Clinical characteristics of intractable or persistent hiccups and nausea associated with herpes zoster.

AIM: Intractable or persistent hiccups and nausea (IHN) are rarely associated with herpes zoster (HZ-IHN). We aimed to identify the clinical characteristics of HZ-IHN by comparing them with those of neuromyelitis optica spectrum disorder associated with IHN (NMOSD-IHN). METHODS: We collected 8 patients with HZ-IHN and 12 patients with NMOSD-IHN diagnosed between 2002 and 2020 from medical databases. Medical records including clinical information, laboratory data on serum anti-aquaporin 4 (AQP4) antibodies, serological or cerebrospinal fluid findings for the varicella zoster virus, medullary MRI findings, and efficacy of intravenous methylprednisolone pulse (IVMP) therapy were analyzed retrospectively. RESULTS: The age of onset (69 ± 13 years versus 46 ± 17 years, P = 0.003), percentage of men [7/8 patients (88%) versus 3/12 patients (25%), P = 0.020], serum CRP levels (1.41 ± 1.17 mg/dL versus 0.14 ± 0.33 mg/dL, P = 0.018), and frequency of hemi-cranial nerve involvement [6/8 patients (75%) versus 1/12 patients (8%), P = 0.004] were significantly higher in patients with HZ-IHN than in those with NMOSD-IHN. The hypoglossal and vagus nerves were involved in 5/8 patients (63%) with HZ-IHN. Other clinical parameters, excluding anti-AQP4 antibodies, were similar to those of NMOSD-IHN. MRI revealed ipsilateral hemi-dorsal medullar hyper-intense lesions in 5/8 patients (63%) with HZ-IHN. Acyclovir with IVMP therapy was effective for HZ-IHN. CONCLUSION: Clinicians should include HZ-IHN in the differential diagnosis for IHN, and promptly administer acyclovir and IVMP therapy. HZ-IHN is frequently accompanied by lower hemi-cranial nerve palsies and ipsilateral hemi-dorsal medullary hyper-intensity on MRI. DATA AVAILABLE STATEMENT: The authors confirm that the data supporting the findings of this study are available within the article (Tables 1 and 2), or its supplementary materials (Table S1).

Clinicopathological findings of a mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome overlap patient with a novel m.3482A>G mutation in MT-ND1.

We report clinicopathological findings of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome (MELAS/LS) associated with a novel m.3482A>G mutation in MT-ND1. A 41-year-old woman had experienced multiple stroke-like episodes since age 16. She developed akinetic mutism two months before admission to our hospital. Neurological examination revealed akinetic mutism, bilateral deafness, and muscular atrophy. Cerebrospinal fluid tests revealed elevated pyruvate and lactate levels. Fluid-attenuated inversion recovery images on magnetic resonance imaging showed hyperintense areas in the right frontal and both sides of temporal and occipital lobes, both sides of the striatum, and the midbrain. Muscle biopsy revealed strongly succinate dehydrogenase-reactive blood vessels. L-arginine therapy improved her consciousness and prevented further stroke-like episodes. However, she died from aspiration pneumonia. Postmortem autopsy revealed scattered infarct-like lesions with cavitation in the cerebral cortex and necrotic lesions in the striatum and midbrain. The patient was pathologically confirmed as having MELAS/LS based on two characteristic clinicopathological findings: presenting MELAS/LS overlap phenotype and effectiveness of L-arginine treatment.

Clinicopathological findings of a long-term survivor of V180I genetic Creutzfeldt-Jakob disease.

The clinical characteristics of genetic Creutzfeldt-Jakob disease (gCJD) with a V180I mutation in the PRNP gene (V180I gCJD) are unique: elderly-onset, gradual progression, sporadic fashion, and cortical oedematous hyper-intensity on diffusion-weighted MRI (DW-MRI). This phenotype may become a potential target of future clinical therapeutic trials. The average disease duration of V180I gCJD patients is 23-27 months; however, considerably long-term survivors are also reported. The factors influencing survival and the clinicopathological characteristics of long-term survivors remain unknown. Herein, we report clinicopathological findings of a long-term survivor of V180I gCJD. A 78-year old woman was admitted to our hospital due to dementia and left hand tremor approximately 1.5 months after symptom onset. Neurological examination revealed dementia, frontal signs, and left hand tremor at admission. She had no family history of dementia or other neurological disease. DW-MRI revealed cortical oedematous hyper-intensities in the bilateral frontal lobes and the right temporal and parietal lobes. PRNP gene analysis indicated a V180I mutation with methionine homozygosity at codon 129. The symptoms gradually progressed, and she died of aspiration pneumonia 61 months after symptom onset. Neuropathological examination revealed severe cerebral atrophy with moderate to severe gliosis, but the brainstem was well preserved. Various-sized and non-confluent vacuole type spongiform changes were extensively observed in the cerebral cortices. Prion protein (PrP) immunostaining revealed weak and synaptic-type PrP deposits in the cerebral cortices. We consider that long-term tube feeding, and very mild brainstem involvement may be associated with the long-term survival of our V180I gCJD patient.

