H-intensity scale score to estimate CSF GluN1 antibody titers with one-time immunostaining using a commercial assay.

Introduction: Anti-NMDA receptor encephalitis is an autoimmune disorder caused by autoantibodies (abs) against the conformational epitope on GluN1 subunits. GluN1-abs have been determined with cell-based assay (CBA) co-expressing GluN1/GluN2 subunits. However, commercial fixed CBA expressing only GluN1 subunit has increasingly been used in clinical practice. The ab titers can be determined with serial dilutions, but its clinical significance remains unclear. We aimed to develop an H-intensity scale (HIS) score to estimate GluN1-ab titers in cerebrospinal fluid (CSF) with one-time immunostaining using both commercial CBA and immunohistochemistry and report its usefulness. "H" is the initial of a patient with high CSF GluN1-ab titers (1:2,048). Methods: We first determined the reliability of CBA in 370 patients with suspected autoimmune encephalitis by comparing the results between commercial CBA and established assay in Dalmau's Lab. Then, we made positive control panels using the patient H's CSF diluted in a fourfold serial dilution method (1:2, 1:8, 1:32, 1:128, 1:512, and 1:2,048). Based on the panels, we scored the intensity of ab reactivity of 79 GluN1-ab-positive patients' CSF (diluted at 1:2) on a scale from 0 to 6 (with ≥1 considered positive). To assess inter-assay reliability, we performed immunostaining twice in 21 patients' CSF. We investigated an association between the score of CSF obtained at diagnosis and the clinical/paraclinical features. Results: The sensitivity and specificity of CBA were 93.7% (95% CI: 86.0-97.3) and 98.6% (95% CI: 96.5-99.5), respectively. Linear regression analysis showed a good agreement between the scores of the first and second assays. Patients with a typical spectrum, need for mechanical ventilation support, autonomic symptoms/central hypoventilation, dyskinesias, speech dysfunction, decreased level of consciousness, preceding headache, ovarian teratoma, and CSF leukocyte count >20 cells/µL had a higher median HIS score than those without, but HIS score was not associated with sex, age at onset, or seizure. HIS score at diagnosis had a significant effect on 1-year functional status. Discussion: The severity of disease and four of the six core symptoms were associated with higher GluN1-ab titers in CSF at diagnosis, which may play a role in poor 1-year functional status. An incomplete phenotype can be attributed to low CSF GluN1-ab titers.

Neuronal surface antigen-specific immunostaining pattern on a rat brain immunohistochemistry in autoimmune encephalitis.

A variety of neuronal surface (NS) antibodies (NS-Ab) have been identified in autoimmune encephalitis (AE). Tissue-based assay (TBA) using a rodent brain immunohistochemistry (IHC) is used to screen NS-Ab, while cell-based assay (CBA) to determine NS antigens. Commercial rat brain IHC is currently available but its clinical relevance remains unclear. Immunostaining patterns of NS antigens have not been extensively studied yet. To address these issues, we assessed a predictive value of "neuropil pattern" and "GFAP pattern" on commercial IHC in 261 patients, and characterized an immunostaining pattern of 7 NS antigens (NMDAR, LGI1, GABAaR, GABAbR, AMPAR, Caspr2, GluK2). Sensitivity and specificity of "neuropil pattern" for predicting NS-Ab were 66.0% (95% CI 55.7-75.3), and 98.2% (95% CI 94.8-99.6), respectively. False-positive rate was 1.8% (3/164) while false-negative rate was 34.0% (33/97). In all 3 false-positive patients, neuropil-like staining was attributed to high titers of GAD65-Ab. In 33 false-negative patients, NMDAR was most frequently identified (n=18 [54.5%], 16/18 [88.9%] had low titers [< 1:32]), followed by GABAaR (n=5). Of 261 patients, 25 (9.6%) had either GFAP (n=21) or GFAP-mimicking pattern (n=4). GFAP-Ab were identified in 21 of 31 patients examined with CBA (20 with GFAP pattern, 1 with GFAP-mimicking pattern). Immunostaining pattern of each NS antigen was as follows: 1) NMDAR revealed homogenous reactivity in the dentate gyrus molecular layer (DG-ML) with less intense dot-like reactivity in the cerebellar granular layer (CB-GL); 2) both GABAaR and GluK2 revealed intense dot-like reactivity in the CB-GL, but GABAaR revealed homogenous reactivity in the DG-ML while GluK2 revealed intense reactivity along the inner layer of the DG-ML; and 3) LGI1, Caspr2, GABAbR, and AMPAR revealed intense reactivity in the cerebellar ML (CB-ML) but LGI1 revealed intense reactivity along the middle layer of the DG-ML. Whereas, Caspr2, GABAbR, and AMPAR revealed similar reactivity in the DG-ML but some difference in other regions. TBA is useful not only for screening NS- or GFAP-Ab but also for estimating NS antigens; however, negative results should be interpreted cautiously because "neuropil pattern" may be missed on commercial IHC when antibody titers are low. Antigen-specific immunoreactivity is a useful biomarker of AE.

