Repetitive compound muscle action potentials in electrophysiological diagnosis of congenital myasthenic syndromes: A case report and review of literature

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of disorders, characterized by dysfunction of neuromuscular junction (NMJ) transmission. These syndromes are genetically inherited and are present since birth. Some have characteristic clinical or electrodiagnostic features but in many cases determination of the specific form requires genetic studies or specialized morphological and electrophysiological studies on muscle tissue. We report a case of a 4-year-old boy with progressive ptosis and limitation of ocular movements who was diagnosed as slow-channel CMS based on the characteristic electrodiagnostic features. Repetitive compound muscle action potentials (R-CMAPs) were recorded after single nerve stimulus, with decremental response after repetitive trains performed at 3 Hz. CMSs are at times clinically difficult to distinguish from acquired myasthenia. The characteristic clinical and electrodiagnostic features help in the diagnosis and enable rational therapy. In this article we discuss the characteristics of synaptic R-CMAPs.


Introduction
Myasthenia gravis (MG) in infancy and childhood are of two types: congenital or acquired. Congenital myasthenic syndrome (CMS) includes a number of phenotypically and genetically heterogeneous disorders that are familial, with aff ected persons lacking autoantibodies against acetylcholine receptor (AChR). [1] Based upon clinical, ultrastructural, in vitro electrophysiological, and molecular genetic methods of study, these heterogeneous types of CMS have recently been tentatively classifi ed. [2] However, in most of the centers where advanced investigations are not possible, the diagnosis of CMS depends on the clinical features and the characteristic fi ndings in neurophysiological studies. We report a case where the presence of double CMAP (R-CMAP) helped in the diagnosis of defi nite CMS.

Case Report
A 4-year-old-boy, born of nonconsanguineous parentage and with normal developmental milestones, presented with drooping of both eyelids of 1 year's duration. There was minimal diurnal fluctuation but there was history of worsening of the symptom on exertion. Neurological examination showed bilateral asymmetric ptosis and restriction of the extraocular muscles, with minimal signs of fatigability on exertion. No delayed pupillary light refl ex was present. There was selective and severe weakness of the centers. The differentiation from autoimmune MG is important, as CMS does not respond to either thymectomy or immunosuppressive therapy. Two major features distinguish CMS from acquired MG, namely positive family history and absence of AChR antibodies. While a positive family history favors a diagnosis of CMS, a negative family history does not exclude it. [2] The demonstration of R-CMAPs in completely resting muscle in the absence of a medication eff ect due to cholinesterase inhibitors is specifi c for diagnosis of CMS. Repetitive CMAPs in CMS are seen in two varieties, namely end-plate AChE deficiency (synaptic defect) and slow-channel syndrome (postsynaptic defect). The diagnostic clues for end-plate AChE defi ciency are presence of R-CMAPs, refractoriness to cholinesterase medications, and delayed pupillary refl exes. In addition to the presence R-CMAPs, selective weakness of cervical muscles, wrist, and fi nger extensors and an autosomal dominant mode of inheritance favor the diagnosis of slowchannel CMS.
R-CMAPs seen aft er a single shock can be classifi ed as being of either 'synaptic' or 'neural' origin. Synaptic R-CMAPs involve double (and rarely triple or more) discharges in disorders of the neuromuscular synapse, either because excess acetylcholine (ACh) remains present aft er the fi rst discharge or because the normal amount of ACh causes reactivation in the slow-channel syndrome. Synaptic R-CMAPs may be initiated in the synapse, but they also depend on neural processes. The similarities between the 'double discharges' seen in partially denervated muscles (neural CMAPs) and in synaptic R-CMAPs make their distinction very diffi cult [ Table 1]. The neural R-CMAPs occur in a group of diseases characterized by excess motor unit activity [i.e., continuous motor unit activity, Isaac syndrome, and neuromyotonia (NMT)].
In synaptic R-CMAPs seen after a single stimulus, characteristically, the amplitude of the fi rst CMAP is larger than that of the second. On repetitive nerve stimulation, the decremental response occurs fi rst in the second CMAP rather than in the fi rst CMAP, as was seen in our case. Repeated stimulation diminishes the amount of available ACh; if the decline were to continue, the amount of ACh would change from an excess to a shortage. In electromyography (EMG) terms, the second component should disappear before the fi rst component starts to show a decrement. [3] Latencies of 5-8 ms or 7-10 ms may occur between the fi rst and second discharges. [4] In contrast, decrements of the fi rst and second discharges may occur simultaneously. This can only be explained by diff ering abnormalities: that is, excess ACh causes repeated fi ring at some synapses, whereas a shortage causes others not to respond at all.
In clinical practice, the most common cause of R-CMAPs is cholinesterase medication. In its absence, and when repetitive discharges are present, CMSs can be reliably diagnosed in common practice. Our case illustrates the importance of electrophysiological testing in myasthenia: it aids early diagnosis of CMS and helps avoid unnecessary investigations and treatments like steroids, plasma exchange, and even thymectomy. In institutions like ours, where molecular diagnosis of CMS is not possible, the presence of synaptic R-CMAPs can aid in the diagnosis of CMS.