Neurol Med Chir (Tokyo) 45, 221¿231, 2005

Hypothalamic Hamartoma

Kazunori ARITA,KaoruKURISU, Yoshihiro KIURA,KojiIIDA*, and Hiroshi OTSUBO*

Department of Neurosurgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima; *Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada

Abstract The incidence of hypothalamic hamartomas (HHs) has increased since the introduction of magnetic resonance (MR) imaging. The etiology of this anomaly and the pathogenesis of its peculiar symptoms remain unclear, but recent electrophysiological, neuroimaging, and clinical studies have yielded important data. Categorizing HHs by the degree of hypothalamic involvement has contributed to the accurate prediction of their prognosis and to improved treatment strategies. Rather than undergoing corticectomy, HH patients with medically intractable are now treated with that targets the HH per se, e.g. HH removal, disconnection from the , stereotactic irradiation, and radiofrequency lesioning. Although surgical intervention carries risks, total eradication or disconnec- tion of the lesion leads to cessation or reduction of seizures and improves the cognitive and behavioral status of these patients. Precocious puberty in HH patients is safely controlled by long-acting gonadotropin-releasing hormone agonists. The accumulation of knowledge regarding the pathogenesis of symptoms and the development of safe, effective treatment modalities may lead to earlier interven- tion in young HH patients and prevent the decline in their cognitive abilities and quality of life. This review of hypothalamic hamartomas presents current classifications, pathophysiologies, and treatment modalities.

Key words: hypothalamic hamartoma, , gelastic , precocious puberty, classification

Introduction MR imaging.

Hypothalamic hamartomas (HHs) are non-neoplas- Pathology tic, heterotopic nodules resembling the normal gray matter of the hypothalamus.15,46) Between 1934 and HHs occur as a round or ovoid mass between 5 and 1963, only around 30 cases have been described.74) 50 mm diameter, usually about 10–30 mm. The Despite their rarity, HHs have become well known tumors are either embedded in the hypothalamus or because of the characteristic symptoms of central- attached to it via a wide or narrow interface.15,46) type precocious puberty (CPP) and gelastic sei- Some are attached by a stalk, called a ``peduncle.'' zures.2,5,8,11,72,76) Due to advances in magnetic HHs are very rarely located in the interpeduncular resonance (MR) imaging, the number of cases of HH or prepontine cisterns without direct connection to has been on the rise.5,19,26,42,48) the hypothalamus.6,53,54) In the late 1990s we proposed a new classification HHs primarily consist of mature neurons inter- of HHs that takes into account the MR imaging mingledwithglialcells.3,46) The neurons resemble appearance and discussed treatment modalities those in the normal tuber cinereum,75) although large based on this classification.4,5) Recent reports includ- dysplastic neurons are occasionally found in HH ing our papers about the etiologies, symptoms, and patients with seizures.34) There may be moderate treatments of this disease have led to a better under- glial cellularity without neoplastic differentiation.46) standing of its nature and management. This review Myelinated and unmyelinated fibers have been provides an overview of these reports and adds a identified among the cellular components3,15,46) and summary of our 17 patients with HH identified by some of these nerve fiber bundles connect to hypothalamic nuclei.63,74) The lesion may contain Received April 15, 2004; Accepted December 6, ependymal cell lines, suggesting a primordial diver- 2004 ticulum from the third ventricle.2) Ultrastructural

221 222 K. Arita et al.

Table 1 Symptoms associated with hypothalamic hamartoma

Common Rare

Endocrinological precocious puberty acromegaly65) obesity hypopituitarism45) diencephalic syndrome61) Neurological gelastic seizures ``pressure to laugh''70) focal seizures visual impairment72) secondary generalization developmental delay cognitive impairment behavioral disturbance

Symptoms due to accompanying anomaly symptoms of other intracranial abnormality Pallister-Hall syndrome examination has identified neuroendocrine units seizure pattern is usually a gelastic seizure with with neurons containing neurosecretory granules, brief attacks of mechanical laughter starting during blood vessels with fenestrated endothelium, and early infancy.8–10,12,55) Ninety percent of patients double basement membranes.32) with HHs and seizures present with gelastic sei- zures.51) Gelastic seizure was not the initial seizure Etiology type in only a small group of patients who were adults at the onset of epilepsy.48) During the 5th or 6th week of gestation, the ventral Gelastic seizures are initially accompanied by aspect of the neuraxis approaches the anterior tip of little or no impairment of consciousness and no the end of the notochord. HHs may be due to tissue significant abnormalities are detected by scalp displacement during that period.7) HHs are associ- electroencephalography (EEG).8,12) After several ated with neither sexual preponderance nor familial years, gelastic attacks frequently become associated or racial predilection.51) No shared genetic anomaly with consciousness alterations. Seizure semiology has been identified in patients with HH, except for usually evolves into focal motor features, autonomic the group with Pallister-Hall syndrome. A pathologi- phenomena, and/or secondary generalization.8,41,55) cal study found very small hamartomatous nodules Some seizure types and EEG abnormalities are (1.0–1.5 mm in diameter) in the hypothalamus of suggestive of epileptogenic foci in the temporal or 21% of 239 consecutive autopsied cases,66) suggest- frontal lobe.12,40,41) ing that symptomatic HH may be an extreme of a Later on, seizures may become generalized and of normal variation. multiple types, e.g. absence, drop attacks, and tonic, atonic, and tonic-clonic seizures. EEGs typically Symptomatology show slow spike-and-wave patterns.8,55,58,70) Cogni- tive deterioration and behavioral disturbance are Table 1 lists the reported symptoms of patients with frequently seen at this stage. This malignant type of HHs. The two main manifestations are seizures and epilepsy occurs in about half of epileptic HH CPP. Among 277 HH patients, 174 (63%) manifested patients.51) Some concomitantly develop precocious CPP, 170 (61%) had experienced seizures, and 75 puberty.4) (27%) presented with both CPP and seizures.51) A benign form of later-age onset gelastic seizures Asymptomatic cases have also been reported.4,20,51,66) without deterioration has been reported in patients with small, 5–6 mm, hamartomas.70) These individ- I. Seizures uals may report only a strange feeling of ``pressure The age at onset of epilepsy ranged from the 1st to laugh'' and manifest little or no cognitive disor- postnatal day to 27 years (mean 2.5 years, median ders. Their interictal and ictal EEG findings may be 1.0 year).51) Among19HHpatientswithseizures,48) normal. 16 had gelastic seizures, nine had atypical absence, five had drop attacks, four had partial motor sei- II. Cognitive dysfunction and behavioral zures, seven had brief tonic seizures, 11 had com- problems plex partial seizures of the temporal lobe type, In patients with seizure onset during early child- and eight had generalized convulsions. The initial hood, cognitive dysfunction and behavioral

