Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. We identified a series of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical history, seizure types and frequency, antiepileptic drugs, cognitive, social and functional outcome and results of investigations. A systematic neuropathology study was performed, with post-mortem material from three adult cases with Dravet syndrome, in comparison with controls and a range of relevant paediatric tissue. Twenty-two adults with Dravet syndrome, 10 female, were included, median age 39 years (range 20–66). SCN1A structural variation was found in 60% of the adult Dravet patients tested, including one post-mortem case with DNA extracted from brain tissue. Novel mutations were described for 11 adult patients; one patient had three SCN1A mutations. Features of Dravet syndrome in adulthood include multiple seizure types despite polytherapy, and age-dependent evolution in seizure semiology and electroencephalographic pattern. Fever sensitivity persisted through adulthood in 11 cases. Neurological decline occurred in adulthood with cognitive and motor deterioration. Dysphagia may develop in or after the fourth decade of life, leading to significant morbidity, or death. The correct diagnosis at an older age made an impact at several levels. Treatment changes improved seizure control even after years of drug resistance in all three cases with sufficient follow-up after drug changes were instituted; better control led to significant improvement in cognitive performance and quality of life in adulthood in two cases. There was no histopathological hallmark feature of Dravet syndrome in this series. Strikingly, there was remarkable preservation of neurons and interneurons in the neocortex and hippocampi of Dravet adult post-mortem cases. Our study provides evidence that Dravet syndrome is at least in part an epileptic encephalopathy.

Simple and complex forms of dysembryoplastic neuroepithelial tumors (DNTs) are readily recognizable but forms with diffuse growth pattern, and hybrid tumors, that is, mixed DNT and ganglioglioma (DNT/GG), are more contentious entities. Rare DNTs have shown aggressive behavior. We reviewed cortical growth patterns, immunophenotype (including CD34, nestin and calbindin), genetic profile, and outcome in 101 DNT in adults. Simple (n = 18), complex (n = 31), diffuse (n = 35) DNT, and mixed DNT/GG (n = 17) showed no difference in age of onset, associated seizure type, or outcome (67.5% free from seizure; mean follow-up, 6 years). CD34 was seen in 61%, calbindin in 57%, and nestin in 86% of all DNT types; these markers were less common in simple DNT. Peritumoral cortical changes (Layer I hypercellularity [61%], satellite nodules [51.6%]) were frequent, but dyslamination (cortical dysplasia) was not identified. Molecular genetic abnormalities identified in 17 cases were IDH1 mutation (n = 3), 1p/19q loss (n = 10), isolated loss 9q (n = 2), and PTEN loss (n = 3), which were not associated with tumor type or location, higher cell proliferation, or distinguishing clinical features (mean age of epilepsy onset, 9 years; age at surgery = 31 years; 69% free from seizure); none had progression on magnetic resonance imaging (mean follow-up, 6 years). No single feature was predictive of seizure-free outcome, but there was a trend for better outcome in CD34-positive tumors (p = 0.07). One case has shown transformation to a higher grade. This study supports the existence of a range of subtypes of DNT some with overlapping features with ganglioglioma; molecular genetic abnormalities were not predictive of atypical behavior.

Summary Purpose:  Around one‐third of patients undergoing temporal lobe surgery for the treatment of intractable temporal lobe epilepsy with hippocampal sclerosis (HS) fail to become seizure‐free. Identifying reliable predictors of poor surgical outcome would be helpful in management. Atypical patterns of HS may be associated with poorer outcomes. Our aim was to identify atypical HS cases from a large surgical series and to correlate pathology with clinical and outcome data. Methods:  Quantitative neuropathologic evaluation on 165 hippocampal surgical specimens and 21 control hippocampi was carried out on NeuN‐stained sections. Neuronal densities (NDs) were measured in CA4, CA3, CA2, and CA1 subfields. The severity of granule cell dispersion (GCD) was assessed. Results:  Comparison with control ND values identified the following patterns based on the severity and distribution of neuronal loss: classical HS (CHS; n = 60) and total HS (THS; n = 39). Atypical patterns were present in 30% of cases, including end‐folium sclerosis (EFS; n = 5), CA1 predominant pattern (CA1p; n = 9), and indeterminate HS (IHS, n = 35). No HS was noted in 17 cases. Poorest outcomes were noted for no‐HS, and CA1p groups with 33–44% International League Against Epilepsy (ILAE) class I at up to 2 years follow‐up compared to 69% for CHS (p < 0.05). GCD associated with HS type (p < 0.01), but not with outcome. Conclusions:  These findings support the identification and delineation of atypical patterns of HS using quantitative methods. Atypical patterns may represent distinct clinicopathologic subtypes and may have predictive value following epilepsy surgery.

