Neurology_Adams

Neurology_Adams. Alternatively, 1 mg (0.1 mL) of edrophonium is given intravenously; if this dose is tolerated and no definite improvement in strength occurs after 45 s, another 4 to 9 mg is injected. A total dose of 10 mg is rarely necessary. Most patients who respond do so after 3 to 5 mg has been administered. The mild muscarinic effects of edrophonium are blocked by pretreatment with atropine 0.8 mg subcutaneously as for neostigmine. The clinical effect of improved ptosis, extraocular movements, oropharyngeal function, arm and shoulder abduction, or vital capacity persists for no more than 5 min with edrophonium and 60 min with neostigmine.


Neurology_Adams

Neurology_Adams. One caution: with either drug, some patients deteriorate immediately, but briefly, as a result of an increase in pulmonary secretions. A positive test consists of visible (objective) improvement in muscle contractility, fusion of diplopia, or resolution of fatigable ptosis. Dynamometry and measurement of forced vital capacity serve as more objective markers of improvement, or lack of effect. The report of subjective improvement alone is not dependable and one must be distrustful of equivocal test results, which may occur with ocular palsies due to tumors, thyroid disease, Guillain-Barré syndrome (GBS), progressive supranuclear palsy, or carotid aneurysms (pseudoocular myasthenia).


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Neurology_Adams. A negative test with an anticholinesterase agent does not entirely exclude myasthenia gravis but is a strong point against the diagnosis. In a small number of patients with periodic and purely ocular symptoms who later prove to have myasthenia gravis, the edrophonium and neostigmine tests (and electrophysiologic studies and AChR antibody measurements) may be entirely normal during the first or even after several acute episodes. Only later, for inexplicable reasons, do these tests become positive. Finally, the anticholinesterase-inhibiting drugs carry a small risk of inducing ventricular fibrillation and cardiac arrest so that testing should be carried out where emergency support is accessible.


Neurology_Adams

Neurology_Adams. Measurement of receptor antibodies in blood The detection of anti-AChR antibodies provides a reasonably sensitive and highly specific test for the diagnosis of myasthenia. The radioimmunoassay method of detection is accurate and widely used. Serum antibodies are found in 80 to 90 percent of patients with generalized myasthenia gravis and in approximately 60 percent of those whose symptoms are restricted to the ocular muscles (Vincent and Newsom-Davis). For the most part, adults with myasthenia whose sera are persistently negative for AChR antibodies do not differ clinically or electromyographically from those with antibodies with the exception noted below. Persistently negative AChR antibody tests are more frequently found in patients with ocular myasthenia than in patients with generalized weakness. Patients with a thymoma and severe generalized myasthenia are practically always seropositive. Interestingly, the antibody titers usually remain elevated during clinical remissions.


Neurology_Adams

Neurology_Adams. Instances of “seronegative” disease are sometimes due to antibody production against unusual muscle epitopes that are located on or near the acetylcholine receptor; their detection requires a special panel of tests. However, the majority of such cases have been ascribed to IgG antibodies directed against an intracellular muscle-specific kinase (MuSK). This enzyme plays a role in supporting the normal structure of the postsynaptic membrane and in the arrangement of AChR but its main function may be in developmental synaptic differentiation. The illness is possibly acquired late in life because of the high rate or turnover of the neuromuscular junction, with newly formed junctions being physiologically inadequate. The associated clinical syndrome differs from typical myasthenia and was discussed earlier. Also of interest, but not currently used in routine diagnosis, is the presence of antibodies directed against striated muscle in almost half of myasthenic patients and an even higher


Neurology_Adams

Neurology_Adams. earlier. Also of interest, but not currently used in routine diagnosis, is the presence of antibodies directed against striated muscle in almost half of myasthenic patients and an even higher incidence (stated to be 85 percent) in patients who also have a thymoma. Rare instances of seronegative myasthenia with antibodies directed to cortactin, a protein in the pathway of MuSK has been described (Cortes-Vicente et al).


Neurology_Adams

Neurology_Adams. Each of the commonly used diagnostic tests, electrophysiology, edrophonium, and antibodies, proves to be about equally reliable. Kelly and coworkers obtained positive results with single-muscle-fiber recording in 79 percent, with the antireceptor antibody test in 71 percent, and with the edrophonium test in 81 percent. Combined, they confirmed the diagnosis in 95 percent of clinically suspected cases. Presumably, had the anti-MuSK receptor antibody test been available, the sensitivity of serologic diagnosis would have been higher. In keeping with the observation of some myasthenic patients that their weakness improves in the cold, a test has been devised in which an ice pack is placed over a ptotic eyelid for 2 min or to the limit of the patient’s tolerance. Sethi and colleagues found that ptosis was diminished in 8 of 10 patients. In our patients, this effect has not been as consistently evident, but it may be a useful adjunctive test.


Neurology_Adams

Neurology_Adams. Other diagnostic tests performed routinely in essentially all patients with myasthenia gravis include CT of the chest (for the detection of thymic enlargement or thymoma), tests of thyroid function for reasons discussed further on, and in cases of uncertain diagnosis, magnetic resonance imaging of the cranium and orbits to exclude compressive and inflammatory lesions of the cranial nerves and ocular muscles.


Neurology_Adams

Neurology_Adams. We have encountered the following clinical problems in myasthenia: 1. The concurrence of myasthenia gravis and thyrotoxicosis. Thyrotoxicosis may produce a characteristic ocular myopathy and there is a tentative relation to periodic paralysis as indicated in Chap. 45. There is no definite evidence that thyrotoxicosis aggravates myasthenia gravis; some clinicians have even observed an inverse relationship between the severity of the two conditions. Hypothyroidism, however, does worsen the myasthenic symptoms. The ophthalmoplegia of thyrotoxicosis can usually be distinguished by the presence of an associated exophthalmos (early in the disease, exophthalmos may be absent), lack of ptosis, and the lack of definitive response to neostigmine. Polymyositis and inclusion body myopathy are differentiated from myasthenia by lack of involvement of extraocular muscles, but they may affect oropharyngeal muscles, as does myasthenia. Finding the signs of these diseases in combination with those of


Neurology_Adams

Neurology_Adams. from myasthenia by lack of involvement of extraocular muscles, but they may affect oropharyngeal muscles, as does myasthenia. Finding the signs of these diseases in combination with those of myasthenia indicates a concurrence of two independent autoimmune diseases.


Neurology_Adams

Neurology_Adams. 2. The neurasthenic or depressed patient who complains of weakness when actually referring to fatigability. There is no ptosis, strabismus, or dysphagia, though an anxious individual may complain of diplopia (usually of momentary duration when drowsy) and also of tightness in the throat (globus hystericus). A number of such patients claim improvement with neostigmine but objective reversal is always uncertain. Conversely, myasthenia is as often mistaken for hysteria or other emotional illness, mainly because the physician is unfamiliar with myasthenia (or with hysteria) and has been overly impressed with the precipitation of the illness by an emotional crisis. Furthermore, fatigability is a feature of all of these conditions, but only in the psychiatric ones does it extend to the sphere of mental endurance. Those with myasthenia do not usually complain of fatigue of the mind, whereas these are frequent complaints in psychiatric conditions. A similar problem arises frequently on our


Neurology_Adams

Neurology_Adams. of mental endurance. Those with myasthenia do not usually complain of fatigue of the mind, whereas these are frequent complaints in psychiatric conditions. A similar problem arises frequently on our services in judging breathlessness due to anxiety or cardiopulmonary disease in a patient with presumed myasthenia. Careful appraisal of the breathing pattern and determination of the vital capacity or other spirometric measurements are helpful here.


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Neurology_Adams. 3. Progressive external ophthalmoplegia and other restricted myopathies, including the congenital myasthenic states. These may be mistaken for long-established myasthenia gravis. It should be emphasized that the extraocular muscles and levator palpebrae may be permanently damaged by myasthenia and cease to respond to neostigmine. Another possibility is that restricted ocular myasthenia may not respond to anticholinesterase drugs from the beginning and the diagnosis of myasthenia is erroneously excluded. One must then turn to other muscles for clinical and electromyographic and serologic confirmation of the diagnosis.


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Neurology_Adams. 4. Myasthenia with dysarthria and dysphagia, but without ptosis or obvious strabismus. These may be confused with multiple sclerosis, polymyositis, inclusion body myopathy, stroke, motor neuron disease, or some other neurologic disease. Testing with an anticholinesterase inhibitor, single-fiber and repetitive stimulation recording, and measurement of antibodies usually clarifies the matter. 5. The initial manifestations of botulism—blurred vision, diplopia, ptosis, strabismus, and ophthalmoparesis—may be mistaken for myasthenia gravis of acute onset. In botulism, however, the pupils are usually large and unreactive, and the eye signs are followed in rapid succession by involvement of bulbar, trunk, and limb muscles.


Neurology_Adams

Neurology_Adams. 6. Similarly, the oculopharyngeal-brachial and variants of Guillain-Barré syndrome (GBS) in the early stages have many of the features of myasthenia, including ptosis, that may be partially responsive to anticholinesterase drugs. The loss of tendon reflexes, acral paresthesias, and areflexia, or the development of ataxia in the limbs make the diagnosis of GBS at once apparent and detailed electrophysiologic testing distinguishes the two conditions. 7. Intoxication with organophosphate insecticides, because of their capacity to induce a cholinergic crisis, may be confused with a myasthenic crisis (see further on).


Neurology_Adams

Neurology_Adams. Certain other small clinical points may be helpful in differentiating myasthenia from other diseases that affect the cranial musculature. A hanging jaw and hanging head are indicative of myasthenia, whereas complete or asymmetric facial paresis is typical of GBS. Botulism usually affects the pupillary convergence reaction, and GBS does so only when there is complete internal and external ophthalmoplegia; diphtheria affects mainly the accommodative reaction early on. The question of midbrain stroke as a consequence of basilar artery occlusion arises in a case with total ophthalmoplegia; it should be recalled that the level of consciousness is usually reduced if vertical gaze and pupillary reactions are lost in cases of basilar artery stroke; such is not the case in neuromuscular diseases. The myasthenic syndrome of Lambert-Eaton, discussed further on, only occasionally affects the ocular muscles, but is identified by its other clinical and electrophysiologic features. Ocular paresis,


Neurology_Adams

Neurology_Adams. The myasthenic syndrome of Lambert-Eaton, discussed further on, only occasionally affects the ocular muscles, but is identified by its other clinical and electrophysiologic features. Ocular paresis, as may occur in nemaline polymyopathy, oculopharyngeal dystrophy, and thyrotoxic ophthalmic disease, come on too slowly in most cases to be confused with myasthenia gravis. On occasion, the eye movements in myasthenia simulate an internuclear ophthalmoplegia or other “central” sign, even to the extent of including nystagmus in an abducting eye.


