Autosomal Recessive Spinocerebellar Ataxia Type 9 With a Response to Phosphate Repletion: A Case Report.

This provides Class IV evidence. This is a single observational study without controls.


An Exploratory Trial of EPI-589 in Amyotrophic Lateral Sclerosis (EPIC-ALS): Protocol for a Multicenter, Open-Labeled, 24-Week, Single-Group Study

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, with its currently approved drugs, including riluzole and edaravone, showing limited therapeutic effects. Therefore, safe and effective drugs are urgently necessary. EPI-589 is an orally available, small-molecule, novel redox-active agent characterized by highly potent protective effects against oxidative stress with high blood-brain barrier permeability. Given the apparent oxidative stress and mitochondrial dysfunction involvement in the pathogenesis of ALS, EPI-589 may hold promise as a therapeutic agent. This protocol aims to describe the design and rationale for the EPI-589 Early Phase 2 Investigator-Initiated Clinical Trial for ALS (EPIC-ALS). EPIC-ALS is an explorative, open-labeled, single-arm trial that evaluates the safety and tolerability of EPI-589 in patients with ALS. This trial consists of 12-week run-in, 24-week treatment, and 4-week follow-up periods. Patients will receive 500 mg of EPI-589 3 times daily over the 24-week treatment period. Clinical assessments include the mean monthly change of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score. The biomarkers are selected to analyze the effect on oxidative stress and neuronal damage. The plasma biomarkers are 8-hydroxy-2'-deoxyguanosine (8-OHdG), 3-nitrotyrosine (3-NT), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), homocysteine, and creatinine. The cerebrospinal fluid biomarkers are 8-OHdG, 3-NT, NfL, pNfH, and ornithine. The magnetic resonance biomarkers are fractional anisotropy in the corticospinal tract and N-acetylaspartate in the primary motor area. This trial began data collection in September 2021 and is expected to be completed in October 2023. This study can provide useful data to understand the characteristics of EPI-589. Japan Primary Registries Network jRCT2061210031; tinyurl.com/2p84emu6. DERR1-10.2196/42032.


A Pilot Study of A2NTX, a Novel Low-Molecular-Weight Neurotoxin Derived from Subtype A2 for Post-Stroke Lower Limb Spasticity: Comparison with OnabotulinumtoxinA.

= 0.002), but was unaffected in the A2NTX-injected group by day 60, suggesting there was less spread of A2NTX to the upper limb than there was with BOTOX. Being a small-sized pilot investigation with an imbalance in the gender of the subjects, the present study suggested superior efficacy and safety of A2NTX, and warrants a larger scale clinical trial of A2NTX to confirm these preliminary results.


Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups.


Truncal dystonia with isolated middle cerebral artery ischemia: A case report of revascularization therapy for dystonia.

Revascularization therapy improved CBF and truncal dystonia and could be a viable treatment option for dystonia with ischemia in the MCA region. Extensive cerebral ischemia can result in cortical inhibition loss or over-adapted cerebral plasticity and cause dystonia. Revascularization therapy may be useful for patients with dystonia and decreased CBF in the MCA region.


Botulinum toxin injection attenuates nonodontogenic toothache: A case report


Clinical safety and tolerability of A2NTX, a novel low-molecular-weight neurotoxin derived from botulinum neurotoxin subtype A2, in comparison with subtype A1 toxins

All the botulinum type A neurotoxins available for clinical use are of the A1 subtype. We developed a subtype A2 low-molecular-weight (150 kD (kilo Dalton)) neurotoxin (A2NTX) with less spread and faster entry into the motor nerve terminal than A1 in vitro and in vivo. Preliminary clinical studies showed that its efficacy is superior to A1 toxins. We conducted an open study exploring its safety and tolerability profile in comparison with A1LL (LL type A1 toxin, or onabotulinumtoxinA) and a low-molecular-weight (150 kD) A1 neurotoxin (A1NTX). Those who had been using A1LL ( = 90; 50-360 mouse LD50 units) or A1NTX ( = 30; 50-580 units) were switched to A2NTX ( = 120; 25-600 units) from 2010 to 2018 (number of sessions ~27, cumulative doses ~11,640 units per patient). The adverse events for A2NTX included weakness ( = 1, ascribed to alcoholic polyneuropathy), dysphagia (1), local weakness (4), and spread to other muscles (1), whereas those for A1LL or A1NTX comprised weakness ( = 2, A1NTX), dysphagia (8), ptosis (6), local weakness (7), and spread to other muscles (15). After injections, 89 out of 120 patients preferred A2NTX to A1 for the successive sessions. The present study demonstrated that A2NTX had clinical safety up to the dose of 500 units and was well tolerated compared to A1 toxins.


