Hypotonia and Neuromuscular Disease in the Neonate

Diagnosis

Almost any condition that affects the central nervous system (CNS; brain or spinal cord) or peripheral nervous system of a newborn can be expressed by a reduction of tone. Furthermore, most acute or multisystem illness in neonates is accompanied by some degree of hypotonia. Therefore, the examiner initially must consider whether the infant is acutely ill from sepsis, organ failure, metabolic dysfunction, or other systemic illness. In addition, medications given to the mother in the time right before birth can have an effect on the infant's muscle tone. Most commonly implicated is magnesium sulphate to prevent preterm labor. If these illnesses are not present, the next step is to consider whether a primary disorder of the CNS or the peripheral nervous system is the cause. In general, a central cause leads to a reduction in tone out of proportion to the degree of muscle weakness, and the limbs demonstrate antigravity power.

Although this finding is useful, there are exceptions. In some hypotonic neonates, there are abnormalities in both the central and peripheral nervous systems. Examples include congenital muscular dystrophy (CMD); congenital myotonic dystrophy; acid maltase deficiency; cervical spinal cord injury; and some mitochondrial, lysosomal, and peroxisomal disorders. In addition, some disorders that are primarily central may initially present with profound hypotonia and weakness. Examples are Prader-Willi syndrome and acute disease such as hemorrhage or infarction involving the deep central gray matter of the brain or spinal cord. Babies with near total asphyxia typically have involvement of the brainstem and at times the upper spinal cord, and thus typically present with profound hypotonia and absence of reflexes, similar to spinal shock seen in acute spinal cord injuries. Conversely, the infant with a mild congenital myopathy demonstrates some antigravity power in the limbs. Finally, hypotonia might be present in the infant without acute systemic or metabolic illness or abnormalities of the nervous system. In these children, there is an unusual degree of ligamentous laxity such as that seen in Ehlers-Danlos syndrome and osteogenesis imperfecta.

The diagnosis of a neonatal muscle disorder requires a methodical approach similar to that used in the older infant or child. A detailed family, obstetric, and delivery history should be taken. Clues to the presence of a neuromuscular disorder include polyhydramnios, a decrease in fetal movement, and malpresentation, although these conditions can be present in any pregnancy with fetal akinesia (paucity of movement). Information should be obtained about whether there was any birth trauma or asphyxia and on the condition of the infant immediately after delivery.

The general examination begins with observation. Does the infant look sick or distressed? The skin should be examined for pallor, trauma, bruising, or petechiae. Any dysmorphic features or congenital defects of the head, neck, or spine should be noted, as should weight, length, and head size and shape. Each system is then examined with a particular emphasis on respiratory rate, pattern, and diaphragmatic movement; cardiovascular status; the presence of organomegaly; the genitalia; the hips; and the presence of contractures. On neurologic examination, initial observations include the degree of alertness and whether the infant fixes or follows. Posture and spontaneous movements are noted. In particular, movement against gravity should be sought, and the examiner should observe whether movement is greater proximally or distally. When formal examination of the cranial nerves is performed, particular attention should be paid to eye movements. These can be observed as spontaneous movements, elicited by a face or a red ball or induced by gentle rotation of the head (oculovestibular reflex). Caution should be taken when checking this reflex in an infant with possible high cervical cord injury. A lack of fixation or following, but movement with the oculovestibular reflex, suggests a lesion above the brainstem. If the infant is not in severe distress and there is no possibility of cervical spine injury, the degree of hypotonia is assessed by pulling the infant to a sitting position and holding him or her in vertical and horizontal suspension. Passive movement of the joints can assess power and tone in the limbs more gently. Resistance to gentle shaking of an arm or leg also provides a subjective assessment of tone.

