Signaling via toll-like receptor 4 and CD40 in B cells plays a regulatory role in the pathogenesis of multiple sclerosis through interleukin-10 production.

BACKGROUND: B cells play an important role in the development of multiple sclerosis (MS), but can also exhibit regulatory functions through IL-10 production. Toll-like receptors (TLR) and CD40 signaling are likely to be involved in this process. OBJECTIVE: To investigate the ability of MS B cells to produce IL-10 in response to TLR stimulation in the presence or absence of CD40 co-stimulation. METHODS: Peripheral blood mononuclear cells obtained from 34 MS patients and 24 matched healthy participants (HS) were stimulated through either TLR4 or TLR9 alone, or together with CD40. Intracellular cytokine production was analyzed by flow cytometry. RESULTS: The frequency of IL-10-producing cells in total B cells after either TLR9 or CD40 stimulation was significantly lower in MS than HS, regardless of disease phase. The frequency of IL-10 producing B cells after TLR4 stimulation did not differ significantly between HS and MS, regardless of disease phase. TLR4 and CD40 co-stimulation synergistically increased the frequency of IL-10-producing but not pro-inflammatory cytokine-producing B cells at MS relapse. This effect was observed in both CD27- naïve and CD27+ memory B cells. The frequency of IL-10-producing B cells following CD40 stimulation was significantly higher in interferon-ß responders than non-treated MS patients. Finally, we confirmed that the frequency of IL-10-producing B cells positively correlated with IL-10 production quantity by B cells using magnetic-isolated B cells. CONCLUSIONS: Cross-talk between TLR4 and CD40 signaling plays a crucial role in regulating IL-10 production by B cells during MS relapses, which may promote recovery from relapse. CD40 signaling in B cells is involved in the response to interferon-ß in MS. Collectively, TLR4 and CD40 signaling in B cells may provide a promising target for MS therapy.

Lipocalin-type prostaglandin D synthase: a glymphopathy marker in idiopathic hydrocephalus.

Idiopathic normal pressure hydrocephalus in elderly people is considered a form of glymphopathy caused by malfunction of the waste clearance pathway, called the glymphatic system. Tau is a representative waste material similar to amyloid-ß. During neurodegeneration, lipocalin-type prostaglandin D synthase (L-PGDS), a major cerebrospinal fluid (CSF) protein, is reported to act as a chaperone that prevents the neurotoxic aggregation of amyloid-ß. L-PGDS is also a CSF biomarker in idiopathic normal pressure hydrocephalus and significantly correlates with tau concentration, age, and age-related brain white matter changes detected by magnetic resonance imaging. To investigate this glymphopathy, we aimed to analyze white matter changes and contributing factors in vivo and their interactions ex vivo. Cerebrospinal tap tests were performed in 60 patients referred for symptomatic ventriculomegaly. Patients were evaluated using an idiopathic normal pressure hydrocephalus grading scale, mini-mental state examination, frontal assessment battery, and timed up-and-go test. The typical morphological features of high convexity tightness and ventriculomegaly were measured using the callosal angle and Evans index, and parenchymal white matter properties were evaluated with diffusion tensor imaging followed by tract-based spatial statistics. Levels of CSF biomarkers, including tau, amyloid-ß, and L-PGDS, were determined by ELISA, and their interaction, and localization were determined using immunoprecipitation and immunohistochemical analyses. Tract-based spatial statistics for fractional anisotropy revealed clusters that positively correlated with mini-mental state examination, frontal assessment battery, and callosal angle, and clusters that negatively correlated with age, disease duration, idiopathic normal pressure hydrocephalus grading scale, Evans index, and L-PGDS. Other parameters also indicated clusters that correlated with symptoms, microstructural white matter changes, and L-PGDS. Tau co-precipitated with L-PGDS, and colocalization was confirmed in postmortem specimens of neurodegenerative disease obtained from the human Brain Bank. Our study supports the diagnostic value of L-PGDS as a surrogate marker for white matter integrity in idiopathic normal pressure hydrocephalus. These results increase our understanding of the molecular players in the glymphatic system. Moreover, this study indicates the potential utility of enhancing endogenous protective factors to maintain brain homeostasis.

