N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit

Anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody‐mediated synaptic dysfunction. Cerebrospinal fluid–derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline‐configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose‐ and time‐dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms. Ann Neurol 2019;85:771–776     

Movement disorders in children with anti‐NMDAR encephalitis and other autoimmune encephalopathies

Accurate recognition of movement disorder phenomenology may differentiate children with anti‐N‐methyl D‐aspartate receptor (NMDAR) encephalitis, autoimmune basal ganglia encephalitis (BGE), and Sydenham's chorea (SC). Three neurologists blinded to the diagnoses recorded dominant and associated movement disorders seen on videos of 31 patients with anti‐NMDAR encephalitis (n = 10), BGE (n = 12), and SC (n = 9). Stereotypy was only seen in anti‐NMDAR encephalitis (8/10) and not in BGE and SC (P < 0.001). Perseveration was only seen in anti‐NMDAR encephalitis (5/10) and not in BGE and SC (P < 0.001). Akinesia was more commonly seen in BGE (5/12) than in anti‐NMDAR encephalitis (1/10, P = 0.097). Tremor was more commonly seen in BGE (5/12) than in anti‐NMDAR encephalitis (1/10, P = 0.097). Chorea was seen in all groups: anti‐NMDAR encephalitis (4/10), BGE (3/12), and SC (9/9). Likewise, dystonia was seen in all groups: anti‐NMDAR encephalitis (6/10), BGE (7/12), and SC (2/9). Stereotypies or perseveration are suggestive of anti‐NMDAR encephalitis, whereas their absence and the presence of akinesia and tremor is more suggestive of BGE. Chorea and dystonia are least discriminating. © 2014 International Parkinson and Movement Disorder Society     

Genetic predisposition in anti‐LGI1 and anti‐NMDA receptor encephalitis

We performed a genome‐wide association study in 1,194 controls and 150 patients with anti‐N‐methyl‐D‐aspartate receptor (anti‐NMDAR, n = 96) or anti‐leucine‐rich glioma‐inactivated1 (anti‐LGI1, n = 54) autoimmune encephalitis. Anti‐LGI1 encephalitis was highly associated with 27 single‐nucleotide polymorphisms (SNPs) in the HLA‐II region (leading SNP rs2858870 p = 1.22 × 10^?17, OR = 13.66 [7.50–24.87]). Potential associations, below genome‐wide significance, were found with rs72961463 close to the doublecortin‐like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc‐finger genes. HLA allele imputation identified association of anti‐LGI1 encephalitis with HLA‐II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10^?16) and anti‐NMDAR encephalitis with HLA‐I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863–869     

N‐methyl‐D‐aspartate receptor antibody‐associated movement disorder without encephalopathy

N‐methyl‐D‐aspartate receptor (NMDAR) antibody encephalitis is a well‐recognized clinico‐immunological syndrome that presents with a movement disorder, cognitive decline, psychiatric symptoms, and epileptic seizures. A pure monosymptomatic presentation is rare; however, some patients present predominantly with a movement disorder in the absence of encephalopathy. Here, we describe three paediatric patients with an NMDAR antibody‐mediated movement disorder: a 5‐year‐old female with acute onset hemichorea, a 10‐year‐old female with generalized chorea, and a 12‐year‐old male with abdominal myoclonus. These patients did not develop the characteristic encephalopathy syndrome seen in NMDAR encephalitis, but all three had other associated subtle cognitive deficits. The patients demonstrated good responses to immunotherapy.     

Treatment responsive GABA(B)‐receptor limbic encephalitis presenting as new‐onset super‐refractory status epilepticus (NORSE) in a deployed U.S. soldier

A 23‐year‐old, previously healthy, deployed U.S. soldier presented with bilateral temporal lobe seizures recalcitrant to multiple antiepileptic drugs and anti‐seizure anaesthetic agents. He received methylprednisolone, intravenous immunoglobulins, plasma exchange, and rituximab for presumed autoimmune encephalitis before achieving seizure freedom. Six weeks after presentation, the aetiology of his refractory seizures was found to be due to autoantibodies targeting the anti‐GABA(B)‐receptor. This case is noteworthy for being the first reported case of anti‐GABA(B)‐receptor limbic encephalitis presenting with new‐onset refractory status epilepticus (NORSE), a clinical syndrome that often carries a grave prognosis and in which a treatable aetiology is often never discovered. Our case also supports testing for GABA‐receptor autoantibodies and the upfront use of multi‐modal immunotherapy in patients presenting with limbic encephalitis and new refractory seizures.     

Anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis in children and adolescents

Objective

To report the clinical features of anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis in patients ≤ 18 years old.

Methods

Information was obtained by the authors or referring physicians. Antibodies were determined by immunocytochemistry and enzyme‐linked immunosorbent assay (ELISA) using HEK293 cells ectopically expressing NR1.

Results

Over an 8‐month period, 81 patients (12 male) with anti‐NMDAR encephalitis were identified. Thirty‐two (40%) were ≤18 years old (youngest 23 months, median 14 years); 6 were male. The frequency of ovarian teratomas was 56% in women >18 years old, 31% in girls ≤18 years old (p = 0.05), and 9% in girls ≤14 years old (p = 0.008). None of the male patients had tumors. Of 32 patients ≤18 years old, 87.5% presented with behavioral or personality change, sometimes associated with seizures and frequent sleep dysfunction; 9.5% with dyskinesias or dystonia; and 3% with speech reduction. On admission, 53% had severe speech deficits. Eventually, 77% developed seizures, 84% stereotyped movements, 86% autonomic instability, and 23% hypoventilation. Responses to immunotherapy were slow and variable. Overall, 74% had full or substantial recovery after immunotherapy or tumor removal. Neurological relapses occurred in 25%. At the last follow‐up, full recovery occurred more frequently in patients who had a teratoma that was removed (5/8) than in those without a teratoma (4/23; p = 0.03).

Interpretation

Anti‐NMDAR encephalitis is increasingly recognized in children, comprising 40% of all cases. Younger patients are less likely to have tumors. Behavioral and speech problems, seizures, and abnormal movements are common early symptoms. The phenotype resembles that of the adults, although dysautonomia and hypoventilation are less frequent or severe in children. Ann Neurol 2009;66:11–18     

N‐methyl‐D‐aspartate receptor antibodies in pediatric dyskinetic encephalitis lethargica

Encephalitis lethargica (EL) describes an encephalitis with psychiatric, sleep, and extrapyramidal movement disorders. Dyskinetic and Parkinsonian forms have been described. EL shares clinical features with the anti–N‐methyl‐D ‐aspartate receptor (NMDAR‐Ab) encephalitis. We studied 20 sera from pediatric patients with contemporary EL. Ten sera (from 2 males and 8 females, aged 1.3–13 years) and 6/6 cerebrospinal fluid samples were positive for NMDAR‐Ab. NMDAR‐Ab–positive patients had dyskinesias, agitation, seizures, and insomnia, whereas Parkinsonism and somnolence dominated in the NMDAR‐Ab–negative children. We were unable to identify any tumors. The dyskinetic form of EL is an NMDAR‐Ab encephalitis and can affect very young children. Ann Neurol 2009;66:704–709     

N‐methyl‐D‐aspartate receptor antibodies in post–herpes simplex virus encephalitis neurological relapse

Herpes simplex virus encephalitis (HSVE) is a devastating condition that relapses, often with a chorea in children, despite adequate antiviral treatment. At relapse, evidence of viral replication is frequently absent, suggesting that the relapse may be immune‐mediated. Seven children who had a neurological relapse following their initial encephalitis, identified from 20 cases of pediatric HSVE, were studied. Serum and/or cerebrospinal fluid (CSF) were tested for N‐methyl‐D‐aspartate receptor (NMDAR) and other antibodies previously reported in central nervous system autoimmunity. Five of the 7 relapsing children had choreoathetosis; 2 of these were NMDAR antibody–positive, 2 were negative (1 with HSV‐positive CSF), and 1 was not available for testing. An additional patient, who relapsed with cognitive regression but with no movement disorder, was also NMDAR antibody–positive. In 2 of the NMDAR antibody–positive patients who were treated at relapse and in 1 who was treated only after 10 years of having a relapsing encephalopathy, a beneficial response was observed. Neurological relapses after HSVE may frequently be immune‐mediated, particularly in children with chorea. NMDAR antibodies are common, and immunotherapy may be beneficial. © 2013 International Parkinson and Movement Disorder Society     

Intrathecal treatment of anti‐N‐Methyl‐d‐aspartate receptor encephalitis in children

Anti‐NDMA receptor (NMDAR) encephalitis is an auto‐immune condition. There is no uniformly agreed treatment strategy for the disorder in children. We report the use of intrathecal treatment with methotrexate and methylprednisolone in three children (one male, two females, age 10y, 11y, and 14y) with anti‐NMDAR encephalitis, who did not respond to steroids, plasmapheresis, or rituximab. There was significant clinical improvement and stabilization of the anti‐NMDAR antibody titers in cerebrospinal fluid (CSF) and blood in two patients. In the third patient, although anti‐NMDAR antibody titers in CSF decreased, clinical recovery was less satisfactory. Intrathecal treatment with methotrexate and methylprednisolone seems to be a promising alternative treatment for some paediatric cases of resistant anti‐NMDAR encephalitis.     

