Comparison of Different Symptom Assessment Scales for Multiple System Atrophy.

To identify the most sensitive scale for use in clinical trials on multiple system atrophy (MSA), a short and sensitive scale is needed for MSA clinical trials. Potential candidates are the Unified MSA Rating Scale (UMSARS), Scale for the Assessment and Rating of Ataxia (SARA), Berg Balance Scale (BBS), MSA Health-Related Quality of Life scale (MSA-QoL), and Scales for Outcomes in Parkinson's Disease-Autonomic questionnaire (SCOPA-AUT). We enrolled patients with MSA from eight hospitals in Hokkaido, Japan. Board-certified neurologists assessed each patient at 6-month intervals and scored them on the UMSARS, SARA, BBS, MSA-QoL, and SCOPA-AUT. Score changes were evaluated using the standardized response mean (SRM). The correlation between disease duration and each score was examined. The first evaluation was conducted on 85 patients (60 patients with MSA cerebellar ataxia dominant subtype [MSA-C] and 25 patients with MSA Parkinsonism-dominant subtype [MSA-P]). Sixty-nine patients were examined after 6 months and 63 patients after 12 months. The UMSARS Part 4 had the largest SRM after 6 months and the SARA after 12 months. SRMs for MSA-P, the shorter duration group, and the early-onset group were larger than were those for MSA-C, the longer duration group, and the late-onset group. SRMs for items regarding skilled hand activities, walking, and standing were relatively large. Our study indicates that the UMSARS (parts 2 and 4), SARA, and BBS are sensitive scales for evaluating MSA progression over 12 months. Items with large SRMs effectively evaluated short-term changes.

Influence of family dynamics on burden among family caregivers in aging Japan.

BACKGROUND: Long-term care for the elderly is largely shouldered by their family, representing a serious burden in a hyper-aging society. However, although family dynamics are known to play an important role in such care, the influence of caring for the elderly on burden among caregiving family members is poorly understood. OBJECTIVE: To examine the influence of family dynamics on burden experienced by family caregivers. METHODS: We conducted a cross-sectional study at six primary care clinics, involving 199 caregivers of adult care receivers who need long-term care. Participants were divided into three groups based on tertile of Index of Family Dynamics for Long-term Care (IF-Long score), where higher scores imply poorer relationships between care receivers and caregiving family: best, <2; intermediate, 2 to <5; worst, ≥5. The mean differences in burden index of caregivers (BIC-11) between the three groups were estimated by linear regression model with adjustment for care receiver's activity of daily living and cognitive function. RESULTS: Mean age of caregivers was 63.2 years (with 40.7% aged ≥ 65 years). BIC-11 scores were higher in the worst IF-Long group (adjusted mean difference: 4.4, 95% confidence interval: 1.2 to 7.5) than in the best IF-Long group. We also detected a positive trend between IF-Long score and BIC-11 score (P-value for trend <0.01). CONCLUSION: Our findings indicate that family dynamics strongly influences burden experienced by caregiving family members, regardless of the care receiver's degree of cognitive impairment. These results underscore the importance of evaluating relationships between care receivers and their caregivers when discussing a care regimen for care receivers.

Epidemiology of Multiple System Atrophy in Hokkaido, the Northernmost Island of Japan.

Multiple system atrophy (MSA) is an intractable neurodegenerative disorder that is characterized by various combinations of autonomic failure, cerebellar ataxia, and parkinsonism. We conducted an epidemiological study of MSA using the combined data of a national registry system and a postal survey in Hokkaido, Japan. A postal survey was conducted in 2013 based on national registry data from 2006 to 2011. This survey contained the current status of each patient with MSA that had been collected from attending physicians and recorded into a national registry. Survey items included date, outcomes, primary symptoms, and activities of daily living at the last medical examination. Confirmation data of the diagnosis by a board-certified neurologist was also collected. Based on the national registry data, 1,092 patients with MSA were selected as our target population. The response rate of the postal survey was 81% (885/1,092). After excluding inappropriate responses, 839 patients with MSA were analyzed. Forty-nine percent of the patients were male, and the mean onset age was 62.1 ± 10.4 years. A Kaplan-Meier survival curve revealed that patients with onset symptoms of cerebellar ataxia had a better prognosis than those with onset of parkinsonism or autonomic failure (p < 0.01). Additionally, we found that a higher onset age was associated with poor prognosis. We found that patients with cerebellar ataxia at onset had a better survival prognosis than those with parkinsonism or autonomic failure at onset and that patients with an older age at onset had a worse survival prognosis.

