Cavernous sinus dural arteriovenous fistula treated with transvenous embolization through facial vein: A case report.

Background: Although the inferior petrosal sinus (IPS) is the most common approach route for transvenous embolization (TVE) of cavernous sinus dural arteriovenous fistulas (CSDAVFs), other routes should be chosen in cases which the IPS is occluded. We report a case in which the superior ophthalmic vein (SOV) approach through the facial vein (FV) was the first choice to achieve radical cure of a hemorrhage-onset CSDAVF. Case Description: An 81-year-old female presented with a history of transarterial embolization (TAE) and TVE for the left CSDAVF 27 years ago. She was transported to us with a chief complaint of consciousness disturbance, and head computed tomography (CT) showed subcortical hemorrhage in the right frontal lobe. Cerebral angiography revealed CSDAVF with draining into the right SOV and right superficial middle cerebral vein (SMCV). Angiography, computed tomography venography, and contrast-enhanced magnetic resonance imaging did not show IPS, but the outflow pathways to the SOV, FV, and internal jugular vein were confirmed, so an approach through the FV was selected. Conclusion: The FV was selected through the right femoral vein and thanks to the distal access catheter (DAC) being guided to the SOV, the microcatheter could be easily guided to the SMCV through the cavernous sinus (CS). TVE was performed, complete occlusion was confirmed. When preoperative occlusion of the IPS was confirmed, the FV was useful for the first choice of route, and the use of DAC allowed us to complete the treatment accurately and quickly.

T cells from MS Patients with High Disease Severity Are Insensitive to an Immune-Suppressive Effect of Sulfatide.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Its early phase is characterized by a relapse-remitting disease course, followed by disability progression in the later stage. While chronic inflammation accompanied with degeneration is well-established as the key pathological feature, the pathogenesis of MS, particularly progressive MS, remains elusive. Sulfatide is a major glycolipid component of myelin, and previous studies in experimental autoimmune encephalomyelitis mouse models have demonstrated it to have immune-protective functions. Notably, sulfatide concentration is increased in the serum and cerebrospinal fluid of patients with MS, particularly those in a progressive disease course. Here, we show that the myelin-glycolipid sulfatide displays an ability to suppress the proliferation of polyclonally activated human T cells. Importantly, this suppressive effect was impaired in T cells obtained from MS patients having higher disability status. Therefore, it is plausible that progression of MS is associated with an escape from the immune-regulatory effect of sulfatide. Our study suggests that, although the precise mechanisms remain unrevealed, an escape of T cells from immunosuppression by sulfatide is associated with disease progression in the advanced stage. Further studies will provide novel insights into the pathogenesis of MS, particularly regarding disease progression, and help develop novel treatment strategies for this challenging disease.

Immune Skew of Circulating Follicular Helper T Cells Associates With Myasthenia Gravis Severity.

OBJECTIVE: To clarify functional alterations of follicular helper T cells (Tfh) in myasthenia gravis (MG) because Tfh play important roles in helping B cells generate antibody-producing cells. METHODS: A total of 24 immunotherapy-naive patients with anti-acetylcholine receptor (AchR) antibody-positive MG and 18 age-matched healthy subjects (HS) were enrolled. Samples from 6 patients were available for posttreatment analysis. Subsets of circulating Tfh (cTfh) and B cells were identified by flow cytometry analysis of surface molecules. Cytokine production by isolated cTfh subsets from 5 patients with MG and 5 HS was measured in vitro. Analysis was performed to examine the correlation between the frequency of cTfh subsets and that of plasmablasts and between cTfh subsets and the quantitative MG score. RESULTS: cTfh increased with elevated expression of inducible T-cell costimulator (ICOS) in patients with MG. cTfh shifted to Th2 and Th17 over Th1 in MG. ICOShighcTfh produced significantly higher levels of interleukin (IL)-21, IL-4, and IL-17A than ICOSlow cTfh only in patients with MG. The frequency of cTfh within CD4 T cells was more closely associated with disease severity than the serum anti-AchR antibody titer and frequency of plasmablasts within B cells. Abnormalities of cTfh were improved after immunotherapy in parallel with clinical improvement. CONCLUSIONS: Alternation of cTfh is a key feature in the development of MG and may become a biomarker for disease severity and therapeutic efficacy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the level of cTfh is associated with disease severity in patients with MG.

