Neonatal hypotonia and neuromuscular disorders



Chapter 13: Neonatal hypotonia and neuromuscular disorders


Crystal Jing Jing Yeo, Jahannaz Dastgir, Basil T. Darras



Gaps in knowledge




Introduction


Neonatal hypotonia, often referred to as the “floppy infant,” is the main presenting clinical feature of most neuromuscular diseases of early life.1 However, disorders of the central nervous system (CNS) may also manifest with hypotonia. In this chapter, we will attempt to (1) define hypotonia, (2) discuss the physical examination and assessment of the hypotonic infant, (3) discuss the differential anatomic diagnosis of hypotonia, (4) summarize the most common neuromuscular disorders presenting principally with hypotonia, and (5) present our stepwise diagnostic approach to the investigation of neonatal hypotonia.


Definition of hypotonia


Two types of muscle tone can be assessed clinically: postural and phasic. Postural (antigravity) tone is a sustained, low-intensity muscle contraction in response to gravity. It is mediated by both gamma and alpha motor neuron systems in the spinal cord, and it is assessed clinically by passive manipulation of the limbs. Phasic tone is a brief contraction in response to a high-intensity stretch. It is mediated by the alpha motor neuron system only and is examined clinically by eliciting the muscle stretch reflexes. Hypotonia is defined as reduction in postural tone, with or without a change in phasic tone. When postural tone is depressed, the trunk and limbs cannot overcome gravity and the child appears hypotonic or floppy.


An approximate caudal-rostral progression in the development of muscle tone has been described by Sainte-Anne Dargassies.2 At postconceptional age of 28 weeks, there is minimal resistance to passive manipulation in all limbs; by 32 weeks, flexor tone can be appreciated in the lower extremities; and by 36 weeks, flexor tone is also present in the upper limbs. By term, strong flexor tone in all four limbs can be demonstrated by passive movements.


Physical examination and assessment of a hypotonic child


Volpe3 describes the physical examination of a hypotonic infant in detail. Following a careful general physical examination, the neurological assessment should include an evaluation of primary neonatal reflexes, a sensory examination, and most importantly, a motor examination (Box 13.1). General physical examination may reveal organomegaly, skin changes, dysmorphic features, contractures, abnormalities of the genitalia, respiratory rate or pattern irregularities, or evidence of traumatic injury (e.g., bruising, petechiae). The general examination may also be normal. Abnormal primary neonatal reflexes refer to their persistence. In normal infants, the Moro reflex disappears by 6 months of age,4,5 the palmar grasp becomes less obvious after 2 months of age, and the tonic neck response should diminish by 6 to 7 months of age.4−6 Sensation can be tested by withdrawal from a stimulus (e.g., touching the infant with a small brush), and abnormalities in sensation may suggest the presence of a congenital neuropathy (e.g., hereditary motor-sensory or sensory-autonomic neuropathies), but, admittedly, this is difficult to assess in infants.



The motor examination includes assessment of posture, muscle tone, mobility, muscle power, and muscle stretch reflexes. When assessing muscle tone, the infant’s head should be placed in the midline in order to eliminate the effect of the tonic neck response. Minimal resistance to passive manipulation of arms or legs is an important clinical feature of hypotonia. Weak cry, poor suck, and poor respiratory effort may be noted in an otherwise very alert infant. Pectus excavatum or carinatum is sometimes seen, reflecting long-standing weakness of chest wall musculature. Most hypotonic infants demonstrate a classic “frog-like” posture: full abduction and external rotation of the legs as well as a flaccid extension or flexion of the arms. Congenital dislocation of the hips may be noted because poor muscle tone in utero failed to maintain the femoral head in the acetabulum. Another sign of intrauterine hypotonia and limited fetal movements is arthrogryposis (i.e., contractures of multiple joints). Spontaneous antigravity movements of limbs may be absent or decreased. In a full-term newborn or older infant, passive movement of the infant’s elbow across the midline produces a positive “scarf sign.” Similarly, a positive heel-to-ear test is readily demonstrated by opposing the heel to the ear. Finally, muscle stretch reflexes may be normal, brisk or hypoactive (i.e., absent or decreased).


