspect. Atrophy of the humeral muscles is characteristic of FSHD. A limited battery of tests can be used to evaluate a suspected myopathy. Nearly all patients require serum enzyme level measurements and electrodiagnostic studies as screening tools to differentiate muscle disorders from other motor unit diseases. The other tests described— DNA studies, the forearm exercise test, and muscle biopsy—are used to diagnose specific types of myopathies.


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InternalMed_Harrison. Serum Enzymes CK is the preferred muscle enzyme to measure in the evaluation of myopathies. Damage to muscle causes the CK to leak from the muscle fiber to the serum. The MM isoenzyme predominates in skeletal muscle, whereas creatine kinase-myocardial bound (CKMB) is the marker for cardiac muscle. Serum CK can be elevated in normal individuals without provocation, presumably on a genetic basis or after strenuous activity, minor trauma (including the EMG needle), a prolonged muscle cramp, or a generalized seizure. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), aldolase, and lactic dehydrogenase (LDH) are enzymes sharing an origin in both muscle and liver. Problems arise when the levels of these enzymes are found to be elevated in a routine screening battery, leading to the erroneous assumption that liver disease is present when in fact muscle could be the cause. An elevated γ-glutamyl transferase (GGT) helps to establish a liver origin because this enzyme is not


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InternalMed_Harrison. to the erroneous assumption that liver disease is present when in fact muscle could be the cause. An elevated γ-glutamyl transferase (GGT) helps to establish a liver origin because this enzyme is not found in muscle.


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InternalMed_Harrison. Electrodiagnostic Studies EMG, repetitive nerve stimulation, and nerve conduction studies (Chap. 442e) are essential methods for evaluation of the patient with suspected muscle disease. In combination, they provide the information necessary to differentiate myopathies from neuropathies and neuromuscular junction diseases. Routine nerve conduction studies are typically normal in myopathies but reduced amplitudes of compound muscle action potentials may be seen in atrophied muscles. The needle EMG may reveal irritability on needle placement suggestive of a necrotizing myopathy (inflammatory myopathies, dystrophies, toxic myopathies, myotonic myopathies), whereas a lack of irritability is characteristic of long-standing myopathic disorders (muscular dystrophies, endocrine myopathies, disuse atrophy, and many of the metabolic myopathies). In addition, the EMG may demonstrate myotonic discharges that will narrow the differential diagnosis (Table 462e-4). Another important EMG finding is


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InternalMed_Harrison. atrophy, and many of the metabolic myopathies). In addition, the EMG may demonstrate myotonic discharges that will narrow the differential diagnosis (Table 462e-4). Another important EMG finding is the presence of short-duration, small-amplitude, polyphasic motor unit action potentials (MUAPs). Such MUAPs can be seen in both myopathic and neuropathic disorders; however, the recruitment or firing pattern is different. In myopathies, the MUAPs fire early but at a normal rate to compensate for the loss of individual muscle fibers, whereas in neurogenic disorders the MUAPs fire faster. The EMG is usually normal in steroid or disuse myopathy, both of which are associated with type 2 fiber atrophy; this is because the EMG preferentially assesses the physiologic function of type 1 fibers. The EMG can also be invaluable in helping to choose an appropriately affected muscle to sample for biopsy.


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InternalMed_Harrison. DNA Analysis This serves as an important tool for the definitive diagnosis of many muscle disorders. Nevertheless, there are a number of limitations in currently available molecular diagnostics. For example, in Duchenne and Becker dystrophies, two-thirds of patients have deletion or duplication mutations in the dystrophin gene that are easy to detect, while the remainder have point mutations that are much more difficult to find. For patients without identifiable gene defects, the muscle biopsy remains the main diagnostic tool. Cholesterol-lowering agents (statin medications, fibrates) Cyclosporine Chloroquine Glycogen storage disordersa (Pompe’s disease, branching enzyme deficiency, debranching enzyme deficiency) Myofibrillar myopathies (MFM)a aAssociated with myotonic discharges on electromyography but no clinical myotonia.