Neurol Med Chir (Tokyo) 45, May, 2005 Hypothalamic Hamartoma 223 problems are commonly progressive.4,51,55) Develop- of Pallister-Hall syndrome is HH,29) but other mental delays correlate with the severity, frequency, manifestations include holoprosencephaly, deficient and variety of the seizure patterns.8,25,55) Of all olfactory bulbs and tracts, hypopituitarism, bifida reported patients with HH, 49% manifested cogni- epiglottis, craniofacial anomalies, polydactyly, tive disturbance and 31% had behavioral problems; imperforate anus, and renal anomalies.31) The all of them had seizures.51) The behavioral problems craniofacial anomalies are attributed to the disrup- have been described as restlessness, violence tion by the HH of midline development. The first including severe rage attacks, emotional instability, six reported patients were in serious condition at obsession, autism, and anti-social behavior.30,72) In birth and died within 10 days, and subsequent the majority of these patients, medical and psycho- reports have stressed the ominous nature of this syn- logical treatment frequently failed, so institutionali- drome.31) However, some patients have prolonged zation was often considered.55) survival and Pallister-Hall syndrome is not invaria- bly lethal.73) Fewer than 15% of patients with this III. CPP syndrome experience seizures, which are milder HHs are recognized as a major etiological factor than in patients with HHs.9) in CPP, and were present in 14–36% of patients with TheearlytermforwhatisnowknownasHHwas organic CPP.14,57) Conversely, more than half of hamartoblastoma, derived from the presence of patients with HHs manifested CPP.4,51) Pubertal primitive germ cells, which seemed to indicate manifestations include deepening of the voice and neoplastic potential, in the hypothalamic mass of enlarged testes and penis in males, breast develop- dead neonates.17) Subsequent pathological examina- ment and menses in females, and excessive skeletal tion of these lesions in older patients revealed that and muscular development, pubic hair, and adoles- they consisted of mature neurons and astrocytes, cent personality in both sexes.2,68) Patients with CPP findings compatible with hamartoma.31,67) secondary to HH showed a pubertal response to the gonadotropin-releasing hormone (GnRH)-stimula- Image Diagnosis and tion test.24,43) CPP due to HH tends to occur sig- Classification of HHs nificantly earlier than idiopathic CPP.13) The first manifestation of CPP in patients with HH occurs I. Image diagnosis before age 2 years in 82% of cases13) and occasional- Because of their characteristic MR imaging find- ly before their 1st birthday.2,14,47,69,76) Rapid progres- ings, HHs are readily identified in patients with the sion of pubertal signs and bone age advancement are typical clinical symptoms. T1-weighted MR imaging additional characteristics of CPP with HH.13,44) shows a noncalcified, nonenhanced solid mass

isointense to the gray matter; T2-weighted imaging IV. Other manifestations and concomitant shows an iso- or hyperintense mass.4,11,51,72) The size lesions of the lesion does not change in the course of long- There is a report on high rate of obesity among term follow up and changes in signal intensity are patients with HH.20) Hypothalamic-pituitary func- the exception.1) Differential diagnoses in children tion is generally well preserved. A rare case of HH withahypothalamictumorpresentingwithCPP was associated with hypogonadotropic include , optic , arachnoid cyst, hypogonadism and deficiency.45) germ-cell tumor, and craniopharyngioma.44,72) The HH manifesting as acromegaly due to excessive presence of calcification, cysts, positive enhance- growth hormone-releasing hormone secretion,65) ment, volume changes, and different signal intensity diencephalic syndrome,61) or progressive visual im- on MR imaging can differentiate these tumors from pairment is exceptional.72) HH. There are very rare coexisting intracranial abnor- malities including supra- or infratentorial arachnoid II. Anatomo-topographical classification of HHs cysts, callosal agenesis, hemispheric dysgenesis, and (Fig. 1) cerebellar hypoplasia.5,6,53) Deficient olfactory bulbs Boyko et al.11) classified HHs into two types, and tracts and optic anomalies were described in peduncular and sessile, based on the attachment cases of Pallister-Hall syndrome.29,31) to the hypothalamus, with a higher incidence of seizures in children with sessile hamartomas. V. Pallister-Hall syndrome Ambiguities regarding the criteria to distinguish Pallister-Hall syndrome was characterized by HH between the two categories resulted in invalid criti- (designated hamartoblastoma), polydactyly, and cism,43) but restriction of sessile to lesions with a various visceral anomalies.29) The primary feature broad and unconstricted interface with the

