Reversible Pisa syndrome caused by chronic subdural hematoma in a patient with Parkinson's disease: a case report.

BACKGROUND: Pisa syndrome (PS), characterized by lateral trunk flexion, is quite common in patients with Parkinson's disease (PD). Patients with PS are older and have a significantly longer disease duration, more severe motor phenotype, ongoing combined treatment with levodopa and dopamine agonists, and higher levodopa equivalent daily dose. We describe here, to the best of our knowledge, the first case of a woman with PD who developed acute-onset PS caused by chronic subdural hematoma (CSDH). CASE PRESENTATION: A 70-year-old woman developed acute-onset lateral flexion of her trunk to the left side while standing, and she was admitted to our hospital. One month before, she had a mild head trauma with loss of consciousness. At 65 years of age, she noticed difficulty with walking and clumsiness with her hands. She was diagnosed as having PD (Hoehn and Yahr stage 2) and levodopa was initiated. Her symptoms were markedly improved. At 67 years of age, she developed orthostatic hypotension and was treated sequentially with fluids, compression stockings, and midodrine. Urgently performed brain computed tomography (CT) showed a CSDH in the right hemisphere resulting in a marked compression of the hemisphere. After surgical evacuation, her PS disappeared. She has fully recovered to her preoperative level of function. CONCLUSION: The present case provides a valuable insight, that is, the mesial frontal lobe and its connections from the posterior parietal cortex play crucial roles in maintaining the body schema and in the pathophysiology of PS. This case suggests that CSDH should be considered when clinicians examine acute-onset PS, even in patients with neurodegenerative disorders such as PD. Appropriate patient triage and timely neurosurgical intervention should be considered.

Mesial Frontal Lobe Infarction Presenting as Pisa Syndrome.

Pisa syndrome is usually seen in patients with Alzheimer's disease treated with a cholinesterase inhibitor, dementia with Lewy bodies, Parkinson's disease, or atypical parkinsonism including multiple system atrophy. An 86-year-old woman presented with an acute onset of lateral flexion of her trunk to the left side, i.e., Pisa syndrome. She also showed left hemiparesis predominantly in her lower extremity. Her diffusion-weighted magnetic resonance images showed acute infarction in the right premotor area and supplementary motor area. Clopidogrel (75 mg daily) was prescribed. After two weeks from the onset of symptoms, her Pisa syndrome improved. The pathophysiology of Pisa syndrome has not yet been fully understood, but different mechanisms have been assumed. In this patient, it is possible that the infarction in her unilateral frontal lobe impaired the information processing from the temporoparietal cortex to the frontal lobe, including the premotor area and supplementary motor area for anticipatory postural control.

COQ2 variants in Parkinson's disease and multiple system atrophy.

Coenzyme Q2, polyprenyltransferase (COQ2) variants have been reported to be associated with multiple system atrophy (MSA). However, the relationship between COQ2 variants and familial Parkinson's disease (PD) remains unclear. We investigated the frequency of COQ2 variants and clinical symptoms among familial PD and MSA. We screened COQ2 using the Sanger method in 123 patients with familial PD, 52 patients with sporadic PD, and 39 patients with clinically diagnosed MSA. Clinical information was collected from medical records for the patients with COQ2 variants. Allele frequencies of detected rare non-synonymous variants were compared by public database of the Exome Aggregation Consortium (ExAC) and Japanese genetic variation database, using Fisher's exact test. We detected two probands with rare variants in COQ2, the p.P157S from Family A, whose patient was clinically diagnosed as having juvenile PD, and the p.H15 N/p.G331S from Family B, whose patients shared common symptoms of PD. Furthermore, in an association study comparing these familial PD and MSA cases with a public variant database, eight non synonymous variants were detected in COQ2. Three of these were very rare variants, namely, p.P157S, p.L261Qfs*4, and p.G331S, and one variant, p.G21S, was found to show a significant association with familial PD. COQ2 variants rarely may associate with the disease onset of familial PD. Our findings contribute to an understanding of COQ2 variants in neurodegenerative disorders.

