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.

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.

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.

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.

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.

Myasthenia gravis induced by avelumab.

Neurological immune-related adverse events are potentially life-threatening complications of immune checkpoint inhibitors. Myasthenia gravis (MG) is a rare complication of treatment with inhibitors of programmed cell death protein 1 (PD)-1 and PD ligand 1 (PD-L1). We present a patient who developed seronegative MG resulting in respiratory failure while being treated with avelumab for metastatic, treatment-refractory ovarian cancer. Her MG went into remission following steroids and maintenance intravenous immunoglobulin treatment. We conclude that MG is a rare, but potentially life-threatening immune-related adverse event of avelumab therapy. This case provides support to the hypothesis that PD-1/PD-L1 signaling may have a protective role in MG.

Severe Relapse of Vaccine-Induced Guillain-Barré Syndrome After Treatment With Nivolumab.

Cancer immunotherapy with checkpoint inhibitors may result in neuromuscular immune-related adverse reactions, including Guillain-Barré syndrome (GBS)-like disease. On the other hand, checkpoint inhibitor therapy may result in exacerbation of underlying autoimmune diseases such as myasthenia gravis and multiple sclerosis. We present a patient who developed a severe and fatal relapse of postvaccination GBS after he was treated with nivolumab, a monoclonal antibody directed to programmed death-1 (PD-1), during a GBS treatment-related fluctuation. We recommend that caution be exercised in starting treatment with PD-1 inhibitors in the acute stage or early in the recovery period of GBS.

Facial Palsy Induced by Checkpoint Blockade: A Single Center Retrospective Study.

The augmented immune response caused by immune checkpoint inhibitors leads to the emergence of a class of side effects called immune-related adverse events (irAEs). Facial palsy (FP) is rarely reported as an irAE. In this retrospective study, we reviewed the records of 353 patients treated with immunotherapy in our center from 2015-2018. We identified 4 male patients and 1 female patient with FP. Four had metastatic melanoma and were treated with ipilimumab either as monotherapy or in combination with nivolumab or pembrolizumab. The remaining patient had metastatic bladder cancer, treated with atezolizumab. FP was unilateral and occurred 1-23 weeks after starting immunotherapy. FP was part of a more diffuse neuropathic process in 3 of our patients. Lymphocytic pleocytosis was seen in the cerebrospinal fluid of 3 patients who had lumbar punctures. Magnetic resonance imaging showed enhancement of the intracranial portion of the affected facial nerve in 4 patients. The outcome was favorable in all of the patients noting that 1 patient had incomplete recovery. We conclude that FP, in isolation or as a part of a polyneuropathy, is common among neurological irAEs associated with checkpoint inhibitors and generally has a good prognosis.

Neonatal Hypoxia Results in Peripheral Nerve Abnormalities.

Although the adverse effects of neonatal hypoxia associated with premature birth on the central nervous system are well known, the contribution of hypoxic damage to the peripheral nervous system (PNS) has not been addressed. We demonstrate that neonatal hypoxia results in hypomyelination and delayed axonal sorting in mice leading to electrophysiological and motor deficits that persist into adulthood. These findings support a potential role for PNS hypoxic damage in the motor impairment that results from premature birth and suggest that therapies designed to protect the PNS may provide clinical benefit.

Head-drop: A frequent feature of late-onset myasthenia gravis.

INTRODUCTION: Head-drop is often encountered in myasthenia gravis (MG) patients, but its frequency and clinical course have not been studied systematically. METHODS: In a retrospective study of a cohort of MG patients seen over a period of 11 years in a tertiary medical center, we assessed the clinical characteristics of patients who had head-drop. RESULTS: Of 146 generalized MG patients, 15 had head-drop during the course of their disease. Head-drop patients had older age of onset than those who did not have head-drop (mean age of onset 59.1 vs. 42.3 years) and were predominantly men. Head-drop was present in 23% of patients > 60 versus 6% of those < 60 years, and it improved in 9 of 11 patients with treatment directed to generalized MG. CONCLUSIONS: Head-drop is a common, treatment-responsive manifestation of late-onset MG. Muscle Nerve 56: 441-444, 2017.

Intermuscular coherence in amyotrophic lateral sclerosis: A preliminary assessment.

