Thermoregulation: From basic neuroscience to clinical neurology, part 2

This month (December, 2018), an extensive two-part book on thermoregulation [1,2] was released by Elsevier within the series “Handbook of Clinical Neurology” – one of the time-honored publications in the field of neurosciences published since the 1960s. As emphasized in Jürgen Werner’s review of Part 1 of the Handbook [3], it has been a long time since a comprehensive treatise of animal and human thermoregulation was put together. More importantly, a two-volume elaboration of nearly all aspects of body temperature regulation, such as the present project, has never been published before. In addition to this, the new book presents the entire complex theme of normal and pathological aspects of thermoregulation in the framework of Clinical Neurology, encompassing the continuum of functional aspects from normal and pathological physiology to clinical practice and other practical details of importance, including pertinent therapeutic means – all discussed on the basis of up-to-date information and pertinent theoretical background, animal experimental data and human medical experience.

Most of the main pathophysiological and clinical points of interest have been handled in some detail by the volume editor in his introductory chapter (The thermoregulation system and how it works). The author, Andrej A. Romanovsky, has successfully exposed the salient sub-topics of normal and abnormal thermoregulatory phenomena occurring in the context of relevant animal or human fields. His chapter is followed by 53 other chapters, each commissioned to the best international experts of the field in question, with the length of the text largely being proportional to the importance and the amount of strong evidence available on the topic. Here, we review Part 2 of the book; this part consists of sections VI, VII and VIII.

Section VI: Normal and abnormal body core and peripheral temperatures

This section starts with the description of the modern methods of measuring body temperature in animal experiments and in human clinical practice (chapter 29, Body temperature and clinical thermometry), expertly written by Charmaine Childs. In spite of being a relatively simple physical parameter, temperature should be measured as precisely and non-invasively as possible, which is not as easy as one would think. Another challenge in temperature measurements is to find points or areas faithfully representing reality in time and space. Even though core temperature has been regarded as the regulated parameter, it cannot be defined on the basis of one single value, not to speak about the variability of skin temperature, an indicator of peripheral (or shell) temperature. As rightly emphasized by the author, normal body temperature is still an elusive concept. The same is valid for brain temperature (see chapter 30, Brain temperature: From physiology and pharmacology to neuropathology, by Eugene A. Kiyatkin). Both of these chapters are to be praised for their thoroughness in covering broad aspects of the techniques and for the detailed treaties on the importance of the measuring site within an organ, with the brain temperature having a double role: as a factor reflecting neural activity, but also as a factor affecting brain functions. Chapter 30 also discusses drug-induced hyperthermia resulting in irreversible damage of brain cells, profound leakage of the brain-blood barrier, and multiple functional perturbations that can, in certain instances, be incompatible with life. The complexities of considering brain temperature within the frameworks of physiological regulation and homeostasis are also handled in detail in this chapter.

Three other chapters describe the classical forms of hyperthermia, such as heat exhaustion (chapter 31), heatstroke (chapter 32) and malignant hyperthermia (chapter 38). The first two topics are well-treated as types of the continuum in insufficient defense against excessive heat-generation by emphasizing the pathophysiological background and explaining the progressive burden on circulatory function, salt-water homeostasis and energy balance. It is rightly pointed out that the upper part of the body temperature scale (the range of body core temperature in homeothermic animals and man compatible with survival) is much more dangerous that the lower part. Malignant hyperthermia is a special form of potentially life-threatening hyperthermia that results from the combination of a genetic trait affecting skeletal muscles, as well as the use of certain anesthetics or muscle relaxants. The good news is that a drug has been available for some decades to efficiently prevent or counterbalance this form of otherwise deadly hyperthermia (see chapter 38).

Two other chapters can be grouped as those discussing various disorders of thermoregulation that can be characterized either by increases or decreases of core temperature resulting either from immunological, neurological of pharmacological factors (fever or stress, respectively), and not from external thermal stimuli (see chapters 34 and 35). In all these cases, hyper- or hypothermia is the result of modifications in central nervous system mechanisms that regulate body temperature. An extensive treatise on the phenomenon fever can be found in chapter 34, by András Garami, Alexandre A. Steiner and Andrej A. Romanovsky, one of the most elaborate texts in this handbook. In addition to the detailed discussion of the known mechanisms of fever genesis studied in different animal models, evidence is presented in favor of the beneficial nature of rises in body temperature. The most intriguing aspect of this chapter is the two-sided nature of thermoregulatory changes that may develop during systemic inflammation. In particular, depending on the severity of infection in humans or on the dose of the dose of bacterial products given to experimental animals, hypothermia alone or in combination with fever may occur. Another modifying factor could be ambient temperature. As opposed to simple biological reasoning prevailing in some medical practice, not only the rise in body temperature but also hypothermia may have some survival value, since the latter phenomenon was shown to be regulated – as indicated by some common thermoregulatory mechanisms, such the double role of physiological and behavioral effectors leading either to a rise or a fall in core temperature. The authors interpret the rise of body temperature in infection as a sign of disease-fighting, and hypothermia as a sign of disease tolerance.

