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Nobutaka Hattori,1 Yoshiko Okada,2 Yayoi Kawata,3 Yoshihiko Furusawa,3 Takumi Imai,4 Hisako Yoshida,4 Mihoko Ota,3 Masaki Arai,3 Ayumi Shintani,4 Jovelle Fernandez3 1Department of Neurology, Juntendo University, Tokyo, Japan; 2Japan Parkinson Congress, Tokyo, Japan; 3Japan Medical Office, Takeda Pharmaceutical Company Limited, Tokyo, Japan; 4Department of Medical Statistics, Graduate School of Medicine, Osaka Metropolitan University, Osaka, JapanCorrespondence: Yoshihiko Furusawa, Japan Medical Office, Takeda Pharmaceutical Company Limited, 2 Chome-1-1 Nihonbashihoncho, Chuo City, Tokyo, 103-0023, Japan, Tel +81-3-3278-2111, Fax +81-3-3278-2000, Email yoshihiko.furusawa@takeda.comObjective: 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.Keywords: Parkinson’s disease, COVID-19, questionnaire design, caregiver burden

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.

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° ± 13.9° to 11.7 ± 14.6°. At Day 90, the average neck flexion angle was 15.3° ± 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.

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 ).

Brain-computer interfaces (BCIs) show potential as neuroprosthetic and neurorehabilitative interventions for patients with motor impairments. However, recent evidence suggests that BCIs depend on c...

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.

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.

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.

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.

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.

We report a case of subcutaneous and mediastinal emphysema in a 39-year-old woman with late-onset Pompe disease who was undergoing non-invasive positive pressure ventilation (NPPV). Although the patient had a history of pneumothorax, she did not present with pneumothorax at the time of admission. She had not undergone adequate respiratory rehabilitation, which resulted in decreased respiratory compliance. We speculated that the emphysema had been caused by an increase in the airway pressure due to NPPV. Decrease in inspiratory pressure of NPPV from 14 cm H2O to 9 cm H2O made the patient dyspneic and hypoxic. Cuirass ventilation by itself resulted in dyspnea and hypoxia. By using a combination of cuirass ventilation (control mode) and NPPV (assist/control mode), we were able to decrease the inspiratory pressure to 7 cm H2O. After 26 days of treatment, the patient recovered from subcutaneous and mediastinal emphysema. After the treatment, her maximum inspiratory capacity was increased from 400 ml to 600 ml, which indicates increased thoracic compliance. Thus, a combination of cuirass ventilation and NPPV is beneficial in managing barotrauma that may occur during NPPV in a respirator-dependent patient.

A 20 year-old woman with myotonic dystrophy type 1 (DM1) presented with fatigue, daytime somnolence, and sudden poor responsiveness. Blood glucose was measured before and after each meal for 4 days, and hypoglycemia was confirmed twice, although neither perspiration nor palpitations occurred in the hypoglycemic state. On a 75 g oral glucose tolerance test (OGTT), fasting blood glucose level was 83 mg/dl, and fasting blood immunoreactive insulin (IRI) level was 5.96 microIU/ml. However, IRI increased to 528 microIU/ml at 60 minutes and blood glucose decreased to 57 mg/dl at 120 minutes of the OGTT. The patient was diagnosed with reactive hypoglycemia due to excessive insulin secretion. Oral administration of pioglitazone improved the excessive insulin secretion as assessed by OGTT. After starting treatment, hypoglycemia was not detected either pre- or post-prandially. After 10 months of treatment, blood glucose level after glucose loading was higher than fasting blood glucose level during OGTT, and the IRI area under the curve of the OGTT decreased. We considered that hypoglycemia unawareness resulted from recurrent hypoglycemic episodes in this patient. Pioglitazone was effective in improving hyperinsulinemia and reactive hypoglycemia in nondiabetic DM1.

We report an autopsy case of advanced late-onset Pompe disease (juvenile type). At 15 years-of-age, the patient experienced proximal weakness and subsequently required non-invasive positive pressure ventilation. Enzyme replacement therapy was initiated at 37 years-of-age, which improved pinch power and alleviated respiratory distress. At age 41 years, repetitive pneumothorax led to respiratory failure and death. Autopsy excluding the brain showed few vacuoles and periodic acid–Schiff-positive fibers in the left rectus femoris, compared with the contralateral muscle biopsy carried out at 21 years-of-age. Vacuolar changes were also less evident than previous autopsy cases without enzyme replacement therapy. The findings suggest that enzyme replacement therapy might have suppressed myovacuolopathy in our patient with advanced late-onset Pompe disease. Apart from vacuolopathy, the autopsied muscle showed marked myofiber atrophy and fibrosis, suggesting that disuse atrophy could have contributed to the muscle weakness.

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.

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.