INTRODUCTION: Simple laboratory tests of upper motor neuron involvement in amyotrophic lateral sclerosis (ALS) are not available. Intermuscular coherence has been shown to distinguish patients with primary lateral sclerosis, a pure upper motor neuron disorder, from normal subjects, suggesting it could be useful for assessing ALS. We aimed to determine whether intermuscular coherence can distinguish ALS patients from normal subjects. METHODS: We measured biceps brachii and brachioradialis activity using surface electromyography while subjects held the elbow at flexion and the forearm in semipronation. Intermuscular coherence was calculated at between 20 and 40 Hz in 15 ALS patients and 15 normal subjects. RESULTS: On average, intermuscular coherence was 3.8-fold greater in normal subjects than in ALS patients (P < 0.01), and it distinguished ALS patients from normal subjects with a sensitivity of 87% and specificity of 87%. CONCLUSION: Intermuscular coherence measurement is a rapid, painless method that may detect upper motor neuron dysfunction in ALS. Muscle Nerve 55: 862-868, 2017.

Gastrostomy tube placement is safe in advanced amyotrophic lateral sclerosis.

OBJECTIVES: To evaluate the safety and effect on survival of insertion of a gastrostomy tube (G-tube) in patients with amyotrophic lateral sclerosis (ALS) who have upright forced vital capacity (uFVC) ≤ 50% predicted. Current guidelines, which are based on higher rates of post-procedure complications in ALS patients with advanced respiratory dysfunction, have led to a recommendation to perform G-tube insertion before the FVC drops to <50% predicted, even when the patient has no significant dysphagia. METHODS: We assessed 41 ALS patients who received a G-tube, mostly by insertion of a percutaneous endoscopic gastrostomy (PEG) tube by a dedicated team that included a gastroenterologist and one of two anesthesiologists using Monitored Anesthesia Care with deep sedation, and 61 patients who did not receive a G-tube. uFVC was ≤50% predicted in 12 of 41 patients who received a G-tube and in 18 of 61 who did not. RESULTS: The procedure was safe regardless of FVC status, with low rates of post-operative complications in both low and high FVC groups. There was no survival benefit for patients who received a G-tube when compared with those who did not. DISCUSSION: PEG insertion is safe in ALS patients with significant respiratory muscle weakness when performed by a dedicated team, which suggests that the recommendation for G-tube placement should not be based on the patient's respiratory status.

Impaired regulatory B cells in myasthenia gravis.

Regulatory B cells (Bregs) attenuate the severity of experimental autoimmune myasthenia gravis (EAMG) in an interleukin-10 (IL-10)-dependent manner. The goal of this study was to investigate the role of human Bregs in MG focusing on CD19(+)CD1d(hi) CD5(+) and CD19(+)CD24(hi)CD38(hi) subsets. We found that MG patients exhibited a decrease in the frequency of both Breg subsets and IL-10 producing B cells within each subset, which correlated with disease severity. In addition, there was impaired suppression of Th1 polarization in MG. These findings, taken together with EAMG data, indicate that Bregs play an important role in regulating the severity of MG.

Adenomatous polyposis coli regulates radial axonal sorting and myelination in the PNS.

The tumor suppressor protein adenomatous polyposis coli (APC) is multifunctional - it participates in the canonical Wnt/ß-catenin signal transduction pathway as well as modulating cytoskeleton function. Although APC is expressed by Schwann cells, the role that it plays in these cells and in the myelination of the peripheral nervous system (PNS) is unknown. Therefore, we used the Cre-lox approach to generate a mouse model in which APC expression is specifically eliminated from Schwann cells. These mice display hindlimb weakness and impaired axonal conduction in sciatic nerves. Detailed morphological analyses revealed that APC loss delays radial axonal sorting and PNS myelination. Furthermore, APC loss delays Schwann cell differentiation in vivo, which correlates with persistent activation of the Wnt signaling pathway and results in perturbed extension of Schwann cell processes and disrupted lamellipodia formation. In addition, APC-deficient Schwann cells display a transient diminution of proliferative capacity. Our data indicate that APC is required by Schwann cells for their timely differentiation to mature, myelinating cells and plays a crucial role in radial axonal sorting and PNS myelination.