Late-onset Tay-Sachs disease presenting with a neuromuscular phenotype-a case series.

BACKGROUND AND PURPOSE: Tay-Sachs disease is a rare and often fatal, autosomal recessive, lysosomal storage disease. Deficiency in ß-hexosaminidase leads to accumulation of GM2 ganglioside resulting in neuronal swelling and degeneration. Typical onset is in infancy with developmental regression and early death. Late-onset Tay-Sachs disease (LOTS) is extremely rare, especially in the non-Ashkenazi Jewish population, and is characterized by a more indolent presentation typically encompassing features of cerebellar and anterior horn cell dysfunction in addition to extrapyramidal and neuropsychiatric symptoms. CASES: A case series of four unrelated patients of non-Ashkenazi Jewish origin with a predominantly, and in some cases pure, neuromuscular phenotype with evidence of a motor neuronopathy on electromyography is presented. Cerebellar atrophy, reported to be a ubiquitous feature in LOTS, was absent in all patients. CONCLUSION: This case series provides evidence to support a pure neuromuscular phenotype in LOTS, which should be considered in the differential diagnosis of anterior horn cell disorders.

A Machine Learning Approach for Sex and Age Classification of Paediatric EEGs.

Electroencephalography (EEG) is an important investigation of childhood seizures and other brain disorders. Expert visual analysis of EEGs can estimate subjects' age based on the presence of particular maturational features. The sex of a child, however, cannot be determined by visual inspection. In this study, we explored sex and age differences in the EEGs of 351 healthy male and female children aged between 6 and 10 years. We developed machine learning-based methods to classify the sex and age of healthy children from their EEGs. This preliminary study based on small EEG numbers demonstrates the potential for machine learning in helping with age determination in healthy children. This may be useful in distinguishing developmentally normal from developmentally delayed children. The model performed poorly for estimation of biological sex. However, we achieved 66.67% accuracy in age prediction allowing a 1 year error, on the test set.

Amplitude Integrated Electroencephalography: Simulated Assessment of Neonatal Seizure Detection in PICU Patients.

OBJECTIVES: Amplitude integrated electroencephalography (aEEG) is a mainstay of care in neonatal ICUs; however, knowledge gaps exist in relation to its accuracy for identifying seizures in older children. We aimed to review the diagnostic accuracy of existing neonatal seizure detection criteria for seizure detection in older children in hospital. DESIGN: Retrospective study. SETTING: PICU/Neurophysiology Department in Dublin. PATIENTS: One hundred twenty patients (2 mo to 16 yr old) were chosen from a database of formal 10-20 system, 21-lead electroencephalography recordings (2012-2020), comprising 30 studies with seizures, 90 without. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Electroencephalography studies containing electrographic seizures (ESzs) were annotated to describe number, duration, distribution, and spread. Two-channel aEEG (using leads C3-P3, C4-P4) recordings were generated and independently reviewed by a professional specialist in clinical neurophysiology blinded to outcome and without reference to the raw electroencephalography trace. Logistic regression was used to identify factors associated with correct seizure identification on aEEG. Median patient age was 6.1 years. Abnormal recordings featured 123 seizures. Status epilepticus (SE) was evident by electroencephalography in 10 cases. Using neonatal criteria, aEEG had a sensitivity of 70% and negative predictive value of 90% for identifying any ESz. Accurate detection of individual seizures was diminished when seizures were very short or occurred during waking. Sensitivity for individual seizures was 81% when seizures less than 1 minute were excluded. aEEG correctly identified SE in 70% of the 10 cases, although ESz were confirmed to be present in 80% of this subpopulation. CONCLUSIONS: aEEG criteria for neonatal seizure identification can be applied with caution to older children and should be supplemented by formal electroencephalography. Seizure identification is better for longer seizures and those arising from sleep. SE is not always recognized by aEEG among older children.

Amplitude integrated electroencephalography - Reference values in children aged 2 months to 16 years.

