Pitt Niehusmann

Diagnostic Value of N-methyl-D-aspartate Receptor Antibodies in Women With New-Onset Epilepsy

BACKGROUND In women younger than 45 years, a new form of encephalitis associated with ovarian teratoma and presenting with seizures and psychiatric symptoms has been described. Most patients have antibodies to NR1/NR2 heteromers of the N-methyl-D-aspartate receptor (NMDAR). OBJECTIVE To assess the frequency and significance of antibodies to NMDAR in otherwise unexplained new-onset epilepsies in young women. DESIGN Prospective cohort study. SETTING University department of epileptology. PATIENTS From January 1, 2005, to June 30, 2007, we identified 19 female patients aged 15 to 45 years with unexplained new-onset epilepsy. In addition, we studied 61 cerebrospinal fluid-serum sample pairs from patients with other cryptogenic epilepsies and 11 cerebrospinal fluid-serum sample pairs from surgically treated patients with epilepsy with no evident encephalitic abnormalities. MAIN OUTCOME MEASURES Antibodies to NMDAR and characteristics of affected patients. RESULTS Five of the 19 patients had antibodies against NMDAR. These patients had diffuse cerebral dysfunction and seizure origins. Psychiatric symptoms and pleocytosis were significantly associated with this group of patients. The disease course was episodic, in part relapsing-remitting, with full recoveries either spontaneously or after corticosteroid or intravenous immunoglobulin treatments. Only 1 patient had a neoplasm (multiple neuroendocrine tumors that included the ovaries) identified to date. In the control series, one 22-year-old man with a cryptogenic, severely encephalopathic seizure disorder was NMDAR antibody positive, and he also recovered fully. CONCLUSIONS Anti-NMDAR encephalitis accounts for a relevant proportion of otherwise unexplained new-onset epilepsies. Patients harboring NMDAR antibodies usually have prominent psychiatric symptoms and pleocytosis, and they may develop hypoventilation. Anti-NMDAR encephalitis is not always paraneoplastic.

Simple and complex dysembryoplastic neuroepithelial tumors (DNT) variants: clinical profile, MRI, and histopathology

IntroductionDysembryoplastic neuroepithelial tumors (DNTs) are long-term epilepsy associated tumors subdivided into simple and complex variants. The purpose of this study was to relate different DNT components identified on magnetic resonance imaging (MRI) to histopathological features and to test the hypothesis that glial nodules as a histopathological feature of complex variants induce an occasional glioma misdiagnosis.MethodsClinical, MRI, and histopathologic features of DNTs operated between 1988 and 2008 were reviewed.ResultsFrom a total of 61 DNTs, 48 simple and 13 complex variants were identified. Multiple or single pseudocysts in a cortical/subcortical location with small cysts sometimes separated from the tumor represented the glioneuronal element and were found in all DNTs. FLAIR hyperintense tissue was found between pseudocysts but—in neocortical DNTs—also circumscript in deeper tumor parts. Calcification and hemorrhages in this location occurred in four of 13 complex variants, and one of these patients was also the only one with tumor growth. Patients with complex variants had earlier seizure onset, and complex variants were more often located outside the temporal lobe. Although complex variants represented a higher diagnostic challenge, misdiagnoses also occurred in simple variants. One of five of DNTs showed contrast enhancement, which varied on follow-up studies with enhancing parts becoming nonenhancing and vice versa.ConclusionThe glioneuronal element is readily identifiable on MRI and should be considered to support the DNT diagnosis. Complex DNT variants have a different clinical profile and a more variable histopathological and MRI appearance; however, misdiagnoses occasionally also occur in simple variants.

Focal cortical dysplasia type IIb: completeness of cortical, not subcortical, resection is necessary for seizure freedom.

Purpose:  Focal cortical dysplasia type IIb (FCD IIb) lesions are highly epileptogenic and frequently cause pharmacoresistant epilepsy. Complete surgical resection leads to seizure freedom in most cases. However, the term “complete” resection is controversial with regard to the necessity of performing resections of the subcortical zone, which is frequently seen in these lesions on magnetic resonance imaging (MRI).

Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus

Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo.

