DIFFERENTIAL DIAGNOSIS FOR EARLY RESPIRATORY DISTRESS IN INFANCY
The differential diagnosis of lower motor neuron disorders with perinatal respiratory distress is fairly limited.
Generally, respiratory distress within the first few days of life can be seen in SMA type I, congenital hypomyelinating neuropathy, congenital myasthenia, transient neonatal myasthenia, congenital myotonic muscular dystrophy, neurogenic arthrogryposis, and x-linked myotubular myopathy. These disorders are easily differentiated with EDSs and in some instances molecular genetic findings. For example, congenital myotonic muscular dystrophy may be definitively diagnosed with molecular genetic studies at the chromosome 19ql3.3 locus. In congenital hypomyelinating neuropathy, sensory conduction abnormalities are unrecordable and motor NCVs are markedly slowed down (2-5 m/s) with temporal dispersion and low-amplitude evoked potentials (see Figure 6.6). SMA patients show normal sensory conductions, decreased CMAP amplitudes, occasional fibrillations, and decreased numbness of MUAPs. Congenital myasthenia patients show normal sensory conductions, normal motor NCVs, and abnormalities on repetitive nerve stimulation studies. X-linked myotubular myopathy patients show profuse fibrillations and myopathic MUAPs on EMG and diagnosis is confirmed by muscle biopsy.
ACUTE ONSET INFANTILE HYPOTONIA
Acute onset hypotonia in a previously normal infant should warrant an evaluation to rule out acute inflammatory demyelinating polyneuropathy (AIDP), infantile botulism, infantile polymyositis, an infantile form of myasthenia, a toxic process, or acute onset myelopathy. Repetitive motor nerve stimulation studies should be performed under the following circumstances: (a) there is constipation, bulbar involvement, and/or respiratory distress; (b) an infant presents with ptosis or extraocular muscle weakness; (c) CMAP amplitudes are severely reduced; (d) "myopathic" MUAPs are present; (e) a repetitive CMAP is observed after single supramaximal stimulation on routine NCS, suggestive of a diagnosis of congenital myasthenia with congenital acetylcholinesterase (AChE) deficiency or classic slow-channel syndrome.
MOTOR NEURON DISORDERS (EG, SMA)
SMA is perhaps the most common lower motor neuron disorder causing infantile hypotonia. The predictive value of needle electromyography (EMG) in the diagnosis of SMA has been established (40-43), but the need for EDSs has diminished over the years, given the 95% or greater sensitivity of SMN gene studies. As SMA remains an important consideration in infantile hypotonia, a review of the electrodiagnostic findings is useful.
The findings in this motor neuron disorder have largely been consistent with motor axonal loss, denervation, and (among persons less severely affected)
FIGURE 6.6 Median nerve conduction in a 5-year-old child with congenital hypomyelinating neuropathy documented by sural nerve biopsy and molecular genetic studies of the EGRF 2 gene. Distal latency is markedly prolonged at 19.6 milliseconds. There is reduced compound muscle action potential amplitude, at 0.367 mV, conduction block (note the drop in amplitude from distal to proximal), and conduction velocity at 4 m/s.
reinnervation. Traditional electrodiagnostic criteria for motor neuron disease are not suitable for patients with childhood SMA. For example, Buchthal (45) found that many infants with SMA did not meet strict criteria for motor neuron disease. If clinical findings suggest SMA, study of at least two muscles innervated by different nerve roots and peripheral nerves in at least three extremities is indicated (46). In the infant, spontaneous activity may be more readily determined with the study of muscles that are not as commonly recruited, such as the vastus lateralis, gastrocnemius, triceps, and first dorsal interosseous. Recruitment and motor unit characteristics can be assessed in muscles that are readily activated such as the anterior tibialis, iliopsoas, biceps, and flexor digitorum sublimis (45). The paraspinal muscles are usually not studied due to poor relaxation, and the experienced pediatric electrodiagnostic medicine consultant usually defers needle evaluation of the tongue in the hypotonic infant.
Although some authors (46) have described high-density fibrillation potentials in infants with poorer outlook, most studies have not demonstrated abundant fibrillation potentials in the infantile form (46—48). In SMA III, the incidence of fibrillation potentials ranged from 20% to 40% in one series (49) to 64% in another (50). The incidence of fibrillation potentials in SMA III does not approach the level seen in SMA 1. Additionally, spontaneous activity has been more frequently observed in the lower extremities than upper limbs, and proximal more than distal muscles in SMA III (49). The degree of spontaneous activity has not been found to be independently associated with a worse prognosis in SMA (43). Fasciculations are uncommonly observed in SMA Type I and appear more commonly in SMA II and III (46—48). In younger patients, fasciculations are difficult to distinguish from spontaneously firing MUAPs. In relaxed muscles, some motor units exhibit a spontaneous rhythmic firing (47,48,51).