Muscle tone can be evaluated further by performing the traction response, vertical suspension, and horizontal suspension maneuvers.7


Traction response


To elicit the traction response, the examiner grasps the infant’s hands and wrists and slowly raises the infant from the supine to a seated position. The normal infant’s head is maintained at midline or at least for a few seconds when the seated position is reached. However, the hypotonic infant tends to have significant head lag when pulled to the seated position and will not maintain his/her head erect when sitting.


Vertical suspension


The examiner places both hands beneath the infant’s armpits and lifts the infant straight up. In a normal infant, the shoulder muscles press down against the examiner’s hands and enable him/her to suspend vertically without falling. When the normal infant is in vertical suspension, the head is maintained in the midline and hips, knees, and ankles are in flexion. When this maneuver is performed in the hypotonic infant, the infant slips through the examiner’s hands with both legs usually extended.


Horizontal suspension


The examiner uses one hand to support the infant’s trunk in a prone position and observes the resulting posture. A normal infant flexes or fully extends the limbs, straightens the back, and maintains the head in the midline position for at least a few seconds. The hypotonic infant’s head and limbs hang loosely and the trunk “drapes over” the examiner’s hand.


Some clinicians use signs borrowed from the premature infant examination (described above), such as the “scarf sign” (i.e., approximation of elbow to opposite shoulder) or “heel to ear or chin,” in an effort to quantitate muscle tone. We do not use these routinely in the assessment of tone but have found them useful in the diagnosis of congenital laxity of ligaments.


Differential anatomic diagnosis of hypotonia


Neonatal hypotonia may be the manifestation of pathology involving the CNS, the peripheral nervous system (i.e., lower motor unit), or both (Box 13.2). In infants with cerebral or central hypotonia, nearly two-thirds of cases, the perinatal or prenatal history may suggest a CNS insult. There may also be associated global (rather than an isolated gross-motor) developmental delay, occasionally seizures, microcephaly, dysmorphic features, and/or malformation of the brain and/or other organs. Central hypotonia may be associated with brisk and/or persistent primitive reflexes and normal-brisk muscle stretch reflexes. The degree of weakness noted in these infants is usually less than the degree of hypotonia (“nonparalytic” hypotonia) (Table 13.1). In lower motor unit hypotonia or peripheral hypotonia, developmental delay is primarily gross-motor and is associated with absent or depressed muscle stretch reflexes and/or muscle atrophy and fasciculations of the tongue. In general, antigravity limb movements are decreased and cannot be elicited via postural reflexes. In these infants, the degree of weakness is proportional or in excess of the degree of hypotonia (“paralytic” hypotonia) (Table 13.1). Trauma to the high cervical cord due to traction in breech or cervical presentation may also initially manifest itself as flaccid paralysis, which may be asymmetric, and absent muscle stretch reflexes; later on, however, upper motor neuron signs develop.




Because muscle tone is also determined by the visco-elastic properties of muscle and joints, connective tissue disorders such as Marfan, Ehlers-Danlos syndromes, osteogenesis imperfecta and also benign laxity of the ligaments can present with hypotonia. In addition, there is combined cerebral and lower motor unit hypotonia seen in infants and older children with congenital myotonic dystrophy, some congenital muscular dystrophies (CMD), peroxisomal disorders, mitochondrial encephalomyopathies, neuroaxonal dystrophy, leukodystrophies (e.g., globoid cell leukodystrophy), familial dysautonomia, and asphyxia secondary to motor unit disease (Box 13.3). Further, hypotonia without significant weakness may be a feature of systemic diseases such as sepsis, congenital heart disease, hypothyroidism, rickets, renal tubular acidosis, and others.



