Abstract

An 18-year-old woman with a history of focal epilepsy presents with increasingly frequent seizures, encephalopathy, multiple laboratory abnormalities, and hypothermia. During her hospital course, her symptoms waxed and waned. Multiple etiologies of her symptoms were considered, but the spontaneous resolution of her symptoms and an abnormal MRI of the brain revealed the final diagnosis.

An 18-year-old woman with a history of focal epilepsy secondary to multifocal neonatal brain infarcts, hydrocephalus requiring ventriculoperitoneal shunt placement (with no history of revision), and static encephalopathy presented to an outside hospital because of increasingly frequent seizures, weight loss, and encephalopathy. She previously lived at home with family but started spending most of her time in a group home during the preceding 6 weeks. The patient’s medications included zonisamide, eslicarbazepine, aripiprazole, extended-release methylphenidate, and a combined oral contraceptive pill; there was no history of noncompliance. While she was at the group home, her dose of zonisamide was increased from 100mg to 150mg daily although her recent seizure frequency had remained unchanged at 1 seizure per month.

Two weeks before presentation, her mother noticed that she was not “acting like herself.” Typically, the patient has excellent receptive language with limited expressive language. However, she can say individual words to express her desires, and she is able to make decisions when presented with choices. She can walk, run, and play certain sports. She is typically cooperative with requests. However, over those 2 weeks, her mother noted that the patient appeared easily fatigued with a decreased overall activity level, had a “wobbly” gait, demonstrated difficulty coordinating fine movements, and had decreased receptive and expressive language beyond her baseline level.

Her mother subsequently decreased zonisamide back to 100mg daily. Her symptoms improved, but she had 3 of her typical seizures shortly thereafter. Per the recommendation of her outpatient neurologist, her dose was increased back to 150mg daily. The patient had no further seizures, but her fatigue, ataxia, sialorrhea, and twitching further worsened. Zonisamide was decreased to 125mg daily because of concern for zonisamide toxicity. She then had 4 more breakthrough seizures in addition to continuing sedation, ataxia, and sialorrhea, which prompted her mother to bring her to an outside emergency department for evaluation.

On presentation to the emergency department, her temperature was 31.3 °C, pulse was 48 beats per minute, blood pressure was 116/64, and respiratory rate was 14. Her physical examination revealed intermittent eye tracking with periods of staring off. Her neurologic examination was otherwise nonfocal and at her baseline. There was no seizure-like activity noted on continuous EEG. Her initial laboratory results were notable for an alanine aminotransferase (ALT) level of 99 U/L, aspartate aminotransferase (AST) level of 50 U/L, borderline low white blood count of 4500 cells/uL, and anemia and thrombocytopenia (hemoglobin 11.5 g/dL and 123 000 platelets/uL). Blood cultures were drawn, and rewarming was started. Because of her vital sign abnormalities and a concern for possible ventriculoperitoneal shunt malfunction, she was transferred to our PICU for stabilization and urgent evaluation by pediatric neurosurgery.

Dr Quinsey, how does a shunt malfunction typically present in a pediatric patient? What else is on your differential?

Classic shunt malfunction symptoms include headache, vomiting, and somnolence.1  Children with seizure disorders can have increased seizures. As intracranial pressure becomes critically high, patients will have a Cushing’s response with bradycardia and hypertension. Most shunt malfunctions present with hours or days of progressive symptoms. If there is distal failure or pseudocyst, this can slowly progress over weeks. In children, approximately 50% of all shunts will fail at 2 years from implantation.2 

Another consideration is shunt infection. There is a ≥5% rate of infection associated with placement or revision surgery.2  Symptoms include fever, headache, vomiting, and somnolence. As with malfunction, children with seizure disorders can have increased seizures. After 1 year from any shunt surgery, the risk of shunt infection decreases dramatically unless it is a ventriculoatrial shunt because bacteremia can infect such shunts.3  However, a pseudocyst infection or sterile pseudocyst can develop years after shunt surgery. These patients present with malfunction or infection symptoms and abdominal pain.2 

