Intravenous phenytoin is a commonly used antiepileptic drug for emergent treatment of seizures. Common side effects include ataxia, nystagmus, confusion, and nausea.Reference Kim, Jo, Park, Han and Lee 1 Rhabdomyolysis is a rare adverse effect of phenytoin. The first reported case of rhabdomyolysis associated with phenytoin was in 1976Reference Michael and Mitch 2 and only a handful of cases have since been reported.Reference Kim, Jo, Park, Han and Lee 1 , Reference Santos-Calle, Borras-Blasco, Navarro-Ruiz and Plaza Macias 3 , Reference Olaniran, Keshishyan and Assallum 4 We present a case of acute painful proximal muscle weakness and markedly elevated creatine kinase (CK) levels in a 63-year-old woman immediately following intravenous loading of phenytoin that resolved rapidly with discontinuation of phenytoin.
Our patient initially presented to the emergency department by ambulance after she had a witnessed first generalized tonic-clonic seizure lasting <1 minute. In retrospect, she had a suspected first focal seizure with impaired awareness (5-10 minutes of expressive language difficulty) a few hours earlier. After arriving in the emergency department, she had a second witnessed generalized tonic-clonic seizure lasting <1 minute. She received a total intravenous phenytoin loading dose of 20 mg/kg, with a plan to continue oral phenytoin 300 mg each evening. Her history was significant for longstanding schizophrenia, which had been stable on treatment with clozapine for many years. There was no other significant past medical or surgical history. There was no history of alcohol or drug use.
The following morning upon assessment by the attending neurologist, she had a normal neurological exam with the exception of multidirectional nystagmus, appendicular ataxia, and negative myoclonus at the wrists that had the appearance of asterixis. Asterixis is a recognized but uncommon clinical sign of phenytoin toxicity.Reference Chi, Chua and Kong 5 Overall, her exam was consistent with phenytoin toxicity.
Her laboratory investigations on admission are detailed in Table 1 and were unremarkable. A plain CT head on the day of admission was normal. An electroencephalogram demonstrated diffuse background is slowing without lateralizing features or epileptiform discharges. An MRI brain was unremarkable. Two days following her intravenous phenytoin and after she had received another 300 mg orally the evening before, her phenytoin level was within the therapeutic range at 54 umol/L (40-80 umol/L).
Initial patient laboratory investigations on the day of admission with associated normal values and units
ALP = alkaline phosphate; ALT = alanine aminotransferase; CK = creatine kinase; eGFR = estimated glomerular filtration rate; GGT = gamma-glutamyltransferase; INR = international normalised ratio; LD = lactate dehydrogenase; MHHC = mean corpuscular hemoglobin concentration; MVC = mean corpuscular volume; RBC = red blood cell count; RDW = red blood cell distribution width; TSH = thyroid stimulating hormone; WBC = white blood cell count.
On post-admission day 3 (PAD#3), she complained of myalgias and was found to have a proximal pattern of muscle weakness as follows (right/left): shoulder abduction 4−/4, elbow flexion 5/4+, elbow extension 4−/4, and hip flexion 3/3; with all more distal muscle groups in the upper and lower limbs graded as 5/5. Her reflexes were grade 2+ throughout and her plantar responses were flexor. Her CK level was found to be elevated at 23,661 U/L (PAD#3). Her phenytoin was stopped, and she was instead started on lamotrigine 25 mg daily with a plan for a slow upward titration. She was started on aggressive intravenous fluid resuscitation with normal saline for presumed rhabdomyolysis. Over the next 2 days, she regained full power. She did not develop acute kidney injury.
Her CK levels were retrospectively tested using previously collected serum samples. Her initial CK level on the day she presented (PAD#0) was 129 U/L (after her seizures but before her phenytoin load). This increased to 15,508 U/L by PAD#2. Her CK level peaked on PAD#4 (the day after her phenytoin was stopped) at 26,659 U/L and then began to trend downward (Figure 1). An MRI of the C-Spine was unremarkable. Electromyography/nerve conduction studies had been ordered but were cancelled due to the complete resolution of her weakness.
Creatine kinase (CK) levels at various days over the patient’s hospital admission. Phenytoin initiation and stop dates are indicated. Creatine kinase levels peaked at 26,659 U/L and quickly trended downwardly after cessation of phenytoin and aggressive supportive therapy.
The patient was discharged from hospital after 1 week. She had no further seizure activity. Her CK level 5 days after discharge was 391 U/L. Despite the rarity of phenytoin-induced rhabdomyolysis, we believe that her acute onset myalgias, proximal weakness, and hyperCKemia was related to her exposure to phenytoin because of the close temporal correlation and pattern of weakness consistent with a drug-induced myopathy. Moreover, a causative role for phenytoin is further supported by the complete clinical and laboratory resolution following discontinuation of phenytoin. Similar cases of phenytoin-induced rhabdomyolysis have been reported in the literature that are similar to our patient’s presentation without an associated hypersensitivity reaction.Reference Kim, Jo, Park, Han and Lee 1 , Reference Santos-Calle, Borras-Blasco, Navarro-Ruiz and Plaza Macias 3 , Reference Olaniran, Keshishyan and Assallum 4 Although seizure activity itself can be associated with elevated CK, the CK level in our patient was not elevated until PAD#2 and she had no further seizure activity in hospital. It is difficult to exclude the possibility that the patient’s hyperCKemia could have been a delayed consequence of her initial seizure activity,Reference Mishra and Dave 6 but such cases are usually associated with status epilepticus and dehydration and are not typically associated with a proximal pattern of weakness. Our patient had two very brief generalized tonic-clonic seizures and was immediately treated with intravenous fluids.
Clozapine overdose has also been reported to cause rhabdomyolysis,Reference Jansman, Crommelin, van Hout and Meulenbelt 7 but this was seen with a clozapine level 5× the upper limit of normal. Our patient had been stable on clozapine for years and there was no indication that she had overdosed. Her clozapine level was within the therapeutic window at 1575 nmol (1070-1835 nmol/L). Although both clozapine and phenytoin have been implicated in rhabdomyolysis, concurrent exposure to phenytoin (a potent CYP3A4 inducer) would be expected to decrease clozapine exposure and efficacy. Moreover, there were no clinical findings to suggest neuroleptic malignant syndrome in our patient.
The mechanism by which phenytoin could cause rhabdomyolysis is unclear. In theory, rhabdomyolysis could be precipitated by any drug that either impairs production of ATP, increases energy requirements beyond the rate of ATP production, and/or leads to accumulation of myoplasmic intracellular calcium.Reference Huerta-Alardin, Varon and Marik 8 Increased intracellular calcium initiates protease cascades that cause further cellular injury and further impairment of calcium homeostasis. The mechanism by which phenytoin might induce rhabdomyolysis is a topic that requires further research.
Rhabdomyolysis is a severe consequence of muscle necrosis that can lead to complications such as acute kidney injury. Fortunately, an elevated CK was found quickly in our patient and she responded well to prompt cessation of phenytoin and supportive therapy. Drug-induced rhabdomyolysis may be overlooked due to a subclinical presentation without common features.Reference Coco and Klasner 9 Although rare, phenytoin-induced rhabdomyolysis should be considered when a patient develops myalgias, proximal muscle weakness, or has increased CK levels despite adequate seizure control.
Disclosure The authors have nothing to disclose.
Statement of Authorship RM contributed to drafting the manuscript and clinical information on the case. TB contributed to critical revision of the manuscript and clinical information on the case.