Neuromuscular diseases in infancy present primarily with hypotonia and weakness; however, infants with severe hypotonia but only marginal weakness usually do not have a disorder of the lower motor unit (anterior horn cell, peripheral and cranial nerves, neuromuscular junction, and muscle). These infants may have genetic conditions, metabolic disturbances, or systemic disorders (e.g., congenital heart disease, renal failure). Early on, neonates with CNS pathology may present with profound hypotonia, decreased reflexes, and moderate to severe but transient weakness; however, they also tend to have seizures, obtundation, cranial nerve abnormalities, and/or history of perinatal asphyxia. With recovery, they gradually develop better strength, increased muscle stretch reflexes and muscle tone. This is in contrast to the asphyxiated infants with disorders of the lower motor unit, in whom the weakness, hypotonia, and hyporeflexia persist. Alternatively, profound weakness and hypotonia without signs of CNS involvement occur in newborn infants with isolated neuromuscular disease and no history of perinatal asphyxia. Muscle stretch reflexes vary depending on the anatomical level of pathology along the motor unit (i.e., prominent hyporeflexia or total areflexia in anterior horn cell disorders and neuropathies, reduced reflexes in proportion to the degree of weakness in myopathies, and often normal reflexes in disorders of the neuromuscular junction). Again, approximately two-thirds of patients with neonatal hypotonia have cerebral etiologies and one-third have lower motor unit diseases.8


Box 13.4 lists the most common causes of cerebral (central) hypotonia. Prasad and Prasad9 review the metabolic and genetic disorders presenting with hypotonia and suggest a diagnostic algorithm.



Common neuromuscular disorders presenting principally with hypotonia


This chapter will review the most frequent genetic and acquired disorders of the lower motor unit (Table 13.2). Most of these conditions present with hypotonia.



Anterior horn cell/peripheral nerve disorders


Spinal muscular atrophies

Three clinical variants have been described based on the rate of progression and age at onset of the disease: (1) SMA Type I, or Werdnig-Hoffmann disease, (2) intermediate SMA, or SMA Type II, and (3) SMA Type III, or Kugelberg-Welander disease.10,11 Here, we will discuss primarily SMA Type I, which may be seen clinically during infancy.


SMA Type I, Werdnig-Hoffmann disease

Generalized hypotonia and weakness may be noted during the first 6 months of life, and in 95% of the cases before the age of 4 months. Prenatal onset has been described and it is experienced by the mother as weakening of fetal movements during the last trimester of the pregnancy. At birth or in the first 6 months of life, weak sucking, difficulty with swallowing, labored breathing, extreme hypotonia, severe weakness, and hyperabduction of the hips (“frog legs”) become apparent. Arthrogryposis multiplex congenita is uncommon in SMA Type I but, nonetheless, has been observed rarely in infants who are symptomatic at birth; this is known as SMA Type 0 or Type Ia. Type I SMA patients never sit unsupported.10,12 Examination shows hypotonia, areflexia, and weakness typically affecting the lower extremities earlier and more severely than the upper extremities and the proximal muscles more often than the distal ones. The anterior/posterior diameter of the thorax is decreased and there may be pectus excavatum with paradoxical respirations. As the disease advances, there is paralysis of the bulbar muscles, loss of the cough reflex, and an inaudible cry. Wasting and fasciculations of the tongue may be observed, but they can be easily confused with simple tongue tremors. Without disease-modifying treatments, death usually occurs in the first year or less often in the second year of life, most commonly related to aspiration pneumonia. An unusual genetically distinct variety of SMA related to diaphragmatic paralysis (spinal muscular atrophy with respiratory distress Type I, SMARD1) has been described, presenting primarily with respiratory distress in the first 2 months of life before any skeletal muscle involvement. In classic SMA Type I, the respiratory insufficiency is due to intercostal rather than diaphragmatic paralysis.13


Although used rarely, the electromyogram (EMG) may reveal excessive spontaneous activity during the first 3 months of life consisting of multiple discharges at a frequency 5 to 15 Hz in relaxed muscles, which persist during sleep. Fibrillation potentials may also appear later on. Motor unit potentials are increased in duration, and many are polyphasic and poorly recruited by voluntary activation. Muscle biopsy examination demonstrates small and large-group atrophy, with intermixed groups of hypertrophic fibers. The hypertrophic fibers are histochemically Type I fibers while the atrophic fibers are Type I and Type II.10 Postmortem histologic examination of the spinal cord shows loss of anterior horn cells. CPK can be mildly to moderately elevated, usually up to 5 times the upper limit of normal. Given the availability of genetic diagnosis, EMG and, in particular, muscle biopsy are used only rarely in the diagnosis of SMA.


