Myotoxicity Induced by Antiepileptic Drugs: Could be a Rare but Serious Adverse Event?

Abstract

Antiepileptic drugs (AEDs) are used in various pathologies such as including epilepsy, migraine, neuropathic pain, etc. They can improve symptoms but cause adverse events (ADRs). Case reports have reported that one rare but serious AED-induced adverse reaction that has appeared in case reports is myotoxicity from rhabdomyolysis. Rhabdomyolysis can be induced by a therapeutically dosed occur with therapeutic doses of antiepileptic drugs and is in most cases reversible, although rarely it can cause serious complications. Clinical manifestations of rhabdomyolysis range from a single isolated asymptomatic rise in serum CK levels to severe electrolyte imbalances, cardiac arrhythmia, acute and disseminated renal failure, intravascular coagulation, and other symptoms. Many clinical cases reported that both conventional older and newer AEDs, as well as propofol, can cause rhabdomyolysis, even if there are no conclusive data. It has recently been shown that genetic factors certainly contribute to adverse reactions of antiepileptic drugs. A study of genetic polymorphism in patients with AED-induced rhabdomyolysis may be useful to explain the rarity of this adverse event and to improve the treatment of these AED patients, in terms of AED type and dose adjustment.

Introduction

Drugs given to patients to improve symptoms or the disease itself can cause unwanted and sometimes harmful adverse drug reactions (ADRs) either alone or in combination with other drugs.^1–4 Skeletal muscle is an important target in common site of ADRs, both because it is an organ withhas a rich blood supply and because it is an easy target forcommonly involved in metabolic disorders. Drugs can cause direct or indirect myotoxicity.⁵ A direct mechanism of mMyotoxicity can be caused directly by an interaction with muscle organelles (eg mitochondria, lysosomes, myofibrillar proteins) or by modifying muscle antigens, following an immunological and/or inflammatory reaction.⁵ An indirect mechanism of myotoxicity can be determined byMyotoxicity may also be produced indirectly via systemic effects such as instability in electrolytes, or reduced oxygen supply for the production of energetic conditions that have a secondary influence on muscle function.⁵ A condition one manifestation of acute and potentially fatal myotoxicity is represented by rhabdomyolysis.⁵ Myopathies can be caused by several numerous drugs, such as including statins, d-penicillamine, zidovudine, colchicine, (hydroxy) chloroquine hydroxychloroquine, emetine, and corticosteroids, although they are typically classified as viewed rare events,^6–9 but it is not generally considered an issue for antiseizure medications. The development of rhabdomyolysis related to drug treatment has been reported in hospitalized patients under close medical supervision.¹⁰ Jiang et al.¹¹ reviewing literature data revealed that rhabdomyolysis is a rare manifestation of AED treatment, and it is strongly related to the type of AED used. However, the absence of case-control clinical studies could suggest that this adverse event may be a neglected risk in therapy with these agents. In the present study, we reviewed the data on antiepileptic drug-induced rhabdomyolysis.

Methods

PubMed, Embase, Cochrane library and reference lists have beenwere searched for articles published until February 20, 2021, using the keywords “myotoxicity”, “antiepileptic drugs”, “adverse events”, “rhabdomyolysis”, “pharmacogenomics”. Secondary searches have included articles cited in sources identified by the previous search. Randomized control trials (RCTs), open trials, case series, and case reports have been also enclosed.

Rhabdomyoliysis

A drug-induced myopathy is defined as the subacute and rarely acute, reversible, manifestation of myopathic symptoms, such as muscle weakness, fatigue, myalgia, cramps, creatine kinase (CK) increase or myoglobinuria, which occurs in patients without muscle disease when exposed to therapeutic doses of some drugs.^7,12,13 One of the severe symptoms of muscle toxicity is rhabdomyolysis. It is characterized by general fatigue and an altered blood test, characterized by elevated plasma levels of the CK enzyme, and urine that takes on a reddish-brown color due to the presence of myoglobin (myoglobinuria).^7,14,15 Rhabdomyolysis is a muscle disease caused by a breakdown of the integrity of skeletal muscle cells, with the release of electrolytes and muscle enzymes (e.g. myoglobin CK and lactate dehydrogenase) in the blood causing cellular dysfunction.^14,16 Clinical manifestations of rhabdomyolysis range from an asymptomatic increase in serum CK levels, up to severe electrolyte imbalance, cardiac arrhythmia, renal failure and intravascular coagulation (DIC).^17,18 Typical signs and symptoms of rhabdomyolysis includes acute or subacute myalgia, muscle weakness, mostly proximal lower limb muscles and urinary pigmentation (due to the presence of myosin > 1.5–3.0 mg/L), which together are called the rhabdomyolysis syndrome triad.^19–21 However, the likelihood of a patient presenting with a simultaneous triad is less than 10%.²²

