Introduction. Clinical manifestations. Overview

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1 Hypothalamic hamartoma with gelastic seizures John F Kerrigan MD ( Dr. Kerrigan of Barrow Neurological Institute at Phoenix Children's Hospital and University of Arizona College of Medicine has no relevant financial relationships to disclose. ) Jerome Engel Jr MD PhD, editor. ( Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, has no relevant financial relationships to disclose.) Originally released March 27, 2001; last updated October 17, 2017; expires October 17, 2020 Introduction Overview In this article, the author provides a review of hypothalamic hamartoma, with an emphasis on treatment options. Hypothalamic hamartoma is a rare malformation in the ventral hypothalamus, resulting in treatment-resistant (drugresistant) epilepsy, including gelastic seizures. However, multiple surgical approaches are now available. Treatment should be individualized to the patient's clinical course and the surgical anatomy of the hypothalamic hamartoma. Stereotactic thermoablation with near real-time MR thermography is the most recent surgical treatment option for this disease. New publications describe relatively favorable outcomes for safety and efficacy. Key points Hypothalamic hamartoma should be considered in any patient with gelastic seizures and in any child with early onset of precocious puberty. Seizures associated with hypothalamic hamartoma are rarely controlled with antiepilepsy drugs. Cognitive impairment and psychiatric symptoms are common comorbid features with hypothalamic hamartoma and epilepsy. Surgical treatment of the hypothalamic hamartoma can control seizures and stabilize (or even improve) cognitive and psychiatric symptoms. The best surgical approach is chosen after considering each patient's clinical course and surgical anatomy. Historical note and terminology The first description of hypothalamic hamartoma as a cause of precocious puberty (and probably gelastic seizures, although the symptoms were not recognized as such) was published in 1934 (Le Marquand and Russell 1934). In 1958, List and colleagues recognized the association between hypothalamic hamartoma and gelastic seizures (List et al 1958). In 1988, Berkovic and colleagues described 4 children with hypothalamic hamartoma, treatment-resistant epilepsy, and progressive neurobehavioral deficits, providing the first definitive description of the catastrophic epilepsy syndrome that we recognize today (Berkovic et al 1988). Hypothalamic hamartoma can cause 2 distinct clinical syndromes (Boyko et al 1991; Valdueza et al 1994; Arita et al 1999; Debeneix et al 2001; Jung et al 2003). Central precocious puberty is associated with hypothalamic hamartoma lesions that attach anteriorly to the ventral hypothalamus, near the tuber cinereum and pituitary stalk. These have been classified as parahypothalamic or pedunculated based on the local anatomy. The second syndrome consists of the neurologic symptoms, usually beginning with gelastic (laughing) seizures, but often progressing to additional, more disabling seizure types, along with cognitive impairment and behavioral symptoms. These hypothalamic hamartoma lesions attach posteriorly in the ventral hypothalamus, in the region of the mammillary bodies, and have been referred to as intrahypothalamic or sessile. Approximately 40% of hypothalamic hamartoma patients with epilepsy also have central precocious puberty, due to larger lesions that have both an anterior and posterior plane of attachment to the hypothalamus. Clinical manifestations Presentation and course

2 Hypothalamic hamartoma can cause central precocious puberty, with an isosexual pattern of developing secondary sexual characteristics (that is, abnormally early progression through the normal sequence of thelarche, adrenarche, and menarche seen with normal puberty). Hypothalamic hamartoma is a particularly common cause of central precocious puberty in young children and should always be excluded by MRI of the brain in boys or girls with central precocious puberty who are younger than 6 years of age (Jung and Ojeda 2002). Most children with central precocious puberty alone do not experience epilepsy or the other neurobehavioral symptoms noted below. Approximately 40% of children with hypothalamic hamartoma and epilepsy experience central precocious puberty. In our experience, gelastic seizures are usually the first manifestation in this group. However, clinical diversity from patient to patient is 1 of the hallmark features of the hypothalamic hamartoma syndrome, and exceptions to the usual clinical rules should always be anticipated. Gelastic seizures are the prototypical seizure type associated with hypothalamic hamartoma (Harvey and Freeman 2007). For those patients with epilepsy, gelastic seizures are usually the first seizure type and occur very early in life. The correct diagnosis is often delayed, but the majority of hypothalamic hamartoma patients begin having gelastic seizures before 1 year of age, and many of these begin during the first month of life. Gelastic seizures are brief (duration is usually less than 20 seconds) and frequent (usually with multiple gelastic seizures per day). They may mimic true laughter but more often are peculiar and mirthless even to the casual observer, and may incorporate behavioral elements of grimacing or crying (dacrystic seizures). They may or may not be associated with altered consciousness, which is often difficult to determine in infants. They can be very subtle, or even subjective, as pressure to laugh as an ictal manifestation is reported in adults (Sturm et al 2000). Gelastic seizures are rarely controlled with antiepilepsy drug therapy (Tassinari et al 1997; Freeman and Eeg-Olofsson 2007). Unfortunately, additional types of seizures develop in 80% of patients. These additional seizures can be disabling. Complex partial seizures are most common, and can mimic seizures that arise from either temporal or frontal lobe regions. Generalized