In 1990, all three types of autosomal recessive SMA were mapped to a single locus on chromosome 5q11.2-13.3.14 Subsequently, in 1995, two groups reported the preferential deletion of two genes, the survival motor neuron (SMN)15,16 and the neuronal apoptosis inhibitory protein gene (NAIP)17 in SMA patients. Homozygous deletions of exon 7 or exons 7 and 8 of the telomeric copy of the SMN gene (SMN1) can be detected in 90% to 95% of patients with SMA, regardless of severity (Types I, II, and III).15 Most of the remaining patients have deletion of SMN1 in one allele and a point mutation in the other; a very small fraction of the deletion-negative patients has rare nonchromosome 5 types of SMA. Commercially available assays for the homozygous loss of exon 7 or exons 7 and 8 of the SMN1 gene thus provide a highly correlated marker for the prenatal and postnatal diagnosis of SMA Type I. NAIP deletions are seen in over 45% of SMA Type I and less than 20% of Type II and Type III SMA patients.17 Despite the occurrence of NAIP deletions, NAIP has not been proven to be important in the pathogenesis of SMA.


Since 2017, three SMN protein augmenting therapies, nusinersen, onasemnogene abeparvovec-xioi, and risdiplam, have become available for SMA patients and can substantially improve clinical outcomes with early treatment.18 Testing for deletion of SMN1 exon 7/8 is now included in routine newborn screening in 39 states across the United States and internationally.19,20 This allows 91% of SMA infants to be diagnosed in the United States in the first week of life for the early initiation of treatment.


SMA Type II, SMA Type III

Most patients with SMA Type II and III are normal at birth. In a series of 19 infants who were later classified as SMA Type II, all of them were found to be normal at birth.21 The onset of the disease, however, is before the age of 18 months and typically after the age of 6 months.22 Patients can sit unsupported but never stand. Survival to ages 5 and 25 years is 98.5% and 68.5%, respectively, was reported in patients with disease-modifying treatments. Many patients with SMA Type III achieve normal gross motor milestones early on and often into later childhood. The onset of symptoms is usually after the age of 18 months (either before the age of 3 years [Type IIIa] or after [Type IIIb]) and patients can stand alone; lifespan is almost normal. The SMA phenotype is determined, at least in part, by the number of copies of the centromeric copy of the SMN gene, known as SMN2 (which produces a small amount (∼10%) of full-length SMN protein); patients with milder phenotypes tend to have more copies of SMN2. Most SMA Type I patients have one to two copies of SMN2 (80%), while most SMA Type II patients have two or three copies (82% have three copies), and the vast majority (96%) of SMA Type III patients have three or four copies of SMN2.23 Treatment with SMN augmenting therapy is recommended in SMA patients with up to four copies of SMN2.24


Congenital neuropathies

Congenital hypomyelinating and axonal neuropathies

Fourteen infants with neuropathy were reviewed by Sladky.25 He described nine infants with demyelinating neuropathy, including four with hypomyelination, three with steroid-responsive chronic inflammatory demyelinating polyneuropathy (CIDP), and two with a leukodystrophy. Four of five axonal neuropathies in the same sibship were X-linked and one was a sporadic case. Neonates with congenital neuropathies usually present with severe hypotonia, weakness, and hyporeflexia or areflexia closely resembling SMA Type I. However, cerebrospinal fluid protein is elevated in most infants with congenital neuropathies, not a finding in SMA Type I. EMG and nerve conduction studies (NCS) are not only important for confirming the diagnosis and distinguishing between neuropathies and SMA Type I, but they can also help identify whether demyelinating or axonal features. Nevertheless, electrophysiological studies may be unable to differentiate between inherited noninflammatory and acquired inflammatory neuropathies. Though sural nerve biopsy may help establish the diagnosis, it may not exclude CIDP. A number of infants with congenital neuropathies may also have the early onset of hereditary motor and sensory neuropathies (HMSN) such as Charcot-Marie-Tooth (CMT)1A and CMT1B (known as Dejerine-Sottas disease), CMT 4E (neonatal hypotonia and arthrogryposis), a metabolic disease such as mitochondrial cytopathy or a leukodystrophy, hereditary sensory and autonomic neuropathy (e.g., Riley-Day syndrome), or giant axonal neuropathy.


