[Fisher Syndrome].

Fisher syndrome is recognized as a variant of Guillain-Barré syndrome, encompassing acute onset immune-mediated neuropathies marked by the classical triad of ataxia, areflexia, and ophthalmoplegia. Generally, Fisher syndrome follows a self-limited course with a good prognosis. Ophthalmoplegia, typically bilateral, progresses to complete external ophthalmoplegia within 1-2 weeks. Ataxia, often very severe, may cause an inability to walk without support despite normal strength. Fisher syndrome is also frequently concomitant with additional clinical features, including ptosis, internal ophthalmoplegia, facial nerve palsy, sensory deficits, and bulbar palsy. The confirmation of an antecedent infection is often established. Among the ganglioside antibodies, anti-GQ1b antibodies exhibit positivity in over 80% of patients. The syndrome manifests in three distinct types: a partial subtype exhibiting only a subset of the triad symptoms, Bickerstaff's brainstem encephalitis marked by impaired consciousness and pyramidal tract signs, and an overlapping subtype with Guillain-Barré syndrome, characterized by weakness in the extremities.

Case report: Early-onset Parkinson's disease with lower limb spasticity in a new DJ-1/PARK7 patient.

Rare autosomal recessive variants in DJ-1, a causative gene for early-onset Parkinson's disease, have been associated with a variety of clinical syndromes in a limited number of patients. Here, we report a case of a novel DJ-1 variant in a 39-year-old man with a 4-year history of parkinsonism, cognitive dysfunction, and lower limb spasticity. He was diagnosed with Parkinson's disease. Genetic testing of the patient revealed compound heterozygous variants in the DJ-1 gene (exon 6 deletion + c.242dup), of which exon 6 deletion was a novel variant. We conclude that variants in DJ-1 should be considered possible causes of early-onset parkinsonism with spasticity and cognitive impairment, as in this case.

Axon terminal hypertrophy of striatal projection neurons with levodopa-induced dyskinesia priming.

Background: A rat model of levodopa-induced dyskinesia (LID) showed enlarged axon terminals of striatal direct pathway neurons in the internal segment of the globus pallidus (GPi) with excessive gamma-aminobutyric acid (GABA) storage in them. Massive GABA release to GPi upon levodopa administration determines the emergence of LID. Objectives: We examined whether LID and axon terminal hypertrophy gradually develop with repeated levodopa treatment in Parkinsonian rats to examine if the hypertrophy reflects dyskinesia priming. Methods: 6-hydroxydopamine-lesioned hemiparkinsonian rats were randomly allocated to receive saline injections (placebo group, 14 days; n = 4), injections of 6 mg/kg levodopa methyl ester combined with 12.5 mg/kg benserazide (levodopa-treated groups, 3-day-treatment; n = 4, 7-day-treatment; n = 4, 14-day-treatment; n = 4), or injections of 6 mg/kg levodopa methyl ester with 12.5 mg/kg benserazide and 1 mg/kg 8-hydroxy-2-(di-n-propylamino)tetralin for 14 days (8-OH-DPAT-treated group; n = 4). We evaluated abnormal involuntary movement (AIM) scores and axon terminals in the GPi. Results: The AIM score increased with levodopa treatment, as did the hypertrophy of axon terminals in the GPi, showing an increased number of synaptic vesicles in hypertrophied terminals. Conclusion: Increased GABA storage in axon terminals of the direct pathway neurons represents the priming process of LID.

The effect of guardians' health literacy on the child's spending time at home: A cross-sectional study among Japanese schoolchildren.

Background: The contents of children's daily activities and the amount of time spent on them has been directly linked to their health and development. Parental health behavior has also been considered a key factor, and the aim of this study was to determine the relationship between parent/guardian health literacy (HL) and their child's time spent at home by behavioral types. The study was conducted in elementary schools in Japan. Method: The target subjects for this study were elementary schoolchildren (all grades, aged 6 to 12 years) and their parents/guardians, and almost 3000 schoolchildren and their parents/guardians in the Northern and Southern districts in Japan participated. The questionnaire for parents/guardians included amount of time spent per day on the seven major behavioral contents of their child's time at home, on weekdays and weekends, respectively, and a shortened five-item health literacy (HL) scale. Parent/guardian HL results were categorized into two groups (low HL group and high HL group), and we analyzed the association between the HL and child's time spent at home by behavioral contents. Results: Children in the high HL parent/guardian group spent significantly less time watching TV and playing games than those in the low HL group, both on weekdays and weekends. Time spent playing outside on weekdays and on hobbies on weekdays and weekends was significantly longer for children in the high HL parent/guardian group than in the low HL group. Results of logistic regression analyses adjusted for confounders showed that higher parental/guardian HL reduced children's spending more than 30 minutes watching TV or playing games and increased children's spending more than 30 minutes on outside playing and doing hobbies. Conclusions: Parental/guardian HL affected the child's time spent at home. The results could suggest that increasing parental/guardian HL has strong potential to improve children's major lifestyle behaviors．.