The prevalence, course and clinical correlates of migraine in Parkinson's disease: A multicentre case-controlled study.

Background Previous studies have reported a lower migraine prevalence in Parkinson's disease (PD) patients and improvements in migraine headaches after PD onset, but the clinical association of migraines with PD is unclear. Methods We analysed headache and migraine prevalence and clinical correlates in 436 PD patients (mean age, 69.3 ± 7.8 years) and 401 age- and sex-matched controls (mean age, 69.2 ± 8.6 years) in a case-controlled, multicentre study. Migraines were diagnosed by a questionnaire developed according to the International Classification of Headache Disorders, second edition. We evaluated changes in headache intensity, frequency and severity over several years around the onset of PD among PD patients with headaches or migraines, and over the past several years among control subjects with headaches or migraines. Results PD patients had lower lifetime (9.6% vs. 18.0%) and 1-year (6.7% vs. 11.0%) migraine prevalences than controls. However, lifetime (38.5% vs. 38.9%) and 1-year (26.1% vs. 26.2%) headache prevalence did not differ between PD patients and controls. After adjusting for gender, timing of the evaluation of headache changes, and recall period, PD patients with headaches or migraines exhibited a pronounced reduction in the intensity, frequency and overall severity of their headaches and migraines after the onset of PD compared with controls with headaches or migraines. PD patients with migraines exhibited a higher rate of depression and higher Pittsburgh Sleep Quality Index and PD sleep scale-2 scores than those without headaches. Conclusion While overall headache and migraine severity reduced after PD onset, the presence of migraines was associated with sleep disturbances and depression in PD patients.

Impact of sleep-related symptoms on clinical motor subtypes and disability in Parkinson's disease: a multicentre cross-sectional study.

OBJECTIVES: To investigate the impact of sleep disturbances on Parkinson's disease (PD) clinical motor subtypes and disease-related disability in a multicentre setting. METHODS: We report a cross-sectional relationship between sleep-related symptoms and clinical motor subtypes (tremor dominant (TD); intermediate; postural instability and gait disturbances (PIGDs)) identified in a multicentre study, including 436 patients with PD and 401 age-matched controls. PD-related sleep problems (PD-SP), excessive daytime sleepiness (EDS) and probable REM sleep behaviour disorder (pRBD) were evaluated using the PD sleep scale (PDSS)-2, Epworth Sleepiness Scale (ESS) and RBD screening questionnaire-Japanese version (RBDSQ-J), respectively. RESULTS: PD-SP (PDSS-2 ≥18; 35.1% vs 7.0%), EDS (ESS ≥10; 37.8% vs 15.5%) and pRBD (RBDSQ-J ≥5; 35.1% vs 7.7%) were more common in patients with PD than in controls. The prevalence of restless legs syndrome did not differ between patients with PD and controls (3.4% vs 2.7%). After adjusting for age, sex, disease duration and Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) part III score, the PIGD group had higher PDSS-2 and ESS scores than the TD group. The RBDSQ-J scores did not differ among the TD, intermediate and PIGD groups. A stepwise regression model predicting the MDS-UPDRS part II score identified the Hoehn and Yahr stage, followed by the number of sleep-related symptoms (PD-SP, EDS and pRBD), disease duration, MDS-UPDRS part III score, PIGD subtype, depression and MDS-UPDRS part IV score as significant predictors. CONCLUSION: Our study found a significant relationship between sleep disturbances and clinical motor subtypes. An increased number of sleep-related symptoms had an impact on disease-related disability.

A randomized double-blind multi-center trial of hydrogen water for Parkinson's disease: protocol and baseline characteristics.

