First evidence of tick-borne encephalitis (TBE) outside of Hokkaido Island in Japan.

Tick-borne encephalitis (TBE) is an infection of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is endemic in parts of Europe and Asia. TBEV is transmitted to humans primarily by Ixodes ticks. There have been 5 TBE cases identified in Japan, all on the northern island of Hokkaido. Rodents with TBEV antibodies and Ixodes ticks have been identified throughout Japan, indicating that TBEV infection might be undiagnosed in Japan. Residual serum and cerebrospinal fluid (CSF) collected in 2010-2021 from 520 patients ≥1 year-of-age previously hospitalized with encephalitis or meningitis of unknown etiology at 15 hospitals (including 13 hospitals outside of Hokkaido) were screened by ELISA for TBEV IgG and IgM antibodies; TBEV infection was confirmed by the gold standard neutralization test. Residual serum was available from 331 (63.6%) patients and CSF from 430 (82.6%) patients; both serum and CSF were available from 189 (36.3%). Two patients were TBE cases: a female aged 61 years hospitalized for 104 days in Oita (2000 km south of Hokkaido) and a male aged 24 years hospitalized for 11 days in Tokyo (1200 km south of Hokkaido). Retrospective testing also identified a previous TBEV infection in a female aged 45 years hospitalized for 12 days in Okayama (1700 km south of Hokkaido). TBEV infection should be considered as a potential cause of encephalitis or meningitis in Japan. TBE cases are likely undiagnosed in Japan, including outside of Hokkaido, due to limited clinical awareness and lack of availability of TBE diagnostic tests.

Visualization of Parkinsonian Tongue Tremor on Ultrasonography.

This case report describes involuntary trembling of the tongue accompanied by throat discomfort and affected voice quality in a patient with a history of hypertension and ventricular extrasystole.

RGMa Signal in Macrophages Induces Neutrophil-Related Astrocytopathy in NMO.

OBJECTIVE: Repulsive guidance molecule-a (RGMa) is a glycosylphosphatidylinositol-linked glycoprotein which has multiple functions including axon growth inhibition and immune regulation. However, its role in the pathophysiology of neuromyelitis optica (NMO) is poorly understood. Perivascular astrocytopathy, which is induced by the leakage of aquaporin-4 (AQP4)-specific IgG into the central nervous system parenchyma, is a key feature of NMO pathology. We investigated the RGMa involvement in the pathology of NMO astrocytopathy, and tested a therapeutic potential of humanized anti-RGMa monoclonal antibody (RGMa-mAb). METHODS: Using a clinically relevant NMO rat model, we evaluated the therapeutic effect of a RGMa-mAb by behavioral testing, immunohistochemistry, and gene expression assay. We further performed in vitro experiments to address the RGMa-signaling in macrophages. RESULTS: In both NMO rats and an NMO-autopsied sample, RGMa was expressed by the spared neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. AQP4-IgG-induced astrocytopathy and clinical exacerbation in NMO rats were ameliorated by RGMa-mAb treatment. RGMa-mAb treatment significantly suppressed neutrophil infiltration, and decreased the expression of neutrophil chemoattractants. Interestingly, neogenin-expressing macrophages accumulated in the lesion expressed CXCL2, a strong neutrophil chemoattractant, and further analysis revealed that RGMa directly regulated CXCL2 expression in macrophages. Finally, we found that our NMO rats developed neuropathic pain, and RGMa-mAb treatment effectively ameliorated the severity of neuropathic pain. INTERPRETATION: RGMa signaling in infiltrated macrophages is a critical driver of neutrophil-related astrocytopathy in NMO lesions, and RGMa-mAb may provide an efficient therapeutic strategy for NMO-associated neuropathic pain and motor deficits in patients with NMO. ANN NEUROL 2022;91:532-547.

Connexins in neuromyelitis optica: a link between astrocytopathy and demyelination.

