Deriving pediatric nerve conduction normal values in the very young (<3 years).

OBJECTIVE: This work describes our efforts to obtain nerve conduction studies normal values in a pediatric cohort between birth and 3 years of age using the extrapolated norms or e-norms method. Interpretation of these studies poses major challenges when no reliable normal values can be found in the literature. METHODS: The e-norms method was used to derive a reference range of upper and lower extremity sensory and motor nerve conductions normal values from a pediatric cohort referred to an EMG Laboratory for nerve conduction studies. RESULTS: E-norms were calculated for Median, Ulnar, Superficial Peroneal, Sural, and Medial Plantar sensory studies, and for Median, Ulnar, Peroneal, and Tibial motor studies. CONCLUSIONS: Pediatric electrodiagnostic testing is a very challenging undertaking. The ability to obtain and use normal values from the neurophysiologist's own referral pool adds great value to their diagnostic work-up. SIGNIFICANCE: EMG and nerve conduction studies can yield invaluable information in the diagnostic work-up of young infants. Using the e-norms method improves on the analysis and interpretation of electrophysiological studies in this age group.

Use of stimulated electromyography in the analysis of the neuromuscular junction in children.

A screening test is required to diagnose disorders of the neuromuscular junction (NMJ) in children. This Review describes the development of stimulation potential analysis with concentric needle electrodes (SPACE). This nomenclature was chosen to distinguish the technique from single-fiber methodology because of the difficulties in identifying single-fiber potentials in most studies, particularly those with the most severe abnormalities of the NMJ. Performed on orbicularis oculi in children with proven or probable disorders of the NMJ, it demonstrated a sensitivity of 84%, specificity of 71%, negative predictive value of 95%, and positive predictive value of 36%. It is well tolerated and within the capability of any clinical neurophysiologist. When combined with a full electrodiagnostic examination, SPACE provides invaluable information about children with NMJ disorders, whose diagnosis often is difficult. Muscle Nerve 56: 841-847, 2017.

Assessing neuromuscular junction stability from stimulated EMG in children.

OBJECTIVE: We present our 9-year experience of stimulated EMG potential analysis using concentric electrodes (SPACE) to evaluate neuromuscular junction (NMJ) disorders in awake children. The technique uses high frequency filtration of stimulated motor unit potentials and applies peak detection software to estimate mean consecutive difference (MCD). METHODS: SPACE was carried out in orbicularis oculi of 878 children (377 girls; median age 47months) between 2007 and 2015, stimulating the facial nerve with a monopolar cathode. Mean MCD-index (MCD-I) was expressed as a ratio of the measured MCD to the upper normal limit. Diagnostic accuracy was calculated for primary NMJ disorders based on the 660 cases with clinical follow-up data. RESULTS: Primary NMJ disorders were present in 106 children, including 46 with genetically confirmed congenital myasthenic syndrome (CMS). Mean MCD-I was two times higher in children with primary NMJ disorders compared to others (205±108µs vs 94±38µs, p<0.005). After excluding children with neuronopathies, an MCD-I >100% had 84% sensitivity and 74% specificity for the primary NMJ disorders. Receiver operating characteristics (ROC) curve identified an MCD-I >115% as providing best diagnostic accuracy with sensitivity of 77% and specificity of 84%. CONCLUSION: SPACE is practicable and safe in unsedated children. SIGNIFICANCE: In combination with routine EMG, it has high diagnostic accuracy and can facilitate recognition of paediatric NMJ transmission disorders.

Determining jitter values in the very young by use of the e-norms methodology.

INTRODUCTION: The diagnosis of myasthenia gravis in very young infants is a challenging one. In young infants, stimulated single-fiber electromyography (StimSFEMG) is the most appropriate technique, but it has serious limitations due to the absence of reference values in this subpopulation. Here we present our efforts to derive a reference range of jitter in a patient cohort of infants <3 years of age using the extrapolated norms, or e-norms, technique. METHODS: The e-norms method was used to calculate jitter mean consecutive difference (MCD) descriptive statistics for children <3 years of age. RESULTS: The e-norms derived jitter upper MCD limit was 45 µs in children <1 year, 33 µs in those <2 years, and 26 in those <3 years of age. CONCLUSION: In the absence of jitter reference values for the very young, the e-norms method can be used as an alternative to derive these values from laboratory cohorts. Muscle Nerve 55: 51-54, 2017.

Perception of pain during electromyography in children: A prospective study.

