Abstract
This case report describes a female with p.Lys4876Arg amino acid change in the ryanodine receptor type 1 (RYR1) and a sibling who died of malignant hyperthermia (MH) during anesthesia. After her diagnosis as MH susceptible, this patient was administered low-dose dantrolene daily for greater than 25 years for treatment of chronic muscle spasm and pain in her lower extremities and back limiting sleep. Her creatine phosphokinase (CPK) was as high as 2390 IU/L during labor and 900 IU at rest. With 25 mg dantrolene daily, muscle cramps were eliminated, and sleep was improved. Gait instability was noted with dantrolene in the morning, but not when taken at bedtime. There was no evidence of liver injury. This case suggests that low dose dantrolene by mouth could be considered for the treatment of chronic muscle pain in individuals with MH susceptibility.
Keywords
INTRODUCTION
Malignant hyperthermia (MH) is well recognized as a hypermetabolic disorder of skeletal muscle in the presence of volatile anesthetic gases and the depolarizing muscle relaxant succinylcholine [1]. MH events have also been observed in people after vigorous exercise [2] and when stressed by heat [3] or other factors [4, 5]. The ryanodine receptor type one gene (
Dantrolene IV is the mainstay of therapy for acute MH events. Dantrolene has been shown to bind the N-terminal region of skeletal muscle ryanodine receptor [7] and decrease calcium release from the sarcoplasmic reticulum [8]. The effects of IV dantrolene have been described [9]. Oral dantrolene sodium has been used to treat spasticity [10], and as prophylaxis prior to anesthesia in MHS people [11], but little has been published regarding the effect of oral dantrolene in relieving cramps and muscle pain in MHS people [12]. We report a case of long-term oral dantrolene administration to treat chronic muscular symptoms in a MHS person.
CASE REPORT
The patient was a well-developed, well-nourished 39 year old white female when she presented forevaluation of MH susceptibility in 1977 because of an extensive family history of anesthetic complications (Fig. 1). This patient’s sibling died during halothane anesthesia for minor surgery. Her uncle died unexpectedly in the perioperative period and her aunt died during childbirth in warm weather. Her father did not report his family anesthetic history when he experienced rigidity during anesthesia and severe muscle pain postoperatively. The patient had undergone uncomplicated anesthetics without exposure to anesthetic drugs known to trigger MH. These included dilation and curettage during nitrous oxide in 1967 and right parotidectomy with ketamine in 1973 where creatine phosphokinase (CPK) was monitored perioperatively (Table 1) [13]. The patient also had two vaginal deliveries with spinal anesthesia in 1969 and 1974. She was found to have elevated CPK levels prior to pregnancy with further elevations in CPK, lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) prior to and after labor [14] (Table 1).
The patient was evaluated at the MH Diagnostic Testing Center in Toronto, Canada and underwent biopsy of the vastus lateralis with very abnormal results that confirmed MHS. This examination was preformed prior to standardization of the caffeine halothane muscle contracture test. At the time of muscle biopsy, she complained of leg and calf cramping as well as muscular back pain affecting her sleep. The patient was of average build with normal vital signs, intact cranial nerves, normal deep tendon reflexes and appropriate muscle strength. She took no medicines. The patient was employed as a nurse. Laboratory studies were significant for elevated serum CPK, LDH and AST (Table 1) with normal serum electrolytes, thyroid, coagulation and renal studies. Given muscle contracture testing results, the MH Diagnostic Center Director recommended that this patient take 25 mg dantrolene by mouth daily for the treatment of muscle cramps.
The patient was followed clinically for over 25 years by the MH Diagnostic Center Director as well as a local anesthesiologist. After 1-2 weeks of therapy, the patient no longer had muscle cramps and had improved sleep. She elected to take dantrolene at bedtime to avoid some gait imbalance if taken in the morning. In 1993 the patient had not been taking dantrolene for about two months due to a change in social situation. She noted return of muscle cramping in her legs and back as well as more difficulty sleeping. CPK was 1,266 IU/L, LDH 974 IU/L, AST 55 IU/L and alanine aminotransferase (ALT) 88 IU/L (Table 1). Other lab tests including total and direct bilirubin, electrolytes, calcium, magnesium and lipids were unremarkable. She was restarted on dantrolene at the same dose, 25 mg PO at night.
