Takahiro Iizuka

Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen

BACKGROUND Some encephalitides or seizure disorders once thought idiopathic now seem to be immune mediated. We aimed to describe the clinical features of one such disorder and to identify the autoantigen involved. METHODS 15 patients who were suspected to have paraneoplastic or immune-mediated limbic encephalitis were clinically assessed. Confocal microscopy, immunoprecipitation, and mass spectrometry were used to characterise the autoantigen. An assay of HEK293 cells transfected with rodent GABA(B1) or GABA(B2) receptor subunits was used as a serological test. 91 patients with encephalitis suspected to be paraneoplastic or immune mediated and 13 individuals with syndromes associated with antibodies to glutamic acid decarboxylase 65 were used as controls. FINDINGS All patients presented with early or prominent seizures; other symptoms, MRI, and electroencephalography findings were consistent with predominant limbic dysfunction. All patients had antibodies (mainly IgG1) against a neuronal cell-surface antigen; in three patients antibodies were detected only in CSF. Immunoprecipitation and mass spectrometry showed that the antibodies recognise the B1 subunit of the GABA(B) receptor, an inhibitory receptor that has been associated with seizures and memory dysfunction when disrupted. Confocal microscopy showed colocalisation of the antibody with GABA(B) receptors. Seven of 15 patients had tumours, five of which were small-cell lung cancer, and seven patients had non-neuronal autoantibodies. Although nine of ten patients who received immunotherapy and cancer treatment (when a tumour was found) showed neurological improvement, none of the four patients who were not similarly treated improved (p=0.005). Low levels of GABA(B1) receptor antibodies were identified in two of 104 controls (p<0.0001). INTERPRETATION GABA(B) receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies. FUNDING National Institutes of Health.

Overlapping demyelinating syndromes and anti–N-methyl-D-aspartate receptor encephalitis.

To report the clinical, radiological, and immunological association of demyelinating disorders with anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis.

Slowly progressive spread of the stroke-like lesions in MELAS

Background: Little is known about temporal and spatial progression of the stroke-like lesion during the acute stage of the stroke-like episode in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Methods: In four stroke-like episodes of MELAS observed in three patients, MRI, EEG, and SPECT were studied consecutively within the first month of the onset. Results: The first presenting symptoms were headache in all four stroke-like episodes, followed by hemianopsia, psychosis, and aphasia. In three episodes, epileptic seizure developed subsequently in close association with a progression of stroke-like lesion. In all four episodes, serial MRI showed a slowly progressive spread of the stroke-like lesion evolving from the temporal cortex to the surrounding parietal or occipital cortex over a few weeks following the onset of initial symptoms. Apparent diffusion coefficient (ADC) maps showed slightly decreased ADC values in the actively evolving brain lesions compared with those in nonaffected regions of the brain. EEG showed a pattern of focal periodic epileptiform discharges in three episodes. SPECT showed a focal hyperemia in all four stroke-like lesions, in two of which focal hyperemia persisted for the first month. A T1-weighted hyperintense cortical signal on MRI compatible with cortical laminar necrosis was seen during the subacute stage of all stroke-like lesions. Conclusion: Slowly and progressively spreading stroke-like lesions on MRI may reflect ongoing neuronal metabolic derangement associated with concomitant vasogenic edema provoked by prolonged epileptic seizure activities.

Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome

Background The pathogenesis of stroke-like episodes in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) remains unknown. Methods Fourteen stroke-like episodes in six patients with MELAS were studied using clinical, neuroradiologic, and electrophysiologic approaches. In two patients postmortem examination was done. Results Headache and epileptic seizure were the most common presenting symptoms. In 13 of 14 episodes the cerebral cortex was primarily involved with variable subcortical edema particularly in the temporal, occipital, and parietal cortex. Repeated MRI performed in two episodes revealed progressive spread of the cortical lesion to the surrounding cortex for a few weeks after the onset of symptoms. In 6 of 11 episodes T1-weighted hyperintense cortical signal compatible with cortical laminar necrosis was seen during subacute stage of the episode. Fat-suppression MRI confirmed intracortical gyral hemorrhage in one episode. Petechial gyral microhemorrhages were also pathologically confirmed in the autopsy of another patient. In 9 of 11 episodes focal epileptiform discharges on EEG were noted in the acute brain lesion. In seven of nine episodes focal cortical hyperperfusion was seen in SPECT studies. Conclusion The stroke-like episodes in MELAS may reflect neuronal hyperexcitability, which increases energy demand and creates energy imbalance between energy requirement and adequate availability of adenosine triphosphate due to oxidative phosphorylation defect particularly in the susceptible neuronal population, causing cortical necrosis. The episodic nature of stroke-like episodes is unexplained.

