Autoimmune encephalitis in children and adolescents.

BACKGROUND: Autoimmune encephalitides with neural and glial antibodies have become an attractive field in neurology because the antibodies are syndrome-specific, explain the pathogenesis, indicate the likelihood of an underlying tumor, and often predict a good response to immunotherapy. The relevance and the management of antibody-associated encephalitides in the pediatric age group are to be discussed. MAIN BODY: Subacutely evolving, complex neuropsychiatric conditions that are otherwise unexplained should raise the suspicion of autoimmune encephalitis. Determination of autoantibodies is the key diagnostic step. It is recommended to study cerebrospinal fluid and serum in parallel to yield highest diagnostic sensitivity and specificity. The most frequently found antibodies are those against the N-methyl-D-asparate receptor, an antigen on the neural cell surface. The second most frequent antibody is directed against glutamic acid decarboxylase 65 kDa, an intracellular protein, often found in chronic conditions with questionable inflammatory activity. Immunotherapy is the mainstay of treatment in autoimmune encephalitides. Steroids, apheresis and intravenous immunoglobulin are first-line interventions. Rituximab or cyclophosphamide are given as second-line treatments. Patients with surface antibodies usually respond well to immunotherapy whereas cases with antibodies against intracellular antigens most often do not. CONCLUSION: With few exceptions, the experience in adult patients with autoimmune encephalitides can be applied to patients in the pediatric age range.

Very long-term outcome in resected and non-resected patients with temporal lobe epilepsy with medial temporal lobe sclerosis: A multiple case-study.

PURPOSE: To investigate the very long-term (i.e., ≥15 years) seizure, cognitive and psycho-social outcomes in resected patients (RP) with TLE compared to control patients not having undergone epilepsy surgery. METHODS: We applied a multiple case-study design including three non-resected patients (NRP) who were compared to a group of six RP. The latter were matched to the NRP according to clinical-demographic data. Outcome measures were various seizure, cognitive, and psycho-social variables. RESULTS: Patients were 56-72 years old. Seizure and AED outcome was more favourable among RP. RP reported better self-perceived overall health but higher subjective memory complaints. Upon formal neuropsychological testing, RP presented with lower verbal memory scores. Very long-term memory decline was evident in left-sided RP with good baseline memory scores, while RP with lower baseline performance, right-sided RP and NRP remained stable. Seizure-freedom had remarkable effects on the relationship between objective and subjective outcome: seizure-free patients, in general, subjectively reported the best psychosocial and cognitive outcome - irrespective of neuropsychological test results. CONCLUSION: Our study suggests positive effects of TLE surgery in the very long-term course of ≥15 years postoperatively. Long-term seizure-freedom appears to have the strongest impact on patients' subjectively perceived psycho-social and cognitive outcome and may even outweigh actual memory disturbances and/or decline. Overall, our data do not support the assumption of a generally accelerated cognitive decline in patients with TLE.

[Principles of autoimmune and paraneoplastic encephalitis]. / Grundlagen autoimmuner und paraneoplastischer Enzephalitiden.

The paraneoplastic and autoimmune encephalitides are now well-established entities. Detection of neural autoantibodies enables specific diagnoses, provides information on the underlying disease pathophysiology, immunological treatability and the likelihood of a tumor being the underlying cause. This is true for the "high ranking" neural antibodies that have been established in the context of circumscribed clinical images and in consideration of large control groups, have been found in the same way by other laboratories and they respond to immunotherapy. The immune reaction can be triggered by tumors and virus encephalitides, e.g. N­methyl-D-aspartate (NMDA) receptor antibodies. In some cases a genetic predisposition has been shown. Some antibodies are formed peripherally, others intrathecally. The route of the antibodies into the brain can be via the blood-brain barrier or cerebrospinal fluid (CSF). In the brain itself, the antibodies lead to an internalization of antigenic receptors, such as NMDA and α­amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, or to nerve-destroying activation of the classical complement cascade. In other conditions, cytotoxic T cells are at the core of the pathophysiology. For diagnostic purposes, the testing of CSF-serum pairs with broad spectrum antigen panels is recommended. Therapeutically, the aim is to suppress the production of pathogenic antibodies or even to eliminate them directly. A sequence of first-line treatment (steroids, intravenous immunoglobulins and/or apheresis) and second-line treatment (rituximab and/or cyclophosphamide) has been established.