Neurology_Adams

Neurology_Adams. The treatment of this disease involves the careful use of two groups of drugs—anticholinesterases and immunosuppressants including corticosteroids and in special acute circumstances, plasma exchange and intravenous immune globulin. An elective thymectomy is appropriate in many patients as discussed below. Consensus guidelines for treatment of myasthenia were issued in 2016 (see Sanders et al) but readers are advised to use clinical judgment in each case and consult the literature for newer versions as they appear.


Neurology_Adams

Neurology_Adams. Anticholinesterase drugs The two drugs that give the best results in ameliorating myasthenic weakness are neostigmine (Prostigmin) and pyridostigmine (Mestinon), the latter being preferred by most clinicians and patients. The usual dose of pyridostigmine is 30 to 90 mg given every 6 h (typically a 60-mg pill is tried first); the oral dose of neostigmine ranges from 7.5 to 45 mg given every 2 to 6 h. Extended-action forms of both drugs are available but are given at bedtime mainly to patients who complain of weakness during the night or early morning hours. The dosage of these drugs and their frequency of administration vary considerably from patient to patient, but we agree with Drachman (2003) that the maximal useful dosage of pyridostigmine rarely exceeds 120 mg given every 3 h. Table 46-1 lists the approximate dose-equivalents of these various drugs.


Neurology_Adams

Neurology_Adams. For mild cases, for patients in partial remission after thymectomy, and for purely ocular myasthenia, the use of anticholinesterase drugs may be the only form of therapy necessary for some period of time (ocular myasthenia often responds well to small doses of corticosteroids as noted further on). Although these drugs seldom relieve symptoms completely (the response of ocular symptoms is typically incomplete), most such patients are able to function well.


Neurology_Adams

Neurology_Adams. Glucocorticoids For the patient with moderate to severe generalized weakness who is responding inadequately to anticholinesterase drugs, the long-term administration of corticosteroids is the most consistently effective form of treatment, as described in a large series of patients by Pascuzzi and colleagues. Small doses of corticosteroids (prednisone 15 to 25 mg daily) alone or in combination with azathioprine (see later) are also often adequate to control ocular myasthenia. However, one must be prepared to contend with the side effects of long-term corticosteroid therapy and we hesitate to undertake such a program in children or patients with severe diabetes or other diseases that are likely to be aggravated. Because recent experience with the newer immunosuppressive agents was not incorporated into most prior series, the uniform use of steroids might not be correct.


Neurology_Adams

Neurology_Adams. The usual form of corticosteroid therapy is prednisone (or corresponding doses of prednisolone), beginning with 15 to 20 mg/d and increasing the dose gradually until a satisfactory clinical response is obtained or until a daily dose of 50 to 60 mg is reached. With higher doses or more rapid elevations of the doses, worsening of weakness in the first weeks may occur and hospitalization and careful observation for respiratory difficulty may be advisable. Improvement after the initiation of corticosteroids occurs over a few weeks. Once the maximal effect from prednisone has been attained, the dosage can be reduced gradually over months to the lowest point at which it is still effective. Our practice has been to then attempt to institute an alternate-day schedule, which diminishes the side effects; some patients have done better with a modest difference in dose from 1 day to the next, rather than omitting a dose entirely on alternate days. Potassium supplements and antacids should be


Neurology_Adams

Neurology_Adams. effects; some patients have done better with a modest difference in dose from 1 day to the next, rather than omitting a dose entirely on alternate days. Potassium supplements and antacids should be prescribed liberally if needed, as with any chronic corticosteroid regime and consideration should be given to prophylaxis with antibiotics for Pneumocystis infection, and bisphosphonate for osteoporosis if long-term treatment is anticipated. At the outset of steroid therapy, anticholinesterase drugs are given simultaneously; as the patient improves, the dosage of the latter may be adjusted downward.


Neurology_Adams

Neurology_Adams. Azathioprine and other immunosuppressive drugs Azathioprine is a useful adjunct to steroids in patients who cannot tolerate or fail to respond to prednisone. It has been possible to manage the disease reasonably well in a few of patients with azathioprine alone, but there is no study to support this practice (see Palace et al, 1998). Treatment typically begins with 50 mg (1 tablet) bid for a few days; if this is tolerated, the dosage is raised to 2 to 3 mg/kg/d (150 to 250 mg daily). However, improvement occurs much more slowly than with corticosteroids and a significant response may not be evident for many months to a year (Witte et al). Liver function tests and blood cell count should be checked regularly. The Myasthenia Gravis Clinical Study Group found that the most severe forms of the disease, particularly those resistant to either prednisone or azathioprine alone, benefit from the combination of the two medications. Azathioprine is a prodrug of mercaptopurine, which is


Neurology_Adams

Neurology_Adams. of the disease, particularly those resistant to either prednisone or azathioprine alone, benefit from the combination of the two medications. Azathioprine is a prodrug of mercaptopurine, which is metabolized principally by thiopurine methyltransferase (TPMT). Approximately 3 per 100,000 persons are deficient in the enzyme, for which reason, some clinicians measure its level before initiating azathioprine in order to avoid bone marrow toxicity; it has not been our practice to do so. There are many variant alleles of TPMT and a larger number of patients have partial deficiency of the enzyme or even excessive enzyme activity but it has not been clear how to utilize this information in myasthenia. Azathioprine interacts with other drugs such as allopurinol and warfarin.


Neurology_Adams

Neurology_Adams. Cyclosporine is another immunosuppressive drug that has shown benefit in clinical trials (Tindall et al). It is given in 2 divided doses daily, to a total of 6 mg/kg, but not often used currently because of serious side effects (hypertension, nephrotoxicity) and its high cost. Because of the success of alternative regimens, we have had occasion over the years to use cyclosporine only once for myasthenia. Mycophenolate is currently being used as an adjunct to corticosteroids and has been beneficial in several small trials but failed to demonstrate similar effect in larger controlled studies. The clinical improvement, when it does occur, has generally occurred sooner than it does with azathioprine (Meriggioli et al). Diarrhea was the main adverse effect. Several experts in the field believe that mycophenolate is preferable to most of the adjunctive medications and in some milder cases may be effective alone, but reconciling this view with recent failed trials is vexing.


Neurology_Adams

Neurology_Adams. De Feo and coworkers have used cyclophosphamide administered in intravenous pulses; they were able to remove 5 of their 12 patients from steroids, but the appropriate use of this potent agent is not clear and we have resorted to it infrequently. Drachman and colleagues (2003), as well as others, describe a regimen of high-dose cyclophosphamide (50 mg/kg/d for 4 consecutive days) followed by granulocyte-stimulating factor to “reboot” the immune system in refractory cases. This approach has risks but may be justified if all other measures have failed. Liver function and white blood cell count require monitoring. On the basis of pilot trials, many other drugs, for example, tacrolimus as reported by Ponseti and colleagues, rituximab, and etanercept have come into use in patients who are dependent on or resistant to corticosteroids, including those with antibodies to MuSK (Diaz-Manera et al).


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Neurology_Adams. Plasma exchange and intravenous immune globulin For severe myasthenia that is refractory to treatment with anticholinesterase drugs and prednisone, or during an acute period of worsening, one must resort to other measures. Striking temporary remissions (2 to 8 weeks) may be obtained by the use of plasma exchange. This form of treatment may be lifesaving during a myasthenic crisis. It also finds use before and after thymectomy and at the start of immunosuppressive drug therapy. Plasma exchange is also helpful in limiting the aforementioned weakness that is often induced by the institution of high-dose corticosteroids. The number and volume of exchanges required in these circumstances is somewhat arbitrary but they tend to be less than those required for GBS; several exchanges of 2 to 3.5 L each (totaling approximately 125 mL/kg) performed over a week usually suffice. The removed plasma is replaced with albumin and saline. It has been estimated that a 2-L exchange will remove 80 percent


Neurology_Adams

Neurology_Adams. each (totaling approximately 125 mL/kg) performed over a week usually suffice. The removed plasma is replaced with albumin and saline. It has been estimated that a 2-L exchange will remove 80 percent of circulating antibodies and that this will be reflected in reduced ACh antibody levels in 3 to 5 days. There is only an approximate correlation between a reduction in the titer of anti-AChR antibody and the degree of clinical improvement. In a crisis requiring plasma exchanges and mechanical ventilation, it has been our practice to discontinue or curtail the use of anticholinesterase drugs and resume them as the patient is being weaned from the ventilator. Also, it may be that sensitivity to these drugs may be enhanced in the hours after an exchange so that their dosages must be adjusted accordingly.


Neurology_Adams

Neurology_Adams. A small number of patients respond so well to plasma exchange and find the side effects of steroids so intolerable that they choose to be maintained with 2 to 3 exchanges every several weeks or months. Immuno–adsorption, a technique similar to plasma exchange that removes antibodies and immune complexes by passing blood over a tryptophan column, is less cumbersome than conventional plasma exchange and has been effective, but experience with this procedure is limited.


Neurology_Adams

Neurology_Adams. Intravenous immune globulin is similarly useful in the short-term control of acutely worsening myasthenia. The usual dose is 2 g/kg given in divided doses over 3 to 5 days. Several small series suggest that the effect is equivalent to a series of plasma exchanges. However, plasma exchange and immune globulin have been subjected to only limited systematic study or comparison and, while these treatments are invaluable in deteriorated patients or those in crisis, they offer only short-term benefit. In two separate small studies, Gajdos and colleagues and Barth et al found no difference between intravenous immune globulin (IVIg) and plasma exchange (1997) and no difference between IVIg 1 g/kg/d given for 1 or 2 days (2005) in myasthenic exacerbations, most cases of which were less severe than typical crisis.


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Neurology_Adams. Thymectomy This operation, first introduced by Blalock, despite the absence of proof in trials, is considered an appropriate procedure for many patients with generalized myasthenia gravis between puberty and 55 years of age. The surgery is performed electively and not during an acute deterioration of myasthenia. The remission rate after thymectomy is approximately 35 percent provided that the procedure is done in the first year or 2 after onset of the disease, and another 50 percent will improve to some extent (Buckingham et al). The remission rate is progressively lower, but not negligible, if the operation is postponed beyond this time. In patients with myasthenia restricted to the ocular muscles for a year or longer, the prognosis is so good that thymectomy is unnecessary. The response to thymectomy is not evident for several months and is usually maximal by approximately 3 years. In favorably responding cases, levels of circulating receptor antibody are reduced or disappear


Neurology_Adams

Neurology_Adams. to thymectomy is not evident for several months and is usually maximal by approximately 3 years. In favorably responding cases, levels of circulating receptor antibody are reduced or disappear entirely. If possible, thymectomy should be postponed until puberty because of the importance of the gland in the development of the immune system, but juvenile myasthenia is also quite responsive. The results are not as predictable in patients who harbor a thymoma.