Status epilepticus suspected autoimmune: Neuronal surface antibodies and main clinical features.

OBJECTIVES: Status epilepticus (SE) can be associated with neuronal surface antibodies (NS-Abs) but NS-Ab detection rate remains unknown in patients with SE of unclear etiology at symptom presentation but suspected of having an autoimmune etiology (SE suspected autoimmune). We aimed to determine the NS-Ab detection rate and the clinical features that predict the presence of NS-Abs in patients with SE suspected autoimmune. METHODS: We retrospectively reviewed the clinical information of 137 patients with SE suspected autoimmune who underwent testing for NS-Abs between January 2007 and September 2020. NS-Abs were examined in both serum and cerebrospinal fluid (CSF) obtained at symptom onset with established assays. We classified brain magnetic resonance imaging (MRI) findings into unremarkable, autoimmune limbic encephalitis (ALE) (bilateral abnormalities highly restricted to the medial temporal lobes), ALE-Plus (ALE pattern and additional extramedial temporal lobe abnormalities), multifocal cortico-subcortical (MCS), or other pattern. We compared the clinical features between patients with and without NS-Abs. RESULTS: Forty-four patients (32.1%) had NS-Abs, including 35 N-methyl-d-aspartate receptor (NMDAR) (one with concurrent γ-aminobutyric acid B receptor [GABAbR] and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor [AMPAR]), 5 γ-aminobutyric acid A receptor (GABAaR), 2 leucine-rich glioma-inactivated 1(LGI1), 1 GABAbR, and 1 unknown antigens. Compared with NS-Ab-negative patients, NS-Ab-positive patients were more likely to have a preceding headache (56.8% vs 26.7%), preceding psychobehavioral or memory alterations (65.9% vs 20.4%), involuntary movements (79.5% vs 16.1%), CSF pleocytosis (81.8% vs 62.0%), elevated immunoglobulin G (IgG) index (45.2% vs 15.6%), oligoclonal bands (51.5% vs 9.5%), tumor (47.7% vs 8.6%), and higher APE2 score (median of 9 vs 7), and they were less likely to have an ALE-Plus pattern (2.3% vs 23.7%). However, preceding fever and ALE or MCS pattern were not different between the two groups of patients. SIGNIFICANCE: When an autoimmune etiology was suspected, there was a relatively high likelihood (one of three patients) of identifying NS-Abs. Some clinical features (preceding symptoms, inflammatory CSF) predict a higher likelihood of finding NS-Ab positivity, but the ALE-Plus MRI pattern is more likely suggestive of NS-Ab negativity.

Asymptomatic acute ischemic lesions in intracerebral hemorrhage: Its frequency, MRI features, and risk factors.

BACKGROUND: Asymptomatic acute ischemic lesions (AIL) may be coincidentally found on brain magnetic resonance imaging (MRI) obtained during the acute phase of intracerebral hemorrhage, but its clinical significance has yet to be determined. The objective of this study is to determine the frequency of asymptomatic AIL, its characteristic features of brain MRI and risk factors in patients with acute intracerebral hemorrhage. METHODS: We retrospectively reviewed the clinical information of 108 patients with intracerebral hemorrhage who underwent brain MRIs within 30 days of hospitalization between April 2013 and January 2018. We determined the frequency of asymptomatic AIL, its brain MRI features, and risk factors. RESULTS: AIL was found in 26 of 108 patients; symptomatic in 2 and asymptomatic in 24 (22.2%). Asymptomatic AIL were small, multiple, mainly distributed to the white matter in the anterior circulation (22/24, 91.7%), and occasionally seen in deep watershed areas (15/24, 62.5%). Only 2 patients had severe major vessel stenosis. Asymptomatic AIL was associated with high mean blood pressure (BP) on admission (> 145 mmHg), excessive drug-induced reduction in mean BP (≥ 55 mmHg), and large hemorrhage (> 31 mL in volume). CONCLUSIONS: Asymptomatic AIL were found in 22.2% of patients with intracerebral hemorrhage within 30 days of hospitalization. Asymptomatic AIL were often small, multiple and occasionally developed in deep watershed areas despite the absence of major vessel stenosis. High mean BP on admission, excessive drug-induced BP reduction, and larger hemorrhage may be a risk factor for development of asymptomatic AIL.

