Lambert-Eaton Myasthenic Syndrome Complicated by anti-GABAB Receptor Encephalitis.

A 74-year-old man experienced diplopia, generalized muscle weakness, and acute respiratory failure. He was diagnosed with Lambert-Eaton myasthenic syndrome (LEMS) and treated with immunotherapy, but no improvement was observed, and additional symptoms, including central apnea and hallucinations, appeared. Subsequent serum and cerebrospinal fluid (CSF) analyses confirmed the presence of GABAB receptor antibodies, indicating the coexistence of autoimmune encephalitis. Although there were no findings of malignancy, it is highly likely that occult small-cell lung carcinoma was present. When atypical symptoms occur in patients with LEMS, it is important to consider the possibility of concomitant autoimmune encephalitis.

[Diagnosis of cryoglobulinemic vasculitis based on B symptoms and peripheral neuropathy: a case report].

A man in his 50s presented with a 2-month history of paresthesia and hypoesthesia of the extremities and B symptoms including low-grade fever, weight loss, and night sweats. He also reported a 3-year history of skin discoloration in cold weather. Laboratory test results showed a high white blood cell count and elevated serum C-reactive protein and rheumatoid factor (RF) levels. Complement levels were low, and tests for cryoglobulin showed positive results. Computed tomography revealed generalized lymphadenopathy, and 18F-fluorodeoxyglucose-positron emission tomography showed increased uptake; therefore, we performed cervical lymph node and muscle biopsies. The patient was diagnosed with nodular marginal zone lymphoma and cryoglobulinemic vasculitis (CV) and received chemotherapy and steroid treatment with improvement in symptoms. CV is a rare immune complex small-vessel vasculitis. It is important to measure RF and complement levels and consider infections, collagen diseases, and hematological disorders in the differential diagnosis in patients with suspected vasculitis or CV.

Practice of Hereditary ATTR Amyloidosis in Non-endemic Areas of Japan.

Objective Hereditary ATTR (ATTRv) amyloidosis was once an incurable disease; however, in recent years, disease-modifying therapies, such as tafamidis and patisiran, have become available. We herein report the medical care situation in an ATTRv amyloidosis non-endemic area of Japan. Methods We confirmed the information in the medical records of our department and analyzed the data retrospectively. Patients Patients with ATTRv amyloidosis who were treated in our department between 2010 and 2021 were included. Results A total of 15 ATTRv amyloidosis cases (8 men and 7 women) were treated in our department during the study period; 9 patients had a family history, and the transthyretin V30M (p.V50M) gene mutation was present in 66% of cases. The average age of the onset was 57 years old, with 73% of the initial symptoms being dysesthesia and 13% being autonomic dysfunction. Ten patients were treated with tafamidis and nine with patisiran. Although it took a long time to start treatment among our experienced cases, there were some cases in which treatment could be introduced relatively early. Conclusion ATTRv amyloidosis is treatable and should be included in the differential diagnosis of neuropathy so that it can be diagnosed early and introduced into treatment. In the near future, the presymptomatic diagnosis of ATTRv amyloidosis and genetic counseling will become more important.

Clinical features of anti-mitochondrial M2 antibody-positive myositis: case series of 17 patients.

OBJECTIVE: In 2012, a large number of myositis cases with anti-mitochondrial M2 (AMA-M2) antibody, which had well been known as the serological hallmark for primary biliary cholangitis (PBC), were reported in Japan. Recently, some case series from Japan, France, America, China and India have shown that approximately 2.5% to 19.5% of patients with myositis have AMA-M2 antibody. The objective of this study was to clarify the prevalence, clinical features, treatment outcome, and severity determinants of AMA-M2 positive myositis. METHODS: This study was a multicenter observational study. We enrolled patients who were diagnosed with myositis during a ten-year period between 2012 and 2021. RESULTS: Of the total of 185 patients with inflammatory myopathy, 17 patients were positive for AMA-M2 antibody. The typical symptoms were weakness mainly involving paravertebral muscles, weight loss, respiratory failure, and cardiac complications. Thirteen of the 17 patients had cardiac complications. A strong correlation was found between respiratory failure and modified Rankin Scale (mRS) score. A strong correlation was also found between respiratory failure and body weight, indicating that weight loss can be an indicator of potential progression of respiratory failure. Six of the 17 patients were complicated by malignancy. CONCLUSIONS: This study showed significant correlations between % vital capacity (VC), body mass index (BMI), and mRS score in patients with AMA-M2-positive myositis. Immunotherapy often improved CK level and respiratory dysfunction. We therefore propose that %VC and BMI should be monitored as disease indicators in treatment of AMA-M2-positive myositis.

Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments.

BACKGROUND AND AIMS: Some hereditary transthyretin (ATTRv) amyloidosis patients are misdiagnosed as Charcot-Marie-Tooth disease (CMT) at onset. We assess the findings to identify ATTRv amyloidosis among patients with suspected CMT to screen transthyretin gene variants for treatments. METHODS: We assessed clinical, cerebrospinal fluid, and electrophysiological findings by comparing ATTRv amyloidosis patients with suspected CMT (n = 10) and CMT patients (n = 489). RESULTS: The median (interquartile range) age at onset of neurological symptoms was 69 (64.2-70) years in the ATTRv amyloidosis vs 12 (5-37.2) years in CMT group (Mann-Whitney U, p < 0.01). The proportion of patients with initial sensory symptoms was 70% in the ATTRv amyloidosis group vs 7.1% in CMT group (Fisher's exact, p < 0.01). The proportion of patients with histories of suspected chronic inflammatory demyelinating polyneuropathy (CIDP) were 50% in the ATTRv amyloidosis group vs 8.7% in CMT group (Fisher's exact, p < .01). Other measures and outcomes were not different between the two groups. Five of the six patients with ATTRv amyloidosis received treatment and survived. INTERPRETATION: For effective treatments, the transthyretin gene should be screened in patients with suspected CMT with old age at onset of neurological symptoms, initial sensory symptoms, and histories of suspected CIDP.

Progressive multifocal leukoencephalopathy with mild clinical conditions and detection of archetype-like JC virus in cerebrospinal fluid.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system with a poor prognosis and is primarily caused by JC virus (JCV) with a mutation called prototype. We encountered a case of PML with moderate progression and analyzed the mutational patterns of JCV in the cerebrospinal fluid (CSF). A 19-year-old Japanese woman with mild neurological symptoms was diagnosed with combined immunodeficiency following pneumocystis pneumonia. Brain magnetic resonance imaging scan showed multiple brain lesions, and real-time polymerase chain reaction testing detected JCV in the CSF, leading to the diagnosis of PML. The disease course of PML was stable after administration of mefloquine and mirtazapine with immunoglobulin replacement therapy. In the JCV genome cloned from the patient CSF, DNA sequences of the gene encoding the capsid protein (VP1) and the non-coding control region exhibited small mutations. However, they were quite similar to those of the archetype JCV, which persists asymptomatically in healthy individuals. These findings provide insight into the mutational characteristics of JCV in PML with mild symptoms and progression.

Correlation of active contact location with weight gain after subthalamic nucleus deep brain stimulation: a case series.

BACKGROUND: Weight gain (WG) is a frequently reported side effect of subthalamic deep brain stimulation; however, the underlying mechanisms remain unclear. The active contact locations influence the clinical outcomes of subthalamic deep brain stimulation, but it is unclear whether WG is directly associated with the active contact locations. We aimed to determine whether WG is associated with the subthalamic deep brain stimulation active contact locations. METHODS: We enrolled 14 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation between 2013 and 2019. Bodyweight and body mass index were measured before and one year following the surgery. The Lead-DBS Matlab toolbox was used to determine the active contact locations based on magnetic resonance imaging and computed tomography. We also created sweet spot maps for WG using voxel-wise statistics, based on volume of tissue activation and the WG of each patient. Fluorodeoxyglucose-positron emission tomography data were also acquired before and one year following surgery, and statistical parametric mapping was used to evaluate changes in brain metabolism. We examined which brain regions' metabolism fluctuation significantly correlated with increased body mass index scores and positron emission tomography data. RESULTS: One year after surgery, the body mass index increase was 2.03 kg/m2. The sweet spots for WG were bilateral, mainly located dorsally outside of the subthalamic nucleus (STN). Furthermore, WG was correlated with increased metabolism in the left limbic and associative regions, including the middle temporal gyrus, inferior frontal gyrus, and orbital gyrus. CONCLUSIONS: Although the mechanisms underlying WG following subthalamic deep brain stimulation are possibly multifactorial, our findings suggest that dorsal stimulation outside of STN may lead to WG. The metabolic changes in limbic and associative cortical regions after STN-DBS may also be one of the mechanisms underlying WG. Further studies are warranted to confirm whether dorsal stimulation outside of STN changes the activities of these cortical regions.