Neurology_Adams

Neurology_Adams. It is only recently that an adequate randomized trial by Wolfe and colleagues has affirmed the usefulness of thymectomy. Beyond the demonstration of effect of the procedure over 3 years when coupled with alternate day prednisone compared to alternate day prednisone alone, certain of the outcomes of the trial were instructive but tentative due to the small number of patients enrolled: medical complications were lower in the surgical group as a result of reduced requirement for prednisone and immunosuppressive drugs, and the effects of the operation were clearer in women than in men. Viewing the Kaplan-Meier curves of that trial, it appears broadly that the effect of thymectomy was maximal at approximately 6 months and remained stable thereafter.


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Neurology_Adams. A suprasternal approach for removal of the gland has been developed and results in less postoperative pain and morbidity than occurs with a transsternal thoracotomy but the transsternal operation may be preferable because it assures a more complete removal of thymic tissue. Thymectomy is best performed in a hospital where there is close collaboration between the thoracic surgeon and the neurologist. If the patient is weak preoperatively, a course of plasma exchange or immune globulin may be given preceding the surgical procedure. Large “stress doses” of corticosteroids seem to be unnecessary in most patients who have been taking these medications chronically. After operation, respiratory assistance must be available if needed. Neostigmine intramuscularly may be given every 3 to 6 h postoperatively. Usually the dose requirement is about 75 percent of that taken before surgery. As improvement occurs, oral medications are resumed as remission is not anticipated for many months or longer


Neurology_Adams

Neurology_Adams. Usually the dose requirement is about 75 percent of that taken before surgery. As improvement occurs, oral medications are resumed as remission is not anticipated for many months or longer as noted above.


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Neurology_Adams. Thymectomy may also be a safe and effective treatment in elderly patients with myasthenia. In 12 such individuals, Olanow and associates reported complete remission in 9 and clinical improvement in the remainder. The improvement in older patients is less convincing than it is in the younger group, in part because the thymus is atrophic. Nonetheless, some of our patients who were older than age 60 years did benefit. The abovementioned clinical trial did not include patients over age 65 years.


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Neurology_Adams. Removal of the thymus gland is also indicated in practically all patients in whom thymoma is detected by CT of the chest. The tumor can be locally invasive but rarely metastasizes. The operative approach is through the anterior thorax, with adequate exposure to remove all the tumor tissue. If the tumor cannot be removed completely, the remaining tissue should be treated with focused radiation. Local spread and lymph node invasion have been treated with combinations of chemotherapy including cisplatin, but it is not very satisfactory. Park and colleagues concluded from a large retrospective study of metastatic cases that chemotherapy offers some benefit in terms of survival, but this remains controversial. Despite this endorsement of thymectomy for generalized myasthenia, it has remained an unproven therapy by a modern trial and attempts to recruit patients for such an endeavor have been difficult.


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Neurology_Adams. A rapid and severe deterioration of the myasthenia, termed myasthenic crisis, can bring the patient to the brink of respiratory failure in a matter of hours. A respiratory infection or excessive use of sedative medications or drugs with a potential for blocking neuromuscular transmission may precede the myasthenic crisis. We have encountered numerous cases in which oropharyngeal weakness has led to aspiration pneumonia, which, in turn, precipitated a crisis. Just as often, a precipitating event is not evident. Rarely, a respiratory arrest is the first manifestation of crisis. Such events may occur at any time after the diagnosis of myasthenia, but half are evident within 12 to 18 months. In an early but still salient experience with 53 patients in myasthenic crisis at the Columbia-Presbyterian Medical Center, pneumonia was the most frequent precipitating event, but no cause could be determined in almost one-third of cases (Thomas et al).


Neurology_Adams

Neurology_Adams. Incipient respiratory failure is usually marked by a reduction of vital capacity, often accompanied by restlessness, anxiety, diaphoresis, or tremor. Once the diaphragm fails, movements of the chest wall and abdomen become paradoxical (the abdomen moves inward during inspiration) or there may be shallow excursions of the chest, alternating with paradoxical movements as discussed in Chap. 25 where the characteristics of neuromuscular respiratory failure are described. In an emergency, after clearing of the airway, such a patient can be supported briefly by a tight-fitting face mask and manual bag (Ambu) breathing. The chest wall will be very compliant as a result of muscular weakness.


Neurology_Adams

Neurology_Adams. Management of the crisis entails timely and careful intubation followed by mechanical ventilation in a critical care unit that is equipped to attend to the medical and neurologic needs of such patients. Respiratory failure in a few patients can be managed by the use of bilevel positive airway pressure (BIPAP) according to Rabinstein and Wijdicks, but in our experience, this has not been consistently effective in avoiding endotracheal intubation. One must cope with both the oropharyngeal weakness and secretions that endanger the airway, and the diaphragmatic weakness. Anticholinesterase drugs, which exaggerate secretions, are best withdrawn at the time of intubation. A useful maneuver is to allow the patient to remain off cholinergic drugs for several days while on a ventilator; there is often a heightened response to the reinstitution of medications after this period. The use of plasma exchange or intravenous gamma globulin as described earlier, is equivalently effective in hastening


Neurology_Adams

Neurology_Adams. a heightened response to the reinstitution of medications after this period. The use of plasma exchange or intravenous gamma globulin as described earlier, is equivalently effective in hastening improvement and weaning from the ventilator. Some of our colleagues have used high-dose corticosteroid infusions in these circumstances but this measure has not been particularly successful in our unit and, in the short run, carries the risk of inducing worsening of the weakness (Panegyres et al).


Neurology_Adams

Neurology_Adams. Patients with myasthenic crisis generally respond to plasma exchange or to immunoglobulin infusions in 1 or 2 days, but more often a week or more is required for recovery after a full course of 4 to 5 exchanges or 3 to 5 g/kg IVIg given in divided daily doses. Whether the previously mentioned studies (e.g., Gajdos et al) comparing the 2 treatments and comparing doses of IVIg in myasthenic exacerbations are pertinent to crisis is unknown but we almost always institute one or the other soon after it as it is apparent that respiratory failure is imminent or worsening.


Neurology_Adams

Neurology_Adams. It is generally best to wait 2 or 3 weeks before committing a patient to tracheostomy. When weaning from the ventilator is anticipated, anticholinesterase agents are reintroduced slowly, and treatment with corticosteroids can be instituted if necessary. Oral doses of 60 mg pyridostigmine or 15 mg neostigmine are roughly equivalent to 0.5 to 1 mg neostigmine intravenously and 1.5 to 2 mg intramuscularly, as noted in Table 46-1. The management of the critically ill patient with myasthenia is reviewed in the monograph by Ropper and colleagues.


Neurology_Adams

Neurology_Adams. Most patients with myasthenic crisis take several weeks to recover, and a few of our patients have remained ventilator-dependent for months. In the extensive experience of 53 patients from Columbia-Presbyterian, half of the patients could be safely extubated within 2 weeks and three-quarters by a month (Thomas et al). There were 7 deaths among 53 patients, reflecting the gravity of this syndrome even in the modern era of intensive care. Atelectasis, severe anemia, congestive heart failure, and clostridial diarrhea (associated with antibiotic use) portend a prolonged period of generalized weakness and intubation. From time to time, one encounters a patient in whom respiration and ambulation do not improve for many months after a myasthenic crisis. In our experience these have been middle-aged or older patients, usually women, in whom an element of hyperthyroidism or hypothyroidism may have been operative. They become wasted as the proximal limb and axial muscles, including the


Neurology_Adams

Neurology_Adams. middle-aged or older patients, usually women, in whom an element of hyperthyroidism or hypothyroidism may have been operative. They become wasted as the proximal limb and axial muscles, including the diaphragm, fail to recover their power, even though the ocular and oropharyngeal muscles improve. The role of corticosteroids in producing a concomitant proximal myopathy is a consideration that can be solved by careful electrophysiologic examination.


Neurology_Adams

Neurology_Adams. If the response to anticholinesterase drugs is poor and progressively larger doses are not relieving symptoms, there is consideration of a cholinergic crisis. In our own experience with more than 80 patients of severe myasthenia in an intensive care unit, we have been persuaded of the occurrence of a cholinergic crisis only rarely. This consists of a relatively rapid increase in muscular weakness, usually coupled with the adverse muscarinic effects of the anticholinesterase drug (nausea, vomiting, pallor, sweating, salivation, bronchorrhea, colic, diarrhea, miosis, bradycardia). An impending cholinergic effect is betrayed by constriction of pupils. If the blood pressure falls with bradycardia, 0.6 mg atropine sulfate may be given slowly by the intravenous route. Neostigmine or repetitive stimulation may be used to determine whether or not weakness is to the result of an excess of anticholinesterase medications. However, this test has been misleading and undoubtedly has contributed to


Neurology_Adams

Neurology_Adams. stimulation may be used to determine whether or not weakness is to the result of an excess of anticholinesterase medications. However, this test has been misleading and undoubtedly has contributed to an overestimation of the frequency and importance of the cholinergic crisis. Infection, or the natural course of the disease, has been far more common causes of acutely worsening weakness and respiratory failure.


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Neurology_Adams. The only recourse in cases of long-standing and severe, intractable myasthenia is to continue an average dose of corticosteroids, immunosuppressive, and anticholinesterase medications with intermittent trials of immune globulin or plasma exchanges. This is also a desperate situation in which high-dose cyclophosphamide followed by granulocyte-stimulating factor, as mentioned earlier, may result in slow improvement. Other agents such as rituximab may be tried. Whether thymectomy, undoubtedly risky in these sick patients, effects severe and long-established myasthenia is not known but its effects in any case, would be delayed.