Limbic encephalitis with LGI1 antibodies in a 14-year-old boy.

Limbic encephalitis (LE) with antibodies against leucine-rich glioma inactivated protein 1 (LGI1) is an auto-antibody mediated disorder with characteristic symptoms as dysfunction of memory, faciobrachial dystonic seizures and neuropsychiatric symptoms as emotional lability. Limbic encephalitis with LGI1 antibodies has been known so far as a disease of adults. We describe the case of a 14-year-old boy presenting with typical dysfunction of memory and LGI1 antibodies. To the best of our knowledge, this is the youngest patient with LGI1 antibody mediated limbic encephalitis described so far. Improved knowledge of this autoimmune syndrome in children and adolescents permit rapid immunomodulatory treatment, which could help to prevent irreversible lesions, such as hippocampal atrophy.

Intrathecal immunoglobulin synthesis in patients with symptomatic epilepsy and epilepsy of unknown etiology ('cryptogenic').

BACKGROUND AND PURPOSE: To compare the frequency of intrathecal immunoglobulin (Ig) synthesis in patients with symptomatic epilepsy and epilepsy of unknown etiology ('cryptogenic'). METHODS: Patients with epileptic (n = 301) and non-epileptic (n = 10) seizures were retrospectively screened for autochthonous intrathecal Ig synthesis and oligoclonal bands (OCBs) in the cerebrospinal fluid. RESULTS: Intrathecal IgG/OCBs were detected in 8% of patients with epilepsies of unknown etiology, 5% of patients with first seizures of unknown cause and 0-4% of patients with epilepsy due to brain tumors, cerebrovascular disease or other etiologies. Intrathecal IgG/OCBs were not seen in patients with psychogenic seizures. Identical OCBs in serum and cerebrospinal fluid were more common in all patient groups (10-40% depending on underlying etiology). CONCLUSIONS: Intrathecal IgG synthesis/OCBs were observed slightly more frequently in patients with 'cryptogenic' epilepsy and with first seizures of unknown etiology than in other patient groups. However, this remained an infrequent finding and thus we could not confirm humoral immunity as a leading disease mechanism in patients with epilepsy in general or with unknown etiology in particular.

Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome.

BACKGROUND AND PURPOSE: To clarify the relevance of titres of IgG antibodies against contactin-associated protein-2 (CASPR2) in diagnosing anti-CASPR2 encephalitis and to describe features and outcomes. METHODS: This was a retrospective analysis of 64 patients with CASPR2 antibodies, categorized independently as 'autoimmune encephalitis' or 'other disease'. Logistic regression methods were performed to identify potential predictors of 'autoimmune encephalitis' in addition to CASPR2 antibodies. RESULTS: An upfront CASPR2 antibody serum titre cut-off at ≥1:200 had a diagnostic sensitivity of 85% and a specificity of 81%. Logistic regression analyses indicated that, in addition to titre, encephalitic magnetic resonance imaging (MRI) was a significant predictor of 'autoimmune encephalitis' (Nagelkerke's R2 = 0.81, P < 0.001) with high sensitivity (84%) and very high specificity (100%). Patients with CASPR2 antibodies and an estimated probability of >70% of having anti-CASPR2 encephalitis (n = 22) had limbic encephalitis (n = 18, one patient plus ataxia), Morvan syndrome (n = 2) or a hyperkinetic movement disorder (n = 2). Median modified Rankin score (mRS) at diagnosis was 3 (range 1-4). Twenty patients were male; median age was 64 (range 54-75) years; 5/15 patients with cerebrospinal fluid data had intrathecal CASPR2 antibody synthesis, and 12/19 with follow-ups >3 months (median 12 months, range 4-43 months) improved by ≥1 mRS point resulting in a median mRS of 2 (range 0-6; one death; all but one having received immunotherapy); and 2/15 patients with follow-up MRI developed hippocampal atrophy. CONCLUSIONS: Only higher CASPR2 serum antibody titres indicate anti-CASPR2 encephalitis, and diagnostic accuracy increases if MRI findings are considered. Anti-CASPR2 encephalitis has characteristic features and a favourable outcome with immunotherapy.

