SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy.

OBJECTIVE: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. METHODS: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. RESULTS: We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). CONCLUSIONS: SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.

Somatic GNAQ mutation in the forme fruste of Sturge-Weber syndrome.

OBJECTIVE: To determine whether the GNAQ R183Q mutation is present in the forme fruste cases of Sturge-Weber syndrome (SWS) to establish a definitive molecular diagnosis. METHODS: We used sensitive droplet digital PCR (ddPCR) to detect and quantify the GNAQ mutation in tissues from epilepsy surgery in 4 patients with leptomeningeal angiomatosis; none had ocular or cutaneous manifestations. RESULTS: Low levels of the GNAQ mutation were detected in the brain tissue of all 4 cases-ranging from 0.42% to 7.1% frequency-but not in blood-derived DNA. Molecular evaluation confirmed the diagnosis in 1 case in which the radiologic and pathologic data were equivocal. CONCLUSIONS: We detected the mutation at low levels, consistent with mosaicism in the brain or skin (1.0%-18.1%) of classic cases. Our data confirm that the forme fruste is part of the spectrum of SWS, with the same molecular mechanism as the classic disease and that ddPCR is helpful where conventional diagnosis is uncertain.

Sensitive quantitative detection of somatic mosaic mutation in "double cortex" syndrome.

Somatic mutation of the lissencephaly-1 gene is a cause of subcortical band heterotopia ("double cortex"). The severity of the phenotype depends on the level of mutation in brain tissue. Detecting and quantifying low-level somatic mosaic mutations is challenging. Here, we utilized droplet digital PCR, a sensitive method to detect low-level mutation. Droplet digital PCR was used in concert with classic genotyping techniques (SNaPshot assays and pyrosequencing) to detect and characterize the tissue mosaicism of a somatic mutation (LIS1 c.190A>T; p.K64X) in a patient with posterior bilateral SBH and refractory epilepsy. The high sensitivity of droplet digital PCR and the ability to target individual DNA molecules allowed us to detect the mutation at low level in the brain, despite the low quality of the DNA sample derived from formalin-fixed paraffin-embedded tissue. This low mutation frequency in the brain was consistent with the relatively subtle malformation resolved by magnetic resonance imaging. The presence of the mutation in other tissues from the patient permitted us to predict the timing of mutagenesis. This sensitive methodology will have utility for a variety of other brain malformation syndromes associated with epilepsy for which historical pathological specimens are available and specific somatic mosaic mutations are predicted.

Fatal Cerebral Edema With Status Epilepticus in Children With Dravet Syndrome: Report of 5 Cases.

Dravet syndrome (DS) is a well-recognized developmental and epileptic encephalopathy associated with SCN1A mutations and 15% mortality by 20 years. Although over half of cases succumb to sudden unexpected death in epilepsy, the cause of death in the remainder is poorly defined. We describe the clinical, radiologic, and pathologic characteristics of a cohort of children with DS and SCN1A mutations who developed fatal cerebral edema causing mass effect after fever-associated status epilepticus. Cases were identified from a review of children with DS enrolled in the Epilepsy Genetics Research Program at The University of Melbourne, Austin Health, who died after fever-associated status epilepticus. Five children were identified, all of whom presented with fever-associated convulsive status epilepticus, developed severe brain swelling, and died. All had de novo SCN1A mutations. Fever of 40°C or greater was measured in all cases. Signs of brainstem dysfunction, indicating cerebral herniation, were first noted 3 to 5 days after initial presentation in 4 patients, though were apparent as early as 24 hours in 1 case. When MRI was performed early in a patient's course, focal regions of cortical diffusion restriction were noted. Later MRI studies demonstrated diffuse cytotoxic edema, with severe cerebral herniation. Postmortem studies revealed diffuse brain edema and widespread neuronal damage. Laminar necrosis was seen in 1 case. Cerebral edema leading to fatal brain herniation is an important, previously unreported sequela of status epilepticus in children with DS. This potentially remediable complication may be a significant contributor to the early mortality of DS.

Magnetic resonance imaging features of gemistocytic astrocytoma.