AIM: Amplitude integrated electroencephalography (aEEG) is a bedside neuromonitoring tool, standard within neonatal critical care provision. Its application in children is increasing but normative data underpinning such use are lacking. We present a dataset of normative aEEG values for children aged 2 months to 16 years. METHODS: This retrospective observational cohort study derives aEEG normative amplitude characteristics from electroencephalograms (EEGs) recorded in Children's Health Ireland at Crumlin. aEEG was derived from 350 normal EEGs, recorded in children aged 2 months to 16 years. Supplementary aEEGs were derived from children with abnormal EEG traces. Median upper and lower margin amplitudes and bandwidth were calculated from 5 min waking and sleeping EEG epochs. RESULTS: aEEG amplitudes vary with age and state, increasing over the first 2 years of life before diminishing. Upper and lower margin amplitudes and bandwidth are greater during sleep for children <6 years. Reference ranges may be cohorted into two groups (upper and lower reference limits; <6 years - 38 µV/7 µV awake, 54 µV/10 µV asleep; >6 years - 33 µV/5 µV awake, 36 µV/6 µV asleep). CONCLUSION: aEEG traces evolve with age in childhood and differ from neonatal values. We provide a comprehensive set of aEEG normatives to facilitate clinical interpretation in older children.

Does specificity of electrodiagnostic test referrals predict test outcome in children?

INTRODUCTION/AIMS: Electrodiagnostic testing (EDX) is important in evaluation of pediatric neuromuscular disease. Non-specific referrals have emerged as a leading reason for EDX in recent years. We examine whether referral-specificity is predictive of test outcomes in children. METHODS: EDX referrals and outcomes were audited over a 7-year period from 2013 to 2020 at CHI-Crumlin. Pre-test details were coded and compared to EDX outcomes using multinomial logistic regression. RESULTS: EDX studies were performed in 702 children (median age 10.2 years). In 36% of patients, EDX-referrals did not specify any pre-test diagnosis. Mononeuropathy (24%) and polyneuropathy (15%) were the leading pre-specified diagnoses as well as the most common test outcomes. Neurology and orthopedics/plastic surgery contributed the majority of referrals. Metabolic medicine and hematology/oncology were most likely to pre-specify a working diagnosis and were the specialties with both the highest proportion of abnormal outcomes and referral accuracy. EDX abnormality was present in 42% of patients and was predicted by specificity of referral and the absence of pain as a leading symptom. The accuracy of specified pre-test diagnoses was highest for suspected anterior horn cell disorders (67%). Accuracy of referrals, as well as abnormal test outcomes, were negatively predicted by the presence of pain as a leading symptom. DISCUSSION: EDX is informative in children but the likelihood of abnormal test-outcomes is diminished when a pre-specified working diagnosis is lacking or when the primary reason for referral is pain.

Neurophysiological and ophthalmological findings of SPG7-related spastic ataxia: a phenotype study in an Irish cohort.

BACKGROUND: Mutations in SPG7 are increasingly identified as a common cause of spastic ataxia. We describe a cohort of Irish patients with recessive SPG7-associated phenotype. METHODS: Comprehensive phenotyping was performed with documentation of clinical, neurophysiological, optical coherence tomography (OCT) and genetic data from individuals with SPG7 attending two academic neurology units in Dublin, including the National Ataxia Clinic. RESULTS: Thirty-two symptomatic individuals from 25 families were identified. Mean age at onset was 39.1 years (range 12-61), mean disease duration 17.8 years (range 5-45), mean disease severity as quantified with the scale for the assessment and rating of ataxia 9/40 (range 3-29). All individuals displayed variable ataxia and spasticity within a spastic-ataxic phenotype, and additional ocular abnormalities. Two had spasmodic dysphonia and three had colour vision deficiency. Brain imaging consistently revealed cerebellar atrophy (n = 29); neurophysiology demonstrated a length-dependent large-fibre axonal neuropathy in 2/27 studied. The commonest variant was c.1529C > T (p.Ala510Val), present in 21 families. Five novel variants were identified. No significant thinning of average retinal nerve fibre layer (RNFL) was demonstrated on OCT (p = 0.61), but temporal quadrant reduction was evident compared to controls (p < 0.05), with significant average and temporal RNFL decline over time. Disease duration, severity and visual acuity were not correlated with RNFL thickness. CONCLUSIONS: Our results highlight that recessive SPG7 mutations may account for spastic ataxia with peripheral neuropathy in only a small proportion of patients. RNFL abnormalities with predominant temporal RNFL reduction are common and OCT should be considered part of the routine assessment in spastic ataxia.

