Isolated bulbar palsy and dysphagia in children with respiratory symptoms.

Oropharyngeal dysphagia can cause chronic aspiration leading to significant respiratory symptoms. When dysphagia is diagnosed, an underlying cause is sought. We present a case series of 15 children diagnosed aged 6 months to 5 years (mean 2y 5mo; 11 males, four females) over a 6-year period, who were found to have an isolated bulbar palsy on genioglossus electromyography, with no accompanying neurological or neurodevelopmental disorder. Eight children had dysphagia but a normal EMG. In those with isolated bulbar palsy, management included thickened fluids (n=13), cooled boiled water (n=1), and nasogastric tube feeding (n=1). Follow-up over 1 to 8 years (mean 5y) showed complete resolution in six children, improvement in four children, and no improvement in five children (including two requiring fluids via a gastrostomy). Eight children no longer had any respiratory symptoms. Isolated bulbar palsy is under-recognized and has not been reported previously as a cause of significant dysphagia in children.

A novel homozygous variant extending the peripheral myelin protein 22 by 9 amino acids causes early-onset Charcot-Marie-Tooth disease with predominant severe sensory ataxia.

Peripheral myelin protein 22 (PMP22) related neuropathies account for over 50% of inherited peripheral neuropathies. A gene copy variation results in CMT1A (duplication) and hereditary neuropathy with liability to pressure palsies (HNPP; single deletion). Point mutations comprise both phenotypes. The underlying pathological mechanisms are incompletely understood and biallelic mutations of PMP22 are very rare. We describe a 9-year-old girl who presented before the age of 1 year with severe locomotor delay. She now requires support for standing and walking in view of her severe sensory ataxia. Strikingly, her muscle power and bulk are close to normal in all segments. Nerve conduction studies showed sensory-motor velocities below 5 m/s. Genetic analysis revealed a homozygous sequence change in the PMP22 gene causing the loss of termination codon (c.483A > G; p.[*161Trpext*10]), extending the protein by 9 amino acids. Both heterozygous parents have neurophysiological abnormalities consistent with HNPP, consistent with this being a loss-of-function mutation. PMP22-deficient human models are rare but important to decipher the physiological function of the PMP22 protein in vivo. The predominance of large fiber sensory involvement in this and other rare similar cases suggests a pivotal role played by PMP22 in the embryogenesis of dorsal root ganglia in humans.

Intraoperative electrophysiology during single-level selective dorsal rhizotomy: technique, stimulation threshold, and response data in a series of 145 patients.

OBJECTIVE: Selective dorsal rhizotomy (SDR) is effective at permanently reducing spasticity in children with spastic cerebral palsy. The value of intraoperative neurophysiological monitoring in this procedure remains controversial, and its robustness has been questioned. This study describes the authors' institutional electrophysiological technique (based on the technique of Park et al.), intraoperative findings, robustness, value to the procedure, and occurrence of new motor or sphincter deficits. METHODS: The authors analyzed electrophysiological data of all children who underwent SDR at their center between September 2013 and February 2019. All patients underwent bilateral SDR through a single-level laminotomy at the conus and with transection of about 60% of the L2-S2 afferent rootlets (guided by intraoperative electrophysiology) and about 50% of L1 afferent roots (nonselectively). RESULTS: One hundred forty-five patients underwent SDR (64% male, mean age 6 years and 7 months, range 2 years and 9 months to 14 years and 10 months). Dorsal roots were distinguished from ventral roots anatomically and electrophysiologically, by assessing responses on free-running electromyography (EMG) and determining stimulation thresholds (≥ 0.2 mA in all dorsal rootlets). Root level was determined anatomically and electrophysiologically by assessing electromyographic response to stimulation. Median stimulation threshold was lower in sacral compared to lumbar roots (p < 0.001), and 16% higher on the first operated (right) side (p = 0.023), but unrelated to age, sex, or functional status. Similarly, responses to tetanic stimulation were consistent: 87% were graded 3+ or 4+, with similar distributions between sides. This was also unrelated to age, sex, and functional status. The L2-S2 rootlets were divided (median 60%, range 50%-67%), guided by response to tetanic stimulation at threshold amplitude. No new motor or sphincter deficits were observed, suggesting sparing of ventral roots and sphincteric innervation, respectively. CONCLUSIONS: This electrophysiological technique appears robust and reproducible, allowing reliable identification of afferent nerve roots, definition of root levels, and guidance for rootlet division. Only a direct comparative study will establish whether intraoperative electrophysiology during SDR minimizes risk of new motor or sphincter worsening and/or maximizes functional outcome.

