Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study.

OBJECTIVE: To evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS). METHODS: 373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration ≤36 months) were randomly assigned to placebo, 25 mg or 50 mg of methylcobalamin groups. The primary endpoints were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182. Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered ≤12 months after symptom onset). RESULTS: No significant differences were detected in either primary endpoint (minimal p value=0.087). However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (≤12 months' duration) showed longer time intervals to the primary event (p<0.025) and less decreases in the ALSFRS-R score (p<0.025) than the placebo group. The incidence of treatment-related adverse events was similar and low in all groups. CONCLUSION: Although ultra-high-dose methylcobalamin did not show significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early. TRIAL REGISTRATION NUMBER: NCT00444613.

A case of pure autotopagnosia following Creutzfeldt-Jakob disease.

A 69-year-old male (N.A.) with Creutzfeldt-Jakob disease showed pure autotopagnosia. We administered tests evaluating his ability to name his own body parts, to point to body parts (his own and examiner's), and to recognize positional relationships between his body parts by verbal questions and responses. We found impaired localization of the patient's own body parts by pointing and impaired recognition of positional relationships between his body parts. However, there was no impairment in naming his own body parts or in localizing the examiner's body parts. The results suggest a pure autotopagnosia in N.A. leading to an impairment of recognition of the spatial position of his body parts in a three-dimensional body representation within the egocentric reference frame. We were able to rule out the possibility that his pattern of performance could have been due to a disability in programming reaching movements of the arm.

Prevalence of human T-lymphotropic virus type 1 carriers among pregnant women in Hokkaido, Japan.

As there is a risk of MTCT of HTLV-1, the HSGP HTLV-1 MTCT was organized in 2011. To determine how many pregnant women are infected with HTLV-1 in Hokkaido, which is the northernmost and the second largest island in Japan with a population of 5,467,000 and 39,392 newborns in 2011, the HSGP HTLV-1 MTCT asked all facilities that may care for pregnant women in Hokkaido in July 2013 to provide information on the number of pregnant women who underwent screening for anti-HTLV-1 antibody using particle agglutination or chemiluminescent enzyme immunoassay, and the numbers of those with positive, equivocal, and negative test results in the screening and confirmation tests using western blotting or PCR methods in 2012, respectively. A total of 111 facilities participated in this study and provided information on 33,617 pregnant women who underwent screening in 2012, corresponding to approximately 85% of all pregnant women who gave birth in Hokkaido in 2012. Of 81 candidates for a confirmation test because of positive (n = 77) or equivocal (n = 4) results on screening, 63 (78%) underwent the confirmation test and, finally, 34 (0.1%) and 33,563 (99.8%) women were judged to be HTLV-1 carriers and non-carriers, respectively. It was concluded that the prevalence rate of HTLV-1 carriers was low, one per 1000 pregnant women in Hokkaido. Approximately 40 infants are born yearly to mothers infected with HTLV-1 in Hokkaido.

Intramuscular interferon beta-1a is effective in Japanese patients with relapsing-remitting multiple sclerosis: a pre-treatment versus treatment comparison study of gadolinium-enhanced MRI brain lesions.

BACKGROUND AND OBJECTIVE: Interferon beta (IFNß) is standard therapy for multiple sclerosis (MS). The efficacy of intramuscular (IM) IFNß-1a (AVONEX(®)) was assessed in 25 Japanese patients with relapsing-remitting MS (RRMS). METHODS: Patients with RRMS not previously treated with IFNß or other disease-modifying therapies were included in this 36-week study. The primary outcome was the average total number of gadolinium-enhanced lesions detected on four brain MRI scans during the last 12 weeks of 24 weeks' treatment with IM IFNß-1a 30 µg once weekly compared with the number during the 12-week pre-treatment period. Lesions were counted by blinded investigators. RESULTS: IM IFNß-1a significantly decreased the median number of gadolinium-enhanced lesions from 2.5 to 0.3 (p < 0.0001) compared with pre-treatment values. The median number of new gadolinium-enhanced lesions also decreased significantly from 2.0 to 0.3 (p = 0.0002). Serum neopterin was induced in a manner similar to that observed previously in a Caucasian RRMS population. No new adverse events occurred during the study. CONCLUSION: This first study of IM IFNß-1a in Japanese patients with RRMS demonstrated a level of efficacy similar to that reported in Caucasian patients based on an assessment of pre-treatment and post-treatment gadolinium-enhanced lesions.