Clinicopathological findings of an MM2-cortical-type sporadic Creutzfeldt-Jakob disease patient with cortical blindness during a course of glaucoma and age-related macular degeneration.

Here, we report an autopsy-verified patient with MM2-coritical-type sporadic Creutzfeldt-Jakob disease (MM2C-type sCJD) presenting cortical blindness during a course of glaucoma and age-related macular degeneration, and focus on the difficulties involved in early clinical diagnosis. An 83-year-old man was admitted to our hospital 15 months after the onset of cortical blindness, and 9 months after the onset of progressive dementia. Neurological examination revealed dementia, frontal signs, visual disturbance, dysphagia, myoclonus and exaggerated tendon reflexes in the four extremities. Diffusion-weighted MRI (DW-MRI) showed cortical hyperintensities predominantly in the bilateral occipital lobes. PRNP gene analysis showed no mutations with methionine homozygosity at codon 129. Cerebrospinal fluid (CSF) examination revealed elevation of 14-3-3 and total tau protein. The symptoms progressed gradually, and the patient died of aspiration pneumonia, 30 months after the onset. Neuropathological examination revealed extensive large confluent vacuole-type spongiform changes in the cerebral cortices. Prion protein (PrP) immunostaining showed perivascular and plaque-type PrP deposits. We diagnosed our patient as MM2C-type sCJD. There are two difficulties in the early clinical diagnosis of MM2C-type sCJD with ocular disease in the elderly; delayed utilization of DW-MRI, and accompaniment of ocular disease. For early diagnosis of MM2C-type sCJD, we conclude that clinician should perform DW-MRI for patients with isolated dementia or cortical visual disturbance.

Functional evaluation of PDGFB-variants in idiopathic basal ganglia calcification, using patient-derived iPS cells.

Causative genes in patients with idiopathic basal ganglia calcification (IBGC) (also called primary familial brain calcification (PFBC)) have been reported in the past several years. In this study, we surveyed the clinical and neuroimaging data of 70 sporadic patients and 16 families (86 unrelated probands in total) in Japan, and studied variants of PDGFB gene in the patients. Variant analyses of PDGFB showed four novel pathogenic variants, namely, two splice site variants (c.160 + 2T > A and c.457-1G > T), one deletion variant (c.33_34delCT), and one insertion variant (c.342_343insG). Moreover, we developed iPS cells (iPSCs) from three patients with PDGFB variants (c.160 + 2T > A, c.457-1G > T, and c.33_34 delCT) and induced endothelial cells. Enzyme-linked immunoassay analysis showed that the levels of PDGF-BB, a homodimer of PDGF-B, in the blood sera of patients with PDGFB variants were significantly decreased to 34.0% of that of the control levels. Those in the culture media of the endothelial cells derived from iPSCs of patients also significantly decreased to 58.6% of the control levels. As the endothelial cells developed from iPSCs of the patients showed a phenotype of the disease, further studies using IBGC-specific iPSCs will give us more information on the pathophysiology and the therapy of IBGC in the future.

Long-term clinical follow-up of a patient with non-paraneoplastic cerebellar ataxia associated with anti-mGluR1 autoantibodies.

The clinical features of cerebellar ataxia associated with anti-metabotropic glutamate receptor 1 (mGluR1) autoantibodies, a rare autoimmune-mediated cerebellar ataxia, remain to be elucidated. Here, we describe a patient with non-paraneoplastic cerebellar ataxia associated with anti-mGluR1 autoantibodies, who was followed up over 5 years. She presented with relapses and remissions of subacute progressive cerebellar ataxia that were responsive to immunotherapy. Although serum anti-mGluR1 autoantibodies were continuously detected and cerebellar atrophy gradually progressed, repeated intravenous immunoglobulin therapy and oral immunosuppressants ensured cerebellar ataxia remained at almost the same level during the observation period.

Inorganic phosphorus (Pi) in CSF is a biomarker for SLC20A2-associated idiopathic basal ganglia calcification (IBGC1).

