Pre-operative exercise and pyrexia as modifying factors in malignant hyperthermia (MH)

Riazi, Sheila; Bersselaar, Luuk R. van den; Islander, Gunilla; Heytens, L.; Snoeck, M.M.J.; Bjorksten, Andrew R.; Gillies, Robyn; Dranitsaris, George; Hellblom, Anna; Treves, Susan; Kunst, Gudrun; Voermans, Nicol C.; Jungbluth, Heinz

doi:10.1016/j.nmd.2022.06.003

Cited by 16 publications

(15 citation statements)

References 40 publications

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“… 7 ERM and MH have conventionally been considered episodic phenotypes that occur in otherwise healthy individuals carrying gain-of-function RYR1 variants in response to an external trigger such as pharmacological agents, strenuous exercise, viral illnesses or a combination of the above. 2 , 8 , 9 …”

Section: Introductionmentioning

confidence: 99%

Neuromuscular symptoms in patients with RYR1-related malignant hyperthermia and rhabdomyolysis

Bersselaar

Jungbluth

Kruijt

et al. 2022

Brain Communications

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Malignant hyperthermia and exertional rhabdomyolysis have conventionally been considered episodic phenotypes that occur in otherwise healthy individuals in response to an external trigger. However, recent studies have demonstrated a clinical and histopathological continuum between patients with a history of malignant hyperthermia susceptibility and/or exertional rhabdomyolysis and RYR1-related congenital myopathies. We hypothesize that patients with a history of RYR1-related exertional rhabdomyolysis or malignant hyperthermia susceptibility do have permanent neuromuscular symptoms between malignant hyperthermia or exertional rhabdomyolysis episodes. We performed a prospective cross-sectional observational clinical study of neuromuscular features in patients with a history of RYR1-related exertional rhabdomyolysis and/or malignant hyperthermia susceptibility (n = 40) compared to healthy controls (n = 80). Patients with an RYR1-related congenital myopathy, manifesting as muscle weakness preceding other symptoms as well as other (neuromuscular) diseases resulting in muscle weakness were excluded. Study procedures included a standardized history of neuromuscular symptoms, a review of all relevant ancillary diagnostic tests performed up to the point of inclusion and a comprehensive, standardized neuromuscular assessment. Results of the standardized neuromuscular history were compared to healthy controls. Results of the neuromuscular assessment were compared to validated reference values. The proportion of patients suffering from cramps (P < 0.001), myalgia (P < 0.001) and exertional myalgia (P < 0.001) was higher compared to healthy controls. Health care professionals were consulted because of apparent neuromuscular symptoms by 17/40 (42.5%) patients and 7/80 (8.8%) healthy controls (P < 0.001). Apart from elevated creatine kinase levels in 19/40 (47.5%) patients and mild abnormalities on muscle biopsies identified in 13/16 (81.3%), ancillary investigations were normal in most patients. The Medical Research Council sum score, spirometry and results of functional measurements were also mostly normal. Three of 40 patients (7.5%) suffered from late-onset muscle weakness, most prominent in the proximal lower extremity muscles. Patients with RYR1 variants resulting in malignant hyperthermia susceptibility and/or exertional rhabdomyolysis frequently report additional neuromuscular symptoms such as myalgia and muscle cramps compared to healthy controls. These symptoms result in frequent consultation of health care professionals and sometimes in unnecessary invasive diagnostic procedures. Most patients do have normal strength at a younger age but may develop muscle weakness later in life.

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Section: Introductionmentioning

confidence: 99%

Neuromuscular symptoms in patients with RYR1-related malignant hyperthermia and rhabdomyolysis

Bersselaar

Jungbluth

Kruijt

et al. 2022

Brain Communications

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“…35 There is a clinical continuum between RYR1related congenital myopathies, exertional myalgia, rhabdomyolysis, and MH, emphasizing the need for a common treatment approach. 4,5 Moreover, the use of dantrolene for these conditions in isolated cases has shown promising results. 8 In conclusion, we provide evidence that oral dantrolene in appropriate doses is tolerated by MHS patients and might provide relief from myopathic symptoms such as myalgia, fatigue, and rhabdomyolysis.…”

Section: Discussionmentioning

confidence: 99%

“…35 There is a clinical continuum between RYR1 -related congenital myopathies, exertional myalgia, rhabdomyolysis, and MH, emphasizing the need for a common treatment approach. 4,5 Moreover, the use of dantrolene for these conditions in isolated cases has shown promising results. 8…”