On admission to the PICU, the patient’s temperature was 34.4 °C. Complete blood count confirmed pancytopenia (white blood cell [WBC] count 4100 cells/uL, hemoglobin 10.4g/dL, and 131 000 platelets/uL). C-reactive protein (CRP) was elevated at 50.8mg/L (normal <10mg/L). A urinalysis result was positive for moderate blood; she was not menstruating, and a specimen was obtained by catheterization. A urine toxicology screen result was positive for benzodiazepines (which can be detected in urine for up to 30 days in the case of long-acting medications).4  A computed tomography scan of the brain and radiograph shunt series were unremarkable. After normal imaging, shunt malfunction was considered distinctly unlikely. An EEG revealed diffuse encephalopathy (absence of posterior dominant rhythm, poor organization, prominently θ-range activity with superimposed β secondary to benzodiazepine use, atypical sleep states, and abundant interictal discharges); no electrographic seizures were identified. Because the patient’s seizures had previously been managed by a neurologist at an outside practice, baseline EEG was not available for comparison. Her physical examination was notable for instability with standing and difficulty maintaining balance while walking, although she was able to sit up without support. No other specific cerebellar signs (such as nystagmus or intention tremor) were present, although her encephalopathic state did prevent a more detailed neurologic examination. With additional time under a warming blanket, repeat temperature 4 hours later was 36.6 °C.

Dr Pizzuto, besides shunt malfunction and status epilepticus, what diagnoses need to be considered in an urgent fashion for a patient with this presentation, and what are the next steps that you would take in working her up?

The patient presents with encephalopathy, ataxia, sialorrhea, hypothermia, and bradycardia. Laboratory findings were notable for mild cytopenias and elevated CRP. Altered mental status can be a sign of poor systemic perfusion, so the first step is to ensure that there are signs of adequate perfusion and hemodynamic stability.

Concurrent with stabilization, a differential diagnosis should be developed. Because shunt malfunction and increased intracranial pressure had been excluded, diagnoses including sepsis and toxic ingestion should be investigated. Sepsis is less likely given the bradycardia and cannot be ruled out, so prompt management is warranted, including blood cultures and broad-spectrum antibiotics as quickly as possible (ideally within 60 minutes of initial evaluation). Toxic ingestion, including alcohol or drug overdose, is also a consideration. Drug levels should be sent. A thorough medication history for the patient, as well as for the entire household, should be obtained. An electrocardiogram should be performed to evaluate the bradycardia and for any concerning toxin findings, such as atrioventricular heart block or QTc prolongation.5,6 

If concern for toxic ingestion persists, consultation with local poison control can be beneficial with treatment based on the presumed offending agent(s). Other rare conditions to include in the differential diagnosis would be an endocrinopathy, including hypothyroidism or adrenal insufficiency, other central nervous system infections, such as meningitis or encephalitis, new onset of seizures, or an autoimmune process, such as lupus.

In the PICU, the patient remained hemodynamically stable with no signs of reduced perfusion. She received 1 dose of ceftriaxone. A coronavirus disease 2019 polymerase chain reaction test result was negative. Serum ethanol, acetaminophen, and salicylate levels were within normal limits. The electrocardiogram revealed normal sinus rhythm with nonspecific T wave abnormalities. At this point, toxic ingestion causing the patient’s symptoms was thought to be unlikely. Thyroid hormones and adrenal function tests were within normal limits. Given the recent increase in seizure frequency and antiseizure medication (ASM) changes, pediatric neurology was consulted.

Dr Trau, what are the common causes of increasing seizure frequency and ataxia, and what are the typical side effects for her ASM?