Disturbances of neuromuscular transmission


Transient neonatal myasthenia gravis

This syndrome results from the transplacental transfer of circulating anti-acetylcholine receptor (AChR) antibodies from a myasthenic mother. It develops in about 10% to 20% of infants born to myasthenic mothers. The syndrome usually presents within hours of birth but may be delayed for up to 3 days; the main features are feeding difficulties (87%), generalized weakness (69%), respiratory difficulties (65%), weak cry (60%), facial diplegia (54%), ptosis (50%), and sometimes external ophthalmoplegia. Respiratory failure is uncommon, but it may occur. The presence of arthrogryposis, pulmonary hypoplasia, polyhydramnios, weak fetal movements, or stillbirth signifies onset in utero. The severity of the disease in infants correlates poorly with clinical severity in mothers and with maternal antibody titer; however, falling antibody titers correlate with clinical improvement. Infants with transient neonatal myasthenia gravis (TNMG) are born to mothers with a relatively high ratio of antibodies directed against the fetal versus the adult AChR. TNMG may rarely occur in infants born to seronegative mothers and may rarely be secondary to anti-MuSK antibodies.26 The mean duration of symptoms is 18 days, with a range of 5 days to 3 months. The diagnosis is confirmed by demonstrating high serum concentration of AChR antibody in newborn infants. Though less frequently utilized, diagnosis may also be confirmed via reversal of the symptoms with edrophonium chloride (Tensilon), given either as an intramuscular or subcutaneous injection of 0.04 to 0.15 mg/kg or 0.1 mg/kg body weight intravenously delivered in fractional amounts over a number of minutes after a test dose of 0.01 mg/kg. Clinical improvement becomes apparent in a few minutes after the intravenous administration of edrophonium chloride and may last for 10 to 15 minutes. Given the possibility of cardiac bradyarrhythmias subsequent to the intravenous use of edrophonium chloride, however, the intramuscular and subcutaneous routes are preferable in newborn infants. In severely compromised neonates, an exchange transfusion should be attempted. For infants with only feeding and swallowing problems, a longer-lasting effect (1–3 hours) may be achieved by the intramuscular or subcutaneous injection of about 0.05 mg/kg per dose neostigmine methyl sulfate 15 to 30 minutes before each feeding, though this may induce increased tracheal secretions. The same medication can also be administered through a nasogastric tube at ten times the parenteral dose (0.5 mg/kg/dose) 45 to 60 minutes prior to feeding.


Acquired autoimmune myasthenia gravis

Only minor differences exist between acquired autoimmune myasthenia gravis in children and adults, but the onset of symptoms is always after age 6 months and in most cases after 2 years.


Congenital myasthenic syndromes

Congenital myasthenic syndromes can be classified according to the site of the defect, that is, presynaptic, postsynaptic, synaptic, and mixed.27 These are defects of neuromuscular transmission, and the classification and main features of the most common forms are shown in Table 13.3. Congenital myasthenic syndromes usually present in infancy with generalized hypotonia and fluctuating weakness, weak cry and suck, respiratory distress, apnea, and feeding difficulties. Fluctuating ptosis, ophthalmoparesis, and fatigability on exertion may also be present during infancy and childhood. Later on, delayed motor milestones may be noted and will, in some cases, progress during adolescence and adulthood. Testing for anti-AChR antibodies is negative. The diagnosis is based on clinical history and examination, family history (if present), EMG findings, and the clinical response to acetylcholinesterase inhibitors and confirmed with genetic testing. Tensilon (edrophonium chloride) chloride testing, though less frequently in use today, is positive in most types of congenital myasthenic syndromes, except in the classic slow channel syndrome and in congenital end-plate acetylcholinesterase deficiency (see Table 13.3). If clinical response to edrophonium chloride occurs, long-term treatment with neostigmine or pyridostigmine may be needed. In most cases, however, detailed EMG studies, in vitro microphysiologic, ultrastructural, and histochemical studies of intercostal muscle biopsies have been used to establish the diagnosis. Nevertheless, currently genetic testing may be the first step in the work-up of individuals suspected of the diagnosis. Treatments may also be tailored to the specific mutation with medications such as albuterol or ephedrine.



