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.

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.

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.

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.

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.

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.

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.

Early seizures after temporal lobectomy predict subsequent seizure recurrence.

Patients are understandably anxious if seizures occur immediately after temporal lobectomy. Such "neighborhood" seizures are commonly regarded as irrelevant to seizure outcome and discounted in outcome measurement. We conducted an in-depth examination of early postoperative seizures (<28 days) and outcome. The risk of recurrence at one postoperative year was calculated using Poisson regression, and statistical adjustments were made for preoperative pathology. Of 321 patients, 69 (22%) experienced early postoperative seizures. These early seizures were associated with subsequent seizure recurrence (rate ratio [RR] 5.9; 95% confidence interval [CI], 4.1-8.4). Among patients with early seizures, the only significant factor was the presence of seizure precipitants, which was associated with a lower recurrence risk. However, when compared with patients with no early seizures, those with precipitants to early seizures had a higher risk of recurrence (RR, 3.0; 95% CI, 1.8-5.2). The risk was higher again for patients without precipitants to early seizures (RR, 7.6; 95% CI, 5.0-11.5). Early seizures and other seizure recurrences in the first postoperative year did not differ in their effect on subsequent outcome (X(2) [3] = 3.4, p = 0.33). We conclude that early postoperative seizures are associated with subsequent seizure recurrence. These findings have implications for patient counseling and the measurement of outcome.

Glioneuronal tumours in neurofibromatosis type 1: MRI-pathological study.

Neurofibromatosis type 1 (NF1) is an inherited disorder in which affected individuals develop both benign and malignant tumours at an increased frequency. Glioneuronal tumours, such as ganglioglioma and dysembryoplastic neuroepithelial tumour, have been previously reported in patients with NF1. We describe two patients with glioneuronal tumours and typical clinical features of NF1. Molecular analysis of these tumours did not demonstrate loss of the NF1 gene by fluorescence in situ hybridization (FISH) or immunohistochemistry analysis, suggesting they might not be causally associated with gross defects in NF1 expression. Because of the excellent prognosis following the resection of these tumours, it is important to distinguish them from other NF1-associated tumours.

Subtle microscopic abnormalities in hippocampal sclerosis do not predict clinical features of temporal lobe epilepsy.

PURPOSE: Subtle microdysplastic features are found in some patients with hippocampal sclerosis (HS) and refractory temporal lobe epilepsy. The significance of these findings is unknown. We investigated their frequency, relation to the pattern of HS, and clinical associations. METHODS: One-hundred forty patients with histologically confirmed HS (mean age at operation, 35 years; 85 women) were analyzed. The presence of HS and subtle structural abnormalities (SSAs) in the mesial temporal lobe and in the lateral neocortical tissue was assessed in detail. Antecedents, seizure characteristics, two verbal memory tests, and outcome in HS patients with and without SSAs were determined. RESULTS: SSAs were found in 60 (43%) of the 140 HS patients, being mesial only in 32 of the 60 cases, and lateral only in nine cases; the remaining 19 cases had both mesial and lateral abnormalities. The frequency of SSA was not related to the pattern of HS or other tested variables. Prolonged febrile convulsions were present in 26 (44%) patients with SSAs, and in 26 (34%) patients (not significant) without SSAs. The outcome after surgery did not differ between patients with SSAs (incidence rate ratio for seizure recurrence, 0.9; 95% confidence interval, 0.5-1.6) compared with patients without SSAs (reference ratio, 1). CONCLUSIONS: Forty-three percent of HS patients have SSAs in their lobectomy specimens. The presence of SSAs does not predict clinical characteristics, such as presence of prolonged febrile convulsions, postsurgical outcome, or neuropsychological performance, nor does it correlate with the histologic pattern of HS.

Temporal lobe dysembryoplastic neuroepithelial tumour: significance of discordant interictal spikes.

PURPOSE: Dysembryoplastic neuroepithelial tumours (DNET) are an important cause of refractory partial epilepsies. They usually occur within dysplastic cortex and tend to affect the temporal lobes. The EEG of these patients is characterised by slowing and/or epileptiform abnormalities with a multifocal distribution. We studied the EEG features of epilepsy patients with a temporal lobe DNET to assess the relationship of EEG abnormalities with the localisation of the tumour and the clinical features. METHODS: We retrospectively reviewed 16 patients with unilateral, temporal lobe DNET on MRI. The EEG abnormalities were classified as concordant to the lesion when the EEG discharges were confined to the ipsilateral temporal lobe or discordant when EEG discharges were found in other areas. Clinical and epilepsy characteristics were compared between patients with concordant and discordant EEG. RESULTS: Focal EEG abnormalities were found in 81% of the patients; 6/16 patients had concordant EEG abnormalities, and 7/16 patients had discordant EEG abnormalities. Epilepsy severity prior to the operation, antecedents and post-operative outcome were not different between patients with concordant or discordant EEG abnormalities. CONCLUSION: Patients with temporal lobe DNET often show EEG discharges discordant to the tumour. However, they do not appear to predict the clinical and epilepsy characteristics of these patients.

Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence.

