Gait instability, ophthalmoplegia, and chorea with orofacial dyskinesia in a man with anti-Ri antibodies: a case report.

A 79-year-old man was admitted for 2 weeks of dizziness, followed by diplopia, involuntary movement and progressive gait disturbances. Neurologic examination revealed horizontal and vertical gaze paresis, bilateral choreiform movement with orofacial dyskinesia, and limb/truncal ataxia. MRI revealed fluid-attenuated inversion recovery image-hyperintense signal abnormalities in the dorsal midbrain, pontine and medulla. Within another few days, the patient developed type II acute respiratory failure requiring artificial invasive ventilation. Because autoimmune encephalitis was suspected, he received intravenous immunoglobulin therapy followed by intravenous methylprednisolone, but only his ophthalmoplegia improved minimally. Serological tests were positive for anti-Ri onconeural antibodies. CT-guided mediastinal lymph node biopsy was performed and revealed small cell lung carcinoma. We report the rare manifestation of anti-Ri antibody-associated paraneoplastic neurological syndrome (PNS), and this case can alert us to the importance of respiratory management in this diverse neurologic disease. Furthermore, PNSs positive for anti-Ri antibodies should be added to the list of differential diagnoses of chorea with orofacial dyskinesia.

Can calcitonin gene-related peptide monoclonal antibodies ameliorate writer's cramp and migraine?

Recently, calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) have become available as a prophylactic treatment for migraine and have shown high efficacy and safety in clinical practice. CGRP mAbs have been reported to be effective not only for migraine but also for other comorbidities, such as psychiatric complications in patients with migraine. However, there are no reports examining the effect of CGRP mAbs on dystonia. We treated a patient with comorbid migraine and focal task-specific dystonia (writer's cramp) with a CGRP mAb (erenumab) because of an increase in monthly migraine days despite the addition of migraine prophylaxis. In this patient, erenumab treatment for 3 months led to improvements in symptoms of both focal dystonia and migraine, suggesting a role for CGRP in the pathophysiology of both conditions.

Associations between the burdens of comorbid sleep problems, central sensitization, and headache-related disability in patients with migraine.

Objective: Sleep disturbances are common in migraine patients and affect quality of life. Central sensitization (CS) is likely to play a role in the increased severity and chronicity of migraine. We hypothesized that the number of comorbid sleep problems would affect headache-related disability through the effects of central sensitization (CS). Methods: We performed a cross-sectional study including 215 consecutive patients with migraine. Insomnia was defined as a Pittsburgh Sleep Quality Index (PSQI) global score greater than 5. Probable REM sleep behavior disorder (pRBD) was defined as an RBD screening score of 5 or greater. Excessive daytime sleepiness (EDS) was defined as an Epworth Sleepiness Scale score of 10 or higher. Suspected sleep apnea (SA) was defined as patients with snoring or sleep apnea witnessed 3 or more nights a week. CS was assessed by the Central Sensitization Inventory (CSI). Results: Restless legs syndrome, insomnia, EDS, SA and pRBD were observed in 25.6%, 71.6%, 34.4%, 10.2%, and 21.4%, respectively, of the patients. At least one sleep problem was present in 87.0% of the patients. According to the results of the multinomial logistic regression analysis with no sleep problems as a reference, after we corrected for adjustment factors, the Migraine Disability Assessment (MIDAS) score significantly increased when three or more comorbid sleep problems were present. According to our mediation analysis, an increased number of sleep problems had a direct effect on the MIDAS score after we adjusted for other variables, and the CSI score was indirectly involved in this association. Conclusion: The present study showed an association between migraine-related disability and the burden of multiple sleep problems, which was partially mediated by CS.

Impact of autonomic symptoms on the clinical course of Parkinson's disease.