LGI‐1 antibody encephalitis in a seven‐year‐old girl

LGI‐1 antibody encephalitis is a rare autoimmune limbic encephalitis which has been reported predominantly in adults. Seizures in LGI‐1 antibody encephalitis exhibit significant semiological variability. Faciobrachial dystonic seizures are characteristically seen in this condition and have so far been described only in adults. Other seizure types have also been reported. We describe the case of a seven‐year‐old girl with LGI‐1 limbic encephalitis who presented with acute new‐onset seizures, and rapidly deteriorated over the course of a few weeks with very frequent seizures and encephalopathy, becoming non‐verbal and non‐ambulatory. The electroclinical presentation of this child with LGI‐1 encephalitis makes this case unique and further highlights the importance of a high index of suspicion for diagnosis in young children. Early diagnosis can lead to prompt and appropriate treatment with immunotherapy, and potential harmful treatments such as pharmacological coma can be avoided. To the best of our knowledge, this is the youngest case ever reporter. [Published with video sequences]     

N‐methyl‐d‐aspartate (NMDA) receptor antibodies encephalitis mimicking an autistic regression

Expressive dysphasia and mutism are common clinical features in children and adults with N‐methyl‐d ‐aspartate receptor antibodies (NMDAR‐Ab) encephalitis, and are likely to result from NMDAR hypofunction. A prodromal loss of social and communication skills can typify that of an autistic regression, particularly when presenting under the age of 3 years. Here we describe two toddlers who presented with developmental regression, particularly of their social communication skills, mimicking an autistic regression, who were found to have NMDAR‐Ab in the serum and cerebrospinal fluid. Although both patients had some other neurological features, they were subtle, which resulted in delayed diagnosis of NMDAR‐Ab encephalitis. Importantly, immunotherapy was beneficial in both patients, with significant improvement of their language skills and behaviour.     

PET‐positive extralimbic presentation of anti‐glutamic acid decarboxylase antibody‐associated encephalitis

Anti‐glutamic acid decarboxylase (GAD) antibody‐associated autoimmune encephalitis has been reported mostly as limbic encephalitis. Only few cases with extralimbic involvement are reported with limited investigation. Here, we report an extensive investigation with MRI, PET, and pathological examination. A 66‐year‐old Japanese female with a history of hypothyroidism, colon cancer, pheochromocytoma, and thymoma‐associated myasthenia gravis presented with generalised tonic‐clonic seizures. MRI showed multiple hyperintense lesions and PET showed hypermetabolic lesions in the brain. Biopsy showed non‐specific gliosis, microglial proliferation, and perivascular lymphohistiocytic infiltrates. Various neuronal antibodies were negative, except for anti‐GAD antibody. Anti‐GAD antibody‐associated encephalitis is an increasingly recognised CNS disease. Pathophysiology of this encephalitis is unclear. While PET showed hypermetabolic lesions, the biopsy showed non‐specific changes. The treatments may include immunosuppressants, IVIg, and plasma exchange. One should consider to measure this antibody, in addition to others, when autoimmune encephalitis is suspected [Published with video sequences].     

HSV encephalitis-induced anti-NMDAR encephalitis in a 67-year-old woman: report of a case and review of the literature

Herpes simplex virus (HSV) encephalitis can induce an autoimmune encephalitis mediated by autoantibodies against the N-methyl-D-aspartate receptor (NMDAR). Post-HSV NMDAR encephalitis and de novo NMDAR encephalitis have been more commonly described in children and young adults. We describe the case of a 67-year-old woman with post-HSV NMDAR encephalitis and review the relevant literature. Clinical, serological, neurophysiological, and imaging evaluations were undertaken in the evaluation of this patient. A literature review was performed. Nearly 2 months after a typical course of HSV encephalitis confirmed by HSV polymerase chain reaction studies from the spinal fluid and treated with intravenous acyclovir, a 67-year-old woman suffered neurological deterioration. There was no evidence of active HSV infection, but NMDAR antibodies were found in her serum and spinal fluid. The patient improved after initiation of immunosuppressive therapy. All patients who experience new or recurrent neurological symptoms following recovery from HSV encephalitis should be evaluated for post-infectious autoimmune encephalitis, including NMDAR encephalitis.     