Neurology_Adams

Neurology_Adams. Management of anesthesia and pregnancy in the myasthenic patient Surgical procedures of any type are often sufficiently stressful to produce decompensation of the disease. If the patient is unable to take medications orally, anticholinesterase agents may be given intramuscularly (approximately one-thirtieth of the oral dose of pyridostigmine and one-tenth the oral dose of neostigmine listed in Table 46-1). If corticosteroids were being used, they may be continued and the dose generally left unchanged; large “stress” doses are generally unnecessary, as mentioned earlier in the discussion of thymectomy. Neuromuscular blocking agents of the noncompetitive type may have a very prolonged effect in these patients and should be avoided as part of the anesthetic regimen. If they are necessary for some reason, a period of mechanical ventilation should be anticipated. In contrast, the dose of succinylcholine (which is not recommended) required to produce muscle relaxation may be larger than


Neurology_Adams

Neurology_Adams. for some reason, a period of mechanical ventilation should be anticipated. In contrast, the dose of succinylcholine (which is not recommended) required to produce muscle relaxation may be larger than usual. Any drug, the use of which is contemplated in anesthetic and postsurgical management, should be checked against the list of agents that are capable of exaggerating myasthenic weakness (see further on).


Neurology_Adams

Neurology_Adams. Pregnancy is usually uncomplicated in patients with myasthenia but some women who are partially treated for myasthenia and have generalized weakness may have difficulty in assisting with vaginal delivery. However, the use of intravenous cholinesterase inhibitors is contraindicated because of the possibility of inducing uterine contractions, and cytotoxic drugs are generally avoided during pregnancy because of the potential for fetal abnormalities. Also, magnesium is not recommended for the treatment of eclampsia because its neuromuscular blocking effects may worsen myasthenic weakness. Delivery usually proceeds normally, and breast-feeding is not thought to be a problem with regard to the transmission of AChR antibodies. Almost half of women with myasthenia have an exacerbation of varying degree in the several weeks postpartum. A rapidly dropping level of alpha-fetoprotein has been implicated as this protein inhibits binding of antiacetylcholine antibodies to postsynaptic receptors.


Neurology_Adams

Neurology_Adams. degree in the several weeks postpartum. A rapidly dropping level of alpha-fetoprotein has been implicated as this protein inhibits binding of antiacetylcholine antibodies to postsynaptic receptors. The issues of neonatal myasthenia and of reduced intrauterine movements with arthrogryposis are considered later.


Neurology_Adams

Neurology_Adams. Considered here are several disorders of neuromuscular transmission characterized clinically by muscular weakness and fatigability but differing in mechanism from autoimmune myasthenia gravis. The Lambert-Eaton myasthenic syndrome, neonatal myasthenia, the congenital myasthenic syndromes, and the myasthenic syndromes induced by drugs and toxins are the main disorders in this group. Two additional important diseases—botulism and organophosphate poisoning—are described elsewhere in the book. The Myasthenic-Myopathic Syndrome of


Neurology_Adams

Neurology_Adams. This special form of neuromuscular disorder that in a few ways simulates myasthenia gravis, is observed most often in patients with small cell carcinoma of the lung, was first described by Lambert, Eaton, and Rooke in 1956 and further by Eaton and Lambert in 1957. Unlike myasthenia gravis, the muscles of the trunk, shoulder girdle, pelvic girdle, and lower extremities are the ones that become weak and fatigable. The first symptoms are difficulty in arising from a chair, climbing stairs, and walking; the shoulder muscles are usually affected later. Although ptosis, diplopia, dysarthria, and dysphagia may occur, presentation with these symptoms is distinctly unusual. Increasing weakness after exertion stamps the condition as myasthenic, but in direct contrast to myasthenia gravis, there may be a temporary increase in muscle power during the first few contractions. The tendon reflexes are often diminished but complete abolition of the reflexes should raise the question of an associated


Neurology_Adams

Neurology_Adams. be a temporary increase in muscle power during the first few contractions. The tendon reflexes are often diminished but complete abolition of the reflexes should raise the question of an associated carcinomatous polyneuropathy. Fasciculations are not seen.


Neurology_Adams

Neurology_Adams. An instructive review of this disease by O’Neill and colleagues consisted of 50 well-studied cases, in which they described proximal leg weakness in all, arm weakness in 39, diplopia in 25, ptosis in 21, and dysarthria in 12. Symptoms were paresthesias, aching pain (suggesting arthritis), and a number of autonomic disturbances, such as dryness of the mouth, constipation, difficult micturition, and impotence. This latter group of symptoms gives the syndrome an unmistakable stamp as discussed further on under “Diagnosis.” One should not be surprised to find other neurologic manifestations of neoplasia (e.g., polyneuropathy, polymyositis or dermatomyositis, multifocal leukoencephalopathy, cerebellar degeneration, as discussed in Chap. 30).


Neurology_Adams

Neurology_Adams. The onset of weakness is subacute and the course, variably progressive. Males are affected far more often than females (5:1). The weakness may precede discovery of the tumor by months or years. Approximately 60 percent of cases are associated with small cell lung cancer, but small numbers have also occurred with carcinoma of the breast, prostate, stomach, and rectum, and with lymphomas; in about one-third of patients, no tumor is found. Some cases are associated with other autoimmune diseases, but most are paraneoplastic or idiopathic. The condition may occur in children, usually with no relation to tumor. In the tumor cases, death usually occurs in a few months or years from the effect of the neoplasm; the idiopathic ones fluctuate over years.


Neurology_Adams

Neurology_Adams. The response to neostigmine and pyridostigmine is poor or at least unpredictable, and this finding in a myasthenic patient should bring the diagnosis of Lambert-Eaton syndrome to mind. In contrast, d-tubocurarine, suxamethonium chloride, gallamine, and other muscle relaxants have a deleterious effect and may cause fatality, just as in myasthenia gravis.


Neurology_Adams

Neurology_Adams. Conventional electrodiagnostic studies show no abnormality in the peripheral nerves. A single stimulus of nerve may evoke a low-amplitude muscle action potential (in contrast to myasthenia gravis, in which it is normal or nearly so) whereas at fast rates of stimulation (50 per s as shown in Fig. 2-15B) or following strong voluntary contraction (for 15 s or longer) there is a marked increase in the amplitude of action potentials (incrementing response hence the term “inverse myasthenia,” which has been applied to Lambert-Eaton syndrome [LEMS]). Single-fiber recordings show an increase in “jitter” as in myasthenia gravis, as described in Chap. 2.


Neurology_Adams

Neurology_Adams. Elmquist and Lambert, from a series of studies of excised muscle, deduced that there is a defect in the release of ACh quanta from the presynaptic nerve terminals, akin to the effects of botulinum toxin, magnesium excess, and neomycin. The presynaptic vesicles themselves appear to be normal in morphology and content. Also in contrast to myasthenia gravis, the surface area of the postsynaptic receptor membrane in this syndrome is actually increased (A.G. Engel, 1976). The physiologic mechanism in Lambert-Eaton myasthenic syndrome is a loss of voltage-gated calcium channels on the presynaptic motor nerve terminal. The calcium channels become cross-linked and aggregated by IgG autoantibodies, ultimately reducing the number of functioning channels (Fukunaga et al). These antibodies against a specific component of the presynaptic membrane have the effect of reducing the presynaptic release of ACh, virtually the opposite of myasthenia gravis.


Neurology_Adams

Neurology_Adams. A serologic test for these antibodies (anti-VGKC) is available and is performed to confirm the diagnosis. Even in patients without detectable antibodies against voltage-gated calcium channels, passive transfer experiments indicate the presence of a circulating factor with similar activity. Muscle biopsy is normal or shows only the same slight, nonspecific changes as in myasthenia gravis. The thymus is, of course, normal.


Neurology_Adams

Neurology_Adams. Recognition of the Lambert-Eaton syndrome should lead to a search for an occult tumor, particularly of the lung. A positron emission tomography (PET) scan of the body may be useful for this purpose, although CT of the lungs is usually adequate. If found, it should be treated; this alone may result in improvement in the neurologic syndrome. If none is found, the search should be repeated at regular intervals, as the tumors at first are small and may be inapparent even at autopsy. Numerous cases of the more typical paraneoplastic syndromes discussed in Chap. 30, such as cerebellar degeneration, may coexist with the Lambert-Eaton syndrome, most of them are a result of small cell lung cancer (see Mason and colleagues) while others are a result of idiopathic antibodies to the calcium channels.


Neurology_Adams

Neurology_Adams. Treatment Most patients with this disorder benefit mildly or moderately from administration of 3,4-diaminopyridine (3,4-DAP), an agent that blocks potassium channels in the distal motor terminal, thus prolonging depolarizations and enhancing the release of ACh vesicles. The drug is given as 20 mg, up to 5 times a day, either alone or in conjunction with pyridostigmine (Lundh et al). It is not approved by the FDA in the United States and must be obtained from specialty pharmacies but nonetheless, has replaced the formerly used guanidine hydrochloride that had hematologic and renal toxicity with long-term use. With regard to long-term relief, numerous regimens have been tried and favored by different groups. Streib and Rothner were able to achieve improvement with prednisone. Dau and Denys have claimed the best results in nontumor cases with repeated courses of plasmapheresis in combination with prednisone and azathioprine. Intravenous immune globulin has also been effective in a few


Neurology_Adams

Neurology_Adams. have claimed the best results in nontumor cases with repeated courses of plasmapheresis in combination with prednisone and azathioprine. Intravenous immune globulin has also been effective in a few reported cases. Bain and coworkers indicate that the benefit is a result of reduction in calcium channel autoantibodies, but the mechanism whereby intravenous immune globulin produces this effect could not be established. Many clinicians prefer alternate-day administration of prednisone and azathioprine (prednisone 25 to 60 mg/d, and azathioprine 2 to 3 mg/kg body weight daily) supplemented intermittently as needed by intravenous immune globulin. The response to treatment tends to be slow, over a period of months and sometimes up to a year. Some patients recover fully; in others, restoration of power is incomplete.


Neurology_Adams

Neurology_Adams. Diagnosis A syndrome of symmetrical weakness and fatigability of proximal muscles coupled with dry mouth, sphincter disturbances, aching muscles, and diminished reflexes are diagnostic. The illnesses with which it might be confused are myasthenia gravis, inclusion body myopathy, and polymyositis. There is a superficial resemblance to hysterical paralysis, where the patient may do better with encouragement on making a succession of voluntary contractions, and arthritis, where pain hampers the first movements more than the successive ones. Then the electrodiagnostic and specific serologic tests are of value.


Neurology_Adams

Neurology_Adams. An estimated 10 to 20 percent of babies born to mothers with myasthenia show transient signs of myasthenia (hypotonia, weak cry, and suck). This transitory phenomenon is apparent at birth and has a mean duration of about 2 to 5 weeks; recovery is usually complete within 2 months of birth (rarely longer), without later relapse. Uncommonly, the mother with myasthenia reports reduced intrauterine movements, suggesting a dangerous degree of myasthenia in the fetus. A few of these children will be born with arthrogryposis, the result of a sustained period of intrauterine immobility, and this complication tends to recur in subsequent births.


