No Cause for Ecstasy

By Lewis Nelson, MD

A 22-year-old man was brought to the emergency department after falling in the bathroom. His roommates reported that the patient had a seizure, although it is unclear if the fall was the cause of his seizure or a sequela. The previous night the patient had gone to a dance club, where he had "had a few drinks" and may have used recreational drugs. His vital signs in the emergency department were normal; he was awake but lethargic.

An electrocardiogram, pulse oximetry, fingerstick glucose, and computed tomography (CT) of the head were normal. The patient's laboratory values revealed a serum sodium of 120 mEq/L, a serum osmolality of 245 mOsm/L, and a urine osmolality of 491 mOsm/L. After the patient was inadvertently given intravenous 0.9% sodium chloride, his serum sodium fell to 107 mEq/L. Infusion of 3% hypertonic saline improved his serum sodium level and mental status. Medical history was negative.

 
POSSIBLE ETIOLOGIES OF SEIZURE

The differential diagnosis of a drug-induced seizure is lengthy, involving common and treatable causes of seizure such as hypoglycemia. In particular, the possibility of ethanol-induced hypoglycemia should be considered and assessed. Although profound ethanol intoxication is associated with seizures, such cases are uncommon. Ethanol withdrawal seizures, sometimes termed "rum-fits," are common in an emergency department population but unlikely in a patient of this young age. Such seizures typically begin 12 to 24 hours following the last drink. (Although self-limited, they are generally treated with benzodiazepines to prevent the development of delirium tremens.)

Many other drugs are commonly available at dance clubs and several are prominently associated with seizures. Heroin or other opioids occasionally produce hypoxia-related seizures, which occur due to the profound respiratory depressant effects of these drugs. This patient's normal pulse oximetry and respiratory rate rule that out, however. Gamma-hydroxybutyrate (GHB) and its precursors, gammabutyrolactone and butanediol, are used by dance club patrons as euphoriants and sedatives. Excessive dosing of GHB rapidly produces coma. Seizures occur occasionally although their mechanism is not yet fully defined. Gamma-hydroxybutyrate is very rapidly metabolized and the clinical effects would not be expected to persist the following morning, but withdrawal from GHB and its congeners may cause seizures.

Ketamine, a dissociative anesthetic agent, has a modest but growing following among club patrons for its clinical effects, which are often described as dysphoric rather than euphoric. It is likely that ketamine-induced seizures are rare since the drug has prominent anticonvulsant activity mediated by antagonism of the excitatory neurotransmitter glutamate.

Cocaine use can cause seizures by direct pharmacologic means, such as sodium channel blockade, or by causing cerebrovascular ischemia or hemorrhage. However, this patient's normal vital signs essentially eliminate acute cocaine intoxication as a diagnostic possibility. Evaluation for intracranial complications of cocaine use requires further evaluation.

Methamphetamine similarly produces dramatic alterations in users' vital signs. It is less frequently associated with seizures since it lacks the sodium channel effects of cocaine. Methylenedioxymethamphetamine (MDMA), or ecstasy in street argot, is an amphetamine derivative with a duration of effect of approximately six hours. At dance clubs, where it is widely used, patrons under the influence dance continuously until the drug's euphoric effects subside.

 
MANAGING DRUG-INDUCED SEIZURES

Seizures should be rapidly brought under control to prevent the development of life-threatening complications such as hyperthermia, hypoxia, or rhabdomyolysis. Glucose and oxygen should be administered as needed. The optimal method for terminating an unrelenting seizure is the intravenous administration of a benzodiazepine—in practice, usually either diazepam or lorazepam. Patients with suspected poisoning whose seizures remain refractory to these interventions should receive 5 grams of intravenous pyridoxine to deal with the possibility of isoniazid poisoning. Continuing seizure activity may require administration of a barbiturate (preferably a rapidly acting agent such as pentobarbital).

During or immediately following the termination of a seizure, patients should be assessed for hyperthermia and ventilatory status and an attempt should be made to determine the etiology of the seizure. Most patients with new-onset seizures for which no reversible etiology has been identified should have an assessment of their glucose and electrolytes in addition to a cranial CT. The exact timing of these tests is controversial, but they should be performed as promptly as possible.

 
EFFECTS OF MDMA

As a derivative of amphetamine, MDMA shares many of the parent agent's pharmacologic and clinical properties. Amphetamines enhance the release of biogenic amines (norepinephrine, dopamine, and serotonin) mainly by altering their presynaptic vesicular packaging. However, MDMA is less active than methamphetamine at potentiating norepinephrine release and is associated with dramatically less autonomic stimulation. Importantly, MDMA—perhaps due to its double-ring structure—has more pronounced effects on serotonin release than methamphetamine. Clinically, this translates into more profound psychedelic effects, including distortions and illusions. But despite its categorization as a hallucinogenic amphetamine, MDMA does not produce overt hallucinations. Rather, it produces an elevation in the user's mood and sense of well-being. Psychotherapists have attempted to enhance the therapeutic relationship through the use of MDMA as an "entactogen," or an agent that enhances introspection.

However, these attractive psychoactive serotonergic effects of MDMA are not without a price. In both animal models and human subjects, the habitual use of MDMA produces demonstrable neuronal toxicity that likely relates to the excitatory effects of serotonin. Although only beginning to be defined, chronic MDMA use risks this loss of serotonergic neurons with resultant alterations in cognition, mood, sleep, and memory. Each of these brain processes utilizes serotonin. The acute adverse effects include life-threatening hyperthermia and its sequelae, and this presentation may actually represent a form of the serotonin syndrome.

Furthermore, and particularly relevant to this case, serotonin is the neurotransmitter intimately related to the regulation of antidiuretic hormone (ADH) release. When serotonin is overabundant, excessive release of ADH may produce the syndrome of inappropriate ADH (SIADH), the most important consequence of which is hyponatremia. This syndrome may be aggravated or masked by exercise-induced loss of intravascular volume (as from dancing), which also causes ADH release and confounds the differentiation of SIADH from appropriate ADH release. Moreover, hyponatremia may be intensified by repletion of salt and water losses with water or other nonelectrolyte solutions.

Management of SIADH must emphasize volume restriction, since saline administration generally worsens the hyponatremia. In the presence of life-threatening complications of hyponatremia, such as status epilepticus, sufficient hypertonic saline to raise the serum sodium above 120 mEq/L is beneficial. In patients with volume depletion, repletion of intravascular volume with normal saline may be appropriate. Based on his adverse response to normal saline, this patient likely had true SIADH