Long-Term Selegiline Monotherapy for the Treatment of Early Parkinson Disease.

OBJECTIVES: The aim of this open-label study was to investigate the long-term safety and efficacy of selegiline as monotherapy in Japanese patients with early Parkinson disease (PD). METHODS: We conducted a 56-week prospective study in patients with early PD (N = 134) who had previously completed the randomized, double-blind, placebo-controlled phase III trial of selegiline monotherapy for 12 weeks. In the present study, dosing was titrated from 2.5 to 10 mg/d in increments of 2.5 mg/d for 2 weeks. From the seventh week, the dosage was maintained at 10 mg/d until week 56. The primary outcome was any change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score (part I + II + III) from baseline. Secondary outcomes, including changes in the UPDRS subscores and safety profile, were also evaluated. RESULTS: Ninety-one (67.9%) patients completed the 56-week study. Treatment with selegiline significantly reduced total UPDRS score from week 4 (mean ± SD, -2.62 ± 3.83; P < 0.0001) to week 56 (-3.39 ± 9.27; P < 0.01). The peak effect was seen at week 20 (-5.79 ± 5.57; P < 0.0001). In addition, we found similar improvements in the UPDRS parts II and III scores. The incidence rate of adverse drug reactions was 44.3% (58 patients) and did not increase during the period of 10 mg selegiline administration. CONCLUSIONS: Long-term monotherapy with selegiline (10 mg/d) was effective and well tolerated in patients with early PD in this 56-week study.

Functions and dysfunctions of the basal ganglia in humans.

Involuntary movements and parkinsonism have been interesting and important topics in neurology since the last century. The development of anatomical and physiological studies of the neural circuitry of motor systems has encouraged the study of movement disorders by means of pathophysiology and brain imaging.Multichannel electromyography from affected muscles has generated objective and analytical data on chorea, ballism, athetosis, and dystonia. Studies using floor reaction forces revealed the pathophysiology of freezing of gait in parkinsonism. Akinesia and bradykinesia are attributable to dysfunctions in the basal ganglia, frontal lobe, and parieto-occipital visual association cortex.Reciprocal innervation is an essential mechanism of smooth voluntary movement. Spinal reflexes on reciprocal innervation has been investigated in awake humans, and the pathophysiology of spasticity and Parkinson's disease were revealed as a result. Clinical applications for the treatment and evaluation of status have been developed.For future studies, detailed neural mechanisms underlying the development of motor disorders in basal ganglia diseases and recovery by interventions including surgery and neurorehabilitation are important.

[Gastric myxoid epithelioid gastrointestinal stromal tumor harboring PDGFRA gene mutation:a case report].

A 67-year-old man visited our hospital with an enlarging abdominal mass several months after he had first noticed his symptoms. An elastic firm tumor was palpated on the left side of the abdomen upon physical examination. The blood test results were normal. Contrast-enhanced computed tomography of the abdomen revealed a 10-cm-diameter homogeneous low-density cystic tumor located at the dorsal portion of the gastric corpus. Enhancement of a few net-like structures was noted, but most of the lesion was not enhanced. Gastroendoscopy revealed the lesion to be a submucosal tumor with a smooth mucosal surface and no ulceration. Endoscopic ultrasonography showed the tumor arising from the fourth layer of the gastric wall. The tumor was completely resected by laparotomy and partial gastrectomy. It was capsulated and contained serous fluid with little solid tissue. Histologically, there were sparse tumor cells within the myxoid interstitium. Immunostaining results were weakly positive for KIT and CD34-positive accompanied by mast cell infiltration. A platelet-derived growth factor receptor alpha (PDGFRA) exon 18 (D842V) mutation was identified, and the lesion was ultimately diagnosed as myxoid epithelioid gastrointestinal stromal tumor (GIST) of intermediate- and low-risk according to Fletcher's classification and Miettinen's classifications, respectively. GISTs with PDGFRA D842V mutations are reportedly resistant to imatinib, and GISTs originating from the stomach are reportedly less malignant than others. The patient was observed without adjuvant therapy after surgery because of the relatively low risk of metastasis or recurrence and the potential risk of imatinib resistance. No recurrence was observed for ≥5 years after the surgery. We herein report this rare case and describe its clinical characteristics.

