Shapiro Syndrome Secondary to a Vein of Galen Malformation Responding to Cyproheptadine: A Case Report and Review
Mansour H, Hmaimess G, Tohme R, Alam W, Ezzeddine L and Adem C
Published on: 2019-09-10
Though extremely rare, Shapiro syndrome classically presents with a triad of hypothermia, hyperhidrosis, and agenesis of corpus callosum. Around 50 cases of Shapiro syndrome have been reported to date. Interestingly, while Shapiro Syndrome is idiopathic, it is postulated that Vein of Gaven Malformation (VAGM) can lead to compression of the hypothalamus and corpus callosum, leading to underdevelopment of the corpus callosum and manifestations of Shapiro Syndrome. Here we report the case of a 5-month-old baby boy, with history of VAGM, and controlled epilepsy presenting with symptoms mimicking Shapiro Syndrome, with a successful response to Cyproheptadine.
KeywordsShapiro Syndrome; Vein of Gallen; Cyproheptadine; Hypothermia
First described in 1969 by Shapiro et al., Shapiro syndrome is a rare condition presenting with the triad of recurrent hypothermia, hyperhidrosis, and agenesis of the corpus callosum partial or complete; in which the latter is a hallmark of the disease [1,2]. It is theorized that the hypothermia is due to a decrease in the temperature set-point in the hypothalamus, with consequent psychological and neurological manifestations . Reports of around 50 cases of Shapiro Syndrome exist worldwide . Though, the corpus callosum agenesis can be a part of a syndrome or a complication of an idiopathic derangement of the neuronal migration, there has been one reported case of VAGM leading to underdevelopment of the corpus callosum through mechanical compression . Here we report the case of a Vein of Galen malformation leading to compression of the hypothalamus and a thinning of the corpus callosum leading to a Shapiro syndrome in 5 months old boy, with successful resolution of presenting hypothermia with Cyproheptadine, a serotonin antagonist.
We report here a 5-month-old male patient with a known history of Vein of Galen malformation who presented to our care for management of hypothermia. The child is a term baby born by caesarian section due to dystocia, to first degree consanguineous parents.
The child was clinically stable until the age of 2 months when he started displaying macrocephaly associated with 10 episodes per day of right sided clonic seizures. A brain MRI showed aneurysmal malformation of the vein of Galen, and partial agenesis of the corpus callosum, with dilated cardiomyopathy found on cardiac ultrasound, consistent with high output cardiac failure due to shunting of the cardiac output through the Galen Vein lesion. An Electroencephalogram was done and showed typical hypsarrhythmia associated with neuro-motor regression, in favor of West epilepsy. He was subsequently treated with embolization of the vein of Galen and started on anti-epileptics, namely Vigabatrine, Valproate, Topiramate, and Levetiracetam. The heart failure was treated with Furosemide.
At 3 months of age, patient had recurrence of seizures with increased severity. Brain CT done showed right frontal epidural hematoma, 1 cm in thickness, so he was transferred to Pediatrics Intensive Care Unit (PICU), where repeat brain CT showed no change. After stabilization, a second session of embolization of the Vein of Galen was done. At 5 months of age, the patient started experiencing progression of his symptoms with generalized tonic-clonic seizure episodes lasting 40 minutes, which responded to an increase in the doses of the anti-epileptic drugs, always staying within the recommended therapeutic levels, meanwhile; the patient started to have acute episodes of hypothermia (ranging between 33.5 and 35.0 degrees celcius) associated with pallor and diaphoresis, of a duration of 15 to 40 minutes duration per episode, with a recurrence of 3-4 episodes per 24 hours, without change in oxygen saturation and a cardiac rhythm always above the lower threshold of normal . As a baseline, before the appearance of the episodes as outside these episodes, the patient has axial hypotonia with spasticity of the four limbs, unable to fix nor follow, hold his head, or vocalize. The patient has a macrocephaly with a head circumberence at the 95th percentile, no skin hypo or hyper pigmented lesions. The patient has non bulging but pulsating fontanels. No other dysmorphological signs are noted. Cardiac and pulmonary examination was within normal limits. There was no hepatosplenomegaly. Full infectious workup was done, pan cultures were taken, with a respiratory viral panel, complete blood count with differential, C-reactive protein, liver function tests, chest X-ray, as well as a repeat brain CT scan, and Brain MRI were performed, and all these investigations were non-significant except for partial agenesis of the corpus callosum [Figures 1,2]. Thus, infection was ruled out as a cause of his presentation. A metabolic work up was done as well with arterial lactic acid level and pyruvic acid level as well as ammonia levels, and a follow up of glucose blood levels were performed and showed no abnormal values. Considering his history of Vein of Galen malformation and the hypothermia, Vein of Galen compression of the hypothalamus mimicking Shapiro syndrome was considered, and a trial of cyproheptadine hydrochloride was proposed, with the patient started on cyproheptadine hydrochloride of 0.25 mg/kg/day PO divided q8h. The episodes of hypothermia, pallor and hyperhydrosis resolved 24 hours after initiation of the cyproheptadine hydrochloride. To date, patient has shown no recurrence upon daily follow up over a period of 2-and-a-half months.
