A rare case of concomitant Lambert-Eaton myasthenic syndrome and syndrome of inappropriate antidiuretic hormone secretion in a patient with small cell lung carcinoma.

Small cell lung carcinoma (SCLC) is a neuroendocrine carcinoma with a poor prognosis and is a common cause of paraneoplastic syndromes. Paraneoplastic syndromes are characterized by neurological and endocrinological problems in patients with malignancy and are often associated with difficulty in induction of chemotherapy. Here we report the case of a patient with SCLC concomitant with two paraneoplastic syndromes, syndrome of inappropriate antidiuretic hormone secretion (SIADH) and Lambert-Eaton myasthenic syndrome (LEMS), who was treated with a platinum-doublet chemotherapy regimen. A 66-year-old male patient presented with a 1-month history of progressive proximal muscle weakness, ataxia gait and 5 kg of body weight loss. The laboratory tests revealed hyponatremia due to SIADH and the existence of antibodies against P/Q-type voltage-gated calcium channels. The nerve conduction study showed a low amplitude of compound muscle action potential (0.38 mv), a 34% decrement on 3-Hz stimulation, and a 1939% increment after maximum voluntary contraction in 10 seconds (7.75 mv). The endobronchial ultrasound transbronchial needle aspiration biopsy revealed the pathological findings of SCLC. A 2-cycle chemotherapy regimen of irinotecan plus cisplatin resulted in temporary tumor shrinkage that lasted 2 months, but the improvement of proximal muscle weakness and hyponatremia were maintained over the tumor re-progression period after chemotherapy. Although paraneoplastic syndromes accelerate the decrease in performance status, chemotherapy for SCLC may improve symptoms related to paraneoplastic syndromes and could be considered in similar cases.

Spectral and theoretical analysis of derivatives of 1,2,3,3-tetramethyl-3H-indolium iodide (TMI), a highly selective derivatization reagent of cyanide, and their utility for the analysis of cyanide concentrations in beverages.

We develop a specific derivatization gas chromatography-mass spectrometry (GC-MS) method for cyanide using 1,2,3,3-tetramethyl-3H-indium iodide as the derivatization reagent. The derivative compounds were synthesized and characterized using 1H nuclear magnetic resonance (NMR), 13C NMR, and Fourier transform infrared (FT-IR) spectroscopy. The high selectivity of this derivatization for cyanide is supported by calculations and activation energy comparisons. We applied this method to pure water, green tea, orange juice, coffee cafe au lait, and milk. Derivatization was performed by diluting 20 µL of sample solution with 0.1 M NaOH and adding 100 µL of saturated borax solution and 100 µL of 8 mM TMI solution, each drink was completed in 5 min at room temperature, and selected ion (m/z = 200) monitoring analysis was linear (R2 > 0.998) at 0.15 to 15 µM, with detection limits of 4-11 µM were shown. This method is expected to be widely used in forensic toxicology analysis and can be applied to beverages, which are forensically important field samples.

Detailed Analysis of Neurological Symptoms and Sensory Disturbances Due to Chronic Arsenic Exposure in Toroku, Japan.

As a result of population growth and the development of tube wells, humans' exposure to arsenic has increased over the past few decades. The natural course of organ damage secondary to arsenic exposure is not yet well understood. In Toroku, Japan, an arsenic mine was intermittently operated from 1920 to 1962, and residents were exposed to high concentrations of arsenic. In this paper, we analyzed 190 consecutive residents for whom detailed records of neurological symptoms and findings were obtained from 1974 to 2005. All participants were interviewed regarding the presence of general, skin, hearing, respiratory, and neurological symptoms. Neurological symptoms were classified into extremity numbness or pain, constipation, dyshidrosis, sensory loss, and muscle atrophy. Superficial and vibratory sensation was also evaluated. More than 80% of participants experienced extremity numbness, and numbness was the most common neurological symptom. Numbness was associated with superficial sensory disturbance, and was correlated with the subsequent development of other neurological symptoms, including autonomic and motor symptoms. No previous studies have investigated the natural course of chronic arsenic intoxication; thus, these data serve as a guide for detecting early symptoms due to arsenic exposure.

ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function.

Derlin family members (Derlins) are primarily known as components of the endoplasmic reticulum-associated degradation pathway that eliminates misfolded proteins. Here we report a function of Derlins in the brain development. Deletion of Derlin-1 or Derlin-2 in the central nervous system of mice impaired postnatal brain development, particularly of the cerebellum and striatum, and induced motor control deficits. Derlin-1 or Derlin-2 deficiency reduced neurite outgrowth in vitro and in vivo and surprisingly also inhibited sterol regulatory element binding protein 2 (SREBP-2)-mediated brain cholesterol biosynthesis. In addition, reduced neurite outgrowth due to Derlin-1 deficiency was rescued by SREBP-2 pathway activation. Overall, our findings demonstrate that Derlins sustain brain cholesterol biosynthesis, which is essential for appropriate postnatal brain development and function.

[A case of hemichorea due to insular and parietal cortical infarctions].

A 70-year-old man visited our hospital with a chief complaint of involuntary movements, diagnosed as chorea, involving the right upper and lower limbs. Brain MRI showed acute cerebral infarctions involving the left insular and parietal cortices. Chorea is usually due to dysfunction of components of the basal ganglia pathways, such as the caudate nucleus or subthalamic nucleus, and is rarely caused by lesions of the insular or parietal cortex. Here, we describe a case of cerebral infarctions in the left insular and parietal cortices and chorea of the right limbs, and discuss the relationship between the mechanism of chorea and insular and parietal cortical lesions.

Human liver-expressed antimicrobial peptide 2 elevation in the cerebrospinal fluid in bacterial meningitis.

OBJECTIVE: To study the presence of liver-expressed antimicrobial peptide 2 (LEAP2) in human cerebrospinal fluid (CSF) and to measure its concentrations in neurological disorders. MATERIALS & METHODS: We identified the presence of LEAP2 in human CSF by chromatographic analysis and a LEAP2-specific enzyme immunoassay. We measured LEAP2 concentrations in the CSF of 35 patients with neurological disorders. RESULTS: CSF LEAP2 concentrations in the bacterial meningitis group (mean ± SD, 9.32 ± 3.76 ng/ml) were significantly higher (p < .05) than those in the other four groups (psychosomatic disorder, 0.56 ± 0.15 ng/ml; peripheral autoimmune disease, 1.00 ± 0.60 ng/ml; multiple sclerosis, 0.62 ± 0.30 ng/ml; aseptic meningitis, 1.59 ± 0.69 ng/ml). CONCLUSIONS: This is the first study to identify the presence of human LEAP2 in the CSF. Levels of LEAP2 were increased in the CSF of patients with bacterial meningitis. LEAP2 may have potential as a biomarker for bacterial meningitis.

Meta-iodobenzylguanidine myocardial scintigraphy in Perry disease.

INTRODUCTION: Perry disease (Perry syndrome), a hereditary TAR DNA-binding protein 43 (TDP-43) proteinopathy, is caused by dynactin subunit 1 (DCNT1) mutations and is characterized by rapidly progressive parkinsonism accompanied by depression, apathy, unexpected weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is considered a diagnostic biomarker for Lewy body disease (LBD), as denervation of cardiac sympathetic nerves is a pathological feature in LBD. However, our previous studies have reported a decreased cardiac uptake of MIBG in patients with Perry disease. In this study, we aimed to correlate the MIBG myocardial scintigraphy findings with clinical features in Perry disease. METHODS: We evaluated data obtained from a multicenter survey of patients of Japanese origin with suspected Perry disease, who visited neurology departments in Japan from January 2010 to December 2018. We screened each patient's DNA for the DCTN1 mutation using Sanger sequencing and obtained the clinical details of all patients including findings from their MIBG myocardial scintigraphy. RESULTS: We identified two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. The majority of patients (7/8, 87.5%) showed a decrease in cardiac uptake (heart to mediastinum ratio) in MIBG myocardial scintigraphy. These patients commonly presented with symptoms related to autonomic dysfunction: constipation, fecal incontinence, urinary disturbance, and orthostatic hypotension. CONCLUSIONS: MIBG myocardial scintigraphy may be a useful biomarker of autonomic dysfunction in Perry disease.

