Neuromuscular junction disorders in newborns and infants

INTRODUCTION — Weakness and hypotonia in newborns can be caused by several conditions, including neuromuscular disorders of the neuromuscular junction. These rare conditions include transient acquired neonatal myasthenia gravis, congenital myasthenia, elevated levels of magnesium or aminoglycosides, and infantile botulism. They are characterized by abnormal neuromuscular transmission leading to muscle fatigability and weakness. Most of these disorders are transient, but congenital forms are permanent.

Identifying potential neuromuscular causes of hypotonia and weakness (table 1) begins with a thorough clinical assessment. The initial assessment of infants with hypotonia and/or weakness is reviewed separately. (See "Approach to the infant with hypotonia and weakness".)

Peripheral nerve and muscle disorders that may cause weakness in newborns and infants are discussed elsewhere. (See "Overview of peripheral nerve and muscle disorders causing hypotonia in the newborn".)

NEONATAL MYASTHENIA GRAVIS — Transient neonatal myasthenia gravis (MG) occurs in 10 to 20 percent of infants born to mothers with MG [1]. Most mothers of affected infants have active clinical disease, although some may have little or no evidence of myasthenia or may be in remission [2,3].

MG is an autoimmune disorder caused by antibodies that usually are directed against the acetylcholine receptor (AChR), resulting in postsynaptic inhibition of neuromuscular transmission [4,5]. (See "Pathogenesis of myasthenia gravis".)

Maternal AChR antibodies transferred to the fetus are responsible for transient neonatal MG [1]. Higher ratios of antibodies directed against the fetal versus the adult type of AChR in mothers with MG are correlated with an increased likelihood of transmitting the disorder [6].

Rarely, there are persistent myopathic sequelae related to the fetal acetylcholine receptor inactivation syndrome (FARIS) that may be more common than previously recognized [7]. Although the precise pathophysiologic mechanism is not established, this condition is probably related to elevated levels of maternal AChR antibodies directed against the fetal subunit of the AChR receptor, causing abnormal endplate development of the embryonic neuromuscular junction in a subset of infants [7-9]. The facial and bulbar musculature may be particularly susceptible to permanent injury caused by this process.

Among mothers with a child affected by transient neonatal MG, the risk of recurrence with subsequent pregnancies is approximately 75 percent [1,4,10]. Women with known or suspected MG should receive appropriate counseling regarding the risk and management of transient neonatal MG in future children [11].

Clinical features — Neonatal MG typically presents within a few hours of birth. Signs are nearly always apparent by the third day of age [1,10,12]. More severely affected infants have a history of polyhydramnios and may have arthrogryposis multiplex (multiple joint contractures) at birth [13].

Newborns with myasthenia have generalized weakness and hypotonia [4]. However, deep tendon reflexes are always present. Facial diplegia often occurs; ptosis and ophthalmoplegia occur less often. Bulbar weakness is frequent, leading to poor sucking and swallowing and a weak cry [12]. Pooling of secretions and respiratory muscle weakness may contribute to respiratory failure and the need for assisted ventilation.

With prompt diagnosis and appropriate management, most newborns recover within a few weeks (see 'Prognosis' below). Treatment is more difficult and recovery is slower in more severely affected patients and when the diagnosis is delayed.

In the rare FARIS, there are persistent manifestations characterized by facial and bulbar myopathy or arthrogryposis multiplex congenita, sometimes accompanied by hearing loss or pyloric stenosis [7,9].

Diagnosis — The diagnosis of neonatal MG should be suspected in the infant of a mother with myasthenia. If the mother does not have known disease, the diagnostic test is the response of the infant to administration of an acetylcholinesterase inhibitor. The agent used most commonly is neostigmine methylsulfate (0.15 mg/kg intramuscularly or subcutaneously).

This test should be performed only in a setting where resuscitation can readily be performed. When the test is diagnostic, neostigmine results in clinical improvement that begins in approximately 15 minutes and continues for one to three hours. Success should be determined by a measurable response (eg, an improvement in ventilation or time to drink an amount of fluid) of >15 percent. Atropine may be needed to control muscarinic side effects, such as diarrhea and increased tracheal secretions.

