Granuloma, vasculitis, and demyelination in sarcoid neuropathy.

BACKGROUND: Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified. METHODS: We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non-caseating epithelioid cell granuloma in their sural nerve biopsy specimens. RESULTS: Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients. CONCLUSIONS: Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy.

NOTCH2NLC GGC repeat expansion causes retinal pathology with intranuclear inclusions throughout the retina and causes visual impairment.

The retinal pathology of genetically confirmed neuronal intranuclear inclusion disease (NIID) is yet unknown. We report the ocular findings in four NIID patients with NOTCH2NLC GGC repeat expansion to investigate the pathology of retinopathy. All four NIID patients were diagnosed by skin biopsy and NOTCH2NLC GGC repeat analysis. Ocular findings in patients with NIID were studied using fundus photographs, optical coherence tomographic images (OCT), and full-field electroretinograms (ERGs). The histopathology of the retina was studied on autopsy samples from two cases with immunohistochemistry. All patients had an expansion of the GGC repeat (87-134 repeats) in the NOTCH2NLC. Two patients were legally blind and had been diagnosed with retinitis pigmentosa prior to the diagnosis of NIID and assessed with whole exome sequencing to rule out comorbidity with other retinal diseases. Fundus photographs around the posterior pole showed chorioretinal atrophy in the peripapillary regions. OCT showed thinning of the retina. ERGs showed various abnormalities in cases. The histopathology of autopsy samples showed diffusely scattered intranuclear inclusions throughout the retina from the retinal pigment epithelium to the ganglion cell layer, and optic nerve glial cells. And severe gliosis was observed in retina and optic nerve. The NOTCH2NLC GGC repeat expansion causes numerous intranuclear inclusions in the retina and optic nerve cells and gliosis. Visual dysfunction could be the first sign of NIID. We should consider NIID as one of the causes of retinal dystrophy and investigate the GGC repeat expansion in NOTCH2NLC.

Clinical Features of Female Carriers and Prodromal Male Patients With Spinal and Bulbar Muscular Atrophy.

BACKGROUND AND OBJECTIVES: To assess the clinical and electrophysiologic features of female carriers and early-stage male patients with spinal and bulbar muscular atrophy (SBMA) to elucidate the early pathophysiologic changes of the disease. METHODS: Female carriers, early-stage male patients with SBMA, and age-matched male and female healthy controls were recruited. The results of motor functional scales, motor unit number estimation, dual-energy X-ray absorptiometry, and peripheral blood tests were compared between female carriers and healthy female controls and between patients with SBMA and healthy male controls. EMG was also investigated in female carriers. RESULTS: We enrolled 21 female carriers and 11 early-stage male patients. Seventeen female and 14 male age-matched healthy controls were also enrolled. Female carriers experienced early-stage symptoms such as muscle cramps more frequently than healthy female controls. Decreased motor unit number estimation and EMG abnormalities including high amplitude or polyphasic potentials were observed in female carriers together with mild muscle weakness in neck flexion and a slow walking speed. Changes of muscle-related markers, including serum creatine kinase and dual-energy X-ray absorptiometry, were clearly detected in early-stage male patients with SBMA, but not in female carriers. DISCUSSION: The present study revealed that female carriers of SBMA manifest mild muscular weakness associated with changes in neurogenic biomarkers. Conversely, male patients showed neurogenic and myopathic changes even at the early stage. These results suggest a testosterone-independent neurodegenerative pathophysiology in female SBMA carriers.

Development of a functional composite for the evaluation of spinal and bulbar muscular atrophy.

This study aimed to develop a functional measurement that combines quantitative motor evaluation index of various body regions in patients with spinal and bulbar muscular atrophy (SBMA). We assessed subjects with SBMA and healthy controls with quantitative muscle strength measurements and functional scales. We selected tongue pressure, grip power, % peak expiratory flow (%PEF), timed walking test, and % forced vital capacity (%FVC) as components. By combining these values with Z-score, we created a functional composite (SBMA functional composite: SBMAFC). We also calculated the standardized response mean to compare the sensitivity of SBMAFC with that of existing measurements. A total of 97 genetically confirmed patients with SBMA and 36 age- and sex-matched healthy controls were enrolled. In the longitudinal analysis, the standardized response mean of SBMAFC was larger than that of existing rating scales. Receiver operating characteristic (ROC) analysis demonstrated that the SBMAFC is capable of distinguishing between subjects with early-stage SBMA and healthy controls. SBMAFC is more sensitive to disease progression than existing functional rating scales and is a potential outcome measure in clinical trials of SBMA.

Mexiletine in spinal and bulbar muscular atrophy: a randomized controlled trial.

