All three diseases feature autonomic instability, which can include signs like fever, tachycardia, hypertension, and diaphoresis.
All three diseases also present with muscle rigidity, although the extent varies by disease. For example, the rigidity in neuroleptic malignant syndrome is often severe and “lead pipe”, while the rigidity in serotonin syndrome is less so.
Malignant hyperthermia patients have a genetic predisposition due to mutations in skeletal muscle ion channels. Ryanodine receptor 1, coded by the RYR1 gene, is a commonly affected calcium channel that controls calcium release from the sarcoplasmic reticulum. Mutations in this channel result in excessive calcium accumulation within muscle cells after exposure to anesthetics or succinylcholine.
A common trigger for malignant hyperthermia is inhaled anesthetics given during surgery, such as halothane and isoflurane. Therefore, suspect malignant hyperthermia if a post-surgical patient develops the acute onset of autonomic symptoms and muscle rigidity.
Succinylcholine is a depolarizing neuromuscular blocking agent often used during procedures to paralyze muscles and facilitate intubation. In myocytes with mutated calcium channels, however, succinylcholine will trigger excess calcium release and lead to malignant hyperthermia.
Dantrolene is the treatment for malignant hyperthermia. It directly inhibits the ryanodine receptor in myocytes, thereby preventing calcium release from the sarcoplasmic reticulum of muscle cells.
Neuroleptic malignant syndrome occurs after prolonged exposure to antidopaminergic medications. This dopamine blockade can lead to both nervous system and musculoskeletal dysfunction. Antipsychotics like haloperidol, fluphenazine, clozapine, and risperidone are common causes. Antiemetics that are dopamine antagonists can also cause it, like metoclopramide or promethazine.
Neuroleptic malignant syndrome (NMS) presents with extreme muscle rigidity and hyporeflexia. The decreased reflexes are key in differentiating between NMS and serotonin syndrome since serotonin presents with increased reflexes. Additionally, the muscle rigidity in NMS is often extreme and “lead pipe”, whereas rigidity is less severe in serotonin syndrome.
Because NMS is associated with such extreme muscle rigidity, muscle breakdown often occurs, releasing creatine kinase and myoglobin into the bloodstream. Myoglobinuria occurs when the kidneys filter myoglobin into the urine and can lead to acute renal failure. Labs will show increased creatine kinase.
Similar to its use in malignant hyperthermia, dantrolene can treat NMS by directly acting on skeletal calcium channels and preventing release of calcium from the sarcoplasmic reticulum. Bromocriptine, a dopamine agonist, is another medication used to directly counteract the effects of antidopaminergics. Lastly, the causative medications should be discontinued.
Serotonin syndrome is caused by excess serotonin levels from serotonergic medications that increase the levels of the neurotransmitter. There are many medications that can cause this, and combining them increases the risk. Implicated medications include psychiatric meds like SSRIs (eg., sertraline, escitalopram), MAOIs (eg., selegiline, phenelzine), SNRIs, or tricyclic antidepressants (TCAs). Other serotonergic medications include ondansetron, triptans, and linezolid.
Serotonin syndrome patients will exhibit fast, brisk reflexes, termed hyperreflexia. This is in contrast to neuroleptic malignant syndrome, which has hyporeflexia.
Serotonin syndrome is characterized by neuromuscular hyperactivity, which differentiates it from neuroleptic malignant syndrome and malignant hyperthermia, which lack these features. Neuromuscular hyperactivity can include clonus (involuntary muscle twitches), as well as ataxia and tremors.
Cyproheptadine is a direct antiserotonergic agent with antihistamine and anticholinergic properties as well. It will provide antagonism at serotonin receptors, counteracting the effects of the serotonergic medications that caused the syndrome.
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