Statin-induced debilitating weakness and myopathy.

A large percentage of the US population is either receiving or should be considered for statin therapy. Whether through primary or secondary prevention for atherosclerotic disease, statins remain one of the mainstay options available to physicians. Myalgias are the most commonly reported side effects, though largely self-limited and subjective in nature. Here, we report a case of drug-related myonecrosis following long-term use of atorvastatin. Prompt recognition of the condition and initiation of treatment is paramount to control the disease's progression. While high-dose steroids are first line, quick escalation to methotrexate, IVIG or rituximab should be considered in refractory cases. This decision is guided by monitoring of serum markers such as CK and transaminases. The goal is quick normalisation of these enzymes, signalling cessation of underlying muscle necrosis. Patients may never regain full function and treatment can last months to years.

Patient-reported muscle symptoms and their characterization in a hypertensive population eligible for statin therapy: An exploratory study.

BACKGROUND AND AIMS: Statin-associated muscle symptoms (SAMS) are claimed to be frequent in clinical practice. We evaluated the prevalence and characteristics of patient-reported muscle symptoms (PRMS) attributed to drugs/nutraceuticals in hypertensive patients, focusing the attention on statin treatment. METHODS AND RESULTS: Observational study on 390 consecutive outpatients. All patients were asked the following question: "Have you ever taken a drug/nutraceutical that you think gave you muscle symptoms?". Patients who answered "yes" were evaluated with a modified version of the SAMS-clinical index (SAMS-CI). Mean age: 60.5 ± 13.5 years (males 53.8%.). Patients who have ever taken a statin: 250. Patients who have never taken a statin: 140. Prevalence of PRMS (48.5% of the entire study population) did not differ between groups (p = 0.217). Only age, followed by number of drugs taken, was significantly associated with PRMS at multivariate analysis. A high prevalence of low scores to all the questions of "modified" SAMS-CI was found in both groups. Localization and pattern of PRMS did not differ between groups (p = 0.170). Timing of PRMS onset after starting the drug (p = 0.036) and timing of improvement after withdrawal (p = 0.002) were associated with statin therapy. CONCLUSION: PRMS are highly prevalent among the hypertensive population and are believed to be drug-related, especially with aging and regardless of whether the drug taken is a statin or not. These findings are in line with the growing evidence that subjective muscle symptoms are often misattributed to statins, while they may more likely be related to the nocebo/drucebo effect or to other common undiagnosed conditions.

Unveiling the Rare Complication: Statin-Induced Immune-Mediated Necrotizing Myopathy.

BACKGROUND Statin-induced necrotizing autoimmune myopathy is an exceptionally rare yet severe complication of statin therapy that may develop in individuals at any time during their exposure to statins. The development of proximal muscle weakness, muscle pain, and elevated creatine kinase (CK) levels in patients while taking statins should prompt clinical consideration of statin-induced myopathy. The pathophysiology arises from the production of auto-antibodies, which target the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) enzyme, leading to the aggressive breakdown of myofibrils. CASE REPORT Here, we present a case of a 59-year-old woman with a medical history of dyslipidemia who developed anti-HMG-CoA reductase antibodies after taking atorvastatin. She came to the emergency department with complaints of severe proximal muscle weakness. The laboratory workup showed an elevated CK level up to 12 000 IU/L. Despite discontinuing atorvastatin, the patient's elevated CK levels persisted. The patient underwent a muscle biopsy, demonstrating myofibril necrosis. Serological analysis showed anti-HMG-CoA reductase antibodies in the patient's serum, which led to the diagnosis of immune-mediated necrotizing myopathy due to statins. The patient's statin therapy was promptly discontinued, and she was treated with a high dose of IV corticosteroids. After the patient's discharge, brief discontinuation of the corticosteroids resulted in CK elevation and a return of symptoms. This led to the second re-admission and restarting of corticosteroids until stabilization and discharge. CONCLUSIONS This case represents an important reminder for clinicians to recognize the possibility of statin-induced immune-mediated necrotizing myopathy in patients presenting with proximal muscle weakness while taking a statin, notwithstanding the rarity of this condition.

Mimicking Ding's Roll Method on Notexin-Induced Muscle Injury in Rats.