Effective Treatment with Tocilizumab in a Rheumatoid Arthritis Patient Complicated with Human T-cell Leukemia Virus Type 1-associated Myelopathy.

A 61-year-old woman with human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and interstitial pneumonia (IP) was admitted to our hospital. She complained of sicca symptoms, polyarthralgia, and swollen joints. She was diagnosed with rheumatoid arthritis (RA) and Sjögren's syndrome. Methotrexate and anti-tumor necrosis factor therapy were not utilized because of the inclusion of severe respiratory disorders among the complications and the neurological symptoms of HAM/TSP. Tocilizumab monotherapy improved the RA disease activity without exacerbating HAM/TSP. The present case suggests that tocilizumab might be a suitable treatment option in patients with RA and HAM/TSP.

Spiral drawing: Quantitative analysis and artificial-intelligence-based diagnosis using a smartphone.

BACKGROUND: The evaluation of neurological examination in clinical practice still remains qualitative or semi-quantitative, and the results often vary depending on an examiner's skill level and are less objective. In this study, we developed a smartphone-based application to investigate quantifying neurological examinations using hand-drawn spirals and diagnose patients with tremor using artificial intelligence (AI). METHODS: This study included 24 and 26 patients with essential tremor (ET) and cerebellar disease (CD), respectively, and 41 age-matched normal controls (NCs). We obtained 69, 46, and 56 hand-drawn spirals from the NC, ET, and CD groups, respectively, as image data captured by smartphones. The patients traced a printed reference spiral. The length of this spiral was compared with the reference spiral length (% of spiral length) and the total deviation area between these spirals was calculated. The server also estimates the diagnostic probability through AI. RESULTS: The quantified spiral analysis (% of spiral length and deviation area) significantly correlated with disease severity in each disease group, and significant differences in the deviation area were observed among all groups. The AI diagnosis showed 79%, 70%, and 73% accuracies for the NC, ET, and CD groups, respectively. CONCLUSION: This study indicates the possibility of using a smartphone as a medical examination tool and demonstrates the application of AI in neurological examinations.

Polypharmacy Associated with Cognitive Decline in Newly Diagnosed Parkinson's Disease: A Cross-Sectional Study.

AIMS: Polypharmacy is well known to affect cognitive function in community-dwelling older adults. However, the effect of polypharmacy on cognitive function in patients with newly diagnosed Parkinson's disease remains unknown. Here, we evaluated the association between polypharmacy and cognitive function in patients with newly diagnosed Parkinson's disease. METHODS: This cross-sectional study enrolled 131 consecutive hospitalized patients with newly diagnosed Parkinson's disease. Cognitive function was evaluated with the Mini-Mental State Examination and analyzed between groups of patients with or without polypharmacy. Comparisons were adjusted for confounders by performing inverse probability weighting with propensity scores. RESULTS: After inverse probability weighting, patients in the polypharmacy group had a significantly lower Mini-Mental State Examination score than patients in the nonpolypharmacy group (26.2 vs. 27.7, p = 0.001). CONCLUSION: Polypharmacy was associated with cognitive decline in patients with newly diagnosed Parkinson's disease. This finding suggests that medication reduction might serve as a promising intervention to prevent the development of dementia in patients with early Parkinson's disease. Further prospective studies are needed to determine whether medication reduction improves cognitive function in patients with newly diagnosed Parkinson's disease.

