Recurrent embolic stroke associated with adenomyosis: A single case report and literature review.

INTRODUCTION: Uterine adenomyosis is a benign disorder in which endometrial glands and stroma are present within the myometrium. There have been several case reports of cerebral infarction associated with adenomyosis, but their clinical characteristics, optimal treatment, and prognosis have not been systematically reviewed. METHODS: A case of cerebral infarction with adenomyosis is reported, and a comprehensive systematic literature search using the PubMed database was conducted. RESULTS: A 42-year-old woman, previously diagnosed with adenomyosis, developed multiple cerebral infarctions during menstruation. Her CA125 level was 293 U/mL, and treatment with edoxaban 30 mg was started. Seven days after hospital discharge, she had her subsequent menstrual period and then developed a recurrent stroke. Her CA125 level was 743 U/mL on readmission. A hysterectomy was performed, and the patient has had no further stroke recurrence. A systematic review identified 19 cases with cerebral infarction associated with adenomyosis, including the present case. The patients' clinical characteristics included young age (44.7 ± 6.2 years), stroke development during menstruation (85%), multiple infarctions affecting ≥ 3 vessel territories (39%), and high levels of CA125 and D-dimer (810.6 ± 888.4 U/mL, and 10.3 ± 18.6 µg/mL, respectively). Antithrombotic therapy was given to 14 patients, but recurrent stroke occurred in 5 (36%) patients. Hysterectomy was conducted in 5 and 4 patients with initial and recurrent stokes, respectively, and there were no further recurrences thereafter. CONCLUSION: Cerebral infarction associated with adenomyosis has specific clinical characteristics. Antithrombotic therapy was insufficient, and hysterectomy should particularly be considered in cases of recurrent stroke.

Variants in saposin D domain of prosaposin gene linked to Parkinson's disease.

Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease.

Sympathetic outflow to skin predicts central autonomic dysfunction in multiple system atrophy.

BACKGROUND: To find out the physiological method for evaluating the severity of central autonomic dysfunction, we performed detailed evaluation of cutaneous vasomotor neural function in a comparatively large sample of multiple system atrophy (MSA). METHODS: We evaluated cutaneous vasomotor neural function in 24 MSA patients. Skin sympathetic nerve activity (SSNA) and sympathetic skin response (SSR) and skin blood flow (skin vasomotor reflex [SVR]) were recorded at rest, as well as reflex changes after electrical stimulation. The parameters investigated were SSNA frequency at rest, reflex latency and amplitude of SSNA reflex bursts, absolute decrease and percent reduction of SVR, recovery time, and spontaneous SVR and SSR frequency. RESULTS: There were negative correlations between resting SSNA and disease duration or the SCOPA-AUT score, but these were not significant. SSNA reflex latency displayed significant positive correlations with disease duration and SCOPA-AUT score (p < 0.001 and p < 0.01, respectively). In all five patients who underwent the same examination twice, SSNA reflex latency was significantly longer at the second examination than at the first examination (p < 0.005). A significant positive correlation was identified between recovery time of skin blood flow and SCOPA-AUT score or reflex latency (p < 0.05). Significant correlations were not observed between SCOPA-AUT score or disease duration and other parameters. CONCLUSIONS: These results suggest that some MSA patients with a comparatively short duration of disease potentially have impaired thermoregulatory function. Measurement of sympathetic outflow to the skin is potentially a useful tool for predicting the severity of central autonomic dysfunction in MSA.

Spinocerebellar ataxia type 31 associated with REM sleep behavior disorder: a case report.

BACKGROUND: Spinocerebellar ataxia type 31 (SCA 31) is a slowly progressive neurodegenerative disorder characterized by pure cerebellar ataxia. Unlike other CAG repeat diseases, sleep-related problems have not been reported in patients with SCA 31 so far. CASE PRESENTATION: A 67-year-old woman was admitted to our hospital with dysarthria and gait disturbance after onset age of 62 years. Neurological examination revealed pure cerebellar ataxia. Genetic analysis detected expansion of a TGGAA repeat in the coding region of the BEAN/TK2 gene on chromosome 16p22.1, confirming the diagnosis of SCA 31. One year later, her husband noticed the patient talking loudly during sleep once or twice a week. Overnight polysomnography showed rapid eye movement sleep without atonia. Cardiac scintigraphy with iodine-123-labeled meta-iodobenzylguanidine revealed a low heart/mediastinum ratio, indicating reduced uptake, and a high washout rate. CONCLUSION: To our knowledge, this is the first report of a patient with SCA 31 associated with rapid eye movement sleep behavior disorder (RBD). In the future, evaluation of autonomic function, assessment of the frequency of RBD, and performance of cardiac iodine-123-labeled meta-iodobenzylguanidine scintigraphy in a larger number of SCA 31 patients could be useful to resolve important issues regarding the mechanism of RBD.

