The Effect of Neuronal CoQ10 Deficiency and Mitochondrial Dysfunction on a Rotenone-Induced Neuronal Cell Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder currently affecting the ageing population. Although the aetiology of PD has yet to be fully elucidated, environmental factors such as exposure to the naturally occurring neurotoxin rotenone has been associated with an increased risk of developing PD. Rotenone inhibits mitochondrial respiratory chain (MRC) complex I activity as well as induces dopaminergic neuronal death. The aim of the present study was to investigate the underlying mechanisms of rotenone-induced mitochondrial dysfunction and oxidative stress in an in vitro SH-SY5Y neuronal cell model of PD and to assess the ability of pre-treatment with Coenzyme Q10 (CoQ10) to ameliorate oxidative stress in this model. Spectrophotometric determination of the mitochondrial enzyme activities and fluorescence probe studies of reactive oxygen species (ROS) production was assessed. Significant inhibition of MRC complex I and II-III activities was observed, together with a significant loss of neuronal viability, CoQ10 status, and ATP synthesis. Additionally, significant increases were observed in intracellular and mitochondrial ROS production. Remarkably, CoQ10 supplementation was found to reduce ROS formation. These results have indicated mitochondrial dysfunction and increased oxidative stress in a rotenone-induced neuronal cell model of PD that was ameliorated by CoQ10 supplementation.

Zonisamide-induced distal renal tubular acidosis and critical hypokalaemia.

A woman in her 20s presented with rapidly progressive muscle weakness and a 1-month preceding history of fatigability, nausea and vomiting. She was found to have critical hypokalaemia (K+ 1.8 mmol/L), a prolonged corrected QT interval (581 ms) and a normal anion gap metabolic acidosis (pH 7.15) due to zonisamide-induced distal (type 1) renal tubular acidosis. She was admitted to the intensive care unit for potassium replacement and alkali therapy. Clinical and biochemical improvement ensued, and she was discharged after a 27-day inpatient stay.

A Case of Statin-Associated Autoimmune Myopathy: Management and Treatment.

Elevated lipid panels are associated with an increased risk of cardiovascular disease. Management of heart disease with lipid lowering agents play a vital role in medicine. Statins are one group of medications that are widely utilized in the medical field to decrease the risk of atherosclerotic disease. Statins work by inhibiting the hepatic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Although statins are one of the most effective drugs for secondary and primary prevention of heart disease, they are not without risks and side effects such as hepatotoxicity and myopathy. We present a case of a male patient who developed progressively worsening muscle weakness and elevated muscle enzyme markers upon initiation of a statin. His symptoms persisted despite a trial of an alternative statin and subsequent discontinuation of all statin medications. A multitude of possible etiologies were considered and ranged from infectious, autoimmune, cancerous, to congenital in nature. Environmental factors, such as exposure to medications or toxins, were also considered as one of the possible precipitating factors. The association between his statin consumption and muscle weakness were not easily apparent at first. He required further workup including physical examination, electromyography, panel of myositis antibodies, and muscle biopsy. After clinical suspicion and elevated antibodies to HMGCR beyond the normal limit, he was discovered to have statin-associated autoimmune myopathy. The patient improved with the treatment of immunosuppressive agent's prednisone and methotrexate.

Progressive proximal muscle weakness with subacute onset in an elderly patient: a case report. / Debilidad muscular proximal progresiva de inicio subagudo en un paciente anciano: descripción de un caso.