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InternalMed_Harrison. Forearm Exercise Test In myopathies with intermittent symptoms, and especially those associated with myoglobinuria, there may be a defect in glycolysis. Many variations of the forearm exercise test exist. For safety, the test should not be performed under ischemic conditions to avoid an unnecessary insult to the muscle, causing rhabdomyolysis. The test is performed by placing a small indwelling catheter into an antecubital vein. A baseline blood sample is obtained for lactic acid and ammonia. The forearm muscles are exercised by asking the patient to vigorously open and close the hand for 1 min. Blood is then obtained at intervals of 1, 2, 4, 6, and 10 min for comparison with the baseline sample. A threeto fourfold rise of lactic acid is typical. The simultaneous measurement of ammonia serves as a control, because it should also rise with exercise. In patients with myophosphorylase deficiency or other glycolytic defects, the lactic acid rise will be absent or below normal, while the


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InternalMed_Harrison. as a control, because it should also rise with exercise. In patients with myophosphorylase deficiency or other glycolytic defects, the lactic acid rise will be absent or below normal, while the rise in ammonia will reach control values. If there is lack of effort, neither lactic acid nor ammonia will rise. Patients with selective failure to increase ammonia may have myoadenylate deaminase deficiency. This condition has been reported to be a cause of myoglobinuria, but deficiency of this enzyme in asymptomatic individuals makes interpretation controversial.


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InternalMed_Harrison. Muscle Biopsy Muscle biopsy is an important step in establishing the diagnosis of a suspected myopathy. The biopsy is usually obtained from a quadriceps or biceps brachii muscle, less commonly from a deltoid muscle. Evaluation includes a combination of techniques—light microscopy, histochemistry, immunocytochemistry with a battery of antibodies, and electron microscopy. Not all techniques are needed for every case. A specific diagnosis can be established in many disorders. Endomysial inflammatory cells surrounding and invading muscle fibers are seen in polymyositis; similar endomysial infiltrates associated 462e-5 with muscle fibers containing rimmed vacuoles and amyloid deposits consisting of SMI-31-, p62-, and TDP-43-positive inclusions within fibers are characteristic of inclusion body myositis; and perivascular, perimysial inflammation associated with perifascicular atrophy is a feature of dermatomyositis. In addition, the congenital myopathies have distinctive light and electron


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InternalMed_Harrison. myositis; and perivascular, perimysial inflammation associated with perifascicular atrophy is a feature of dermatomyositis. In addition, the congenital myopathies have distinctive light and electron microscopy features essential for diagnosis. Mitochondrial and metabolic (e.g., glycogen and lipid storage diseases) myopathies also demonstrate distinctive histochemical and electron-microscopic profiles. Biopsied muscle tissue can be sent for metabolic enzyme or mitochondrial DNA analyses. A battery of antibodies is available for the identification of abnormal proteins to help diagnose specific types of muscular dystrophies. Western blot analysis on muscle specimens can be performed to determine whether specific muscle proteins are reduced in quantity or are of abnormal size.


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InternalMed_Harrison. Muscular dystrophy refers to a group of hereditary progressive diseases each with unique phenotypic and genetic features (Tables 462e-5, 462e-6, and 462e-7). This X-linked recessive disorder, sometimes also called pseudohypertrophic muscular dystrophy, has an incidence of ~1 per 5200 live-born males. Clinical Features Duchenne dystrophy is present at birth, but the disorder usually becomes apparent between ages 3 and 5 years. The boys fall frequently and have difficulty keeping up with friends when Myotonica AD DM1: Expansion Childhood to adult; pos-Slowly progressive weakness of face, shoulder Cardiac conduction (DM1, DM2) CTG repeat sibly infancy if mother girdle, and foot dorsiflexion defects affected (DM1 only) DM2: Expansion FSHD1 AD DUX4 4q Childhood to adult Slowly progressive weakness of face, shoulder Deafness girdle, and foot dorsiflexion


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InternalMed_Harrison. DM2: Expansion FSHD1 AD DUX4 4q Childhood to adult Slowly progressive weakness of face, shoulder Deafness girdle, and foot dorsiflexion Oculopharyngeal AD Expansion, poly-Fifth to sixth decade Slowly progressive weakness of extraocular, — A RNA binding pharyngeal, and limb muscles protein aTwo forms of myotonic dystrophy, DM1 and DM2, have been identified. Many features overlap (see text). Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system; XR, X-linked recessive.


