Tatsuya Fukumoto

Introduction/Aims: Needle electromyography (EMG) in the bulbar region aids in the diagnosis of amyotrophic lateral sclerosis (ALS) but remains technically challenging. The genioglossus muscle (GM) is commonly examined; however, pain and poor relaxation may limit its evaluation. The trapezius is an alternative target but is innervated by the spinal accessory nerve. We investigated the utility of the anterior belly of the digastric muscle (ABDM), innervated by the trigeminal nerve, for bulbar EMG evaluation. Methods: In this unblinded, prospective observational study, consecutive patients with suspected ALS underwent needle EMG of the ABDM, GM, masseter muscle (MM), and trapezius. Relaxation levels, EMG abnormalities, and pain (100‐mm visual analog scale [VAS]) were assessed. Results: Twenty‐seven clinically diagnosed ALS patients were analyzed. Relaxation was better in the ABDM than in the GM ( p < 0.001) and comparable to that in the MM and trapezius. Fasciculation potentials were detected more often in the ABDM (52%) than in the GM (0%) and MM (22%; p = 0.039) and were comparable to the trapezius (59%). Chronic denervation occurred at similar frequencies across muscles (33%–59%). The combination of abnormal spontaneous activity and chronic denervation was most frequent in the ABDM (37%). Pain was lower with the ABDM (median VAS score of 21) than with the GM (28; p = 0.0052) and MM (32; p < 0.001) and was similar to the trapezius (23). Discussion: The ABDM may be a practical additional target for bulbar EMG in ALS, with favorable relaxation, lower pain, and potentially improved electrodiagnostic yield.

Percutaneous transesophageal gastro‐tubing provides enteral access when endoscopic gastrostomy is not feasible, but delayed vascular injury is seldom reported. We describe a 73‐year‐old woman with amyotrophic lateral sclerosis and prior gastrectomy who became ventilator‐dependent and underwent percutaneous transesophageal gastro‐tubing. More than 1 year later, she developed recurrent cervical bleeding that progressed to massive pulsatile hemorrhage requiring transfusion. Contrast‐enhanced computed tomography showed the tract abutting the thyroid gland, whereas catheter angiography identified a pseudoaneurysm of the left thyroid artery. Selective transarterial embolization with coils and n‐butyl cyanoacrylate achieved definitive hemostasis without recurrence. Re‐insertion of percutaneous transesophageal gastro‐tubing was avoided, and nutrition was maintained via a nasoenteric tube and a central venous port. This case highlights thyroid artery hemorrhage as a potentially fatal, delayed complication of long‐term percutaneous transesophageal gastro‐tubing in amyotrophic lateral sclerosis. We emphasize optimal preprocedural planning, prevention, and a rapid, appropriate response to bleeding.

Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (anti-AMPAR) encephalitis manifests as limbic encephalitis in adults and is often associated with cancer. Although some reports suggest that it may occur in children, the clinical features in this population, as well as the prognostic factors and long-term outcomes in children and adults, are unknown. We performed a retrospective, international collaborative study of patients with anti-AMPAR encephalitis. Clinical information was reviewed, together with data from published pediatric patients. Clinical features of children and adults were compared with nonparametric tests. Survival rates (Kaplan-Meier curves) were compared using log-rank tests. Prognostic factors of poor outcome (modified Rankin Scale score >2) were identified using logistic regression models. A total of 115 patients were included, of whom 84 (71 adults, 13 children) had only AMPAR antibodies and 31 (27 adults, 4 children) had additional concurrent neural antibodies. Among patients with AMPAR antibodies alone, tumors were identified in 37 adults (56%) and none of the children (p < 0.0001). Children were more likely than adults to have behavioral/psychiatric symptoms (5/13, 39%, vs 8/71, 11%, p = 0.026) at onset, cerebellar dysfunction (6/13, 46%, vs 7/68, 10% p = 0.005) or movement disorders (5/13, 39%, vs 8/67, 12%, p = 0.032) during the disease course, and extratemporal brain MRI lesions (4/9, 44%, vs 5/44, 11%, p = 0.035). Among 34 patients with prolonged follow-up (>24 months), long-term neurocognitive sequelae were reported in 23 (68%), all adults. Failure to respond to first-line immunotherapy at multivariable analysis predicted a poor outcome (OR 8.0, 95% CI 1.1-59.2, p = 0.043). Among the 31 patients with concurrent neural autoantibodies, 22 (79%) had a tumor; those with high-risk antibodies had lower survival rates (p = 0.008). Children and adults with anti-AMPAR encephalitis show distinct clinical-radiologic features. At long-term follow-up, 68% of patients, all adults, have neurologic sequelae, with failure to respond to first-line immunotherapy being associated with worse outcomes.

Spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative disorders caused by pathogenic variants in more than 40 genes with diverse cellular functions. In this study, we identified the c.247C>T p.(Arg83Trp) variant in RAB3A , encoding a small GTPase involved in membrane-associated regulated exocytosis, in two families with cerebellar ataxia. Affected individuals presented with adult-onset, gradually progressive cerebellar symptoms, often accompanied by mild gait spasticity and tremors. Variable features of neurodevelopmental disorders were also observed. Brain MRI consistently revealed cerebellar atrophy, often accentuated in the vermis, and neuropathological examinations demonstrated diffuse cerebellar cortical degeneration. Functionally, the R83W mutation lies within the conserved switch II region of Rab3A, a domain critical for effector interaction. Although the mutant Rab3A R83W retained GTP-binding affinity, it failed to bind the key effector proteins RIM1 and Rabphilin-3A, highlighting the functional importance of R83 in effector complex formation, as supported by structural analysis. In PC12 cells, the R83W mutant exhibited diffuse cytoplasmic localization, in contrast to the vesicle- and neurite-tip localization of the wild-type and GTP-bound Rab3A mutant. The concordant localization pattern of R83W and GDP-bound Rab3A mutants suggests that R83W-induced mislocalization results from a failure to engage downstream effector proteins. In frozen sections of the mouse cerebellum, Rab3A was predominantly localized to parallel fiber terminals and was absent from postsynaptic Purkinje cells. These findings suggest that disruption of the interaction between Rab3A and its effector proteins may underlie disease pathogenesis, possibly involving presynaptic dysfunction at parallel fiber–Purkinje cell synapses mediated by the Rab3A–RIM1 complex.

Repeat expansion diseases, particularly those involving GC-rich motifs, have been increasingly recognized as contributors to neurological and neuromuscular disorders. Amyotrophic lateral sclerosis (ALS) has been linked to several such expansions, including intermediate-length repeats in genes implicated in oculopharyngodistal myopathy (OPDM). To investigate the possible involvement of CGG repeat expansions in ALS, 424 ALS patients and 312 controls of Japanese descent were screened for expansions in five genes associated with repeat expansion disorders, namely GIPC1 , RILPL1 , FMR1 , AFF2 , and NUTM2BAS1 . Repeat-primed PCR and fragment analysis revealed that four ALS patients exhibited abnormal CGG expansions in GIPC1 (33–55 repeats), whereas two control individuals harbored expanded alleles (67 and 83 repeats). No expansions in the other genes were detected. Long-read sequencing confirmed repeat sizes and showed sequence instability. Histopathological analysis of ALS patients with GIPC1 expansion demonstrated classical ALS pathology, including phosphorylated TDP-43-positive inclusions. RNA fluorescence in situ hybridization revealed nuclear foci containing GIPC1 repeat RNA exclusively in ALS patients with GIPC1 expansions, suggesting RNA-mediated toxicity. These findings indicate that a subset of ALS patients present with intermediate CGG expansions in GIPC1 , which may represent a novel pathogenic mechanism analogous to other noncoding repeat disorders. Given that GIPC1 full expansions are associated with OPDM, these results support the hypothesis of a pathological continuum between neurodegeneration and myopathy driven by repeat length and sequence context. Nonetheless, further investigations into the potential of GIPC1 CGG expansions as genetic risk factors or modifiers in ALS are warranted.

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.