[Reverse Chaddock sign].

It is widely accepted that the Babinski reflex is the most well-known and important pathological reflex in clinical neurology. Among many other pathological reflexes that elicit an upgoing great toe, such as Chaddock, Oppenheim, Gordon, Schaefer, and Stransky, only the Chaddock reflex is said to be as sensitive as the Babinski reflex. The optimal receptive fields of the Babinski and Chaddock reflexes are the lateral plantar surface and the external inframalleolar area of the dorsum, respectively. It has been said that the Babinski reflex, obtained by stroking the sole, is by far the best and most reliable method of eliciting an upgoing great toe. However, the Chaddock reflex, the external malleolar sign, is also considered sensitive and reliable according to the literature and everyday neurological practice. The major problems in eliciting the Babinski reflex by stroking the lateral part of the sole are false positive or negative responses due to foot withdrawal, tonic foot response, or some equivocal movements. On the other hand, according to my clinical experience, the external inframalleolar area, which is the receptive field of the Chaddock reflex, is definitely suitable for eliciting the upgoing great toe. In fact, the newly proposed method to stimulate the dorsum of the foot from the medial to the lateral side, which I term the "reversed Chaddock method," is equally sensitive to demonstrate pyramidal tract involvement. With the "reversed Chaddock method", the receptive field of the Chaddock reflex may be postulated to be in the territory of the sural nerve, which could be supported by the better response obtained on stimulation of the postero-lateral calf than the anterior shin. With regard to the receptive fields of the Babinski and Chaddock reflexes, the first sacral dermatome (S1) is also considered a reflexogenous zone, but since the dermatome shows marked overlapping, the zones vary among individuals. As upgoing toe responses are consistently observed in the case of pyramidal tract dysfunction by both the Chaddock reflex and the reversed Chaddock method, the external inframalleolar area of the dorsum as a reflexogenous zone is considered very important. In conclusion, this method, termed the "reversed Chaddock method," is not only effective but can also help avoid false positive results due to foot withdrawal or tonic foot responses elicited on stroking the sole. I would like to propose the "reverse Chaddock sign (Tashiro sign)" as one of the 15 pathological reflexes involving the foot.

Neck rigidity as a physical manifestation of higher brain hypo-function/dysfunction.

A total of 308 patients, who received inpatient rehabilitation in department of Neurology in Sapporo City General Hospital, were studied. The patients were divided into four subgroups according to the presence or absence of Parkinsonism and the location of organic neurological lesions: group A consisted of 47 patients with brain lesions who presented with Parkinsonism; group B consisted of 135 patients with manifestations deriving from brain disorders other than Parkinsonism; group C consisted of 68 patients with manifestations deriving from spinal cord, peripheral nerve, and muscle disorders; and group D consisted of 58 patients with non-organic functional disorders and patients with organic lesions not responsible for clinical manifestations. The patients were administered a battery of 5 tests for evaluating frontal lobe and/or higher brain function. In result, our study confirmed higher brain/frontal lobe dysfunction to affect the grade of neck rigidity unless there is an interruption, in the control of peripheral organs, by the brain. Consequently the association between higher brain/frontal lobe dysfunction and the grade of neck rigidity were confirmed. Although neck rigidity may be a minor clinical manifestation, it can provide important clues to brain function.

Smooth-pursuit eye movement--a convenient bedside indicator for evaluating frontal lobe and intellectual function.