INTRODUCTION: Statins are some of the most widely prescribed medications. Although statins are generally well tolerated, they can lead to musculoskeletal side effects. Statin-induced necrotizing autoimmune myositis (SINAM) is a rare condition and the prevalence is only 1 per 100,000 people. This disorder is characterized by progressive and severe symmetric muscle weakness, marked elevation of creatine kinase and persistent symptoms despite statin discontinuation. Electromyography commonly shows a nonspecific irritable myopathy pattern indistinguishable from other inflammatory myopathies. Muscle biopsy shows the presence of necrotic fibers, regenerating fibers without significant inflammatory cells and diffuse or focal upregulation of major histocompatibility complex class I expression. The anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies represent a characteristic serological feature of SINAM. CASE REPORT: We present a patient who developed progressive muscle weakness after taking simvastatin for the last seven years. At initial presentation, her creatine kinase level was 2,954 U/L and anti-HMGCR antibodies were positive. The biopsy showed a profound myopathic features with numerous necrotic fibers, some regenerating fibers and perimysial inflammatory cell infiltrate, combined with a diffuse overexpression of major histocompatibility complex class I products. She was diagnosed with SINAM, statin was suspended and a high dose of systemic corticosteroids, intravenous immunoglobulin therapy and methotrexate was started. At three-month follow-up, she had significant improvement in muscle strength and creatine kinase level returned to normal. CONCLUSION: In this case, exclusion of inflammatory myopathies, metabolic muscle disorders and other neurological diseases is necessary for establishing a reliable diagnosis. In SINAM, simply discontinuing statin is often insufficient and aggressive immunosuppression or immunomodulation therapy is needed to achieve disease remission. This case aims to demonstrate that statins can induce serious muscular diseases that require aggressive immunosuppression.

TITLE: Debilidad muscular proximal progresiva de inicio subagudo en un paciente anciano: descripción de un caso.Introducción. Las estatinas son de los medicamentos más recetados. Aunque las estatinas generalmente se toleran bien, pueden provocar efectos secundarios musculoesqueléticos. La miopatía autoinmune necrotizante inducida por estatinas (SINAM) es una afección rara y la prevalencia sólo es de 1 de cada 100.000 personas. Este trastorno se caracteriza por debilidad muscular simétrica progresiva y grave, elevación marcada de la creatincinasa y síntomas persistentes a pesar de la interrupción de la estatina. La electromiografía suele mostrar un patrón de miopatía irritable inespecífico, indistinguible de otras miopatías inflamatorias. La biopsia muscular muestra la presencia de fibras necróticas, fibras en regeneración sin células inflamatorias significativas y una regulación positiva difusa o focal de la expresión del complejo mayor de histocompatibilidad de clase I. Los anticuerpos anti-3-hidroxi-3-metilglutaril-coenzima A (anti-HMG-CoA) reductasa representan un rasgo serológico característico de la SINAM. Caso clínico. Presentamos a un paciente que desarrolló debilidad muscular progresiva después de tomar simvastatina durante los últimos siete años. En la presentación inicial, su nivel de creatincinasa fue de 2.954 U/L y los anticuerpos anti-HMG-CoA reductasa fueron positivos. La biopsia mostró rasgos miopáticos profundos con numerosas fibras necróticas, algunas fibras en regeneración e infiltrado de células inflamatorias perimisial, combinado con una sobreexpresión difusa del complejo mayor de histocompatibilidad de clase I. Se le diagnosticó SINAM, se suspendió la estatina y se inició una dosis alta de corticoides sistémicos, inmunoglobulina intravenosa y metotrexato. Después de tres meses de seguimiento, tuvo una mejora significativa en la fuerza muscular y el nivel de creatincinasa volvió a la normalidad. Conclusiones. En este caso, la exclusión de miopatías inflamatorias, trastornos musculares metabólicos y otras enfermedades neurológicas es necesaria para establecer un diagnóstico fidedigno. En la SINAM, la simple suspensión de las estatinas a menudo es insuficiente, y es necesaria una terapia de inmunosupresión o inmunomodulación agresiva para lograr la remisión de la enfermedad. Este caso tiene como objetivo demostrar que las estatinas pueden inducir enfermedades musculares graves que requieren una inmunosupresión agresiva.

Challenges in the diagnosis and management of immune-mediated necrotising myopathy (IMNM) in a patient on long-term statins.