Subthalamic nucleus deep brain stimulation restores normal rapid eye movement sleep in Parkinson's disease.

BACKGROUND: In Parkinson's disease, sleep disturbance is a common occurrence. METHODS: We evaluated sleep in 10 patients with Parkinson's disease (age, 57.5 ± 9.8 years; disease duration, 12.3 ± 2.7 years) before and after subthalamic nucleus deep brain stimulation using the Parkinson's disease sleep scale and polysomnography. RESULTS: Their total sleep scale scores and daytime sleepiness subscale scores significantly improved after subthalamic nucleus-deep brain stimulation. The novel findings from this study significantly increased normal rapid eye movement sleep, and decreased abnormal rapid eye movement sleep without atonia after deep brain stimulation in patients with Parkinson's disease. The improved total sleep scale score correlated with decreased wakefulness after sleep onset. Moreover, improved daytime sleepiness correlated with increased normal rapid eye movement sleep time. Sleep improvement did not significantly correlate with resolution of motor complication or reduced dopaminergic dosages. CONCLUSIONS: Subthalamic nucleus-deep brain stimulation may have beneficial effects on sleep disturbance in advanced Parkinson's disease by restoring sleep architecture and normal rapid eye movement sleep.

SARS-CoV-2-related Progressive Brain White Matter Lesion Associated with an Increased Cerebrospinal Fluid Level of IL-6.

We herein report a 49-year-old man with a fever, diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. After two weeks of hospitalization, he suddenly mentioned visual field impairment. Computed tomography and magnetic resonance imaging revealed white matter damage and vasogenic edema. Cerebrospinal fluid showed increased levels of interleukin (IL)-6. His symptoms and white matter lesion deteriorated. After treatment with intravenous methylprednisolone therapy and plasmapheresis, his symptoms and white matter lesion improved gradually. We suspect that our patient was affected by a secondary hyperinflammatory syndrome related to cytokines, alone or in combination with direct viral injury through endothelial cell damage. The IL-6 levels were elevated only in the cerebrospinal fluid, suggesting focal central nervous system inflammation.

Radiological and Laboratory Features of Multiple Sclerosis Patients With Immunosuppressive Therapy: A Multicenter Retrospective Study in Japan.

Background: Multiple sclerosis (MS) is a relapsing, inflammatory, and demyelinating disease of central nervous system showing marked clinical heterogeneity. Many factors might influence the choice of relapse prevention drug, and treatment response varies among patients. Despite the enlargement of disease-modifying drugs for MS (MS-DMDs), some patients have been treated with corticosteroid and/or immunosuppressant (CS/IS). Objective: To clarify the radiological and laboratory features of MS treated with CS/IS for relapse prevention. Methods: Clinical records including radiological and laboratory findings, and drugs used for relapse prevention were reviewed retrospectively. Results: Out of 92 consecutive MS patients, 25 (27%) were treated with CS/IS. The followings were observed less frequently in patients treated with CS/IS than in those with MS-DMDs: three or more periventricular lesions, ovoid lesions, subcortical lesions, typical contrast-enhancing lesions, negative for serum autoantibodies, and positive for oligoclonal bands in the cerebrospinal fluid. Multiple logistic regression analysis revealed that the absence of typical contrast-enhancing lesions and positivity for serum autoantibodies were independent factors associated with CS/IS prescription (odds ratio 25.027 and 14.537, respectively). Conclusion: In this cohort of Japanese patients clinically diagnosed with MS, radiological and serological findings atypical of MS were observed more frequently in patients treated with CS/IS than in those with MS-DMDs as a part of MS therapy. The absence of contrast-enhancing lesions typical of MS and positivity for serum autoantibodies were independent factors strongly associated with CS/IS use.

