Episodic Hypothermia with Mutism in an Older Woman
Episodic spontaneous hypothermia is rare and occurs in a range of brain pathology, including congenital brain malformations, and acquired traumatic, ischemic, neoplastic, or inflammatory mechanisms involving the hypothalamus. Reports of patients with prominent hypothermia in the absence of evidence of structural brain lesions or other cause have been described in the literature,1-4 and reviewed.5 Confusion or mutism is a frequently observed clinical feature. The underlying pathology in most cases is unknown, but is likely to involve dysfunction in areas of the hypothalamus concerned with thermoregulation.
Mrs. F, an 86-year-old female, presented to the emergency department with episodic spontaneous hypothermia and mutism numerous times over a five-year period. On each of the 11 admissions, all but two of which occurred during the colder months of the year, the peripheral body temperature recorded on arrival ranged from 86.5 degrees F (30.3 degrees C) to 93.5 degrees F (34.2 degrees C) (mean, 91.2 degrees F [32.9 degrees C]; SD 1.1). Marked hypertension was invariably present, often with bradycardia. On several occasions asterixis was demonstrable. No hyperhidrosis was observed. Mrs. F was not diabetic. Her regular medications were aspirin, bendroflumethiazide, and ramipril, and she was taking senna and lactulose for constipation. The patient was a nonsmoker and did not consume alcohol. Her cohabiting husband was present at each admission and showed no signs of hypothermia.
Consistent findings on each admission were: a normocytic anemia with hemoglobin 9-11 g/dL (reference range, 13.5-16.5 g/dL); mean cell volume range, 80 fL to 85 fL (reference range, 80-98 fL); a mild hyponatremia with sodium ranging from 129 mEq/L to 133 mEq/L (reference range, 135-145 mEq/L); and a raised urea of 20-46 mg/dL (reference range, 7-20 mg/dL). A single raised ammonia level of 55 µg of nitrogen/dL (reference range, 15-50 µg of nitrogen/dL) was detected during one admission, and on a separate occasion two discrete urine samples were positive for porphobilinogen, but with a negative simultaneous blood porphyrin screen.
Normal investigations included standard liver enzyme, renal and bone profile assays, erythrocyte sedimentation rate, C-reactive protein, vitamin B12, random serum glucose, thyroid function tests, cortisol, folate and ferritin, and arterial pH level. Septic screening tests were consistently negative. Urinary organic acid and drug assays for methadone, opiates, tricyclics, salicylate, benzodiazepines, cocaine, cannabinoids, barbiturates, paracetamol, phenothiazines, and amphetamines were negative, as was a 24-hour urinary catecholamine screen. Syphilis and hepatitis B and C serologies were negative. Anti-nuclear, anti-thyroid peroxidase, and anti-voltage–gated potassium channel antibody screens were negative.
Magnetic resonance imaging (MRI) of the brain showed generalized atrophy, with several small white-matter hyperintensities considered to represent chronic small-vessel ischemia; both were typical of findings in other subjects of similar age. Cerebrospinal fluid constituents (cell count, protein, and glucose) were normal. Electroencephalography (EEG) shortly after admission showed nonspecific diffuse slow wave activity without epileptiform features. An ultrasound scan and 3-phase contrast angiographic computed tomography scan of the abdomen to detect portosystemic shunting were unremarkable.
Interictal neuropsychological and psychiatric evaluations were unremarkable. On each occasion the hypothermia, mutism, marked hypertension, and bradycardia resolved within three to five days with only supportive re-warming therapy and intravenous fluid resuscitation. Re-warming took between 2.5 and 14 hours (mean, 8.5 hr; SD 3.8). The patient returned to normal function between episodes.
A simple home environmental cause for the recurrent hypothermia was not isolated, although episodes coincided with the colder months of the year on nine of 11 occasions. The patient’s husband was unaffected despite being in the same room as Mrs. F prior to each admission, and there was no evidence for a primary psychiatric basis for admission, nor obvious secondary gain when explored.
The single raised serum ammonia, with asterixis and diffuse slow wave activity on EEG, led to the consideration of the possibility of portosystemic venous shunting and metabolic encephalopathy. There was no obvious relation to a high protein dietary load in the patient, nor abnormality of liver function noted, but occult shunts are described even in those without obvious cirrhosis.6 Although invasive celiac artery angiography was not performed, it was felt that a significant occult shunt was effectively excluded.