INTRODUCTION: Idiopathic basal ganglia calcification (IBGC), also called Fahr's disease or recently primary familial brain calcification (PFBC), is characterized by abnormal deposits of minerals including calcium mainly and phosphate in the brain. Mutations in SLC20A2 (IBGC1 (merged with former IBGC2 and IBGC3)), which encodes PiT-2, a phosphate transporter, is the major cause of IBGC. Recently, Slc20a2-KO mice have been showed to have elevated levels of inorganic phosphorus (Pi) in cerebrospinal fluid (CSF); however, CSF Pi levels in patients with IBGC have not been fully examined. METHODS: We investigated the cases of 29 patients with IBGC including six patients with SLC20A2 mutation and three patients with PDGFB mutation, and 13 controls. The levels of sodium (Na), potassium (K), chloride (Cl), calcium (Ca), and Pi in sera and CSF were determined by potentiometry and colorimetry. Moreover, clinical manifestations were investigated in the IBGC patients with high Pi levels in CSF. RESULTS: The study revealed that the average level of Pi in the CSF of the total group of patients with IBGC is significantly higher than that of the control group, and the levels of Pi in CSF of the IBGC patients with SLC20A2 mutations are significantly higher than those of the IBGC patients with PDGFB mutations, the other IBGC patients and controls. CONCLUSION: Results of this study suggest that the levels of CSF Pi will be a good biomarker for IBGC1.

Relationship between number of drugs and duration of hospital stay in older patients with neuromuscular diseases.

AIM: Older patients are considered to be at high risk for developing adverse drug reactions (ADR), because they commonly receive multidrug therapy despite changes in pharmacokinetic function with age. In the present study, we assessed the relationship between the number of prescribed drugs and the incidence of ADR or the time to discharge in older patients with neuromuscular disease. METHODS: A retrospective study was carried out among 135 older patients (aged ≥65 years) who were admitted to the neurology ward from October 2007 through December 2011. Drugs that possess a high risk for initiation of grade ≥2 ADR were determined using logistic regression analysis. RESULTS: A total of 38 patients (28.1%) experienced grade ≥2 ADR. Multivariate logistic regression analysis showed that corticosteroids, antibiotics, enteric nutrients and insulin were significant risks for grade ≥2 ADR. Notably, the time to discharge extended as the grade of ADR increased, with mean values of 24.4 days for grade 0, 38.3 days for grade 1, 47.5 days for grade 2 and 73.1 days for grade 3-4 events. Furthermore, the number of high-risk drugs for grade ≥2 ADR correlated well with the incidence of grade ≥2 events (R = 0.964, P = 0.008), as well as with the time to discharge (R = 0.473, P < 0.001). CONCLUSIONS: Older patients receiving multidrug therapy using corticosteroids, antibiotics, enteric nutrients, or insulin were at high risk for grade ≥2 ADR and prolongation of hospital stay. Geriatr Gerontol Int 2018; 18: 1018-1024.

Higher levels of progranulin in cerebrospinal fluid of patients with lymphoma and carcinoma with CNS metastasis.

Assessing central nervous system (CNS) involvement in patients with lymphoma or carcinoma is important in determining therapy and prognosis. Progranulin (PGRN) is a secreted glycosylated protein with roles in cancer growth and survival; it is highly expressed in aggressive cancer cell lines and specimens from many cancer types. We examined PRGN levels by Enzyme Immuno-Assay (EIA) in cerebrospinal fluid (CSF) samples from 230 patients, including 18 with lymphoma [12 with CNS metastasis (CNS+); 6 without CNS metastasis (CNS-)], 21 with carcinomas (10 CNS+; 11 CNS-), and 191 control patients with non-cancer neurological diseases, and compared PRGN levels among these disease groups. Median CSF PGRN levels in the CNS+ lymphoma group were significantly higher than in the CNS- lymphoma and control non-cancer groups; and were also significantly higher in the CNS+ carcinoma group than in the CNS- carcinoma and control groups, except for patients with infectious neurological disorders. Receiver operating characteristic curve analyses revealed that CSF PGRN levels distinguished CNS+ lymphoma from CNS- lymphoma and non-cancer neurological diseases [area under curve (AUC): 0.969]; and distinguished CNS+ carcinomas from CNS- carcinomas and non-cancer neurological diseases (AUC: 0.918). We report here, for the first time, that CSF PGRN levels are higher in patients with CNS+ lymphoma and carcinomas compared to corresponding CNS- diseases. This would imply that measuring CSF PGRN levels could be used to monitor CNS+ lymphoma and metastasis.

Drug-induced Pressure Ulcers in a Middle-aged Patient with Early-stage Parkinson's Disease.