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InternalMed_Harrison. LGMD1A Onset second to eighth decade Serum CK 2× normal Myotilin playing. Running, jumping, and hopping are invariably abnormal. By age 5 years, muscle weakness is obvious by muscle testing. On getting up from the floor, the patient uses his hands to climb up himself (Gowers’ maneuver [Fig. 462e-4]). Contractures of the heel cords and iliotibial bands become apparent by age 6 years, when toe walking is associated with a lordotic posture. Loss of muscle strength is progressive, with predilection for proximal limb muscles and the neck flexors; leg involvement is more severe than arm involvement. Between ages 8 and 10 years, walking may require the use of braces; joint contractures and limitations of hip flexion, knee, elbow, and wrist extension are made worse by prolonged sitting. Prior to the use of glucocorticoids, most boys became wheelchair dependent by 12 years of age. Contractures become fixed, and a progressive scoliosis often develops that may be associated with pain. The chest


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InternalMed_Harrison. the use of glucocorticoids, most boys became wheelchair dependent by 12 years of age. Contractures become fixed, and a progressive scoliosis often develops that may be associated with pain. The chest deformity with scoliosis impairs pulmonary function, which is already diminished by muscle weakness. By age 16–18 years, patients are predisposed to serious, sometimes fatal pulmonary infections. Other causes of death include aspiration of food and acute gastric dilation.


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InternalMed_Harrison. A cardiac cause of death is uncommon despite the presence of a cardiomyopathy in almost all patients. Congestive heart failure seldom occurs except with severe stress such as pneumonia. Cardiac arrhythmias are rare. The typical electrocardiogram (ECG) shows an increased net RS in lead V1; deep, narrow Q waves in the precordial leads; and tall right precordial R waves in V1. Intellectual impairment in Duchenne dystrophy is common; the average intelligence quotient (IQ) is ~1 standard deviation (SD) below the mean. Impairment of intellectual function appears to be nonprogressive and affects verbal ability more than performance.


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InternalMed_Harrison. Laboratory Features Serum CK levels are invariably elevated to between 20 and 100 times normal. The levels are abnormal at birth but decline late in the disease because of inactivity and loss of muscle mass. EMG demonstrates features typical of myopathy. The muscle biopsy shows muscle fibers of varying size as well as small groups of necrotic and regenerating fibers. Connective tissue and fat replace lost muscle fibers. A definitive diagnosis of Duchenne dystrophy can be established on the basis of dystrophin deficiency in a biopsy of muscle tissue or mutation analysis on peripheral blood leukocytes, as discussed below.


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InternalMed_Harrison. Duchenne dystrophy is caused by a mutation of the gene that encodes dystrophin, a 427-kDa protein localized to the inner surface of the sarcolemma of the muscle fiber. The dystrophin gene is >2000 kb in size and thus is one of the largest identified human genes. It is localized to the short arm of the X chromosome at Xp21. The most common gene mutation is a deletion. The size varies but does not correlate with disease severity. Deletions are not uniformly distributed over the gene but rather are most common near the beginning (5′ end) and middle of the gene. Less often, Duchenne dystrophy is caused by a gene duplication or point mutation. Identification of a specific mutation allows for an unequivocal diagnosis, makes possible accurate testing of potential carriers, and is useful for prenatal diagnosis.


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InternalMed_Harrison. A diagnosis of Duchenne dystrophy can also be made by Western blot analysis of muscle biopsy specimens, revealing abnormalities on the quantity and molecular weight of dystrophin protein. In addition, immunocytochemical staining of muscle with dystrophin antibodies can be used to demonstrate absence or deficiency of dystrophin localizing to the sarcolemmal membrane. Carriers of the disease may demonstrate a mosaic pattern, but dystrophin analysis of muscle biopsy specimens for carrier detection is not reliable.


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InternalMed_Harrison. Pathogenesis Dystrophin is part of a large complex of sarcolemmal proteins and glycoproteins (Fig. 462e-6). Dystrophin binds to F-actin at its amino terminus and to β-dystroglycan at the carboxyl terminus. β-Dystroglycan complexes to α-dystroglycan, which binds to laminin in the extracellular matrix (ECM). Laminin has a heterotrimeric molecular structure arranged in the shape of a cross with one heavy chain and two light chains, β1 and γ1. The laminin heavy chain of skeletal muscle is designated laminin α2. Collagen proteins IV and VI are also found in the ECM. Like β-dystroglycan, the transmembrane sarcoglycan proteins also bind to dystrophin; these five proteins (designated αthrough ε-sarcoglycan) complex tightly with each other. More recently, other membrane proteins implicated in muscular dystrophy have been found to be loosely affiliated with constituents of the dystrophin complex. These include caveolin-3, α7 integrin, and collagen VI.