Ding's roll method is one of the most commonly used manipulations in traditional Chinese massage (Tuina) clinics and one of the most influential contemporary Tuina manipulations in China. It is based on the traditional rolling method commonly used in the one finger Zen genre and named Ding's roll method. Due to its anti-inflammatory and blood circulation-promoting effects, Ding's rolling method has sound therapeutic effects on myopathy. Because of the large area of force applied to human skin, Ding's roll method is challenging to perform on experimental animals with small skin areas, such as rats and rabbits. Additionally, the strength of Tuina applied to the human body differs from that applied to experimental animals, so it may happen that the strength is too high or too low to achieve the therapeutic effect of Tuina during the experiment. This experiment aims to create a simple massager suitable for rats based on Ding's rolling manipulation parameters (strength, frequency, Tuina duration). The device can standardize manipulation in animal experiments and reduce the variation in Tuina force applied to different animals due to subjective factors. A rat model of notexin-induced skeletal muscle injury was established, and plasma injury markers creatine kinase (CK) and fatty acid binding protein 3 (FABP3) were used to assess the therapeutic effect of Tuina on skeletal muscle injury. The results showed that this Tuina massager could reduce the levels of CK and FABP3 expression and slow down the degree of skeletal muscle injury. Therefore, the Tuina massager described here, mimicking Ding's roll method, contributes to standardizing Tuina manipulation in experimental research and is of great help for subsequent research on the molecular mechanism of Tuina for myopathy.

Neutral lipid storage disease with myopathy and myotonia associated to pathogenic variants on PNPLA2 and CLCN1 genes: case report.

BACKGROUND: Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy predominantly proximal in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case of association of pathogenic variants on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen's congenital myotonia. CASE PRESENTATION: We describe a patient with chronic proximal myopathy, subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan's anomaly, a hallmark of NLSD-M. A genetic panel was collected using next-generation sequencing (NGS) technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described. CONCLUSIONS: Although uncommon, it is important to remember the possibility of association of pathogenic variants to explain a specific neuromuscular disease phenotype. The use of a range of complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases.

A case of myopathy and markedly elevated creatine kinase levels with hypocalcemia, hypomagnesemia, and hyposelenemia due to short bowel syndrome after rectal cancer resection.

A 66-year-old Japanese man was referred to our hospital with myalgia and muscle weakness. He had a history of rectal cancer, which invaded into the urinary bladder and ileum and was treated with chemotherapy, radiotherapy, resection of the rectum, colostomy, and ileal conduit construction. He showed recurrent markedly elevated serum creatine kinase levels and concurrent hypocalcemia. Muscle magnetic resonance imaging demonstrated abnormal signals in the proximal limb muscles, and needle electromyography showed myopathic changes. Further examination revealed hypomagnesemia and hyposelenemia with underlying short bowel syndrome. Calcium, magnesium and selenium supplementation improved his symptoms and laboratory findings.

Statin Intolerance: A Review and Update.

OBJECTIVE: To review the evidence of existing literature on the management of statin intolerance. METHODS: We searched for literature pertaining to statin intolerance and treatments in PubMed. We reviewed articles published between 2005 and 2022. RESULTS: Statin-associated myalgia is the most common adverse effect of statin therapy and the most common reason for statin discontinuation. The risk factors for statin intolerance include unexplained muscle pain with other lipid-lowering therapy, unexplained cramps, a history of increased creatine kinase levels, a family history of muscle symptoms, and a family history of muscle symptoms with lipid therapy. Vitamin D repletion and coenzyme Q supplementation may help alleviate the musculoskeletal effects of statins. Trials of different types of statins and different dosing regimens are recommended to improve tolerability. The use of statins in individuals who perform regular exercise requires closer attention to muscular symptoms and creatine kinase levels; however, it does not preclude the use of statins. CONCLUSION: Management of the adverse effects of statin therapy and improving statin tolerability are key to achieving optimum cardiovascular benefits. Identifying statin-associated adverse effects and managing them appropriately can reduce unnecessary statin discontinuation and subsequently provide longer cardiovascular protection.

Ichthyosis, cataracts, and motor delay in an infant: A case of Chanarin-Dorfman syndrome.

Chanarin-Dorfman syndrome (CDS) is a rare, autosomal recessive disorder of impaired triacylglycerol catabolism leading to cytoplasmic deposition of triglycerides in various cell types. We describe the case of an 8-month-old boy with cataracts, strabismus, motor delays, and an ichthyosiform rash since birth. Genetic testing revealed a pathogenic variant of the ABHD5 gene, suggestive of CDS, and further workup demonstrated hepatic steatosis and myopathy. His ichthyosis improved with initiation of a diet low in very long-chain fatty acids and medium-chain fatty acid supplementation.

Mushroom supplements triggering a flare of HMGCR immune mediated necrotising myopathy.

