Intermuscular coherence as an early biomarker for amyotrophic lateral sclerosis: The protocol for a prospective, multicenter study.

OBJECTIVE: To describe the protocol of a prospective study to test the validity of intermuscular coherence (IMC) as a diagnostic tool and biomarker of upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). METHODS: This is a multicenter, prospective study. IMC of muscle pairs in the upper and lower limbs is gathered in ∼650 subjects across three groups using surface electrodes and conventional electromyography (EMG) machines. The following subjects will be tested: 1) neurotypical controls; 2) patients with symptomatology suggestive for early ALS but not meeting probable or definite ALS by Awaji Criteria; 3) patients with a known ALS mimic. The recruitment period is between 3/31/2021 and 12/31/2025. Written consent will be sought from the subject or the subject's legally authorized representative during enrollment. RESULTS: The endpoints of this study include: 1) whether adding IMC to the Awaji ALS criteria improve its sensitivity in early ALS and can allow for diagnosis earlier; 2) constructing a database of IMC across different ages, genders, and ethnicities. SIGNIFICANCE: This study may validate a new inexpensive, painless, and widely available tool for the diagnosis of ALS.

Added load increases the peak frequency of intermuscular coherence.

Cortical motor neuron activity appears to drive lower motor neurons through two distinct frequency bands: the ß range (15-30 Hz) during weak muscle contractions and γ range (30-50 Hz) during strong contractions. It is unknown whether the frequency of cortical drive shifts continuously or abruptly between the ß and γ frequency bands as contraction strength changes. Intermuscular coherence (IMC) between synergistic arm muscles was used to assess how the frequency of common neuronal drive shifts with increasing contraction strength. Muscle activity was recorded by surface electromyography (EMG) from the biceps and brachioradialis in nine healthy adults performing 30-second isometric holds with added loads. IMC was calculated across the two muscle groups during the isometric contraction. Significant IMC was present in the 20 to 50 Hz range with all loads. Repeated measures ANOVA show the peak frequency of IMC increased significantly when load was added, from a peak of 32.7 Hz with no added load, to 35.3 Hz, 35.7 Hz, and 36.3 Hz with three-, five-, and ten-pound loads respectively. An increase in IMC frequency occurs in response to added load, suggesting that cortical drive functions over a range of frequencies as a function of an isometric contraction against load.

Intermuscular Coherence in Spinocerebellar Ataxias 3 and 6: a Preliminary Study.

Spinocerebellar ataxias (SCAs) are familial neurodegenerative diseases involving the cerebellum and spinocerebellar tracts. While there is variable involvement of corticospinal tracts (CST), dorsal root ganglia, and motor neurons in SCA3, SCA6 is characterized by a pure, late-onset ataxia. Abnormal intermuscular coherence in the beta-gamma frequency range (IMCßγ) implies a lack of integrity of CST or the afferent input from the acting muscles. We test the hypothesis that IMCßγ has the potential to be a biomarker of disease activity in SCA3 but not SCA6. Intermuscular coherence between biceps brachii and brachioradialis muscles was measured from surface EMG waveforms in SCA3 (N = 16) and SCA6 (N = 20) patients and in neurotypical subjects (N = 23). IMC peak frequencies were present in the ß range in SCA patients and in the γ range in neurotypical subjects. The difference between IMC amplitudes in the γ and ß ranges was significant when comparing neurotypical control subjects to SCA3 (p < 0.01) and SCA6 (p = 0.01) patients. IMCßγ amplitude was smaller in SCA3 patients compared to neurotypical subjects (p < 0.05), but not different between SCA3 and SCA6 patients or between SCA6 and neurotypical subjects. IMC metrics can differentiate SCA patients from normal controls.

Long-term effects of pancreatic islet transplantation on polyneuropathy in patients with brittle diabetes: A single-center experience.

INTRODUCTION/AIMS: Pancreatic islet transplantation (ITx) is increasingly used in patients with brittle type 1 diabetes (T1D). If successful, ITx results in insulin-free euglycemia, but its application is limited by a need for lifelong immunosuppression. The aim of this study was to assess the long-term effects of ITx on the occurrence and course of polyneuropathy in a cohort of patients with brittle T1D. METHODS: In this prospective, single-center study, 13 patients (4 males and 9 females) with brittle T1D had a baseline neurological exam with the calculation of Utah Neuropathy Scale (UNS) and a limited nerve conduction study before ITx, and about yearly after in the patients who achieved insulin independence. RESULTS: Patients were followed for a period of 17 to 133 months. There was no significant difference between UNS and nerve conduction study parameters at baseline and at the end of follow-up, except for significant decreases in peroneal (50.34 ± 6.12 vs. 52.42 ± 6.47 ms, P = 0.005) and ulnar (27.5 ± 2.15 vs. 29.45 ± 2.10 ms, P = 0.009) F-wave latencies and an increase in ulnar sensory nerve conduction velocity (49.98 ± 6.27 vs. 47.19 ± 5.36 m/s, P = 0.04). DISCUSSION: If successful, ITx has a good long-term safety profile for peripheral nerve toxicity, and a favorable effect on diabetic neuropathy.