Immune-mediated necrotising myopathy (IMNM) is a severe and poorly understood complication of statin use. Prompt management with immunosuppressive treatment is often needed to control the condition, which differs from the management of the more commonly recognised statin-induced myopathy. We present a case report and brief review of the literature regarding the pathogenesis, diagnosis, and management of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) positive IMNM (HMGCR IMNM). There are no randomised clinical trials, but several smaller studies and cases suggest a triple therapy of corticosteroids, IVIG, and a corticosteroid-sparing immunosuppressant appears efficacious in patients with IMNM and proximal weakness. The mechanism of statin-induced IMNM is uncertain, and this is further complicated by the reports of HMGCR IMNM in statin-naïve patients, including children. We present a case of biopsy-confirmed HMGCR IMNM in a woman taking daily statins for treatment of hypercholesterolaemia for 4 years. She presented with symptoms consistent with a urinary tract infection (UTI), including muscle weakness. She was treated as an isolated case of UTI. One month later, she presented again with worsening weakness in her shoulders and hips. Creatine kinase was elevated, and MRI showed increased signal with STIR sequences in both thighs. Anti-HMGCR was positive and leg biopsy-confirmed necrotising changes. Stopping her statin prescription and a short course of prednisolone did not improve her muscle weakness. Adding methotrexate resulted in eventual resolution of her symptoms. IMNM should be considered as a differential in any patient taking statins presenting with muscle weakness, and this case suggests that immunosuppressant therapy in addition to cessation of statins is effective at treating IMNM. Clinical trials are needed to further investigate the efficacy of different combinations of immunosuppressants.

The effectiveness and side effects of pyridostigmine in the treatment of myasthenia gravis: a cross-sectional study.

Pyridostigmine is the most commonly used drug in the symptomatic treatment of myasthenia gravis (MG); however, research into its effectiveness and side effects is scarce. The aim of this study was to assess the effectiveness, prevalence of side effects and net benefit of pyridostigmine. All MG patients participating in the Dutch-Belgian myasthenia patient registry were included. A dynamic online questionnaire was developed to assess the effectiveness, side effects and net benefit of pyridostigmine. Out of 642 invited patients, 410 patients (64%) fully completed the questionnaire; 61% reported that they currently used pyridostigmine, 36% had discontinued pyridostigmine and 2% reported to never have used pyridostigmine. Patients reported a median effectiveness of 60, IQR 28-78 and net benefit of 65, IQR 45-84. Of all patients currently using pyridostigmine, 91% reported side effects (vs. 55% in the control group). Most frequently reported side effects were flatulence, urinary urgency, muscle cramps, blurred vision and hyperhidrosis. In the group of patients who discontinued pyridostigmine, side effects were the reason for discontinuation in 26%. Diarrhea, abdominal cramps and muscle twitching were the most frequently cited reasons to discontinue pyridostigmine. These results can be used to guide shared decision making prior to starting symptomatic treatment for MG.

Bone-Muscle Crosstalk: Musculoskeletal Complications of Chemotherapy.

PURPOSE OF REVIEW: Chemotherapy drugs combat tumor cells and reduce metastasis. However, a significant side effect of some chemotherapy strategies is loss of skeletal muscle and bone. In cancer patients, maintenance of lean tissue is a positive prognostic indicator of outcomes and helps to minimize the toxicity associated with chemotherapy. Bone-muscle crosstalk plays an important role in the function of the musculoskeletal system and this review will focus on recent findings in preclinical and clinical studies that shed light on chemotherapy-induced bone-muscle crosstalk. RECENT FINDINGS: Chemotherapy-induced loss of bone and skeletal muscle are important clinical problems. Bone antiresorptive drugs prevent skeletal muscle weakness in preclinical models. Chemotherapy-induced loss of bone can cause muscle weakness through both changes in endocrine signaling and mechanical loading between muscle and bone. Chemotherapy-induced changes to bone-muscle crosstalk have implications for treatment strategies and patient quality of life. Recent findings have begun to determine the role of chemotherapy in bone-muscle crosstalk and this review summarizes the most relevant clinical and preclinical studies.

