Relationship of Levetiracetam and Serum Creatine Phosphokinase in Children with Epilepsy.

Dear editor,

We read with great interest the recently published article titled “Effect of levetiracetam usage on serum creatine phosphokinase concentration in patients with epilepsy” by Incecik et al.[1] The authors have found out that 3 of 160 children had hyperCKemia at 1 month after starting levetiracetam and thus concluded that levetiracetam may cause rhabdomyolysis. However, we wish to add a few points.

The authors have measured serum CPK levels as a measure of rhabdomyolysis, but there are three isoenzymes of serum CPK such as CPK-BB (specific for brain and lung), CPK-MM (specific for muscle), and CPK-MB (specific for myocardium).[2] Serum CPK is rather a nonspecific biomarker to indicate muscle damage. It would have been ideal for authors to measure serum CPK-MM isoenzymes at least in these three patients with raised serum CPK levels to determine the site of origin. As the authors have mentioned seizures can elevate serum CPK levels, especially serum CPK-BB, and in some cases CPK-MM also after a prolonged seizure, especially generalized tonic–clonic seizure.[3] Thus, it would have been better if the authors would have collected information regarding the duration of last seizure, the time interval between last seizure and blood sampling for serum CPK level to provide more evident causal association, apart from the parameters the authors have included in the analysis (such as generalized or focal seizures and frequency of seizures). The other two risk factors for the elevation of serum CPK which the authors have not considered are recent administration of intramuscular injections and recent viral illness (might be an indicator of clinical/subclinical viral myositis). One of the children with elevated serum CPK was having myalgia and discomfort in the lower limb also. Although muscle biopsy was not performed in these cases, muscle ultrasound or MRI muscle would have provided useful clinical information in this regard noninvasively.[4]

The authors have analyzed serum CPK level as dichotomous categorical value (whether elevated or not at 1 month after initiation of therapy). However, more precise information could have been obtained if the authors would have compared the average serum CPK levels of all study participants at baseline and after 1 month as a continuous variable. It would have revealed information regarding the subclinical elevation of serum CPK in some patients, although the value remained within the range of 26–204 IU/L. The authors have mentioned out of three patients two were on polytherapy, although they did not mention the name of other antiepileptic drugs. As antiepileptic drugs such as valproate and even phenytoin are associated with elevated serum CPK levels sometimes, how, the authors pinpointed to levetiracetam as the causative of elevated serum CPK levels and stopped the drug remains ambiguous. The authors have also not mentioned whether other antiepileptic drugs were also modified in these three children and whether there was any breakthrough seizure after stopping levetiracetam. In such cases, the Naranjo adverse effect probability scale would have been an ideal option to determine the presence of a real causal association.[5] The authors have also administered hydration to avoid potential complications, which reduces serum CPK levels as such and thus compromises the reliability of causal association in these cases.

Two of these three children had neurological deficits but did not mention whether they had spasticity or dystonia as a co-morbidity, which can also cause elevated serum CPK level. The reliability of univariate analysis for determining risk factors for elevated serum CPK is also limited as the authors have used the chi-square test for the purpose as mentioned in statistical analysis and there are only three children with elevated serum CPK, which was further subgrouped according to presence or absence of risk factors. In such cases, the authors could have used Yate’s correction or Fisher’s exact test for more reliable results.[67]

Lastly, we feel the authors could have replaced the repeated use of words like “partial seizure” and “mental retardation” in the manuscript. Recent most ILAE classification of seizures proposed in 2017 has already replaced “partial seizure” with “focal seizure” and the term “mental retardation” has also been replaced by “intellectual disability,” as the original term was more stigmatizing.[8]

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