Epilepsy in dystrophinopathies: A retrospective cohort and review of the literature.

OBJECTIVE: This study aimed to assess the prevalence and characteristics of epilepsy in dystrophinopathies within a cohort of 142 patients at a tertiary neuromuscular center in Istanbul, Turkey. METHODS: We recorded the age at seizure onset, seizure type, family history, history of febrile seizures, treatment, and EEG results. Epilepsy was classified according to the latest International League Against Epilepsy (ILAE) classification. RESULTS: Of the 142 DMD patients, 8 experienced epileptic seizures (5.6 %). The median age of the patients was 11 years (8.0-15.2). The median age for the first DMD symptoms was 24 months (16.5-37.5). All seizures were consistent with generalized tonic-clonic seizures. Three patients are currently on anti-seizure medication. SIGNIFICANCE: The prevalence of epilepsy in our study (5.6 %) exceeds that of the general pediatric population (0.5-1 %). However, the frequency of febrile seizures in children with dystrophinopathy is similar to that of the general population.

The Prevalence of Headache Disorders in Children and Adolescents in Istanbul: A School-Based Study.

BACKGROUND: Headache among children and adolescents is an important health problem. In this school-based epidemiological study conducted in Istanbul, we aimed to reveal the frequency of headaches in this population, define the risk factors associated with headaches, and establish the effect of headaches on the quality of life in this population. METHODS: The child and adolescent versions of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation structured questionnaire were conducted in 30 schools in Istanbul. The diagnosis was made based on the International Classification of Headache Disorders III-(ICHD-3) beta version. Risk factors associated with headaches were analyzed in a binary logistic regression model. RESULTS: Among the 5944 students (boys = 3011 [50.7%], girls 2933 [49.3%]) who completed the survey and were enrolled in this study, 3354 (56.4%) reported a headache ever. The prevalence of headaches was significantly higher in girls (62.6% vs. 50.4%, P < 0.001). Migraine prevalence was found to be 5.2%, whereas tension-type headache (TTH) prevalence was 26.1%. Being a female, age, living on the European side, and headache history in the family were found to be associated with an increased risk of having a headache. Pupils with headaches reported that they missed an average of 0.5 ± 1.5 school days due to headaches. CONCLUSION: TTH was found to be the most common headache syndrome in Istanbul metropolitan area. Considering the effect of headaches on school success and quality of life in childhood, it is clear that the correct diagnosis of headaches and careful handling of risk factors are crucial for this population.

Distribution of peripheral blood mononuclear cell subtypes in patients with West syndrome: Impact of synacthen treatment.

BACKGROUND: West Syndrome (WS) is an epileptic encephalopathy that typically occurs in infants and is characterized by hypsarrhythmia, infantile spasms, and neurodevelopmental impairment. Demonstration of autoantibodies and cytokines in some WS patients and favorable response to immunotherapy have implicated inflammation as a putative trigger of epileptiform activity in WS. Our aim was to provide additional support for altered inflammatory responses in WS through peripheral blood immunophenotype analysis. METHODS: Eight WS cases treated with synacthen and 11 age- and sex-matched healthy volunteers were included. Peripheral blood mononuclear cells (PBMC) were isolated and immunophenotyping was performed in pre-treatment baseline (8 patients) and 3 months post-treatment (6 patients) samples. The analysis included PBMC expressing NFκB transcription and NLRP3 inflammasome factors. RESULTS: In pre-treatment baseline samples, switched memory B cells (CD19+IgD-CD27+) were significantly reduced, whereas plasma cells (CD19+CD38+CD138+) and cytotoxic T cells (CD3+CD8+) were significantly increased. Regulatory T and B cell ratios were not significantly altered. Synacthen treatment only marginally reduced helper T cell ratios and did not significantly change other T, B, NK and NKT cell and monocyte ratios. CONCLUSIONS: Our findings lend further support for the involvement of inflammation-related mechanisms in WS. New-onset WS patients are inclined to display increased plasma cells in the peripheral blood. Synacthen treatment does not show a beneficial effect on most effector acquired and innate immunity subsets.

Peri-ictal headache: An underestimated prognostic finding associated with idiopathic epilepsies.

OBJECTIVE: There are a handful of studies investigating peri-ictal headache (PIH) and its clinical associations in patients with idiopathic/genetic epilepsies (I/GE). This multi-center study aimed to investigate PIH, which is an ignored comorbid condition in patients with I/GE, by headache experts and epileptologists working together. METHODS: The data were collected from a cross-sectional large study, using two structured questionnaires for headache and epilepsy features, fulfilled by neurologists. Headaches were classified according to the International Classification of Headache Disorders, third edition, whereas seizure and syndrome types were diagnosed according to International League Against Epilepsy criteria. The patients with a headache starting 24 hours before the onset of the seizure (preictal) or within 3 hours after the seizure (postictal) were defined as patients with PIH. We compared demographic and clinical differences between two groups of patients with and without PIH statistically and used ROC curves to determine a threshold of the total number of seizure triggers associated with the occurrence of PIH. RESULTS: Among 809 (531 females, 65.6%) consecutive patients with I/GE, 105 (13%) patients reported PIH (22 preictal, 82 postictal headaches, and one with both types). Peri-ictal headache was more frequently reported by females and those having a family history of migraine or epilepsy, and it was significantly associated with lower rates of seizure freedom for more than five years, drug resistance, and use of polytherapy, remarkably. Moreover, ROC curves showed that having more than 3 seizure triggers was associated with the presence of PIH. CONCLUSION: Our findings revealed that PIH may be linked to poor outcomes in I/GEs and seems to be related to a lower ictal threshold precipitated by multiple triggers. Future prospective studies will illuminate the unknown underlying mechanisms and appropriate management strategies for PIH to improve the prognosis.