When considering breakthrough seizures, many potential causes must be considered. Infections and fever can lower the seizure threshold and make seizures more likely even in the absence of central nervous system infection. For this patient, bacterial infection was considered less likely given the negative culture results to date. Viral infection was still in the differential given her initial hypothermia and elevated CRP. Nonadherence to prescribed ASM can also make seizures more likely. Given our patient’s history of changes in living situations, missed ASM doses must be considered. Metabolic derangements (glucose, calcium, magnesium, etc) can result in increased seizure frequency. Ironically, certain ASM can result in paradoxically increased seizure frequency, as well. Emotional stressors, sleep deprivation, menstrual patterns (catamenial epilepsy), intoxicants, head injury or anoxic injury, and medications that lower the seizure threshold or act as cytochrome P450-inducers (depending on the ASM) can also all contribute to breakthrough seizures.7 

Acute-onset ataxia has a wide-ranging differential. The length of symptom duration, as well as neurologic examination, can help localize the lesion and identify the disorder. Most presentations with a duration of <48 hours are typically caused by postinfectious acute cerebellar ataxia (usually due to nonspecific viral infections), toxic ingestion, or Guillain-Barre syndrome (GBS).8  Acute cerebellar ataxia must be differentiated from acute cerebellitis, which is characterized by neuroimaging as cerebellar edema and can be life-threatening. Acute disseminated encephalomyelitis can present with ataxia, encephalopathy, seizures, and white matter changes on neuroimaging. A history of previous neurologic deficits should prompt consideration of multiple sclerosis. Toxic causes of ataxia include ingestion of medications (including benzodiazepines, ASM, dextromethorphan, alcohol, and various illicit drugs among others).

Peripheral nervous system disorders can likewise present with ataxia. GBS is characterized by areflexia or hyporeflexia, along with symmetric ascending lower extremity weakness. It is typically postinfectious and is classically associated with Campylobacter jejunii infection.9  Lumbar puncture sometimes reveals cytoalbuminologic dissociation (although frequently it is not seen early in the disease course), and imaging of the lumbar spine may reveal enhancing nerve roots. Miller-Fisher syndrome is a GBS variant that presents with ataxia, areflexia, and ophthalmoplegia.

Other lesional causes of ataxia include acute transverse myelitis, which can be postinfectious and idiopathic and can be seen in multiple sclerosis. However, acute transverse myelitis typically presents with paraparesis. Bickerstaff brainstem encephalitis is another rare condition characterized by ataxia, ophthalmoplegia, encephalopathy, elevated serum anti-GQ1 antibodies, and white matter lesions on imaging.

Vascular events, including acute ischemic stroke and hemorrhagic stroke, can cause acute ataxia. Infectious disorders, such as meningitis, rhombencephalitis, and labyrinthitis, may present similarly. First-time presentations of ataxia or recurrent episodes of acute ataxia can be seen with various neurometabolic disorders, including episodic ataxias, inborn errors of metabolism, and vitamin deficiencies. Conversion disorder must be considered but is typically a diagnosis of exclusion.

Neuropsychiatric medications, including ASM, can have many side effects, and many can affect the metabolism of other drugs as well. At the time of presentation, our patient was taking zonisamide, eslicarbazepine, aripiprazole, methylphenidate, and a combined oral contraceptive pill (OCP). Potential medication side effects relevant in our patient’s case included multiple potential side effects from zonisamide (ataxia and paradoxically increased seizures, decreased appetite and weight loss, and sedation), eslicarbazepine (ataxia and abnormal gait, cognitive dysfunction, decreased hemoglobin, and, rarely, other cytopenias), and aripiprazole (cytopenias, hypothermia, and abnormal gait). Interestingly, zonisamide is associated with hypohidrosis and resulting hyperthermia (not hypothermia). Eslicarbazepine is a moderate CYP3A4 inducer and can lower serum concentrations of several medications, including aripiprazole and zonisamide. Zonisamide and aripiprazole are reported to cause bradycardia in <1% of patients, but none of the patient’s other medications alone or in combination provide a probable explanation for her bradycardia.

