Glutamate receptor GluR3 antibodies and death of cortical cells.

Rasmussen's encephalitis (RE), a childhood disease characterized by epileptic seizures associated with progressive destruction of a single cerebral hemisphere, is an autoimmune disease in which one of the autoantigens is a glutamate receptor, GluR3. The improvement of some affected children following plasma exchange that removed circulating GluR3 antibodies (anti-GluR3) suggested that anti-GluR3 gained access to the central nervous system where it exerted deleterious effects. Here, we demonstrate that a subset of rabbits immunized with a GluR3 fusion protein develops a neurological disorder mimicking RE. Anti-GluR3 IgG isolated from serum of both ill and healthy GluR3-immunized animals promoted death of cultured cortical cells by a complement-dependent mechanism. IgG immunoreactivity decorated neurons and their processes in neocortex and hippocampus in ill but not in healthy rabbits. Moreover, both IgG and complement membrane attack complex (MAC) immunoreactivity was evident on neurons and their processes in the cortex of a subset of patients with RE. We suggest that access of IgG to epitopes in the central nervous system triggers complement-mediated neuronal damage and contributes to the pathogenesis of both this animal model and RE.

Type 1 diabetes mellitus and drug-resistant epilepsy: presence of high titer of anti-glutamic acid decarboxylase autoantibodies in serum and cerebrospinal fluid.

A 55-year-old man who was diagnosed as having type 1 diabetes mellitus (DM) at the age of 50 years was started on insulin therapy. At 54 years old of age, he suddenly developed complex partial seizures, which frequently occurred despite intensive anti-epileptic drug therapy. Neurological examination on admission revealed hyporeflexia in bilateral upper and lower extremities without any muscle rigidity, painful spasm or cerebellar ataxia. Laboratory examination showed poor glycemic control with increased glycated hemoglobin levels. Positive anti-thyroglobulin antibodies and anti-thyroid peroxidase (TPO) antibodies and slight elevation of TSH levels are consistent with subclinical hypothyroidism due to Hashimoto's thyroiditis. A high titer of anti-glutamic acid decarboxylase (GAD) antibodies was detected in the patient's serum and cerebrospinal fluid (CSF). Electroencephalography showed temporal spikes, consistent with complex partial seizure. This is a very rare case presenting with concomitant type 1 diabetes and drug-resistant epilepsy associated with high titers of circulating and CSF anti-GAD antibodies.

[11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitis.

This study was designed to explore the feasibility of PET using [11C](R)-PK11195 as an in vivo marker of activated microglia/brain macrophages for the assessment of neuroinflammation in Rasmussen's encephalitis (RE). [11C](R)-PK11195 PET was carried out in four normal subjects, two patients with histologically confirmed RE, and three patients with clinically stable hippocampal sclerosis and low seizure frequency. Binding potential maps showing specific binding of [11C](R)-PK11195 were generated for each subject. Regional binding potential values were calculated for anatomically defined regions of interest after coregistration to and spatial transformation into the subjects' own MRI. In one patient with RE who underwent hemispherectomy, the resected, paraffin-embedded brain tissue was stained with an antibody (CR3/43) that labels activated human microglia. Whereas specific binding of [11C](R)-PK11195 in clinically stable hippocampal sclerosis was similar to that in normal brain, patients with RE showed a focal and diffuse increase in binding throughout the affected hemisphere. In RE, [11C](R)-PK11195 PET can reveal in vivo the characteristic, unilateral pattern known from postmortem neuropathologic study. PET imaging of activated microglia/brain macrophages offers a tool for investigation of a range of brain diseases where neuroinflammation is a component and in which conventional MRI does not unequivocally indicate an inflammatory tissue reaction. [11C](R)-PK11195 PET may help in the choice of appropriate biopsy sites and, further, may allow assessment of the efficacy of antiinflammatory disease-modifying treatment.

Low levels of somatostatin-like immunoreactivity in neocortex resected from presumed seizure foci in epileptic patients.

The concentration of somatostatin-like immunoreactivity (SS-LI) was determined by radioimmunoassay in neocortical tissue resected from 20 patients with pharmacologically intractable complex partial seizures. Most resections included either the anterior temporal pole neocortex (15 cases) or cingulate gyrus neocortex (3 cases). The concentration of SS-LI was lowest in cortical tissue immediately adjacent to cortical tumors. Preoperative electrical recordings suggested that this tissue was the seizure focus. In vitro recordings showed that this tissue also exhibited abnormal hyperexcitable synaptic responses. Higher levels of SS-LI, similar to normal values previously reported in human cortex, were present in non-focal temporal neocortical tissue (resected from patients in whom the seizure focus was in the ipsilateral hippocampus) in which no hyperexcitable synaptic activity was present in vitro. The functional loss of inhibitory transmitters suggested by the low SS-LI levels might provide a theoretical basis for the hyperexcitability observed in vivo and in vitro.

Cyclophosphamide for anti-GAD antibody-positive refractory status epilepticus.

