Publications by authors named "Koji Abe"

577 Publications

Immediate Beneficial Effect of Makeup Therapy on Behavioral and Psychological Symptoms of Dementia and Facial Appearance Analyzed by Artificial Intelligence Software.

J Alzheimers Dis 2021 Jul 5. Epub 2021 Jul 5.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan.

Background: Possible benefits of makeup therapy, in terms of immediate and late effects on cognitive and affective functions, have not been fully proved for dementia patients.

Objective: To evaluate the immediate effect of makeup therapy on dementia patients.

Methods: Female nursing home residents with dementia received either only skin care treatment (control group, n = 17) or skin care plus makeup therapy treatment (makeup therapy group, n = 19). Cognitive, affective, and activity of daily living (ADL) scores were evaluated before and just after treatments. Apparent age and emotion were also evaluated with artificial intelligence (AI) software.

Results: Makeup therapy significantly improved Abe's behavioral and psychological symptoms of dementia (BPSD) score (ABS,  *p <  0.05). AI software judged that makeup therapy significantly made the apparent age younger ( *p <  0.05). In particular, patients with moderate ADL scores had a significantly higher happiness score in makeup therapy ( *p <  0.05), with a modest correlation to the Mini-Mental State Examination (MMSE, r = 0.42,  *p <  0.05). The severe baseline MMSE group reported a greater feeling of satisfaction following makeup therapy ( *p <  0.05).

Conclusion: The present makeup therapy is a promising non-pharmacological approach to immediately alleviate BPSD in female dementia patients, and the present AI software quickly and quantitatively evaluated the beneficial effects of makeup therapy on facial appearance.
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http://dx.doi.org/10.3233/JAD-210284DOI Listing
July 2021

A Case of Miller-Fisher Syndrome with Syndrome of Inappropriate Secretion of Antidiuretic Hormone.

Case Rep Neurol 2021 May-Aug;13(2):380-383. Epub 2021 Jun 14.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

We report a 72-year-old woman with Miller-Fisher syndrome (MFS) with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). She developed diplopia and unsteady gait a week after an upper respiratory infection. Neurologic examination revealed ophthalmoplegia, ataxia, symmetrical weakness, numbness, and areflexia. She underwent intravenous immunoglobulin therapy. Her serum sodium concentration decreased to 119 mEq/L on day 12. She had low plasma osmolarity (254 mosm/kg), high urine osmolarity (457 mosm/kg), and high urine sodium level (73 mEq/L), while the blood level of antidiuretic hormone was normal. Anti-GD1b immunoglobulin G (IgG), -GQ1b IgG, -GT1a IgG, and -Gal-C IgM antibodies were positive. We diagnosed her with MFS overlapping with SIADH. Four weeks after onset, her symptoms recovered. The elevation of anti-GD1b, -GQ1b, and -GT1a antibodies that recognize disialosyl residue may be pathologically related to SIADH.
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http://dx.doi.org/10.1159/000516919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255708PMC
June 2021

Accelerated accumulation of fibrinogen peptide chains with Aβ deposition in Alzheimer's disease (AD) mice and human AD brains.

Brain Res 2021 Jun 29;1767:147569. Epub 2021 Jun 29.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. Electronic address:

Alzheimer's disease (AD) is a common neurodegenerative disease that is characterized by the abnormal accumulation of intracellular and extracellular amyloid-β (Aβ) as well as disruption of the blood brain barrier (BBB). Fibrinogen plays an essential role in regulating thrombosis, wound healing, and other biological functions. In the present study, we investigated the relationship between three polypeptide chains α, β, and γ (FGA, FGB, and FGG) and Aβ deposition in the APP23 plus chronic cerebral hypoperfusion (CCH) mice model as well as the human AD brain. FGA, FGB, and FGG accumulated when Aβ was deposited in neural cells and cerebral vessels. This deposition was significantly higher in AD plus CCH mice models relative to wild-type brains, and in human AD brains compared to control brains. The present study demonstrates that FGA, FGB, and FGG are associated with AD progress, and can thus be potential targets for the diagnosis and therapy of AD.
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http://dx.doi.org/10.1016/j.brainres.2021.147569DOI Listing
June 2021

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

J Neurol 2021 Jun 30. Epub 2021 Jun 30.

Central Coordinating Unit, Clinical Research Support Center, The University of Tokyo Hospital, Tokyo, Japan.

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.
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http://dx.doi.org/10.1007/s00415-021-10670-yDOI Listing
June 2021

Early detection of cognitive decline in mild cognitive impairment and Alzheimer's disease with a novel eye tracking test.

