hypothalamic hamartoma with gelastic seizures

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Hypothalamic hamartoma s napadajima gelastic SuradniciJohn F Kerrigan MD , autor. Dr. Kerrigan mjesta Barrow neurološkog instituta u Phoenix Dječjebolnice i Sveučilišta u Arizoni College of Medicine nema relevantnih financijskih odnosa za otkriti. Jerome Engel Jr. MD PhD , editor. Dr. Engel Škole David Geffen medicine na University of California, Los Angeles, dobili naknadu od Medtronics za konzultantske rada.

Bivši autor (i)

Orvar EEG-Olofsson MD PhD i Goran Brandberg MD (izvorni autori) Datumi objavljivanjaIzvorno objavio 27. ožujka 2001; zadnji put izmijenjena 9. studeni 2012, istječe 9. studenoga2015

Ključne točke• Hypothalamic hamartoma treba uzeti u obzir u svakom djetetu s gelastic napadaji ili rano rani

pubertet centralno.• Napadaji povezane s hipotalamus hamartoma rijetko se kontrolira s antiepilepsy lijekova.• Kognitivno oštećenje i psihijatrijski simptomi su zajedničke značajke s bolesna hipotalamus

hamartoma iepilepsije .

• Kirurško liječenje od hipotalamusa hamartoma mogu kontrolirati napadaje i stabilizirati (ili čakpoboljšati) kognitivne i psihijatrijskih simptoma.

• najbolji kirurški pristup je izabran nakon razmatranja svakog klinički tijek bolesti i kirurškianatomiju.

Povi jesna bilješka i nomenklaturaPrvi opis hipotalamus hamartoma kao uzrok rani pubertet (a vjerojatno igelastic napadaji , iako

su simptomi nisu priznate kao takve) je objavljena u 1934(Le Marquand i Russell 1934) . U 1958,popis i kolege prepoznali povezanost između hipotalamusahamartoma igelastic napadaji (Popis etal 1958) . Godine 1988, Berkovic i kolege opisao 4 djece s hipotalamusa hamartoma, liječenjeotporanepilepsije , i progresivne neurobihevioralnih deficiti, pod uvjetom da je prvi definitivni opiskatastrofalnog epilepsije sindroma koji mi prepoznajemo danas(Berkovic et al 1988) .

Hypothalamic hamartoma može uzrokovati dvije različite kliničke sindrome (Boyko et al, 1991;Valdueza et al 1994; Arita et al 1999; Debeneix et al 2001; Jung et al 2003) . Središnji ranipubertet povezan s hipotalamusa hamartoma lezije koje ne polažu anteriorno u trbušnojhipotalamusa, u blizini gomolja cinereum i hipofize stabljici. To su klasificirani kao"parahypothalamic" ili "peteljkom" temelji se na lokalnoj anatomije.

Drugi sindrom sastoji od neuroloških simptoma, obično počinju s gelastic (smijeh) napadajima, aličesto napreduje na dodatne, više ovršnih onemogućavaju vrsta, zajedno s kognitivnimoštećenjima i bihevioralnih simptoma. Ove hipotalamus hamartoma lezije pridaju pozadi u trbušnojhipotalamusu, u regiji od mammillary tijela, te su se spominju kao "intrahypothalamic" ili "sjede".Oko 40% od hipotalamusa hamartoma bolesnika sa epilepsijom imaju središnju rani pubertet, zbogveće lezije koje imaju i prednji i stražnji zrakoplov vezanosti u hipotalamusu.

Kliničke manifestacijeHypothalamic hamartoma može uzrokovati središnji rani pubertet, s isosexual uzorak razvoja

sekundarnih spolnih obilježja (koji je, neuobičajeno rano napredovanje kroz normalan slijedthelarche, adrenarche i menarhe vidjeti s normalnim pubertetu). Hypothalamic hamartoma jeosobito čest uzrok središnje rani pubertet kod male djece i uvijek bi trebala biti izuzetaMR mozga

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kod dječaka ili djevojčice s centralnim rani pubertet koji su mlađi od 6 godina(Jung i Ojeda 2002) .Većina djece sa središnje rani pubertet samo ne iskustvoepilepsije ili drugih neurobihevioralnihsimptomi navedeno u nastavku. Oko 40% djece s hipotalamushamartoma i epilepsiju iskustvacentralno rani pubertet. Prema našem iskustvu,gelastic napadi su obično prva manifestacija uovoj skupini. Međutim, klinička raznolikosti od pacijenta do pacijenta je jedan od Hallmark obilježjahipotalamusa hamartoma sindroma, i iznimke od pravila uobičajenim kliničkim uvijek trebapredvidjeti.

