Brief Communication
Hypothalamic Dysfunction Without Hamartomas Causing Gelastic Seizures in Optic Nerve Hypoplasia
Journal of Child Neurology 2015, Vol. 30(2) 233-237 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814527156 jcn.sagepub.com
Cassandra Fink, MPH1, Mark Borchert, MD1, Carrie Zaslow Simon, MD2, and Clifford Saper, MD, PhD3
Abstract This report describes gelastic seizures in patients with optic nerve hypoplasia and hypothalamic dysfunction without hypothalamic hamartoma. All participants (n ¼ 4) from the optic nerve hypoplasia registry study at Children’s Hospital Los Angeles presenting with gelastic seizures were included. The clinical and pathology characteristics include hypothalamic dysgenesis and dysfunction, but no hamartomas. Optic nerve hypoplasia is the only reported condition with gelastic seizures without hypothalamic hamartomas, suggesting that hypothalamic disorganization alone can cause gelastic seizures. Keywords epilepsy, hypopituitarism, ophthalmic condition Received September 20, 2013. Received revised December 10, 2013. Accepted for publication February 13, 2014.
Gelastic seizures are defined by inappropriate stereotyped laughter in the absence of external precipitants.1 They are usually associated with hypothalamic hamartomas and rarely occur with other lesions impinging on the third ventricle, or in the absence of hypothalamic lesions.2,3 One case has been reported with optic nerve hypoplasia and panhypopituitarism.4 Optic nerve hypoplasia, the leading congenital cause of blindness in children, is associated with hypothalamic dysfunction that can occur in the absence of neuroradiographic abnormalities.5 We report 4 cases of gelastic seizures in children with optic nerve hypoplasia and hypothalamic dysfunction without hamartoma.
Methods From a registry of 262 children with optic nerve hypoplasia, 4 participants were described as having gelastic seizures. With institutional review board approval and written informed consent, vision, endocrinologic, neuroradiographic, and neuropsychological data are prospectively collected on registry participants. Following case selection, a pediatric neuroradiologist reviewed the MRIs for cases 2 to 4 under 2 conditions: (1) masked to the patient population and reason for review and then (2) after being asked to look specifically for hypothalamic abnormalities and hamartomas. We report the clinical and pathologic features of these 4 children.
Case 1 A term infant was admitted to the neonatal intensive care unit with hypoglycemia. At age 7 days, she was diagnosed with optic nerve
hypoplasia in the left eye and persistent hyperplastic primary vitreous in the right eye. A magnetic resonance imaging (MRI) revealed arachnoid cysts in the perimesencephalic cistern, flattening of the posterior brainstem and interdigitation of the gyri in the inferior frontal region. She was subsequently diagnosed with diabetes insipidus, adrenal insufficiency, hypothyroidism with thyroid-stimulating hormone deficiency, and growth hormone deficiency. Hypothalamic dysfunction included temperature instability (33-34 C while sleeping to 38-39 C while crying in a 21 C room) and fragmented sleep. An electroencephalography (EEG) showed background 1- to 3-Hz delta activity suggesting generalized encephalopathy. A neurologist diagnosed infantile spasms after viewing the EEG and a videotape of the spasms. At 18 months of age, a repeat EEG showed the presence of focal spikes and slowing in the left frontotemporal region with no evidence of hypsarrhythmia. She was subsequently diagnosed with hydrocephalus and a shunt was placed, which was later removed. Developmentally, she remained at the infant level and frequently cried inconsolably. At age 4 years, she developed gelastic seizures consisting of giggles and slow jerks toward one side
1
The Vision Center, Division of Ophthalmology, Children’s Hospital Los Angeles, Los Angeles, CA, USA 2 North Shore - Long Island Jewish Health System at Hofstra University, Long Island, NY, USA 3 Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA Corresponding Author: Cassandra Fink, MPH, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, MS 93, Los Angeles, CA 90027, USA. Email: [email protected]
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Figure 1. Photomicrographs series demonstrating immunohistochemical staining of the brain in Case 1. (A) Neurons in the medial septal nucleus, stained for choline acetyltransferase (ChAT), demonstrating preservation of the normal morphology and numbers of cholinergic neurons in the medial septal nucleus. (B) There were also normal numbers of tyrosine hydroxylase immunoreactive neurons in the posterior lateral hypothalamus, and (C) nigrostriatal axons as they enter the striatum. (D) There were only a few remaining neurons immunoreactive for arginine vasopressin in the supraoptic nucleus (E) or agouti-related protein neuron in the arcuate nucleus. (F) There were normal numbers of melanin-concentrating hormone-immunoreactive neurons in the posterior lateral hypothalamus. Scale ¼ 0.1 mm. without any