PURPOSE: Patients with Parkinson's disease (PD) exhibit various degrees of autonomic symptoms, which may be associated with Lewy body pathology distributed extensively in the autonomic nervous system. We hypothesized that the severity of autonomic symptoms reflects the severity of PD-related pathology, resulting in poor outcomes. The purpose of this study was to evaluate the impact of autonomic symptoms on PD progression. METHODS: We conducted a follow-up study among consecutive patients with PD at Dokkyo Medical University Hospital. Patients underwent comprehensive baseline evaluations and were classified into high and low autonomic symptom groups using the Scale for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT). The Kaplan‒Meier survival curves were used to analyze the time to discontinuation of their visits because of PD-related endpoints and to evaluate the association with high SCOPA-AUT scores. RESULTS: Of the 101 patients, 74 (73%) met the inclusion criteria. During the follow-up period (mean 1654 days), 22/74 patients reached PD-related endpoints (death, 4; hospitalization, 9; nursing home institutionalization, 9). PD patients with high SCOPA-AUT scores reached the endpoints faster than those with low SCOPA-AUT scores. A high SCOPA-AUT score, including gastrointestinal, urinary, and thermoregulation domains; high motor symptom scores; and low specific binding ratios (SBRs) on 123I FP-CIT-SPECT (DAT-SPECT) were associated with reaching PD-related endpoints. A high SCOPA-AUT score was associated with reaching the endpoints even after adjustment for covariates. CONCLUSIONS: Patients with high autonomic symptom scores had a greater risk of reaching PD-related endpoints than patients with low autonomic symptom scores.

Impact of diabetes and glycated hemoglobin level on the clinical manifestations of Parkinson's disease.

BACKGROUND: The coexistence of diabetes mellitus (DM) has been suggested to accelerate the progression of Parkinson's disease (PD) and make the phenotype more severe. In this study, we investigated whether DM or glycated hemoglobin (HbA1c) levels affect the differences in motor and nonmotor symptoms. METHODS: We conducted a cross-sectional study including 140 consecutive Japanese patients with PD for whom medical history and serum HbA1c records were available. The PD patients with a DM diagnosis were classified into the diabetes-complicated group (PD-DM) and the nondiabetes-complicated group (PD-no DM). Next, patients were classified based on a median HbA1c value of 5.7, and clinical parameters were compared. The correlations between HbA1c levels and other clinical variables were analyzed. RESULTS: Of 140 patients, 23 patients (16%) had DM. Compared to PD-no DM patients, PD-DM patients showed lower MMSE scores. Compared to the lower HbA1c group, the higher HbA1c group showed a higher MDS-UPDRS part III score and a lower metaiodobenzylguanidine (MIBG) scintigraphy heart-to-mediastinum (H/M) ratio. HbA1c levels were positively correlated with age and the MDS-UPDRS part III score and negatively correlated with the MMSE score and H/M ratio on cardiac MIBG scintigraphy. Binary logistic regression analysis, which included age, sex, disease duration, and MMSE and MDS-UPDRS part III scores as independent variables, revealed that a lower MMSE score was an independent contributor to PD-DM and PD with high HbA1c levels. CONCLUSIONS: DM complications and high HbA1c levels may affect cognitive function in patients with PD.

Factors contributing to sleep disturbances and excessive daytime sleepiness in patients with Parkinson's disease.

