[Sarcoid Peripheral Neuropathy and Myopathy: A Diagnostic and Therapeutic Challenge].

Sarcoidosis is an idiopathic granulomatous multi-organ disease, primarily affecting the respiratory system, eyes, and skin, with less involvement in peripheral neurons and muscles. Sarcoid peripheral neuropathy encompasses cranial and spinal nerve impairment. Muscle involvement is often asymptomatic and revealed through imaging. Symptomatic muscle involvement is categorized into three clinical types: nodular myopathy, acute myopathy, and chronic myopathy. The identification of noncaseating granulomas in peripheral nerves or muscles, coupled with the exclusion of other diseases, is essential for establishing a definitive diagnosis of sarcoid peripheral neuropathy and myopathy. Sarcoid neuropathy and myopathy are typically managed with high-dose corticosteroids, immunosuppressants, or a combination of both. In recent times, the use of TNF-alpha inhibitors has notably increased. However, these conditions often exhibit resistance to treatment and may necessitate prolonged therapeutic interventions. Therefore, comprehensive examinations should be conducted before considering immunotherapy. Due to the rarity of these conditions, research on manifestation-specific treatments is lacking, and standard treatments for sarcoid neuropathy and myopathy have not been established. Additional treatment options for sarcoid neuropathy and myopathy are expected to become available in the future.

[Steroid-Resistant Central Nervous System Sarcoidosis: The Selections of Multi-Agent Combination as the Initial Treatment].

Sarcoidosis is a granulomatous multiorgan disease of unknown etiology that commonly affects the respiratory system, eyes, and skin, and less commonly affects the nervous system. Because of its rarity, a standard treatment for central nervous system (CNS) sarcoidosis has not yet been established. Corticosteroids remain the cornerstone of CNS sarcoidosis treatment. However, CNS sarcoidosis, other than isolated facial nerve paralysis, is often refractory to treatment and requires long-term corticosteroid treatment. In particular, patients with hydrocephalus have a high mortality rate and a lack of response to this treatment. Therefore, immunosuppressants, including TNF-α inhibitors and corticosteroids, should be considered as the initial treatment. For older patients, it is important to pay attention to infection as an adverse event and to the toxicity of the therapeutic agents. Because steroid-related adverse events are more common in the older patient group, the lowest effective dose should be used, and the treatment duration should be kept as short as possible after careful evaluation of disease activity. Corticosteroid-sparing agents are effective at reducing the cumulative toxicity of corticosteroids. Recently, various new potential agents have emerged and their efficacy has been assessed. It is expected that more treatment options will be available for CNS sarcoidosis in future.

Spinal cord sarcoidosis in Japan: utility of cerebrospinal fluid examination and nerve conduction study for diagnosis and prognosis prediction.

Spinal cord sarcoidosis (SCS) is rare, and its diagnosis is challenging. We examined clinical, laboratory, and imaging features in patients with SCS to obtain useful clues for diagnosis and prognosis. Eleven consecutive patients (four males, seven females) at a single Japanese institution were investigated. Median age at onset was 66 years old. The most frequent site affected, other than the nervous system, was the respiratory system. While histological confirmation of non-caseating granulomas was often found there, no patient had respiratory symptoms. Peripheral nerve involvement was detected in 64% of patients. Soluble IL-2 receptor (sIL-2R) levels in serum and cerebrospinal fluid (CSF) were elevated in 64% and 45% of patients, respectively, and this finding was more common than elevation of angiotensin-converting enzyme (ACE). 18F-fluorodeoxyglucose (FDG) positron emission tomography showed abnormally high uptake in spinal lesions of all examined patients. Although corticosteroids were administrated to all patients, and immuno-suppressants were prescribed to six (55%), the modified Rankin Scale was unchanged or worsened in four (36%) patients during the follow-up period. Neurological exacerbation of myelopathy was seen in four (36%) patients. Complete response rate was only seen in 9%. High levels of cell count, protein, ACE, and sIL-2R in CSF were significantly more frequent in patients with a marked improvement after immunotherapy than in the other patients. These results suggest that high serum and CSF sIL-2R, high uptake of FDG, and peripheral nerve involvement are indicative of SCS. Given that SCS is commonly intractable, CSF abnormalities may predict efficacy of immunotherapies.

GRP78 Antibodies Are Associated With Blood-Brain Barrier Breakdown in Anti-Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorder.