specific precipitants. The diagnosis was not confirmed by EEG. The patient was maintained on Depakote, and subsequently Artane. At 6 years of age, the patient died from sepsis. Gross examination of the brain at autopsy showed atresia of the optic nerves and tracts. There were polymicrogyria and gray matter heterotopias, especially along the surface of the lateral ventricles. The fibrous septum was fenestrated, but microscopic evaluation of the basal forebrain and hypothalamus showed preservation of the neural components of the septum, including the cholinergic neurons of the medial septal nucleus (Figure 1A). The anterior two-thirds of the hypothalamus (from the levels of the preoptic area to the ventromedial nucleus) failed to develop, with only a small number of neurons in a disorganized neuropil remaining at this level (Figure 2). Immunohistochemical staining
for arginine vasopressin, which is normally present in the paraventricular, supraoptic, and suprachiasmatic nuclei, disclosed only a few immunoreactive neurons with axons coursing toward the midline along the base of the brain, but there was no clear median eminence (Figure 1D). Agouti-related protein is found in the arcuate nucleus, which is thought to drive feeding behavior. Only a few surviving neurons could be identified immunohistochemically (Figure 1E). Despite the paucity of normal structures in the rostral two-thirds of the hypothalamus, immunohistochemical staining for tyrosine hydroxylase demonstrated the normal appearance of the nigrostriatal bundle, which runs through the lateral hypothalamus at these levels (Figure 1B), as well as normal dopaminergic innervation of the striatum (Figure 1C), indicating that the integrity of the remaining tissue had not been disrupted (eg, by an infarct or infection). The caudal
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Figure 3. Magnetic resonance imaging (MRI) in case 2. (A) Axial T2-weighted MRI through base of the third ventricle shows no hamartomas in the hypothalamus. (B) Sagittal T1-weighted MRI shows hypoplastic corpus callosum.
Figure 2. A low power photomontage showing the remaining rostral hypothalamus in Case 1. Neurons are disorganized, no clear nuclear structure, and immunostaining at this level (Figure 1 D-E) showed only a few scattered remaining neurons of each chemical phenotype. A cortical heterotopia was present adjacent to the rostral hypothalamic remnant. Scale ¼ 1 mm. hypothalamus was intact, including the mammillary bodies and tuberomammillary nuclei. Immunohistochemical staining for melaninconcentrating hormone (Figure 1F) and for tyrosine hydroxylase in the A11 dopaminergic neurons (Figure 1B), which are found at this level, showed normal neuron numbers and morphology. No hamartomas were present in the hypothalamus, although a cortical heterotopia was located nearby (Figure 2).
Case 2 A term infant was hospitalized for the first 3 days of life for jaundice. At 2 months of age, she developed right-sided focal seizures and was hospitalized for a subdural/intraventricular hemorrhage secondary to vitamin K deficiency, diabetes insipidus, hypothyroidism, and adrenal insufficiency. Ophthalmic evaluation revealed bilateral optic nerve hypoplasia. The patient was later treated with growth hormone because of decreased growth velocity. An MRI of the brain revealed mild generalized atrophy and borderline prominence of the ventricular system, specifically expanded extraaxial cerebrospinal fluid space along the frontoparietal regions, worse on the left than the right, but no hypothalamic or pituitary abnormalities (Figure 3). At 10 months of age, the patient started to have spontaneous, inappropriate laughing spells. Concurrently, she began to suffer from dysautonomic spells and grand mal seizures. At 1 year of age, she developed tonic-clonic seizures. EEG showed independently occurring left frontocentral and right frontotemporal spikes. At age 26 months, the patient was admitted for idiopathic fever lasting 4 weeks, accompanied by decreased appetite, weight loss, increased seizure activity, increased spasmodic movements, and periods of inconsolable crying. The patient’s fever was attributed to ‘‘hypothalamic storm’’ and treated with chlorpromazine. The patient continued to have episodes of inappropriate, spontaneous laughing spells, which her neurologist diagnosed as gelastic seizures. The patient’s gelastic seizures occurred in 2 forms: (1) inappropriate,
spontaneous laughter hysterical in quality with occasional shrieking sounds not prompted by any stimuli. These episodes lasted several seconds to 1 minute each, and could occur either singly or in clusters, sometimes occurring during sleep; (2) the same spontaneous laughing, accompanied by complete loss of muscle tone in which the patient’s body becomes limp and her eyes roll back. During these episodes, she was unresponsive for several seconds. The patient was prescribed lamotrigine, levetiracetam, and zonisamide. Although these medications controlled her grand mal seizures, she continues to suffer almost daily from gelastic seizures.