There is little information available relevant to long-term seizure outcome after anterior temporal lobectomy, particularly at extended postoperative periods. The aim of this study was an in-depth examination of patterns of longitudinal outcome and potential risk factors for seizure recurrence after lobectomy, utilizing a large patient sample with long follow-up. Included were 325 patients who underwent anterior temporal lobectomy between 1978 and 1998 (mean follow-up 9.6 +/- 4.2 years). Retrospective data were analysed using survival analysis and multivariate regression with Cox proportional hazard models. The probability of complete seizure freedom at 2 years post-surgery was 55.3% [95% confidence interval (CI) 50-61]; at 5 years, 47.7% (95% CI 42-53); and at 10 postoperative years it was 41% (95% CI 36-48). Patients with discrete abnormalities preoperatively (i.e. lesions and hippocampal sclerosis) had a significantly higher probability of seizure freedom than patients without obvious abnormality. The latter group had a pattern of recurrence similar to that in patients with lesions outside the area of excision. After adjustment for preoperative pathology, only the presence of preoperative secondarily generalized seizures had a significant association with recurrence [occasional preoperative generalized seizures, hazard ratio (HR) 1.6, 95% CI 1.1-2.3; frequent seizures, HR 2.0, 95% CI 1.4-2.9 compared with absence of preoperative generalized seizures]. Duration of preoperative epilepsy, age of seizure onset and age at surgery did not have an effect on outcome. Patients with two seizure-free postoperative years had a 74% (95% CI 66-81) probability of seizure freedom by 10 postoperative years. This late seizure recurrence was not associated with any identified risk factors. Specifically, patients with hippocampal sclerosis were not at higher risk. Surprisingly, complete discontinuation of anti-epileptic drugs (AEDs) after two postoperative years was not associated with an increased risk of recurrence (HR 1.03, 95% CI 0.5-2.1). This may be because selection of patients for AED discontinuation is biased towards those individuals perceived as 'low risk'. The results of this study indicate that the lack of an obvious abnormality or the presence of diffuse pathology, and preoperative secondarily generalized seizures are risk factors for recurrence after surgery. Late recurrence after initial seizure freedom is not a rare event; risk factors specific to this phenomenon are as yet unidentified.

Increased anterior temporal lobe T2 times in cases of hippocampal sclerosis: a multi-echo T2 relaxometry study at 3 T.

BACKGROUND AND PURPOSE: Increased T2 relaxation times in the ipsilateral hippocampus are present in patients with hippocampal sclerosis. Visual assessment of T2-weighted images of these patients suggests increased signal intensity in the anterior temporal lobe as well. Our aim was to assess hippocampal and anterior temporal T2 relaxation times in patients with partial epilepsy by using a new T2-relaxometry sequence implemented by using a 3-T General Electric imaging unit. METHODS: Coronal view T2 maps were generated by using an eight-echo Carr-Purcell-Meiboom-Gill sequence (TE, 28-231) with an acquisition time of 7 min on a 3-T General Electric Signa Horizon LX imaging unit. T2 relaxation times were measured in the hippocampus and anterior temporal lobe of 30 healthy control volunteers and 20 patients with partial epilepsy. RESULTS: For the 30 control volunteers, the mean hippocampal T2 relaxation time was 98 +/- 2.8 ms. In all measured areas, the asymmetry index was small (<0.01). For the 15 patients with independent evidence of hippocampal sclerosis established by visual, volumetric, and, when available, pathologic criteria, mean hippocampal T2 relaxation times were 118 +/- 7 ms (P <.0001) on the ipsilateral side and 101 +/- 4 ms (P =.005) on the contralateral side. The T2 values were also increased in the anterior temporal lobe (ipsilateral: 82 +/- 6 ms, P <.0001; contralateral: 79 +/- 6 ms, P =.01) as compared with the values for the control volunteers (75 +/- 3 ms). The five patients with focal cortical dysplasia had hippocampal T2 relaxation times that were not different from control values. CONCLUSION: T2 relaxometry at 3 T is feasible and useful and confirmed marked ipsilateral hippocampal signal intensity increase in patients with hippocampal sclerosis. Importantly, definite signal intensity change was also present in the anterior temporal lobe. T2 relaxometry is a sensitive means of identifying abnormalities in the hippocampus and other brain structures.

Hippocampal pathology in refractory temporal lobe epilepsy: T2-weighted signal change reflects dentate gliosis.

BACKGROUND: The MR and pathologic features of hippocampal sclerosis (HS) are well described and include volume decrease and T2-weighted signal increase for MRI, and neuron cell loss and gliosis for pathology. OBJECTIVE: To confirm the established correlation between hippocampal volumes and neuron cell counts, and to study the still controversial association between signal change and gliosis. METHODS: The authors studied 44 patients (22 men and 22 women; mean age at surgery, 37 years) with refractory temporal lobe epilepsy. Quantitative assessment of hippocampal volumes and T2 relaxometry, and neuron and glial cell count in the region CA1 and molecular layer of the dentate gyrus was performed. The proportion of glial fibrillary acidic protein (GFAP)-positive glial cells (reactive astrocytes) was indicated. RESULTS: In a stepwise regression, the ipsilateral hippocampal volume was predicted best by the neuron cell count in the dentate gyrus (p = 0.005, r = 0.4). Hippocampal T2 time, however, was predicted best by the glial cell count in the dentate gyrus (p = 0.01, r = 0.4). None of the other cell counts contributed to either model. In the dentate, 31% of the glial cells were reactive astrocytes, whereas in CA1, 5% were reactive. CONCLUSION: The results confirmed the correlation between hippocampal volumes and neuron cell counts. T2-weighted signal increase in the hippocampus was mainly influenced by gliosis in the dentate gyrus, where a high proportion of glial cells show abnormal activity. This activity may reflect changes important in the development of hippocampal epileptogenicity.