Pathological findings in a patient with non-dystrophic myotonia with a mutation of the SCN4A gene; a case report.

BACKGROUND: Non-dystrophic myotonias (NDMs) are skeletal muscle disorders involving myotonia distinct from myotonic dystrophy. It has been reported that the muscle pathology is usually normal or comprises mild myopathic changes in NDMs. We describe various pathological findings mimicking those of myotonic dystrophy (DM) in biopsied muscle specimens from a patient with NDMs with a long disease duration. CASE PRESENTATION: A 66-year-old Japanease man presented eye closure myotonia, percussion myotonia and grip myotonia together with the warm-up phenomenon and cold aggravation from early childhood. On genetic analysis, a heterozygous mutation of the SCN4A gene (c.2065 C > T, p.L689F), with no mutation of the CLCN1, DMPK, or ZNF9/CNBP gene, was detected. He was diagnosed as having NDMs. A biopsy of the biceps brachii muscle showed increasing fiber size variation, internal nuclei, chained nuclei, necrotic fibers, fiber splitting, endomysial fibrosis, pyknotic nuclear clumps and disorganized intermyofibrillar networks. Sarcoplasmic masses, tubular aggregates and ragged-red fibers were absent. CONCLUSION: It is noteworthy that the present study revealed various pathological findings resembling those seen in DM, although the pathology is usually normal or mild in NDMs. The pathological similarities may be due to muscular modification with long-standing myotonia or excessive muscle contraction based on abnormal channel activity.

Vasomotor regulation in patients with multiple system atrophy.

To investigate the vasomotor regulation in multiple system atrophy (MSA), we simultaneously recorded muscle sympathetic nerve activity (MSNA), heart rate, and blood pressure in 14 MSA patients without syncope and 18 healthy subjects. Resting MSNA bursts were significantly less frequent in MSA patients than healthy subjects (p < 0.001), while the increase of MSNA bursts with head-up tilt was significantly greater in MSA patients (p < 0.01). In patients with MSA, orthostatic hypotension may be prevented by an augmented MSNA response.

Muscle sympathetic nerve activity in frontotemporal lobar degeneration is similar to amyotrophic lateral sclerosis.

PURPOSE: To determine whether frontotemporal lobar degeneration (FTLD) is associated with similar cardiovascular autonomic dysfunction to that seen in amyotrophic lateral sclerosis (ALS), we compared cardiovascular parameters between ALS patients and patients with FTLD. METHODS: In ten patients with FTLD (mean age ± SD: 71.6 ± 4.6 years) and 12 patients with ALS (mean age ± SD: 71.4 ± 4.6 years), MSNA (using microneurography), heart rate (HR), and blood pressure (BP) were recorded simultaneously. RESULTS: MSNA was significantly higher in both groups of patients compared with the controls (p < 0.01), while there were no significant differences in MSNA between the patients with FTLD and those with ALS. During head-up tilt, changes in HR, BP, and the frequency of MSNA bursts were smaller in the patients than in controls (p < 0.05 or p < 0.01). CONCLUSIONS: Patients with FTLD and ALS showed similar dysfunction of HR, BP, and sympathetic outflow to muscles.

Changes in sympathetic thermoregulatory function with aging.

We recorded skin sympathetic nerve activity (SSNA), SSR, and SVR in 30 subjects. SSNA and SVR showed a slight decrease and spontaneous changes in resting SSR were significantly less frequent in older subjects compared with younger subjects (p < 0.05). There was no significant relationship between age and the reflex latency or amplitude of SSNA, SSR, and SVR in response to electrical stimulation.

Novel mutations in the PNPLA6 gene in Boucher-Neuhäuser syndrome.

On whole-exome sequencing, a novel compound heterozygous mutation (c.2923A>G/c.3523_3524insTGTCCG, p.T975A/p.1175_1176insVS) and a novel homozygous one (c.3534G>C, p.W1178C) in the PNPLA6 gene were identified in sporadic and familial Japanese patients with Boucher-Neuhäuser syndrome (BNS), respectively. However, we did not find any mutations in the PNPLA6 gene in 88 patients with autosomal recessive hereditary spastic paraplegia (ARHSP). Our study confirmed the earlier report that a PNPLA6 mutation causes BNS. This is the first report on PNPLA6 mutations in non-Caucasian patients. Meanwhile, PNPLA6 mutations might be extremely rare in Japanese ARHSP patients. Moreover, we first found hypersegmented neutrophils in two BNS patients with PNPLA6 mutations.

A Japanese SCA5 family with a novel three-nucleotide in-frame deletion mutation in the SPTBN2 gene: a clinical and genetic study.