Cliniconeuropathologic correlations show astroglial albumin storage as a common factor in epileptogenic vascular lesions

Purpose:  Intracerebral vascular malformations including cavernous angiomas (CAs) and arteriovenous malformations (AVMs) are an important cause of chronic pharmacoresistant epilepsies. Little is known about the pathogenetic basis of epilepsy in patients with vascular malformations. Intracerebral deposits of iron‐containing blood products have been generally regarded as responsible for the strong epileptogenic potential of CAs. Here, we have analyzed whether blood–brain barrier (BBB) dysfunction and subsequent astrocytic albumin uptake, recently described as critical trigger of focal epilepsy, represent pathogenetic factors in vascular lesion–associated epileptogenesis.

In vivo mapping of hippocampal subfields in mesial temporal lobe epilepsy: Relation to histopathology

A particularly popular automated magnetic resonance imaging (MRI) hippocampal subfield mapping technique is the one described by Van Leemput et al. (2009: Hippocampus 19:549–557) that is currently distributed with FreeSurfer software. This method assesses the probabilistic locations of subfields based on a priori knowledge of subfield topology determined from high‐field MRI. Many studies have applied this technique to conventionally acquired T1‐weighted MRI data. In the present study, we investigated the relationship between this technique applied to conventional T1‐weighted MRI data acquired at 3 T and postsurgical hippocampal histology in patients with medically intractable mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS). Patients with mTLE (n = 82) exhibited significant volume loss of ipsilateral CA1, CA2‐3, CA4‐dentate gyrus (DG), subiculum, and fimbria relative to controls (n = 81). Histopathological analysis indicated that the most significant neuronal loss was observed in CA1, then CA4 and CA3, and more subtle neuronal loss in CA2, consistent with classical HS. Neuronal density of CA1 significantly correlated with MRI‐determined volume of CA1, and increasingly so with CA2‐3 and CA4–DG. Patients with increased HS based on histopathology had greater volume loss of the ipsilateral hippocampal regions on MRI. We conclude by suggesting that whilst time efficient and fully reproducible when applied to conventional single acquisition sequences, the use of the automated subfield technique described here may necessitate the application to multiacquisition high‐resolution MR sequences for accurate delineation of hippocampal subfields. Hum Brain Mapp 35:4718–4728, 2014.

Presence of human herpes virus 6 DNA exclusively in temporal lobe epilepsy brain tissue of patients with history of encephalitis.

Temporal lobe epilepsy (TLE) is frequently associated with mesial temporal sclerosis (MTS). Many etiologic aspects of TLE are still unresolved. Here, we aimed to analyze the presence of human herpes virus 6 (HHV‐6) DNA in distinct TLE pathologies. Nested polymerase chain reaction (PCR) in surgical tissue from 38 pharmacoresistant TLE patients and 10 autopsy controls revealed HHV‐6 DNA in 55.6% of the TLE patients with a history of encephalitis, involving MTS and gliotic hippocampi without substantial neurodegeneration, but not in lesion‐associated TLE or nonlesional MTS with or without a history of complex febrile seizures (CFS). HHV‐6 protein was present in only one patient’s tissue. Our data argue against HHV‐6 as a major local pathogenetic factor in MTS hippocampi after CFS. The high detection rate of HHV‐6 DNA suggests a potential pathogenetic role of HHV‐6 in TLE patients with a history of encephalitis.

Large-scale analysis of viral nucleic acid spectrum in temporal lobe epilepsy biopsies.

Chronic inflammatory processes are important promotors of temporal lobe epilepsy (TLE) development. Based on human herpesvirus 6 (HHV‐6) DNA detection in brain tissue from patients with TLE, an association of persistent viral infection with TLE has been discussed. Individual studies reported increased HHV‐6 DNA in patients with clinical signs of previous inflammatory brain reaction, that is, febrile seizures or meningoencephalitis. However, detection rates vary considerably between different studies. Here we performed a large‐scale analysis of viral DNA/RNA spectrum in high‐quality TLE biopsies. In addition to all Herpesviridae, we addressed potentially relevant neurotropic RNA viruses.