Paediatric myasthenia gravis: Prognostic factors for drug free remission.

Our aim was to identify clinical outcomes, serological features and possible prognostic indicators of paediatric myasthenia gravis (MG). We collected 74 MG patients with disease onset before the age of 16 years (73% pre-pubertal onset defined as ≤10 years), seen regularly at two UK specialist centres, over a period of 11 years. The cohort was multi-ethnic, with a high number of non-Caucasians (52%). Ocular presentation was seen in 38 (51%) and only 8 (21%) of these generalised. Fifty-two (70%) patients had antibodies to the acetylcholine receptor (AChR) measured by radioimmunoprecipitation, 10 (14%) had antibodies only to clustered AChRs detected by a cell based assay, 3 (4%) had muscle-specific kinase and one (1%) low-density lipoprotein receptor-related protein 4 antibody. Only 8 (11%) had no detectable antibodies. Seventeen patients attained drug free remission (Kaplan Meyer survival curve estimates 25% by 7 years). Several factors were associated with a higher likelihood of free remission: onset age ≤10 years, Asian and Caucasian races, lack of AChR antibodies on RIA, and normal repetitive nerve stimulation at diagnosis. However, in a multifactorial regression analysis, the antibody status was the only significant predictor for drug free remission, with 60% of patients with antibodies only to clustered AChR achieving this outcome. Complete drug free remission is not uncommon in paediatric MG and several factors appear to influence this outcome with antibody status being the most important. These factors can be easily evaluated at diagnosis, and may help to determine whose patients are likely to require more intensive treatments.

Early electrodiagnosis in the management of neonatal brachial plexus palsy: A systematic review.

Neonatal brachial plexus palsy (NBPP) is a prominent form of newborn morbidity with a potentially disabling persistence. Neurosurgical intervention is indicated in select NBPP patients. Early prognostic assessment would facilitate rational selection of those infants for surgery. We conducted a systematic literature review to determine the prognostic value of early electrodiagnosis (EDx) in NBPP. We included 16 observational studies with a total sample size of 747 children. Risk of bias and quality of evidence were rated. Wide variation was found in EDx techniques, outcome algorithms, and decisionmaking. Nevertheless, the most methodologically sound studies support the use of EDx, at standardized time-frames, as a key prognostic modality for complementing clinical judgment and neuroimaging. An accurate knowledge of the underlying anatomy of the nerve injury helps to counsel families and to guide reconstructive strategy.

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.

Two Cases of Guillain-Barré Syndrome Variants Presenting With Dysautonomia.

We describe 2 pediatric cases presenting with posterior reversible encephalopathy syndrome secondary to autonomic dysfunction preceding the onset of motor symptoms in Guillain-Barré syndrome variants. Patient 1 presented acutely with encephalopathy, cerebellar signs, hypertension, lower limb weakness, and respiratory decompensation. Magnetic resonance imaging (MRI) brain showed occipital lesions consistent with posterior reversible encephalopathy syndrome. Nerve conduction studies were consistent with Miller-Fisher syndrome. After intravenous immunoglobulin and plasmapheresis, he improved clinically with radiological resolution. Patient 2 presented with headache, leg pain, seizures, and significant hypertension. Brain MRI was normal but spine MRI revealed enhancement of the cauda equina ventral nerve roots. She was areflexic with lower limb weakness a few days after intensive care unit admission and made a significant improvement after treatment with intravenous immunoglobulin. In children presenting with posterior reversible encephalopathy syndrome in the absent of other causes of primary hypertension, Guillain-Barré syndrome variants are an important differential etiology, presenting with autonomic dysfunction, even before signs of motor weakness become evident.