It is important to note that OCPs are metabolized by the cytochrome P450 system, and inducers of those systems (which include ASM, such as phenobarbital, phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, felbamate, and topiramate) may decrease the effectiveness of OCPs.

To narrow the possible differential diagnoses, the first step should be to obtain a complete neurologic history and examination. Inquiring about the presence of an antecedent infection, previous head/neck trauma, and potential toxic ingestions should be done. Laboratories should be obtained, including serum ASM levels, complete blood count, and complete metabolic profile. The patient’s newborn screen results should be reviewed, if available. An MRI scan of the brain and/or spinal cord and a lumbar puncture should be considered as part of the initial workup, as well.10 

Because many of the patient’s symptoms (ataxia, seizures, weight loss, drowsiness) could be attributed to zonisamide toxicity, and the timeline of her symptom onset corresponded to a dose increase, zonisamide was decreased back to 100mg nightly. Hypohidrosis was not present in the patient. Her mother reported that the patient often felt “clammy” to the touch, indicating possible hyperhidrosis, although this was not noted in the hospital. To prevent breakthrough seizures, eslicarbazepine was increased from 600mg in the morning and 800mg at night to 800mg twice daily. ASM levels were drawn. An MRI of the brain (Fig 1) revealed dysgenesis of the corpus callosum, encephalomalacia of the right temporoparietal region and left frontal lobe, and mildly low-lying cerebellar tonsils (a common and benign finding) consistent with her previous MRIs.

FIGURE 1

MRI of the brain (A) T1 sagittal sequence MRI scan of the brain revealing dysplasia of the corpus callosum and mildly low-lying cerebellar tonsils, (B) T1 axial sequence MRI scan of the brain revealing right temporoparietal encephalomalacia, and (C) T1 axial sequence MRI scan of the brain revealing encephalomalacia of the left frontal lobe.

FIGURE 1

MRI of the brain (A) T1 sagittal sequence MRI scan of the brain revealing dysplasia of the corpus callosum and mildly low-lying cerebellar tonsils, (B) T1 axial sequence MRI scan of the brain revealing right temporoparietal encephalomalacia, and (C) T1 axial sequence MRI scan of the brain revealing encephalomalacia of the left frontal lobe.

Close modal

Her encephalopathy and ataxia rapidly improved over the course of 2 days. Because the patient was clinically improving, she was transferred from the PICU to the pediatric floor. At the time of transfer, AST and ALT decreased to 39 U/L and 86 U/L, CRP decreased to 29.7mg/L, and platelet count had improved to 162 platelets/ul. Her temperature had normalized without the need for continued rewarming. However, her WBC count had decreased to 3.4 × 109/L from 4.1 × 109/L, and her absolute neutrophil count (ANC) had decreased to 1.1 × 109/L from 2.7 × 109/L.

Dr Rearick, as the receiving hospitalist, what are your assessment and planned next steps? How concerned are you about the patient’s laboratory abnormalities?

It is important to note that she was doing well clinically, having returned to her baseline with the hypothermia resolved, CRP improved, and no further concerns about seizure activity or changes in mental status. Antibiotics were discontinued given that culture results remained negative and clinical improvement was faster than would be expected with a bacterial infection. Although it was reassuring that she had improved, her laboratory abnormalities and initial profound hypothermia were not attributable to zonisamide toxicity and remained unexplained.

The role of the general pediatrics team at this point, considering her complex presentation and continued diagnostic uncertainty, was additional monitoring in the hospital to ensure continued clinical stability, as well as to monitor for any further seizure activity on her new ASM regimen.