[Pharmacological treatment of women with epilepsy before and during pregnancy]. / Pharmakologische Epilepsietherapie bei Kinderwunsch und in der Schwangerschaft.

In the vast majority of women with epilepsy, no complications occur during pregnancy. Important for that is early, preconceptional counseling and close surveillance during pregnancy. The aim should be to maintain the best possible seizure control without occurrence of generalized tonic-clonic seizures while using antiepileptic drugs and with the lowest possible risk of malformations. The warnings for the prescription of valproic acid in women of reproductive age were tightened because of the dose-dependent increase in the malformation rate and other risks, especially regarding adverse effects on childhood cognitive development. The pharmacokinetics of antiepileptic drugs in pregnancy require monitoring of serum drug levels and an early dose adjustment. Breastfeeding should be encouraged in women with epilepsy taking antiepileptic drugs as long as infants are closely monitored with respect to possible sedation and poor drinking.

Subjective memory complaints in patients with epilepsy: The role of depression, psychological distress, and attentional functions.

While objective memory dysfunctions have been thoroughly investigated in patients with epilepsy, assessment of subjective memory complaints (SMC) remains challenging. Former studies have demonstrated an impact of patients' depressive mood on SMC. However, the impact of more general psychological distress and cognitive functioning in non-memory domains on SMC has only received little attention so far. We therefore sought to determine the factors which may particularly predict SMC in a sample of patients with focal epilepsy (n=99) who accomplished (1) a comprehensive neuropsychological assessment, (2) a subjective memory questionnaire, and (3) scales of self-rated depressive mood and psychological distress. General psychological distress (as measured by the Symptom Checklist- 90-Revised) accounted for a high proportion of SMC and, critically, explained more variance than depressive mood as a single factor (as measured by the Beck Depression Inventory II). Furthermore, SMC were predicted by recall measures of a verbal serial learning task, but also by measures of attention, importantly. Hence, our data firstly indicate that beyond the impact of depressive mood, SMC may be more accurately explained by psychological distress in a more general sense. Secondly, our study provides evidence that patients' estimation of subjective memory is not solely based on functioning in memory domains. Attentional resources may also be critical for patients' perception of everyday memory functioning.

Supratentorial white matter blurring associated with voltage-gated potassium channel-complex limbic encephalitis.

INTRODUCTION: Limbic encephalitis (LE) associated with voltage-gated potassium channel-complex antibodies (VGKC-LE) is frequently non-paraneoplastic and associated with marked improvement following corticosteroid therapy. Mesial temporal lobe abnormalities are present in around 80 % of patients. If associated or preceded by faciobrachial dystonic seizures, basal ganglia signal changes may occur. In some patients, blurring of the supratentorial white matter on T2-weighted images (SWMB) may be seen. The purpose of this study was to evaluate the incidence of SWMB and whether it is specific for VGKC-LE. METHODS: Two experienced neuroradiologists independently evaluated signal abnormalities on FLAIR MRI in 79 patients with LE while unaware on the antibody type. RESULTS: SWMB was independently assessed as present in 10 of 36 (28 %) compared to 2 (5 %) of 43 non-VGKC patients (p = 0.009). It was not related to the presence of LGI1 or CASPR2 proteins of VGKC antibodies. MRI showed increased temporomesial FLAIR signal in 22 (61 %) VGKC compared to 14 (33 %) non-VGKC patients (p = 0.013), and extratemporomesial structures were affected in one VGKC (3 %) compared to 11 (26 %) non-VGKC patients (p = 0.005). CONCLUSION: SWMB is a newly described MRI sign rather specific for VGKC-LE.

Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies.

