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.

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.

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.

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.

Venous thromboembolism after diaphragm pacing in amyotrophic lateral sclerosis.

INTRODUCTION: Patients with amyotrophic lateral sclerosis (ALS) are prone to venous thromboembolism (VTE) and secondary complications. Because there is an increased incidence of VTE after surgical procedures, placement of a Diaphragm Pacing System (DPS) in ALS patients as treatment for respiratory muscle weakness could potentially increase the incidence of VTE, especially in patients with limited mobility. METHODS: We implanted a DPS in 10 ALS patients who met the criteria for this procedure. They underwent a preoperative evaluation as recommended by the guidelines. RESULTS: We report 2 patients with no symptoms of deep vein thrombosis (DVT) before the surgical procedure who then developed perioperative VTE. CONCLUSIONS: These patients highlight the need to consider preoperative screening for DVT and postoperative thromboprophylaxis in high-risk ALS patients who undergo DPS placement.

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 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.

A randomized open-label study of sodium valproate vs sumatriptan and metoclopramide for prolonged migraine headache.

OBJECTIVE: The objective of this study is to compare the efficacy and tolerability of intravenous valproic acid (iVPA) with intramuscular metoclopramide + subcutaneous (SQ) sumatriptan for prolonged acute migraine. BACKGROUND: Intravenous valproic acid has been explored as a possible treatment of acute migraine. Sumatriptan and newer generation triptans are also effective for migraine. However, iVPA has not yet been compared with triptans in head-to-head studies. METHODS: Patients presenting with moderate to severe intensity migraine without aura were randomized to receive either 400 mg of iVPA or 10 mg intramuscular metoclopramide + 6 mg SQ sumatriptan (30 patients in each study arm). The severity of headache and other associated symptoms such as photophobia and phonophobia were assessed at baseline and after 20 minutes and 1, 2, 4, and 24 hours. The primary end point was to compare the efficacy of the 2 study treatments in relieving headache from moderate-severe to none-mild and of other associated symptoms within a period of 24 hours. RESULTS: Pain relief from severe or moderate to mild or none was obtained in 53.3% of subjects in the iVPA arm and 23.3% in the metoclopramide + sumatriptan arm at 1 hour following treatment (P = .033), whereas 60% and 30% reported pain relief at 2 hour (P = .037). There was no other significant difference in alleviation of associated migraine symptoms between the 2 arms. No serious adverse effects were noted. CONCLUSION: Treatment with iVPA was more effective than metoclopramide + SQ sumatriptan during the first 2 hours in patients with a prolonged migraine.

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.

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.

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.

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.

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.