State of the Art Topics on Malignant Hyperthermia Sheila Riazi, MSc, MD, FRCPC University Health Network, Toronto, Canada

Member, board of directors of MHAUS Member, international professional advisory council on MH Funded by NIH (NIAMS), CIHR, PSI, Ontario Ministry of Health & University of Toronto

Outline What all anesthesiologists need to know about MH (Pathophysiology, Epidemiology, and clinical care with new practice-changing knowledge) Current diagnostic tests for MH and dilemmas of genetic testing Phenotypic variability in MH susceptible patients

Pharmacogenetics disorder of skeletal muscle cells What is MH? Pharmacogenetics disorder of skeletal muscle cells Clinical incidence: 1 in 10,000 1 in 400 individuals carries a pathogenic mutation causing MH (Gonsalves et al, Anesthesiology, 2015) Variable Penetrance Morbidity >35% & mortality rate: 12-15% (Larach et al, Anesth & Analg 2010; Rosero et al Anesthesiology, 2009)

Why does MH occur?

When does MH occur? Fulminant: onset of full blown syndrome within minutes of induction of GA Indolent: more often with current volatile Visoiu et al, Anesth & Analg, 2014 Onset: Intra-operative: 175 (5-720) min PACU: 22.5 (5-72) min Riazi et al, Anesth & Analg, 2014

Increase in Intracellular Ca2+ Contracture (rigidity) Heat Excess lactate O2 consumption CO2 production Cell breakdown Hyperthermia (66.7%) Tachycardia (hypertension) (62.0%) Tachypnea/ inc MV Increase ETCO2 (51.9%) Rigidity: MMR (34.9%) or generalized (25.6%) Ventricular dysrrhythmia (22.5%) Skin mottling (17.1%) Riazi et al, Anesth & Analg, 2014

Importance of Temperature Monitoring The risk of dying from an MH episode has increased approximately 7 fold when compared to a previous cohort. (Larach et al, Anesth & Analg, 2014) Recommended to use temperature monitoring for cases beyond 30 minutes duration.

Treatment of MH crisis = Supportive (cooling down, hyperventilation and discontinuing the triggers) Dantrolene (2.5-10 mg/kg) = 36 Vials 3 Vials

Early Dantrolene Use With 20 minutes delay in dantrolene administration, complication rates increases to 30%, and delay of 50 minutes of longer results in 100% complication rate. (Riazi et al, Anesth & Analg, 2014)

Caffeine-Halothane Contracture Test (CHCT)

Normal response Abnormal response Calculated Value 95% CI Sensitivity 97% 84-100% Specificity 78% 69-85% Allen GC et al, 1998

CHCT Testing Centers in North America Toronto General Hospital
Malignant Hyperthermia Investigation Unit
 Uniformed Services University of the Health Sciences
Bethesda, MD (Military & Civilian)
 University of California Davis, CA
 University of Minnesota Minneapolis, MN Wake Forest Baptist Medical Center, Winston-Salem, NC

Fujii J, Otsu K, Zorzato F, de Leon S, Khanna VK, Weiler JE, Obrien PJ, MacLennan DH. Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science. 1991 Jul 26;253(5018):448-51.

Genetics of MH Current sensitivity is ~60% (Negative genetic screen cannot be diagnostic). There are 35 causative mutations listed for MH (www.emhg.org). Over 400 variants were identified in three involved genes (RYR1, CACNA1S, STAC3) with unknown functionality. Exome sequencing has been unsuccessful in identifying any other gene associated with MH. Our group has started different approach (linkage analysis and exome sequencing, as well genome sequencing).

Guideline for genetic testing of at risk patients Hopkins et al, BJA, 2015

Complex Genetics CGS: 73 0.3 1.2 Gly341Arg 0.0 1.7 0.9 3.2 Ø RYR1 0.1 Gen rigidity CK: 22000 Temp: 39.2 ETCO2:67 HR: 140 Myoglobinuria pH: 7.12

Phenotypic variability of MH patients Patients with possible MH reaction Family members of MHS patients. Others (referred by neurologists): Idiopathic hyperCKemia/myopathy >2 episodes of rhabdomyolysis Between 1992-2014, a total of 136 patients were referred for non-MH reasons and underwent CHCT testing (87/136). Idiopathic high CK (47/71) Heat or exercise induced rhabdomyolysis (9/15) High CK and rhabdomyolysis (2/3) Other reasons (unexplained myopathy, post infection rhabdomyolysis)

Non-reaction MH positive probands CHCT values were significantly lower compared to the patients with MH reaction. 31% of CHCT+ had at least one RYR1 variant (not polymorphism). Timmins et al, Anesthesiology 2015 CHCT+ non-reaction MH history Caffeine (g contracture), Mean (SD) 0.5 (0.8) 2.2 (2.0) Halothane (g contracture), Mean (SD) 2.3 (1.7) 4.0 (1.2)

Evidence in literature There is an association between MH and exertional or heat induced rhabdomyolysis: Various reports show 30-75% positive CHCT or genetics (RYR1 mutations) among the second group. (Figarella-Branger et al, 1993; Wappler et al, 2001; Dlamini et al, 2013; Fiszer et al, 2015)

MH susceptible patients with non anesthetic-induced rhabdomyolysis Kraeva et al, Can J Anesth, 2017

Metabolic dysfunction in anesthetic induced MH positive patients Thompson et al, Anesth & Analg, 2017, In Press

There was a negative correlation between Fatigue Index during the Wingate Test and OXPHOS ATP production rate during the 31P-MRS 30-second exercise bout (r=-0.392, p<0.05).

Summary and Conclusion MH still exists, and its prevalence contradicts the “rare disease” category, but variable penetrance significantly affects the incidence of the observed clinical events. Morbidity and mortality from MH has been increased in the past decade, partly because of delayed diagnosis and treatment. We still need to learn more about genetics of MH. With the current genetic knowledge, it is too complex to serve as reliable diagnostic test.

MH EHI RYR-1 myopathies Are there predictive factors in MHS that make them more sensitive to heat and exercise, or myopathic?

MHAUS Scientific Conference Save the Date September 23rd & 24th 2017 MHAUS Scientific Conference MALIGNANT HYPERTHERMIA: Risks & Associated Muscle Disorders