Pontine stroke in a patient with Chronic Progressive External Ophthalmoplegia (CPEO): a case report.

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease with slowly progressive bilateral ptosis and symmetric ophthalmoplegia due to a genetic mutation that results in defective oxidative phosphorylation. Common genes that are implicated in CPEO include POLG, RRM2B, ANT1 and PEO1/TWNK. Here, we report a case of a patient diagnosed with CPEO caused by a novel mutation in PEO/TWNK after suffering a right pontine stroke. CASE PRESENTATION: A 70-year-old man with history of chronic progressive bilateral ptosis and ophthalmoplegia, as well as similar ocular symptoms in his father and grandfather, presented with acute onset of right hemifacial weakness and dysarthria. Brain MRI revealed an acute ischemic stroke in the right dorsal pons. The patient did not experience diplopia due to severe baseline ophthalmoplegia. Creatine kinase was elevated to 6,080 U/L upon admission and normalized over the course of one week; electromyography revealed a myopathic process. Genetic testing revealed a novel mutation c.1510G > A (p. Ala504Thr) in a pathogenic "hot spot" of the C10ORF2 gene (TWNK/PEO1), which is associated with CPEO. The mutation appears to be deleterious using several pathogenicity prediction tools. CONCLUSIONS: This case report describes a patient with late-onset CPEO caused by a novel, likely pathogenic, mutation in the TWNK gene. Although the patient presented with a pontine stroke, it manifested with solely new onset facial palsy, as he had a severe underlying ophthalmoplegia secondary to his CPEO.

Intermuscular coherence in spinocerebellar ataxias 3 and 6: a preliminary study.

Objective : Spinocerebellar ataxias (SCAs) are familial neurodegenerative diseases involving the cerebellum and spinocerebellar tracts. While there is variable involvement of corticospinal tracts (CST), dorsal root ganglia, and motor neurons in SCA3, SCA6 is characterized by a pure, late-onset ataxia. Abnormal intermuscular coherence in the beta-gamma frequency range (IMCbg) implies lack of integrity of CST or the afferent input from the acting muscles. We test the hypothesis that IMCbg has the potential to be a biomarker of disease activity in SCA3 but not SCA6. Methods: Intermuscular coherence between biceps and brachioradialis muscles was measured from surface EMG waveforms in SCA3 (N=16) and SCA6 (N=20) patients, and in neurotypical subjects (N=23). Results: IMC peak frequencies were present in the b range in SCA patients and in the g range in neurotypical subjects. The difference between IMC amplitudes in the g and b ranges was significant when comparing neurotypical control subjects to SCA3 (p < 0.01) and SCA6 (p = 0.01) patients. IMCbg amplitude was smaller in SCA3 patients compared to neurotypical subjects (p<0.05), but not different between SCA3 and SCA6 patients or between SCA6 and neurotypical subjects. Conclusion/significance: IMC metrics can differentiate SCA patients from normal controls.

99m Technetium-pyrophosphate bone scan: A potential biomarker for the burden of transthyretin amyloidosis in skeletal muscle: A preliminary study.

INTRODUCTION/AIMS: Transthyretin amyloidosis (ATTR) proteins can infiltrate skeletal muscle and infrequently cause a myopathy. 99m Technetium-pyrophosphate (99m Tc-PYP) is a validated biomarker for cardiac involvement in variant and wild-type ATTR (ATTRv and ATTRwt, respectively). The aim of this study was to test the hypothesis that 99m Tc-PYP is a biomarker for muscle burden of ATTR. METHODS: Radioisotope uptake in the deltoid muscles of patients with ATTR was compared to uptake in control subjects without amyloidosis in a retrospective study. 99m Tc-PYP scans were evaluated in 11 patients with ATTR (7 ATTRv, 4 ATTRwt) and 14 control subjects. Mean count (MC) values were measured in circular regions of interest (ROIs) 2.5-3.8 cm2 in area. Tracer uptake was quantified in the heart, contralateral chest (CC), and deltoid muscles. RESULTS: Tracer uptake was significantly higher over the deltoids and heart but not the CC, in patients with ATTR than in control subjects. MC values were 120.1 ± 43.7 (mean ± SD) in ATTR patients and 78.9 ± 20.4 in control subjects over the heart (p = 0.005), 73.3± 21.0 and 63.5 ± 14.4 over CC (p = 0.09), and 37.0 ± 11.7 and 26.0 ± 7.1 averaged over both deltoid muscles (p = 0.014). DISCUSSION: 99m Tc-PYP is a potential biomarker for ATTR amyloid burden in skeletal muscle.