Gelastic napadaji su prototip napadaja povezan s hipotalamusa hamartoma (Harvey i Freeman2007) . U bolesnika sepilepsije, gelastic napadi su obično prvi napadaj tipa i javljaju vrlo rano u

životu. Točna dijagnoza često kasni, ali većina hipotalamusa hamartoma bolesnika početisgelastic napadaji prije 1 godine starosti, a mnogi od njih počinju tijekom prvog mjeseca života.Gelastic napadaji su kratki (trajanje je obično manje od 20 sekundi) i često (najčešće s višegelastic napadaja dnevno). Oni mogu oponašati pravi smijeh, ali češće su svojevrsni ineraspoložen i na povremeni promatrač, a može uključivati ponašanja elemente mrštenja i plače(dacrystic napadaji). Oni ne mogu ili mogu biti povezani s promijenjenom svijesti, koja je čestoteško odrediti u dojenčadi. Oni mogu biti vrlo suptilna, ili čak i subjektivno, kao "pritisak da sesmijati" kao ictal manifestacije je izvijestio u odraslih(Sturm et al 2000) . Gelastic napadaji rijetkose kontrolira s antiepilepsy terapije lijekovima(Tassinari et al, 1997; Freeman i EEG-Olofsson 2007).

Nažalost, dodatne vrste napadaja razvijaju se u oko 80% bolesnika. Ti dodatni napadi moguonemogućiti.Kompleksni parcijalni napadaji su najčešći, a može oponašati napadaja koji se javljajuna bilo svjetovnom ili frontalnom režnju regijama. Generalizirani vrste napadaja može sadržavatitonik-clonic, tonik, oslabljen, ili čak i izostanak. Teško pogođeni pacijenti mogu razviti epileptičneencefalopatije sa svim značajkamaLennox-Gastaut sindrom , uključujući i pad napada(Berkovic isur 2003; Freeman et al 2003) . Oko 5% djece s hipotalamusa hamartoma razvijaju infantilnispazmi(Kerrigan i dr. 2007a) .

Značajne kognitivni deficiti javljaju se u oko 80% bolesnika, a mogu biti progresivni, do 50%(Quiske et al 2006) . Kad blage, poteškoće s brzinu obrade ikratkoročne memorije su najčešći.Međutim, 50% od hipotalamusa hamartoma bolesnika s liječenja epilepsije otporne će pasti umentalno retardirane rasponu (full-scale koeficijent inteligencije [IQ] ili razvojne Kvocijent [DQ]manje od 70)(Prigatano et al 2008) . Neki pacijenti iskustvo razvojna regresija i gubitak prethodnonaučenih sposobnosti, obično se javljaju u vrijeme kada se napadaji pogoršaju.

Psihijatrijski problemi također su uobičajeni za kohorti pacijenata s hipotalamusa hamartoma iepilepsije (Veendrick-Meekes i sur 2007) . Djeca s hipotalamusa hamartoma i epilepsije mogu imatiopozicijske izazivajući nered-(83%), deficit pažnje / hiperaktivni poremećaj (75%),provestiporemećaj (33%), i poremećaj raspoloženja (17%)(Weissenberger et al 2001) . Bijes napada, kojise sastoje od agresivnog a ponekad i destruktivno ponašanje proizlazi iz manjih frustracija, suposeban problem za pacijente s hipotalamusa hamartoma i epilepsije, a ponekad može biti najvišeonemogućiti aspekt bolesti(Ng i sur 2011) . Bolesnici s hipotalamusa hamartoma i epilepsije susmanjene zdravstvene kvalitete života u usporedbi s dobi-podudarne djece s kroničnimmigrene ilidrugih oblika epilepsije(Park et al 2013) .

Klinička vinjetePacijent je 5-year-old, desnom rukom djevojka s poviješću liječenja otporan epilepsija povezana

shipotalamus hamartoma . Njezina majka je trudnoća bila uredna, a ona doživjela nekompliciranvaginalni porod. Svojevrsna, visoko-stereotipno ponašanje zabilježeno je tijekom prvog tjednaživota, kasnije dijagnosticirangelastic napadaji . To se sastoji od neisprovociranog cerekanje, upratnji uplašene izgled sa širom otvorenih očiju, i stiskanje od šake. To rijetko traje duže od 15sekundi, ali došlo i do 40 puta dnevno. Njen rani razvoj je normalno za dob.

