Encephalitis of unknown etiology with anti-GluR epsilon2 autoantibody, showing divergent neuroradiologic and clinical findings.
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Adult↗
Biomedical subjects
Yukitoshi Takahashi
Publications and source records attributed to Yukitoshi Takahashi.
Acute cerebellar ataxia and consecutive cerebellitis produced by glutamate receptor delta2 autoantibody.
Acute cerebellar ataxia is usually a self-limited benign disease, which may develop in children after certain viral infections or vaccinations. There are several reports of acute cerebellar ataxia associated with autoantibodies. Glutamate receptor delta2, a member of the glutamate receptor family, is predominantly expressed in cerebellar Purkinje cells and plays a crucial role in cerebellar functions. To date anti-GluRdelta2 autoantibody was detected in a patient with chronic cerebellitis. Herein, an 18-month-old boy presented with cerebellar ataxia 9 days following a mild respiratory tract infection. Although cerebellar ataxia gradually improved, it worsened yet again following mumps and varicella virus infection. Cerebro-spinal fluid examination and magnetic resonance imaging of the brain demonstrated pleocytosis and meningeal enhancement, respectively. Furthermore, glutamate receptor delta2 autoantibody was detected in serum and cerebro-spinal fluid. Thus, we believe that the glutamate receptor delta2 autoantibody may play a role in cerebellar ataxia and consecutive cerebellitis.
Autoantibodies↗
Acute encephalitis with refractory, repetitive partial seizures: case reports of this unusual post-encephalitic epilepsy.
We report on three acute encephalitis patients with refractory, repetitive partial seizures (AERRPS). All three suffered acute febrile episodes associated with status epilepticus, which necessitated high-dose barbiturate therapy under artificial ventilation for several weeks. Electroencephalography (EEG) revealed a predominance of diffuse epileptiform discharges initially, subsequently developing into periodic bursts of these discharges. Reduction of the barbiturate dosage resulted in clinical and subclinical partial seizures appearing repetitively in clusters. Prolonged fever persisted for 2-3 months, even several weeks after normalization of cell counts in the cerebrospinal fluid. The EEG showed an improvement after resolution of this fever, and seizures became less frequent, although still intractable. Oral administration of high-dose barbiturate and benzodiazepines were partially effective during the acute phase, and a barbiturate dependency, lasting for years, was noted in one patient. Steroid administration was effective in stopping the febrile episodes in one patient, with concurrent improvement in seizure control. Magnetic resonance imaging showed enhancement of bitemporal cortical areas in one patient, and high signal intensity on T2 weighted image in the bilateral claustrum in another patient. Diffuse cortical atrophy appeared within two months after the onset of encephalitis in all patients. The evolution of the seizures and EEG findings suggested a high degree of cortical excitability in AERRPS. In this report, we propose a tentative therapeutic regimen for seizure control in this condition. We also hypothesize that a prolonged inflammatory process exists in the cerebral cortex with AERRPS, and may be pivotal in the epileptogenesis.
Acute Disease↗
A case of acute cerebellitis accompanied by autoantibodies against glutamate receptor delta2.
A 13-year-old boy presented with a six-day history of headache and gradually developed severe meningeal irritation symptoms. Brain magnetic resonance imaging revealed left cerebellar swelling and obstructive hydrocephalus. Then he showed transient ataxia, but recovered without any sequelae soon after high dose steroid therapy. IgG type of autoantibodies against glutamate receptor delta2 (GluRdelta2) were detected in the serum, but not in the cerebrospinal fluid in his early clinical course. It was suggested that autoantibodies against GluRdelta2 might not have injured the tissue due to the immunological action, but might be induced as a consequence of cerebellar damage. Early steroid treatment for acute cerebellitis might have been effective to prevent the progress of the disease and improve the prognosis.
Adolescent↗
Acute encephalopathy with refractory status epilepticus: bilateral mesial temporal and claustral lesions, associated with a peripheral marker of oxidative DNA damage.