Case 3 A term infant with a complicated delivery, requiring resuscitation with CPR, was hospitalized for 2 weeks during the neonatal period because of jaundice and hypoglycemia (glucose of 12 mg/dL). He was found to have corticotropin deficiency and hypothyroidism. An EEG on day of life 4 was moderately abnormal and suggestive of diffuse cerebral dysfunction. He was discharged with the diagnosis of optic nerve hypoplasia on hydrocortisone and Synthroid. The patient was later started on growth hormone replacement therapy and desmopressin (DDAVP). An MRI of the brain at 1 year of age revealed partial agenesis of the corpus callosum. The patient had no history of seizures until he presented with episodes of laughing and loss of muscle control at 41 months of age, which his neurologist characterized as gelastic seizures. The episodes involve a laugh that is characteristically different than his typical happy laugh and combined with loss of body control resulting in falls. The episodes last approximately 30 seconds and occurred several times per week at their height. A sleep EEG performed at 55 months of age demonstrated left occipital epileptiform discharges during sleep. Treatment with levetiracetam has controlled his seizures.
Case 4 A female term infant was admitted to the neonatal intensive care unit for cyanosis, temperature instability, jaundice, and hypernatremia. An MRI showed diffuse cerebral underdevelopment and enlargement of the temporal horn of the left lateral ventricle without hypothalamic or pituitary abnormalities. The patient was discharged from the neonatal intensive care unit with a diagnosis of optic nerve hypoplasia, hypothyroidism, adrenal insufficiency, and diabetes insipidus.
236 Beginning at 4 months of age, the patient was repeatedly hospitalized for respiratory distress and presumed sepsis with fevers. She developed generalized seizures at 4 months of age, which resolved with phenytoin treatment. An EEG revealed diffuse slowing bilaterally, consistent with a postictal state, frequent to near-continuous sharp and spike wave discharges over the left frontal-central head region, and occasional independent and synchronous right central sharps over the right frontal head region. Nine tonic seizures were captured during the overnight EEG. Shortly after her first birthday, a gastrostomy tube and tracheostomy were placed. At age 16 months, she developed episodes of smiling and giggling lasting 5 to 8 seconds and occurring in clusters up to 4 to 5 times a day. Her neurologist reviewed her most recent MRI for hypothalamic hamartoma and confirmed that the patient had gelastic seizures in the absence of hypothalamic hamartoma. In addition to gelastic seizures, her neurologist identified complex partial seizures, secondarily generalized seizures consisting of tonic stiffening with eye rolling lasting 1 to 2 minutes, and a reflex seizure occurring in the context of a loud high-pitched sound. The patient is treated with phenobarbital and topiramate.
Discussion A pediatric neuroradiologist confirmed no hypothalamic abnormalities or hamartomas present on MRI. These cases demonstrate that gelastic seizures can occur in patients with optic nerve hypoplasia who do not have hypothalamic hamartomas; however, all 4 patients had early signs of hypothalamic dysfunction and neuroradiographic abnormalities in other regions of the brain. Gelastic seizures associated with hypothalamic hamartomas originate in the hamartoma itself, usually in the posterior third of the hypothalamus.6,7 The mechanism of epileptogenesis is not fully understood. Resected preparations of hypothalamic hamartomas have shown that hypothalamic hamartoma neurons can fire spontaneously with intrinsic pacemaker-like activity.8 This spontaneous activity was subsequently recorded in situ using direct endoscopic visualization.8 Fenoglio et al9 also demonstrated intrinsic activity in hypothalamic hamartoma preparations in situ, which identified 2 populations of neurons: small g-aminobutyric acid (GABA)– expressing neurons and large, quiescent, pyramidal-like neurons. Their research proposes that the small GABAergic interneurons have pacemaker-like firing that synchronizes the output of the large neurons to nearby limbic structures resulting in gelastic seizures.9 This mechanism is unlikely in our patients who have no hamartomas, and at least in case 1, lack the clusters of neurons identified by Fenoglio et al9 in hamartomas. Optic nerve hypoplasia is the only condition reported to be associated with gelastic seizures without masses in the hypothalamus. This suggests that hypothalamic disorganization with or without hamartomas can cause gelastic seizures. Hypothalamic hamartomas are thought to cause seizures because they contain 2 populations of neurons, large projection-type neurons and smaller GABAergic interneurons.10,11 The GABAergic cells are spontaneously active, and they innervate the projection-type neurons. However, the latter cells have particularly high intracellular chloride levels, so they are depolarized, as opposed to the more typical suppression, by
