Drug-induced myopathy is caused by direct or indirect effects of toxic substances on the muscle. The mechanisms of indirect effects include development of electrolyte disturbances, excessive energy requirements, or secondary immunologic reactions. Symptoms typically occur weeks to months after administration of the drug and usually improve or resolve within weeks after discontinuation of the offending agent. They range from mild muscle pain to severe weakness complicated by rhabdomyolysis, which in turn can cause renal failure and electrolyte abnormalities. Because it is a potentially reversible condition, early recognition is important.
Myotoxicity due to antidopaminergic medication has been described in several conditions including rhabdomyolysis without neuroleptic malignant syndrome (NMS).1,2 Meltzer et al2 reported a marked increase in creatine kinase (CK) levels in approximately 10% of patients treated with clozapine, risperidone, melperone, olanzapine, haloperidol, or loxapine. Another study showed that an elevated CK level was observed in 17% of patients who presented to the hospital after olanzapine injections.3 Packard et al4 reported that 10.5% of patients admitted with rhabdomyolysis were on antidopaminergic medications.
The mechanism of increased serum CK associated with antidopaminergic medication is still unclear; it has been suggested that increased cell membrane permeability allows CK to diffuse into the circulation across the very high transmembrane gradient.2,3
A 29-year-old man with a history of obsessive compulsive disorder and Tourette syndrome taking ziprasidone 40 mg daily was brought to the emergency department with 2 months of worsening dyspnea. He reported normal childhood developmental milestones and denied any family history of myopathy. Blood pressure was 137/84 mm Hg, heart rate was 106 bpm, and body temperature was 97.6 F. He was alert and oriented, and cranial nerve examination was normal. Motor strength examination revealed proximal (MRC scale 2–4/5) as well as neck flexion (MRC scale 4/5) and extension (MRC scale 3/5) weakness without muscle rigidity or tremors. Sensory examination showed no deficits on vibratory and pinprick testing. Reflexes were diffusely reduced. He required intubation for worsening respiratory status complicated by aspiration pneumonia. Serum CK level was 3318 units/L. Serum lactate was initially elevated to 3.7 mmol/L, which was normalized by hospital day 5. There was no evidence of myoglobinuria, and urine toxicology screening was negative.
Further history-taking and records from outside hospitals revealed that a year before the presentation to our hospital, after an increased risperidone dose from 0.5 to 1 mg daily, he had developed similar severe proximal muscle weakness involving the respiratory muscles, with an elevated CK level of 5932 units/L. Electromyography at that time revealed early recruitment of motor unit action potential with reduced amplitude consistent with a myopathic process. Biopsy of the gastrocnemius muscle was also consistent with a myopathic process, with many myofibers with bright eosinophilic granular sarcoplasm, as well as degenerating fibers with a mild lymphocytic infiltrate (Figs. 1A–C). The granular fibers did not have the typical features of ragged-red fibers, with the granules being large and bright eosinophilic, and occupying much of the sarcoplasm. SDH and COX reactions showed no ragged blue or COX-negative fibers, respectively. Although some heavily-affected fibers appeared vacuolar, acid-phosphatase and electron microscopic examination did not show definitive vacuoles or autophagic debris.
On day 2 of the presentation to our hospital, ziprasidone was discontinued for possible toxic myopathy, and prednisone 60 mg daily was started for possible inflammatory and/or autoimmune etiology. After multiple weaning failures due to ineffective cough, tracheotomy was performed on day 11.
A second muscle biopsy was performed at our institution from the adductor longus, which was selected after a muscle magnetic resonance imaging revealed the presence of edematous changes. The biopsy showed predominantly regenerative changes with significantly decreased numbers of inflammatory cells, degenerating fibers, and fibers with granular changes compared to the first biopsy (Fig. 1D). Electron microscopic examination revealed many fibers with disturbed internal architecture. There was an increased number of mitochondria, which were mostly swollen, but no abnormal forms or inclusions were seen. The mitochondria were associated with lipid droplets. These increased numbers of mitochondria and lipid droplets were scattered throughout the sarcoplasm of affected myofibers, forming large groups and distorting the myofibrillary network, which remained as minute residual structures in extreme examples (Fig. 2).
Blood-based acid alpha-glucosidase activity assay was normal, and genetic testing was negative for limb–girdle muscular dystrophy. Over time off ziprasidone, he gradually improved and was successfully decannulated. He was discharged from our hospital, and prednisone was discontinued after treatment for 3 months. Nine months after discharge, he showed full recovery of strength and normalization of CK levels to 62 units/L. His neurologic condition was likely attributed to toxic myopathy secondary to antidopaminergic medication.
This is a unique case of toxic myopathy characterized by severe proximal weakness and significantly elevated CK level secondary to antidopaminergic medication. NMS may occur in patients taking antidopaminergic medications that can result in elevated CK level and acute renal failure. Sachdev et al5 proposed clinical and laboratory features of NMS that include elevated temperature, extrapyramidal symptoms (notably rigidity, chorea, dystonia, and tremor), autonomic instability, altered consciousness, laboratory derangements (CK level and leukocytosis), and catatonic symptoms (mutism and posturing). Based on the absence of these clinical findings, our patient did not have NMS.
One of the unique features of our case, which has not been previously reported to our knowledge, is that our patient developed severe proximal weakness involving the respiratory muscles after starting antidopaminergic medications. Scelsa et al6 followed weekly CK levels in 37 consecutive clozapine-treated outpatients with chronic psychotic disorders. Twenty-nine patients (78%) had CK elevation. Among the 29 patients with elevated CK, only 6/18 patients with documented neuromuscular examinations had proximal weakness that was graded as mild in all 6. None of them had respiratory muscle weakness. There have been a few pediatric cases reported with muscle weakness secondary to antidopaminergic medication, but in those, respiratory muscle weakness was also not reported.7
It is important to note that our patient developed first episode of weakness after risperidone was increased from 0.5 to 1 mg daily. The dose dependence of antidopaminergic medication toxicity has been previously described.3 Kilicaslan et al7 reported a 5.5-year-old boy whose weakness resolved after reducing risperidone from 0.5 to 0.25 mg daily. A retrospective study of patients with olanzapine overdoses showed that the prevalence of elevated CK levels was positively correlated with the stated quantity of olanzapine ingested.3 These findings could suggest that CK levels may need to be monitored when adjusting antidopaminergic medications. In Scelsa's study, all patients with weakness had CK levels higher than 725 units/L.6
Our patient developed recurrent toxic myopathy on 2 different antidopaminergic medications (risperidone and ziprasidone). Recurrent rhabdomyolysis in patients on antidopaminergic medication has been described, but most of them are associated with coexisting medical conditions, including hyponatremia secondary to psychogenic polydipsia.8,9 Aggarwal et al10 reported a unique case of a 23-year-old man with schizoaffective disorder who developed rhabdomyolysis on multiple occasions associated with 4 different antidopaminergic medications.
The clinical and histologic improvement in response to discontinuation of the suspected medication supports the notion that the pathological changes are most likely due to a toxic effect of the medication. It can also be suggested, based on the pathologic findings, that this toxic effect likely targets mitochondria through a yet unexplained mechanism.11
In conclusion, we report a unique case of severe toxic myopathy associated with antidopaminergic medications that presented with recurrent respiratory muscle weakness in a dose-dependent manner with 1 of the 2 medications involved. CK level may be an early indicator of this condition as well as NMS in patients taking antidopaminergic medication and would be warranted with any suggestion of muscle weakness to prevent potentially life-threatening complications.
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