Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10 years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

Survey on the Impact of the COVID-19 Pandemic on Patients with Parkinson's Disease and Their Caregivers in Japan.

Objective: The coronavirus disease 2019 (COVID-19) pandemic changed the lives of patients with Parkinson's disease (PD) and their caregivers. This study aimed to investigate changes in patient behavior and PD symptoms and their effect on caregiver burden resulting from the COVID-19 pandemic in Japan. Methods: This nationwide, observational, cross-sectional survey included patients with self-reported PD and caregivers (members of the Japan Parkinson's Disease Association). The primary objective was to evaluate changes in behaviors, self-assessed PD symptoms, and caregiver burden from pre-COVID-19 (February 2020) to post-national state of emergency (August 2020 and February 2021). Results: Responses from 1883 patients and 1382 caregivers from 7610 distributed surveys were analyzed. Mean (standard deviation) age of patients and caregivers was 71.6 (8.2) and 68.5 (11.4) years, respectively; 41.6% of patients had a Hoehn and Yahr (HY) scale of 3. Patients (>40.0%) reported decreased frequency of going out. Most patients (>70.0%) reported no change in treatment visit frequency, voluntary training, or rehabilitation and nursing care insurance services. Symptoms worsened for approximately 7-30% of patients; the proportion with HY scale 4-5 increased from pre-COVID-19 (25.2%) to February 2021 (40.1%). Aggravated symptoms included bradykinesia, walking, gait speed, depressed mood, fatigue, and apathy. Caregivers' burden increased because of patients' worsened symptoms and reduced time going out. Conclusion: Control measures during infectious disease epidemics should consider that patients' symptoms may worsen; therefore, patient and caregiver support is needed to reduce burden of care.

Analytical and clinical validity of wearable, multi-sensor technology for assessment of motor function in patients with Parkinson's disease in Japan.

Continuous, objective monitoring of motor signs and symptoms may help improve tracking of disease progression and treatment response in Parkinson's disease (PD). This study assessed the analytical and clinical validity of multi-sensor smartwatch measurements in hospitalized and home-based settings (96 patients with PD; mean wear time 19 h/day) using a twice-daily virtual motor examination (VME) at times representing medication OFF/ON states. Digital measurement performance was better during inpatient clinical assessments for composite V-scores than single-sensor-derived features for bradykinesia (Spearman |r|= 0.63, reliability = 0.72), tremor (|r|= 0.41, reliability = 0.65), and overall motor features (|r|= 0.70, reliability = 0.67). Composite levodopa effect sizes during hospitalization were 0.51-1.44 for clinical assessments and 0.56-1.37 for VMEs. Reliability of digital measurements during home-based VMEs was 0.62-0.80 for scores derived from weekly averages and 0.24-0.66 for daily measurements. These results show that unsupervised digital measurements of motor features with wrist-worn sensors are sensitive to medication state and are reliable in naturalistic settings.Trial Registration: Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC-CTI): JapicCTI-194825; Registered June 25, 2019.

Remote Patient Monitoring for Neuropsychiatric Disorders: A Scoping Review of Current Trends and Future Perspectives from Recent Publications and Upcoming Clinical Trials.

Introduction: Telemedicine and remote patient monitoring are rapidly growing fields. This scoping review provides an update on remote patient monitoring for neuropsychiatric disorders from recent publications and upcoming clinical trials. Methods: Publications (PubMed and ICHUSHI; published January 2010 to February 2021) and trials (ClinicalTrials.gov and Japanese registries; active or recruiting by March 2021) that assessed wearable devices for remote management and/or monitoring of patients with neuropsychiatric disorders were searched. The review focuses on disorders with ≥3 publications. Results: We identified 44 publications and 51 active or recruiting trials, mostly from 2019 or 2020. Research on digital devices was most common for Parkinson's disease (11 publications and 19 trials), primarily for monitoring motor symptoms and/or preventing falls. Other disorders (3-5 publications each) included epilepsy (electroencephalogram [EEG] and seizure prediction), sleep disorder (sleep outcomes and behavioral therapies), multiple sclerosis (physical activity and symptoms), depression (physical activity, symptoms, and behavioral therapies), and amyotrophic lateral sclerosis (symptoms). Very few studies focused on newly emerging technologies (e.g., in-ear EEG and portable oximeters), and few studies integrated remote symptom monitoring with telemedicine. Discussion: Currently, development of digital devices for daily symptom monitoring is focused on Parkinson's disease. For the diseases reviewed, studies mostly focused on physical activity rather than psychiatric or nonmotor symptoms. Although the validity and usefulness of many devices are established, models for implementing remote patient monitoring in telehealth settings have not been established. Conclusions: Verification of the clinical effectiveness of digital devices combined with telemedicine is needed to further advance remote patient care for neuropsychiatric disorders.

