Chronic glucocorticoid management in neuromuscular disease: A survey of neuromuscular neurologists.

INTRODUCTION/AIMS: Glucocorticoids (GC) are first-line therapy for many neuromuscular diseases. There is a lack of guidelines regarding the prevention and management of GC complications in the context of neuromuscular disease, introducing the potential for practice variation, that may compromise quality of care. Our aim was to evaluate the practice patterns among Canadian adult neuromuscular neurologists on the screening, management, and treatment of GC-related complications and to identify variances in practice. METHODS: A web-based anonymous questionnaire was disseminated to 99 Canadian adult neuromuscular neurologists. Questions addressed patterns of screening, prevention, monitoring, and treatment of GC-induced adverse events, including infection prophylaxis, vaccination, bone health, hyperglycemia, and other complications. RESULTS: Seventy-one percent completed the survey. Of those, 52% perform screening blood work prior to initiating GC, 56% screen for infections, and 18% for osteoporosis. The majority monitor glycemic control and blood pressure (>85%). Thirty-two (46%) reported that they do not primarily monitor GC complications, but rather provide recommendations to the primary care physician. Pneumocystis jiroveci pneumonia prophylaxis was never used by 29%, and 29% recommend vaccinations prior to GC initiation. Calcium supplementation was recommended by 80% to prevent osteoporosis. Only 36% were aware of any existing guidelines for preventing GC complications, and 91% endorsed a need for neurology-specific guidelines. DISCUSSION: There is substantial variability in the management of GC adverse effects among neuromuscular neurologists, often not corresponding to limited published literature. Our results support the need for improved education and neurology-specific guidelines to help standardize practice and improve and prevent complications.

On-chip 3D neuromuscular model for drug screening and precision medicine in neuromuscular disease.

This protocol describes the design, fabrication and use of a 3D physiological and pathophysiological motor unit model consisting of motor neurons coupled to skeletal muscles interacting via the neuromuscular junction (NMJ) within a microfluidic device. This model facilitates imaging and quantitative functional assessment. The 'NMJ chip' enables real-time, live imaging of axonal outgrowth, NMJ formation and muscle maturation, as well as synchronization of motor neuron activity and muscle contraction under optogenetic control for the study of normal physiological events. The proposed protocol takes ~2-3 months to be implemented. Pathological behaviors associated with various neuromuscular diseases, such as regression of motor neuron axons, motor neuron death, and muscle degradation and atrophy can also be recapitulated in this system. Disease models can be created by the use of patient-derived induced pluripotent stem cells to generate both the motor neurons and skeletal muscle cells used. This is demonstrated by the use of cells from a patient with sporadic amyotrophic lateral sclerosis but can be applied more generally to models of neuromuscular disease, such as spinal muscular atrophy, NMJ disorder and muscular dystrophy. Models such as this hold considerable potential for applications in precision medicine, drug screening and disease risk assessment.

The Autophagy Signaling Pathway: A Potential Multifunctional Therapeutic Target of Curcumin in Neurological and Neuromuscular Diseases.

Autophagy is the major intracellular machinery for degrading proteins, lipids, polysaccharides, and organelles. This cellular process is essential for the maintenance of the correct cellular balance in both physiological and stress conditions. Because of its role in maintaining cellular homeostasis, dysregulation of autophagy leads to various disease manifestations, such as inflammation, metabolic alterations, aging, and neurodegeneration. A common feature of many neurologic and neuromuscular diseases is the alteration of the autophagy-lysosomal pathways. For this reason, autophagy is considered a target for the prevention and/or cure of these diseases. Dietary intake of polyphenols has been demonstrated to prevent/ameliorate several of these diseases. Thus, natural products that can modulate the autophagy machinery are considered a promising therapeutic strategy. In particular, curcumin, a phenolic compound widely used as a dietary supplement, exerts an important effect in modulating autophagy. Herein, we report on the current knowledge concerning the role of curcumin in modulating the autophagy machinery in various neurological and neuromuscular diseases as well as its role in restoring the autophagy molecular mechanism in several cell types that have different effects on the progression of neurological and neuromuscular disorders.