Some experts prefer the acetylcholinesterase inhibitor edrophonium (0.15 mg/kg intramuscularly or subcutaneously, or intravenously in fractional amounts delivered over several minutes after a test dose of 0.03 mg/kg), but it is no longer available in the United States, Canada, the United Kingdom, the European Union, or many other countries. This agent acts more rapidly than neostigmine, and muscarinic side effects are less intense. However, respiratory arrest has been reported [1].

Complications of prematurity or hypoxic-ischemic encephalopathy may occasionally interfere with an infant's response to administration of an acetylcholinesterase inhibitor. In these cases, repetitive nerve stimulation can be used to confirm the diagnosis [14]. This test compares the amplitude of the fifth evoked compound muscle action potential with the first, before and after administration of an acetylcholinesterase inhibiting agent. A positive response is reduction of the fifth action potential by 10 percent or more and reversal of this decrement by the acetylcholinesterase inhibitor [1].

Management — Management of neonatal myasthenia is supportive. Small frequent feedings are provided by nasogastric or orogastric tube, and assisted ventilation is provided when indicated. In addition, neostigmine methylsulfate (0.05 to 0.1 mg/kg intramuscularly or subcutaneously) is given 30 minutes before each feeding. When feeding and respiratory abnormalities have improved, the drug can be given orally (0.5 to 1.0 mg/kg orally approximately 45 minutes prior to feeding). Excessive doses may result in increased secretions, diarrhea, weakness, and muscle fasciculations.

With continued clinical improvement, the neostigmine dose can be lowered gradually. In addition, the course of the disease can be monitored by repeat nerve stimulation testing and measurement of acetylcholine receptor antibodies.

In one case of a child (age 5 years) with severe facial muscle weakness due to suspected FARIS, prior treatment with pyridostigmine was not beneficial, but there was significant symptom improvement with albuterol [15].

Prognosis — With prompt diagnosis and appropriate management, most newborns recover within a few weeks; 90 percent of patients recover fully before reaching two months of age [1]. Tube feeding and assisted ventilation rarely are required for longer than one to two weeks. The average duration of pharmacologic treatment is four weeks.

Although data are limited to a few cases, FARIS has been associated with a broad spectrum of severity, ranging from profound arthrogryposis, respiratory weakness, and early death to mild but permanent weakness of the facial and bulbar muscles [7,9].

CONGENITAL MYASTHENIC SYNDROMES — The congenital myasthenic syndromes (CMS) are uncommon causes of neuromuscular junction failure in newborns and children (table 2). These heterogeneous disorders are caused by genetic defects in presynaptic, synaptic basal lamina, and postsynaptic components of the neuromuscular junction [16-20]. There is no involvement of the immune system [21].

The more common types of CMS (table 2) include the following [17,19,22]:

●Primary acetylcholine receptor (AChR) deficiency, the most frequent type, caused by recessive pathologic variants in any of the AChR subunit genes (CHRNA, CHRNB, CHRND, or CHRNE); most occur in the epsilon subunit (CHRNE)

●RAPSN genetic variants, causing impaired clustering of AChR

●COLQ genetic variants, leading to endplate acetylcholinesterase deficiency

●DOK7 genetic variants, resulting in aberrant synaptic maturation and maintenance

●CHAT genetic variants, causing presynaptic defects in acetyltransferase

●Fast channel syndrome with abbreviated AChR channel opening, caused by variants in the AChR subunit genes (CHRNA, CHRNB, CHRND, or CHRNE)

●Slow channel syndrome with prolonged AChR channel opening, also caused by variants in the AChR subunit genes (CHRNA, CHRNB, CHRND, or CHRNE)

Clinical features — All forms of CMS are characterized by fatigable weakness, but some forms have distinct phenotypes (table 3). Newborns with CMS frequently have ptosis, in contrast to patients with transient neonatal myasthenia gravis. In addition, several subtypes of CMS (eg, AChR deficiency, acetylcholinesterase deficiency, and fast channel syndrome) typically demonstrate ophthalmoplegia [21]. Bulbar and respiratory muscle weakness are common features in these subtypes. Affected infants may have fluctuating generalized hypotonia and weakness and life-threatening episodes of apnea [23]. Arthrogryposis may be present at birth [23,24].