Hydroxyl-methyl-glutaryl-Co-A reductase (HMGCR) immune mediated necrotising myopathy (IMNM) is a rare autoimmune myositis that is thought to be triggered by statins and responds to immunomodulation. We report a case of a woman in her 30s with HMGCR IMNM without a history of statin exposure who had a clear flare of her myositis after beginning mushroom supplements. Mushrooms are natural HMGCR inhibitors, and this is the first case to demonstrate a flare triggered by mushrooms in a patient with known HMGCR IMNM. This case highlights the importance of reviewing diet and supplements in patients with IMNM. It also emphasises the importance of strict statin avoidance for patients with IMNM even when the myositis is under good control.

Hypothyroid myopathy with periodic paralysis as the main symptom: a case report and literature review.

Hypothyroid myopathy is a skeletal muscle disease caused by hypothyroidism. However, patients with hypothyroidism are often misdiagnosed as polymyositis if they do not have a clear history of thyroid gland or obvious hypometabolic symptoms, but with myasthenia and myalgia as the main symptoms or the first symptoms. Moreover, hypothyroid myopathy with periodic paralysis as the first symptom is rare in clinic. In this study, we summarized the clinical data of 1 case of hypothyroid myopathy with periodic paralysis as the first symptom in our clinical diagnosis and treatment. A 27-year-old male patient with recurrent periodic paralysis was found with hypothyroidism during a most recent attack of myasthenia and was diagnosed with hypothyroid myopathy, which was relieved after oral administration of levothyroxine. We also found 13 similar cases reported internationally, and summarized their clinical characteristics, diagnosis, and treatment methods to provide reference for the clinical diagnosis and treatment of such cases. In general, periodic paralysis may be the main symptom or even the first symptom of hypothyroid myopathy, which is easy to be confused with renal tubular acidosis (RTA) or other autoimmune diseases. The diagnosis is mainly based on the detection of thyroid function and thyroid autoantibodies. Timely supplement of thyroxine and correction of electrolyte disorders are the key to treatment.

Diagnostic challenges in metabolic myopathies.

INTRODUCTION: Metabolic myopathies comprise a clinically etiological diverse group of disorders caused by defects in cellular energy metabolism including the breakdown of carbohydrates and fatty acids, which include glycogen storage diseases and fatty acid oxidation disorders. Their wide clinical spectrum ranges from infantile severe multisystemic disorders to adult-onset myopathies. To suspect in adults these disorders, clinical features such as exercise intolerance and recurrent myoglobinuria need investigation while another group presents fixed weakness and cardiomyopathy as a clinical pattern. AREAS COVERED: In metabolic myopathies, clinical manifestations are important to guide diagnostic tests used in order to lead to the correct diagnosis. The authors searched in literature the most recent techniques developed. The authors present an overview of the most common phenotypes of Pompe disease and what is currently known about the mechanism of ERT treatment. The most common disorders of lipid metabolism are overviewed, with their possible dietary or supplementary treatments. EXPERT COMMENTARY: The clinical suspicion is the clue to conduct in-depth investigations in suspected cases of metabolic myopathies that lead to the final diagnosis with biochemical molecular studies and often nowadays by the use of Next Generation Sequencing (NGS) to determine gene mutations.

Proctalgia Syndromes: Update in Diagnosis and Management.

PURPOSE OF REVIEW: Functional anorectal pain syndromes are a neglected yet often disabling clinical entity resulting in significant economic and psychological burden to the patient. The aim of this review is to update the practicing gastroenterologist/coloproctologist on the diagnosis and management of these complicated disorders. RECENT FINDINGS: The updated Rome foundation diagnostic criteria (Rome IV) for functional anorectal pain subgroups chronic proctalgia (levator ani syndrome and unspecified functional anorectal pain) and acute proctalgia (proctalgia fugax) on the basis of symptom duration and digital rectal examination findings. Chronic proctalgia is thought to be secondary to paradoxical pelvic floor contraction in many patients and biofeedback to improve the defecation effort has proven effective for over 90% in the short term. Unfortunately, management of proctalgia fugax remains challenging and treatment outcomes modest at best. A number of therapies to relax the pelvic floor may be employed to improve symptoms in functional anorectal pain syndromes; however, only biofeedback to improve defaecatory dynamics in patients with levator ani syndrome has proven effectiveness in a randomized setting. Further investigation of treatment approaches in proctalgia fugax is required.

PPARγ activation by pioglitazone does not suppress cravings for alcohol, and is associated with a risk of myopathy in treatment seeking alcohol dependent patients: a randomized controlled proof of principle study.

