[A case of Charcot-Marie-Tooth disease type 2 caused by homozygous MME gene mutation].

The patient is a 44-year-old man. His parents are consanguineous. He experienced muscle weakness in his toe and distal tingling sensation in his feet at 42 years of age, which gradually progressed. Additionally, a marked cyanotic discoloration of the feet appeared and worsened progressively. Neurological examination revealed loss of tendon reflexes and distal muscle weakness in the lower extremities. Findings from nerve conduction studies indicated axonal polyneuropathy. Upon detection of the MME gene mutation, the patient was diagnosed with autosomal-recessive Charcot-Marie-Tooth disease 2T (ARCMT2T). In this case, cyanosis of the lower extremities possibly was associated with ARCMT2T, and it was suggested to be due to neprilysin deletion linked with the MME mutation. This represents the first documented occurrence of cyanosis as a distinctive feature of CMT with MME mutation.

Superior cerebellar peduncle atrophy of progressive supranuclear palsy on phase difference enhanced imaging: a comparison with Parkinson's disease.

PURPOSE: Phase difference enhanced (PADRE) imaging can enhance myelin density and delineate the superior cerebellar peduncle (SCP). We aimed to determine if SCP atrophy was distinguishable on PADRE imaging and evaluate its diagnostic performance compared with previous MRI progressive supranuclear palsy (PSP) findings. METHODS: Two reviewers measured the SCP widths on PADRE in 20 PSP and 31 Parkinson's disease (PD) patients. The SCP and middle cerebellar peduncle (MCP) widths and the pons and midbrain areas were measured on 3D-T1WI, and the ratio of the area of the pons to the area of the midbrain, the MCP/SCP ratio, and the magnetic resonance parkinsonism index (MRPI) were calculated. We used the Steel-Dwass test to compare PSP, PD, and HS, and receiver operating characteristic curve (ROC) analyses to assess the sensitivity and specificity for diagnosing PSP from PD. A comparison of ROC curves was performed between the SCP on PADRE and these 3D-T1WI parameters. RESULTS: In radiologist 1, the SCP on PADRE in PSP (1.1 ± 0.3 mm) was significantly smaller than those in PD (2.4 ± 0.4 mm) (P < 0.001); the area under the curve (AUC) was 0.97. At a 1.75-mm cutoff value, the diagnostic sensitivity and specificity for differentiating PSP from PD were 93.5% and 100%, respectively. The AUC of the SCP on PADRE was significantly higher than the 3D-T1WI parameters (the SCP, MCP, pons area, MCP/SCP ratio, and MRPI). CONCLUSION: Assessing SCP with PADRE imaging may yield high diagnostic accuracy for discriminating PSP from PD.

Optic radiation atrophy in Lewy body disease with visual hallucination on phase difference enhanced magnetic resonance images.

Visual hallucinations (VH) occur commonly in Lewy body disease (LBD), including Parkinson's disease (PD), PD with dementia, and dementia with Lewy bodies. We aimed to use phase difference enhanced imaging (PADRE) to assess structural abnormalities of optic radiation (OR) in patients with Lewy body disease (LBD) concomitant with VH. Firstly, two radiologists reviewed the OR appearances in healthy subjects (HS) on PADRE. Next, based on the OR abnormalities, two reviewers assessed the PADRE images from 18 HS and 38 and 110 patients with LBD, with and without VH, respectively, in a blinded manner. Finally, all patients with LBD without VH were eventually followed up for at least 5 years after magnetic resonance imaging to determine the appearance of VH. The radiologists identified three layers, namely external sagittal stratum, internal sagittal stratum, and tapetum, in OR on the PADRE in HS. Moreover, they were able to consensually define the OR as abnormal when the layers were obscured and the disappearance of the cranial side. The sensitivity/specificity of abnormal OR for each case was 68%/81% (LBD with VH vs. LBD without VH). Furthermore, VH appeared in 12 of the 21 (57%) patients with LBD and abnormal OR during the follow-up period. However, no patients without abnormal OR reported VH. Patients with LBD and VH demonstrated the abnormal OR. This, in turn, might be a useful marker to distinguish the patients with VH from those without VH and HS. Moreover, abnormal OR on PADRE may precede the appearance of VH in LBD.

Olfactory Dysfunction Reflects Disease Progression in Japanese Patients with Multiple Sclerosis.