INTRODUCTION: Electrodiagnostic examination is perceived as a painful examination. An accurate assessment of its discomfort would be valuable to children, their parents, and clinicians. METHODS: We performed a prospective study of pediatric patients seen over 3 months at 1 center. Pain was scored for both nerve conduction studies and needle electromyography (EMG) on validated scales, depending on the child's age and in comparison with venipuncture. RESULTS: In 100 cases the pain recorded fell within the moderate range on the scoring systems used. Sixty-six percent of patients described the pain to be equivalent or less than that with venipuncture. EMG of > 1 muscle or a proximal muscle produced more pain in patients <4 years of age. CONCLUSIONS: When discussing the test with patients, the physician should reassure the patient and parents regarding the degree of pain that may be encountered, which is not materially different from venipuncture. Muscle Nerve 54: 422-426, 2016.

E-norms: a method to extrapolate reference values from a laboratory population.

PURPOSE: Collecting reference values in subpopulations such as infants and children can pose a daunting challenge to gather through epidemiologic studies. The authors propose to evaluate a method the authors refer to as extrapolated norms (e-norms) to derive Stimulated Single Fiber EMG jitter reference values from the laboratory data of pediatric and adult cohorts. Single Fiber EMG studies are considered the gold standard test for evaluation of neuromuscular transmission disorders. METHODS: Data that lie in the plateau part of an inverted S curve derived from sorted jitter data were used to calculate descriptive statistics for pediatric and adult e-norms jitter. RESULTS: The e-norms derived jitter was 22 ± 2.83 µs for our pediatric and 21 ± 2.79 µs for our adult cohort. Our adult e-norms values compared favorably with the 22 ± 1.99 µs published jitter range derived from a healthy adult cohort. CONCLUSIONS: The e-norms method the authors describe seems to be useful in recovering reference ranges when such values are difficult to obtain, such as in a pediatric subpopulation.

Brown-Vialetto-van Laere syndrome: a riboflavin responsive neuronopathy of infancy with singular features.

We report the case of a previously healthy child presenting at 6 months of age with mild feeding difficulties and then developing hypotonia, progressive bulbar palsy with respiratory compromise and lower motor neuron signs, causing her to spend 4 months in the Paediatric Intensive Care Unit. Neurophysiological studies demonstrated a motor neuronopathy involving anterior horn cells and cranial nerve nuclei and abnormal brainstem auditory evoked potentials, leading to a diagnosis of Brown-Vialetto-van Laere Syndrome, confirmed by genetic testing (SLC52A3). Magnetic Resonance Imaging showed signal changes in the dorsal column of the spinal cord. She developed a coarse face and abnormal hair pattern. Sustained clinical improvement has been observed during almost 4 years of high-dose riboflavin therapy.

DOK7 congenital myasthenic syndrome in childhood: early diagnostic clues in 23 children.

Mutations in DOK7 are a common cause of congenital myasthenia. Treatment with ephedrine or salbutamol is effective, but diagnosis is often delayed. The aim of our study was to find early clues to the diagnosis of DOK7 congenital myasthenic syndrome. We included 23 children of 20 families. Onset of symptoms ranged from birth to age 3 years. 13 presented at birth with feeding difficulties, 11 with stridor (documented vocal cord palsy in 7), 3/11 with hypotonia/poor head control. Weakness was more pronounced proximally in all, axial in early presenting infants. Muscle biopsy showed non-specific features in 15/16, type 1 fibre predominance in 14/16, areas devoid of oxidative enzyme activity in 7/16. Muscle imaging was normal in 8/10, 2/10 showed mild non-specific changes. A diagnostic clue suggesting CMS rather than myopathy was the discrepancy between muscle imaging or histology findings compared with the degree of weakness. Repetitive nerve stimulation and stimulation single fibre electromyography were pathological in 9/17 and 13/14, respectively. In conclusion, stridor and feeding difficulties at birth or progressive weakness despite normal milestones in infancy point to the diagnosis and should lead to neurophysiological and genetic investigation. Fatigability can be absent or easily missed in the first years of life.

Nerve conduction studies and needle EMG in very small children.

Nerve conduction studies and needle EMG in children under two years of age present a considerable technical challenge to the neurophysiologist. However, with adaptations of both the equipment used and the methods applied, useful results can be obtained in most cases. Normative data exists against which results can be compared exists but are not comprehensive and often the experience of the practitioner is most important for interpretation of the results. Conditions, which are diagnosed fall under the broad categories of disorders of nerve, anterior horn cell, muscle or neuromuscular junction, with certain conditions seen more commonly than in older children. Examples include hypomyelinating neuropathy, SMARD, myotonic dystrophy, congenital myasthenic syndrome, and neonatal brachial plexopathy. While few practitioners perform EMG in children so young the rewards may be considerable with information obtained that is almost always important in the management of the children. It is feasible for any trained neurophysiologists to do and more should be encouraged to offer this service which comprises one quarter of the author's clinical case load.

Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies.

Many clinical features of autosomal centronuclear myopathies (CNM) and X-linked myotubular myopathy (XLMTM) are common to congenital myasthenic syndromes (CMS). We describe three children whose clinical and electrophysiological findings originally suggested CMS, in whom CNM was diagnosed pathologically, though not yet genetically characterised. A fourth case, with XLMTM, also showed electrophysiological features of a neuromuscular transmission defect. Three (including the XLMTM case) showed improved strength with acetylcholinesterase inhibitor treatment. We also studied neuromuscular junction structure and function in the MTM1 knockdown zebrafish model of XLMTM, demonstrating abnormal neuromuscular junction organization; anticholinesterase therapy resulted in marked clinical response. These observations suggest that a neuromuscular transmission defect may accompany CNM and contribute to muscle weakness. Muscle biopsy should be considered in infants suspected to have CMS, especially if treatment response is incomplete, or no CMS gene mutation is identified. Treatment with acetylcholinesterase inhibitors may benefit some CNM patients. This warrants further confirmation.

Congenital stridor with feeding difficulty as a presenting symptom of Dok7 congenital myasthenic syndrome.

OBJECTIVE: The congenital myasthenic syndromes (CMS) are a group of genetic disorders of neuromuscular transmission causing fatigable weakness. Symptoms may be present from birth, but diagnosis is often delayed for several years, notably in post-synaptic CMS due to mutations in the DOK7 gene. Recently, we noted a subgroup of children with CMS in whom congenital stridor and bilateral vocal cord palsy predated other symptoms. All had mutations in the DOK7 gene. The purpose of this study was to review our population of DOK7 CMS patients with congenital stridor and assess whether there were other phenotypic features which might raise suspicion of a diagnosis of CMS in the neonatal period, in the absence of limb weakness and ptosis and prompt earlier referral for neurophysiological investigation, genetic diagnosis and appropriate treatment. METHODS: A retrospective case review of 11 DOK7 CMS patients at a tertiary referral centre. RESULTS: Six patients were identified with DOK7 mutations and congenital stridor, four requiring intubation soon after birth. Four patients had a diagnosis of bilateral vocal cord palsy and three required tracheostomy, successfully decannulated in one after 3 years. All six patients had difficulty with feeding, with weak suck and swallow necessitating nasogastric feeding in five, two of whom required gastrostomy. Despite all six children having had neonatal symptoms, the mean age at CMS diagnosis was 5 years and 9 months. CONCLUSION: CMS, particularly caused by mutations in the DOK7 gene, is a rare but treatable cause of congenital stridor in the neonate. A combination of congenital stridor, especially with an apparently idiopathic bilateral vocal cord palsy and weak suck and swallow should alert the clinician to the possibility of CMS and prompt early referral for neurophysiology and genetic investigations. Confirmation of a CMS diagnosis enables treatment to be initiated, informed management of the VCP and anticipation of myasthenic symptoms, particularly life-threatening respiratory decompensation. Treatment may allow early decannulation or possible avoidance of tracheostomy. At least 12 genes are known to cause CMS; the presence of congenital stridor may help target genetic diagnosis.

A new analytical method to diagnose congenital myasthenia with stimulated single-fiber electromyography.

Stimulated single-fiber electromyography (SSF-EMG) is useful to assess neuromuscular junction (NMJ) abnormalities in children. Conventionally mean consecutive difference (MCD) analysis measures the jitter for each muscle-fiber potential. We present a new algorithm that analyzes the entire SSF-EMG waveform. Cross-correlational coefficients (between 0-1.0) are calculated for consecutive pairs of 100 SSF-EMG waveforms obtained at each needle position in orbicularis oculi, and averaged. A lower normal limit (0.722, mean -3 SD) was established from 123 SSF-EMG samples in 10 adult control subjects, and applied to SSF-EMG data from 23 children referred for a suspected myasthenic syndrome. Results were compared with MCD analysis and related to the final clinical diagnosis. Our results showed that compared with conventional MCD measurement, the new algorithm had better specificity (87% vs. 53%) but similar sensitivity (88% for both). These findings indicate that the cross-correlational method is a useful predictor of NMJ dysfunction in children.