Current Treatment of Myasthenia Gravis.

Myasthenia gravis (MG) is the most extensively studied antibody-mediated disease in humans. Substantial progress has been made in the treatment of MG in the last century, resulting in a change of its natural course from a disease with poor prognosis with a high mortality rate in the early 20th century to a treatable condition with a large proportion of patients attaining very good disease control. This review summarizes the current treatment options for MG, including non-immunosuppressive and immunosuppressive treatments, as well as thymectomy and targeted immunomodulatory drugs.

Progressive Multiple Mononeuropathy in a Patient With Familial Transthyretin Amyloidosis After Liver Transplantation.

ABSTRACT: Valine 122 isoleucine (V122I) is the most common mutation associated with familial transthyretin-related amyloidosis (fATTR) in the metropolitan United States. V122I-related fATTR usually presents with cardiomyopathy. When polyneuropathy is encountered, it is usually mild, distal, and axonal in nature. Although liver transplantation improves survival for fATTR neuropathy patients, neuropathy may progress post liver transplantation because of the deposition of wild-type transthyretin. We report a patient with homozygous V122I mutation who presented with asymmetrical, upper limb predominant neuropathy rather early in his disease course, which progressed for a period of 5 years after liver transplantation before stabilization with the initiation of patisiran.

Clinical predictors of chimeric antigen receptor T-cell therapy neurotoxicity: a single-center study.

Aims: Neurotoxicity (NT) is a common complication of chimeric antigen receptor (CAR) T-cell therapy. Data on early clinical identifiers for impending severe NT are lacking. Methods: The authors performed a retrospective study on 26 adult relapsed/refractory diffuse large B cell lymphoma patients treated with commercial CAR T-cell therapy (December 2017 - September 2018). Results: NT of any grade and severe NT occurred in 88 and 31% of patients, respectively. Dysgraphia (p < 0.01), disorientation (p = 0.01) and inattention (p = 0.018) were associated with severe NT, with positive predictive values of 100, 87.5 and 87.5%, respectively. Dysnomia was not associated with severe NT. Conclusion: In the authors' limited cohort, the dysgraphia, disorientation and inattention components of the CAR T-cell therapy-associated toxicity 10 scoring system were significantly associated with and predictive of impending severe NT.

Lay abstract Neurotoxicity (NT) is a common complication of chimeric antigen receptor (CAR) T-cell therapy. Information on early signs and symptoms of impending severe NT is lacking. The authors studied 26 adult patients with relapsed/refractory diffuse large B cell lymphoma who received commercial CAR T-cell therapy for the development of NT. The authors found that NT was common, with 31% of patients experiencing severe NT. In this relatively small patient population, the authors found that impaired writing, disorientation and poor attention, which are components of the CAR T-cell therapy-associated toxicity 10 scoring system, were significantly associated with and predictive of impending severe NT.

Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations.

Myasthenia gravis (MG) is an autoimmune neurological disorder characterized by defective transmission at the neuromuscular junction. The incidence of the disease is 4.1 to 30 cases per million person-years, and the prevalence rate ranges from 150 to 200 cases per million. MG is considered a classic example of antibody-mediated autoimmune disease. Most patients with MG have autoantibodies against the acetylcholine receptors (AChRs). Less commonly identified autoantibodies include those targeted to muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (Lrp4), and agrin. These autoantibodies disrupt cholinergic transmission between nerve terminals and muscle fibers by causing downregulation, destruction, functional blocking of AChRs, or disrupting the clustering of AChRs in the postsynaptic membrane. The core clinical manifestation of MG is fatigable muscle weakness, which may affect ocular, bulbar, respiratory and limb muscles. Clinical manifestations vary according to the type of autoantibody, and whether a thymoma is present.

Drugs That Induce or Cause Deterioration of Myasthenia Gravis: An Update.

