0025-7974/95/7405-0268$03.00/0 MEDICINE Copyright © 1995 by Williams & Wilkins Vol. 74, No. 5 Printed in U.S.A. Spontaneous Periodic Hypothermia RICHARD T. KLoos, M.D. Introduction The hypothalamus acts as the body’s main “ther- mostat” (111), with a central thermoreceptor sensi- tivity of + 0.2 °C (115). The hypothalamus defends the “set point” temperature, which can be altered by central nervous system (CNS) disease or pyrogens. Hypothermia is arbitrarily defined as a core tempera- ture of less than 35 °C (95.0 °F) (101, 115). Poikilo- thermia is defined as variance of more than 2 °C secondary to ambient temperature changes (78). Normally, the mean body temperature varies diur- nally, with an early morning nadir, late afternoon to early evening zenith, and mean amplitude of variabil- ity of 0.5 °C (0.9 °F) (79, 98). Over a 24-hour period, the normal oral temperature varies between a 5th percentile low of 35.7 °C (96.3 °F) and a 95th percen- tile high of 37.6 °C (99.6 °F) (79). The mean normal oral temperature is 36.8 °C (98.2 °F), with women maintaining temperatures slightly higher than men (79). Women manifest a small rise in basal body temperature (0.2-0.5 °C) in response to the thermo- genic effect of progesterone during the luteal phase of the menstrual cycle (19). Two hypothalamic cen- ters act reciprocally to maintain body temperature. The posterior center conserves heat by inducing va- soconstriction, shivering, and perhaps by raising the metabolic rate. The anterior center (preoptic ante- rior hypothalamic area) controls heat dissipation by stimulating a caudal hypothalamic region which in- duces vasodilatation and sweating (Figure 1) (54, 82, 91, 111). Hypothermia may occur in multiple clinical set- tings including induced or accidental, metabolic, protein-calorie malnutrition, drug-induced, dermal dysfunction, sepsis, and hypothalamic and CNS dys- function (101). Destruction of the anterior “heat loss” center may cause hyperthermia, while bilateral posterior hypothalamic lesions may result in hypo- From the Division of Endocrinology and Metabolism and the Division of Nuclear Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan. Financial support for manuscript preparation provided by the NIH Training Program in Endocrinology and Metabolism 5 T32 DK07245-17. Address reprint requests to: Richard T. Kloos, MD, University of Michigan Medical Center, University Hospital, 1500 E. Medical Center Drive, B1G412 Box 0028, Ann Arbor, MI 48109-0028. 268 thermia or poikilothermia (54, 82). Persistent hypo- thermia or poikilothermia due to thermoregulatory dysfunction with associated hypothalamic damage is well recognized (8, 9, 23, 29, 39, 62, 66, 78, 80, 99, 101, 111). Acute CNS dysfunction with hypothalamic involvement is recognized to cause transient hypo- thermia (74). Periodic hypothermia has been observed with agenesis of the corpus callosum (Shapiro syndrome) (111, with CNS abnormalities affecting structures related to thermoregulation (17, 21, 30, 37, 75, 89, 96, 129), and, very rarely, without an associated sys- temic disease or obvious brain lesion (24, 29, 40, 81, 114, 116, 121). These last cases are distinct from other recurrent cases such as from environmental exposure. Most of these unusual patients appear to defend a lowered temperature set point by active body heat dissipation through vasodilatation and sweating, and decreased generation of heat (5, 74, 75). These dramatic episodes have been varyingly referred to as “periodic,” “recurrent,” “intermittent,” “remittent,” and “episodic.” The author recently encountered a patient with recurrent episodes of marked hypothermia without an associated CNS structural abnormality (referred to here as “spontaneous periodic hypothermia”). A review of all similar cases identified through a search of the MEDLINE (National Library of Medicine, Bethesda, MD) data base or referenced by other au- thors during an extensive literature search is assem- bled here in an attempt to provide a comprehensive clinical picture of this rare disorder. Illustrative Case A 57-year-old white man was referred in October 1993 for recur- rent episodes of hypothermia with profuse sweating, nausea, and vomiting. His past medical history included a concussive motor vehicle injury in the late 1950s, and again in 1965 (age 29 years). The latter was associated with an unknown duration of uncon- sciousness and multiple traumatic injuries including blood in the anterior chamber of the right eye and a compound and commi- nuted mandibular fracture with an otherwise normal skull X ray. His history also included 20 years of smoking 2-3 packs of ciga- rettes per day, essential hypertension, coronary artery disease with 2 myocardial infarctions, and 2 coronary angioplasties. The patient had been stationed in east Asia during the Korean War. Purified protein derivative skin testing for tuberculosis was nega- SPONTANEOUS PERIODIC HYPOTHERMIA 269 Anterior commissure Paraventricular nucleus Preoptic nucleus Dorsomedial nucleus Posterior nucleus Mammillary body Ventromedial nucleus Supraoptic nucleus Infundibular nucleus Fic. 1. Ventricular surface of the hypothalamus illustrating ap- proximate locations of the most important hypothalamic nuclei (reproduced with permission from reference 54). tive in 1987. The family history included seizures in 1 of 4 brothers (whose son also had seizures), a cerebrovascular accident, type II diabetes mellitus, and coronary artery disease. No family mem- bers had experienced episodes of hypothermia. The patient's so- cial history included 1 cola per day and no coffee, tea, or alcohol. Medications included nifedipine (Procardia