BACKGROUND AND OBJECTIVES: To analyze (1) the effect of immunoglobulin G (IgG) from patients with anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disorder on the blood-brain barrier (BBB) endothelial cells and (2) the positivity of glucose-regulated protein 78 (GRP78) antibodies in MOG-Ab-associated disorders. METHODS: IgG was purified from sera with patients with MOG-Ab-associated disorder in the acute phase (acute MOG, n = 15), in the stable stage (stable MOG, n = 14), healthy controls (HCs, n = 9), and disease controls (DCs, n = 27). Human brain microvascular endothelial cells (BMECs) were incubated with IgG, and the number of nuclear NF-κB p65-positive cells in BMECs using high-content imaging system and the quantitative messenger RNA change in gene expression over the whole transcriptome using RNA-seq were analyzed. GRP78 antibodies from patient IgGs were detected by Western blotting. RESULTS: IgG in the acute MOG group significantly induced the nuclear translocation of NF-κB and increased the vascular cell adhesion molecule 1/intercellular adhesion molecule 1 expression/permeability of 10-kDa dextran compared with that from the stable MOG and HC/DC groups. RNA-seq and pathway analysis revealed that NF-κB signaling and oxidative stress (NQO1) play key roles. The NQO1 and Nrf2 protein amounts were significantly decreased after exposure to IgG in the acute MOG group. The rate of GRP78 antibody positivity in the acute MOG group (10/15, 67% [95% confidence interval, 38%-88%]) was significantly higher than that in the stable MOG group (5/14, 36% [13%-65%]), multiple sclerosis group (4/29, 14% [4%-32%]), the DCs (3/27, 11% [2%-29%]), or HCs (0/9, 0%). Removal of GRP78 antibodies from MOG-IgG reduced the effect on NF-κB nuclear translocation and increased permeability. DISCUSSION: GRP78 antibodies may be associated with BBB dysfunction in MOG-Ab-associated disorder.

Exploring lipophilic compounds that induce BDNF secretion in astrocytes beyond the BBB using a new multi-cultured human in vitro BBB model.

Brain-derived neurotrophic factor (BDNF) cannot cross the blood-brain barrier (BBB) when administered peripherally, which hinders its therapeutic potential. We utilized an in vitro BBB model-a tri-culture of a human endothelial cell line, a pericyte cell line, and an astrocyte cell line-to study the effect of twenty candidate lipophilic compounds on stimulating BDNF secretion in pericytes and astrocytes. The prostaglandin E2 receptor 4 agonist and sphingosine-1-phosphate receptor 5 agonist facilitated secretion of BDNF in the astrocyte, but did not decrease the transendothelial electrical resistance. These compounds may be promising agents for neurodegenerative and neuroinflammatory diseases.

New BBB Model Reveals That IL-6 Blockade Suppressed the BBB Disorder, Preventing Onset of NMOSD.

BACKGROUND AND OBJECTIVES: To evaluate the pathophysiology of neuromyelitis optica spectrum disorder (NMOSD) and the therapeutic mechanism and levels of interleukin-6 (IL-6) blockade (satralizumab), especially with respect to blood-brain barrier (BBB) disruption with the new in vitro and ex vivo human BBB models and in vivo model. METHODS: We constructed new static in vitro and flow-based ex vivo models for evaluating continued barrier function, leukocyte transmigration, and intracerebral transferability of neuromyelitis optica-immunoglobulin G (NMO-IgG) and satralizumab across the BBB using the newly established triple coculture system that are specialized to closely mimic endothelial cell contact of pericytes and endfeet of astrocytes. In the in vivo study, we assessed the effects of an anti-IL-6 receptor antibody for mice (MR16-1) on in vivo BBB disruption in mice with experimental autoimmune encephalomyelitis in which IL-6 concentration in the spinal cord dramatically increases. RESULTS: In vitro and ex vivo experiments demonstrated that NMO-IgG increased intracerebral transferability of satralizumab and NMO-IgG and that satralizumab suppressed the NMO-IgG-induced transmigration of T cells and barrier dysfunction. In the in vivo study, the blockade of IL-6 signaling suppressed the migration of T cells into the spinal cord and prevented the increased BBB permeability. DISCUSSION: These results suggest that (1) our triple-cultured in vitro and in ex vivo BBB models are ideal for evaluating barrier function, leukocyte transmigration, and intracerebral transferability; (2) NMO-IgG increased the intracerebral transferability of NMO-IgG via decreasing barrier function and induced secretion of IL-6 from astrocytes causing more dysfunction of the barrier and disrupting controlled cellular infiltration; and (3) satralizumab, which can pass through the BBB in the presence of NMO-IgG, suppresses the BBB dysfunction and the infiltration of inflammatory cells, leading to prevention of onset of NMOSD.