seizure types can include tonic-clonic, tonic, atonic, or even absence. Severely affected patients can develop epileptic encephalopathies with all the features of Lennox-Gastaut syndrome, including drop attacks (Berkovic et al 2003; Freeman et al 2003). Approximately 5% of children with hypothalamic hamartoma develop infantile spasms (Kerrigan et al 2007a). Significant cognitive deficits occur in roughly 80% of patients and may be progressive in up to 50% (Quiske et al 2006). When mild, difficulties with processing speed and short-term memory are most common. However, 50% of hypothalamic hamartoma patients with treatment-resistant epilepsy are intellectually disabled (full-scale intelligence quotient [IQ] or developmental quotient [DQ] less than 70) (Prigatano et al 2008). Some patients experience developmental regression and loss of previously learned abilities, usually occurring at the time when seizures worsen. Psychiatric problems are also common for the cohort of patients with hypothalamic hamartoma and epilepsy (Veendrick-Meekes et al 2007). Children with hypothalamic hamartoma and epilepsy may have oppositional-defiant disorder (83%), attention deficit/hyperactivity disorder (75%), conduct disorder (33%), and mood disorder (17%) (Weissenberger et al 2001). Rage attacks, consisting of aggressive and sometimes destructive behavior arising from minor frustration, are a particular problem for patients with hypothalamic hamartoma and epilepsy and can sometimes be the most disabling aspect of the disease (Ng et al 2011). Patients with hypothalamic hamartoma and epilepsy have decreased health-related quality of life compared to age-matched children with chronic migraine or other forms of epilepsy (Park et al 2013). Prognosis and complications For those patients with hypothalamic hamartoma and central precocious puberty only, the prognosis is favorable. Almost all of these patients respond to medical therapy with gonadotropin-releasing hormone (GnRH) agonists (Mahachoklertwattana et al 1993). Once the normal age range for puberty is reached, medical therapy is discontinued, and the normal developmental program of puberty occurs. These patients typically do not have neurologic problems later in life. For those patients with gelastic seizures, the prognosis is highly variable. Patients with onset of gelastic seizures during adolescence or adulthood (approximately 10% of the population of patients with hypothalamic hamartoma and epilepsy) can have a relatively benign prognosis and may not go on to experience other seizure types or cognitive issues (Mullatti et al 2003).

3 However, the more common scenario with hypothalamic hamartoma and epilepsy is that gelastic seizures begin early, prior to 5 years of age and often before 1 year of age. These patients are at high risk (80% likelihood) of developing additional seizure types, and 50% have a clinical course consistent with an epileptic encephalopathy, with objective evidence of deterioration in cognition or behavioral health (Berkovic et al 1988; Kerrigan et al 2005). Early intervention with surgical therapy may favorably influence this outcome, as will be discussed below. Clinical vignette The patient was a 5-year-old, right-handed girl with a history of treatment-resistant epilepsy associated with hypothalamic hamartoma. Her mother's pregnancy was normal, and she experienced an uncomplicated vaginal delivery. Peculiar, highly-stereotyped behaviors were noted during the first week of life, later diagnosed as gelastic seizures. These consisted of unprovoked giggling, accompanied by a frightened look with eyes wide open, and clenching of the fists. These rarely lasted longer than 15 seconds but occurred up to 40 times per day. Her early development was normal for age. At 3 years of age, she developed complex partial seizures, usually beginning with the gelastic features but leading to activity arrest, behavioral unresponsiveness, and staring. She was lethargic after these events and would sometimes sleep. She was experiencing up to 5 of these daily. Brain MRI demonstrated a hypothalamic hamartoma almost filling the third ventricle and attached to the left side immediately above the mammillary body. The brain MRI was otherwise normal. An EEG demonstrated rare interictal spikes over the left midtemporal region. Three of her usual gelastic seizures were captured, which were associated with diffuse and nonlocalizing rhythmical features on the simultaneous EEG. Seizure frequency was unaffected by trials of antiepilepsy drugs including levetiracetam, oxcarbazepine, and topiramate. She was described as deteriorating with her socialization and behavior, with severe mood swings and tantrums, and failing to make progress with learning and language skills. There were no recognized endocrine problems. She was evaluated at our center for surgical treatment at 4.5 years of age, with up to 10 brief complex partial seizures per day. Her family was concerned about her social skills and failure to make developmental progress. Neuropsychological testing revealed Full Scale IQ 82, Verbal IQ 82, and Performance IQ 84. Processing speed was notable as a relative strength. She had significant deficits with language-based skills relative to visual motor skills. Review of her films at multidisciplinary conference showed the lesion to be Delalande Classification Type II (Delalande and Fohlen 2003). Based on the surgical anatomy (hypothalamic hamartoma lesion completely above the floor of the third ventricle and insufficient room within the third ventricle to maneuver a surgical endoscope), a transcallosal interforniceal approach was recommended for optimal resection. Her postoperative course was uneventful, and she was discharged on the fourth postoperative day. She did not experience diabetes insipidus or obvious short-term memory problems. Postoperative MRI showed no residual hypothalamic hamartoma. One year following surgery, she was completely free of seizures while taking 1 antiepilepsy drug. Previously thin for her age, she