Measuring the effects of pre-test probability on out-patient first EEG investigation in children - A guide to evidence-based EEG triage in a pandemic.

INTRODUCTION: The yield of epileptiform EEG abnormalities is lower in unselected Paediatric populations than in prospective studies of incident seizures or prevalent epilepsy studies. At a time of limited capacity, it is important to match available EEG resources to children who are most likely to benefit. In this study we evaluated a prospective triage tool for estimating the likelihood of epileptiform abnormality in children's first out-patient EEG. METHODS: We prospectively triaged 1865 out-patient referrals to the largest Paediatric EEG laboratory in Ireland. Based on a structured algorithm, we dichotomized first EEG referrals into priority and non-priority groups and assigned one of 5 sub-levels based on anticipated EEG yield. EEGs were reported by a single Consultant in Clinical Neurophysiology. RESULTS: Triage designated 757 (41 %) EEG referrals as non-priority. Priority exceeded non-priority referrals for all age groups except children between 18 months and 3.5 years. EEGs showed a two-fold higher incidence of interictal epileptiform abnormalities for priority referrals (36 % vs 18 %, p < 0.001). Rates of interictal epileptiform abnormality correlated with the 5 sub-levels of triage (p < 0.01). Epileptiform yield was highest (39 %) for children over 5 years vs 17 % for those under 5 years (p < 0.00001); these rates increased to 49 % and 20 % respectively for priority referrals. CONCLUSION: Structured pre-test triage of EEG referrals can identify children who have the greatest likelihood of epileptiform abnormality. In a mixed population of Paediatric referrals, the epileptiform yield of first time EEG is 49 % for children over 5 years who are referred with an appropriate EEG indication. This is subject to much variability with epileptiform yields as low as 13 % in younger children with non-priority referrals. The use of a structured triage algorithm can help to optimise utility of EEG in situations of limited laboratory capacity.

EEG in the Pediatric Intensive Care Unit: An Irish Experience.

INTRODUCTION: Evidence for continuous EEG monitoring in the pediatric intensive care unit (PICU) is increasing. However, 24/7 access to EEG is not routinely available in most centers, and clinical management is often informed by more limited EEG resources. The experience of EEG was reviewed in a tertiary PICU where 24/7 EEG cover is unavailable. METHODS: Retrospective EEG and clinical review of 108 PICU patients. Correlations were carried out between EEG and clinical variables including mortality. The role of EEG in clinical decision making was documented. RESULTS: One hundred ninety-six EEGs were carried out in 108 PICU patients over 2.5 years (434 hours of recording). After exclusion of 1 outlying patient with epileptic encephalopathy, 136 EEGs (median duration, 65 minutes; range, 20 minutes to 4 hours 40 minutes) were included. Sixty-two patients (57%) were less than 12 months old. Seizures were detected in 18 of 107 patients (17%); 74% of seizures were subclinical; 72% occurred within the first 30 minutes of recording. Adverse EEG findings were associated with high mortality. Antiepileptic drug use was high in the studied population irrespective of EEG seizure detection. Prevalence of epileptiform discharges and EEG seizures diminished with increasing levels of sedation. CONCLUSIONS: EEG provides important diagnostic information in a large proportion of PICU patients. In the absence of 24/7 EEG availability, empirical antiepileptic drug utilization is high.

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.

Transcriptional regulator PRDM12 is essential for human pain perception.

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

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.

Correction and transformation of normative neurophysiological data: is there added value in the diagnosis of distal symmetrical peripheral neuropathy?

INTRODUCTION: Despite theoretical advantages, the practical impact of mathematical correction of normative electrodiagnostic data is poorly quantified. METHODS: One hundred five healthy volunteers had clinical and neurophysiological assessment. The effects of age, height, gender, weight, and body mass index were explored using stepwise regression modeling. Reference values were derived from raw and adjusted data, which were transformed to allow appropriate use of parametric statistics. The diagnostic accuracy of derived limits was tested in patients at risk of distal symmetric peripheral neuropathy (DSPN) from chemotherapy. RESULTS: The variability of our normative data was reduced by up to 69% through the use of regression modeling, but the overall benefits of mathematical correction were marginal. The most accurate reference limits were established using the 2.5th and 97.5th percentiles of the raw data. CONCLUSIONS: Stepwise statistical regression and mathematical transformation improve the distribution of normative data, but their practical impact for diagnosis of distal symmetrical polyneuropathy is small.

