Efficacy of apraclonidine eye drops in treating ptosis secondary to myasthenia gravis: A pilot clinical trial.

INTRODUCTION/AIMS: Most patients with myasthenia gravis (MG) develop ocular manifestations during their illness and up to 22% may have isolated ocular myasthenia gravis (OMG). Apraclonidine elevates the eyelid by activating alpha-2 receptors on Muller's muscle, an accessory eyelid elevator muscle. In this study we evaluate the effect of apraclonidine in alleviating ptosis secondary to MG. METHODS: This clinical trial (NCT05045248) was done at the American University of Beirut Medical Center. Patients with ptosis secondary to MG were administered two drops of apraclonidine 0.5% solution to the most affected eye. We measured palpebral fissure height (PF), marginal reflex distance-1 (MRD1), marginal reflex distance-2 (MRD2), and levator function (LF) before drug administration and at 1, 5, 30, and 60 minutes after administration. RESULTS: Ten participants were enrolled in the study. Improvement in all eyelid measurements was noted in all participants as early as 1 minute after apraclonidine administration. From baseline to 60 minutes after administration, average PF increased from 8.8 ± 1.9 mm to 14.2 ± 2.6 mm, MRD-1 from 1.7 ± 1.4 mm to 5.4 ± 2.9 mm, MRD-2 from 7.1 ± 1.3 mm to 8.8 ± 1.7 mm, and LF from 13.4 ± 2.9 mm to 17.5 ± 2.4 mm. All increases were statistically significant. DISCUSSION: Apraclonidine may alleviate ptosis secondary to MG and may be an effective alternative treatment for this group of patients.

An open label pilot study of the safety and tolerability of perampanel in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Perampanel, a selective noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist, is capable of slowing the progression of the amyotrophic lateral sclerosis (ALS) phenotype and increasing the number of anterior horn cells in transgenic mice. Trials of perampanel in epilepsy showed a favorable tolerability profile. In this study we aimed to determine the tolerability and safety of perampanel in patients with ALS. METHODS: Enrolled subjects were started on 2 mg/day of perampanel and the dose was increased by 2 mg/day every week to a maximum dose of 8 mg/day. Our primary outcome measure was tolerability, which was evaluated by monitoring adverse events. The secondary outcome measure was clinical progression, assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and spirometry. RESULTS: Six participants were enrolled. All had adverse events, mostly behavioral. Two completed the trial and the other four withdrew due to adverse events. All participants reported resolution of these events after discontinuation of the drug. The trial was halted due to the large number of adverse events. DISCUSSION: The use of perampanel in this study of ALS was limited by its poor tolerability.

Loss of Sarm1 does not suppress motor neuron degeneration in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

Axon degeneration occurs in all neurodegenerative diseases, but the molecular pathways regulating axon destruction during neurodegeneration are poorly understood. Sterile Alpha and TIR Motif Containing 1 (Sarm1) is an essential component of the prodegenerative pathway driving axon degeneration after axotomy and represents an appealing target for therapeutic intervention in neurological conditions involving axon loss. Amyotrophic lateral sclerosis (ALS) is characterized by rapid, progressive motor neuron degeneration and muscle atrophy, causing paralysis and death. Patient tissue and animal models of ALS show destruction of upper and lower motor neuron cell bodies and loss of their associated axons. Here, we investigate whether loss of Sarm1 can mitigate motor neuron degeneration in the SOD1G93A mouse model of ALS. We found no change in survival, behavioral, electrophysiogical or histopathological outcomes in SOD1G93A mice null for Sarm1. Blocking Sarm1-mediated axon destruction alone is therefore not sufficient to suppress SOD1G93A-induced neurodegeneration. Our data suggest the molecular pathways driving axon loss in ALS may be Sarm1-independent or involve genetic pathways that act in a redundant fashion with Sarm1.

ALS-linked protein disulfide isomerase variants cause motor dysfunction.

Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized fourALS-linked mutations recently identified in two majorPDIgenes,PDIA1 andPDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of thesePDIvariants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutantPDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of thesePDImutants. Finally, targetingERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifiesERproteostasis imbalance as a risk factor forALS, driving initial stages of the disease.

Common Entrapment Neuropathies.

Entrapment neuropathies are defined as compression of peripheral nerves due to known or unknown causes. The high incidence and variety of presentations require a comprehensive knowledge of these conditions, especially in neurology and orthopedic surgery clinical practices. Detailed knowledge of topographic anatomy, clinical manifestations, and appropriate use of electrophysiological studies with selective addition of neuromuscular ultrasonography are needed to establish an early and accurate diagnosis to advice patients and provide them with a comprehensive treatment plan. In this article, we discuss the most common forms of entrapment neuropathies in the upper and lower extremities.

Guillain-Barre Syndrome.

Guillain-Barre syndrome (GBS) is the leading cause of acute paralysis that can potentially affect all of the human population. GBS is believed to be an immune-mediated disease, possibly triggered by a recent infection, and driven by an immune attack targeting the peripheral nervous system. GBS can be divided into several subtypes depending on the phenotype, pathophysiology, and neurophysiological features. Unfortunately, morbidity and mortality rates are still high despite the current understanding of the pathophysiology and available treatment options. Additional research is still needed to shed more light into the pathogenesis for a better understanding and treatment of this condition.

Adeno-associated virus-delivered artificial microRNA extends survival and delays paralysis in an amyotrophic lateral sclerosis mouse model.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons, resulting in progressive muscle weakness, paralysis, and death within 5 years of diagnosis. About 10% of cases are inherited, of which 20% are due to mutations in the superoxide dismutase 1 (SOD1) gene. Riluzole, the only US Food and Drug Administration-approved ALS drug, prolongs survival by only a few months. Experiments in transgenic ALS mouse models have shown decreasing levels of mutant SOD1 protein as a potential therapeutic approach. We sought to develop an efficient adeno-associated virus (AAV)-mediated RNAi gene therapy for ALS. METHODS: A single-stranded AAV9 vector encoding an artificial microRNA against human SOD1 was injected into the cerebral lateral ventricles of neonatal SOD1(G93A) mice, and impact on disease progression and survival was assessed. RESULTS: This therapy extended median survival by 50% and delayed hindlimb paralysis, with animals remaining ambulatory until the humane endpoint, which was due to rapid body weight loss. AAV9-treated SOD1(G93A) mice showed reduction of mutant human SOD1 mRNA levels in upper and lower motor neurons and significant improvements in multiple parameters including the numbers of spinal motor neurons, diameter of ventral root axons, and extent of neuroinflammation in the SOD1(G93A) spinal cord. Mice also showed previously unexplored changes in pulmonary function, with AAV9-treated SOD1(G93A) mice displaying a phenotype reminiscent of patient pathophysiology. INTERPRETATION: These studies clearly demonstrate that an AAV9-delivered SOD1-specific artificial microRNA is an effective and translatable therapeutic approach for ALS.

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that causes motor neuron degeneration, progressive motor dysfunction, paralysis, and death. Although multiple causes have been identified for this disease, >95% of ALS cases show aggregation of transactive response DNA binding protein (TDP-43) accompanied by its nuclear depletion. Therefore, the TDP-43 pathology may be a converging point in the pathogenesis that originates from various initial triggers. The aggregation is thought to result from TDP-43 misfolding, which could generate cellular toxicity. However, the aggregation as well as the nuclear depletion could also lead to a partial loss of TDP-43 function or TDP-43 dysfunction. To investigate the impact of TDP-43 dysfunction, we generated a transgenic mouse model for a partial loss of TDP-43 function using transgenic RNAi. These mice show ubiquitous transgene expression and TDP-43 knockdown in both the periphery and the central nervous system (CNS). Strikingly, these mice develop progressive neurodegeneration prominently in cortical layer V and spinal ventral horn, motor dysfunction, paralysis, and death. Furthermore, examination of splicing patterns of TDP-43 target genes in human ALS revealed changes consistent with TDP-43 dysfunction. These results suggest that the CNS, particularly motor neurons, possess a heightened vulnerability to TDP-43 dysfunction. Additionally, because TDP-43 knockdown predominantly occur in astrocytes in the spinal cord of these mice, our results suggest that TDP-43 dysfunction in astrocytes is an important driver for motor neuron degeneration and clinical phenotypes of ALS.