To date, four families with spinocerebellar ataxia type 5 (SCA5) with four distinct mutations in the spectrin, beta, nonerythrocytic 2 gene (SPTBN2) have been reported worldwide. In the present study, we identified the first Japanese family with SCA5, and analyzed this family clinically and genetically. The clinical features of the five patients in this family revealed late-onset autosomal-dominant pure cerebellar ataxia. We collected DNA samples from the majority of the family members across two generations, and exome sequencing combined with Sanger sequencing revealed a novel heterozygous three-nucleotide in-frame deletion mutation (c.2608_2610delGAG) in exon 14 of the SPTBN2 gene. This mutation cosegregated with the disease in the family and resulted in a glutamic acid deletion (p.E870del) in the sixth spectrin repeat, which is highly conserved in the SPTBN2 gene. This is the first three-nucleotide in-frame deletion mutation in this region of the beta-3 spectrin protein highly likely to be pathogenic based on exome and bioinformatic data.

Case report: Atypical case of autoimmune glial fibrillary acidic protein astrocytopathy following COVID-19 vaccination refractory to immunosuppressive treatments.

A 54-year-old Japanese man presented with headache and fever the day after SARS-CoV-2 vaccination. He became deeply unconscious within a week. Brain MRI showed periventricular linear enhancements and a few spotty lesions in the cerebral white matter. Cerebrospinal fluid (CSF) testing showed mild pleocytosis. He was treated with intravenous methylprednisolone and plasma exchange. However, the white matter lesions enlarged to involve the brainstem and cerebellum, and long cord spinal lesions appeared. Anti-glial fibrillary acidic protein (GFAP) antibody was positive in the CSF and serum, and he was therefore diagnosed as autoimmune GFAP-astrocytopathy (GFAP-A). In addition, high-dose immunoglobulin therapy was administered twice, but his symptoms did not improve; the white matter lesions enlarged further, and modified Rankin Scale score increased to 5. A brain biopsy specimen showed infiltration of macrophages and CD4 + lymphocytes together with neuron and oligodendrocytic injuries and glial scar. Although GFAP-A generally responds well to steroids, the present case developed GFAP-A following SARS-CoV-2 vaccination, with refractory to intensive immunosuppressive therapy and atypical pathologic findings of infiltration of CD4 + lymphocytes and demyelination.

Temporal prolongation of decreased skin blood flow causes cold limbs in Parkinson's disease.

To unravel the pathogenesis of cold limbs in Parkinson's disease, we evaluated cutaneous vasomotor neural function in 25 Parkinson's disease patients with or without cold limbs and 20 healthy controls. We measured resting skin sympathetic nerve activity, as well as reflex changes of skin blood flow and skin sympathetic nerve activity after electrical stimulation, with the parameters including skin sympathetic nerve activity frequency at rest, the amplitude of reflex bursts, the absolute decrease and percent reduction of blood flow, and the recovery time which was calculated as the interval from the start of blood flow reduction until the return to baseline cutaneous blood flow. The resting frequency of skin sympathetic nerve activity was significantly lower in patients with Parkinson's disease than in controls (p < 0.01). There were no significant differences between the patients and controls with respect to the amplitude of skin sympathetic nerve activity and the absolute decrease or percent reduction of blood flow volume. In the controls, the recovery time (9.4 ± 1.2), which was similar to Parkinson's disease patients without cold limbs (9.0 ± 0.7), while the recovery time ranged (15.7 ± 3.2) in Parkinson's disease patients with cold limbs. Recovery was significantly slower in these patients compared with the other groups (p < 0.05). It is possible that cold limbs might arise due to impaired circulation based on prolonged vasoconstriction by peripheral autonomic impairments, in addition to central autonomic dysfunction in Parkinson's disease.

[A case of ataxic gait disturbance due to 1-bromopropane neurotoxicity].

A 55-year-old man presented a slowly progressive sensory disorder, predominantly in both lower limbs, and gait disturbance. Neurological examinations revealed abnormal sensation and spasticity in both lower limbs, and a wide-based gait. Although examination revealed mild hyperchloremia and decreased motor conduction velocity in the peroneal nerve, head and whole spine MRI, and spinal fluid examination were normal. His job history revealed he had been engaged in metal cleaning work using 1-bromopropane (1-BP) for three years. His serum bromide concentration was increased to 175.6 mg/l (standard value: 5 or less), so we diagnosed him as having 1-BP neurotoxicity. The serum bromide concentration decreased after avoidance of exposure to 1-BP, but the gait disturbance remained. It was considered that we should obtain a detailed job history and measure the serum bromide concentration in patients with a sensory disorder in the extremities and gait disturbance of unknown origin.