Most patients recover well after a period of hyperthermia, but patients exposed to higher temperatures for longer periods of time are more at risk of complications, which in extreme cases may progress to multi-organ failure and death. The risk may be significant; heatstroke, for example, is associated with a mortality rate of 40 % [
4] to 64 % [
2].
Patients who become acutely hyperthermic often display signs of neurological dysfunction. The neurological injury may manifest in several ways, including cognitive dysfunction, agitation, seizures, unsteadiness, or disturbance of consciousness from lethargy to coma. Neurological dysfunction in heatstroke is well described, and has been recognised since at least Roman times [
5]. Indeed, the presence of neurological dysfunction is required for the diagnosis of EHS in combination with hyperthermia. Cognitive dysfunction also happens quickly with hyperthermia and may take various forms.
Cognitive dysfunction
Cognition refers to mental abilities and processes, and includes memory, knowledge, attention, reasoning, problem solving, and comprehension. The precise anatomical location of each aspect is not known, and probably involves connections across numerous parts of the brain [
6] including the cerebellum [
7].
Hyperthermia, even if mild and only occurring for a short period, may cause cognitive impairment. In a few cases, this may be permanent. Hyperthermia has been shown to adversely affect attention [
8], memory [
9], and processing of information [
10] acutely. Some of the cognitive processes may be affected by hyperthermia more than others. Short-term memory processing, for example, may be more affected than attentional processes [
11].
Cognitive impairment may occur after exposure to more modest temperatures, and after shorter periods of time, than has previously been recognised. One study of induced hyperthermia in healthy volunteers showed that memory was impaired at a core temperature of only 38.8 °C compared with normothermia [
12]. Artificially induced hyperthermia may induce cognitive impairment after only 1 to 2 h of temperature elevation [
10,
13]. Cognitive changes may not occur immediately at the time of hyperthermic insult, but instead develop a short time (60–120 min) after the cessation of the insult [
13].
Functional neuroimaging supports there being a large number of pathways and connections in cognitive pathways, with many of these being affected acutely in hyperthermia. In general, connections appear to be increased around the limbic system [
14], consistent with the observed changes in memory and learning ability. The dorsolateral prefrontal cortex (involved in executive functions—for example, memory, cognition, and reasoning), and the intraparietal sulcus (involved in processing and memory) also show increased activity in acute cerebral hyperthermia [
15]. Conversely, connections in other parts of the brain, including the temporal, frontal and occipital lobes, appear to be reduced in acute hyperthermia [
14].
Hyperthermia-induced changes in short-term memory formation can also be detected using electroencephalography. The electrical response of the brain to a specific cognitive or sensory event is termed an ‘event-related potential’ (ERP). If the brain is subjected to a repeated identical sound, and then an alternate sound is introduced, the ERP is altered, termed ‘mismatch negativity’ (MMN). MMN has validity in studies into auditory memory formation. Subjects exposed to hyperthermia for as little as 1 h show significant decline in MMN compared with a control group [
10], consistent with clinical observations of a decline in short-term memory.
However, it is not clear whether hyperthermia per se is causing these acute cognitive changes, or if the heat is affecting changes through or in combination with other mechanisms. If hyperthermic subjects are kept well hydrated, cognitive impairment may be minimal, suggesting that some of the cognitive dysfunction is due to dehydration. Body weight loss of 1.0–1.5 kg has been reported in studies of cognitive change [
13], suggesting dehydration, and it is not clear what effect this has on the cognitive function.
While advancing age is associated with a reduced cognitive baseline, hyperthermia may not reduce function proportionately more than in younger people [
16]. While baseline accuracy and ability in attention, memory, and reaction was lower in older volunteers than younger, hyperthermia did not alter these reactions differently in the two groups.
In the majority of cases, patients recover fully from the acute cognitive dysfunction. Some, however, are left with persistent changes in attention, memory, or personality [
17]. These may be mild, or severe, up to and including severe global dementia. They have been reported after CHS [
18], EHS [
19], and drug-induced hyperthermia [
20,
21].
Neurological effects
Neurological manifestations of hyperthermia have been divided into three groups according to the time sequence in which they occur: the acute stage, the convalescent period, and the period of permanent deficits. The magnitude and the duration of the hyperthermia are thought to influence the development of neurological manifestations. In addition, genotypic and phenotypic differences in the physiological response to hyperthermia (for example, in the inflammatory response, or the induction of thermoprotective mechanisms) may also affect an individual’s risk of developing neurological deficits.