Drug-induced pressure ulcer (DIPU), which is a newly recognized adverse drug reaction, is associated with the administration of psychiatric drugs in geriatric patients with dementia. The notification of the causative drugs is crucial to the treatment of DIPU. We herein report the case of a 56-year-old woman with early-stage Parkinson's disease who developed DIPUs after starting olanzapine treatment for depressive symptoms. Our findings illustrate that if an akinetic patient with pressure ulcers is encountered, the patient's medication should be reviewed by a multidisciplinary team, to evaluate whether the development of the pressure ulcer is drug-related, regardless of the patient's age.

Cerebrospinal Fluid C-C Motif Chemokine Ligand 2 Correlates with Brain Atrophy and Cognitive Impairment in Alzheimer's Disease.

BACKGROUND: Chronic neuroinflammation has been implicated in Alzheimer's disease (AD) pathology. OBJECTIVE: To investigate the association between cytokine and anti-amyloid-ß (Aß) autoantibody levels and the degree of brain atrophy and cognitive impairment in AD patients. METHODS: Cerebrospinal fluid (CSF) levels of C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8, C-X-C motif chemokine ligand 10, interleukin 6, and anti-Aß autoantibody were evaluated in 69 AD patients. Serum levels of CCL2 and anti-Aß autoantibody were also examined. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets the volumes of interest (VOI) in medial temporal structures. Cognitive function was evaluated by neuropsychological testing, including the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). RESULTS: CSF CCL2 levels correlated significantly with the severity (p = 0.023) and the extent (p = 0.022) of VOI atrophy, and with the extent of gray matter atrophy (p = 0.039) in AD patients. CSF anti-Aß autoantibody levels were inversely correlated with the severity of VOI atrophy (p = 0.020), the extent of VOI atrophy (p = 0.015), and the ratio of VOI/GM atrophy (r = -0.358, p = 0.004). CSF CCL2 levels were also inversely correlated with MMSE (p = 0.0497) and FAB scores (p = 0.016). CONCLUSIONS: CSF CCL2 levels are associated with the degree of medial temporal lobe and gray matter atrophy, and cognitive decline in AD.

[A case of hyperammonemia resulting from urinary tract infection caused by urease-producing bacteria in a Parkinson's disease patient with drug-induced urinary retention].

A 71-year-old woman with a 9-year history of Parkinson's disease was admitted to our hospital emergently because of consciousness disturbance. Her consciousness level was 200 on the Japan coma scale (JCS), and she presented with tenderness and distension of the lower abdomen. Brain computed tomography showed normal findings. Blood tests showed an increased ammonia level (209 µg/dl) with normal AST and ALT levels. We catheterized the bladder for urinary retention. Five hours after admission, the blood ammonia level decreased to 38 µg/dl, and her consciousness level improved dramatically. Corynebacterium urearyticum, a bacterial species that produces urease, was detected by urine culture. Therefore, she was diagnosed with hyperammonemic encephalopathy resulting from urinary tract infection caused by urease-producing bacteria. In this case, urologic active agents had been administered to treat neurogenic bladder. We suspect that these drugs caused urinary obstruction and urinary tract infection. It is important to recognize that obstructive urinary tract infection caused by urease-producing bacteria can cause hyperammonemia. Neurological disorders, such as Parkinson's disease, tend to complicate neurogenic bladder. This disease should be considered in elderly patients with Parkinson's disease who are receiving urologic active drugs.

Clinical findings of a probable case of MM2-cortical-type sporadic Creutzfeldt-Jakob disease with antibodies to anti-N-terminus of α-enolase.

We report the case of a 76-year-old woman presenting with 47-month history of progressive dementia and cortical blindness with no family history. Antibodies against thyroid glands and the N-terminus of α-enolase (NAE) were detected in her serum. Neurological examination revealed progressive dementia, frontal signs, visual disturbance, and exaggerated bilateral tendon reflexes in both legs. Diffusion MRI showed cortical hyper-intensities in the bilateral occipital and parietal, and the left frontal and temporal cortices. 99mTc-ethyl cysteinate dimer-single photon emission computed tomography indicated decreased regional cerebral blood flow throughout the bilateral parietal lobes and partially in the left frontal and temporal lobes. PRNP gene analysis showed no mutations with methionine homozygosity at codon 129 in peripheral blood. Cerebrospinal fluid examination, including 14-3-3 and total tau protein detection, revealed normal levels; however, prion proteins were amplified by the real-time quaking-induced conversion method. Hashimoto's encephalopathy was excluded on the basis of unresponsiveness to corticosteroids. The symptoms progressed slowly. Periodic sharp-wave complexes were observed on electroencephalogram 36 months after the onset of symptoms; the patient reached a state of akinetic mutism at 47 months. This was a probable case of MM2-cortical-type sCJD with anti-NAE antibodies based on the World Health Organization (WHO) diagnostic criteria for sCJD, genetic information, and the slowly progressive course. However, this case did not meet with the probable WHO diagnostic criteria until 3 years after symptom onset, highlighting the difficulty of diagnosing a living case of the MM2-type of sCJD. Therefore, establishment of clinical diagnostic criteria for MM2-type of sCJD is required.