Altered amantadine effects after repetitive treatment for l-dopa-induced involuntary movements in a rat model of Parkinson's disease.

BACKGROUND: l-3,4-dihydroxyphenylalanine (l-dopa) is the most effective drug for Parkinson's disease (PD); however, most PD patients develop motor fluctuations including wearing-off and l-dopa-induced dyskinesia (LID). Amantadine is beneficial for improving the motor symptoms, reducing "off" time, and ameliorating LID, although its long-term efficacy remains unknown. OBJECTIVES: To investigate the effects of amantadine on PD and LID using a rat model with repetitive drug treatment. METHOD: We utilized 6-hydroxydopamine injections to develop a hemiparkinsonian rat model. The rats were assigned to four groups: five rats received l-dopa and benserazide for 31 days, six rats received l-dopa and benserazide plus amantadine for 31 days, five rats received l-dopa and benserazide for 15 days followed by l-dopa and benserazide plus amantadine for 16 days, and five rats received l-dopa and benserazide plus amantadine for 15 days followed by l-dopa and benserazide treatment for 16 days. We evaluated the l-dopa-induced abnormal involuntary movements on treatment days 1, 7, 14, 16, 22, and 29. Subsequently, immunohistochemistry for drebrin was performed. RESULTS: l-dopa-induced abnormal movements were reduced on the first day of amantadine treatment, and these effects disappeared with repetitive treatment. In contrast, the extension of l-dopa "on" time was observed after repetitive amantadine treatment. All groups showed enlarged drebrin immunoreactive dots in the dopamine-denervated striatum, indicating that amantadine did not prevent priming effects of repetitive l-dopa treatment. CONCLUSION: Anti-LID effect of amantadine diminished after repetitive treatment, and the effect of amantadine on wearing-off emerged after repetitive treatment in a hemiparkinsonian rat model. Fluctuations in amantadine effects should be considered when using it in clinical settings.

CA19-9 in Combination with Methylated HOXA1 and SST Is Useful to Diagnose Stage I Pancreatic Cancer.

INTRODUCTION: We previously developed a novel methylation assay, the combined restriction digital PCR (CORD) assay, consisting of treatment of DNA with methylation-sensitive restriction enzymes and droplet digital PCR. METHODS: In this study, we assessed the diagnostic performance of serum methylated Homeobox A1 (mHOXA1) and methylated somatostatin (mSST) using the CORD assay in combination with CA19-9 for pancreatic cancer using serum samples from 82 healthy individuals, 13 patients with benign pancreatic disease, 3 patients with branched-duct intraductal papillary mucinous neoplasm, and 91 patients with pancreatic cancer. RESULTS: For the single marker tests, sensitivity for all stages of pancreatic cancer, stage I cancer, and specificity were, respectively, 71.4%, 50.0%, and 94.9% for CA19-9; 51.6%, 68.8%, and 90.8% for mHOXA1; and 50.1%, 68.8%, and 94.9% for mSST. Those for the combined marker tests were, respectively, 86.8%, 81.3%, and 85.7% for combined mHOXA1 and CA19-9; 86.8%, 87.5%, and 89.8% for combined mSST and CA19-9; and 89.0%, 87.5%, and 85.7% for all three markers combined. CONCLUSION: The combination of mHOXA1 and mSST with CA19-9 appears to be useful to detect pancreatic cancer even at an early stage.

An autopsy case of amyotrophic lateral sclerosis with striatonigral and pallidoluysian degeneration and cat's-eye-shaped neuronal nuclear inclusions.