Effects of rasagiline on Parkinson's Disease Questionnaire (PDQ-39) emotional well-being domain in patients with Parkinson's disease: A post-hoc analysis of clinical trials in Japan.

BACKGROUND: Identifying the factors that influence health-related quality of life (HRQoL) is of great scientific interest, but a potential causal relationship between treatment and HRQoL has yet to be fully elucidated. Japanese patients reported better HRQoL outcomes on the Parkinson's Disease Questionnaire (PDQ-39) emotional well-being domain, a 6-question subset of the PDQ-39 which is considered to reflect the emotional aspects of the disease-specific HRQoL, when treated with rasagiline, than placebo, in both a monotherapy clinical trial (NCT02337725) and an adjunctive therapy clinical trial in patients with wearing-off phenomena (NCT02337738). OBJECTIVE: To investigate how rasagiline exerts its effect on the PDQ-39 emotional well-being domain in Japanese patients with Parkinson's disease. METHODS: A path analysis was performed to assess the direct treatment effects of rasagiline on the PDQ-39 emotional well-being domain and the effects mediated indirectly through the influence on items related to motor symptoms by a post-hoc analysis of two clinical trials in Japan. RESULTS: In the monotherapy trial, the PDQ-39 emotional well-being domain was mainly affected indirectly through items related to motor symptoms (80.7%) composed of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II (67.2%) and Part III (13.5%). In the adjunctive therapy trial, the PDQ-39 emotional well-being domain was also mainly influenced indirectly through effects on items related to motor symptoms (1 mg/day: 54.7%, 0.5 mg/day: 57.6%) composed of MDS-UPDRS Part II (1 mg/day: 35.6%, 0.5 mg/day: 40.9%), Part III (1 mg/day: 8.0%, 0.5 mg/day: 8.3%) and mean daily OFF-time (1 mg/day: 11.1%, 0.5 mg/day: 8.4%). CONCLUSIONS: The effects of rasagiline on the PDQ-39 emotional well-being domain were mediated primarily by influence on the subjective aspects of motor experiences of daily living.

DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the nonpathogenic TTTTA repeat expansion in TNRC6A.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disease characterized by adult-onset tremulous hand movement, myoclonus, and infrequent epileptic seizures. Recently, intronic expansion of unstable TTTCA/TTTTA pentanucleotide repeats in SAMD12, TNRC6A, or RAPGEF2 was identified as pathological mutations in Japanese BAFME pedigrees. To confirm these mutations, we performed a genetic analysis on 12 Japanese BAFME pedigrees. A total of 143 participants, including 43 familial patients, 5 suspected patients, 3 sporadic nonfamilial patients, 22 unaffected familial members, and 70 unrelated controls, were screened for expanded abnormal pentanucleotide repeats in SAMD12, TNRC6A, RAPGEF2, YEAT2, MARCH6, and STARD7. DNA samples were analyzed using Southern blotting, long-range polymerase chain reaction (PCR), repeat-primed PCR, and long-range PCR followed by Southern blotting. Of the 51 individuals with clinically diagnosed or suspected BAFME, 49 carried a SAMD12 allele with an expanded TTTCA/TTTTA pentanucleotide repeat. Genetic and clinical anticipation was observed. As in previous reports, the one patient with homozygous mutant alleles showed more severe symptoms than the heterozygous carriers. In addition, screening for expanded pentanucleotide repeats in TNRC6A revealed that the frequency of expanded TTTTA repeat alleles in the BAFME group was significantly higher than in the control group. All patients who were clinically diagnosed with BAFME, including those in the original family reported by Yasuda, carried abnormally expanded TTTCA/TTTTA repeat alleles of SAMD12. Patients with BAFME also frequently carried a TTTTA repeat expansion in TNRC6A, suggesting that there may be unknown factors in the ancestry of patients with BAFME that make pentanucleotide repeats unstable.