Neurol Med Chir (Tokyo) 45, May, 2005 224 K. Arita et al. hypothalamus provides a relatively good correlation and there is distortion of the third ventricle. The key with seizure attacks. Despite this restriction, some point in this classification is the degree of hypotha- lesions of the sessile type were not associated with lamic displacement, i.e. clear, minimal, or absent on seizures, because the lesions did not involve the MR imaging. PHHs are usually associated with CPP hypothalamus or displace the third ventricle.4,7) without seizures or developmental delay, and so are We previously proposed a different classification non-disabling.4) IHHs, on the other hand, are gener- of HHs into parahypothalamic and intrahypotha- ally associated with medically intractable seizures. lamic (PHH and IHH, respectively). This classifica- Two thirds of IHH patients suffer severe develop- tion is well correlated with the clinical presentation mental delays and cognitive impairments, and suffer and subsequent clinical course (Table 2).4) PHHs are poor quality of life. attached only to the floor of the third ventricle or Figure 2A shows MR images of a 7-year-old girl suspended from it by a peduncle. IHHs involve the with CPP. The lesion was typical PHH, which hypothalamus or are enveloped by the hypothalamus corresponded to the peduncular type in Boyko's classification.11) Figure 2B shows MR images of a 2-year-old boy with frequent gelastic and tonic seizures. Develop- mental delay was also noted. The lesion was typical IHH, which was inserted in the hypothalamus. The third ventricular floor was severely distorted. The lesion is the sessile type according to Boyko's classification.11) Figure 2C shows MR images of a 9-year-old boy with CPP but no seizures. There was an oval lesion attached to the hypothalamus via a broad interface, however, the hypothalamus per se was not involved. This is the sessile type according to Boyko's classifi- cation,11) leading to the expectation of seizures. Our classification categorizes this lesion as PHH because the third ventricle is free of deformity, leading to the Fig. 1 Proposed classifications for hypothalamic expectation of no seizures. In fact, this patient did hamartomas based on magnetic resonance not experience seizures. imaging findings. The triangle depicts the Very recently, even patients with PHH were degree of third ventricular deformity reported to suffer seizures, suggesting that epileptic (hypothalamic involvement) where － and patients with PHH generally had later seizure onset ＋ indicate absence and presence of and a lower incidence of gelastic seizures than hypothalamic involvement, respectively. patients with IHH.48)

Table 2 Summary of our 17 cases with hypothalamic hamartoma diagnosed by magnetic resonance imaging (Hiroshima University Hospital, 1988–2004)

Intrahypothalamic type Parahypothalamic type

Total cases 7 (4 males, 3 females) 10 (3 males, 7 females) Onset age (year) 2.9±5.0 (0.1–14) 3.1±3.4 (0.2–9.3) Size (mm) 16.9±6.7 (10–28) 16.5±6.3 (7–24) Symptoms seizures 7 0 precocious puberty 3 7 developmental delay 5 0 asymptomatic 0 3 Medical treatment AED, ineffective GnRH agonist, effective Follow-upperiod(month) 45.1±30.0 (24–124) 42.3±31.1 (6–90) GOS score at the latest visit V: 2, IV: 1, III: 3 V: 10

AED: antiepileptic drugs, GnRH: long-acting gonadotropin-releasing hormone, GOS: Glasgow Outcome Scale (V: able to return to work or school, IV: moderate disability, III: severe disability).

Neurol Med Chir (Tokyo) 45, May, 2005 Hypothalamic Hamartoma 225

Valdueza et al.72) classified HHs into two types with four subtypes. Type 1 is a relatively small lesion that is attached to the tuber cinereum (type 1a) or mammillary body (type 1b) via a peduncle and usually presents with precocious puberty. Type 2 is a relatively large lesion that displaces the hypothala- mus slightly (type 2a) or markedly (type 2b) and is associated with seizures. Type 1 roughly coincides with our PHH type, and type 2 with our IHH type. However, true peduncles have been identified in only 8% of HHs, so categorization based on the presence or absence of a peduncle is not widely applicable to HHs.4) Delalande and Fohlen21) proposed another classifi- cation of HH with seizures that is directly correlated with the surgical approach. Type I has an implanta- tion plane horizontal to the hypothalamus, type II has a vertical insertion plane and is located intraven- tricularly, type III combines the features of types I and II, and type IV is comprised of giant hamarto- mas.

Underlying Pathophysiology of Symptoms

I. Seizures The EEG features and seizure manifestations resemble complex partial seizures arising from the temporal and/or frontal lobes, suggesting the hypothesis that cortical dysgenesis associated with HH is a source of the seizures and requires resec- tion.12) However, all cortical resections performed Fig. 2 A: A 7-year-old girl with precocious puber- under this hypothesis failed to control the seizures. ty. Coronal (left) and sagittal (right)T1- weighted magnetic resonance (MR) images Mechanical compression of the hypothalamus in- revealing a parahypothalamic type hamar- cluding the mammillary body is also considered an toma, which corresponds to the peduncular important mechanism for seizures.72) The size of the type hamartoma in Boyko's classification. lesion was thought to be a significant factor in the A short peduncle is observed (arrow). B: A production of seizures.43) Of 38 patients, 16 with 2-year-old boy with medically intractable lesions larger than 1 cm presented with seizures seizures and developmental delay. Coronal whereas none of 18 patients with lesions smaller T1-weighted without (left)andsagittal than 1 cm ever suffered seizures. On the other hand, T1-weighted with gadolinium (right)MR we found no significant difference between IHH images showing typical intrahypothalamic with and PHH without seizures with respect to mass type hamartoma inserted in the hypothala- 4) mus, which corresponds to the sessile type size. in Boyko's classification. C: A 9-year-old Evidence has accumulated that the source of boy with precocious puberty but no gelastic seizures is the hamartoma per se.10,26) Direct seizures. Coronal (left)andsagittal(right) EEG recordings from hamartomas showed that

