Takamichi Hattori

Clinical features and prognosis of Miller Fisher syndrome

Article abstract— The authors reviewed the clinical features and outcome of Miller Fisher syndrome (MFS) for 50 consecutive patients with MFS including 28 patients who received no immunotherapy. Besides the characteristic clinical triad (ophthalmoplegia, ataxia, and areflexia), pupillary abnormalities, blepharoptosis, and facial palsy are frequent in MFS, whereas sensory loss is unusual despite the presence of profound ataxia. Patients with MFS usually had good recovery and no residual deficits.

Questionnaire-based assessment of pelvic organ dysfunction in Parkinson's disease

Although patients with Parkinsons disease (PD) experience pelvic organ dysfunction of the urinary bladder, bowel and genital organs, an accurate incidence of the dysfunction and its characteristics have yet to be ascertained. We devised a detailed questionnaire on these three pelvic organ functions in PD patients and control subjects, in our search for a hallmark that would distinguish between the two groups. The PD group comprised 115 patients; 52 men and 63 women, age range 35-69 (average 59) years old, average duration of illness 6 years, median Hoehn and Yahr stage 3. All were taking levodopa with/without dopamine agonists. The control group comprised 391 local individuals who were undergoing an annual health survey; 271 men and 120 women, age range 30-69 (average 48) years old. The questionnaire had three parts: bladder (nine questions), bowel (four questions), and sexual (three questions for women, five for men) function. Each question was scored from 0 (none) to 3 (severe) with an additional quality of life (QOL) index scored from 0 (satisfied) to 3 (extremely dissatisfied). The completion rate was 100% for bladder and bowel functions, whereas for sexual function, it was 95% (control) and 88% (PD) for men and 82% (control) and 60% (PD) for women. As compared with the control group, the frequency of dysfunction in the PD group was significantly higher for urinary urgency (women 42%, men 54%), daytime frequency (28%, 16%), nighttime frequency (53%, 63%), urgency incontinence (25%, 28%), retardation (44% of men), prolongation/poor stream (men 70%), straining (women 28%); constipation (63%, 69%), difficulty in expulsion (men 57%), diarrhea (men 21%); decrease in libido (84%, 83%), decrease in sexual intercourse (55%, 88%), decrease in orgasm (men 87%), and in men, decreases in erection (79%) and ejaculation (79%). The QOL index for the PD patients was significantly higher for bladder (27%, 28%) and bowel (46%, 59%) but not for sexual dysfunction, despite the groups high prevalence of sexual dysfunction. In the PD patients, fecal incontinence was associated with urinary incontinence. Stress urinary incontinence and a decrease in libido were more common in women than in men. Bladder and bowel dysfunction, but not sexual dysfunction increased with the Hoehn and Yahr stage. Sexual dysfunction, but neither bladder nor bowel dysfunction, increased with age. Patients taking levodopa and bromocriptine more frequently had bladder (voiding phase) dysfunction than those taking levodopa only. The findings show that bladder, bowel and sexual dysfunction are all prominent in patients with PD. Amelioration of pelvic organ dysfunction, particularly bowel dysfunction which most affects the quality of life, therefore should be a primary target in the treatment of patients with PD.

Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET

Objective: To characterize brain cholinergic deficits in Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB). Methods: Participants included 18 patients with PD, 21 patients with PDD/DLB, and 26 healthy controls. The PD group consisted of nine patients with early PD, each with a disease duration of less than 3 years, five of whom were de novo PD patients, and nine patients with advanced PD, each with a disease duration greater than or equal to 3 years. The PDD/DLB group consisted of 10 patients with PDD and 11 patients with DLB. All subjects underwent PET scans with N-[11C]-methyl-4-piperidyl acetate to measure brain acetylcholinesterase (AChE) activity. Brain AChE activity levels were estimated voxel-by-voxel in a three-compartment analysis using the arterial input function, and compared among our subject groups through both voxel-based analysis using the statistical parametric mapping software SPM5 and volume-of-interest analysis. Results: Among patients with PD, AChE activity was significantly decreased in the cerebral cortex and especially in the medial occipital cortex (% reduction compared with the normal mean = −12%) (false discovery rate–corrected p value <0.01). Patients with PDD/DLB, however, had even lower AChE activity in the cerebral cortex (% reduction = −27%) (p < 0.01). There was no significant difference between early PD and advanced PD groups or between DLB and PDD groups in the amount by which regional AChE activity in the brain was reduced. Conclusions: Brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. It begins in early Parkinson disease, and is more widespread and profound in both Parkinson disease with dementia and dementia with Lewy bodies.

Mutations in COQ2 in familial and sporadic multiple-system atrophy the multiple-system atrophy research collaboration

BACKGROUND Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components. METHODS In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography. RESULTS We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population. CONCLUSIONS Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.).