Optic Neuropathy with Features Suggestive of Optic Neuritis in Cerebrotendinous Xanthomatosis.

We describe our encounter with a 39-year-old man who exhibited acute painless visual loss and progressive gait disturbance. He had tendinous xanthoma and several neuroophthalmological findings indicative of optic neuropathy in the right eye, including afferent pupillary defect, cecocentral scotoma, and optic disc swelling. Neurological examination showed cerebellar ataxia and pyramidal weakness. Brain magnetic resonance imaging revealed bilateral swelling in the optic nerves with gadolinium-enhancement suggesting optic neuritis, an enlarged fourth ventricle, atrophy of the cerebellum, and hyperintensities in the bilateral dentate nuclei. The patient was diagnosed with cerebrotendinous xanthomatosis (CTX) based on an elevated serum cholestanol level and a homozygous missense mutation in CYP27A1. CTX is a genetic lipid storage disease caused by dysfunction of the mitochondrial enzyme sterol 27-hydroxylase. With respect to ophthalmological manifestations, juvenile cataracts and optic neuropathy are common findings in patients with CTX, but there have been no reports of optic neuropathy with features suggestive of optic neuritis. Thus, this case illustrates that clinicians should consider a diagnosis of CTX in patients with cardinal features of CTX even if the patients show signs indicative of optic neuritis.

18F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging evaluation of chorea.

Chorea is thought to be caused by deactivation of the indirect pathway in the basal ganglia circuit. However, few imaging studies have evaluated the basal ganglia circuit in actual patients with chorea. We investigated the lesions and mechanisms underlying chorea using brain magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). This retrospective case series included three patients with chorea caused by different diseases: hyperglycemic chorea, Huntington's disease, and subarachnoid hemorrhage. All the patients showed dysfunction in the striatum detected by both MRI and FDG-PET. These neuroimaging findings confirm the theory that chorea is related to an impairment of the indirect pathway of basal ganglia circuit.

Clinical Symptoms, Neurological Signs, and Electrophysiological Findings in Surviving Residents with Probable Arsenic Exposure in Toroku, Japan.

Chronic arsenic intoxication is known to cause multisystem impairment and is still a major threat to public health in many countries. In Toroku, a small village in Japan, arsenic mines operated from 1920 to 1962, and residents suffered serious sequelae of arsenic intoxication. We have performed annual medical examinations of these residents since 1974, allowing us to characterize participants' long-term health following their last exposure to arsenic. The participants could not be described as having "chronic arsenic intoxication," because their blood arsenic levels were not measured. In this study, we defined them as having "probable arsenic intoxication." Symptoms frequently involved the sensory nervous system, skin, and upper respiratory system (89.1-97.8%). In an analysis of neurological findings, sensory neuropathy was common, and more than half of the participants complained of hearing impairment. Longitudinal assessment with neurological examinations and nerve conduction studies revealed that sensory dysfunction gradually worsened, even after exposure cessation. However, we could not conclude that arsenic caused the long-term decline of sensory function due to a lack of comparisons with age-matched healthy controls. This is the first study to characterize the longitudinal sequelae after probable arsenic exposure. Our study will be helpful to assess the prognosis of patients worldwide who still suffer from chronic arsenic intoxication.

A Japanese Case of CADASIL with a Rare Mutation in Exon 24 of the NOTCH3 Gene.

A 50-year-old man with a family history of stroke and depression slowly developed brain lesions. Magnetic resonance imaging revealed hyperintense lesions in the diffuse white matter, external capsules, and temporal poles on T2-weighted imaging. A heterozygous mutation c.3879C>G in exon 24 of the NOTCH3 gene (p.Cys1293Trp) was detected, confirming a diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Exon 24 mutations are rather rare and this represents the first Japanese case of CADASIL.

Disinhibited Blink Reflex Recovery Is Related to Lateral Trunk Flexion in Parkinson Disease.