Physicians' responses to computerized drug interaction alerts with password overrides.

BACKGROUND: Although evidence has suggested that computerized drug-drug interaction alert systems may reduce the occurrence of drug-drug interactions, the numerous reminders and alerts generated by such systems could represent an excessive burden for clinicians, resulting in a high override rate of not only unimportant, but also important alerts. METHODS: We analyzed physicians' responses to alerts of relative contraindications and contraindications for coadministration in a computerized drug-drug interaction alert system at Hokkaido University Hospital. In this system, the physician must enter a password to override an alert and continue an order. All of the drug-drug interaction alerts generated between December 2011 and November 2012 at Hokkaido University Hospital were included in this study. RESULTS: The system generated a total of 170 alerts of relative contraindications and contraindication for coadministration; 59 (34.7 %) of the corresponding orders were cancelled after the alert was accepted, and 111 (65.3 %) were overridden. The most frequent contraindication alert was for the combination of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and fibrates. No incidents involving drug-drug interactions were reported among patients who were prescribed contraindicated drug pairs after an override. CONCLUSIONS: Although computerized drug-drug interaction alert systems that require password overrides appear useful for promoting medication safety, having to enter passwords to override alerts may represent an excessive burden for the prescribing physician. Therefore, both patient safety and physicians' workloads should be taken into consideration in future designs of computerized drug-drug interaction alert systems.

Mentoring the next generation of physician-scientists in Japan: a cross-sectional survey of mentees in six academic medical centers.

BACKGROUND: Physician-scientists play key roles in biomedical research across the globe, yet prior studies have found that it is increasingly difficult to recruit and retain physician-scientists in research careers. Access to quality research mentorship may help to ameliorate this problem in the U.S., but there is virtually no information on mentoring in academic medicine in Japan. We conducted a survey to determine the availability and quality of mentoring relationships for trainee physician-scientists in Japan. METHODS: We surveyed 1700 physician-scientists in post-graduate research training programs in 6 academic medical centers in Japan about mentorship characteristics, mentee perceptions of the mentoring relationship, and attitudes about career development. RESULTS: A total of 683 potential physician-scientist mentees completed the survey. Most reported that they had a departmental mentor (91%) with whom they met at least once a month; 48% reported that they were very satisfied with the mentoring available to them. Mentoring pairs were usually initiated by the mentor (85% of the time); respondents identified translational research skills (55%) and grant writing (50%) as unmet needs. Mentoring concerning long-term career planning was significantly associated with the intention to pursue research careers, however this was also identified by some mentees as an unmet need (35% desired assistance; 15% reported receiving it). CONCLUSIONS: More emphasis and formal training in career mentorship may help to support Japanese physician-scientist mentees to develop a sense of self-efficacy to pursue and stay in research careers.

Developing a scale to measure family dynamics related to long-term care, and testing that scale in a multicenter cross-sectional study.

BACKGROUND: As Japan's population ages, more frail elderly people are cared for by members of their family. The dynamics within such families are difficult to study, in part because they are difficult to quantify. We developed a scale for assessing family dynamics related to long-term care. Here we report on the development of that scale, and we present the results of reliability testing and validation testing. METHODS: Two primary-care specialists drafted questions about family dynamics, and discussed them with other primary-care physicians and clinical researchers. The final questionnaire asked about four problems or undesirable situations: disengagement (emotional distance), scapegoating (inappropriate blame), transfer of problems across generations (transfer of unnecessary burden from older to younger generations, trans-generationally displaced revenge), and undesirable behavior (co-dependence). Next, at six general-medicine clinics, doctors evaluated families that had a caregiver and a patient requiring long-term care. The results were analyzed by factor analysis. Cronbach's α was computed, and criterion-related validation tests were done with three types of criteria: relationship before caregiving, ability to do activities of daily living (ADL), and the duration of care. RESULTS: Results were obtained from 199 families. Among the caregivers, 79% were women and their mean age was 63 years. Among the patients, 71% were women and their mean age was 84 years. The results of factor analysis indicated that the scale was unidimensional. Cronbach's α was 0.73. Not having a good relationship before caregiving was associated with significantly worse family dynamics scores, as was greater dependence regarding ADL. CONCLUSIONS: We developed a scale that enables physicians to assess the dynamics of families with a patient and a family caregiver. The scale's scores are reliable and the results of validation testing were generally good. This scale holds promise as a tool both for research and for primary-care practice.