Background: Sleep disturbances and excessive daytime sleepiness (EDS) are common non-motor symptoms in patients with Parkinson's disease (PD). The purpose of this study was to identify the contributors to sleep disturbances, including insomnia, restless legs syndrome, rapid eye movement sleep behavior disorder (RBD), sleep-disordered breathing, nocturnal akinesia and EDS, in patients with PD. Methods: We conducted a cross-sectional study including 128 consecutive Japanese patients with PD. Sleep disturbances and EDS were defined as a PD Sleep Scale-2 (PDSS-2) total score ≥15 and an Epworth Sleepiness Scale (ESS) score >10, respectively. The patients were divided into four groups according to the presence or absence of sleep disturbances and EDS. We evaluated the disease severity, motor symptoms, cognition, olfactory test, the Scales for Outcomes in PD-Autonomic dysfunction (SCOPA-AUT), the Beck Depression Inventory-II (BDI-II), and the RBD Screening Questionnaire Japanese version (RBDSQ-J). Results: Of 128 patients, 64 had neither EDS nor sleep disturbances, 29 had sleep disturbances without EDS, 14 had EDS without sleep disturbances, and 21 had both EDS and sleep disturbances. Patients with sleep disturbances had higher BDI-II scores than those without sleep disturbances. Probable RBD was more frequent in patients with both sleep disturbances and EDS than in those with neither EDS nor sleep disturbances. The SCOPA-AUT score was lower in patients with neither EDS nor sleep disturbances than in patients in the other three groups. Using multivariable logistic regression analysis with neither sleep disturbances nor EDS as a reference group, that the SCOPA-AUT score was an independent contributor to sleep disturbances (adjusted OR, 1.192; 95% CI, 1.065-1.333; P = 0.002) or EDS (OR, 1.245; 95% CI, 1.087-1.424; P = 0.001) and that the BDI-II (OR, 1.121; 95% CI, 1.021-1.230; P = 0.016) and RBDSQ-J scores (OR, 1.235; 95% CI, 1.007-1.516; P = 0.043) as well as the SCOPA-AUT score (OR, 1.137; 95% CI, 1.006-1.285; P = 0.040) were independent contributors to both sleep disturbances and EDS. Conclusions: Autonomic symptoms were associated with patients with sleep disturbances or EDS, and depressive and RBD symptoms in addition to autonomic symptoms were associated with patients with both sleep disturbances and EDS.

Sleep and Autonomic Manifestations in Parkinson's Disease Complicated With Probable Rapid Eye Movement Sleep Behavior Disorder.

Patients with Parkinson's disease (PD) complicated with rapid eye movement sleep behavior disorder (RBD) present with distinct clinical features. The purpose of this study was to determine the clinical features of sleep and autonomic symptoms in PD patients with probable RBD (pRBD). The study included 126 patients with PD. pRBD was defined as having a history of dream-enacting behavior with a total score of 5 or greater on the Japanese version of the RBD Screening Questionnaire (RBDSQ-J). The Parkinson's Disease Sleep Scale-2 (PDSS-2) was used to evaluate sleep disturbances. Scales for Outcomes in Parkinson's Disease-Autonomic dysfunction (SCOPA-AUT) were used to evaluate autonomic symptoms. Clinical assessments included disease severity, motor symptoms, olfaction, depression, cognitive function, levodopa equivalent dose (LED), and cardiac metaiodobenzylguanidine (MIBG) scintigraphy. Correlations between RBDSQ-J total scores and clinical variables were analyzed. Compared to PD patients without pRBD, PD patients with pRBD showed severe hyposmia, severe sleep-related symptoms, severe dysautonomia, and more reduced cardiac MIBG scintigraphy. Within the PDSS-2, the "PD symptoms at night" domain was significantly more severe in PD patients with pRBD. Within the SCOPA-AUT, the "urinary" and "cardiovascular" domains were significantly higher in PD patients with pRBD. In correlation analyses, RBDSQ-J total scores were positively correlated with PDSS-2 total scores, "PD symptoms at night" and "disturbed sleep" domains, Epworth Sleepiness Scale scores, SCOPA-AUT total scores, "urinary," "cardiovascular," and "thermo" domain scores, and LED. RBDSQ-J total scores were negatively correlated with cardiac MIBG scintigraphy uptake. Binary logistic regression analysis showed that PDSS-2 subitem 7 (distressing hallucinations) and SCOPA-AUT subitem 11 (weak stream of urine) were significant determinants for pRBD. Our study showed that PD patients with pRBD had characteristic sleep and autonomic symptoms.

V180I genetic Creutzfeldt-Jakob disease with cardiac sympathetic nerve denervation masquerading as Parkinson's disease: A case report.