BACKGROUND: Our previous randomized double-blind study showed that drinking hydrogen (H2) water for 48 weeks significantly improved the total Unified Parkinson's Disease Rating Scale (UPDRS) score of Parkinson's disease (PD) patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled multi-center trial. METHODS: Changes in the total UPDRS scores from baseline to the 8(th), 24(th), 48(th), and 72(nd) weeks, and after the 8(th) week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total UPDRS score from baseline to the 72(nd) week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the duration until the protocol is finished because additional levodopa is required or until the disease progresses, will also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the hydrogen water group will drink 1000 mL/day of H2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (88 women, 90 men; mean age: 64.2 [SD 9.2] years, total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants; daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14 hospitals and were randomized. DISCUSSION: This study will confirm whether H2 water can improve PD symptoms. TRIAL REGISTRATION: UMIN000010014 (February, 13, 2013).

Middle Cerebral Artery Occlusion Presenting as Upper Limb Monochorea.

BACKGROUND: Hemichorea is usually caused by a structural lesion in the contralateral basal ganglia or subthalamic nuclei or it develops as a form of a neurologic complication including hyperglycemia. We report a rare case of a patient who developed choreic movement in the right upper extremity associated with a contralateral middle cerebral artery (MCA) occlusion. METHODS: A 76-year-old man presented with chorea in the right upper limb, known as monochorea, which occurred after recovery from losing consciousness while standing. He was found to have idiopathic orthostatic hypotension. His diffusion-weighted magnetic resonance imaging did not show signal changes indicative of acute ischemic lesions. A left carotid artery angiogram showed occlusion of the left MCA. (123)I-N-isopropyl-4-iodoamphetamine single-photon emission computed tomography of the brain showed marked hypoperfusion in the left MCA territory. His cerebrovascular reserve capacity determined using acetazolamide was relatively decreased in this territory. This decrease in cerebrovascular reserve capacity, however, did not require surgical treatment, such as extracranial-intracranial bypass surgery. RESULTS: The recurrence of chorea was not observed after antiplatelet therapy and instruction on how to cope with orthostatic hypotension. CONCLUSIONS: It is considered that transient hemodynamic ischemia in the right basal ganglia-thalamocortical circuits because of the combination of MCA occlusion and hypotension was the underlying cause of the monochorea in this patient.Vascular imaging studies for early identification of occlusion or severe stenosis of cerebral major arteries should be carried out in patients acutely presenting with chorea, even in the absence of other clinical signs.

Associations of durations of antiplatelet use and vascular risk factors with the presence of cerebral microbleeds.

The association of the presence of cerebral microbleeds with antiplatelet use remains controversial. Long durations of antiplatelet use and vascular risk factors may have a greater impact on the development of cerebral microbleeds than short durations. The aim of this study was to determine whether the durations of antiplatelet use and vascular risk factors were associated with the presence of cerebral microbleeds in patients with ischemic cerebrovascular disease, who are frequently treated with antiplatelet agents. Two hundred twenty outpatients with ischemic cerebrovascular lesions (eg, cerebral infarcts and/or white matter lesions) detected by magnetic resonance imaging were examined. Patients with a history of cerebral hemorrhage were excluded. Cerebral microbleeds were observed in 71 (32.3%) patients. Deep or infratentorial microbleeds and strictly lobar microbleeds were observed in 53 (24.1%) patients and 18 (8.2%) patients, respectively. Aspirin use (odds ratio, 2.14; 95% confidence interval [CI], 1.02-4.73; P = .04) and a long duration (≥10 years) of aspirin use (odds ratio, 3.75; 95% CI, 1.31-10.86; P = .01) were significantly associated with deep or infratentorial microbleeds in the crude analysis, but this became nonsignificant after adjustment for hypertension and other confounding factors. The prevalence of antiplatelet use was significantly higher in the patients with hypertension than in those without hypertension (72.5% versus 49.1%, P = .002). Hypertension (odds ratio, 2.50; 95% CI, 1.11-6.41; P = .04) was significantly associated with the development of deep or infratentorial microbleeds even after adjustment for confounding factors and the association increased with the duration of hypertension. In conclusion, we found a significant association between aspirin use and deep or infratentorial microbleeds, but this association may reflect the presence of hypertension as a confounding factor.

Practical approach to freezing of gait in Parkinson's disease.