Adrenoleukodystrophy siblings with a novel ABCD1 missense variant presenting with phenotypic differences: a case report and literature review.

Adrenoleukodystrophy (ALD) is an X-linked disease that affects primarily the white matter of the central nervous system and adrenal cortex. A correlation between genotypes and phenotypes has not been observed. Here, we present two Japanese siblings with a novel missense variant (c.1887T > G) in the ABCD1 gene who presented with different clinical phenotypes, i.e., adolescent cerebral and cerebello-brainstem types. We also review the literature focusing on the variation in the clinical phenotypes within ALD families. In our review, 61.9% of sibling pairs presented with the same clinical type of ALD and 59.1% of sibling pairs presented with a similar age of onset. Conversely, 15.4% of sibling pairs had a similar age of onset, but different clinical types of ALD. To observe the correlation between genotypes and phenotypes, it is important to diagnose early and to accumulate reports describing age of onset, first onset symptom, and progression of the symptom.

[Two elderly cases of transthyretin amyloid polyneuropathy without a family history].

We report two cases of transthyretin familial amyloid polyneuropathy (ATTR-FAP) from non-endemic areas. Both cases showed chronic progressive distal limb numbness and weakness. Due to nonspecific symptoms, they were not diagnosed for a long period of time. A nerve conduction study revealed axonal neuropathy in the lower limbs and carpal tunnel syndrome. An echo test showed thickness of the left ventricle, one of the red flag symptom clusters of ATTR-FAP. Genetic analysis revealed a mutation in the transthyretin gene. In cases with chronic progressive neuropathy, it is important to consider a differential diagnosis of ATTR-FAP.

[A case of tibial nerve palsy due to intraneural ganglion cysts].

A 39-year-old man presented with an 8-month history of pain and paresthesia of the right foot sole and difficulty in the right toe dorsiflexion. A neurological examination revealed weakness in performing both the ankle and right foot toe dorsiflexion, reduced right planta pedis sensation, and absent right Achilles tendon reflex. Tinel's sign was present on the right popliteal fossa and medial part of the right ankle. MRI of the right knee showed multiple cystic lesions in his right tibial nerve. The cystic lesions extended from the popliteal fossa and were thought to be intraneural ganglion cysts. On MRI performed 4 months later, most of the cystic lesions spontaneously vanished. Therefore, intraneural ganglia should be considered when atypical mononeuropathy, such as tibial nerve palsy, is present.

Hashimoto's encephalopathy mimicking a brain tumor and its pathological findings: A case report.

Hashimoto's encephalopathy is characterized by the presence of anti-thyroid antibodies with no alternative cause. Patients with Hashimoto's encephalopathy present with various clinical symptoms and magnetic resonance imaging (MRI) findings. To our knowledge, this is the first documented report of Hashimoto's encephalopathy with MRI findings mimicking a brain tumor. The patient was a 41-year-old woman with a history of Hashimoto's disease. She experienced gradually worsening Parkinsonism and an MRI revealed a brain tumor-like lesion at the left caudate nucleus. She underwent a brain biopsy that revealed diffuse gliosis and perivascular lymphocyte infiltration with CD3+ T-cell predominance. No pathological signs of a brain tumor were found. Hashimoto's encephalopathy was suspected based on the patient's history and the presence of anti-thyroid antibodies. Her symptoms and the MRI findings improved with glucocorticoid treatment. Although there exist only a few studies on the pathology of Hashimoto's encephalopathy, our findings were consistent with those of previous reports. Our findings suggest cerebral vasculitis as an underlying etiology of Hashimoto's encephalopathy. We also emphasize the importance of considering Hashimoto's encephalopathy as a differential diagnosis of brain tumors.

Long-term Outcome of Adenosine A2A Receptor Antagonist on Lower Urinary Tract Symptoms in Male Parkinson Disease Patients.

