Real-world evidence on the safety and effectiveness of fingolimod in patients with multiple sclerosis from Taiwan.

BACKGROUND/PURPOSE: Multiple sclerosis is classified as a rare disease in Taiwan. This study evaluated the safety and effectiveness of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) from routine clinical practice in Taiwan. METHODS: In this retrospective, multicentre, observational study, we collected clinical data of patients treated with fingolimod 0.5 mg/day in routine clinical practice between September 2012 and December 2015. Primary outcome was the overall safety of fingolimod; secondary outcome was the annualized relapse rate (ARR). RESULTS: Overall, 62/69 (86.1%) patients were on fingolimod by the end of data collection period. Mean age (±standard deviation [SD]) at inclusion was 37.7 ± 10.10 years; mean duration of MS was 5.4 ± 4.52 years and mean duration of fingolimod exposure was 135.8 patient-years. The most common adverse events (AEs) were bradycardia (21.7%; first-dose related), upper respiratory tract infection, dizziness, and hypoaesthesia (numbness) (11.6% each), followed by urinary tract infection and back pain (7.2% each). Seven patients had liver enzyme-related AEs. Eight patients had absolute lymphocyte counts <0.2 × 103/uL over the study period. One patient developed second degree AV block after first-dosing. Serious AEs were observed in 11 patients (15.9%; mild-to-moderate). No newly developed macular oedema was detected. The ARR was 0.3 ± 0.74 in fingolimod-treated patients and 66.7% of patients were relapse-free. The mean (SD) change from baseline in expanded disability status scale score was -0.30 ± 1.353. CONCLUSION: Fingolimod 0.5 mg/day treatment with an average of 2 years of exposure was associated with a manageable safety profile, and maintained/improved effectiveness in RRMS patients from Taiwan.

Efficacy and safety of iscalimab, a novel anti-CD40 monoclonal antibody, in moderate-to-severe myasthenia gravis: A phase 2 randomized study.

BACKGROUND: Increased morbidity in many patients with myasthenia gravis (MG) on long-term immunosuppression highlights the need for improved treatments. The aim of this study is to investigate the safety and efficacy of iscalimab (CFZ533), a fully human anti-CD40 monoclonal antibody, in patients with moderate-to-severe MG receiving standard-of-care (SoC) therapies. METHODS: In this double-blind, placebo-controlled phase 2 study, symptomatic patients (n = 44) despite SoC were randomized 1:1 to receive intravenous iscalimab (10 mg/kg; n = 22) or placebo (n = 22) every 4 weeks for 6 doses in total. Patients were followed up for 6 months after the last dose. The total duration of the study was 52 weeks. RESULTS: In total, 34 of 44 patients (77.3 %) completed the study. The primary endpoint, Quantitative MG score, did not change significantly between baseline and week 25 for iscalimab (median [90 % CI], -4.07 [-5.67, -2.47]) versus placebo (-2.93 [-4.53, -1.33]); however, non-thymectomized patients (n = 29) showed more favorable results (iscalimab, -4.35 [-6.07, -2.64] vs placebo, -2.26 [-4.16, -0.36]). A statistically significant difference between iscalimab and placebo groups was observed in MG Composite score (adjusted mean change: -4.19 [-6.67, -1.72]; p = 0.007) at week 13, and MG-Activities of Daily Living score (-1.93 [-3.24, -0.62]; p = 0.018) at week 21. Adverse events were comparable between the iscalimab (91 %) and placebo (96 %) groups. CONCLUSION: Iscalimab showed favorable safety and improvements compared with placebo in non-thymectomized patients with moderate-to-severe MG. It did not show any protective effect in patients with moderate-to-severe MG.

Deficiency of electroneutral K+-Cl- cotransporter 3 causes a disruption in impulse propagation along peripheral nerves.