INTRODUCTION: Gemistocytic astrocytoma is the second most common subtype of World Health Organization grade 2 astrocytoma, but has a worse prognosis than other grade 2 lesions. We aim to describe the MR imaging features of histopathologically proven gemistocytic tumours. METHODS: Ethics approval was obtained from both institutions. Patient consent was not required for this retrospective study. We reviewed MR imaging findings of 16 consecutive cases of histopathologically proven gemistocytic astrocytoma and anaplastic astrocytoma with gemistocytic features. RESULTS: Average patient age was 48 years, with a 3:1 male to female ratio. Based on our series, the typical appearance of a gemistocytic astrocytoma is a large, heterogeneous mass most commonly supratentorial and lobar. Regions of cyst formation, partial signal suppression on FLAIR images and contrast enhancement are all common features. Additionally, contrary to previous literature that describes gemistocytic astrocytoma as a purely supratentorial lesion, we present two cases of gemistocytic astrocytoma involving the brainstem. CONCLUSIONS: The possibility of gemistocytic astrocytoma should be considered in patients presenting with large heterogeneous tumours that have regions of cyst formation, partial FLAIR suppression and contrast enhancement. This may be especially useful in reconciling a lesion with high-grade MR imaging features with low-grade histopathology. An infratentorial location does not preclude the diagnosis of gemistocytic astrocytoma.

Myoclonic occipital photosensitive epilepsy with dystonia (MOPED): A familial epilepsy syndrome.

PURPOSE: To describe clinical and EEG phenotypes of a family with an unusual familial epilepsy syndrome characterized by myoclonus and dystonia. METHODS: Family members underwent electroclinical phenotyping including review of EEGs and MRI. DNA from family members was genotyped using Illumina OmniExpress genotyping arrays. Parametric and nonparametric linkage analyses were performed using MERLIN. RESULTS: The disorder followed autosomal dominant (AD) inheritance and affected seven individuals over two generations. Seizures began at a mean of 14.5 years. Six individuals had spontaneous myoclonic seizures, of which five also had photic-induced myoclonus and four had photic-induced occipital seizures. Six individuals had convulsive seizures; generalized in two and focal in four. Photosensitivity was prominent with generalized spike wave and polyspike wave in four individuals of which two also had occipital spikes. MRI scans were normal in the four individuals tested. Extensive metabolic investigation was normal. Juvenile myoclonic epilepsy (JME) occurred in two; and JME overlapping with idiopathic photosensitive epilepsy (IPOE) in four individuals. All three affected males had a more severe disorder than the four affected females. Two males had a progressive neurological disorder with progressive myoclonus epilepsy and deterioration in their early 30s. They developed episodes of paroxysmal cervical dystonia with cognitive decline during periods of poor seizure control. One plateaued after years of poor seizure control but remained intractable with periods of deterioration. The other deteriorated with episodes of status dystonicus and status epilepticus, ataxia and a progressive ophthalmoplegia before succumbing at 38 years. Parametric linkage analysis identified three peaks achieving a maximum LOD score of 1.21. Nonparametric analysis identified eight peaks achieving LOD scores above 0.80. These were not statistically significant. CONCLUSIONS: This is a novel autosomal dominant familial epilepsy syndrome. "Myoclonic occipital photosensitive epilepsy with dystonia" (MOPED) involves a spectrum of phenotypes from JME, sometimes with an IPOE overlap, to progressive myoclonus epilepsy with paroxysmal dystonia.

The surgically remediable syndrome of epilepsy associated with bottom-of-sulcus dysplasia.