GAD65 antibody‐associated autoimmune epilepsy with unique independent bitemporal‐onset ictal asystole

Antibodies against the 65‐kDa isoform of the intracellular enzyme, glutamate decarboxylase (GAD65), have been found in patients with limbic encephalitis and drug‐resistant autoimmune epilepsy. We report a 22‐year‐old female who presented with new‐onset seizures and neuropsychiatric symptoms. Video‐EEG captured unique, independent bitemporal‐onset focal seizures with impaired awareness and ictal asystole. An autoimmune epilepsy panel revealed elevated GAD65 antibodies in the serum (225 nmol/l) and CSF (2.78 nmol/l), while [¹⁸F]‐fluoro‐deoxy‐glucose positron emission tomography showed bitemporal hypometabolism (left > right). The patient was diagnosed with GAD65 antibody‐associated autoimmune epilepsy. Our observation adds to the spectrum of neurocardiac syndromes associated with autoimmune epilepsy.     

Clinical association of intrathecal and mirrored oligoclonal bands in paediatric neurology

Aim Biomarkers such as autoantibodies, neopterin, and oligoclonal bands (OCBs) are increasingly used for the diagnosis of treatable inflammatory central nervous system (CNS) disorders. We investigated the correlation between the results of OCB testing and clinical diagnoses in a large contemporary cohort of children with a broad range of neurological conditions. Method Cerebrospinal fluid (CSF) and serum from 200 children (94 females, 106 males; age range 2mo–15y 10mo, mean age 6y 9mo, SD ±4.9) who underwent CSF investigation for their neurological condition were tested for OCBs using isoelectric focusing. Results The patients were divided into those with inflammatory (n=58) and non‐inflammatory (n=142) CNS disorders. Intrathecal OCBs (OCBs restricted to the CSF) were found in 11 out of 58 (19%) of those with inflammatory CNS disorders compared with none of the 142 patients with non‐inflammatory CNS disorders (p<0.001). Diseases associated with intrathecal OCB were multiple sclerosis, Rasmussen encephalitis, N‐methyl‐d ‐aspartate receptor (NMDAR) encephalitis, voltage‐gated potassium channel (VGKC) encephalopathy, herpes (HSV) encephalitis, ‘other’ encephalitides, acute cerebellar ataxia, and aseptic meningitis. Mirrored OCBs (identical OCBs in the serum and CSF) were less specific but were still found in 14 out of 58 (24%) children with inflammatory CNS disorders compared with only 6 out of 142 (4%) children with non‐inflammatory CNS disorders (p<0.001). Diseases associated with mirrored OCBs included acute disseminated encephalomyelitis (ADEM), VGKC encephalopathy, West syndrome, NMDAR encephalitis, ‘other’ encephalitides, polio‐like illness, Rasmussen encephalitis, cerebral vasculitis, metachromatic leukodystrophy, and bacterial meningitis. Intrathecal OCBs and mirrored OCBs had a positive predictive value for inflammatory CNS disease of 1 (95% confidence interval [CI] 0.68–1) and 0.7 (95% CI 0.46–0.87) respectively. Conclusion Intrathecal OCBs were restricted to patients with inflammatory CNS disorders. They are a useful, but non‐specific, biomarker of CNS inflammation of multiple causes. Mirrored OCBs are less specific, but still support a possible inflammatory CNS disorder. The presence of either intrathecal or mirrored OCBs should raise suspicion of an inflammatory CNS disorder.     

Protective role of noradrenaline in benzo[a]pyrene‐induced learning impairment in developing rat

Benzo[a]pyrene (B[a]P), a carcinogen, affects brain development, learning, and memory. Isolated studies have reported that B[a]P elevates noradrenaline (NA) level that may modulate neuronal growth, learning, and memory. Therefore, we investigated in vivo and in vitro the effects of B[a]P on learning and memory and its possible mechanism of action. Intracisternal administration of B[a]P on postnatal day 5 significantly reduced learning and memory in adolescent rats as observed by probe test using the Morris water maze. The density of both the subunits of the N‐methyl‐D‐aspartate (NMDA) receptor, NMDAR1 and NMDAR2B, significantly increased in the hippocampus. In vitro, B[a]P significantly increased NMDAR1 in both C6 and Neuro2a cell lines, whereas NMDAR2B was significantly increased in C6 but was significantly decreased in Neuro2a. Pretreatment with NA prevented the B[a]P‐induced effect on NMDAR1 expression in both cell lines. However, although NA prevented the B[a]P‐mediated increase in NMDAR2B expression in C6, it further potentiated the decrease of NMDAR2B in Neuro2a cells. Also, NA prevented the B[a]P‐induced increase in intracellular Ca²⁺ both in C6 and in Neuro2a. Our findings show that postnatal exposure of developing rats to B[a]P impairs learning and memory even when the rats became adolescent. We also observed that the effects were mediated by elevated intracellular Ca²⁺ levels and increased expression of NMDAR; furthermore, NA exerted a protective effect by modulating those factors. NA differentially affects neurons and glia, which may have a compensatory role during toxic insults, especially from B[a]P. © 2013 Wiley Periodicals, Inc.     