Nerve conduction requires the fine tuning of ionic currents through delicate interactions between axons and Schwann cells. The K(+)-Cl(-) cotransporter (KCC) family includes four isoforms (KCC1-4) that play an important role in the maintenance of cellular osmotic homeostasis via the coupled electroneutral movement of K(+) and Cl(-) with concurrent water flux. Mutation in SLC12A6 gene encoding KCC3 results in an autosomal recessive disease, known as agenesis of the corpus callosum associated with peripheral neuropathy. Nevertheless, the role of KCC3 in nerve function remains a puzzle. In this study, the microscopic examination of KCC isoforms expressed in peripheral nerves showed high expression of KCC2-4 in nodal segments of the axons and in the perinucleus and microvilli of Schwann cells. The KCC inhibitor [[(dihydroindenyl)oxy]alkanoic acid] but not the Na(+)-K(+)-2Cl(-)-cotransport inhibitor (bumetanide) dose-dependently suppressed the amplitude and area of compound muscle action potential, indicating the involvement of KCC activity in peripheral nerve conduction. Furthermore, the amplitude and area under the curve were smaller, and the nerve conduction velocity was slower in nerves from KCC3(-/-) mice than in nerves from wild-type mice, while the expression pattern of KCC2 and KCC4 was similar in KCC3 kockout and wild-type strains. KCC3(-/-) mice also manifested a prominent motor deficit in the beam-walking test. This is the first study to demonstrate that the K(+)-Cl(-) cotransporter activity of KCC3 contributes to the propagation of action potentials along peripheral nerves.

Epidemiological evidence of altered cardiac autonomic function in subjects with impaired glucose tolerance but not isolated impaired fasting glucose.

CONTEXT: Autonomic dysfunction is present in diabetes mellitus (DM), but no study is available on alteration in cardiac autonomic function (CAF) across different glycemic statuses including normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and DM. OBJECTIVE: Our objective was to examine whether CAF is altered in subjects with IGT and isolated IFG. DESIGN AND SETTING: The study was a stratified systematic cluster sampling design within the general community. PARTICIPANTS: A total of 1440 subjects were classified as NGT (n = 983), isolated IFG (n = 163), IGT (n = 188), and DM (n = 106). MAIN OUTCOME MEASURE: CAF was determined by 1) standard deviation of normal-to-normal (SDNN) or RR interval, power spectrum in low and high frequency (LF, 0.04-0.15 Hz; HF, 0.15-0.40 Hz), and LF/HF ratio in supine position for 5 min; 2) ratio between 30th and 15th RR interval after standing from supine position (30/15 ratio); and 3) average heart rate change during breathing of six deep breaths for 1 min (HR(DB)). RESULTS: Univariate analysis showed significant differences in SDNN, 30/15 ratio, HR(DB), HF power, and LF/HF ratio among subjects with NGT, isolated IFG, IGT, and DM. In multivariate analysis, none of the indices of CAF was related to isolated IFG in the reference group of NGT. IGT and DM were negatively associated with 30/15 ratio and HF power but positively associated with LF/HF ratio. In addition, DM was also related to a lower SDNN. CONCLUSIONS: DM and IGT subjects had an impaired CAF independent of other cardiovascular risk factors. The risk of altered CAF is not apparent in subjects with isolated IFG.

Clinical and Molecular Characterization of PMP22 point mutations in Taiwanese patients with Inherited Neuropathy.