Neuromyelitis optica, a rare neuroinflammatory demyelinating disease of the CNS, is characterized by the presence of specific pathogenic autoantibodies directed against the astrocytic water channel aquaporin 4 (AQP4) and is now considered as an astrocytopathy associated either with complement-dependent astrocyte death or with astrocyte dysfunction. However, the link between astrocyte dysfunction and demyelination remains unclear. We propose glial intercellular communication, supported by connexin hemichannels and gap junctions, to be involved in demyelination process in neuromyelitis optica. Using mature myelinated cultures, we demonstrate that a treatment of 1 h to 48 h with immunoglobulins purified from patients with neuromyelitis optica (NMO-IgG) is responsible for a complement independent demyelination, compared to healthy donors' immunoglobulins (P < 0.001). In parallel, patients' immunoglobulins induce an alteration of connexin expression characterized by a rapid loss of astrocytic connexins at the membrane followed by an increased size of gap junction plaques (+60%; P < 0.01). This was co-observed with connexin dysfunction with gap junction disruption (-57%; P < 0.001) and increased hemichannel opening (+17%; P < 0.001), associated with glutamate release. Blocking connexin 43 hemichannels with a specific peptide was able to prevent demyelination in co-treatment with patients compared to healthy donors' immunoglobulins. By contrast, the blockade of connexin 43 gap junctions with another peptide was detrimental for myelin (myelin density -48%; P < 0.001). Overall, our results suggest that dysregulation of connexins would play a pathogenetic role in neuromyelitis optica. The further identification of mechanisms leading to connexin dysfunction and soluble factors implicated, would provide interesting therapeutic strategies for demyelinating disorders.

Genetic factors for susceptibility to and manifestations of neuromyelitis optica.

OBJECTIVE: To identify genetic factors associated with susceptibility to and clinical features of neuromyelitis optica spectrum disorders (NMOSD). METHODS: Genome-wide single nucleotide polymorphism (SNP) genotyping was conducted in 211 Japanese patients with NMOSD fulfilling the 2006 criteria with or without anti-aquaporin-4 (AQP4) antibody and 1,919 Japanese healthy controls (HCs). HLA-DRB1 and HLA-DPB1 alleles were genotyped in 184 NMOSD cases and 317 HCs. Multiple sclerosis (MS) risk alleles outside the major histocompatibility complex (MHC) region were tested in NMOSD and MS genetic burden (MSGB) scores were compared between HCs and NMOSD. RESULTS: A SNP (rs1964995) in the MHC region was associated with NMOSD susceptibility (odds ratio (OR) = 2.33, P = 4.07 × 10-11 ). HLA-DRB1*08:02 (OR = 2.86, P = 3.03 × 10-4 ) and HLA-DRB1*16:02 (OR = 8.39, P = 1.92 × 10-3 ) were risk alleles for NMOSD susceptibility whereas HLA-DRB1*09:01 was protective (OR = 0.27, P = 1.06 × 10-5 ). Three MS risk variants were associated with susceptibility and MSGB scores were significantly higher in NMOSD than in HCs (P = 0.0095). A SNP in the KCNMA1 (potassium calcium-activated channel subfamily M alpha 1) gene was associated with disability score with genome-wide significance (rs1516512, P = 2.33 × 10-8 ) and transverse myelitis (OR = 1.77, P = 0.011). KCNMA1 was immunohistochemically detected in the perivascular endfeet of astrocytes and its immunoreactivity was markedly diminished in active spinal cord lesions in NMOSD. INTERPRETATION: Specific HLA-DRB1 alleles confer NMOSD susceptibility and KCNMA1 is associated with disability and transverse myelitis in NMOSD.

Genetic screening for potassium channel mutations in Japanese autosomal dominant spinocerebellar ataxia.