Burst spinal cord stimulation for pain and motor function in Parkinson's disease: A case series.

INTRODUCTION: Spinal cord stimulation (SCS) is an established strategy for pain reduction used in whole world including Japan to treat chronic intractable pain. Pain is a frequent comorbidity of Parkinson's disease (PD), leading to poorer quality of life. SCS has been reported to effectively reduce pain in PD and may also improve motor function, but most studies have employed the modality of tonic stimulation. As such, the effects of SCS using the newly developed paradigm of burst stimulation in PD remain relatively unexplored. METHODS: This case series reviewed PD patients who underwent SCS using BurstDR stimulation to treat intractable lower back pain (LBP). Pain and motor outcomes were assessed before and at several timepoints after implantation over a 24-week observation period. RESULTS: Pain indices (visual analogue scale [VAS] and short-form McGill Pain Questionnaire 2 [SF-MPQ-2] scores) improved in nearly all patients. Improvements were especially notable in the dimension of affective pain (SF-MPQ-2). Functional motor improvements were evident in the Unified Parkinson's Disease Rating Scale (UPDRS), especially walking-related items, and timed-up-and-go (TUG) test performance, which generally persisted through week 24 of observation. CONCLUSION: Burst SCS improved pain (especially the affective component) in PD patients with LBP, with effects generally lasting for at least 24 weeks. Neither paresthesia nor obvious adverse events were experienced in any case. Motor symptoms as scored of UPDRS Part III had the trends of improvement in lower limb akinesia at week 24 and gait at week 4. These findings suggest that burst SCS may be an effective treatment option for LBP and may be influenced to gait-related motor symptoms in PD.

Establishment of a Comprehensive Information Infrastructure and a Support Organization for Rare Disease Research in Japan (RADDAR-J).

There are more than 300 research groups for rare diseases in Japan. Although various clinical and genomic information of patients are being collected by the groups, the information is managed individually by each research group and the current practices for managing and sharing research data are not very efficient. Since "rare diseases" are literally rare, the understanding of the underlying disease mechanisms are incomplete and collecting a sufficient number of patients for clinical trials is difficult. Therefore, there is a need to collect and integrate the data and construct a data integration platform for rare disease research. Funded by the Japan Agency for Medical Research and Development, a national research and development project to establish a standard platform and supporting organization for rare disease registries in Japan is currently under way. In this article, we report the background, purpose, process, results, current status, and future plans of this project.

National platform for Rare Diseases Data Registry of Japan.

INTRODUCTION: In Japan, there are approximately 300 projects conducting research on rare diseases supported by the Ministry of Health, Labour and Welfare of Japan (MHLW) and the Japan Agency for Medical Research and Development (AMED). Diverse data, including clinical, genomic, and sample-related data, are generated by these projects. However, at present, such data are managed individually by each project. This makes it difficult for third parties to ascertain the data generated by projects. METHODS: Again this background, at the beginning of 2017, the AMED started the National Platform for Rare Diseases Data Registry of Japan (RADDAR-J), whose mission is to construct a cross-sectional data integration platform incorporating projects supported by the AMED and MHLW. RADDAR-J promotes data sharing by the projects in accordance with the data-sharing policy established by the AMED, which classifies data sharing into three categories based on the strategies used to protect the rights of researchers while promoting data sharing. RADDAR-J integrates and analyzes data shared by each project to add value to the resources and promote secondary use by third parties while protecting the rights of the researchers who shared their data. The platform is designed to provide incentives to projects that shared their data by supporting registry construction or genomic analysis to promote data sharing. RADDAR-J also has the function of data identification to securely integrate data originating from the same person. RADDAR-J accelerates clinical research by encouraging each project to utilize a central ethics committee. RESULTS/CONCLUSION: The use of the platform by projects is expected to lead to streamlined data collection, improved quality assurance, improved access to data, and promotion of joint research and the secondary use of shared data. These benefits will accelerate research into diagnosis and treatment technologies and will hopefully lead to improved quality of life for patients with rare diseases.

