Corrigendum: Sensory nerve action potential in patients with functional neurological disorders with sensory manifestations.

[This corrects the article DOI: 10.3389/fneur.2023.1259887.].

Efficacy and safety of mycophenolate mofetil for steroid reduction in neuromyelitis optica spectrum disorder: a prospective cohort study.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disease that can affect multiple generations and cause complications with long-term prednisolone treatment. This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) in preventing NMOSD relapse while reducing prednisolone dosage. The trial involved nine patients with NMOSD who received MMF along with prednisolone dose reduction. MMF was effective in achieving prednisolone dose reduction without relapse in 77.8% of patients, with a significant decrease in mean annualized relapse rate. All adverse events were mild. The findings suggest that MMF could be a viable treatment option for middle-aged and older patients who require steroid reduction.Clinical trial registration number: jRCT, jRCTs051180080. Registered February 27th, 2019-retrospectively registered, https://jrct.niph.go.jp/en-latest-detail/jRCTs051180080.

Nerve enlargement differs among chronic inflammatory demyelinating polyradiculoneuropathy subtypes and multifocal motor neuropathy.

Objective: We aimed to evaluate differences in ultrasonographic nerve enlargement sites among typical chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), distal CIDP, multifocal CIDP and multifocal motor neuropathy (MMN) in a Japanese population. Methods: We retrospectively reviewed medical records and selected 39 patients (14 with typical CIDP, 7 with multifocal CIDP, 4 with distal CIDP, and 14 with MMN) who underwent ultrasonography. Median and ulnar nerve cross-sectional areas (CSAs) were measured at the wrist, forearm, elbow, and upper arm. CSA ratios for each nerve were calculated as: wrist-to-forearm index (WFI) = wrist CSA/forearm CSA; elbow-to-upper arm index (EUI) = elbow CSA/upper arm CSA; and intranerve CSA variability (INCV) = maximal CSA/minimal CSA. Results: Significant differences were observed among typical CIDP, multifocal CIDP, distal CIDP, and MMN in CSA at the forearm and upper arm in the median nerves (p < 0.05). Patients with multifocal CIDP had lower WFI and EUI and higher INCV than the other groups (p < 0.05). Conclusions: Regardless of the untreated period, compared with other CIDP subtypes and MMN, multifocal CIDP showed a focal and marked nerve enlargement in the Japanese population. Significance: Differences in nerve enlargement site may be an underlying feature of multifocal CIDP.

Sensory nerve action potential in patients with functional neurological disorders with sensory manifestations.

Introduction: Functional neurological disorder (FND) has various clinical manifestations. Even though diagnostic criteria for FND have been proposed, FND characteristics with sensory manifestations have not been elucidated. Therefore, we aimed to investigate the association between sensory nerve action potential (SNAP) amplitudes and FND with sensory manifestations. Methods: We included 76 outpatients with FND with sensory manifestations whose nerve conduction studies were performed retrospectively. Additionally, we defined 121 patients with other neurological diseases who did not have peripheral neuropathy as disease controls. The SNAP amplitudes were compared between the two groups. We also explored the relationship between SNAP amplitudes and FND-specific clinical symptoms in patients with FND. Results: No differences were observed in SNAP amplitudes adjusted for age between patients with FND who had sensory manifestations and disease control patients. Additionally, no differences were observed between patients with FND who had and did not have FND-specific clinical symptoms. Conclusion: The SNAP amplitude in patients with FND who had sensory manifestations was equivalent to that in controls.

[Cingulate seizure as a clinical manifestation of anti-myelin oligodendrocyte glycoprotein antibody-positive cerebral cortical encephalitis of two cases].

We report two male patients who had a sensory seizure, which evolved into a focal impaired awareness tonic seizure, and after that, focal to bilateral tonic-clonic seizure. The first case, a 20-year-old man had been treated with steroids for anti-myelin oligodendrocyte glycoprotein (MOG) antibody-positive optic neuritis. His seizure started with abnormal sensation in the little finger of the left hand, which spread to the left upper and then to the left lower limb. The seizure then evolved into tonic seizures of the upper and lower limbs and he finally lost awareness. The second case, a 19-year-old man experienced floating dizziness while walking, followed by numbness and a pain-like electrical shock in the right upper limb. The right arm somatosensory seizure evolved into a right upper and lower limb tonic seizure, which spread to the bilateral limbs, and finally he lost awareness. Symptoms of both patients improved after the treatment with steroids. Both patients shared a similar high-intensity FLAIR lesion in the posterior midcingulate cortex. Both patients were diagnosed with MOG antibody-positive cerebral cortical encephalitis because of a positive titer of anti-MOG antibody in the serum. Several reports showed involvement of the cingulate gyrus in MOG antibody-positive cerebral cortical encephalitis, but only a few reported seizure semiology in detail. The semiology reported here is consistent with that of cingulate epilepsy or the findings of electrical stimulation of the cingulate cortex, namely, somatosensory (electric shock or heat sensation), motor (tonic posture), and vestibular symptoms (dizziness). Cingulate seizures should be suspected when patients show somatosensory seizures or focal tonic seizures. MOG antibody-positive cerebral cortical encephalitis should be considered as one of the differential diagnoses when the young patient shows the unique symptoms of an acute symptomatic cingulate seizure.