We describe a 12-year-old girl, who had been medicated with theophylline for bronchial asthma and developed acute encephalopathy with refractory status epilepticus, showing bilateral mesial temporal and claustral lesions, which were evident on fluid-attenuated inversion recovery images, obtained with 1.5 T magnetic resonance imaging. To date, oxidative stress has been implicated in aging or various disorders, including inflammatory or degenerative neurological disorders. One of the oxidative stress markers, 8-hydroxydeoxyguanosine, was increased in our patient's cerebro-spinal fluid, plasma and urine. We speculate that augmented oxidative stress was associated with refractory status epilepticus in our patient, accompanying bilateral mesial temporal, claustral lesions and severe neuronal damage. Serial measurements of oxidative stress markers in acute encephalitis, encephalopathy, or status epilepticus could clarify the relationships between acute brain damage and free radicals.
8-Hydroxy-2'-Deoxyguanosine↗
MR imaging and 1H-MR spectroscopy of a case of van der Knaap disease.
Van der Knaap disease, characterized by megalencephalic leukoencephalopathy and subcortical cysts, is a rare and recently defined condition. We discuss here the MR image (MRI) and MR spectroscopy (MRS) features in a 30-year-old man with S93L homozygous mutation in the MLC1 gene. MRI demonstrated high intensity diffuse white matter with T2-weighted image and subcortical cysts in the parietal and temporal lobes and MRS showed mildly reduced N-acetylaspartate (NAA) in areas of severe T2 elongation with a long TE sequence. A peak of lactate/lipid was indicated at a chemical shift of 1.3 ppm with a short TE sequence. The peak for myo-inositol was normal in areas of severe and mild T2 elongation with short TE MRS. These findings suggest that demyelination progresses slowly in van der Knaap disease and that MRS with long and short TE is useful for the evaluation of neural metabolization associated with van der Knaap disease.
Adult↗
"Burst and slow complexes" in nonconvulsive epileptic status.
Generalized 1Hz, burst-and-slow-wave complexes were observed in a comatosed patient with acute disseminated encephalomyelitis (ADEM) when she showed extremely intractable, generalized convulsions and fragmented myoclonus in the whole body. Two types of short-latency SEPs were obtained separately during the burst and slow phase of the EEG (SEP-burst and SEP-slow, respectively), which showed a two fold greater amplitude of N20 in the former than in the latter. This suggests enhanced responsiveness to the peripheral stimuli during the burst phase as compared with the slow phase. CSF and serum were positive for autoantibodies to NMDA receptors. The "burst and slow complexes" reported here are considered to be an atypical EEG pattern of a generalized epileptic phenomenon.
Adult↗
[A child with non-herpetic acute limbic encephalitis affecting the claustrum and hippocampus].
We experienced an 8-year-old-boy with non-herpetic acute limbic encephalitis (NHALE), who developed headache, convulsion, consciousness disturbance, and ataxia following cold like symptoms. Disturbance of short term memory and a change of character were recognized. Myoclonic seizures and generalized tonic clonic convulsions developed, that responded to antiepileptic agents. Although other symptoms resolved spontaneously, short term memory disturbance persisted. Brain MRI demonstrated the lesion involving the bilateral claustrum and right hippocampus. Three months later, the lesion in the claustrum disappeared, but the hippocampus still showed slight hyperintensity on FLAIR image of MRI. Autoantibodies against glutamine receptor were detected in the cerebrospinal fluid and plasma, which suggested the involvement of immunologic disturbances in this disease. In NHALE, many cases have been reported in adults but not in children, and the further attentions should be paid to childhood-onset NHALE.
Basal Ganglia↗
Acute limbic encephalitis: a new entity?
Clinical cases similar to herpes simplex virus (HSV) encephalitis have accumulated in Japan. Detailed examinations have failed to demonstrate HSV infection. Recently, these cases have been named "non-herpetic acute limbic encephalitis". Only a single autopsy case was so far reported in an abstract form, because many cases showed a good prognosis. The case presented here was that following fever, a 59-year-old woman developed disturbance of consciousness and uncontrollable generalized seizures. Brain MRI revealed abnormal signals in the bilateral medial temporal lobe and along the lateral part of the putamen. Autoantibody against the NMDA glutamate receptor (GluR) IgM-epsilon2 was detected in the serum, and the GluR IgG-delta2 antibody was positive in cerebrospinal fluid. She died 12 days after onset. An autopsy examination revealed scattered foci consisting of neuronal loss, neuronophagia and some perivascular lymphocytic infiltration in the hippocampus and amygdala, but no haemorrhagic necrosis in the brain. HSV-1, -2 and human herpes virus-6 were negative immunohistochemically. We believe that our autopsy case may contribute to understanding the neuropathological background of non-herpetic acute limbic encephalitis.
