Marie Hully

Early electro-clinical features may contribute to diagnosis of the anti-NMDA receptor encephalitis in children

OBJECTIVE To describe initial and follow-up electroencephalographic (EEG) characteristics in anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. METHODS Consecutive polygraphic video-EEG recordings were analyzed in nine pediatric patients with anti-NMDAR encephalitis at the initial stage of the disease and during the intermediate period until motor recovery. EEG characteristics in waking and sleep stages as well as EEG correlates of abnormal movements are described. RESULTS In six patients, [corrected] the waking EEG showed preserved background activity and either focal or unilateral hemispheric slowing. These children had more favorable outcome than the three children with diffuse slowing. Unilateral [corrected] abnormal movements contra-lateral to hemispheric or focal slowing were also indicative of milder severity when compared to generalized abnormal movements and diffuse slowing. During non-rapid eye movement (NREM) sleep, a decrease in the expected slow waves and unilateral or diffuse theta-alpha band rhythms were observed in six children, not correlated with the outcome, representing a suggestive EEG pattern of anti-NMDAR encephalitis. [corrected]. CONCLUSIONS In pediatric patients presenting behavioral disorders and abnormal movements, early EEG patterns may be suggestive of anti-NMDAR encephalitis. Moreover early electro-clinical presentation contributes to outcome prediction. SIGNIFICANCE This case series demonstrates that early EEG patterns may be suggestive of anti-NMDAR encephalitis in pediatric patients with behavioral disorders and abnormal movements.

Detection of interferon alpha protein reveals differential levels and cellular sources in disease

Type I interferons (IFNs) are essential mediators of antiviral responses. These cytokines have been implicated in the pathogenesis of autoimmunity, most notably systemic lupus erythematosus (SLE), diabetes mellitus, and dermatomyositis, as well as monogenic type I interferonopathies. Despite a fundamental role in health and disease, the direct quantification of type I IFNs has been challenging. Using single-molecule array (Simoa) digital ELISA technology, we recorded attomolar concentrations of IFN&agr; in healthy donors, viral infection, and complex and monogenic interferonopathies. IFN&agr; protein correlated well with functional activity and IFN-stimulated gene expression. High circulating IFN&agr; levels were associated with increased clinical severity in SLE patients, and a study of the cellular source of IFN&agr; protein indicated disease-specific mechanisms. Measurement of IFN&agr; attomolar concentrations by digital ELISA will enhance our understanding of IFN biology and potentially improve the diagnosis and stratification of pathologies associated with IFN dysregulation.

Patients with dravet syndrome in the era of stiripentol: A French cohort cross-sectional study

OBJECTIVE The aim of this study was to assess outcome and seizure response to treatment with stiripentol (STP) associated to valproate (VPA) and clobazam (CLB), which we have used in our center since the 1990s, in patients with Dravet syndrome (DS). METHODS We performed a cross-sectional study of all DS patients with SCN1A mutations who had at least one visit to our center in 2013. A total of 54 patients were included (32 males, 22 females), whose ages ranged from 2.5 to 22 years. RESULTS Seizure onset ranged from 2 to 9 months (mean 5 months). Treatment started at a mean age of 7 months with valproate (VPA) as first therapy in 83% of patients. STP was prescribed in 96% at an average age of 20 months. At last follow-up (up to 22 years, median 8 years), 96% were still receiving STP, with VPA and clobazam (CLB) in 91%. Additional therapies were prescribed in 72% of patients. Most patients (96%) continued to have clonic or tonic-clonic seizures but they were brief (<5min, with last status epilepticus (SE) episode being before 4 years of age). Seizures occurred weekly (>3/month) in 38% of patients, monthly (1-3/month) in 40%, and yearly in the remaining patients. None presented with daily seizures. Seizure frequency at last visit was related to the age of treatment initiation, the age of last SE, and SCN1A mutation type. CONCLUSIONS Triple therapy with STP, VPA, and CLB was maintained long-term by 96% of this large DS cohort because the reduced frequency and severity of seizures STP provided when added to CLB and VPA was durable. Nevertheless, only a few patients achieved seizure freedom and persisting seizures remains a concern in the majority of patients.

Cerebral vasculitis in severe Kawasaki disease: early detection by magnetic resonance imaging and good outcome after intensive treatment

Kawasaki disease is an acute vasculitis, that has a classic complication of acquired coronary artery aneurysm. Severe forms with multi‐organ involvement or neurological dysfunction are rare. Cerebral vascular involvement has been related to large‐vessel injury or cardioembolism, leading to focal brain infarction. A 4‐year‐old female presented with unusual, rapidly catastrophic Kawasaki disease with refractory shock, acute renal failure, and coma, requiring intensive haemodynamic management. The observation of diffuse micro‐haemorrhages (T2*‐weighted sequence) associated with white matter injury on brain magnetic resonance imaging (MRI) pointed towards lesions of the medium/small blood vessels. Cerebral vasculitis was suspected and the immunosuppressive treatment was increased Subsequently, the patient’s recovery was rapid. On follow‐up severe, bilateral vitritis was evident and surgery improved visual outcome. Early recognition of severe or unusual forms of Kawasaki disease could lead to more favourable outcome using appropriate treatment strategies. Diffuse cerebral micro‐haemorrhages on T2* brain MRI sequences might be a key sign for the diagnosis of medium or small cerebral vessel involvement.