The effectiveness of moisturizer on acute radiation-induced dermatitis in breast cancer patients: a systematic review and meta-analysis.

PURPOSE: We conducted a systematic review and meta-analysis to investigate the effectiveness of moisturizers on acute radiation dermatitis (ARD) in breast cancer patients receiving radiotherapy (RT). METHODS: PubMed, the Cochrane Library, CINAHL, and Ichushi-Web were searched for randomized controlled trials (RCTs) from April 2015 to March 2020. Assessments included type of intervention, cohort, outcomes, and quality of evidence. To evaluate the effect of moisturizer on ARD, we restricted analyses to studies comparing with standard skin care or no treatment. Outcomes were ARD severity and skin-related QOL (quality of life). Eligible studies were identified, and risk ratios and mean differences were extracted to compare outcome data. RESULTS: We screened 210 RCTs along with 14 studies included in a previous iteration of this analysis (2016), supplemented by a hand search (n = 9). Finally, we included 6 RCTs that investigated the effectiveness of standard type moisturizers in breast cancer patients receiving RT. Evidence (weak certainty) suggests that moisturizer use might reduce ≥ grade 3 ARD. QOL assessed by Skindex-16 improved with moisturizer use. Pain and pruritus measured by the visual analog scale (VAS) resulted in a smaller and nonsignificant difference in favor of moisturizer use. However, the certainty of the evidence was very weak in QOL. CONCLUSIONS: The proactive use of moisturizer may play a role in reducing ARD and improving skin-related QOL, although the certainty of the evidence was weak to very weak. Future high-quality RCTs should be initiated to strengthen these results.

Long-Surviving Adult Siblings With Joubert Syndrome Harboring a Novel Compound Heterozygous CPLANE1 Variant.

Background and Objectives: We describe 2 long-surviving siblings with a mild phenotype of Joubert syndrome (JBTS) harboring a novel compound heterozygous missense variant in the CPLANE1 gene. Methods: Targeted sequencing data of 2 middle-aged siblings (sister and brother) with JBTS were analyzed. Results: The patients were older than 60 years and presented with an inborn facial anomaly and ataxia, accompanied by a molar tooth sign on brain MRI. The male patient showed mild intellectual disability, abnormal eye movements, and progressive gait disturbance. Targeted sequencing revealed a compound heterozygous missense variant of CPLANE1 p.Arg1193Cys_Gln1223Pro; c.3577C>T_3668A>C. Multiple in silico assays predicted that the missense sites were pathogenic. Discussion: The phenotype-genotype correlation of CPLANE1 remains controversial, although many cases have been previously reported in children and young adults. Our study revealed a novel pathogenic variant of CPLANE1 in patients, confirming the role of this gene in JBTS, thus providing an opportunity for neurologists to recognize JBTS as a differential diagnosis for chronic progressive ataxia in an aging society.

Clinical Utility of Repetitive Nerve Stimulation Test in Differentiating Multifocal Motor Neuropathy From Progressive Muscular Atrophy.

OBJECTIVES: To evaluate the utility of repetitive nerve stimulation test (RNS) for differentiating multifocal motor neuropathy (MMN) and progressive muscular atrophy (PMA). METHODS: We retrospectively enrolled 20 patients with MMN or PMA. We extracted the results of the initial 3-Hz RNS in the ulnar and accessory nerves and compared the percentage and frequency of abnormal decremental responses between both groups. RESULTS: RNS was performed in 8 ulnar and 9 accessory nerves in patients with MMN, and in 8 ulnar and 10 accessory nerves in patients with PMA. Patients with MMN had a significantly lower decrement percentage (0.6 ± 4.0% in MMN vs. 10.3 ± 6.5% in PMA, P < 0.01) and frequency of abnormal decremental response (0 of 9 in MMN vs. 6 of 10 in PMA, P = 0.01) than patients with PMA in the accessory nerve. CONCLUSIONS: The RNS has clinical utility for differentiating MMN from PMA.

