Acquired Presynaptic Neuromuscular Junction Disorders

Chapter 25

Acquired Presynaptic Neuromuscular Junction Disorders Infant Botulism and Lambert-Eaton Myasthenic Syndrome Ai Sakonju and Thomas O. Crawford

INFANT BOTULISM Botulism is derived from the Latin botulus, for sausage. Van Ermengem in 1897 isolated the spore-forming anaerobe Bacillus botulinum from the spleen of a victim and the contaminated ham involved.1 This toxigenic form of botulism is the best known, and before the advent of modern food processing, was the most common form of botulism in the developed world. There are three other forms of botulism in addition to food-borne toxin ingestion: wound, infant, “adult onset infant botulism,” and iatrogenic. It would have been impossible to recognize infant botulism in an earlier era of high infant mortality, and thus it was not recognized until 1976.2 This form of human botulism is caused by Clostridium botulinum colonization within the flora of the susceptible infant colon and subsequent production of toxin. Infant botulism is now the most common form of human botulism in the developed world.3

Clinical Concerns Typical patients are healthy full-term infants with painless constipation for days to months before onset of weakness. This weakness, poor feeding, a paucity of movement, and seeming lethargy are the most common initial concerns. At presentation, three cardinal features are recognized: symmetrical weakness of bulbar, face, and neck more than appendicular musculature; a nonirritable, awake sensorium; and the absence of fever. Bulbar weakness and poor head support are seen in all patients; ophthalmoparesis and pupillary sluggishness or dilatation are frequent and helpful findings.4 The face is typically expressionless, drooling

is present, and a high-pitched, mewing cry develops that is recognized as characteristic by clinicians in areas of high prevalence. Some infants have a suggestion of fatigability, manifesting as bursts of movement amid a too-immobile restful state. Muscle stretch reflexes are often absent, but their presence does not rule out the diagnosis. Many infants progress rapidly to require assisted ventilation, usually initiated out of concern for a secure airway. Once infant botulism is recognized and treated, patients with the classic syndrome may need ventilatory assistance or airway support for many months, with a mean of 3 weeks.5 Patients typically recover in the reverse order of their symptoms’ appearance, with limb movements reappearing before the infant has a competent airway. In exceptional cases, relapse may occur well into the course of recovery.6

Epidemiology The median age of affected infants is 10 weeks, with 95% being younger than 6 months old. The vast majority of patients are between 1 week and 11 months old, but rare adult cases of “infant botulism” can arise in the setting of severe gastrointestinal illness.7 9 There are case reports of infant botulism starting with symptoms at 38 hours and 54 hours of life due to different forms of Clostridia such as type F.10,11 Although infant botulism is widespread, having been recognized in all regions of the United States12 and four continents,3 clusters of increased incidence in California,13 Utah,14 and the suburban Philadelphia region15 are the best documented. This may be related to soil type and alkalinity. In both Pennsylvania and Utah, many patients were known to have been exposed to nearby construction

B.T. Darras, H. Royden Jones, Jr., M.M. Ryan & D.C. De Vivo (Eds): Neuromuscular Disorders of Infancy, Childhood and Adolescence, Second edition. DOI: http://dx.doi.org/10.1016/B978-0-12-417044-5.00025-1 © 2015 Elsevier Inc. All rights reserved.