Micturitional disturbance after acute hemispheric stroke: analysis of the lesion site by CT and MRI

Micturitional histories and urodynamic studies were performed in 72 acute hemispheric stroke patients. Within 3 months from the onset, 53% of the patients had urinary symptoms including irritative as well as obstructive, and the most common symptom was nocturnal urinary frequency in 36%, which was followed by urge urinary incontinence in 29% and difficulty of voiding in 25% of the patients. We found a correlation between micturitional disturbance with hemiparesis (p <0.05) and not with hemianopsia (p <0.05). Micturitional disturbance was more common in lesions of the frontal lobe (p <0.05) than in those of the occipital lobe. Brain CT or MRI in symptomatic patients showed lesions of anterior and medial surface of the frontal lobe, anterior edge of the paraventricular white matter, genu of the internal capsule and large lesions of putamen or thalamus. Urodynamic studies of 22 symptomatic patients revealed various findings in 91% of them, including detrusor hyperreflexia in 68%, detrusor-sphincter dyssynergia (DSD) in 14% and uninhibited sphincter relaxation in 36%. Patients with urinary retention had atonic cystometrogram and DSD. Detrusor hyperreflexia was noted in lesions of the frontal lobe as well as the basal ganglia, uninhibited sphincter relaxation in the frontal lobe, and detrusor-sphincter dyssynergia common in the basal ganglia. Above findings seem to indicate that anteromedial frontal lobe and its descending pathway, and the basal ganglia seem to be mainly responsible for supranuclear types of pelvic and pudendal nerve dysfunction in our patients with stroke.

Videourodynamic and sphincter motor unit potential analyses in Parkinson's disease and multiple system atrophy

OBJECTIVES Urinary dysfunction is a prominent autonomic feature in Parkinsons disease (PD) and multiple system atrophy (MSA), which is not only troublesome but also a cause of morbidity in these disorders. Recent advances in investigative uroneurology offer a better insight into the underlying pathophysiology and appropriate management for urinary dysfunction. METHODS twenty one patients with PD (15 men, six women, mean age 64 (49–76), mean disease duration 4 years (1–8 years), median Hoehn and Yahr grade 3 (1–4), all taking 300 mg/day of levodopa (100–500 mg)) and 15 with MSA (eight men, seven women, mean age 59 (48–72), mean disease duration 3 years (0.5–6 years)) were recruited. Videourodynamic and sphincter motor unit potential analyses in the patients with PD and MSA were carried out, looking for distinguishing hallmarks that might be useful in the differential diagnosis of these two diseases. RESULTS Urinary symptoms were found in 72% of patients with PD and in 100% with MSA. Filling phase abnormalities in the videourodynamic study included detrusor hyperreflexia in 81% of patients with PD and 56% with MSA, and uninhibited external sphincter relaxation in 33% of patients with PD and 33% of those with MSA. However, open bladder neck at the start of filling was not seen in patients with PD but was present in 53% of those with MSA, suggestive of internal sphincter denervation. Sphincter motor unit potential analysis showed neurogenic motor unit potentials in 5% of patients with PD and in 93% of those with MSA, suggestive of external sphincter denervation. On voiding, detrusor-external sphincter dyssynergia was not seen in patients with PD but was present in 47% of those with MSA. Pressure-flow analysis showed that the Abrams-Griffiths number, a grading of urethral obstruction (outflow obstruction >40), in PD (40 in women and 43 in men) was larger than that in MSA (12 in women and 28 in men). Weak detrusor in PD (66% of women and 40% of men) was less common than that in MSA (71% of women and 63% of men). Postmicturition residuals >100 ml were absent in patients with PD but were present in 47% of patients with MSA. CONCLUSION Patients with PD had less severe urinary dysfunction with little evidence of internal or external sphincter denervation, by contrast with the common findings in MSA. The findings of postmicturition residuals >100 ml, detrusor-external sphincter dyssynergia, open bladder neck at the start of bladder filling, and neurogenic sphincter motor unit potentials are highly suggestive of MSA.

Mosapride citrate, a novel 5-HT4 agonist and partial 5-HT3 antagonist, ameliorates constipation in Parkinsonian patients

Mosapride citrate is a novel selective 5‐HT4 receptor agonist. It facilitates acetylcholine release from the enteric cholinergic neurons. In contrast to cisapride, mosapride does not block K+ channels or D2 dopaminergic receptors. The objective of this study is to perform an open study of mosapride citrates effects on constipation, a prominent lower gastrointestinal tract disorder in parkinsonian patients. A total of 14 parkinsonian patients (7 with Parkinsons disease, 7 with multiple system atrophy; 10 men, 4 women; mean age, 67 years) with constipation (10 with bowel movement < 3 times/week; 14 with difficulty in defecation) were treated with 15 mg/day of mosapride citrate for 3 months. Pre‐ and posttreatment objective parameters in colonic transit time (CTT) and rectoanal videomanometry were obtained. Statistical analysis was made by Students t test. Mosapride was well tolerated by all patients except for 1, who discontinued use of the drug because of epigastric discomfort. None had a worsening of parkinsonism or other adverse events. Thirteen patients reported subjective improvements in bowel frequency (>3 times/week, 13) and difficult defecation (13). Mosapride shortened CTT of the left colon (P < 0.01) and the total colon (P < 0.05). During rectal filling, mosapride lessened the first sensation (P < 0.05) and augmented the amplitude in phasic rectal contraction. During defecation, mosapride augmented the amplitude in rectal contraction (P < 0.05) and lessened the volume of postdefecation residuals. The present study showed for the first time that mosapride citrate augmented lower gastrointestinal tract motility, as shown in CTT and videomanometry, and thereby ameliorated constipation in parkinsonian patients without serious adverse effects.