Lidocaine injections and neck corset wearing improve dropped head syndrome in Parkinson's disease and related disorders.

BACKGROUND: Patients with Parkinson's disease and related disorders (PDRD) may exhibit dropped head syndrome (DHS), which does not yet have an effective treatment. OBJECTIVES: To evaluate the effect of combining lidocaine injection into the bilateral scalene muscles and neck corset wearing on dropped head syndrome. METHODS: We performed needle electromyography assessments of the scalene, sternocleidomastoid (SCM), levator scapulae, splenius capitis, and trapezius muscles. Patients received 2.5-5 ml injections of 1% lidocaine into both sides of the scalene muscles for 4/5 consecutive days and were instructed to wear a neck corset. We measured the neck flexion angle, which formed between the horizontal line and the straight line passing through the ear canal and orbital fossa, before (baseline) and after (Day 8 and Day 90) the intervention. RESULTS: Seven males and eight females (mean age, 68.9 years; range 56 to 85 years) who had PDRD with dropped head syndrome were enrolled in this study. Needle electromyography examination revealed abnormal discharge of the scalene muscles in all patients when the neck position was corrected; however, some patients did not show abnormal discharge of the SCM muscle. At Day 8, we observed an improvement of the neck flexion angle in 13 of the 15 patients, from an average of 27.7°â€¯±â€¯13.9° to 11.7 ±â€¯14.6°. At Day 90, the average neck flexion angle was 15.3°â€¯±â€¯17.2°. CONCLUSIONS: Combining lidocaine injection into the scalene muscles and neck corset wearing is an effective treatment regimen for DHS in patients with PDRD.

Survey on patients with undiagnosed diseases in Japan: potential patient numbers benefiting from Japan's initiative on rare and undiagnosed diseases (IRUD).

BACKGROUND: There is now an international partnership to establish global programs for patients with rare and undiagnosed diseases, involving interdisciplinary expert panels and phenotype-driven genetic analyses utilizing next-generation sequencing and analytics. Whereas it is crucial to have data such as the actual number of undiagnosed patients, to help inform the implementation plan with such programs, there have been no systematic studies to quantitate the numbers of patients principally because of the inherent difficulty in most health systems to identify patients whose condition has not yet been diagnosed and coded. Our national experience with a rare disease program, Nan-Byo which was established in 1972, and the more recently expanded Initiative on Rare and Undiagnosed Diseases (IRUD), provided a unique opportunity to design a cross-sectional study to ascertain the undiagnosed patients in Japan based on the IRUD referral criteria. RESULTS: Two rounds of online surveys were performed: one survey targeting physicians affiliated with general hospitals (GH) and family clinics (FC) (the response rate: 30.6% (242/792)) and one nationwide survey targeting university hospitals (UH) in Japan (47.1% (839/1781)). A high percentage of doctors needing IRUD was seen in pediatrics at GH, FC, while there was a clear demand for IRUD in most departments at UH. We calculated the number of undiagnosed patients in Japan, as the "percentage of doctors needing IRUD" × "number of patients who would be referred to IRUD per doctor needing IRUD (cases/person)" × "total number of doctors in the relevant facilities in Japan (persons)", resulting in 3681 cases in pediatrics/pediatric surgery and 33,703 cases in other departments, for a total of 37,384 cases. CONCLUSIONS: Our study revealed the extant demand for IRUD in most departments and 37,000+ potential patients with undiagnosed diseases in the Japanese health system. These data inform the establishment of an equitable, sustainable, efficient and effective outpatient-based IRUD. These findings would serve as a valuable reference for undiagnosed diseases programs in different international jurisdictions and for countries and regions who also share vision(s) for societal implementation that help to advance international efforts to support patients with rare diseases who are direly waiting for diagnosis, subsequent treatment and care.

Consensus for the measurement of the camptocormia angle in the standing patient.