Acute Disease↗
P-chiral o-phosphinophenol as a P/O hybrid ligand: preparation and use in Cu-catalyzed asymmetric conjugate addition of diethylzinc to acyclic enones.
[reaction: see text] (S)-2-(tert-Butylmethylphosphino)phenol and its methyl ether were synthesized from tert-butyldichlorophosphine via optically active phosphine-boranes as the intermediates. The former compound was used as a P/O hybrid ligand in the Cu-catalyzed asymmetric conjugate addition of diethylzinc to acyclic enones to achieve high enantioselectivity of up to 96%.
Catalysis↗
Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population.
Lafora disease (LD) is a rare autosomal recessive genetic disorder characterized by epilepsy, myoclonus, and progressive neurological deterioration. LD is caused by mutations in the EMP2A gene encoding a protein phosphatase. A second gene for LD, termed NHLRC1 and encoding a putative E3 ubiquitin ligase, was recently identified on chromosome 6p22. The LD is relatively common in southern Europe, the Middle East, and Southeast Asia. A few sporadic cases with typical LD phenotype have been reported from Japan; however, our earlier study failed to find EPM2A mutations in four Japanese families with LD. We recruited four new families from Japan and searched for mutations in EPM2A . All eight families were also screened for NHLRC1 mutations. We found five independent families having novel mutations in NHLRC1. Identified mutations include five missense mutations (p.I153M, p.C160R, p.W219R, p.D245N, and p.R253K) and a deletion mutation (c.897insA; p.S299fs13). We also found a family with a ten base pair deletion (c.822-832del10) in the coding region of EPM2A. In two families, no EPM2A or NHLRC1 mutation was found. Our study, in addition to documenting the genetic and molecular heterogeneity observed for LD, suggests that mutations in the NHLRC1 gene may be a common cause of LD in the Japanese population.
Amino Acid Sequence↗
A case of acute encephalitis with refractory, repetitive partial seizures, presenting autoantibody to glutamate receptor Gluepsilon2.
An 11-year-old male was admitted to our hospital because of high-grade fever, repetitive seizures, and prolonged impairment of consciousness (Glasgow coma scale E1, M5, V1). His seizures were repetitive complex partial seizures that expanded from the unilateral face to the corresponding side of the body. He sometimes developed secondary generalized seizures. While most seizures lasted 1 or 2 min, intractable seizures also frequently (about 5 times/h) occurred. We diagnosed him as encephalitis/encephalopathy, and treated him with artificial respiration, thiamylal sodium, mild hypothermia therapy, steroid pulse therapy, massive gamma-globulin therapy, etc. Afterwards, he had sequelae, such as post-encephalitic epilepsy (same seizures continued to recur), hyperkinesia, impairment of immediate memory, change in character (he became sunny and obstinate), dysgraphia, and mild atrophy of the hippocampus, amygdala, and cerebrum. However, he could still attend a general junior high school. He was diagnosed as acute encephalitis with refractory, repetitive partial seizures (AERRPS). In this case, he was positive for autoantibody to glutamate receptor Gluepsilon2 IgG or IgM in an examination of blood and spinal fluid, and we presumed that this may have influenced his sequelae. In this case, a combination of mild hypothermia therapy, steroid pulse therapy, and massive gamma-globulin therapy was effective.
Autoantibodies↗
Serial MR imaging and 1H-MR spectroscopy of unidentified bright objects in a case of neurofibromatosis type 1.