U 3 godine, ona je razvila složeni parcijalni napadaji , obično počinju s gelastic mogućnosti, ališto je dovelo do uhićenja djelatnosti, ponašanju unresponsiveness, i bulji. Bila je letargično nakontih događaja, a ponekad bi spavati. Ona je doživljava do 5. ovih dnevno. MozakMRI pokazaohipotalamushamartoma almost filling the third ventricle and attached to the left side immediatelyabove the mammillary body. The brain MRI was otherwise normal. An EEG demonstrated rareinterictal spikes over the left midtemporal region. Three of her usual gelastic seizures werecaptured, which were associated with diffuse and nonlocalizing rhythmical features.

Seizure frequency was unaffected by trials of antiepilepsy drugs including levetiracetam,oxcarbazepine, and topiramate. She was described as deteriorating with her socialization andbehavior, with severe mood swings and tantrums, and failing to make progress with learning andlanguage 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 tomake 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 significantdeficits with language-based skills relative to visual motor skills. Review of her films atmultidisciplinary conference showed the lesion to be Delalande Classification Type II (Delalandeand Fohlen 2003). Based on the surgical anatomy (hypothalamic hamartoma lesion completelyabove the floor of the third ventricle and insufficient room within the third ventricle to maneuvera surgical endoscope), a transcallosal interforniceal approach was recommended for optimalresection.

Her postoperative course was uneventful, and she was discharged on the fourth postoperativeday. She did not experience diabetes insipidus or obvious short-term memory problems.Postoperative MRI showed no residual hypothalamic hamartoma. One year following surgery, shewas completely free of seizures while taking 1 antiepilepsy drug. Previously thin for her age, shehad an excessive appetite, and the family struggled to maintain her weight. Her follow-up EEGwas normal. Behavior and socialization were regarded as normal for age, and she seemed to havemade up some lost ground with her cognition and learning. Neuropsychological testing waspending in her local area.

EtiologyThe genetic basis for hypothalamic hamartoma for most patients is unknown. However,

hypothalamic hamartoma is one of the many physical features associated with Pallister-Hallsyndrome (OMIM #146510), which is known to be due to loss-of-function mutations withincertain portions of the GLI3 gene, a transcription factor in the sonic hedgehog intracellularsignaling pathway.

Approximately 25% of patients with sporadic hypothalamic hamartoma and epilepsy havesomatic (tumor-only) mutations within GLI3 (Craig et al 2008; Wallace et al 2008). Additionalcandidate genes, also expressing transcription factors that are known to be involved in ventralforebrain development, have been implicated (Kelberman et al 2006; Kerrigan et al 2007b).

Pathogenesis and pathophysiology Pathology. As a hamartoma, hypothalamic hamartoma lesions contain normal-appearing (ie, not

developmentally immature or neoplastic) cells. However, the frequently observed comment thathypothalamic hamartoma resembles normal grey matter is not correct. Hypothalamic hamartomacontain predominately (90%) small neurons (10 to 12 µm diameter cell bodies) that occur inclusters, with small numbers of intermixed larger neurons. The abundance of neurons and theprominence of neuron clusters vary from case to case (Coons et al 2007). Tracts of myelinatedfibers 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 regions areunknown. Pathophysiology. Hypothalamic hamartoma are associated with central precocious puberty.The exact molecular mechanisms by which this is mediated are unknown. Hypothalamichamartoma lesions universally express gonadotropin-releasing hormone (GnRH) (although there isno experimental support for pulsatile release of GnRH from the hypothalamic hamartoma as the

presumed ectopic generator). Chan and colleagues found that tissue expression of variousmediators 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 thatattached anteriorly in the region of the tuber cinereum and pituitary stalk, whereas thosepatients with epilepsy but without a prior history of central precocious puberty lackedhypothalamic hamartoma attachment to that region (Chan et al 2010).