Journal of Child Neurology 30(2) GABAergic input. Hypothalamic hamartomas that cause gelastic seizures are usually found at the level of the posterior hypothalamus, just adjacent to the mammillary bodies,7 suggesting that the excitatory output of the projection-type neurons can serve as a substrate for the seizures by driving hyperexcitation of structures in the posterior hypothalamus. Case 1 supports the notion that, in the absence of a hamartoma, severe disorganization of the anterior two-thirds of the hypothalamus associated with optic nerve hypoplasia can permit remaining structures in the posterior hypothalamus to become a substrate for gelastic seizures. The anterior hypothalamus contains GABAergic neurons, such as those in the ventrolateral preoptic nucleus, which are known to inhibit neurons in the posterior hypothalamus, such as the histaminergic neurons in the tuberomammillary nucleus.12 It is possible that loss of an inhibitory input from the anterior two-thirds of the hypothalamus can disinhibit neurons in the posterior hypothalamus, causing gelastic seizures. The manifestations of hypothalamic dysfunction in our patients, including temperature instability, fragmented sleep, and panhypopituitarism, indicate that optic nerve hypoplasia is often associated with failure of the anterior two-thirds of the hypothalamus. These cases further support the idea that the posterior hypothalamus is involved in originating the gelastic epileptiform activity. Although the pathways from the posterior hypothalamus that can lead to cortical seizure activation are not known, it is notable that this level contains the histaminergic neurons of the tuberomammillary nucleus and the glutamatergic neurons of the supramammillary nucleus, both of which have direct and presumably excitatory inputs to the hippocampus and the cerebral cortex.13-15 Ictal video-EEG has also reportedly localized gelastic epilepsy to other foci outside of hypothalamic hamartomas including the right temporal lobe16 and frontal lobe.17 It is possible that the hypothalamic site causing gelastic seizures does so by abnormal firing of inputs to these structures. On the other hand, even in patients in whom the gelastic seizures appear to be localized to cortical sites, thorough neuroimaging of the hypothalamus should be performed to rule out a hypothalamic lesion that is disinhibiting seizures at these cortical sites. Acknowledgment The authors wish to thanks Marvin Nelson, MD, for providing the reading of the MRIs for this report.
Author Contributions CF and MB identified the cases. MB cared for the patients. CF and CZS collected and reviewed the medical records and wrote the first draft. CS participated in the autopsy and created Figures 1 and 2. All authors participated in the writing and revision of the manuscript.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Funding
9. Fenoglio KA, Wu J, Kim do Y, et al. Hypothalamic hamartoma: basic mechanisms of intrinsic epileptogenesis. Semin Pediatr Neurol. 2007;14:51-59. 10. Kim do Y, Fenoglio KA, Simeone TA, et al. GABAA receptormediated activation of L-type calcium channels induces neuronal excitation in surgically resected human hypothalamic hamartomas. Epilepsia. 2008;49:861. 11. Beggs J, Nakada S, Fenoglio K, Wu J, Coons S, Kerrigan JF. Hypothalamic hamartomas associated with epilepsy: ultrastructural features. J Neuropathol Exp Neurol. 2008;67: 657-668. 12. Sherin JE, Elmquist JK, Torrealba F, Saper CB. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci. 1998;18:4705-4021. 13. Saper CB. Organization of the cerebral cortical afferent systems in the rat. II. Hypothalamocortical projections. J Comp Neurol. 1985;237:21-46. 14. Panula P, Airaksinen MS, Pirvola U, Kotilainen E. A histaminecontaining neuronal system in human brain. Neuroscience. 1990;34:127-132. 15. Berger B, Esclapez M, Alvarez C, Meyer G, Catala M. Human and monkey fetal brain development of the supramammillaryhippocampal projections: a system involved in the regulation of theta activity. J Comp Neurol. 2001;429:515-529. 16. Chai Y, Adamolekun B. Cryptogenic gelastic epilepsy originating from the right temporal lobe. Med Princ Pract. 2010;19: 153-158. 17. Sartori E, Biraben A, Taussiq D, et al. Gelastic seizures: videoEEG and scintigraphic analysis of a case with a frontal focus; review of the literature and pathophysiological hypotheses. Epileptic Disord. 1999;1:221-228.
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported in part by the One Small Voice Foundationand Grant Number UL1TR000130, Children’s Hospital Los Angeles from the National Center for Advancing Translational Sciences (NCATS) and the National Institute of Health.