On initial observation of a newborn, cerebral dysfunction should be suspected if there are abnormalities in primitive reflexes, poor arousal, paucity of movements in general, or fisting of the hands. Fisting can appear as a “cortical thumb” posture. This is where the thumb is flexed and lies under the first and second fingers. Persistence of this posture is felt to be associated with cerebral dysfunction. The character of the deep tendon reflexes helps distinguish between an upper or lower motor neuron lesion. An upper motor neuron lesion involves descending motor tracts in the brain and spinal cord, whereas a lower motor neuron lesion involves the anterior horn cell, peripheral motor nerve, or muscle. If they are abnormally brisk with clonus, then an upper motor neuron lesion is suggested. Five to ten beats of ankle clonus is considered normal in the infant. Sustained clonus or that which is persistently asymmetric is typically abnormal and suggests an upper motor lesion. If absent, a neuropathic lesion or a severe myopathy is more likely. As mentioned above, infants with near total asphyxia may have absent reflexes despite their lesion being of central origin. Assessment of sensation should be attempted, because this may indicate a spinal cord lesion. Although quite atypical to present in the newborn, abnormalities in sensation could point to a hereditary sensory neuropathy.

Facial diplegia is a particular finding in some neuromuscular disorders and less likely in others. It is most commonly seen in such disorders as congenital myotonic dystrophy and the congenital myasthenic syndromes. It can also be an early feature of severe acute basal ganglia damage. Note should be made of the infant's ability to suck and swallow, the pooling of secretions, the character of the cry, and the presence of tongue fasciculations. The latter is most often seen in acute infantile spinal muscular atrophy (SMA) but can be seen in any condition in which there is hypoglossal motor neuron damage, examples of which include storage disorders such as acid maltase deficiency, hypoxic-ischemic damage, and infantile neuronal degeneration.

Neonatal Neuromuscular Disorders

Neonatal neuromuscular disorders are caused by lesions that affect specific parts of the nervous system, including the anterior horn cell, peripheral nerve, neuromuscular junction, or muscle ( Box 56.1 ). Rapid and continuing advances are being made in our understanding of the molecular genetic basis of these disorders.

There are a number of CNS conditions in which hypotonia is of sufficient severity that a neuromuscular disorder should be suspected. These are not discussed in detail here, but they include chromosomal disorders such as Prader-Willi syndrome and Smith-Magenis syndrome (Smith-Magenis syndrome can be particularly hard to distinguish from a neuromuscular disorder as it can often be associated with hyporeflexia or areflexia), multiple minor congenital anomaly syndromes, and metabolic multisystem disorders.

Spinal Muscular Atrophies

The SMAs are predominantly autosomal recessive disorders characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. The most frequent and best known is infantile SMA, also called Werdnig-Hoffmann disease (SMA type I). Approximately 95% of individuals with SMA are homozygous for a deletion of exon 7 of the survival motor neuron (SMN) gene ( SMN1 ) on chromosome 5q13. Although the phenotype varies in severity and age of onset, the acute infantile subtype is well defined and often presents during the neonatal period. This phenotype tends to “run true” in families. Clinically, infants exhibit a severe symmetric flaccid paralysis, which is characteristically greater in the lower limbs than in the upper limbs and greater proximally than distally.