Hamartin Variants That Are Frequent in Focal Dysplasias and Cortical Tubers Have Reduced Tuberin Binding and Aberrant Subcellular Distribution In Vitro

Focal cortical dysplasia type IIb is characterized by epilepsy-associated malformations that are often composed of balloon cells and dysplastic neurons. There are many histopathologic similarities between focal cortical dysplasia type IIb and cortical tubers in tuberous sclerosis complex (TSC), an autosomal-dominant phakomatosis caused by mutations in the TSC1 or TSC2 genes that encode hamartin and tuberin. We previously found that an allelic variant of TSC1 (hamartinH732Y) is increased in focal cortical dysplasia type IIb. Here, we investigated the subcellular localization of hamartinH732Y and its interaction with tuberin in vitro. Coimmunoprecipitation assays with tuberin revealed reduced tuberin binding of hamartinH732Y compared with wild-type hamartin. Tuberin binding was also reduced for 2 TSC1 stop mutants (hamartinR692X and hamartinR786X) that are present in brain lesions of TSC patients. Colocalization assays of hamartin and tuberin were performed in HEK293T cells, and the subcellular localization of the hamartin variants were studied using immunocytochemistry. There was an impairment of tuberin binding of hamartinH732Y and aberrant nuclear distribution of hamartinH732Y in these cells, whereas hamartinR692X and hamartinR786X were, like wild-type tuberin, localized in the cytoplasm. These data suggest a fundamental functional impairment of hamartinH732Y and the 2 TSC1 stop mutants hamartinR692X and hamartinR786X in vitro. Future studies will be needed to characterize the roles of these TSC1 sequence variants in the genesis of dysplastic epileptogenic developmental brain lesions.

Non-enhancing primary CNS lymphoma

Primary central system lymphomas (PCNSL) are highly proliferative tumors that require aggressive treatment, e.g. using high-dose methotrexate-based chemotherapy. Early histological diagnosis is crucial for proper management of PCNSL. Histological diagnosis is obtained through stereotactic biopsy which is usually performed upon demonstration of the typical hallmarks of PCNSL on MRI. This includes large, preferentially periventricular, homogenously contrast-enhancing lesions [1]. Although the MRI presentation of PCNSL is relatively uniform regarding the appearance as homogenously contrast-enhancing lesion(s), the MRI presentation of PCNSL may very rarely be atypical [2, 3] and may lead to significant delay in diagnosis and therapy initiation in such patients. We here present a patient with the rare case of a PCNSL without contrastenhancement. An 81-year-old patient presented with a 5-week history of rapidly progressive dementia. On examination, he was disoriented and showed psychomotor slowing and gait difficulty. The Mini Mental state examination (MMSE) revealed 16/30 points. He was HIV negative and all serological and biochemical tests were normal. The CSF examination showed just a slight increase in protein content (556 mg/l), no pleocytosis and no atypical cells. The MRI of the brain taken without prior steroid treatment revealed diffuse white matter changes involving both hemispheres. No pathological contrast-enhancement could be detected (Fig. 1). A diagnosis of gliomatosis cerebri was initially suspected. A biopsy was taken from the right frontal lobe. Histological examination revealed a diffuse large cell lymphoma (non-Hodgkin’s lymphoma of germinal B cell origin; Fig. 2). The present case highlights the fact that, in very rare cases, PCNSL may present as a non-enhancing lesion. Non-enhancing presentation was found in 1% of patients in a large series of immunocompetent patients [1] and is just one form of atypical MRI presentation of PCNSL. Another atypical form is the presentation with a central nonenhancing necrosis; this is found in 6–17% of immunocompetent PCNSL patients [1]. PCNSL without contrast uptake are usually caused by angiotropic large cell lymphoma or intravascular lymphomatosis [4]. In contrast, the present case did not show a particular angiotropic pattern but had the typical pattern of a diffuse large cell lymphoma with some perivascular accentuation (Fig. 2c). Unusual non-enhancing presentation may lead to substantial prolongation of definitive diagnosis and start of therapy. This underlines that PCNSL without contrast-enhancement has to be kept in the differential diagnosis of diffuse white matter disorders. Also, it further supports the importance of histologic verification before the onset of therapy. Since histological diagnosis of PCNSL may be greatly hampered by the use of lympholytic steroids prior to biopsy, it M. L. Lachenmayer and E. Blasius contributed equally.