Ethical Approval This research was approved the Children’s Hospital Los Angeles IRB, the Committee on Clinical Investigations (CCI-11-037).
References 1. Shahar E, Kramer U, Mahajnah M, et al. Pediatric-onset gelastic seizures: Clinical data and outcome. Pediatr Neurol. 2007;37:29-34. 2. Arroyo S, Lesser RP, Gordon B, et al. Mirth, laughter and gelastic seizures. Brain. 1993;116(pt 4):757-780. 3. Diebler C, Ponsot G. Hamartomas of the tuber cinereum. Neuroradiology. 1983;25:93-101. 4. Sokol D, Markland O, Walsh L, O’Neil J. Gelastic seizures in an infant without hypothalamic hamartoma: a video case report. Internet J Neurol. 2004;3. 5. Borchert M, Garcia-Filion P. The syndrome of optic nerve hypoplasia. Curr Neurol Neurosci Rep. 2008;8:395-403. 6. Engel J, Pedley TA, eds. Gelastic Seizures. In: Epilepsy: A Comprehensive Textbook, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2007; 619-625. 7. Parvizi J, Le S, Foster BL, et al. Gelastic epilepsy and hypothalamic hamartomas: neuroanatomical analysis of brain lesions in 100 patients. Brain. 2011;134(pt 10):2960-2968. 8. Lekovic GP, Kerrigan, JF, Wait S, et al. In situ single-unit recording of hypothalamic hamartomas under endoscopic direct visualization. Neurosurgery. 2009;65:E1195-E1196.
Hypothalamic Dysfunction Without Hamartomas Causing Gelastic Seizures in Optic Nerve Hypoplasia
Journal of Child Neurology 2015, Vol. 30(2) 233-237 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814527156 jcn.sagepub.com
Cassandra Fink, MPH1, Mark Borchert, MD1, Carrie Zaslow Simon, MD2, and Clifford Saper, MD, PhD3
Abstract This report describes gelastic seizures in patients with optic nerve hypoplasia and hypothalamic dysfunction without hypothalamic hamartoma. All participants (n ¼ 4) from the optic nerve hypoplasia registry study at Children’s Hospital Los Angeles presenting with gelastic seizures were included. The clinical and pathology characteristics include hypothalamic dysgenesis and dysfunction, but no hamartomas. Optic nerve hypoplasia is the only reported condition with gelastic seizures without hypothalamic hamartomas, suggesting that hypothalamic disorganization alone can cause gelastic seizures. Keywords epilepsy, hypopituitarism, ophthalmic condition Received September 20, 2013. Received revised December 10, 2013. Accepted for publication February 13, 2014.
Gelastic seizures are defined by inappropriate stereotyped laughter in the absence of external precipitants.1 They are usually associated with hypothalamic hamartomas and rarely occur with other lesions impinging on the third ventricle, or in the absence of hypothalamic lesions.2,3 One case has been reported with optic nerve hypoplasia and panhypopituitarism.4 Optic nerve hypoplasia, the leading congenital cause of blindness in children, is associated with hypothalamic dysfunction that can occur in the absence of neuroradiographic abnormalities.5 We report 4 cases of gelastic seizures in children with optic nerve hypoplasia and hypothalamic dysfunction without hamartoma.
Methods From a registry of 262 children with optic nerve hypoplasia, 4 participants were described as having gelastic seizures. With institutional review board approval and written informed consent, vision, endocrinologic, neuroradiographic, and neuropsychological data are prospectively collected on registry participants. Following case selection, a pediatric neuroradiologist reviewed the MRIs for cases 2 to 4 under 2 conditions: (1) masked to the patient population and reason for review and then (2) after being asked to look specifically for hypothalamic abnormalities and hamartomas. We report the clinical and pathologic features of these 4 children.