Urinary function in elderly people with and without leukoaraiosis: relation to cognitive and gait function

OBJECTIVES To investigate urinary function in the elderly with and without white matter lesion (leukoaraiosis) in relation to cognitive and gait function. METHODS Sixty three subjects were examined, with mean age 73 (range 62 to 86 years). Subjects with brainstem stroke or with large hemispheric lesions were excluded. Spin echo 1.5 T MRI images were graded from 0 to 4 for severity of white matter lesions. Urinary function was assessed by detailed questionnaire and urodynamic studies were performed in 33 of the subjects, including measurement of postmicturition residuals, water cystometry, and sphincter EMG. A mini mental state examination (MMSE) and examination of gait was also performed and compared with urinary function. RESULTS Urodynamic studies showed subjects with grade 1–4 white matter lesions to have detrusor hyperreflexia more commonly (82%) than those with grade 0 white matter lesions (9%) (p<0.05), indicating that leukoaraiosis was a factor associated with geriatric urinary dysfunction. Postmicturition residuals, low compliance, detrusor-sphincter dyssynergia, and uninhibited sphincter relaxation were also more common in grade 1–4 than in grade 0 white matter lesions, though the difference was not significant. In grade 1 white matter lesions urinary dysfunction (urge urinary incontinence) was more common than cognitive (MMSE<19) (p<0.05) and gait disorders (slowness, short step/festination, and loss of postural reflex) (p<0.05), which increased together with the grade of white matter lesions (p<0.05). CONCLUSIONS Urinary dysfunction is common and probably the early sign in elderly people with leukoaraiosis on MRI.

Randomized, double-blind study of electrical stimulation for urinary incontinence due to detrusor overactivity.

OBJECTIVES To evaluate the usefulness of electrical stimulation for urinary incontinence due to detrusor overactivity in a randomized, double-blind manner. METHODS Sixty-eight patients (29 men, 39 women, 70.0 +/- 11.2 years) were studied. Detrusor overactivity was urodynamically defined as involuntary detrusor contractions of more than 15 cm H(2)O during the filling phase. Ten-hertz square waves of 1-ms pulse duration were used. A vaginal electrode was used in the women and an anal or surface electrode in the men. The stimulation was given for 15 minutes twice daily for 4 weeks. The efficacy was evaluated on the basis of a frequency/volume chart and urodynamic study before and after treatment. RESULTS Thirty-two patients in the active group and 28 in the sham group completed the study. The patient impressions were very good or good in 59% and 39% of the active and the sham group, respectively (P = 0.0354). On the cystometrogram, the bladder capacity at the first desire to void and the maximum desire to void increased significantly (P = 0.0104 and P = 0.0046, respectively) in the active group, but not in the sham group. Seven patients in the active group and 1 patient in the sham group were cured (P = 0.0324); 26 patients (81.3%) in the active group and 9 (32.1%) in the sham group improved (P = 0.0001). Of 17 patients in the active group, 13 remained cured or improved for an average of 8.4 months after completion of the 4-week treatment; in the sham group, 3 of 6 patients were cured or improved for an average of 4.7 months after completion of the 4-week treatment. CONCLUSIONS Electrical stimulation was useful in treating urinary incontinence due to detrusor overactivity.

Positron emission tomographic measurement of acetylcholinesterase activity reveals differential loss of ascending cholinergic systems in Parkinson's disease and progressive supranuclear palsy.

We measured brain acetylcholinesterase activity in 16 patients with Parkinsons disease (PD), 12 patients with progressive supranuclear palsy (PSP), and 13 age‐matched controls, using N‐methyl‐4‐[11C]piperidyl acetate and positron emission tomography. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. In PD patients, there was a significant reduction (−17%) of cerebral cortical k3 compared with normal controls, whereas there was only a nonsignificant reduction (−10%) of cortical k3 in PSP patients. However, there was a prominent reduction (−38%) of thalamic k3 in PSP patients compared with normal controls, whereas there was only a nonsignificant reduction (−13%) of thalamic k3 in PD patients. The results suggest that there is a loss of cholinergic innervation to the cerebral cortex in association with cholinergic innervation to the thalamus in PD, whereas there is a preferential loss of cholinergic innervation to the thalamus in PSP. When the thalamic to cerebral cortical k3 ratio was taken for each subject, PD and PSP were separated, suggesting that positron emission tomography measurement of acetylcholinesterase activity may be useful for differentiating the two similar disorders. Ann Neurol 1999;46:62–69