had an excessive appetite, and the family struggled to maintain her weight. Her follow-up EEG was normal. Behavior and socialization were regarded as normal for age. Postoperative neuropsychological testing showed stable results, with improved performance for verbal expression and vocabulary. Biological basis Etiology and pathogenesis The etiology of hypothalamic hamartoma for most patients is unknown. However, hypothalamic hamartoma is 1 of the many physical features associated with Pallister-Hall syndrome (OMIM #146510), which is known to be due to genomic (total body) loss-of-function mutations within specific portions of the GLI3 gene, which expresses a transcription factor in the sonic hedgehog intracellular signaling pathway. Genetics. Comparison of DNA extracted from surgically-resected hypothalamic hamartoma tissue with DNA derived from leukocytes from the same patient has led to the discovery that at least 40% of sporadic (nonsyndrome-related) hypothalamic hamartoma are associated with (and presumably caused by) a somatic (tumor-only) mutation in GLI3 or multiple other genes that express proteins related to the sonic-hedgehog signaling pathway (Craig et al 2008; Wallace et al 2008; Hildebrand et al 2016). Additional candidate genes, also expressing transcription factors that are known to

4 be involved in ventral forebrain development, have been implicated (Kelberman et al 2006; Kerrigan et al 2007b). Pathology. As a hamartoma, hypothalamic hamartoma lesions contain normal-appearing (ie, not developmentally immature or neoplastic) cells. However, hypothalamic hamartoma tissue is distinct from adjacent normal hypothalamus, which is characterized by nuclei with large neurons. Conversely, hypothalamic hamartoma contain predominately (90%) small neurons (10 to 16 µm diameter cell bodies) that occur in clusters, with relatively sparse intermixed larger neurons. The abundance of neurons and the prominence of neuron clusters vary from case to case (Coons et al 2007). Tracts of myelinated fibers are seen in the immediate subependymal region (that is, at the periphery of the lesions), but the specific details of how hypothalamic hamartoma connect to normal brain networks are unknown. Cellular pathophysiology. Hypothalamic hamartoma are associated with central precocious puberty. The exact molecular mechanisms by which this is mediated are unknown. Hypothalamic hamartoma lesions universally express gonadotropin-releasing hormone (GnRH), although there is no direct experimental support for pulsatile release of GnRH from the hypothalamic hamartoma as the presumed ectopic generator (pulsatile GnRH release is required for normal puberty). Chan and colleagues found that tissue expression of various mediators of normal puberty did not differ between those patients with and without a history of central precocious puberty, but that the attachment of the lesions did differ significantly. Patients with a prior history of central precocious puberty had hypothalamic hamartoma that attached anteriorly in the region of the tuber cinereum and pituitary stalk, whereas those patients with epilepsy but without a prior history of central precocious puberty had lesions that attached posteriorly in the hypothalamus and lacked attachment to the region of the tuber cinereum (Chan et al 2010). Hypothalamic hamartoma are also intrinsically epileptogenic, which has been established by seizure recordings in which electrodes have been surgically implanted into the hypothalamic hamartoma lesion itself (Kahane et al 1994; Munari et al 1995; Berkovic et al 1997; Kuzniecky et al 1997). Experimentation with surgically-resected hypothalamic hamartoma tissue has led to a preliminary cellular model for seizure generation (Wu et al 2015). The small hypothalamic hamartoma neurons (comprising approximately 90% of total hypothalamic hamartoma neurons) appear to be gamma-amino-butyric-acid (GABA) expressing with an interneuron-like phenotype and also possess intrinsic pacemaker-like firing behavior (Wu et al 2005; Coons et al 2007; Beggs et al 2008). Conversely, the large hypothalamic hamartoma neurons (approximately 10% of total hypothalamic hamartoma neurons) have a phenotype consistent with excitatory, projection type neurons. These large neurons also have the functionally immature property of depolarizing and firing in response to GABA agonists (Kim et al 2008; Kim et al 2009; Wu et al 2008; Semaan et al 2015). The immature response of the large hypothalamic hamartoma neurons may lead to the unfavorable balance of excitatory and inhibitory activity that is a requisite feature of epileptic tissue. Work by Wu and colleagues has also suggested that gap junctions are present between hypothalamic hamartoma neurons and may functionally contribute to increased synchrony of cellular firing (Wu et al 2016). Epidemiology" Hypothalamic hamartomas are uncommon. Hypothalamic hamartoma associated with epilepsy is reported to have a prevalence of 1 in 200,000 children and adolescents in Sweden (Brandberg et al 2004) and 1 in 250,000 (capturing children with gelastic seizures) in Israel (Shahar et al 2007). Epidemiological studies addressing the prevalence of hypothalamic hamartoma associated with central precocious puberty are not available. Approximately 40% of patients with hypothalamic hamartoma and treatment-resistant epilepsy have a history of central precocious puberty (Freeman et al 2004). There are no recognized ethnic or geographical differences with respect to the prevalence of hypothalamic hamartoma. A modest (1.5 to 1) male predominance is reported in some studies (Munari et al 2000; Jung et al 2003). The number of completely asymptomatic cases is likely small, although a handful of these patients have been encountered in our experience as a referral center (less than 2% of total cases). Hypothalamic hamartoma as an incidental finding on MR imaging has not been reported in any population-based study. Prevention There are no recognized preventative measures for this congenital malformation.