INTRODUCTION: Camptocormia is characterized by a pathological forward flexion of the trunk, which is reversible when lying and worsened by standing and walking. So far there is no consensus on how to measure the angle of flexion, and studies therefore give differing results. Harmonization is needed for both research and clinical practice. Orthopedic measures are not useful for this purpose. METHODS: Two expert raters independently analyzed the photographs of 39 Parkinson patients with camptocormia while standing. They used four different methods to determine the camptocormia angle. The results were compared statistically. An international Consensus Group reviewed the results and drafted recommendations. RESULTS: The four methods yielded camptocormia angles that differed by up to 50% in the same patient. Inter-rater reliability and test-retest reliability also differed, but were satisfactory to excellent. CONCLUSION: This Consensus Group concluded that two of the methods qualified as reliable measures of the trunk angles in standing patients based on their clinimetric properties. They propose that the 'total camptocomia angle' be the angle between the line from the lateral malleolus to the L5 spinous process and the line between the L5 spinous process and the spinous process of C7. They also propose that the 'upper camptocormia angle' be the angle of the lines between the vertebral fulcrum to the spinous processes of L5 and C7, respectively. An app is provided on the web for these measurements (http://www.neurologie.uni-kiel.de/de/axial-posturale-stoerungen/camptoapp).

Dysphagia Causes Symptom Fluctuations after Oral L-DOPA Treatment in a Patient with Parkinson Disease.

OBJECTIVE: The causes of "delayed-on" and "no-on" phenomena in Parkinson disease (PD) are thought to have some impact on the progress of L-DOPA from the time of ingestion until it reaches the brain and is converted to dopamine. Dysphagia can cause fluctuating symptom expression in L-DOPA therapy for PD. CASE DESCRIPTION: A 69-year-old man with PD presented with "delayed-on" and "no-on" phenomena. The patient developed a gait disorder at age 60 years, and he began coughing on his food during breakfast at age 64 years. Even though he was independent in daily life, he could not eat because of dysphagia in an "off" state. Videofluoroscopic examination of swallowing in an "off" state revealed bradykinesia of the tongue and the retention of tablets in the epiglottic vallecula. We trained him to keep his tongue in strong contact with the upper incisors before swallowing. After rehabilitation of dysphagia, the frequency of "delayed-on" and "no-on" phenomena decreased, and his peak L-DOPA plasma concentration was elevated. Additionally, transdermal rotigotine (RTG) was initiated at a maintenance dose of 9.0 mg. The patient reported improvement in swallowing, and the frequency of "no-on" phenomena decreased. CONCLUSION: In PD patients, the "no-on" phenomenon can be caused by posterior contractile dysfunction of the tongue, and it can be improved with training of the tongue and transdermal RTG administration.

Japan's initiative on rare and undiagnosed diseases (IRUD): towards an end to the diagnostic odyssey.

Japan has been facing challenges relating to specifically defined rare diseases, called Nan-Byo in Japanese (literally 'difficult'+'illness'), and has already taken measures for them since 1972. This governmental support has surely benefited Nan-Byo patients; however, those suffering from medically unidentified conditions do not fall into this scheme and thus still confront difficulty in obtaining an examination, a diagnosis, and a treatment. To identify such rare and often undiagnosed diseases, we must integrate systematic diagnosis by medical experts with phenotypic and genetic data matching. Thus, in collaboration with Nan-Byo researchers and the Japanese universal healthcare system, the Japan Agency for Medical Research and Development launched the Initiative on Rare and Undiagnosed Diseases (IRUD) in 2015. IRUD is an ambitious challenge to construct a comprehensive medical network and an internationally compatible data-sharing framework. Synergizing with existing next-generation sequencing capabilities and other infrastructure, the nationwide medical research consortium has successfully grown to accept more than 2000 undiagnosed registrants by December 2016. We also aim at expanding the concept of microattribution throughout the initiative; that is, proper credit as collaborators shall be given to local primary care physicians, nurses and paramedics, patients, their family members, and those supporting the affected individuals whenever appropriate. As it shares many challenges among similar global efforts, IRUD's future successes and lessons learned will significantly contribute to ongoing international endeavors, involving players in basic research, applied research, and societal implementation.

Mechanism of camptocormia in Parkinson's disease analyzed by tilt table-EMG recording.