"Burnt-out" progressive multifocal leukoencephalopathy in idiopathic CD4+ lymphocytopenia

Progressive multifocal leukoencephalopathy (PML) is a fatal disease caused by John Cunningham virus (JCV) infection; however, a growing number of PML patients now survive longer and achieve remission, largely due to the advent of combination antiretroviral therapy. Several reports have suggested that the pathology in such patients presents only chronic demyelination without characteristic cellular changes, being referred to as "burnt-out" PML. On the other hand, our knowledge of "burnt-out" PML is still substantially limited, especially in patients with non-human immunodeficiency virus infection. Here, we report a case of PML associated with idiopathic CD4 lymphocytopenia (ICL) who presented with spontaneous remission and survived for 11 years after onset. Notably, postmortem examination revealed surprisingly broad "burnt-out" lesions lacking the classic histopathological findings. However, pathogenic JCV-specific DNA sequences was still present in the autopsied brain tissue. This case suggests that complete remission can be achieved with a persistent presence of JCV-specific pathogenic sequences, even after a catastrophic infection. Considering that there have been a few reported cases of PML with ICL with long survival, the long-term survival of our case may share a favorable immunological response that is unique to a subgroup of ICL.


Dystonia and cerebellum: From bench to bedside


Robot-assisted total gastrectomy for gastric cancer in a patient with amyotrophic lateral sclerosis receiving long-term tracheostomy invasive ventilation

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Although affected patients may develop cancers, major surgical intervention has been hampered by its questionable overall benefit due to limited prognosis and risk of postoperative respiratory collapse. A recent study, however, showed that tracheostomy invasive ventilation (TIV) prolonged median survival to 11.3 years; thus, patients with ALS receiving TIV might benefit from major surgery. A 66-year-old man with ALS, who had received TIV and enteral tube feeding for 8 years, presented with bloody stool. The patient also had type 2 diabetes mellitus, stage 4 chronic kidney disease, abdominal aortic aneurysm, and anti-phospholipid syndrome, as well as multiple episodes of pneumonia and catheter-related urinary tract infection treated by antibiotics. Medical examination and esophagogastroduodenoscopy revealed a type 3 tumor in the middle part of the stomach. The patient's preoperative diagnosis was gastric cancer (GC), MU, type3, Less-Post, T3(SS), N1, H0, P0, M0, cStage III. The estimated mortality rate was 30.5%, according to the Japanese National Clinical Database. The patient and his family were fully informed of the risk of surgery; the patient clearly requested curative surgery by eye movement. Thus, robot-assisted total gastrectomy (RATG) was performed. The tissues were extremely fragile and hemorrhagic. The surgical time was 7 h 0 min; intraoperative blood loss was 324 ml. Pathological examination revealed GC, MU, type3, T4a(SE), N2, H0, CY0, P0, M0 fStage IIIB. The postoperative course was uneventful. He has remained in stable condition for 3 months. Our findings suggest that patients with ALS who achieve longer survival with TIV can undergo major cancer surgery, including robot-assisted surgery, which may facilitate a better mid-long-term prognosis. The online version contains supplementary material available at 10.1007/s13691-021-00499-7.