We report the case of a Japanese woman with sporadic amyotrophic lateral sclerosis (ALS) of 28 months' duration who died at the age of 66 years. Postmortem examination revealed moderate loss of neurons and phosphorylated TDP-43 (p-TDP-43)-immunoreactive neuronal and glial cytoplasmic inclusions in the upper and lower motor neurons. Additionally, marked neuronal loss was observed in the neostriatum, globus pallidum, subthalamic nucleus, and substantia nigra. p-TDP-43-immunoreactive inclusions were frequently found in these areas. Neuronal loss and TDP-43 pathology in the motor, striatonigral, and pallidoluysian systems were predominant on the right side. Moreover, p-TDP-43-immunoreactive cat's-eye-shaped neuronal nuclear inclusions (NNIs) were observed in the affected lesions. NNIs in the striatonigral system were also positive for valosin-containing protein (VCP). We diagnosed the patient as having ALS with striatonigral and pallidoluysian degeneration. Patients with ALS rarely experience pallido-nigro-luysian degeneration. To our best knowledge, only one case of ALS combined with striatonigral and pallidoluysian degeneration has been reported. Neuronal loss in the striatonigral and/or pallidoluysian systems has also been reported in patients with ALS with multisystem degeneration accompanied by long-term use of an artificial respirator. Based on these findings, a possibility of an extremely rare subtype of ALS demonstrating selective loss of neurons in the striatonigral and pallidoluysian systems exists; another possibility is that this type could be an early stage or forme fruste of ALS with multisystem degeneration. Although VCP-positive cat's-eye-shaped NNIs have been reported in spinocerebellar ataxia type-2 cases, our case report presents VCP-positive NNIs in a patient with ALS for the first time.

Comparison of two primer-probe sets of Fusobacterium nucleatum using droplet digital polymerase chain reaction for the detection of colorectal neoplasia from faecal samples.

BACKGROUND: Although faecal DNA testing of Fusobacterium nucleatum (Fn) is expected to be useful for colorectal neoplasia detection, there is no standardized quantification method of Fn. We performed this study to establish a possible standardized method. METHODS: In this study, 322 participants including 71 subjects without colorectal neoplasia (control group), 31 patients with non-advanced colorectal adenoma, 93 patients with advanced colorectal adenoma, and 127 patients with colorectal cancer were enrolled. Faecal Fn were quantified by droplet digital PCR (ddPCR) using two PCR primer-probe sets reported previously that are tentatively named Fn1 and Fn2. Fn1 has been used in ddPCR by us and Fn2 has been widely used in quantitative real-time PCR. RESULTS: The Fn copy number using Fn1 was five times higher than that using Fn2, with a linear relationship shown between them. Receiver operating characteristic curve analysis showed the area under the curve (AUC) to be almost the same between Fn1 and Fn2 in discriminating between the control group and the colorectal cancer group (AUC = 0.81 and 0.81, respectively), and between the control/non-advanced colorectal adenoma group and the advanced colorectal adenoma/colorectal cancer group (AUC = 0.74 and 0.74, respectively). CONCLUSIONS: As the diagnostic performance was quite similar between Fn1 and Fn2, ddPCR-based Fn testing using Fn1 and Fn2 could be a possible standardized method for a colorectal neoplasia screening test, considering that Fn levels quantified by Fn1 are about five times higher than those by Fn2.

[Small Fiber Neuropathy with Inadequate Response to Medical Therapy: Diagnosis and Treatment of Small Fiber Neuropathy].

Small-fiber neuropathies are a heterogeneous group of disorders affecting thinly myelinated Aδ and unmyelinated C fibers. Patients generally present with neuropathic pain, while dysesthesia, allodynia, pain, burning sensations, and cold sensations are frequently present in a length-dependent pattern. Additional autonomic features of the gastrointestinal, urinary, or cardiovascular systems are frequently observed. Deep-tendon reflexes and nerve conduction tests yield normal results. Skin biopsy is useful for the diagnosis, and can demonstrate the loss of intraepidermal nerve fibers in small-fiber neuropathy and has a diagnostic sensitivity of 80%. Although many causes of small-fiber neuropathy have been reported, the cause remains unknown in 30-50% of the cases. Treatment is directed at the underlying etiology and is supported with symptomatic treatment.

Accumulation of Nonfibrillar TDP-43 in the Rough Endoplasmic Reticulum Is the Early-Stage Pathology in Amyotrophic Lateral Sclerosis.