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or agricultural soil conditions, with wind and alkaline soil noted in the Utah group.14 There is some suggestion of seasonal variation in susceptibility, with the greatest incidence in the summer and fall when there is no snow and conditions favor spore dissemination,16 but cases do occur year-round in more temperate climates. Whether breast feeding confers a susceptibility risk or protective benefit is controversial. In southeastern Pennsylvania, a casecontrolled epidemiologic survey found that breastfeeding15 was a major factor in relative risk. One report showing cases occurring across all major racial and ethnic groups in California also found that breastfeeding seemed to slow the onset of symptoms, and those who were breastfed had a later age of onset of symptoms (median age of onset 116 days) compared to bottle-fed infants (median age of symptom onset 66 days).3,17 The pathogenic C. botulinum organisms are ubiquitous. C. botulinum is comprised of four phylogenetically distinct species of bacteria that form botulinum neurotoxin, which accounts for the multiple forms of botulinum toxin designated types A through G. Infant botulism is associated almost exclusively with toxin type A or B. The distribution of human disease parallels the regional soil distribution, with type A being common in the Rocky Mountain states and type B infection in the Great Plains states and to the east.16 Unlike the food-borne toxigenic form of human botulism, epidemic outbreaks of infant botulism are not seen. There are no reported cases of disease by fecal-oral contamination from other affected infants, and the affected infant is typically the only ill member of the family. Taken together, these facts suggest that human exposure to C. botulinum spores is a fairly common event, and colonization causing symptomatic weakness reflects features of individual susceptibility more than an effect of random exposure to the organism. Exposure’s partial role in incidence is suggested, however, by an increased relative risk following dietary exposure to honey (odds ratio 9.8) or corn syrup (odds ratio 5.2),18 in which spores may be found. In Europe, as many as 59% of infant botulism cases have been linked to honey with ongoing case reports.19 21 Nonetheless, before the widely distributed American Academy of Pediatrics cautionary recommendation, exposure to honey explained only 16% to 30% of cases in the USA.18,22 There are hints that risk factors change with the age of the infant. In older infants, a history of long-standing infrequent stooling, breastfeeding, and honey or corn syrup exposure is correlated with disease. In infants younger than 2 months of age, only rural residence with presumed aerosolized soil exposure is a risk factor.16,18 The fact that normal intestinal microflora changes with the introduction of formula or solid foods likely plays a role in the ability of C. botulinum to colonize the infant’s colon. This is supported by the fact that in a majority of

the Pennsylvania cases, the infants had first been introduced to non-breast milk foods within 4 weeks of the onset of disease.23 Although breastfeeding is a risk factor for infant botulism, it appears to provide some protection against the most serious, acute presentation of sudden infant death.24 Given these features of epidemiology, it is hard to conceive how any program of prevention could be successful. Infant botulism is a rare disease, and the evidence suggests that host features are more substantial risk factors than exposure. Although breastfeeding is a known risk factor, the clear benefits of breastfeeding outweigh the tiny risk of contracting infant botulism. The single addressable public health factor has already been dealt with—the recommended exclusion of honey and corn syrup from the diet of infants younger than 1 year. More important is a program of education for primary practitioners who, with enhanced awareness and continued vigilance, are best situated to prevent the complications of infant botulism through early diagnosis.

Pathogenesis Infant botulism is caused by colonization of the large intestine by toxin-forming C. botulinum or related organisms.25,26 C. botulinum is not a normal constituent of gut microflora.27 Apparently, its absence is due to competition from other microorganisms: adult germ-free mice support large-intestine colonization, but immediately upon exposure to other normal flora, the colonization is cleared.28 An important exception that may have relevance for human infant botulism is seen during early postnatal development of mice: normal pups of 7 to 13 days can sustain enteric colonization, but older and younger mice cannot.29 Interestingly, like C. botulinum, other Clostridium species are excluded from the gut of breastfed infants, but the addition of any other food supplement results in the occasional appearance of colonization.29 This may explain the increased incidence of breastfeeding in older affected infants23,27 who, with even a small amount of supplementation from other food sources, may become more susceptible to colonization with C. botulinum.30 Clostridia are obligatory anaerobic, Gram-positive, spore-forming rods. In general, they grow best in high pH media, although a combination of temperature, osmolarity, redox potential, the presence of food preservatives, and competing microorganisms affects growth in an interrelated fashion.12 Each strain produces a single toxin type, although the genes for multiple toxins sometimes exist within a strain, and occasionally a single strain produces two types of toxin.31 The C. botulinum species is an aggregate of multiple strains, likely the result of convergent evolutionary branches that have in common the production of botulinum toxins. Since this classification