The onset of this weakness may be identified by the mother, who experiences a decrease or loss of fetal movement during late pregnancy. Although decreased fetal movements may be reported in SMA I (Werdnig-Hoffman disease), this is more commonly reported in patients diagnosed with the prenatal-onset forms of SMA. Respiratory muscle function is poor in the infant. However, it is the intercostal muscles that are weak, because there is relative sparing of the diaphragm. This gives rise to abdominal breathing and a later characteristic bell-shaped deformity of the chest. Deep tendon reflexes are absent or difficult to elicit. The upper cranial nerves are spared, giving rise to an infant with an alert expression, a furrowed brow, and normal eye movements. The bulbar muscles are weak, which is reflected by a weak cry, poor suck and swallow reflexes, pooling of secretions, aspiration, and tongue fasciculations. Cardiac muscle is not affected, and classic arthrogryposis is usually not a feature although rarely it can be. Nerve conduction testing demonstrates normal or slightly decreased motor nerve conduction velocities and normal sensory nerve action potentials. Electromyography shows abnormal spontaneous activity with fibrillations and positive sharp waves as well as an increased mean duration and amplitude of motor unit action potentials, some of which are polyphasic. Serum creatine kinase activity is normal or only slightly elevated. Muscle biopsy reveals large groups of circular atrophic type 1 and 2 muscle fibers ( Fig. 56.1 ). These fibers are interspersed among fascicles of hypertrophied type 1 fibers, which are three or four times normal size and represent fibers reinnervated by sprouting of surviving nerves. This pattern might not be seen during the neonatal period, when there is often only widespread atrophy of type 1 and 2 muscle fibers, making histologic diagnosis difficult. With the advances made in the genetic diagnosis of this disorder, biopsies are rarely needed; however, a later biopsy should show evidence of reinnervation with large hypertrophied fibers and group atrophy.

The infant who presents during the neonatal period with severe acute infantile SMA characterized by profound hypotonia and weakness rarely survives beyond 1 year of age. It is the severity of weakness at the onset that determines outcome in SMA rather than the age of onset, although in most cases the earlier the onset, the greater the weakness. Artificial ventilation of an infant with severe early-onset SMA leads to an alert but completely paralyzed infant who is totally ventilator dependent.

With the identification of the SMN gene in 1995, the diagnosis of SMA has been greatly facilitated, limiting the need for more invasive investigations. Additional understanding of the molecular genetics and protein function may provide insight into potential therapies for this otherwise fatal condition. The SMN coding region on chromosome 5q11.2-13.3 contains a telomeric and centromeric copy of the SMN gene, designated SMN1 and SMN2 , respectively. These genes are nearly identical in their coding sequence. A single nucleotide polymorphism (840C>T) in SMN2 causes disruption of normal translation. The resultant protein produced by the centromeric copy is often truncated and nonfunctional. SMN2 can produce a small amount of full-length protein, providing partial compensation for mutations in SMN1, but the majority must be produced by SMN1. A direct relationship exists between the number of copies of the SMN2 gene and the age of disease onset, with the SMA type I phenotype correlating with the lowest number of SMN2 gene copies. Although continued progress has been made recently in defining the exact function of SMN protein, it still remains to be further defined. It is known to play a role in critical housekeeping function: so-called spliceosomal small nuclear ribonucleoprotein assembly, which is important for all cells. How this translates into loss of the specific motor neuron cell RNA has yet to be elucidated.

In December 2017, nusinersen became the first FDA-approved drug for the treatment of 5q SMA. It is an antisense oligonucleotide and acts to modify pre-mRNA splicing of SMN2 to promote increased production of full-length SMN protein. Results of a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial showed that a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]). These patients also had a statistically significant likelihood of event-free survival. Additional therapy with single-dose gene replacement is currently in clinical trials. Preliminary results are promising. With these emerging therapies, SMA is now a treatable disorder. This opens the door for consideration of this disorder to be included in newborn screening.

There are a number of genetically heterogeneous SMA variants, but most of these do not present during the newborn period. The variants most important in neonatal or prenatal presentations of SMA include SMA with pontocerebellar hypoplasia, X-linked SMA with arthrogryposis owing to mutations in the UBE1 gene, and SMARD1 (spinal muscular atrophy with respiratory distress or distal infantile SMA with diaphragm paralysis) that is caused by mutations in the IGHMBP2 gene, the gene encoding the immunoglobulin µ-binding protein.