Spinocerebellar ataxia (SCA) is a genetically heterogeneous disease characterized by cerebellar ataxia. Many causative genes have been identified to date, the most common etiology being the abnormal expansion of repeat sequences, and the mutation of ion channel genes also play an important role in the development of SCA. Some of them encode calcium and potassium channels. However, due to limited reports about potassium genes in SCA, we screened 192 Japanese individuals with dominantly inherited SCA who had no abnormal repeat expansions of causative genes for potassium channel mutations (KCNC3 for SCA13 and KCND3 for SCA19/SCA22) by target sequencing. As a result, two variants were identified from two patients: c.1973G>A, p.R658Q and c.1018G>A, p.V340M for KCNC3, and no pathogenic variant was identified for KCND3. The newly identified p.V340M exists in the extracellular domain, and p.R658Q exists in the intracellular domain on the C-terminal side, although most of the reported KCNC3 mutations are present at the transmembrane site. Adult-onset and slowly progressive cerebellar ataxia are the main clinical features of SCA13 and SCA19 caused by potassium channel mutations, which was similar in our cases. SCA13 caused by KCNC3 mutations may present with deep sensory loss and cognitive impairment in addition to cerebellar ataxia. In this study, mild deep sensory loss was observed in one case. SCA caused by potassium channel gene mutations is extremely rare, and more cases should be accumulated in the future to elucidate its pathogenesis due to channel dysfunction.

Rheumatoid meningitis can present MRI findings that mimic chronic subdural haematoma.

A 65-year-old woman with long-standing rheumatoid arthritis (RA) experienced a recurrent tingling sensation in her left arm followed by aphasia and a tingling sensation in her right arm. A subsequent imaging study showed bilateral subdural fluid accumulation and we initially diagnosed her with a transient ischaemic attack and chronic subdural haematoma (CSDH). The cerebral spinal fluid study revealed an inflammatory response without any indications of infection or malignant tumours. After a meningeal biopsy, we redefined the diagnosis to rheumatoid meningitis (RM), and the patient showed remarkable improvement with prednisolone administration. RM should be considered as an alternative diagnosis when examining central nervous system diseases in patients with RA, as RM presents a highly variable clinical picture with image findings similar to those of CSDH.

Value of in vivo α-synuclein deposits in Parkinson's disease: A systematic review and meta-analysis.

Previous studies that have investigated the potential of in vivo abnormal α-synuclein deposits as a pathological biomarker for PD included few participants and reported different diagnostic accuracies. Here, we aimed to confirm the diagnostic value of in vivo α-synuclein deposits in PD through a systematic review and meta-analysis, with special emphasis on determining the tissue most suitable for examination and assessing whether anti-native α-synuclein or anti-phosphorylated α-synuclein antibodies should be used. Databases were searched on December 30, 2018. We finally included 41 case-control studies that examined in vivo tissue samples using anti-native α-synuclein or anti-phosphorylated α-synuclein antibody in PD patients and controls. Using a univariate random-effects model, pooled sensitivity and specificity (95% confidence interval) of anti-native α-synuclein antibody were 0.54 (0.49-0.60) and 0.72 (0.68-0.76) for the gastrointestinal tract and 0.76 (0.60-0.89) and 0.60 (0.43-0.74) for the skin. Pooled sensitivity and specificity (95% confidence interval) of anti-phosphorylated α-synuclein antibody were 0.43 (0.37-0.48) and 0.82 (0.78-0.86) for the gastrointestinal tract, 0.76 (0.69-0.82) and 1.00 (0.98-1.00) for the skin, 0.42 (0.26-0.59) and 0.94 (0.84-0.99) for the minor salivary glands, and 0.66 (0.51-0.79) and 0.96 (0.86-1.00) for the submandibular glands. Although ubiquitous heterogeneity between the included studies should be noted when interpreting our results, our analyses demonstrated the following: (1) in vivo α-synuclein immunoreactivity has the potential as a pathological biomarker for PD; (2) anti-phosphorylated α-synuclein antibody consistently has higher specificity than anti-native α-synuclein antibody; and (3) skin biopsy examination using anti-phosphorylated α-synuclein antibody has the best diagnostic accuracy, although feasibility remains an important issue. © 2019 International Parkinson and Movement Disorder Society.