T1-weighted MR images both with gadolini- gelastic seizure activity was strictly linked to ictal um showing a lesion attached to the discharges and remained localized in the lesion.49) hypothalamus via a wide interface. There is Electrical stimulation of the lesion via an implanted no disfigurement of the third ventricle. This electrode also elicited gelastic seizures.27,37) The lesion is the sessile type according to results of ictal single photon emission computed Boyko's classification but parahypothalam- tomography studies and interictal EEG source ic type in our classification. analysis gave further support to the hypothesis of intrinsic epileptogenicity.38,39) MR spectroscopy

Neurol Med Chir (Tokyo) 45, May, 2005 226 K. Arita et al. revealed that the N-acetyl aspartate to creatinine Table 3 Reported modalities to treat hypothalamic ratio was significantly decreased in HH, suggesting hamartomas that HHs contain dysfunctional neurons.34) The improvement or cessation of gelastic seizures by Seizure Antiepileptic drugs Resective surgery surgical removal of the lesion,55,64,72) radiofrequency Disconnection surgery 26,38,56) 5,62) lesioning, or stereotactic radiation supports disconnection from hypothalamus this suggestion. A neuroendocrine mechanism was corpus callosotomy suggested to explain the intrinsic epileptogenesis.6) Stereotactic radiation The HH cells of two patients with seizures con- Radiofrequency thermocoagulation tained Met-enkephalin while those of a patient Vagal nerve stimulation without seizures did not.72) Thus, HHs are recog- Precocious puberty GnRH analogue nized to be directly responsible at least for gelastic Resective surgery seizures. We suspect that the ample neuronal GnRH: long-acting gonadotropin-releasing hormone. network connections between the HH and dien- cephalon that appear to predominate in IHH result in the propagation of ictal activity that originates in the HH.4) Epileptiform activities from temporal facilitate pulsatile luteinizing hormone-releasing and/or frontal lobes are now considered to be a hormone release at the time of normal puberty. spread of seizures originating in the hamartoma.10) Therefore, some HHs may stimulate GnRH secre- The slow spike and wave discharges, seen in the tion from the hypothalamus via the secretion of later stage, are associated with absence, tonic, these glial factors.32) An abnormal afferent neuronal and/or atonic attacks and remain an enigma.8,10) network originating in the HH may stimulate activi- These slow spike and wave discharges do not ty in normal GnRH cells.63,74) Another hypothesis of directly arise from the HH.49) However, the success- mechanical compression suggests that the hypotha- ful removal of HHs produces a gradual decrease lamic system that normally inhibits gonadotropin- in the number of the seizures and gradual improve- secreting cells is disarranged by compression of the ment of EEG abnormalities.26) Activation of a hypothalamus by the HH.3,6,54) stimulating electrode introduced into the HH reproduced these tonic seizures following gelastic Treatment seizures.27) Considering these clinical findings, the intrinsic I. Treatment of seizures (Table 3) epileptogenicity of HH, the contiguity of the lesion Antiepileptic drugs: Gelastic seizures in HH with the mammillothalamic tract, and the purported patients are medically intractable4,9) and very few thalamocortical loop,28) we have formulated the are controlled by antiepileptic drugs alone.72) Focal following hypothesis. Recurrent ictal discharges seizures and tonic and atonic attacks are at best that propagate through networks to the cerebral moderately controlled by these drugs.9) cortex are involved in the alteration of the Surgery: Since the 1960s, HHs have been treated thalamocortical loop and generate the observed slow by surgery. According to a review, 75 (44%) of spike and wave activity.26) Recurrent excitatory 170 HH patients with seizures underwent 87 surgi- damage produced by the spreading of seizure activi- cal procedures consisting of 66 hamartoma resec- ty from the HH through the mammillothalamic tions, four callosotomies, 12 temporal or occipital pathway and associated brain area may cause the lobectomies, and five stereotactic radiofrequency progressive cognitive deterioration in patients with thermo-coagulation procedures.51) Corpus cal- HH.25) losotomy brought a reduction in drop attacks but no change in the other seizure types.12) None of the II. CPP patients who underwent cortical resection ex- The pathomechanisms of CPP in patients with perienced a significant reduction in seizure fre- HH remain controversial. GnRH has been found quency.12) intheHHofpatientswithCPP.1,2,32,60,72) These Surgical intervention has been targeted at the ectopic GnRH-secreting cells appear to activate HH per se. However, total HH removal is not easy, gonadotrophs in the pituitary. However, absence of only 15 of 71 procedures directed at the lesion since GnRHhasbeenreportedinHH.35,44) Astroglial cells the 1960s achieved total or nearly total (À95%) containing transforming growth factor alpha removal.51) Considering only later series,30,55) this (TGFa), but no GnRH neurons, were detected in rate has improved to better than 50%. Postoperative HHs.32) TGFa-producing cells are thought to seizure control is heavily dependent on the extent of