Case 1 A term infant was admitted to the neonatal intensive care unit with hypoglycemia. At age 7 days, she was diagnosed with optic nerve
hypoplasia in the left eye and persistent hyperplastic primary vitreous in the right eye. A magnetic resonance imaging (MRI) revealed arachnoid cysts in the perimesencephalic cistern, flattening of the posterior brainstem and interdigitation of the gyri in the inferior frontal region. She was subsequently diagnosed with diabetes insipidus, adrenal insufficiency, hypothyroidism with thyroid-stimulating hormone deficiency, and growth hormone deficiency. Hypothalamic dysfunction included temperature instability (33-34 C while sleeping to 38-39 C while crying in a 21 C room) and fragmented sleep. An electroencephalography (EEG) showed background 1- to 3-Hz delta activity suggesting generalized encephalopathy. A neurologist diagnosed infantile spasms after viewing the EEG and a videotape of the spasms. At 18 months of age, a repeat EEG showed the presence of focal spikes and slowing in the left frontotemporal region with no evidence of hypsarrhythmia. She was subsequently diagnosed with hydrocephalus and a shunt was placed, which was later removed. Developmentally, she remained at the infant level and frequently cried inconsolably. At age 4 years, she developed gelastic seizures consisting of giggles and slow jerks toward one side
1
The Vision Center, Division of Ophthalmology, Children’s Hospital Los Angeles, Los Angeles, CA, USA 2 North Shore - Long Island Jewish Health System at Hofstra University, Long Island, NY, USA 3 Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA Corresponding Author: Cassandra Fink, MPH, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, MS 93, Los Angeles, CA 90027, USA. Email: [email protected]
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Figure 1. Photomicrographs series demonstrating immunohistochemical staining of the brain in Case 1. (A) Neurons in the medial septal nucleus, stained for choline acetyltransferase (ChAT), demonstrating preservation of the normal morphology and numbers of cholinergic neurons in the medial septal nucleus. (B) There were also normal numbers of tyrosine hydroxylase immunoreactive neurons in the posterior lateral hypothalamus, and (C) nigrostriatal axons as they enter the striatum. (D) There were only a few remaining neurons immunoreactive for arginine vasopressin in the supraoptic nucleus (E) or agouti-related protein neuron in the arcuate nucleus. (F) There were normal numbers of melanin-concentrating hormone-immunoreactive neurons in the posterior lateral hypothalamus. Scale ¼ 0.1 mm. without any specific precipitants. The diagnosis was not confirmed by EEG. The patient was maintained on Depakote, and subsequently Artane. At 6 years of age, the patient died from sepsis. Gross examination of the brain at autopsy showed atresia of the optic nerves and tracts. There were polymicrogyria and gray matter heterotopias, especially along the surface of the lateral ventricles. The fibrous septum was fenestrated, but microscopic evaluation of the basal forebrain and hypothalamus showed preservation of the neural components of the septum, including the cholinergic neurons of the medial septal nucleus (Figure 1A). The anterior two-thirds of the hypothalamus (from the levels of the preoptic area to the ventromedial nucleus) failed to develop, with only a small number of neurons in a disorganized neuropil remaining at this level (Figure 2). Immunohistochemical staining
for arginine vasopressin, which is normally present in the paraventricular, supraoptic, and suprachiasmatic nuclei, disclosed only a few immunoreactive neurons with axons coursing toward the midline along the base of the brain, but there was no clear median eminence (Figure 1D). Agouti-related protein is found in the arcuate nucleus, which is thought to drive feeding behavior. Only a few surviving neurons could be identified immunohistochemically (Figure 1E). Despite the paucity of normal structures in the rostral two-thirds of the hypothalamus, immunohistochemical staining for tyrosine hydroxylase demonstrated the normal appearance of the nigrostriatal bundle, which runs through the lateral hypothalamus at these levels (Figure 1B), as well as normal dopaminergic innervation of the striatum (Figure 1C), indicating that the integrity of the remaining tissue had not been disrupted (eg, by an infarct or infection). The caudal
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Figure 3. Magnetic resonance imaging (MRI) in case 2. (A) Axial T2-weighted MRI through base of the third ventricle shows no hamartomas in the hypothalamus. (B) Sagittal T1-weighted MRI shows hypoplastic corpus callosum.
Figure 2. A low power photomontage showing the remaining rostral hypothalamus in Case 1. Neurons are disorganized, no clear nuclear structure, and immunostaining at this level (Figure 1 D-E) showed only a few scattered remaining neurons of each chemical phenotype. A cortical heterotopia was present adjacent to the rostral hypothalamic remnant. Scale ¼ 1 mm. hypothalamus was intact, including the mammillary bodies and tuberomammillary nuclei. Immunohistochemical staining for melaninconcentrating hormone (Figure 1F) and for tyrosine hydroxylase in the A11 dopaminergic neurons (Figure 1B), which are found at this level, showed normal neuron numbers and morphology. No hamartomas were present in the hypothalamus, although a cortical heterotopia was located nearby (Figure 2).