[Neuronal intranuclear inclusion disease with prolonged impaired consciousness and status epilepticus: a case report].

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease presenting with various manifestations including dementia, weakness, transient impaired consciousness, encephalitis-like episodes and also epileptic seizures. However, the nature of epileptic seizures, focal or generalized onset, remains unclear. A man at age 76 was admitted to a local hospital due to febrile impaired consciousness lasting several days. During the hospital stay, a generalized convulsion occurred, and afterward he remained obtunded. He was transferred to our hospital for further treatment. One additional seizure occurred while on an ambulance to our hospital and two additional seizures shortly after the arrival, which indicated convulsive status epilepticus (SE). The ictal EEG showed low amplitude fast activity arising from the left centro-parietal area with an evolutionary pattern. The clinical concomitant was the contralateral versive seizure evolving to a bilateral convulsion. Inter-ictal epileptiform abnormalities seen on the tracings taken on later days consisted of brief potentially ictal rhythmic discharges (B(I)RDs) and frequent sharp waves recorded from both frontal areas. These findings along with the ictal discharges would indicate a multifocal epileptic disorder in this patient. Diffusion weighted images (DWIs) of this patient showed hyperintensity signals in the cortico-medullary junctions in the bilateral frontal and the left parietal regions. Skin biopsy revealed characteristic intranuclear inclusions, and hence the diagnosis of NIID was made. The regions of epileptic foci on EEG corresponded well to the hyperintensity areas in DWIs, which suggests the cerebral cortices near the DWI hyperintensity could be more hyperactive than other regions. This case report suggests that some of the prolonged impaired consciousness and the encephalitis-like episodes in NIID could be related to epileptic seizures and even non-convulsive SE or a post-ictal twilight state after an unwitnessed convulsion. This issue should be further studied for the appropriate treatment of episodic encephalopathy and epileptic seizures in NIID.

[A case of painful seizure accompanying ictal paresis and homonymous hemianopia due to post-stroke epilepsy].

A 69-year-old female with an old infarct of the left parietotemporal lobe was admitted for the evaluation of suspected painful seizures accompanying ictal paresis. The painful seizure and ictal paresis involved her right extremities without convulsions, although intermittent tremulous movements were noted on the right upper extremity. She also showed right hemianopia during the seizure. Ictal scalp EEG demonstrated lateralized rhythmic sharply contoured delta activity intermingled with a large amount of spikes, sharp waves, and fast activity mainly on the posterior half of the left hemisphere. Ictal MRI showed restricted diffusion in the postcentral gyrus and dilatation of distal branches of the left middle cerebral artery (MCA). 99mTc-ECD SPECT revealed hyperperfusion on the left parietal cortex. Treatment with antiepileptic drugs successfully prevented seizure recurrence, then she was discharged home. On the follow-up SPECT after 1 month, the abnormal hyperperfusion disappeared. MRI demonstrated resolution of the restricted diffusion and the MCA dilatation. Taken together with the EEG abnormality and the transient abnormalities in SPECT and MRI, we concluded that her seizures were epileptic and that her painful seizures likely arise from the left primary somatosensory cortex. The mechanism of ictal paresis would be attributed to some disturbed functional architecture in the left primary motor cortex leading to loss of normal motor function through epileptic interference by ictal discharges. The same mechanism in the visual cortex could be assumed for her ictal hemianopia. Painful seizure and ictal paresis each is rarely encountered, even more so the combination thereof. These ictal manifestations might be difficult to differentiate from transient ischemic attack or postictal paresis, and thus EEG is essential to diagnose this treatable condition.

Nocturnal Hypertension in Multiple System Atrophy May Cause Posterior Reversible Encephalopathy Syndrome.