5 Differential diagnosis Precocious puberty can be isosexual (early initiation of the complete developmental program of puberty) or isolated to the changes that accompany abnormal female sex steroid production (thelarche = breast development and menarche = female reproductive changes leading to menses) or male sex steroid production (adrenarche = axillary and pubic hair in both genders, and changes involving the scrotum and penis in males). A full discussion of the differential diagnosis of early puberty is beyond the scope of this article. Consultation with a pediatric endocrinologist is recommended. Hypothalamic hamartoma is 1 of the most common causes of central (isosexual) precocious puberty in children younger than 6 years of age. Brain MRI to exclude hypothalamic hamartoma as a cause of precocious puberty in this age group is indicated. For patients with gelastic seizures, one must always exclude hypothalamic hamartoma as a cause with high-resolution MRI. However, gelastic seizures can arise from other brain regions, most commonly from temporal and frontal lobe structures (Arroyo et al 1993; Cheung et al 2007; Savasta et al 2014). Aside from hypothalamic hamartoma, other pathologies occurring in or adjacent to the hypothalamus (such as craniopharyngioma, juvenile pilocytic astrocytoma, optic nerve glioma, and colloid cyst of the third ventricle) are rarely associated with gelastic seizures. Diagnostic workup Magnetic resonance imaging. MRI is the most appropriate structural imaging technology for diagnosing (or excluding) hypothalamic hamartoma (Freeman et al 2004; Harvey and Freeman 2007). Coronal, axial, and sagittal T1- and T2-weighted and fluid-attenuated inversion recovery (FLAIR) images are recommended. For diagnosis and surgical planning, we find coronal T2 fast spin echo (FSE) with thin cuts and minimal slice gaps to be the single most useful sequence. Sedation is usually required for young or uncooperative patients to minimize movement and to obtain highquality images. We recommend at least 1 follow-up MRI to exclude a progressive mass lesion. However, there is good evidence that hypothalamic hamartoma do not grow or expand relative to the normal growth trajectory of the brain (Mahachoklertwattana et al 1993; Turjman et al 1996; Freeman et al 2004). Serial imaging is usually not required. Gadolinium administration (contrast enhancement) is recommend for the initial (or first follow-up) imaging study to exclude a contrast-enhancing lesion. Hypothalamic hamartoma lesions do not enhance. Cystic components occur in approximately 1% to 2% of hypothalamic haratoma (Prasad et al 2000; Manjila et al 2014). Hypothalamic hamartoma have MRI signal characteristics similar to that of normal grey matter, particularly if the lesions are small. Larger lesions commonly show high signal features with T2-weighted and FLAIR imaging relative to normal grey matter, which correlates with decreased neuronal density as shown by magnetic resonance spectroscopy (Amstutz et al 2006) and stereology on pathological specimens (Kerrigan et al 2013). Hypothalamic hamartoma lesions vary tremendously in size. In our series of over 200 patients undergoing surgical treatment, the mean hypothalamic hamartoma lesion volume is 1.74 cm3 (median 0.57 cm3; range 0.04 to cm3 [using the technique for calculating the volume of an ellipsoid, derived from conventional measurements of the 3 major axes]). There are 2 clinicopathological (and clinicoradiological) subtypes based on the location of the hypothalamic hamartoma lesion relative to the floor of the third ventricle. These 2 phenotypes have been recognized by multiple authors over the years (Boyko et al 1991; Valdueza et al 1994; Arita et al 1999; Debeneix et al 2001; Jung et al 2003). The first phenotype consists of central precocious puberty and hypothalamic hamartoma lesions that are characterized as parahypothalamic (referring to the position of the lesion as located below the floor of the third ventricle and usually having a horizontal base of attachment to the ventral surface of the hypothalamus) or pedunculated (referring to the presence of a stalk or infundibulum that results in the attachment). The second phenotype consists of epilepsy (usually including gelastic seizures) and the cognitive and psychiatric symptoms that accompany the epilepsy. These hypothalamic hamartoma lesions are characterized as intrahypothalamic (referring to the presence of the hypothalamic hamartoma within the third ventricle and having at least some plane of attachment to the vertical wall (or walls) of the third ventricle) or sessile (referring to a broad base of attachment rather than a peduncle). Research has added diagnostic emphasis on the region of hypothalamic hamartoma attachment along the anterior to posterior axis of the ventral hypothalamus. For patients with central precocious puberty, there appears to be universal attachment of the hypothalamic hamartoma lesion to the region of the tuber cinereum and pituitary stalk in the

6 anterior hypothalamus (regardless of the presence or absence of a peduncle) (Chan et al 2010). For patients with epilepsy, there appears to be universal attachment to the region of the mammillary bodies in the posterior hypothalamus (Parvizi et al 2011). Patients with attachment to both the anterior and posterior regions (correlating with large hypothalamic hamartoma lesions) have both central precocious puberty and epilepsy (approximately 40% of hypothalamic hamartoma patients with treatment-resistant epilepsy also have a history of central precocious puberty). In summary, the clinical phenotype of a patient with hypothalamic hamartoma can usually be predicted by the sagittal MRI sequences. Most hypothalamic hamartoma lesions are not accompanied by abnormalities located elsewhere in the brain. However, approximately 5% of hypothalamic hamartoma patients do have other brain findings with a diverse range of features, usually malformations. These include periventricular nodular heterotopias, malformations of cortical development, or even midline developmental defects such as holoprosencephaly, optic pathway dysplasia, or dysgenesis of the corpus callosum (Boyko et al 1991; Freeman et al 2004; Kelberman et al 2006; Ng et al 2008). Sisodiya and colleagues suggested that diffuse cerebral anomalies may be present in hypothalamic hamartoma patients when examined with sophisticated 3-dimensional imaging tools that are more sensitive to cortical morphology relative to standard visual analysis, but these have not been widely applied to resolve this question 1 way or the other (Sisodiya et al 1997). Although the location of attachment of the hypothalamic hamartoma is predictive of the clinical phenotype (see above), the details of synaptic contact and network connectivity between the hypothalamic hamartoma and normal brain are unknown. There is circumstantial evidence from functional imaging techniques that hypothalamic hamartoma associated with epilepsy connect with the limbic circuit (including mammillary bodies, mammillothalamic tracts, anterior nucleus of the thalamus, cingulate gyrus, and mesial temporal structures) (Boerwinkle et al 2016; Usami et al 2016). This may explain why complex partial seizures associated with hypothalamic hamartoma often mimic seizures of temporal lobe origin (Cascino et al 1993). However, it also appears likely that gelastic seizures with hypothalamic hamartoma are associated with functional network connectivity to the dorsal pons and associated brainstem and cerebellar structures, possibly via the