Arthrogryposis multiplex congenita is a heterogeneous group of disorders characterized by congenital contractures of multiple joints. It is typically the result of decreased fetal movement and can have multiple etiologies from neurogenic, muscular, and genetic syndromes, as well as connective tissue disorders. Many times, the specific etiology cannot be found. The neurogenic arthrogryposes are genetically heterogeneous, and both autosomal recessive and X-linked inheritance have been reported. A subgroup of neurogenic arthrogryposis is allelic with SMA type I, and deletions of SMN gene have been reported. These disorders are of variable severity. Some show no progression, and muscle strength can even improve. In other cases, bulbar and respiratory function is severely affected, and the prognosis is poor. In the X-linked form, there is disease progression and early death.

As noted above, infants with SMARD1 can present as neonates with congenital contractures along with their severe SMA presentation. Traumatic high cervical spinal cord injury (see Chapter 29 ) is a rare cause of myelopathy that can be misdiagnosed as SMA. In the absence of an asphyxial brain injury, the infant is alert with no cranial nerve signs. The myelopathy is manifested as a flaccid areflexic paralysis, which might be asymmetric. Clues to the diagnosis include evidence of trauma such as bruising or fractures and normal results on cranial nerve examination. After a few days, evidence of the myelopathy becomes more apparent with the appearance of bladder distention, priapism, and an absence of sweating below the level of the spinal lesion. Sensory testing is difficult but can be assessed by demonstrating facial grimacing to a prick on the face but no response below the neck (see Chapter 29 ).

In severe hypoxic–ischemic injury, there can be an areflexic flaccid paralysis resulting from death of spinal motor neurons. However, there are also signs of an encephalopathy and multiorgan system damage.

Hereditary Motor and Sensory Neuropathies

The hereditary motor and sensory neuropathies are a genetically heterogeneous group of disorders with a spectrum of phenotypes that includes Charcot-Marie-Tooth disease types 1 and 2, hereditary neuropathy with liability to pressure palsies, Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy. These diseases may demonstrate an autosomal dominant, autosomal recessive, or X-linked mode of inheritance. Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies are demyelinating neuropathies, whereas Charcot-Marie-Tooth disease type 2 is an axonal disorder. Congenital onset is unusual, and these three forms of hereditary motor and sensory neuropathy most often present in the older child or young adult. The two types that may present in the neonate include congenital hypomyelinating neuropathy and, less commonly, Dejerine-Sottas syndrome.

Clinical manifestations vary. Affected infants are weak, hypotonic, and areflexic. The weakness is generalized, but a greater distal weakness might be detected. Arthrogryposis may be present in more severe forms. There are usually swallowing and respiratory difficulties. Sometimes facial weakness is present, but extraocular movements are usually normal. Any associated sensory loss is difficult to detect clinically. Prognosis depends on the initial degree of weakness. In some cases, there is an improvement in strength.

The disorders are characterized by markedly decreased motor nerve conduction velocities (typically less than 10 m/s) and elevated cerebrospinal fluid protein. Sural nerve biopsy in relatively mild cases shows varying degrees of hypomyelination with atypical onion-bulb formation. (Nerve biopsy in the neonatal period would be less likely to show the onion bulb formation.) More severe cases may show complete lack of myelin. These disorders result from mutations in different genes. Moreover, different mutations in the same gene cause different phenotypes (Charcot-Marie-Tooth disease type 1, Dejerine-Sottas syndrome, congenital hypomyelinating neuropathy) and, at present, the clinical phenotype cannot always be predicted on the basis of the gene mutation. Identified alleles include Schwann cell genes involved in the formation, structure, and maintenance of peripheral myelin ( EGR2 , PMP22 , MPZ , CX32 , 6JB1 , PRX ), neuronal genes involved in axonal transport ( NEFL ), and genes affecting both Schwann cell and neuronal structure ( MTMR2 ). Testing for these mutations is available on a clinical basis.