Point mutations in the peripheral myelin protein 22 (PMP22) gene have been identified to cause demyelinating Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsy (HNPP). To investigate the mutation spectrum of PMP22 in Han-Chinese population residing in Taiwan, 53 patients with molecularly unassigned demyelinating CMT and 52 patients with HNPP-like neuropathy of unknown genetic causes were screened for PMP22 mutations by Sanger sequencing. Three point mutations were identified in four patients with demyelinating CMT, including c.256 C > T (p.Q86X) in two, and c.310delA (p.I104FfsX7) and c.319 + 1G > A in one each. One PMP22 missense mutation, c.124 T > C (p.C42R), was identified in a patient with HNPP-like neuropathy. The clinical presentations of these mutations vary from mild HNPP-like syndrome to severe infantile-onset demyelinating CMT. In vitro analyses revealed that both PMP22 p.Q86X and p.I104FfsX7 mutations result in truncated PMP22 proteins that are almost totally retained within cytosol, whereas the p.C42R mutation partially impairs cell membrane localization of PMP22 protein. In conclusion, PMP22 point mutations account for 7.5% and 1.9% of demyelinating CMT and HNPP patients with unknown genetic causes, respectively. This study delineates the clinical and molecular features of PMP22 point mutations in Taiwan, and emphasizes their roles in demyelinating CMT or HNPP-like neuropathy.

KCC3 deficiency-induced disruption of paranodal loops and impairment of axonal excitability in the peripheral nervous system.

The autosomal recessive Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum (HMSN/ACC) is associated with the dysfunction of the K(+)-Cl(-) cotransporter type 3 (KCC3), which is an electroneutral cotransporter. We previously found that the inhibition of KCC3 cotransporter activity reduces the propagation of action potentials in the peripheral nervous system (PNS). However, the pathogenesis by which KCC3 deficiency impairs peripheral nerve function remains to be examined. Thus, we conducted imaging and electrophysiological studies in the peripheral nerves of KCC3(-/-) mice at various ages. Analysis using transmission electron microscopy (TEM) revealed an age-dependent progressive swelling of microvilli and disorganization of paranodal loops in KCC3(-/-) nerves. Yet, no mislocated voltage-dependent channels were observed between the nodes and juxtaparanodes of KCC3(-/-) nerves. However, electrophysiological studies using the threshold tracking technique indicated a reduced stimulus-response curve slope with an elevated rheobase, a decreased strength-duration time constant, diminished persistent Na(+) currents, and an outward deviation of threshold electrotonus in KCC3(-/-) nerves compared to wild-type nerves. These functional changes indicate an overall reduction in axonal excitability and suggest an increase in paranodal conductance, which was relevant to the pathology at the paranode. Altogether, our findings highlight the importance of KCC3 in maintaining paranodal integrity and in optimizing the propagation of action potentials along peripheral nerves.

Expanding genotype/phenotype of neuromuscular diseases by comprehensive target capture/NGS.

OBJECTIVE: To establish and evaluate the effectiveness of a comprehensive next-generation sequencing (NGS) approach to simultaneously analyze all genes known to be responsible for the most clinically and genetically heterogeneous neuromuscular diseases (NMDs) involving spinal motoneurons, neuromuscular junctions, nerves, and muscles. METHODS: All coding exons and at least 20 bp of flanking intronic sequences of 236 genes causing NMDs were enriched by using SeqCap EZ solution-based capture and enrichment method followed by massively parallel sequencing on Illumina HiSeq2000. RESULTS: The target gene capture/deep sequencing provides an average coverage of ∼1,000× per nucleotide. Thirty-five unrelated NMD families (38 patients) with clinical and/or muscle pathologic diagnoses but without identified causative genetic defects were analyzed. Deleterious mutations were found in 29 families (83%). Definitive causative mutations were identified in 21 families (60%) and likely diagnoses were established in 8 families (23%). Six families were left without diagnosis due to uncertainty in phenotype/genotype correlation and/or unidentified causative genes. Using this comprehensive panel, we not only identified mutations in expected genes but also expanded phenotype/genotype among different subcategories of NMDs. CONCLUSIONS: Target gene capture/deep sequencing approach can greatly improve the genetic diagnosis of NMDs. This study demonstrated the power of NGS in confirming and expanding clinical phenotypes/genotypes of the extremely heterogeneous NMDs. Confirmed molecular diagnoses of NMDs can assist in genetic counseling and carrier detection as well as guide therapeutic options for treatable disorders.

Is the stimulation frequency of the repetitive nerve stimulation test that you choose appropriate?