Gait apraxia as a presenting sign of Gerstmann-Sträussler-Scheinker disease


Long-Term Follow-Up of 12 Patients Treated with Bilateral Pallidal Stimulation for Tardive Dystonia

Tardive dystonia (TD) is a side effect of prolonged dopamine receptor antagonist intake. TD can be a chronic disabling movement disorder despite medical treatment. We previously demonstrated successful outcomes in six patients with TD using deep brain stimulation (DBS); however, more patients are needed to better understand the efficacy of DBS for treating TD. We assessed the outcomes of 12 patients with TD who underwent globus pallidus internus (GPi) DBS by extending the follow-up period of previously reported patients and enrolling six additional patients. All patients were refractory to pharmacotherapy and were referred for surgical intervention by movement disorder neurologists. In all patients, DBS electrodes were implanted bilaterally within the GPi under general anesthesia. The mean ages at TD onset and surgery were 39.2 ± 12.3 years and 44.6 ± 12.3 years, respectively. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) performed the preoperative and postoperative evaluations. The average BFMDRS improvement rate at 1 month postoperatively was 75.6 ± 27.6% ( < 0.001). Ten patients were assessed in the long term (78.0 ± 50.4 months after surgery), and the long-term BFMDRS improvement was 78.0 ± 20.4%. Two patients responded poorly to DBS. Both had a longer duration from TD onset to surgery and older age at surgery. A cognitive and psychiatric decline was observed in the oldest patients, while no such decline ware observed in the younger patients. In most patients with TD, GPi-DBS could be a beneficial therapeutic option for long-term relief of TD.


A novel COL4A1 variant associated with recurrent epistaxis and glioblastoma


An autopsy report of a familial amyotrophic lateral sclerosis case carrying VCP Arg487His mutation with a unique TDP-43 proteinopathy

We here report an autopsy case of familial amyotrophic lateral sclerosis (ALS) with p.Arg487His mutation in the valosin-containing protein (VCP) gene (VCP), in which upper motor neurons (UMNs) were predominantly involved. Moreover, our patient developed symptoms of frontotemporal dementia later in life and pathologically exhibited numerous phosphorylated transactivation response DNA-binding protein of 43 kDa (p-TDP-43)-positive neuronal cytoplasmic inclusions and short dystrophic neurites with a few lentiform neuronal intranuclear inclusions, sharing the features of frontotemporal lobar degeneration with TDP-43 pathology type A pattern. A review of previous reports of ALS with VCP mutations suggests that our case is unique in terms of its UMN-predominant lesion pattern and distribution of p-TDP-43 pathology. Thus, this case report effectively expands the clinical and pathological phenotype of ALS in patients with a VCP mutation.


Reversible mixed perfusion on 123 I-IMP SPECT in anti-AMPA receptor encephalitis: A case report


Ataxia with vitamin E deficiency in the Philippines: A case report of two siblings.

Here we report two siblings with ataxia and peripheral neuropathy. One patient showed head tremors. Genetic analysis revealed a mutation in the hepatic α-tocopherol transfer protein (α-TTP) gene (TTPA) on chromosome 8q13. They were diagnosed with ataxia with vitamin E deficiency which is firstly reported in the Philippines. As the symptoms of ataxia with vitamin E deficiency can be alleviated with lifelong vitamin E administration, differential diagnosis from similar syndromes is important. In addition, ataxia with vitamin E deficiency causes movement disorders. Therefore, a common hereditary disease in the Philippines, X-linked dystonia-parkinsonism, could be another differential diagnosis. The Philippines is an archipelago comprising 7,107 islands, and the prevalence of rare hereditary diseases among the populations of small islands is still unclear. For neurologists, establishing a system of genetic diagnosis and counseling in rural areas remains challenging. These unresolved problems should be addressed in the near future. J. Med. Invest. 68 : 400-403, August, 2021.

The Journal of Medical Investigation : JMI


Neuropsychiatric systemic lupus erythematosus with cerebellar vasculitis and obstructive hydrocephalus requiring decompressive craniectomy.

A 36-year-old woman who had been diagnosed with systemic lupus erythematosus (SLE) was admitted to our hospital due to increasing disease SLE activity. Despite the intensification of immunosuppressive treatment, headache newly developed and worsened. Magnetic resonance imaging (MRI) revealed spreading of a high-intensity area along the sulci of the bilateral cerebellar hemispheres. She was diagnosed with neuropsychiatric SLE and methylprednisolone (mPSL) pulse therapy was started. However, consciousness disorder due to cerebellar oedema with obstructive hydrocephalus appeared and required decompressive craniectomy. The histological findings of the biopsy specimens from cerebellar vermis were compatible with features of vasculitis. She was successfully treated adding intravenous cyclophosphamide therapy.