Neurology_Adams

Neurology_Adams. It has long been assumed that neonatal myasthenia is a result of the passive transplacental transfer of AChR antibodies. This explanation is not entirely satisfactory insofar as maternal AChR antibodies are transferred from mother to fetus in all AChR antibody-positive pregnancies and the incidence and severity of neonatal myasthenia gravis do not correlate with the severity or duration of the mother’s illness or with the serum level of the maternal AChR antibody. In fact, neonatal myasthenia may occur when the mother is in remission. Administration of plasma exchange and anticholinesterase drugs to the infant may be useful in hastening recovery from neonatal myasthenia.


Neurology_Adams

Neurology_Adams. Administration of plasma exchange and anticholinesterase drugs to the infant may be useful in hastening recovery from neonatal myasthenia. Sporadically in the medical literature, there have appeared reports of a benign congenital myopathy in which myasthenic features could be recognized in the neonatal period or soon thereafter. The affected infants had been born to mothers who did not have myasthenia and were in the past described under headings such as “Myasthenia Gravis in the Newborn” and “Familial Infantile Myasthenia” (Greer and Schotland; Robertson et al) to distinguish the condition from passively transmitted neonatal myasthenia.


Neurology_Adams

Neurology_Adams. In the 1970s and 1980s, after the autoimmune basis of myasthenia gravis was established and its morphologic and physiologic features defined, the differences between this disease and the familial infantile forms became evident. Since then, at least 8 distinct and rare congenital myasthenic syndromes have been delineated on the basis of their electrophysiologic and ultrastructural features, and a number of others have been partially characterized. As indicated in Table 46-3, the congenital myasthenic syndromes are inherited defects in components of the presynaptic, synaptic, or postsynaptic junctional apparatus. Broadly speaking, the defects involve resynthesis or packaging of ACh or a paucity of synaptic vesicles (presynaptic); deficient quantal release; a deficiency of endplate ACh esterase (synaptic); or kinetic abnormalities in the AChR channels, or AChR deficiency (postsynaptic). It has been estimated that in three-fourths of the cases, the defect is postsynaptic.


Neurology_Adams

Neurology_Adams. These disorders are distinguished by neonatal onset, fluctuating and sometimes progressive weakness that may be quite severe, sometimes pronounced muscle hypotrophy, persistent ptosis, and seronegativity for anti-AChR and anti-MuSK antibodies. Moreover, heritability (typically autosomal recessive) is suggested by familial occurrence of the disorders among siblings. The most important clue to the disease in the neonate is an increase in ptosis and in bulbar and respiratory weakness with crying. Later in infancy these symptoms, as well as fluctuating ocular palsies and abnormal fatigability, are brought out by other types of sustained activities. Motor milestones may be delayed. In some cases, the myasthenic weakness and fatigability do not become evident until the second and third decades of life. Testing with anticholinesterase drugs is inconsistently positive in a few forms of congenital myasthenia as mentioned further on, but it usually is negative.


Neurology_Adams

Neurology_Adams. Two of the congenital myasthenic diseases—fast channel syndrome and slow channel syndrome—are consequences of mutations in AChR subunits that accelerate (fast channel) and slow (slow channel) the kinetics of gating of receptor channel (Croxen et al). Another well-characterized type, usually causing arthrogryposis and recurrent apneic spells but occasionally having an adult onset (as late as 48 years) has been traced to mutations in the “rapsyn” gene. The rapsyn protein plays a role in maintaining the integrity of the postsynaptic membrane (see Burke et al). Deficiency of the enzyme required to synthesize and package ACh in vesicles (choline acetyltransferase) causes a congenital myopathy with episodes of stress-induced apnea. In another type, the synaptic vesicles form poorly and are reduced in number. Being largely presynaptic defects, both of these disorders respond to acetylcholine esterase (AChE) inhibitors. In comparison, children with congenital myasthenia as a result of


Neurology_Adams

Neurology_Adams. reduced in number. Being largely presynaptic defects, both of these disorders respond to acetylcholine esterase (AChE) inhibitors. In comparison, children with congenital myasthenia as a result of deficiency of AChE deteriorate markedly if given AChE inhibitors. Three disorders affecting postsynaptic structures (the fast-channel syndrome, AChR deficiency, and the myasthenic syndromes associated with deficiencies of rapsyn and plectin) also respond to AChE inhibition and 3,4-DAP, although both agents are hazardous in individuals with the slow-channel syndrome.


Neurology_Adams

Neurology_Adams. Another recently discovered congenital myasthenia is caused by a recessive mutation in DOK-7 that causes a simplified structure of the synapse but no alteration in acetylcholine receptors (Beeson et al). The clinical features as described by Palace and colleagues (2007) are of a limb-girdle pattern of weakness that causes a delay in walking after the child has reached other normal motor milestones and of ptosis from an early age. A further category of congenital syndromes of defects in the presynaptic quantal release of acetylcholine have been described by Milone and colleagues and an intriguing prenatal myasthenic disease called Escobar syndrome (arthrogryposis, pterygia, and respiratory distress) has been traced to mutations in the gamma subunit of the acetylcholine receptor, a component expressed only in fetal life and replaced with maturity by the epsilon subunit (see Hoffmann and coworkers).


Neurology_Adams

Neurology_Adams. The studies of A.G. Engel have systematically defined and classified these disorders in a series of extensive investigations of more than 100 cases. A detailed account of this work can be found in his review with Ohno and Sine and in the chapter on the subject in his monograph Myasthenia Gravis and Myasthenic Disorders. Other Drugs and by Environmental Toxins (See Chap. 41 and Table 46-2)


Neurology_Adams

Neurology_Adams. Other Drugs and by Environmental Toxins (See Chap. 41 and Table 46-2) Many drugs can cause a myasthenic syndrome or a worsening of myasthenia gravis by their action on preor postsynaptic structures. In the case of a nonmyasthenic patient, this is most likely to happen in the presence of hepatic or renal disease that allows excessive accumulation of the causative agent. The myasthenic state in these conditions is acute and lasts hours or days, with full recovery provided that the patient does not succumb to respiratory failure. The ocular, facial, and bulbar muscles are involved, just as in native myasthenia. The treatment is to provide respiratory support, discontinue the offending drug, and attempt to reverse the conduction block at the motor endplate by infusions of calcium gluconate, potassium, and anticholinesterases, along the lines suggested by Argov and Mastaglia.


Neurology_Adams

Neurology_Adams. There are more than 30 drugs in current clinical use (other than anesthetic agents) that may, under certain circumstances, interfere with neuromuscular transmission in otherwise normal individuals. Of these, the most important are the aminoglycoside and quinolone antibiotics. Myasthenic weakness has been reported with 18 different antibiotics but particularly neomycin, kanamycin (less so with gentamicin), colistin, streptomycin, polymyxin B, and certain tetracyclines (McQuillen et al; Pittinger et al). It has been shown that these drugs impair transmitter release by interfering with calcium ion fluxes at nerve terminals. The fluorinated quinolones (fluoroquinolones)—typified by ciprofloxacin—affect both preand postsynaptic activity. They are especially hazardous when given to patients with myasthenia but they may be used if necessary to treat infections in patients who are already receiving ventilatory support.


Neurology_Adams

Neurology_Adams. Other agents—particularly the organophosphate insecticides and nerve gases—cause paralysis by binding to cholinesterase and blocking the hydrolysis of ACh. The endplate remains depolarized and is refractory to neural stimuli. The most notable of these agents are (1) botulinum toxin, which binds to cholinergic motor endings, blocking quantal release of ACh; (2) black widow spider venom, which causes a massive release of ACh, resulting in muscular contraction and then paralysis from a lack of ACh; (3) d-tubocurarine, which binds to AChR; (4) suxamethonium and decamethonium, which also bind to AChR; (5) organophosphates, which bind irreversibly to AChE; and (6) malathion and parathion, which inhibit AChE. The actions of all these agents except for the organophosphate “nerve gases” are transitory.


Neurology_Adams

Neurology_Adams. The administration of d-penicillamine has also caused an unusual type of myasthenia. The weakness is typical in that rest increases strength—as do neostigmine and edrophonium—and the electrophysiologic findings are also the same. In such cases, Vincent and associates (1978) found anti-AChR antibodies in the serum; hence, one must assume that this is a form of induced autoimmune myasthenia gravis. In these respects it differs from the weakness caused by aminoglycosides (see review by Swift). Rarely, typical autoimmune myasthenia gravis develops as part of a chronic graft-versus-host disease in long-term (2to 3-year) survivors of allogeneic marrow transplants.


Neurology_Adams

Neurology_Adams. A large group of naturally occurring environmental neurotoxins are known to act at the neuromuscular junction and to induce muscle paralysis of a pattern like that of myasthenia gravis. Venoms of certain snakes, spiders, and ticks are common and well-known animal poisons, as are ciguatera and related toxins (from fish that have ingested certain dinoflagellates), curare (from plants), and Clostridium botulinum—all of which are discussed in other parts of this book, particularly Chap. 41. Poisoning by these natural neurotoxins constitutes an important public health hazard in many parts of the world. This class of disorders of neuromuscular transmission has been reviewed by Senanayake and Roman. MYOTONIAS, PERIODIC PARALYSES, AND STATES OF PERSISTENT MUSCLE FIBER ACTIVITY (CHANNELOPATHIES)


Neurology_Adams

Neurology_Adams. This section considers a category of disorders that is characterized by disturbances of the electrical excitability of the skeletal muscle membrane. Although the main manifestations are episodes of generalized paralysis and myotonia, there are many others. Another related group of diseases are unified by spontaneous and persistent muscle fiber activity and these are addressed in a later part of this chapter. The myotonias have been historically categorized as a special group of muscle diseases unified by the clinical sign of myotonia and were aligned in older classifications with the muscular dystrophies. This view was based on myotonia as it was understood in the classic form of myotonic dystrophy, a subject discussed in Chap. 45. Similarly, before fundamental knowledge of their mechanism was revealed, the periodic paralyses (better called episodic paralysis) were considered to be metabolic diseases of muscle. However, it has become evident that most diseases that feature prominent


Neurology_Adams

Neurology_Adams. was revealed, the periodic paralyses (better called episodic paralysis) were considered to be metabolic diseases of muscle. However, it has become evident that most diseases that feature prominent myotonia and the processes that cause episodic muscular paralysis are neither degenerative nor dystrophic. Clinical and electrophysiologic studies show that myotonia is an elemental feature of many nondystrophic conditions, foremost among them are the hyperkalemic form of periodic paralysis and myotonia congenita. Most of these diseases are caused by mutations in genes that code for chloride, sodium, calcium, or potassium ion channels in the muscle membrane, and they are referred to as ion channel diseases, or “channelopathies” (see Ryan and Ptácek). Within this group there are also instances of muscle conditions that display no myotonia but only periodic paralysis.