Clinically based score predicting cryptogenic NORSE at the early stage of status epilepticus.

OBJECTIVE: To determine whether a clinically based score predicts cryptogenic new-onset refractory status epilepticus (C-NORSE) at the early stage of status epilepticus (SE) with prominent motor symptoms (SE-M) of unclear etiology. METHODS: The score (range 0-6) included 6 clinical features: highly refractoriness to antiseizure drugs, previously healthy individual, presence of prodromal fever, absence of prodromal psychobehavioral or memory alterations, absence of dyskinesias, and symmetric brain MRI abnormalities (the first 2 mandatory). We retrospectively assessed the usefulness of a high scale score (≥5) in predicting C-NORSE in 83 patients with SE-M of unclear etiology, who underwent testing for neuronal surface antibodies (NS-Abs) between January 2007, and December 2019. RESULTS: Thirty-one (37.3%) patients had a high score. Patients with a high score had more frequent prodromal fever (28/31 vs 24/52), mechanical ventilatory support (31/31 vs 36/52), and symmetric MRI abnormalities (26/31 vs 12/52), had less frequent involuntary movements (2/31 vs 30/52), and had absent prodromal psychobehavioral alterations (0/31 vs 27/52), CSF oligoclonal band detection (0/27 vs 11/38), tumor association (0/31 vs 13/52), or NS-Abs (0/31 vs 29/52) than those with a low score (<5). Thirty-three patients (median age, 27 years; 18 [54.5%] female) were finally regarded as C-NORSE. The sensitivity and specificity of a high score for predicting C-NORSE were 93.9% (95% CI 0.87-0.94) and 100% (95% CI 0.95-1.00), respectively. CONCLUSIONS: Patients with a high score in the indicated scale are more likely to have C-NORSE, making it a useful diagnostic tool at the early stage of SE-M before antibody test results become available.

Correction to: A cluster of disseminated small cortical lesions in MELAS: its distinctive clinical and neuroimaging features.

The author would like to correct the errors in the publication of the original article. The corrected details are given below for your reading.

A cluster of disseminated small cortical lesions in MELAS: its distinctive clinical and neuroimaging features.

OBJECTIVES: To investigate a diversity of stroke-like episodes (SLEs) in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and report a disseminated form of SLEs (D-SLEs) attributed to a cluster of disseminated small cortical lesions. METHODS: We retrospectively reviewed the clinical information of 27 MELAS patients seen at Kitasato University Hospital between January 1990 and April 2018. Among those, we selected 13 patients with m.3243A>G mutation [median age at onset, 35 years (11-68 years), two pediatric onset < 17 years] who had at least one SLE. SLEs were classified into classic or non-classic based on characteristic features of stroke-like lesions. RESULTS: 44 SLEs were identified during a median observational period of 119 months (3-240 months). Among those, 29 (65.9%) were classic SLEs (C-SLEs) mainly attributed to a single continuous lobular lesion incongruent to vascular territory and occasionally accompanied by a gradual spread associated with hyperperfusion and persistent seizure activity. The remaining 15 were non-classic attributed to sparsely distributed (n = 10), disseminated (n = 4) or cerebellar lesions (n = 1). C-SLEs developed in all patients but non-classic SLEs in 5; D-SLEs developed in 4 patients accounting for 4 of 44 SLEs (9.1%). Non-classic SLEs developed more frequently in pediatric-onset than in adult-onset patients (12/15 vs. 3/29, p < 0.0001). SLEs began with acute onset of symptoms in 42 SLEs (95.5%), but D-SLEs of 2 adult-onset patients began with ill-defined subacute-onset fluctuating encephalopathy. CONCLUSIONS: This study showed a diversity of SLEs in patients with m.3243A>G mutation. Further studies are required to elucidate the pathophysiological mechanisms of non-classic SLEs including D-SLEs.

Prodromal headache in anti-NMDAR encephalitis: An epiphenomenon of NMDAR autoimmunity.