J Neurol Sci 2021 Jun 3;427:117529. Epub 2021 Jun 3.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. Electronic address:

Due to an increasing number of dementia patients, the development of a rapid and sensitive method for cognitive assessment is awaited. Here, we examined the usefulness of a novel and short (3 min) eye tracking device to evaluate the cognitive function of normal control (NC, n = 52), mild cognitive impairment (MCI, n = 52), and Alzheimer's disease (AD, n = 70) subjects. Eye tracking total score declined significantly in MCI (**p < 0.01 vs NC) and AD (**p < 0.01 vs NC, p < 0.01 vs MCI), and correlated well with the mini-mental state examination (MMSE) score (r = 0.57, *p < 0.05). Furthermore, the eye tracking test, especially memory and deductive reasoning tasks, effectively discriminated NC, MCI and AD. The present novel eye tracking test clearly discriminated cognitive functions among NC, MCI, and AD subjects, thereby providing an advantage for the early detection of MCI and AD in screening.
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http://dx.doi.org/10.1016/j.jns.2021.117529DOI Listing
June 2021

Author Correction: Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis.

Sci Rep 2021 Jun 14;11(1):12828. Epub 2021 Jun 14.

Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

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http://dx.doi.org/10.1038/s41598-021-91963-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203677PMC
June 2021

Microbleeds and clinical outcome in acute mild stroke patients treated with antiplatelet therapy: ADS post-hoc analysis.

J Clin Neurosci 2021 Jul 12;89:216-222. Epub 2021 May 12.

Department of Neurology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; Department of Stroke Medicine, Kawasaki Medical School, Kurashiki, Japan.

Background And Purpose: In this post-hoc analysis using acute dual study dataset, the impacts of cerebral microbleeds (MBs) after mild stroke on clinical outcome were investigated.

Methods: The number of MBs on admission was categorized as 1) no MBs, 2) MBs 1-4, 3) MBs 5-9, and 4) MBs ≥ 10. The efficacy outcome was defined as neurological deterioration and stroke recurrence within 14 days. Safety outcomes included ICH and/or SAH as well as extracranial hemorrhages.

Results: Of the 1102 patients, 780 (71%) had no MBs on admission, while 230 (21%) had MBs 1-4, 48 (4%) had MBs 5-9, and 44 (4%) had MBs ≥ 10. The number of MBs was not associated with the neurological deterioration and/or stroke recurrence (p = 0.934), ICH and/or SAH (p = 0.743), and extracranial hemorrhage (p = 0.205). Favorable outcome was seem in 84% in the No MBs group, 83% in the MBs 1-4, 94% in the MBs 5-9, and 85% in the MBs ≥ 10 (p = 0.304). Combined cilostazol and aspirin therapy did not alter any rates of efficacy and safety outcomes among the no MBs, MBs 1-4, MBs 5-9, and MBs ≥ 10 groups compared to aspirin alone (all p > 0.05). By multivariate regression analysis, a history of ICH and diastolic blood pressure were the independent parameters to all of the MBs criteria (presence, MBs ≥ 5, and MBs ≥ 10).

Conclusions: MBs did not alter the clinical outcome at 3 months of onset. Elevated diastolic blood pressure and a history of ICH were the essential parameters related to the MBs.
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http://dx.doi.org/10.1016/j.jocn.2021.04.028DOI Listing
July 2021

Differential cytokine profiles in pediatric patients with PFAPA syndrome and recurrent tonsillitis.

J Med Invest 2021 ;68(1.2):38-41

Department of Otolaryngology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan.

Objective : An attempt was made to identify characteristic cytokine profiles to distinguish periodic fever with aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPAS) from recurrent tonsillitis, of which clinical manifestations are similar to those of PFAPAS in children. Methods : Serum concentrations of IL-6, IL-4 and IFN-γ were measured during febrile episodes in pediatric patients. Results : The levels of IL-6 during febrile episodes were markedly increased above the upper limit of normal ranges in patients with both PFAPAS and recurrent tonsillitis, but there were no significant differences between groups. The levels of IL-4 during febrile episodes in PFAPAS patients were significantly lower than those in recurrent tonsillitis patients. The levels of IFN-γ during febrile episodes in PFAPAS patients were significantly higher than those in recurrent tonsillitis patients. Conclusion : In pediatric patients with PFAPAS, despite an increase of IL-6, IL-4 was suppressed with a marked increase of IFN-γ during febrile episodes. On the contrary, in febrile pediatric patients with recurrent tonsillitis, both IL-6 and IL-4, but not IFN-γ were increased. The characteristic cytokine profiles of IL-6, IL-4 and IFN-γ can be used for differential diagnosis of PFAPAS from recurrent tonsillitis in children in clinical ear, nose and throat (ENT) settings. J. Med. Invest. 68 : 38-41, February, 2021.
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http://dx.doi.org/10.2152/jmi.68.38DOI Listing
January 2021

A new combined index of SUVmax of lymph node in PET / CT by a weighting coefficient plus its maximum minor axis in CECT to evaluate occult lymph node metastasis in clinical N0 patients with tongue cancer.