mammillotegmental tracts (Boerwinkle et al 2016; Usami et al 2016). Computed tomography imaging. CT imaging detects large hypothalamic hamartoma lesions but is not adequate to fully characterize soft-tissue mass lesions in this region of the brain. Additionally, many small hypothalamic hamartoma lesions are missed entirely with CT. Normal CT imaging does not exclude a diagnosis of hypothalamic hamartoma. Electroencephalogram. Although EEG is a conventional and usually useful study for patients with epilepsy, there are limitations that must be recognized when interpreting EEG results on patients with gelastic seizures and hypothalamic hamartoma (Harvey and Freeman 2007). Perhaps most importantly, EEG with standard electrode placement has significantly reduced sensitivity for gelastic seizures. That is, for patients that have exclusively gelastic seizures (more likely in younger hypothalamic hamartoma patients), the interictal recordings are often normal (Tassinari et al 1997). Ictal recordings, capturing gelastic seizure events, often show no change on the simultaneous EEG recording (Sher and Brown 1976). Troester and colleagues have reported EEG findings on a cohort of 133 hypothalamic hamartoma patients undergoing presurgical evaluation. Based on scalp EEG and standard visual analysis, 56% of all patients experiencing gelastic seizures (and 75% of all gelastic seizure events) did not show a change on the ictal EEG (Troester et al 2011). The interictal and ictal EEG is more likely to show abnormalities in older patients with additional seizure types (Tassinari et al 1997). Here, the problem is a relative lack of specificity, with a diversity of focal and generalized epileptiform changes (Tassinari et al 1997; Munari et al 2000; Troester et al 2011). Interictal focal spikes can be seen from virtually any brain region but are most common over the temporal regions, correlating with the concept that partial seizures arising in the hypothalamic hamartoma probably spread through limbic pathways and can mimic temporal lobe epilepsy (Troester et al 2011). Generalized EEG abnormalities are also commonly observed, including generalized spike-wave discharges, consistent with epileptic encephalopathies such as Lennox-Gastaut syndrome (Berkovic et al 1988; Munari et al 2000; Freeman et al 2003). Generalized EEG abnormalities often correlate with generalized seizures types, including tonic, atonic, tonic-clonic, and absence. Patients with infantile spasms may have hypsarrhythmia (Kerrigan et al 2007a). Surgical implantation of recording depth wires into the brain, including placement into the hypothalamic hamartoma,

7 has shown that gelastic seizures (and some of the other seizure types) originate in the hypothalamic hamartoma itself, demonstrating that the hypothalamic hamartoma is intrinsically epileptogenic (Munari et al 1995; Kuzniecky et al 1997; Palmini et al 2002; Kahane et al 2003). Other seizures, more commonly those with generalized EEG and clinical features, arise from neocortical brain regions without onset in the hypothalamic hamartoma (Munari et al 1995; Freeman et al 2003; Kahane et al 2003). These neocortical seizure foci likely arise over time through a process known as secondary epileptogenesis (Kerrigan et al 2005). However, seizures arising from these distant neocortical foci may disappear over weeks or months following surgical resection of the hypothalamic hamartoma, a process known as the running down phenomenon (Freeman et al 2003; Kerrigan et al 2005; Ng et al 2006). As the hypothalamic hamartoma is the appropriate surgical target for most patients, intracranial recordings with surgical implantation of depth electrodes is usually not recommended. Single photon emission computed tomography. Ictal studies have shown hyperperfusion in the hypothalamic hamartoma and thalamus (Iannetti et al 1997; Kuzniecky et al 1997). This may be regarded as a noninvasive confirmatory test but need not be considered standard in clinical practice. Positron emission tomography. PET imaging following administration of 18F-flouro-deoxyglucose (FDG) shows generally nonspecific features when obtained during the interictal state. Ictal studies with FDG administration and PET imaging have demonstrated increased metabolism in the hypothalamic hamartoma (Palmini et al 2005; Shahar et al 2008). As with SPECT, FDG-PET may be regarded as a noninvasive confirmatory test but need not be considered standard in clinical practice. Magnetoencephalography. Magnetic dipole mapping within the intracranial space can identify spike origination within hypothalamic hamartoma (Leal et al 2002; Leal et al 2006). MEG may be regarded as a noninvasive confirmatory test but need not be considered standard in clinical practice. Management Medical treatment. Central precocious puberty. Patients with hypothalamic hamartoma and central precocious puberty are treated with gonadotropin-releasing hormone (GnRH) agonists, usually with once-monthly intramuscular injection of leuprolide or related compounds (Mahachoklertwattana et al 1993; de Brito et al 1999). Intramuscular depot formulations of leuprolide give rise to consistently high GnRH agonist levels and mask the pulsatile release of GnRH that is required to trigger puberty. For those rare central precocious puberty patients who fail to respond to medical management (or are hypersensitive to GnRH agonist compounds), surgical resection of the hypothalamic hamartoma is effective for arresting early puberty (Li et al 2014; Manjila et al 2014). Once the normal age range for puberty is reached, medical therapy is discontinued, and the normal developmental program of puberty occurs. Gelastic seizures and epilepsy. There are no published trials (controlled or otherwise) of antiepilepsy drug therapy for hypothalamic hamartoma. Probably less than 5% of patients with hypothalamic hamartoma and epilepsy are optimally controlled on antiepilepsy drugs alone, although reports from referral centers likely include ascertainment bias with regard to describing antiepilepsy drug treatment resistance (Kerrigan et al 2005). Antiepilepsy drugs seem to be particularly ineffective against gelastic seizures, whereas they probably do decrease the frequency (without providing complete control) of other seizure types. There is no evidence for the superiority of 1 antiepilepsy drug over another in this regard. We recommend a trial of at least 2 antiepilepsy drugs before making a determination of treatment resistance and considering surgical therapy. Hypothalamic hamartoma patients with epilepsy usually have at least 1 seizure per day (often many more), so therapeutic trials of antiepilepsy drugs do not take a long time. The ketogenic diet is a treatment option for patients with hypothalamic hamartoma and epilepsy (Chapman et al 2011). Cognitive deficits. All patients with hypothalamic hamartoma and epilepsy should undergo neuropsychological assessment. A diverse spectrum of deficits is possible from normal to severe intellectual disability (Prigatano et al 2008). There are no cognitive interventions that are specific to hypothalamic hamartoma, but awareness of deficits and intervention with special needs education or functional rehabilitation is recommended. Psychiatric symptoms. Psychiatric symptoms (most commonly consisting of poor frustration tolerance and rage attacks but may include mood disorder, depression, anxiety, attention deficit disorder, and obsessive-compulsive disorder) may be the most disabling aspect of hypothalamic hamartoma for some patients (Weissenberger et al 2001).