OBJECTIVE: Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure. METHODS: In our previously conducted observational study, we assessed nerve conduction and grip strength to examine the effect of cold exposure on motor function, based on which we conducted a randomized controlled trial to evaluate the efficacy and safety of mexiletine hydrochloride in SBMA (MEXPRESS). RESULTS: In the observational study, 51 consecutive patients with SBMA and 18 healthy controls (HCs) were enrolled. Of the patients with SBMA, 88.0% experienced cold paresis. Patients with SBMA exhibited greater prolongation of ulnar nerve distal latency under cold (SBMA, 5.6 ± 1.1 msec; HC, 4.3 ± 0.6 msec; p <0.001); the change in the distal latencies between room temperature and cold exposure conditions correlated with the change in grip power. In the MEXPRESS trial, 20 participants took mexiletine or lactose, three times a day for 4 weeks with a crossover design. There was no difference in distal latencies at room temperature and under cold exposure between mexiletine and placebo groups as the primary endpoint. However, tongue pressure and 10-sec grip and release test under cold exposure were improved in the mexiletine group. There were no serious adverse events throughout the study period. INTERPRETATION: Cold paresis is common and associated with prolongation of distal latency in SBMA. The results of the phase II clinical trial revealed that mexiletine showed short-term safety, but it did not restore cold exposure-induced prolongation of distal latency.

Quantitative evaluation of upper limb ataxia in spinocerebellar ataxias.

OBJECTIVE: To quantitatively evaluate upper limb ataxia using a novel pen-like sensor device in patients with spinocerebellar ataxia (SCA) and to assess its validity, reliability, and sensitivity to disease progression. METHODS: We designed a cross-sectional and longitudinal study of patients with SCA and healthy controls. Upper limb ataxia was evaluated using a device that measures the three-dimensional position every 10 msec. Participants were instructed to move a pen-like part of the device iteratively between two buttons. We evaluated the time, length, velocity, and variation coefficient of the stroke, and calculated the distortion index using the mean squared error. The following scales were also evaluated: Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and the nine-hole pegboard test. Subjects were followed 12 months after the baseline evaluation. RESULTS: A total of 42 patients with SCA and 33 healthy controls were enrolled and evaluated. For all ataxia indices measured using the device there were significant differences between healthy controls and patients with SCA. Among the ataxia indices, the distortion index showed the strongest correlation with the SARA and ICARS upper limb score (Pearson's r = 0.647 and 0.722, respectively). Test-retest reliability was high for most of the ataxia indices. In the longitudinal analysis, the distortion index showed high standardized response mean and adjusted effect size, regardless of disease severity. INTERPRETATION: Our study demonstrated that the distortion index is a reliable functional marker that is sensitive to longitudinal change in patients with SCA.

Ratio of urinary N-terminal titin fragment to urinary creatinine is a novel biomarker for amyotrophic lateral sclerosis.

OBJECTIVE: We aimed to investigate the validity of urinary N-terminal titin fragment as a biomarker for amyotrophic lateral sclerosis (ALS). METHODS: We consecutively enrolled patients with ALS (n=70) and healthy controls (HC) (n=43). We assessed the urinary titin N-terminal fragment, urinary neurotrophin receptor p75 extracellular domain, serum neurofilament light chain (NfL), motor functional measurements and prognosis. We used urinary creatinine (Cr) levels to normalise the urinary levels of titin fragment. RESULTS: Compared with HC, patients with ALS had significantly increased urinary levels of titin N-terminal fragment normalised with Cr (titin/Cr) (ALS, 27.2 pmol/mg/dL; HC, 5.8 pmol/mg/dL; p<0.001), which were correlated with the scores of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (r=-0.422, p<0.001). A Cox proportional hazards model demonstrated that the high urinary level of titin/Cr was a survival predictor in patients with ALS. Multivariate analysis of prognostic factors showed that the urinary titin/Cr and serum NfL were independent factors for poor prognosis. CONCLUSIONS: Our findings indicate that urinary N-terminal titin fragment is a non-invasive measure of muscle damage in ALS, which could be applied in disease monitoring and prediction of disease progression, in combination with serum NfL.

Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis.

OBJECTIVE: To assess the changes of muscle-related biomarkers at the early stage of amyotrophic lateral sclerosis, and to confirm these findings in an experimental animal model. METHODS: Thirty-nine subjects with sporadic amyotrophic lateral sclerosis and 20 healthy controls were enrolled and longitudinally evaluated. We evaluated serum creatine kinase and creatinine levels and appendicular lean soft-tissue mass using dual X-ray absorptiometry. The levels of biomarkers at early ALS stages were estimated using linear mixed models with unstructured correlation and random intercepts. We also analyzed the longitudinal changes of serum creatine kinase and creatinine, together with the mRNA levels of acetylcholine receptor subunit γ (Chrng) and muscle-associated receptor tyrosine kinase, markers of denervation, in the gastrocnemius muscle of superoxide dismutase 1 (SOD1)G93A transgenic mice, an animal model of amyotrophic lateral sclerosis. RESULTS: The estimated levels of creatine kinase were higher in subjects with amyotrophic lateral sclerosis at the early stage than in healthy controls, although the estimated appendicular lean soft-tissue mass and creatinine levels were equivalent between both groups, suggesting that the elevation of creatine kinase precedes both muscular atrophy and subjective motor symptoms in sporadic amyotrophic lateral sclerosis. In SOD1G93A mice, the serum levels of creatine kinase were elevated at 9 weeks of age (peri-onset) when Chrng started to be up-regulated, and were then down-regulated at 15 weeks of age, consistent with the clinical data from patients with sporadic amyotrophic lateral sclerosis. INTERPRETATION: Creatine kinase elevation precedes muscular atrophy and reflects muscle denervation at the early stage.