Japanese Familial Cases of Frontotemporal Dementia and Parkinsonism with N279K Tau Gene Mutation.

BACKGROUND: Mutations in the tau gene linked to chromosome 17 cause frontotemporal dementia and parkinsonism (FTDP-17). OBJECTIVE: This study presents 3 Japanese familial cases diagnosed with N279K tau gene mutation, including 1 autopsy-confirmed case. METHODS: We compared the clinical presentations, cognitive functions, and images between the 3 familial cases diagnosed with N279K mutation. RESULTS: All 3 patients presented symptoms in their early 40s. One patient showed severe cognitive dysfunction and died in his sixth year after onset. The remaining 2 cases presented with parkinsonism-dominant clinical features. Among the 2 cases, 1 presented the characteristic symptoms of progressive supranuclear palsy. The pathological features of the dementia-dominant case showed frontal and temporal lobe-dominant neuronal loss and gliosis. Tau-positive neuronal and glial inclusions were found throughout. Further, tufted astrocytes and globose tangles were present whereas there were no Pick bodies and astrocytic plaques, compatible with pathology-confirmed frontotemporal lobar degeneration (FTLD) -tau subtypes. CONCLUSIONS: Patients with FTDP-17 can be classified into the following 2 major groups: dementia and parkinsonism-plus predominant phenotypes. Among our 3 cases, 1 showed dementia predominance whereas the other 2 showed parkinsonism predominance. Mutations in the microtubule-associated protein tau (MAPT) present with several pathological features. Clinically, our case presented a behavioral variant frontotemporal dementia (bvFTD). However, morphologically, the observed glial and neuronal pathology met the criteria for progressive supranuclear palsy (PSP). This study highlights the clinical heterogeneity within and between families with same MAPT mutation. Few pathologically confirmed PSP cases have been reported with mutations in MAPT.

Acute Brainstem Dysfunction Caused by Cavernous Sinus Dural Arteriovenous Fistula.

Symptoms of cavernous sinus dural arteriovenous fistula depend on the drainage patterns and are very diverse. Among these, brainstem dysfunction is a rare but serious complication. Here, we describe a case with isolated and rapidly progressive brainstem dysfunction due to cavernous sinus dural arteriovenous fistula. An 80-year-old woman presented with a 2-day history of progressive gait disturbance. Neurological examination revealed mild confusion, dysarthria, and left hemiparesis. Magnetic resonance imaging (MRI) revealed pontine swelling without evidence of infarction. Magnetic resonance angiography suggested a faint abnormality near the cavernous sinus. Dural arteriovenous fistula was suspected, and digital subtraction angiography was planned for the next day. Her condition had progressed to coma by the next morning. Pontine swelling worsened, and hyperintensity appeared on diffusion-weighted imaging. Digital subtraction angiography revealed a right-sided cavernous sinus dural arteriovenous fistula with venous reflux into the posterior fossa. Orbital or ocular symptoms had preceded brainstem symptoms in all nine previously reported cases, but brainstem symptoms were the only presentation in our case, making the diagnosis difficult. Some dural arteriovenous fistulas mimic inflammatory diseases when the clinical course is acute. Prompt diagnosis using enhanced computed tomography or MRI and emergent treatment are needed to avoid permanent sequelae.

The first Japanese patient with variant Creutzfeldt-Jakob disease (vCJD).