Glutamic acid decarboxylase (GAD) is the enzyme which catalyzes the production of gamma aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system (CNS). There is increasing evidence that severe GAD autoimmunity may be associated with refractory epilepsy. Immunomodulation and GABAergic drugs have been suggested as treatment options. We report here for the first time on a patient with sudden onset of refractory status epilepticus in the presence of strong intrathecal anti-GAD antibody synthesis who was successfully treated with cyclophosphamide, and give an overview of available data on epilepsy associated with GAD autoimmunity.

Autoantibodies to glutamic acid decarboxylase in palatal myoclonus and epilepsy.

We report the presence of serum autoantibodies directed against glutamic acid decarboxylase in a patient with epilepsy and palatal myoclonus not associated with brain lesions. Glutamic acid decarboxylase antibody reactivity was dependent on the presence of carboxy-terminal amino acids, similar to that reported in patients with stiff-man syndrome. Marked reduction in the frequency of epileptic attacks and improvement in palatal myoclonus occurred when benzodiazepine was administered and phenytoin was gradually tapered. Testing for anti-glutamic acid decarboxylase antibodies may be indicated in patients with palatal myoclonus and with convulsive disorders refractory to therapy.

[Successful induction of tolerance in an epilepsy patient with phenobarbital allergy]. / Erfolgreiche Toleranzinduktion bei einer Epilepsiepatientin mit Phenobarbitalallergie.

We report on a 32-year-old female patient who had had a history of complex partial seizures since the age of 14. Phenobarbital was the most effective anticonvulsant drug in this patient. However, the drug treatment was complicated by a phenobarbital-induced exanthematous eruption. Reintroduction of the phenobarbital some years later resulted in a skin rash again; therefore, treatment with this substance had to be discontinued a second time. Because of the satisfactory antiepileptic efficacy, phenobarbital was introduced a third time using a desensitization procedure with increased oral doses, starting with a dose of 1 mg. After a daily dose of 90 mg phenobarbital, on day 6 an exanthematous eruption appeared. The exanthem disappeared parallel to a dose reduction of phenobarbital and with a gradually increasing dosage up to a maintenance dose of 200 mg. Tolerance to the allergic effect of phenobarbital was preserved and the seizure frequency was significantly reduced by phenobarbital monotherapy with a daily dose of 200-175 mg.

[Hemiatrophia faciei progressiva and tonic pupil]. / Hemiatrophia faciei progressiva und Pupillotonie.

BACKGROUND: A variety of infectious and autoimmune diseases are described in association with pupillotonia. To our knowledge there is only one report on pupillotonia associated with hemiatrophia faciei. We describe another patient with this rare association. The aim is to investigate possible associations between both diseases. PATIENT: A twenty five-year-old male patient with hemiatrophia faciei, epilepsy and pupillotonia of the right eye since his twelfth birthday was presented for the first time at the age of fourteen at our institution. The patient underwent a complete neurological and paediatric as well as otolaryngological investigation; there was also an investigation by the internist. The patient also underwent a complete serological investigation for infectious and autoimmune disorders as well as an investigation of the local and systemic vascular reactivity by the "Ocular cold pressor test". The follow-up time is 11 years. RESULTS: The clinical picture of our patient was an association of hemiatrophia faciei, epilepsy and pupillotonia. There was no evidence of a local hyperactivity of the sympathetic nervous system. The serological investigation showed an elevated value of antinuclear antibodies. CONCLUSIONS: We assume that in our case the pupillotonia as well as the hemiatrophia faciei and the epilepsy is caused by a common autoimmune factor. All other aetiologies for these three diseases were excluded. Furthermore, the occurrence of pupillotonia, hemiatrophia faciei and epilepsy was simultaneous.

Use of intravenous immunoglobulins in drug-resistant epilepsy.

Among the 257 pediatric patients examined, 104 were classified as having drug-resistant epilepsy (DRE). In all of them genetic, metabolic, chromosomal and infectious causes were investigated, and brain imaging with computed tomography scans and nuclear magnetic resonance were obtained. Since treatment with gammaglobulins (GGs) has been reported to be useful in pediatric cases of epilepsy, informed consent for GGs treatment was obtained in 43 patients with DRE. The etiology or evidence of brain lesions was identified in 16 of them. In 31 of these patients, neither conventional drug treatment, nor a trial with adrenocorticotropic hormone was successful. Intact monomeric GGs, 400 mg/kg, were given intravenously. A second dose was given after 15 days and, thereafter, every 21 days for a maximum of ten injections (protocol A), or every 2nd day for a maximum of five doses (protocol B). In every patient, the type of epilepsy was identified according to the classification of the International League Against Epilepsy. The frequency of seizures was recorded for a period beginning at least 6 months before the administration of GGs. Immunological evaluation was also performed before and after the treatment with GGs. A transient decrease of the seizure frequency was noted in 12 subjects. In another patient with infantile idiopathic myoclonic epilepsy, seizures disappeared for 30 months. In 1 case a persistent 80% reduction in the number of seizures was observed. A persistent disappearance of seizures was noted in a subject with complex partial seizures (CPS) that followed an idiopathic infantile spasm syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)