XL 60-90 mg po qd, Pfizer Pratt Pharmaceuticals, New York, NY), lisinopril (Prinivil 10-20 mg po qd, Merck, West Point, PA), sucralfate (Carafate 1 g po qid, Marion Merrell Dow, Kansas City, MO), and infrequent sublingual nitroglycerin. The patient’s first episode of hypothermia occurred in 1975, with a second in 1987. These episodes became more frequent, recurring 1-2 times per year, until 6-7 episodes occurred in 1993. No provocative stimulus was identified. At onset, the patient expe- rienced a “funny feeling” in his head and nausea. The sensation was powerful, consuming, and combined with a sense of weak- ness, incoordination, and gait unsteadiness, which made him feel like “falling over and dying” and like he “didn’t care what hap- pened” to him. During this time he wanted to lie down. The incoordination and gait unsteadiness were described as similar to being drunk. He vomited multiple times and was flushed. Head movements did not worsen the symptoms. Associated with these events he felt very hot, perspired profusely, and his body tempera- ture plummeted to as low as 33.3 °C (92.0 °F) orally and at the tympanic membrane. When he was hypothermic, he stated that he did not feel cold, but his wife noted that his skin felt cold to the touch, “as if he had just been brought out of a freezer,” and that it was “clammy.” The nausea and vomiting usually lasted 3-4 hours (occasionally longer), and were followed by complaints of feeling cool without associated chills. His face then turned “white.” The feeling in his head, general weakness with a sense of being “drained,” and incoordination gradually disappeared over 1-2 days. He was unsure of how long it took his temperature to recover, although he recalled 1 episode of hypothermia lasting 2 days. There were no associated complaints of abdominal pain, headache, diarrhea, confusion, wheezing, rash, seizure activity, or shakiness. Episodes were not related to meals, time of day, or season. He had normal erections and sexual function. Between episodes of hypothermia, the patient was without complaint. In March 1993 the patient developed pneumonia and mounted a fever to 39.2 °C (102.5 °F) orally. In April 1993 the patient presented to a local hospital with hypothermia. As his oral temperature was 33.9 °C (93.1 °F), he was treated with warm blankets and his next oral temperature was 35.1 °C (95.1 °F), with subsequent variable measurements as high as 36.1 °C (97.0 °F). Physical examination was normal except for cool, pale skin. Multichannel chemistry, electrolyte profile, and complete blood count (CBC) were normal except for hemato- crit 0.384 (reference values: 0.42-0.52), random glucose 7.76 mmol/L (3.58-5.78), cholesterol 6.01 mmoVL (2.77-5.18), and tri- glycerides 2.68 mmol/L (0.40-1.69). Thyroid stimulating hormone (TSH) and free thyroxin index were normal. Aerobic and anaero- bic blood cultures were negative. Chest X ray (CXR) revealed a shallow inspiratory effort, crowding of the basilar lung markings, peripheral pulmonary vessels at the upper limits of normal, but no definite infiltrate or cardiac decompensation. Magnetic resonance imaging (MRI) of the brain 7 days later revealed mild generalized cortical atrophy, left maxillary antral sinusitis, and an intact cor- pus callosum. In June 1993 the patient presented to a local hospital with another episode of hypothermia. Vital signs included an oral tem- perature of 34.4 °C (93.9 °F), pulse 68 beats per minute, respira- tions 16 per minute, and blood pressure 112/72 mmHg. He was noted to appear ill, with pale, cool, and diaphoretic skin with sweat beading on his face and chest. Apart from an unstable gait, the examination was otherwise normal. Warm blankets were applied, and his oral temperature was then measured at 34.7 °C (94.5 °F). Laboratory studies revealed a normal amylase, lactate dehydrogenase (LDH), and CBC. Multichannel chemistry and electrolyte profiles were unchanged except for mild elevation of aspartate aminotransferase (AST) 0.83 kat/L (0.08-0.67). Serial creatinine kinase (CK) levels ranged from 7.60-8.55 wkat/L (0.58- 6.23) with 1%-2% CK-MB (0-4). The erythrocyte sedimentation rate (ESR) was elevated to 50 mnV/hour (0-15). CXR was normal. Urinalysis (U/A) revealed a specific gravity of 1.021 (1.016-1.022), no glucose, and trace ketones. Urine, fecal, and blood cultures were without pathogens. The stool was negative for heme, white blood cells, and ova and parasites. Abdominal ultrasound and computed tomography of the abdomen and pelvis were non- contributory. Subsequent 24-hour urine studies revealed 5-hydroxyindole acetic acid (5-HIAA) 37.8 and 55.4 ymol (0-31.4), with normal epinephrine, norepinephrine, dopamine, and vanillylmandelic acid (VMA). A malaria smear was negative. Biopsy of a 5-6 mm by 34 mm sessile nodular elevation of the ascending colonic mucosa noted at colonoscopy demonstrated intramucosal lymphoid aggregates. Distal rectal and anal canal mucosa revealed mild to moderate proctitis. Esophagogastroduodenoscopy (EGD) revealed diffuse mild to moderate gastritis with a very prominent prepyloric antral region mucosal fold. Histologic evaluation dem- onstrated chronic duodenitis, and the gastric antrum revealed chronic gastritis with organisms consistent with Helicobacter. Five-hour oral glucose tolerance testing revealed a fasting glucose 270 KLOOS of 5.72 mmol/L with a glucose curve diagnostic of diabetes melli- tus, and no subsequent hypoglycemia. The glycohemoglobin A, was 0.059 SI (<0.067) with a height of 172.7 cm and weight of 98.4 kg. Repeat 24-hour urine studies demonstrated normal VMA, norepinephrine, epinephrine, metanephrine, normetanephrine, and 