CMS has been associated with sudden death in infancy in severe cases [25,26]. For most patients, CMS improves with age, but spontaneous exacerbations may occur. Exacerbations may also be triggered by increased or intense activity, febrile illness, or stress. Exacerbations of CMS symptoms during pregnancy may be common but are typically transient [27].

Some types of CMS can present later in infancy or childhood.

●The Dok-7 myasthenia syndrome, a congenital myasthenia related to recessive pathologic variants of the DOK7 gene, typically becomes symptomatic around age 2 or 3 years, and later onset in adolescence or adulthood has also been reported [28,29]. Limb-girdle distribution weakness is typical; eye movements are usually spared [21]. One study of six patients with DOK7 variants found marked phenotypic variability, although all shared the limb-girdle pattern of weakness [30]. In the two most severely affected patients, the onset of weakness and respiratory failure occurred at birth.

●Manifestations of RAPSN congenital myasthenia range from severe neonatal hypotonia and arthrogryposis to mild limb muscle weakness [31,32]. Ophthalmoplegia is rare [21]. Early onset is most common but late onset has been described [32,33]. Most patients respond to acetylcholinesterase inhibitors.

●DPAGT1 gene variants lead to a CMS with prominent limb-girdle weakness and minimal bulbar symptoms, with sparing of eye movements [21,34]. The median age of onset is 2 years (range 0.5 to 7 years). Tubular aggregates are a characteristic feature on muscle biopsy.

Diagnosis — The diagnosis of CMS (table 3) should be suspected in the setting of fatigable weakness affecting mainly the ocular and bulbar muscles, onset at birth to early childhood, and a positive family history [17]. Nonetheless, some types of CMS present later in life, and some present with a limb-girdle distribution of weakness with little or no involvement of the cranial muscles [17,20,21,35,36].

A diagnostic response to acetylcholinesterase inhibitors may be useful if it is positive. However, some disorders, such as DOK7, slow channel syndrome, and COLQ, may be refractory to these agents or worsened by administration [21]. A decremental response to repetitive nerve stimulation at low frequency (2 Hz) supports the diagnosis, though infants with choline acetyltransferase CMS due to CHAT genetic variants require prolonged stimulation at a higher frequency (10 Hz) to induce a response.

Targeted genetic testing can be diagnostic when phenotypic characteristics suggest specific genetic variants that cause CMS (table 3) [17]. Next-generation whole-exome sequencing can identify causative genetic variants when targeted genetic testing is not feasible or is nondiagnostic. A definitive genetic diagnosis is useful for guiding treatment, prognosis, and genetic counseling [17,21].

Management — The treatment of CMS depends upon the specific disorder (algorithm 1) [17]. A trial of acetylcholinesterase inhibitor treatment (eg, pyridostigmine) is warranted for some but not all types of CMS; certain disorders (eg, DOK7, slow channel syndrome, and COLQ CMS) have a risk of worsening with pyridostigmine and 3,4-diaminopyridine (3,4-DAP) [21].

For subtypes of CMS that respond to pyridostigmine (eg, primary AChR deficiency, RAPSN, fast channel syndrome, CHAT, glycosylation pathway defects), adjunctive treatment with 3,4-DAP can be beneficial [16,17]. Limited data suggest that albuterol (salbutamol) or ephedrine improves muscle strength and mobility in patients with acetylcholine receptor deficiency caused by CHRNE variants [37].

Albuterol (salbutamol) or ephedrine can be used to treat CMS caused by DOK7 and COLQ genetic variants [16,17,20,38]. Fluoxetine, quinidine, or quinine may be used to treat slow channel syndrome [17,39-41].