Acute deficits
Acute neurological deficits have been described after hyperthermia from a number of causes, including heat illness and drugs. Deficits are well recognised after CHS—in the acute phase, many patients have disturbance of consciousness up to and including deep coma. Of 87 patients with CHS after a Mecca pilgrimage, all had a reduced level of consciousness, and 25 (29 %) were deeply comatose [
22]. Constricted pupils were reported in all cases in this series, with 17 (20 %) showing automatisms, including chewing, swallowing, and lip smacking. Delirium, lethargy, disorientation, seizures, hypertonia, and hypotonia are also described [
23].
Acute neurological damage after drug-induced hyperthermia has been reported to result from malignant hyperthermia (MH) [
24] and neuroleptic malignant syndrome (NMS) [
20]. Most survivors of NMS recover completely, with a mean recovery time of 7–11 days [
20]; the incidence of long-term sequelae has been reported at 3.33 % [
21].
Persisting deficits
Neurological deficits that persist after the acute phase are well described. The incidence is difficult to discern; of 87 patients who developed CHS during the same Mecca pilgrimage, 75 (87 %) made a full recovery, 10 patients (11 %) died, and two (3 % of the survivors) recovered but developed pancerebellar syndrome [
22]. Of 36 patients with EHS, eight (22 %) died, two (7 % of the survivors) had cognitive impairment, and a further two (7 %) had neurological signs, one with paraplegia, and one with cerebellar disturbance [
17].
However, the mortality and morbidity after a severe episode may be more significant than these data suggest; if patients require admission to an ICU for management of hyperthermia, the mortality may approach 50 % to 65 % [
2,
25], and persistent neurological effects may affect 50 % of survivors [
25]. Early deaths are usually from multi-organ failure but, in one study, 50 % of the deaths were comatose or tetraplegic [
2]. In one series of patients admitted to ICU with CHS after a heatwave, 33 % had significant neurological impairment, and 33 % of patients had mild impairment at discharge. Only 24 % of patients had no neurological impairment [
23].
Persistent neurological deficits have been reported after CHS (the majority) and EHS. Cases after drug-induced hyperthermia are also reported, but are much rarer. Drugs known to cause hyperthermia and persistent neurological deficits include those responsible for neuroleptic malignant syndrome [
20,
26‐
29], and the serotonin syndrome [
30], and Chinese herbal medications [
31].
Cerebellar dysfunction is by far the predominant clinical picture in cases of persistent neurological dysfunction [
17,
18,
22,
25,
32‐
35]. Ataxia, dysarthria, and co-ordination problems are common; nystagmus is more rarely reported [
32]. Of the five reported cases of persistent neurological dysfunction after NMS, all showed cerebellar signs [
20,
26‐
29]. Less common is damage to the cerebral cortex [
34,
36], brain stem [
37], spinal cord [
17], and the peripheral nervous system [
25]. Frontal dysfunction is rare, but has been reported. Basal ganglia dysfunction is reported after heatstroke [
34], and is well recognised after NMS [
21,
38]; the latter may represent the effects of treatment in some patients rather than damage from hyperthermia. Clinical features are usually bilateral. Neurological dysfunction may be profound; a persistent vegetative state has been reported [
39]. Patients may show signs of improvement over weeks or months [
36] but, in some cases, it may persist for many months or years [
18]. Recovery may be minimal or absent [
33]. In the vast majority of these reported cases, a core body temperature of 40 °C or higher is recorded.
Hyperthermia after brain damage
Fever after brain injury is common, affecting over 70 % of patients after a traumatic brain injury (TBI) [
40] and in more than 50 % of patients after a subarachnoid haemorrhage (SAH) [
41]. In a proportion, the fever is related to the neurological injury rather than infection; non-infective fever may account for up to one third of cases of fever after a stroke and may affect over a third of patients after TBI [
42]. Development of a fever is associated with poor outcome; a fever worsens functional disability and mortality after a stroke [
43] and SAH [
44].
Adverse effects occur with only small changes in temperature; variations in the brain temperature of just 1 °C can critically affect the extent of secondary brain injury after a primary insult [
43]. Mortality after a stroke has been shown to increase at temperatures above 37.9 °C [
45], and with a temperature of above 38 °C following TBI [
46].