Amyotrophic Lateral Sclerosis: Review.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily affecting the upper and lower motor neurons. The lifetime risk of developing ALS is estimated at 1:350 for men and 1:500 for women, higher for those who have served in the military. The diagnosis remains clinical with electrodiagnostic support. Alternative diagnoses can usually be ruled out by the use of neuroimaging studies and laboratory evaluation. Perhaps because ALS is a diagnosis of exclusion, there is a substantial delay in diagnosis, upward of 12 months after the onset of symptoms, and most patients see three or more providers in the course of the diagnostic process. Once diagnosed, patients are best medically managed in a multidisciplinary care setting, an approach that has been shown to prolong survival and improve quality of life. Riluzole is the only disease-modifying therapy approved by the Food and Drug Administration, but numerous symptomatic therapies exist. In the past 20 years, ALS has become the focus of intense investigation by a worldwide community of basic scientists, and for clinical investigators the disease is an active area of research, with stem cell therapies, gene therapies, and a host of small molecule agents under investigation at various stages of clinical and preclinical development.

Phosphoglycerate mutase deficiency with tubular aggregates in a patient from Panama.

INTRODUCTION: Phosphoglycerate mutase deficiency (PGAM) is a rare metabolic myopathy that results in terminal block in glycogenolysis. Clinically, patients with PGAM deficiency are asymptomatic, except when they engage in brief, strenuous efforts, which may trigger myalgias, cramps, muscle necrosis, and myoglobinuria. An unusual pathologic feature of PGAM deficiency is the association with tubular aggregates. METHODS: We report an African-American patient from Panama with partial deficiency of PGAM who presented with asymptomatic elevation of creatine kinase levels and tubular aggregates on muscle biopsy. RESULTS: Muscle biopsies showed subsarcolemmal and sarcolemmal tubular aggregates in type 2 fibers. Muscle PGAM enzymatic activity was decreased and gene sequencing revealed a heterozygous mutation in codon 78 of exon 1 of the PGAM2 gene, which is located on the short arm of chromosome 7. CONCLUSIONS: PGAM deficiency has been reported in 14 patients, 9 of whom were of African-American ethnicity, and in 5 (36%) tubular aggregates were seen on muscle biopsy. Contrary to previously reported cases, our patient was initially asymptomatic. This further expands the PGAM deficiency phenotype.

Low-level overexpression of wild type TDP-43 causes late-onset, progressive neurodegeneration and paralysis in mice.

Modestly increased expression of transactive response DNA binding protein (TDP-43) gene have been reported in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neuromuscular diseases. However, whether this modest elevation triggers neurodegeneration is not known. Although high levels of TDP-43 overexpression have been modeled in mice and shown to cause early death, models with low-level overexpression that mimic the human condition have not been established. In this study, transgenic mice overexpressing wild type TDP-43 at less than 60% above the endogenous CNS levels were constructed, and their phenotypes analyzed by a variety of techniques, including biochemical, molecular, histological, behavioral techniques and electromyography. The TDP-43 transgene was expressed in neurons, astrocytes, and oligodendrocytes in the cortex and predominantly in astrocytes and oligodendrocytes in the spinal cord. The mice developed a reproducible progressive weakness ending in paralysis in mid-life. Detailed analysis showed ~30% loss of large pyramidal neurons in the layer V motor cortex; in the spinal cord, severe demyelination was accompanied by oligodendrocyte injury, protein aggregation, astrogliosis and microgliosis, and elevation of neuroinflammation. Surprisingly, there was no loss of lower motor neurons in the lumbar spinal cord despite the complete paralysis of the hindlimbs. However, denervation was detected at the neuromuscular junction. These results demonstrate that low-level TDP-43 overexpression can cause diverse aspects of ALS, including late-onset and progressive motor dysfunction, neuroinflammation, and neurodegeneration. Our findings suggest that persistent modest elevations in TDP-43 expression can lead to ALS and other neurological disorders involving TDP-43 proteinopathy. Because of the predictable and progressive clinical paralytic phenotype, this transgenic mouse model will be useful in preclinical trial of therapeutics targeting neurological disorders associated with elevated levels of TDP-43.