5-HIAA. The patient was instructed to record his oral temperature in the morning and at night daily while asymptomatic, and more frequently should an episode occur. At 11:50 AM December 2, 1993, the patient noted the onset of a mild episode of hypothermia (Figures 2 and 3). He presented to the hospital where his oral temperature was measured by the nursing staff. The patient vom- ited 5 times before the nausea and hypothermia resolved at ap- proximately 2:30 PM (160 minutes total). Vital signs included a blood pressure of 155/80 mmHg without orthostatic changes. His pulse rate was 60-68 beats/min. The skin was of normal thickness, cool and clammy, with no violaceous striae or hyperpigmentation. Neurologic examination was normal. Laboratory evaluation re- vealed a normal CBC except for 7.6 X 10°/L neutrophils (2.0-7.5), and platelets of 193 x 10°/L (200-400). Electrolyte and chemistry profiles were unchanged except for the elevation of alanine ami- notransferase (ALT) 1.15 wkat/L (0-0.75). U/A, CK, urinary 5-HIAA, human pancreatic polypeptide, urine and serum seroto- nin, and serum neuron specific enolase were normal. Brain posi- tron emission tomography (PET) 22 hours after the onset of symp- toms (patient was no longer hypothermic) with '*F-2- flourodeoxyglucose was normal. Sympathetic skin responses of 38 Fic. 2. Patient’s oral temperature over 57 days. Small square = patient’s oral tem- perature; unfilled circle = hypothermia; large square = 5th percentile oral temper- ature lower limit; filled circle = 95th per- centile oral temperature upper limit. Oral Temperature (°C) the wrist and foot were normal to volitional (inspiration) and extrinsic (startle) stimuli. There was no evidence of small fiber neuropathy or significant peripheral sympathetic dysfunction. Electroencephalogram (EEG) during wakefulness and drowsi- ness, 26 hours after symptom onset, suggested a mild focal distur- bance of cortical neuronal function over both temporal regions with occasional bitemporal theta slowing in the 5-6 Hz range of low-to-moderate amplitude. No epileptiform activity was seen, and no seizures were recorded. Approximately 48 hours after the onset of symptoms the patient reported resolution of his general- ized weakness and gait unsteadiness. Subsequent laboratory testing included a low baseline free tes- tosterone of 33 pmol/L (34.6-104) with a normal total testosterone of 10.1 nmol/L (8.7-32.9), luteinizing hormone (LH) of 3.1 IU/L, follicle stimulating hormone (FSH) of 3.3 IU/L, and prolactin of 6.2 ug/L. Repeat free and total testosterone values 6 weeks later were normal at 34.9 pmol/L and 10.2 nmolV/L, respectively. Simulta- neous samples sent to another laboratory revealed total testoster- one of 10.9 nmoV/L (10.4—41.5), and free testosterone of 163 pmol/ L (811-1,038). Insulin-induced hypoglycemia evoked symptoms of drowsiness, sweating, and heart palpitations with normal re- sponses of growth hormone (GH), adrenocorticotropic hormone (ACTH), cortisol, and arginine vasopressin (AVP, antidiuretic hor- mone) (10). Repeat MRI of the brain, before and after gadolinium adminis- tration, revealed mild brain volume loss based on the prominent ventricular system and subarachnoid spaces for age. The corpus carbamazepine | episode onset 2 S Fic. 3. Detailed view of patient’s oral tem- perature during hypothermic episode seen in Figure 2. (See Figure 2 legend.) Oral Temperature (*C) & 34 episode onset + ———— 2400 0600 1200 1800 2400 0600 1200 1800 2400 0600 1200 1800 2400 0600 16 17 18 19 Hours and Days SPONTANEOUS PERIODIC HYPOTHERMIA 271 callosum, hypothalamus, and pituitary were normal. Oral carbamazepine (Tegretol, Basel Pharmaceuticals, Ciba- Geigy, Summit, NJ) was initiated, and the dose titrated upward. With serum trough levels below 31 «mol/L, the patient twice experienced mild episode onset symptoms with the sensation in his head, nausea, minimal or no vomiting, weakness, mild diapho- resis, and an urgent sense to lie down. The temperature declined only mildly (always above 36.1 °C [97.0 °F]), and each episode resolved within 30 to 60 minutes. The patient had never before experienced such “abbreviated” episodes, the last of which oc- curred January 15, 1994. With carbamazepine 800 mg/d, the pa- tient had mild CNS side effects, no further hypothermic episodes, and a trough serum level of 29 umol/L. The patient was intolerant of 1,000 mg/d with increased CNS side effects including mild confusion and impaired judgment, slight speech disturbance, drowsiness, incoordination/unsteadiness, and feelings he de- scribed as “woozy” and a sense of being “in another place.” At the patient's request, alternative therapy with clonidine 0.1 mg po bid was begun March 10, 1994, and subsequently converted to the Catapres-TTS-2 transdermal system (Boehringer Ingelheim, Ridgefield, CT). A hypothermic episode occurred July 20, 1994, with an oral temperature nadir of 35.0 °C, and clonidine therapy was discontinued. Further carbamazepine therapy and a trial of phenytoin (Dilantin, Extended Phenytoin Sodium Capsules USP, Parke-Davis, Morris Plains, NJ) were refused. The patient had no further episodes since discontinuation of clonidine. Discussion Clinical presentation This case is consistent with previously reported cases of spontaneous periodic hypothermia. In those cases, the periodicity of hypothermic episodes ranged from hours to years, and episodes lasted hours to weeks (Tables 1 and 2). Frequent body temperature measurements below the normal 5th percentile were recorded while this patient was asymptomatic, and a normal diurnal variation was present (Figures 2 and 3). Some patients have