Neurological response to early removal of ovarian teratoma in anti-NMDAR encephalitis

We report an 18-year-old woman with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, who developed psychiatric symptoms, progressive unresponsiveness, dyskinesias, hypoventilation, hypersalivation and seizures. Early removal of an ovarian teratoma followed by plasma exchange and corticosteroids resulted in a prompt neurological response and eventual full recovery. Serial analysis of antibodies to NR1/NR2B heteromers of the NMDAR showed an early decrease of serum titres, although the cerebrospinal fluid titres correlated better with clinical outcome. The patients’ antibodies reacted with areas of the tumour that contained NMDAR-expressing tissue. Search for and removal of a teratoma should be promptly considered after the diagnosis of anti-NMDAR encephalitis.

Late-onset anti-NMDA receptor encephalitis.

Objective: To describe the clinical features and outcome of anti–NMDA receptor (NMDAR) encephalitis in patients ≥45 years old. Method: Observational cohort study. Results: In a cohort of 661 patients with anti-NMDAR encephalitis, we identified 31 patients ≥45 years old. Compared with younger adults (18–44 years), older patients were more often male (45% vs 12%, p < 0.0001), had lower frequency of tumors (23% vs 51%, p = 0.002; rarely teratomas), had longer median time to diagnosis (8 vs 4 weeks, p = 0.009) and treatment (7 vs 4 weeks, p = 0.039), and had less favorable outcome (modified Rankin Scale score 0–2 at 2 years, 60% vs 80%, p < 0.026). In multivariable analysis, younger age (odds ratio [OR] 0.15, confidence interval [CI] 0.05–0.39, p = 0.0001), early treatment (OR 0.60, CI 0.47–0.78, p < 0.0001), no need for intensive care (OR 0.09, CI 0.04–0.22, p < 0.0001), and longer follow-up (p < 0.0001) were associated with good outcome. Rituximab and cyclophosphamide were effective when first-line immunotherapies failed (OR 2.93, CI 1.10–7.76, p = 0.031). Overall, 60% of patients older than 45 years had full or substantial recovery at 24 months follow-up. Conclusions: Anti-NMDAR encephalitis is less severe in patients ≥45 years old than in young adults, but the outcome is poorer in older patients. In this age group, delays in diagnosis and treatment are more frequent than in younger patients. The frequency of underlying tumors is low, but if present they are usually carcinomas instead of teratomas in younger patients. Early and aggressive immunotherapy will likely improve the clinical outcome.

Regional cerebral blood flow and cerebrovascular reactivity during chronic stage of stroke-like episodes in MELAS — Implication of neurovascular cellular mechanism

BACKGROUND Ischemic vascular hypothesis as a causative role in the pathogenesis of stroke-like episodes in MELAS remains to be debated. METHODS This study consisted of two parts. Part 1 is a clinicoradiological study during acute stage of 18 consecutive stroke-like episodes in six patients with MELAS. Part 2 is a SPECT study to assess the regional cerebrovascular reactivity (rCVR) to acetazolamide during chronic stage in five patients with MELAS. RESULTS Headache and epileptic seizure were the most common presenting symptoms. Unique features of acute stroke-like lesions included progressive spread of cortical lesions with vasogenic edema, focal periodic epileptiform discharges, focal hyperperfusion, and cortical laminar necrosis during subacute stage. During chronic stage, SPECT showed hypoperfusion in non-affected occipital cortex in three patients as well as in previously affected regions in four. The rCVR was preserved in three patients, focally impaired in one, and extensively impaired in one, but relatively preserved in the occipital cortex in all patients. CONCLUSIONS Stroke-like episodes could be non-ischemic neurovascular events initiated by neuronal hyperexcitability. Once neuronal hyperexcitability develops in a focal brain region, epileptic activities depolarize adjacent neurons, leading to a propagation of epileptic activities into the surrounding cortex, and resulting in energy imbalance. The mechanisms for neuronal hyperexcitability remain to be elucidated.

Clinical and Immunologic Investigations in Patients With Stiff-Person Spectrum Disorder