PURPOSE: Temporal lobe epilepsy with antibodies (abs) against the glutamic acid decarboxylase 65 isoform (GAD-TLE) is known as an immune-mediated neurological syndrome. Here we evaluate the therapy response to various immunotherapies and epilepsy surgery in this syndrome. METHOD: All patients with GAD-TLE and follow-up data and stored serum and CSF samples, identified and treated at the Bonn centre from 2002 to 2010, were studied retrospectively. Seizure freedom for ≥1 year and reduction of ≥50%, i.e. therapy response, were assessed. GAD-ab titres and neuropsychological performances were documented prior and after individual interventions. RESULTS: Thirteen patients with GAD-TLE were identified with the following seizure responses: corticosteroids (5 responders out of 11 treated patients); i.v. immunoglobulins (1/5), apheresis therapy (1/8); and natalizumab (1/1), selective amygdala-hippocampectomy (2/3). None of the patients achieved sustained seizure freedom apart from one patient. This patient was on antiepileptic drug treatment after discontinuation of immunotherapy. CONCLUSION: The seizure response to immunotherapies in patients with GAD-TLE was poor. Corticosteroids were the most effective regarding seizure response. Especially the poor effects of apheresis therapies support the idea that GAD-abs are not directly pathogenic. None of three patients was seizure-free after temporal lobe surgery suggesting that GAD-TLE patients respond worse than others to this type of intervention. Our results reflect the chronic course of the disease with low likelihood for patients with GAD-TLE to attain long-term seizure freedom.

Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.

BACKGROUND: Two novel antibodies (abs) directed to γ-aminobutyric acid B receptor (GABA(B)R) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in patients with limbic encephalitis (LE) were first described by the Philadelphia/Barcelona groups and confirmed by the Mayo group. We present a novel series for further clinical and paraclinical refinement. METHODS: Serum and cerebrospinal fluid samples from a diagnostic laboratory were selected if found to be positive for GABA(B)R or AMPAR abs within a broad antineuronal ab panel. Data were retrospectively compiled. RESULTS: In 10 patients, we detected abs to GABA(B)R. Median age was 70 years. Five of them were diagnosed with small cell lung cancer (SCLC). Intrathecal GABA(B)R ab synthesis was found in all six patients with sufficient data available (median ab-index: 76.8). On MRI, we found bilateral mediotemporal and in two cases cortical abnormalities. EEG revealed encephalopathy, partly with epileptiform discharges. Five patients received immunotherapy, two patients tumour treatment and three both therapies. Three patients died, in five patients cognitive functions declined, one patient improved slightly and one patient fully recovered. AMPAR abs were detected in three patients with mnestic disturbances. Median age was 60.7 years. The only female patient was diagnosed with ovarian cancer. None of the patients had intrathecal ab synthesis. MRI findings showed bilateral mediotemporal abnormalities. EEG was normal in all patients. Two of the three immunologically treated patients improved, one patient stabilised on a low level. DISCUSSION: GABA(B)R and AMPAR abs are well associated with LE. GABA(B)R abs lead to severe clinical, neuroradiological and EEG abnormalities with poorer outcome.

Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity.

In limbic encephalitis (LE) with antibodies (Abs) to the voltage-gated potassium channel complex (VGKC), the Abs are mainly directed to the VGKC-complex proteins, leucine-rich, glioma inactivated 1 protein (LGI1) or contactin-associated protein-like 2 (CASPR-2) or neither. Here, we relate the outcomes of VGKC-LE patients to the presence of Abs to LGI1, CASPR-2 or neither antigen (LGI1/CASPR-2-Ab(-)). Clinical, neuropsychology and MRI data were obtained from patient records for all LE patients from the Bonn Epilepsy Centre positive for VGKC-Abs by radioimmunoprecipitation assay between 2002 and 2011. Eighteen VGKC-LE patients were identified: nine patients (50 %) had LGI1-Abs, three (16 %) had CASPR-2-Abs; and six (33 %) were negative for both LGI1- and CASPR-2-Abs. At first assessment, the groups did not differ clinically or radiologically, but faciobrachial dystonic seizures were only observed in two LGI1-Ab(+) patients. All patients received monthly intravenous methylprednisolone (MP) pulses. At the most recent follow up (median 26 months), thirteen (72 %) were seizure-free, and seizure-freedom rates did not differ between the Ab groups. Hippocampal atrophy had developed in 7/9 LGI1-Ab(+) patients, but in none of the CASPR-2-Ab(+) or LGI/CASPR-2-Ab(-) patients (p = 0.003). While all subgroups improved, memory scores only normalized in six patients (33 %) and LGI1-Ab(+) patients were left with significantly poorer memory than the other two subgroups. Most VGKC-LE patients become seizure-free with pulsed monthly MP, but memory outcome is less favourable. Hippocampal atrophy and poor memory recovery is common in patients with LGI1-Abs and suggests permanent functional damage. More intense immunotherapies could improve outcomes in LGI1-Ab(+)-LE.