RATIONALE: Proinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPARγ) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPARγ activity may have therapeutic potential in alcohol dependence. OBJECTIVES: We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving. METHODS: Participants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated. RESULTS: The study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-α, or MCP-1 were unaffected by pioglitazone treatment. CONCLUSIONS: Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence. CLINICAL TRIAL REGISTRATION: NCT01631630.

Primary carnitine deficiency - diagnosis after heart transplantation: better late than never!

BACKGROUND: Primary carnitine deficiency due to mutations in the SLC22A5 gene is a rare but well-treatable metabolic disorder that puts patients at risk for metabolic decompensations, skeletal and cardiac myopathy and sudden cardiac death. RESULTS: We report on a 7-year-old boy diagnosed with primary carnitine deficiency 2 years after successful heart transplantation thanks his younger sister's having been identified via expanded newborn screening during a pilot study evaluating an extension of the German newborn screening panel. CONCLUSION: As L-carnitine supplementation can prevent and mostly reverse clinical symptoms of primary carnitine deficiency, all patients with cardiomyopathy should be investigated for primary carnitine deficiency even if newborn screening results were unremarkable.

An overview of statin-induced myopathy and perspectives for the future.

Introduction: Statins remain the most commonly prescribed lipid-lowering drug class for the treatment of atherosclerotic cardiovascular disease. Their well-recognized side effects are known as statin-associated muscle symptom (SAMS). Some advances in this field have been made in recent years, but the understanding of the mechanisms has lagged. Investigating the specific role of the anti-HMGCR autoantibody, pharmacokinetic genetic variants, characterization of the known phenotypes of statin toxicity, in relation to clinical markers of disease, is of high importance.Areas covered: We summarized currently available findings (on PubMed) related to SAMS and discussed the therapeutic approaches, risk factors, drug interactions, potential novel systems, algorithms and biomarkers for SAMS detection. CoQ10 supplementation has been suggested as a complementary approach to manage SAMS, while vitamin D levels may be useful for both the diagnosis and management.Expert Opinion/Commentary: Further studies might help to understand the easiest way to diagnose SAMS, suitable prevention and an effective non-statin therapy. This review sheds new light on the future directions in both research and clinical practice, which will help with rapid risk assessment, identification of the SAMS risk factors in order to decrease the incidence of statins' adverse effects, and the most effective therapy.

[Follow-up study in German Hunting Terrier dogs with exercise induced metabolic myopathy]. / Verlaufsuntersuchungen bei Deutschen Jagdterriern mit belastungsabhängiger metabolischer Myopathie.

OBJECTIVE: Exercise induced metabolic myopathy in German Hunting Terrier dogs is an autosomal-recessively inherited disorder, caused by a nonsense variant of the gene encoding for the very long-chain acyl-CoA-dehydrogenase (VLCAD) enzyme. Clinical signs include exercise- induced fatigue, muscle pain and weakness. In the present study, the long-term course of this disease was investigated over a period of 1 year in 9 affected German Hunting Terriers. The dogs were treated symptomatically with oral L-carnitine, coenzyme Q10 and a special diet characterized by a low content of long-chain fatty acids and a high proportion of carbohydrates. MATERIAL AND METHODS: In 9 affected dogs, the phenotype as well as clinical, laboratory parameters, and histopathological findings are described (time point 1) and compared to follow-up examinations 1 year later (time point 2). At both time points clinical and neurological examinations, complete blood cell count, clinical chemistry profile and the concentration of brain natriuretic peptide (NT-proBNP) were investigated. RESULTS: In the follow-up examinations, the same post-exercise clinical signs were present as in the initial presentation of the homozygous dogs. Dark-brownish discoloration of the urine, weakness, myalgia as well as stiff and tetraparetic gait were apparant. All hematological values and the concentration of NT-proBNP were within the relevant reference ranges. Plasma CK and ALT activities were compared between the first presentation and the follow- up examination and no significant differences were detected (pCK = 0.31, pALT = 0.64). Signs of myopathy remained unchanged throughout the examination period. CONCLUSION AND CLINICAL RELEVANCE: Oral supplementation with L-carnitine, coenzyme Q10 and the special dietary management did not result in any improvement of clinical signs or laboratory parameters. No progression of the disease was observed. The prognosis for affected dogs remains cautious as long-term observations of affected dogs over several years are lacking. Our findings provide further important information on inherited disorders of mitochondrial ß-oxidation in dogs, especially focused on the exercise induced metabolic myopathy in the German Hunting Terrier. This may provide new insights for novel treatment modalities in conjuntion with the development of improved breeding guidelines.

Mitochondrial and Metabolic Myopathies.