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InternalMed_Harrison. aUdd’s type distal myopathy is a form of titin deficiency with only distal muscle weakness (see Table 462e-9). Abbreviations: CK, creatine kinase; EMG, electromyography; NCS, nerve conduction studies; POMT1, protein-O-mannosyltransferase 1; POMT2, protein-O-mannosyltransferase 2; POMGNT1, O-linked mannose beta 1,2-N-acetylglucosaminyltransferase; TNPO3, transportin 3; TRAPC11, transport (trafficking) protein particle complex, subunit 11. in the cell membrane and Golgi complex.


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InternalMed_Harrison. in the cell membrane and Golgi complex. Dystrophin localizes to the cytoplasmic face of the muscle cell membrane. It complexes with two transmembrane protein complexes, the dystroglycans and the sarcoglycans. The dystroglycans bind to the extracellular matrix protein merosin, which is also complexed with β1 and α7 integrins (Tables 462e-5, 462e-6, and 462e-7). Dysferlin complexes with caveolin-3 (which binds to neuronal nitric oxide synthase, or nNOS) but not with the dystrophin-associated proteins or the integrins. In some of the congenital dystrophies and limb-girdle muscular dystrophies (LGMDs), there is loss of function of different enzymes that glycosylate α-dystroglycan, which thereby inhibits proper binding to merosin: POMT1, POMT2, POMGnT1, Fukutin, Fukutin-related protein, and LARGE.


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InternalMed_Harrison. The dystrophin-glycoprotein complex appears to confer stability to the sarcolemma, although the function of each individual component of the complex is incompletely understood. Deficiency of one member of the complex may cause abnormalities in other components. For example, a primary deficiency of dystrophin (Duchenne dystrophy) may lead to secondary loss of the sarcoglycans and dystroglycan. The primary loss of a single sarcoglycan (see “Limb-Girdle Muscular Dystrophy,” below) results in a secondary loss of other sarcoglycans in the membrane without uniformly affecting dystrophin. In either instance, disruption of the dystrophin-glycoprotein complexes weakens the sarcolemma, causing membrane tears and a cascade of events leading to muscle fiber necrosis. This sequence of events occurs repeatedly during the life of a patient with muscular dystrophy.


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InternalMed_Harrison. Glucocorticoids, administered as prednisone in a dose of 0.75 mg/kg per day, significantly slow progression of Duchenne dystrophy for up to 3 years. Some patients cannot tolerate glucocorticoid therapy; weight gain and increased risk of fractures in particular represent a significant deterrent for some boys. As in other recessively inherited dystrophies presumed to arise from loss of function of a critical muscle gene, there is optimism that Duchenne disease may benefit from novel therapies that either replace the defective gene or missing protein or implement downstream corrections (e.g., skipping mutated exons or reading through mutations that introduce stop codons). This less severe form of X-linked recessive muscular dystrophy results from allelic defects of the same gene responsible for Duchenne dystrophy. Becker muscular dystrophy is ~10 times less frequent than Duchenne.


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InternalMed_Harrison. Clinical Features The pattern of muscle wasting in Becker muscular dystrophy closely resembles that seen in Duchenne. Proximal muscles, especially of the lower extremities, are prominently involved. As the disease progresses, weakness becomes more generalized. Significant facial muscle weakness is not a feature. Hypertrophy of muscles, particularly in the calves, is an early and prominent finding. Most patients with Becker dystrophy first experience difficulties between ages 5 and 15 years, although onset in the third or fourth decade or even later can occur. By definition, patients with Becker dystrophy walk beyond age 15, whereas patients with Duchenne dystrophy are typically in a wheelchair by the age of 12. Patients with Becker dystrophy have a reduced life expectancy, but most survive into the fourth or fifth decade.


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InternalMed_Harrison. Mental retardation may occur in Becker dystrophy, but it is not as common as in Duchenne. Cardiac involvement occurs in Becker dystrophy and may result in heart failure; some patients manifest with only heart failure. Other less common presentations are asymptomatic hyper-CK-emia, myalgias without weakness, and myoglobinuria.