Saccadic oscillations as a biomarker of clinical symptoms in amyotrophic lateral sclerosis.

BACKGROUND: Among eye movements in amyotrophic lateral sclerosis (ALS), we identified the characteristics of square-wave jerks (SWJs) seen during times without visual fixation (VF) and analyzed their relationships with clinical parameters. MATERIALS AND METHODS: Clinical symptoms were evaluated and eye movements were tested using electronystagmography in 15 patients with ALS (10 men, 5 women; mean age, 66.9 ± 10.5 years). SWJs with and without VF were recorded, and their characteristics were identified. Relationships between each SWJ parameter and clinical symptoms were evaluated. Results were compared with eye movement data from 18 healthy individuals. RESULTS: The frequency of SWJs without VF was significantly higher in the ALS group than in the healthy group (P < 0.001). When the condition was changed from VF to no-VF in the ALS group, the frequency of SWJs was significantly higher in healthy subjects (P = 0.004). A positive correlation was seen between frequency of SWJs and percentage predicted forced vital capacity (%FVC) (R = 0.546, P = 0.035). CONCLUSION: The frequency of SWJs was higher with VF in healthy people, and was suppressed without VF. In contrast, the frequency of SWJs was not suppressed without VF in ALS patients. This suggests that SWJs without VF have some clinical significance in ALS patients. Moreover, a relationship was noted between the parameters of SWJs without VF in ALS patients and results of pulmonary function tests, suggesting that SWJs during times without VF may offer a clinical parameter of ALS.

[Waldenström macroglobulinemia complicated by peripheral neuropathy due to neural infiltration].

A 51-year-old man with the chief complaint of glove- and stocking-type dysesthesia for >3 years was diagnosed with Waldenström's macroglobulinemia (WM) based on IgM-type M-proteinemia, bone marrow infiltration of plasmacytoid B cells, multiple lymphadenopathies, and splenomegaly. A nerve conduction examination suggested demyelinating neuropathy. Serum anti-myelin-associated glycoprotein antibody was negative. Sural nerve biopsy showed myelin thinning, suggesting demyelination. Axonal damage and tumor cell infiltration in the intrafascicular epineurium were also observed. After chemotherapies with rituximab and bendamustine, M-proteinemia and lymphadenopathies disappeared. However, abnormalities in the nerve conduction examination and dysesthesia were only slightly alleviated. As articles describing patients with WM with peripheral nerve infiltration are limited, we report this case with a literature review.

Splice-site mutations in KIF5A in the Japanese case series of amyotrophic lateral sclerosis.

Our objective was to investigate the frequency of KIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants in KIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF < 0.01) in KIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants in KIF5A were also described. LoF variants were identified only in the probands of two families with FALS, both of which were 3' splice-site variants leading to exon skipping and an altered C-terminal domain, located in the mutational hotspot causing FALS, and were considered to be pathogenic for FALS. Rare missense variants in KIF5A were identified in five patients with SALS (1.13%) and 11 control subjects (0.95%, carrier frequency), which were not significantly different. Consequently, the pathogenic LoF variants in KIF5A accounted for 2.1% of all FALS families in this study. These patients suffered from ALS characteristically associated with the predominant involvement of upper motor neuron. In conclusion, we identified two pathogenic splice-site variants in KIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants in KIF5A in the Japanese series.

Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study.

Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.

Immunohistochemical characterization of CD33 expression on microglia in Nasu-Hakola disease brains.