Nocturnal hypertension (NH) is a symptom of cardiovascular dysautonomia in multiple system atrophy (MSA); however, care and medication are often insufficient. We herein report a patient with MSA who showed posterior reversible encephalopathy syndrome (PRES) caused by hypertension during sleep. He presented clinically with total blindness; T2-weighted magnetic resonance imaging showed high signal intensities in the bilateral subcortical occipital-temporal lobes. His PRES was completely reversed by blood pressure control. NH may contribute to the development of PRES. The appropriate assessment and management of hemodynamic changes in MSA, including NH, is necessary to prevent severe complications such as PRES.

[Contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging was useful in detecting inflammation of the meninges in neuropsychiatric systemic lupus erythematosus: a case report].

A 49-year-old woman was admitted to our hospital with recurrent episodes of paresthesia attacks evolving in 5 to 15 minutes from the left hand to the left leg through the left trunk. Neurological examination revealed cortical sensory disturbance in her left hand. Although contrast-enhanced T1-weighted MRI findings were unremarkable, contrast-enhanced fluid-attenuated inversion recovery (FLAIR) MRI revealed abnormal leptomeningeal enhancement over the sulcus of the parietal lobe, including the sulcus around the postcentral gyrus. Because we assumed the cause of the recurrent sensory attack to be meningeal inflammation around the primary somatosensory cortex, we treated this patient by increasing the dose of prednisolone. The increase in prednisolone dose completely resolved the symptom, as well as the abnormal leptomeningeal enhancement on contrast-enhanced FLAIR MRI. In patients with suspected meningeal inflammation, contrast-enhanced FLAIR MRI, which is reported to be more sensitive than contrast-enhanced T1-weighted MRI in detecting subtle abnormal leptomeningeal enhancement, should be the modality of choice.

Incongruous, incomplete, homonymous hemianopia due to an infarction localized to the lateral geniculate body.

A 45-year-old male was admitted with an acute-onset visual field defect. Goldmann perimetry revealed an incongruent, incomplete right homonymous hemianopia. The left eye showed a wedge-shaped, horizontal right hemianopia, whereas the right eye showed constriction of the right visual hemifield. MRI showed acute infarction localized to the left lateral geniculate body (LGB). LGB has a dual blood supply: from the anterior choroidal artery and from the lateral posterior choroidal artery (LPChA). The LPChA territory of LGB receives projection from the retinal area around the macula and horizontal meridian. Therefore, an LPChA territory infarction of LGB can cause a wedge-shaped, horizontal visual field defect. The visual field defect in our patient would be caused by an LPChA territory infarction of LGB. Our patient showed an incongruent homonymous hemianopia. LGB has six laminae, with the ipsilateral retinal fibers terminating in layers two, three, and five and the crossed fibers terminating in layers one, four, and six. The laminar structure provides the anatomical basis for the incongruous visual field defects in a case of partial lesion of LGB. Based on the present data, we believe that an ischemic lesion localized to LGB should be considered in patients presenting with incongruous, incomplete homonymous hemianopia.

Persistent lesion hyperintensity on brain diffusion-weighted MRI is an early sign of intravascular lymphoma.

A 63-year-old man presented with right-sided hemianopia and unsteady gait. Brain MRI revealed multiple hyperintense infarct-like lesions on diffusion-weighted images (DWI). Hyperintensity persisted in some of these lesions even after 6 weeks, although his symptoms were ameliorated then. The patient developed episodic dizziness and a transient event of apraxia at 18 weeks after the first episode. Brain MRI revealed additional hyperintense lesions on DWI, which persisted even after 7 weeks. Eventually, the patient manifested cauda equina syndrome 39 weeks after the first episode. Brain MRI showed the presence of new lesions in addition to the persistent hyperintense lesions on DWI over 21 weeks in the right frontal lobe. Based on laboratory findings and the pathological assessment of bone marrow and random skin biopsies, the patient was diagnosed with intravascular lymphoma (IVL). Persistent hyperintense lesions on DWI of brain MRI may precede the clinical exacerbation of IVL.