BACKGROUND: We previously classified camptocormia of Parkinson's disease (PD) into upper and lower types based on the inflection point, and reported improvement of upper camptocormia after lidocaine injection into the external oblique. However, the exact pathophysiology of this phenomenon remains obscure. METHODS: Surface electromyography (sEMG) was recorded in 11 PD patients with upper camptocormia, 11 PD patients with lower camptocormia, and 10 age-matched PD patients without postural deformity. Electrodes were positioned above the external oblique, hip flexors and paraspinal muscles at Th11 level bilaterally. Recording commenced with the patient in supine position on a tilt table, and continued when the table was tilted up to vertical position. Lidocaine was injected into the external oblique in patients with upper camptocormia and the psoas major in patients with lower camptocormia. RESULTS: All patients with upper and lower camptocormia developed the corresponding camptocormic posture during tilt up. The onset of camptocormic posture was preceded by the appearance of sEMG activity in the external oblique in 10 out of 11 patients with upper camptocormia, but less frequently in patients with lower camptocormia and the controls. Hip flexors sEMG activity was recorded in almost all patients. Posture was improved in 8 out of 9 patients with upper camptocormia, and 9 out of 11 patients with lower camptocormia following injections of lidocaine. CONCLUSIONS: The results suggest the external oblique is involved, at least in part, in the development of upper camptocormia. Although EMG findings cannot differentiate pathogenicity, the psoas major is probably involved in lower camptocormia.

Long-term effect of repeated lidocaine injections into the external oblique for upper camptocormia in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is occasionally complicated by camptocormia. In a previous study, we classified camptocormia into upper and lower types based on the inflection point, and reported that lidocaine injection into the external oblique muscle, but not into the internal oblique or rectus abdomen, improved upper camptocormia in PD. The effect of a single lidocaine injection disappeared over a period of few days. In this study, we used repeated lidocaine injections into the external oblique for 4-5 days and evaluated the effects of such treatment for up to 90 days. METHODS: The study subjects were 12 patients with PD and upper camptocormia who were treated with repeated lidocaine injections into the bilateral external oblique followed by rehabilitation. The effect of treatment was evaluated by measuring the angle of truncal flexion before and after the injection. Patients who showed improvement with repeated injections were evaluated during a 90-day period. RESULTS: Eight out of 12 patients showed significant improvement in posture after a single lidocaine injection. However, the effect subsided several days after treatment. Repeated injections produced long-term improvement in 9 out of 12 patients, which was maintained during the 90-day observation period in eight of these patients. CONCLUSIONS: Our results showed that repeated lidocaine injections into the external oblique improved upper camptocormia, and that the effect was maintained in the majority of patients during the 90-day observation period, indicating that repeated lidocaine injections into the external oblique have therapeutic effect on upper camptocormia in patients with Parkinson's disease.

Effects of enzyme replacement therapy on five patients with advanced late-onset glycogen storage disease type II: a 2-year follow-up study.

We examined the efficacy of 2-year enzyme replacement therapy (ERT) using recombinant human α-glucosidase (GAA; Myozyme®) in five long-term ventilator-dependent adults and aged patients with advanced, late-onset glycogen storage disease type II (GSDII, also known as Pompe disease). Although all patients had advanced respiratory failure and were ventilator-dependent for more than 6 years, four showed obvious improvements in muscle strength, pulmonary function, and activities of daily living after ERT. Improvement in each parameter was more prominent in the first year than in the second year. Values in the second year were still significantly better than those at study entry and indicate stabilization in the clinical status of all patients. These results suggest that ERT continues to be effective in the second year of treatment even in patients suffering from advanced late-onset GSDII disease with severe respiratory failure.

[Monthly low-dose immunoglobulin infusion as a maintenance therapy for multifocal motor neuropathy may reduce allergic adverse effects: a case report].

A 41-year-old man with multiple motor neuropathy developed weakness of the left hand at the age of 35 years. The weakness gradually progressed to his right hand. High-dose intravenous immunoglobulin (IVIg) therapy (0.4 g/kg for 5 consecutive days) improved the muscle weakness in the hands but led to the development of generalized severe pompholyx that spread to the skin over the entire body. Because muscle weakness of the hands worsened several months after IVIg therapy, we attempted another course of IVIg therapy. However, antiallergic agents and oral corticosteroids did not suppress the pompholyx induced by the high-dose IVIg. Hence, the treatment was switched to low-dose immunoglobulin therapy (0.4 g/kg for one day) once every month. After more than 8 months of low-dose therapy, only mild form of pompholyx remained and the muscle strength was maintained without further deterioration.