Infantile botulism

Patients developing botulism in infancy are normal at birth but between the age of 10 days and 12 months (median age at presentation is 10 weeks) develop acutely severe weakness, dysphagia, constipation, weak cry, severe hypotonia, and respiratory insufficiency.28 On examination, there is diffuse hypotonia and weakness, ptosis, ophthalmoplegia with pupillary involvement (mydriasis) in some cases, reduced gag reflex, and usually preservation of muscle stretch reflexes.29 The history of presentation is suggestive of a descending pattern of paralysis. Affected infants tend to deteriorate if given aminoglycosides or other neuromuscular blocking agents. On EMG examination, the compound motor unit potential amplitude is low at rest; repetitive stimulation at 2 to 5 Hz typically produces decrement, but with 20 to 50 Hz stimulation, facilitation of 125% to 3000% is seen in almost all cases. To demonstrate the increment, however, a prolonged period of stimulation (10–20 seconds) may be required.30 During infancy, the pathogenesis of botulism is different. The Clostridium botulinum (C. botulinum) is ingested, colonizes the intestinal tract, and produces toxin in situ. This is in contrast to older children and adults in whom the disease is related to ingestion of food contaminated by preformed exotoxin.31 The diagnosis in infants is confirmed by isolation of the organism in stool. Infantile botulism is a self-limited disease, but the period of profound hypotonia can last from 2 to 6 weeks, so the infant should be observed in the intensive care unit and be supported, if respiratory failure occurs. Botulinum immune globulin (BIG) seems to be safe and reduces the duration of the disease, the cost of hospitalization, and the severity of illness.32


Magnesium intoxication

Generalized weakness, hypotonia and mental status changes may be seen in infants born to mothers treated with high doses of magnesium sulfate for eclampsia. Because this is a self-limited condition brought about by elevated magnesium levels that impair neuromuscular transmission, specialized testing (e.g., EMG/NCS) is not necessary. These infants may have depressed deep tendon reflexes, abdominal distension secondary to ileus, and irregularities of cardiac rhythm. Aminoglycoside antibiotics may worsen the hypotonia in small preterm infants with hypermagnesemia because of increased neuromuscular blockade and, therefore they should be used with caution.


Muscle disorders


The muscle disorders reviewed in this chapter usually present with hypotonia and weakness during infancy; however, a later onset may occur. They are listed in Box 13.5.



Congenital muscular dystrophies


In CMDs, the muscle biopsy is abnormal (it shows features often seen in the major muscular dystrophies of later onset); however, there are no unique identifying features and thus the need for genetic confirmation.


CMDs can be classified into two major groups depending on the association with structural brain abnormalities on neuroimaging studies or autopsy examination.33 The CMDs without structural CNS anomalies, also known as “Classical” CMD, form a heterogenous group of disorders. In the second group, i.e., those with associated structural CNS abnormalities, concomitant eye involvement, and clinical evidence of significant neurological dysfunction may be evident. The latter group includes Fukuyama muscular dystrophy (FMD), Walker-Warburg syndrome (WWS), and muscle-eye-brain disease (MEBD) (Box 13.6; Table 13.4). A biochemical classification has been proposed as well (Table 13.5).


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Mar 23, 2024 | Posted by in NEUROLOGY | Comments Off on Neonatal hypotonia and neuromuscular disorders

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