In July, 2008, a 67-year-old woman with refractory depression was referred to our institute. In 2006, she had a thymectomy for thymoma. In January, 2008, after experiencing family discord, she lost her appetite, and her bodyweight decreased by 5 kg in 1 month. She became pessimistic and self-recriminating and made several suicide attempts. CT showed no evidence of a recurrence of the thymoma. Neurological examination showed only slight muscle weakness of her limbs, but the cause of her anorexia remained unclear despite further in-hospital examinations such as gastrointestinal tract endoscopies and systemic contrast-enhanced CT. She was diagnosed as having depression and was transferred to a regional psychiatric hospital, where she was treated sequentially with sertraline, paroxetine, clomipramine, and nortrip tyline, and augmentation lithium. These treatments were ineff ective, and her body weight decreased from 60 kg to 33·5 kg. She was then transferred to us. Her depressed mood, decreased interests, hypogeusia, anorexia, insomnia, anxious restlessness, decreased energy and fatigue, guilty feelings, poor concentration, and suicidal ideation persisted. She fulfi lled the DSM-IV diagnostic criteria for major depressive disorder. Her total score on the 17-item Hamilton Depression Rating Scale (total-HDRS) was 40. She could walk and had no ocular and bulbar symptoms, but neurological examinations showed mild proximal muscle weakness and atrophy of her limbs. Blood test results indicated hypoalbuminaemia (albumin 3·4 g/dL); other investi gations including CT chest, tumour markers, electro encephalography, and brain MRI were normal. Ten sessions of electroconvulsive therapy (ECT) were done in September, but the depressive symptoms persisted. She stopped taking medication, other than quetiapine as required (prescribed by us), but at the end of October, she suddenly developed impaired con sciousness with a reduced respiratory rate. A blood gas analysis showed carbon dioxide narcosis, and she was immediately placed on a ventilator. No evidence of pulmonary disease was found, and a diagnosis of myasthenic crisis was made on the basis of a high acetylcholine receptor antibody (AchR-Ab) titre (120 nmol/L), waning on the Harvey-Masland test, and a history of thymoma. She was treated with plasmapheresis and immunoadsorption followed by prednisolone treatment (maximum dose, 50 mg/day). Her respiratory function subsequently improved, and she was extubated. In December, she was treated with pyridostigmine (180 mg/day). As the anti-AchR-Ab titre decreased, totalHDRS score improved substantially without antidepressant therapy (fi gure). Her long-lasting depressive symptoms improved completely, and her bodyweight recovered to 40 kg; she was discharged in July, 2009. When last seen in September, 2009, both her depression and myasthenia gravis were in remission. The pathology of depressive symptoms associated with myasthenia gravis, including the hypothalamo-pituitaryadrenal axis dysfunction resulting from chronic stress and central cholinergic defi cit, is controversial and remains to be elucidated. Although some patients with major depressive disorder complicated with myasthenia gravis improve after ECT, the potential to misdiagnose myasthenia gravis as depression has been highlighted. 20% of people with myasthenia gravis are initially diagnosed as having a psychiatric disorder, and improvements in depressive symptoms associated with improvements in myasthenia gravis have been reported. Whether depressive symptoms in individual cases are attributable to myasthenia gravis or major depressive disorder should be investigated. Since the AchR-Ab titre and the depressive symptoms improved over time in our case, we concluded that the patient’s depressive symptoms could predominantly be attributed to myasthenia gravis. When managing treatment-resistant depressive patients, the medical history must be suffi ciently considered.

In consideration of the treatment for multiple cerebral aneurysms occurring in association with subarachnoid hemorrhage, it is sometimes difficult to determine which therapeutic strategy should be used when it is difficult to detect the ruptured aneurysm by CT or angiography and difficult to clip all the aneurysms using one approach. This study was conducted to examine indications and problems of coil embolization in the acute stage in such a situation, based on our experience in 9 patients. The patients were aged between 29 to 91 years (mean 61.6 years), and the severity on admission was recorded according to the World Federation of Neurosurgical Societies (WFNS) Grade I in 6 patients, Grade II in 2 patients, and grade IV in 1 patient. The number of aneurysms was 2 in 5 patients, 3 in 3 patients, and 4 in 1 patient. Four patients underwent embolization for all the aneurysms simultaneously, 3 patients underwent embolization for a single aneurysm and then underwent clipping of other aneurysms, and 2 patients were considered to be eligible for surgery and underwent clipping, but since no rupture was detected, they underwent embolization for all the remaining aneurysms. Seven patients made satisfactory progress, but 1 patient developed an embolic complication. Another patient developed recurrent hemorrhage from the untreated aneurysm, so additional clipping was performed. Coil embolization is beneficial in that treatment is completed simultaneously, but has problems in that it cannot be determined whether or not the embolized aneurysm is the ruptured one, embolic complications may occur, and long-term prognosis is unknown.