Freezing of gait in Parkinson's disease and related disorders is common and very disabling. It usually occurs in the advanced stages, although mild forms may develop earlier. Freezing can occur on turning, in narrow spaces, immediately before reaching a destination, and in stressful situations. Dual tasking (motor or cognitive load) aggravates the problem. Freezing of gait in Parkinson's disease usually occurs in the 'off' rather than in the 'on' state. It is, therefore, not entirely drug-resistant; the first step in medical treatment is to ensure adequate dopaminergic stimulation to reduce the 'off' state. There is no good evidence for any specific drug to alleviate freezing. Visual or auditory cues are very helpful as behavioural therapy. Assistive devices, such as a wheeled walker sometimes help. Deep brain stimulation of the subthalamic nucleus may alleviate freezing in the 'off' state. Because of the complexity of freezing, individual patients need a careful assessment-particularly in relation to motor fluctuation-to optimise their treatment.

Subacute Progressive Hearing Loss and Lower Body Parkinsonism in Primary Sjögren's Syndrome.

In primary Sjögren's syndrome, it is extremely rare to observe subacute progressive lower-body parkinsonism with severe sensory hearing loss responsive to corticosteroid therapy. Sjögren's syndrome can cause heterogeneous symptoms; therefore, its diagnosis and introduction of treatment are prone to be delayed, particularly in cases without sicca symptoms or seronegative cases, which are more likely to be seen in patients with neurological complications. This report may help clinicians identify atypical early neurological symptoms in primary Sjögren's syndrome.

My History in Juntendo University.

With my retirement as a professor, I would like to review my 47-year history of studying and working at Juntendo University. I was admitted to Juntendo University School of Medicine in 1976, and after graduation I joined the Department of Neurology in 1982, where Professor Hirotaro Narabayashi was the founding chairman. I became particularly interested in movement disorders and neurophysiology. The second chairman, Professor Yoshikuni Mizuno, established an American-style neurology training system. From 1992 to 1994, I studied electrophysiology at the University of Calgary in Canada, and my family and I enjoyed life in Canada very much. In 2000, I moved to Juntendo Izu-Nagaoka Hospital, now renamed Juntendo Shizuoka Hospital. I instructed young neurologists to write case reports in English. Owing to this achievement, the third chairman, Professor Nobutaka Hattori, recommended me to be a recipient of Alumni Scientific Award and to become a professor of neurology in 2009. I also became an executive officer of the Asian and Oceanian Section of the International Parkinson and Movement Disorders Society from 2015 to 2019. In 2017, I was appointed as the dean of the Faculty of Health Science and Nursing. I devoted myself to improving the nursing education and then I received the Best Professor Award twice. The level of the faculty improved, so that all the students were able to pass the National Nursing Examination consistently. In conclusion, I thank all my colleagues, faculty members, and family for letting me have valuable experiences and memories in Juntendo University.

Associations between non-motor symptoms and patient characteristics in Parkinson's disease: a multicenter cross-sectional study.

Objective: Parkinson's disease (PD) is characterized by various non-motor symptoms (NMS), such as constipation, olfactory disturbance, sleep disturbance, mental disorders, and motor symptoms. This study aimed to investigate factors associated with NMS in patients with PD. Methods: Symptoms of PD were evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parts I-IV. NMS was assessed using the MDS-UPDRS Part I (self-assessment of NMS) and rapid eye movement sleep behavior disorder (RBD) questionnaires. Patients were categorized by age into <70 years and ≥ 70 years (older adults) groups, according to disease duration into early-stage and advanced-stage groups with a cut-off value of 5 years for motor symptoms, and by sex into male and female groups. Results: A total of 431 patients with PD (202 males and 229 females) with a mean age of 67.7 years, a mean disease duration of 6.4 years, and a mean Part I total score of 9.9 participated in this study. The Part I total score was significantly positively correlated (p < 0.01) with disease duration and Part II, III, and IV scores. For Part I sub-item scores, the older group had significantly higher scores for cognitive impairment, hallucinations, sleep problems, urinary problems, and constipation than the <70 years group, whereas the advanced-stage group had significantly higher scores for hallucinations, sleep problems, daytime sleepiness, pain, urinary problems, and constipation (p < 0.05) than the early-stage group. Anxiety was higher in female patients than in male patients, whereas daytime sleepiness, urinary problems, and RBD were higher in male patients than in female patients (p < 0.05). Factors affecting Part I included disease duration, Part II total scores, Part IV total scores, and RBD. Conclusion: According to the self-questionnaire assessment, NMS was highly severe in older adult patients, those with longer illness duration, subjective and objective motor function impairments, and RBD. Sex-based differences were also observed.