Hypothalamic hamartoma are also intrinsically epileptogenic, which has been demonstrated byseizure recordings in which electrodes have been surgically implanted into the hypothalamichamartoma lesion itself (Kahane et al 1994; Munari et al 1995; Berkovic et al 1997; Kuzniecky etal 1997). A comprehensive cellular model for seizure genesis in hypothalamic hamartoma is notyet available (Fenoglio et al 2007). However, 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 possess intrinsicpacemaker-like firing behavior (Wu et al 2005; Coons et al 2007; Beggs et al 2008). Conversely,the large hypothalamic hamartoma neuron (approximately 10% of total hypothalamic hamartomaneurons and likely an excitatory projection cell) has the immature functional property of depolarizing and firing in response to GABA agonists (Kim et al 2008; 2009; Wu et al 2008). The









immature response of the large hypothalamic hamartoma neurons may lead to the unfavorablebalance of excitatory and inhibitory activity that is a requisite feature of epileptic tissue.

Epidemiology Hypothalamic hamartomas are uncommon. Hypothalamic hamartoma associated with epilepsy isreported to have a prevalence of 1 in 200,000 children and adolescents in Sweden (Brandberg etal 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 hypothalamichamartoma 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 likelysmall, although a handful of these patients have been encountered in our experience as a referralcenter (less than 2% of total cases requesting evaluation). Hypothalamic hamartoma as anincidental finding on MR imaging has not been reported in any population-based study.

PreventionThere are no recognized preventative measures for this congenital malformation.

Dif f erential diagnosisPrecocious 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 tomenses) or male sex steroid production (adrenarche = axillary and pubic hair in both genders, andchanges involving the scrotum and penis in males). A full discussion of the differential diagnosisof early puberty is beyond the scope of this summary. Consultation with a pediatricendocrinologist is recommended. Hypothalamic hamartoma is one of the most common causes of central (isosexual) precocious puberty in children younger than 6 years of age. Brain MRI toexclude 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 acause with high-resolution MRI. However, gelastic seizures can arise from other brain regions,most commonly from mesial temporal and frontal lobe structures (Arroyo et al 1993; Cheung et al2007). Aside from hypothalamic hamartoma, other pathologies occurring in or adjacent to thehypothalamus (such as craniopharyngioma, juvenile pilocyt ic astrocytoma, optic nerve glioma,and colloid cyst of the third ventricle) are generally not associated with gelastic seizures.

Diagnostic workup Magnetic resonance imaging. MRI is the most appropriate structural imaging technology fordiagnosing (or excluding) hypothalamic hamartoma (Freeman et al 2004; Harvey and Freeman2007). 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 fastspin 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 toobtain high-quality images.

We recommend at least one follow-up MRI to exclude a progressive mass lesion. However, thereis good evidence that hypothalamic hamartoma do not grow or expand relative to the normalgrowth trajectory of the brain (Mahachoklertwattana et al 1993; Turjman et al 1996; Freeman etal 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-enhancinglesion. Hypothalamic hamartoma lesions do not enhance.

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 decreasedneuronal density as shown by magnetic resonance spectroscopy (Amstutz et al 2006) andstereology on pathological specimens (Kerrigan et al 2012). Approximately 5% of hypothalamichamartoma lesions may have intralesional cysts (Prasad et al 2000). Hypothalamic hamartomalesions vary tremendously in size. In our series of over 175 cases undergoing surgical treatment,the mean hypothalamic hamartoma lesion volume is 1.74 cm3 (median 0.57 cm3; range 0.04 to









20.04 cm3 [using the technique for calculating the volume of an ellipsoid, derived fromconventional 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 two 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 locatedbelow 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 orinfundibulum that results in the attachment). Conversely, the second phenotype consists of

epilepsy (usually including gelastic seizures) and the cognitive and psychiatric symptoms thataccompany the epilepsy with hypothalamic hamartoma lesions that are characterized as

intrahypothalamic (referring to the presence of the hypothalamic hamartoma within the thirdventricle 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 or lack of a peduncle).

Recent research has supported these concepts but has also placed additional emphasis of 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 anterior hypothalamus (regardless of the presence or absence of apeduncle) (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 al2011). Patients with attachment to both the anterior and posterior regions (correlating, not

surprisingly, with large hypothalamic hamartoma lesions) have both central precocious pubertyand 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 examining 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 corpuscallosum (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 than standard visual analysis, but these have not been widelyapplied to resolve this question one way or the other (Sisodiya et al 1997).

Computed tomography imaging. CT imaging detects large hypothalamic hamartoma lesionsbut 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 very useful study for

patients with epilepsy, there are limitations that must be recognized when interpreting EEGresults 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 changeon the simultaneous EEG recording (Sher and Brown 1976). Troester and colleagues have

reported EEG findings on a cohort of 133 hypothalamic hamartoma patients undergoingpresurgical 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 in

the ictal EEG (Troester et al 2011).