Statin-Associated Myalgias and Muscle Injury-Recognizing and Managing Both While Still Lowering the Low-Density Lipoprotein.

Although statins are generally safe and well tolerated, some patients experience muscle complaints that can be attributed to their use. Those with muscle discomfort but no demonstrable muscle weakness or creatine kinase (CK) elevations may have statin-associated muscle symptoms. Individuals with elevated CK levels, with or without muscle discomfort or weakness, may have statin-associated myotoxicity. Rare patients have statin-associated autoimmune myopathy, a disease characterized by proximal muscle weakness, elevated CK levels, and autoantibodies recognizing hydroxy-methyl-glutaryl coenzyme A reductase. In this review, the author provides the clinician with a practical approach to diagnosing and managing patients with each of these statin side effects.

Muscle pain and muscle weakness in COVID19 patients: Cross-talk with statins - Preliminary results.

BACKGROUND: Muscle pain and muscle weakness, common symptoms among statin-treated patients, may worsen with COVID-19 infection. AIMS: The aim of the paper was to find out if concomitant COVID-19 infections increase the frequency of specific side effects of statins such as muscle pain and muscle weakness. METHOD: A total of 66 patients diagnosed with COVID-19 without comorbidities participated in the study. The patients were divided into two groups: statin-users who had not experienced adverse effects of statins in the past (statin group (SG)) and patients who had not used any drugs in the past six months (control group (CG)). The severity of muscle pain and creatinine kinase (CK) activity was evaluated in each patient, and muscle weakness was confirmed by a dynamometer test (grip strength on both hands). RESULTS: In SG, muscle pain was more common and it was characterized by a high level of intensity. Muscle weakness occurred more frequently in the SG and it was more frequent compared to CG. The CK parameter was observed to be higher in the SG compared to the CG and was often associated with the severity of muscle pain in the range of moderate to severe. CONCLUSIONS: Our study indicates that COVID-19 is associated with the higher risk of occurrence of typical statin-related side effects, especially with more advanced age, which should be considered in future trials and treatments.

Botulinum Toxin for Essential Tremor and Hands Tremor in the Neurological Diseases: A Meta-Analysis of Randomized Controlled Trials.

Tremor is a common movement disorder. Essential tremor (ET) is the most common etiology of tremor, while hands tremor is the most disabling type of tremor. This study aimed to explore the effects of Botulinum toxin (BoNT) on tremor within 6 weeks of treatment, and the muscular weakness adverse effect within 6 weeks specifically in randomized controlled trials. PubMed, Embase, and Cochrane Library databases were searched. Tremor severity and grip strength after BoNT treatment were investigated. BoNT significantly attenuated hand tremor severity in patients with either essential tremor (ET), Parkinson's disease or multiple sclerosis (Standardized mean difference [SMD] = -0.59, 95% confidence interval [CI], -0.95 to -0.24, p = 0.001, I2 = 46%). Regarding people with ET, BoNT significantly reduced their tremor severity, including hands tremor and head tremor within 6 weeks of treatment (SMD = -0.58, 95% CI, -0.28 to -0.88, p = 0.002, I2 = 0%). Electromyography (EMG) but not anatomical guidance BoNT injection provided significant benefit on the relief of tremor in both conditions. The principal adverse event was weakness, but it did not worse within 6 weeks of BoNT treatment (SMD = -0.35, 95% CI, -0.83 to 0.12, p = 0.07, I2 = 57%), as assessed by the subjective grip strength. In conclusion, BoNT was an effective treatment for the hand tremor and ET, and EMG guidance injection was preferred. In addition, the muscular weakness adverse effect was not significant.

Balanced modulation of neuromuscular synaptic transmission via M1 and M2 muscarinic receptors during inhibition of cholinesterases.

Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year. The pathways activated during OP compound poisoning via overstimulation of muscarinic acetylcholine receptors (mAChRs) play a decisive role in toxidrome. The antidotal therapy includes atropine, which is a nonspecific blocker of all mAChR subtypes. Atropine is efficient for mitigating depression in respiratory control centers but does not benefit patients with OP-induced skeletal muscle weakness. By using an ex vivo model of OP-induced muscle weakness, we studied the effects of the M1/M4 mAChR antagonist pirenzepine and the M2/M4 mAChR antagonist methoctramine on the force of mouse diaphragm muscle contraction. It was shown that weakness caused by the application of paraoxon can be significantly prevented by methoctramine (1 µM). However, neither pirenzepine (0.1 µM) nor atropine (1 µM) was able to prevent muscle weakness. Moreover, the application of pirenzepine significantly reduced the positive effect of methoctramine. Thus, balanced modulation of neuromuscular synaptic transmission via M1 and M2 mAChRs contributes to paraoxon-induced muscle weakness. It was shown that methoctramine (10 µmol/kg, i.p.) and atropine (50 µmol/kg, i.p.) were equieffective toward increasing the survival of mice poisoned with a 2xLD50 dose of paraoxon.

Severe Generalized Weakness, Paraplegia following administration of Oxaliplatin in a patient with refractory T-cell non-Hodgkin lymphoma: A case report.

INTRODUCTION: Oxaliplatin is a third-generation platinum compound that used extensively for the treatment of various types of cancer especially gastrointestinal neoplasms. The main dose-limiting toxicities of oxaliplatin are hematological toxicity and peripheral sensory neuropathy. CASE REPORT: A 42-year-old man with refractory peripheral T-cell lymphoma (PTCL) was admitted to receive GEMOX chemotherapy regimen (gemcitabine, oxaliplatin). Three days after receiving his third cycle of chemotherapy regimen, he was re-admitted to the emergency department with complaint of severe generalized weakness, and paraplegia in the lower extremities. According to clinical and para-clinical findings, chronic sensorimotor polyneuropathy with ongoing axonal loss was confirmed. MANAGEMENT & OUTCOME: Intravenous dexamethasone 8 mg three times daily was started at the time of admission for the patient. Muscle weakness and sensory impairment improved dramatically within 10 days and the patient was able to walk with assistance. DISCUSSION: Several cases of neuropathy following oxaliplatin and only one case with gemcitabine-based chemotherapy regimen have been previously reported. However, motor symptoms are rare unless in the setting of acute neuropathy due to oxaliplatin. The most striking finding of our study was the incidence of a chronic sensorimotor axonaldemyelinating polyneuropathy in a patient who were subjected to oxaliplatin therapy. In conclusion, we report a case of severe generalized weakness and paraplegia following administration of Oxaliplatin.

Severe Motor Weakness Due to Disturbance in Peripheral Nerves Following Tisagenlecleucel Treatment.

BACKGROUND: Neurotoxicity is one of the dangerous complications of chimeric antigen receptor (CAR) T-cell therapy, while its pathophysiology remains to be fully understood. Motor weakness not associated with central nervous system (CNS) toxicity has rarely been reported after CAR T-cell therapy. CASE REPORT: A 42-year-old female with a refractory diffuse large B-cell lymphoma received tisagenlecleucel (tisa-cel) and developed cytokine release syndrome (CRS) on day 3. She was treated with tocilizumab and methylprednisolone, which resolved CRS promptly. On day 7, motor weakness in lower extremities appeared, and she gradually became unable to walk without showing any other symptoms attributed to CNS disturbances. Whereas dexamethasone and tocilizumab were ineffective, neuropathy improved after high dose chemotherapy followed by autologous stem cell transplantation. Nerve conduction study (NCS) in lower extremities showed a decline in compound muscle action potential amplitude along with worsening of motor weakness, which was restored after improvement of symptoms. Based on symptoms and NCS, her motor weakness was thought to be due to disturbance in peripheral nerves. CONCLUSION: This study reports a patient who developed severe motor weakness due to disturbance in peripheral nerves after tisa-cel therapy. Neurotoxicity of non-CNS origin should also be noted in CAR T-cell therapy.

