Discussion
Hyperthermia is a potentially dangerous condition that can cause severe multiple organ failure, including brain damage (1) . Hyperthermia should quickly be suspected in patients who collapse on hot days, especially if there are factors involved that would impede cooling (2) . Our case report illustrates the vulnerability of the brain to high temperatures and shows that diagnosis can be difficult in the first hours and days (1, 3, 4) .
To improve the prognosis after heat stroke, the most important treatment is rapid cooling, intravenous fluids and treatment of complications (2) . Our patient did not undergo active cooling upon arrival, but he was admitted to hospital, where the temperature was markedly lower than outside, and quickly received adequate fluid therapy and intensive care.
Heat stroke was not considered as a diagnosis initially, as the patient's high temperature and unconsciousness on arrival raised suspicion of sepsis and possible meningitis. Additional tests revealed no signs of infection, and by the time heat stroke became a pertinent diagnosis, the patient's body temperature had already decreased spontaneously. The patient was unconscious on arrival and was promptly placed on respiratory support. The extent of his brain damage therefore remained unknown until he regained consciousness one week later.
Hyperthermia is defined as a core body temperature above 37.5 ºC, and arises due to inadequate thermoregulation (1, 4, 5) . Symptoms of hyperthermia include varying degrees of tachycardia, hyperventilation, hypotension, feelings of loss of strength/weakness, nausea and dizziness.
A body temperature above 40 ºC is classified as severe hyperthermia, and is accompanied by an increase in both oxygen demand and metabolic rate. Blood is shunted from the internal organs to the skin and muscles. There is also a risk of gastrointestinal ischaemia. A core body temperature above 40 °C, together with symptoms of central nervous system dysfunction, is classified as heat stroke . The most common symptoms of heat stroke are altered mental status, slurred speech, agitation, inappropriate behaviour, impaired coordination, delirium, seizures and coma.
Common complications of severe hyperthermia are acute respiratory failure, disseminated intravascular coagulation, acute renal failure, rhabdomyolysis, acute liver failure, hypoglycaemia, arrhythmias, cardiac dysfunction, seizures and damage to brain tissue. The prognosis is very variable. The mortality rate is 21–63%, depending on the degree to which body temperature is elevated, the time before cooling and the number of organ systems affected. Recommended treatment is removal of clothing, application of a cooling blanket, and provision of cool drinks or cool intravenous fluids (4) .
Hepatocytes, vascular endothelial cells and neurons, particularly in the cerebellum (3) , are highly sensitive to hyperthermia. In severe cases, such as in the current case report, multiple organ failure, disseminated intravascular coagulation and cerebral/cerebellar long-term effects may occur.
Body temperature is normally maintained within a tightly controlled range (Fig. 1), and the body's total heat load is due to a combination of metabolic processes and absorption of heat from the environment. Upon an increase in core body temperature, the preoptic nucleus of the anterior hypothalamus will stimulate efferent fibres in the autonomic nervous system to trigger both sweating and cutaneous vasodilation. Individuals will also typically change their behaviour by minimising skeletal muscle use, withdrawing to a cooler environment and removing items of clothing.
Figure 1 The hypothalamus sends signals to arterial smooth muscle, the sweat glands, smooth muscle surrounding hairs in the skin, skeletal muscles, the adrenal glands, and the thyroid gland to raise or lower the body temperature
Evaporation through the skin is the most effective way of regulating body temperature in warm environments (1, 2, 4) . Our patient engaged in physical labour while wearing whole-body rubber overalls on a very hot day, which generated both internal and external heat as well as preventing evaporation through the skin.
The patient had a very high core body temperature, fully at the limit of what the body can tolerate, and quickly developed severe symptoms due to hyperthermia. At a body temperature of 42 ºC, oxidative phosphorylation is reduced and enzyme function decreases. Denaturation of proteins may occur, and a cytokine-mediated systemic inflammatory response is initiated. The production of heat shock proteins also increases (1, 4, 6) (6–9) .