Liver failure occurs in 25% of patients with rhabdomyolysis and results from the release of proteases causing liver inflammation.²³ Multiple organ failure is the leading cause of death in patients with rhabdomyolysis and is determined by the release of inflammatory mediators causing endothelial damage, coagulopathies and sepsis.²² Both physical and non-physical factors can induce rhabdomyolysis (Table 1).^10,20 Torres et al.¹⁵ documented that the most common causes of rhabdomyolysis among adults were drugs and alcohol abuse, trauma and prolonged bed rest. The main causes of rhabdomyolysis in children are viral infections, trauma, connective tissue diseases, exercise and drugs overdose.^24–29 Primary drugs that induce rhabdomyolysis include statins and psychotropic substances.^30–34 Antiepileptic drugs-induced rhabdomyolysis may cause symptomatic CK elevation as well as serious complications, such as arrhythmia, electrolytes imbalance, acute renal failure, hypovolemic and disseminated intravascular shock coagulation.¹¹

Table 1. Physical and Non-Physical Factors can Induce Rhabdomyolysis.

Physical factors		Non-physical factors
Trauma (as the main factor) Extrusion Excessive exercise Muscle ischemia Body temperature changes		Drugs Narcotics Infections Electrolyte imbalance Endocrine diseases Autoimmune diseases Genetic defects

AEDs Induced Muscle Toxicity

Both conventional older (e.g. benzodiazepines, carbamazepine, phenobarbital, phenytoin and valproate) and newer AEDs (e.g. felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide)^35,36 can cause myotoxicity and rhabdomyolysis (Figure 1).

Figure 1.

Miotoxicity Induced by Antiepileptic Drugs (AEDs)

Conventional Older AEDs

Phenytoin

Several years ago, Engel et al.³⁷ described the development of myalgia, fever, skin rash, increase in serum CK levels (242,000 IU/L) and brown urine in 22-year-old black man treated for 3 months with phenytoin (300 mg/day). A diagnosis of phenytoin-induced rhabdomyolysis was postulated and the drug was discontinued with a normalization of both symptoms and laboratory tests. Some years later, Santos-Calle et al.³⁸ described a patient who, 5 days after phenytoin administration (250 mg/iv), developed a marked increase in CK values (54,000 IU/L) that as normalized after phenytoin discontinuation. Korman and Olson,³⁹ reported a case of phenytoin-induced rhabdomyolysis with associated renal and hepatic failure. A 33-year-old man, with convulsions (phenytoin 1,000 mg/day), induced an increase in serum CK levels (2,370 UI/L) with normalization after 6 days.⁴⁰ A 27-year-old man with seizures, phenytoin (500 mg/day) add on valproic acid and levetiracetam induced an increase in serum CK levels (7,769 IU/L) that returned to normal levels after discontinuation of phenytoin, suggesting the latter drug was the culprit.⁴¹ In a 37-year-old man with status epilepticus a 7 days treatment with phenytoin induced an increase of serum CK levels (3,825 IU/L) that returned to the normal values when phenytoin was discontinued.⁴²