Eleven years after a brief visit to some European countries, a 48-year-old Japanese man developed writing difficulty, irritability and general fatigue. Then he complained of dysesthetic pains in his legs, for which benzodiazepines were prescribed. However, at the time pulvinar sign was retrospectively confirmed on brain MRI. Eighteen months after the onset, his gait became ataxic with rapid deterioration of mental status over the following several months. Thirty-one months after the onset, he became akinetic and mute with periodic synchronous discharges on EEG, and died at the age of 51. The total clinical course was approximately 43 months. Pathological examination revealed the characteristic alterations of spongiform encephalopathy, severe in the thalamus, moderate but widely spread in the cerebral cortices, and moderate in the cerebellum. Abundant amyloid plaques were easily identified in the cerebral cortex and the cerebellum on HE staining. Immunohistochemistry for abnormal prion protein (PrP(sc)) confirmed amyloid plaques in several forms, such as florid, uni- and multi-centric plaques as well as perineuronal and periaxonal deposits in the basal ganglia and synaptic patterns in the thalami. A Western blotting study identified type 2B protease-resistant PrP. This is the first Japanese patient who was definitely diagnosed as variant Creutzfeldt-Jakob disease (vCJD). The pathological findings were similar to those of previous reports of vCJD in the UK. However, the changes were much more severe both in degree and distribution, probably due to a longer duration of the illness than those in the UK.

[An advantage of T2*-weighted MRI for early detection of straight sinus thrombosis: a case report].

A 44-year-old man presented with a 12-day history of severe non-throbbing headache. He showed no physical abnormality but obesity. On day 12, ring-shaped low intensity lesions inside straight sinus were revealed on T2*-weighted MRI image (T2*WI). On the following day (day 13), he was found unresponsive at home, and ambulated with disturbed consciousness. FLAIR and diffusion-weighted MRI image disclosed high intensity signals in bilateral thalamus which were postulated as vasogenic edema. MR venography and conventional cerebral angiography showed an absence of flow in inferior sagittal sinus, vein of Galen, and straight sinus. These findings confirmed the diagnosis of cerebral venous thrombosis (CVT). Anticoagulant treatment was introduced and his consciousness level was gradually improved. On day 43, he was discharged with no neurological sequelae. A delay of correct diagnosis and treatment with CVT can lead to devastating disability or even to death. An early diagnosis of CVT is often dismissed owing to the nonspecific symptoms such as headache and nausea. Recent reports described high sensitivity of T2*WI for detecting CVT. Alterations in blood flow and oxyhemoglobin reduced products, deoxyhemoglobin, in thrombosed veins often produce the magnetic susceptibility on T2*WI. A detection of ring-shaped low intensity lesions within venous sinus on T2*WI were quite rare, and the signal changes of these sinus lesions were successfully visualized by chronological T2*WI. Taken together, our case implies that T2*WI is the powerful tool for the early detection of CVT, even before the critical symptoms might happen.

[A case of anti-AQP4 antibody-positive recurrent myelitis overlapped with autoimmune disorders including incomplete CREST syndrome revealed multiple discontinuous cord lesions].

A 65-year-old woman presenting with multiple autoimmune disorders including incomplete CREST overlapping with aquaporin 4 (AQP4) antibody-positive recurrent myelitis was reported. She also clinically suffered from Sjogren syndrome and primary biliary cirrhosis (PBC). She had dysesthesia below C4 level, mild motor weakness and hyperreflexia without pathological reflexes on bilateral lower extremities. A T2-weighted MRI indicated multiple discontinuous spinal cord lesions at C1-5 and T7/8. A visual evoked potential study disclosed bilateral prolonged latency of P100. She clinically manifested not only incomplete CREST syndrome (facial teleangiectasia, sclerodactyly in bilateral fingers, and Raynaud's phenomenon), but also Sjögren (sicca syndrome) and PBC (jaundice). Immunoserological study showed that she was positive for anti-nuclear, anti-centromere, and anti-AQP4 (= NMO-IgG) antibodies. A combination therapy with corticosteroid and plasmapheresis was effective for all clinical symptoms. Therefore, this case stresses on the relevance of anti-AQP 4 antibody to the other overlapping autoimmune disorders, such as CREST syndrome, when recurrent myelitis is clinically diagnosed.

[Acute myelitis with Brown-Séquard syndrome complicated with subjective sudomotor laterality and ileocecal abscess without right abdominal pain].