Section: Discussionmentioning

confidence: 99%

“…2,3 A recent report suggested that a history of strenuous exercise or pyrexia within 72 hours before general anesthesia may increase the risk of developing MH in patients with predisposing genotypes. 4 Exertional myalgia and rhabdomyolysis may be indeed more common manifestations of pathogenic RYR1 genotypes than MH itself. 5 MH is caused by calcium dyshomeostasis in skeletal myocytes associated with mutations in the RYR1, and-less frequently-in calcium voltage-gated channel subunit alpha1 S gene (CACNA1S) and SH3 and cysteine rich domain 3 gene (STAC3).…”

Section: Glossarymentioning

confidence: 99%

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Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia–Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability

Moreno

Kraeva

Zvaritch

et al. 2022

Anesthesia &Amp; Analgesia

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BACKGROUND: Patients susceptible to malignant hyperthermia (MH) may experience disabling manifestations of an unspecified myopathy outside the context of anesthesia, including myalgia, fatigue, or episodic rhabdomyolysis. Clinical observations suggest that oral dantrolene may relief myopathic symptoms in MH-susceptible (MHS) patients. However, high-dose oral dantrolene has been associated with severe hepatotoxicity. METHODS: In a retrospective database review (1994–2018), we investigated a cohort of patients who were diagnosed as MHS by a positive caffeine-halothane contracture test (CHCT), had myopathic manifestations, and received oral dantrolene. Our aim was to investigate the occurrence of serious adverse effects and the adherence to oral dantrolene therapy. We also explored factors associated with self-reported clinical improvement, considering as nonresponders patients with intolerable adverse effects or who reported no improvement 8 weeks after starting treatment. RESULTS: Among 476 MHS patients with positive CHCT, 193 had muscle symptoms, 164 started oral dantrolene, 27 refused treatment, and 2 were excluded due to abnormal liver function before starting therapy. There were no serious adverse effects reported. Forty-six of 164 patients (28%; 95% confidence interval [CI], 22%–35%) experienced mild to moderate adverse effects. Twenty-two patients (22/164, 13%; 95% CI, 9%–19%) discontinued treatment, among which 16 due to adverse effects and 6 due to lack of improvement. One hundred forty-two patients (87%; 95% CI, 80%–90%) adhered to therapy and reported improvement of myalgia (n = 78), fatigue (n = 32), or rhabdomyolysis/hiperCKemia (n = 32). The proportion of responders was larger among patients with MH history than among those referred due to a clinical myopathy with nonpertinent anesthetic history (97% vs 79%, respectively; 95% CI of the difference, 8.5–28; P < .001). Patients with a sarcoplasmic reticulum Ca2+ release channel ryanodine receptor gene (RYR1) variant had higher odds of responding to dantrolene treatment (OR, 6.4; 95% CI, 1.3–30.9; P = .013). Dantrolene median dose was 50 (25–400) and 200 (25–400) mg·day–1 in responders and nonresponders, respectively. CONCLUSIONS: We found that oral dantrolene produced no serious adverse effects within the reported dose range, and was well tolerated by most MH-susceptible patients presenting myopathic symptoms. Our study provides dosing and adverse effect data as a basis for further randomized controlled clinical trials to determine the efficacy of oral dantrolene for symptomatic relief in MHS-related myopathies.

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“RYR1 and the cerebellum”: scientific commentary on “Defective Cerebellar Ryanodine Receptor Type 1 and Endoplasmic Reticulum Calcium ‘Leak’ in Tremor Pathophysiology”

Jungbluth,

Famili,

Helmich

et al. 2024

Acta Neuropathol

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Pre-operative exercise and pyrexia as modifying factors in malignant hyperthermia (MH)

Cited by 16 publications

References 40 publications

Neuromuscular symptoms in patients with RYR1-related malignant hyperthermia and rhabdomyolysis

Neuromuscular symptoms in patients with RYR1-related malignant hyperthermia and rhabdomyolysis

Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia–Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability

“RYR1 and the cerebellum”: scientific commentary on “Defective Cerebellar Ryanodine Receptor Type 1 and Endoplasmic Reticulum Calcium ‘Leak’ in Tremor Pathophysiology”

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