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Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co-twins with abnormal brain imaging and compared them to population-based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia-ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy-Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p = .0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p < .0001. Recurrent association with twin-twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause.

Perinatal stroke is a significant cause of severe epilepsy, including epileptic spasms. Although epileptic spasms due to underlying structural lesion often respond poorly to treatment and evolve into drug-resistant epilepsy, outcomes are not uniformly poor, and predictors of outcomes are not well described. We performed a single-institution retrospective review of epileptic spasms following perinatal stroke to determine if outcome depended on vascular subtype. We identified 24 children with epileptic spasms due to perinatal ischemic stroke: 11 cases of perinatal arterial stroke and 13 cases of perinatal venous infarct. Initial response to treatment was similar between groups; however, although children with perinatal arterial stroke who responded to epileptic spasms therapy had high rates of seizure freedom, many children with perinatal venous infarct, regardless of initial response, had residual drug-resistant epilepsy. We consider whether the mechanism for epileptogenesis may be different between arterial and venous strokes, and whether these 2 groups should be monitored for epileptic spasms, and subsequent epilepsy, differently.

Purpose Children with cerebral visual impairment (CVI) often have abnormal visual orienting behaviors due to impaired or damaged visual cortex. Alternatively, visual-cortical function is intact but visual information is not transformed downstream into an appropriate oculomotor output (visuomotor dysfunction). We examined visual, anatomic, and oculomotor assessments to distinguish visuomotor dysfunction from CVI associated with severely reduced visual-cortical response. Methods We reviewed the medical records from children with CVI having abnormal visual orienting behaviors, normal ocular examinations, and born near term. Relevant data were visual evoked potentials (VEPs), Teller card acuity, eye movements recorded by video-oculography (VOG), and neuroimaging (magnetic resonance imaging [MRI]) including diffusion tensor imaging (DTI) tractography. Results Thirty subjects had visuomotor dysfunction based on a normal VEP; of these 33% had a normal MRI and 67% had white matter abnormalities associated with metabolic disease and/or decreased volume of brain parenchyma. VOG recordings showed smooth pursuit gains were uniformly reduced and saccades were dysmetric but followed the main sequence. Ten subjects had severe CVI based on VEPs at noise levels; visual acuities and MRI findings overlapped those of the visuomotor dysfunction group. Developmental delay, seizures, microcephaly, and hypotonia were common across all groups. All subjects with an abnormal conventional MRI had abnormal metrics on DTI tractography from the occipital lobe. Conclusions A subset of patients with CVI have abnormal visual orienting behaviors despite a normal VEP (visuomotor dysfunction). A majority have abnormal white matter metrics on tractography suggesting a downstream defect in sensorimotor transformation. Clinically, visuomotor dysfunction is indistinguishable from severe CVI.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.

BACKGROUND AND PURPOSE: The ketogenic diet, including both classic and modified forms, is an alternative to antiepileptic medications used in the treatment of drug-resistant epilepsy. We sought to evaluate the utility of proton MR spectroscopy for the detection of β-hydroxybutyrate in a cohort of children with epilepsy treated with the ketogenic diet and to correlate brain parenchymal metabolite ratios obtained from spectroscopy with β-hydroxybutyrate serum concentrations. MATERIALS AND METHODS: Twenty-three spectroscopic datasets acquired at a TE of 288 ms in children on the ketogenic diet were analyzed with LCModel using a modified basis set that included a simulated β-hydroxybutyrate resonance. Brain parenchymal metabolite ratios were calculated. Metabolite ratios were compared with serum β-hydroxybutyrate concentrations, and partial correlation coefficients were calculated using patient age as a covariate. RESULTS: β-hydroxybutyrate blood levels were highly correlated to brain β-hydroxybutyrate levels, referenced as either choline, creatine, or N -acetylaspartate. They were inversely but more weakly associated with N -acetylaspartate, regardless of the ratio denominator. No strong concordance with lactate was demonstrated. CONCLUSIONS: Clinical MR spectroscopy in pediatric patients on the ketogenic diet demonstrated measurable β-hydroxybutyrate, with a strong correlation to β-hydroxybutyrate blood levels. These findings may serve as an effective tool for noninvasive monitoring of ketosis in this population. An inverse correlation between serum β-hydroxybutyrate levels and brain tissue N -acetylaspartate suggests that altered amino acid handling contributes to the antiepileptogenic effect of the ketogenic diet.

OBJECTIVEThe potential loss of motor function after cerebral hemispherectomy is a common cause of anguish for patients, their families, and their physicians. The deficits these patients face are individually unique, but as a whole they provide a framework to understand the mechanisms underlying cortical reorganization of motor function. This study investigated whether preoperative functional MRI (fMRI) and diffusion tensor imaging (DTI) could predict the postoperative preservation of hand motor function.METHODSThirteen independent reviewers analyzed sensorimotor fMRI and colored fractional anisotropy (CoFA)–DTI maps in 25 patients undergoing functional hemispherectomy for treatment of intractable seizures. Pre- and postoperative gross hand motor function were categorized and correlated with fMRI and DTI findings, specifically, abnormally located motor activation on fMRI and corticospinal tract atrophy on DTI.RESULTSNormal sensorimotor cortical activation on preoperative fMRI was significantly associated with severe decline in postoperative motor function, demonstrating 92.9% sensitivity (95% CI 0.661–0.998) and 100% specificity (95% CI 0.715–1.00). Bilaterally robust, symmetric corticospinal tracts on CoFA-DTI maps were significantly associated with severe postoperative motor decline, demonstrating 85.7% sensitivity (95% CI 0.572–0.982) and 100% specificity (95% CI 0.715–1.00). Interpreting the fMR images, the reviewers achieved a Fleiss’ kappa coefficient (κ) for interrater agreement of κ = 0.69, indicating good agreement (p < 0.01). When interpreting the CoFA-DTI maps, the reviewers achieved κ = 0.64, again indicating good agreement (p < 0.01).CONCLUSIONSFunctional hemispherectomy offers a high potential for seizure freedom without debilitating functional deficits in certain instances. Patients likely to retain preoperative motor function can be identified prior to hemispherectomy, where fMRI or DTI suggests that cortical reorganization of motor function has occurred prior to the operation.