Potential therapeutic implications of ergogenic compounds on pathophysiology induced by traumatic brain injury: A narrative review.

Traumatic brain injury (TBI) is a devastating condition that often triggers a sequel of neurological disorders that can last throughout lifespan. From a metabolic viewpoint, the compromising of the energy metabolism of the brain has produced evidence linking the severity of brain injury to the extent of disturbances in the cerebral metabolism. The cerebral metabolic crisis, however, displays that regional heterogeneity varies temporally post-injury. It is important to note that energy generation and mitochondrial function are closely related and interconnected with delayed secondary manifestations of brain injury, including early neuromotor dysfunction, cognitive impairment, and post-traumatic epilepsy (PTE). Given the extent of post-traumatic changes in neuronal function and the possibility of amplifying secondary cascades, different therapies designed to minimize damage and retain/restore cellular function after TBI are currently being studied. One of the possible strategies may be the inclusion of ergogenic compounds, which is a class of supplements that typically includes ingredients used by athletes to enhance their performance. The combination of these compounds offers specific physiological advantages, which include enhanced energy availability/metabolism and improved buffering capacity. However, the literature on their effects in certain biological systems and neurological diseases, such as TBI, has yet to be determined. Thus, the present review aims to discuss the role of ergogenic compounds popularly used in secondary damage induced by this neurological injury. In this narrative review, we also discuss how the results from animal studies can be applied to TBI clinical settings.

Successful Improvement of Pain Symptomatology in a Suspected Case of Cramp-Fasciculation Syndrome via Interventional Pain Treatment.

Peripheral nerve hyperexcitability (PNH) syndromes are a rare set of neuromuscular disorders that include cramp-fasciculation syndrome (CFS) and Isaacs syndrome (IS). Successful treatment of these diseases has been achieved with antiepileptic medications; however, chronic pain symptoms can persist. We provide a case report of a 25-year-old female who has suffered from painful severe muscle spasms and fasciculations since childhood. With CFS as our working diagnosis, a treatment regimen using interventional pain techniques, including sympathetic chain blocks, ketamine infusions, and trigger point injections, resulted in a significant decrease in the patient's chronic pain symptoms. This case offers a novel application of interventional pain procedures and may help further our understanding of PNH syndromes.

Neuromuscular degenerative effects of Ankaferd Blood Stopper® in mouse sciatic nerve model.

PURPOSE: Ankaferd Blood Stopper® (ABS), a licenced medicinal herbal extract, is commonly used as an effective topical haemostatic agent. This study is designed to investigate whether topical ABS application may cause peripheral nerve degeneration and neuromuscular dysfunction in a mouse sciatic nerve model. METHODS: Twenty mice were randomly divided into two groups; an ABS treated experimental group and a saline-treated control group. Left sciatic nerves were treated with 0.3 ml of ABS in the experimental group and 0.3 ml of sterile saline in the control group for 5 min. Peripheral nerve degeneration and neuromuscular dysfunction were evaluated by behavioural tests, electrophysiological analysis and weight ratio comparison of target muscles. RESULTS: The motor function, assessed by the sciatic function index, was significantly impaired in ABS-treated animals as compared to the animals treated with saline. Motor coordination, evaluated with the rotarod test, was significantly decreased (-42%) in ABS-treated animals compared to the saline-treated animals. The degree of pain, assessed by the reaction latency to thermal stimuli (hot-plate test), was significantly prolonged (313%) in ABS-treated mice when compared to the saline-treated mice. ABS-treated mice showed a significant reduction in motor nerve conduction velocity (MNCV) (-52%) and the compound muscle action potential (CMAP) (-47%); however, it significantly prolonged onset latency (23%). The gastrocnemius muscles weight ratio of the ABS group was considerably lower than that of the control group. CONCLUSIONS: These findings demonstrate that ABS triggers peripheral nerve degeneration and functional impairment and, thus promotes a deterioration of sciatic nerves.

Naturally occurring plant polyphenols as potential therapies for inherited neuromuscular diseases.