Two separate urine samples registered positive for porphobilinogens in the presence of mild hyponatremia, consistent with acute intermittent porphyria (AIP). Hypothermia as a manifestation of acute porphyria has not been described, and it was felt improbable that porphyria would present so late in life and without abdominal pain. (A population-based Swedish study based on 190 women with AIP observed a mean age of 52 years [range, 19-76 yr] and acute abdominal pain in 99%.7) Assuming these results were spurious, 24-hour urinary porphyrin levels were not established, and the most likely explanation for the hyponatremia was considered to be thiazide diuretic therapy, although voltage-gated potassium channel-related limbic encephalitis was also considered and excluded.8
Mrs. F showed no evidence of structural brain abnormality using MRI. The classic congenital malformation associated with episodic hypothermia is Shapiro’s syndrome, where agenesis of the corpus callosum is associated with a more diffuse basal forebrain malformation including the anterior hypothalamus.9 This syndrome is frequently accompanied by periodic hypothermia, with some patients exhibiting a cognitive deficit and/or hyperhidrosis. Psychotic symptoms may also be prominent. Shapiro and colleagues9 concurred with Penfield1 in ascribing the dysfunction in these patients to a form of diencephalic epilepsy. The hypothermia is believed to originate primarily from hypothalamic dysfunction rather than the agenesis of the corpus callosum, because callosotomy in humans does not cause hypothermia,10,11 whereas stimulation of the preoptic anterior hypothalamic region in animals does.12 Treatment with clomipramine or clonidine has been reported to have varying, but generally poor, efficacy.5,13,14
Acquired injury to the anterior hypothalamus has been proposed to account for episodic hypothermia in a number of case reports. These include discrete inflammatory,15 traumatic,16 and neoplastic17,18 changes that have been demonstrable with standard brain imaging techniques. However, Thomas and Green19 presented a case of episodic hypothermia in a 39-year-old woman with no evidence of gross structural brain changes, as in Mrs. F’s case and others.3,14,20 Thomas and Green described a “hypothermic flap” on examination, possibly similar to the asterixis that was observed in this case. The paroxysmal hypertension with bradycardia seen in Mrs. F has been described in patients with episodic hypothermia,14 as has normocytic anemia.16
Some authors have postulated an epileptic basis for episodic hypothermia on the basis of EEG changes and some responsiveness to antiepileptic therapy.14,20 However, others have noted that several case reports with antiepileptic drug trials have failed,5 and argue that the EEG changes may be secondary4—a view that the authors of this case report would concur with.
Mrs. F had evidence of chronic ischemic cerebrovascular disease on brain MRI. This is a common finding in this age group and, while it may be a predisposing factor, selective and bilateral microvascular ischemia involving the anterior hypothalamus seems unlikely. A degenerative or autoimmune process has not been excluded. The episodic nature of the hypothermia in the patient might be a result of failure to induce compensatory warming mechanisms following a reduced body temperature occurring in the colder months of the year. Such pathology might occur more commonly in the elderly population than is generally recognized and contribute to the multifactorial hypothermia often seen in this age group. While exposure, often through inadequate home central heating, may be an important precipitant of hypothermia in the elderly population, there may be an additional biological predisposition centered on hypothalamic dysfunction that is underrecognized at present and warrants further study. It is currently uncertain whether drugs such as clonidine or clomipramine, which can be of benefit in Shapiro’s syndrome, are consistently beneficial in patients with other causes of episodic hypothermia.16,21
Primary hypothalamic dysfunction should be considered in the differential diagnosis of paroxysmal hypothermia in the elderly population. Diffuse small-vessel cerebrovascular disease may be a contributing factor.
Outcome of the Case Patient
Mrs. F made a full functional recovery after each presentation. She had no recollection of events during the hypothermic periods of her admissions and remains anxious to avoid further episodes. Drug therapy with clonidine or clomipramine was not initiated due to contraindications. The patient, her husband, and her primary care physician have been given advice to take extra precautions to keep warm during the colder months, and Mrs. F was given a letter to carry with her at all times explaining her condition. At the time of this article going to press, there have been no further admissions.
The authors report no relevant financial relationships.
Dr. Goodfellow and Ms. Manning are from Oxford University Medical School, Oxford; Drs. Pati, Bogdanovic, and Littleton are from the Department of Neurology, John Radcliffe Hospital, Oxford; and Dr. Turner and Professor Ebers are from the Oxford University Department of Clinical Neurology, Oxford, UK.
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