RATIONALE: Creutzfeldt-Jakob disease (CJD) with a point mutation of valine to isoleucine at codon 180 of the prion protein gene (V180I) is the most frequent form of genetic CJD in Japan. However, peripheral nerve involvement, especially cardiac sympathetic denervation, has not been investigated in cases with V180I genetic CJD.We herein report a genetically confirmed case of V180I genetic CJD presenting with parkinsonism and cardiac sympathetic nerve denervation. PATIENT CONCERNS: The patient was a 79-year-old Japanese woman who presented with subacute progressive gait disturbance and cognitive impairment. Clinical diagnosis of Parkinson's disease (PD) with mild cognitive impairment was initially suspected based on parkinsonism, such as bradykinesia, rigidity and tremor, and reduced accumulation of cardiac meta-iodobenzylguanidine (MIBG) scintigraphy. INTERVENTIONS: Based on parkinsonism and impaired cardiac MIBG findings, levodopa/decarboxylase inhibitor was administered up to 300 mg/day; however, her symptoms were not improved. OUTCOMES: Her motor and cognitive function progressively deteriorated. DIAGNOSIS: Although the patient had no family history of CJD, genetic CJD was diagnosed according to extensive hyperintensities in the bilateral cortices on diffusion-weighted magnetic resonance images, positive tau protein and 14-3-3 protein in the cerebrospinal fluid and a V180I mutation with methionine homozygosity at codon 129 by prion protein gene analysis. LESSONS: We should be aware that reduced uptake of cardiac MIBG scintigraphy in patients presenting with parkinsonism cannot confirm a diagnosis of PD. CJD should be considered when patients show a rapid progressive clinical course with atypical manifestations of PD.

Combination of midbrain-to-pontine ratio and cardiac MIBG scintigraphy to differentiate Parkinson's disease from multiple system atrophy and progressive supranuclear palsy.

BACKGROUND: An early clinical differentiation between Parkinson's disease (PD) and multiple system atrophy (MSA) or progressive supranuclear palsy (PSP) remains a challenge. The purpose of this study was to evaluate the usefulness of the combination use of midbrain-to-pontine ratio (M/P ratio) from magnetic resonance imaging (MRI) with cardiac 123I-metaiodobenzylguanidine (MIBG) uptake for differentiating PD from MSA and PSP. METHODS: Ninety-six parkinsonian patients (70 PD, aged 68.5 ±â€¯9.5 years; 16 MSA, aged 67.9 ±â€¯7.5 years; 10 PSP, aged 70.4 ±â€¯9.4 years) who underwent MRI and cardiac MIBG scintigraphy were included in this study. Receiver operating characteristic (ROC) curve analysis was used to assess the sensitivity and specificity for distinguishing PD from MSA and PSP patients. The diagnostic accuracy of these tests was also assessed among patients at the early disease stage (defined as patients with a disease duration of 3 years or less). RESULTS: The individual diagnostic sensitivity of the M/P ratio and cardiac MIBG scintigraphy was 87.1% and 67.1% in PD vs. MSA and 78.6% and 67.1% in PD vs. PSP, respectively. The diagnostic specificity of the M/P ratio and cardiac MIBG scintigraphy was 56.3% and 100% in PD vs. MSA and 70.0% and 90% in PD vs. PSP, respectively. With the optimal cutoff values, at least one positive result (either the M/P ratio or cardiac MIBG revealed abnormalities) improved sensitivity (95.7%) without decrease of specificity (56.3%) in PD vs. MSA, as well as in PD vs. PSP (100% sensitivity, 70.0% specificity). In contrast, both positive results of two tests had good specificity but low sensitivity in PD vs. MSA (60.0% sensitivity and 100% specificity) and in PD vs. PSP (47.1% sensitivity and 90% specificity). Similar trends were observed in early-stage patients. CONCLUSION: Although M/P ratio alone was potentially useful for distinguishing PD from MSA or PSP, the combined use with cardiac MIBG scintigraphy can further improve the diagnostic accuracy of PD from MSA or PSP.

Leg restlessness preceding the onset of motor symptoms of Parkinson disease: A case series of 5 patients.