main- tained interval body temperatures in the frankly low to low-normal range (24, 37, 75, 106, 121). Hyper- hidrosis has been a frequent and prominent feature, and is consistent with stimulation of the anterior hypothalamic thermoregulatory center (2-4, 16, 22, 52, 55). However, Slotki et al reported the absence of diaphoresis (116), Sheth et al reported the onset of sweating towards recovery (114), and 2 other reports (75, 107) noted no consistent relationship between the profuse sweating and temperature changes. Yet, when warming was attempted in 2 of these cases, both patients “defended” their lowered set points. The patient presented here was not formally tested to demonstrate defense of a temporarily lowered set point. The fact that he did not complain of being cold during the acute phase of the hypothermia, however, argues strongly for a temporarily lowered set point. Further, while application of warming blankets was twice followed by mildly increased temperatures, one may argue that this patient’s episodes were usu- ally of short duration, and that he may have been in the process of spontaneously recovering and begin- ning to employ systemic heat conservation measures such as those he described with his spontaneous recoveries when he would feel cool and his face would turn white. This possibility is supported by the fact that with the first warm blanket intervention, the patient was noted to be pale, and not diaphoretic. On the second occasion, he was no longer diapho- retic before the repeated temperature determination. Urine specific gravity measurements during acute episodes have ranged from 1.021 to 1.025; this docu- ments the presence of AVP. Potential causes for AVP stimulation in this setting may include nausea/vom- iting, adrenergic stimuli, emotional stress, and hypo- volemia secondary to profound diaphoresis. The stimulatory effect of opiates on AVP release, the effects of AVP on thermoregulation, and the poten- tial role toward hypothermia are discussed below. Of note, this patient reported diaphoresis with codeine ingestion. No abnormality of thirst or water metabo- lism was noted during or between episodes, however. Previous authors (6, 75, 121) have noted abnormal liver function tests in patients with periods of hypo- thermia, which may be accounted for by hypoperfu- sion of the liver due to reduced splanchnic blood flow. Another possible explanation of this patient’s mild hepatic transaminase abnormalities is fatty in- filtration of the liver secondary to obesity and diabe- tes mellitus. Abnormalities of sex hormones and go- nadotropins in similar cases from the literature are discussed below. Interpretation of this patient’s low free testosterone is complicated by his normal LH and FSH, advanced age compared to that of subjects used for assay normalization (testosterone levels normally fall with aging), and normal sexual func- tion. A gonadotropin releasing hormone stimulation test has not been performed. Ataxia has been men- tioned by previous authors (24, 29, 75, 121). Of note, this patient’s altered gait appeared to persist tempo- rarily despite resolution of the hypothermia. While this patient’s diagnosis of type II diabetes mellitus is the most likely explanation for his ran- domly elevated glucose values at the time of hypo- thermia, decreased glucose utilization and impaired insulin release as a cause of impaired oral glucose tolerance testing during hypothermia has been dem- onstrated (72, 101, 111, 122). Further, vasopressin has been found to increase hepatic glucose produc- tion (14, 15, 44, 56, 119, 126), and to stimulate pancre- atic glucagon release (31, 32). Glucagon in turn rap- idly stimulates hepatic glucose production (15, 95). 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Aydesor9yre 1961 aUON auOGreqousyd Terqera9 ‘Dad AM POP 44 g ut saposidg TT Sox Sox IK TZ d 6% asuodse; speny, 8n1 uonem¢ aa yesuQ qeax snuq a een Ayyepoyw Bursewy SNO aposidyy saposidq Jo Aouenbaly jeunouqy SaINZIOg qe aBy X9g aouaiajay sPTULIayjodAy arpoyiod snoauequods WIM syuened ‘1 ATAVL TABLE 2. Cases of periodic hypothermia with insufficient CNS imaging Abnormal Drug Response Sodium amytal Complete Amytal Drug Tried CNS Imaging Episode Frequency Seizures Age at Modality Skull X rays Duration EEG Not done Onset Sex Reference Year of Episodes Annually for 4-6 wk with multiple episodes/d Approximately 2 hr No 12 yr 59 1934 Complete Skull X rays 2-3 hr Annually for 2-3 mo with episodes each Not done No morning Variable, daily morning attacks for 1942 29 1961 None tried None Skull X rays Approximately 2d Yes No 10 yr M 16 d recorded SPONTANEOUS PERIODIC HYPOTHERMIA 273 vessels on chest X ray were deemed at the upper limits of normal during 1 hypothermic episode (5, 101). The patient’s exhaustion and abnormal EEG (while he was no longer hypothermic) are consistent with cases previously reported. This is the first case of spontaneous periodic hypo- thermia to have a PET evaluation of cerebral glucose metabolism; no functional abnormality was demon- strated. This is the first case of spontaneous periodic hypothermia to respond possibly to carbamazepine, however, a temporary spontaneous remission is not excluded. Although Hines and Bannick (59) reported a prodrome of nausea and vomiting, this is the first reported case of nausea and vomiting occurring con- sistently at the episode onset. Interestingly, 2 cases (85, 130) of recurrent hyperthermia have been re- ported with nausea and vomiting as part of the epi- sodic symptomatology. Of note, gastrointestinal ef- fects have been demonstrated (41, 42) in animals with stimulation of the anterior