Christian G. Bien

N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes.

Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6–121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a median of 10–20 days, the onset of movement disorders, reduction in consciousness and dysautonomia. This temporal dichotomy was also seen in the timing of cerebrospinal fluid, electroencephalographic and in the rather infrequent cerebral imaging changes. Overall, our data support a model in which the early features are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands. The immunological events and neuronal mechanisms underlying these observations need to be explored further, but one possibility is that the early stage represents diffusion of serum antibodies into the cortical grey matter, whereas the later stage results from secondary expansion of the immunological repertoire within the intrathecal compartment acting on subcortical neurons. Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stage.

Autoantibodies associated with diseases of the CNS: new developments and future challenges

Several CNS disorders associated with specific antibodies to ion channels, receptors, and other synaptic proteins have been recognised over the past 10 years, and can be often successfully treated with immunotherapies. Antibodies to components of voltage-gated potassium channel complexes (VGKCs), NMDA receptors (NMDARs), AMPA receptors (AMPARs), GABA type B receptors (GABA(B)Rs), and glycine receptors (GlyRs) can be identified in patients and are associated with various clinical presentations, such as limbic encephalitis and complex and diffuse encephalopathies. These diseases can be associated with tumours, but they are more often non-paraneoplastic, and antibody assays can help with diagnosis. The new specialty of immunotherapy-responsive CNS disorders is likely to expand further as more antibody targets are discovered. Recent findings raise many questions about the classification of these diseases, the relation between antibodies and specific clinical phenotypes, the relative pathological roles of serum and intrathecal antibodies, the mechanisms of autoantibody generation, and the development of optimum treatment strategies.

International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: A Task Force report from the ILAE Commission on Diagnostic Methods

Hippocampal sclerosis (HS) is the most frequent histopathology encountered in patients with drug‐resistant temporal lobe epilepsy (TLE). Over the past decades, various attempts have been made to classify specific patterns of hippocampal neuronal cell loss and correlate subtypes with postsurgical outcome. However, no international consensus about definitions and terminology has been achieved. A task force reviewed previous classification schemes and proposes a system based on semiquantitative hippocampal cell loss patterns that can be applied in any histopathology laboratory. Interobserver and intraobserver agreement studies reached consensus to classify three types in anatomically well‐preserved hippocampal specimens: HS International League Against Epilepsy (ILAE) type 1 refers always to severe neuronal cell loss and gliosis predominantly in CA1 and CA4 regions, compared to CA1 predominant neuronal cell loss and gliosis (HS ILAE type 2), or CA4 predominant neuronal cell loss and gliosis (HS ILAE type 3). Surgical hippocampus specimens obtained from patients with TLE may also show normal content of neurons with reactive gliosis only (no‐HS). HS ILAE type 1 is more often associated with a history of initial precipitating injuries before age 5 years, with early seizure onset, and favorable postsurgical seizure control. CA1 predominant HS ILAE type 2 and CA4 predominant HS ILAE type 3 have been studied less systematically so far, but some reports point to less favorable outcome, and to differences regarding epilepsy history, including age of seizure onset. The proposed international consensus classification will aid in the characterization of specific clinicopathologic syndromes, and explore variability in imaging and electrophysiology findings, and in postsurgical seizure control.

Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis.

Antibodies to glutamic acid decarboxylase (GAD) have been described in a few patients with temporal lobe epilepsies consistent with limbic encephalitis (LE). We studied a cohort of patients with recent‐onset temporal lobe epilepsy caused by LE to test for GAD antibody positivity and response to immunotherapies.

Destruction of neurons by cytotoxic T cells: A new pathogenic mechanism in rasmussen's encephalitis

Rasmussens encephalitis is a progressive epileptic disorder characterized by unihemispheric lymphocytic infiltrates, microglial nodules, and neuronal loss leading to the destruction of the affected hemisphere. In this study, immunohistochemical evaluation of specimens from 11 patients revealed lymphocytic infiltrates that consisted mainly of CD3+CD8+ T cells. Of these cells, 7.0% lay in direct apposition to MHC class I+ neurons. Confocal laser microscopy revealed that these lymphocytes contained granzyme B in a polar orientation toward these perikarya. Single neurons underwent apoptosis. These findings indicate that a T‐cell–mediated cytotoxic reaction induces neuronal death in Rasmussens encephalitis. This study directly shows, for what we believe is the first time, that a cytotoxic T‐cell mechanism contributes to loss of neurons in human brain disease.

Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition

The concept of antibody mediated CNS disorders is relatively recent. The classical CNS paraneoplastic neurological syndromes are thought to be T cell mediated, and the onconeural antibodies merely biomarkers for the presence of the tumour. Thus it was thought that antibodies rarely, if ever, cause CNS disease. Over the past 10 years, identification of autoimmune forms of encephalitis with antibodies against neuronal surface antigens, particularly the voltage gated potassium channel complex proteins or the glutamate N-methyl-D-aspartate receptor, have shown that CNS disorders, often without associated tumours, can be antibody mediated and benefit from immunomodulatory therapies. The clinical spectrum of these diseases is not yet fully explored, there may be others yet to be discovered and some types of more common disorders (eg, epilepsy or psychosis) may prove to have an autoimmune basis. Here, the known conditions associated with neuronal surface antibodies are briefly reviewed, some general aspects of these syndromes are considered and guidelines that could help in the recognition of further disorders are suggested.

Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy.

Objective: Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is the most frequent diagnosis in autopsy and surgical epilepsy series. TLE-HS usually starts during childhood or adolescence. There have been few studies of adult-onset disease. We recognized that some adult individuals have evidence of limbic encephalitis (LE), an autoimmune condition of adult life, which we proposed might lead directly to this syndrome. Methods: We performed a retrospective analysis of history, clinical and paraclinical findings, brain MRI, and outcome of surgical treatment including histopathology (if available) of all patients with TLE-HS presenting to this tertiary center within 6 years of epilepsy onset between 1999 and 2005. Results: Thirty-eight patients were identified, with median age at epilepsy onset of 37.8 years. Eleven patients (29%) were classified as having secondary HS (e.g., after head trauma, febrile seizures). Seven patients (11%) were classified as idiopathic. However, 9 patients (24%) had a diagnosis of definite LE, and another 11 individuals (29%) showed the typical LE pattern of MRI findings with hippocampal swelling evolving into atrophy with continuous FLAIR/T2 signal increase; they were diagnosed as possible LE. Bilateral abnormalities were more frequent in the two LE subgroups (60%) than in the two non-LE subgroups (22%; p = 0.025). Histopathology was performed in one patient with possible LE shortly after disease onset and showed a typical T cell infiltration and loss of hippocampal neurons. Conclusions: Temporal lobe epilepsy with hippocampal sclerosis can manifest in adult life. Around half the patients have evidence consistent with an autoimmune process. If confirmed, this should have implications for diagnosis, prevention, and treatment.

Characteristics and Surgical Outcomes of Patients With Refractory Magnetic Resonance Imaging–Negative Epilepsies

OBJECTIVE To explore several characteristics of patients with pharmacoresistant epilepsy without distinct lesions on magnetic resonance images (MRI(-)), who account for a relevant proportion of presurgical patient cohorts. DESIGN Retrospective case series. SETTING University epilepsy center. PATIENTS A cohort of 1200 patients who had comprehensive presurgical assessment from January 1, 2000, through December 31, 2006. MAIN OUTCOME MEASURES Frequency of MRI(-) patients in the total presurgical cohort, seizure-free outcome rates in patients who had surgery and those who did not, outcome predictors, and spatial properties of epileptogenic areas in MRI(-) patients with epilepsy. All MRI(-) patients were retrospectively analyzed. Presurgical MRIs were reevaluated for subtle cortical dysplasias by postprocessing and visual reassessment. RESULTS One-hundred ninety MRI(-) patients were identified (16% of all presurgical candidates); 29 (15%) had surgery. Eleven (38%) became seizure free (including those with auras only; 45%). Surgical therapy was more frequently offered to MRI(+) patients (76%; P < .001), and their outcome was also superior (66% seizure-free; P = .001). The seizure-free rate of 16% in MRI(-) patients who did not have surgery was, however, inferior to that of the MRI(-) patients who did (P = .008). Nine MRI(-) patients who had surgery had distinct histopathological lesions, 8 of which turned out to be retrospectively detectable on presurgical MRI. Seven of the MRI(-) but histopathologically lesional patients became seizure free compared with only 4 of 20 patients without histopathological lesions (P = .003). Three-fifths of the histopathologically nonlesional patients had multifocal or extensive epileptogenic areas. CONCLUSIONS Patients with epilepsy who are MRI(-) can be successfully treated with surgery. Improved sensitivity of MRI will improve the outcomes of presurgically studied patients. Surgical failures in patients without histopathological lesions mostly result from extensive epileptogenic areas.

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.

Diagnosis and staging of Rasmussen’s encephalitis by serial MRI and histopathology

Objective: To correlate MRI and histopathologic findings in patients with Rasmussen’s encephalitis (RE). Patients and methods: MRI features of 10 patients with RE were studied on serial scans. In surgical specimens from these patients, densities of T lymphocytes, microglial cells and nodules, and reactive astrocytes were evaluated. Results: Densities of T cells, microglial nodules, and astrocytes were inversely correlated to disease duration. MRI abnormalities had a focal onset and spread across one hemisphere. The following course of MRI abnormalities in a given brain region was observed: on very early scans, the cortex was swollen and showed a hyperintense T2/fluid-attenuated inversion recovery signal. Consecutively, progressive atrophy of the affected hemisphere occurred. Correlation of MRI features with quantitative histopathology revealed that there was a higher number of T cells and reactive astrocytes in the earlier MRI stages compared with the late (merely atrophic) stage. Conclusion: These data suggest a disease course in RE with the highest inflammatory intensity in the early stages and a subsequent decrease in inflammation. The MRI abnormalities and their characteristic sequence may help to identify patients with RE and to obtain informative biopsies.