Objective Olfactory dysfunction is an important clinical feature in patients with multiple sclerosis (MS). The incidence and extent of olfactory dysfunction are reportedly higher in secondary progressive (SP) MS than in relapsing and remitting (RR) MS. We investigated the use of olfactory dysfunction for evaluating the disease status of Japanese patients with MS. Methods Olfactory identification was evaluated using the Odor Stick Identification Test for the Japanese (OSIT-J) in patients with RRMS (n=40) and SPMS (n=11) and compared the findings with those of healthy controls (n=40). Patients with RRMS for more than 10 years (L-RRMS, n=10) were included in the RRMS group. The cognitive function was evaluated using the Japanese version of the Wechsler Adult Intelligence Scale, 3rd edition. The third ventricle width (3rd VW) was measured as a marker of central brain atrophy using magnetic resonance imaging. Results SPMS patients had significantly lower OSIT-J scores than RRMS and L-RRMS patients. More SPMS patients had OSIT-J scores below the lower limit of the normal score (LLN) than RRMS patients. The LLN effectively discriminated between RRMS and SPMS (sensitivity 70%, specificity 91.5%, area under the curve 0.933, 95% confidence interval 0.874-1.000). Patients with SPMS had a significantly lower processing speed and larger 3rd VW than those with RRMS or L-RRMS. Conclusion The olfactory dysfunction was worse, along with cognitive impairment and brain atrophy, in SPMS patients than in RRMS patients, independent of disease duration, in our Japanese population. This directly reflected the disease progression and may have been able to distinguish SPMS from RRMS, independent of ethnic and cultural background.

Compassionate open-label use of rituximab following a randomised clinical trial against neuromyelitis optica (RIN-2 study): B cell monitoring-based administration.

OBJECTIVE: The aim of the RIN-2 study was a compassionate use of rituximab (RTX) for patients who completed the RIN-1 study, a multicentre, randomised, double-blind, placebo-controlled trial of RTX. We also investigated the long-term safety and efficacy of RTX. METHODS: A study design was a prospective open-label extension study following the RIN-1 study. RTX was infused repeatedly under monthly monitoring of CD19-positive and CD 20-positive B cell lymphocyte subsets from 24 weeks after an infusion. RESULTS: Thirty-three (87%) of 38 patients of the RIN-1 study were enrolled from February 2016 to March 2019 at six sites in Japan. In RIN-2, RTX was administered three times (median, range 1-5 times), and the interval of RTX administrations were 9.5 [2.5] months (mean [SD]). The observation period was 20.5 [10.1] months. During the trial, three patients dropped out due to two withdrawals and one adverse event. During the study, 28 (90%) of 31 patients were treated with RTX monotherapy. Neuromyelitis optica (NMO) relapses were observed in two patients. The annualized relapse rate (ARR) was 0.035 counts per person-years, ∼1/10th compared with 0.321 in the placebo arm of the RIN-1 study. We observed 14 severe adverse events in six (18%) and 156 adverse events, of which 135 were grade 1, 11 were grade 2 and 10 were grade 3. CONCLUSIONS: Under B cell monitoring, the interval of RTX re-infusion was elongated to nine months, and NMO relapses were suppressed with 0.035 of ARR.

Unclassified subtype of Guillain-Barré syndrome is associated with quick recovery.

Electrophysiological classification of Guillain-Barré syndrome (GBS) is important for predicting its clinical course; however, few reports discuss GBS patients who do not conform to the acute inflammatory demyelinating polyneuropathy (AIDP) or acute motor axonal neuropathy (AMAN) classifications. Therefore, the present study assessed the features of unclassified types of GBS and compared them to those of AIDP and AMAN. We compared clinical symptoms, nerve conduction, and laboratory data among patients with AIDP, AMAN, and unclassified subtypes of GBS, according to criteria developed by Rajabally, Hadden, and Ho. According to the Rajabally criteria, the F wave frequency in the upper and lower extremities was higher in the unclassified subgroup than in the AIDP and AMAN subgroups; however, according to the Hadden and Ho criteria, the F wave frequency in only the lower extremities was higher in the unclassified subgroup than in the other subgroups. The unclassified subgroup showed better prognosis using the Rajabally criteria. Classification with the Rajabally criteria is useful for predicting prognosis and determining treatment in patients with GBS. Moreover, unclassified patients exhibit the quickest recovery.

Hydration of the Zwitterionic and Protonated Forms of Glycine Betaine Probed by Soft X-ray Emission Spectroscopy Coupled with Chemometrics.