Chapter | 25 Acquired Presynaptic Neuromuscular Junction Disorders

of species was developed, other Clostridium species have been found to produce botulinum toxin, thus demonstrating the difficulty of representing the complexity of bacterial phylogeny with a single nomenclature.32 Botulinum toxin is the most toxic substance known. The lethal ingested dose is estimated to be less than 1 nanogram/kg body weight.33 Although abundant toxin is produced in the colon in infant botulism, apparently only a minute amount is absorbed. In the human infant, C. botulinum behaves more like the normal flora than an enteric pathogen; it does not invade the colonic mucosa, and there is no direct cytotoxic effect. The colon must therefore be a good barrier to toxin uptake, but more proximal regions of the gastrointestinal tract are likely not barriers to absorption, given the expression of symptoms with only minute toxin ingestion. The fact that many infants with symptomatic botulism have a history of chronic constipation18 suggests that diminished intestinal motility is a cause as well as a consequence of infant botulism. These infants may be at higher risk for colonization in the first place, they may be more likely to absorb the toxin once it is made by reflux through the length of the colon and the ileocecal junction, or both possibilities may be true. Breastfeeding is associated with increased colonic motility, which may explain the later onset and less severe expression, though not the increased incidence, of infant botulism in breastfed infants. The various exquisitely tailored botulinum toxins are likely the consequence of complex pathways of convergent evolution. Seven different serotypes have evolved, designated by the letters A through G. The botulinum toxins are similar in action to tetanus toxin, although the targeted cell differs: tetanus toxin affects Renshaw cells of the spinal cord while botulinum toxin alters the secretive exocytosis of motor neurons of the brain stem and spinal cord. Botulinum toxin is synthesized initially as a large 150-kDa protein that is autocleaved into two fragments bonded by disulfide links. The larger 100-kDa heavy-chain fragment of each of the botulinum toxins is responsible for binding to a variety of specific gangliosides that characterize the axon terminus of cholinergic motor neurons.34 Once internalized by endosomic uptake, the light chain separates and escapes the endosome into the cytoplasm of the presynaptic terminal. Here, a zinc-dependent protease function of the light chain targets one of three proteins essential to the sequence of synaptic vesicle docking and exocytosis. These targeted proteins are enzymatically cleaved at a site distinct for each toxin type. Types A and E toxin cleave a protein known as SNAP 25. Types B, D, F, and G (as well as the short chain of the tetanus toxin) cleave a critical vesicle-associated membrane protein (VAMP, also known as synaptobrevin). Botulinum toxin type C cleaves the syntaxin molecule.35 40 The consequence of inactivation of any one of these crucial docking

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proteins is an inability to release quanta of acetylcholine from the presynaptic terminal in response to an action potential.41 The remarkable potency of botulinum toxin stems from this combination of high-affinity uptake at presynaptic terminals, mediated by the 100-kDa fragment, and highly efficient enzymatic protease activity mediated by the 50-kDa fragment. Recovery from this intoxication requires the spontaneous degradation of the toxin and the synthesis and transport of new SNAP 25, VAMP, or syntaxin protein from the neuronal perikaryon. Morphologically, recovery is associated with new sprouting from the presynaptic terminal in the neuromuscular junction; whether this is a necessary feature of recovery is not known. While the muscle is denervated, there is spread of the acetylcholine receptor from the site of the original junction, but with recovery of synaptic quantal release, the regular arrangement of the synapse is reestablished. Subtle differences in the frequency of spontaneous quantal release of acetylcholine are apparent in the different forms of botulinum toxin.42 With type B cleavage of VAMP only, the stimulated release of acetylcholine quanta is inhibited. In contrast, with type A cleavage of SNAP 25, both stimulated and spontaneous quantal release of acetylcholine are inhibited. This difference may be associated with more significant denervation responses in muscle affected by type A toxin, with greater alteration of resting membrane potential and frequency of abnormal spontaneous activity. These differences may be reflected in single-fiber electrophysiologic studies.42

Differential Diagnosis and Evaluation The differential for subacute onset of hypotonia may be very broad, but due to the age at presentation the bias may lean towards infectious etiologies. Clinical suspicion for botulism must remain high in order to proceed toward appropriate evaluations in a timely manner. Actual clinical mimics were described by a review of 681 cases of infant botulism from 1992 to 2005 in which 32 patients (4.7%) met the clinical diagnosis of infant botulism but were not laboratory confirmed and subsequently were given a different diagnosis. Of those without laboratory confirmation, 28% had no other diagnosis and were felt to have clinical botulism. The remainder 23 patients fell into five diagnostic categories including metabolic disorders (25%, including glutaric aciduria type 1, maple syrup urine disease, Leigh’s syndrome), miscellaneous (22%, including GBS variants, central demyelinating disease, cerebral infarct), SMA type 1 (16%), and infectious diseases (9%, RSV, enterovirus encephalitis)43 (Box 25.1). Evaluations may include cerebrospinal fluid examination, but a spinal tap may be dangerous as there may be impending respiratory compromise. Other overlapping

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BOX 25.1 Infantile Botulism Differential Diagnosis G G

G G G G G G

Inborn errors of metabolism Peripheral neuropathies with cranial nerve involvement: Guillain-Barre´ syndrome variants such as Pharyngealcervical-brachial variant, “Miller-Fisher syndrome,” or Bickerstaff encephalitis Poliomyelitis Central demyelination or infarction Spinal muscular atrophy type 1 Infections: viral encephalitides, RSV infection Congenital myasthenic syndromes Organophosphate poisoning or acquired electrolyte disturbances