Standards for quantification of EMG and neurography.

This document is an update and extension of ICCN Standards published in 1999. It is the consensus of experts on the current status of EMG and Neurography methods. A panel of authors from different countries with different approach to routines in neurophysiological methods was chosen based on their particular interest and previous publications. Each member of the panel submitted a section on their particular area of interest and these submissions were circulated among the panel members for edits and comments. This process continued until a consensus was reached. The document covers EMG topics such as conventional EMG, Macro EMG, applications of surface EMG and electrical impedance myography. Single Fiber EMG is not included, since it is the topic in a separate IFCN document. A neurography section covers topics such as motor and sensory neurography, F wave recordings, H-reflex, short segment recordings, CMAP scan and motor unit number methods. Other sections cover repetitive nerve stimulation and Pediatric electrodiagnostic testing. Each method includes a description of methodologies, pitfalls, and the use of reference values. Clinical applications accompany some of these sections.

Guidelines for single fiber EMG.

This document is the consensus of international experts on the current status of Single Fiber EMG (SFEMG) and the measurement of neuromuscular jitter with concentric needle electrodes (CNE - CN-jitter). The panel of authors was chosen based on their particular interests and previous publications within a specific area of SFEMG or CN-jitter. Each member of the panel was asked to submit a section on their particular area of interest and these submissions were circulated among the panel members for edits and comments. This process continued until a consensus was reached. Donald Sanders and Erik Stålberg then edited the final document.

Acquired neuromyotonia in children with CASPR2 and LGI1 antibodies.

Acquired neuromyotonia is a form of peripheral nerve hyperexcitability. In adults, pathogenic antibodies that target the extracellular domains of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) have been reported. We describe three paediatric patients with acquired neuromyotonia and CASPR2 and LGI1 serum antibodies. They all presented with acute-onset myokymia and pain in the lower limbs; one patient also had muscle weakness. Electromyography was suggestive of peripheral nerve hyperexcitability. Two patients improved without immunotherapy; one treated patient remained immunotherapy-dependent. Although not fatal, acquired paediatric neuromyotonia can be disabling. It is amenable to symptomatic treatment or may undergo spontaneous recovery. More severe cases may require rational immunotherapy. WHAT THIS PAPER ADDS: The symptoms of neuromyotonia may resolve spontaneously or may require sodium channel blockers. Patients with debilitating symptoms who are refractory to symptomatic therapy may require immunotherapy.

NEUROMIOTONÍA ADQUIRIDA EN NIÑOS CON ANTICUERPOS CASPR2 Y LGI1: La neuromiotonía adquirida es una forma de hiperexcitabilidad de los nervios periféricos. En algunos adultos, se han notificado anticuerpos patógenos que se dirigen a los dominios extracelulares de la proteína 1 inactivada por glioma rico en leucina (LGI1) y la proteína 2 asociada a contactina (CASPR2). Describimos tres pacientes pediátricos con neuromiotonía adquirida y anticuerpos séricos CASPR2 y LGI1. Todos presentaban mioquimia de inicio agudo y dolor en las extremidades inferiores; un paciente también tenía debilidad muscular. La electromiografía sugirió hiperexcitabilidad del nervio periférico. Dos pacientes mejoraron sin inmunoterapia; un paciente tratado permaneció dependiente de la inmunoterapia. Aunque no es fatal, la neuromiotonía pediátrica adquirida puede ser incapacitante. Es susceptible de tratamiento sintomático o puede sufrir una recuperación espontánea. Los casos más graves pueden requerir inmunoterapia racional.