Soft X-ray absorption and emission spectra of glycine betaine (GB) have been measured at the O K-edge in neutral and strongly acidic solutions. The absorption spectra of the neutral solutions have a resonance peak at 532.6 eV, assigned to the transition to the π* orbital, whereas in the acidic solutions, the peak is shifted by -0.3 eV. The emission spectra taken as a function of the GB concentration have been analyzed by means of a modified classical least-squares regression method to obtain the hydration number of the solute. The analysis is successful when the emission spectra have been acquired at the energy of a slightly detuned resonance, giving 28 and 24 as the minimum values for the zwitterionic and protonated GB, respectively. The number of 28 accords with the reported values for the number of water molecules in the first hydration layer of the zwitterion and is greater than that obtained by other experimental techniques. The obtained numbers are used to discuss the hydration structure of GB with the aid of ab initio molecular orbital calculations. The hydration structure of the protonated form of GB is explored for the first time.

HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data.

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD.

Signal intensity of cerebral gyri in corticobasal syndrome on phase difference enhanced magnetic resonance images: Comparison of progressive supranuclear palsy and Parkinson's disease.

We evaluated cerebral gyri (CG) on phase difference enhanced imaging (PADRE) of corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Parkinson's disease (PD) patients to determine whether it is possible to discriminate among them on an individual basis. Two radiologists reviewed appearance of the normal CG and that of CBS patients on PADRE, and deviations from the appearance of the normal CG were recorded. Next, based on the CG abnormalities, two other reviewers reviewed PADRE images from 12 CBS, 14 PSP, and 30 PD patients. In healthy subjects on the PADRE images, the signal intensity (SI) of the gray matter (GM) was homogeneously, slightly hyperintense to the subcortical white matter (SCWM), and the SI of the SCWM was homogeneously hypointense. In CBS patients, hypointense layer in superficial GM and disappearance of hypointense in SCWM. The frequency of the abnormal findings on PADRE in the blinded manner by two readers was 100% (12/12), 3% (1/30), and 29% (4/14 in Reader 1) or 36% (5/14 in Reader 2) in CBS PD, and PSP patients, respectively. Laterality of the PADRE findings was showed in 12 (100%) CBS patients and 3 (21%) PSP, but not in any PD patients. The previously reported typical findings in CBS on conventional magnetic resonance image (MRIs) were observed in only 42% (5/12) of CBS patients. In conclusion, the abnormal findings in CG on PADRE appears more useful than conventional MRI findings for discriminating CBS from PD on an individual basis.

Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Pharmacological prevention against relapses in patients with neuromyelitis optica spectrum disorder (NMOSD) is developing rapidly. We aimed to investigate the safety and efficacy of rituximab, an anti-CD20 monoclonal antibody, against relapses in patients with NMOSD. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled clinical trial at eight hospitals in Japan. Patients aged 16-80 years with NMOSD who were seropositive for aquaporin 4 (AQP4) antibody, were taking 5-30 mg/day oral steroids, and had an Expanded Disability Status Scale (EDSS) score of 7·0 or less were eligible for the study. Individuals taking any other immunosuppressants were excluded. Participants were randomly allocated (1:1) either rituximab or placebo by a computer-aided dynamic random allocation system. The doses of concomitant steroid (converted to equivalent doses of prednisolone) and relapses in previous 2 years were set as stratification factors. Participants and those assessing outcomes were unaware of group assignments. Rituximab (375 mg/m2) was administered intravenously every week for 4 weeks, then 6-month interval dosing was done (1000 mg every 2 weeks, at 24 weeks and 48 weeks after randomisation). A matching placebo was administered intravenously. Concomitant oral prednisolone was gradually reduced to 2-5 mg/day, according to the protocol. The primary outcome was time to first relapse within 72 weeks. Relapses were defined as patient-reported symptoms or any new signs consistent with CNS lesions and attributable objective changes in MRI or visual evoked potential. The primary analysis was done in the full analysis set (all randomly assigned patients) and safety analyses were done in the safety analysis set (all patients who received at least one infusion of assigned treatment). The primary analysis was by intention-to-treat principles. This trial is registered with the UMIN clinical trial registry, UMIN000013453. FINDINGS: Between May 10, 2014, and Aug 15, 2017, 38 participants were recruited and randomly allocated either rituximab (n=19) or placebo (n=19). Three (16%) patients assigned rituximab discontinued the study and were analysed as censored cases. Seven (37%) relapses occurred in patients allocated placebo and none were recorded in patients assigned rituximab (group difference 36·8%, 95% CI 12·3-65·5; log-rank p=0·0058). Eight serious adverse events were recorded, four events in three (16%) patients assigned rituximab (lumbar compression fracture and infection around nail of right foot [n=1], diplopia [n=1], and uterine cancer [n=1]) and four events in two (11%) people allocated to placebo (exacerbation of glaucoma and bleeding in the right eye chamber after surgery [n=1], and visual impairment and asymptomatic white matter brain lesion on MRI [n=1]); all patients recovered. No deaths were reported. INTERPRETATION: Rituximab prevented relapses for 72 weeks in patients with NMOSD who were AQP4 antibody-positive. This study is limited by its small sample size and inclusion of participants with mild disease activity. However, our results suggest that rituximab could be useful maintenance therapy for individuals with NMOSD who are AQP4 antibody-positive. FUNDING: Japanese Ministry of Health, Labour and Welfare, Japan Agency for Medical Research and Development, and Zenyaku Kogyo.