Abbreviation: RSV 5 Respiratory syncytial virus.

syndromes include electrolyte disturbances including hypoor hypercalcemia, hypernatremia, hypo- or hyperkalemia, hypo- or hypermagnesemia, and hypoglycemia. The prospect of an inborn error of metabolism should be considered in very young infants who become lethargic after the initiation of enteral feedings, as well as in any infant newly challenged by fasting or intercurrent infection. In very young infants in whom the possibility of an inborn error is high, initial serum and urine samples should be saved for later, more definitive analysis, if indicated. Other rare causes of weakness in previously healthy infants include organophosphate poisoning, which presents with additional signs of cholinergic excess. Poisoning with heavy metals may cause a chronic or acute flaccid state in infants. Now exceptionally rare, infantile poliomyelitis generally accompanies vaccination with live attenuated virus, although transmission from contact with another recently vaccinated infant can be a source of the virus. Vaccineassociated poliomyelitis usually involves back-mutation to a virulent state in the type 3 polio serotype. Alternatively, it can affect some infants with unsuspected immune deficiency in a more chronic fashion. The syndrome of infantile polio is quite different from that of infant botulism however, with recent diarrhea, a low fever on presentation, irritability, and aseptic meningitis evident. The weakness of infantile polio may or may not be asymmetrical during the acute phase. Another possible but unusual diagnosis is Guillain-Barre´ syndrome (GBS), which is exceptionally rare in infants, (see Chapter 23). GBS should be distinguished by electrophysiologic criteria and elevation of cerebrospinal fluid protein as the disease progresses. One of the most difficult diagnoses to distinguish from infant botulism is an unrecognized heritable disorder of the neuromuscular junction, known as a congenital myasthenic syndrome. These infants present with increased weakness precipitated by some form of metabolic stress. Like infants with botulism, such infants characteristically

have ocular involvement (though rarely pupillary sluggishness) and bulbar weakness greater than limb weakness. The use of edrophonium in the diagnosis can be confusing because infants with botulism may be transiently stronger. With the congenital myasthenic syndromes, the history is often one of a more indolent process, though this can overlap with milder, chronic forms of infant botulism. The two disorders are best distinguished by electrophysiologic studies and recovery of toxin or organism from the stool. Nearly all infants suspected of having infant botulism must first be considered to have a serious systemic or central nervous system infection; appropriate cultures should be obtained, and prophylactic antibiotics administered. Early laboratory tests also need to include determination of glucose, electrolytes, calcium, magnesium, acid-base status, anion gap, and ammonia levels. Intravenous glucose can be started, but enteral feedings should be held pending results. Plasma and urine specimens for toxicology and metabolic studies must be obtained in case their evaluation is warranted by later developments. The diagnosis can be made most rapidly by electrophysiologic studies. In the most carefully documented study, an incremental response to rapid repetitive stimulation (20 or 50 Hz), found in 92% of patients, was the most sensitive and specific finding (Figure 25.1). Slower rates of repetitive stimulation produce variable results.44 Concentric needle electromyography is also sensitive but less specific, with many patients demonstrating shortduration, low-amplitude motor unit potentials and abnormal spontaneous activity.4,44 Several technical problems can undermine the sensitivity of the conventional rapid repetitive stimulation test for incremental compound muscle action potential (CMAP) amplitude,45 including inadequate immobilization of the limb, studying a nervemuscle combination that has a very low CMAP amplitude below a physiologic threshold allowing increment, or studying a muscle that already has a normal CMAP amplitude and cannot increment further. One frequent error is to unwittingly study a nerve-muscle combination that has been transiently incremented by the baby’s exercising the muscle during the set-up for rapid repetitive stimulation. Concentric needle electromyographic studies demonstrate frequent brief, small-amplitude, polyphasic, voluntary motor unit potentials reflecting denervation of a portion of the array of muscle fibers innervated by each motor axon. This finding, along with the frequent presence of abnormal spontaneous fibrillation and positive sharp-wave potentials, is also seen in other disorders of infants and is not specific for infant botulism. Studies of jitter with a stimulated single-fiber electrode may have enhanced sensitivity over conventional rapid repetitive stimulation. This method is technically easy in weak infants and requires a much lower-level stimulus, making it less painful. A positive result is