Characteristics of Guillain-Barré syndrome in a Lebanese tertiary care center.

Guillain-Barré Syndrome (GBS) is a group of acute inflammatory disorders that share a clinical presentation of progressive polyradiculo-neuropathy. Data on GBS in the Middle East and Lebanon are scarce; hence, we explored the characteristics of patients presenting with GBS to a tertiary care center in Beirut, Lebanon. This was a single-centered retrospective study over a 12-year period. We reviewed the charts of patients presenting with GBS to the American University of Beirut medical center and examined their presentation, management and outcome. 61 patients were included, with the majority being males. 59% of the patients reported an infection prior to admission. 77% had sensory and motor symptoms and 69% were diagnosed with acute inflammatory demyelinating polyneuropathy (AIDP). 57% of patients had initial symptoms in the lower extremities, 25% experienced cranial neuropathies, and 26% complained of pain. 77% were managed by intravenous immunoglobulin with a median hospital stay of 6.5 days. AIDP was noted to be the most prevalent GBS variant in Lebanon. More than 50% had an unfavorable outcome at discharge, which raises the need for better treatment and management approaches.

Nonmotor Symptoms in Amyotrophic Lateral Sclerosis and Their Correlation With Disease Progression.

OBJECTIVES: Motor neuron disease is a progressive neurodegenerative disease involving upper and lower motor neurons. Nonmotor symptoms (NMS) are part of disease manifestation. We aim to report the prevalence and severity of NMS in patients with motor neuron disease (MND) in Lebanon. . METHODS: Fifty-eight patients diagnosed with MND at the American University of Beirut Medical Center were interviewed using the NMS Scale. The prevalence of these symptoms was assessed and correlated with disease progression. RESULTS: All our patients had at least 2 NMS with an average total score of 15.8. Symptoms reported in more than half of the patients were fatigue, depression, dysphagia, lack of motivation, pain, change in weight, anxiety, constipation, and lack of pleasure. A significant correlation was found between the total NMS score and Amyotrophic Lateral Sclerosis Functional Rating Scale score (P = 0.002) and between the NMS score corresponding to mental health and Amyotrophic Lateral Sclerosis Functional Rating Scale score (P = 0.012). Patients with bulbar symptoms had a significantly higher NMS score corresponding to gastrointestinal symptoms (P < 0.0001). It is important to note that NMS such as dysphagia could be related to motor neuron involvement. CONCLUSIONS: NMS are commonly reported in patients with MND and seem to positively correlate with disease progression. Treating NMS is a critical aspect of the clinical care delivered to patients with MND to maintain a good quality of life.

Absent sural responses in tethered cord syndrome.

Context: Tethered cord syndrome is a progressive condition usually diagnosed early in life, and leads to a diversity of manifestations including neurologic, urologic, and orthopedic dysfunction.Findings: We report two cases of tethered cord syndrome associated with a unilaterally absent sural sensory response on nerve conduction studies while other causes of this finding being excluded.Conclusion/clinical relevance: We believe that this finding is caused by a selective injury of sensory fibers at the level or distal to the dorsal root ganglia.

Added sampling improves reproducibility of multipoint motor unit estimates.