Transcription Factor c-Maf Promotes Immunoregulation of Programmed Cell Death 1-Expressed CD8+ T Cells in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. CD8+ T cells are prominently found at inflammatory sites. Recent advances in understanding checkpoint molecules, including programmed cell death 1 (PD-1), expressed on CD8+ T cells, highlight the immune regulatory roles of this T-cell subset; however, the role of CD8+ T cells in MS is unclear. Thus, we aimed to reveal the characteristics of PD-1-expressed (PD-1+) CD8+ T cells in MS. METHODS: We performed a cohort, case-control study for phenotyping analysis of PD-1+CD8+ T cells in disease remission and flare states using CSF and peripheral blood samples of 45 patients with MS or clinically isolated syndrome and 12 healthy subjects. We further analyzed the transcriptome of sorted PD-1+CD8+ T cells obtained from interferon (IFN)-ß-treated patients and validated their regulatory machinery using in vitro cell culture assays with lentiviral gene transfer. RESULTS: In the disease remission state, PD-1+CD8+ T cells were decreased in the peripheral blood of patients with MS and resolved in patients treated with IFN-ß treatment who showed immune regulatory cytokine interleukin (IL)-10 expression. In the disease flare state, we found that PD-1+CD8+ T cells were enriched in the CSF, which predicted a good response to subsequent IV steroid therapy. Transcriptome analysis of sorted PD-1+CD8+ T cells revealed the transcription factor c-Maf as a potential major regulator of the gene module, including multiple coinhibitory molecules. Furthermore, c-Maf expressed in CD8+ T cells induced PD-1 expression and production of IL-10 as well as suppressed alloactivated CD4+ T-cell survival. DISCUSSION: This study uncovered a favorable role of PD-1+CD8+ T cells against MS and demonstrated that c-Maf-driven IL-10 is an immune regulatory machinery.

Clinical and pathological characteristics of later onset multiple system atrophy.

BACKGROUND: In the current consensus criteria, onset after age 75 is considered as non-supporting for diagnosis of multiples system atrophy (MSA); however, some MSA patients present after age 75. Clinical and pathological characteristics of such later onset MSA (LO-MSA) compared to usual onset MSA (UO-MSA) remain poorly understood. METHODS: The clinical cohort included patients from Kobe University Hospital and Amagasaki General Medical Center Hospital, while the autopsy cohort was from the brain bank at Mayo Clinic Florida. We identified 83 patients in the clinical cohort and 193 patients in the autopsy cohort. We divided MSA into two groups according to age at onset: UO-MSA (≤ 75) and LO-MSA (> 75). We compared clinical features and outcomes between the two groups in the clinical cohort and compared the findings to the autopsy cohort. RESULTS: LO-MSA accounted for 8% in the clinical cohort and 5% in the autopsy cohort. The median time from onset to death or to life-saving tracheostomy was significantly shorter in LO-MSA than in UO-MSA in both cohorts (4.8 vs 7.9 years in the clinical cohort and 3.9 vs 7.5 years in the autopsy cohort; P = 0.043 and P < 0.0001, respectively). The median time from diagnosis to death was less than 3 years in LO-MSA in the clinical cohort. CONCLUSIONS: Some MSA patients have late age of onset and short survival, limiting time for clinical decision making. MSA should be considered in the differential diagnosis of elderly patients with autonomic symptoms and extrapyramidal and/or cerebellar syndromes.

Voxel-based analysis of age and gender effects on striatal [123I] FP-CIT binding in healthy Japanese adults.

OBJECTIVE: Although previous studies have investigated age and gender effects on striatal subregional dopamine transporter (DaT) binding, these studies were mostly based on a conventional regions of interest-based analysis. Here, we investigated age and gender effects on striatal DaT binding at the voxel level, using a multicenter database of [(123)I] N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane ([(123)I] FP-CIT)-single photon emission computed tomography (SPECT) scans in 256 healthy Japanese adults. METHODS: We used the Southampton method to calculate the specific binding ratios (SBRs) of each subject's striatum and then converted the [123I] FP-CIT SPECT images to quantitative SBRs images. To investigate the effects of age and gender effects on striatal DaT binding, we performed a voxel-based analysis using statistical parametric mapping. Gender differences were also compared between young to middle-aged subjects and elderly subjects (age threshold: 60 years). RESULTS: When all subjects were explored as a group, DaT binding throughout the striatum decreased with advancing age. Among all subjects, the females showed higher DaT binding in the bilateral caudate compared to the males. In the young to middle-aged subjects, the females showed higher DaT binding throughout the striatum (with a slight caudate predominance) versus the males. In the elderly, there were no gender differences in striatal DaT binding. CONCLUSION: Our findings of striatal subregional age- and gender-related differences may provide useful information to construct a more detailed DaT database in healthy Japanese subjects.

Immunotherapy-responsive Non-paraneoplastic Encephalitis with Antibodies against GAD, LGI1, and GABAA Receptor.