OBJECTIVES: In addition to motor symptoms, bladder dysfunction is a major clinical issue in patients with Parkinson disease (PD). Istradefylline is adenosine A2A receptor antagonist approved for PD patients with wearing-off symptoms. The aim of this study was to determine the long-term effects of istradefylline on lower urinary tract symptoms (LUTSs) in PD patients. METHODS: We enrolled 14 male PD patients. The mean age of patients was 73 years (61-77 years), the Hoehn-Yahr stage was 2 (2-3), and disease duration was 9 years (3-28 years). The effects of istradefylline (20 mg/d) on LUTSs in PD patients with motor complications after 3, 6, and 12 months of therapy were evaluated based on the International Prostate Symptom Score and Overactive Bladder Symptom Score before and after its administration. RESULTS: Motor symptoms significantly improved at 12 months' administration (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale part III: 30.0 ± 12.9 vs 13.8 ± 8.1; P < 0.01). Significant improvements were also observed in the answers provided on urinary questionnaires (International Prostate Symptom Score, 14.4 ± 7.6 vs 8.5 ± 6.8; Overactive Bladder Symptom Score, 6.9 ± 2.8 vs 5.5 ± 3.7; P < 0.05). Nighttime urinary frequency and the percentage of the nocturnal urine volume also improved significantly at 3 months' administration (P < 0.01). CONCLUSIONS: Istradefylline effectively improved not only motor symptoms, but also LUTSs in patients with PD.

[A retrospective study of the effects of 3,4-diaminopyridine treatment in Lambert-Eaton myasthenic syndrome].

In this independent clinical study, we analyzed retrospectively the clinical features of 9 cases (6 male and 3 female) of Lambert-Eaton myasthenic syndrome that were administered 3,4-diaminopyridine (3,4-DAP). Four cases showed no cancer and 5 cases had small cell lung carcinoma. Seven cases were positive for anti voltage-gated calcium channel antibodies. Activities of daily living (ADL) were improved by 3,4-DAP in 8 cases that showed mainly weakness of the extremities, but did not improve ADL in 1 case with cerebellar ataxia of paraneoplastic cerebellar degeneration (PCD). Seven cases showed autonomic symptoms, and 6 cases were improved with 3,4-DAP. The maintenance dose varied widely among individuals, with a single dose ranging from 10 to 40 mg. Each patient was prescribed a maintenance dose 3 to 7 times a day. The daily dosage ranged from 36 to 100 mg. Two cases showed adverse effects to the treatment. Of those 2 cases, 1 case treated at 45 mg/day discontinued treatment, but another case treated at 100 mg/day reduced the dosage and continued treatment. The administration period was 1 to 149 months. Three cases have continued 3,4-DAP for more than 10 years. Four cases have discontinued 3,4-DAP, with 2 cases discontinuing due to death, 1 case discontinuing due to progression of cancer, and 1 case discontinuing due to an adverse reaction. Our results suggest that 3,4-DAP treatment is effective for weakness and autonomic symptoms, but may be ineffective for ataxia of PCD. Treatment with 3,4-DAP can be tolerated for a long period, but the optimal dosage varies widely among individuals.

The Efficacy of Istradefylline for Treating Mild Wearing-Off in Parkinson Disease.

OBJECTIVES: The adenosine A2A antagonist istradefylline has been used to treat Parkinson disease (PD) with symptoms of wearing-off since 2013 in Japan. Previous randomized controlled trials of istradefylline compared with placebo included PD patients experiencing an average daily OFF time of more than 2 hours. The purpose of this study is to assess the efficacy of 20 mg/d istradefylline in PD subjects experiencing an average daily OFF time of 3 hours or less. METHODS: Fifteen patients were enrolled into this retrospective study. They received 20 mg/d istradefylline for 12 weeks. Changes in the Unified Parkinson's Disease Rating Scale part III scores in the ON state (ON-UPDRS-III) scores and daily OFF time were assessed at baseline and after 4, 8, and 12 weeks of administration of istradefylline. RESULTS: At baseline, all subjects had shorter daily OFF times, lower doses of L-DOPA and higher ON-UPDRS-III scores than those in previous randomized controlled trials. Twelve weeks of istradefylline significantly reduced ON-UPDRS-III scores (P < 0.001, Wilcoxon signed rank test). Eleven patients (73%) showed more than 50% reductions in ON-UPDRS-III scores. Improvement of ON-UPDRS-III was significantly correlated with baseline ON-UPDRS-III, and the mean ON-UPDRS-III score at end point was 12.1. CONCLUSIONS: Our result suggests that 20 mg/d istradefylline significantly improved motor functions in PD patients with mild wearing-off.