hypothalamus. Pathophysiology There is general agreement among authors that an altered central thermoregulatory mechanism is the determining factor for the fluctuating body tempera- tures of both Shapiro syndrome and spontaneous periodic hypothermia. In the 1934 report of Hines and Bannick (59), atropine sulfate alleviated the sweating but did not affect the temperature curve. Rather, the patient developed a prolonged “hot pe- riod,” most likely representing a decreased ability to dissipate heat via sweating to accommodate the new thermoregulatory set point. In most cases (5, 29, 75, 111, 121), attempts to warm these hypothermic patients have resulted in profuse sweating. There is evidence to suggest decreased heat generation in the setting of spontaneous periodic hypothermia despite the low core body temperature (5, 75, 114). At- tempted cooling while patients were hypothermic has resulted in shivering and body heat conserva- tion. Several patients, including the present case, have demonstrated a febrile response to infection or diagnostic challenge (114); some during a hypo- thermic episode (40, 50, 111, 116, 121). Taken to- gether, this evidence supports a “reset thermostat” concept with coordination between heat loss and conservation mechanisms, and the presence of an intact autonomic nervous system regulating the ef- ferent vasomotor pathways (29, 75, 89, 111). Sheth et al (114) reported that immediate external warming altered the course in 2 of 3 patients, however, and proposed an abnormal anterior hypothalamic extra- pyramidal shivering mechanism rather than an alter- ation of set point. In addition to episodes of frank hypothermia and evidence suggesting a reset thermostat (in most 274 KLOOS cases), subtle abnormalities of thermoregulation have also been documented. Duff et al (29), in their second case, reported a delayed response to intrave- nous pyrogen and suggested a temperature-regulat- ing mechanism abnormality beyond a lowered set point. Shapiro et al (111) noted impaired shivering and a delayed recovery from hypothermia in their second case. Slotki and Oelbaum (116) documented mild abnormalities of central thermoregulation be- tween attacks in a patient with spontaneous periodic hypothermia. The patients reported by Maehle (81) and Duff et al (29) had reversed diurnal temperature rhythms during attacks. Possible causal mechanisms The inciting pathophysiologic mechanism(s) lead- ing to the hypothermia and generally apparent “re- setting of the thermostat” remains unknown. It would be challenging to explain these recurring events, often beginning well into adult life and with intervals between “attacks” spanning hours to years, based solely on some mechanism which is continu- ally present (that is, a degenerative, irritative, neuro- chemical, or structural abnormality). Given the epi- sodic nature of the syndrome, it seems logical that the overriding mechanism(s) is itself most likely intermittent. Degenerative processes: An intermittent, slowly progressing degenerative process might account for the progressive increase in frequency or severity of episodes seen in some cases (40, 59, 63, 75, 92, 111). Duff et al (29) reported that mental deterioration occurred in a patient with spontaneous periodic hy- pothermia with continued periods of hypothermia, despite control of generalized seizure activity. Sha- piro et al (111) noted that in both their cases the body temperature between episodes gradually de- clined over the years. However, the best evidence for a degenerative mechanism is the severe neuronal loss and nonspecific fibrillary gliosis described by Noel et al (92) in the arcuate nucleus and premam- millary formations of the posterior infundibular nu- clei at autopsy in their patient with Shapiro syn- drome. Conversely, Engel and Aring (35) described a young man without hypothermia but with repeated paroxysms of rhinorrhea, coldness, shivering, chills, pallor of the extremities, fluctuating blood pressure, and spiking temperature, followed by abrupt temper- ature reduction toward normal with profuse sweat- ing and flushing. Autopsy revealed cystic degenera- tion of the dorsomedial nucleus, the internal medullary lamina, and the lateral nuclei of the right thalamus: no hypothalamic pathology was men- tioned. To my knowledge, no other cases have been reported for which there are histologic data, and only recently have high resolution imaging modal- ities become available. Neurochemical dysfunction: An intermittent neu- rochemical dysfunction might be another basis for the episodic nature of these attacks. Neurotransmit- ters in humans known to modulate thermoregulation include dopamine, acetylcholine, serotonin (5, 114), prostaglandins, and several neuropeptides (26, 74). A biochemical agent directly responsible for the al- terations of temperature seen in patients with spon- taneous periodic hypothermia or Shapiro syndrome, however, is unknown. Catecholamine levels have been found to be elevated in some cases of spontane- ous periodic hypothermia (24) and Shapiro syn- drome (89, 107). Two such patients have received the catecholamine release inhibitor clonidine, 1 with success (24). A second patient (125) successfully treated with clonidine had normal plasma and uri- nary catecholamines; the authors of the latter report argued for a central, rather than peripheral, site of pharmacologic action. Catecholamines have multi- ple effects on heat generation and loss (60). Cloni- dine is also known to exert a central hypothermic effect mediated by o-adrenoceptors in rats (131), and hypothermia has been noted in humans as a symptom of clonidine toxicity (1). Clonidine has also