A succinct treatise of the question of stress-induced thermoregulatory modifications, as found in animals and men, is presented by Takakazu Oka in chapter 35. A clear picture is given by the author about the factors that determine the direction of thermoregulatory changes (hyperthermia or hypothermia) during and after the application of stressors of different modalities. Although some aspects of stress-induced hypothermia may resemble fever, the pathomechanism of stress-induced hyperthermia is probably distinct from that of pyrogen-induced fever.

Two chapters deal drug-induced hypothermia, either associated with drug abuse (chapter 36, by Jon Eric Sprague, Chris Riley and Edward M. Mills) or representing a complication of psychiatric treatment, that is, neuroleptic malignant syndrome and serotonin syndrome (chapter 39, by Laura M. Tormoehlen and Daniel Edward Rusyniak).

Three categories of induced hypothermia are dealt with in chapters 33, 37 and 41: accidental hypothermia, anesthesia-induced hypothermia and perioperative hypothermia, respectively. The first of these chapters gives a short overview of the history of human hypothermia that can develop upon severe cold exposure followed by a description of its physiological consequences (deficient organ functions) that ultimately may be incompatible with survival. The authors of this chapter – Peter Paal, Hermann Brugger and Giacomo Strapazzon – also summarize important points regarding hypothermia treatment. The topics of chapters 37 and 41 are somewhat overlapping, with an important difference that the former, by Rainer Lenhardt, gives a detailed description of the effects of drugs used for general vs. neuroaxial anesthesia, while the latter, by Kurt Ruetzler and Andrea Kurz, deals with the combined effects of surgical interventions, including the anesthetic usage. In the latter chapter, the idea is presented that even a 1–3°C fall in body core temperature during surgery can be disadvantageous in terms of the length of recovery and the frequency and severity of postsurgical complications.

Chapter 40 discusses the so-called acral coldness (reduced blood flow in distal areas of the limbs) and summarizes the pathophysiology of three related syndromes with largely unknown etiology: the Reynaud’s phenomenon, acrocyanosis and primary pernio. The authors, Tone Kristin Bergersen and Lars Walløe, emphasize that these forms of reduced blood flow are not genuine thermoregulatory syndromes, but that their severity heavily depends on ambient temperature. All of the abovementioned syndromes, as well as decreases of limb circulation in diabetes mellitus, may lead to limb necrosis.

Section VII: Thermoregulation in neurological disease

This section is dedicated to the thermoregulatory dysfunctions occurring in neurological diseases. Many important neurological disorders are included such as multiple sclerosis (chapter 42), epilepsy (chapter 45) and neurodegenerative disorders like Parkinson disease (chapter 43), Alzheimer disease (chapter 44), and amyotrophic lateral sclerosis (chapter 46). Of the genetically determined neurological illnesses, Huntington’s disease is included (chapter 47). Section VII also covers neuropathies (chapter 48), as well as traumatic brain and spinal cord injuries (chapters 49 and 50, respectively).

Multiple sclerosis research is currently in the focus of interest in neurology and neuroscience. Overwhelming new information has been recently published about the immunological background of this disease, and new drugs are being developed, based on this information. Thermoregulatory dysfunction in multiple sclerosis is becoming the new focus of interest [4]. Chapter 42, written by Scott L. Davis, Ollie Jay and Thad E. Wilson, summarizes the present knowledge of thermoregulatory dysfunction in this disease and gives inspiration for further research to better understand the increased temperature sensitivity in multiple sclerosis – a major determinant of the quality of life of these patients.

Chapter 43, authored by Elizabeth A. Coon and Phillip A. Low, makes a convincing point that disorders of thermoregulation are major contributors to non-motor symptoms in Parkinson’s disease. Detailed analysis of alterations in thermoregulation can help to differentiate Parkinson’s disease from various forms of parkinsonism, such as multiple system atrophy. This chapter also contains valuable information on the parkinsonism-hyperpyrexia syndrome, a rare but potentially lethal complication occurring when antiparkinsonian medications are reduced or discontinued.

Chapter 44, entitled “Hypothermia as a risk factor for Alzheimer disease” proposes a really unorthodox approach to better understand the etiology of Alzheimer disease and is an interesting reading. For the authors of the present review, the most impressive paragraph is the one in which the authors, Maria Camila Almeida and Daniel Carneiro Carrettiero, speculate about a role of anesthesia-induced reduction in body temperature in triggering postoperative cognitive decline, which is an important complication of surgical interventions in the elderly.