A 62-year-old man showed abnormal behavior. Brain magnetic resonance imaging revealed multifocal lesions on T2-weighted images. Initial screening revealed that he was seropositive for antibodies against glutamate decarboxylase, which usually indicates treatment resistance to autoimmune encephalitis (AE). Intensive immunosuppressive therapies, however, improved the neurological symptoms. In line with this, we also detected seropositivity for antibodies against leucine-rich glioma-inactivated 1 and gamma-aminobutyric acid A receptor (GABAAR). Brain imaging and treatment responsiveness suggested that antibodies against GABAAR were the main cause of symptoms. Furthermore, the patient showed the presence of triple anti-neural antibodies in the absence of malignancy and had a favorable clinical course.

FKRP mutations cause congenital muscular dystrophy 1C and limb-girdle muscular dystrophy 2I in Asian patients.

Mutation in the fukutin-related protein (FKRP) gene causes alpha-dystroglycanopathies, a group of autosomal recessive disorders associated with defective glycosylated alpha-dystroglycan (α-DG). The disease phenotype shows a broad spectrum, from the most severe congenital form involving brain and eye anomalies to milder limb-girdle form. FKRP-related alpha-dystroglycanopathies are common in European countries. However, a limited number of patients have been reported in Asian countries. Here, we presented the clinical, pathological, and genetic findings of nine patients with FKRP mutations identified at a single muscle repository center in Japan. Three and six patients were diagnosed with congenital muscular dystrophy type 1C and limb-girdle muscular dystrophy 2I, respectively. None of our Asian patients showed the most severe form of alpha-dystroglycanopathy. While all patients showed a reduction in glycosylated α-DG levels, to variable degrees, these levels did not correlate to clinical severity. Fifteen distinct pathogenic mutations were identified in our cohort, including five novel mutations. Unlike in the populations belonging to European countries, no common mutation was found in our cohort.

[A case of spinal cord infarction accompanied with neuromyelitis optica spectrum pathophysiology].

We report a 60-year-old woman who developed spinal cord infarction (SCI) with anti-aquaporin (AQP) 4 antibody seropositive. She was admitted to our hospital with acute onset of flaccid paraparesis and urinary disturbances that completed within a few minutes after acute pain in her lower back. Neurological examination revealed flaccid paraparesis, bladder and bowel dysfunction and dissociated sensory loss below the level of Th11 spinal cord segment. Diffusion weighted imaging (DWI) and T2-wighted imaging (T2WI) of thoracic spine MRI showed high signal intensity in the spinal cord between Th9 and Th12 vertebral levels with decreased apparent diffusion coefficient (ADC). We diagnosed her as having SCI. Thereafter the serum examination on admission was reported as positive for anti-aquaporin 4 (AQP4) antibody. Cerebrospinal fluid (CSF) analysis revealed pleocytosis, and the spinal cord lesions became enlarged in MRI on 12 days after the onset. We, therefore, suspected that the pathophysiology of neuromyelitis optica spectrum disorder (NMOSD) accompanied SCI. The patient underwent two courses of high dose intravenous methylprednisolone (IVMP) for three days (1 g/day). Her neurological symptoms did not improve significantly, but the size of T2WI MRI high signal lesion improved to that of the initial MRI scan. Anti-AQP4 antibody seropositivity may have modified the SCI pathology in the present patient.

Effect of Heparinoid Moisturizer on Quality of Life in Patients with Acute Radiation Skin Damage Following Hypofractionated Radiation Therapy After Breast-Conserving Surgery: A Randomized Controlled Study.

BACKGROUND: With few research reports on the effects of moisturizer use for dry skin associated with radiotherapy after breast-conserving surgery on patient quality of life (QOL), we conducted a randomized controlled trial to investigate this effect. METHODS: Patients with breast cancer were randomly assigned to receive either heparinoid moisturizer (Group M) or no treatment (Group C). Group M was instructed to apply heparinoid moisturizer during 3 weeks of hypofractionated whole-breast irradiation with or without boost until 4 weeks after completion of irradiation. Skin-related QOL was assessed using the Dermatology Life Quality Index (DLQI) for 7 weeks. The primary endpoint was total DLQI score at 4 weeks after the start date. RESULTS: In total, 35 patients in Group M and 37 patients in Group C were analyzed. The DLQI total score (2.06 ± 2.17: mean ± SD) at 4 weeks in Group M was slightly lower than in Group C (2.16 ± 2.13) but with no significant difference (p = 0.894). The "Symptoms and feelings" subscore indicated significant worsening at 3 weeks and maintained until 7 weeks in Group C. There was no significant change for this subscore during radiotherapy in Group M, and it significantly increased after radiotherapy (4-5 weeks) and returned to baseline in 7 weeks. The period of subscore worsening was shorter in Group M than in Group C. CONCLUSION: Concomitant and extended use of heparinoid moisturizer with radiation therapy may improve the QOL of breast cancer patients impaired by dry skin for patients with breast cancer.