There are no evidence-based guidelines on the preferred approach to treating early-life epilepsy. We examined initial therapy selection in a contemporary US cohort of children with newly diagnosed, nonsyndromic, early-life epilepsy (onset before age three years).Seventeen pediatric epilepsy centers participated in a prospective cohort study of children with newly diagnosed epilepsy with onset under 36 months of age. Details regarding demographics, seizure types, and initial medication selections were obtained from medical records.About half of the 495 enrolled children with new-onset, nonsyndromic epilepsy were less than 12 months old at the time of diagnosis (n = 263, 53%) and about half (n = 260, 52%) had epilepsy with focal features. Of 464 who were treated with monotherapy, 95% received one of five drugs: levetiracetam (n = 291, 63%), oxcarbazepine (n = 67, 14%), phenobarbital (n = 57, 12%), topiramate (n = 16, 3.4%), and zonisamide (n = 13, 2.8%). Phenobarbital was prescribed first for 50 of 163 (31%) infants less than six months old versus seven of 300 (2.3%) of children six months or older (P 0.0001). Although the first treatment varied across study centers (P 0.0001), levetiracetam was the most commonly prescribed medication regardless of epilepsy presentation (focal, generalized, mixed/uncertain). Between the first and second treatment choices, 367 (74%) of children received levetiracetam within the first year after diagnosis.Without any specific effort, the pediatric epilepsy community has developed an unexpectedly consistent approach to initial treatment selection for early-life epilepsy. This suggests that a standard practice is emerging and could be utilized as a widely acceptable basis of comparison in future drug studies.

Background The rare, X‐linked neurodegenerative disorder, Mohr–Tranebjaerg syndrome (also called deafness‐dystonia‐optic neuronopathy [DDON] syndrome), is caused by mutations in the TIMM8A gene. DDON syndrome is characterized by dystonia, early‐onset deafness, and various other neurological manifestations. The TIMM8A gene product localizes to the intermembrane space in mitochondria where it functions in the import of nuclear‐encoded proteins into the mitochondrial inner membrane. Frameshifts or premature stops represent the majority of mutations in TIMM8A that cause DDON syndrome. However, missense mutations have also been reported that result in loss of the TIMM8A gene product. Methods We report a novel TIMM8A variant in a patient with DDON syndrome that alters the initiation codon and employed functional analyses to determine the significance of the variant and its impact on mitochondrial morphology. Results The novel base change in the TIMM8A gene (c.1A>T, p.Met1Leu) results in no detectable protein and a reduction in TIMM8A transcript abundance. We observed a commensurate decrease in the steady‐state level of the Tim13 protein (the binding partner of Tim8a) but no decrease in TIMM13 transcripts. Patient fibroblasts exhibited elongation and/or increased fusion of mitochondria, consistent with prior reports. Conclusion This case expands the spectrum of mutations that cause DDON syndrome and demonstrates effects on mitochondrial morphology that are consistent with prior reports., We report a novel TIMM8A variant in a patient with DDON syndrome that alters the initiation codon, resulting in no detectable protein and a reduction in TIMM8A transcript abundance. Decreased steady‐state level of the Tim13 protein and elongation and/or increased fusion of mitochondria were also observed in patient cells. This case expands the spectrum of mutations that cause DDON syndrome.

Importance Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose. Objective To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome. Design, Setting, and Participants This double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) recruited patients from April 13, 2015, to November 10, 2017, with follow-up completed on April 9, 2018. Of 285 patients screened from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel, 86 were excluded, and 199 were randomized. Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug. Data were analyzed from November 16 (date of unblinding) to December 13 (date of final outputs), 2018, based on intention to treat and per protocol. Interventions Patients received cannabidiol oral solution at a dose of 10 or 20 mg/kg per day (CBD10 and CBD20 groups, respectively) or matched placebo in 2 equally divided doses for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were blinded to group assignment. Main Outcomes and Measures The primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score. Results Of 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%;P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%;P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium. Conclusions and Relevance Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety. Trial Registration ClinicalTrials.gov Identifier:NCT02224703

Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum. Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate. Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls. Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.

RATIONALE: Early-life epilepsies (ELEs) include some of the most challenging forms of epilepsy to manage. Given recent diagnostic and therapeutic advances, a contemporary assessment of the immediate short-term outcomes can provide a valuable framework for identifying priorities and benchmarks for evaluating quality improvement efforts. METHODS: Children with newly diagnosed epilepsy and onset

Solid organ transplants are rarely performed in both adult and pediatric patients with primary mitochondrial disease. Poor outcomes have been described in case reports and small case series. It is unclear whether the underlying genetic disease has a significant impact on post-transplant morbidity and mortality. Data were obtained for 35 patients from 17 Mitochondrial Disease Centers across North America, the United Kingdom and Australia. Patient outcomes were noted after liver, kidney or heart transplantation. Excluding patients with POLG-related disease, post-transplant survival approached or met outcomes seen in non-mitochondrial disease transplant patients. The majority of mitochondrial disease patients did not have worsening of their mitochondrial disease within 90-days post-transplant. Post-transplant complications, including organ rejection, were not a common occurrence and were generally treatable. Many patients did not have a mitochondrial disease considered or diagnosed prior to transplantation. In conclusion, patients with mitochondrial disease in this cohort generally tolerated solid-organ transplantation. Such patients may not need to be excluded from transplant solely for their mitochondrial diagnosis; additional caution may be needed for patients with POLG-related disease. Transplant teams should be aware of mitochondrial disease as an etiology for organ-failure and consider appropriate consultation in patients without a known cause of their symptoms.