J Med Invest 2021 ;68(1.2):154-158

Department of Otolaryngology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.

To predict occult nodal metastasis in clinical N0 patients with tongue cancer, we developed combined index (CI) : SUVmax of the largest lymph node in PET / CT by weighting coefficient plus its maximum minor axis (< 10 mm) in contrast-enhanced CT (CECT). In this retrospective study, 57 clinical N0 patients with tongue cancer, who underwent elective supraomohyoid neck dissection at cervical levels of I-III were enrolled. The cutoff value of SUVmax of 2.0 obtained using receiver operating characteristic (ROC) analysis predicted the postoperative positive cervical levels containing metastatic lymph nodes from clinical N0 cervical levels in tongue cancer patients with a sensitivity of 54.5% and a specificity of 78.2%. The cutoff value of CI with weighting coefficient of 1.5 obtained using ROC analysis was 9.8 at the maximum area under the curve of 0.750. The cutoff value of 9.8 predicted the postoperative positive cervical levels containing metastatic lymph nodes from clinical N0 cervical levels in tongue cancer patients with a sensitivity of 68.2% and a specificity of 81.5%. These findings suggest that CI of functional PET / CT and morphological CECT components might improve the diagnostic performance of occult nodal metastasis to select clinical N0 patients with tongue cancer preferable for elective neck dissection. J. Med. Invest. 68 : 154-158, February, 2021.
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http://dx.doi.org/10.2152/jmi.68.154DOI Listing
January 2021

Neuroprotective effects of Scallop-derived plasmalogen in a mouse model of ischemic stroke.

Brain Res 2021 Sep 12;1766:147516. Epub 2021 May 12.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kitaku, Okayama 700-8558, Japan. Electronic address:

Scallop-derived plasmalogen (sPlas) has both anti-oxidative and anti-inflammation activities, but its efficacy has not been investigated in ischemic stroke models where oxidative stress, inflammation, and neurovascular unit (NVU) damage accelerates pathophysiological progression. Therefore, in the present study, we aimed to assess the neuroprotective effects of sPlas in ischemic stroke by using a transient middle cerebral artery occlusion (tMCAO) mouse model. After the pretreatment of vehicle or sPlas (10 mg/kg/day) for 14 days, adult male mice were subjected to tMCAO for 60 min, then continuously treated with vehicle or sPlas during reperfusion and for an additional 5 days. The administration of sPlas significantly improved motor deficits (corner and rotarod tests, *p < 0.05 vs vehicle), enhanced serum antioxidative activity (OXY-adsorbent and d-ROMs tests, *p < 0.05 vs vehicle), reduced infarction volume (*p < 0.05 vs vehicle), decreased the expression of two oxidative stress markers, 4-HNE (*p < 0.05 vs vehicle) and 8-OHdG (*p < 0.05 vs vehicle), decreased the expression of pro-inflammatory markers Iba-1 (**p < 0.01 vs vehicle), IL-1β (**p < 0.01 vs vehicle), and TNF-α (**p < 0.01 vs vehicle), and alleviated NVU damage (collagen IV, MMP9, and GFAP/collagen IV, *p < 0.05 vs vehicle). Our present findings are the first to demonstrate the neuroprotective effects of sPlas on acute ischemic stroke mice at 5 d after tMCAO via anti-oxidative stress, anti-inflammation, and improvement of NVU damage, suggesting the potential of sPlas in preventing and treating ischemic stroke.
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http://dx.doi.org/10.1016/j.brainres.2021.147516DOI Listing
September 2021

Switching the Proteolytic System from the Ubiquitin-Proteasome System to Autophagy in the Spinal Cord of an Amyotrophic Lateral Sclerosis Mouse Model.

Neuroscience 2021 07 8;466:47-57. Epub 2021 May 8.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-Ku, Okayama 700-8558, Japan. Electronic address:

The degradation of damaged proteins takes place via two major proteolytic pathways: the ubiquitin-proteasome system (UPS) and autophagy. However, since it is unclear how these two proteolytic pathways contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), we investigated the switching mechanism from UPS to autophagy by pharmacologically modifying these pathways by treating the spinal cords of female ALS mouse model bearing G93A human SOD1 (G93A mice) with MG132 or 3-methyladenine (3MA). G93A mice exhibited a progressive increase in the amount of ubiquitin and p62 aggregates, BAG3 expression, and LC3-II/LC3-I ratio in both astroglia and motor neurons. Treatment with MG132 or 3MA significantly increased the clinical hanging wire score and exacerbated α-motor neuron loss at 18 weeks in G93A mice, and increased the amount of ubiquitin, p62 aggregates, and BAG3 expression. This study's results demonstrate that the molecular switch from UPS to autophagy occurred not only in motor neurons but also in astroglia at the end stage (18 weeks) when the autophagic flux was impaired in G93A mice. This finding suggests that the defense system was disrupted against aggregate-prone protein production in ALS.
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http://dx.doi.org/10.1016/j.neuroscience.2021.04.034DOI Listing
July 2021

Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases.