Chapter | 25 Acquired Presynaptic Neuromuscular Junction Disorders

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FIGURE 25.1 Tracing derived from first author’s patient with confirmed type A infantile botulism. Recording of the right abductor digiti minimi (ADM) muscle with 50 Hz repetitive nerve stimulation shows .50% facilitation of the baseline compound muscle action potential (CMAP).

reported when abnormal jitter between the stimulus artifact and an isolated single muscle fiber potential decreases with an increasing stimulation rate, similar to that expected with Lambert-Eaton myasthenic syndrome. Autoimmune myasthenia and other postsynaptic disorders would be expected to have increasing jitter with an increased stimulation rate. Most infants have both toxin and organism recoverable from the stool, although local logistical concerns may favor one test over the other. Because affected babies have a reduced stooling frequency, the fluid recovered from a gentle 20-mL saline enema contains enough material to test for the toxin. The blood is usually, but not always, negative for toxin. Stool can remain positive for culture and toxin for a long time, though others report that it is clear within 1 month of diagnosis.46 Polymerase chain reaction techniques have been developed47 that may be incrementally more sensitive but are not yet in routine use.

Therapy Prior to the introduction of human botulism immune globulin (Baby-BIG), approved by the Food and Drug Administration in October 2003, treatment was largely supportive with respiratory and nutritional care. BabyBIG is comprised of immunoglobulin isolated from donor plasma immunized with pentavalent botulinum toxoid (ABCDE).48 A 5-year randomized placebo-controlled trial treating with Baby-BIG vs. IVIg showed a significant reduction in morbidity with reduction in length of hospital stay and duration of intubation by a mean of 3 weeks. This study was followed by another 5-year open-label study and a 30-year retrospective review49 that recapitulated findings. Mean intensive care stay was reduced by 3.2 weeks, mechanical ventilation by 2.6 weeks, and tube feeding by 6.4 weeks. This resulted in significant cost reduction as well. Although the cost of BIG is high (approximately $45,000 in 2005), the overall savings in

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hospital stay and morbidity were far more significant with an estimated $34.2 million in hospital charges that were avoided.48 BIG has been demonstrated to be of benefit in infant botulism when given within the first 3 days after admission to the hospital.50 Equine-derived botulinum antitoxin is not used in infants because of the high incidence of rash and anaphylaxis and the potential for lifelong sensitization to horse serum products. A Cochrane review also supports BIG as the only medical treatment that showed significant effect compared to 3,4-diaminopyridine (3,4 DAP), plasma exchange, equine antitoxin, and guanidine.51 Baby BIG is available worldwide by the California Department of Health Services Infant Botulism Prevention Program (telephone, 1-510-231-7600; up to date as of 8/ 2014). Because of the necessity for quick treatment, BIG can be administered on the strength of a classic history and physical examination (details at the California Department of Health Infant Botulism Prevention and Treatment Program website52), with laboratory confirmation of the diagnosis and botulinum toxin type to follow. Other than administration of BIG, primary management consists of respiratory and nutritional management. At-risk infants should be watched carefully in the intensive care unit and intubated early when signs of airway compromise, bulbar dysfunction, or respiratory insufficiency arise. Infants who require an artificial airway do so for weeks and may acquire a respiratory virus that can prolong their ventilator requirement. Most now agree that despite this long-term requirement, tracheostomy is rarely indicated5 because normal lung compliance and a weak chest wall permit full ventilation even with a slightly small, uncuffed tube that has some degree of air leak. Under such conditions, few patients develop airway strictures, even with long periods of intubation.53 Because infants often recover in the reverse order of the original progression, the clinician may be faced with the odd circumstance of an infant intubated for weakness who has good arm and leg muscle power. Some have advocated the return of head stability as a predictor of adequate airway competence.54 Others wait for the maximum inspiratory pressure to exceed 225 cm H2O and the return of protective airway reflexes.5 In either case, it is just as important to follow the infant’s airway after extubation, during recovery from the disease, as it is when the child first presents. Throughout the illness, the capacity for enhanced fatigue of airway and respiratory muscles is a greater concern than is baseline weakness. Given the severe constipation, concern about enteral feedings led many to give infants parenteral alimentation in the past. Many infants do not tolerate bolus feedings by nasogastric tube, but most can be adequately nourished by continuous nasogastric feedings, beginning slowly, as early as 3 days after presentation.5 Concern about