A 20-year-old man with a rare neurodegenerative disease developed hypermetabolic symptoms with dyskinesia after a third ventriculostomy for hydrocephalus. The initial presentation was concerning for an acute dystonic reaction after metoclopramide was administered for nausea. He concurrently developed hypermetabolic symptoms, including hyperthermia, tachycardia, and a lactic acidosis. The diagnosis was broadened to include neuroleptic malignant syndrome, serotonin syndrome, and malignant hyperthermia. Although perhaps less intellectually satisfying but more true to clinical reality, we did not isolate a single diagnosis but treated effectively all 3 with dantrolene sodium and benzodiazepine.

Introduction This retrospective descriptive study was undertaken to further define the intelligence profiles of children with mitochondrial disorders, in the context of seizures and age of symptom onset. Methods We retrospectively identified forty-nine pediatric patients with definitive mitochondrial disease diagnoses and complete intelligence or adaptive functioning testing data. Patients were 0–216 months at onset of symptoms and 61–250 months of age at testing. Twenty-four of 49 patients had seizures. Twenty-one of the 24 patients with seizures had medically intractable seizures. All patients had Wechsler Intellectual Quotient (IQ) testing, except nine patients with seizures who were unable to engage in IQ testing and were assessed with a structured parent interview measure, the Vineland Adaptive Behavior Scales. We used descriptive and exploratory data analysis methods to characterize test results. Results Distribution of ages for patients with the Vineland assessment was younger than those given the Wechsler. The median overall score (combining Wechsler and Vineland summary scores) for all patients was 85 (interquartile range [IQR]: 50, 102), with the group without seizures obtaining a higher median Full Scale IQ (FSIQ) of 100 (IQR: 86, 109), compared to the group with seizures with a median FSIQ of 67 (IQR: 49.5, 89), a difference that is both statistically and clinically different (Δ = 33; 95% CI: 9, 52). The adaptive function measure was composed of patients only with intractable epilepsy and yielded the lowest overall median summary score of 43 (IQR: 37, 50). This general trend in differences between the FSIQ scores of the groups with and without seizures was also seen across all subscale measures analyzed—IQ index scores and two subtest scores, Digit Span and Coding—though differences were not always statistically different. Vargha–Delaney's A effect sizes ranged between 0.68 and 0.90, trends that mirrored those of distributional and median differences. Groups without versus with seizures differed most distinctly in Performance IQ (PIQ), with the group without seizures' median PIQ being 100 (IQR 94, 112) versus the group with seizures' median PIQ being 63 (IQR 54, 84), a difference of 37 points (95% CI). Discussion Results suggest that patients with mitochondrial diseases with seizures and early onset disease represent a worse cognitive phenotype, as compared with those with no seizures, who can have average intelligence. Results are discussed in the context of current literature.

The clinical diagnosis of malformations of cortical development (MCDs) is often challenging due to the complexity of the brain malformation by neuroimaging, the rarity of individual malformation syndromes, and the rapidly evolving genetic landscape of these disorders facilitated with the use of Next Generation Sequencing (NGS) methods. While the clinical and molecular diagnosis of severe cortical malformations, such as classic lissencephaly, is often straightforward, the diagnosis of more subtle and complex types of cortical malformations, such as pachygyria and polymicrogyria (PMG), can be more challenging due to limited knowledge regarding their genetic etiologies. Here, we report two individuals with the same de novo KIF5C mutation who present with subtle malformations of cortical development, early onset epilepsy and significant neurodevelopmental and behavioral issues including absent language. Our data, combined with the limited literature on KIF5C mutations, to date, support that KIF5C mutations are associated with a neurodevelopmental disorder characterized by infantile onset epilepsy, and subtle but recognizable types of brain malformations. We also show that the spectrum of KIF5C mutations is narrow, as five out of the six identified individuals have mutations affecting amino acid Glu237. Therefore, the identification of the clinical and neuroimaging features of this disorder may strongly facilitate rapid and efficient molecular diagnosis.

The SCN1A gene has been implicated in the etiology of various forms of epilepsy. New research has linked this gene to specific types of epilepsy, all of which present in infancy or early childhood. This study examines the time course and pathology of pediatric patients who have a mutation in the SCN1A gene in order to open a discussion regarding the key trends of this form of epilepsy as well as important clinical considerations in management for patients who present with symptoms relating to the SCN1A mutations. We retrospectively examined 20 patients who presented to the clinic with focal seizures, as well as were positive for an SCN1A genetic mutation. Despite the small sample size, we were able to find important trends in the time course of the disorder as well as important areas of clinical practice that must be taken into consideration for these patients.

The widespread patient use of artisanal cannabis preparations has preceded quality validation of cannabis use for epilepsy. Neurologists and cannabinoid specialists are increasingly in a position to monitor and guide the use of herbal cannabis in epilepsy patients. We report the retrospective data on efficacy and adverse effects of artisanal cannabis in Patients with medically refractory epilepsy with mixed etiologies in Washington State, California, and Maine. Clinical considerations, including potential risks and benefits, challenges related to artisanal preparations, and cannabinoid dosing, are discussed.Of 272 combined patients from Washington State and California, 37 (14%) found cannabis ineffective at reducing seizures, 29 (15%) experienced a 1-25% reduction in seizures, 60 (18%) experienced a 26-50% reduction in seizures, 45 (17%) experienced a 51-75% reduction in seizures, 75 (28%) experienced a 76-99% reduction in seizures, and 26 (10%) experienced a complete clinical response. Overall, adverse effects were mild and infrequent, and beneficial side effects such as increased alertness were reported. The majority of patients used cannabidiol (CBD)-enriched artisanal formulas, some with the addition of delta-9-tetrahydrocannabinol (THC) and tetrahydrocannabinolic acid (THCA). Four case reports are included that illustrate clinical responses at doses0.1mg/kg/day, biphasic dose-response effects, the use of THCA for seizure prevention, the use of THC for seizure rescue, and the synergy of cannabinoids and terpenoids in artisanal preparations. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy".