Neurol Med Chir (Tokyo) 45, May, 2005 Hypothalamic Hamartoma 227 removal.51) Of 15 patients with HHs totally or sub- free and the other eight showed dramatic improve- totally removed, 10 became seizure-free and five ment during a mean follow up of 28 months. Two manifested significant improvements. However, patients became hemiplegic postoperatively. Among significant improvement was obtained in only seven four patients with hamartoma very recently treated of 37 patients who underwent partial removal. with endoscopic disconnection in Korea, two Gelastic seizures generally subside soon after the patients became seizure-free and the other two complete removal of the HH.26) Other types of sei- obtained marked improvement.16) No surgical mor- zures decrease gradually in frequency and improve- bidity ensued. ment of EEG abnormalities over the course of sever- The trans-lamina terminalis approach is another al postoperative months has been reported.26,33,52,64,72) possible corridor to the lesion, however, there are These improvements were usually accompanied by currently insufficient data to judge its useful- moderate to marked improvements in cognitive ness.36,37) functions and behavioral problems.30,52,55,64,72) The surgical approach to HHs must take into con- To approach the HHs surgically, pterional, sub- sideration the location, size, and the degree of temporal, transcallosal interforniceal, subtemporo- hypothalamic involvement. Total removal may not pterygial, trans-lateral ventricular, and trans-lamina be necessary as disconnecting the HH from the terminalis routes have been used. hypothalamus may eliminate the spreading of The pterional approach is the one most familiar to epileptic discharges. neurosurgeons. However, because IHHs associated Radiosurgery:Asdirectsurgerytolesionsinthe with seizures are at least partially embedded in the hypothalamus entails inherent surgical risks, includ- hypothalamus, total visualization of the lesion is ing mortality,30,55,76) less invasive modalities have impossible. Neurovascular structures in the been developed. These include stereotactic radiosur- suprasellar cistern also limit surgical corridors. gery using a linear accelerator in two patients.1,49) Treatment of 13 patients by resection mainly via the Thefollow-upperiodswereshort,andthelackof pterional route encountered surgical complications improvements was attributed to the relatively low in seven cases, including thalamic or capsular radiation dose used to cover the hamartoma.49) infarction leading to transient hemiparesis in four In 1998, we reported the first HH patient who patients.55) underwent gamma knife radiosurgery (GKS).5) We The subtemporal route has similar limitations. In obtained complete seizure cessation in this patient.5) one series, all six patients who underwent resection Since then, others have found GKS useful in patients via the subtemporal route developed transient oculo- with HHs.21,62,71) In a multicenter study, 10 patients motor palsy; two patients exhibited significant with HH and intractable epilepsy were treated by neurological symptoms postoperatively.59) GKS.62) Themediandoseatthemarginalisodosewas The transcallosal interforniceal trans-third ven- 15.25 Gy (range 12–20 Gy, mean 15.5 Gy). A maximal tricular approach, which facilitates dissection of the dose of 10 Gy was delivered to the optic pathways in HH from the wall of the third ventricle under direct each case. All 10 patients experienced improvement operative vision, has been used in 17 patients.30,64) Of and four were seizure-free after this treatment. these, 10 underwent total or nearly total (À95%) No side effects were reported. The mean interval resection, and seven received 25–90% resection. Ten to seizure reduction was 9 months (range 3–36 patients are now free of seizures and in five the months). The marginal dose exceeded 17 Gy in all frequency of seizures was reduced by more than patients treated successfully. Of other two patients, 90%. Operative morbidity included thalamic infarct one experienced more than 90% reduction in gelas- in two patients, transient somnolence in seven, tic seizures and the other became seizure-free after hypernatremia in eight, and appetite stimulation in GKS.23) GKS in four patients resulted in continuing nine. decrease in both seizure frequency and intensity Delalande et al.22) introduced the subtemporo- during 12–68 month follow up.71) All four patients pterygial approach. Of five patients, three manifest- became socially re-integrated. ed surgical morbidity, and two of these suffered Although GKS may induce transient seizure postoperative hemiparesis. They now favor discon- exacerbation and several months may be needed for nection surgery, i.e. detaching the HH from the the cessation of seizures,5,62,71) GKS can significantly hypothalamus.21) They also tested the usefulness of improve seizure control. To date, no serious compli- transventricular endoscopic and/or pterional ap- cations have been reported. However, the long-term proaches to treat HHs categorized as type II or III in adverse effects of high-energy radiation to the their classification.21) Among16patientswhounder- hypothalamus must be monitored and optimal doses went disconnection surgery, eight became seizure- must be identified.