Quantitative assessment of gait bradykinesia in Parkinson's disease using a portable gait rhythmogram.

To quantify gait bradykinesia during daily activity in patients with Parkinson's disease (PD), we measured movement-induced accelerations over more than 24h in 50 patients with PD and 17 age-matched normal controls, using a new device, the portable gait rhythmogram. Acceleration values induced by various movements, averaged each 10 min, exhibited a gamma distribution. The mean value of the distribution curve was used as an index of the "amount of overall movement per 24h". Characteristic changes were observed in both the gait cycle and gait acceleration. During hypokinesia, the gait cycle became either faster or slower. A number of patients with marked akinesia/bradykinesia showed a reduced and narrow range of gait acceleration, i.e., a range of floor reaction forces. The results suggest that assessment of the combination of changes in gait cycle and gait acceleration can quantitatively define the severity of gait bradykinesia.

Cerebral infarction developing in a patient without cancer with a markedly elevated level of mucinous tumor marker.

Previous studies have shown the possible role of mucin in cerebral infarction associated with coagulation abnormalities in patients with cancer, particularly adenocarcinoma. We report a 42-year-old woman who developed motor aphasia and cerebral infarction in the left frontal lobe and right parietal lobe. A mucinous tumor marker, CA125 level, was markedly elevated at 1750 U/mL (normal, <36 U/mL), and the D-dimer level was 6.0 µg/mL (normal, <1 µg/mL). She had adenomyosis and no malignancy was revealed. The CA125 and the D-dimer levels became normal after treatment of adenomyosis. Our findings suggest for the first time that marked elevation of mucinous tumor marker level may cause cerebral infarction even in benign conditions.

Gradient echo T2*-weighted magnetic resonance imaging revealing cerebral microbleeds in a patient with microscopic polyangiitis complicated by cerebrovascular disease.

A 67-year-old woman developed alveolar hemorrhage and was positive for the myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA). She was diagnosed as having probable microscopic polyangiitis (MPA) in accordance with the Japanese criteria. Brain computed tomographic and magnetic resonance imaging (MRI) scans revealed asymptomatic chronic cerebral hemorrhage and white matter lesions. She also later developed thalamic infarction. Gradient echo T2-weighted MRI showed cerebral microbleeds. Cerebral microbleeds in our patient represent bleeding-prone necrotizing vasculitis, which is a characteristic pathologic feature of MPA. Although cerebrovascular disease is not major complication of MPA, cerebral hemorrhage occurs more frequently than ischemic infarction, and it can be critical and fatal. Brain MRIs, including gradient echo T2-weighted imaging, should be performed on patients diagnosed as or suspected of having MPA to assess the risk of cerebral hemorrhage.

Cerebral infarcts associated with adenomyosis among middle-aged women.

Cerebral infarcts associated with hypercoagulability in malignant tumors have been well recognized. However, reports on cerebral infarcts in patients with a benign gynecologic tumor, such as adenomyosis, are extremely limited. We report the cases of 4 patients with adenomyosis and cerebral infarcts, all without obvious evidence of conventional causes of cerebral infarcts. Brain magnetic resonance imaging revealed multiple cerebral infarcts in both cortical and subcortical areas in all the patients and in different arterial territories in 3 patients. Two patients also had systemic embolism in the fingers or kidneys. One patient had thrombi in the brachiocephalic trunk and left subclavian artery. The levels of coagulation markers were elevated in the acute phase of cerebral infarcts. Although cerebral infarcts might be uncommon in adenomyosis patients, these patients might be potentially at risk of developing cerebral infarcts associated with hypercoagulability related to increased mucinous tumor marker levels, menstruation-related coagulopathy, or increased tissue factor expression levels. Additional study is required to determine the mechanism underlying the development of cerebral infarcts in adenomyosis; however, physicians need to pay particular attention to those who have hypercoagulability with adenomyosis among middle-aged women.