Importance Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are associated with significant childhood morbidity and mortality. Objective To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly. Design, Setting, and Participants Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children’s Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase–AKT (serine/threonine kinase)–mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations. Main Outcomes and Measures Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders. Results Low-level mosaic mutations ofMTORwere identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation ofMTOR(p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation ofMTOR(p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, allMTORmutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size. Conclusions and Relevance In this study, mutations ofMTORwere associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations ofMTORand pigmentary mosaicism in skin.

Epilepsy surgery is common in the face of benign brain tumors, but rarely for patients with a history of malignant brain tumors. Seizures are a common sequelae in survivors of malignant pediatric brain tumors. Medical management alone may not adequately treat epilepsy, including in this group. We report four cases of patients who previously underwent gross total resection, radiation therapy, and chemotherapy for successful treatment of malignant brain neoplasia, yet suffered from medically intractable seizures. All underwent surgery for treatment of epilepsy with extension of the original resection. Despite the aggressive primary treatment of the neoplasm, and the potential for diffuse cerebral insults, all benefited from focal surgical resection. Aggressive surgical management of intractable epilepsy can be considered in survivors of malignant brain tumors.

BACKGROUND AND PURPOSE: Often diagnosed at birth or in early childhood, mitochondrial disease presents with a variety of clinical symptoms, particularly in organs and tissues that require high energetic demand such as brain, heart, liver, and skeletal muscles. In a group of pediatric patients identified as having complex I or I/III deficits on muscle biopsy but with white matter tissue appearing qualitatively normal for age, we hypothesized that quantitative DTI analyses might unmask disturbance in microstructural integrity. MATERIALS AND METHODS: In a retrospective study, DTI and structural MR brain imaging data from 10 pediatric patients with confirmed mitochondrial disease and 10 clinical control subjects were matched for age, sex, scanning parameters, and date of examination. Paired TBSS was performed to evaluate differences in FA, MD, and the separate diffusion direction terms (λr and λa). RESULTS: In patients with mitochondrial disease, significant widespread reductions in FA values were shown in white matter tracts. Mean diffusivity values were significantly increased in patients, having a sparser distribution of affected regions compared with FA. Separate diffusion maps showed significant increase in λr and no significant changes in λa. CONCLUSIONS: Despite qualitatively normal-appearing white matter tissues, patients with complex I or I/III deficiency have widespread microstructural changes measurable with quantitative DTI.

The most common mitochondrial DNA (mtDNA) mutations giving rise to Leigh syndrome reside in the MTATP6 gene. We report a rare mutation, m. 9185 T>C that gives rise to a progressive, but episodic pattern of neurological impairment with partial recovery. Disease progression corresponded to febrile viral illness and nuclear magnetic resonance imaging (MRI) changes. The patient displayed nearly 100% homoplasmy, while his asymptomatic mother was 30%. Phenotypically, exacerbations of muscle weakness with endurance intolerance, dysarthric speech, ataxia, and eyelid ptosis accompanied febrile viral illness. This case demonstrates an episodic pattern of febrile illness-induced disease exacerbation with corresponding MRI changes.

Missense mutations in the gene for polymerase gamma 1 (POLG1) cause a number of phenotypically heterogeneous mitochondrial diseases, most commonly progressive external ophthalmoplegia, and are characterized by the accumulation of multiple, large-scale deletions of mitochondrial DNA. The triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) has been demonstrated in a small subset of patients with POLG1 mutations. We report a sporadic case of an 80-year-old compound heterozygote man who presented with SANDO and was found to have three known pathogenic mutations in the POLG1 gene (p.T251I/p.P587L/p.G848S). To our knowledge, none of these mutations have been demonstrated previously in SANDO. This patient's late presentation illustrates that a mitochondrial disorder should be considered regardless of age if the clinical symptoms warrant.

PurposeTo review our clinical experience and determine if there are appropriate signs and symptoms to consider POLG sequencing prior to valproic acid (VPA) dosing in patients with seizures.MethodsFour patients who developed VPA-induced hepatotoxicity were examined for POLG sequence variations. A subsequent chart review was used to describe clinical course prior to and after VPA dosing.ResultsFour patients of multiple different ethnicities, age 3–18 years, developed VPA-induced hepatotoxicity. All were given VPA due to intractable partial seizures. Three of the patients had developed epilepsia partialis continua. The time from VPA exposure to liver failure was between 2 and 3 months. Liver failure was reversible in one patient. Molecular studies revealed homozygous p.R597W or p.A467T mutations in two patients. The other two patients showed compound heterozygous mutations, p.A467T/p.Q68X and p.L83P/p.G888S. Clinical findings and POLG mutations were diagnostic of Alpers–Huttenlocher syndrome.ConclusionOur cases underscore several important findings: POLG mutations have been observed in every ethnic group studied to date; early predominance of epileptiform discharges over the occipital region is common in POLG-induced epilepsy; the EEG and MRI findings varying between patients and stages of the disease; and VPA dosing at any stage of Alpers–Huttenlocher syndrome can precipitate liver failure. Our data support an emerging proposal that POLG gene testing should be considered in any child or adolescent who presents or develops intractable seizures with or without status epilepticus or epilepsia partialis continua, particularly when there is a history of psychomotor regression.

