Walter and Carraretto Critical Care (2016) 20:199 DOI 10.1186/s13054-016-1376-4 REVIEW Open Access The neurological and cognitive consequences of hyperthermia Edward James Walter* and Mike Carraretto Abstract Non-infective causes of hyperthermia include heat ill- ness and drug-induced hyperthermia. Heatstroke is the An elevated temperature has many aetiologies, both most severe form of heat illness, and is of two forms: infective and non-infective, and while the fever of sepsis Classical heatstroke (CHS) occurs after exposure to ex- probably confers benefit, there is increasing evidence treme environmental conditions; for example, in heat that the central nervous system is particularly vulnerable waves. Exertional heatstroke (EHS) may occur after to damage from hyperthermia. A single episode of strenuous physical activity, and may be seen in endur- hyperthermia may cause short-term neurological and ance athletes, the military, and others. Hyperthermia is cognitive dysfunction, which may be prolonged or associated with a number of pharmaceutical agents. Im- become permanent. The cerebellum is particularly mediate cooling is the mainstay of treatment, with a intolerant to the effects of heat. Hyperthermia in the delay in a reduction in the temperature associated with presence of acute brain injury worsens outcome. The increased mortality [2]. In CHS, cooling to below 38.9 ° thermotoxicity involved occurs via cellular, local, and C within 60 min is associated with a trend towards im- systemic mechanisms. This article reviews both the proved survival [3]. Further discussion on treatment is cognitive and neurological consequences and examines outside the scope of this review and is the subject of a the mechanisms of cerebral damage caused by high separate review in this series. temperature. The neurological and cognitive sequelae of elevated Keywords: Brain injury, Fever, Hyperthermia, Cognition, temperature on the brain may be marked during the ini- Cerebellum tial event and also persist to a much later stage or re- main permanent despite fever resolution. In this article, we briefly review the cognitive and neurological effects Background of hyperthermia on the brain, and examine some of the An elevated temperature by whatever cause, infective or proposed mechanisms by which cerebral damage is non-infective, affects many organ systems of the body, caused. sometimes with damage which is irreversible, and may lead to death. A temperature of 37.5 °C or greater at any point during an admission to the intensive care unit Clinical patterns (ICU) trends towards a worse outcome, and becomes Most patients recover well after a period of hyperther- significant at temperatures greater than 38.5 °C [1]. mia, but patients exposed to higher temperatures for There is emerging evidence that the central nervous sys- longer periods of time are more at risk of complications, tem is especially vulnerable to hyperthermia, particularly which in extreme cases may progress to multi-organ fail- if prolonged or excessive. Only in sepsis is there a likeli- ure and death. The risk may be significant; heatstroke, hood that some levels of temperature elevation may af- for example, is associated with a mortality rate of 40 % ford teleological benefits leading to a survival benefit, [4] to 64 % [2]. but once the temperature rises above 40 °C it is once Patients who become acutely hyperthermic often dis- again associated with a worse outcome [1]. play signs of neurological dysfunction. The neurological injury may manifest in several ways, including cognitive dysfunction, agitation, seizures, unsteadiness, or disturb- ance of consciousness from lethargy to coma. Neuro- * Correspondence: [email protected] Department of Intensive Care Medicine, Royal Surrey County Hospital, logical dysfunction in heatstroke is well described, and Egerton Road, Guildford, Surrey GU2 7XX, UK has been recognised since at least Roman times [5]. © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Walter and Carraretto Critical Care (2016) 20:199 Page 2 of 8 Indeed, the presence of neurological dysfunction is re- compared with a control group [10], consistent with quired for the diagnosis of EHS in combination with clinical observations of a decline in short-term memory. hyperthermia. Cognitive dysfunction also happens quickly However, it is not clear whether hyperthermia per se is with hyperthermia and may take various forms. causing these acute cognitive changes, or if the heat is af- fecting changes through or in combination with other Cognitive dysfunction mechanisms. If hyperthermic subjects are kept well hy- Cognition refers to mental abilities and processes, and drated, cognitive impairment may be minimal, suggesting includes memory, knowledge, attention, reasoning, prob- that some of the cognitive dysfunction is due to dehydra- lem solving, and comprehension. The precise anatomical tion. Body weight loss of 1.0–1.5 kg has been reported in location of each aspect is not known, and probably in- studies of cognitive change [13], suggesting dehydration, volves connections across numerous parts of the brain and it is not clear what effect this has on the cognitive [6] including the cerebellum [7]. function. Hyperthermia, even if mild and only occurring for a While advancing age is associated with a reduced cog- short period, may cause cognitive impairment. In a few nitive baseline, hyperthermia may not reduce function cases, this may be permanent. Hyperthermia has been proportionately more than in younger people [16]. While shown to adversely affect attention [8], memory [9], and baseline accuracy and ability in attention, memory, and processing of information [10] acutely. Some of the cogni- reaction was lower in older volunteers than younger, tive processes may be affected by hyperthermia more than hyperthermia did not alter these reactions differently in others. Short-term memory processing, for example, may the two groups. be more affected than attentional processes [11]. In the majority of cases, patients recover fully from Cognitive impairment may occur after exposure to the acute cognitive dysfunction. Some, however, are left more modest temperatures, and after shorter periods of with persistent changes in attention, memory, or person- time, than has previously been recognised. One study of ality [17]. These may be mild, or severe, up to and in- induced hyperthermia in healthy volunteers showed that cluding severe global dementia. They have been reported memory was impaired at a core temperature of only after CHS [18], EHS [19], and drug-induced hyperther- 38.8 °C compared with normothermia [12]. Artificially mia [20, 21]. induced hyperthermia may induce cognitive impairment after only 1 to 2 h of temperature elevation [10, 13]. Neurological effects Cognitive changes may not occur immediately at the Neurological manifestations of hyperthermia have been time of hyperthermic insult, but instead develop a short divided into three groups according to the time sequence time (60–120 min) after the cessation of the insult [13]. in which they occur: the acute stage, the convalescent Functional neuroimaging supports there being a large period, and the period of permanent deficits. The magni- number of pathways and connections in cognitive path- tude and the duration of the hyperthermia are thought to ways, with many of these being affected acutely in hyper- influence the development of neurological manifestations. thermia. In general, connections appear to be increased In addition, genotypic and phenotypic differences in the around the limbic system [14], consistent with the ob- physiological response to hyperthermia (for example, in served changes in memory and learning ability. The the inflammatory response, or the induction of thermo- dorsolateral prefrontal cortex (involved in executive func- protective mechanisms) may also affect an individual’srisk tions—for example, memory, cognition, and reasoning), of developing neurological deficits. and the intraparietal sulcus (involved in processing and memory) also show increased activity in acute cerebral hyperthermia [15]. Conversely, connections in other parts Acute deficits of the brain, including the temporal, frontal and occipital Acute neurological deficits have been described after lobes, appear to be reduced in acute hyperthermia [14]. hyperthermia from a number of causes, including heat Hyperthermia-induced changes in short-term memory illness and drugs. Deficits are well recognised after formation can also be detected using electroencephalog- CHS—in the acute phase, many patients have disturb- raphy. The electrical response of the brain to a specific ance of consciousness up to and including deep coma. cognitive or sensory event is termed an ‘event-related Of 87 patients with CHS after a Mecca pilgrimage, all potential’ (ERP). If the brain is subjected to a repeated had a reduced level of consciousness, and 25 (29 %) were identical sound, and then an alternate sound is intro-