Cells 2021 Apr 20;10(4). Epub 2021 Apr 20.

Department of Stem Cell Biology and Histology, School of Medicine, Tohoku University, Sendai 980-8575, Japan.

Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.
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http://dx.doi.org/10.3390/cells10040961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074773PMC
April 2021

Nodal Peripheral T-cell Lymphoma with T Follicular Helper Phenotype Presenting as Chorea during Treatment: A Case Report and Literature Review.

Intern Med 2021 Apr 5. Epub 2021 Apr 5.

Department of Hematology and Oncology, Okayama University Hospital, Japan.

A 72-year-old man presented with chorea while undergoing treatment for recurrence of nodal peripheral T-cell lymphoma with T follicular helper (TFH) phenotype. An examination by brain N-isopropyl-p-iodoamphetamine (I-IMP)-single photon emission computed tomography (SPECT) revealed no abnormalities other than a decreased cerebral blood flow (CBF) in the left striatum. After four courses of salvage chemotherapy, his clinical symptoms and asymmetric cerebral perfusion improved, suggesting that the decreased CBF had caused chorea. The significance of brain SPECT has not been fully clarified in patients with chorea-associated malignant lymphoma, warranting further investigations. Brain SPECT is an alternative approach to identify abnormalities in such patients.
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http://dx.doi.org/10.2169/internalmedicine.7180-21DOI Listing
April 2021

Two Cases of Probable Neuro-Behçet's Disease with Longitudinally Extensive Transverse Myelitis.

Case Rep Neurol 2021 Jan-Apr;13(1):78-83. Epub 2021 Feb 8.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

We report 2 cases of probable neuro-Behçet's disease (NBD) with longitudinally extensive transverse myelitis (LETM). In both cases, the patients presented paraplegia, as well as sensory, bladder, and rectal disturbances. Magnetic resonance imaging (MRI) of patient 1 showed continuous high signal intensity extending from the midbrain to the entire spinal cord in the central part of the cord on T2-weighted imaging (T2WI). Spinal MRI of patient 2 revealed high signal intensity extending from Th2 to Th10 in the central part of the cord on T2WI. Both patients received high-dose methylprednisolone. A continuous lesion from the midbrain to the entire spinal cord as in patient 1 has not been previously reported. Patient 2 dramatically improved by infliximab therapy. The present cases suggest that NBD should be considered as a differential diagnosis in patients with LETM.
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http://dx.doi.org/10.1159/000512323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923906PMC
February 2021

Effect of edaravone on pregnant mice and their developing fetuses subjected to placental ischemia.

Reprod Biol Endocrinol 2021 Feb 6;19(1):19. Epub 2021 Feb 6.

Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan.

Growing evidence indicates that reduced uterine perfusion pressure (RUPP) triggers the cascade of events leading to preeclampsia. Edaravone is a powerful free radical scavenger used for the treatment of ischemia/reperfusion diseases due to its anti-oxidative stress and anti-inflammatory properties. Here we investigate the effect of edaravone (3 mg/kg) on different maternal and fetal outcomes of RUPP-induced placental ischemia mice model. RUPP surgery was performed on gestation day (GD) 13 followed by edaravone injection from GD14 to GD18, sacrifice day. The results showed that edaravone injection significantly decreased the maternal blood pressure (113.2 ± 2.3 mmHg) compared with RUPP group (131.5 ± 1.9 mmHg). Edaravone increased fetal survival rate (75.4%) compared with RUPP group (54.4%), increased fetal length, weights, and feto-placental ratio (7.2 and 5.7 for RUPP and RUPP-Edaravone groups, respectively) compared with RUPP group. In addition, RUPP resulted in many fetal morphological abnormalities as well as severe delayed ossification, however edaravone decreased the morphological abnormalities and increased the ossification of the fetal endoskeleton. Edaravone improved the histopathological structure of the maternal kidney and heart as well as decreased the elevated blood urea and creatinine levels (31.5 ± 0.15 mg/dl (RUPP), 25.6 ± 0.1 mg/dl (RUPP+edaravone) for urea and 5.4 ± 0.1 mg/dl (RUPP), 3.5 ± 0.1 mg/dl (RUPP+edaravone) for creatinine) and decreased cleaved caspase-3 expression in the maternal kidney. In conclusion, this study demonstrated that our RUPP mice model recapitulated preeclampsia symptoms and edaravone injection ameliorated most of these abnormalities suggesting its effectiveness and potential application in preeclampsia treatment regimes.
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http://dx.doi.org/10.1186/s12958-021-00707-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866881PMC
February 2021

Cerebral Microbleeds in Patients with Parkinson's Disease and Dementia with Lewy Bodies: Comparison Using Magnetic Resonance Imaging and 99 mTc-ECD SPECT Subtraction Imaging.