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by formation of multifocal bone cysts and development of leukoencephalopathy, caused by genetic mutations of either DNAX-activation protein 12 (DAP12) or triggering receptor expressed on myeloid cells 2 (TREM2). Although increasing evidence suggests a defect in microglial TREM2/DAP12 function in NHD, the molecular mechanism underlying leukoencephalopathy with relevance to microglial dysfunction remains unknown. TREM2, by transmitting signals via the immunoreceptor tyrosine-based activation motif (ITAM) of DAP12, stimulates phagocytic activity of microglia, and ITAM signaling is counterbalanced by sialic acid-binding immunoglobulin (Ig)-like lectins (Siglecs)-mediated immunoreceptor tyrosine-based inhibitory motif (ITIM) signaling. To investigate a role of CD33, a member of the Siglecs family acting as a negative regulator of microglia activation, in the pathology of NHD, we studied CD33 expression patterns in five NHD brains and 11 controls by immunohistochemistry. In NHD brains, CD33 was identified exclusively on ramified and amoeboid microglia accumulated in demyelinated white matter lesions but not expressed in astrocytes, oligodendrocytes, or neurons. However, the number of CD33-immunoreactive microglia showed great variability from case to case and from lesion to lesion without significant differences between NHD and control brains. These results do not support the view that CD33-expressing microglia play a central role in the development of leukoencephalopathy in NHD brains.

Genetic and Functional Analyses of Patients with Marked Hypo-High-Density Lipoprotein Cholesterolemia.

AIM: This study aimed to analyze two cases of marked hypo-high-density lipoprotein (HDL) cholesterolemia to identify mutations in ATP-binding cassette transporter A1 (ABCA1) and elucidate the molecular mechanism by which these novel pathological mutations contribute to hypo-HDL cholesterolemia in Tangier disease. METHODS: Wild type and mutant expression plasmids containing a FLAG tag inserted at the C-terminus of the human ABCA1 gene were generated and transfected into HEK293T cells. ABCA1 protein expression and cholesterol efflux were evaluated via Western blotting and efflux assay. The difference in the rate of change in protein expression was evaluated when proteolytic and protein-producing systems were inhibited. RESULTS: In case 1, a 20-year-old woman presented with a chief complaint of gait disturbance. Her HDL-C level was only 6.2 mg/dL. Tangier disease was suspected because of muscle weakness, decreased nerve conduction velocity, and splenomegaly. Whole-exome analysis showed compound heterozygosity for a W484* nonsense mutation and S1343I missense mutation, which confirmed Tangier disease. Cholesterol efflux decreased by a mixture of W484* and S1343I mutations. The S1343I mutation decreased the protein production rate but increased the degradation rate, decreasing the protein levels. This patient also had Krabbe disease. The endogenous ABCA1 protein level of macrophage cell decreased by knocking down its internal galactocerebrosidase.Case 2, a 51-year-old woman who underwent tonsillectomy presented with peripheral neuropathy, corneal opacity, and HDL-C of 3.4 mg/dL. Whole-exome analysis revealed compound heterozygosity for R579* and R1572* nonsense mutations, which confirmed Tangier disease. CONCLUSION: Case 1 is a new ABCA1 mutation with complex pathogenicity, namely, a W484*/S1343I compound heterozygote with marked hypo-HDL cholesterolemia. Analyses of the compound heterozygous mutations indicated that decreases in ABCA1 protein levels and cholesterol efflux activity caused by the novel S1343I mutation combined with loss of W484* protein activity could lead to marked hypo-HDL cholesterolemia. Galactocerebrosidase dysfunction could also be a potential confounding factor for ABCA1 protein function.

Characteristics of hypersomnia due to inflammatory demyelinating diseases of the central nervous system.