Genetic Survey of Autosomal Recessive Peripheral Neuropathy Cases Unravels High Genetic Heterogeneity in a Turkish Cohort.

BACKGROUND AND OBJECTIVES: Inherited peripheral neuropathies (IPNs) are a group of genetic disorders of the peripheral nervous system in which neuropathy is the only or the most predominant clinical feature. The most common type of IPN is Charcot-Marie-Tooth (CMT) disease. Autosomal recessive CMT (ARCMT) is generally more severe than dominant CMT and its genetic basis is poorly understood due to high clinical and genetic diversity. Here, we report clinical and genetic findings from 56 consanguineous Turkish families initially diagnosed with CMT disease. METHODS: We initially screened the GDAP1 gene in our cohort as it is the most commonly mutated ARCMT gene. Next, whole-exome sequencing and homozygosity mapping based on whole-exome sequencing (HOMWES) analysis was performed. To understand the molecular impact of candidate causative genes, functional analyses were performed in patient primary fibroblasts. RESULTS: Biallelic recurrent mutations in the GDAP1 gene have been identified in 6 patients. Whole-exome sequencing and HOMWES analysis revealed 16 recurrent and 13 novel disease-causing alleles in known IPN-related genes and 2 novel candidate genes: 1 for a CMT-like disease and 1 for autosomal recessive cerebellar ataxia with axonal neuropathy. We have achieved a potential genetic diagnosis rate of 62.5% (35/56 families) in our cohort. Considering only the variants that meet the American College for Medical Genetics and Genomics (ACMG) classification as pathogenic or likely pathogenic, the definitive diagnosis rate was 55.35% (31/56 families). DISCUSSION: This study paints a genetic landscape of the Turkish ARCMT population and reports additional candidate genes that might help enlighten the mechanism of pathogenesis of the disease.

LBSL: Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations.

OBJECTIVE: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes. METHODS: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function. RESULTS: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function. CONCLUSIONS: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.

Ulnar nerve entrapment neuropathy at the elbow: relationship between the electrophysiological findings and neuropathic pain.

[Purpose] Ulnar nerve neuropathies are the second most commonly seen entrapment neuropathies of the upper extremities after carpal tunnel syndrome. In this study, we aimed to evaluate pain among ulnar neuropathy patients by the Leeds assessment of neuropathic symptoms and signs pain scale and determine if it correlated with the severity of electrophysiologicalfindings. [Subjects and Methods] We studied 34 patients with clinical and electrophysiological ulnar nerve neuropathies at the elbow. After diagnosis of ulnar neuropathy at the elbow, all patients underwent the Turkish version of the Leeds assessment of neuropathic symptoms and signs pain scale. [Results] The ulnar entrapment neuropathy at the elbow was classified as class-2, class-3, class-4, and class-5 (Padua Distal Ulnar Neuropathy classification) for 15, 14, 4, and 1 patient, respectively. No patient included in class-1 was detected. According to Leeds assessment of neuropathic symptoms and signs pain scale, 24 patients scored under 12 points. The number of patients who achieved more than 12 points was 10. Groups were compared by using the χ(2) test, and no difference was detected. There was no correlation between the Leeds assessment of neuropathic symptoms and signs pain scale and electromyographic findings. [Conclusion] We found that the severity of electrophysiologic findings of ulnar nerve entrapment at the elbow did not differ between neuropathic and non-neuropathic groups as assessed by the Leeds assessment of neuropathic symptoms and signs pain scale.

Inflammatory Demyelinating Diseases of Childhood: Case Report and Literature Review.

Multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) are demyelinating inflammatory diseases, considered to have a striking pathophysiological resemblance. However, due to the differences in both clinical course and clinical approaches, it is important to differentiate between the two conditions, to plan further investigations and therapy protocols. These diseases have similar but also distinct clinical, radiological and cerebrospinal fluid (CSF) findings. ADEM is typically a monophasic disease of children. MS occurs generally in adult age, but uncommonly may develop in childhood with variable features. Our case is a 14 year-old-girl, presented with a three-month history of left hemiparesis, followed by right hemiparesis, cerebellar signs, myelitis and cortical visual disturbances. Based on the clinical follow-up, MR and CSF findings, our patient was diagnosed with relapsing tumefactive multiple sclerosis. Steroid treatment was not significantly effective, however the patient has benefited from plasmapheresis clinically and radiologically. Our patient is still being followed under the disease modifying therapy without any relapse.