Hereditary Sensory and Autonomic Neuropathies

The hereditary sensory and autonomic neuropathies are characterized by selective involvement of peripheral sensory and autonomic neurons ( Box 56.2 ). These disorders are autosomal recessive with the exception of hereditary sensory and autonomic neuropathy type I, which is autosomal dominant. All present with varying degrees of autonomic dysfunction or insensitivity to pain and temperature. In some, there is absence of the normal axonal flare response to intradermal injection of histamine. In the older child, there is striking self-mutilation.

The best known of the hereditary sensory neuropathies is familial dysautonomia (Riley-Day syndrome; hereditary sensory and autonomic neuropathy type III). This disorder has a high carrier rate in individuals of Ashkenazi Jewish descent and has been mapped to chromosome 9q31-q33. Mutations in the gene for IkB kinase-associated protein ( IKBKAP ) account for 99% of affected individuals. The clinical diagnosis of familial dysautonomia is based on five cardinal criteria: (1) absence of overflow tears, (2) absence of lingual fungiform papillae, (3) depressed patellar reflexes, (4) lack of axonal flare reaction after intradermal injection of histamine, and (5) Ashkenazi Jewish extraction. Additional clinical features typically include hypotonia, labile temperature and blood pressure, breath holding, pallor, poor feeding, failure to thrive, vomiting, loose stools, and irritability.

Treatment of these disorders is mainly supportive, and survival has improved with modern medical therapies. Patients who reach adulthood continue to demonstrate slow progression of their disease. Cognition may be impaired in some forms of the disease.

Clinical testing is available for familial dysautonomia. Until more molecular genetic information is available, differentiation between the other various hereditary sensory neuropathies will continue to be made by distinct characteristics of the history and examination, sensory nerve conduction and action potential size, and changes on sural nerve biopsy.

Congenital central hypoventilation syndrome should be considered in the differential diagnosis of a neonate presenting with an autonomic neuropathy. The classic neonatal form of this disease presents with an infant with hypotonia, decreased or absent deep tendon reflexes, hypoventilation with absence of response to hypercarbia, and autonomic dysfunction. These infants typically have a mutation in the PHOX2B gene and are at risk for Hirschsprung disease and tumors of neural crest origin.

Neuromuscular Junction Disorders

Neuromuscular junction disorders are infrequent causes of weakness during the neonatal period. The principal conditions include transient acquired neonatal myasthenia, congenital myasthenia, infantile botulism, and toxic amounts of magnesium or aminoglycosides. These disorders are characterized by abnormal neuromuscular transmission, which is manifested by abnormal muscle fatigability and weakness that is sometimes permanent, particularly in the congenital forms.

Autoimmune myasthenia gravis in children and adults is caused by autoantibodies directed against neuromuscular junction proteins. In 80% of patients, acetylcholine receptor antibodies are detected in the serum. In the remaining patients, other pathologic antibodies, including those directed against muscle-specific kinase, interfere with the normal function of the acetylcholine receptor, resulting in disease.

In acquired neonatal myasthenia gravis, the disease is more often active in the mother. However, she may have less obvious disease, be in remission, or not show clinical manifestations until after the pregnancy. Transfer of immunoglobulin G antibodies occurs readily across the placenta. However, typical features develop in only 20% of infants born to mothers with myasthenia. The proportion of maternal immunoglobulin G antibodies directed against the fetal type versus the adult type of acetylcholine receptor appears to have a strong influence on neonatal manifestations. Although there is no correlation between maternal antibody titers or disease severity and the development of neonatal myasthenia, there is an inverse relationship between maternal disease duration and the incidence of neonatal myasthenia. Maternal thymectomy may be protective against neonatal disease.

The disorder usually presents within a few hours of birth, and onset after the third day has not been reported. The most common presentation is generalized weakness and hypotonia. Bulbar weakness is usually present, with feeding difficulties from poor sucking and swallowing, and a weak cry. Facial diplegia can be prominent, but ptosis and ophthalmoplegia are seen less frequently. Pooling of secretions and respiratory difficulties occasionally necessitate artificial ventilation. Deep tendon reflexes are normal. Assuming a correct diagnosis and management, most infants recover within a few weeks. Some infants are severely affected with a history of polyhydramnios and the presence of arthrogryposis multiplex at birth. Treatment is more difficult, and recovery is slower in these infants.