8 Pharmacotherapy for these target symptoms, utilizing standard medications, should be considered when appropriate. However, there are no studies that provide evidence on the pharmacotherapy of psychiatric problems in the hypothalamic hamartoma population. Neurosurgical treatment. General comments. Surgical interventions for hypothalamic hamartoma are usually undertaken to treat refractory epilepsy. From a historical perspective, this is an evolving and still unsettled field, which has moved rapidly from the 1990s (in which surgical intervention was usually not possible or was ill-advised) to 2017 (in which we have multiple surgical treatment choices). New innovations have occurred regularly over the past decade, and today some of the newest and perhaps most-promising innovations have only preliminary peer-reviewed evidence regarding safety and efficacy (Pati et al 2013). Consequently, this is a dynamic space. It is important to recognize that neocortical resection is usually not the appropriate treatment choice for patients with hypothalamic hamartoma and epilepsy. Even for those patients with evidence of secondary epileptogenesis, in which seizures are arising from neocortical regions, these seizures may disappear with removal or treatment of the hypothalamic hamartoma lesion (the running-down phenomenon). Neocortical resection has a poor track record for improving seizures in patients with hypothalamic hamartoma and epilepsy (Cascino et al 1993). It appears likely that surgical treatment in adults with long-standing epilepsy is associated with a lower success rate and a higher likelihood of complications (Drees et al 2012). The natural history of hypothalamic hamartoma associated with epilepsy is dynamic, rather than static. Patients develop additional seizures types along with cognitive and psychiatric problems over time. Some patients will functionally deteriorate with loss of previously acquired skills and developmental milestones. Secondary epileptogenesis (leading to the risk of seizures initiating at distant sites) also occurs over time. Accordingly, for those with disabling seizures or significant cognitive or behavioral impairments, a proactive approach with earlier surgical intervention should be considered. Success of surgery for controlling seizures correlates with younger age at time of surgery and a shorter lifetime duration of epilepsy at time of surgery (Ng et al 2006; Schulze-Bonhage et al 2008). The likelihood of improved cognition subsequent to hypothalamic hamartoma surgery also correlates with younger age at the time of surgery (Wethe et al 2013). An independent predictor of surgical success for controlling seizures is the extent of hypothalamic hamartoma resection: completely resected lesions are more likely to result in complete seizure control (Ng et al 2006). Selecting the single best surgical treatment for hypothalamic hamartoma patients is based on an appreciation of the natural history (stable vs. deteriorating), which, in turn, influences the degree of urgency for immediate (resection, disconnection, or thermal destruction) versus delayed (gamma knife radiosurgery) treatment. Equally important is the surgical anatomy, which is unique to each patient. Classification and surgical anatomy. Several classification systems have been proposed for hypothalamic hamartoma (Boyko et al 1991; Valdueza et al 1994; Arita et al 1999; Debeneix et al 2001; Delalande and Fohlen 2003). We prefer the system proposed by Delalande and Fohlen as it most directly translates into the realm of surgical planning. Undoubtedly other classification systems will be preferred in the future as presently unanticipated treatment options become available. Type I. Hypothalamic hamartoma lesion in which the horizontal plane of attachment is completely below the floor of the third ventricle. These would correspond to the designation parahypothalamic and would often correspond with those lesions that are pedunculated. Many of the lesions that cause central precocious puberty would be Type I. However, Type I lesions with a broad base of attachment that includes the region of the mammillary bodies can also cause epilepsy. Type II. Hypothalamic hamartoma lesion in which there is a vertical plane of attachment to the walls of the third ventricle, completely above the floor of the third ventricle. These would be the classic intrahypothalamic lesions, and would always be considered sessile because a stalk or peduncle is not present. These are highly associated with epilepsy, and infrequently associated with central precocious puberty. Type III. Hypothalamic hamartoma lesion in which the plane of attachment is both above and below the floor of the third ventricle, and thereby possessing a plane of attachment that is both vertical (in the third ventricle) and horizontal

9 (attached to the inferior surface of the hypothalamus). These are larger lesions than Type II and often include attachment that extends anteriorly (to the region of the tuber cinereum) and posteriorly (to the region of the mammillary bodies). Consequently, these hypothalamic hamartoma lesions often include both central precocious puberty and epilepsy. Type IV. These were characterized as giant hypothalamic hamartoma lesions by Delalande (Delalande and Fohlen 2003), without offering clear criteria for the boundary between Types III and IV. Our research group currently utilizes a volume of 4 cm3 as the boundary between III and IV (as determined by utilizing the volume of an ellipsoid from the 3 major axes). However, the surgical planning considerations for Types III and IV are similar. Pterional (orbitozygomatic) approach. This was the usual way of resecting hypothalamic hamartoma lesions prior to 1999 (Palmini et al 2002). When this approach was used for all hypothalamic hamartoma patients, efficacy was