PURPOSE: Lateral trunk flexion is often observed in patients with Parkinson disease (PD) and causes poor quality of life. Asymmetrical function of the basal ganglia is believed to be the main cause of lateral trunk flexion, and dysfunction of the basal ganglia facilitates the blink reflex by disinhibiting the spinal trigeminal nucleus. Our aim was to investigate whether a disinhibited blink reflex recovery curve (BRrc) was associated with lateral trunk flexion in PD patients. METHODS: We enrolled 21 PD patients, including 11 with marked lateral trunk flexion (F-PD) and 10 with normal posture (N-PD), and 10 normal controls. Blink reflex recovery curves at interstimulus intervals of 200, 300, and 500 ms were compared between F-PD, N-PD, and normal controls. RESULTS: The BRrc in F-PD patients was more disinhibited than in N-PD patients and controls, and this disinhibition was asymmetrical. CONCLUSIONS: The asymmetrically disinhibited BRrc in F-PD patients was associated with lateral trunk flexion. This is the first neurophysiological study of patients with PD with abnormal posture. Examination of the BRrc may permit early detection of asymmetrical basal ganglia dysfunction that can eventually cause lateral trunk flexion.

Clinical and mutational spectrum of Japanese patients with recessive variants in SH3TC2.

SH3TC2, known as the causative gene of autosomal recessive demyelinating Charcot-Marie-Tooth type 4C (CMT4C), was also found linked to a mild mononeuropathy of the median nerve with an autosomal dominant inheritance pattern. Using DNA microarray, Illumina MiSeq, and Ion proton, we carried out gene panel sequencing among 1483 Japanese CMT patients, containing 397 patients with demyelinating CMT. From seven patients with demyelinating CMT, we identified eight recessive variants in the SH3TC2 gene, consisting of five novel (pathogenic/likely pathogenic) and three reported variants. Additionally, from two patients with axonal CMT, we detected a reported recessive variant, p.Arg77Trp, which was herein reclassified as variant with unknown significance. Of the seven CMT4C patients (six females and one male), 2/7 patients developed symptoms at their first decade, and 5/7 patients lost their ambulation around age 50. Scoliosis was observed from more than half (4/7) of these patients, whereas hearing loss is the most common symptom of central nervous system (6/7). No median nerve mononeuropathy was recorded from their family members. We identified recessive variants in SH3TC2 from 1.76% of demyelinating CMT patients. An uncommon gender difference was recognized and the wild spectrum of these variants suggests mutational diversity of SH3TC2 in Japan.

Ghrelin alleviates paclitaxel-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions in mice.

Paclitaxel is an effective chemotherapeutic agent, but has some treatment-limiting adverse effects that markedly decrease patients' quality of life. Peripheral neuropathy is one of these, and no treatment for it has been established yet. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is secreted from the stomach and has widespread effects on multiple systems. We investigated the pharmacological potential of ghrelin in preventing paclitaxel-induced peripheral neuropathy using wild-type mice, ghrelin-null mice, and growth hormone secretagogue receptor-null mice. In wild-type mice, ghrelin administration alleviated mechanical and thermal hypersensitivity, and partially prevented neuronal loss of small unmyelinated intraepidermal nerve fibers but not large myelinated nerve fibers. Moreover, ghrelin administration decreased plasma oxidative and nitrosative stress and increased the expression of uncoupling protein 2 (UCP2) and superoxide dismutase 2 (SOD2) in the dorsal root ganglia, which are mitochondrial antioxidant proteins, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a regulator of mitochondrial number. Both ghrelin-null mice and growth hormone secretagogue receptor-null mice developed more severe nerve injuries than wild-type mice. Our results suggest that ghrelin administration exerts a protective effect against paclitaxel-induced neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions, and that endogenous ghrelin has a neuroprotective effect that is mediated by ghrelin/growth hormone secretagogue receptor signaling. Ghrelin could be a promising therapeutic agent for the management of this intractable disease.