In This Case Study
- A 53-year-old woman was admitted for episodes of hypothermia, mostly occuring at night. The patient had recently been diagnosed with HIV with a viral load >750,000 and a CD4 count of 65
- The Pathways Consult Service at Massachusetts General Hospital took up the case and sought to identify the root cause of her cyclical episodes, as well as to determine whether there was a link between her hypothermia and the rest of her symptoms
- The team hypothesized that an autoimmune process related to immune reconstitution on HIV treatment led to the dysfunction of temperature regulation and that the resulting hypothermia led to multisystem injuries
A 53-year-old woman was admitted for episodes of hypothermia. The episodes, which mostly occurred at night, were first documented as an incidental observation during a hospitalization two years prior to the consult. At that time, she was put on treatment for a new diagnosis of HIV with a viral load >750,000 and a CD4 count of 65. Over the following two years, she also developed fatigue, syncope, bradycardia (now with a pacemaker), hypoglycemia, pancreatitis and pancytopenia. No endocrine abnormalities were found, but she was empirically treated with physiologic doses of prednisone for potential adrenal insufficiency and levothyroxine for subclinical hypothyroidism. Her brain MRIs demonstrated only a Rathke's cleft cyst.
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During the current admission, her hypothermia (to 85° F) was observed on a nightly basis, documented by both temporal and rectal temperatures. During the episodes, she remained alert with warm extremities and good capillary refill and did not shiver nor complain of feeling cold. Her temperature corrected to normal during the day. The Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on two key questions:
- What mechanism underlies the patient's cyclic hypothermia?
- Can her hypothermia explain the rest of her symptoms?
Body temperature is regulated by the preoptic area (POA) of the hypothalamus, which serves as the body's thermostat, interpreting signals from the core and peripheral thermosensors, and then regulating the sympathetic nervous system to control thermogenesis, according to findings published in Advances in Physiology Education. The diurnal pattern of temperature in humans, falling at night by about one degree, arises from the circadian rhythmicity of POA signaling, which is controlled by the suprachiasmatic nucleus. In mice, lesions in the POA can cause an exaggerated drop in body temperature at night, as reported in Neuroreport. The principal thermosensors are transient receptor potential (TRP) channels that are expressed in the periphery and centrally in the POA. Described in Frontiers in Neuroscience, many of these channels have endogenous and exogenous agonists; for example, a heat-sensing channel TRPV1 is activated by capsaicin, and TRPM8, a cold-sensing channel, is activated by menthol.
Hypothermia also is associated with hypothalamic lesions in humans—for example, lesions caused by multiple sclerosis or by limbic encephalitis from paraneoplastic syndromes or autoimmunity, according to findings published in Multiple Sclerosis Journal and the Journal of Neurology, Neurosurgery and Psychiatry. This patient's episodes of hypothermia have increased in frequency over the last two years, correlating with the treatment of her HIV and reconstitution of her CD4 T cell levels, and setting where emergent autoimmunity has been observed in many patients, as reported in Biofactors and Rinsho Shinkeigaku. No MRI defect was noted in her hypothalamus, but lesions in the hypothalamus are difficult to image, observed only in a fraction of patients with hypothermia related to multiple sclerosis (Multiple Sclerosis Journal).
What might be target proteins? Limbic encephalitis is associated with several known antibodies, such as to the NMDA channel. One possibility, in this case, might be the TRP channels, particularly cold-sensing channels, such as TRPM8. Without functioning TRPM8, the cold-sensing neurons would fail to fire as the patient's temperature naturally drops at night, interrupting the normal feedback loop of temperature homeostasis and leading to pronounced nocturnal hypothermia.
Considerable effort has been directed at creating a unifying diagnosis for the wide range of symptoms that she has developed over the last two years that might also explain her hypothermia. However, such a diagnosis has proven elusive. Perhaps, instead, these symptoms are not part of disease-causing hypothermia but sequelae of the hypothermia itself. Accidental hypothermia is known to lead to pancytopenia, hypoglycemia, bradycardia and pancreatitis, according to findings published in QJM. Without the ability to sense a drop in temperature, the patient is likely to experience prolonged hypothermic periods at night when she is not in the hospital, potentially explaining the unusual pattern of multisystem organ damage that had perplexed her medical teams. Thus, elucidating the mechanism driving her hypothermia can also clarify how to approach her other symptoms, here suggesting that preventing the hypothermia may be the most effective strategy to improve her multisystem illness. Thus, the Pathways Consult Service hypothesized that an autoimmune process related to immune reconstitution on HIV treatment led to the dysfunction of temperature regulation, likely through dysfunction of the POA, and that the resulting hypothermia led to multisystem injuries.
Summary and Future Steps
How the set point for core body temperature control is chosen is unknown. Recent evidence suggests a potential role for hypothalamic TRP channels. The change in her thermal set point correlated with therapy for HIV infection, known to occasionally precipitate autoimmunity as CD4 cells are restored. Because of the question of autoimmunity, the patient underwent a lumbar puncture and was found to have no evidence for a monoclonal B cell or unusual T cell population on flow cytometry. Given this corroborating evidence and her persistent symptoms, and despite concerns about the use of corticosteroids in HIV, she was put on high-dose steroids, with marked improvement in her hypothermia. While that response is good news, high-dose steroids are not viable as a long-term option and alternative forms of immunomodulation will need to be explored. A potential future direction would be to explore the target of the presumed auto-antibody response, for example, to see if they affected the TRP channel or might bind to other antigens of the hypothalamus.
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