Background: Neuromyelitis optica spectrum disorder (NMOSD) diagnostic criteria for inflammatory demyelinating central nervous system diseases included symptomatic narcolepsy; however, no relevant case-control studies exist. We aimed to examine the relationship among cerebrospinal fluid orexin-A (CSF-OX) levels, cataplexy and diencephalic syndrome; determine risk factors for low-and-intermediate CSF-OX levels (≤200 pg/mL) and quantify hypothalamic intensity using MRI. Methods: This ancillary retrospective case-control study included 50 patients with hypersomnia and 68 controls (among 3000 patients) from Akita University, the University of Tsukuba and community hospitals (200 facilities). Outcomes were CSF-OX level and MRI hypothalamus-to-caudate-nucleus-intensity ratio. Risk factors were age, sex, hypersomnolence and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130%. Logistic regression was performed for the association between the risk factors and CSF-OX levels ≤200 pg/mL. Results: The hypersomnia group (n=50) had significantly more cases of NMOSD (p<0.001), diencephalic syndrome (p=0.006), corticosteroid use (p=0.011), hypothalamic lesions (p<0.023) and early treatment (p<0.001). No cataplexy occurred. In the hypersomnia group, the median CSF-OX level was 160.5 (IQR 108.4-236.5) pg/mL and median MRI hypothalamus-to-caudate-nucleus-intensity ratio was 127.6% (IQR 115.3-149.1). Significant risk factors were hypersomnolence (adjusted OR (AOR) 6.95; 95% CI 2.64 to 18.29; p<0.001) and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% (AOR 6.33; 95% CI 1.18 to 34.09; p=0.032). The latter was less sensitive in predicting CSF-OX levels ≤200 pg/mL. Cases with MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% had a higher rate of diencephalic syndrome (p<0.001, V=0.59). Conclusions: Considering orexin as reflected by CSF-OX levels and MRI hypothalamus-to-caudate-nucleus-intensity ratio may help diagnose hypersomnia with diencephalic syndrome.

Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). METHODS: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. RESULTS: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.

Clinical Application of the Vestibular Stimulation Effect on Balance Disorders with Dementia.

BACKGROUND: In a previous study on Alzheimer's disease (AD), we showed that vestibular dysfunction derived from cerebral disorders contributes to balance disorders. No previous clinical study has attempted to prevent the progression of balance disorders in dementia patients through vestibular stimulation using an air caloric device. OBJECTIVE: The purpose of this pilot study was to delay the progression of balance disorders by inducing vestibular compensation, specifically by utilizing the effect of vestibular stimulation to activate the cerebrum. METHODS: Fifteen individuals were randomized and classified into a stimulation group or a nonstimulation group. Eight AD patients underwent vestibular stimulation every 2 weeks for 6 months in the stimulation group. Seven AD patients participated in the nonstimulation group (the control group). Both groups were subsequently evaluated using a Mini-Mental State Examination (MMSE), stepping test, caloric test, and smooth pursuit eye movement test just before starting the study and 6 months later. RESULTS: For balance parameters, the various tests did not show any significant differences between the two groups. However, in the stepping test, the decline rate tended to be higher in the nonstimulation group than in the stimulation group. The stimulation group's rate of decline in MMSE scores was lower than that of the nonstimulation group (p=0.015). No adverse events were tracked during the present study. CONCLUSION: Repeated vestibular stimulation might help patients retain greater balance and higher function. To prove these effects, the future clinical application will require an increased number of cases and longer periods of vestibular stimulation. This study showed that vestibular stimulation by air caloric device is safe and tolerable in patients with AD.

Efficacy of bezafibrate for preventing myopathic attacks in patients with very long-chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks. PATIENTS AND METHODS: We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions. RESULTS: The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients' ability to conduct everyday activities was also improved by the treatment. CONCLUSION: Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.

The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.

To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.

Thunderclap headache without hypertension in a patient with pheochromocytoma.

Pheochromocytoma is a well known, catecholamine-producing tumor characterized by hypertension, headache, hyperglycemia, hypermetabolism, and hyperhydrosis. Approximately 65% of cases of pheochromocytoma were shown to be associated with hypertension. A case of pheochromocytoma that presented with thunderclap headache (TCH) and palpitations is reported. The patient never showed hypertension during the course of the disease. Paroxysmal headache and palpitations led to the identification of the underlying condition, and the final diagnosis was confirmed by histopathological examination of a surgical specimen. Pheochromocytoma should be identified as a less common although important cause of TCH. In addition, due to its lack of utility in identifying this disorder, negative cranial imaging may impede further investigation of extracranial lesions that may be the cause of a patient's headache. According to the International Classification of Headache Disorders (ICHD)-II, headache attributed to pheochromocytoma usually develops concomitantly with an abrupt increase in blood pressure. In our case, however, hypertension was never observed, even when the patient was symptomatic. This is the first report of a case of pheochromocytoma with TCH without hypertension.