been reported (87) to suppress paroxysms in a pa- tient with “central autonomic epilepsy” without dis- ordered temperature control. AVP is known to affect thermoregulation (25, 27, 67, 76, 85, 94, 123). Its secretion is triggered by emo- tional stress (93, 124), hypoglycemia (10-12, 34, 68, 69, 128), nausea/vomiting (102, 104, 112), adrenergic stimuli (7, 13, 84, 108, 109) (catecholamines), and other stimuli. Infusion of AVP into humans (127) produces peripheral vascular changes similar to those seen during hypoglycemia (128). These changes appear similar, if not identical, to those demonstrated in 1 well-studied case (40) of sponta- neous periodic hypothermia. Reactive hypoglycemia was suggested (but not strictly diagnosed) in a previ- ous report (29). Hypoglycemia is accompanied by a fall in body temperature (28), which is thought to be part of a thermoregulatory mechanism to protect the brain from the harmful effects of glucose depri- vation (46). In humans, heat loss during hypoglyce- mia occurs despite an increase in nonshivering heat production (43), and is associated with high skin blood flow due to arteriovenous shunting, sweating, and depressed shivering (128). Further, Brandt et al (17) reported a child with subacute necrotizing en- cephalomyelopathy (Leigh syndrome) with complex neurologic attacks which included periods of hypo- thermia. Brain and CSF analysis revealed elevation of endogenous opioids (endorphin fractions, met- and leu-enkephalins). Morphine and narcotic ana- SPONTANEOUS PERIODIC HYPOTHERMIA 275 logues are known to enhance AVP release (49, 100). Naloxone, a narcotic and endogenous opiate antago- nist devoid of agonist properties, dramatically re- versed the child’s symptoms but only intermittently and for short time periods. Another study (88) re- ported that naloxone reversed the syndrome of inap- propriate antidiuretic hormone (SIADH). This finding suggested that SIADH could be caused by excessive secretion of endogenous opioids in the neurohypophyseal system (88). Naloxone resulted in a temperature increase to normal in a patient with Shapiro syndrome during 1 of 2 trials (89), and a slight temperature increase in another patient (75). Other authors (125) have reported unsuccessful tri- als. Previous case reports of Shapiro syndrome have suggested possible abnormalities of water metabo- lism, and previous authors have considered the role of AVP in Shapiro syndrome, but most have found the possibility unlikely (71, 92, 125). Trritative mechanisms: An etiology based on in- termittent irritation could theoretically occur via several mechanisms. An inflammatory process such as an autoimmune disease or immunologic process (61) seems unlikely given the lack of associated sys- temic manifestations, the failure of exogenous ste- roids in all attempts, and the absence of diagnostic or suggestive histologic data. An infectious etiology seems equally unlikely given the extensive search by multiple authors for such an agent, prolonged empirical antibiotic trials, and lack of supportive his- tologic data. An intermittent, irritative process due to nongeneralized seizure activity of the hypothala- mic structures, or a resulting postictal period, re- mains a possibility. However, enthusiasm for this latter mechanism appears to be waning. Diencephalic epilepsy: In 1907, Gowers (48) ob- served episodes of behavioral changes, sweating, re- duced body temperature, and chills in several pa- tients, and regarded these events as focal seizures of the “vegetative nervous system.” In 1929, Penfield (96) reported a patient with a third ventricle tumor, markedly increased intracranial pressure, and a de- fect through the corpus callosum. He proposed that mechanical irritation lead to “diencephalic auto- nomic epilepsy”; symptoms included flushing, dia- phoresis, and a fall in temperature “well below nor- mal” during the most severe attacks. With an obvious central nervous system structural abnormality, such as in the Penfield case, an epileptic event is clearly possible. One can propose other theoretical mecha- nisms to account for recurrent thermoregulatory dysfunction in this patient, however, such as recur- rent transient local ischemia, pressure, or hypoxia. In Shapiro syndrome and spontaneous periodic hy- pothermia, the latter mechanisms seem less likely. Seventeen of 24 cases (5, 24, 37, 75, 81, 107, 114, 125) of Shapiro syndrome or spontaneous periodic hypothermia reported abnormal EEG findings, in- cluding nonspecific abnormalities. Five cases (29, 50, 73, 120, 121) are reported to manifest seizures. Twenty-two cases (5, 20, 24, 29, 33, 37, 40, 50, 51, 59, 63, 75, 81, 106, 107, 111, 114, 120, 121, 125) report anticonvulsant drug therapy trials: 5 (24, 50, 59, 63, 111) resulted in resolution, and 3 (51, 75, 81) had partial or temporary improvements. Shapiro et al (111) proposed that the “paroxysmal, involuntary, repetitive and stereotyped neuronal discharges, by all criteria, [fell] within the definition of epilepsy.” Further, it was argued that the signs and symptoms of temperature alteration, behavior changes, and EEG abnormalities all fell within the functional do- main of the diencephalon. Should these periodic episodes of hypothermia be of epileptic origin, the lower-than-expected response rate to anticonvulsive medications is unexplained (albeit a relatively narrow range of tested anticonvul- sants). Recent studies (83, 117) have documented that carbamazepine is more effective than phenobar- bital, phenytoin, primidone, and valproate in control- ling partial seizures. Treatment trials with this agent for spontaneous periodic hypothermia (5, 40, 114) and