Differential Diagnosis in Neurology

Topic 12. Muscle Disease

12.10. Malignant Hyperthermia

  • Genetics: (3 syndromes):
    • Syndrome I:
      • Mutation of the RYR1 gene
      • Located on chromosome 19q 13.1
      • Linkage to this location occurs most commonly in patients
    • Syndrome II:
      • Chromosome 17q 11.6–q24 (mutation)
      • Mutation is close to a subunit of the sodium channel
    • Syndrome III:
      • Chromosome 7q21–q22 (disease locus)
      • CACNL2A (mutation locus):
        • L-Type dihydropteridine (DHP) receptor voltage gated calcium channel
    • Syndrome IV:
      • Chromosome 3q13.1 (disease mutation locus)
    • Syndrome V:
      • Chromosome 1q31–q32 (mutation)
      • Mutation is in a subunit of the DHP calcium channel receptor (CACNL1A3)
    • Syndrome VI:
      • Mutation is on chromosome 5
  • Central core disease:
    • Allelic to MH
    • Attacks are similar to the genetic forms of the disease
    • Pathogenesis is the same
  • MH-like attacks are reported in different myopathies:
    • Clinical features of these attacks:
      • Muscle rigidity during anesthesia due to excessive muscular depolarization
      • Increased cytosolic calcium levels
    • Specific myopathies that are associated with MH-like episodes:
      • Myotonia congenita
      • Dystrophinopathies
      • Myotonic dystrophy
      • Brodie's disease
      • Phosphorylase deficiency
      • Multicore disease
      • Periodic paralysis
      • Carnitine palmityl transferase deficiency
      • King–Denborough syndrome:
        • Short stature
        • Undescended testicle
        • High-arched palate
        • Kyphosis, lordosis, scoliosis
        • Pectus carinatum
        • Small chin, low set ears
      • Evans myopathy:
        • Proximal muscle weakness and wasting
        • Sporadic muscle hypertrophy (individual muscles)
        • Ptosis
        • Elevated CK
        • Non-specific muscle biopsy findings
  • Clinical features of malignant hyperthermia:
    • Triggered by any volatile agent:
      • Halothane
      • Succinylcholine (onset more abrupt)
    • Body temperature rises quickly with anesthesia:
      • May exceed 109 degrees Fahrenheit
    • Temperature usually drops 1–2 degrees at the start of anesthesia in normal persons
    • Arterial blood carbon dioxide tension greater than 100 mm Hg; severe cyanosis
    • Arterial blood pH may fall to a pH of less than seven
    • Tachycardia
    • 75% of patients demonstrate muscle rigidity during acute MH:
      • Contractures not contractions occur
      • May progress to rigor and death
      • Increased permeability of muscle with:
        • Increased serum K+
        • Increased ionized calcium
        • Increased CK (to 100,000 units)
        • Total calcium may be increased
        • Myoglobulin release with myoglobinuria
        • Marked muscle edema
        • CK returns to normal in approximately two weeks
    • Rarely an attack may begin post operatively
  • Muscle biopsy of susceptible patients:
    • Normal in some patients
    • Non-specific findings:
      • Internal nuclei
      • Moth eaten fibers
      • Super contracted myofibrils
      • Target fibers
      • Necrosis and regeneration
      • Mitochondrial alternations
      • Inclusion bodies
  • Contracture of prepared skeletal muscle to:
    • Halothane
    • Caffeine
    • Release of ionized calcium from the endoplasmic reticulum triggered by ryanodine receptors
  • Associated clinical findings:
    • Cardiac involvement during MH:
      • Tachycardia, dysrhythmia
      • Hypotension
      • Decline of cardiac output
      • Cardiac arrest
      • Fivefold increase in myocardial O2 utilization; 8 fold decrease of myocardial efficiency; sympathetically mediated
      • Other cardiac manifestations:
        • Sudden death
        • Cardiomyopathy (non-specific)
        • Abnormal thallium cardiac scans
    • Central nervous symptoms:
      • Secondary to:
        • Increased temperature
        • Acidosis
        • Hyperkalemia
        • Hypoxia
      • Coma
      • Areflexia
      • Cerebral edema
      • Sympathetic nervous system role in maintenance or initiation of MH is controversial

Pharmacologic Agents that Initiate MH

Depolarizing agents

  • Succinylcholine increases:
    • Temperature
    • O2 Consumption
    • Lactate production
    • In conjunction with volatile anesthetic provokes fulminant MH
  • Clinical features:
    • Exaggerated fasciculations
    • Muscle rigidity
    • Trismus early (not always present)
    • Muscle rigidity may occur

Alternate Responses to Succinylcholine

  • Muscle contracture (asymptomatic)
  • Change in muscle membrane permeability with contracture causes:
    • Myoglobinuria
    • Increased CK release
    • May occur in non-susceptible patients
    • Increased by halothane
    • Decreased by d-tubocurarine

Non-Depolarizing Muscle Relaxants

  • Non-depolarizing relaxants
    • Delay or attenuate the effects of halothane
  • Effects are reversed by cholinergic agonists

Dantrolene Administered for MH Event

  • Decreases sarcoplasmic calcium release
  • Decreases abnormal contracture responses in isolated muscle
  • Controls metabolic imbalances (acidosis, increased ion fluxes, sympathetic overactivity)
  • High doses produces muscle weakness
  • Prolonged use may cause hepatic dysfunction

Hyperthermic Episodes Unrelated to Anesthesia

  • In humans MH is overwhelming triggered by anesthetic agents
  • Associated conditions unrelated to anesthesia:
    • Unexplained sudden death in susceptible families
    • Susceptible patients may develop nonspecific cardiomyopathy
    • Febrile episodes for years
    • Stress
    • Exercise

Differential Diagnosis of Malignant Hyperthermia

The diagnosis of malignant hyperthermia is relatively straight forward. A volatile anesthetic agent or succinylcholine used during induction of anesthesia causes an elevation rather than depression of temperature, tachycardia, masseter rigidity, increase in end tidal CO2 and acidosis.

Suspicion of malignant hyperthermia should be raised if a family member of the patient has died or had a major complication during uncomplicated anesthesia. An increased resting CK in a patient with an affected family member is also a clue that the individual is at risk. Baseline CK may be normal in MH patients. The congenital myopathies, muscular dystrophies, phosphorylase deficiency, carnitine palmityl transferase deficiency and periodic paralysis have all been implicated in MH or a MH-like syndrome. Rarely familial malignant hyperthermia occurs.

Differential Diagnosis of Uncontrolled Metabolic State of Abrupt Onset

  • Rhabdomyolysis:
    • Anesthetic agents
    • Drug induced
  • Exercise
  • Acute intermittent porphyria
  • Ketamine induced catatonia
  • Thyroid storm:
    • Precipitated by surgery
    • Anesthetics
  • Hyperkalemia following succinylcholine
  • Agents and illnesses that have produced MH responses in humans:
    • Ketamine
    • Phencyclidine
    • Viral infections
    • Lymphoma
    • MAO inhibitors
    • Tranquilizers
    • Tricyclic antidepressants
  • Malignant neuroleptic syndrome
    • Higher doses of neuroleptics trigger the illness; occasionally it is idiosyncratic
    • Clinical syndrome:
      • High fever
      • Rigidity
      • Coma
      • Tachycardia
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