Infantile spasms are the defining seizures of West syndrome, a severe form of early life epilepsy with poorly-understood pathophysiology. We present a novel comparative analysis of infants with spasms versus other seizure-types and identify clinical, etiological, and molecular-genetic factors preferentially predisposing to spasms. We compared ages, clinical etiologies, and associated-genes between spasms and non-spasms groups in a multicenter cohort of 509 infants (

The authors conducted a multiinstitutional, retrospective analysis to better define outcome and prognostic indicators for temporal lobe epilepsy surgery for suspected mesial temporal sclerosis (MTS) in young children.Data were collected for all children undergoing temporal resections at four epilepsy centers over approximately 10 years. Children with a histopathological diagnosis of neoplasm were excluded. Forty-nine patients (28 boys and 21 girls) were included in the study. Their mean age at surgery was 9.1 years (range 1.25-13.9 years). The mean age at seizure onset was 3.2 years (range birth-10 years). Histopathological examination demonstrated MTS in 26 cases, gliosis in nine, dysplasia in five, gliosis with dysplasia in four, and nonspecific or normal findings in five. Forty-one anterior temporal lobectomies (nine tailored) and eight selective amygdalohippocam-pectomies were performed (28 left side, 21 right side). Twenty-nine children (59.2%) underwent invasive monitoring. Operative complications included extraaxial hematomas (two cases), cerebrospinal fluid leaks (two cases), and hydrocephalus (one case), each in children undergoing invasive monitoring. The mean duration of follow up was 26.4 months (range 5-74 months) overall and 23.9 months (range 6-74 months) for the Engel Class I subgroup. Outcomes at the most recent follow-up examination were categorized as Engel Class I-II in 31 (63.3%) of 49 children overall, 20 (76.9%) of 26 children with confirmed MTS, four (36.4%) of 11 children with gliosis, and four (57.1%) of seven children with dysplasia. All patients who underwent selective amygdalohippocampectomies had confirmed MTS and Engel Class I outcomes. Patients with more than one seizure type (p = 0.048) or moderate to severe developmental delay (p = 0.03) had significantly worse outcomes (Engel Class III or IV). Age at seizure onset, age at surgery, and duration of seizure disorder were not significantly related to outcome. There was a trend for bilateral or extratemporal findings on electroencephalography (EEG) (p = 0.157), high preoperative seizure frequency (p = 0.097), and magnetic resonance (MR) imaging findings inconsistent with MTS (p = 0.142) to be associated with worse outcome, although it did not reach statistical significance. In only 12 (46.1%) of the 26 patients with confirmed MTS was the condition prospectively diagnosed on preoperative MR imaging.Younger children with temporal lobe epilepsy have satisfying surgical outcomes, particularly when MTS is present. Magnetic resonance imaging may not be as sensitive in detecting MTS in children as in older patients. Negative predictors identified include multiple seizure types and preoperative developmental delay. Multifocal or bilateral EEG findings, high preoperative seizure frequency, and MR imaging findings inconsistent with MTS also independently suggested worse outcome.

OBJECT Outcomes of focal resection in young children with early-onset epilepsy are varied in the literature due to study differences. In this paper, the authors sought to define the effect of focal resection in a small homogeneous sample of children who were otherwise cognitively intact, but who required early surgical treatment. Preservation of and age-appropriate development of intelligence following focal resection was hypothesized. METHODS Cognitive outcome after focal resection was retrospectively reviewed for 15 cognitively intact children who were operated on at the ages of 2–6 years for lesion-related, early-onset epilepsy. Intelligence was tested prior to and after surgery. Effect sizes and confidence intervals for means and standard deviations were used to infer changes and differences in intelligence between 1) groups (pre vs post), 2) left versus right hemisphere resections, and 3) short versus long duration of seizures prior to resection. RESULTS No group changes from baseline occurred in Full Scale, verbal, or nonverbal IQ. No change from baseline intelligence occurred in children who underwent left or right hemisphere surgery, including no group effect on verbal scores following surgery in the dominant hemisphere. Patients with seizure durations of less than 6 months prior to resection showed improvement from their presurgical baseline in contrast to those with seizure duration of greater than 6 months prior to surgery, particularly in Wechsler Full Scale IQ and nonverbal intelligence. CONCLUSIONS This study suggests that surgical treatment of focal seizures in cognitively intact preschool children is likely to result in seizure remediation, antiepileptic drug discontinuation, and no significant decrement in intelligence. The latter finding is particularly significant in light of the longstanding concern associated with performing resections in the language-dominant hemisphere. Importantly, shorter seizure duration prior to resection can result in improved cognitive outcome, suggesting that surgery for this population should occur sooner to help improve intelligence outcomes.

Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondria] Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondria! disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource (GEM.app) that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases. (C) 2014 Elsevier Inc. All rights reserved.

Objectives.—To describe the occurrence of cerebral venous thrombosis in a 40-year-old man whose cerebral event was induced by a poor golf swing, to review the literature on possible mechanisms producing venous thrombosis, and to compare this case with the literature. Background.—Headache is the most frequent symptom in patients with cerebral venous thrombosis. However, patients presenting with a headache due to cerebral venous thrombosis are uncommon. The known risk factors for thrombosis include both acquired and genetic factors. When the interaction of these two groups occurs, the magnitude of this interaction is thought to produce a dynamic state that can favor thrombosis. Our case report illustrates that moderate levels of anticardiolipin antibodies together with the mild trauma of a golf swing can induce a cerebral venous thrombosis. This case also suggests that although headache is rarely due to cerebral venous thrombosis, it should be excluded by good medical acumen and testing. Results.—Minor trauma induced by a poor golf swing was chronologically related to the development of a progressive cerebral venous thrombosis. The patient had none of the risk factors associated with a predisposition to venous thrombosis: hypercoagulable state, concurrent infection, pregnancy/puerperium, collagen vascular disorder, malignancy, migraine, false-positive VDRL, previous deep vein thrombosis, renal disease, factor V Leiden, or a hematological disorder. There was no anatomical abnormality that would predispose the patient to a cerebral venous thrombosis. The only laboratory abnormality was a moderate anticardiolipin antibody level (25 GPL). The patient was placed on warfarin sodium therapy and is currently without clinical sequela from the venous thrombotic event. Conclusions.—Under certain circumstances, minor trauma can induce cerebral venous thrombosis. A review of the literature indicates that cerebral venous thrombosis in the presence of anticardiolipin antibodies and in the absence of systemic lupus erythematosus is a rare event. Previously, only major traumatic events have been reported to be associated with cerebral venous thromboses. The chronological development of cerebral venous thrombosis after a faulty golf swing strongly indicates that given a background of moderate levels of anticardiolipin antibodies, even minor trauma can induce a venous thrombotic event.