OBJECTIVE: To investigate the nature of prodromal headache in anti-NMDA receptor (NMDAR) encephalitis. METHODS: Retrospective review of the clinical information of 39 patients with anti-NMDAR encephalitis admitted between January 1999 and September 2017. Five patients with an atypical presentation were excluded. Thus, in 34 patients (median 27 years [range, 12-47 years]; 28 [82%] female), the clinical features were compared between patients who initially reported headache and those who did not report. RESULTS: Twenty-two patients (65%) reported headache either transiently (n = 5) or continuously (n = 17). Encephalitic symptoms (psychobehavioral memory alterations, seizure, dyskinesias, or altered level of consciousness) developed in 20 patients with median 5.5 days (range, 1-29 days) after headache onset. In one patient, NMDAR antibodies were detected in CSF 3 days after headache onset. Patients with headache had more frequently fever (14/22 [64%] vs. 2/12 [17%] p = 0.013) and higher CSF pleocytosis (median white blood cells 79/µl [range, 6-311/µl] vs. 30/µl [range, 2-69/µl], p = 0.035) than those without headache, but there was no difference in gender, age at onset, seizure, migraine, CSF oligoclonal band detection, elevated IgG index, tumor association, or brain MRI abnormalities between them. CONCLUSIONS: Headache often developed with fever and pleocytosis, but it was rapidly replaced by psychiatric symptoms. Based on current knowledge on the antibody-mediated mechanisms that cause a decrease of synaptic NMDAR through crosslinking and internalization leading to a state mimicking "dissociative anesthesia," we speculated that prodromal headache is not likely caused by direct effect of the autoantibodies but rather meningeal inflammation (noninfectious aseptic meningitis) that occurs in parallel to intrathecal antibody synthesis as an epiphenomenon of NMDAR autoimmunity. Psychobehavioral alterations following headache is an important clue to the diagnosis.

Practical issues in measuring autoantibodies to neuronal cell-surface antigens in autoimmune neurological disorders: 190 cases.

OBJECTIVES: To address practical issues in measuring autoantibodies to neuronal cell-surface antigens (NSAs) in various autoimmune neurological disorders (ANDs). METHODS: We retrospectively reviewed the clinical information of 221 patients with clinically suspected ANDs who underwent antibody testing for NSAs between January 2007 and September 2017. 31 were excluded. In 190 patients, antibody-detection rate (ADR) and antibody-phenotype association were assessed. RESULTS: Fifty-four patients had NSA-antibodies: NMDA receptor (NMDAR) (n = 39), AMPA receptor (n = 3), leucine-rich glioma inactivated 1 (LGI1) (n = 3), glycine receptor (GlyR) (n = 3), GABA(A) receptor (n = 2), GABA(B) receptor (n = 1), metabotrophic glutamate receptor 5 (n = 1), or unknown (n = 6); 3 had multiple NSA-antibodies. ADR in patients with diagnostic criteria for "possible autoimmune encephalitis (AE)", "probable anti-NMDAR encephalitis", "definite autoimmune limbic encephalitis (ALE)", and "stiff-person spectrum disorder (SPSD)", was 34% (46/134), 85% (34/40), 46% (11/24), and 22% (4/18), respectively, but NSA-antibodies were not identified in 11 patients with systemic autoimmune disorders (SADs). Among 134 patients with "possible AE" criteria, NMDAR-antibodies were more frequently identified in patients with typical anti-NMDAR encephalitis than those without (34/40 [85%] vs. 4/94 [4%], p < 0.0001). LGI1-antibodies were identified in patients with ALE but not in the others (3/24 [13%] vs. 0/110 [0%], p = 0.005). GlyR-antibodies were identified in those with stiff-person syndrome plus (2/8, 25%) or stiff-limb syndrome (1/6, 17%). CONCLUSIONS: NSA-antibodies were most frequently identified in "probable anti-NMDAR encephalitis", followed by "definite ALE", "possible AE", and "SPSD", but not identified in SADs. NMDAR, LGI1 and GlyR were associated with clinical phenotype. Cell-surface antigens should be determined based on individual phenotype.

Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial.

BACKGROUND: Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. METHODS: This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3-5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. FINDINGS: Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42-78; n=14) in the eculizumab group, and 45% (20-73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. INTERPRETATION: The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. FUNDING: The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.

Pitfalls in clinical diagnosis of anti-NMDA receptor encephalitis.