Respiratory care is an important aspect of management, since hypoventilation can occur in all subtypes of CMS [21]. Some patients may benefit from noninvasive ventilation at home.

ELEVATED MAGNESIUM OR AMINOGLYCOSIDE LEVELS — Excessive concentrations of magnesium or aminoglycosides may inhibit neuromuscular transmission in newborns.

Hypermagnesemia — Hypermagnesemia blocks calcium release, resulting in a presynaptic failure of acetylcholine release [42]. Neonatal hypermagnesemia usually results from maternal administration of magnesium sulfate.

Affected infants are depressed and have generalized hypotonia. Treatment generally consists of supportive care and monitoring. In severe cases, respiratory depression with apnea may occur. Hypermagnesemia also may result in decreased gastrointestinal motility and meconium plug syndrome.

Aminoglycoside toxicity — Excess aminoglycoside levels, especially in combination with neuromuscular blockers, may lead to prolonged weakness caused by a presynaptic block. Bladder, bowel, and pupillary functions may be depressed [43]. Hypocalcemia accentuates the neurotoxic effects of aminoglycosides and hypermagnesemia.

INFANT BOTULISM — Infant botulism results from intestinal colonization by Clostridium botulinum, which produces a neurotoxin that blocks presynaptic cholinergic transmission, affecting skeletal and smooth muscle and autonomic function [44]. (See "Botulism".)

Epidemiology — Infant botulism affects infants between one week and 12 months of age, but most cases occur between two and eight months of age; the median age of onset is three to four months [45,46].

Clostridium species that cause infant botulism include types A, B, E, and F [47-50]. Typing is based upon the antigenic specificities of the toxin produced. The vast majority of cases are due to infection with types A or B [47,51]. Type A is more prevalent in the western United States, and type B is more prevalent in the eastern United States.

While infant botulism occurs worldwide, the disease occurs more commonly in areas where environmental conditions favor persistence of spores in the soil, including Pennsylvania, Utah, and California in North America [46,52-54]. Most cases in the United States are thought to result from ingestion of environmental dust containing C. botulinum spores, and residence near activities that disturb the soil such as construction or agricultural cultivation may enhance exposure. Foodborne cases can result from ingestion of wild honey or home canned foods contaminated with C. botulinum spores [55].

Young age and the absence of competitive bowel flora are factors that predispose to vulnerability [56]. Colostrum in breast milk offers some protection, but breastfed infants may become susceptible during the transition to formula or solid foods.

Clinical features — The clinical features result from progressive neuromuscular blockade and range from mild to severe. Muscles innervated by the cranial nerves are affected first, followed by those of the trunk, extremities, and diaphragm [57].

Infants typically present with constipation and poor feeding. This presentation is followed by progressive hypotonia and weakness. Loss of deep tendon reflexes appears to occur more commonly in type B infection [46]. Cranial nerve dysfunction is manifested by decreased gag and suck, diminished range of eye movement, pupillary paralysis, and ptosis. Autonomic signs include decreased tearing and salivation, fluctuating heart rate and blood pressure, and flushed skin.

Infant botulism may present with or progress to life-threatening respiratory failure, and serious complications may develop during the course. In a clinical trial, most infants required intensive care and about half required mechanical ventilation [58]. In atypical cases, infants may present with catastrophic collapse or rapid deterioration following brief periods of poor feeding but without the typical initial complaints of constipation, ptosis, or facial weakness [59].

Prior to the advent of human-derived botulism immune globulin (BIG-IV) treatment, the duration of illness was usually one to two months, and occasional infants might relapse [60]. Untreated type A infant botulism was longer in duration and more severe than type B illness [58].

Diagnosis — The diagnosis of infant botulism should be suspected in any infant with acute onset of weak suck, ptosis, inactivity, and constipation. However, infant botulism is a rare disorder, and the diagnosis is often missed [47]. As an example, the diagnosis was suspected on admission in only half of the infants enrolled in a randomized trial who had laboratory-confirmed infant botulism [58].