Serial study using MR imaging and 1H-MR spectroscopy (1H-MRS) of unidentified bright objects (UBO) in a 9-year-old boy with neurofibromatosis type 1 (NF1) is described. UBO was indicated in the left globus pallidum at 3 years old, then appeared in the right globus pallidum at 5 years old along with left hemiconvulsion. These UBO gradually disappeared over several years. On 1H-MRS, the ratios of N-acetylaspartate (NAA)/creatine and that of choline/creatine were each mildly reduced in the UBO. These ratios improved in parallel with disappearance of the UBO. In addition, elevation of the lactate/lipid peak was shown in UBO during the early stage, however, it disappeared in the latter. The longitudinal follow-up using MR image and 1H-MRS was useful for metabolic evaluation of UBO in patients with NF1.
Brain↗
A common variable immunodeficient patient who developed acute disseminated encephalomyelitis followed by the Lennox-Gastaut syndrome.
Common variable immunodeficiency (CVID) is a primary disorder characterized by impaired antibody production. CVID patients may develop recurrent infections, autoimmune disorders, and malignant lymphomas, but to our knowledge, there is no report on CVID patients who develop acute disseminated encephalomyelitis (ADEM) or the Lennox-Gastaut syndrome. We describe a 1-yr-old female CVID patient with ADEM who evolutionally manifested the Lennox-Gastaut syndrome. She was admitted with convulsions and T2-weighted magnetic resonance imaging (MRI) revealed high-intensity areas in the right temporal lobe and the left fronto-parietal region but she became conscious soon. Her serum findings showed severe hypogammaglobulinemia and a follow up MRI revealed that these areas had diminished. Consequently, she was diagnosed as having CVID with ADEM. After 5 months, she fell to having tonic and absence seizures and we diagnosed her as having the Lennox-Gastaut syndrome from electroencephalograms (EEG) and the seizure pattern. She is now 7 yr old and her tonic seizures are controlled with valproic acid, clobazam, and immunoglobulin replacement therapy which is administrated every 2 wk. It is well known that the immune and neurologic systems have a close relationship. We suspect that a genetic defect in the immune system of our patient might also be associated with the neurologic disorders of ADEM and the Lennox-Gastaut syndrome.
Common Variable Immunodeficiency↗
Autoantibodies and cell-mediated autoimmunity to NMDA-type GluRepsilon2 in patients with Rasmussen's encephalitis and chronic progressive epilepsia partialis continua.
PURPOSE: To evaluate antibody-mediated and cytotoxic T cell-mediated pathogenicity that has been implicated as the autoimmune pathophysiological mechanism in Rasmussen's encephalitis. METHODS: We examined autoantibodies against the N-methyl-d-aspartate glutamate receptor (NMDA-type GluR) epsilon2 subunit and its epitopes in serum and CSF samples from 20 patients [five histologically proven (definitive) Rasmussen's encephalitis with epilepsia partialis continua (EPC), four definitive Rasmussen's encephalitis without EPC, and 11 clinical Rasmussen's encephalitis with EPC]. We examined 3H-thymidine uptake into lymphocytes after stimulation by GluRs. RESULTS: All nine definitive patients (five patients with EPC and four without EPC), and 10 of 11 clinical Rasmussen's encephalitis patients had the autoantibodies. In four patients, the autoantibodies were absent in early stage when epileptic seizures had already become frequent, and appeared subsequently. In two patients, the autoantibodies persisted in the serum after frontal lobe resection or functional hemispherectomy, although epileptic seizures were completely controlled. Autoantibodies to the C2 epitope predominated, while autoantibodies to the extracellular N epitope were rare. The mean 3H-thymidine uptake ratios (stimulation by GluRepsilon2-containing homogenates/stimulation by PHA) were significantly higher in definitive and clinical Rasmussen encephalitis patients than in controls. The mean 3H-thymidine uptake ratios (relative to PHA) were significantly higher for GluRepsilon2-containing homogenate than for control homogenate or GluRdelta2-containing homogenate. CONCLUSIONS: Autoantibodies against GluRepsilon2 may be one of the diagnostic markers for Rasmussen's encephalitis with and without EPC. Patients have activated T cells stimulated by GluRepsilon2 in peripheral blood circulation. We speculate that cellular autoimmunity and the subsequent humoral autoimmunity against GluRepsilon2 may contribute to the pathophysiological processes in Rasmussen's encephalitis.