Gait bradykinesia in Parkinson's disease: a change in the motor program which controls the synergy of gait.

This study examined how gait bradykinesia is changed by the motor programming in Parkinson's disease. Thirty-five idiopathic Parkinson's disease patients and nine age-matched healthy subjects participated in this study. After the patients fixated on a visual-fixation target (conditioning-stimulus), the voluntary-gait was triggered by a visual on-stimulus. While the subject walked on a level floor, soleus, tibialis anterior EMG latencies, and the y-axis-vector of the sole-floor reaction force were examined. Three paradigms were used to distinguish between the off-/on-latencies. The gap-task: the visual-fixation target was turned off; 200 ms before the on-stimulus was engaged (resulting in a 200 ms-gap). EMG latency was not influenced by the visual-fixation target. The overlap-task: the on-stimulus was turned on during the visual-fixation target presentation (200 ms-overlap). The no-gap-task: the fixation target was turned off and the on-stimulus was turned on simultaneously. The onset of EMG pause following the tonic soleus EMG was defined as the off-latency of posture (termination). The onset of the tibialis anterior EMG burst was defined as the on-latency of gait (initiation). In the gap-task, the on-latency was unchanged in all of the subjects. In Parkinson's disease, the visual-fixation target prolonged both the off-/on-latencies in the overlap-task. In all tasks, the off-latency was prolonged and the off-/on-latencies were unsynchronized, which changed the synergic movement to a slow, short-step-gait. The synergy of gait was regulated by two independent sensory-motor programs of the off- and on-latency levels. In Parkinson's disease, the delayed gait initiation was due to the difficulty in terminating the sensory-motor program which controls the subject's fixation. The dynamic gait bradykinesia was involved in the difficulty (long off-latency) in terminating the motor program of the prior posture/movement.

A Randomized Double-Blind Placebo-Controlled Phase III Trial of Selegiline Monotherapy for Early Parkinson Disease.

BACKGROUND: In Japan, selegiline has been approved for combination therapy with levodopa for Parkinson disease (PD). We conducted a trial of selegiline monotherapy for early PD. METHODS: In this 12-week controlled phase III trial, a total of 292 subjects were randomized to receive placebo (n = 146) (full analysis set 140) or selegiline (n = 146) (full analysis set 139). The primary outcome measure was the change in the Unified Parkinson Disease Rating Scale part I + II + III total score from baseline to the final visit. Other secondary measures and a safety profile were evaluated. RESULTS: Selegiline monotherapy reduced the primary outcome measure by -6.26 ± 7.86 compared with the placebo -3.14 ± 6.98 (mean ± SD, P = 0.0005 by analysis of covariance). There was no significant difference in the number of adverse events between the 2 groups (P > 0.05). CONCLUSIONS: Selegiline monotherapy reduced the total Unified Parkinson Disease Rating Scale part I + II + III score and was well tolerated in Japanese patients with early PD.

[The nerve agent sarin: history, clinical manifestations, and treatment].

Organic phosphate pesticides were used worldwide after World War II and experiences on poisoning and treatment have been accumulated. An organic phosphate "nerve agent" Sarin was used in two terrorist attacks in Japan in the 1990s. Sarin effects on humans were well documented in these two incidents. Sarin gas inhalation caused instantaneous death by respiratory arrest in several victims in Matsumoto. Severely injured victims presenting with coma and generalized convulsion were resuscitated and recovered rapidly without sequelae. Miosis and blurred-dark vision, ocular pain, copious secretions from respiratory and gastrointestinal tract (muscarinic effects), and headache were common in severely to slightly affected victims. Plasma cholinesterase (ChE) activity decreased in parallel with the severity of signs and symptoms in victims. Oximes, atropine sulphate, diazepam, and ample intravenous infusion were effective treatments. Follow-up examinations on victims were conducted up to 10 years in Matsumoto, and 5 years in Tokyo. No neurological sequelae or abnormalities were observed after 1 year, except for a few EEG abnormalities or delay in sensory nerve conduction velocity. Posttraumatic stress disorder (PTSD) was observed in several of the victims in the 5-year follow up, irrespective of the severity of poisoning at Matsumoto. Psychological symptoms continue in victims of both incidents.