Functional hemispherectomy is a well-recognized surgical option for the treatment of unihemispheric medically intractable epilepsy. While the resultant motor deficits are a well-known and expected consequence of the procedure, the impact on other cortical functions has been less well defined. As the cortical control of swallowing would appear to be threatened after hemispherectomy, the authors retrospectively studied a pediatric population that underwent functional hemispherectomy for medically intractable epilepsy to characterize the incidence and severity of dysphagia after surgery.A retrospective cohort (n = 39) of pediatric patients who underwent hemispherectomy at a single institution was identified, and available clinical records were reviewed. Additionally, the authors examined available MR images for integrity of the thalamus and basal ganglia before and after hemispherectomy. Clinical and video fluoroscopic assessments of speech pathology were reviewed, and the presence, type, and duration of pre- and postoperative dysphagia were recorded.New-onset, transient dysphagia occurred in 26% of patients after hemispherectomy along with worsening of preexisting dysphagia noted in an additional 15%. Clinical symptoms lasted a median of 19 days. Increased duration of symptoms was seen with late (14 days postoperative) pharyngeal swallow dysfunction when compared with oral dysphagia alone. Neonatal stroke as a cause for seizures decreased the likelihood of postoperative dysphagia. There was no association with seizure freedom or postoperative hydrocephalus.New-onset dysphagia is a frequent and clinically significant consequence of hemispherectomy for intractable epilepsy in pediatric patients. This dysphagia was always self-limited except in those patients in whom preexisting dysphagia was noted.

Summary Purpose To review the efficacy and tolerability of stiripentol in the treatment of U.S. children with Dravet syndrome. Methods U.S. clinicians who had prescribed stiripentol for two or more children with Dravet syndrome between March 2005 and 2012 were contacted to request participation in this retrospective study. Data collected included overall seizure frequency, frequency of prolonged seizures, and use of rescue medications and emergency room (ER)/hospital visits in the year preceding stiripentol initiation, and with stiripentol therapy. We separately assessed efficacy in the following treatment groups: group A, stiripentol without clobazam or valproate; group B, stiripentol with clobazam but without valproate; group C, stiripentol with valproate but without clobazam; and group D, stiripentol with clobazam and valproate. In addition, adverse effects were recorded. Key Findings Thirteen of 16 clinicians contacted for study participated and provided data on 82 children. Stiripentol was initiated a median of 6.0 years after seizure onset and 1.2 years after diagnosis of Dravet syndrome. Compared to baseline, overall seizure frequency was reduced in 2/6 in group A, 28/35 in group B, 8/14 in group C, and 30/48 in group D. All children with prolonged seizure frequency greater than quarterly during the baseline period experienced a reduction in this frequency on the various treatment arms with stiripentol. Similarly, 2/4 patients in group A, 25/25 in group B, 5/10 in group C, and 26/33 in group D experienced reduction in frequency of rescue medication use and 1/1 in group A, 12/12 in group B, 3/5 in group C, and 18/19 in group D had reduction in frequency of ER/hospital visits. Adverse effects were reported in 38, most commonly sedation and reduced appetite. Four patients (5%) discontinued stiripentol for adverse effects and two (2%) for lack of efficacy. Significance Stiripentol is an effective and well-tolerated therapy that markedly reduced frequency of prolonged seizures in Dravet syndrome.

Intraoperative electrocorticography (ECoG) is commonly used to guide the extent of resection, especially in lesion-associated intractable epilepsy. Interictal epileptiform discharges on postresective ECoG (post-ECoG) have been predictive of seizure recurrence in some studies, particularly in adults undergoing medial temporal lobectomy, frontal lesionectomy, or low-grade glioma resection. The predictive value of postresective discharges in pediatric epilepsy surgery has not been extensively studied.The authors retrospectively examined the charts of all 52 pediatric patients who had undergone surgery with post-ECoG and had more than 1 year of follow-up between October 1, 2003, and October 1, 2009.Of the 52 pediatric patients, 37 patients showed residual discharges at the end of their resection and 73% of these patients were seizure free, whereas 15 patients had no residual discharges and 60% of them were seizure-free, which was not significantly different (p = 0.36, chi-square).Electrocorticography-guided surgery was associated with excellent postsurgical outcome. Although this sample size was too small to detect a subtle difference, absence of epileptiform discharges on post-ECoG does not appear to predict seizure freedom in all pediatric patients referred for epilepsy surgery. Future studies with larger study samples would be necessary to confirm this finding and determine whether post-ECoG may be useful in some subsets of pediatric epilepsy surgery candidates.

The current diagnostic approach for mitochondrial disorders requires invasive procedures such as muscle biopsy and multiple biochemical testing but the results are often inconclusive. Clinical sequencing tests are available only for a limited number of genes. Recently, massively parallel sequencing has become a powerful tool for testing genetically heterogeneous conditions such as mitochondrial disorders.Targeted next-generation sequencing was performed on 26 patients with known or suspected mitochondrial disorders using in-solution capture for the exons of 908 known and candidate nuclear genes and an Illumina genome analyzer.None of the 18 patients with various abnormal respiratory chain complex (RCC) activities had molecular defects in either subunits or assembly factors of mitochondrial RCC enzymes except a reference control sample with known mutations in SURF1. Instead, several variants in known pathogenic genes including CPT2, POLG, PDSS1, UBE3A, SDHD, and a few potentially pathogenic variants in candidate genes such as MTO1 or SCL7A13 were identified.Sequencing only nuclear genes for RCC subunits and assembly factors may not provide the diagnostic answers for suspected patients with mitochondrial disorders. The present findings indicate that the diagnostic spectrum of mitochondrial disorders is much broader than previously thought, which could potentially lead to misdiagnosis and/or inappropriate treatment. Overall analytic sensitivity and precision appear acceptable for clinical testing. Despite the limitations in finding mutations in all patients, the present findings underscore the considerable clinical benefits of targeted next-generation sequencing and serve as a prototype for extending the clinical evaluation in this clinically heterogeneous patient group.