The leading differential diagnoses for the slightly elevated transaminases and multiple cytopenias in the setting of the patient’s clinical presentation are infection (especially viral) and medication side effects. A resolving viral infection could explain the temperature instability, bone marrow suppression, and CRP elevation. It would be reasonable to test for specific viruses, but also would not be surprising if a specific viral culprit is never identified. A chest radiograph was obtained to complete the evaluation for common bacterial infections and was normal, and blood cultures remained without growth. Her ASM might account for hematologic abnormalities and elevated transaminases but would not explain the elevated CRP or hypothermia. Ceftriaxone can also cause neutropenia, but it was stopped after 1 dose. A careful review of all her medications including potential side effects and monitoring parameters was otherwise unrevealing.

Nutritional deficiency and hematologic malignancy are additional important considerations given the patient’s recent weight loss and cytopenias. It is reassuring that the cytopenias appeared to be mild and notable that her WBC count was initially normal and that the thrombocytopenia had resolved. It is appropriate to review a peripheral smear as the next step to ensure that no malignant cells were present, but it would also be reasonable to continue to trend these values without extensive workup given the minimal abnormalities. A further downtrend in ANC with the development of severe neutropenia or multiple persistent cytopenias should prompt additional evaluation and hematology consultation.

At this point, the patient had returned to her neurologic baseline without further seizures. Repeat tests were obtained and were notable for down-trending CRP, AST, and ALT. Her WBC count remained low, but her ANC improved. A parvovirus antibody assay result was negative, and an Epstein-Barr virus antibody assay indicated a past infection. However, her temperature once again dropped to 33.9 °C (93 °F). Forced air rewarming was started, and over the next few hours, her temperature slowly normalized. She had a single brief seizure the next morning, but she remained normothermic and stable for the remainder of her hospitalization

Dr Trau, what is the neurologic basis for thermoregulation? Given the spontaneous resolution of her symptoms, can a single cause explain her various symptoms on presentation?

Neurologically, the full mechanism of thermoregulation remains incompletely understood.11  The preoptic area (POA) of the hypothalamus is thought to control the “set point” and may be affected by endogenous or exogenous sources. The limbic system, brainstem, spinal cord, and sympathetic ganglia are also involved. Fluctuations in internal temperature are detected by thermoreceptors throughout the body and feed back to the hypothalamus. Thermoreceptors are typically found in the skin, spinal cord, visceral organs, and brain. Thermal signals synapse in the dorsal horn of the spinal cord and cross over to ascend in the contralateral spinothalamic tract. They then synapse in the lateral parabrachial nucleus at the junction of the midbrain and pons with further projections to the somatosensory cortex and POA. After sensing the temperature in the POA, efferent pathways leave the hypothalamus and travel to physiologic and behavioral receptors. The complexity of the thermoregulatory response depends on the magnitude of temperature fluctuations as well as the organs affected. Physiologic responses to decreasing bodily temperature include thermogenesis regulated by brown adipose tissues, skeletal muscle shivering, and vasoconstriction of the skin to prevent further heat loss. Warmth-seeking behavior is also triggered.11 

Acquired injury of the POA of the hypothalamus (for example ischemia, hemorrhage from the anterior communicating artery, or trauma) can present with periodic hypothermia and encephalopathy in the acute phase after injury or even years later.12,13  Tumors of the hypothalamus (primary or metastatic) are potential causes of periodic hypothermia. Less commonly, focal seizures in the POA can be associated with episodes but are difficult to detect on standard scalp EEG. Several cases of multiple sclerosis have been associated with episodic hypothermia as have cases of sarcoidosis and mitochondrial diseases.14  One case of periodic hypothermia was described in relation to infection with HIV, and another was described in a patient with forebrain malformation.13,15 