Motor unit number estimation (MUNE) has been used to track motor unit attrition. Studies have used the modified multiple-point stimulation (MPS) technique, collecting three surface motor unit action potentials (sMUAPs) from 3 sites to calculate MUNE. Factoring additional sMUAPs should theoretically improve reproducibility, but the optimal number has not been defined. We evaluated the effect of increased sMUAP sampling on test-retest reproducibility of the modified MPS MUNE technique and found that MUNE reproducibility increased with additional sampling. Muscle Nerve, 2010.

Kennedy's disease: an under-recognized motor neuron disorder.

Kennedy's disease or spinal bulbar muscular atrophy is a rare, inherited and slowly progressive multisystem disease mostly manifesting with a motor neuron disease phenotype leading to disability. The slow progression, partial androgen insensitivity, electrophysiological evidence of sensory neuronopathy, and relatively spared central nervous system pathways help differentiate it from amyotrophic lateral sclerosis. To date, there is no treatment or cure with clinical care mainly focused on accurate diagnosis, symptom management, patient education, and genetic counselling.

Characteristics of amyotrophic lateral sclerosis in Lebanon-a chart review.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily manifesting as motor deficits. It is caused by motor neuron death and leads to progressive disability and demise. It can present at any age, manifest as several phenotypes, and may have a variable progression pattern. Methods: This retrospective study is based on chart review of subjects presenting to the American University of Beirut Medical Center from June 2015 till March 2020. It aims to describe the characteristics of ALS in Lebanon. Results: Out of 140 subjects identified, 113 had classical ALS. The mean age in classical and atypical ALS were 55.5 and 55.6 years, male gender was predominant in both groups, and the mean duration from disease onset to diagnosis was 10 months in classic ALS compared to 22 months in atypical ALS. The median survival in subjects with classical ALS was 31 months which was significantly lower than atypical ALS phenotypes of 41.5 months. Additionally, more than half of patients (57%) were found to have a moderate ALSFRS-R progression rate. Conclusions: The study is the first to report the characteristics of amyotrophic lateral sclerosis in Lebanon. Moreover, we were able to categorize patients with classical phenotype according to disease progression using the ALSFRS-R score which can be a useful tool in determining disease prognosis at an early stage.

Adult onset Sandhoff disease: a rare mimicker of amyotrophic lateral sclerosis.

Sandhoff disease is an under-recognized disease that may present as a lower motor neuron disorder in adulthood. We report the case of siblings presenting in their late 40s with a motor neuron disease phenotype and were misdiagnosed as amyotrophic lateral sclerosis and later found to have Sandhoff disease. Sandhoff disease should be considered in patients presenting with a slowly progressive predominately lower motor neuron disorder. A simple low-cost blood test can confirm the diagnosis.

Traumatic Brain Injury: Oxidative Stress and Novel Anti-Oxidants Such as Mitoquinone and Edaravone.

Traumatic brain injury (TBI) is a major health concern worldwide and is classified based on severity into mild, moderate, and severe. The mechanical injury in TBI leads to a metabolic and ionic imbalance, which eventually leads to excessive production of reactive oxygen species (ROS) and a state of oxidative stress. To date, no drug has been approved by the food and drug administration (FDA) for the treatment of TBI. Nevertheless, it is thought that targeting the pathology mechanisms would alleviate the consequences of TBI. For that purpose, antioxidants have been considered as treatment options in TBI and were shown to have a neuroprotective effect. In this review, we will discuss oxidative stress in TBI, the history of antioxidant utilization in the treatment of TBI, and we will focus on two novel antioxidants, mitoquinone (MitoQ) and edaravone. MitoQ can cross the blood brain barrier and cellular membranes to accumulate in the mitochondria and is thought to activate the Nrf2/ARE pathway leading to an increase in the expression of antioxidant enzymes. Edaravone is a free radical scavenger that leads to the mitigation of damage resulting from oxidative stress with a possible association to the activation of the Nrf2/ARE pathway as well.