The interictal and ictal EEG is more likely to show abnormalities in older patients with additionalseizure 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 aremost 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 asLennox-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 thehypothalamic hamartoma, 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; Kahaneet 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 al1995; Freeman et al 2003; Kahane et al 2003). These neocortical seizure foci likely arise overtime 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 followingsurgical resection of the hypothalamic hamartoma, a process known as the “running downphenomenon” (Freeman et al 2003; Kerrigan et al 2005; Ng et al 2006). As the hypothalamichamartoma is the appropriate surgical target for most patients, intracranial recordings withsurgical implantation of depth electrodes is usually not recommended. Single photon emission computed tomography. Ictal studies have shown hyperperfusion inthe hypothalamic hamartoma and thalamus (Iannetti et al 1997; Kuzniecky et al 1997). This maybe regarded as a noninvasive confirmatory test but need not be considered standard in clinicalpractice. Positron emission tomography. PET imaging following administration of 18F-flouro-deoxyglucose (FDG) shows generally nonspecific features when obtained during the interictalstate. Ictal studies with FDG administration and PET imaging have demonstrated increasedmetabolism in the hypothalamic hamartoma (Palmini et al 2005; Shahar et al 2008). As withSPECT, FDG-PET may be regarded as a noninvasive confirmatory test but need not be consideredstandard in c linical pract ice. Magnetoencephalography. Magnetic dipole mapping within the intracranial space can identifyspike origination within hypothalamic hamartoma (Leal et al 2002; 2006). MEG may be regardedas a noninvasive confirmatory test but need not be considered standard in clinical practice.

Prognosis and complicationsFor those patients with hypothalamic hamartoma and central precocious puberty only, the

prognosis is quite favorable. Almost all of these patients respond to medical therapy withgonadotropin-releasing hormone (GnRH) agonists (Mahachoklertwattana et al 1993). Once thenormal age range for puberty is reached, medical therapy is discontinued, and the normaldevelopmental program of puberty occurs. These patients typically do not have neurologicproblems 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 andmay not go on to experience other seizure types or cognitive issues (Mullati et al 2003).

However, the more common scenario with hypothalamic hamartoma and epilepsy is that gelasticseizures begin early, prior to 5 years of age and often before 1 year of age. These patients areat high risk (80% likelihood) of developing additional seizure types, and 50% have a clinicalcourse consistent with an epileptic encephalopathy, with objective evidence of deterioration incognition or behavioral health (Berkovic et al 1988; Kerrigan et al 2005). Early intervention withsurgical therapy may favorably influence this outcome, as will be discussed below.

Management Medical treatment.

Central precocious puberty. Patients with hypothalamic hamartoma and central precociouspuberty are treated with gonadotropin-releasing hormone (GnRH) agonists, usually with once-

monthly intramuscular injection of leuprolide or related compounds (Mahachoklertwattana et al1993; de Brito et al 1999). Intramuscular depot formulations of leuprolide give rise to consistentlyhigh GnRH agonist levels and mask the pulsatile release of GnRH that is required to triggerpuberty. For those rare central precocious puberty patients who fail to respond to medicalmanagement (or are hypersensitive to GnRH agonist compounds), surgical resection of thehypothalamic hamartoma is effective for arresting early puberty. 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 thefrequency (without providing complete control) of other seizure types. There is no evidence for

the superiority of one antiepilepsy drug over another in this regard. We recommend a trial of 2 or3 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 severely

mentally handicapped (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 frustrationtolerance and rage attacks but with a host of difficulties that may include mood disorder and

depression, anxiety, attention deficit disorder, and obsessive-compulsive disorder) may be themost disabling aspect of hypothalamic hamartoma for some patients (Weissenberger et al 2001).

Pharmacotherapy for these target symptoms, utilizing standard medications, should be consideredwhen appropriate. However, there are no studies that address 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 a very recently evolving and still

unsettled field in which we have moved rapidly from the 1990s (in which surgical intervention was

usually not possible or was ill-advised) to 2012 (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 lack peer-reviewed evidence regarding safetyand efficacy. Consequently, this is a dynamic space.

It is important to recognize that neocortical resection is usually not the appropriate treatmentchoice 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 very poor track record forimproving seizures in patients with hypothalamic hamartoma and epilepsy (Cascino et al 1993).