Patients with Parkinson disease (PD) often show restless legs syndrome (RLS), leg motor restlessness (LMR) and other leg restlessness (OLR) related to sensorimotor symptoms.Here, we describe 5 patients who presented with leg restlessness as an early manifestation of PD.In case 1, the patient had leg restlessness that was not LMR or RLS and preceded the onset of motor symptoms by 1 year. In case 2, LMR preceded motor symptoms by 2 years. Case 3 had unilateral RLS symptoms on the left side of the body for 33 years. Two and a half years after the spread of RLS symptoms to the right leg with increased frequency of left-sided RLS symptoms, the patient developed PD at the age of 58 years. In cases 4 and 5, RLS symptoms preceded motor symptoms by 3 months and 1 month, respectively. All patients developed Parkinsonism within 3 years (median, 1.0 year; range 0.083-2.5 years) after initial onset or exacerbation of leg restlessness. All patients had frequent leg restlessness symptoms (6-7 days per week). In our series, the preceding leg restlessness was unilateral and confined to the dominant side of the subsequent Parkinsonism, or preceding leg restlessness was bilateral but dominant on the dominant side of the subsequent Parkinsonism.Clinicians should be aware that late-onset leg restlessness (>50 years of age) including RLS, LMR, and OLR, particularly if frequent and asymmetrical, can be an early nonmotor manifestation of PD.

Serum insulin-like growth factor-1 levels in neurodegenerative diseases.

BACKGROUND: We investigated serum insulin-like growth factor (IGF)-1 levels in patients with neurodegenerative diseases and correlated these levels with clinical parameters. METHODS: One hundred and fifty-six patients with neurodegenerative diseases were included in this study, and serum IGF-1 levels were determined. RESULTS: Serum IGF-1 levels (mean ± standard error) were not significantly different among the patients with different neurodegenerative diseases: Parkinson's disease (PD; n = 73), 112.1 ± 5.1 ng/mL; progressive supranuclear palsy (n = 15), 102.9 ± 8.3 ng/mL; multiple system atrophy (n = 22), 103.1 ± 37.6 ng/mL; Alzheimer's disease (AD; n = 18), 102.2 ± 9.4 ng/mL; amyotrophic lateral sclerosis (n = 6), 105.5 ± 27.4 ng/mL; dementia with Lewy bodies (n = 14), 82.4 ± 7.4 ng/mL; frontotemporal dementia (n = 6), 90.0 ± 17.0 ng/mL; and corticobasal syndrome (n = 2), 118.0 ± 14.0 ng/mL. In patients with PD, serum IGF-1 levels were negatively correlated with age and modified Rankin scale (mRS) scores and positively correlated with the striatal dopamine transporter-specific binding ratio and the frontal assessment battery score. In patients with AD, serum IGF-1 levels were negatively correlated with age, disease duration, and mRS scores. CONCLUSION: We found correlations of serum IGF-1 levels with frontal lobe and striatal dopaminergic function and disability in PD patients and with disability in AD patients. The usefulness of measuring serum IGF-1 levels for monitoring disease progression in neurodegenerative diseases requires further studies.

Autonomic Symptoms Correlate with Non-Autonomic Non-Motor Symptoms and Sleep Problems in Patients with Parkinson's Disease.

OBJECTIVE: The objective of this study was to clarify the relationship between autonomic and non-autonomic non-motor symptoms in patients with Parkinson's disease (PD). METHODS: Sixty-five PD patients were included in this study (27 men and 38 women; aged 68.5 ± 10.0; Hoehn and Yahr (HY) stage 2.6 ± 1.1). The autonomic symptoms were evaluated by the Japanese version of the Scales for outcomes in PD autonomic (SCOPA-AUT) questionnaire. The patients were assessed with the mini-mental state examination (MMSE), PD sleep evaluation scale-2 (PDSS-2), Epworth sleepiness scale (ESS) and Beck's depression inventory II (BDI-II). The Non-Motor Symptom Scale (NMSS) total scores and subscores of non-autonomic non-motor symptom domains (sleep/fatigue, mood/cognition, perceptual problems/hallucination, and attention/memory) were evaluated. A dopamine transporter (DAT) scan, metaiodobenzylguanidine (MIBG) myocardial scintigraphy, and card type olfactory identification test (open essence [OE, Wako]) were performed. RESULTS: The SCOPA-AUT total score was positively correlated with the disease duration, HY stage, levodopa equivalent dose, PDSS-2, ESS, BDI-II and non-autonomic NMSS and inversely correlated with the MMSE. The high-SCOPA-AUT group (≥9) had lower MMSE scores and higher PDSS-2, ESS, BDI-II and non-motor NMSS scores than the low-SCOPA-AUT group (< 9). The DAT scan, MIBG uptake and OE score did not differ between the groups. In a stepwise linear regression analysis, which excluded possibly overlapping items among the scales, the subtotals of PDSS-2 items, except for item 8 (nocturia), (p < 0.0001) and non-autonomic NMSS domains (p = 0.00040) were significant predictors of the total SCOPA-AUT score. CONCLUSION: Our study shows significant correlations among autonomic symptoms, PD-related sleep problems and non-autonomic non-motor symptoms in PD patients.