Altered features of monocytes in adult onset leukoencephalopathy with axonal spheroids and pigmented glia: A clue to the pathomechanism of microglial dyshomeostasis.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal-dominant type of leukoencephalopathy caused by gene mutation of colony stimulating factor 1 receptor, which is expressed mainly on monocyte lineage cells such as monocytes in the peripheral blood and microglia in the brain. Hence, microglial dysfunction is regarded as critical in the pathogenesis of ALSP. However, functional changes in these cells have not been elucidated. In this study, we report the phenotypic and functional alterations of monocytes in four patients with ALSP. Flow cytometric analysis revealed altered expression of antigen presentation- and migration-related molecules, an inflammatory shift in cytokine production and phagocytic impairment in ALSP monocytes. We speculate that the observed altered features of monocytes are mostly shared by microglial cells, leading to the clinical history and pathological characteristics of ALSP. Our analysis of PB monocytes provides novel insights into the pathogenesis of ALSP.

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.

Beneficial Effect of Bendamustine in a Patient with Anti-MAG/SGPG Neuropathy and Bing-Neel Syndrome Associated with Waldenström Macroglobulinemia: A Case Report.

A 71-year-old man with Waldenström macroglobulinemia (WM) presented with a slowly progressive sensory disturbance and mild weakness predominantly affecting the distal portion of the limbs over the course of 6 months. Cervical magnetic resonance imaging (MRI) showed a long hyperintense lesion at the C1-C4 level. Nerve conduction studies (NCS) revealed prolongation of distal latency, slowed conduction velocity, and conduction block. His serum IgM level was increased, and he was positive for anti-myelin-associated glycoprotein (MAG) and anti-sulfoglucuronyl paragloboside (SGPG) IgM antibodies. Based on the presence of anti-MAG/SGPG antibodies and a single atypical cell with lymphoplasmacytic character in the cerebral spinal fluid, he was diagnosed as having anti-MAG/SGPG neuropathy and Bing-Neel syndrome (BNS) associated with WM. Following 6 cycles of bendamustine monotherapy, the patient's neurological impairment improved; and the serum IgM level became normalized. Furthermore, NCS findings indicated improvement; and the hyperintense lesion on MRI had almost completely disappeared. The present findings suggest that bendamustine monotherapy is effective not only for WM but also for its associated MAG/SGPG neuropathy and BNS.

Two cases of sporadic adult-onset neuronal intranuclear inclusion disease preceded by urinary disturbance for many years.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease defined by the presence of eosinophilic hyaline intranuclear inclusions. The initial and main clinical feature of adult-onset NIID is predominantly dementia. We present herein 2 cases of sporadic adult-onset NIID with longstanding urinary disturbance prior to development of other neurological symptoms. Case 1: A 71-year-old woman was admitted after she lost consciousness while bathing. She presented slowly progressive bladder dysfunction starting at the age of 40. Recently, she complained of recurrent light-headedness on standing. Her neurological findings showed miosis, muscle weakness, rigidity, hyporeflexia, sensory disturbance, cerebellar ataxia, and orthostatic hypotension. Case 2: A 68-year-old man was admitted because of episodes of transient loss of consciousness. Ten years earlier, he had developed urinary dysfunction. His neurological findings revealed cognitive dysfunction, cerebellar ataxia, and hyporeflexia. Both patients had leukoencephalopathy and motor-sensory neuropathy. In both cases, diffusion-weighted imaging showed high-intensity signals in the corticomedurally junction; and skin biopsy samples revealed ubiquitin-positive intranuclear inclusions. Therefore, we made a diagnosis of adult-onset NIID. Although numerous cases of this disorder have been reported in the past, there were only a few cases showing the development of other neurological symptoms after longstanding urinary disturbance. Our cases suggest that it is worthwhile considering the possibility of NIID in cases with a long-term history of neurogenic bladder dysfunction.