A 47-year-old man presented with left shoulder pain and muscle weakness in the left limbs on November 2017. On the next day, he experienced dysesthesia of the right limbs and hypohidrosis of the left limbs and developed thermal hypoalgesia in right side of body and muscle weakness of the left upper and lower limbs progressed. He was diagnosed with acute myelitis and Brown-Séquard syndrome, based on cervical MRI scan. Muscle strength improved after steroid therapy and plasma exchange. He experienced complications of intraabdominal abscess in the right side during immunological therapy, although he only had a symptom of left abdominal pain, without pain in the right side. It is noteworthy that abdominal hypoalgesia can be associated with Brown-Séquard syndrome. Characteristically, MRI revealed bilateral lesions at the C3/4 cervical spine level. This report shows that in Brown-Séquard syndrome associated with bilateral spinal lesions, the abdominal visceral sensory pathway, in addition to the somatosensory pathway, could be impaired bilaterally, resulting in aggravation of abdominal hypoalgesia.

Clinical characteristics of autoimmune disorders in the central nervous system associated with myasthenia gravis.

Myasthenia gravis (MG) is occasionally associated with autoimmune diseases in the central nervous system (CNS), such as neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), Morvan syndrome, and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Here, we report five original cases associated with autoimmune disorders in the CNS among 42 patients with MG in a single tertiary hospital in Japan (11.9%). In four of these five cases, the second disease developed when the preceding disease was unstable. Accurate diagnosis of the newly developing disease may be difficult in such cases, because some neurological symptoms can be seen in both disorders. This implies the great importance of recognizing the possible co-occurrence of MG and disorders in the CNS. In addition, a comprehensive review of the literature revealed distinct clinical characteristics depending on the associated disease in the CNS, including thymic pathology and temporal relationship between MG and associated CNS disorders. Notably, NMOSD usually develops after the onset of MG and thymectomy, in clear contrast to MS. Thymoma is highly prevalent among patients with Morvan syndrome, in contract to cases with NMOSD and MS. The analysis of clinical characteristics, representing the first such investigation to the best of our knowledge, suggests different pathogeneses of these autoimmune diseases in the CNS, and provides significant implications for clinical practice.

Sudden-onset C8 Radiculopathy due to a Plexiform Schwannoma of the Cervical Nerve Root.

Plexiform schwannoma is a rare variant of schwannomas and usually presents with chronic symptoms. We herein report a case of cervical nerve plexiform schwannoma that presented with unusually sudden severe left radiculopathy of the eighth cervical nerve after physical exercise. Coronal short-tau inversion recovery (STIR) magnetic resonance imaging (MRI) revealed a multinodular tumor along the eighth cervical nerve. The tumor was partially resected. A pathological analysis revealed that the tumor was a schwannoma, and we diagnosed the case as a plexiform schwannoma. The unusual sudden-onset presentation in this case was considered to be caused by the unusual localization of the tumor involving the nerve root and mechanical stress due to physical exercise.

Pael receptor is involved in dopamine metabolism in the nigrostriatal system.

Pael receptor (Pael-R) has been identified as one of the substrates of Parkin, a ubiquitin ligase responsible for autosomal recessive juvenile Parkinsonism (AR-JP). When Parkin is inactivated, unfolded Pael-R accumulates in the endoplasmic reticulum and results in neuronal death by unfolded protein stress, suggesting that Pael-R has an important role in the pathogenesis of AR-JP. Here we report the analyses on Pael-R-deficient (KO) and Pael-R-transgenic (Tg) mice. The striatal dopamine (DA) level of Pael-R KO mice was only 60% of that in normal mice, while in Pael-R Tg mice, striatal 3,4-dihydroxyphenylacetic acid (DOPAC) as well as vesicular DA content increased. Moreover, the nigrostriatal dopaminergic neurons of Pael-R Tg mice are more vulnerable to Parkinson's disease-related neurotoxins while those of Pael-R KO mice are less. These results strongly suggest that the Pael-R signal regulates the amount of DA in the dopaminergic neurons and that excessive Pael-R expression renders dopaminergic neurons susceptible to chronic DA toxicity.