J Alzheimers Dis 2021 ;80(1):331-335

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan.

Background: Cerebral microbleeds (CMBs) in patients with Parkinson's disease (PD) or dementia with Lewy bodies (DLB) have not been adequately studied.

Objective: This study aims to find a difference in the total number, prevalence, and common locations of CMBs between PD and DLB and evaluate 99 mTc-ECD SPECT subtraction images of these two diseases.

Methods: We examined 112 patients with PD (53 males and 59 females; age: 77.4±3.6 years) and 28 age-matched patients with DLB (15 males and 13 females; age: 77.1±6.7 years) using brain magnetic resonance imaging (MRI) and 99 mTc-ECD SPECT subtraction imaging.

Results: The total number of CMBs was higher in patients with DLB (41.2%) than in those with PD (11.5%), and the prevalence was significantly higher in the former (0.7±1.1) than the latter (0.2±0.5, p < 0.05). The odds ratio was 5.4 (95% confidence interval [CI]: 1.7-17.4). Furthermore, CMBs were commonly located in the basal ganglia of patients with PD (6 out of 87 patients) but in the occipital lobe of patients with DLB (8 out of 17 patients). 99 mTc-ECD SPECT subtraction imaging indicated lower cerebral blood flow in the posterior cingulate gyrus among the patients with CMB-positive DLB than among those with CMB-positive PD; additionally, the cerebral blood flow was lower in the bilateral basal ganglia and midbrain among patients with CMB-positive DLB compared to those with CMB-negative DLB.

Conclusion: A reduction in occipital glucose metabolism may be related to CMBs in the occipital lobe of patients with DLB.
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http://dx.doi.org/10.3233/JAD-201495DOI Listing
January 2021

Neuropsychiatric Symptoms Assessment: Cross-cultural Adaptation and Validation of the Portuguese Abe's BPSD Score (ABS).

Clin Gerontol 2021 Jan 25:1-15. Epub 2021 Jan 25.

CINTESIS - Center for Health Technology and Services Research, Faculty of Medicine, University of Porto, Porto, Portugal.

: This study aims to report on the development and psychometric properties of the Portuguese-language Abe's BPSD score (ABS) to screen for neuropsychiatric symptoms (NPS).: ISPOR and COSMIN recommendations were followed to translate and culturally adapt the ABS. A validation study was conducted to assess the psychometric properties of the newly-translated instrument. Outpatients attending a psychogeriatric consultation were included by consecutive referrals and were assessed with the ABS, the Neuropsychiatric Inventory (NPI) and NPI Caregiver Distress scale (NPI-D), and the Mini-Mental State Examination (MMSE). The ABS reliability (internal consistency, item-total correlations, inter-rater and test-retest reliability), validity (concurrent and convergent), feasibility and diagnostic accuracy were examined.: Overall, 107 participants were included. The ABS Cronbach alpha was 0.672, and item-total correlations ranged from -0.056 to 0.546. Strong inter-rater (ICC 0.997; 95%CI: 0.995-0.999) and test-retest reliability (ICC 0.976; 95%CI: 0.958-0.986) were found. Concurrent validity with NPI was high (r = 0.847, < .001), and correlations with MMSE and NPI-D were also significant. An exploratory threshold score ≥2 is proposed to identify clinically relevant NPS.: Data provide satisfactory proof of ABS psychometric characteristics. Nevertheless, some items exhibited less optimal properties.: The newly-translated instrument proved to be relevant, valid and easy to use in a real geriatric clinical setting.
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http://dx.doi.org/10.1080/07317115.2021.1873881DOI Listing
January 2021

Detection of cutaneous prion protein deposits could help diagnose GPI-anchorless prion disease with neuropathy.

Eur J Neurol 2021 Jun 22;28(6):2133-2137. Epub 2021 Jan 22.

Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background And Purpose: To investigate prion protein (PrP) deposits in cutaneous tissues of patients of glycosylphosphatidylinositol (GPI)-anchorless prion diseases with neuropathy.

Methods: Cutaneous tissue samples from three patients with GPI-anchorless prion diseases were obtained, two cutaneous biopsy samples from the lower leg of Case 1 (Y162X) and Case 3 (D178fs25), and a cutaneous sample taken from the abdomen during an autopsy of Case 2 (D178fs25). We performed immunohistochemistry for PrP to look for abnormal PrP deposits.

Results: PrP deposits were observed in the dermal papilla, the sweat glands, the hair follicles, the arrector pili muscles, and peripheral nerves of all examined cases of GPI-anchorless prion disease with neuropathy. The abnormal PrP accumulation was frequently localized at the basement membrane, and colocalized with laminin.

