Naomi Tominaga

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.

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.

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.

Abnormal myocardial scintigraphy in a GTP cyclohydrolase 1 mutation carrier with Parkinson's disease.

Mutations in the GTP cyclohydrolase 1 (GCH1) gene cause dihydroxyphenylalanine (DOPA) -responsive dystonia (DRD; DYT5, Segawa disease). Adult-onset parkinsonism rarely develops in GCH1 mutation carriers without dystonia. In these patients, the symptoms are thought to be an age-specific presentation of DRD and do not reflect nigral degeneration. A recent paper reported [123-iodine]-fluoropropyl-2 beta-carbomethoxy3 beta-(4-iodophenylnortropane) single-photon emission computed tomography (dopamine transporter [DAT] imaging) abnormalities in some GCH1 mutation carriers with parkinsonism that indicated the presence of nigral degeneration, the mechanism of which remains unknown. Ryan and colleagues suggested that a-synuclein protein levels have some interaction with GCH1 activity and tetrahydrobiopterin (BH4) levels and that the mechanisms may explain the risk for Parkinson’s disease (PD). We have recently performed imaging studies, including I-meta-iodobenzylguanidine (I-MIBG) myocardial scintigraphy, on a previously reported patient with a GCH1 mutation. Our patient noticed tremor in the upper limbs at the age of 47. He was diagnosed with PD because of right-dominant mild rigidity and small-stepped gait. His 34-year-old niece presented with DOPA-responsive limb dystonia consistent with a clinical diagnosis of DYT5, later confirmed by a GCH1 gene mutation (1 vs 3 1 1G>A). Our patient shares this GCH1 mutation. Low-dose L-DOPA, first administered to our patient at the age of 48, was effective initially, but the patient developed dyskinesia, wearing-off phenomena, sleep behavior disorder, cognitive dysfunction, hallucinations, and orthostatic hypotension that worsened over time. We performed DAT imaging and I-MIGB scintigraphy when the patient was 70 years old. DAT imaging revealed bilateral reduction of tracer uptake, and I-MIBG scintigraphy showed a low heart/medium sternum (H/M) ratio at the late phase (1.34); findings consistent with sporadic PD (Fig. 1A, B). BH4 (2.58 nM) and neopterin (4.15 nM) were abnormally reduced in CSF, as usually observed in DYT5. In his niece with DYT5, DAT imaging was normal, and the late-phase H/M ratio was normal (3.47) (Fig. 1C,D). Our results were consistent with the previous finding: normal in DRD but reduced in parkinsonian patients with GCH1 mutation. MIBG is actively transported into noradrenaline granules at sympathetic nerve terminals by a noradrenaline transporter. Its low uptake has recently been observed in PD, and it is known to be useful when distinguishing PD from other neurodegenerative parkinsonisms. The abnormal uptake of MIBG is thought to reflect a-synuclein accumulation in the epicardial nerves. Moreover, I-MIBG uptake is normal in familial PARK2 without Lewy body pathology. Therefore, abnormal MIBG scintigraphy could be a marker of Lewy body pathology or synucleinopathy. This is the first report of an MIBG scintigraphy finding in patients with a GCH1 mutation. In autopsy cases of DRD, BH4 and neopterin were reduced in the substantia nigra without Lewy bodies. No pathological studies have been performed on GCH1 mutation carriers with parkinsonian features without dystonia. The relation between Lewy body and GCH1 mutation is still a mystery. In our patient diagnosed with PD, MIBG scintigraphy showed an abnormally decreased H/M ratio. The clinical course and examinations were similar to sporadic PD with Lewy bodies. One possibility is that a carrier of GCH1 mutation accidentally also had an idiopathic PD. Another possibility is that a GCH1 mutation could be one of the risk factors for PD. Further investigations are required to establish which explanation is more plausible.

Autoimmune brachial amyotrophic diplegia and sensory neuronopathy with Sjögren's syndrome: A case report.

A 47-year-old Japanese woman presented with hand weakness and sensory symptoms. She was diagnosed with SS at 28 years of age, when sicca symptoms developed. She had been treated symptomatically without immunotherapy because she had no extra-glandular manifestations. Two years before admission tingling in the digits of her hands gradually developed and spread to all limbs. Twomonths before admission she noticed hand weakness. She visited another hospital and underwent nerve conduction studies, which showed reduction in sensory nerve action potentials (SNAP) amplitude without changes in compound muscle action potentials (CMAP) amplitude. She was referred to our hospital. On examination, shewas cognitively intact; she hadweakness in her upper limbs bilaterally, with muscle strength of 4/5 in proximal and 3/5 in distal muscles (grip strength 20 kg [right] and 16 kg [left]), but no weakness was seen in lower limbs. Thenar and interossei muscles were slightly atrophic. She had profound loss of vibration sense in upper limbs but onlymildly impaired in lower limbs; she had decreased sensation to pinprick, temperature and light touchwith a stocking-andglove distribution, and diffuse areflexia, but no pyramidal sign, sensory level, or bladder dysfunction. Romberg sign was positive, but she was able to walk in tandem. She was admitted 3 days later. Blood test-results on admission (day 1) showed leukopenia (white blood cells 1800/mm), microcytic hypochromic anemia (Hb 9.5 g/dl) and elevated erythrocyte sedimentation rate (43 mm/h), which had remained elevated since 13 years ago (range, 38 to 61mm/h). Antibody test was positive for Ro/SS-A (1:64), Tg (2440 U/ml, normal b0.3), and ANA (1:160) but negative for HIV, HTLV-1, TPO, MPO-ANCA, La/SS-B, gangliosides (IgM-GM1, IgG-GM1, IgG-GD1a, IgG-GalNAc-GD1a, and

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

To investigate the nature of prodromal headache in anti‐NMDA receptor (NMDAR) encephalitis.