OBJECTIVES: To report pitfalls in the clinical diagnosis of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: We retrospectively reviewed the clinical information of 221 patients with clinically suspected autoimmune neurological disorders who underwent testing for autoantibodies against neuronal cell-surface antigens between January 1, 2007 and September 10, 2017. Forty-one patients met the diagnostic criteria for probable anti-NMDAR encephalitis (probable criteria), but one was excluded because neither serum nor CSF was examined at the active stage. Thus, in 220 patients, sensitivity and specificity of the probable criteria were assessed. RESULTS: NMDAR-antibodies were detected in 34 of 40 patients (85%) with the probable criteria; however, 2 of the 6 antibody-negative patients had ovarian teratoma. The median age at onset was higher in antibody-negative patients than those with antibodies (49 vs. 27 years, p = 0.015). The age at onset was associated with the probability of antibody detection (p = 0.014); the probability was less than 50% in patients aged 50 years or older. NMDAR-antibodies were also detected in 5 of 180 patients who did not fulfill the probable criteria; these patients presented with isolated epileptic syndrome (n = 2), atypical demyelinating syndrome (n = 2; one with aquaporin 4 antibodies), and autoimmune post-herpes simplex encephalitis (post-HSE) (n = 1). Sensitivity and specificity of the probable criteria was 87.2 and 96.7%, respectively. CONCLUSION: The probable criteria are valid, but the diversity of clinical phenotype should be taken into account in diagnosing anti-NMDAR encephalitis particularly in patients aged 50 years or older, or with isolated epileptic syndrome, atypical demyelinating syndrome, or post-HSE.

Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia.

Spinocerebellar ataxia 19/22 (SCA19/22) is a rare type of autosomal dominant SCA that was previously described in 11 families. We report the case of a 30-year-old Japanese man presenting with intellectual disability, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy, and electroencephalograms showed paroxysmal sharp waves during hyperventilation and photic stimulation. Trio whole-exome sequencing analysis of DNA samples from the patient and his parents revealed a de novo novel missense mutation (c.1150G>A, p.G384S) in KCND3, the causative gene of SCA19/22, substituting for evolutionally conserved glycine. The mutation was predicted to be functionally deleterious by bioinformatic analysis. Although pure cerebellar ataxia is the most common clinical feature in SCA19/22 families, extracerebellar symptoms including intellectual disability and myoclonus are reported in a limited number of families, suggesting a genotype-phenotype correlation for particular mutations. Although autosomal recessive diseases are more common in patients with early onset sporadic cerebellar ataxia, the present study emphasizes that such a possibility of de novo mutation should be considered.

A clinical predictive score for postoperative myasthenic crisis.

OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disease mostly caused by autoantibodies against acetylcholine receptor associated with thymus abnormalities. Thymectomy has been proven to be an efficacious treatment for patients with MG, but postoperative myasthenic crisis often occurs and is a major complication. We aimed to develop and validate a simple scoring system based on clinical characteristics in the preoperative status to predict the risk of postoperative myasthenic crisis. METHODS: We studied 393 patients with MG who underwent thymectomy at 6 tertiary centers in Japan (275 patients for derivation and 118 for validation). Clinical characteristics, such as gender, age at onset and operation, body mass index, disease duration, MG subtype, severity, symptoms, preoperative therapy, operative data, and laboratory data, were reviewed retrospectively. A multivariate logistic regression with LASSO penalties was used to determine the factors associated with postoperative myasthenic crisis, and a score was assigned. Finally, the predictive score was evaluated using bootstrapping technique in the derivation and validation groups. RESULTS: Multivariate logistic regression identified 3 clinical factors for predicting postoperative myasthenic crisis risk: (1) vital capacity < 80%, (2) disease duration < 3 months, and (3) bulbar symptoms immediately before thymectomy. The postoperative myasthenic crisis predictive score, ranging from 0 to 6 points, had areas under the curve of 0.84 (0.66-0.96) in the derivation group and 0.80 (0.62-0.95) in the validation group. INTERPRETATION: A simple scoring system based on 3 preoperative clinical characteristics can predict the possibility of postoperative myasthenic crisis. Ann Neurol 2017;82:841-849.

Cryptogenic NORSE: Its distinctive clinical features and response to immunotherapy.