There are several lines of laboratory-based evidence emerging to suggest that purified polyphenol compounds such as resveratrol, found naturally in red grapes, epigallocatechin galate from green tea and curcumin from turmeric, might be useful for the treatment of various inherited neuromuscular diseases, including spinal muscular atrophy, Duchenne muscular dystrophy and Charcot-Marie-Tooth disease. Here, we critically examine the scientific evidence related to the known molecular effects that these polyphenols have on different models of inherited neuromuscular disease, with particular attention to problems with the validity of in vitro evidence. We also present proteomic evidence that polyphenols have in vitro effects on cells related to metal ion chelation in cell-culture media. Although their precise mechanisms of action remain somewhat elusive, polyphenols could be an attractive approach to therapy for inherited neuromuscular disease, especially since they may be safer to use on young children, compared with some of the other drug candidates.

Response of serum carboxylated and undercarboxylated osteocalcin to risedronate monotherapy and combined therapy with vitamin K(2) in corticosteroid-treated patients: a pilot study.

OBJECTIVE: The aim of this study was to investigate the responses of serum osteocalcin (OC), undercarboxylated osteocalcin (ucOC) and N-terminal telopeptide of type I collagen (NTx) to corticosteroids, and to examine the effects of risedronate therapy with or without vitamin K(2) supplementation on bone metabolic markers in corticosteroid-treated patients. METHODS: Sixteen patients on corticosteroid therapy for neuromuscular disorders were assigned randomly to 2 groups (A: risedronate monotherapy, n=8; B: combined risedronate and vitamin K(2) therapy, n=8) and treated for 1 year. Another 6 patients who received intravenous steroid pulse therapy were assigned to group C for investigation of the effects of corticosteroids on OC and ucOC 1 month after pulse therapy. RESULTS: Serial measurements revealed that significant decreases of OC, ucOC and NTx persisted with a similar time course profile during 1 year of treatment in groups A and B, and between-group analysis failed to demonstrate any additional effects of vitamin K(2) on risedronate therapy. Intravenous steroid pulse therapy induced a transient depression of OC and ucOC within 1 week in group C. CONCLUSION: These results indicate that serum concentrations of OC and ucOC become consistently low during corticosteroid administration despite risedronate therapy with or without vitamin K(2) supplementation, and the serum ucOC level may not be a reliable indicator of vitamin K status under corticosteroid administration.

The role of patient advocacy organisations in neuromuscular disease R&D--The case of the Dutch neuromuscular disease association VSN.

This article investigates to what extent patient advocacy organisations play a role in influencing R&D and policymaking for rare neuromuscular diseases. The Dutch neuromuscular disease organisation VSN is studied in depth. A brief history of the VSN is sketched along with the international embedding of the organisation. Then, a more general perspective is provided on the reasons and extent of the involvement of patient organisations (and especially the VSN) in innovation processes. Lastly, internal mechanisms are presented that can best be applied by these organisations. The VSN adheres to a rare, long-term vision on drug innovation that requires long-term planning and policy and vision creation and steering the direction of science and technology. At the same time, other actors like scientific organisations and science policymakers and managers can benefit from these lessons to learn how to deal with patients and patient organisations in the future.

Coenzyme Q10 in neuromuscular and neurodegenerative disorders.

Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has be implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency.

Cognitive effects of creatine ethyl ester supplementation.

Supplementation with creatine-based substances as a means of enhancing athletic performance has become widespread. Until recently, however, the effects of creatine supplementation on cognitive performance has been given little attention. This study used a new form of creatine--creatine ethyl ester--to investigate whether supplementation would improve performance in five cognitive tasks, using a double-blind, placebo-controlled study. Creatine dosing led to an improvement over the placebo condition on several measures. Although creatine seems to facilitate cognition on some tasks, these results require replication using objective measures of compliance. The improvement is discussed in the context of research examining the influence of brain energy capacity on cognitive performance.

[The endogenous cannabinoid system. Therapeutic implications for neurologic and psychiatric disorders]. / Das endogene Cannabinoidsystem. Therapeutische Implikationen der Cannabinoide bei neurologisch-psychiatrischen Erkrankungen.