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Other treatment modalities: Stereotactic radio- GnRH therapy. Based on this experience, medical frequency destruction of the lesion is another less treatment with long-acting GnRH agonists should invasive treatment modality.27,38,48,56) After ther- first be tried in children with CPP due to HH mocoagulation, two patients became seizure-free because major craniotomy entails risks and the without complications.27,38) Immediate improvement surgical outcome is uncertain.69) of seizure control was noted in one patient.48) Others Stereotactic irradiation may represent an alterna- mentioned that thermocoagulation was not success- tive treatment for CPP, however, at present available ful.50,64) data are sparse. One of our five patients who under- In three of six patients treated by vagal nerve went GKS presented with CPP before the treatment. stimulation, some reduction in seizure frequency Although his seizures subsided starting 1 year post- was obtained and remarkable improvements, not GKS, his CPP did not improve. Another of our related to seizure control, were noted in behavioral patients developed CPP 2 years after GKS. Despite problems.50) However, more data must be analyzed the improvement of epileptic conditions, CPP was before the usefulness of this treatment modality can not resolved by radiosurgery.73) At present, CPP be determined. alone does not appear to be a good justification for subjecting HH patients to GKS. II. Treatment for CPP (Table 3) A review of patients with HH and CPP surgically III. Surgical indications treated since 1958 found that treatment outcomes CPP is generally controlled safely and effectively were poor.68) Only eight of 22 surgically treated by GnRH agonist treatment. Thus, surgical treat- patients manifested arrested puberty or clinical ment should be considered if the GnRH treatment regression. However, surgical results for CPP have fails. markedly improved2,11,42,47) and postoperative com- On the contrary, multiple antiepileptic drugs plete disappearance without complications of symp- usually fail to control seizures secondary to IHH. toms and signs of CPP has been reported in a total Eradication of HH has been known to result in good of 19 patients.2,11,42,47) Theoretically, surgery for HH control of seizures and improvement of cognitive presenting with only CPP is less risky than surgery function. Therefore, early surgical intervention for HH with seizures, because the lesions in the should be seriously considered for IHH. To avoid former instance do not seriously involve the complications pertaining to the direct surgical hypothalamus.4,11,72) Simple transection of the stalk approach to the hypothalamic lesion, various in peduncular HHs may cure the endocrine dysfunc- modifications including radiosurgery, radiofre- tion without serious risks.15) quency lesioning, and endoscopic disconnection Long-acting GnRH agonists are now the first have been introduced. Because of its safety, the choice for idiopathic CPP.18,19,24) Continuous GnRH authors prefer radiosurgery to direct surgical stimulation with long-acting GnRH agonist inhibits removal. Considering progressive developmental gonadotropin secretion and stops pubertal matura- delay,10,25) this treatment modality should be tion.19) GnRH analogue treatment also produced proposed when medical treatments appear to be regression in secondary sexual characteristics, ineffective. Trans-ventricular removal or disconnec- slowed the skeletal maturation rate, and preserved tion may be a choice if radiosurgery fails to control the growth potential in patients with CPP and HH.18) seizures. Usefulness of this treatment strategy will AdversesideeffectsofGnRHtherapyarerare.24) be proven by longitudinal follow up of seizure con- However, GnRH treatment is expensive and may trol and adverse effect in many patients. be necessary for years.2) Also, the muscularity, increased appetite, and adolescent personality Conclusion problems may not be reversed. Seizure activity is usually not improved by GnRH treatment, although Studies during the last 2 decades have led to a better two exceptional cases were reported.75) On the other understanding of the pathophysiology underlying hand,fiveof18HHpatientstreatedwithGnRH the symptoms of HH. Using our categorization, HHs developed seizures.24) can be segregated into two types based on their Incomplete CPP reversal and persistence of anatomo-topographic relationship to the hypothala- endocrine abnormalities were found in patients mus. Our categories correlate well with the with CPP and HH who had undergone resective sur- manifestation and prognosis of HHs. The essential gery.69) Two lesions in six HH patients with CPP treatment of CPP is administration of GnRH for were totally resected, however, CPP did not subside safety and efficacy. Recent advances in microsurgi- after surgery and one patient required adjuvant cal techniques and the introduction of radiosurgery