Anti-C1q autoantibodies in patients with neuromyelitis optica spectrum disorders.

We examined anti-complement C1q (C1q) autoantibody levels in serum and cerebrospinal fluid (CSF) samples of patients with neuromyelitis optica spectrum disorders (NMOSD). We analyzed the correlations between anti-C1q autoantibody levels and the clinical and other CSF characteristics of NMOSD. Serum and CSF anti-C1q autoantibody levels increased during the acute phase of NMOSD, reverting to the same levels as controls during remission. CSF anti-C1q autoantibody levels during the acute phase correlated with several markers reflecting disease severity, Expanded Disability Status Scale worsening, spinal cord lesion length in cases with myelitis, CSF protein and interleukin-6 levels, and CSF/serum albumin ratios.

An autopsy-verified case of steroid-responsive encephalopathy with convulsion and a false-positive result from the real-time quaking-induced conversion assay.

We report an autopsy-verified case of steroid-responsive encephalopathy with convulsion and a false-positive result from the real-time quaking-induced conversion (RT-QUIC) assay. A 61-year-old Japanese man presented with acute onset of consciousness disturbance, and convulsions, but without a past medical or family history of progressive dementia, epilepsy, or prion disease. Brain diffusion and fluid-attenuated inverted recovery MR images revealed edematous cortical hyper-intensity, which diminished after the acute phase. Steroid pulse therapy was partially effective, although he continued to have dementia with myoclonus and psychiatric symptoms, despite resolution of the consciousness disturbance. Cerebrospinal fluid (CSF) analysis revealed a normal cell count, with significantly elevated levels of 14-3-3 protein and total tau protein. In addition, prion protein in the CSF was slowly amplified by the RT-QUIC assay. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. The patient died of sudden cardiac arrest at 3 months after the onset of symptoms. The positive result from the RT-QUIC assay led us to suspect involvement of prion disease, although a postmortem assessment revealed that he had pathological changes after convulsion, and no prion disease. This case indicates that convulsion may cause false-positive RT-QUIC results, and that a postmortem evaluation remains the gold standard for diagnosing similar cases.

Acute-Onset Severe Occipital Neuralgia Associated With High Cervical Lesion in Patients With Neuromyelitis Optica Spectrum Disorder.

OBJECTIVE: To address occipital neuralgia in patients with neuromyelitis optica spectrum disorder (NMOSD). BACKGROUND: NMOSD is an inflammatory demyelinating disease that commonly presents with pain; however, headache symptoms have received little attention. METHODS: We presented three cases of NMOSD in which the patients experienced acute-onset, severe, and steroid-responsive occipital neuralgia. All patients provided consent to use their demographic and imaging data retrospectively. RESULTS: In all three cases, MRI revealed a new high-intensity area in the cervical cord at the C1-C3 level of the spine, which was diminished in two of the three cases after corticosteroid pulse therapy. CONCLUSION: Our cases support the recognition of NMOSD as a cause of secondary headache. As patients with NMOSD experience severe occipital neuralgia, a relapse should be considered and a cervical MRI should be performed.

The effects of Brazilian green propolis that contains flavonols against mutant copper-zinc superoxide dismutase-mediated toxicity.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. The purpose of this study was to clarify effects of brazilian green propolis and the active ingredient against ALS-associated mutant copper-zinc superoxide dismutase (SOD1)-mediated toxicity. Ethanol extract of brazilian green propolis (EBGP) protected N2a cells against mutant SOD1-induced neurotoxicity and reduced aggregated mutant SOD1 by induction of autophagy. Kaempferide and kaempferol, the active ingredients of EBGP, also inhibited mutant SOD1-induced cell death and reduced the intracellular mutant SOD1 aggregates. Both kaempferide and kaempferol significantly suppressed mutant SOD1-induced superoxide in mitochondria. Western blot analysis showed that kaempferol potentially induced autophagy via the AMP-activated protein kinase (AMPK) - the mammalian target of rapamycin (mTOR) pathway. These results suggest that EBGP containing the active ingredient against mutant SOD1-mediated toxicity is a promising medicine or health food for prevention and treatment of ALS.