low and the complication rate was high (Palmini et al 2002). However, for Type I patients (with a horizontal plane of attachment below the floor of the third ventricle), this is the optimal surgical approach for resection. Abla and colleagues report a cohort of 10 patients in whom the choice of pterional resection was individualized to their surgical anatomy (Abla et al 2011). With at least 1 year of follow-up, 40% are completely seizure-free (66% of those with 100% hypothalamic hamartoma resection). An additional 40% are at least 50% improved with seizure frequency. See Table 1 for additional details. Transcallosal anterior interforniceal approach. This surgical approach was pioneered by Walter Dandy in 1923 for lesions within the third ventricle. However, Jeffrey Rosenfeld of Melbourne, Australia was the first to utilize this surgical approach for hypothalamic hamartoma (Rosenfeld et al 2001). This approach revolutionized hypothalamic hamartoma surgery, providing the first major step forward with respect to the surgical treatment of this disease. Two large uncontrolled outcome studies report similar results. Harvey and colleagues, with a cohort of 29 patients, reported complete seizure control in 52% (Harvey et al 2003), whereas Ng and colleagues, with 26 patients, reported complete seizure control in 54% (Ng et al 2006). Deficits with short-term memory emerged as a possible complication, with residual postoperative impairment of short-term memory in 8% of subjects (same result in both studies). See Table 1 for additional details. Transcallosal resection is a treatment option for those patients with hypothalamic hamartoma lesions with vertical attachment to the walls of the third ventricle (Types II to IV), particularly for those with large lesions that fill the third ventricle (as with the illustrative case noted previously) or for lesions with bilateral attachment. Transventricular endoscopic approach. Two large uncontrolled trials report similar findings: Procaccini and colleagues report a cohort of 33 patients undergoing endoscopic hypothalamic hamartoma resection, with complete seizurecontrol in 49% (Procaccini et al 2006), whereas Ng and colleagues have published a cohort of 37 patients, with complete seizure control in 49% (Ng et al 2008). Small ischemic infarcts of the thalamus (usually asymptomatic and detected on diffusion-weighted postoperative MRI) emerged as a complication in 30%, possibly due to trauma to small perforating arteries with manipulation of the endoscope (Ng et al 2008). Endoscopic resection is a treatment option for those with smaller intraventricular hypothalamic hamartoma lesions (Type II), particularly with those that have a clearly unilateral base of attachment. See Table 1 for additional details. Wethe and colleagues at Barrow have reported the postoperative neuropsychological testing results for patients with hypothalamic hamartoma and treatment-resistant epilepsy (Wethe et al 2013). Of the cohort of 32 patients, 63% underwent endoscopic resection. For the entire cohort, there was a statistically significant improvement in full-scale intelligence quotient (IQ), with a pre-operative mean of 83.0 and postoperative mean 91.3 (p<0.001). For the entire group, there was no significant difference between preoperative and postoperative scores relating to learning and memory, although individual patients did demonstrate diverse (some favorable and others unfavorable) changes between pre-and postoperative testing. Improvement in cognitive functioning was most likely to occur in patients who were younger at the time of surgery (and had a shorter lifetime duration of epilepsy) and in those with lower scores with preoperative testing. Combined or staged approach for hypothalamic hamartoma surgery. For patients with hypothalamic hamartoma Type III and IV, which have attachment both above and below the normal position of the floor of the third ventricle (and, therefore, have both vertical and horizontal planes of attachment), a staged approach may be required, with resection

10 from above (either endoscopically or by the transcallosal approach) and subsequently from below by the pterional approach (Gore et al 2006). As yet, there are no large cohorts published that are specific to the staged approach. Gamma knife radiosurgery. Treatment with Gamma knife radiosurgery delivers a subnecrotizing dose of radiation to the responsible epileptic lesion. Although the exact cellular mechanisms are unknown, it likely does involve neuronal death rather than purely modulatory effects (Kerrigan et al 2013). The side effect profile is excellent with little or no risk of short-term adverse events. Regis and colleagues report a cohort of 27 patients undergoing Gamma knife treatment for hypothalamic hamartoma and epilepsy, with complete seizure control in 37% after a minimum of 3 years of follow-up (Regis et al 2006). Abla and colleagues report a cohort of 10 patients who underwent Gamma knife surgery, with 40% seizure-free at follow-up (Abla et al 2010). The relative weakness for Gamma knife radiosurgery as a treatment choice is the need to wait for efficacy, which commonly occurs 6 to 18 months after treatment. Perhaps 50% of patients will have transient worsening of seizure frequency during a window of time several weeks to several months after Gamma knife surgery. Accordingly, we favor the use of Gamma knife for those patients who are stable, that is, able to tolerate the wait time for efficacy. This is more likely to be the case in patients who are older with gelastic seizures as their only seizure type. One must also factor in the proximity of the optic tracts, which are particularly radiosensitive structures. See Table 1 for additional details. Interstitial radiosurgery. A single center has reported their experience with stereotactic implantation