[A double-blind comparative study to evaluate the efficacy and safety of NerBloc® (rimabotulinumtoxinB) administered in a single dose to patients with cervical dystonia].

We conducted a single-dose, placebo-controlled, double-blind, dose-response study of NerBloc®(rimabotulinumtoxinB) in patients with cervical dystonia (placebo, 2,500 U, 5,000 U, 10,000 U). The primary endpoint, the change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-total score at 4 weeks post dose from baseline, showed a significant improvement in all treatment groups (2,500 U, 5,000 U, 10,000 U) compared with the placebo group. As for the secondary endpoints, the change of TWSTRS subscales, severity, disability and pain scores, at 4 weeks post dose in 10,000 U group, showed a significant improvement compared with the placebo group, however, no significant differences were observed between 2,500 U or 5,000 U and placebo group. The subject's and physician's global assessments (visual analog scale; VAS) at 4 weeks post dose also showed significant improvement in all treatment groups relative to the placebo group, whereas subject's pain assessment (VAS) at 4 weeks post dose did not show significant improvement in any of treatment groups. The incidence rate of adverse events was not substantially different between the placebo group and 2,500 or 5,000 U group, but significantly higher in 10,000 U group than in the placebo group. Adverse events frequently observed in active drug groups included dry mouth/thirst and dysphagia, all of which were mild in severity. There were no adverse events that led to death, serious disorders or study discontinuations. The incidence rate of abnormal laboratory values did not show significant difference in any of parameters between the placebo group and any of treatment groups. NerBloc® possessing muscle relaxing effect is expected to be a potential treatment to improve symptoms of cervical dystonia. Clinically recommended dose will range from 2,500 U to 10,000 U. In this study, 10,000 U group was the most effective and the effect lasted the longest. The efficacy and safety profile of NerBloc ® in this study was similar to that in AN072-009 study conducted in the US.

Difficulty in terminating the preceding movement/posture explains the impaired initiation of new movements in Parkinson's disease.

To determine whether the difficulty of initiating volitional movements in Parkinson's disease is primarily due to impaired termination of preceding movement/posture or to impaired initiation of new movement, patients with Parkinson's disease and age-matched controls were first asked to visually fixate a stationary spot and simultaneously align wrist position accurately with it. They were then requested to make rapid movements of eyes and wrist to a test stimulus presented in the peripheral visual field. We analyzed latencies of ocular and manual movements to the test stimulus in two conditions; in the overlap task the stationary spot remained on during illumination of the test stimulus requiring subjects to terminate fixation and wrist positioning themselves to initiate new movements. In the gap task, the stationary spot was turned off 200 ms before illuminating the test stimulus. Latencies of ocular and manual movements were prolonged in the overlap task than those in the gap task. Effects of fixation/wrist positioning on the latency of new movement were evaluated by the difference in latencies between the overlap and gap tasks normalized by the latency difference of the controls. These ratios increased exponentially as Parkinson's stage increased, suggesting the latency prolongation in patients with stage III and IV Parkinson's disease under the overlap condition primarily reflected the contribution of difficulty to terminate existing fixation/wrist positioning.

[Education and training in neurology: update].