Conclusion: Immunohistochemical detection of PrP in cutaneous samples could be used to definitively diagnose GPI-anchorless PrP disease with neuropathy.
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http://dx.doi.org/10.1111/ene.14720DOI Listing
June 2021

4-Hydroxyl-2-Nonenal Localized Expression Pattern in Retrieved Clots is Associated with Large Artery Atherosclerosis in Stroke Patients.

J Stroke Cerebrovasc Dis 2021 Mar 4;30(3):105583. Epub 2021 Jan 4.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558, Japan. Electronic address:

Objectives: The relationship between stroke etiology and clot pathology remains controversial.

Materials And Methods: We performed histological analysis of clots retrieved from 52 acute ischemic stroke patients using hematoxylin and eosin staining and immunohistochemistry (CD42b and oxidative/hypoxic stress markers). The correlations between clot composition and the stroke etiological group (i.e., cardioembolic, cryptogenic, or large artery atherosclerosis) were assessed.

Results: Of the 52 clots analyzed, there were no significant differences in histopathologic composition (e.g., white blood cells, red blood cells, fibrin, and platelets) between the 3 etiological groups (P = .92). By contrast, all large artery atherosclerosis clots showed a localized pattern with the oxidative stress marker 4-hydroxyl-2-nonenal (P < .01). From all 52 clots, 4-hydroxyl-2-nonenal expression patterns were localized in 28.8% of clots, diffuse in 57.7% of clots, and no signal in 13.5% of clots.

Conclusions: A localized pattern of 4-hydroxyl-2-nonenal staining may be a novel and effective marker for large artery atherosclerosis (sensitivity 100%, specificity 82%).
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105583DOI Listing
March 2021

A Unique Case of Encephalopathy with an Elevated IgG-4 and Extremely High Interleukin-6 Level and Delayed Myelodysplastic Syndrome.

Intern Med 2021 Jul 29;60(13):2125-2128. Epub 2020 Dec 29.

Departments of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan.

We herein report a 75-year-old man who developed disturbed consciousness with polynuclear cell dominant pleocytosis and low glucose and extremely high interleukin (IL)-6 levels in his cerebrospinal fluid. The biopsy specimen from his right supraclavicular lymph node showed the infiltration of inflammatory cells positive for IgG, IgG4 and IL-6. Prednisolone and azathioprine administered under suspicion of IgG4-related disease (IgG4-RD) or multicentric Castleman's disease (MCD) successfully remitted the symptoms. However, he developed myelodysplastic syndrome (MDS) and died 18 months later. The extremely high IL-6 may have been related to the rare neurological manifestations and development of MDS in the present case.
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http://dx.doi.org/10.2169/internalmedicine.6098-20DOI Listing
July 2021

Hypoxic stress visualized in the cervical spinal cord of ALS patients.

Neurol Res 2021 Jun 30;43(6):429-433. Epub 2020 Dec 30.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease. Hypoxic stress is suspected as the pathogenesis of ALS, however, no positron emission tomography (PET) study for hypoxic stress has been conducted in the spinal cord of ALS patients.: In the present study, we examined cervical spinal hypoxic stress of nineALS patients with upper extremity (U/E) atrophy byF-fluoromisonidazole (FMISO) PET.: On the ipsilateral side of C1 and C5 levels, F-FMISO uptake increased significantly compared with the contralateral side (* < 0.05) and the control subject (** < 0.01). In addition, a strong correlation was found between F-FMISO uptake of the C5 level and the rate of progression of the ALS FRS-R score (R = 0.781, * = 0.013).: These results indicate that hypoxic stress increased in the spinal cord of ALS patients with a close link to ALS progression. Both hypoxic stress and a compromised response to hypoxia, which may lead to subsequent motor neuron death, could be a potential therapeutic target for ALS.
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http://dx.doi.org/10.1080/01616412.2020.1866383DOI Listing
June 2021

Cilostazol Addition to Aspirin could not Reduce the Neurological Deterioration in TOAST Subtypes: ADS Post-Hoc Analysis.

J Stroke Cerebrovasc Dis 2021 Feb 2;30(2):105494. Epub 2020 Dec 2.

Department of Neurological Science, Nippon Medical School Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan; Department of Stroke Medicine, Kawasaki Medical School, Kurashiki, Japan.

Background: Our previous trial acute dual study (ADS) reported that dual antiplatelet therapy (DAPT) using cilostazol and aspirin did not reduce the rate of short-term neurological worsening in non-cardioembolic stroke patients. Present post-hoc analysis investigated whether the impact of combined cilostazol and aspirin differed among stroke subtypes and factors associated with neurological deterioration and/or stroke recurrence.