Adolescent↗
Reflex seizures in patients with malformations of cortical development and refractory epilepsy.
PURPOSE: Malformations of cortical development (MCDs) are usually highly epileptogenic, and their hyperexcitability could facilitate the occurrence of reflex seizures. We sought to characterize reflex seizures in patients with MCDs and refractory epilepsy. METHODS: Clinical, electrographic, and neuroimaging data were reviewed in eight patients with MCDs who had reflex seizures reproduced during presurgical evaluation. RESULTS: All eight patients had both reflex and spontaneous seizures. In six, however, drop attacks or axial myoclonic seizures occurred only upon specific sensory stimulation. Reflex seizures were induced by more than one type of stimulus in most patients, but anatomofunctional correlations could usually be invoked. Six patients had significant intellectual impairment. Surgical resection controlled seizures in two patients. CONCLUSIONS: Reflex seizures in patients with MCDs may be medically refractory and may often manifest as drop attacks or axial myoclonus. Surgical resection of focal lesions can bring reflex seizures under control. Putative mechanisms related to the relatively low frequency of reflex seizures in MCDs are discussed.
Adolescent↗
[Subacute encephalitis with anti-glutamate receptor antibodies presented with epilepsia partialis continua].
A previously healthy 32-year-old man visited our clinic with a 5-week history of involuntary movement. Examination demonstrated continuous myoclonic jerks in the left elbow. Two days later, he developed generalized convulsion. Electroencephalography demonstrated small spikes over the right central region. Thus, we made a diagnosis of epilepsia partialis continua (EPC) with a secondary generalization. On admission, serum electrolytes, glucose and ceruloplasmin levels, and amino acid analysis were unremarkable. HIV serology was negative. Anticardiolipin, anti-MPO ANCA, and anti-Hu antibodies were negative. The cerebrospinal fluid (CSF) showed 151/microl lymphocytes and 23/microl polymorphs, 70 mg/dl of glucose, and 61 mg/dl of protein. Autoantibodies against the glutamate receptor subunits epsilon-2 and delta-2 were detected in the serum and CSF. Cranial MRI was unremarkable. Treatment with acyclovir and high-dose methylprednisolone failed to halt the jerks. Two weeks after admission, he developed status epilepticus, which necessitated general anesthesia. Intravenous immunoglobulin infusion gave no beneficial effects. Two months after the onset of the status epilepticus, his convulsions were controlled with zonisamide, clobazam, and carbamazepine. While he had no motor dysfunctions, he had loss of spontaneity and memory impairment. This report suggests that EPC might be the initial symptom of subacute encephalitis with a possible autoimmune mechanism.
Adult↗
[A case of non-herpetic acute encephalitis with autoantibodies for ionotropic glutamate receptor delta2 and epsilon2].
We report a 45-year-old woman admitted to our hospital due to fever, consciousness disturbance, and severe seizures. Based on her signs and symptoms and clinical course, a diagnosis of non-herpetic acute encephalitis was made. She received antibiotic drugs, acyclovir, gamma-globulin, and steroid pulse therapy (methylprednisolone 1 g/day, 3 days). The patient's signs, symptoms and severe seizure showed marked improvement, but she still showed monthly seizure attacks and both anterograde and retrograde amnesia Viral infection and autoimmune response after viral infection may have been involved in non-herpetic acute encephalitis in our patient. Recently, autoantibodies to GluRepsilon2 and VGKC were reported in cases of non-herpetic acute limbic encephalitis (NHALE). In our patient, we detected IgM type autoantibody to GluRdelta2 and epsilon2 in both the CSF and serum, and these antibodies normalized in the CSF with the clinical course. Autoantibodies to GluRdelta2 and epsilon2 may be involved in the clinical symptoms and pathogenesis of non herpetic acute limbic encephalitis. This is the first report of MRI-positive non-herpetic acute encephalitis with autoantibodies to GluRdelta2 and epsilon2.
Acute Disease↗