Progress in basic neurosciences and advances in technology in the last decades have contributed to clarification of neural mechanisms in behavior or cognition in health and disease. They have elaborated diagnosis and treatment of nervous diseases remarkably. Needs in neurologists in both primary and specific medical services are rapidly increasing, with aging society and progresses in medical care in Japan. Attraction of neurology for students and junior residents is a great concern of Japanese Society of Neurology. In the undergraduate education, recent achievement in basic neurosciences including neurogenetics, molecular cytology, physio-pathology and imaging technique should be taught comprehensively. In the early postgraduate course for two years, neurology is either elective or obligatory depending on the curriculum of training institutions. Work at the stroke care unit is strongly recommended in the course of emergency service, which is mandatory. Experiences in acute infectious diseases, in various stages of neurodegenerative diseases, in collaboration with other specialist doctors for systemic diseases including metabolic or collagen diseases, in collaboration with other medical personnel in care of dementia are all included in advanced stages of postgraduate education before board examination. In summary, studies for practical services as well as clinical researches, teaching of symptoms and signs based on neural functions, and socio-economical issues for chronic nervous diseases in aged society are important in the education in neurology.

Early addition of selegiline to L-Dopa treatment is beneficial for patients with Parkinson disease.

OBJECTIVES: To evaluate the clinical outcome of Parkinson disease (PD) patients treated with selegiline (with L-Dopa/decarboxylase inhibitor) in the early stage of the disease in comparison with that of late-stage use of selegiline. METHODS: The study and the reference groups were extracted from a large database of the registry of all selegiline users (4692) between year 1998 and 2003 according to the defined criteria. The study group consisted of 106 PD patients who received selegiline within 5 years from the onset of the disease and were followed up for 7 years in average. The reference group consisted of 585 PD patients with comparable disease duration who received selegiline for 16 weeks from 9 to 11 years (mean [SD], 9.9 [0.7]) after the onset of the disease, and the evaluation was made before and after the treatment with selegiline. RESULTS: The sum of the Unified Parkinson's Disease Rating Scale (UPDRS) scores of 6 major motor symptoms of the study group was significantly lower than that of the reference group (mean [SD], 7.78 [4.30] vs 11.41 [3.88]; P < 0.0001) when compared at a point with the same disease duration (9.8 [1.7] vs 9.9 [0.7] years). The mean UPDRS score of the reference group after 4 months' treatment with selegiline did not reach that of the study group (mean [SD], 9.40 [3.76] vs 7.78 [4.30]; P = 0.0002). CONCLUSIONS: The clinical outcome as evaluated by the selected UPDRS motor scores was better for L-Dopa-treated patients who received selegiline within 5 years from the onset compared with those who received selegiline approximately 10 years from the onset.

[Inter-rater reliability while using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) in patients with cervical dystonia].

We examined the inter-rater reliability for the evaluation of patients with cervical dystonia by using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) (translated into Japanese). The TWSTRS is a rating scale that assesses patients with cervical dystonia by grading their symptoms on a subscale of severity, disability, and pain. This study used to TWSTRS-severity scores to examine the inter-rater reliability among 27 evaluators (neurologists) by using videotaped images of 2 patients. Along with the total-severity score on the TWSTRS, the intra-class correlation (ICC) and the lower limit of the 95% confidence interval were calculated as indices of inter-rater reliability. A high ICC of 0.745 was obtained. The ICC obtained from another study conducted outside Japan was 0.763, which is almost equivalent to the result of our study. Thus, the TWSTRS has a favorable inter-rater reliability which suggests that this scale was sufficiently reliable to be used as an accurate and easily available rating tool during the treatment of cervical dystonia.

The clinical spectrum of freezing of gait in Parkinson's disease.

Freezing of gait (FOG) is a common and very disabling symptom in Parkinson's disease (PD). It is usually observed in the advanced stage of the disease, although a mild form can be seen in the early stage. Although some studies have suggested that longer duration of dopaminergic treatment is associated with FOG, the disease progression alone may be responsible for the development of FOG. FOG can be experienced on turning, in narrow spaces, while reaching a destination, and in stressful situations. In PD, FOG is strongly associated with motor fluctuation. FOG is commonly observed in the "off" state and is observed less frequently in the "on" state. Dual tasking (cognitive load) aggravates FOG. Visual or auditory cues often resolve FOG. Analysis of gait revealed that the stepping rhythm suddenly jumps into high frequency (4-5 Hz) in FOG (hastening), and that floor reaction forces are disregulated. Since the hastening phenomenon was also reported in patients with lesions in the striatum and/or the frontal lobe, fronto-basal ganglia projections are considered essential for FOG. Careful observation and gait pattern analysis may lead to a successful management of individual PD patients with FOG.