In 2003 this patient was further evaluated in a study reported as an abstract [15] involving adductor pollicis surface electromyography. In three conditions, not taking dantrolene for 7 days, while taking 25 mg/day dantrolene and later 75 mg/day dantrolene, muscle response to increasing stimulus frequency from 0.1 Hz to 50 Hz was recorded. This study showed signs of muscle fatigue, fade in response to higher stimulus frequency, which were lessened by increasing exposure to dantrolene. When off dantrolene during this testing period, the patient noted difficulty sleeping due to muscle pain, especially in her back. The patient’s CPK was tracked throughout the study (Table 1). The patient did not note any adverse effects at the 75 mg/day dose of oral dantrolene.
This patient and many of her relatives (Fig. 1) participated in a study of MH genetics in which the entire
DISCUSSION
There have been other cases reported in which oral dantrolene has been used to treat sporadic MH symptoms, however we report the daily use of dantrolene in a MHS person for decades without significant adverse effects. Ogletree et al. [12] reported a 17 year-old male athlete who complained of cramping in the neck, back and shoulders approximately 30 minutes after exercise. These episodes lasted between 30 minutes and 3 hours. The patient also reported that he perspired more than other athletes. Because of these persistent symptoms, the patient underwent muscle contracture testing with results diagnostic of MHS. He was prescribed oral dantrolene as needed to abort episodes of muscle cramping. No follow-up was reported. In a study of patients referred for caffeine-halothane contracture testing (CHCT) for non-anesthetic indications, oral dantrolene was titrated from 25 mg daily to increasing dosages leading to improved musculoskeletal symptoms in 28/34 (82%) of CHCT positive patients [17]. The importance of chronic muscular pain to MHS individuals is unknown and may be underreported.
Our patient had elevated and variable CPK throughout the course of her life. Because of the known variability of CPK in individuals with primary muscle disorders, and the fact that these observations are from only one patient, the conclusion that dantrolene was responsible for the decrease in CPK, improvement in symptoms and decrease in fade of the compound electromyogram during high stimulus frequency is open to debate. A larger controlled study is needed to support this conclusion.
The most common adverse effects of dantrolene, given in the absence of anesthetics, are drowsiness (30%), dizziness (14%) and nausea and vomiting (9%), malaise, weakness and fatigue [18]. Dantrolene has been shown to cause dose dependent decreases in grip strength [9, 19]. Dantrolene has also been associated with hepatic injury when used chronically at high doses [20]. There were no clinical or laboratory indications of hepatic injury in our patient. The elevations of CPK, AST & ALT observed in this patient prior to dantrolene therapy may have been due to MHS, though other causes were not pursued. Her dose was not adjusted other than a short experimental period [15] as her symptoms were relieved with only 25 mg daily. Oral dantrolene has been shown to reach protective levels within 24 hours [11] making the response to therapy in our patient expected.
The Lys4876Arg mutation in RYR1 in our patient and her family has not yet been proven to be a cause of MH by strict European Malignant Hyperthermia Group standards (https://emhg.org/fileadmin/EMHG/redaktion/Guidelines/Mutationcriteria2003.pdf) beca-use there have not been invitro studies published showing that this mutation decreases sensitivity to agonists of RYR1. However, it is one of the hundreds of
We present a case of low dose oral dantrolene for the treatment of cramps and chronic muscle pain in an MHS individual. Given the pharmacodynamics of dantrolene and the pathophysiology of MH, dantrolene may be a reasonable choice for the treatment of muscle pain and cramps in MHS individuals and possibly other disorders with increased intracellular calcium in skeletal muscle. Dantrolene has been effective in the treatment of muscle pain in other myopathies, including muscle phosphoglycerate mutase deficiency with tubular aggregates and Thomsen’s disease [24, 25]. Clinical and laboratory monitoring should be focused on symptoms as described above, maintenance of adequate muscle strength, and liver function testing. Until controlled trials are performed, the potential benefits of chronic dantrolene therapy in MHS people will remain anecdotal.
This patient’s life, and her experience of the death of her sibling, is an illustration of the advancement of the study of MH, from the recognition of this condition as an inheritable cause of peri-operative death, to the recognition of genetic mutations that are the source of MHS. This patient contributed to a further step in the understanding of MHS as a chronic muscular condition that may be ameliorated.
Conflict of interest
The authors have no conflict of interest to report.
Footnotes
ACKNOWLEDGMENTS
We acknowledge the support of the not-for-profit Malignant Hyperthermia Association of the United States to the North American Malignant Hyperthermia Registry of MHAUS and the support of the Department of Anesthesiology in the University of Pittsburgh School of Medicine, without which the data that resulted in this report would not have been accumulated.