PURPOSE OF REVIEW: This article provides an overview of mitochondrial and metabolic biology, the genetic mechanisms causing mitochondrial diseases, the clinical features of mitochondrial diseases, lipid myopathies, and glycogen storage diseases, all with a focus on those syndromes and diseases associated with myopathy. Over the past decade, advances in genetic testing have revolutionized patient evaluation. The main goal of this review is to give the clinician the basic understanding to recognize patients at risk of these diseases using the standard history and physical examination. RECENT FINDINGS: Primary mitochondrial disease is the current designation for the illnesses resulting from genetic mutations in genes whose protein products are necessary for mitochondrial structure or function. In most circumstances, more than one organ system is involved in mitochondrial disease, and the value of the classic clinical features as originally described early in the history of mitochondrial diseases has reemerged as being important to identifying patients who may have a primary mitochondrial disease. The use of the genetic laboratory has become the most powerful tool for confirming a diagnosis, and nuances of using genetic results will be discussed in this article. Treatment for mitochondrial disease is symptomatic, with less emphasis on vitamin and supplement therapy than in the past. Clinical trials using pharmacologic agents are in progress, with the field attempting to define proper goals of treatment. Several standard accepted therapies exist for many of the metabolic myopathies. SUMMARY: Mitochondrial, lipid, and glycogen diseases are not uncommon causes of multisystem organ dysfunction, with the neurologic features, especially myopathy, occurring as a predominant feature. Early recognition requires basic knowledge of the varied clinical phenotypes before moving forward with a screening evaluation and possibly a genetic evaluation. Aside from a few specific diseases for which there are recommended interventions, treatment for the majority of these disorders remains symptomatic, with clinical trials currently in progress that will hopefully result in standard treatments.

A newborn with seizures born to a mother diagnosed with primary carnitine deficiency.

BACKGROUND: Maternofetal carnitine transport through the placenta is the main route of fetal carnitine uptake. Decreased free carnitine levels discovered by newborn screening has identified many asymptomatic adult women with systemic primary carnitine deficiency (PCD). Here, we presented amplitude integrated electroencephalogram (aEEG) and magnetic resonance imaging (MRI) findings from a neonate with epilepsy whose mother was carnitine deficient. CASE PRESENTATION: A one-day-old female newborn was admitted after experiencing seizures for half a day; status epilepticus was found on the continuous normal voltage background pattern with immature sleep-wake cycling during aEEG monitoring. On T1-weighted, T2-weighted, FLAIR, and DWI head MRI, there were various degrees of hyperintense signals and diffusion restrictions in the deep white matter of the right hemisphere. Tandem mass spectrometry discovered carnitine deficiency on the second day, which elevated to normal by the 9th day before L-carnitine supplementation was started. The patient was treated with phenobarbital after admission. No further seizures were noted by day 5. It was confirmed that the patient's mother had a low level of serum-free carnitine. Gene analyses revealed that the newborn had heterozygote mutations on c.1400C > G of the SLC22A5 gene, and her mother had homozygous mutations on c.1400C > G. The patient had a good outcome at the 8-month follow up. CONCLUSIONS: Maternal carnitine deficiency that occurs during the perinatal period may manifest as secondary epilepsy with cerebral injury in neonates. The short-term neurodevelopmental outcomes were good. Early diagnosis of asymptomatic PCD in female patients can provide guidance for future pregnancies.

Effect of Perioperative Neuromuscular Electrical Stimulation in Patients Undergoing Cardiovascular Surgery: A Pilot Randomized Controlled Trial.

A randomized, controlled trial was conducted to examine the effects of perioperative neuromuscular electrical stimulation on muscle proteolysis and physical function using blinded assessment of physical function. Consecutive patients undergoing cardiovascular surgery were screened for eligibility as study subjects. Participants were randomly assigned to receive either neuromuscular electrical stimulation or the usual postoperative mobilization program. The intervention group received neuromuscular electrical stimulation on bilateral legs 8 times before and after surgery. The primary outcomes were the mean 3-methylhistidine concentration corrected for urinary creatinine content from baseline to postoperative day 6, and knee extensor isometric muscle strength on postoperative day 7. Secondary outcomes were usual walking speed and grip strength. Physical therapists blinded to patient allocation performed measurements of physical function. Of 498 consecutive patients screened for eligibility, 119 participants (intervention group, n = 60; control group, n = 59) were enrolled. In the overall subjects, there were no differences in any outcomes between the intervention and control groups. The results demonstrated no significant effects of neuromuscular electrical stimulation on muscle proteolysis and physical function after cardiovascular surgery, suggesting the need to explore indications for neuromuscular electrical stimulation and to clarify the effects in terms of the dose-response relationship.