Chapter 45, written by Sebastian Pollandt and Thomas P. Bleck, explores several aspects of thermoregulation in epilepsy. It discusses the bidirectional relationship between body temperature and seizures: hyperthermia can induce epilepsy, and epileptic seizure may provoke an increase in body temperature. It is well known that hyperthermia can induce seizures in childhood. A febrile seizure during childhood is a risk factor for the development of epilepsy in adulthood. Numerous mutations in genes encoding ion channels have been identified, and cytokines (such as interleukins) have also been implicated in febrile seizures, together with an enhanced susceptibility to provoke seizures later in life [5]. The authors also present an excellent overview of thermoregulation impairments in in epileptic seizures, including both convulsive and non-convulsive status epilepticus.

Chapter 46, authored by Luc Dupuis, Åsa Petersen and Patrick Weydt, summarizes body temperature dysregulation in amyotrophic lateral sclerosis. This is a major adult-onset motor neuron disease, but – contrary to the authors’ statement – it is relatively rarely manifested clinically, pathologically or genetically in association with frontotemporal dementia. The most common cause of dementia (after Alzheimer’s disease) is vascular dementia [6]. Nevertheless, it is important to identify the thermoregulatory changes in amyotrophic lateral sclerosis, and the authors perform this task brilliantly.

Chapter 47, written by Patrick Weydt, Luc Dupuis and Åsa Petersen, describes the thermoregulatory disorders found in Huntington disease. This chapter is an excellent synopsis of studies of Huntington disease in animal models, which have revealed striking and informative examples of body temperature dysregulation. This information paves a way for future translational studies.

Chapter 48, authored by Robert D. Fealey, deals with thermoregulation in neuropathies. It is a useful, comprehensive source of new data related to thermoregulatory sweating impairment in neuropathy. Chapter 49, by Ram Gowda, Matthew Jaffa and Neeraj Badjatia, deals with thermoregulation in brain injury. The major message of the chapter is that targeted temperature management trials, unfortunately, were not effective in decreasing brain damage in traumatic brain injury or stroke, whether ischemic or hemorrhagic. Despite the negative results of these trials, the targeted temperature management approach continues to be investigated in clinical trials (see also chapter 51). Chapter 50, authored by Mike J. Price1 and Michelle Trbovich, deals with thermoregulation following spinal cord injury. It is evident that there is a reduced afferent input to the brain and a decrease in the efferent output to thermoeffectors (cutaneous vasomotor and sweating) below the level of spinal cord lesion. The chapter ends with a message that physical fitness is an important component in decreasing dysfunctions of thermoregulation in patients with spinal cord injury.

Section VIII: Therapeutic interventions

The authors of chapter 51, Fernando Mayor Basto and Patrick D. Lyden, describe the use of hypothermia in acute ischemic stroke therapy. They emphasize that therapeutic hypothermia has proved to be an extremely powerful neuroprotectant and is the most promising treatment for patients with acute ischemic stroke. In particular, it preserves neuronal vitality by modulating several metabolic pathways, inflammation, apoptosis, and preservation of the neurovascular unit. Furthermore, new modes of hypothermic treatment that combine cooling with other therapeutic modalities (such as thrombolysis) and new technologies allowing safer and faster improvement of the patient are discussed. The next chapter (52) follows up on this subject by discussing other aspects of neuroprotection. Still, the authors of this chapter, Jae H. Choi and John Pile-Spellman, provide a sophisticated practical description of the novel techniques available in the field. Also, attention is called by the authors to novel invasive extracorporeal techniques and minimally invasive endovascular intra-arterial systems that are under development for more effective selective cooling of specific brain areas.

An emerging therapeutic method used in oncology is discussed in chapter 53 by Riadh W. Y. Habash. In particular, the application of therapeutic hyperthermia alone or in combination with other therapeutic modalities is described. Emphasis is given to the technical limitations and standardization of heat delivery to the tumor site. The viability of heat therapy in oncology has been increased drastically due to the development of modern hardware and software for heat delivery and temperature measurement.

The concluding chapter (54) is a state-of-the-art summary of antipyretic therapy, an important filed of clinical pharmacology. The authors, Jonathan James Lee and Daniel L. Simmons, start with the classical antipyretic drug, aspirin, the fever-reducing effect of which has turned out to be due to inhibiting prostaglandin synthesis. A systematic treatise of the biochemistry of enzymes and receptors involved in prostaglandin-mediated signal transduction, including – among others – prostaglandin H2, prostaglandin E2, and EP receptors, constitutes the largest part of this chapter. The TRPV1 channel is also discussed. The chapter ends with a discussion of the clinical use of established antipyretics, as well as of novel medicinal agents under clinical trials and topics for future research.

Conclusion

The two-volume handbook [1,2], reviewed by Werner [3] and herein, can be regarded as a valuable, comprehensive source of information on the present-day knowledge on the physical, biochemical, physiological, pathophysiological and clinical aspects of thermoregulation. This timely publication, edited and written by experts in all important aspects of thermoregulation, can be recommended to scientists, neurologists and anyone who may be interested in the thermoregulation aspects of biology and medicine, broadly defined.