DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY
CLINICAL LETTER
Spontaneous periodic hypothermia and hyperhidrosis: a possibly novel cerebral neurotransmitter disorder MARCELO RODRIGUES MASRUHA | JAIME LIN | JULIANA HARUMI ARITA | EDUARDO FERREIRA DE CASTRO NETO | DBORA AMADO SCERNI | ESPER ABRffiO CAVALHEIRO | MARIA DA GRAA NAFFAH MAZZACORATTI | LUIZ CELSO PEREIRA VILANOVA Department of Neurology and Neurosurgery, Federal University of S¼o Paulo, S¼o Paulo, Brazil. Correspondence to: Dr Marcelo Rodrigues Masruha at Department of Neurology and Neurosurgery, Rue Botucatu no. 720, Federal University of S¼o Paulo, S¼o Paulo 04023-900, Brazil. E-mail:
[email protected]
PUBLICATION DATA
Accepted for publication 2nd November 2010. Published online.
Spontaneous periodic episodes of hypothermia still defy medical knowledge. In 1969, Shapiro et al. described the first two cases of spontaneous periodic hypothermia associated with agenesis of the corpus callosum. Recently, Dundar et al. reported a case of spontaneous periodic hypothermia and hyperhidrosis without corpus callosum agenesis, suggesting that the periodic episodes of hypothermia might be of epileptiform origin. Here we describe two paediatric patients with spontaneous periodic hypothermia without corpus callosum agenesis and demonstrate, to our knowledge for the first time, altered levels of neurotransmitter metabolites within the cerebrospinal fluid.
Hypothermia, defined as a core temperature lower than 35C, may be the result of several conditions: accidental causes (drugs, intoxication, exposure to extreme cold temperatures); endocrine conditions (hypothyroidism); and central or peripheral neurological disorders.1,2 Spontaneous periodic episodes of hypothermia, however, still defy medical knowledge. In 1969, Shapiro et al.3 described the first two cases of spontaneous periodic hypothermia associated with agenesis of the corpus callosum. Since then, over 50 cases have been reported with several attempts to undercover its pathophysiology.2 Structural, epileptiform, or biochemical abnormalities were suggested as possible causes; however, the definite underlying process remains unclear. Recently, Dundar et al.1 reported a case of spontaneous periodic hypothermia and hyperhidrosis without corpus callosum agenesis, suggesting that the periodic episodes of hypothermia may be of epileptiform origin. We describe two paediatric patients with spontaneous periodic hypothermia without corpus callosum agenesis and demonstrate, to our knowledge for the first time, altered levels of neurotransmitter metabolites within the cerebrospinal fluid. The Sa˜o Paulo hospital ethics committee approved this clinical letter and the parents gave informed consent for publication.
CASE REPORTS Case 1 A 4-year-old female was admitted with spontaneous episodes of dysthermia (hyper- and hypothermia), sweating, and drowsª The Authors. Journal compilation ª Mac Keith Press 2010
iness of about 2 week’s duration. The attacks occurred daily, lasted about 1 to 3 hours and presented spontaneous remission, regardless of any therapeutic attempt (Table I). During the hypothermic attacks, she sweated profusely and felt faint; her skin was pale and cool. The physical examination was otherwise normal. She was born of non-consanguineous parents, with an uneventful gestational and neonatal history. She also showed normal neurodevelopment and there was no family history of neurological disorders. Laboratory findings included hematocrit at 35%, hemoglobin at 13.1g ⁄ dL, a white blood cell count of 9200 ⁄ mL, and a platelet count of 193 000 ⁄ mL. Blood urea nitrogen, serum creatinine, liver function tests, fasting blood sugar, serum electrolytes, serum uric acid, erythrocyte sedimentation rate, C-reactive protein, thyroid function tests, adrenocorticotropic hormone, and urinalysis produced normal results. Electrocardiography, echocardiography, and Holter monitorization demonstrated normal results. Cranial magnetic resonance imaging (MRI) also demonstrated normal results, indicating an intact corpus callosum. A 72-hour video-electroencephalogram record showed no abnormalities; no epileptiform activity was evident during dysthermic events. Positron emission tomography was also normal, but it was performed in an asymptomatic period. The determination of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) was performed according to the method of denaturing high performance liquid chromatography (DHPLC), which showed decreased levels of these metabolites (Table II). The DOI: 10.1111/j.1469-8749.2010.03854.x 1
CSF sample (10ml) was taken in the morning by lumbar puncture. There was no contamination with blood and the child was not using any kind of medication by this time. The patient was treated with carbamazepine, cyproheptadine, and fluoxetine, but the episodes have not stopped. She has maintained these symptoms since March 2009.
