[Muscle-Specific Receptor Tyrosine Kinase Antibody Positive Myasthenia Gravis].

Reportedly, patients with muscle-specific kinase (MuSK) antibody-positive myasthenia gravis (MG) account for approximately 3.0% of all patients with MG in Japan. Compared with patients who have acetylcholine receptor antibody-positive MG, those with MuSK antibody-positive MG show young-onset disease with female predominance, a low rate of ocular involvement (5.9%), and greater severity of dysphagia. The aforementioned types of MG are indistinguishable based on clinical symptoms and electrophysiological tests, and measurement of MuSK antibodies is essential for diagnosis. Thymectomy and complement inhibitors are not indicated for treatment, and acetylcholinesterase inhibitors, steroids, immunosuppressants, plasma exchange, intravenous immunoglobulin therapy, and neonatal Fc receptor inhibitors are used.

[Diagnosis and Treatment of Lambert-Eaton Myasthenic Syndrome].

Approximately 90% of patients with Lambert-Eaton myasthenic syndrome (LEMS) show positive P/Q-type voltage-gated calcium channels antibodies, which can be broadly classified clinically as paraneoplastic, particularly with small cell lung carcinoma and non-paraneoplastic without cancer. The first Japanese guideline for LEMS was developed in May 2022 as MG/LEMS Practice Guideline 2022. This article describes the epidemiology, symptoms, diagnosis, examination, treatment, and prognosis of this condition, based on the LEMS guidelines.

Pseudohypoxic Brain Swelling after Unilateral Burr Hole Drainage: A Novel Case Report.

An 85-year-old man underwent emergency right trepanation and drainage for a symptomatic chronic subdural hematoma. Pseudohypoxic brain swelling (PHBS) was suspected because magnetic resonance imaging revealed diffuse brain swelling. Although cerebrospinal fluid (CSF) leakage was not obvious during or after surgery, most of the reported PHBS cases have leaked CSF during craniotomy or spine surgery. PHBS has not been previously reported in patients without obvious CSF leakage or after unilateral burr hole drainage. Herein, we report an extremely rare case with a literature review investigating its pathogenesis and clinical features.

Allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia/lymphoma with HTLV-1-associated myelopathy.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for adult T-cell leukemia/lymphoma (ATL), but comorbidities increase transplant-related mortality. Here we report the outcome of allo-HSCT in a patient with ATL with human T-cell leukemia virus type I (HTLV-1)-associated myelopathy-tropical spastic paraparesis (HAM/TSP). A 48-year-old man was diagnosed with HAM/TSP and started prednisolone therapy. Ten years later, he developed lymphoma-type ATL. At the diagnosis of ATL, Osame's Motor Disability Score (OMDS) was 4. When prednisolone was gradually tapered and stopped following chemotherapy for ATL, HAM/TSP symptoms recurred (OMDS 7). Bone marrow transplantation from a human leukocyte antigen allele 8/8 matched unrelated donor was performed while ATL was in partial remission. Neutrophil engraftment with complete donor chimerism was achieved on day 19 after allo-HSCT. Mild gait improvement (OMDS 5) was observed on day 30. Although ATL relapsed on day 275, progression of HAM/TSP symptoms was not observed. Furthermore, there was no clear progression of HAM/TSP symptoms after donor lymphocyte infusions. The outcome of this case suggests that ATL patients with HAM/TSP tolerate allo-HSCT and donor lymphocyte infusions.

[A Case of Flexion Contracture Associated with Hypopituitarism].

A 72-year-old Japanese man developed progressive disturbance in ambulation with flexion contractures 5years before this admission. At 49 years of age, he was diagnosed with hypopituitarism after an operation for a Rathke's cleft. On admission, he could not fully extend his knees and hips because of painful muscle stiffness of the lower extremities. Initially, we suspected Stiff-person syndrome and initiated diazepam, which had no effect. Serum anti-glutamic acid decarboxylase antibody was negative. Next, we suspected flexion contractures associated with hypopituitarism. Endocrine evaluation revealed that ACTH, cortisol, and other hormone levels were lower than those reported in the previous evaluation. We treated the patient with hydrocortisone and his symptoms dramatically improved. It is rare for patients with hypopituitarism to have flexion contracture. This case suggests that we should consider hypopituitararism in the setting of flexion contractures. (Received October 18, 2018; Accepted March 26, 2019; Published June 1, 2019).