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.

Altered T cell phenotypes associated with clinical relapse of multiple sclerosis patients receiving fingolimod therapy.

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease. Fingolimod, a highly effective disease-modifying drug for MS, retains CCR7+ central memory T cells in which autoaggressive T cells putatively exist, in secondary lymphoid organs, although relapse may still occur in some patients. Here, we analyzed the T cell phenotypes of fingolimod-treated, fingolimod-untreated patients, and healthy subjects. The frequency of CD56+ T cells and granzyme B-, perforin-, and Fas ligand-positive T cells significantly increased during fingolimod treatment. Each T cell subpopulation further increased during relapse. Interestingly, T cells from fingolimod-treated patients exhibited interferon-γ biased production, and more myelin basic protein-reactive cells was noted in CD56+ than in CD56- T cells. It is likely that the altered T cell phenotypes play a role in MS relapse in fingolimod-treated patients. Further clinical studies are necessary to investigate whether altered T cell phenotypes are a biomarker for relapse under fingolimod therapy.

Thrombotic microangiopathy caused by interferon ß-1b for multiple sclerosis: a case report.

A 41-year-old man with a history of multiple sclerosis (MS) developed thrombotic microangiopathy after taking interferon ß-1b for 10 years. Although the relapse of his MS was well controlled under normal blood pressure, he had persistent nausea, anorexia, gait disturbance and visual disorder 1 month before admission. He showed lethargy and high blood pressure (180/102 mmHg). Laboratory test results revealed anemia and thrombocytopenia, elevated LDH and renal dysfunction. Urinary dipstick showed a 2+ result for proteinuria and 3+ for hematuria. Schizocyte were present and haptoglobin decreased, and we diagnosed him with possible thrombotic microangiopathy (TMA). Magnetic resonance image indicated posterior reversible encephalopathy syndrome (PRES), which could be accelerated by TMA. After discontinuing interferon ß-1b, high dose intravenous methylpredonisolone, anti-hypertension therapy and plasma exchange was started. Because a mild decrease in ADAMTS13 activity and absence of ADAMTS 13 inhibitor could not cause thrombotic thrombocytopenic purpura, plasma exchange was stopped. The patient's renal function recovered and PRES resolved, and he was discharged with slightly decrease of visual acuity. We suggest that his TMA was likely caused by interferon ß-1b, resulting in PRES in a patient with multiple sclerosis. We report this rare case and also review the literature.

[Patient of myofibrillar myopathy associated with muscle cramp and distal muscle involvement].

A 53-year-old man presented mild, but gradually worsening, distal-dominant upper bilateral limbs weakness and muscle cramp in both legs from the age of 30. He had no obvious muscle atrophy during the course of the disease. Muscle biopsy of the right lateral vastus muscle showed myopathic changes with round or helical hyaline inclusions in eosinophilic on H&E staining and dark green on modified Gomori trichrome. There were also non-rimmed vacuoles. NADH-TR showed lack of enzymic activity in areas corresponding to the inclusions. Immunohistochemistry demonstrated abnormal accumulation of desmin and myotilin in fibers with inclusions. Given these pathological findings, he was diagnosed with myofibrillar myopathy (MFM). Because MFM is genetically heterogeneous, its clinical manifestations are reported as variable. While MFM patients are sometimes reported to develop serious conditions such as severe weakness, cardiomyopathy or respiratory failure, which require a pacemaker or mechanical ventilator, our case only had mild distal dominant limb weakness and muscle cramps. Our patient suggests that we must consider MFM as a differential diagnosis in adult onset distal myopathies.