The Movement Disorder Society Criteria: Its Clinical Usefulness in Multiple System Atrophy.

Objective In 2022, Wenning et al. proposed the Movement Disorder Society Criteria (MDS Criteria) for the Diagnosis of Multiple System Atrophy (MSA). These criteria were expected to provide useful alternatives to the second consensus statement. We examined trends in these diagnostic criteria. Methods We used patient data registered with the Hokkaido Rare Disease Consortium for Multiple System Atrophy, which has been recruiting patients with MSA through medical facilities in Hokkaido since November 2014. Patients were evaluated according to the MDS criteria based on neurological examinations and imaging findings at three separate times: the first evaluation, the time of enrollment (diagnosis), and the most recent evaluation (final evaluation). Results The MDS criteria were examined in 68 of 244 patients enrolled between November 2014 and July 2022. At the initial evaluation, the classifications were as follows: clinically established (n=27; 39.7%); clinically probable (n=13; 19.1%); possible prodromal (n=12; 17.6%); and negative (did not meet criteria (n=16; 23.5%). At the time of diagnosis, the classifications were as follows: clinically established (n=45; 66.2%); clinically probable (n=12; 17.6%); possible prodromal (n=4; 5.9%); and negative (n=7; 10.3%). At the final evaluation, the classifications were as follows: clinically established (n=52; 76.5%); clinically probable (n=9; 13.2%); possible prodromal (n=2; 2.9%); and negative (n=5; 7.4%). Conclusions We were able to clarify the changes in the criteria values and transition of patients due to the clarification of imaging and supportive findings in the MDS criteria.

3D neuromelanin-sensitive magnetic resonance imaging with semi-automated volume measurement of the substantia nigra pars compacta for diagnosis of Parkinson's disease.

INTRODUCTION: Neuromelanin-sensitive MRI has been reported to be used in the diagnosis of Parkinson's disease (PD), which results from loss of dopamine-producing cells in the substantia nigra pars compacta (SNc). In this study, we aimed to apply a 3D turbo field echo (TFE) sequence for neuromelanin-sensitive MRI and to evaluate the diagnostic performance of semi-automated method for measurement of SNc volume in patients with PD. METHODS: We examined 18 PD patients and 27 healthy volunteers (control subjects). A 3D TFE technique with off-resonance magnetization transfer pulse was used for neuromelanin-sensitive MRI on a 3T scanner. The SNc volume was semi-automatically measured using a region-growing technique at various thresholds (ranging from 1.66 to 2.48), with the signals measured relative to that for the superior cerebellar peduncle. Receiver operating characteristic (ROC) analysis was performed at all thresholds. Intra-rater reproducibility was evaluated by intraclass correlation coefficient (ICC). RESULTS: The average SNc volume in the PD group was significantly smaller than that in the control group at all the thresholds (P < 0.01, student t test). At higher thresholds (>2.0), the area under the curve of ROC (Az) increased (0.88). In addition, we observed balanced sensitivity and specificity (0.83 and 0.85, respectively). At lower thresholds, sensitivity tended to increase but specificity reduced in comparison with that at higher thresholds. ICC was larger than 0.9 when the threshold was over 1.86. CONCLUSIONS: Our method can distinguish the PD group from the control group with high sensitivity and specificity, especially for early stage of PD.

Smoking and younger age at onset in anti-acetylcholine receptor antibody-positive myasthenia gravis.

Smoking is a known risk factor for the development and progression of several autoimmune diseases. Previous studies have pointed out the association of smoking with the development and worsening of symptoms in myasthenia gravis (MG), but further investigation is necessary to confirm this association. Smoking history was investigated in a cross-sectional study of 139 patients with anti-acetylcholine receptor antibody-positive MG, and the association of smoking history with the age at the onset of MG was analyzed. Patients who had been smoking at the onset of MG were significantly younger compared with those who had never smoked or had quit before the onset of MG. A linear regression analysis adjusting for sex and the presence/absence of thymoma showed a significant association between smoking at onset and younger age at onset (regression coefficient -9.05; 95% confidence interval, -17.6, -0.51; p = 0.039). Among patients with smoking exposure within 10 years prior to or at the onset of MG, women were significantly younger at the onset of MG compared with men. Our results suggest that smoking is an independent risk factor for the earlier development of anti-acetylcholine receptor antibody-positive MG and further support the putative link between smoking and MG.

Association of Smoking and Generalized Manifestations of Myasthenia Gravis.