Neurology_Adams

Neurology_Adams. Given that these are disorders of muscle membrane excitability, it is not surprising that the primary defects are in voltage-dependent ion channels. By analogy, it was anticipated that ion channelopathies would be implicated in 2 other categories of disease in which there is altered membrane excitability, namely the epilepsies and certain cardiac arrhythmias and indeed, this has proven to be the case (see discussion in Chap. 15 on the epilepsies). In the process, several new forms of nondystrophic myotonia have been defined. Molecular studies, notably those of Rüdel, Lehmann-Horn (2004), and Ricker and their associates, identified the fundamental defects in the myotonias and episodic paralyses and clarified their relationships. The biology of the ion channels and their disease-related mutations are reviewed by Hanna and colleagues, by Cannon, and by Heatwole and colleagues.


Neurology_Adams

Neurology_Adams. Cannon, and by Heatwole and colleagues. Table 46-4 summarizes the main features of the ion channel diseases affecting muscle and the individual members of the group are described as follows. This is an uncommon disease of skeletal muscle that begins in early life and is characterized by myotonia, muscular hypertrophy, nonprogressive course, and dominant inheritance. It is distinctly different from myotonic dystrophy, which is characterized by a progressive degeneration of muscle fibers and has a different genetic basis. Thomsen disease is caused by one of several inherited molecular defects in the voltage-dependent chloride channel gene (CLCN1), (see Koch et al). It is interesting that most mutations behave as dominant traits, whereas others have either a dominant or recessive pattern of inheritance (see Table 46-4). The physiologic mechanism whereby these mutations alter ion fluxes across the muscle membrane and cause myotonia is described further on.


Neurology_Adams

Neurology_Adams. History The disorder was first brought to the attention of the medical profession in 1876 by Julius Thomsen, a Danish physician who himself suffered from the disease, as did 20 members of his family over 4 generations. His designation of ataxia muscularis was not correct, but his description left no doubt as to the nature of the condition in that it featured “tonic cramps in voluntary muscles associated with an inherited psychical indisposition.” The latter aspect of the condition was not borne out by subsequent studies and is now thought to be his erroneous speculation as to causality. In 1881, Strümpell assigned the name myotonia congenita to the disease and in 1883, Westphal referred to it as Thomsen’s disease. Erb provided the first description of its pathology and called attention to 2 additional unique features: muscular hyperexcitability and hypertrophy. In 1923, Nissen, Thomsen’s great-nephew, extended the original genealogy to 35 cases in 7 generations, and in 1948,


Neurology_Adams

Neurology_Adams. to 2 additional unique features: muscular hyperexcitability and hypertrophy. In 1923, Nissen, Thomsen’s great-nephew, extended the original genealogy to 35 cases in 7 generations, and in 1948, Thomasen’s monograph is still a useful clinical reference.


Neurology_Adams

Neurology_Adams. Myotonia, a tonic spasm of muscle after forceful voluntary contraction, stands as the cardinal feature and is best represented in this disease. As emphasized in Chaps. 2 and 45, this phenomenon reflects electrical hyperexcitability of the muscle membrane. The electrophysiologic representation of the spasm is shown in Fig. 2-19 and a description of the physiology can be found in Chap. 2. It is most pronounced after a period of inactivity. Repeated contractions “wear it out,” so to speak, and the later movements in a series become more swift and effective. Rarely, the converse is observed—where only the later movements of a series induce myotonia (myotonia paradoxica); usually this is a feature of another condition, cold-induced paramyotonia congenita (see further on). Unlike cramp, the myotonic spasm is painless but after prolonged activity, nocturnal myalgia (a pinching-aching sensation in the overactive muscles) may develop and prove distressing. Close observation reveals a softness


Neurology_Adams

Neurology_Adams. spasm is painless but after prolonged activity, nocturnal myalgia (a pinching-aching sensation in the overactive muscles) may develop and prove distressing. Close observation reveals a softness of the muscles during rest and the initial contraction appears not to be significantly slowed.


Neurology_Adams

Neurology_Adams. The disease, myotonia congenital, as mentioned above is usually inherited as a dominant trait so that most often, other members of the family have been affected. Its congenital nature may be evident even in the crib, where the infant’s eyes are noted to open slowly after it has been crying or sneezing and its legs are conspicuously stiff as the child tries to take its first steps. In other cases, the myotonia becomes evident only later in the first or second decade. The muscles are generously proportioned and may become hypertrophied but seldom to the degree observed in the recessive form of the disease described further on.


Neurology_Adams

Neurology_Adams. Despite their muscular appearance, these patients are inept in athletic pursuits as a result of the myotonia. When severe, myotonia affects all skeletal muscles but is especially prominent in the lower limbs. Attempts to walk and run are impeded to the extent that the patient stumbles and falls. Other limb and trunk muscles are also thrown into spasm, as are those of the face and upper limbs. One of the characteristic features is grip myotonia in which the patient is unable to release a handshake and must slowly open the fingers one at a time. Occasionally a sudden noise or fright may cause generalized stiffness and falling. Small, gentle movements such as blinking or elicitation of a tendon reflex do not initiate myotonia, whereas strong closure of the eyelids, as in a sneeze, sets up a spasm that may prevent complete opening of the eyes for many seconds. Spasms of extraocular muscles occur in some instances, leading to strabismus. If the patient has not spoken for a time, there is


Neurology_Adams

Neurology_Adams. spasm that may prevent complete opening of the eyes for many seconds. Spasms of extraocular muscles occur in some instances, leading to strabismus. If the patient has not spoken for a time, there is sometimes a striking dysarthria. Arising at night, the patient cannot walk without first moving the legs for a few minutes. After a period of rest, the patient may have difficulty in arising from a chair or climbing stairs. Loosening of one set of muscles after a succession of contractions does not prevent the appearance of myotonia in another area, nor in the same ones if used in another pattern of movement. Smooth and cardiac muscles are not affected and intelligence is normal. Lacking also are the narrow face, frontal balding, cataracts, and endocrine changes typical of myotonic dystrophy that is discussed in Chap. 45. Myotonia that is evident in infancy is far more likely to represent myotonia congenita than myotonic dystrophy, in which myotonia rarely has its onset in the first few


Neurology_Adams

Neurology_Adams. that is discussed in Chap. 45. Myotonia that is evident in infancy is far more likely to represent myotonia congenita than myotonic dystrophy, in which myotonia rarely has its onset in the first few years of life.


Neurology_Adams

Neurology_Adams. Myotonia can also be induced in most cases by tapping a muscle belly with a percussion hammer (percussion myotonia). Unlike the lump or ridge produced in hypothyroid or cachectic muscle (myoedema), the myotonic contraction involves an entire fasciculus or an entire muscle and, unlike the phenomenon of idiomuscular irritability (contraction of a fascicle in response to striking the muscle), it persists for several seconds. If tapped, the tongue shows a similar reaction. An electrical stimulus delivered to the motor point in a muscle induces a prolonged contraction (Erb myotonic reaction). In Thomsen disease, as in virtually all forms of myotonia, the stiffness is somewhat exaggerated in cold. On a cold day, affected individuals may have a prolonged grimace with closed eyes after a sneeze. We encountered two brothers with this disorder who described diving into a cool swimming pool on a hot summer day and having to lie nearly motionless at the bottom of the pool for several seconds


Neurology_Adams

Neurology_Adams. We encountered two brothers with this disorder who described diving into a cool swimming pool on a hot summer day and having to lie nearly motionless at the bottom of the pool for several seconds until the muscle stiffness abated enough to allow them to swim to the top. However, as mentioned, prominent cold-induced myotonia, is more characteristic of paramyotonia congenita (see later).


Neurology_Adams

Neurology_Adams. Biopsy reveals no abnormality other than enlargement of muscle fibers, and this change occurs only in hypertrophied muscles. As often happens in fibers of increased volume, central nucleation is somewhat more frequent than it is in normal muscle. The large fibers contain increased numbers of normally structured myofibrils. In well-fixed biopsy material examined under the electron microscope, Schröder and Adams discerned no significant morphologic changes. Myotonia levior was the name applied by DeJong to a dominantly inherited form of myotonia congenita in which the symptoms are milder and of later onset than those of Thomsen disease. In 2 patients of a myotonia levior family, Lehmann-Horn and coworkers (1995) identified a mutation of the same chloride ion channel (CLCN1) that is implicated in Thomsen’s disease. Thus it appears that myotonia levior is simply a mild form of Thomsen disease.


Neurology_Adams

Neurology_Adams. Diagnosis In patients who complain of spasms, cramping, and stiffness, myotonia must be distinguished from several of the disorders of persistent muscle activity described further on and in Chap. 45. None of these disorders displays percussion myotonia or the typical electromyogram (EMG) abnormality of myotonic discharge. The only possible exceptions are the Schwartz-Jampel syndrome of hereditary stiffness combined with short stature and muscle hypertrophy, and stiff man syndrome which are discussed further on and in Chap. 45.


Neurology_Adams

Neurology_Adams. Uncertainty in diagnosis arises in patients who have only myotonia in early life and later prove to have classic (type 1) myotonic dystrophy or who notice myotonia in adulthood with mild proximal weakness and are found to have type 2 myotonic dystrophy (see later). The myotonia in myotonic dystrophy is usually mild and in several families that we have followed, some degree of weakness and the typical facies of myotonic dystrophy could be appreciated even in early childhood. This is not the case in the less-frequent type 2 myotonic dystrophy in which there are no dysmorphic features (also called proximal myotonic myopathy [PROMM]; see Chap. 45 and further on). In paramyotonia congenita there is also myotonia of early onset, but, again, it tends to be mild, involving mainly the orbicularis oculi, levator palpebrae, and tongue; the diagnosis of paramyotonia is seldom in doubt because of the worsening with continued activity and prominent cold-induced episodes of myotonia and paralysis.