Neurol Med Chir (Tokyo) 45, May, 2005 Hypothalamic Hamartoma 229 have led to the improvement or cessation of medical- 14) ChemaitillyW,TrivinC,AdanL,GallV,Sainte-Rose ly intractable seizures and better quality of life for C, Brauner R: Central precocious puberty: clinical HH patients. and laboratory features. Clin Endocrinol (Oxf) 54: 289–294, 2001 15) Chen TC, Gonazalez-Gomez I, McComb JG: Uncom- References mon glial tumors, in Kaye AH, Laws E Jr (eds): Brain Tumors, ed 2. London, Churchill Livingstone, 2001, 1) Akai T, Okamoto K, Iizuka H, Kakinuma H, Nojima pp 591–597 T: Treatments of hamartoma with neuroendoscopic 16) Choi J, Yang K, Kim T, Chang J, Chang J, Lee B, Kim surgery and stereotactic radiosurgery: a case report. D: Endoscopic disconnection for hypothalamic Minim Invasive Neurosurg 45: 235–239, 2002 hamartoma with intractable seizure. J Neurosurg 100: 2) Albright AL, Lee PA: Neurosurgical treatment of 506–511, 2004 hypothalamic hamartomas causing precocious 17) Clarren SK, Alvord EC Jr, Hall JG: Congenital puberty. JNeurosurg78: 77–82, 1993 hypothalamic hamartoblastoma, hypopituitarism, 3) Alvarez-Garijo JA, Albiach VJ, Vila MM, Mulas F, imperforate anus, and postaxial polydactyly — a new Esquembre V: Precocious puberty and hypothalamic syndrome? Part II: Neuropathological considera- hamartoma with total recovery after surgical treat- tions. Am J Med Genet 7: 75–83, 1980 ment. Case report. JNeurosurg58: 583–585, 1983 18) Comite F, Pescovitz OH, Rieth KG, Dwyer AJ, Hench 4) Arita K, Ikawa F, Kurisu K, Sumida M, Harada K, K, McNemar A, Loriaux DL, Cutler GB Jr: Luteiniz- Uozumi T, Monden S, Yoshida J, Nishi Y: The ing hormone-releasing hormone analog treatment of relationship between magnetic resonance imaging boys with hypothalamic hamartoma and true findings and clinical manifestations of hypothalamic precocious puberty. J Clin Endocrinol Metab 59: hamartoma. J Neurosurg 91: 212–220, 1999 888–892, 1984 5) AritaK,KurisuK,IidaK,HanayaR,AkimitsuT, 19) Conn PM, Crowley WF Jr: Gonadotropin-releasing Hibino S, Pant B, Hamasaki M, Shinagawa S: Subsi- hormone and its analogue. NEnglJMed324: 93–103, dence of seizure induced by stereotactic radiation in 1991 a patient with hypothalamic hamartoma. J Neurosurg 20) Debeneix C, Bourgeois M, Trivin C, Sainte-Rose C, 89: 645–648, 1998 Brauner R: Hypothalamic hamartoma: comparison 6) Balagura S, Shuman K, Sobel EH: Precocious puberty of clinical presentation and magnetic resonance of cerebral origin. Surg Neurol 11: 315–326, 1979 images. Horm Res 56: 12–18, 2001 7) Beningfield SJ, Bonnici F, Cremin BJ: Magnetic 21) Delalande O, Fohlen M: Disconnecting surgical treat- resonance imaging of hypothalamic hamartomas. Br ment of hypothalamic hamartoma in children and JRadiol61: 1177–1180, 1988 adults with refractory epilepsy and proposal of a new 8) Berkovic SF, Andermann F, Melanson D, Ethier RE, classification. Neurol Med Chir (Tokyo) 43: 61–68, Feindel W, Gloor P: Hypothalamic hamartomas and 2003 ictal laughter: Evolution of a characteristic epileptic 22) Delalande O, Fohlen M, Jalin C, Pinard J, Rodriguez syndrome and diagnostic value of magnetic D, Villeneuve N, Kaminska A, Chiron C, Chiron C, resonance imaging. Ann Neurol 23: 429–439, 1988 Robert G, Dulac O, Ponsot G: Surgical treatment of 9) Berkovic SF, Arzimanoglou A, Kuzniecky R, Harvey epilepsy due to hypothalamic hamartoma: technique AS, Palmini A, Andermann F: Hypothalamic hamar- and preliminary results of five cases. Epilepsia 39 toma and seizures: a treatable epileptic en- Suppl 6: 90–91, 1998 (abstract) cephalopathy. Epilepsia 44: 969–973, 2003 23) Dunoyer C, Ragheb J, Resnick T, Alvarez L, Jayakar 10) Berkovic SF, Kuzniecky RI, Andermann F: Human P, Altman N, Wolf A, Duchowny M: The use of epileptogenesis and hypothalamic hamartomas: new stereotactic radiosurgery to treat intractable child- lessons from an experiment of nature. Epilepsia 38: hood partial epilepsy. Epilepsia 43: 292–300, 2002 1–3, 1997 24) Feuillan PP, Jones JV, Barnes K, Oerter-Klein K, 11) Boyko OB, Curnes JT, Oakes WJ, Burger PC: Hamar- Cutler GB Jr: Reproductive axis after discontinuation tomas of the tuber cinereum: CT, MR, and pathologic of gonadotropin-releasing hormone analog treatment findings. AJNR Am J Neuroradiol 12: 310–314, 1991 of girls with precocious puberty: long term follow-up 12) Cascino GD, Andermann F, Berkovic SF, Kuzniecky comparing girls with hypothalamic hamartoma to RI, Sharbrough FW, Keene DL, Bladin PF, Kelly PJ, those with idiopathic precocious puberty. JClin Olivier A, Feindel W: Gelastic seizures and hypotha- Endocrinol Metab 84: 44–49, 1999 lamic hamartomas: evaluation of patients under- 25) Frattali CM, Liow K, Craig GH, Korenman LM, going chronic intracranial EEG monitoring and out- Makhlouf F, Sato S, Biesecker LG, Theodore WH: come of surgical treatment. Neurology 43: 747–750, Cognitive deficits in children with gelastic seizures 1993 and hypothalamic hamartoma. Neurology 57: 43–46, 13) Cassio A, Cacciari E, Zucchini S, Balsamo A, Diegoli 2001 M, Orsini F: Central precocious puberty: clinical and 26) Freeman JL, Harvey AS, Rosenfeld JV, Wrennall JA, imaging aspects. J Pediatr Endocrinol Metab 13 Suppl Bailey CA, Berkovic SF: in 1: 703–708, 2000 hypothalamic hamartoma: evolution and postopera-

Neurol Med Chir (Tokyo) 45, May, 2005 230 K. Arita et al.