Objective Smoking is a known risk factor for the development and progression of autoimmune diseases. Previous studies in ocular myasthenia gravis (MG) patients showed that smoking is associated with the severity of symptoms and progression to generalized MG. However, whether smoking affects MG symptoms in patients with a broader clinical spectrum of presentations is unknown. Therefore, in this study, the associations of smoking with the clinical characteristics of MG were analyzed in a cohort of patients including those with generalized, seronegative, and thymoma-associated MG. Methods The smoking history was investigated in a cross-sectional study of 187 patients with MG followed in a referral hospital for neurology. The association of smoking with MG-activities of daily living score at survey, the presence of generalized manifestations, and the age of onset was assessed using multiple regression models. Results Neither current nor prior smoking habit was associated with the MG-activities of daily living score at survey. However, smoking exposure after MG onset was significantly associated with the presence of generalized manifestations during the disease course (odds ratio, 3.57; 95% confidence interval, 1.04, 12.3). The smoking history before or at onset of MG was not associated with the age of onset. Conclusion Smoking exposure after the onset is associated with generalized manifestations of MG in our cohort of patients with a broad clinical spectrum of presentations.

[Gliomatosis cerebri with multifocal progressive lesions on MRI].

A 77-year-old woman with cognitive impairment and multifocal progressive lesions on brain MRI was admitted to our hospital. Analysis of blood and cerebrospinal fluid showed no evidence of infection, autoimmune disease, or metabolic abnormalities. Histological examination of biopsied tissue from a lesion in the right frontal lobe revealed an abnormally increased glial cell density with enlarged nuclei and a high MIB-1 index. These pathological findings coupled with her progressive clinical history indicated a diagnosis of gliomatosis cerebri. General characteristics of gliomatosis cerebri include diffuse infiltrative lesions in neuroimaging with or without mass effect. However, the present case showed unusual multifocal manifestations in brain MRI. Therefore, histopathological examination must be taken into account for a proper diagnosis.

Multiple system atrophy in Hokkaido, Japan: a prospective registry study of natural history and symptom assessment scales followed for 5 years.

OBJECTIVES: Multiple system atrophy (MSA) is a refractory neurodegenerative disease, but novel treatments are anticipated. An accurate natural history of MSA is important for clinical trials, but is insufficient. This regional registry was launched to complement clinical information on MSA. SETTING: Patient recruitment started in November 2014 and is ongoing at the time of submission. The number of participating facilities was 66. Postal surveys were sent to medical facilities and patients with MSA in Hokkaido, Japan. PARTICIPANTS: After obtaining written consent from 196 participants, 184 overview surveys and 115 detailed surveys were conducted. PRIMARY AND SECONDARY OUTCOME MEASURES: An overview survey evaluated conformity to diagnostic criteria and a detailed survey implemented an annual assessment based on the Unified Multiple System Atrophy Rating Scale (UMSARS). RESULTS: At the time of registration, 58.2% of patients were diagnosed with cerebellar symptoms predominant type MSA (MSA-C) and 29.9% were diagnosed with parkinsonism predominant type MSA (MSA-P). UMSARS Part Ⅳ score of 4 or 5 accounted for 53.8% of participants. The higher the UMSARS Part Ⅳ score, the higher the proportion of MSA-P. At baseline, levodopa was used by 69 patients (37.5%) and the average levodopa dose was 406.7 mg/day. The frequency of levodopa use increased over time. Eleven cases changed from MSA-C to MSA-P during the study, but the opposite was not observed. Information about survival and causes of death was collected on 54 cases. Half of deaths were respiratory-related. Sudden death was recorded even in the group with UMSARS Part Ⅳ score of 1. CONCLUSIONS: This study is the first large-scale prospective MSA cohort study in Asia. MSA-C was dominant, but the use of antiparkinsonian drugs increased over the study period. Changes from MSA-C to MSA-P occurred, but not vice versa.

Analysis of the Implementation of Blood Tests Specified in the Package Insert After Prescription of Thiamazole.