Our patient’s MRI scan revealed dysgenesis of the corpus callosum but no evidence of hypothalamic pathology. Periodic hypothermia was noted to be associated with isolated agenesis of the corpus callosum without hypothalamic involvement by Shapiro, Williams, and Plum in 1969, and <100 cases have been described since then.14,16  Subsequently termed Shapiro syndrome, patients may have episodes of periodic hypothermia starting at any age. The corpus callosum may be dysplastic or completely absent. The episodes can last for minutes to days, may recur daily, or may resolve for years between episodes. Hyperhidrosis and lethargy are frequently encountered as well. A similar condition (episodic spontaneous hypothermia with hyperhidrosis) exists without corpus callosum involvement. Although classically associated with hyperhidrosis, a literature review found that only 42% of patients with periodic hypothermia presented with hyperhidrosis, and only 50% of cases revealed lesions of the corpus callosum.17  Shapiro syndrome and spontaneous periodic hypothermia have been associated with ataxia, gait instability, hyponatremia, asterixis, bradycardia, elevated transaminases, and cytopenias.12,14,1820  Proposed etiologies of cytopenias include sequestration in the spleen and liver, bone marrow suppression, and/or marginalization.21 

Despite the known association between dysgenesis of the corpus callosum and periodic hypothermia in Shapiro syndrome, the exact mechanism remains unknown.17  However, the diagnosis must be considered in the setting of these 2 findings because all of the patient’s symptoms could otherwise not be explained. Without a firm diagnosis, further unnecessary and risky testing and/or treatment might have otherwise been pursued.

Various medications to treat the periodic hypothermia have been tried with some success, including clonidine, clomipramine, and cyproheptadine. Other medical treatments have included carbamazepine, chlorpromazine, and glycopyrrolate.14,17 

Our patient’s presentation is consistent with Shapiro syndrome/Shapiro syndrome variant. She presented with rapid waxing and waning periods of hypothermia, encephalopathy, and ataxia, although she did not have overt hyperhidrosis. An MRI scan of the brain (Fig 1) during her workup revealed dysgenesis of the corpus callosum (along with encephalomalacia in the right temporoparietal and left frontal lobes secondary to her history of multifocal infarctions). A laboratory workup revealed cytopenias and elevated transaminases, which spontaneously improved. Although an underlying nonspecific viral infection may have contributed to her presentation or potentially triggered it, the rapid onset, waxing and waning nature, and abrupt resolution of her overall presentation cannot be solely attributable to a viral infection. Similarly, while ataxia can be a side effect of various ASM, including eslicarbazepine, the rapid resolution after 1 held dose followed by recurrence and resolution the next day is inconsistent with a medication side effect. Her weight loss was thought likely to be due to decreased caloric intake in the setting of her living situation transition.

She was discharged from the hospital several days after her initial presentation after the resolution of her symptoms and laboratory abnormalities. She presented to the hospital again 1 month later with another identical episode, this time without any recent medication changes, that likewise resolved in <3 days. Several months later she had a third episode, which further confirms the diagnosis of Shapiro syndrome.

Ms Zbornik contributed to the conception, design, and drafting of the manuscript and the acquisition of data; Dr Rearick contributed to the conception, design, and drafting of the manuscript; Drs Pizzuto, Quinsey, and Enyart helped draft the manuscript; Dr Trau conceptualized and designed the study, contributed to data collection, coordinated and supervised data collection, and drafted and reviewed the manuscript; and all authors revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.