OBJECTIVE: To determine clinical and EEG features that might help identify patients with epilepsy harboring small, intrinsically epileptogenic, surgically treatable, bottom-of-sulcus dysplasias (BOSDs). METHODS: Retrospective review of clinical records, EEG, MRI, and histopathology in 32 patients with drug-resistant epilepsy and MRI-positive (72% 3.0 tesla), pathologically proven (type 2B cortical dysplasia) BOSDs operated at our centers during 2005-2013. RESULTS: Localization of BOSDs was frontal in 19, insula in 5, parietal in 5, and temporal in 3, on the convexity or interhemispheric surfaces. BOSDs were missed on initial MRI at our centers in 22% of patients. Patients presented with focal seizures during infancy in 9, preschool years in 15, and school years in 8 (median age 5 years). Seizures were stereotyped, predominantly nocturnal, and typically nonconvulsive, with semiology referable to the fronto-central or perisylvian regions. Seizures occurred at high frequency during active periods, but often went into prolonged remission with carbamazepine or phenytoin. Intellect was normal or borderline, except in patients with seizure onset during infancy. Scalp EEG frequently revealed localized interictal epileptiform discharges and ictal rhythms. Patients underwent lesionectomy (median age 14 years) guided by electrocorticography and MRI, with prior intracranial EEG monitoring in only one patient. Twenty-eight patients (88%) became seizure-free, and 20 discontinued antiepileptic medication (median follow-up 4.1 years). CONCLUSIONS: In patients with cryptogenic focal epilepsy, this clinical presentation and course should prompt review of or repeat MRI, looking for a BOSD in the frontal, parietal, or insula cortex. If a BOSD is identified, the patient might be considered for single-stage lesionectomy.

Radiation induced malignant peripheral nerve sheath tumour of the second cervical nerve.

We report a 44-year-old with progressive quadriparesis due to a dumbbell malignant peripheral nerve sheath tumour (MPNST) of the second cervical nerve, 17 years after whole brain radiotherapy for a pineal germinoma. To our knowledge this is the first case of radiation induced high cervical MPNST arising from a benign neurofibroma.

Is focal cortical dysplasia sporadic? Family evidence for genetic susceptibility.

Focal cortical dysplasia is a common cortical malformation and an important cause of epilepsy. There is evidence for shared molecular mechanisms underlying cortical dysplasia, ganglioglioma, hemimegalencephaly, and dysembryoplastic neuroepithelial tumor. However, there are no familial reports of typical cortical dysplasia or co-occurrence of cortical dysplasia and related lesions within the same pedigree. We report the clinical, imaging, and histologic features of six pedigrees with familial cortical dysplasia and related lesions. Twelve patients from six pedigrees were ascertained from pediatric and adult epilepsy centers, eleven of whom underwent epilepsy surgery. Pedigree data, clinical information, neuroimaging findings, and histopathologic features are presented. The families comprise brothers with focal cortical dysplasia, a male and his sister with focal cortical dysplasia, a female with focal cortical dysplasia and her brother with hemimegalencephaly, a female with focal cortical dysplasia and her female first cousin with ganglioglioma, a female with focal cortical dysplasia and her male cousin with dysembryoplastic neuroepithelial tumor, and a female and her nephew with focal cortical dysplasia. This series shows that focal cortical dysplasia can be familial and provides clinical evidence suggesting that cortical dysplasia, hemimegalencephaly, ganglioglioma, and dysembryoplastic neuroepithelial tumors may share common genetic determinants.

Lymphoma of the trigeminal nerve--the need for histological diagnosis.

CNS lymphoma involving the trigeminal nerve is a rare condition which presents as a cavernous sinus lesion. It may mimic the radiological appearance of other lesions, and biopsy is essential before considering empirical radiotherapy for lesions in this region. We report the radiological, histopathological and operative findings of a primary non Hodgkin B cell lymphoma involving the trigeminal nerve.

Long-term seizure outcome and risk factors for recurrence after extratemporal epilepsy surgery.