OBJECTIVES: The antithyroid drug thiamazole has long been known to cause the serious adverse effect of agranulocytosis, and performing regular blood tests is listed among the warnings on the package insert. We conducted a retrospective survey of how often doctors conducted blood tests in accordance with the package insert when thiamazole was prescribed at our hospital. METHODS: The subjects were patients to whom thiamazole was newly prescribed at our hospital between April 2004 and March 2012. During the target period, thiamazole was newly prescribed to 438 patients. RESULTS: We found that blood tests after prescription of thiamazole as listed in the warning section on the package insert are not performed sufficiently. The rate at which white blood cell counts were obtained decreased over time. The rate at which differential leukocyte counts were obtained was approximately 80% of white blood cell counts at all observational time points. In contrast, the percentage of subjects whose white blood cell counts were measured increased according to a time-trend analysis. CONCLUSIONS: This study revealed that blood tests after prescription of thiamazole as listed in the warning section on the package insert are not performed sufficiently at our hospital. The rate at which differential leukocyte counts were obtained was approximately 80% of white blood cell counts at all observational periods. Physician education should be more rigorously performed than presently done, and automatic generation of warnings that urge blood tests and patient education regarding the importance of blood tests is also important.

[Reliability of blood gas analyzers for measuring lactate levels in cerebrospinal fluid].

The lactate levels in the cerebrospinal fluid (CSF) can be used to distinguish bacterial meningitis from aseptic meningitis. However, it is usually difficult to promptly measure the lactate levels. There are certain blood gas analyzers that can be used to easily and promptly obtain glucose and lactose data. We ascertained whether the lactate and glucose levels from CSF samples can be analyzed by blood gas analyzers, and we subsequently compared the data obtained with that measured at the laboratory. In this study, we measured the cell counts and the protein, glucose, and lactate levels in 62 CSF samples obtained from 51 patients. Of these 62 samples, lactate and glucose of 17 samples were also measured by a blood gas analyzer. There were no significant differences in the lactate and glucose levels between the data measured at the laboratory and that measured by the blood gas analyzer. In conclusion, we consider that rapid measurement of the lactate and glucose levels in CSF samples by blood gas analyzers can be considerably reliable in clinical practice.

Downbeat positioning nystagmus is a common clinical feature despite variable phenotypes in an FHM1 family.

Clinical examinations and mutational analyses were carried out in three patients of a Japanese familial hemiplegic migraine (FHM) pedigree. Each affected member demonstrated a broad clinical spectrum that included hemiplegic migraine with progressive cerebellar ataxia, migraine without aura, and episodic ataxia. Despite this variability, all members exhibited marked downbeat positioning nystagmus, and magnetic resonance images (MRI) all showed cerebellar atrophy predominantly of the cerebellar vermis. All affected members had a T666M missense mutation in the protein encoded by the CACNA1A gene (calcium channel, voltage-dependent, P/Q type, alpha 1A subunit). Although clinical features associated with the T666M CACNA1A mutation are highly variable, downbeat positioning nystagmus may be an important clinical feature of this disease.

[Idiopathic intracranial hypertension without headache detected during a routine health check].

A 47-year-old woman was admitted to our hospital with an optic disc edema detected during a routine health check. On admission, she exhibited bilateral optic disc edema without headache and no visual disturbance. Her cerebrospinal pressure was 440 mmH2O, but we detected no abnormalities in the CSF, blood tests, brain MRI or MRV. Therefore, she was diagnosed with idiopathic intracranial hypertension (IIH). Treatment with acetazolamide reduced the cerebrospinal pressure. We suggest that examination of the optic fundi is sufficient to diagnose both IIH without headache and IIH with atypical symptoms.

Effects of age and glucose levels on lactate levels in cerebrospinal fluid examination of neurodegenerative diseases.

Despite recent studies examining the association between neurodegenerative diseases and mitochondrial dysfunction, there are not sufficient data on factors that influence cerebrospinal fluid (CSF) lactate levels. Thus, we investigated factors that affect CSF lactate levels in neurodegenerative diseases. We extracted laboratory findings, including CSF lactate, glucose, and protein levels, and demographic and background information, including age and gender, from the electronic medical records of patients with neurodegenerative diseases in order to explore factors that have an impact CSF lactate levels. These patients had been admitted to our department and underwent a CSF examination between April 2007 and March 2015. Data from 83 patients (average age 64.5years; 45 males and 38 females) were analyzed. The patients' diagnoses included amyotrophic lateral sclerosis, multiple system atrophy, spinocerebellar degeneration, corticobasal syndrome, Parkinson's disease, and Huntington's disease. CSF lactate levels were higher in patients with a neurodegenerative disease who were aged 65years and older relative to those who were aged under 65years (p<0.05), and CSF lactate and glucose levels showed a moderate positive correlation (r=0.487). Age and CSF glucose levels influenced CSF lactate levels even after adjusting for gender, age, CSF protein levels, and CSF glucose levels. When investigating CSF lactate levels in neurodegenerative diseases, it is necessary to consider patients' age and CSF glucose levels.