[Spinal Cord Sarcoidosis].

Spinal cord sarcoidosis is rare, but often appears as a diagnostic challenge in myelopathy of unknown origin. Although definite diagnosis requires histological confirmation of non-caseating epithelioid granuloma in the spinal cord, it is hardly obtained due to the invasiveness of the biopsy procedure. Hence, extensive searches for involvement of other organs involvement should be prompted, including biopsy of the most "promising" and "easy touch" lesions identified in individual patients. Spinal sarcoidosis is generally treated with high-dose corticosteroids, immunosuppressants, or both, but it is often refractory to treatment and requires a long treatment period. Therefore, extensive examinations to evaluate the likelihood of sarcoidosis should be carried out before the initiation of immunotherapy, especially in cases without histological confirmation.

Charcot-Marie-Tooth disease type 2 caused by homozygous MME gene mutation superimposed by chronic inflammatory demyelinating polyneuropathy.

We report a 59-year-old Japanese male who developed gradually worsening weakness and numbness of distal four extremities since age 50. His parents were first cousins, and blood and cerebral spinal examinations were unremarkable. Homozygous mutation of MME gene was detected and thus he was diagnosed as autosomal-recessive Charcot-Marie-Tooth disease 2T (AR-CMT2T); however, electrophysiological examinations revealed scattered demyelinative changes including elongated terminal latency in several peripheral nerve trunks. Sural nerve biopsy showed endoneurial edema and a lot of thinly myelinated nerve fibers with uneven distribution of remnant myelinated fibers within and between fascicles. Immunoglobulin treatment was initiated considering the possibility of superimposed inflammation and demyelination, and immediate clinical as well as electrophysiological improvements were noted. Our findings indicate that AR-CMT2T caused by MME mutation predisposes to a superimposed inflammatory demyelinating neuropathy. This is the first report which documented the co-existence of CMT2 and chronic inflammatory demyelinating polyneuropathy (CIDP); however, in the peripheral nervous system, neprilysin, a product of MME gene, is more abundant in myelin sheath than in axonal component. The fragility of myelin sheath due to mutated neprilysin may trigger the detrimental immune response against peripheral myelin in this patient.

Autocrine MMP-2/9 secretion increases the BBB permeability in neuromyelitis optica.

OBJECTIVE: Pathological breakdown of the blood-brain barrier (BBB) is thought to constitute the beginning of the disease process in neuromyelitis optica (NMO). In the current study, we investigated possible molecular mechanisms responsible for the breakdown of BBB using NMO sera. METHODS: We analysed the effects of sera obtained from anti-aquaporin 4 (AQP4) antibody-positive NMO spectrum disorder (NMOSD) patients, multiple sclerosis (MS) patients and control subjects on the production of claudin-5, matrix-metalloproteinases (MMPs)-2/9, and vascular cell adhesion protein-1 (VCAM-1) in human brain microvascular endothelial cells (BMECs). We also examined whether immunoglobulin G (IgG) purified from NMOSD sera influences the claudin-5 or VCAM-1 protein expression. RESULTS: The disturbance of BBB properties in BMECs following exposure to NMOSD sera was restored after adding the MMP inhibitor, GM6001. The secretion of MMP-2/9 by BMECs significantly increased after applying the NMOSD sera. The sera from NMOSD patients also increased both the MMP-2/9 secretion and the VCAM-1 protein level by BMECs. The IgG purified from NMOSD sera did not influence the BBB properties or the amount of MMP-2/9 proteins, although it did increase the amount of VCAM-1 proteins in BMECs. Reduction in anti-AQP4 antibody titre was not correlated with a reduction in VCAM-1 expression. CONCLUSIONS: The autocrine secretion of MMP-2/9 by BMECs induced by humoral factors, other than IgG, in sera obtained from NMOSD patients potentially increases BBB permeability. IgG obtained from NMOSD sera, apart from anti-AQP4 antibodies, affect the BBB by upregulating VCAM, thereby facilitating the entry of inflammatory cells into the central nervous system.