Facial nerve atrophy in patients with amyotrophic lateral sclerosis: Evaluation with fast imaging employing steady-state acquisition (FIESTA).

BACKGROUND: In amyotrophic lateral sclerosis (ALS), motor neurons in the brainstem markedly deplete, whereas sensory neurons are less severely affected. PURPOSE: To determine whether facial nerve (FN) measurement on 3D fast imaging employing steady-state acquisition (FIESTA) is useful for ALS diagnosis. STUDY TYPE: Retrospective. SUBJECTS: Fifteen ALS patients and 16 controls. FIELD STRENGTH/SEQUENCE: 3T FIESTA MR. ASSESSMENT: The cross-sectional area of the FN and cochlear nerve (CN) were measured, and the FN/CN ratio (FCR) was assessed. For qualitative assessment, the FN cross-sectional area was compared with that of the CN and the following scores were assigned: score 1 (large), the FN is larger than the CN; score 2 (almost equal), the size difference between the FN and CN is within 10%; score 3 (small), the FN is smaller than the CN (10-50%); score 4 (significantly small), size of the FN is less than half the size of the CN. STATISTICAL TESTS: The differences in FCR between the ALS patients and the controls were tested using the Wilcoxon Mann-Whitney U-test. For the qualitative and quantitative assessments, we performed a receiver operating characteristic analysis for the diagnosis of ALS with an abnormal finding as score 3 or 4. RESULTS: The mean FCR was significantly smaller for ALS patients (0.71 ± 0.17) than for controls (0.95 ± 0.08) (P < 0.001) and the area under the curve was 0.93. When an FN score was 3 or 4, indicative of FN atrophy, the sensitivity and specificity values of FIESTA for discriminating ALS patients from controls were 93.3% (14/15) and 90.0% (18/20), respectively. DATA CONCLUSION: The FN atrophy revealed on FIESTA, which may reflect lower motor neuron impairment in ALS, allowed us to distinguish ALS patients from controls with a high degree of accuracy. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:757-766.

Olfactory identification associates with cognitive function and the third ventricle width in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Olfactory dysfunction is a known clinical feature of multiple sclerosis (MS). Some studies have shown that odor identification impairment is an essential feature associated with cognitive function in MS. This study investigates the relationship between olfactory identification and the disease state, including cognitive function and central brain volume, to evaluate the utility of olfactory identification in the clinical assessment of relapsing-remitting (RR) MS. METHODS: Forty patients with RRMS and 40 healthy controls (HCs) were included. Their olfactory identification was measured using the Odor Stick Identification Test for the Japanese (OSIT-J). Cognitive function was evaluated by the Japanese version of the Wechsler Adult Intelligence Scale, 3rd edition (WAIS-III), and depressive mood was evaluated by the Center for Epidemiologic Studies Depression Scale. Magnetic resonance imaging was used to measure the third ventricle width (3rd VW) as a marker of central brain atrophy. RESULTS: RRMS patients had a significantly lower OSIT-J score than HCs. The OSIT-J score was significantly lower in RRMS patients with low processing speed (PS) and working memory (WM) scores than RRMS patients with normal PS or WM scores. The OSIT-J score was significantly related to the PS, WM, and the 3rd VW. The OSIT-J score also showed a mild correlation with the expanded disability status scale and disease duration, but not with the number of clinical attacks or patient's age. CONCLUSIONS: Our results suggest that olfactory identification impairment occurs in association with cognitive dysfunction and central brain atrophy. Thus, olfactory identification is a possible disease marker of RRMS as with cognitive impairment, especially PS, reflecting the diffuse neurodegeneration in RRMS.

