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For Pathologists

The forensic biology signature of excited delirium includes dysregulated dopamine transporters (hyperdopaminergic state), elevated heat shock proteins (hyperthermia), and immediate early gene activation as a marker of paranoid aggression (c-fos protein).

We validated analytical techniques and criteria to assist pathologic and forensic-medical diagnosis of sudden and unexpected excited delirium deaths associated with the use of less lethal technologies. The proposed technical approach is based on our ability to identify highly reliable surrogate markers of excited delirium in postmortem specimens from victims who die suddenly, often in police custody.

Dysregulated Dopamine Transporters and Hyperdopaminergic State

We have demonstrated that there is a defect in the regulation of the dopamine transporter in these victims (Staley et al., 1994;1995b; Wetli et al., 1996; Mash et al., 2002). The failure to upregulate the dopamine transporter with chronic cocaine abuse leads to a hyperdopaminergic state and this in turn, leads to the psychotic symptoms and hyperthermia. 

Excited delirum cases show lower levels of dopamine transporters (DAT) as shown in the figure below. In comparison to other cocaine abusers, there is a large reduction in number of DAT sites in brain. Cocaine-related excited delirum cases have the same concentration of cocaine in the brain as measured in other chronic abusers who die suddenly without evidence of preterminal delirum.
































Saturation binding curves for WIN 35,428 binding and dopamine uptake to the DAT in human striatum(Top Panel). Functional Dopamine uptake(Center and bottom panels) . Taken from Mash et al., 2002; 2008.


Hyperthermia and Elevated Heat Shock Proteins

A second reliable biomarker is the induction of heat shock genes in brain specimens from cases of cocaine-related excited delirium. We also observe similar elevations in cases of acute exhaustive mania. Using high throughput gene expression profiling, we observed elevated levels of some members of the heat shock protein family and immediate early gene transcripts (c-fos) in the amygdala of excited delirium victims. 















Heat shock proteins, also called stress proteins, are induced when the cell undergoes various forms of stress, including heat or cold (Sun and McRae, 2005).

Upregulation of heat shock proteins in excited delirium (ED) deaths. 

Since heat shock proteins are elevated in cases of increased temperature, this measure serves as a surrogate marker of hyperthermia (Mash et al., 2008). Hyperthemia occurs in most cases of excited delirium. However, often the forensic investigators fail to measure a core body temperature immediately after death, resulting in a critical piece of missed forensic evidence for assigning excited delirium as a cause of death. Thus, this measure provides a useful surrogate marker of hyperthermia for these in-custody death cases.

Abbreviations: CTRL, age-matched and drug-free controls; COC, cocaine fatalities without excited delirium; ED, excited delirium.

Paranoid Aggression and the c-fos Protein

Social defeat stress in aggressive confrontations, leads to functional activation of the immediate early gene c-fos in the amygdala, which contributes to a dysregulation of dopaminergic activity (Miczek et al., 2004). These observations provide the rationale for obtaining standardized reference values for dopamine transporter, heat shock proteins, and immediate early gene transcripts in cases of excited delirium, since the patterns differ between cocaine users who die with and without excited delirium.  Similar results have been observed in our laboratory for cases of sudden in custody deaths associated with methamphetamine abuse and for acute exhaustive mania.




Upregulation of immediate early genes demonstrate abnormal activation of amygdala circuits in excited delirium deaths.

The immediate early gene c-fos is regulated with a short time course of 2 - 6 hours, consistent with time course of the abnormal behavioral activation that occurs in victims of excited delirium.  Acute exposure to stress has been shown to activate c-fos expression in the amygala of the brain. The amygdala is a key brain region that modulates fear, vigilance, emotion and anxiety. 

Abbreviations: CTRL, age-matched and drug-free controls; COC, cocaine fatalities without excited delirium; ED, excited delirium.






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