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 atdistant sites) also occurs over time. Accordingly, for those with disabling seizures or significant

cognitive or behavioral impairments, earlier surgical intervention is indicated, and delayed surgicalintervention is to be avoided. 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 (Wetheet al in press). An independent predictor of surgical success for controlling seizures is the extent

of hypothalamic hamartoma resection: completely resected lesions are more likely to result incomplete seizure control (Ng et al 2006).

Selecting the single best surgical treatment for hypothalamic hamartoma patients is based on

an appreciation of their natural history (stable versus deteriorating), which, in turn, influences

the degree of urgency for immediate (resection, disconnection, or thermal destruction) versusdelayed (gamma knife radiosurgery) efficacy. Equally important is the surgical anatomy, which is

unique to each patient.

Classification and surgical anatomy. Several classification systems have been proposed forhypothalamic 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 classificationsystems will be preferred in the future as presently unanticipated treatment options becomeavailable. Type I . Hypothalamic hamartoma lesion in which the horizontal plane of attachment iscompletely 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 Ilesions with a broad base of attachment that includes the region of the mammillary bodies can

also cause epilepsy. Type I I . Hypothalamic hamartoma lesion in which there is a vertical plane of attachment to thewalls of the third ventric le, c ompletely above the floor of the third ventricle. These would be theclassic “intrahypothalamic” lesions, and would always be considered “sessile” because a stalk orpeduncle is not present. These are highly associated with epilepsy, and infrequently assoc iatedwith central precocious puberty. Type I I I . Hypothalamic hamartoma lesion in which the plane of attachment is both above andbelow the floor of the third ventricle, and thereby possessing a plane of at tachment that is bothvertical (in the third ventricle) and horizontal (attached to the inferior surface of thehypothalamus). These are larger lesions than Type II and often include attachment that extendsanteriorly (to the region of the tuber cinereum) and posteriorly (to the region of the mammillarybodies). Consequently, these hypothalamic hamartoma lesions often include both central

precocious puberty and epilepsy. Type I V . These were characterized as “giant” hypothalamic hamartoma lesions by Delalande(Delalande and Fohlen 2003), without offering clear criteria for the boundary between Types IIIand IV. Our research group currently utilizes a volume of 6 cm3 as the boundary between III andIV (as determined by utilizing the volume of an ellipsoid from the 3 major axes). However, thesurgical planning considerations for Types III and IV are similar.

Pterional (orbitozygomatic) approach. This was the usual way of resecting hypothalamichamartoma lesions prior to 1999 (Palmini et al 2002). When this approach was used for allhypothalamic hamartoma patients, efficacy was low and the complication rate was high (Palminiet al 2002). However, for Type I patients (with a horizontal plane of attachment below the floorof the third ventricle), this is the optimal surgical approach. Abla and colleagues report a cohortof 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 least50% improved with seizure frequency. See Table 1 for additional details.

Transcallosal anterior interforniceal approach. This surgical approach was pioneered by WalterDandy 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 etal 2001). This approach “revolutionized” hypothalamic hamartoma surgery, providing the firstmajor step forward with respect to the surgical treatment of this disease.

Two large uncontrolled outcome studies report similar results. Harvey and colleagues, with acohort of 29 patients, reported complete seizure control in 52% (Harvey et al 2003), whereas Ngand 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 foradditional details.

Transcallosal resection is a treatment option for those patients with hypothalamic hamartomalesions with vertical attachment to the walls of the third ventricle (Types II to IV), particularlyfor those with large lesions that fill the third ventricle (as with the illustrative case notedpreviously) 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 hypothalamichamartoma resection, with complete seizure-control in 49% (Procaccini et al 2006), whereas Ngand colleagues have published a cohort of 37 patients, with complete seizure control in 49% (Nget al 2008). Small ischemic infarcts of the thalamus (usually asymptomatic and detected ondiffusion-weighted postoperative MRI) emerged as a complication in 30%, possibly due to traumato small perforating arteries with manipulation of the endoscope (Ng et al 2008).

Endoscopic resection is a treatment option for those with smaller intraventricular hypothalamichamartoma lesions (Type II), particularly with those that have a clearly unilateral base of attachment. See Table 1 for additional details.

Combined or staged approach for hypothalamic hamartoma surgery. For patients withhypothalamic 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 andhorizontal planes of attachment), a staged approach may be required, with resection 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. For patients with epilepsy, including epilepsy related to hypothalamic

hamartoma, gamma knife radiosurgery delivers a subnecrotizing dose of radiation to the

responsible lesion. Although the exact cellular mechanisms are unknown, it likely does involveneuronal death rather than purely modulatory effects (Kerrigan et al 2012). 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 3years 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 radiosensitivestructures. See Table 1 for additional details.