Case 2 A term infant was hospitalized for the first 3 days of life for jaundice. At 2 months of age, she developed right-sided focal seizures and was hospitalized for a subdural/intraventricular hemorrhage secondary to vitamin K deficiency, diabetes insipidus, hypothyroidism, and adrenal insufficiency. Ophthalmic evaluation revealed bilateral optic nerve hypoplasia. The patient was later treated with growth hormone because of decreased growth velocity. An MRI of the brain revealed mild generalized atrophy and borderline prominence of the ventricular system, specifically expanded extraaxial cerebrospinal fluid space along the frontoparietal regions, worse on the left than the right, but no hypothalamic or pituitary abnormalities (Figure 3). At 10 months of age, the patient started to have spontaneous, inappropriate laughing spells. Concurrently, she began to suffer from dysautonomic spells and grand mal seizures. At 1 year of age, she developed tonic-clonic seizures. EEG showed independently occurring left frontocentral and right frontotemporal spikes. At age 26 months, the patient was admitted for idiopathic fever lasting 4 weeks, accompanied by decreased appetite, weight loss, increased seizure activity, increased spasmodic movements, and periods of inconsolable crying. The patient’s fever was attributed to ‘‘hypothalamic storm’’ and treated with chlorpromazine. The patient continued to have episodes of inappropriate, spontaneous laughing spells, which her neurologist diagnosed as gelastic seizures. The patient’s gelastic seizures occurred in 2 forms: (1) inappropriate,
spontaneous laughter hysterical in quality with occasional shrieking sounds not prompted by any stimuli. These episodes lasted several seconds to 1 minute each, and could occur either singly or in clusters, sometimes occurring during sleep; (2) the same spontaneous laughing, accompanied by complete loss of muscle tone in which the patient’s body becomes limp and her eyes roll back. During these episodes, she was unresponsive for several seconds. The patient was prescribed lamotrigine, levetiracetam, and zonisamide. Although these medications controlled her grand mal seizures, she continues to suffer almost daily from gelastic seizures.
Case 3 A term infant with a complicated delivery, requiring resuscitation with CPR, was hospitalized for 2 weeks during the neonatal period because of jaundice and hypoglycemia (glucose of 12 mg/dL). He was found to have corticotropin deficiency and hypothyroidism. An EEG on day of life 4 was moderately abnormal and suggestive of diffuse cerebral dysfunction. He was discharged with the diagnosis of optic nerve hypoplasia on hydrocortisone and Synthroid. The patient was later started on growth hormone replacement therapy and desmopressin (DDAVP). An MRI of the brain at 1 year of age revealed partial agenesis of the corpus callosum. The patient had no history of seizures until he presented with episodes of laughing and loss of muscle control at 41 months of age, which his neurologist characterized as gelastic seizures. The episodes involve a laugh that is characteristically different than his typical happy laugh and combined with loss of body control resulting in falls. The episodes last approximately 30 seconds and occurred several times per week at their height. A sleep EEG performed at 55 months of age demonstrated left occipital epileptiform discharges during sleep. Treatment with levetiracetam has controlled his seizures.
Case 4 A female term infant was admitted to the neonatal intensive care unit for cyanosis, temperature instability, jaundice, and hypernatremia. An MRI showed diffuse cerebral underdevelopment and enlargement of the temporal horn of the left lateral ventricle without hypothalamic or pituitary abnormalities. The patient was discharged from the neonatal intensive care unit with a diagnosis of optic nerve hypoplasia, hypothyroidism, adrenal insufficiency, and diabetes insipidus.
236 Beginning at 4 months of age, the patient was repeatedly hospitalized for respiratory distress and presumed sepsis with fevers. She developed generalized seizures at 4 months of age, which resolved with phenytoin treatment. An EEG revealed diffuse slowing bilaterally, consistent with a postictal state, frequent to near-continuous sharp and spike wave discharges over the left frontal-central head region, and occasional independent and synchronous right central sharps over the right frontal head region. Nine tonic seizures were captured during the overnight EEG. Shortly after her first birthday, a gastrostomy tube and tracheostomy were placed. At age 16 months, she developed episodes of smiling and giggling lasting 5 to 8 seconds and occurring in clusters up to 4 to 5 times a day. Her neurologist reviewed her most recent MRI for hypothalamic hamartoma and confirmed that the patient had gelastic seizures in the absence of hypothalamic hamartoma. In addition to gelastic seizures, her neurologist identified complex partial seizures, secondarily generalized seizures consisting of tonic stiffening with eye rolling lasting 1 to 2 minutes, and a reflex seizure occurring in the context of a loud high-pitched sound. The patient is treated with phenobarbital and topiramate.