In 1969, a rare entity known as Shapiro Syndrome (SS) was first described, and it was characterized by a triad of hypothermia, hyperhidrosis, and agenesis of the corpus callosum . Only around 50 cases have been reported so far. Alternatively, two different entities have come to present, though both are even rarer. Variant Shapiro Syndrome denotes Shapiro syndrome with preservation of the corpus callosum, with less than 10 cases having been reported so far; it presents with both hypothermia and hyperhidrosis, though hypothermia is more common . One possible etiology of Variant Shapiro Syndrome has been reported in a case of a 49-year-old with recurrent episodes of hypothermia post contusional brain injury, with damage to the anterior corpus callosum . Similarly, another case of head trauma with a proposed, secondary induced, trans-synaptic degeneration of neurons in the hypothalamic area resulting in the hypothalamic dysfunction was reported . In contrast, an idiopathic case of Variant SS was reported in a 4-year-old boy with recurrent bouts of hypothermia and hyperhidrosis, but with normal corpus callosum, and normal neurodevelopment . On the other hand, a new entity has emerged, known as Reverse Shapiro Syndrome, in which instead of hypothermia, patients displayed hyperthermia. Less than 5 cases have been reported in the literature, with one case involving a 9-month-old girl presenting with fever of unknown origin who had agenesis of corpus callosum , and another case of a 3 months old female with reverse Shapiro’s syndrome who did not show any response to any treatment . Another recent case was that of a 5-month old boy with West syndrome, likely causing neuronal inflammation and consequent hypothalamic syndrome leading to reverse SS . None of the cases could be explained with infectious, endocrinological, or metabolic etiologies. Several mechanisms have been proposed, with callosal agenesis as the sole cause of hypothermia being disproven as callosotomy did not lead to defective thermoregulation .
One popular theory is based on hypothalamic dysfunction. The hypothalamus is central in thermo regulation and any disruption can result in unexpected thermal changes, be it hypo- or hyperthermia . Another theory has basis in neurochemistry and proposes that developmental lesions reduce the number of afferent inputs to the hypothalamic thermoregulatory center resulting in the dysregulation of the dopamine related thermoregulatory function and a dopamine super-sensitivity [1,9]. It has been postulated that seizures can lead to neuronal inflammation, and subsequent hypothalamic dysfunction leading to thermal dysregulation [12,13]. No definitive guidelines exist regarding treatment of SS and its variants, with different approaches having been reported in literature.
A case of a 4-year-old girl diagnosed with Shapiro Syndrome Variant was successfully treated with Pizofen after failure of carbamazepine . Alternatively, carbamazepine proved to be successful in the treatment of a 34-year-old man with recurrent bouts of hyperhidrosis, diagnosed later with Shapiro Syndrome . Interestingly, a case of SS was reported in a 31-year-old female complaining of recurrent episodes of hyperhidrosis and depression. She was found to have corpus callosum agenesis and was successfully treated with amitriptyline and valproate , to note that our patient was already on valproic acid before the occurrence of the SS .
Treatments that are most widely used, given the limited data available, are dopamine agonists  and antiserotonergic agents like cyproheptadine , with reports of successful abortion or control of these episodes . Upon review, it was found that most cases of SS occur in younger patients with hypothermia a hallmark, and hyperhidrosis a strong association. Corpus callosum agenesis did not rule out SS but was rather associated with a variant form. Importantly, on follow-up, episodes of hypothermia seemed to be self-limited with spontaneous resolution over time, independent of medication use . I this patient we have a Vein of Galen Malformation leading to a Shapiro Syndrome. VAGM is an extremely rare vascular abnormality, with a reported incidence of 1:25000 deliveries . Diagnosis is usually made postnatal, while antenatal diagnosis, is made during the third trimester, frequently after the 34th week of gestation .
Aneurysm of the vein of Galen was first described in 1937 by Jaeger et al . Malformations of the vein of Galen arise early in embryogenesis in the 20-40 mm fetus, when blood vessels are still simple endothelial tubes [21,22]. Following an anatomic analysis of 23 cases of vein of Galen aneurysm, it was determined that the aneurysmal sac is likely the persistence of the embryonic median prosencephalic vein of Markowski, not the vein of Galen [22,23]. Clinical presentation of VAGM depends on the size of the aneurysm, with symptoms including congestive heart failure due to shunting of the cardiac output through the lesion , seizures due to compression of nearby cerebral structures, and hydrocephalus due to compression of the Sylvian aqueduct .
Rarely, the increased size of VAGH can lead to underdevelopment of the corpus callosum due to mechanical compression of the embryonic cells forming the corpus callosum, as reported in a case of VAGM diagnosed at the 23rd week of gestation, which resulted in callosal hypoplasia . This compression can lead to either complete, or partial agenesis . Additionally, since the Vein of Galen aneurysm can vary in size, it can lead to compression of different brain structures and tissues , therefore we can postulate that VAGM can compress the hypothalamus leading to decrease in the temperature set-point with consequent hypothermic manifestation, and with the compression of the corpus callosum leading to its underdevelopment, it can lead to Shapiro Syndrome. Therefore, as with Shapiro Syndrome, hypothermic episodes can be treated with either dopaminergic , or anti-serotonergic medication .
Even though a rare underdiagnosed and overlooked entity, Shapiro Syndrome should be considered in patient with either anatomical agenesis of the corpus callosum as well as in patient with the risk of physiopathological or functional dysfunction of the corpus callosum, primary or secondary. This disease should be included as a differential diagnosis in patients showing unexplained episodes of hypothermia, as a sign of hypothalamic dysfunction. The basis and the physiopathology of this syndrome remain to be well understood and investigated, but a therapeutic trial with cyproheptadine should be considered in patients exhibiting Shapiro Syndrome.
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Figure 1: Brain MRI, coronal FLAIR showing thinning of the Corpus Callosum.
Figure 2: Sagittal cut of CT brain showing Vein of Galen Malformation (VGAM) with subsequent dilatation of the lateral ventricle. The corpus callosum is continuous and thin.