For about 5,000 years, cannabis has been used as a therapeutic agent. There has been growing interest in the medical use of cannabinoids. This is based on the discovery that cannabinoids act with specific receptors (CB1 and CB2). CB1 receptors are located in specific brain areas (e.g. cerebellum, basal ganglia, and hippocampus) and CB2 receptors on cells of the immune system. Endogenous ligands of the cannabinoid receptors were also discovered (e.g. anandamids). Many physiologic processes are modulated by the two subtypes of cannabinoid receptor: motor functions, memory, appetite, and pain. These innovative neurobiologic/pharmacologic findings could possibly lead to the use of synthetic and natural cannabinoids as therapeutic agents in various areas. Until now, cannabinoids were used as antiemetic agents in chemotherapy-induced emesis and in patients with HIV-wasting syndrome. Evidence suggests that cannabinoids may prove useful in some other diseases, e.g. movement disorders such as Gilles de la Tourette's syndrome, multiple sclerosis, and pain. These new findings also explain the acute adverse effects following cannabis use.

Natural history of Oppenheim's dystonia (DYT1) in Israel.

The question of whether a fetus carrying the GAG deletion on the DYT1 gene responsible for Oppenheim's dystonia should be aborted is frequently raised. The objective of this study was to characterize the clinical spectrum and natural course of Oppenheim's dystonia in Israel. Thirty-three patients (19 male) with genetically confirmed Oppenheim's dystonia were evaluated. The Dystonia Rating Scale (maximum score 120) and the Disability Scale (maximum score 30) were used to score severity at the last visit. After a mean of 15.5 +/- 13.8 years of symptoms, the mean Dystonia Rating Scale and Disability Scale scores were 22.7 +/- 14.7 and 7.7 +/- 4.3, respectively. Twenty-one patients (63.6%) have progressed into generalized dystonia. Five patients (15%) are wheelchair bound and three (9%) are using walking aids. All patients have normal cognitive function. Baclofen, trihexyphenidyl, and botulinum toxin were the drugs used. Nine patients (one patient had both) underwent neurosurgical intervention: thalamotomy for six (two bilateral) and pallidotomy for four (three bilateral). The bilateral pallidotomy provided only short-term benefit. The modern treatments combining drugs, botulinum toxin, and functional neurosurgery allow most patients with Oppenheim's dystonia to have independence and a relatively good quality of life.

Effects of high-dose propofol on succinylcholine-induced fasciculations and myalgia.

BACKGROUND: The purpose of this prospective study was to determine the effects of high-dose propofol on the incidence of fasciculations and myalgia, and to evaluate changes in creatine kinase levels following the administration of succinylcholine in 90 women who underwent laparoscopy. METHODS: Patients were randomly assigned to one of three groups. Induction of anesthesia was performed with thiopentone 5 mg kg(-1) in Group I (n = 30), propofol 2 mg kg(-1) in Group II (n = 30), and propofol 3.5 mg kg(-1) in Group III (n = 30). Then succinylcholine 1 mg kg(-1) was administered to the patients for intubation. RESULTS: Fasciculation was absent in 20% of Group III patients, and no vigorous fasciculation occurred in this group. Furthermore, the severity of fasciculation in Group III was significantly lower than in the other two groups (P = 0.01). Seventy per cent of patients had no myalgia in Group III, 39.2% in Group II and 37% in Group I (P = 0.007). Severity of myalgia was also significantly lower in Group III compared with the other two groups (P = 0.011). Post-operative creatine kinase levels were significantly higher than their baseline values in Groups I and II (P < 0.0001). CONCLUSION: Administration of propofol 3.5 mg kg-1 is effective in reducing fasciculations and myalgia after succinylcholine.

[A new toy: upswing in curare use in Spanish anesthesia]. / A new toy: la irrupción del curare en la anestesia española (1946).