Interstitial radiosurgery. A single center has reported their experience with stereotacticimplantation 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 treatedpatients, 38% were seizure-free. Transient cerebral edema was noted in 26%. See Table 1 for

additional details.Stereotactic 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 report a cohort of 19 patients undergoing stereotactic

thermoablation of hypothalamic hamartoma for treatment-resistant epilepsy. With at least 1 yearof follow-up, they report 68% of patients are completely seizure-free, with universal improvement

in cognition and no long-term residual impact on short-term memory (Kameyama et al 2009).

Conversely, in a cohort of 10 patients, Kuzniecky and Guthrie reported seizure freedom in 20% of

patients (Kuzniecky and Guthrie 2003). See Table 1 for additional details.Stereotactic laser-mediated thermoablation with real-t ime MR thermography. This surgical

technique is the newest innovation for treatment of hypothalamic hamartoma with epilepsy,consisting of stereotactic thermoablation with the added safety measure of near real-time

magnetic resonance thermography. This added safety measure turns off the delivery of heat-

inducing energy when temperature parameters are reached at preselected margins.

As yet, a cohort of patients treated with this modality has not been published. A relatively small

number of patients have been treated to date, some of whom are approaching 1 year aftersurgery.

Table 1. Neurosurgical interventions for hypothalamic hamartoma

Age at

surgery(years)

HH lesion

size

Seizure efficacy Cognitive and

psychiatricoutcome

Most common

adverse event

Transcallosal interforniceal approach (Harvey et al 2003):

N=29; Mean follow-up=30 months

4-23mean: 10.0

Diameterrange from0.7 to 4.2

cm

Seizure-free 52% >90% reduction

24%

50-90% reduction

NA Transient STM 48% Residual STM 14%

Small thalamic

infarcts 7%









10%

No improvement

14%

Transcallosal interforniceal approach (Ng et al 2006):


2.1 - 24.2

mean: 10.0

Volume

mean 3.9cm3

Seizure-free 54%

>90% reduction

35%

50-90% reduction4%

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):


0.75 - 34mean: 10.5

NA Seizure-free 49%

Engel class II andII improvement

49%

No improvement

3%

Cognitiveimprovement 65%

Behavioral

improvement 75%

(subjective report)

STM NA

Weight gain 15%

Panhypopituitarism6%

Transient DI 3%

Transventricular endoscopic approach (Ng et al 2008):

N=37; Median follow-up=21 months

0.6 - 55

median:11.8

Volume

mean 1.0cm3

Seizure-free 49%

>90% reduction

22%

50-90% reduction22%

No improvement

8%

Cognitive

improvement NA

Behavioralimprovement 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

2.5-33

mean: 8.4

NA Seizure-free 15%

>90% reduction

38%

50-90% reduction

23%

No improvement23%

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):










0.7 - 42.7mean: 18.3

Volumemean=2.9

cm3

Seizure-free 40%

>90% reduction

10%

50-90% reduction

30%

No Improvement

20%

Cognitiveimprovement 40%

Behavioral

improvement 20%

(subjective report)

Transient STM 40%

Residual STM 30%

Weight Gain 40%

DI 20%

Gamma Knife radiosurgery (Regis et al 2006):

N=27; Minimum follow-up=36 months

3 - 50

mean: 19.7

Maximal

diameter

mean

1.1cm

Seizure-free 37%

“Very much

improved” 22%

NA Transient worsening

of seizures 15%

Transient

poikilothermia 11%

Gamma Knife radiosurgery (Abla et al 2011):N=10; Follow-up 18-81 months (mean 43)

5.7 – 29.3

mean: 15.1

Volume

Mean=0.7cm3

Seizure-free 40%

>90% reduction

0%

50-90% reduction

30%

No improvement

10%

(For those

patients withoutsubsequent

surgical resection,n=2)

Cognitive

improvement 30%

Behavioralimprovement 50%

Transient STM 0%

Residual STM 0%

Weight gain 20%

Transient

poikilothermia 10%

Stereotactic thermoablation (Kuzniecky and Guthrie 2003):N=10; Follow-up=18-72 months (mean=43.2)

2 - 30

mean: 15.9

NA Seizure-free 20%

>90% reduction

30%

50-90% reduction

30%

No improvement10%

(For those

patients withoutsubsequent

surgical resection,

n=1)