ALT

alanine aminotransferase

ASM

antiseizure medication

AST

aspartate aminotransferase

CRP

C-reactive protein

GBS

Guillain-Barre syndrome

OCP

oral contraceptive pill

POA

preoptic area

WBC

white blood cell

1
Kim
TY
,
Stewart
G
,
Voth
M
, et al
.
Signs and symptoms of cerebrospinal fluid shunt malfunction in the pediatric emergency department
.
Pediatr Emerg Care
.
2006
;
22
(
1
):
28
34
2
Hanak
BW
,
Bonow
RH
,
Harris
CA
,
Browd
SR
.
Cerebrospinal fluid shunting complications in children
.
Pediatr Neurosurg
.
2017
;
52
(
6
):
381
400
3
Al-Schameri
AR
,
Hamed
J
,
Baltsavias
G
, et al
.
Ventriculoatrial shunts in adults, incidence of infection, and significant risk factors: a single-center experience
.
World Neurosurg
.
2016
;
94
:
345
351
4
Kale
N
.
Urine drug tests: ordering and interpreting results
.
Am Fam Physician
.
2019
;
99
(
1
):
33
39
5
Patel
MM
,
Travers
CD
,
Stockwell
JA
, et al
.
Analysis of interventions required in 12,021 children with acute intoxications admitted to PICUs
.
Pediatr Crit Care Med
.
2017
;
18
(
7
):
e281
e289
6
Weiss
SL
,
Peters
MJ
,
Alhazzani
W
, et al
.
Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children
.
Pediatr Crit Care Med
.
2020
;
21
(
2
):
e52
e106
7
Bauer
D
,
Quigg
M
.
Optimizing management of medically responsive epilepsy
.
Continuum (Minneap Minn)
.
2019
;
25
(
2
):
343
361
8
Martínez-González
MJ
,
Martínez-González
S
,
García-Ribes
A
, et al
.
Acute onset ataxia in infancy: its aetiology, treatment and follow-up
.
Rev Neurol
.
2006
;
42
(
6
):
321
324
9
Shahrizaila
N
,
Lehmann
HC
,
Kuwabara
S
.
Guillain-Barré syndrome
.
Lancet
.
2021
;
397
(
10280
):
1214
1228
10
Caffarelli
M
,
Kimia
AA
,
Torres
AR
.
Acute ataxia in children: a review of the differential diagnosis and evaluation in the emergency department
.
Pediatr Neurol
.
2016
;
65
:
14
30
11
Tan
CL
,
Knight
ZA
.
Regulation of body temperature by the nervous system
.
Neuron
.
2018
;
98
(
1
):
31
48
12
Kloos
RT
.
Spontaneous periodic hypothermia
.
Medicine (Baltimore)
.
1995
;
74
(
5
):
268
280
13
Hemelsoet
DM
,
De Bleecker
JL
.
Post-traumatic spontaneous recurrent hypothermia: a variant of Shapiro’s syndrome
.
Eur J Neurol
.
2007
;
14
(
2
):
224
227
14
Blondin
NA
.
Diagnosis and management of periodic hypothermia
.
Neurol Clin Pract
.
2014
;
4
(
1
):
26
33
15
Okechukwu
CN
,
Pesanti
E
.
Episodic spontaneous hyperhidrosis hypothermia in human immunodeficiency virus-positive patients
.
Clin Infect Dis
.
1999
;
29
(
1
):
210
16
Shapiro
WR
,
Williams
GH
,
Plum
F
.
Spontaneous recurrent hypothermia accompanying agenesis of the corpus callosum
.
Brain
.
1969
;
92
(
2
):
423
436
17
Tambasco
N
.
Shapiro’s syndrome: defining the clinical spectrum of the spontaneous paroxysmal hypothermia syndrome
.
Eur J Paediatr Neurol
.
2014
;
18
(
4
):
453
457
18
Fratantoni
K
,
Hauer
JM
.
Chronic pancytopenia due to centrally mediated hypothermia in two children with severe neurological impairment
.
Children (Basel)
.
2020
;
7
(
4
):
E31
19
Tambasco
N
.
Long-term follow-up in pediatric patients with paroxysmal hypothermia (Shapiro’s syndrome)
.
Eur J Paediatr Neurol
.
2018
;
22
(
6
):
1081
1086
20
Mooradian
AD
,
Morley
GK
,
McGeachie
R
, et al
.
Spontaneous periodic hypothermia
.
Neurology
.
1984
;
34
(
1
):
c79
82
21
Lo
L
,
Singer
ST
,
Vichinsky
E
.
Pancytopenia induced by hypothermia
.
J Pediatr Hematol Oncol
.
2002
;
24
(
8
):
681
684