The repetitive nerve stimulation test (RNST) has been a useful method in the diagnosis of myasthenia gravis (MG). In clinical practice, a short train of repetitive stimulation is usually given at 3 Hz. Although it was documented that lower stimulation frequencies could offer a greater sensitivity, no study has been done to testify the most sensitive stimulation frequency for RNST. To find out an optimal stimulation frequency, we performed RNST at 0.5, 1, 3, 5, 7, 10, 15 and 20 Hz in 15 MG patients and 5 healthy subjects. The results showed that the decremental response was most often seen at 7 Hz rather than at 3 Hz. To augment the sensitivity in the diagnosis of MG, RNST should be performed stimulation not only at 3Hz but also at other frequencies, preferably 7 Hz.

Asymmetrical delayed encephalopathy after acute CO intoxication: a case report.

We report a patient suffering from delayed encephalopathy 21 days after an acute CO intoxication. The initial magnetic resonance (MR) images in the acute stage show a recent infarct corresponding to a right middle cerebral artery (MCA) stenosis. MR images on the 24th day post-intoxication show typical changes of delayed encephalopathy. These changes were much more prominent on the areas corresponding to right MCA territory while less severe on the other parts. The finding suggests an ischemic component contributes to carbon monoxide related delayed brain injury.

Altered cardiac autonomic function may precede insulin resistance in metabolic syndrome.

BACKGROUND: Previous studies on the change of cardiac autonomic function and insulin resistance in metabolic syndrome recruited subjects with cardiovascular-related disease and defined metabolic abnormality with a more severe cutoff. We explored the alteration of cardiac autonomic function and insulin resistance in predisease community dwellers with different numbers of metabolic abnormalities. METHODS: A total of 1298 subjects were classified as none (n=539), one (n=378), 2 (n=218), and 3 or more metabolic abnormalities (n=154). Insulin resistance was calculated by homeostatic model assessment. Cardiac autonomic function included 5-minute standard deviation of R-R interval, low- and high-frequency power spectrum, and low-/high-frequency power spectrum ratio, the ratio of the longest R-R interval around the 30th beat and the shortest R-R interval around the 15th beat after standing, and the ratio of the longest expiratory R-R interval to the shortest inspiratory R-R interval during deep breathing. RESULTS: Subjects with a single metabolic abnormality or more had a lower standard deviation of R-R interval and expiratory/inspiratory ratio than subjects without metabolic abnormality in multivariate analysis. Subjects with 3 or more metabolic abnormalities had a higher low-/high-frequency power spectrum ratio, but a lower high-frequency power. Insulin resistance was higher in groups with 2 metabolic abnormalities or more, but not in the group with one metabolic abnormality, than those without metabolic abnormality. CONCLUSIONS: Cardiac autonomic function altered in predisease subjects with one or more metabolic abnormalities, while insulin resistance existed in subjects with 2 or more metabolic abnormalities. Thus, autonomic function change may precede insulin resistance in the initiation of metabolic syndrome.

Epidemiological study on the effect of pre-hypertension and family history of hypertension on cardiac autonomic function.

OBJECTIVES: This study sought to examine the hypothesis that cardiac autonomic function (CAF) is altered in pre-hypertensive subjects and normotensive subjects with a family history of hypertension (FHH). BACKGROUND: The findings on the FHH effect in CAF have been inconsistent, and little is known about altered CAF in pre-hypertensive subjects under The Seventh Report of the Joint National Commission on High Blood Pressure criteria of normotension and pre-hypertension. METHODS: A total of 1,436 community dwellers were classified as having normotension without FHH (NT[-]), normotension with FHH (NT[+]), pre-hypertension, and hypertension. Cardiac autonomic function was determined by standard deviation of RR intervals (SDNN), power spectrum in low frequencies (LF) and high frequencies (HF) and LF/HF ratio in supine position for 5 min, the ratio between the longest RR interval at approximately the 30th beat and the shortest RR interval at approximately the 15th beat after standing (30 max/15 min ratio), and the ratio between the longest RR interval during expiration and the shortest RR interval during inspiration (E/I ratio). RESULTS: There was a significant difference in all CAF indexes among subjects with NT(-), NT(+), pre-hypertension, and hypertension. Multivariate analyses with an analysis of covariance model showed that 30 max/15 min ratio, E/I ratio, and HF power decreased in subjects with NT(+), pre-hypertension, and hypertension when compared with NT(-) subjects. Pre-hypertensive and hypertensive subjects displayed higher square roots of LF/HF ratios. Only pre-hypertensive subjects had higher LF power. CONCLUSIONS: Our study provides evidence that CAF plays a role in pre-hypertension and that altered autonomic function is already present in subjects with FHH. An autonomic imbalance shifting with augmented sympathetic tone was more enhanced in pre-hypertension.