A 16-month-old girl with a history of Prader-Willi syndrome and progressive macrocephaly manifested large, bilateral, subdural hemorrhages of differing ages on magnetic resonance imaging. Subsequent evaluation revealed a deficiency of von Willebrand factor, but after repeated evaluations, no conclusive evidence of nonaccidental trauma became apparent. Subdural hemorrhages of varying ages are frequently associated with nonaccidental trauma during early childhood. However, several uncommon conditions may present as subdural hemorrhages and thus mimic nonaccidental trauma. Our patient demonstrates a combination of Prader-Willi syndrome, von Willebrand factor deficiency, and enlargement of the extra-axial spaces. All of these in isolation were associated with subdural hemorrhages. We review the scant literature on subdural hemorrhages in Prader-Willi syndrome and other conditions that mimic nonaccidental trauma.

Organ transplantation in multisystemic mitochondrial cytopathies is usually not performed because of perceived untoward complications. We report three patients with demonstrated oxidative phosphorylation defects and dilated cardiomyopathy who underwent cardiac transplant. All three patients tolerated immunosuppression medications and have had an excellent long-term outcome. Our results suggest that with proper patient selection in this population, cardiac transplantation is feasible and can have good outcomes.

The authors describe their experience with functional MR (fMR) imaging in children as young as 5 years of age, or even younger in developmental age equivalent. Functional MR imaging can be useful for identifying eloquent cortex prior to surgical intervention. Most fMR imaging clinical work has been done in adults, and although children as young as 8 years of age have been included in larger clinical series, cases in younger children are rarely reported.The authors reviewed presurgical fMR images in eight patients who were 8 years of age or younger, six of whom were 5 or 6 years of age. Each patient had undergone neuropsychological testing. Three patients functioned at a below-average level, with adaptive functioning age scores of 3 to 4 years. Self-paced finger tapping (with passive movement in one patient) and silent language tasks were used as activation tasks. The language task was modified for younger children, for whom the same (not novel) stimuli were used for extensive practice ahead of time and in the MR imaging unit. Patient preparation involved techniques such as having experienced staff present to work with patients and providing external management during imaging. Six of eight patients had extensive training and practice prior to the procedure. In the two youngest patients, this training included use of a mock MR unit.All cases yielded successful imaging. Finger tapping in all seven of the patients who could perform it demonstrated focal motor activation in the frontal-parietal region, with expected activation elsewhere, including in the cerebellum. Three of four patients had the expected verb generation task activations, with left-hemisphere dominance, including a 6-year-old child who functioned at the 3-year, 9-month level. The only child (an 8-year-old) who was not prepared prior to the imaging session for the verb generation task failed this task due to movement artifact.Despite the challenges of successfully using fMR imaging in very young and clinically involved patients, these studies can be performed successfully in children with a chronological age of 5 or 6 years and a developmental age as young as 3 or 4 years.

Investigate whether patients on vigabatrin demonstrated new-onset and reversible T(2)-weighted magnetic resonance imaging (MRI) abnormalities.MRI of patients treated during vigabatrin therapy was reviewed, following detection of new basal ganglia, thalamus, and corpus callosum hyperintensities in an infant treated for infantile spasms. Patients were assessed for age at time of MRI, diagnosis, duration, and dose, MRI findings pre-, on, and postvigabatrin, concomitant medications, and clinical correlation. These findings were compared to MRI in patients with infantile spasms who did not receive vigabatrin.Twenty-three patients were identified as having MRI during the course of vigabatrin therapy. After excluding the index case, we detected new and reversible basal ganglia, thalamic, brainstem, or dentate nucleus abnormalities in 7 of 22 (32%) patients treated with vigabatrin. All findings were reversible following discontinuation of therapy. Diffusion-weighted imaging (DWI) was positive with apparent diffusion coefficient (ADC) maps demonstrating restricted diffusion. Affected versus unaffected patients, respectively, had a median age of 11 months versus 5 years, therapy duration 3 months versus 12 months, and dosage 170 mg/kg/day versus 87 mg/kg/day. All affected patients were treated for infantile spasms; none of 56 patients with infantile spasms who were not treated with vigabatrin showed the same abnormalities.MRI abnormalities attributable to vigabatrin, characterized by new-onset and reversible T(2)-weighted hyperintensities and restricted diffusion in thalami, globus pallidus, dentate nuclei, brainstem, or corpus callosum were identified in 8 of 23 patients. Young age and relatively high dose appear to be risk factors.

Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, time-dependent evolution of symptoms, overlapping phenotypes, and inconsistencies in muscle pathology findings, definitive diagnosis relies on the molecular finding of deleterious mutations. We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%). Two mutant alleles were identified in 31 unrelated index patients with autosomal recessive POLG-related disorders. Among them, 20 (67%) had Alpers syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients carrying one altered POLG allele were found. A total of 25 novel alterations were identified, including 6 null mutations. We describe the predicted structural/functional and clinical importance of the previously unreported missense variants and discuss their likelihood of being pathogenic. In conclusion, sequence analysis allows the identification of mutations responsible for POLG-related disorders and, in most of the autosomal recessive cases where two mutant alleles are found in trans, finding deleterious mutations can provide an unequivocal diagnosis of the disease.

Apnea as an isolated manifestation of seizures is well described in neonates but is only occasionally observed in infants. This article reports 3 infants presenting with apneic events as the main manifestation of seizure, documented by video electroencephalogram, all with mesial temporal lobe lesions. The 3 infants, after normal pregnancy and delivery at term, showed the first apnea at the age of 4 to 10 months. Although the interictal electroencephalogram result was often normal, ictal video electroencephalogram in all infants showed focal rhythmic discharges with or without generalization. Magnetic resonance imaging showed an inferior mesial temporal lobe mass lesion in all infants. All patients underwent lesion removal, and they are seizure free with normal psychomotor development.