Can Pallidal Deep Brain Stimulation Rescue Borderline Dystonia? Possible Coexistence of Functional (Psychogenic) and Organic Components.

The diagnosis and treatment of functional movement disorders are challenging for clinicians who manage patients with movement disorders. The borderline between functional and organic dystonia is often ambiguous. Patients with functional dystonia are poor responders to pallidal deep brain stimulation (DBS) and are not good candidates for DBS surgery. Thus, if patients with medically refractory dystonia have functional features, they are usually left untreated with DBS surgery. In order to investigate the outcome of functional dystonia in response to pallidal DBS surgery, we retrospectively included five patients with this condition. Their dystonia was diagnosed as organic by dystonia specialists and also as functional according to the Fahn and Williams criteria or the Gupta and Lang Proposed Revisions. Microelectrode recordings in the globus pallidus internus of all patients showed a cell-firing pattern of bursting with interburst intervals, which is considered typical of organic dystonia. Although their clinical course after DBS surgery was incongruent to organic dystonia, the outcome was good. Our results question the possibility to clearly differentiate functional dystonia from organic dystonia. We hypothesized that functional dystonia can coexist with organic dystonia, and that medically intractable dystonia with combined functional and organic features can be successfully treated by DBS surgery.


Efficacy of Istradefylline for the Treatment of ADCY5-Related Disease

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エタンブトールによる脱髄性末梢神経障害により急速進行性の歩行障害を呈した結核性胸膜炎の1例

日本結核・非結核性抗酸菌症学会

日本結核・非結核性抗酸菌症学会


Hung-up Knee Jerk in Huntington's Disease


Successful treatment of progressive multifocal leukoencephalopathy with mirtazapine and mefloquine in refractory myeloma


Co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis: a clinical-pathological case report.

Our case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course.

A 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5 months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP.


PMP22-related disease: A novel splice site acceptor variant and intrafamilial phenotype variability.

PMP22 is the most frequent mutated gene in Charcot-Marie-Tooth disease (CMT) type 1A. Another phenotype, hereditary neuropathy with pressure palsies (HNPP), could be caused by PMP22 mutations. PMP22 encodes a peripheral myelin protein with molecular weight 22-kDa. Various pathomechanisms have been postulated in PMP22-related disease, including dysfunction due to missense mutations, and alteration of a gene dose due to duplication/deletion mutations. We identified a novel PMP22 splice site acceptor variant, c.179-1G>A, in a patient with adult-onset chronic generalized polyneuropathy and two asymptomatic family members. Pathophysiological features of the members mainly overlapped with those reported in HNPP, but broad intrafamilial clinical variations were observed. PMP22 transcripts lacking of exon 4 were produced by the variant, presumably leading to in-frame deletion of 47 amino acids. The variant was also shown to exert effect on dosage of PMP22 mRNA. The complex molecular pathology would lead to the unique clinical and pathophysiological conditions.


Distinct Incidence of Takotsubo Syndrome Between Amyotrophic Lateral Sclerosis and Synucleinopathies: A Cohort Study.

Takotsubo syndrome (TTS) is an acute cardiac syndrome characterized by regional left ventricular dysfunction with a peculiar circumferential pattern, which typically results in apical ballooning. Evidence indicates a pivotal role of catecholamines in TTS, and researchers have discussed multiple hypotheses on the etiology, including multivessel coronary spasm, myocardial stunning, excessive transient ventricular afterload, and cardiac sympathetic overactivity with local noradrenaline spillover. Although central nervous system disorders, such as stroke and epilepsy, are known to trigger TTS, the incidence and clinical features of TTS in neurodegenerative disorders are poorly understood. Here, we retrospectively examined TTS cases in a single-center cohort composed of 250 patients with amyotrophic lateral sclerosis (ALS) and 870 patients with synucleinopathies [582 patients with Parkinson's disease (PD), 125 patients with dementia with Lewy bodies (DLB), and 163 patients with multiple system atrophy (MSA)] and identified 4 (1.6%, including 2 women) cases with ALS and no cases with synucleinopathies. Two ALS patients underwent autopsy and the pathological findings were compatible with the chronological changes identified in catecholamine-induced cardiomyopathy. A literature review identified 16 TTS cases with ALS, 1 case each with PD and DLB, and no cases with MSA. When current and previous TTS cases with ALS were concatenated: 55% (11/20) were female; 35% (7/20) had a bulbar-onset and 45% (9/20) had a limb-onset; the mean age of TTS onset was 63.3 ± 9.0 years and the mean interval time from ALS onset to TTS development was 4.9 ± 3.0 years; no (0/16) patients developed TTS within 12 months after ALS onset; 50% (10/20) underwent artificial ventilations; the mortality was 17% (3/18); and most cases had precipitating factors, and TTS development was associated with gastrostomy, tracheostomy, or infections in 45% (9/20) of the patients. This study demonstrated that ALS is a considerable predisposing factor of TTS and that synucleinopathies rarely cause TTS. The distinct TTS incidence between ALS and synucleinopathies may be due to cardiac sympathetic overactivity in ALS and may also be affected by cardiac sympathetic denervation in synucleinopathies. Moreover, the etiology of TTS in ALS may be reasonably explained by the two-hit theory.