We hypothesized that smooth-pursuit eye movement is related to higher brain functions and that its impairment (iSPEM) could be useful in diagnosing neurological dysfunctions. We prospectively examined 305 patients and studied the relations between iSPEM and five items that reflect intellectual and/or frontal lobe function (dementia, sucking, snouting, hand grasping, elbow flexion response). We divided these patients into four subgroups: group A, patients with cerebellar ataxia as the presenting manifestation and with main lesions in the cerebellum; group B, patients with main lesions in brain regions other than the cerebellum; group C, patients with main lesions in the spinal cord, peripheral nerves, and muscles; and group D, patients with non-organic functional disorders, such as paroxysmal attacks and physical pain. Consequently, iSPEM was significantly (p<0.01) related to impairment in intellectual and frontal lobe functions in patients with cerebral lesions, and it also can be regarded as being equivalent to primitive reflexes.

Difference in the effects of tandospirone on ataxia in various types of spinocerebellar degeneration: an open-label study.

The aim of this study was to investigate the effects of tandospirone on ataxia in various types of spinocerebellar degeneration (SCD). Fifteen milligram per day of tandospirone was administered to 39 patients with SCD (spinocerebellar atrophy (SCA) 1, five patients; SCA2, six patients; Machado-Joseph disease (MJD), 14 patient; SCA6, five patients; multiple system atrophy-cerebellar type (MSA-C), seven patients; and multiple system atrophy-Parkinson type (MSA-P), two patients). All patients were assessed before and 4 weeks after administration of the drug using the international cooperative ataxia rating scale total score (ARS), total length traveled (TLT) of body stabilometry, and a self-rating depression scale. Statistically, ARS showed a significant difference in MJD (p = 0.005) and SCA6 (p = 0.043). TLT also showed a significant difference in MJD (p = 0.002) and SCA6 (p = 0.043). Eight of 39 patients (SCA1, 1/5; SCA2, 0/6; MJD, 4/14; SCA6, 3/5; MSA-C, 0/7; and MSA-P, 0/2) showed more than a five point reduction in ARS, and 13 of 39 patients (SCA1, 0/5; SCA2, 1/6; MJD, 8/14; SCA6, 4/5; MSA-C, 0/7; and MSA-P, 0/2) showed a reduction of TLT. Our data indicate that the effects of tandospirone on ataxia are different between types of SCD. Therefore, tandospirone is useful for cerebellar ataxia in patients with MJD and SCA6.

Absence seizures with myoclonic seizures as an early manifestation of dentato-rubro-pallido-luysian atrophy (DRPLA): a follow-up clinical course of twelve years.

Typical absence seizures and isolated myoclonic seizures are both classified as age-related generalized seizures and are considered to be benign neurological manifestations. Concomitance of the two types of seizure is considered benign if it does not accompany other types of seizures or other neurological problems. We followed up a ten-year-old girl with isolated absence and myoclonic seizures whose family history of mental and neurological signs was initially not disclosed. After several years, the family history of neurological and mental problems was finally disclosed, and the diagnosis of dentato-rubro-pallido-luysian atrophy (DRPLA) was confirmed. The patient's clinical course was slowly progressive, and by age 21 she was in a nearly vegetative state. We would like to alert clinicians to consider DRPLA when diagnosing patients with absence and/or myoclonic seizures, even when they present the clinical features of benign epilepsies in the early stage.

Pure topographical disorientation following a right forceps major of the splenium lesion: a case study.

A 72-year-old man with pure topographical disorientation following a focal hemorrhage in the right forceps major of splenium was assessed at 2 weeks and 3 months after the onset. Initially, he could identify familiar buildings and landmarks, but noted topographical disorientation, dysfunction in sense of quarters, and in visuo-spatial function. The improvement of topographical disorientation was attained in 3 months, while the inability of the sense of quarters and manipulating visuo-spatial information remained unchanged. These results suggested the heading disorientation was accompanied with impaired sense of quarters, although disabled sense of quarters continued beyond the recovery of heading disorientation.

Effects of caffeine on the freezing of gait in Parkinson's disease.