GRP78 antibodies damage the blood-brain barrier and relate to cerebellar degeneration in Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction caused by autoantibodies binding to P/Q-type voltage-gated calcium channels. Breakdown of the blood-brain barrier and diffusion of cerebellar granule/Purkinje cell-reactive autoantibodies into the CNS are critical for the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome. We recently found evidence that glucose-regulated protein 78 (GRP78) autoantibodies in the plasma of patients with neuromyelitis optica promote the CNS access of AQP4 autoantibodies. In the present study, we investigated whether the GRP78 autoantibodies in PCD-LEMS IgG boost the brain uptake of cerebellar cell-reactive antibodies across the blood-brain barrier and facilitate cerebellar dysfunction. We first evaluated the effects of purified IgG from PCD-LEMS or PCD patients on the blood-brain barrier function in human brain microvascular endothelial cells using a high content imaging system with nuclear factor κB p65 and intracellular adhesion molecule 1 (ICAM1) immunostaining. Next, we identified GRP78 autoantibodies causing blood-brain barrier permeability in PCD-LEMS IgG by co-immunoprecipitation and the living cell-based antibody binding assays. Exposure of brain microvascular endothelial cells to IgG from PCD-LEMS patients induced nuclear factor κB p65 nuclear translocation, ICAM1 upregulation, reduced claudin-5 expression, increased permeability and increased autocrine IL-1ß and IL-8 secretion; the IgG from patients with Lambert-Eaton myasthenic syndrome did not have these effects. We detected GRP78 autoantibodies in the IgG of LEMS-PCD (83.3%, n = 18), but observed fewer in patients with LEMS (6.6%, n = 15) and none were observed in the control subjects (n = 8). The depletion of GRP78 autoantibodies reduced the biological effect of LEMS-PCD IgG on brain microvascular endothelial cells. These findings suggest that GRP78 autoantibodies play a role beyond neuromyelitis optica and that they have direct implications in the phenotypic differences between PCD-LEMS and LEMS.

[Paraneoplastic Cerebellar Degeneration with Lambert-Eaton Myasthenic Syndrome: A Report of an Effectively Treated Case and Systematic Review of Japanese Cases].

A 63-year-old female who developed dizziness, diplopia and subsequent gait disturbance from September X-1 year was analyzed. The first neurological findings in May X year revealed cerebellar ataxia, weakness in the proximal limbs, decreased tendon reflexes, and autonomic symptoms (ADL:mRS 3). Furthermore, an incremental phenomenon was observed in the repetitive nerve stimulation test, and she was diagnosed with Lambert-Eaton myasthenic syndrome (LEMS) based on the serum P/Q-type calcium channel (VGCC) antibody positivity. In addition, small cell lung cancer was detected by chest CT and bronchoscopy, and her cerebellar ataxia was diagnosed as paraneoplastic cerebellar degeneration (PCD). Therefore, the patient underwent chemotherapy and radiotherapy from June in X year. Six months after initiation of treatment, her cerebellar ataxia had almost disappeared and she could walk without assistance (ADL:mRS 1). The P/Q-type VGCC antibodies were also negative at that time. Cases wherein cerebellar ataxia resolved almost completely in parallel with disappearance of the serum P/Q-type VGCC antibodies are of great interest. We conducted a systematic literature review of PCD-LEMS cases in Japan reported since P/Q-type calcium channel antibody measurement was reported in 1995. As a result, 13 cases (including our study) that concurrently displayed cerebellar ataxia and LEMS were selected. The average age of the 13 patients (10 males and 3 females) was 61.5 years. Small cell carcinoma was complicated in 11 patients (10 in the lung and 1 in the oropharynx); in the other 2 patients, cancer was not found at the time of reporting (the observation period was as short as 1-2 months). The time from onset to treatment ranged between 1 week and 10 months. While 1 of the 13 patients developed cerebellar ataxia during the subsequent course of the treatment, the remaining 12 had already developed cerebellar ataxia and LEMS symptoms, although their main neurologic finding was cerebellar ataxia and they were subsequently diagnosed with LEMS after electrophysiological testing and autoantibody detection. Small cell carcinoma was found in 11 patients. We define the pathology following such a certain clinical course as PCD-LEMS. The P/Q-type VGCC antibodies were positive in 11 of the 13 cases, although their antibody titers were not necessarily very high. Treatment for the associated small cell carcinoma might have improved the neurological findings in 9 of the 11 PCD-LEMS patients. The P/Q-type VGCC antibodies were measured before and after the treatment. The PCD-LEMS symptoms improved in all patients and their antibody titers decreased. These findings indicate that P/Q-type VGCC antibodies are involved in the pathology of PCD-LEMS. Appropriate and timely treatment, at least in PCD-LEMS patients in Japan, that actively treats any associated cancer can be expected to improve not only life prognosis but also cerebellar ataxia. (Received October 15, 2018; Accepted November 5, 2018; Published January 1, 2019).