Examining the effects of age, sex, and body mass index on normative median motor nerve excitability measurements.

OBJECTIVES: The purpose of this study was to build a large reference database of excitability measures in normal subjects and to examine the effects of age, sex, and BMI. METHODS: One hundred and five healthy subjects had median motor nerve excitability testing performed at the wrist using the automated threshold-tracking program, QTRAC. Statistical linear regression was used to explore relationships between nerve excitability and the independent variables. RESULTS: The main effect of age is a reduced superexcitability. Lesser effects are flattening of the normalized stimulus response curve and reduction in threshold change following strong hyperpolarizing currents. Females have lower thresholds than males and small but significant differences in voltage-gated potassium channel (KCNQ) mediated properties (late subexcitability, accommodation half time, and threshold undershoot following depolarizing electrotonus), as well as a small increase in superexcitability. BMI has no influence on nerve excitability data and does not explain sex-related differences in threshold. CONCLUSIONS: Age and sex have few and small effects on excitability parameters. SIGNIFICANCE: The expression of nodal KCNQ channels appears to be greater in females. Age-related increases in subexcitability may be attributable to changes in the muscle fibre and not the nerve.

Sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) in a sibling pair with a homozygous p.A467T POLG mutation.

Two siblings who developed fifth-decade-onset, concurrent progressive sensory ataxia, dysarthria, and ophthalmoparesis were found to be homozygous for the p.A467T mutation of the polymerase gamma (POLG) gene. The clinical course in both subjects was progression to severe disability. The enlarging spectrum of sensory ataxic neuropathies associated with mitochondrial DNA (mtDNA) instability and POLG mutations should be recognized and considered in the differential diagnosis of this unusual presentation.

Epidemiology and classification of epilepsy: gender comparisons.

Epilepsy is a common disease. The cumulative lifetime risks for epilepsy and for any unprovoked seizure are 3.1% and 4.1%, respectively, in industrialized countries. Estimate of annual incidence of epilepsy are as high as 43 cases per 100,000 of the population in so-called developed countries, and are almost double this figure in the developing world. Within this there is a growing appreciation of gender differences in the epidemiology of epilepsy and of specific epilepsy syndromes. In 1993, the International League Against Epilepsy (ILAE) proposed simplified classification guidelines to facilitate epidemiologic work in epilepsy, and to allow meaningful comparison between studies undertaken at different times and in different parts of the world. Since then, a number of national studies have been completed, adding to the existing data of already well-established databases such as the Rochester Epidemiology Project. There is broad agreement between studies that females have a marginally lower incidence of epilepsy and unprovoked seizures than males. This difference is usually attributed to male's greater exposure to risk factors for lesional epilepsy and acute symptomatic seizures. On the other hand, idiopathic generalized epilepsies (IGEs), which may represent some 15-20% of all epilepsies, are more common among females. Also, the behavior of some common epilepsy syndromes such as mesial temporal sclerosis may differ between genders with isolated auras more common among females and secondary seizure spread more likely in males. Trends toward gender differences are also seen in other important aspects of epilepsy. These include the incidence of status epilepticus (more common in men), incidence of sudden unexpected death in epilepsy (SUDEP), prognosis, and mortality.

GAD antibody positive paraneoplastic stiff person syndrome in a patient with renal cell carcinoma.

Stiff person syndrome (SPS) is an unusual cause of muscle rigidity and spasms. It is believed to have an autoimmune pathogenesis and is associated with autoantibodies to glutamic acid decarboxylase (GAD). Paraneoplastic SPS (PSPS) has been described mainly in relation to breast cancer and is associated with antibodies to amphiphysin. Few reports of PSPS document the finding of GAD autoantibodies. We present the first reported case of anti-GAD positive PSPS in a 53-year-old male with occult renal carcinoma. Clinical benefit was marked following nephrectomy and intravenous immunoglobulin treatment. Renal carcinoma should be considered in patients with SPS.