Shapiro syndrome (125) have occurred 5 times previously and failed. However, only a low daily dose of 400 mg was employed in 1 case (40), dose was not specified in the others (5, 114, 125), and none reported trough serum levels achieved. Yet, despite frequent EEG abnormalities, seizure foci have not been identified frequently, and some (29, 111) have speculated that the EEG abnormalities were in part areflection of the hypothermia. Further, it is difficult to understand how an epileptic event (as well as the other mentioned theoretical mechanisms) would establish a new set point with essentially intact ther- moregulatory mechanisms to defend it, and not just thermoregulatory dysfunction. On the other hand, if in fact these periodic epi- sodes of hypothermia are of epileptic origin, one must account for why these patients would be pre- disposed to recurrent nongeneralized seizure activ- ity involving hypothalamic structures. The presence of a degenerative, irritative, or structural abnormal- ity could serve as such a nidus which may be very subtle and not detected by CT, MRI, PET, or standard postmortem analysis. Consideration was given above to the former 2 theoretical processes. Agene- sis of the corpus callosum is a developmental struc- tural anomaly associated with closure of the anterior neural tube (58). Some individuals with agenesis of the corpus callosum appear clinically normal (36); others have associated additional gross midline and random structural abnormalities (18, 53, 77, 86). Se- vere developmental defects are associated with early 276 KLOOS mortality, mental and physical retardation, and gen- eralized and focal seizure activity. Milder anomalies have been associated with a more normal life span, but most patients with milder anomalies have epi- lepsy (often with adult onset), and many have mild mental retardation (111). The importance of the cor- pus callosum as a structure linking communication between the 2 hemispheres (118), and not as the center for thermoregulatory function has been well established. Surgical section of the corpus callosum does not result in hypothermia or seizures (47). Pa- tients with agenesis of the corpus callosum do not have deficits in interhemispheric transfer of informa- tion, possibly due to compensation by other path- ways, although they do manifest defects in perceptu- omotor coordination (36, 45, 65, 113, 118). Thus, if structural abnormalities are important in the occur- rence of Shapiro syndrome and spontaneous peri- odic hypothermia, they are likely to be defects that are only associated with agenesis of the corpus callo- sum, and whose extent and severity account for the presence and variability of the hypothermic episodes (111). Thus, it is likely that while one focuses on the grossly obvious presence or absence of the corpus callosum to distinguish Shapiro syndrome from spontaneous periodic hypothermia, a spectrum of less obvious (and etiologically more important) mid- line abnormalities may exist. This de-emphasis on the corpus callosum would explain the discrepancy between the not uncommon absence of the corpus callosum (approximately 1-3 per 1,000 CT scans [37, 70]), and the rarity of Shapiro syndrome. Associated episodic abnormalities The notion of a temporary focal dysfunction, or even discharge, that encompassed more than the thermoregulatory centers could explain some of the associated abnormalities documented during peri- ods of hypothermia in patients with Shapiro syn- drome and spontaneous periodic hypothermia. Al- though these reports involving facial asymmetry (29), abnormal sex hormones and gonadotropins (106, 116), secondary amenorrhea (121), prolactin (116), and TSH (71, 75) may arguably all be ac- counted for by acute illness or assay variability, the possibilities of associated hypothalamic-pituitary dysfunction should be noted. This same point is made in the second patient described by Duff et al (29) with spontaneous periodic hypothermia, who, together with periods of hypothermia, had reversed diurnal temperature rhythm and large volumes of dilute urine made at night. This abnormality may imply dysfunction of the hypothalamic-posterior pi- tuitary antidiuretic hormone system, although they stated that diabetes insipidus was not present. It may also be accounted for by abnormal renal tubular reabsorption of sodium and water secondary to hy- pothermia (90, 110). However, other cases (71, 89) of Shapiro syndrome have had abnormalities of water metabolism reported. Mooradian et al (89) proposed an abnormality of posterior pituitary function in their patient with Shapiro syndrome whose arginine vasopressin failed to rise in response to insulin-in- duced hypoglycemia, although water deprivation testing was consistent with primary polydipsia. Ko- vacs et al (71) reported thirst and vasopressin levels typical of downward resetting of the osmostat during hypothermia, and absent thirst and vasopressin re- sponses between attacks. Several authors have re- ported the association of paroxysmal hypertension with spontaneous periodic hypothermia (5, 24, 114) and Shapiro syndrome (107). These reports are intri- guing given the close proximity of the vasomotor center, controlling arterial blood pressure, to the an- terior hypothalamic region (57). Associated baseline abnormalities The frequent relationship between structure and function raises the question of whether previously reported cases of Shapiro syndrome or spontaneous periodic hypothermia had baseline abnormalities be- yond those present during hypothermic episodes. As mentioned earlier, Noel et al (92) described focal abnormalities in the infundibular nuclei