Neurology_Adams

Neurology_Adams. In patients with very large muscles, one must consider not only myotonia congenita but also familial hyperdevelopment, hypothyroid myopathy, the Bruck-de Lange syndrome (congenital hypertrophy of muscles, mental retardation, and extrapyramidal movement disorder), Becker myotonia (see later), Duchenne dystrophy, and most of all, hypertrophic myopathy (hypertrophia musculorum vera); this last disease is of interest because the aberrant protein (myostatin) and gene defect have been characterized. Muscle hypertrophy is not, of course, a feature of myotonic dystrophy. The demonstration of myotonia by percussion and EMG study usually resolves the problem, although in exceptional cases of Thomsen disease, the persistence of contraction may be difficult to demonstrate. In hypothyroidism, the EMG may show bizarre high-frequency (pseudomyotonic) discharges; however, true myotonia does not occur, myoedema is prominent, and, along with other signs of thyroid deficiency, there is slowing of


Neurology_Adams

Neurology_Adams. EMG may show bizarre high-frequency (pseudomyotonic) discharges; however, true myotonia does not occur, myoedema is prominent, and, along with other signs of thyroid deficiency, there is slowing of contraction and relaxation of tendon reflexes not seen in myotonia congenita.


Neurology_Adams

Neurology_Adams. Treatment Quinine is effective in reducing myotonia but is now used infrequently because of the (low) risk of causing torsade de pointes. Procainamide, 250 to 500 mg qid, and mexiletine, 100 to 300 mg tid, are beneficial in relieving the myotonia but, they too, have fallen out of favor for various reasons. Phenytoin, 100 mg tid, is useful in some cases. The cardiac antiarrhythmic drug tocainide (1,200 mg daily) has also proved effective, but it sometimes causes agranulocytosis and is no longer recommended. A trial has shown that mexilintie may be useful in a group of rare non-dystrophic myotonias (Statland et al).


Neurology_Adams

Neurology_Adams. This is a second form of congenital myotonia, inherited as an autosomal recessive trait. Like the dominant Thomsen form, it is caused by an allelic mutation of the gene encoding the chloride ion channel of the muscle fiber membrane. The clinical features of the dominant and recessive types are similar except that myotonia in the recessive type does not become manifest until 10 to 14 years of age, or even later, and tends to be more severe in the dominantly inherited variety. The myotonia appears first in the lower limbs and spreads to the trunk, arms, and face. Hypertrophy is invariably present. There may be associated mild distal weakness and atrophy; this was found in the forearms in 28 percent of Becker’s 148 patients and in the sternocleidomastoids in 19 percent. Dorsiflexion of the feet was limited and fibrous contractures were common. Weakness may also be present in the proximal leg and arm muscles. The most troublesome aspect of the disease is the transient weakness that


Neurology_Adams

Neurology_Adams. the feet was limited and fibrous contractures were common. Weakness may also be present in the proximal leg and arm muscles. The most troublesome aspect of the disease is the transient weakness that follows initial muscle contraction after a period of inactivity. Progression of the disease continues to about 30 years of age, and according to Sun and Streib, the course of the illness thereafter remains unchanged. In contrast to Thomsen disease, the creatine kinase (CK) may be elevated. Testicular atrophy, cardiac abnormality, frontal baldness, and cataracts—the features that characterize myotonic dystrophy—are conspicuously absent.


Neurology_Adams

Neurology_Adams. The main diseases in this category are hyperkalemic periodic paralysis and paramyotonia congenita. The derivative disorders normokalemic periodic paralysis, acetazolamide-responsive myotonia, myotonia fluctuans, and myotonia permanens are variants of hyperkalemic periodic paralysis. All of them are caused by mutations in the gene encoding the alpha subunit of the membrane-bound voltage-gated sodium channel in skeletal muscle (SCN4A).


Neurology_Adams

Neurology_Adams. The essential features of this disease are episodic generalized weakness of fairly rapid onset and a rise in serum potassium during attacks. Weakness appearing after a period of rest that follows exercise is particularly characteristic. This type of periodic paralysis was first described and distinguished from the more common (hypokalemic) form by Tyler and colleagues in 1951. Five years later, Gamstorp described 2 additional families with the disorder and named it adynamia episodica hereditaria. As further examples were reported, it was noted that in many of them there were minor degrees of myotonia, which brought the condition into relation with paramyotonia congenita (see further on). Hyperkalemic periodic paralysis is associated with a defect in the alpha subunit of the sodium channel gene (Fontaine et al, 1990). It is now appreciated that there are distinct variants of hyperkalemic periodic paralysis that are genetically distinct. All are associated with membrane


Neurology_Adams

Neurology_Adams. sodium channel gene (Fontaine et al, 1990). It is now appreciated that there are distinct variants of hyperkalemic periodic paralysis that are genetically distinct. All are associated with membrane hyperexcitability because of delays in sodium channel inactivation following membrane depolarization, as discussed later.


Neurology_Adams

Neurology_Adams. The pattern of inheritance is autosomal dominant as noted, with an onset usually in infancy and childhood. Characteristically, attacks of weakness occur before breakfast and later in the day, particularly when resting following exercise. In the latter case, the weakness appears after 20 to 30 min of becoming sedentary. The patient notes difficulty that begins in the legs, thighs, and lower back and spreads to the hands, forearms, and shoulders over minutes or more. Only in the severest attacks are the neck and cranial muscles involved; respiratory muscles are usually spared. As the muscles become inexcitable, tendon reflexes are diminished or lost. Attacks usually last 15 to 60 min, and recovery can be hastened by mild exercise. After an attack, mild weakness may persist for a day or 2. In severe cases, the attacks may occur every day; during late adolescence and the adult years, when the patient becomes more sedentary, the attacks may diminish and even cease entirely. In certain


Neurology_Adams

Neurology_Adams. 2. In severe cases, the attacks may occur every day; during late adolescence and the adult years, when the patient becomes more sedentary, the attacks may diminish and even cease entirely. In certain muscle groups, if myotonia coexists, it is difficult to separate the effects of weakness from those of myotonia. Indeed, when an attack of paresis is prevented by continuous movement, firm, painful lumps may form in the calf muscles. Usually, however, the presence of myotonia can only be detected electromyographically. Some patients with repeated attacks may be left with a permanent weakness and wasting of the proximal limb muscles.


Neurology_Adams

Neurology_Adams. During the attack of weakness serum K rises, often, but not always, up to 5 to 6 mmol/L. This is associated with increased amplitude of T waves in the electrocardiogram (ECG) and a fall in the serum Na level (because of entry of Na into muscle). With increased urinary excretion of K, the serum K falls and the attack terminates. Between attacks serum K is usually normal or only slightly elevated. The attacks of paralysis are virtually alike in all clinical variants of the disease. In the paramyotonic form discussed below, the attacks are associated with paradoxical myotonia (myotonia induced by exercise and also by cold).


Neurology_Adams

Neurology_Adams. The provocative test, undertaken under careful supervision when the patient is functioning normally, consists of the oral administration of 2 g of KCl in a sugar-free liquid repeated every 2 h for 4 doses, if that many are necessary to provoke an attack. The test is given in the fasting state, ideally just after exercise. The weakness typically has a latency of 1 to 2 h after the administration of K. The patient must be carefully monitored by ECG and frequent serum estimations of serum potassium. The test should never be undertaken in the presence of an attack of weakness, or when there is reduced renal function, or in those with diabetes requiring insulin. The treatment of this syndrome is the same as that for paramyotonia congenita, described further on.


Neurology_Adams

Neurology_Adams. The treatment of this syndrome is the same as that for paramyotonia congenita, described further on. Normokalemic periodic paralysis This form of episodic paralysis resembles the hyperkalemic form in practically all respects except that serum potassium does not increase out of the normal range, even during the most severe attacks. However, some patients with normokalemic periodic paralysis are sensitive to potassium loading (Poskanzer and Kerr); other kindreds are not (Meyers et al). The disorder is also transmitted as an autosomal dominant trait and the basic defect has proved to stem from the same mutation as that of hyperkalemic periodic paralysis of which it may be considered a variant.


Neurology_Adams

Neurology_Adams. Clinical manifestations In this disease, attacks of periodic paralysis are associated with myotonia, which may be paradoxical in type—that is, developing during exercise and worsening as the exercise continues. In addition, a widespread myotonia, often coupled with weakness, is induced by exposure to cold. In some patients, the myotonia can be elicited even in a warm environment. The weakness may be diffuse, as in hyperkalemic periodic paralysis, or limited to the part of the body that is cooled. As commented in the earlier sections, cold exaggerates many types of myotonia to some extent, but this property is most characteristic of paramyotonia and it is in this condition that cold-induced weakness persists for up to several hours once started, even after the body is rewarmed. Percussion myotonia can be evoked in the tongue and thenar eminence. According to Haass and colleagues, myotonia that is constantly present in a warm environment diminishes with repeated contraction, whereas


Neurology_Adams

Neurology_Adams. myotonia can be evoked in the tongue and thenar eminence. According to Haass and colleagues, myotonia that is constantly present in a warm environment diminishes with repeated contraction, whereas myotonia induced by cold increases with repeated contraction (paradoxical myotonia).


Neurology_Adams

Neurology_Adams. Like hyperkalemic periodic paralysis, paramyotonia congenita is transmitted in an autosomal dominant manner and both diseases have been linked to the same gene (SCN4A), which encodes the alpha subunit of the muscle membrane sodium channel; the two mutations are allelic.


Neurology_Adams

Neurology_Adams. Laboratory findings In both hyperkalemic periodic paralysis and paramyotonia congenita, the serum K is usually above the normal range during bouts of weakness, but paralysis has been observed at levels of 5 mEq/L and lower. Each patient appears to have a critical level of serum K, which, if exceeded, will be associated with weakness. (This has led some authors to term the periodic paralysis as potassium dependent.) The administration of KCl, raising serum K to above 7 mEq/L, a level that has no effect on normal individuals, invariably induces an attack. As mentioned earlier, the ECG must be monitored during such provocative testing. The EMG shows myotonic discharge in all muscles, even at normal temperatures. The CK may be elevated.


Neurology_Adams

Neurology_Adams. In vitro studies of muscle from patients with cold-induced stiffness and weakness have shown that as temperature is reduced, the muscle membrane is progressively depolarized to the point where the fibers are inexcitable (Lehmann-Horn et al, 1987). A sodium channel blocker (tetrodotoxin) prevents the cold-induced depolarization. In patients with paramyotonia, but not in those with hyperkalemic periodic paralysis, Subramony and colleagues observed a diminution of the compound muscle action potential in response to the cooling of muscle, largely settling the argument as to whether the two syndromes (hyperkalemic paralysis and paramyotonia) are the same or different.