Associations between probable REM sleep behavior disorder, olfactory disturbance, and clinical symptoms in Parkinson's disease: A multicenter cross-sectional study.

BACKGROUND: Rapid eye movement sleep behavior disorder (RBD) and olfactory dysfunction are useful for early diagnosis of Parkinson's disease (PD). RBD and severe olfactory dysfunction are also regarded as risk factors for cognitive impairment in PD. This study aimed to assess the associations between RBD, olfactory function, and clinical symptoms in patients with PD. METHODS: The participants were 404 patients with non-demented PD. Probable RBD (pRBD) was determined using the Japanese version of the RBD screening questionnaire (RBDSQ-J) and the RBD Single-Question Screen (RBD1Q). Olfactory function was evaluated using the odor identification test for Japanese. Clinical symptoms were evaluated using the Movement Disorder Society Revision of the Unified PD Rating Scale (MDS-UPDRS) parts I-IV. RESULTS: In total, 134 (33.2%) patients indicated a history of pRBD as determined by the RBD1Q and 136 (33.7%) by the RBDSQ-J based on a cutoff value of 6 points. Moreover, 101 patients were diagnosed as pRBD by both questionnaires, 35 by the RBDSQ-J only, and 33 by the RBD1Q only. The MDS-UPDRS parts I-III scores were significantly higher and disease duration significantly longer in the pRBD group. pRBD was significantly associated with male gender and the MDS-UPDRS part I score. The olfactory identification function was significantly reduced in the pRBD group. CONCLUSIONS: About 33% of the patients with PD had pRBD based on the questionnaires, and both motor and non-motor functions were significantly decreased in these patients. These results suggest that more extensive degeneration occurred in patients with non-demented PD with RBD.

Non-motor symptoms depending on motor severity in Japanese patients with Parkinson's disease: A multicenter cross-sectional study.

BACKGROUND: Although non-motor symptoms (NMS) in patients with Parkinson's disease (PD) often worsen as the severity of motor symptoms (MS) increases, few studies have assessed the associated factors of non-motor symptoms. OBJECTIVE: This study aims to determine whether the presence of NMS in PD patients is associated with or independent from the severity of MS considering confounders. METHODS: The registry of PD patients from seven facilities in Japan was used. Multiple logistic regression was performed with each domain and item of the Non-motor Symptoms Scale (NMSS) as objective variables. Severity of motor symptoms was assessed by Hoehn & Yahr stage (HY stage) as an explanatory variable. The analysis was adjusted for sex, age, disease duration, presence/absence of wearing off and dyskinesia, clinical phenotypes and Levodopa equivalent daily dose. RESULTS: A total of 1037 patients were analyzed. Analysis by NMSS domain showed higher odds ratios (ORs) in patients with higher HY stages compared with patients with lower HY stages for domains D1 (cardiovascular), D2 (sleep/fatigue), D3 (mood/apathy), D4 (perceptual problems/hallucinations), D5 (attention/memory), and D6 (gastrointestinal) (ORs: 1.54-2.72, P < .05). However, only domains D7 (urinary) and D8 (sexual dysfunction) were not associated with HY stage. Item 2 (fainting) and Item 14 (delusions) showed higher ORs in the HY stage 4-5 (ORs: 9.95 and 5.92, P < .05). CONCLUSIONS: Most NMS worsened with exacerbation of MS in PD patients, however some NMS domains were also affected with other factors. These findings contribute to the understanding of the clinical picture of PD and may improve personalized medicine and research in PD.