Serum samples for botulinum toxin are often negative in cases of infant botulism. The diagnosis is supported by the isolation of C. botulinum spores from the stool and is confirmed by the identification of botulinum toxin in stool samples [46]. Fecal excretion may be identified for up to several weeks after symptom onset. However, detection varies by botulism subtype and assay [61]. In addition, stool sample collection can be difficult because constipation is a nearly constant feature of infant botulism. Further, stool sample assays do not yield timely results. Anaerobic cultures often take up to six days for growth and identification of the organism, and initial detection of toxin requires one to four days [62].

The delays with these confirmatory tests are important since, as described in the next section, therapy should be administered as early as possible [63]. Thus, a presumptive diagnosis should be made based upon the clinical presentation and electrophysiologic findings while the confirmatory stool studies are pending. Electromyography (EMG) findings consistent with infant botulism are not pathognomonic and may not be present early in the course of the disease [64]. Nevertheless, certain EMG findings support the diagnosis of botulism when coupled with the appropriate clinical presentation:

●Repetitive nerve stimulation at rates of 20 to 50 Hz with an abnormal incremental response. An incremental response to 50 Hz stimulation is seen in 92 percent of infants with botulism poisoning, compared with 20 percent of normal infants [65-67].

●EMG showing short-duration, low-amplitude motor unit potentials [65].

The differential diagnosis for infant botulism includes brainstem encephalitis, cerebral infarction, dehydration, drug ingestion, Guillain-Barré syndrome, Lambert-Eaton myasthenic syndrome, metabolic encephalopathy, myasthenia gravis, neuromuscular disorders, and sepsis.

In clinical practice, spinal muscular atrophy type I and metabolic disorders are the most frequent mimics of infant botulism. This conclusion comes from a chart review of all 681 cases of suspected infant botulism treated with human botulism immune globulin from 1992 through mid-2005 [68]. Thirty-two infants (4.7 percent) did not have laboratory-confirmed infant botulism; the final diagnoses included the following categories:

●Spinal muscular atrophy type 1 (n = 5). (See "Spinal muscular atrophy".)

●Metabolic disorders (n = 8), including mitochondrial disorders (n = 4).

●Other infectious diseases (n = 3).

●Miscellaneous (n = 7), including a case of Miller Fisher variant of Guillain-Barré syndrome. (See "Guillain-Barré syndrome in children: Epidemiology, clinical features, and diagnosis".)

●Probable infant botulism (n = 9) in cases where laboratory studies to establish the diagnosis were not requested or were not performed.

Treatment — Any infant with clinical signs, symptoms, or history suspicious for botulism should be hospitalized immediately and meticulously monitored for signs of respiratory failure.

For suspected infant botulism occurring in any state, the California Department of Health Services, Infant Botulism Treatment and Prevention Program should be contacted (www.infantbotulism.org/ or 1-510-231-7600).

Botulism immune globulin intravenous (BIG-IV or BabyBIG), a human-derived botulinum antitoxin, is safe and effective therapy for infant botulism and should be administered as early as possible [58,63,69]. Treatment should not be delayed while awaiting results of confirmatory tests.

The benefit of BIG-IV was conclusively demonstrated in a randomized controlled trial of 122 infants with infant botulism (75 caused by type A toxin and 47 by type B toxin) who were randomly assigned to treatment with BIG-IV or placebo [58]. The following significant benefits were noted with BIG-IV compared with placebo:

●A reduced mean duration of hospital stay, which was the primary outcome measure (2.6 versus 5.7 weeks)

●A reduced mean duration of intensive care (1.8 versus 5 weeks), mechanical ventilation (1.8 versus 4.4 weeks), and tube or intravenous feeding (3.6 versus 10 weeks)

●Mean hospital charges were reduced by $89,000 (in 2004 United States dollars)

●In preplanned subgroup analyses, BIG-IV treatment was beneficial for both type A and type B infant botulism

No serious adverse events were associated with BIG-IV therapy.