NA

(improvement in

“most” patients)

Transient STM 10%

Transient CN III

paresis 10%

Stereotactic thermoablation (Kameyama et al 2009):

N=19 Follow-u =12-132 months mean=37









2 -36mean=16.6

Maximaldiameter1.4 cm

Seizure-free 68% Engel class II 0% Engel class III32% No Improvement

0%

Cognitiveimprovement 100%(pre- and postneuropsychologicaltesting; p<0.0001) Behavioralimprovement 53%

Transient STM 11% Residual STM 0% Transientpoikilothermia 21%

Stereotactic interstitial radiosurgery (Schulze-Bonhage et al 2008):N=24; Follow-up=12-60 months (mean=24) 3 – 46mean=21.9

Volume1.2 cm3

Seizure-free 38% Engel class II 21% Engel class III21% Engel IV 37% 54% TreatedTwice

Cognitiveimprovement NA(pre- and postneuropsychologicaltesting;P= NS on groupwisebasis) Behavioralimprovement NA

Residual STM 11% Transient cerebraledema 26% Weight gain 21%

Concluding comments. The single best treatment choice for each patient cannot be

completely evidence-based at this time. Clinical judgment is required. Head-to-head trialsbetween the different surgical treatment options for patients with hypothalamic hamartoma andepilepsy are unlikely given the uncommon nature of the condition and lack of funding forexpensive trials of this nature. In addition, new technologies are emerging now and probably inthe future.

Hypothalamic hamartoma patients are diverse with respect to their symptoms and their naturalhistory. Hypothalamic hamartoma lesions vary tremendously with respect to their size, position,and attachment. Accordingly, treatment decisions should be individualized to the circumstancesof each case and the expertise of each center (Polkey 2003; Maixner 2006; Rosenfeld 2011; Waitet al 2011). Ideally, referral centers for hypothalamic hamartoma should be able to offer most orall treatment modalities, and can, therefore, make the best decision for each patient without alot of bias for one technique.

PregnancyWomen with hypothalamic hamartoma are capable of pregnancy and successful childbirth. We

are not aware of any obstetrical issues for this patient cohort. For those women withhypothalamic hamartoma trying to become pregnant, consultation with a reproductiveendocrinologist may be useful due to possible endocrine dysfunction within the reproductive axis.

AnesthesiaHypothalamic hamartoma pat ients with no prior history of hypothalamic hamartoma surgery are

not likely to be at risk from anesthesia. However, hypothalamic hamartoma patients who haveundergone prior surgical resection in the hypothalamus may have deficits relating to sodium andelectrolyte balance (diabetes insipidus) or adrenal or thyroid insufficiency. Preoperativeevaluation for these possible defic its is indicated.

ICD codesICD-9:Benign neoplasm of brain: 225.0Other forms of epilepsy and recurrent seizures, without mention of intractable epilepsy: 345.80 ICD-10:Benign neoplasm of brain, supratentorial: D33.0









Epilepsies and epileptic syndromes undetermined as to whether they are focal or generalized:G40.8

Associated disordersEpilepsyGelastic seizuresMental retardationPervasive developmental disorders

Seizures

Related summariesAttention deficit hyperactivity disorderAutistic spectrum disordersGelastic seizuresNeurofibromatosis type 1Oral-facial-digital syndromesPathological laughterTuberous sclerosis complex

Dif f erential diagnosistemporal lobe lesionsfrontal lobe lesionsbrainstem lesionsPallister-Hall syndromecombination of gelastic seizures and precocious puberty without signs of hypothalamichamartomasolid craniopharyngiomahypothalamic gliomagerminoma

DemographicsFor more specific demographic information, see the Epidemiology, Etiology, and Pathogenesis andpathophysiology sections of this clinical summary.

Age0-01 months01-23 months02-05 years06-12 years13-18 years

Population

None selectively affected. OccupationNone selectively affected.

Sexmale>female, >1.5:1

Family historyNone

Heredity

None

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**References especially recommended by the author or editor for general reading.

This is one of several clinical summaries originally developed as off icial descriptions of epileptic

seizures and syndromes under the auspices of the International League Against Epilepsy (I LAE)

Task Force on Classif ication and Terminology. It is now maintained by MedLink by agreement

with the ILAE and may no longer ref lect the official position of the ILAE.

hypothalamic hamartoma with gelastic seizures

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