Voluntary MUAPs frequently fire with an increased frequency although recruitment frequency may be difficult to determine consistently in infants. Compared to age-matched norms, MUAPs show longer duration, particularly in older subjects, and higher amplitude; however, a bimodal distribution may be seen with some concomitant low-amplitude short-duration potentials (47). Large-amplitude, long-duration MUAPs may be absent in many infants with SMA I but more commonly observed in SMA II and III (46). The percentage of large-amplitude MUAPs increase with the duration of the disease (48). Other signs of reinnervation, such as polyphasic MUAPs may be observed in more chronic and mild SMA. These polyphasic MUAPs may include late components such as satellite or nascent potentials. There may also be temporal instability of the waveform observed in individual MUAPs. Reduced recruitment (an incomplete interference pattern) with maximal effort is perhaps the most consistent finding in all SMA types (see Figure 6.7). In one series (43), the amplitude of MUAPs and degree of decrement in recruitment pattern were not individually associated with worse prognosis.
Motor NCVs and CMAP amplitude have been shown to be reduced in many patients with infantile SMA. The degree of motor conduction slowing (if present) tends to be mild and greater than 70% of the lower limit of normal (48,50,52-54). Reduction of motor conductions to
FIGURE 6.7 Incomplete or reduced interference pattern in spinal muscular atrophy type II. Note the large amplitude motor unit action potential (3,000 uV) firing at 25 Hz.
less than 70% of the lower limit of normal is described as an exclusionary criterion for SMA (55). The mild slowing of motor conductions is present to the same degree over distal and proximal segments as determined by M- and F-wave responses (53). The slowing of conduction is generally seen in those with correspondingly low-amplitude CMAPs and is thought to be due to selective loss of the fastest conducting fibers from large motor units. Alternatively, arrested myelination in utero has been proposed to explain this slowing in motor conduction noted in some SMA cases at birth (43). Survival has been found to be longer for those SMA infants with normal MCVs over a distal segment (43). Significant reductions in CMAP amplitudes have been frequently reported for SMAs I to III (43,46,50). Kuntz (50) reported a tendency toward greater reductions in CMAP amplitude among patients with earlier age of onset and shorter survival.
Sensory NCSs in SMA show essentially normal sensory CVs and SNAP amplitudes. Significant abnormalities in sensory studies exclude a diagnosis of SMA (55), while minor abnormalities in sensory CVs have infrequently been noted in SMA (52,56,57). Such rare sensory abnormalities have not been reported in SMA patients with diagnostic confirmation by molecular genetic studies.
CMAP amplitude and motor unit number estimation (MUNE) have increasingly been used in recent years as potential biomarkers for clinical trials in SMA. In one study (58), denervation was assessed in 89 SMA I, II, and III subjects via MUNE and maximum compound muscle action potential (CMAP) studies, and results correlated with SMN2 copy, age, and function. MUNE and maximum CMAP values of the ulnar nerve were distinct among SMA subtypes. Changes in MUNE and maximum CMAP values over time were dependent on age,
SMA type, and SMN2 copy number. SMN2 copy number less than 3 (consistent with SMA I) was correlated with lower MUNE and maximum CMAP values and worse functional outcomes. As SMN2 copy number increased, so did functional status. Change in MUNE longitudinally over the time intervals examined in this study was not statistically significant for any SMA cohort. However, a decline in maximum CMAP over time was apparent in SMA2 subjects. Age-dependent decline in MUNE and maximum CMAP was apparent in both SMA I and SMA II subjects, with age as an independent factor regardless of type. Maximum CMAP at the time of the initial assessment was most predictive of functional outcome. Prospective longitudinal studies in four prenatally diagnosed infants demonstrated significant progressive denervation in association with symptomatic onset or functional decline. In another study (59), MUNE values correlated with Hammersmith Functional Motor Scale (HFMS) scores. Increased single motor unit action potential (SMUP) amplitude values correlated with decreased HFMS scores. The study confirmed that the MUNE method is a useful tool reflecting motor unit loss in SMA, and it is easy to perform and well tolerated.
In a recent longitudinal study, 62 children with SMA types II and III were observed prospectively for up to 42 months (60). Longitudinal electrophysiologic data were collected, including compound motor action potential (CMAP), SMUP amplitude, and MUNE. Significant motor neuron loss and compensatory collateral reinnervation were noted at baseline. Over time, there was a significant mean increase in MUNE (4.92 units/year), a mean decrease in SMUP amplitude (-6.32 uV/year), and stable CMAP amplitude. The unexpected longitudinal results differed from findings in amyotrophic lateral sclerosis studies, perhaps indicating that compensatory processes in SMA involve new motor unit development. A better understanding of the mechanisms of motor unit decline and compensation in SMA will be important for assessing novel therapeutic strategies and for providing key insights into disease pathophysiology. MUNE and CMAP amplitudes seem to be sensitive parameters reflecting motor dysfunction in SMA but additional longitudinal studies are needed.
To investigate these measures as biomarkers of treatment response, MUNE and sciatic CMAP measurements were obtained in SMNA7 mice treated with antisense oligonucleotide (ASO) or gene therapy (61). ASO-treated SMNA7 mice were similar to controls at days 12 and 30. CMAP reduction persisted in ASO-treated SMNA7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN. SMN restoring therapies result in preserved MUNE and gradual repair of CMAP responses. This provides preclinical evidence for the utilization of CMAP and MUNE as biomarkers in future SMA clinical trials.