A Rasmussen encephalitis,autoimmune encephalitis,and mitochondrial disease mimicker: expanding the DNM1L‐associated intractable epilepsy and encephalopathy phenotype

Dynamin‐1‐like protein (DNM1L) gene variants have been linked to childhood refractory epilepsy, developmental delay, encephalopathy, microcephaly, and progressive diffuse cerebral atrophy. However, only a few cases have been reported in the literature and there is still a limited amount of information about the symptomatology and pathophysiology associated with pathogenic variants of DNM1L. We report a 10‐year‐old girl with a one‐year history of mild learning disorder and absence seizures who presented with new‐onset focal status epilepticus which progressed to severe encephalopathy and asymmetric hemispheric cerebral atrophy. Differential diagnosis included mitochondrial disease, Rasmussen's encephalitis, and autoimmune encephalitis. Disease progressed from one hemisphere to the other despite anti‐seizure medications, hemispherectomy, vagus nerve stimulator, ketogenic diet, and immunomodulators. Continued cerebral atrophy and refractory seizures evolved until death four years after initial presentation. Post‐mortem whole‐exome sequencing revealed a pathogenic DNM1L variant. This paper presents a novel case of adolescent‐onset DNM1L‐related intractable epilepsy and encephalopathy.     

A case of anti‐NMDA receptor encephalitis revealed by insular epilepsy

Anti‐N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system that typically manifests predominantly as a psychiatric disorder. However, other manifestations such as epileptic seizures, abnormal movements, and memory or language complications are not unusual. Here, we report the case of a young man who presented with a new‐onset epilepsy, with ictal semiology suggestive of insular involvement; this hypothesis was supported by a PET‐CT study. Anti‐NMDAR antibodies were found in the CSF, confirming the diagnosis of anti‐NMDAR encephalitis. A review of the literature reveals that epilepsy can be the first manifestation of NMDAR encephalitis, with a clear male predominance. Despite its rarity, neurologists should consider this diagnosis for any young patient developing a new‐onset epilepsy with temporal or insular features, particularly if the patient is male. Other cognitive or behavioural signs, even very subtle, should also prompt diagnosis.     

Glycine site agonists of the N‐methyl‐d‐aspartate receptor and Parkinson's disease: A hypothesis

Limitations of current pharmacological approaches to Parkinson's disease (PD) highlight the need for the development of nondopaminergic therapeutic strategies. The potential role of glutamatergic neurotransmission modulators, including those active at the N‐methyl‐D‐aspartate receptor (NMDAR), is presently under investigation. Most literature proposes the use of NMDAR antagonists based on neurodegenerative theories of NMDAR function. Nevertheless, NMDAR antagonism has proven disappointing in clinical trials and may be associated with serious adverse events. More recent theories indicate that NMDAR target selectivity may be a cardinal prerequisite for efficacy, with present efforts being devoted primarily to development of NMDAR‐NR2B subunit antagonists. We propose a novel hypothesis according to which NMDAR stimulation, accomplished through allosteric modulation via the glycine modulatory site, may be beneficial in late‐phase PD. This hypothesis stems from: (1) meta‐analysis of randomized controlled trials performed in schizophrenia, indicating that glycine site agonists (eg, glycine, D‐serine) alleviate antipsychotic‐induced parkinsonian symptoms; (2) clinical observations indicating that NMDAR hypofunction is associated with motor disturbances; (3) results of a preliminary D‐serine trial in PD; (4) data indicating glycine efficacy in a rat tardive dyskinesia model; and (5) no evidence of excitotoxic damage following chronic high‐dose glycine nutritional supplementation. This hypothesis is discussed in the context of glycine site agonist effects on intrasynaptic NMDAR subunits and striatal synaptic plasticity. © 2013 Movement Disorder Society