Valproic Acid

A case of multiorgan failure caused by valproic acid was firstly described in an adult several years ago.⁴³ A combination of hepatotoxicity and rhabdomyolysis associated with acute kidney injury has been reported in two patients receiving VPA therapy for psychiatric disorders.⁴⁴ The development of rhabdomyolysis was also described in children. In particular, Roodhooft et al.⁴⁵ reported a child with rhabdomyolysis and renal failure after valproic acid-treatment. Some years later, Chattergoon et al.⁴⁶ reported two children with multiorgan failure with disseminated intravascular coagulation 9 days after lamotrigine was added to valproic acid. In neonate suffering from a large unbalanced insertion of genetic material of the chromosome 2 (region q23 – q31) to chromosome 11. The unbalanced insertion of genetic material included SCN (neuronal sodium channel) 1A, SCN2A, SCN2A1, SCN3A and SCN7A gene, was linked to various forms of epilepsy. A neonate developed severe rhabdomyolysis (CK: 8,746 U/L, myoglobin 1,570 μg/L) 10 days after the beginning of a off-label treatment with valproic acid for epileptic seizures. VPA discontinuation induced a decrease in both CK and myoglobin serum levels that returned to normal values within one week.⁴⁷ Kottlors et al.⁴⁸ described the development of rhabdomyolysis, myoglobinuria and acute renal failure during the treatment with VPA in a patient with enzyme acyl carnitine transferase type II (CPAII), suggesting that VPA should be used with caution in these patients.

Newer AEDs

Levetiracetam

In an epileptic patient treated with valcporic acid, Akiyama et al.⁴⁹ documented that the addition of levetiracetam (LEV) caused back muscle pain and lower limbs weakness. Laboratory analysis revealed an increase in serum CK values (2,410 IU/L). Levetiracetam was discontinued with a rapid improvement in both clinical symptoms and laboratory values. Reversible rhabdomyolysis related to LEV therapy was reported in young^50,51 as well as in adult people.^52,53 In particular, Thomas et al.⁵² reported, in a 62-year-old male, a progressive increase in serum CK levels (19,000 IU/L) 12 hours after LEV treatment. Moinuddin et al.⁵³ documented the development of rhabdomyolysis with an increase in serum CK levels 36 hours after the beginning of LEV treatment; in 5 of 13 cases this manifestation was associated back pain and muscle pain, suggesting the need for careful observation, in particular during the initial treatment.

Gabapentin

The development of myopathy or rhabdomyolysis during gabapentin treatment was commonly described in diabetic woman. In particular, Tuccori et al.⁵⁴ reported the case of a diabetic woman who developed severe myopathy during gabapentin therapy (450 mg/day) with elevated CK, myoglobin and creatinine levels, with complete recovery 10 days after AED discontinuation. A 63-year-old diabetic woman developed rhabdomyolysis three weeks after gabapentin (900 mg/day) treatment.⁵⁵ Some years later, Falconi et al., documented the development of rhabdomyolysis in a 65-year-old diabetic patient three days after she stat a gabapentin treatment.⁵⁶ The development of myositis with elevated serum CK levels (44360 UI/L) was reported in a 31-year-old female with neuropathic pain during a 3 weeks treatment with gabapentin (3000 mg once daily).⁵⁷ More recently was reported the development of gabapentin-induced rhabdomyolysis, under both normal dosage and overdose conditions that required a renal replacement therapy,^58,59 suggesting that muscular toxicity during gabapentin treatment is not dose- or time-related.

Lamotrigine

Several years ago, Schaub et al.⁶⁰ described the development of rhabdomyolysis (CK:7770 IU/L; myoglobin: 3600 g/L; creatinine: 234 μmol/ L) 2 weeks after the addition of lamotrigine (LTG; total dose 100 mg) to carbamazepine (1000 mg/day) and clonazepam (2 mg/day). About 3 years later, Chattergoon et al.⁴⁶ described the development of multiorgan dysfunction in two children during lamotrigine treatment. More recently, some authors described the development of rhabdomyolysis (CK p to 6,517 IU/L) in depressed patients treated with lamotrigine.^61,62 In particular, Karaoulanis et al.⁶² described this manifestation after an overdose of lamotrigine (6 gr). Finally, a multi-organ syndrome was described in a 11-year-old epileptic patient after 13 days of lamotrigine monotherapy.⁶³