The introduction of curare for general anesthesia by Harold Griffith in 1942 was one of the most important moments in the development of anesthesiology. However, several years passed before curare came to be used in Spain. We review the early application of curare and the role played by Robert Macintosh, Professor of Anaesthesia at Oxford, in introducing the drug to Spain.

Relation of endometriosis and neuromuscular disease of the gastrointestinal tract: new insights.

OBJECTIVE: To investigate the neuromuscular activity of the gastrointestinal tract by antroduodenal manometry in women with endometriosis documented by laparoscopy, to assess the effects of diet and drug therapy on symptoms, and to assess the bacterial overgrowth that is commonly associated with these nerve diseases. DESIGN: Prospective, open-label study. SETTING: A clinical center for the care of women's health. PATIENT(S): Fifty women with endometriosis documented by laparoscopy and gastrointestinal tract symptoms characterized by chronic abdominal pain, nausea, vomiting, early satiety, bloating and distention, and altered bowel habits. INTERVENTION(S): Motility of the gastrointestinal tract was recorded and bacterial overgrowth was assessed. Treatment consisted of dietary changes, including reduction of glycemic carbohydrates, balancing with omega 9 oils, elimination of foods with caffeine and tyramine, and addition of omega 3 fatty acids, as well as drug therapy with clonazepam (0.25 mg 3 times per day). RESULT(S): All 50 women showed a characteristic motility change (ampulla of Vater-duodenal wall spasm, a seizure equivalent of the enteric nervous system). Forty of the women showed bacterial overgrowth. There was a significant reduction in the total symptom score after 8 weeks of treatment. CONCLUSION(S): This study suggests that endometriosis and gastrointestinal tract symptoms are a result of the dysfunction of hollow organs. Correction of the biochemical imbalance of the eicosanoid system and the hypersecretion of insulin that results from excessive intake of glycemic carbohydrates and lack of essential fatty acids significantly decreases symptoms in patients with endometriosis and associated neuromuscular disease of the gastrointestinal tract.

A quantitative study of the pancuronium antagonism at the motor endplate in human organophosphorus intoxication.

Nine patients with organophosphorus (OP) intoxication developing neuromuscular transmission defects were given pancuronium 1, 2, or 4 mg intravenously (IV). Thirteen patient controls with hypoxic encephalopathy received similar dosages. The responses were monitored electrophysiologically using single and repetitive nerve stimulation (20 and 50 Hz). In OP patients, pancuronium did not alter the amplitude of the single CMAP, whereas its repetitive discharges were reduced. Severe neuromuscular blocks were reversed only partially by pancuronium 4 mg. In less severe blocks, 1 and 2 mg resulted in marked improvement. In the patient controls, pancuronium 4 mg induced a severe neuromuscular block but not with 1 and 2 mg. Pancuronium dosages necessary to reverse severe OP-induced neuromuscular blockade produce a neuromuscular block when AChE activity is normal. Low dosages have little effect on normal neuromuscular transmission, but improve the block to a mild degree and may be useful as part of treatment in OP intoxications.

Possible involvement of a gamma-hydroxybutyric acid receptor in startle disease.

Startle disease or hyperreflexia is an autosomal dominant neurological disorder, with a neonatal onset, characterized by muscular hypertonia and myoclonic jerks, exaggerated by the slightest stimulus. Low concentrations of free gamma-aminobutyric acid (GABA) have been found in the cerebrospinal fluid of two affected infants. The involvement of GABA or its receptors has been raised and the use of GABA-agonist drugs has been suggested. We report a newborn with startle disease who also had a low concentration of GABA in the cerebrospinal fluid. No clinical improvement was observed with progabide, a GABA agonist. Furthermore, a high dose (100 mg/kg) of gamma-hydroxybutyrate (GHB) did not improve muscular stiffness and failed to induce general anesthesia. GHB, currently used as an effective general anaesthetic, is a structural analogue of GABA. It is present naturally at low concentrations in the brain and is regarded as an inhibitory neurotransmitter. Two specific GHB receptors, distinct from the GABA receptors, have been identified in rat brain. Failure to induce general anesthesia with a high dose of GHB suggests that one of these receptors could be involved in startle disease.