Sympathetic disturbances increase risk of sudden cardiac arrest in sporadic ALS.

BACKGROUND: ALS exclusively involves motor neurons, however, accumulating evidence suggests involvement of sympathetic neurons, as in other diseases including Parkinson's disease and multiple system atrophy. In these diseases increased risk of sudden cardiac arrest is established, while that in ALS remains uncertain. METHODS: The authors retrospectively studied 12 pathologically confirmed sporadic ALS patients who received no assisted ventilation. Among them, two patients died of sudden cardiac arrest. Changes in QTc interval and dispersion, indices of sympathetic activities obtainable by routine electrocardiograms, were evaluated at the early stage and the terminal stage. Pathologically, intermediolateral nucleus (IML) sympathetic neurons in the upper thoracic cord were examined. RESULTS: The QTc intervals and dispersion were significantly increased at the terminal stage compared with that at the early stage (p<0.01). The numbers of IML neurons were significantly lower in ALS patients than in controls (p=0.017), and had linear inverse correlation with the rate of increases in maximum QTc interval and QTc dispersion (p=0.01, r=-0.915 and p=0.02, r=-0.884). Notably, two patients with sudden cardiac arrest showed longer QTc interval, larger QTc dispersion, and lower number of IML neurons than most of others. CONCLUSIONS: Patients with ALS had reduced sympathetic activities at the terminal stage of disease, presumably due to neuronal loss in IML, which may increase risk of sudden cardiac arrest. Thus, prolonged QTc intervals and increased QTc dispersion may suggest an increased risk of sudden death in ALS, as in other neurodegenerative diseases.

Bilateral Vertebral Artery Aneurysms at the Atlantoaxial Joint Level Causing Recurrent Stroke.

Vertebral arteries (VAs) are vulnerable to mechanical stress between the atlas and axis, and subsequent VA dissection can cause posterior circulation infarction. We herein present a rare but informative case of bilateral VA aneurysms that caused recurrent stroke. The localization of the aneurysms and dynamic angiography with neck movement suggested a pathogenesis related to chronic mechanical injury of the VAs, though no skeletal abnormality was detected. The recurrences stopped and both aneurysms shrank after neck collar fixation and after the combination use of antithrombotics. For patients with posterior circulation infarction of unknown origin, a careful evaluation of VAs with physicians paying special attention to the atlantoaxial joint level is therefore recommended.

Electrocardiography as the First Step for the Further Examination of Cardiac Involvement in Myasthenia Gravis.

INTRODUCTION: Cardiac involvement of myasthenia gravis (MG) accompanies a poor prognosis. In the present study, we aimed to investigate the relationship between ECG abnormality and cardiac involvement. METHODS: Of 178 patients diagnosed with MG between 2001 and 2013 at our hospital, we retrospectively analyzed consecutive 58 patients who underwent both ECG and echocardiography and without underlying cardiovascular disease. ECG abnormalities were defined by computer-assigned Minnesota-codes. Cardiac damage was defined as either (1) ejection fraction (EF) <55% on echocardiography or (2) elevated E/e', the ratio of mitral velocity to early diastolic velocity of the mitral annulus >8 on echocardiography. RESULTS: Thirty-three patients (56.8%) had ECG abnormality. An elevated E/e' was observed in patients with ECG abnormality compared to those without ECG abnormality (11.2 ± 3.2, 8.7 ± 2.2, resp., p = 0.03). Among patients with ECG abnormality, 14 of 15 patients showed cardiac damage. Among patients without ECG abnormality, 6 of 33 patients showed cardiac damage (p = 0.003). Reduced EF was observed in five patients (8.6%) with ECG abnormality and none in patients without ECG abnormality. CONCLUSIONS: ECG may aid as the first step for the further examination of cardiac damage in patients with MG.