The long-term pathological effects of chronic epilepsy on normal brain ageing are unknown. Previous clinical and epidemiological studies show progressive cognitive decline in subsets of patients and an increased prevalence of Alzheimer's disease in epilepsy. In a post-mortem series of 138 patients with long-term, mainly drug-resistant epilepsy, we carried out Braak staging for Alzheimer's disease neurofibrillary pathology using tau protein immunohistochemistry. The stages were compared with clinicopathological factors, including seizure history and presence of old traumatic brain injury. Overall, 31% of cases were Braak Stage 0, 36% Stage I/II, 31% Stage III/IV and 2% Stage V/VI. The mean age at death was 56.5 years and correlated with Braak stage (P < 0.001). Analysis of Braak stages within age groups showed a significant increase in mid-Braak stages (III/IV), in middle age (40–65 years) compared with data from an ageing non-epilepsy series (P < 0.01). There was no clear relationship between seizure type (generalized or complex partial), seizure frequency, age of onset and duration of epilepsy with Braak stage although higher Braak stages were noted with focal more than with generalized epilepsy syndromes (P < 0.01). In 30% of patients, there was pathological evidence of traumatic brain injury that was significantly associated with higher Braak stages (P < 0.001). Cerebrovascular disease present in 40.3% and cortical malformations in 11.3% were not significantly associated with Braak stage. Astrocytic-tau protein correlated with the presence of both traumatic brain injury (P < 0.01) and high Braak stage (P < 0.001). Hippocampal sclerosis, identified in 40% (bilateral in 48%), was not associated with higher Braak stages, but asymmetrical patterns of tau protein accumulation within the sclerotic hippocampus were noted. In over half of patients with cognitive decline, the Braak stage was low indicating causes other than Alzheimer's disease pathology. In summary, there is evidence of accelerated brain ageing in severe chronic epilepsy although progression to high Braak stages was infrequent. Traumatic brain injury, but not seizures, was associated with tau protein accumulation in this series. It is likely that Alzheimer's disease pathology is not the sole explanation for cognitive decline associated with epilepsy.

Widespread changes involving neocortical and mesial temporal lobe structures can be present in patients with temporal lobe epilepsy and hippocampal sclerosis. The incidence, pathology, and clinical significance of neocortical temporal lobe sclerosis (TLS) are not well characterized. We identified TLS in 30 of 272 surgically treated cases of hippocampal sclerosis. Temporal lobe sclerosis was defined by variable reduction of neurons from cortical layers II/III and laminar gliosis; it was typically accompanied by additional architectural abnormalities of layer II, that is, abnormal neuronal orientation and aggregation. Quantitative analysis including tessellation methods for the distribution of layer II neurons supported these observations. In 40% of cases, there was a gradient of TLS with more severe involvement toward the temporal pole, possibly signifying involvement of hippocampal projection pathways. There was a history of a febrile seizure as an initial precipitating injury in 73% of patients with TLS compared with 36% without TLS; no other clinical differences between TLS and non-TLS cases were identified. Temporal lobe sclerosis was not evident preoperatively by neuroimaging. No obvious effect of TLS on seizure outcome was noted after temporal lobe resection; 73% became seizure-free at 2-year follow-up. In conclusion, approximately 11% of surgically treated hippocampal sclerosis is accompanied by TLS. Temporal lobe sclerosis is likely an acquired process with accompanying reorganizational dysplasia and an extension of mesial temporal sclerosis rather than a separate pathological entity.