gastroesophageal reflux with aspiration has prompted some to use the nasojejunal route for tube feeding.55 Caloric requirements in the absence of physical activity are significantly reduced. Many infants experience altered autonomic function, including sudden unexplained alterations in heart rate, blood pressure, or skin color. These are usually mild, transient, or both and rarely require specific therapy.15 Some of these changes are undoubtedly due to supersensitivity of cholinergic autonomic terminals after functional denervation by the toxin. Urinary retention may require intermittent catheterization to prevent bladder infections. Some very young infants develop the syndrome of inappropriate antidiuretic hormone secretion, especially early in the disease, just after being placed on positive-pressure ventilators. This should respond to fluid restriction and usually resolves spontaneously over several days to a week. Left unrecognized or untreated, the low sodium values that result can cause serious, anticonvulsantrefractory seizures. Although many infants are given antibiotics immediately upon presentation because of the possibility of unrecognized sepsis, further treatment with antibiotics has not been successful and might be harmful, either by perpetuating C. botulinum colonization of the gut with the alteration of normal enteric flora, or by increasing the release of botulinum toxin, which is in high concentration within the organism. In particular, treatment with aminoglycoside antibiotics may be contraindicated because of the potential for increased neuromuscular blockade.56 Giving specific foods such as yogurt in an attempt to alter the normal colonic flora has not been tried systematically, but the results with individual patients have not been striking. Although colonic enemas may theoretically reduce the enteric burden of toxin, there is concern that they may also increase absorption. Because recovery from infant botulism is very good once the diagnosis is made and appropriate supportive care is initiated, there is little enthusiasm for these treatments that may carry some risk. Treatment with acetylcholine esterase blockers produces mixed results. Although some infants may worsen during convalescence, relapse after full recovery is not seen.6 Some infants may harbor toxin in the colon well after recovery, suggesting that some degree of circulating humeral antibody aids in absorption of residual toxin taken up systemically.13,23 Very importantly, the parents need to be assured of the probable good outcome for their infant, despite the prospect of a prolonged intensive care hospitalization. Parents should be encouraged early on to establish a regular routine that includes time away from the hospital. This will enable them to better tolerate the personal stress associated with a prolonged intensive care stay.

Chapter | 25 Acquired Presynaptic Neuromuscular Junction Disorders

LAMBERT-EATON MYASTHENIC SYNDROME An acquired immune-mediated presynaptic neuromuscular junction disorder, Lambert-Eaton myasthenic syndrome (LEMS) is typically divided into two forms based on whether there is an underlying neoplasm or not; that is, paraneoplastic and nonparaneoplastic, respectively. In children, the associated neoplasms have included leukemia, neuroblastoma and Wilms’ tumor, whereas in adults it is classically associated with small cell lung cancer as first described in 1956.57 Transient neonatal LEMS has been described as well and may be due to placental crossover of maternal antibodies causing hypotonia at birth lasting only for a few weeks and requiring only supportive care.58 Adult LEMS occurs in approximately 0.5 per million.58 Although the incidence is unknown, pediatric LEMS is much rarer than infantile botulism, with less than two dozen LEMS cases reported in the literature to date. The classic syndrome occurs in adults as an immune-mediated disorder associated with P/Q-type voltage-gated calcium channel antibodies found in 85 90% of patients.59

Clinical Concerns LEMS presents as a clinical triad of proximal muscle weakness, hyporeflexia, and autonomic symptoms. This is essentially confirmed in a review of nearly a dozen reported cases of pediatric LEMS: progressive proximal muscle weakness was the initial symptom in the majority, and ptosis in 3 of 12 reported children.60 Ptosis may be a potentially serious sign since, in this review, the three patients with ptosis were found to have malignancy. Other initial presenting features included ophthalmoparesis, bulbar weakness with dysarthria, dysphagia, fatigable weakness, dysautonomia with constipation, dry mouth, and nonspecific pain including muscle aches.60 In adults, approximately 62% had extraocular or bulbar symptoms.61 Autonomic symptoms at onset may be missed in young patients with limited ability to express these types of symptoms. On examination there may be signs of proximal muscle weakness including waddling gait, facial weakness, and eye movement abnormalities or ptosis. In particular, a characteristic feature is the potentiation of muscle stretch reflexes after maximal voluntary contraction in proximally weak patients with hypoactive or absent reflexes at baseline. One technique is to extend the knee against resistance for about 10 seconds and then test the patellar reflex which should be amplified in the classic patient. There may also be amplification of strength in a patient after brief maximal voluntary contraction that can be misinterpreted as “functional weakness,” suggesting the incorrect diagnosis of conversion disorder.