Potential usefulness of signal intensity of cerebral gyri on quantitative susceptibility mapping for discriminating corticobasal degeneration from progressive supranuclear palsy and Parkinson's disease.

PURPOSE: The typical MRI findings in corticobasal degeneration (CBD), which have been described in previous reports, may be non-specific. We evaluated cerebral gyri (CG) using quantitative susceptibility mapping (QSM) images of patients with CBD, progressive supranuclear palsy (PSP), and Parkinson's disease (PD) to determine the possibility of discriminating them on an individual basis. METHODS: After reviewing the normal appearances on QSM on 16 healthy subjects, two radiologists assessed abnormal findings from 12 CBD, 14 PSP, and 30 PD patients. For conventional MRI, two radiologists independently reviewed typical CBD findings that have been previously reported. We also investigated three autopsy cases including one each of CBD, PSP, and PD to reveal the histopathological basis of MRI findings. RESULTS: CBD-specific findings included three layers; a higher susceptibility layer in superficial GM, a lower susceptibility layer, and a higher susceptibility layer in corticomedullary junction, with frequencies of 83% (10/12) in CBD, 21% (3/14) in PSP, and 0% (0/30) in PD patients. The typical CBD findings on conventional MRI were observed in only 42% (5/12) of CBD patients. Ferritin-positive microglia accumulated in the superficial gray matter (third cortical layer) and corticomedullary junction in CBD patients. CONCLUSIONS: The CG findings on QSM images may be more useful than those on conventional MRI for discriminating CBD from PD on an individual basis. Based on postmortem pathological data, cortical QSM hyperintensity might be an expression of ferritin-positive microglia.

Late-onset Myasthenia Gravis Accompanied by Amyotrophic Lateral Sclerosis with Antibodies against the Acetylcholine Receptor and Low-density Lipoprotein Receptor-related Protein 4.

An 82-year-old woman developed neck weakness and dysarthria with antibodies against acetylcholine receptor (AChR) and low-density lipoprotein receptor-related protein 4 (LRP4). Myasthenia gravis (MG) was diagnosed by edrophonium and repetitive nerve stimulation tests. Her symptoms resolved completely by immunotherapy. One year later, she presented with muscle weakness and bulbar palsy accompanied by atrophy and fasciculation. Her tendon reflexes were brisk, and Babinski's sign was positive. She was diagnosed with probable amyotrophic lateral sclerosis (ALS). Immunotherapy did not improve her symptoms, and she ultimately died of respiratory failure. MG and ALS may share a pathophysiology, including anti-LRP4 antibodies at the neuromuscular junction.

Intravenous immunoglobulin for maintenance treatment of chronic inflammatory demyelinating polyneuropathy: a multicentre, open-label, 52-week phase III trial.

OBJECTIVE: Short-term efficacy of induction therapy with intravenous immunoglobulin (Ig) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is well established. However, data of previous studies on maintenance therapy were limited up to 24-week treatment period. We aimed to investigate the efficacy and safety of longer-term intravenous Ig therapy for 52 weeks. METHODS: This study was an open-label phase 3 clinical trial conducted in 49 Japanese tertiary centres. 49 patients with CIDP who fulfilled diagnostic criteria were included. After an induction intravenous Ig therapy (0.4 g/kg/day for five consecutive days), maintenance dose intravenous Ig (1.0 g/kg) was given every 3 weeks for up to 52 weeks. The primary outcome measures were the responder rate at week 28 and relapse rate at week 52. The response and relapse were defined with the adjusted Inflammatory Neuropathy Cause and Treatment scale. RESULTS: At week 28, the responder rate was 77.6% (38/49 patients; 95% CI 63% to 88%), and the 38 responders continued the maintenance therapy. At week 52, 4 of the 38 (10.5%) had a relapse (95% CI 3% to 25%). During 52 weeks, 34 (69.4%) of the 49 enrolled patients had a maintained improvement. Adverse events were reported in 94% of the patients; two patients (66-year-old and 76-year-old men with hypertension or diabetes) developed cerebral infarction (lacunar infarct with good recovery), and the other adverse effects were mild and resolved by the end of the study period. CONCLUSIONS: Maintenance treatment with 1.0 g/kg intravenous Ig every 3 weeks is an efficacious therapy for patients with CIDP, and approximately 70% of them had a sustained remission for 52 weeks. Thrombotic complications should be carefully monitored, particularly in elderly patients with vascular risk factors. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01824251).