IMPORTANCE Symptoms of stiff-person syndrome (SPS), stiff-limb syndrome (SLS), or progressive encephalomyelitis with rigidity, myoclonus, or other symptoms (SPS-plus) can occur with several autoantibodies, but the relative frequency of each antibody, syndrome specificity, and prognostic implications are unclear. OBJECTIVE To report the clinical and immunologic findings of a large cohort of patients with stiff-person spectrum disorder (SPSD), including SPS, SLS, and SPS-plus. DESIGN, SETTING, AND PATIENTS This study retrospectively examined a case series (January 1, 1998, through December 31, 2014) of immunologic investigations performed in a neuroimmunology referral center. The study included 121 patients with clinical features of SPSD. Data analysis was performed from July 1, 2015, through November 1, 2015. MAIN OUTCOMES AND MEASURES Analysis of clinical-immunologic associations, including autoantibodies to 8 proteins expressed in inhibitory synapses. RESULTS The median age of the patients was 51 years (interquartile range, 40-61 years), and 75 (62.0%) were female. Fifty (41.3%) had SPS, 37 (30.6%) had SPS-plus, 24 (19.8%) had SLS, and 10 (8.3%) had SPS or SLS overlapping with ataxia, epilepsy, or encephalitis. Fifty-two patients (43.0%) had glutamic acid decarboxylase (GAD65) antibodies (2 with γ-aminobutyric acid-A [GABA-A] receptor antibodies), 24 (19.8%) had α1-subunit of the glycine receptor (GlyR) antibodies (2 with GAD65 antibodies), 5 (4.1%) had other antibodies, and 40 (33.1%) tested negative for antibodies. None had gephyrin or glycine transporter antibodies. Among the main immunologic groups (GAD65 antibodies, GlyR antibodies, and antibody negative), those with GAD65 antibodies were more likely to be female (45 [86.5%] of 52, 8 [36.4%] of 22, and 18 [45.0%] of 40, respectively; P < .001), have systemic autoimmunity (34 [65.4%] of 52, 7 [31.8%] of 22, and 13 [32.5%] of 40, respectively; P = .004), and have longer delays in being tested for antibodies (median, 3 vs 0.5 and 1 year; P < .001). Patients with GAD65 antibodies were more likely to develop SPS (27 [51.9%] of 52) or overlapping syndromes (8 [15.4%] of 52) than patients with GlyR antibodies (5 [22.7%] and 0 [0%] of 22, respectively), who more often developed SPS-plus (12 [54.5%] of 22 vs 7 [13.5%] in those with GAD65 antibodies); antibody-negative patients had an intermediate syndrome distribution. In multivariable analysis, symptom severity (P = .001) and immunologic group (P = .01) were independently associated with outcome. Compared with patients with GlyR antibodies, those with GAD65 antibodies (odds ratio, 11.1, 95% CI, 2.3-53.7; P = .003) had worse outcome. Patients without antibodies had similar outcome than patients with GlyR antibodies (odds ratio, 4.2, 95% CI, 0.9-20.0; P = .07). CONCLUSIONS AND RELEVANCE In SPSD, symptom severity and presence and type of antibodies are predictors of outcome.

Glycine receptor antibodies are detected in progressive encephalomyelitis with rigidity and myoclonus (PERM) but not in saccadic oscillations

Glycine receptor (GlyR) antibodies were recently identified in a few patients with progressive encephalomyelitis with rigidity and myoclonus (PERM); none of these patients had antibodies against glutamic acid decarboxylase (GAD). An inhibitory glycinergic transmission defect has also been implicated in the mechanism underlying saccadic oscillations, including ocular flutter or opsoclonus; GlyR antibodies have not been reported in these patients. The purpose was to determine whether GlyR antibodies are found in patients with PERM, ocular flutter syndrome (OFS), and opsoclonus-myoclonus syndrome (OMS). GlyR antibodies were first measured in archived sera and CSF from five patients, including one patient with GAD antibody-positive PERM, two patients with OFS, and two patients with OMS. GlyR antibodies were also measured in archived sera from nine other adult patients with OMS. GlyR antibodies and GAD antibodies were both found at high titers in the serum and CSF of the patient with PERM, and their levels paralleled disease activity over time. GlyR antibodies were not found at significant levels in 13 patients with saccadic oscillations. GlyR and GAD antibodies can co-exist in PERM and follow the clinical course. Although saccadic oscillations are a feature of this condition, GlyR antibodies are not commonly found in patients with isolated saccadic oscillations.

Neurovascular changes in prolonged migraine aura in FHM with a novel ATP1A2 gene mutation

Objectives To report cerebral blood flow changes during attacks of hemiplegic migraine with prolonged aura (HMPA) longer than 24 h in patients with familial hemiplegic migraine (FHM) with a novel gene mutation. Methods The authors performed serial neuroimaging studies during acute stage and after recovery of aura symptoms in eight HMPA attacks in two affected individuals of the Japanese family of FHM during a 10-year-observational period. The authors also performed a mutational analysis for all exons of the CACNA1A, ATP1A2 and SCN1A genes in three individuals of this family. Results Each patient had an individual ‘predominantly affected hemisphere,’ that is, susceptible to hemiplegia during an HMPA attack. Migraine aura lasted 4 to 12 days. Neuroimaging studies performed on days 1 to 4 showed hyperperfusion in the affected hemisphere contralateral to hemiplegia in five attacks, hypoperfusion in three, middle cerebral artery vasodilation in five and augmented vasogenic leakage with cortical oedema in one. Hyperperfusion developed more frequently than hypoperfusion in the ‘predominantly affected hemisphere,’ whereas only hypoperfusion developed in the ‘non-predominantly affected hemisphere.’ All changes were fully reversible. The authors identified a novel heterozygous p.H916L mutation in the ATP1A2 gene in all three individuals. Conclusions Although the perfusion state could be different depending on the time course of migraine or the timing of scans in relation to cortical spreading depression, prolonged aura symptoms in this family were frequently associated with hyperperfusion and middle cerebral artery vasodilation. Hyperperfusion tended to occur in the ‘predominantly affected hemisphere,’ but the mechanism of HMPA awaits further investigations on additional cases of FHM2.