Caffeine is a nonselective competitive blockade of adenosine A1 and A2A receptors. In this report, we studied the efficacy of 100 mg of caffeine per day on the freezing of gait (FOG) for patients with Parkinson's disease. Different subtypes of FOG showed different therapeutic responses to caffeine. Caffeine improved "total akinesia" type of FOG, but had no effect on "trembling in place." Tolerance developed to the beneficial effect of caffeine on FOG within a few months, but a 2-week caffeine withdrawal period could restore the effect of caffeine.

Nationwide survey of juvenile muscular atrophy of distal upper extremity (Hirayama disease) in Japan.

Juvenile muscular atrophy of the distal upper extremity (JMADUE, Hirayama disease) was first reported in 1959 as 'juvenile muscular atrophy of unilateral upper extremity'. Since then, similar patients in their teens or 20s have been described, under a variety of names, not only in Japan, but also in other Asian countries, as well as Europe and North America. Biomechanical abnormalities associated with JMADUE have recently been reported through various imaging examinations, proposing its disease mechanism. Since JMADUE differs from motor neuron disease, or spinal muscular atrophy, this disease entity should be more widely recognized, and early detection and effective treatments should be considered. We report an epidemiological study in Japan. Two nationwide questionnaire-based surveys, conducted in Japan from 1996 to 1998, identified 333 cases. The numbers of patients per year, distribution of ages at onset, mode of onset, time lapse between onset and quiescence, neurological signs and symptoms, imaging findings, and the effects of conservative treatments were analyzed. The peak age was 15 to 17 years, with a marked male preponderance, usually a slow onset and progression, and quiescence six or fewer years after onset. There was a predominantly unilateral hand and forearm involvement with 'cold paresis'. The imaging findings are described.

Brain SPECT analysis by 3D-SSP and clinical features of Parkinson's disease.

OBJECTIVE: The aim of the present study is to investigate the association of symptoms in Parkinson's disease (PD) with cerebral perfusion on single photon emission computed tomography (SPECT). The clinical features of PD were compared with SPECT images of the brain obtained by three-dimensional stereotactic surface projection (3D-SSP) analysis. PATIENTS AND METHODS: Thirty-eight patients who had PD without dementia (17 men and 21 women with a mean age of 68.6 +/- 4.7 years) were enrolled in this study. Their symptoms were rated using the unified Parkinson's disease rating scale (UPDRS). Within a week, all patients were examined by SPECT with 1-123, and reconstructed images were analyzed with 3D-SSP using an image-analysis software, iSSP ver. 3.5. Data on brain surface perfusion extracted by 3D-SSP analysis were compared between the PD patients and the normal control group. The same comparisons were made for subgroups of PD patients with severe symptoms, such as tremor, gait disturbance, bradykinesia, and the UPDRS motor score. RESULTS: Cerebral perfusion was decreased at the anterior cingulate cortex and occipital lobe of the PD patients compared with the normal controls. In the subgroups with severe gait disturbance and severe bradykinesia, additional hypoperfusion was seen at the lateral frontal association and lateral temporal association and the medial frontal gyrus, and by the pixel-by-pixel comparison, perfusion was significantly decreased (p < 0.05) at the medial frontal gyrus and anterior cingulate cortex compared with the normal control group. CONCLUSION: In PD patients, severe gait disturbance and bradykinesia may be correlated with hypoperfusion of the medial aspect of the frontal lobe. This suggests that functional disturbance of the supplementary motor area and other parts of the frontal lobe are involved in the development of gait disturbance and bradykinesia in PD.

Brain SPECT analysis by 3D-SSP and phenotype of Parkinson's disease.