OBJECTIVE: To report the distinctive clinical features of cryptogenic new-onset refractory status epilepticus (C-NORSE) and the C-NORSE score based on initial clinical assessments. METHODS: A retrospective study was conducted for 136 patients with clinically suspected autoimmune encephalitis who underwent testing for autoantibodies to neuronal surface antigens between January 1, 2007, and August 31, 2016. Eleven patients with C-NORSE were identified. Their clinical features were compared with those of 32 patients with anti-NMDA receptor encephalitis (NMDARE). RESULTS: The clinical outcome of 11 patients (median age, 27 years; 7 [64%] women) with C-NORSE was evaluated after a median follow-up of 11 months (range, 6-111 months). Status epilepticus was frequently preceded by fever (10/11 [91%]). Brain MRIs showed symmetric T2/fluid-attenuated inversion recovery hyperintensities (8/11 [73%]) and brain atrophy (9/11 [82%]). Only 2 of the 10 treated patients responded to the first-line immunotherapy, and 4 of the 5 patients treated with IV cyclophosphamide responded to the therapy. The long-term outcome was poor in 8 patients (73%). Compared with 32 patients with NMDARE (median age, 27 years; 24 [75%] women), those with C-NORSE had more frequent prodromal fever, status epilepticus, ventilatory support, and symmetric brain MRI abnormalities, had less frequent involuntary movements, absent psychobehavioral symptoms, CSF oligoclonal bands, or tumor association, and had a worse outcome. The C-NORSE score was higher in patients with C-NORSE than those with NMDARE. CONCLUSIONS: Patients with C-NORSE have a spectrum of clinical-immunological features different from those with NMDARE. The C-NORSE score may be useful for discrimination between them. Some patients could respond to immunotherapy.

Association of Progressive Cerebellar Atrophy With Long-term Outcome in Patients With Anti-N-Methyl-d-Aspartate Receptor Encephalitis.

IMPORTANCE: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder that occurs with IgG antibodies against the GluN1 subunit of NMDAR. Some patients develop reversible diffuse cerebral atrophy (DCA), but the long-term clinical significance of progressive brain and cerebellar atrophy is unknown. OBJECTIVE: To report the long-term clinical implications of DCA and cerebellar atrophy in anti-NMDAR encephalitis. DESIGN, SETTING, AND PARTICIPANTS: A retrospective observational study and long-term imaging investigation was conducted in the Department of Neurology at Kitasato University. Fifteen patients with anti-NMDAR encephalitis admitted to Kitasato University Hospital between January 1, 1999, and December 31, 2014, were included; data analysis was conducted between July 15, 2015, and January 18, 2016. EXPOSURES: Neurologic examination, immunotherapy, and magnetic resonance imaging (MRI) studies were performed. MAIN OUTCOMES AND MEASURES: Long-term MRI changes in association with disease severity, serious complications (eg, pulmonary embolism, septic shock, and rhabdomyolysis), treatment, and outcome. RESULTS: The clinical outcome of 15 patients (median age, 21 years, [range, 14-46 years]; 10 [67%] female) was evaluated after a median follow-up of 68 months (range, 10-179 months). Thirteen patients (87%) received first-line immunotherapy (intravenous high-dose methylprednisolone, intravenous immunoglobulin, and plasma exchange alone or combined), and 4 individuals (27%) also received cyclophosphamide; 2 patients (13%) did not receive immunotherapy. In 5 patients (33%), ovarian teratoma was found and removed. Serious complications developed in 4 patients (27%). Follow-up MRI revealed DCA in 5 patients (33%) that, in 2 individuals (13%), was associated with progressive cerebellar atrophy. Long-term outcome was good in 13 patients (87%) and poor in the other 2 individuals (13%). Although cerebellar atrophy was associated with poor long-term outcome (2 of 2 vs 0 of 13 patients; P = .01), other features, such as DCA without cerebellar atrophy, serious complications, ventilatory support, or prolonged hospitalization, were not associated with a poor outcome. Five patients with DCA had longer hospitalizations (11.1 vs 2.4 months; P = .002), required ventilatory support more frequently (5 of 5 vs 4 of 10 patients; P = .04), and developed more serious complications (4 of 5 vs 0 of 10 patients; P = .004) compared with those without DCA. Although DCA was reversible, cerebellar atrophy was irreversible. CONCLUSIONS AND RELEVANCE: In anti-NMDAR encephalitis, DCA can be reversible and does not imply a poor clinical outcome. In contrast, cerebellar atrophy was irreversible and associated with a poor outcome. This observation deserves further study to confirm progressive cerebellar atrophy as a prognostic marker of poor outcome.