Neurology_Adams

Neurology_Adams. Some patients with paramyotonia, like those with certain other forms of periodic paralysis, may in later life slowly develop a myopathy that causes persistent weakness. In some cases this is sufficiently severe that it mimics the pattern of late-onset limb-girdle muscular dystrophy. However, in the case of paramyotonia there are relatively few histologic changes, primarily vacuoles in some of the muscle fibers and minimal evidence of myofiber degeneration.


Neurology_Adams

Neurology_Adams. Treatment Most patients with hyperkalemic periodic paralysis and its variants benefit from prophylactic use of the carbonic anhydrase inhibitor acetazolamide, 125 to 250 mg bid or tid (paradoxically, as it has a tendency to produce potassium retention). Acetazolamide reduces the frequency of attacks and may provide some relief from myotonia. There are no controlled studies of acetazolamide in these disorders, but trials of the related carbonic anhydrase inhibitor, dichlorphenamide demonstrated a reduced frequency of paralytic spells in both hyperand hypokalemic forms of periodic paralysis (Tawil et al and Sansone et al). However, in some patients the attacks of hyperkalemic paralysis and of paramyotonia congenita are too infrequent, too brief, or too mild to require continuous treatment.


Neurology_Adams

Neurology_Adams. The administration of diuretics such as hydrochlorothiazide (0.5 g daily), keeping the serum K below 5 mEq/L, also prevents attacks but risks inducing dangerous degrees of hypokalemia. When the myotonia is more troublesome than the weakness, mexiletine 200 mg tid is perhaps the best alternative, because it prevents both coldand exercise-induced myotonia but it does not influence frequency of acute attacks. Some additional benefit may be gained by adding inhaled beta-adrenergic agonists such as albuterol or salbutamol. Some studies suggest that 1 agent in this class, clenbuterol, may have a direct effect in blocking the sodium channel, independent of its activation of adrenergic receptors. Procainamide or the lidocaine derivative tocainide, in doses of 400 to 1,200 mg daily, is also useful for the myotonia (tocainide carries a small risk of agranulocytosis).


Neurology_Adams

Neurology_Adams. For the treatment of an acute and severe episode, intravenous calcium gluconate (1 to 2 g) often restores power. If after a few minutes this treatment is unsuccessful, intravenous glucose or glucose and insulin and hydrochlorothiazide should be tried so as to reduce the serum potassium concentration.


Neurology_Adams

Neurology_Adams. Several other clinical presentations of hereditary periodic paralysis have been linked to mutations of the gene encoding the alpha subunit of the skeletal muscle sodium channel and probably represent variants of the disease. One of these, described by Ricker and colleagues, has been designated myotonia fluctuans, because muscle stiffness fluctuated in severity from day to day. In other respects the clinical features resemble those of myotonia congenita, including provocation of attacks of myotonia by exercise. The muscle stiffness is only slightly sensitive to cold but is markedly aggravated by the ingestion of potassium and, interestingly, never progresses to muscular weakness or paralysis. Myotonia permanens is the name given to a severe, persistent myotonia and marked hypertrophy of muscles, particularly of the neck and shoulders. The EMG discloses continuous muscle activity. This disease was discovered in the course of genotyping a patient who earlier had been reported by Spaans


Neurology_Adams

Neurology_Adams. particularly of the neck and shoulders. The EMG discloses continuous muscle activity. This disease was discovered in the course of genotyping a patient who earlier had been reported by Spaans and associates as an example of “myogenic” Schwartz-Jampel syndrome, but it affects the same channel as in hyperkalemic periodic paralysis.


Neurology_Adams

Neurology_Adams. Trudell and colleagues studied 14 patients from a large kindred with autosomal dominant myotonia, the main feature of which was periodic worsening of myotonia accompanied by muscle pain and stiffness, most severe in the face and hands. The symptoms were enhanced by cold (suggesting paramyotonia) and severe stiffness and palpable rigidity followed within 15 min of the ingestion of potassium but neither of these measures provoked muscle weakness. Muscle biopsy disclosed a normal ratio of types 1, 2A, and 2B fibers, further distinguishing this disorder from typical myotonia congenita, where 2B fibers may be reduced in number. All patients in this family who were treated with the carbonic anhydrase inhibitor acetazolamide had a dramatic resolution of symptoms within 24 h, hence the name acetazolamide-responsive myotonia. This disorder has been linked to the same molecular alteration of the sodium channel gene as occurs in hyperkalemic periodic paralysis (Ptácek et al, 1994b).


Neurology_Adams

Neurology_Adams. Rosenfeld and coworkers described yet another form of painful congenital myotonia attributable to a novel mutation in the sodium channel alpha-subunit gene (SCN4A). Affected members of this family experienced debilitating pain, particularly severe in the intercostal muscles. Also, the pain was resistant to treatment with acetazolamide and other antimyotonic drugs (mexiletine and tocainamide) and could not be provoked by ingestion of potassium-rich foods, differing from even rarer similar cases that are acetazolamide responsive. Finally, in regard to disorders of the sodium channel, it should be mentioned that the marine toxins (ciguatoxin, tetrodotoxin, saxitoxin), discussed in Chap. 41, produce their effects on the peripheral and central nerves by blocking sodium channels, but have little obvious effect on muscle function. Pathophysiology of Myotonia and Hyperkalemic Periodic Paralysis (See Also Chap. 2)


Neurology_Adams

Neurology_Adams. Pathophysiology of Myotonia and Hyperkalemic Periodic Paralysis (See Also Chap. 2) In both myotonia congenita and hyperkalemic paralysis, the absence of major morphologic changes and the prominence of the myotonic phenomenon in individual muscle fibers is consistent with a disorder of the sodium channel. This is also compatible with the observation that myotonia persists after the administration of curare, thereby exonerating neural input as the source of myofiber hyperexcitability.


Neurology_Adams

Neurology_Adams. The electromyographic pattern of a myotonic muscle reveals highly characteristic discharges that persist following the cessation of voluntary contraction. The tension of the myotonic muscle fibers is slow to diminish as a result of these greatly prolonged trains of muscle action potentials (see Fig. 2-19). Some of these afterdischarge potentials are the size of fibrillations, but others are as large as normal motor units. Thus myotonia can be distinguished electrophysiologically from contracture (e.g., that encountered in McArdle disease, in which the muscle is electrically silent). In experiments conducted in the 1940s, Denny-Brown and Foley, stimulating single muscle fibers directly, found that myotonic discharges could be elicited only by a volley of stimuli and not by a single stimulus. They also noted that the series of myotonic potentials progressively diminished in size. Percussion elicits myotonia by imparting a brief but relatively intense repetitive excitation of the muscle


Neurology_Adams

Neurology_Adams. They also noted that the series of myotonic potentials progressively diminished in size. Percussion elicits myotonia by imparting a brief but relatively intense repetitive excitation of the muscle membrane.


Neurology_Adams

Neurology_Adams. The biophysical basis of myotonia is now well understood in terms of the functioning of chloride and sodium channels in the muscle membrane and internal structures. The correspondence between mathematical models of the electrical properties of the membrane and the clinical features of the myotonic and periodic paralyses is quite remarkable. During the normal action potential in all neural and muscular tissue, membrane depolarization is terminated by 2 events: the depolarization-induced inactivation of the sodium channel (which ends the inward sodium current) and the subsequent action of the outward potassium current. In muscle, the termination of an action potential requires an additional factor. Because of its large size, excitation of the muscle fiber involves depolarization that propagates not only along the cell surface but also radially into the center of the muscle cell through the transverse tubules (T tubules). The tubules are very narrow structures whose internal spaces are


Neurology_Adams

Neurology_Adams. not only along the cell surface but also radially into the center of the muscle cell through the transverse tubules (T tubules). The tubules are very narrow structures whose internal spaces are in continuity with the extracellular space. When the repolarizing outward potassium current is activated, potassium ions flood into the tubules from the muscle cytoplasm. By itself, this tubular K accumulation would depolarize the muscle membrane and prolong excitation. Normally, this does not occur because there is a large opposing chloride conductance in the tubules that counteracts the influence of potassium accumulation.


Neurology_Adams

Neurology_Adams. The first clues to the importance of the chloride channel in this electrical stabilizing process were obtained by Bryant who performed in vitro studies of myotonic goat muscle and found a reduced chloride conductance in the transverse tubular system. Subsequent studies of muscle from patients with myotonia congenita by Lipicky and Bryant (1971) demonstrated a similarly low chloride conductance. That a mutation in a muscle chloride channel could produce myotonia was confirmed in a mouse model by Jentsch and Steinmeyer and colleagues (see Koch et al), who subsequently also described the first human chloride channel (CLCN1) mutations.


Neurology_Adams

Neurology_Adams. As indicated, an essential event for normal repolarization of an excitable membrane is the rapid inactivation of the inward sodium current. This process of rapid, complete sodium channel inactivation is impaired by the sodium channel mutations implicated in hyperkalemic periodic paralysis. The mutations cause imperfect inactivation of the channel and lead to aberrant and early reopenings. Repolarization is then incomplete, rendering the muscle cell more readily re-excited; it is this hyperexcitability that causes the myotonia of hyperkalemic periodic paralysis. The problem becomes self-reinforcing because, as the membrane fails to repolarize fully, its electrolytic inactivation becomes increasingly less effective. If this process is not aborted, the result is such excessive depolarization that the muscle cell ultimately becomes unexcitable—a state that corresponds to the paralytic phase of hyperkalemic periodic paralysis. These features are evident in hyperkalemic muscle in vitro


Neurology_Adams

Neurology_Adams. that the muscle cell ultimately becomes unexcitable—a state that corresponds to the paralytic phase of hyperkalemic periodic paralysis. These features are evident in hyperkalemic muscle in vitro (Cannon et al) and can be recapitulated in computer simulations of aberrant channels. Presumably, over several hours, a variety of compensatory mechanisms (e.g., activation of Na-K adenosine triphosphatase [ATPase] pumps) restores the baseline excitability of the muscle membrane.


Neurology_Adams

Neurology_Adams. This is the best-known form of periodic paralysis. The history of the disease is difficult to trace, but the first unmistakable account was probably that of Hartwig in 1874, followed by the accounts of Westphal (1885) and Oppenheim (1891). Goldflam (in 1895) first called attention to the remarkable vacuolization of the muscle fibers that is characteristic of the process. In 1937, Aitken and associates described the occurrence of low serum potassium during attacks of paralysis and reversal of the paralysis by the administration of potassium, thus setting the stage for subsequent differentiation from the hyperkalemic forms of periodic paralysis. For English-speaking readers, Talbott’s monograph serves as the best historical review of the subject and includes all cases that had been reported prior to 1941; the more contemporary reviews by Layzer and by Lehmann-Horn and their associates (2004) are valuable.