Compound heterozygote mutations in the SIGMAR1 gene in an oldest-old patient with amyotrophic lateral sclerosis.


Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.

We further demonstrate the allelic heterogeneity and phenotypic variations of KMT2B-associated disease. Haploinsufficiency is one of molecular pathomechanisms underlying the disease. Cardinal clinical features include combined dystonia accompanying mild psychomotor disability. Cerebellum would be affected in KMT2B-associated disease.


Multi-disciplinary approach for dystonia patients by treatment with deep brain stimulation

ジストニアDBS治療における多職種連携


Neurologic attack and dynamic perfusion abnormality in neuronal intranuclear inclusion disease


A novel compound heterozygous TH mutation in a Japanese case of dopa-responsive dystonia with mild clinical course.


Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability.

Mutations in REEP1 have been identified in three types of neurological disorders, autosomal dominant form of Hereditary Spastic Paraplegia type 31 (SPG31), autosomal dominant distal hereditary motor neuronopathy type VB (HMN5B), and autosomal recessive form of congenital axonal neuropathy and diaphragmatic palsy. Previous studies demonstrated different molecular pathogenesis in SPG31, including loss-of-function, gain-of-function and haploinsufficiency. A four-generation family from Japan, including 12 members, was investigated clinically and genetically. Seven affected members displayed pure spastic paraplegia. Impression of genetic anticipation was observed in the family, including tendency of earlier age-at-onset and increasing severity in subsequent generations. Genetic analysis revealed a heterozygous intronic variant, c.303+2T > A, in REEP1, which segregated with disease, and was also identified in one unaffected member. The variant causes exon 4 skipping leading to frame shift and a truncated transcript identified by complementary DNA sequencing of reverse transcription polymerase chain reaction products. Measurement of REEP1 transcripts in lymphocytes demonstrated a reduction through nonsense mediated mRNA decay (NMD). Our study demonstrated further evidence of allelic heterogeneity in SPG31, mutant REEP1 mRNA dosage effects through NMD and intra-familial phenotype variability.


Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability.

Mutations in SPG4/SPAST are the most frequent molecular aetiology in the autosomal dominant form of hereditary spastic paraplegia (HSP). Loss-of-function and haploinsufficiency in SPAST have been demonstrated and the pure form of spastic paraplegia is a main clinical manifestation. This study is to explore the novel SPAST splice site donor variant, c.1004+3A>C, in seven patients from two families, one from Italy and the other from Japan. Exon 6 is skipped out by the variant, leading to a premature termination of translation, p.Gly290Trpfs*5. Measurement of SPAST transcripts in lymphocytes demonstrated a reduction through nonsense-mediated mRNA decay (NMD). Intra- and inter-familial phenotypic variations were observed, including age-at-onset, severity of spasticity, and scoliosis. Our study demonstrated further evidence of allelic heterogeneity in SPG4, dosage effects through NMD, and broad clinical features of the SPAST mutation.


ジストニアに対する脳深部刺激療法:淡蒼球刺激と視床刺激の併用

ジストニアに対する脳深部刺激療法:淡蒼球刺激と視床刺激の併用


Choreoathetosis, Dystonia, and Myoclonus in 3 Siblings With Autosomal Recessive Spinocerebellar Ataxia Type 16.