Case 2 A 16-month-old female patient was referred to neuropaediatric evaluation for recurrent episodes of hypothermia. She was born of non-consanguineous parents, with an uneventful gestational and neonatal history. She also showed normal neurodevelopment and there was no family history of neurological disorders. The patient had been healthy up until she turned 8 months old, at which time she presented her first episode of hypothermia (32C) associated with hyperhidrosis. The episodes started to recur with a frequency of two to three times a week, mainly during sleep. Between the episodes, the patient presented a normal physical examination with a good overall condition. The neurological examination was also unremarkable. Laboratory findings included hematocrit at 32%, hemoglobin at 11.6g ⁄ dL, a white blood cell count of 5700 ⁄ mL, and a platelet count of 276 000 ⁄ mL. Blood urea nitrogen, serum creatinine, liver function tests, fasting blood sugar, serum electrolytes, serum uric acid, erythrocyte sedimentation rate, C-reactive protein, thyroid function tests, adrenocorticotropic hormone, and urinalysis produced normal results. Electrocardiography, echocardiography, and Holter monitorization produced normal results. Cranial MRI also produced normal results, indicating an intact corpus callosum. A 72-hour videoelectroencephalogram record showed no abnormalities; no epileptiform activity was evident during dysthermic events. Positron emission tomography was also normal, but it was performed in an asymptomatic period. CSF neurotransmitter analysis showed decreased levels of 5-HIAA and HVA (Table II). The CSF sample (6ml) was taken in the morning by lumbar puncture. There was no contamination with blood and the child was not using any kind of medication by this time. The patient was treated with carbamazepine, fluoxetine, cyproheptadine, and melatonin, but the episodes have not stopped. She has maintained these symptoms since December 2009.
What this paper adds • To our knowledge this is the first report to show a consistent abnormality in cerebral neurotransmitter levels in patients with spontaneous periodic hypothermia without corpus callosum agenesis.
DISCUSSION Several attempts have been made to explain the pathophysiology of spontaneous periodic hypothermia. In cases of Shapiro syndrome, there is the presence of a triad of spontaneous periodic hypothermia, hyperhidrosis and agenesis of the corpus callosum.2 In those cases, it was suggested that the episodes of hypothermia were due to a paroxystic reset of the hypothalamic thermostat with a lower temperature set point.2 The exact pathophysiological mechanism for this syndrome is not understood. Postulated mechanisms include degenerative processes, neurochemical dysfunction and inflammatory processes, and epileptic activity.4 In our cases, there were no signs of any neurodegenerative, inflammatory, or epileptic condition. In cases where there is no clear evidence of structural abnormalities, such as in Shapiro syndrome, the pathophysiological process behind the episodes of hypothermia is even more challenging. In 2008, Dundar et al.1 reported a case of spontaneous periodic hypothermia with hyperhidrosis without corpus callosum agenesis. After extensive investigation, increased perfusion in the right thalamus, basal ganglia, and inferior frontal areas were revealed using single-photon emission (SPECT) computed tomography during an attack. The authors proposed a dysfunction in the hypothalamic region without structural lesion, and the SPECT results were consistent with a post-ictal period. However, no epileptiform Table II: Cerebrospinal fluid values for 5-HIAA and HVA (nmol ⁄ L) Case 1
Values
Reference values (3–6y)
5-HIAA HVA
13.72 109.22
106–316 304–658
Case 2
Values
Reference values (6mo–2y)
5-HIAA HVA
19.86 153.13
170–490 344–906
Reference values (nmol ⁄ L) according to Ormazabal et al.9
Table I: Body (axilar) temperature curve for 10 consecutive days (C), measured with a mercury thermometer
Case 1 Morning Afternoon Night Case 2 Morning Afternoon Night
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
35.2 34.8 37.4
38.9 39.2 37.8
33.2 32.8 33.5
36.4 36.8 37.2
33 36 36.5
33 33.8 34.6
35.3 34.3 36.8
38.8 33.6 34.2
34.2 35 35
35 33.2 35.8
38.5 35.1 37.2
36.1 33.2 34.8
34.9 35.6 36.2
33.8 35.2 35
34.3 35 36.1
35.2 33 36
33.1 34.8 34.9
38 35.4 36
36.3 34.8 35.8
35 34.8 35.9
2 Developmental Medicine & Child Neurology 2010
activity abnormalities were found in the electroencephalogram investigation.1 Epileptiform activities as the underlying cause of spontaneous periodic hypothermia were previously advocated. However, this has always been questioned because no concrete evidence of seizure activity has ever been documented. Electroencephalography exams performed during the episodes failed to show epileptiform abnormalities, and antiepileptic drugs have been relatively ineffective in treating this disorder.5,6 In our cases, the same extensive investigation was performed showing neither structural nor epileptiform abnormalities. Antiepileptic treatment was also tried with poor response. However, the levels of neurotransmitters in the CSF showed, in both of our cases, consistently decreased levels of 5-HIAA and HVA, and metabolites of serotonin and dopamine. Hypothalamic thermoregulation is highly dependent upon the levels of serotonin and dopamine. Animal models have
shown that elevated levels of hypothalamic 5-HT are associated with hyperthermia and that lower levels of hypothalamic 5-HT are associated with decreases in colon temperature in rats.7 In humans, the role of serotonin in the pathogenesis of spontaneous periodic hypothermia was proposed by Arroyo et al.8 based on the clinical presentation and on relative success with an empirical treatment with cyproheptadine in two patients. This is the first report to show a consistent abnormality in cerebral neurotransmitter levels in patients with spontaneous periodic hypothermia without corpus callosum agenesis. These findings suggest a new route in the investigation and treatment of these patients and categorize this disorder as a possible new cerebral neurotransmitter disorder. ACKNOWLEDGMENTS This study was sponsored by Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo (FAPESP).
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Clinical Letter 3