Discussion A pediatric neuroradiologist confirmed no hypothalamic abnormalities or hamartomas present on MRI. These cases demonstrate that gelastic seizures can occur in patients with optic nerve hypoplasia who do not have hypothalamic hamartomas; however, all 4 patients had early signs of hypothalamic dysfunction and neuroradiographic abnormalities in other regions of the brain. Gelastic seizures associated with hypothalamic hamartomas originate in the hamartoma itself, usually in the posterior third of the hypothalamus.6,7 The mechanism of epileptogenesis is not fully understood. Resected preparations of hypothalamic hamartomas have shown that hypothalamic hamartoma neurons can fire spontaneously with intrinsic pacemaker-like activity.8 This spontaneous activity was subsequently recorded in situ using direct endoscopic visualization.8 Fenoglio et al9 also demonstrated intrinsic activity in hypothalamic hamartoma preparations in situ, which identified 2 populations of neurons: small g-aminobutyric acid (GABA)– expressing neurons and large, quiescent, pyramidal-like neurons. Their research proposes that the small GABAergic interneurons have pacemaker-like firing that synchronizes the output of the large neurons to nearby limbic structures resulting in gelastic seizures.9 This mechanism is unlikely in our patients who have no hamartomas, and at least in case 1, lack the clusters of neurons identified by Fenoglio et al9 in hamartomas. Optic nerve hypoplasia is the only condition reported to be associated with gelastic seizures without masses in the hypothalamus. This suggests that hypothalamic disorganization with or without hamartomas can cause gelastic seizures. Hypothalamic hamartomas are thought to cause seizures because they contain 2 populations of neurons, large projection-type neurons and smaller GABAergic interneurons.10,11 The GABAergic cells are spontaneously active, and they innervate the projection-type neurons. However, the latter cells have particularly high intracellular chloride levels, so they are depolarized, as opposed to the more typical suppression, by
Journal of Child Neurology 30(2) GABAergic input. Hypothalamic hamartomas that cause gelastic seizures are usually found at the level of the posterior hypothalamus, just adjacent to the mammillary bodies,7 suggesting that the excitatory output of the projection-type neurons can serve as a substrate for the seizures by driving hyperexcitation of structures in the posterior hypothalamus. Case 1 supports the notion that, in the absence of a hamartoma, severe disorganization of the anterior two-thirds of the hypothalamus associated with optic nerve hypoplasia can permit remaining structures in the posterior hypothalamus to become a substrate for gelastic seizures. The anterior hypothalamus contains GABAergic neurons, such as those in the ventrolateral preoptic nucleus, which are known to inhibit neurons in the posterior hypothalamus, such as the histaminergic neurons in the tuberomammillary nucleus.12 It is possible that loss of an inhibitory input from the anterior two-thirds of the hypothalamus can disinhibit neurons in the posterior hypothalamus, causing gelastic seizures. The manifestations of hypothalamic dysfunction in our patients, including temperature instability, fragmented sleep, and panhypopituitarism, indicate that optic nerve hypoplasia is often associated with failure of the anterior two-thirds of the hypothalamus. These cases further support the idea that the posterior hypothalamus is involved in originating the gelastic epileptiform activity. Although the pathways from the posterior hypothalamus that can lead to cortical seizure activation are not known, it is notable that this level contains the histaminergic neurons of the tuberomammillary nucleus and the glutamatergic neurons of the supramammillary nucleus, both of which have direct and presumably excitatory inputs to the hippocampus and the cerebral cortex.13-15 Ictal video-EEG has also reportedly localized gelastic epilepsy to other foci outside of hypothalamic hamartomas including the right temporal lobe16 and frontal lobe.17 It is possible that the hypothalamic site causing gelastic seizures does so by abnormal firing of inputs to these structures. On the other hand, even in patients in whom the gelastic seizures appear to be localized to cortical sites, thorough neuroimaging of the hypothalamus should be performed to rule out a hypothalamic lesion that is disinhibiting seizures at these cortical sites. Acknowledgment The authors wish to thanks Marvin Nelson, MD, for providing the reading of the MRIs for this report.
Author Contributions CF and MB identified the cases. MB cared for the patients. CF and CZS collected and reviewed the medical records and wrote the first draft. CS participated in the autopsy and created Figures 1 and 2. All authors participated in the writing and revision of the manuscript.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported in part by the One Small Voice Foundationand Grant Number UL1TR000130, Children’s Hospital Los Angeles from the National Center for Advancing Translational Sciences (NCATS) and the National Institute of Health.
Ethical Approval This research was approved the Children’s Hospital Los Angeles IRB, the Committee on Clinical Investigations (CCI-11-037).
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