The diagnosis of transient neonatal myasthenia should always be suspected in the infant of a mother with active generalized acetylcholine receptor antibody-positive myasthenia gravis. When signs appear, a cholinesterase inhibitor is administered and the response gauged. To be sure of the diagnosis, an unequivocal and objective response should be chosen, such as an improvement in ventilation and oxygenation or sucking ability. Neostigmine methylsulfate, IM or SC, in a dose of 0.15 mg/kg is the preferred diagnostic anticholinesterase agent. The drug takes effect within 15 minutes of injection and lasts 1-3 hours. Muscarinic side effects (diarrhea, increased tracheal secretions) might require the use of atropine in appropriate doses. Although edrophonium chloride has a more rapid onset and less intense muscarinic side effects, there is a risk of respiratory arrest. When necessary, the diagnosis can be confirmed with repetitive nerve stimulation, which should be performed before and after the administration of a cholinesterase inhibitor. A diagnostically positive response occurs when the amplitude of the fifth evoked compound muscle action potential is reduced by 10% or more of the amplitude of the first response, and this decrement is corrected by a cholinesterase inhibitor.

The management of transient neonatal myasthenia gravis must be early and vigorous, because these infants can deteriorate rapidly. Small, frequent tube feedings should be given and early ventilatory support considered. Neostigmine methylsulfate is given in a dose of 0.05-0.1 mg/kg, IM or SC, 30 minutes before feeding. The oral dose of neostigmine is approximately 10 times the intramuscular dose and is given approximately 45 minutes before feeding. Excessive doses can cause diarrhea, increased secretions, muscle fasciculations, and cholinergic weakness. Disappearance of disease activity is monitored clinically by assessing responses to gradual decreases in the anticholinesterase dose. In addition, repetitive nerve stimulation tests can be performed as well as measurement of acetylcholine receptor antibodies. Tube feeding and artificial ventilation are usually not required for longer than 1-2 weeks, and the average duration of treatment is 4 weeks, with recovery in 90% of infants in less than 2 months.

The congenital myasthenic syndromes are infrequent causes of neuromuscular junction failure during the neonatal period but have become increasingly recognized. They are a group of genetic disorders that are acetylcholine receptor antibody negative and are caused by either presynaptic or postsynaptic inherited defects of the neuromuscular junction. Their precise characterization requires sophisticated laboratory techniques, which are not widely available. Those manifested during the neonatal period are shown in Box 56.3 . Postsynaptic disorders of the acetylcholine receptor are the most common. The subunit defect form is associated with significant ptosis and variable ophthalmoplegia. The rapsyn mutation involves a mutation of the receptor-associated protein at the synapse. Typically, this is a more severe presentation than the subunit deficiency. In general, unlike acquired transient neonatal myasthenia gravis, ptosis is usually present in addition to varying degrees of ophthalmoplegia, bulbar palsy, and respiratory weakness. Fluctuating, generalized hypotonia and weakness are seen, and episodes of life-threatening apnea can occur. Exacerbations can be induced by activity, febrile illness, or other stress. These disorders often improve with age, but spontaneous exacerbations occur with a risk of sudden infant death. Arthrogryposis has been reported in one form of the disease. A diagnostic response to cholinesterase inhibitors is variable but useful when positive. Some forms of the disorder, such as congenital endplate cholinesterase deficiency, are refractory to or worsened by cholinesterase inhibitors. The diagnosis is supported by a decremental response to repetitive nerve stimulation at low frequency (2 Hz). However, the low-frequency decremental response can be absent in infants with a defect in acetylcholine resynthesis or packaging but can be induced by prolonged 10-Hz stimulation.