Methods: Using the ADS registry, the rate of neurological deterioration, defined as clinical worsening and/or recurrent stroke, including transient ischemic attack was calculated. Stroke subtypes included large-artery atherosclerosis (LAA), small vessel occlusion (SVO), other determined etiology (Others), and undetermined etiology of stroke (Undetermined).

Results: Data of 1022 patients were analyzed. Deterioration was seen in 104 (10%) patients, and the rates were not markedly different between patients treated with DAPT vs. aspirin in any stroke subtypes: LAA, 19% vs. 11%, (p=0.192); SVO, 10% vs. 10% (p=1.000); Others, 6% vs. 6% (p=1.000); Undetermined, 11% vs. 8% (p=0.590). Diabetes mellitus was the independent factor associated with deterioration (odds ratio 4.360, 95% confidence interval 1.139-16.691, p=0.032) in the LAA group. Age (1.030 [1.004-1.057], p=0.026), systolic blood pressure (1.012 [1.003-1.022], p=0.010), and infarct size (2.550 [1.488-4.371], p=0.001) were associated with deterioration in SVO group, and intracranial stenosis/occlusion was associated with it in the Undetermined group (3.744 [1.138-12.318], p=0.030).

Conclusions: Combined cilostazol and aspirin did not reduce the rate of short-term neurological deterioration in any clinical stroke subtype. The characteristics of patients whose condition deteriorates in the acute period may differ based on the stroke subtypes.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105494DOI Listing
February 2021

A case of type 1 facioscapulohumeral muscular dystrophy (FSHD) with restrictive ventilatory defect and congestive heart failure.

eNeurologicalSci 2020 Dec 15;21:100284. Epub 2020 Oct 15.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan.

[Background] Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disease characterized by asymmetric involvement of muscles in the face, upper extremity, trunk, and lower extremity regions, with variable severity. It was recently reported that restrictive respiratory involvement is more frequent and severe than previously recognized, while cardiac dysfunction other than arrhythmia is still considered extremely rare in FSHD. [Case report] A 59-year-old man presenting with marked muscle atrophy in the trunk and asymmetrical muscle atrophy in the legs was hospitalized because of dyspnea and edema in the face and limbs. Shortness of breath with body movement started from approximately 40 years of age. Muscle biopsy revealed myopathic change with mild to moderate variation in fiber size. The diagnosis of FSHD was made by D4Z4 contraction to three repeats on genetic testing. A pulmonary function test revealed a decline of forced vital capacity (FVC) and a preserved FEV1/FVC indicating restrictive ventilatory defect (RVD). Ultrasonic echocardiogram (UCG) showed diffuse left ventricular hypokinesis, ventricular septum thickening, pericardial effusion, and decreased ejection fraction (LVEF 30%). [Conclusion] Although restrictive ventilatory defect and congestive heart failure are uncommon in FSHD, respiratory and cardiac evaluation may be necessary in patients with FSHD.
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http://dx.doi.org/10.1016/j.ensci.2020.100284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642826PMC
December 2020

Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy.

Brain 2020 12;143(11):3352-3373

Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.

Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease.
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http://dx.doi.org/10.1093/brain/awaa279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719032PMC
December 2020

Protective effects of edaravone on white matter pathology in a novel mouse model of Alzheimer's disease with chronic cerebral hypoperfusion.

J Cereb Blood Flow Metab 2021 06 26;41(6):1437-1448. Epub 2020 Oct 26.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

White matter lesions (WMLs) caused by cerebral chronic hypoperfusion (CCH) may contribute to the pathophysiology of Alzheimer's disease (AD). However, the underlying mechanisms and therapeutic approaches have yet to be totally identified. In the present study, we investigated a potential therapeutic effect of the free radical scavenger edaravone (EDA) on WMLs in our previously reported novel mouse model of AD (APP23) plus CCH with motor and cognitive deficits. Relative to AD with CCH mice at 12 months (M) of age, EDA strongly improved CCH-induced WMLs in the corpus callosum of APP23 mice at 12 M by improving the disruption of white matter integrity, enhancing the proliferation of oligodendrocyte progenitor cells, attenuating endothelium/astrocyte unit dysfunction, and reducing neuroinflammation and oxidative stress. The present study demonstrates that the long-term administration of EDA may provide a promising therapeutic approach for WMLs in AD plus CCH disease with cognitive deficits.
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http://dx.doi.org/10.1177/0271678X20968927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142121PMC
June 2021

Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis.

Sci Rep 2020 10 13;10(1):17102. Epub 2020 Oct 13.

Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Muse cells are endogenous reparative pluripotent-like stem cells distributed in various tissues. They can selectively home to damaged sites after intravenous injection by sensing sphingosine-1-phosphate produced by damaged cells, then exert pleiotropic effects, including tissue protection and spontaneous differentiation into tissue-constituent cells. In G93A-transgenic ALS mice, intravenous injection of 5.0 × 10 cells revealed successful homing of human-Muse cells to the lumbar spinal cords, mainly at the pia-mater and underneath white matter, and exhibited glia-like morphology and GFAP expression. In contrast, such homing or differentiation were not recognized in human mesenchymal stem cells but were instead distributed mainly in the lung. Relative to the vehicle groups, the Muse group significantly improved scores in the rotarod, hanging-wire and muscle strength of lower limbs, recovered the number of motor neurons, and alleviated denervation and myofiber atrophy in lower limb muscles. These results suggest that Muse cells homed in a lesion site-dependent manner and protected the spinal cord against motor neuron death. Muse cells might also be a promising cell source for the treatment of ALS patients.
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http://dx.doi.org/10.1038/s41598-020-74216-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554047PMC
October 2020

Tocilizumab-induced Leukoencephalopathy with a Reversible Clinical Course.

Intern Med 2020 Nov 30;59(22):2927-2930. Epub 2020 Sep 30.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan.

Tocilizumab (TCZ; Actemra/RoActemra) is an anti-interleukin (IL)-6 receptor antibody for the treatment of rheumatoid arthritis (RA) and other autoimmune diseases and cytokine storms. The present case is a 63-year-old female well-controlled RA patient, who presented with a progressive cognitive impairment after 34 months of TCZ administration. Brain magnetic resonance imaging (MRI) showed leukencephalopathy with a lactic acid peak in magnetic resonance spectroscopy (MRS), a decreased blood flow in single photon emission computed tomography (SPECT), and a decreased accumulation in fluorodeoxyglucose positron emission tomography (FDG-PET). The discontinuation of TCZ improved her cognitive function and brain MRI findings at 3 months after drug cessation. The present case suggests that TCZ may sometimes cause leukoencephalopathy after long-term administration, and thus the early discontinuation of TCZ is recommended to achieve a good prognosis.
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http://dx.doi.org/10.2169/internalmedicine.5288-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725625PMC
November 2020

Repeat sizes of NOP56 gene in a Japanese Asidan (SCA36) family with clinical anticipation.

J Neurol Sci 2020 11 21;418:117150. Epub 2020 Sep 21.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2020.117150DOI Listing
November 2020

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis.

Commun Biol 2020 09 23;3(1):526. Epub 2020 Sep 23.

Division of Neurology, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Kanagawa, Japan.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.
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http://dx.doi.org/10.1038/s42003-020-01251-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511394PMC
September 2020

Vestibular and cochlear nerve enhancement on MRI and its correlation with vestibulocochlear functional deficits in patients with Ramsay Hunt syndrome.

Auris Nasus Larynx 2021 Jun 11;48(3):347-352. Epub 2020 Sep 11.

Department of Otolaryngology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.

Objective: The correlation between enhancement of the vestibulocochlear nerves on gadolinium-enhanced magnetic resonance imaging (MRI) and vestibulocochlear functional deficits was examined in patients with Ramsay Hunt syndrome (RHS).

Methods: Nineteen patients with RHS who showed herpes zoster oticus, peripheral facial palsy, and vertigo were enrolled. Canal paresis (CP) in the caloric test, abnormal response to ocular and cervical vestibular myogenic potentials (oVEMP and cVEMP), and refractory sensorineural hearing loss were evaluated. MRI images perpendicular to the internal auditory canal were reconstructed to identify the superior (SVN) and inferior vestibular nerves (IVN) and the cochlear nerve (CV). The signal intensity increase (SIinc) of the four-nerve enhancement was calculated as an index.

Results: Among RHS patients, 79%, 53%, 17% and 26% showed CP in the caloric test, abnormal responses to oVEMP and cVEMP, and refractory sensorineural hearing loss, respectively. SIinc rates of the SVN were significantly increased in RHS patients with CP in the caloric test, and with abnormal responses to oVEMP and cVEMP. SIinc rates of the SVN tended to increase in RHS patients with refractory sensorineural hearing loss (p = 0.052). SIinc rates of the IVN were significantly increased in RHS patients with abnormal responses to oVEMP and cVEMP, and refractory sensorineural hearing loss, but not in those with CP in the caloric test. SIinc rates of the CN were significantly increased in RHS patients with CP in the caloric test, abnormal response to oVEMP and refractory sensorineural hearing loss, but not in those with abnormal response to cVEMP.

Conclusion: In patients with RHS, the origin of vertigo may be superior vestibular neuritis, which is affected by reactive varicella-zoster virus from the geniculate ganglion of the facial nerve through the faciovestibular anastomosis. The results also suggested that in some RHS patients, inferior vestibular neuritis contributes to the development of vertigo and that the origin of refractory sensorineural hearing loss is cochlear neuritis.
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http://dx.doi.org/10.1016/j.anl.2020.08.027DOI Listing
June 2021
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