Biphasic neurovascular changes in prolonged migraine aura in familial hemiplegic migraine type 2.

OBJECTIVE: To report biphasic changes in cerebral blood flow (CBF) in the acute phase of hemiplegic migraine with prolonged aura (HMPA), in which aura symptoms lasted longer than 24 h, in three patients with familial hemiplegic migraine (FHM) carrying a p.H916L mutation in ATP1A2 gene. METHODS: We assessed neurovascular changes with time in the affected cerebral hemisphere corresponding to aura symptoms during the acute phase of HMPA. Arterial spin labelling MRI, SPECT for CBF measurement and EEG in three attacks, in one attack FDG-PET measurement for cerebral metabolism was performed. We evaluated CBF at different phases of aura symptoms in 11 attacks of HMPA. RESULTS: In two attacks, we found biphasic CBF changes beginning with hypoperfusion followed by persistent hyperperfusion. FDG-PET revealed increased cerebral glucose metabolism in the regions corresponding to hyperperfusion on day 4 when aura symptoms still persisted. In four attacks, Z-score-based CBF mapping revealed multifocal hypoperfusion in the early phase. Hypoperfusion in our study was seen within 19 h of the onset of the symptoms in five of seven attacks, while hyperperfusion was seen 18 h or later in eight of nine attacks. EEG showed attenuated alpha activity without paroxysmal discharge. CONCLUSIONS: This is the first report showing biphasic CBF changes during the prolonged aura of FHM2. This study suggested that the results of cross-sectional CBF studies should be interpreted carefully. Initial multifocal hypoperfusion is likely due to functional depression of multifocal origin in the affected hemisphere, but the mechanism of persistent hyperperfusion requires further investigation.

[Clinical spectrum and treatment strategy in anti-NMDA receptor encephalitis: current status and issues].

Anti-NMDA receptor encephalitis is a disorder caused by IgG antibodies to the extracellular conformal epitope of the NR1 subunits. This disorder predominantly affects young female with ovarian teratoma;however, any person of any age, unrelated to gender or the presence of tumor, can be affected. This disorder usually follows multistage beginning with prodromal symptoms, followed by psychiatric symptoms, unresponsive state accompanied by intractable dyskinesias, seizure and central hypoventilation. Diversity of clinical spectrum has recently been emphasized based on antibody detection in various disorders, including schizophrenia, epilepsy, CJD, neuromyelitis optica, and HSV encephalitis, but these data must be cautiously interpreted; low serum titers may be false positive or clinically not relevant. This disorder has been regarded as treatment-responsive; however, only a half of the patients respond to the first-line immunotherapy (corticosteroids, immunoglobulins or plasma exchange) or tumor removal, and 19 percent remain highly disabled at 24 months with an estimated morality rate of 7%. In refractory cases early initiation of the second-line immunotherapy (rituximab and/or cyclophosphamide) recommended; however, it is difficult to follow the recommendation due to many issues, among those, off-label use is the major reason that prevents initiation of the second-line immunotherapy in Japan.

[Clinical spectrum of anti-glycine receptor antibody-associated disease].

Anti-glycine receptor (anti-GlyR) antibodies were first reported in 2008 in a case of progressive encephalomyelitis with myoclonus and rigidity (PERM), which is a variant of stiff-person syndrome (SPS). After that, the antibodies have been studied extensively. At least 40 patients have been reported or presented until May 2013. We reviewed 28 patients (median age 47 years, range 1 to 75 years), whose clinical data are available. Seventeen patients (60%) were male. We classified clinical phenotype into PERM (17), classic SPS (5), variant SPS (5), and others (1: progressive optic atrophy). Nine patients (32%) had ant-GAD antibodies. Accompanied diseases included thyroiditis (5), diabetes mellitus (3), thymoma (3), and Addison's disease (2). Twenty-one patients (75%) treated with immunotherapy or thymectomy improved, but two of six patients without immunotherapy died or developed cardiac arrest. The clinical features suggested that antibody-mediated inhibition of the GlyR on the brainstem nuclei or spinal inhibitory interneurons may cause continuous firing of α motor neurons and paroxysmal excessive response to a variety of afferent impulses, leading to increased stiffness, brainstem signs, trismus, myoclonus, painful spasms or hyperekplexia. Phenotype associated with the anti-GlyR antibodies may be broader than previously thought, but among those PERM is the most common phenotype.