Transactivation response DNA-binding protein 43 (TDP-43)-immunoreactive neuronal cytoplasmic inclusions (NCIs) are the histopathological hallmarks of amyotrophic lateral sclerosis (ALS). They are classified as skein-like inclusions, round inclusions, dot-like inclusions, linear wisps, and diffuse punctate cytoplasmic staining (DPCS). We hypothesized that TDP-43-immunoreactive DPCS may form the early-stage pathology of ALS. Hence, we investigated phosphorylated TDP-43 pathology in the upper and lower motor neurons of patients with ALS and control participants. We designated patients whose disease duration was ≤1 year as short-duration ALS (n = 7) and those whose duration equaled 3-5 years as standard-duration ALS (n = 6). DPCS and skein-like inclusions were the most common NCIs in short-duration and standard-duration ALS, respectively. The density of DPCS was significantly higher in short-duration ALS than that in standard-duration ALS and was inversely correlated with disease duration. DPCS was not ubiquitinated and disappeared after proteinase K treatment, suggesting that it was not aggregated. Immunoelectron microscopy revealed that DPCS corresponded to nonfibrillar TDP-43 localized to the ribosomes of the rough endoplasmic reticulum (ER). These findings suggest that nonfibrillar TDP-43 accumulation in the rough ER is the earliest TDP-43 pathology in ALS, which may be helpful in developing future TDP-43 breakdown strategies for ALS.

Cabergoline, a long-acting dopamine agonist, attenuates L-dopa-induced dyskinesia without L-dopa sparing in a rat model of Parkinson's disease.

Intermittent administration of L-dopa in Parkinson's disease is associated with L-dopa-induced dyskinesia (LID). Long-acting dopamine agonists may reduce the risk of LID by continuous dopaminergic stimulation. We examined the LID-like behavior, preprodynorphin messenger ribonucleic acid (mRNA) expression in the striatum (a neurochemical LID hallmark), and the volume of the entopeduncular nucleus (a pathological LID hallmark) in Parkinson's disease rat models that were treated with L-dopa and cabergoline. Cabergoline co-treatment with L-dopa reduced LID, striatal preprodynorphin mRNA expression, and hypertrophy of the entopeduncular nucleus, indicating that cabergoline has an anti-LID effect independent of the L-dopa-sparing effect.

Effects of Aging on Levo-Dihydroxyphenylalanine- Induced Dyskinesia in a Rat Model of Parkinson's Disease.

BACKGROUND: It remains unclear why patients with young-onset Parkinson's disease more often develop levo-dihydroxyphenylalanine (L-dopa)-induced dyskinesia (LID) and have a more severe form than patients with old-onset Parkinson's disease. Previous studies using animal models have failed to show young-onset Parkinson's disease enhances LID. OBJECTIVES: To evaluate the association of age at dopaminergic denervation (onset age) and initiation of L-dopa treatment (treatment age) with LID development in model rats. METHODS: We established rat models of young- and old-lesioned Parkinson's disease (6-hydroxydopamine lesions at 10 and 88 weeks of age, respectively). Dopaminergic denervation was confirmed by the rotational behavior test using apomorphine. Rats in the young-lesioned group were allocated to either L-dopa treatment at a young or old age, or saline treatment. Rats in the old-lesioned group were allocated to either L-dopa treatment or saline group. We evaluated L-dopa-induced abnormal involuntary movements during the 14-day treatment period. We also examined preprodynorphin mRNA expression in the striatum (a neurochemical hallmark of LID) and the volume of the medial globus pallidus (a pathological hallmark of LID). RESULTS: LID-like behavior was enhanced in L-dopa-treated young-lesioned rats compared with L-dopa-treated old-lesioned rats. Preprodynorphin mRNA expression was higher in L-dopa-treated young-lesioned rats than in in L-dopa-treated old-lesioned rats. The volume of the medial globus pallidus was greater in L-dopa-treated young-lesioned rats than in L-dopa-treated old-lesioned rats. Treatment age did not affect LID-like behavior or the degree of medial globus pallidus hypertrophy in the young-lesioned model. CONCLUSION: Both dopaminergic denervation and L-dopa initiation at a young age contributed to the development of LID; however, the former may be a more important factor.

Isolated myelitis in a patient with Behcet's disease during golimumab therapy.