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder which is characterized by presence of antibodies against acetylcholine receptors (AChRs) or other proteins of the postsynaptic membrane resulting in damage to postsynaptic membrane, decreased number of AChRs or blocking of the receptors by autoantibodies. A number of drugs such as immune checkpoint inhibitors, penicillamine, tyrosine kinase inhibitors and interferons may induce de novo MG by altering the immune homeostasis mechanisms which prevent emergence of autoimmune diseases such as MG. Other drugs, especially certain antibiotics, antiarrhythmics, anesthetics and neuromuscular blockers, have deleterious effects on neuromuscular transmission, resulting in increased weakness in MG or MG-like symptoms in patients who do not have MG, with the latter usually being under medical circumstances such as kidney failure. This review summarizes the drugs which can cause de novo MG, MG exacerbation or MG-like symptoms in nonmyasthenic patients.

Postoperative lumbar paraspinal compartment syndrome.

Lower lumbar paraspinal muscles constitute a compartment as they are surrounded by distinct fascial and bony boundaries. Lumbar paraspinal compartment syndrome is a rare entity, often caused by intense exercise, but also can be a postoperative complication. We present a 60-year-old man with low back pain, numbness in the left lower back and radicular pain in the left lower extremity, which started after a surgery that involved prolonged positioning on the left side 7 years before, and persisted to the day of evaluation. There was an immediate transient rise in the creatine kinase after surgery. Electromyography showed a left lower lumbar-sacral plexopathy and a lumbar spine MRI revealed fatty infiltration of the lower lumbar-sacral paraspinal muscles. The emergence of radicular lower limb pain was likely due to the compression of the proximal portion of lumbar-sacral plexus during the acute stage of rhabdomyolysis.

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS.

OBJECTIVE: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).

Asymptomatic brainstem lesions and pachymeningeal enhancement after anti-PD-1 therapy.

Neurological immune-related adverse events (irAEs) are rare toxicities that occur following immune checkpoint inhibitor therapy. We propose that patients with thymic malignancies and graft-versus-host disease (GVHD) are predisposed to irAEs. We present two asymptomatic patients, one with thymoma and another with GVHD, who developed abnormal brain MRIs after treatment with programmed cell death protein 1 inhibitors. The first patient, with thymic cancer and thymoma, developed pontine enhancing MRI lesions following treatment with pembrolizumab. The second patient, with prior GVHD, developed pachymeningeal enhancement following treatment with nivolumab. IrAEs with abnormal MRI studies, despite asymptomatology, have significant impact on the treatment strategy for these patients.

An atypical presentation of primary central nervous system lymphoma: A case report.

RATIONALE: Primary central nervous system lymphoma (PCNSL) involving the choroid plexus is exceedingly rare. The differential diagnosis for choroid plexus enhancing lesions in addition to lymphoma includes infections, sarcoidosis, tuberculosis, papilloma, meningioma, subependymoma, and metastatic lesions. PATIENT CONCERNS: A 71-year-old man presented with 3 days of episodic memory loss and gait disturbance. Brain magnetic resonance imaging showed homogenously enhancing lesions with mildly restricted diffusion and T2 hypointensity in the lateral ventricles, as well as T2 hyperintensity and enhancement in the right hippocampus. His episodic memory loss was thought to be secondary to subclinical focal seizures, supported by EEG revealing right temporal lobe epileptiform discharges. DIAGNOSES: Large B-cell lymphoma, nongerminal center type was revealed on pathological examination. INTERVENTIONS: Stereotactic biopsy of his right thalamic lesion was performed. OUTCOMES: The patient underwent induction therapy with high-dose methotrexate, temozolomide, and rituximab, which resulted in complete resolution of the enhancing lesions. He then underwent conditioning chemotherapy with carmustine and thiotepa, followed by autologous stem cell transplantation. His PCNSL remains in remission 42 weeks after the onset of symptoms. LESSONS: We report a patient with multifocal PCNSL involving the choroid plexus, who presented with abnormal gait and episodic confusion and memory loss. PCNSL should be considered in the differential diagnosis of acute encephalopathy among immunocompetent older individuals who have choroid plexus enhancing lesions.

Modulation of immune responses by bile acid receptor agonists in myasthenia gravis.

Bile acids bind to multiple receptors, including Takeda G protein-coupled receptor 5 (TGR5) and farnesoid-X-receptors alpha (FXRα). We compared the response of PBMCs to the activation of these receptors in healthy controls and myasthenic patients. We found that TGR5 is a more potent negative regulator of T cell cytokine response than FXRα in both groups. In contrast, TGR5 and FXRα agonists elicit distinct B cell responses in myasthenia compared to controls, specifically on the frequency of IL-6+ B cells and regulatory B cells, as well as IL-10 secretion from PBMCs. We propose that TGR5 is a potential therapeutic target in myasthenia.