Placebo-controlled, double-blind dose-finding study of entacapone in fluctuating parkinsonian patients.

We conducted a multicenter randomized, placebo-controlled double-blind parallel-group study in Japanese Parkinson's disease (PD) patients with wearing-off motor fluctuations to determine the clinical efficacy and safety of entacapone as an adjunct to concomitant treatment with levodopa and a dopa decarboxylase inhibitor (DCI). We randomized 341 patients to receive entacapone 100 or 200 mg or placebo per dose of levodopa/DCI for 8 weeks. The primary efficacy variable was on time change while awake, determined by patients' diaries. Mean baseline on time in each group was approximately 8 hours. Mean on time change at final assessment was 1.4 hours each for entacapone 100-mg and 200-mg groups and by 0.5 hours for the placebo group (P < 0.05). The two entacapone doses were equally efficacious. Adverse events occurred in 79 patients (69.9%) in placebo, 82 (72.6%) in 100 mg, and 98 (86.0%) in 200 mg. The most common adverse event with entacapone was an increase in dyskinesias. The overall safety profile was satisfactory in both entacapone groups. In conclusion, both entacapone 100 and 200 mg were equally effective in increasing on time of PD patients with wearing-off fluctuations, although the safety and tolerability profile appeared more favorable for the 100-mg dose.

On the errors in assessment of severity of involuntary movements using surface EMG.

Surface electromyogram (SEMG) is a useful tool to depict involuntary movements, but evaluation of the intensity of such movements with SEMG over multiple recording instances requires awareness of factors influencing quantified SEMG signals. We investigated the differences in the amplitude of SEMGs due to electrode displacement in isometric voluntary contraction in the upper arm, forearm and lower leg in 8 healthy men. The SEMGs of gross muscle activity simultaneously recorded with 4 electrode pairs from the agonist and antagonist sides in 3 displacement conditions with respect to parallel position, interelectrode distance, and rotation were compared. The amount of EMG integration (equivalent to the average SEMG amplitude) of each electrode pair was compared to the reference electrode pair with interelectrode distance of 40 mm placed on the center of the tested muscles. The average EMG difference ratios ranged 1.1-2.2%/mm in parallel shift, 1.0-1.9%/mm in distance shift, and 0.3-0.6%/degree in rotation shift. Displacement error of electrodes in separate recording instances should be reduced using anatomical landmarks, when SEMG is applied as a quantitative method to evaluate change in the states of involuntary movements.

Visuomotor dependency on an initial fixation target involved in the disorder of visually-guided manual movement in Parkinson's disease.

Role of a central fixation target on the latencies of visually guided manual movement was analyzed on young healthy subjects, age-matched control subjects and patients with Parkinson's disease (Hoehn and Yahr stages II, III, and IV). Two paradigms were used: overlap paradigm where a central fixation target was lighted throughout the test, and gap paradigm where a central fixation target was turned off 200 ms before a peripheral target was lighted. The subject was first asked to fixate the central target then instructed to locate a peripheral target with a laser beam spot, operated with wrist flexion or extension as quickly as possible. Latencies of gap paradigm are always shorter than those of overlap task in all the groups. Latencies of both overlap and gap tasks prolonged from young to elder, from elder to PD II, from PD II to PD III and from PD III to PD IV. Also latencies were extremely prolonged in the overlap tasks and correlated with disease severity. Latencies in the gap tasks were less prolonged as compared with those in the overlap tasks. The visual fixation target prolonged the visuo-motor latency in association with severity of Parkinson's disease.

Randomized, double-blind study of pramipexole with placebo and bromocriptine in advanced Parkinson's disease.

We compared the efficacy and safety of pramipexole (PPX) with placebo in the treatment of advanced Parkinson's disease (PD) as an adjunct to levodopa. A bromocriptine (BR) group was included to enable determination of the noninferiority of PPX relative to BR as the standard treatment.