NEUROMIOTONIA ADQUIRIDA EM CRIANÇAS COM ANTICORPOS PRCAS2 E GIL1: A neuromiotonia adquirida é uma forma de hiperexcitabilidade nervosa periférica. Em alguns adultos, anticorpos patogênicos que visam os domínios extracelulares da proteína glioma-inativada rica em leucina1 (GIL1) e da proteína contactina-associada 2 (PRCAS2) foram reportados. Descrevemos três pacientes pediátricos com neuromiotonia adquirida e anticorpos séricos PRCAS2 e GIL1 CASPR2. Todos apresentaram miocimia de início agudo e dor nos membros inferiores; um paciente também teve fraqueza muscular. A eletromiografia foi sugestiva de hiperexcitabilidade nervosa periférica. Dois pacientes melhoraram sem imunoterapia; um paciente tratado permaneceu imunoterapia-dependente. Embora não seja fatal, a neuromiotomia pediátrica aguda pode ser incapacitante. É responsiva a tratamento sintomático e pode apresentar recuperação espontânea. Casos mais severaos podem requerer imunoterapia racional.

Electromyography and muscle biopsy in paediatric neuromuscular disorders - Evaluation of current practice and literature review.

The conduct and interpretation of electromyography in children is considered difficult and therefore often avoided. We assessed the diagnostic accuracy of the paediatric electromyography protocol used in our tertiary reference centre and compared it to muscle biopsy results and clinical diagnosis. Electromyography was performed in unsedated children with suspected neuromuscular diseases between January 2010 and September 2017 and was analysed quantitatively. Muscle pathology was classified into seven groups based on existing histopathology reports. The clinical diagnosis, including myopathic, neurogenic and non-neuromuscular categories was used as the gold standard. 171 children between the age of 12 days to 17.4 years were included in the analysis. 41 children (24%) were under the age of 2 years at the time of electromyography. 98 (57%) children were diagnosed with a myopathic disorder, 18 (11%) with a neurogenic disease and 55 (32%) as not having a primary neuromuscular disorder. In detecting myopathic disease, electromyography performed as well as muscle biopsy (sensitivity 87.8% for electromyography vs. 84.5% for muscle biopsy; specificity 75.7% vs. 86.4%). This also applied to children under the age of 2 years (sensitivity 81.8% vs. 86.4%). Quantitative analysis of a limited electromyography protocol performed in unsedated children is a very valuable diagnostic tool.

ECEL1 gene related contractural syndrome: Long-term follow-up and update on clinical and pathological aspects.

Autosomal recessive mutations in the ECEL1 gene have recently been associated with a wide phenotypic spectrum including severe congenital contractural syndromes and distal arthrogryposis type 5D (DA5D). Here, we describe four novel families with ECEL1 gene mutations, reporting 15 years of follow-up for four patients and detailed muscle pathological description for three individuals. In particular, we observed mild myopathic features, prominent core-like areas in one individual, and presence of nCAM positive fibres in three patients from 2 unrelated families suggesting a possible problem with innervation. Our findings expand current knowledge concerning the phenotypic and pathological spectrum associated with ECEL1 gene mutations and may suggest novel insights regarding the underlying pathomechanism of the disease.

Neurophysiological Assessment of Abnormalities of the Neuromuscular Junction in Children.

The function of the neuromuscular junction in children is amenable to electrophysiological testing. Of the two tests available, repetitive nerve stimulation is uncomfortable and has a reduced sensitivity compared with single-fibre methodology. The latter is the method of choice, recording the variability in neuromuscular transmission as a value called jitter. It can be performed by voluntary activation of the muscle being examined, which is not suitable in children, or by stimulation techniques. A modification of these techniques, called Stimulated Potential Analysis with Concentric needle Electrodes (SPACE), is well tolerated and can be performed while the child is awake. It has a high sensitivity (84%) for the diagnosis of neuromuscular transmission disorders, the majority of which are myasthenic syndromes, and a moderate specificity (70%). The latter can be improved by the exclusion of neurogenic causes and the determination of the degree of jitter abnormality. Minor jitter abnormalities, under 115% of the upper limit of normal, are usually caused by myopathies with an associated neuromuscular transmission disorder, whereas levels higher than this value are usually associated with one of the myasthenic conditions.

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.

Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome.

We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is crucial for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1lew/lew mice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1 homozygous mutations as a cause of presynaptic CMS. Ann Neurol 2017;81:597-603.

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.