[A case of dropped head syndrome suspected due to Dipeptidyl peptidase (DPP)-4 inhibitor use].

There have been a few reports on Dipeptidyl peptidase (DPP)-4 inhibitor-induced dropped head syndrome. However, there has been no known report on temporal changes in MRI findings. The patient described here was a 63-year-old man who was prescribed oral sitagliptin (50 mg/day) in February 2019. He experienced a dropped head from mid-January 2020, and in early April that year, he was admitted to our hospital for further evaluation. Weakness of the cervical extensor muscles (MMT 3) was noted, and MRI findings showed that the posterior cervical muscle group was hyperintense on short inversion time inversion recovery (STIR). We suspected sitagliptin to be the cause of his dropped head and discontinued it. On the 10th day of admission, his posture improved to the median position. One month after discontinuation of sitagliptin, MRI findings showed an improvement in the STIR hyperintensity of the posterior cervical muscle. In conclusion, if the initiation of a DPP-4 inhibitor results in dropped head syndrome, discontinuation of the drug should be considered.

Risk Factors and Medical Symptoms Associated With Electronic Vapor Product Use Among Adolescents and Young Adults.

The use of electronic vapor products (EVPs) has increased dramatically in the past decade. The objectives of our study were to examine the frequency of EVP use; to identify demographic characteristics, risk-taking behaviors, and beliefs about vaping; and to determine symptoms associated with EVPs among adolescents. A questionnaire addressing these objectives was administered to a convenience sample of subjects aged 12 to 23 years. Among 494 completed questionnaires, 80% of responders were considered experimenters/nonusers (never tried or tried one time) and 20% were considered frequent users (at least once a month). We identified demographic features and risk-taking behaviors associated with EVP use. In the previous 6 months, frequent users were more likely to report headache, cough, sleep disturbances, dehydration, weakness, racing heart, chest pain, and tremors. Our findings provide evidence to support efforts to decrease EVP use through screening, education, and preventative strategies.

Acute sunitinib neurotoxicity.

Sunitinib malate is a multitargeted oral tyrosine kinase inhibitor (TKI) which is used in treatment of metastatic renal cell carcinoma with side effects such as diarrhea, mucositis, asthenia and myelosuppression. Serious toxicity associated with sunitinib is a rare situation. However; there are few cases reported in the literature. As a result of the inhibition that is caused by sunitinib malate agent at the receptor level, vascular endothelial growth factor (VEGF) level increases. These increased VEGF levels are considered to having a positive contribution on neurological side effects. Neurotoxicity that is related with the usage of sunitinib malate for two weeks will be presented in this case report.

Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood. CASE PRESENTATION: A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder. CONCLUSIONS: The increase of ß-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.

[A case of colchicine myopathy in which the long-term use of colchicine hampered the recovery].

A 69-year-old woman was admitted to our hospital because of limb weakness. She was diagnosed to have chronic renal failure due to diabetes mellitus and had suffered from pericardial effusion at 67 years of age. She started taking colchicine 18 months before admission and thereafter gradually developed muscle weakness in her limbs and had become bedridden at the time of admission. The withdrawal of colchicine improved her limb weakness, and therefore we diagnosed her to have colchicine myopathy. Her muscle strength did not completely recover even after six months from cessation of colchicine. It was suggested that renal failure and muscle disuse had prevented the full recovery of her muscles in addition to the long-term use of colchicine. Typical colchicine myopathy improves rapidly, but the long-term use of colchicine is considered to cause muscle weakness. Although the CK level was elevated, the elevated CK and myopathy had been overlooked because the CK baseline was low due to the patient's small amount of muscle mass. Moreover, the estimated GFR was recorded to be higher than her actual renal function due to her small amount of muscle mass, therefore the risk of colchicine myopathy in this case remained unrecognized.