Value of dermatomal somatosensory evoked potentials in detecting acute nerve root injury: an experimental study with special emphasis on stimulus intensity.

STUDY DESIGN: Dermatomal somatosensory-evoked potentials (D-SSEPs) in rats were recorded at the spinal level after L2-, L4-, and L5-dermatome stimulation. Pre- and post-transection patterns and rates of change of corresponding nerve roots were compared to determine accuracy. OBJECTIVE: To investigate characteristics and normal values of D-SSEP elicited from lower limb dermatomes; to determine specificity, sensitivity, and utility of D-SSEP in detecting single-nerve root injury; and to determine optimal stimulation intensity. SUMMARY OF BACKGROUND DATA: D-SSEP allows assessment of single nerve root-specific pathways, electrodiagnosis of lumbosacral radiculopathy, and intraoperative neuromonitoring. Unacceptably low sensitivity and specificity make its value suspect. D-SSEP is insufficiently documented. METHODS: Eight rats were used to specify a standard D-SSEP waveform and its characteristics, evaluate stimulation sites and strengths, and determine appropriate stimulation and recording techniques. The L4 nerve root was transected in one group of 8 rats and the L5 in another. D-SSEPs were recorded at the thoracolumbar junction following submaximal and supramaximal stimulation at the L2, L4, and L5 dermatomal fields. Potentials recorded before transection, and immediately, 1 hour, and 1 week post-transection were compared. RESULTS: Reproducible spinal responses were obtained in all rats on all tests. Stimulation intensity, but not rates, affected amplitude. Relative amplitude reductions in transected-root D-SSEP were larger using submaximal than supramaximal intensity. D-SSEP elicited by submaximal than supramaximal intensity produced fewer false negatives and false positives. CONCLUSIONS: D-SSEP is valuable for detecting acute single nerve root injury. In clinical settings, submaximal dermatomal stimulation identifies conduction abnormalities more consistently and with fewer false negatives and false positives than does supramaximal stimulation. We recommend submaximal stimulation.

Pathophysiology of weakness in a patient with congenital end-plate acetylcholinesterase deficiency.

A Japanese patient with congenital end-plate acetylcholinesterase (AChE) deficiency developed severe proximal and truncal muscle weakness with preservation of distal strength. Electrophysiological studies included a train of stimuli at 3 HZ, which induced a marked decremental response in the deltoid but not in the first dorsal interosseous (FDI) muscle. Single fiber electromyography (EMG) revealed a high blocking rate (23.1 +/- 30.5%, n = 13) with a markedly increased jitter (mean consecutive difference [MCD] 297 +/- 218 micros) in the deltoid, but a low blocking rate (6.2 +/- 7.4%, n = 16) despite an equally increased jitter (MCD 227 +/- 147 micros) in the FDI. In vitro microelectrode study and computer simulation suggested that the combination of a large jitter and a low blocking rate may be ascribed to a reduced end-plate potential (EPP) amplitude with an abnormally prolonged decay time constant (tau). These characteristics may constitute the primary underlying pathophysiologic mechanism in our patient and in similar cases of congenital myasthenic syndrome.