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Diagnostic Evaluations The differential diagnosis for proximal muscle weakness in children is broad. The two main immune mediated diseases that need to be distinguished from LEMS include GBS and myasthenia gravis. In contrast to LEMS, GBS will have associated sensory symptoms and distal involvement. Also, with myasthenia gravis, the typical progression is cranial to caudal, whereas LEMS typically presents in a caudal to cranial fashion with lower extremity weakness initially. Further, acetylcholine receptor antibodies can be obtained to help distinguish autoimmune myasthenia gravis from LEMS. Even rarer than autoimmune myasthenia gravis are the congenital myasthenic syndromes with presynaptic defects. In general, onset of symptoms spans from infancy to childhood and diagnosis requires specific genetic testing as well as electrophysiologic studies, the results of which may be hard to distinguish from acquired LEMS. These patients may present similarly to myopathy patients with severe hypotonia as their predominant feature, and without sophisticated electrophysiologic and other studies, as described in Chapter 26, they may be misdiagnosed. LEMS patients can also present similarly to patients with congenital myopathy with normal CK. The combination of normal CK and low CMAPs in a patient with proximal weakness and no significant muscle atrophy should prompt neuromuscular junction and exercise testing, and thus may prevent an unnecessary muscle biopsy. However, there is no single test alone that confirms the diagnosis and thus LEMS may be under-reported in children. The reliability of elevated voltage-gated calcium channel (VGCC) antibody testing is unknown in pediatric LEMS. In one review, 5 of 11 pediatric patients underwent testing and 4 of them were positive for VGCC antibodies.62 Electrodiagnostic testing is usually helpful but the diagnosis must be suspected in order to obtain the best results and increase the sensitivity of the procedure. Early on, testing may be normal in individuals with LEMS, but on repeat nerve conduction testing the baseline CMAPs may become lower with disease progression. Once low CMAPs are obtained, the differential diagnosis generally includes neuropathy and, in the right clinical setting, a neuromuscular junction defect may be suspected; at this point, specialized exercise testing, repetitive nerve conduction studies, and sometimes single fiber EMG must be requested, as they are not always part of standard EMG testing. Single-fiber electromyography can be done to detect a neuromuscular transmission defect that may be technically difficult to detect in very young children. This can be done using stimulated single fiber EMG as described in the botulism section of this chapter. Most importantly, a characteristic feature associated with LEMS is exercise testing when reduced CMAPs are

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FIGURE 25.2 Left median motor nerve compound muscle action potentials (CMAPs) recorded over the abductor pollicis brevis (APB) muscle. Top trace shows baseline CMAP. Bottom trace shows 276% facilitation of the CMAP 10 seconds after maximal voluntary exercise. Reprinted with permission from Elsevier: Hajjar et al. (2014).60

obtained at baseline. Supportive of LEMS diagnosis is the finding of post-exercise CMAP amplitude increase (facilitation) of .25% from baseline. A baseline CMAP is obtained and then the patient is asked to provide 10 seconds of maximum voluntary contraction of the respective muscle. In LEMS, a repeat CMAP soon after the exercise should reveal significant facilitation (Figure 25.2). More specific testing is obtained next with repetitive motor nerve stimulation. Fast and slow repetitive nerve stimulation will both be abnormal in LEMS patients; however, fast rates or highfrequency stimulation at .10 Hz proves to be the diagnostic test of choice. Repetitive stimulation at low rates such as 3 Hz is usually obtained first and may show a .10% decrement similar to myasthenia gravis patients, thereby confirming a neuromuscular transmission defect. However, the important finding as mentioned above is the increment with high-frequency stimulation at 20 50 Hz after 10 to 20 seconds of brief electrical 10 Hz stimulation to electrically exercise the muscle or less painfully in the cooperative patient by exercising the muscle being examined. An increment of .60% is diagnostic of LEMS with 97% sensitivity and 99% specificity, and excludes myasthenia gravis.63 Facilitation of at least 25% may be acceptable for a diagnosis of LEMS according to the American Association of Electrodiagnostic Medicine.64 In 11 of 11 children who underwent low-frequency repetitive nerve stimulation (1 3 Hz), there was a .10% decrement indicating a neuromuscular junction defect.60 High-frequency (10 50 Hz) repetitive nerve stimulation in 8 of 8 pediatric LEMS patients resulted in an increment of 124% to 500% from baseline with the same number also showing 60% to 1000%