Real-life memory and spatial navigation in patients with focal epilepsy: ecological validity of a virtual reality supermarket task.

Ecological assessment and training of real-life cognitive functions such as visual-spatial abilities in patients with epilepsy remain challenging. Some studies have applied virtual reality (VR) paradigms, but external validity of VR programs has not sufficiently been proven. Patients with focal epilepsy (EG, n=14) accomplished an 8-day program in a VR supermarket, which consisted of learning and buying items on a shopping list. Performance of the EG was compared with that of healthy controls (HCG, n=19). A comprehensive neuropsychological examination was administered. Real-life performance was investigated in a real supermarket. Learning in the VR supermarket was significantly impaired in the EG on different VR measures. Delayed free recall of products did not differ between the EG and the HCG. Virtual reality scores were correlated with neuropsychological measures of visual-spatial cognition, subjective estimates of memory, and performance in the real supermarket. The data indicate that our VR approach allows for the assessment of real-life visual-spatial memory and cognition in patients with focal epilepsy. The multimodal, active, and complex VR paradigm may particularly enhance visual-spatial cognitive resources.

[Pathophysiology of antibody-associated diseases of the central nervous system]. / Pathophysiologie antikörperassoziierter ZNS-Erkrankungen.

Antibodies against intracellular antigens have been known since the 1980s and 1990s but in recent years antibodies against surface antigens have also been discovered. These are "more interesting" than those to intracellular targets in two respects: they result in a better response to immunotherapy and are probably directly pathogenic, which helps to understand the disease mechanisms. There are the destructive and irreversible effects of the antibodies to antigens that are complexed with voltage-gated potassium channels (VGKC complex antibodies), especially antibodies to leucine-rich glioma inactivated 1 (LGI1) on the one hand. On the other hand, antibodies may have reversible functional effects, such as antibodies against the N-methyl-D-aspartate receptor, which cause an internalization of these receptors but do not lead to cell destruction: LGI1 antibodies also seem to have functional, in this case epileptogenic effects. These emerging findings make plausible why antibody-reducing therapies provide opportunities for the restoration of health in affected patients.

[Immune-mediated epilepsy and encephalopathy]. / Immunvermittelte Epilepsien und Enzephalopathien.

During the last decade new knowledge on immune-mediated disorders of the grey substance of the central nervous system (CNS) has been generated. These conditions are associated with seizures in approximately 80% of cases and often present as drug-resistant epilepsies. The discovery of autoantibodies against neural surface antigens was essential for the identification of these disorders. Immune-mediated epilepsies often respond poorly to antiepileptic drugs; however, they do respond in many cases to immunological therapy which offers a chance of overcoming resistance to antiepileptic drugs by immunological treatment.

Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome.

OBJECTIVE: To report the metabotropic glutamate receptor 5 (mGluR5) as the autoantigen of antibodies from 2 patients with Hodgkin lymphoma (HL) and limbic encephalopathy (Ophelia syndrome). METHODS: Immunohistochemistry with brain tissue and cultures of rat hippocampal neurons were used to demonstrate antibodies. Immunoprecipitation, mass spectrometry, and mGluR5-null mice served to identify the antigen. HEK293 cells transfected with mGluR5 or mGluR1 were used to determine immunologic crossreactivity. RESULTS: Both patients developed symptoms consistent with limbic encephalopathy; one had MRI findings typical of this disorder and the other had more extensive radiologic involvement, including parietal and occipital cortex. Patients' sera had antibodies that predominantly reacted with the neuropil of hippocampus and cell surface of live hippocampal neurons. Immunoprecipitation from cultured neurons and mass spectrometry demonstrated that the antigen was mGluR5, a receptor involved in processes of learning and memory. The reactivity of patients' sera was abrogated in brain of mGluR5-null mice, further confirming the antibody specificity. Studies with a large number of controls including 2 patients with cerebellar ataxia and mGluR1 antibodies showed that mGluR5 was only identified by sera of the 2 patients with the Ophelia syndrome, and that despite the homology of this receptor with mGluR1 each autoantigen was specific for a distinct syndrome. CONCLUSIONS: Antibodies to mGluR5 should be considered in patients with symptoms of limbic encephalitis and HL (Ophelia syndrome). Recognition of this disorder is important because it can affect young individuals and is reversible.