in their pa- tient with agenesis of the corpus callosum associ- ated with relapsing hypothermia. The arcuate nuclei are of importance to gonadotropic function (38), and their patient was noted to have testicular atrophy. Gonadotropin levels were not reported, however. Guihard et al (50) reported a child with agenesis of the corpus callosum, primary organic polydipsia with insufficient AVP, craniofacial midline abnor- malities, spontaneous relapsing hypothermia, pitu- itary dwarfism, and precocious puberty. Dutau et al (83) reported a child with Shapiro syndrome, facial- cranial dysraphism, hypotonia, and growth and men- tal retardation. Sheth et al (114) reported spontane- ous periodic hypothermia in a child with moderate mental retardation and developmental aphasia. Ar- royo et al (5) reported a child with spontaneous periodic hypothermia with normal serum triiodothy- ronine (T3) and thyroxine (T4) levels but with an inadequate TSH response to thyroid releasing hor- mone (TRH) stimulation both during and between episodes. Treatment It is difficult to evaluate therapy for spontaneous periodic hypothermia and Shapiro syndrome. Lim- ited data are available due to the rarity of identified cases, the intermittent nature of the disorders, the lack of a control population, and the absence of an animal model. SPONTANEOUS PERIODIC HYPOTHERMIA 277 Maneuvers performed at the onset of an episode and reported to abort an attack in 1 case each have included drying the skin (5) and immediate warming (114). Drug therapy with anticonvulsant agents has been discussed above. Two spontaneous remissions have been reported (29, 114); successful clonidine therapy has been reported previously in 2 of 3 trials (24, 107, 125), and preliminary success has been re- ported (51) in a fourth trial. The serendipitous suc- cess of oxybutynin has been reported (73). Chlor- promazine treatment has been successful in 2 of 4 cases of Shapiro syndrome (37, 75, 106). Interest- ingly, 1 of the 2 successful cases was a patient with episodes of exacerbated hypothermia superimposed on a hypothermic baseline, and both abnormalities resolved (37). Chlorpromazine failed in the 1 case (29) of spontaneous periodic hypothermia in which it was tried. Chlorpromazine, which has been used for the induction of hypothermia for surgery (101), showed transient success in treating a case of peri- odic pyrexia (130). Chlorpromazine’s mechanism of action is unknown. The drug has psychotropic, seda- tive, and antiemetic activities, as well as antiadrener- gic, peripheral anticholinergic, ganglionic blocking, antihistaminic, and antiserotonin effects. It affects all levels of the CNS, primarily the subcortical areas. This drug should be used only with the understand- ing of the risks of tardive dyskinesia and neuroleptic malignant syndrome, as well as its other side effects (97). The antiserotonergic agent cyproheptadine has been used with partial or complete success in 4 cases of spontaneous periodic hypothermia (5, 114), and with transient success in Shapiro syndrome (75). One case of spontaneous periodic hypothermia was treated with total sympathectomy with symptomatic improvement despite consequent postural hypoten- sion (40). Summary Spontaneous periodic hypothermia is a rare syn- drome of recurrent, centrally mediated hypothermia without an identifiable systemic cause or brain le- sion. Most patients defend a temporarily lowered temperature “set point” during episodes of hypother- mia, despite manifesting many well-known systemic consequences of core temperature hypothermia. No case of death directly attributable to an episode of spontaneous periodic hypothermia has been re- ported, although many of the serious systemic ef- fects of hypothermia have been documented in these cases, so it is not unlikely that death may occur. The syndrome’s cause, and that of Shapiro syndrome, remains unknown. Pharmacologic trials to date have been only modestly successful. Anticonvulsant agents, clonidine, and cyproheptadine appear the most likely to succeed, with cyproheptadine being a reasonable first choice. Given that the term “spontaneous periodic hypo- thermia” describes a syndrome, and not a pathophys- iologic mechanism, it is likely to encompass a com- mon eventuality, arrived at via several different pathways. One can postulate mechanisms such as structural abnormalities, trauma, infection, irrita- tion, and degeneration involving strategic locations which create a focus for epileptic or other periodic dysfunction whose scope involves the centers for thermoregulation. The existence of 2 distinct, oppo- sitional thermoregulatory centers would allow for speculation of similar mechanisms accounting for cases of both periodic hypo- and hyperthermia (61). Postmortem data regarding the hypothalamic and surrounding areas from future cases of Shapiro syn- drome and spontaneous periodic hypothermia would be of great interest. Further, more sensitive in vivo testing methods are clearly needed. The role of PET or single photon emission computed tomog- raphy (SPECT) with technetium 99m-labeled hexa- methylpropylene amine oxime (Tc 99m HMPAO) performed acutely during an episode remains to be characterized (64, 103, 105). The term “diencephalic epilepsy” may in fact be accurate, given the periodic episodes of the case presented here and similar cases resulting from non- generalized seizure activity, with or without an un- derlying predisposing lesion. The label diencephalic epilepsy has been merely speculative so far, how- ever, as definitive evidence of seizure activity has not been documented. 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