Amyloid Polyneuropathy and Myocardial Amyloidosis 10 Years after Domino Liver Transplantation from a Patient with a Transthyretin Ser50Arg Mutation.

A 54-year-old man with polycystic liver disease received a domino liver transplantation (DLT) from a patient of hereditary ATTR amyloidosis with the transthyretin Ser50Arg mutation. Ten years after transplantation, he felt a slight numbness in his toes, and cardiac amyloidosis was simultaneously suspected upon a heart function evaluation. Biopsy specimens from the myocardium revealed transthyretin amyloidosis with the Ser50Arg mutation. Oral tafamidis therapy has inhibited the progression of neurological and cardiovascular symptoms this far. We herein report this first case of amyloid polyneuropathy and myocardial amyloidosis after DLT from hereditary ATTR amyloidosis with a transthyretin Ser50Arg mutation and discuss similar cases of other mutations.

[A case of anti-PL7 antibody positive myositis and a clinical and pathological review of the anti-synthetase syndrome].

A 52-year-old woman was admitted to our hospital with muscle pain and an elevated creatine kinase level. She had experienced wrist pain at onset seven years ago. The initial possible diagnoses were rheumatoid arthritis and adult-onset Still disease. The patient received corticosteroid and immunosuppressant therapy but experienced deterioration of symptoms. The symptoms of muscle pain and mild creatine kinase elevation emerged four years prior to her visit. Further elevation of creatine kinase was observed for three months before her visit despite adjusting the immunosuppressant dose. On admission, she presented with muscle moderate weakness of the trunk and extremities and pain of the shoulder and medial thigh muscles. Elevation of muscle enzymes and inflammatory response were also detected, and the anti-PL7 antibody was positive. Muscle biopsy from biceps brachii revealed necrotizing myopathy with necrotic and regenerated muscle fibers. The final diagnosis was anti-PL7 antibody positive myositis. The patient was treated with a higher dose of prednisolone and an adequate dose of tacrolimus. Following this treatment, the symptoms were improved. Anti-ARS (aminoacyl t-RNA synthetase) antibodies such as anti-PL7 antibody are useful in diagnosis and for prognostic prediction. Further investigation of patients with anti-ARS antibodies positive myositis is required.

Usefulness of 11C-methionine-positron emission tomography for the diagnosis of progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating disease of the brain caused by the JC virus that occurs mainly in immunocompromised patients. The prognosis is very poor. As the lesion looks like non- specific leukoencephalopathy, making a diagnosis at the early stage is very difficult. We report three PML cases in which there was a mismatch between (11)C-methionine-positron emission tomography (MET-PET) uptake and (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake. All three cases demonstrated the hyper-uptake of MET around the white matter lesions and hypo-uptake of FDG inside the lesions. We speculate that the infection had ended inside the white matter lesions of these patients, while JC virus infection was ongoing around the lesions, resulting in the increase of methionine metabolism, and the glucose metabolism was reduced or intermediate because inflammatory cells infiltrate PML lesions rarely. Two patients who were diagnosed and treated with mefloquine while the JC virus was at a low level in the cerebrospinal fluid are still alive. We suggest the usefulness of MET-PET for the early diagnosis of PML and early treatment with mefloquine.

Pathological study of subacute autoimmune encephalopathy with anti-AQP4 antibodies in a pregnant woman.

A pregnant woman with extensive brain lesions on magnetic resonance imaging was tested positive for anti-aquaporin4 (AQP4) antibodies. An open biopsy of the left temporal lobe showed pathological changes in both the white and gray matter. Hematoxylin and eosin, Klüver-Barrera, and myelin basic protein staining results were indicative of demyelination in the white matter. Loss of AQP4 and glial fibrillary acidic protein was observed in the white matter, and this finding is consistent with the neuropathological findings of neuromyelitis optica spinal lesions. Moreover, loss of AQP4 was observed in the gray matter. The presence of anti-AQP4 antibodies, and the pathology, led to the diagnosis of anti-AQP4 antibodies-related encephalopathy.