Referral Indications for Malignant Hyperthermia Susceptibility Diagnostics in Patients without Adverse Anesthetic Events in the Era of Next-generation Sequencing

Abstract

Background The introduction of next-generation sequencing into the diagnosis of neuromuscular disorders has resulted in an increased number of newly identified RYR1 variants. We hypothesize that there is an increased referral of patients to Malignant Hyperthermia (MH)-units without a personal/family history of adverse anesthetic events suspected for MH. This retrospective multicenter cohort study evaluates patient referral indications and outcomes for those without a history of an adverse anesthetic event. Methods Patients referred between 2010-2019 to the MH-units in Antwerp, Lund, Nijmegen and Toronto were included. Previously tested patients and relatives of previously tested patients were excluded. Data collection included demographics, referral details, muscle contracture and genetic testing results including REVEL scores. Referral indications were categorized into those with a personal/family history of adverse anesthetic event and other indications including exertional and/or recurrent rhabdomyolysis, RYR1 variant(s) detected in diagnostic testing in the neuromuscular clinic without a specific diagnosis (in a family member), diagnosed RYR1-related myopathy (in a family member), idiopathically elevated resting creatine kinase values, exertional heat stroke and other. Results A total of 520 medical records were included, with the three most frequent referral indications; personal history of an adverse anesthetic event (211/520; 40.6%), family history of an adverse anesthetic event (115/520; 22.1%), and exertional and/or recurrent rhabdomyolysis (46/520; 8.8%). The proportion of patients referred without a personal/family history of an adverse anesthetic event increased to 43.6% (133/305) between 2015-2019 compared to 28.4% (61/215) in 2010-2014 (P<0.001). Patients with a personal/family history of an adverse anesthetic event were more frequently diagnosed as MH susceptible (133/220; 60.5%) than those without (47/120; 39.2%), (P < 0.001). Due to missing data, 180 medical records were excluded. Conclusion The proportion of patients referred to MH-units without a personal/family history of an adverse anesthetic event has increased, with 39.2% (47/120) diagnosed as MH susceptible.

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

“… 1 RYR1 variants also account for a substantial proportion of patients presenting with episodic phenotypes such as exertional rhabdomyolysis 2–4 (ERM) and malignant hyperthermia (MH). 5 , 6 MH is a pharmacogenetic disorder that clinically manifests as a potentially life-threatening hypermetabolic reaction after exposure to volatile anaesthetics or succinylcholine in MH susceptible individuals. 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.…”

“…Based on previous preliminary observations 2 , 6 , 11 , 12 , we hypothesized that patients with a history of RYR1 -related MH susceptibility and/or ERM frequently do have neuromuscular symptoms in between MH and/or ERM episodes. This prospective, cross-sectional, observational clinical study aimed to study neuromuscular symptoms and the healthcare burden caused by such symptoms in patients with a history of RYR1 -related MH susceptibility and/or ERM.…”

European Neuromuscular Centre consensus statement on anaesthesia in patients with neuromuscular disorders

“…Volatile anaesthetics are only strictly contraindicated in patients with NMDs with variants in the RYR1 gene because of the possibility of MH susceptibility [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ], unless the specific variant has been classified as benign for MH according to the ClinGen Variant Curation Expert Panel recommendations for RYR1 pathogenicity classifications in MH susceptibility [ 51 ]. Patients with variants in the CACNA1S and/or STAC3 genes should be referred to an MH investigation centre for advice on the risk of MH before exposure to volatile anaesthetics.…”

“…The following considerations may be helpful: Infants with congenital myopathies, the group at risk for MH [ 45 , 46 , 49 , 50 ], and X‐linked muscular dystrophies due to variants in the dystrophin gene, the group at risk for AIR [ 33 , 34 ], usually have delayed motor milestones, but cognitive development is usually normal [ 19 , 20 , 49 , 88 ]. Infants with hypotonia due to a metabolic disease, the group at risk for propofol infusion syndrome [ 54 , 55 , 56 ], usually present with global developmental delay or other neurological signs, for example, epilepsy and spasticity [ 22 , 91 , 92 ].…”

“…Infants with congenital myopathies, the group at risk for MH [ 45 , 46 , 49 , 50 ], and X‐linked muscular dystrophies due to variants in the dystrophin gene, the group at risk for AIR [ 33 , 34 ], usually have delayed motor milestones, but cognitive development is usually normal [ 19 , 20 , 49 , 88 ].…”