Commonly abused drugs 2421 Excited Delirium

Excited delirium is a drug-induced delirium or psychosis accompanied by agitation and hyperthermia, and often ending with respiratory arrest and sudden death. Cocaine is the drug most often implicated in this syndrome,13 but amphetamines have also been implicated in some cases. The syndrome is not due to any contaminants that may accompany the cocaine sample.

The pathogenesis of cocaine-induced excited delirium is unknown. One hypothesis is that cocaine initially elevates brain dopamine levels causing the delirium. This cocaine-induced

Table 2.4.2.1 Comparison Between Neuroleptic Malignant Syndrome and Cocaine-Induced Agitated Delirium

Symptom NMS

Hyperthermia ++

Delirium ++

Agitation +

Akinesia/rigidity ++

Cocaine delirium

++ = present in almost all cases; + = present in many cases; ± = may occur late during syndrome16

brain dopamine elevation has been demonstrated in animals.14 The syndrome is thought to be similar to the neuroleptic malignant syndrome (NMS) in Parkinson disease patients withdrawn from levodopa, a dopaminergic drug. Patients experience hyperthermia, autonomic instability, and delirium (see Table 2.4.2.1). NMS is characterized by diffuse muscular rigidity, but this is not seen in cocaine-induce excited delirium. One author has suggested that akinesia of the respiratory muscles may be the fatal mechanism of sudden death in these victims.16The neurochemical alterations underlying the cocaine-related syndrome have recently been characterized and are described in Chapter 6.

There are no specific gross or microscopic findings in victims dying of cocaine- induced agitated delirium. A postmortem core body temperature (if taken soon after death) will be elevated. A thorough postmortem examination is essential to rule out other causes of sudden death. Cocaine and its metabolites must be present in toxicology specimens. Victims dying of agitated delirium have postmortem blood cocaine concentrations (average = 0.6 mg/L with range of 0.14 to 0.92 mg/L) that are 10 times lower than those concentrations in cocaine overdose victims.17

Agitated delirium may occur following cocaine ingestion by all routes of administration (snorting, smoking, injection), except chewing coca leaves. The majority of victims are men. Soon after cocaine ingestion, the person becomes paranoid, delirious, and aggressive. The victim is often seen running, yelling, breaking glass and overturning furniture, disrobing, and hiding. Witnesses report that the person has unexpected strength. The victim often becomes calm and quiet before having a cardiopulmonary arrest, often during police custody or medical transport.

This disorder is frequently accompanied by sudden death. Restraint procedures that could compromise respiration should be avoided. The restrained person should be closely observed, especially after the agitation subsides.18

24.2.2 Cerebral Hemorrhage

Drug-induced cerebrovascular disease or stroke is any non-traumatic intracerebral hemorrhage (including subarachnoid hemorrhage) or cerebral infarction that results directly or indirectly from drug ingestion. An accurate clinical history and/or positive toxicologic testing corroborates the recent drug ingestion. Forty-seven percent of patients who are under 35 years old and present with an acute stroke have drug use as a predisposing condition.19 Clinically, a patient with cerebrovascular disease presents with sudden loss of function, neurologic deficit, and involvement of the corresponding vascular supply. If the blood vessel is occluded, ischemia and infarction occur. If the vessel is damaged, hemorrhage results.

Cocaine is frequently associated with intracerebral hemorrhage.20-23 Other stimulant drugs including amphetamine,19,24 phenylpropanolamine,25 phencyclidine,25 pseudoephedrine,25 and methylphenidate19,25 have been associated with intracranial hemorrhage.

Figure 2.4.4 There is an occlusive thrombus in the basilar artery of this 28-year-old cocaine addict.

Cocaine blocks the uptake of catecholamines at adrenergic nerve endings, thus potentiating sympathetic responses and causing a dose dependent elevation of arterial pressure and heart rate in humans26 and dogs.27 Amphetamines can also produce transient hypertension and tachycardia. Intracerebral hemorrhage is postulated to occur from a sudden marked elevation in systemic blood pressure in susceptible persons with pre-existing vascular malformations such as arteriovenous malformations, berry aneurysms, or Charcot- Bouchard microaneurysms in hypertensive individuals. Another postulated mechanism of intraparenchymal hemorrhage in cocaine users is acute increased cerebral blood flow into an area of ischemia produced by prior cocaine-induced vasoconstriction.28 Interestingly, intrauterine exposure to cocaine does not influence the prevalence or severity of intraventricular hemorrhage in the preterm infant.29

Cocaine can cause cerebral infarction by arterial thrombosis, arterial embolism, arterial spasm, and circulatory compromise with secondary cerebral hypoperfusion. In the latter case, cocaine can cause acute myocardial infarction or ventricular arrhythmia resulting in hypotension and secondary cerebral hypoperfusion.

The middle cerebral artery is most commonly affected with resulting sudden paraplegia.30 The anterior cerebral, posterior cerebral, and basilar/vertebral arteries can also be affected causing a variety of clinical signs and symptoms (Figures 2.4.4 and 2.4.5). Most victims develop symptoms suddenly within 3 hours of cocaine ingestion. Other victims wake up with the neurologic deficit after heavy drug use the previous evening.