PURPOSE: We aimed to assess long-term seizure outcome and risk factors for seizure recurrence in a cohort of patients who have undergone extratemporal resection for management of refractory seizures. METHODS: Eighty-one patients underwent extratemporal resection at Austin Health, Melbourne, Australia (1991-2004). Seizure recurrence was any postoperative disabling seizure (complex partial seizure [CPS] ± secondary generalization). Multivariate Cox proportional hazards regression models examined potential preoperative and perioperative risk factors and the risk associated with early postoperative seizures (≤ 28 days postsurgery). The change between preoperative and postoperative seizure frequency was also measured. KEY FINDINGS: Median follow-up was 10.3 years (range 1-17.7). The probabilities of freedom from disabling seizures (on or off antiepileptic medication) were 40.7% (95% confidence interval [CI] 30-51) at 1 month, 23.5% (95% CI 15-33) at 1 year, and 14.7% (95% CI 8-23) at 5 years postoperative. Reduction of disabling seizures to at least 20% of preoperative frequency was attained by 57% of patients at 5 postoperative years. Of the preoperative/perioperative factors, focal cortical dysplasia (FCD) type 1 (hazard ratio [HR] 1.90, 95% CI 1.08-3.34, p = 0.025) and incomplete resection (HR 1.71, 95% CI 1.06-2.76, p = 0.028) were independent recurrence risks. After surgery, an early postoperative seizure was the only factor associated with higher risk (HR 4.28 [2.42-7.57], p = 0.00). SIGNIFICANCE: Distinction between subtypes of focal cortical dysplasia, which can be made using magnetic resonance imaging (MRI) criteria, may be useful for preoperative prognostication. Early seizures after surgery are not benign and may be markers of factors that contribute to seizure recurrence. Most patients achieve substantial reduction in seizure frequency. Further study of the significance of this reduction in terms of surgical "success" or otherwise is required.

Small temporal pole encephaloceles: a treatable cause of "lesion negative" temporal lobe epilepsy.

Epilepsy due to encephaloceles of the temporal pole may be an under recognized, treatable cause of refractory temporal lobe epilepsy (TLE). We describe three adult patients initially labeled "lesion negative" TLE. In all, video­electroencephalography (EEG) revealed ictal theta in the left temporal region and positron emission tomography (PET) showed temporal lobe hypometabolism, but neuropsychology revealed preserved verbal memory. Close inspection of structural magnetic resonance imaging (MRI) suggested subtle abnormalities at the tip of the left temporal lobe. High resolution computed tomography (CT) confirmed bony defects in the inner table of the skull. 3T MRI with fine coronal and sagittal slices indicated cerebrospinal fluid (CSF) and brain tissue protruding into the defects. All proceeded to resection of the temporal tip and became seizure free. Patients with "lesion negative" TLE should have careful review of images covering the temporal pole. If encephalocele is suspected, further imaging with high-resolution CT and MRI can be helpful. Temporal polar resection, sparing mesial structures, appears to be curative.

A phase II trial of primary temozolomide in patients with grade III oligodendroglial brain tumors.

Glial tumors with oligodendroglial components are considered chemo-responsive. Forty newly diagnosed patients (11 anaplastic oligodendrogliomas [OD] and 29 anaplastic oligoastrocytomas [OA]) were enrolled into this multicenter, open-label, single-arm Phase II trial of first-line temozolomide (200 mg/m(2) on days 1-5 every 4 weeks for 6 cycles). The primary endpoint was 6-month progression-free survival (PFS) with response rate (RR), median PFS, and median overall survival (OS) as secondary endpoints. Of 39 evaluable patients at the 6-month time point (median follow-up, 34 months), 6-month PFS was 77% (95% confidence interval [CI], 74.5%-79.3%). There were 15 complete responses (CRs, 38%), 6 partial responses (PRs, 15%), and 9 disease stabilization (23%). The median PFS was 21 months (95% CI, 3-39 months), and the median OS was 43 months (95% CI, 20-66 months). Chromosome 1p/19q codeletions were seen in 47% (18 of 38) of the patients, and O-6-methylguanine-DNA-methyltransferase (MGMT) methylation was seen in 48% (10 of 21) of the patients. All patients with OD showed MGMT methylation and most (71%) had chromosome 1p/19q codeletions. Conversely, fewer patients with OA showed MGMT methylation (23%) or had chromosome 1p/19q codeletions (31%). The presence of either 1p/19q codeletion or MGMT methylation was associated with increased RR at 6 months but not with improved PFS or OS. Only 18% of the patients (7 of 40) experienced treatment-related grade 3/4 toxicities. This regimen was active and well tolerated. These data add to the growing body of data showing that primary chemotherapy may be an acceptable alternative to radiotherapy for patients with gliomas containing oligodendroglial histology.

Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis.

Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive disorder with the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy associated with storage material in the brain. Here, we employed a novel combination of molecular strategies to find the responsible gene and show its effects in an animal model. Utilizing only three unrelated affected individuals and their relatives, we used homozygosity mapping with single-nucleotide polymorphism chips to localize AMRF. We then used microarray-expression analysis to prioritize candidates prior to sequencing. The disorder was mapped to 4q13-21, and microarray-expression analysis identified SCARB2/Limp2, which encodes a lysosomal-membrane protein, as the likely candidate. Mutations in SCARB2/Limp2 were found in all three families used for mapping and subsequently confirmed in two other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein. Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes. This study highlights that recessive genes can be identified with a very small number of subjects. The ancestral lysosomal-membrane protein SCARB2/LIMP-2 is responsible for AMRF. The heterogeneous pathology in the kidney and brain suggests that SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies.

Prolonged interval between sentinel pseudotumoral demyelination and development of primary CNS lymphoma.

Primary central nervous system lymphoma (PCNSL) can be associated with preceding demyelinating pseudotumoral brain lesions. The 'sentinel' demyelinating lesions recede spontaneously or with corticosteroid, and are followed by development of PCNSL typically within 12 months. This report describes a 29 year-old post-partum woman who developed PCNSL 4 years after a biopsy-proven pseudotumoral demyelinating episode. She presented with focal seizures in February 2005. She subsequently developed hemiparesis and raised intracranial pressure. MRI showed two contrast enhancing lesions in the right frontal lobe, which were hypermetabolic on (18)F-FDG PET. A provisional diagnosis of tumefactive multiple sclerosis was made. Symptoms recurred despite multiple courses of high dose corticosteroid. Brain biopsy confirmed large B-cell non-Hodgkin's lymphoma. This patient illustrates the importance of considering PCNSL in patients presenting with a space-occupying lesion, even with previously confirmed demyelination, and that the interval between the two events may be several years.

An unusual case of tumor-to-cavernoma metastasis. A case report and literature review.

BACKGROUND: Metastases of systemic neoplasia to preexisting intracranial mass lesions are uncommon phenomena. Tumor-to-intracranial cavernoma metastases are even more unusual and rarely reported. We describe here a case of melanoma to intracranial cavernoma metastasis. CASE DESCRIPTION: A 39-year-old woman presented after an episode of generalized tonic-clonic seizure on a background of infrequent epilepsy. She was found to have a left parieto-occipital hemorrhagic lesion on imaging studies. The lesion was surgically removed and histopathology showed a metastatic melanoma within a cavernoma. CONCLUSION: This case report represents the third recorded case of tumor-to-intracranial cavernoma metastasis and the first melanoma to intracranial cavernoma metastasis. An extensive literature review of tumor-to-intracranial tumor metastases was conducted and disclosed an increase in reporting of the uncommon phenomenon of metastasis into preexisting intracranial lesions. It should therefore be considered as a differential diagnosis in patients with history of systemic cancer who present with progression of preexistent intracranial lesions.

Long-term seizure outcome following surgery for dysembryoplastic neuroepithelial tumor.

OBJECT: Resection of dysembryoplastic neuroepithelial tumor (DNET) is thought to result in favorable seizure outcome, but long-term follow-up data are scarce. The authors present a review of 18 patients who underwent surgical removal of a DNET: 12 via temporal lobectomy and six via lesionectomy. METHODS: The mean long-term follow up was 10.8 years (median 10.4 years, range 7.8 to 14.8 years), and results obtained during this time period were compared with previously reported short-term (mean 2.7 years) seizure outcome data. In the current study, 66.7% patients had an Engel Class I outcome and 55.6% had an Engel Class IA outcome compared with 77.8% and 55.6%, respectively. Temporal lobectomy (Engel Class I, 83.3%; Engel Class IA, 66.7%) led to a better seizure outcome than lesionectomy (Engel Classes I and IA, 33.3%). Two patients (11.1%) required repeated operation and both had an incomplete lesionectomy initially. CONCLUSIONS: Results indicated that complete resection of a DNET leads to a favorable seizure outcome, with epilepsy cure in those who had experienced early postoperative seizure relief. Long-term seizure outcome after surgery is predictable based on the result of short-term follow up.