Restless legs syndrome, leg motor restlessness and their variants in patients with Parkinson's disease and related disorders.

OBJECTIVE: The objective of this study was to investigate the prevalence of restless leg syndrome (RLS), leg motor restlessness (LMR) and RLS/LMR variants and their relationship with clinical factors in patients with Parkinson's disease (PD) and related disorders. METHODS: Sixty-three PD patients, 17 multiple system atrophy (MSA) patients and 11 progressive supranuclear palsy (PSP) patients were included in this study. Through face-to-face interviews, the patients were diagnosed with RLS/LMR, or with RLS/LMR variants in which the symptoms occur predominantly in body parts other than the legs. RESULTS: The frequency of RLS, LMR, RLS variants and LMR variants was as follows: PD (12.7%, 11.1%, 0% and 1.6%); MSA (5.9%, 11.8%, 0% and 0%); and PSP (0%, 9.1%, 0% and 0%). Restlessness without the urge to move was observed in 25.4% of the PD patients, 11.8% of the MSA patients and 0% of the PSP patients. The PD patients with restlessness exhibited higher Hoehn and Yahr stages and higher scores on the Scales for Outcomes in PD-Autonomic, PD sleep scale-2 and Beck Depression Inventory-II. The olfactory functioning, 123I-MIBG myocardial scintigraphy uptake and dopamine transporter single photon emission computed tomography findings did not differ between the PD patients with restlessness and those without. The severity of RLS was correlated with the autonomic symptoms among the PD patients with restlessness. CONCLUSION: PD with restlessness was characterized by increased autonomic, sleep and depressive symptoms. Further studies including a large sample are warranted to characterize restlessness in PD and related disorders.

Istradefylline improves daytime sleepiness in patients with Parkinson's disease: An open-label, 3-month study.

BACKGROUND: Istradefylline, a selective adenosine A2A receptor antagonist, has been reported to improve daily "off time" and motor symptoms in patients with Parkinson's disease (PD). However, the effect of istradefylline on sleep problems has not been thoroughly investigated. METHODS: We evaluated the effect of istradefylline on daytime sleepiness, sleep disturbances, and motor symptoms in 22 PD patients who were affected by the wearing off phenomenon in an open-label, 3-month study. Participants received 20-40mg/day istradefylline once daily (morning) over a 3-month period. The Epworth Sleepiness Scale (ESS), PD sleep scale (PDSS)-2 and PD Questionnaire (PDQ-8) were administered at baseline, 2weeks, 1month, 2months and 3months. At baseline and 3months, patients were evaluated on the Movement Disorder Society Revision of the Unified PD Rating Scale (MDS-UPDRS) parts III and IV. RESULTS: Twenty-one patients (95.5%) completed the study. At 3months, MDS-UPDRS part III (-5.3, p=0.0002) and part IV (-2.5, p=0.001) scores improved and off time decreased significantly (-50.1min, p=0.0004). PDQ-8 scores were unchanged at 3months. ESS scores decreased significantly at 2months and 3months (-2.4 and -3.3, respectively, p<0.0001), but the total PDSS-2 scores did not change. CONCLUSION: Istradefylline improved daytime sleepiness in PD patients, possibly through its effect on enhancing alertness. In addition, the lack of significant changes in the total PDSS-2 scores over the study period suggests istradefylline had no negative impact on sleep.