[A Case of Neuromyelitis Optica Spectrum Disease with Hypoglycorrhachia].

A 75-year-old Japanese woman developed myelitis 3years prior to her admission. She was diagnosed with HTLV-1-related myelitis and had taken prednisolone. Her myelitis relapsed several times, and serum aquaporin-4 was positive in an ELISA. She developed a sudden headache, consciousness disturbance, dysarthria, and left limb paralysis, and was admitted to our hospital. The CSF analysis revealed pleocytosis dominated by morphonuclear cells and hypoglycorrhachia. Magnetic resonance imaging revealed abnormalities in the corpus callosum, bilateral thalamus, and corticospinal tracts. We initially suspected a relapse of neuromyelitis optica spectrum disorder (NMOSD) and infection. We treated the patient with methylprednisolone pulse and antibacterial and antiviral treatment, which were not effective. Plasmapheresis was performed five times, and she gradually improved. Immunosuppressive treatment was added. It is rare for NMOSD to cause hypoglycorrhachia. This case suggests that infection may trigger an autoimmune response in NMOSD. (Received February 13, 2018; Accepted July 12, 2018; Published October 1, 2018).

[P/Q-type Calcium Channel Antibodies in Lambert-Eaton Myasthenic Syndrome].

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction. Approximately 50-60% of patients with LEMS have a tumor, most often small cell lung cancer (SCLC), making LEMS a paraneoplastic neurological syndrome. In Japan, the clinical picture is a male: female ratio of 3:1; mean age, 62 years (17-80 years); and 61% of LEMS patients have SCLC (SCLC-LEMS), with the remainder of patients having no cancer. Patients with LEMS develop a unique set of clinical characteristics, which include proximal muscle weakness, depressed tendon reflexes with post-tetanic potentiation, and autonomic symptoms. Interestingly, less than 10% of patients with LEMS have cerebellar ataxia (LEMS with paraneoplastic cerebellar degeneration). Considering its pathomechanisms, LEMS is a presynaptic disorder of neuromuscular transmission in which quantal release of acetylcholine is impaired by autoantibodies against P/Q-type voltage-gated calcium channels (P/Q-VGCCs) at active zones reducing quantal release of acetylcholine, although an animal model using immunization with purified P/Q-VGCCs has not yet been established. The diagnosis can be confirmed by finding a reduced compound muscle action potential amplitude that increases by over 60% following maximum voluntary activation or 50 Hz nerve stimulation. Approximately 90% of patients who satisfy the above electrophysiological diagnostic criteria are positive for P/Q-VGCC antibodies have their diagnosis confirmed. Specific tumor therapy in SCLC-LEMS will often improve the neurologic deficit. Tumor removal is the primary treatment for LEMS. If primary tumor screening is negative, screening should be repeated after 3-6 months, followed by screening every 6 months until 2 years post diagnosis. Most patients benefit from 3,4-diaminopyridine being administered with pyridostigmine. In those with severe weakness, high-dose intravenous gamma-globulin (IVIg) or plasmapheresis confers short-term benefits. Prednisone, alone or combined with immunosuppressive drugs, can achieve long-term control of the disorder. The results of a prospective cohort study showed that the presence of LEMS with SCLC had a significant survival advantage independent of other prognostic factors including disease extent, age, sex, performance status, and serum sodium values.