Heat shock proteins are neuroprotective proteins that are produced under stress, for example, during large temperature changes, exposure to ultraviolet light, or wounding. The highest concentration of heat shock proteins is found in the brain, in particular in the cerebellum. An increase in the production of heat shock proteins (as in cases of hyperthermia) leads to increased cytokine release and a sepsis-like reaction, which in turn leads to increased blood-brain barrier permeability, increased cerebral oedema and the risk of cell death in the long term (3) .
Our patient fell victim to heat stroke. Upon arrival at hospital, he had symptoms of heat stroke in the form of high body temperature and unconsciousness. He also developed multiple organ failure shortly after being hospitalised. He sustained significant brain damage as a result of the heat stroke, which is still evident long afterwards.
Heat stroke is a relatively rare condition in Norway, which has few days with very high temperatures. Since the condition is potentially fatal, it is nevertheless important to be aware of it. It is also important for hospital departments to have good procedures in place for rapid diagnosis and treatment of heat stroke, as well as for correct temperature measurement in the emergency department. Several studies have shown poor consistency between tympanic thermometer measurements and core temperature, and it has been concluded that correctly measured rectal temperature is the most accurate non-invasive temperature measurement (10) .
It is possible that had the patient received another type of treatment, such as rapid cooling in the ambulance and in the emergency department, the outcome might have been different. Once in hospital the patient was relatively quickly rehydrated and cooled thanks to the cooler indoor climate. The initial assessment was made difficult by virtue of not knowing the patient's name, previous medical history, the course of events on the day of admission, and whether he was using any medications or intoxicants.
Medications that may increase vulnerability to heat stroke include anticholinergic drugs, antihistamines, beta blockers, diuretics, calcium blockers, laxatives, neuroleptics and tricyclic antidepressants, as well as poisoning with central stimulants such as cocaine and amphetamine (11) . When treating a patient who is unconscious, it is important to obtain as much anamnestic information as possible. Excluding infections will always be a top priority initially.
Kosgallana et al. show in their article that the cerebellum is particularly vulnerable to heat stroke, and that this is often overlooked during clinical examinations (3) . Animal studies, and post-mortem examination of the brain after heat stroke, have shown changes in Purkinje cells as well as cell death, and that the extent of cell damage increases with prolonged hyperthermia.
In spite of major neurological deficits, MRI scans of the brain – including the cerebellum – were unremarkable in our patient. Patients with pronounced cerebellar deficits but initially normal brain MRI have been described in the literature. Atrophy of the cerebellum is often not detected by diagnostic imaging until months or years after the event (3) . Unfortunately, it was not possible to obtain a post-discharge MRI of our patient as his care was continued in another country.
In addition to cerebral oedema and cell death, studies show that hyperthermia may alter the composition of neurotransmitters in the brain (9, 12) . Animal studies demonstrate that if rats are exposed to an environment with a temperature above 38 °C over time, the composition of neurotransmitters in the brain changes. The concentration of GABA and glycine decreases, while that of glutamate and aspartate increases (8) .
In addition to being an excitatory neurotransmitter, glutamate has key roles in cell survival and differentiation as well as in the formation and elimination of synapses in the brain. The presence of glutamate is therefore essential, but high concentrations of glutamate are neurotoxic. Cerebellar Purkinje cells produce GABA and are thus inhibitory. GABA also inhibits glutamate release.
The literature shows that other neurotransmitters are also involved in thermoregulation. Upon an increase in temperature, serotonin, prostaglandins and opioid peptides help to increase the permeability of the blood-brain barrier, with the result that serum proteins and other substances are drawn into the brain extracellular space, contributing to cerebral oedema and cell damage (8) .
Lorazepam, a GABA agonist, had a beneficial effect on the patient's symptoms for a period of time. It is possible that this medication reduced the release of neurotoxic glutamate, but as of yet there is no established treatment for central nervous system symptoms following heat stroke (4) .