The most common sites of cocaine-induced intracerebral hemorrhage are the cerebral hemispheres (57%) followed by the putamen (18%), and subarachnoid and intraventricular sites (Figure 2.4.6 and 2.4.7). Cocaine-induced subarachnoid hemorrhage is usually due to rupture of a pre-existing arteriovenous malformation or berry aneurysm of the cerebral arteries30 (Figure 2.4.8). In a recent retrospective study from San Diego, 21% of victims dying from ruptured berry aneurysms had cocaine or methamphetamine (or both) in their postmortem blood.31 This was higher than the 5% incidence of cocaine or methamphetamine intoxication in all adult autopsies from the same jurisdiction. If no vascular malformation is found to explain the subarachnoid hemorrhage in a drug addict, one must consider a traumatic cause for the subarachnoid hemorrhage (such as extracranial veretebral artery laceration)32 before ascribing it to cocaine or another stimulant. Intraparenchymal hemorrhage due to cocaine use can occur in sites typical of patients with hypertension-related intracerebral hemorrhage. The blood vessels, when examined, are usually normal grossly and microscopically.33 Charcot-Bouchard microaneurysms, typically seen in hypertensive cerebral hemorrhage,34 are not seen in drug-induced intracerebral hemorrhage.

Figure 2.4.5 There is an irregular zone of infarction in the basis pontis of the victim in Figure 2.4.4. He was found comatose at home.

Figure 2.4.6 This 35-year-old woman developed an acute intracerebral hematoma after cocaine use.
Figure 2.4.8 Subarachnoid hemorrhage in cocaine abusers is often due to a berry aneurysm that ruptures from the sudden blood pressure elevation caused by cocaine.

Patients are usually in their third to fifth decades of life with both men and women affected. Intracerebral hemorrhage occurs after snorting, smoking, or injecting cocaine. The time between drug use and symptom onset is usually within 3 hours, but can range from immediate to 12 hours. Most patients present with acute headache or are comatose. Confusion is a less frequent presenting symptom. There is a 36% mortality rate in patients who present to the emergency room with acute stroke strongly linked to recent drug use.19

2.4.2.3 Vasculitis

Cerebral vasculitis has been associated with cocaine and amphetamine use. The association between cerebral vasculitis and cocaine use is tenuous and only supported by a few (eight) case reports, some of which have only angiographic evidence ("beading" or segmental arterial narrowing) of vasculitis with no histologic confirmation (Table 2.4.2). The remaining case reports have histologic evidence of vasculitis but no angiographic narrowing or other abnormalities.37-40 Half of the victims presented with encephalopathy and coma without intracranial hemorrhage or infarction. The other half presented with intracerebral hemorrhage or cerebral infarction. Transient ischemic attacks (TIA) with multifocal segmental arterial stenoses on angiography have been reported in chronic cocaine users. All these patients were young (mean age = 28 years with age range = 22 to 36) with multiple routes of drug administration used (nasal insufflation, smoking, intravenous injection). Histologic examination demonstrated acute and chronic small vessel inflammation. Four cases had lymphocytic infiltration in the cerebral blood vessels. Two cases had polymorphonuclear leukocyte infiltration in the small arteries and venules of the brain. No giant cells or granulomas were seen in any case. The pathogenesis of cocaine-associated cerebral vasculitis remains unknown. Metamphetamine and structurally related drugs have reportedly caused necrotizing cerebral vasculitis.

2.4.2.4 Seizures

Drug-induced seizures are seizures that occur after the ingestion of a drug and are not caused by other pathologic processes (intracranial hemorrhage, blunt head trauma). The drug ingestion should be corroborated by an accurate clinical history or positive toxicology testing.

Cocaine has been reported to lower the threshold for seizures and commonly causes seizures.42 Also cocaine was the most common drug of abuse detected in one series of patients with seizure activity as the primary admitting diagnosis.43 In this series, cocaine was more likely to cause brief, self-limiting seizures compared to the other drugs of abuse (amphetamine, methamphetamine, phencyclidine, sedative-hyponotic withdrawal). Seizure initiation depends not only on binding with serotonin transporter sites but also brain muscarinic and sigma binding sites.44

There are no specific gross or microscopic neuropathologic findings in fatal cocaine-induced seizure victims. Tongue contusions are non-specific findings in patients who die of terminal seizures (Figure 2.4.9).

Cocaine-induced seizures are a common neurologic complication (2.3 to 8.4% of cocaine victims present with seizures to the emergency room)45 and affects both men and women.46 The average age is 27 years with a range of 17 to 42 years. Seizures occur after snorting, smoking, or injecting cocaine. The seizures are usually generalized, tonic- clonic, isolated, and self-limiting. They usually last less than 5 minutes and can occur with first-time and chronic cocaine users. The interval between cocaine ingestion and seizure onset varies from minutes to 12 hours. In one emergency room study, 1 of 137 patients (8%) with cocaine intoxication presented with seizures as their chief problem and none died.45

Table 2.4.2.2 Reported Cases of Cocaine-Associated Vasculitis

Age/

Clinical

Time

Report

Kaye, 1987

Klonoff,

1989 Krendel,

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