The point mutation in the mitochondrial genome tRNALeu (A3243G) is associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). We report a boy presenting with respiratory compromise and hypercarbia owing to severe muscle weakness. Historically, he demonstrated idiopathic growth hormone deficiency, retarded bone age, and exercise avoidance. Owing to severe respiratory compromise out of proportion to expected recovery, a metabolic work-up was performed. Muscle biopsy demonstrated abnormal mitochondria structure and heteroplasmic A3243G mutation. Idiopathic growth hormone deficiency and retarded bone age have not been previously reported in MELAS, and these findings delayed testing for mitochondrial disease. This case demonstrates that isolated muscle weakness in the context of other organ system abnormalities should make the investigator consider MELAS. ( J Child Neurol 2006; 21: 77—79).

Awake craniotomy is a key tool in resection of lesions near critical functional regions, particularly the speech area. Craniotomy with an awake portion for mapping may be performed in carefully selected adolescents and preteenaged children. A number of different regimens may be used for sedation and anesthesia in these cases. We describe two adolescent patients in whom awake craniotomy was performed using an intravenous anesthesia technique with dexmedetomidine and without need for airway instrumentation.

Forty-three children less than 12 years of age having intractable seizures were treated with vagus nerve stimulation. Five children were monitored for12 months, 16 children for 12 to 17 months, and 22 children foror =18 months with overall median seizure reduction of 55%. Thirty-seven percent had at least 90% reduction. Vagus nerve stimulation was effective in children with generalized, mixed, and partial medically refractory seizures.

Object Imaging-guided surgery (IGS) systems are widely used in neurosurgical practice. During epilepsy surgery, the authors routinely use IGS landmarks to localize intracranial electrodes and/or specific brain regions. The authors have developed a technique to coregister these landmarks with pre- and postoperative scans and the Montreal Neurological Institute (MNI) standard space brain MRI to allow 1) localization and identification of tissue anatomy; and 2) identification of Brodmann areas (BAs) of the tissue resected during epilepsy surgery. Tracking tissue in this fashion allows for better correlation of patient outcome to clinical factors, functional neuroimaging findings, and pathological characteristics and molecular studies of resected tissue. Methods Tissue samples were collected in 21 patients. Coordinates from intraoperative tissue localization were downloaded from the IGS system and transformed into patient space, as defined by preoperative high-resolution T1-weighted MRI volume. Tissue landmarks in patient space were then transformed into MNI standard space for identification of the BAs of the tissue samples. Results Anatomical locations of resected tissue were identified from the intraoperative resection landmarks. The BAs were identified for 17 of the 21 patients. The remaining patients had abnormal brain anatomy that could not be meaningfully coregistered with the MNI standard brain without causing extensive distortion. Conclusions This coregistration and landmark tracking technique allows localization of tissue that is resected from patients with epilepsy and identification of the BAs for each resected region. The ability to perform tissue localization allows investigators to relate preoperative, intraoperative, and postoperative functional and anatomical brain imaging to better understand patient outcomes, improve patient safety, and aid in research.

We report a 6-week-old boy with meperidine neurotoxicity. What distinguished our patient from those previously reported was his minimal exposure to therapeutic doses of meperidine in the setting of normal renal function, and no history of sickle cell anemia, cancer, hepatitis, or cirrhosis. In addition, our patient had no abnormal changes in the electroencephalogram during the event. After only 2 doses of meperidine, he exhibited acute orofacial dyskinesias consisting of tongue thrusting, lip pursing, and facial grimacing combined with prominent flexion of the arms and stiffening of his legs. However, a normal sucking response remained. His symptoms resolved over the next 36 hours and did not respond to naloxone. We believe that this unique presentation of meperidine-induced neurotoxicity may be due to changes in the basal ganglia resulting from perinatal hypoxemia.

Purpose To review our cohort of patients with Dravet syndrome and determine if patients with SCN1A mutations can also express mitochondrial disease due to electron transport chain dysfunction. Methods A retrospective chart review was used to describe clinical manifestations and retrieve biochemical testing, neuroimaging, gene sequencing, and electroencephalographic results of patients expressing both mitochondrial disease and Dravet syndrome. Results Two children were found to have pathological mutations in the SCN1A gene and defects in mitochondrial electron transport chain complex activity. Both developed early febrile and medically intractable afebrile seizures with resulting neurocognitive decline. In the first patient, a muscle biopsy demonstrated complex IV dysfunction and in the second patient, complex III dysfunction. Patient 1 had more difficult to control seizures, and had features consistent with severe autism. Patient 2, who had earlier control and less severe seizures, did not have features of autism. Patient 1 had SCN1A missense mutation, c. 3734 G>A and patient 2 had a mutation, c. 3733 C>T, which produces a truncation mutation. Conclusion Our two patients underscore the need to rule out possible co-morbid mitochondrial disease and Dravet syndrome. The treatment of seizures for each is different, with valproic acid being first line treatment in Dravet syndrome and contraindicated in many mitochondrial diseases, due to possible induction of liver failure and death. Failure to pursue complete diagnostic evaluation might influence medication choice, possible seizure control, and developmental outcomes.

A B S T R A C T Purpose: To determine the efficacy of the Modified Atkins Diet (MAD) and Ketogenic Diet (KD) in seizure control within a population of myoclonic-astatic epilepsy (MAE) patients. Methods: This was a retrospective, single center study evaluating the seizure control by high fat diets. Seizure diaries kept by the parents performed seizure counts. All patients met the clinical criteria for MAE. Results: Nine patients met the clinical criteria. We found that both the MAD and KD were efficacious in complete seizure control and allowed other medications to be stopped in seven patients. Two patients had greater than 90% seizure control without medications, one on the KD and the other on the MAD. Seizure freedom has ranged from 13 to 36 months, and during this time four patients have been fully weaned off of diet management. One patient was found to have a mutation in SLC2A1. Conclusion: Our results suggest that strictly defined MAE patients respond to the MAD with prolonged seizure control. Some patients may require the KD for seizure freedom, suggesting a common pathway of increased requirement for fats. Once controlled, those fully responsive to the Diet(s) could be weaned off traditional seizure medications and in many, subsequently off the MAD or KD.