In a subsequent open-label study, 382 infants with infant botulism were treated with BIG-IV within 18 days of hospital admission [58]. For 366 infants treated within seven days of hospital admission, the mean length of hospitalization was 2.2 weeks. Early treatment with BIG-IV was associated with shorter mean length of stay compared with later treatment.

Management of infant botulism is otherwise supportive and includes close monitoring to detect sudden worsening.

Antibiotics should not be prescribed for infant botulism unless indicated for a concurrent infection [63]; there is theoretical concern that lysis of intraluminal C. botulinum could increase the amount of toxin available for absorption [70]. This recommendation is reasonable even though a single BIG-IV infusion should neutralize all botulinum toxin available for absorption for at least six months [58]. Aminoglycoside antibiotics should be avoided because they can rarely cause neuromuscular blockade and thereby exacerbate the paralytic effects of botulism toxin [63].

Penicillin or metronidazole should be used to treat patients with wound botulism after antitoxin has been administered [70]. Aminoglycosides should be avoided because they can potentiate the effects of the toxin. (See 'Aminoglycoside toxicity' above.)

SUMMARY AND RECOMMENDATIONS

●Neuromuscular disorders in newborns – Weakness and hypotonia in newborns can be caused by disorders of the neuromuscular junction. These rare conditions include transient acquired neonatal myasthenia gravis, congenital myasthenia, elevated levels of magnesium or aminoglycosides, and infantile botulism (table 1).

●Transient neonatal myasthenia gravis – Transient neonatal myasthenia gravis occurs in 10 to 20 percent of infants born to mothers with myasthenia gravis. Newborns with myasthenia have generalized weakness and hypotonia. Facial diplegia and bulbar weakness often occur; ptosis and ophthalmoplegia occur less frequently. Neonatal myasthenia gravis typically presents within a few hours of birth, but signs are nearly always apparent by the third day of age. (See 'Neonatal myasthenia gravis' above.)

•If the mother does not have known disease, the diagnostic test is the response of the infant to administration of an acetylcholinesterase inhibitor. Management is supportive.

•Ninety percent of patients recover fully before reaching two months of age.

●Congenital myasthenic syndromes – The congenital myasthenic syndromes are uncommon causes of neuromuscular junction failure in newborns caused by genetic defects of the neuromuscular junction (table 2). Newborns with congenital myasthenia frequently have ptosis, in contrast with patients with the transient disorder, and typically demonstrate ophthalmoplegia and bulbar and respiratory muscle weakness. Affected infants may have fluctuating generalized hypotonia and weakness and life-threatening episodes of apnea. (See 'Congenital myasthenic syndromes' above.)

•A definitive genetic diagnosis is useful for directing treatment, supplying prognosis, and providing genetic counseling. The management of CMS depends upon the specific disorder (algorithm 1).

•Congenital myasthenia often improves with age, but spontaneous exacerbations may occur and sometimes result in sudden death in infancy.

●Elevated magnesium or aminoglycoside levels – Excessive concentrations of magnesium or aminoglycosides may inhibit neuromuscular transmission in newborns. (See 'Elevated magnesium or aminoglycoside levels' above.)

●Infant botulism – Infant botulism affects infants between 1 week and 12 months of age. The clinical features result from progressive neuromuscular blockade and range from mild to severe. Muscles innervated by the cranial nerves are affected first, followed by those of the trunk, extremities, and diaphragm. (See 'Infant botulism' above.)

•The diagnosis should be suspected in any infant with acute onset of weak suck, ptosis, inactivity, and constipation. Infants with clinical signs, symptoms, or history suspicious for botulism should be hospitalized immediately and monitored for signs of respiratory failure.

•Botulism immune globulin intravenous (BIG-IV or BabyBIG) is safe and effective therapy for infant botulism and should be administered as early as possible. Treatment should not be delayed while awaiting results of confirmatory tests.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Geoffrey Miller, MD, who contributed to earlier versions of this topic review.