of radioactive seeds (with subsequent removal) to treat hypothalamic hamartoma with epilepsy (Quiske et al 2007; Schulze-Bonhage et al 2008). In a cohort of 24 treated patients, 38% were seizure-free. Transient cerebral edema was noted in 26%. There is a follow-up report from this same group comparing neuropsychological outcome with pre- and post-operative testing in 26 subjects undergoing interstitial radiosurgery. On a group-wise basis, there were no statistically significant changes in any of the scales used in this study, which placed particular emphasis on learning and memory (Wagner et al 2014). However, like the study reported by Wethe and colleagues, there was a great deal of variation in memory outcome between individual patients. Those with higher pre-operative scores appeared to be at particular risk for postoperative decline (Wagner et al 2014). See Table 1 for additional details. Stereotactic radiofrequency thermoablation. This technique utilizes the delivery of energy to physically heat the hypothalamic hamartoma lesion, thereby resulting in neuronal injury and death in the target. This technique has the advantage of being less invasive relative to open resection but nevertheless still carrying the risk of hemorrhage that accompanies any stereotactic procedure. It has the advantage of immediate effectiveness for those patients who are successfully treated. Kameyama and colleagues provided an updated report on their cohort of 100 patients undergoing stereotactic radiofrequency thermoablation of hypothalamic hamartoma for treatment-resistant epilepsy (Kameyama et al 2016). With at least 1 year of follow-up (median duration of follow-up 3 years), they reported 71% of patients are completely seizure-free. Psychiatric symptoms were reported to be improved (if not completely resolved) in all subjects. For those patients with both pre- and post-operative neuropsychological testing (69% of the cohort), there was a statistically significant group-wise improvement in full-scale IQ (mean increase in postoperative full-scale IQ 6.1 points; p<0.001). Short-term adverse events included Horner syndrome (60%), hyperphagia (28%), and short-term memory loss 8.6%. However, these proved to be transient in most instances. Residual (long-term) complications included delayed puberty (9%), other pituitary dysfunction (2%), and excessive weight gain (7%). See Table 1 for additional details. Stereotactic laser-mediated thermoablation with real-time MR thermography. This surgical technique is the newest innovation for treatment of hypothalamic hamartoma with epilepsy, consisting of stereotactic thermoablation (utilizing a laser-mediated heat source) with the added safety measure of near real-time magnetic resonance thermography. The thermography signal can enable the system to shut off when predetermined temperature parameters are reached at selected anatomical structures during the treatment process in an effort to limit heat-related injury to normal structures. The number of patients treated with this modality is growing rapidly at several centers, but at this time there is still relatively little in the way of peer-reviewed publication of patient outcomes (Curry et al 2012; Wilfong and Curry 2013;

11 Buckley et al 2016). Wilfong and Curry have reported a cohort of 14 hypothalamic hamartoma patients treated with stereotactic laser thermoablation, of which 10 had post-treatment follow-up of at least 6 months. Of these, 90% are seizure free, and there are no permanent or long-term complications noted (Wilfong and Curry 2013). More recently Buckley and colleagues have reported a treatment series of 12 patients with deep epileptic lesions (including 6 patients with hypothalamic hamartoma) (Buckley et al 2016). Of these 6, four (67%) had 100% seizurefreedom with relatively brief follow-up and 2 were substantially improved. Of note, 2 patients had significant unilateral weakness immediately post-op, but this deficit resolved completely within 1 to 2 days. Table 1. Neurosurgical interventions for hypothalamic hamartoma (all studies with at least 10 subjects) Age at surgery (years) HH lesion size Seizure efficacy Transcallosal interforniceal approach (Harvey et al 2003): N=29; Mean follow-up=30 months Cognitive and psychiatric outcome Most common adverse event 4-23 mean: 10.0 Diameter range from 0.7 to 4.2 cm Seizure-free 52% >90% reduction 24% 50-90% reduction 10% No improvement 14% NA Transient STM 48% Residual STM 14% Small thalamic infarcts 7% Transcallosal interforniceal approach (Ng et al 2006): N=26; Mean follow-up=20 months mean: 10.0 Volume mean 3.9 cm3 Seizure-free 54% >90% reduction 35% 50-90% reduction 4% No Improvement 8% Cognitive improvement 65% Behavioral improvement 88% (subjective parent assessment) Transient STM 58% Residual STM 8% Weight gain 19% DI 15% Transventricular endoscopic approach (Procaccini et al 2006): N=33; Mean follow-up=19 months mean: 10.5 NA Seizure-free 49% Engel class II and II improvement 49% No improvement 3% Cognitive improvement 65% Behavioral improvement 75% (subjective report) STM NA Weight gain 15% Panhypopituitarism 6% Transient DI 3% Transventricular endoscopic approach (Ng et al 2008): N=37 ; Median follow-up=21 months median: 11.8 Volume mean 1.0 cm3 Seizure-free 49% >90% reduction 22% 50-90% reduction 22% No improvement 8% Cognitive improvement NA Behavioral improvement NA Transient STM 14% Residual STM 8% Small thalamic infarcts 30% Weight gain NA Pterional approach (Palmini et al 2002): N=13; Mean follow-up=32 months mean: 8.4 NA Seizure-free 15% >90% reduction 38% 50-90% reduction 23% No improvement 23% Cognitive improvement 100% Behavioral improvement 100% (subjective parent assessment) STM NA Weight gain 8% Small thalamic infarcts 30% CN III paresis 30% Pterional approach (Abla et al 2011): N=10; Mean follow-up=37 months