OBJECTIVES: We hypothesize that the regional pattern of blood flow reduction in the brain is different between tremor-dominant Parkinson's disease (PD) and postural instability gait difficulty (PIGD)-dominant PD. We therefore investigated the association of phenotypes in untreated PD with brain perfusion on SPECT using three-dimensional stereotactic surface projection (3D-SSP) technique. PATIENTS AND METHODS: Thirty-three patients who had PD without dementia (12 men and 21 women with a mean age of 67.1+/-6.4 years) were included in this study. Their symptoms were rated using the Unified Parkinson's Disease Rating Scale (UPDRS). Patients were grouped in two phenotypes: tremor and PIGD-dominant groups based on UPDRS components. Around the same time, all patients were examined by N-isopropyl-p[123I] iodoamphetamine single photon emission computed tomography (123I-IMP SPECT), and obtained images were analyzed with 3D-SSP using an image-analysis software, NEUROSTAT. Data on brain surface perfusion extracted by 3D-SSP analysis were compared between the PD patients and the normal control group. The same comparisons were made for subgroups of PD patients. RESULTS: Cerebral perfusion was decreased at the anterior cingulate cortex and primary visual cortex of the PD patients, and especially by the pixel-by-pixel comparison, perfusion was significantly decreased at the right anterior cingulate cortex compared with the normal controls. In the PIGD-dominant group, more severe hypoperfusion was seen at the same regions. In the tremor-dominant group, significant hypoperfusion was not seen compared with the normal controls. CONCLUSIONS: The regional pattern of blood flow reduction in the brain was found to be different between tremor-dominant PD and PIGD-dominant PD. These regional differences were considered to suggest different and disease-specific combinations of underlying pathophysiological and neurochemical processes.

Low-dose levodopa therapy in Japanese patients with Parkinson's disease: a retrospective study.

OBJECTIVE: To investigate the efficacy and the rate of adverse events of chronic low-dose levodopa-carbidopa therapy in Japanese patients with Parkinson's disease (PD). PATIENTS AND METHODS: A total of 92 Japanese PD patients treated with low doses of levodopa from the outset were studied. Both disease-specific motor disabilities and quality of life (QOL) in the patients were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) and the Parkinson's Disease 39 Quality of Life Questionnaire (PDQ39), respectively. RESULTS: In the overall patient group, the mean duration of treatment, the mean daily dose of levodopa, the disability scores and the motor scores of UPDRS were 6.2 years, 186.4 mg, 8.0 and 19.2, respectively. The rates of motor fluctuations, dyskinesias and hallucinations were 8.7%, 6.5% and 14.1%, respectively. The mean summary index of PDQ39 scores was 23.1. Patients with motor fluctuations showed a significantly earlier disease onset. Dose of levodopa, age at onset, and treatment duration were not associated with the occurrence of dyskinesias. Patients with hallucination had higher doses of levodopa and dopamine agonist. CONCLUSIONS: Our results demonstrate that chronic administration of a low-dose levodopa preparation can provide satisfactory benefit with a low incidence of motor complications, and can result in good QOL in Japanese patients with PD. The concomitant use of a small amount of dopamine agonist and amantadine from the outset has partly contributed to a reduced dose of levodopa and the lesser occurrence of motor complications.

Comparison of the clinical courses of the opticospinal and conventional forms of multiple sclerosis in Japan.

We evaluated the clinical courses of 216 patients with multiple sclerosis (MS) diagnosed according to the recommended diagnostic criteria of McDonald et al (10). Sixty-five patients clinically displaying selective involvement of the optic nerves and spinal cord were classified as opticospinal MS (OS-MS), while the other 151 showing disseminated involvement of the central nervous system were classified as conventional MS (C-MS). The disease duration did not differ significantly between the two subtypes (11.2 years vs. 11.5 years). In addition to a higher age of onset, female preponderance and higher Kurtzke's expanded disability status scale (EDSS) scores, the OS-MS patients showed a markedly lower frequency of secondary progressive MS than the C-MS patients (4.6% vs. 29.1%, p=0.0001). The EDSS scores of the C-MS patients were significantly correlated with the disease duration, while those of the OS-MS patients were not. Among the C-MS patients, the frequency of secondary progressive MS was significantly more common in patients with a disease duration of more than 10 years than in those with a shorter duration. These results suggest that the irreversible disability in OS-MS is determined by relapses, rather than by chronic progression, whereas C-MS has a similar clinical course to MS in Westerners.