facilitation after 10 to 30 seconds maximal voluntary effort.59 The increment may be similar to the one seen in previously described infantile botulism because both are presynaptic disorders of the neuromuscular junction. The distinction between the two is based primarily on the clinical presentation and the age of patients with these conditions. Needle EMG reveals small myopathic motor units without fibrillation potentials. This may help distinguish patients with LEMS from a neurogenic disorder such as spinal muscular atrophy. Muscle biopsy has been done in a few patients and is generally nondiagnostic with or without nonspecific findings. Overall, when the clinical presentation is associated with the presence of anti-VGCC antibodies and postexercise CMAP amplitude facilitation along with repetitive motor nerve stimulation findings as described above, the diagnosis of LEMS is almost definite.

Pathogenesis There are several lines of evidence that LEMS is an autoimmune disease mediated by anti-VGCC antibodies. Passive transfer of patients’ immunoglobulin induces similar pathophysiology in mice.64 Patients have improved clinical response to plasma exchange65 and up to 90% of patients with LEMS have detectable P/Q type anti-VGCC antibodies.66 Pediatric LEMS was first described in 1974, associated with childhood leukemia, but the first pediatric patients with a positive VGCC antibody titer were initially reported in 2002.67,68 Muscle biopsies are occasionally performed in LEMS patients, but unless specific neuromuscular junction studies are done on a research basis, no clear pathology is seen. The putative mechanism for aberrant presynaptic neurotransmission is due to blockage of acetylcholine release into the synapse by interference via voltage-gated calcium channel antibodies, resulting in reduced quantal release of neurotransmitter detected by low-frequency repetitive stimulation, which in turn results in a CMAP decrement. Higher rates of electrical stimulation or maximal voluntary contraction essentially induce release of acetylcholine into the neuromuscular junction and an incremental electrical response. This incremental response after highfrequency stimulation is seen in botulism as well and is a characteristic feature of presynaptic neuromuscular junction disorders.

Therapy The initial treatment that was used was guanidine,69 which increases neurotransmitter release at the neuromuscular junction but was retracted due to the risk for bone marrow suppression and renal failure. In the following decade, a similarly acting compound 4-AP (4-aminopyridine) that

Chapter | 25 Acquired Presynaptic Neuromuscular Junction Disorders

increases acetylcholine release via voltage gated potassium channels was used to treat patients with LEMS but was limited due to the increased risk for seizures. A related compound that crosses the blood-brain barrier less readily is 3,4 DAP, which is now considered the treatment of choice. Few randomized placebo controlled trials (RCTs) have been done, partly due to the rarity of the disease. A recent Cochrane review described five RCTs, four of which included 3,4 DAP and one, IVIg.70 Overall, these trials showed that muscle strength was improved after 3,4 DAP administration by testing myometry and other scores of muscle strength and by repeating CMAP testing after medication was administered.71 75 IVIg dosing 2 g/kg over 2 days in the single RCT also resulted in improved muscle strength testing by myometry.76 Muscle strength scores and CMAP amplitudes showed improvement in both groups, 3,4 DAP and IVIg, over a period of days or for up to 8 weeks, respectively. Cost-benefit analysis of using IVIg or 3,4 DAP depended on availability, and both may be costly therapies. Pyridostigmine is also often used in conjunction with 3,4 DAP for symptomatic treatment. No RCTs have been done involving oral immunosuppressive medications such as prednisolone, azathioprine, or cyclosporine, although there are case reports describing good results in pediatric patients with long-term follow-up.60,77,78 In those with paraneoplastic syndrome, treatment of the malignancy generally results in modification if not resolution of LEMS symptoms. Therefore, once the diagnosis is confirmed, the next step for the patient is to undergo rigorous and periodic surveillance screening for malignancy for at least 2 years as suggested by the adult literature.79 However, in children, prognosis may be better than adult onset LEMS; the prevalence of neoplasm is less frequent in childhood LEMS where only 3 of 12 reported patients in the literature were found to have a neoplasm (lymphoproliferative disorders, Wilms’ tumor, neuroblastoma), compared to 60% of adult LEMS patients.60,79,80

SUMMARY As LEMS is a treatable disorder with potential for an occult neoplasm and debilitating progression, this disorder should remain a diagnostic consideration in patients with proximal muscle weakness. It remains a challenging disease to diagnose but patients may display significant improvement in quality of life that makes this disorder worth understanding.

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