Motor neuropathy contributes to crouching in patients with Dravet syndrome

Objective: Since SCN1A is expressed in the motor neuron initial segment, we explored whether motor neuron dysfunction could contribute to gait disturbance and orthopedic misalignment in patients with Dravet syndrome due to SCN1A mutations. Methods: We assessed 12 consecutive patients who presented to our institution between January and March 2013. All of them were older than 2 years and were positive for the SCN1A mutation. We performed nerve conduction velocity studies and needle EMG recordings. Results: We included 4 females and 8 males aged 2 to 17 years (median 7.5 years). All 12 patients showed gait disturbance regardless of age. Tendon reflexes were decreased in 4 of 12 patients. None presented cerebellar signs such as tremor, dysmetria, or adiadochokinesia. Nerve conduction study was normal or nearly normal in all patients, but EMG showed features of chronic denervation. Motor neuropathy/neuronopathy was definite in 7 patients and probable in 3. Conclusions: SCN1A mutations may alter axonal function, causing motor neuropathy/neuronopathy. This may contribute to gait disturbance and orthopedic misalignment, which is characteristic of patients with Dravet syndrome.

Mitochondrial disorders and epilepsy.

INTRODUCTION Mitochondrial respiratory chain defects (RCD) often exhibit multiorgan involvement, affecting mainly tissues with high-energy requirements such as the brain. Epilepsy is frequent during the evolution of mitochondrial disorders (30%) with different presentation in childhood and adulthood in term of type of epilepsy, of efficacy of treatment and also in term of prognosis. STATE OF ART Mitochondrial disorders can begin at any age but the diseases with early onset during childhood have generally severe or fatal outcome in few years. Four age-related epileptic phenotypes could be identified in infancy: infantile spasms, refractory or recurrent status epilepticus, epilepsia partialis continua and myoclonic epilepsy. Except for infantile spasms, epilepsy is difficult to control in most cases (95%). In pediatric patients, mitochondrial epilepsy is more frequent due to mutations in nDNA-located than mtDNA-located genes and vice versa in adults. Ketogenic diet could be an interesting alternative treatment in case of recurrent status epilepticus or pharmacoresistant epilepsy. CONCLUSION Epileptic seizures increase the energy requirements of the metabolically already compromised neurons establishing a vicious cycle resulting in worsening energy failure and neuronal death.

Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

Background Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism. Objectives To better characterise the natural history of PMM2-CDG. Methods Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients. Results The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and hydrops fetalis (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His PMM2 variant harboured by half of the patients, 45 different variants were observed. Conclusions PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

&NA; We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi‐Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult‐onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant‐negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon‐stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64‐25.71) compared with controls (median: 0.93, IQR: 0.57‐1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.

Progressive demyelinating neuropathy correlates with clinical severity in Cockayne syndrome.

OBJECTIVE Cockayne syndrome (CS) is characterized by postnatal growth failure and progressive multi-organ dysfunctions. CSA and CSB gene mutations account for the majority of cases and three degrees of severity are delineated. A peripheral neuropathy is known to be associated with CS but the type, severity and correlation of the nerve involvement with CS subtypes remain unknown in genetically identified patients. METHODS Clinical and nerve conduction studies (NCS) in 25 CS patients with CSA (n=13) CSB (n=12) mutations. RESULTS NCS show a widespread decrease in motor and sensory conduction velocities (CV) in all severe and classical form of CS. In one patient, CV were normal at age 8months but severe slowing was detected at 2years. Conduction block and/or temporal dispersion were observed in 68% of patients. CONCLUSIONS CS is associated with a progressive sensory and motor neuropathy. Signs of segmental demyelination, including conduction blocks, may not be obvious before the age of 2years. CV slowing is correlated with the CS clinical severity. SIGNIFICANCE NCS should be performed in patients with suspected CS as an additional tool to guide the diagnosis before molecular studies. Further studies focused on NCS course are required in order to assess its relevance as a biomarker in research therapy projects.

Unilateral predominance of abnormal movements: A characteristic feature of the pediatric anti-NMDA receptor encephalitis?

Anti-NMDA receptor encephalitis is a treatable autoimmune disease characterized by cognitive, motor and psychiatric features that primarily affects young adults and children. We present a case of a 7-year-old boy with asymmetrical (mainly right hemibody) and abnormal polymorphic movements without concomitant scalpictal EEG changes but had background slowing predominating over the left hemisphere. This report illustrates previous descriptions of asymmetric presentation of abnormal movements in pediatric anti-NMDA receptor encephalitis and emphasizes the importance of video-EEG interpreted within the overall clinical context, to differentiate epileptic from non-epileptic abnormal movements in patients with autoimmune encephalitis.