Propofol

Previous studies have reported that some patients with convulsive refractory status epilepticus have been treated with a sedative drug propofol (PRO). Some experts believe that PRO can be used safely and effectively to provide sedation to critically ill infants and children.⁶⁴ The treatmnt with PRO for a long-time (>48 hours) or with high doses (>4 mg/kg/h) can cause a propofol-related infusion syndrome (PRIS), characterized by metabolic acidosis, hyperkaliemia, heart failure, and rhabdomyolysis (Figure 1).^65–68 When PRIS occurs, PRO should be discontinued immediately and cardiopulmonary support and application of hemodialysis and plasmapheresis should be quickly started.⁶⁹ In pediatric patients, a 66–115 hours treatment with PRO (7.5–10 mg/kg/h) caused PRIS.⁶⁵ In a 17-year-old male patient who began treatment with PRO progressively increased to 292 mg/kg/min after 44 hours he presented with severe lack of oxygen, dark brown urine and CK levels of 83,000 IU/L. PRO is was discontinued after a total dose of 19.275 mg (482 mg/kg) and the patient died 84 hours after treatment and, with autopsy suggesting rhabdomyolysis.⁶⁸ At the time of the present review, there are not data to support the use of PRO in refractory convulsive status epilepticus particularly in children <6-years old.⁷⁰

Conclusions and Directions for future researchs

The case reports cited, although not conclusive evidence, indicate that antiepileptic drug-induced rhabdomyolysis is a rare event, but if not recognized early it can be fatal. Therefore, in the presence of a myotoxicity, a rapid diagnosis with an accurate anamnesis must be do. Laboratory analysis, electromyography, B-mode imaging, magnetic resonance imaging, muscle biopsy will help us diagnose and also differentiate the various types of myopathy and in the presence of rhabdomyolysis and quantify its severity.⁷¹ In presence of myotoxicity after antiepileptic drug treatment, the possibility of an AED-induced toxicity should be evaluated. Several factors may be responsible for the increased development of this ADR induced by antiepileptic drugs: increased age, female gender, comorbidity, poly-therapy and substance use (e.g., coffee and alcohol).^2,72,73 Furthermore, it must be considered that the intake of high doses and for a long time of an AED can be the cause of myotoxicity. Different genetic defects causing various neuromuscular and metabolic disorders, such as mithocondrial disoders and disorders of intramuscular calcium release and excitation-contraction coupling (RYR1) are known to be associated with rhabdomyolisis.^74,75 In some instances, rhabdomyolysis may be due to a combination of genetic factors and environmental causes (e.g. exercise, epileptic seizures, etc). It was found that patients with virally induced rhabdomyolysis had malignant hyperthermia susceptibility (MHS)-associated RYR1 mutations.^76–80 Triggers for rhabdomyolysis are persistent skeletal muscle activity despite symptoms (before getting into the second wind phenomenon), intense exertion, anaerobic activity, isometric contraction and sustained muscle contracture, infection, temperature, emotional stress, diet such as drugs.^74,75,81 Recently, a growing body of evidence suggests that genetic polymorphisms relevant to pharmacokinetic (e.g. drug receptors, transporters and metabolizing enzymes) and pharmacodynamic (e.g. muscle enzymes) predispose to an increased risk of myopathy.^82–86 In particular, there is ample evidence of the association between some human leukocyte antigen (HLA) alleles and an increased risk of idiosyncratic adverse drug reactions. In epileptic patients with the genetic marker HLA-B, the treatment with carbamazepine,^87,88 phenytoin, lamotrigine⁸⁹ and oxcarbazepine⁹⁰ was associated with an increased risk of Stevens-Johnson syndrome. In a prospective multicenter study in epileptic patients treated with normal serum levels of VPA, the presence of the T1405 polymorphism in the carbamoyl phosphate synthase 1 (CPS1) gene could induce hyperammonemia witout liver failure.⁹¹ In epileptic patients, weight gain, a common adverse reaction of VPA, has been associated with the leptin receptor (LEPR) and the anchorine repetitive kinase domain containing gene 1 (ANKK1) polymorphisms.⁹² In a pediatric study on 52 children Budi et al.⁹³ reported that it is possible to reduced the VPA-toxicity adjusting the dosage according to CYP2C9 activity. In the literature, the presence of case reports demonstrating the rarity of myotoxicity from antiepileptic drugs may reiterate the importance of genetic factors in the involvement of this adverse reaction induced by AEDs. In the future, a study of genetic polymorphism in patients with AED-induced rhabdomyolysis could be useful for better treatment of these AED patients, in terms of AED type and dose adjustment.