Tumor necrosis factor-alpha (TNF-α) inhibitors are increasingly used for various autoimmune diseases. Demyelinating events in the CNS, including myelitis, are reportedly associated with TNF-α inhibitor exposure. Behcet's disease rarely involves the spinal cord. A 51-year-old Japanese woman presented with back pain, leg weakness, and numbness during golimumab administration, a TNF-α inhibitor, for Behcet's disease. Magnetic resonance imaging revealed multifocal myelitis in the cervical and thoracic spinal cords. Discontinuation of golimumab and steroid therapy were effective and the symptoms have not relapsed. Although it is possible that the patient's myelitis was part of the symptoms of neuro-Behcet's disease, we believe that golimumab likely played a role in the myelitis development.

Combination of CA19-9 and Blood Free-Circulating Methylated RUNX3 May Be Useful to Diagnose Stage I Pancreatic Cancer.

BACKGROUND: Although serum carbohydrate antigen 19-9 (CA19-9) is widely used as a useful biomarker of pancreatic cancer for monitoring the response to therapy, it is not recommended for screening of early pancreatic cancer because of its limited sensitivity for small tumors. Thus, it is critical to discover novel serum biomarkers to complement CA19-9 in order to improve sensitivity. Although methylated runt-related transcription factor 3 (RUNX3) is a biomarker of pancreatic cancer, its detection by conventional bisulfite-based methylation assays from a small serum sample amount is very difficult. Therefore, we developed a new methylation assay, the combined restriction digital PCR (CORD) assay, that enables counting of even one copy of a methylated gene in a small DNA sample amount without DNA bisulfite treatment. OBJECTIVES: We evaluated the sensitivity and specificity of serum DNA testing of methylated RUNX3 by the CORD assay in combination with and without CA19-9 for the detection of pancreatic cancer in 55 patients with pancreatic cancer, 12 patients with benign pancreatic disease, and 80 healthy individuals. RESULTS: The CORD assay of methylated RUNX3 had a sensitivity of 50.9% (28/55) and specificity of 93.5% (86/92). Combination of the CORD assay of methylated RUNX3 and CA19-9 resulted in a sensitivity of 85.5% (47/55) and specificity of 93.5% (86/92) for all stages of pancreatic cancer and a sensitivity of 77.8% (7/9) for stage I pancreatic cancer. CONCLUSIONS: ombination of the CORD assay and CA19-9 may provide an alternative screening strategy for detecting early-stage pancreatic cancer.

Sensory Nerve Conduction Study with Inching Test in Palmar Digital Neuropathy.

Mild palmar digital neuropathy may be underestimated because selective nerve conduction studies (NCS) of the palmar digital nerve are challenging. We herein report two cases of palmar digital neuropathy. We performed sensory NCS in each finger using the standard approach. Both cases showed a decrease in the amplitude of sensory nerve action potential (SNAP) in the localized finger. Furthermore, the sensory nerve inching test identified the lesion site. When performing NCS in patients with finger sensory impairment, we recommend recording the SNAP in each finger using standard NCS at the wrist, as well as sensory nerve inching testing.

PLA2G6 variants associated with the number of affected alleles in Parkinson's disease in Japan.

This study aimed to evaluate genotype-phenotype correlations of Parkinson's disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.

Semi-Solid Nutrients for Prevention of Enteral Tube Feeding-Related Complications in Japanese Population: A Systematic Review and Meta-Analysis.

The aim of this systematic review was to assess the best available evidence on semi-solid nutrients for prevention of complications associated with enteral tube feeding (ETF). PubMed (MEDLINE), EMBASE, Cochrane Central Register of Controlled Trial, Ichushi-web, and World Health Organization International Clinical Trials Registry Platform databases were searched for relevant articles. Randomized controlled trials (RCTs), cluster RCTs, and crossover trials comparing the effects of semi-solid nutrients with those of control interventions in patients on ETF were included in the review. The primary outcome was development of gastroesophageal reflux (GER). Eight RCTs and five crossover trials involving 889 study participants in total were examined via meta-analysis. The meta-analysis showed that semi-solid nutrients significantly decreased the risk of GER (risk ratio 0.39; 95% confidence interval (CI) 0.21 to 0.73) and the GER index (mean difference -2.93; 95% CI -5.18 to -0.68). Dwell time in the stomach was significantly shortened (standardized mean difference (SMD) -0.50; 95% CI -0.99 to -0.02), as was care time defined as the time needed to prepare and administer the nutrient solution (SMD -8.02; 95% CI -10.94 to -5.10). Semi-solid nutrients significantly decrease the risk of GER and the dwell time in the stomach in adult patients. .