tive resolution. Neurology 60: 762–767, 2003 40) Leal AJR, Moreira A, Robalo C, Ribeiro C: Different 27) Fukuda M, Kameyama S, Wachi M, Tanaka R: electroclinical manifestations of the epilepsy associ- Stereotaxy for hypothalamic hamartoma with ated with hamartomas connecting to the middle or intractable gelastic seizures: technical case report. posterior hypothalamus. Epilepsia 44: 1191–1195, Neurosurgery 44: 1347–1350, 1999 2003 28) Gloor P: Generalized epilepsy with spike and wave 41) Loiseau P, Cohadon F, Cohadon S: Gelastic seizures: discharge: a reinterpretation of its electrographic a review and report of five cases. Epilepsia 12: and clinical manifestation. Epilepsia 20: 571–588, 313–323, 1971 1979 42) Luo S, Li C, Ma Z, Zhang Y, Jia G, Cheng Y: 29) Hall JG, Pallister PD, Clarren SK, Beckwith JB, Microsurgical treatment for hypothalamic hamarto- Wiglesworth FW, Fraser FC, Cho S, Benke PJ, Reed ma in children with precocious puberty. Surg Neurol SD: Congenital hypothalamic hamartoblastoma, 57: 356–362, 2002 hypopituitarism, imperforate anus and postaxial 43) Mahachoklertwattana P, Kaplan SL, Grumbach MM: polydactyly — a new syndrome? Part I: clinical, The luteinizing hormone-releasing hormone-secret- causal, and pathogenetic considerations. Am J Med ing hypothalamic hamartoma is a congenital malfor- Genet 7: 47–74, 1980 mation: natural history. J Clin Endocrinol Metab 77: 30) Harvey AS, Freeman JL, Rosenfeld JV, Zacharin M, 118–124, 1993 Wrennall JA, Baily CA, Berkovic SF: Postoperative 44) Markin RS, Leibrock LG, Huseman CA, McComb course and seizure outcome after transcallosal resec- RD: Hypothalamic hamartoma: a report of 2 cases. tion of hypothalamic hamartoma in seventeen chil- Pediatr Neurosci 13: 19–26, 1987 dren with intractable gelastic epilepsy. Epilepsia 42 45) Martin DD, Seeger U, Ranke MB, Grodd W: MR Suppl 7: 216, 2001 (abstract) imaging and spectroscopy of a tuber cinereum 31) Iafolla K, Fratkin JD, Spiegel PK, Cohen MM Jr, hamartoma in a patient with growth hormone Graham JM Jr: Case report and delineation of the deficiency and hypogonadotropic hypogonadism. congenital hypothalamic hamartoblastoma syn- AJNR Am J Neuroradiol 24: 1177–1180, 2003 drome (Pallister-Hall syndrome). Am J Med Genet 33: 46) McLendon RE, Tien RD: Hypothalamic neuronal 489–499, 1989 hamartomas, in Binger DD, McLendon RE, Bruner 32) Judge DM, Kulin HE, Page R, Santen R, Trapukdi S: JM (eds): Russell and Rubinstein's Pathology of Hypothalamic hamartoma: a source of luteinizing- Tumors of the Central , ed 6, vol 2. hormone-releasing factor in precocious puberty. N London, Arnold, 1998, pp 343–344 Engl J Med 296: 7–10, 1977 47) Mottolese C, Stan H, Bret P, Berlier P, Lapras C: 33) Jung H, Ojeda SR: Pathogenesis of precocious puber- Hypothalamic hamartoma: the role of surgery in a ty in hypothalamic hamartoma. Horm Res 57 Suppl 2: series of eight patients. Childs Nerv Syst 17: 229–236, 31–34, 2002 2001 34) Kahane P, Tassi L, Hoffman D, Francione S, 48) Mullatti N, Selway R, Nashef L, Elwes R, Hanovar M, Gratadou J, Pasquier B, Munari C: Crises dacrys- Chandler C, Morris R, Jarosz J, Buchanan C, Polkey tiques et hamartome hypothalamique: a propos d'une C: The clinical spectrum of epilepsy in children and observation vid áeo-st áer áeo-EEG. 6: 259–279, adults with hypothalamic hamartoma. Epilepsia 44: 1994 (Fre) 1310–1319, 2003 35) Kammer KS, Perlman K, Humphreys RP, Howard NJ: 49) Munari C, Kahane P, Francione S, Hoffmann D, Clinical and surgical aspects of hypothalamic hamar- Tassi L, Cusmai R, Vigevano F, Pasquier B, Betti OO: toma associated with precocious puberty in a 15- Role of the hypothalamic hamartoma in the genesis month-old boy. Childs Brain 7: 150–157, 1980 of gelastic fits (a video-stereo-EEG study). Electroen- 36) Kramer U, Spector S, Nasser W, Siomin V, Fried I, cephalogr Clin Neurophysiol 95: 154–160, 1995 Constantini S: Surgical treatment of hypothalamic 50) Murphy JV, Wheless JW, Schmoll CM: Left vagal hamartoma and refractory seizures: a case report and nerve stimulation in six patients with hypothalamic review of the literature. Pediatr Neurosurg 34: 40–42, hamartomas. Pediatr Neurol 23: 167–168, 2000 2001 51) Nguyen D, Singh S, Zaatreh M, Novotny E, Levy S, 37) Kuzniecky R, Guthrie B, Knowlton R, Faught E, Testa F, Spencer SS: Hypothalamic hamartomas: Backensto E: Minimally invasive surgical manage- seven cases and review of the literature. Epilepsy ment of hypothalamic hamartomas in gelastic Behav 4: 256–258, 2003 epilepsy. Epilepsia 43 Suppl 7: 348, 2002 (abstract) 52) Nishio S, Morioka T, Fukui M, Goto Y: Surgical treat- 38) Kuzniecky R, Guthrie B, Mountz J, Bebin M, Faught ment of intractable seizures due to hypothalamic E, Gilliam F, Liu HG: Intrinsic epileptogenesis of hamartoma. Epilepsia 35: 514–519, 1994 hypothalamic hamartomas in gelastic epilepsy. Ann 53) Nishio S, Morioka T, Hamada Y, Kuromaru R, Fukui Neurol 42: 60–67, 1997 M: Hypothalamic hamartoma associated with an 39) Leal AJ, Passao V, Calado E, Vieira JP, Silva Cunha arachnoid cyst. JClinNeurosci8: 46–48, 2001 JP: Interictal spike EEG source analysis in hypotha- 54) Northfield DW, Russell DS: Pubertas praecox due to lamic hamartoma epilepsy. Clin Neurophysiol 113: hypothalamic hamartoma: report of two cases surviv- 1961–1969, 2002 ing surgical removal of the tumour. JNeurol

Neurol Med Chir (Tokyo) 45, May, 2005 Hypothalamic Hamartoma 231

Neurosurg Psychiatry 30: 166–173, 1967 tous malformations of the posterolateral hypothala- 55) Palmini A, Chandler C, Andermann F, Costa Da mus. Lab Invest 11: 89–97, 1962 Costa J, Paglioli-Neto E, Polkey C, Rosenblatt B, 67) Squires LA, Constantini S, Miller DC, Wisoff JH: Montes J, Martinez JV, Farmer JP, Sinclair B, Aronyk Hypothalamic hamartoma and the Pallister-Hall K, Paglioli E, Coutinho L, Raupp S, Portuguez M: syndrome. Pediatr Neurosurg 22: 303–308, 1995 Resection of the lesion in patients with hypothalamic 68) Starceski PJ, Lee PA, Albright AL, Migeon CJ: hamartomas and catastrophic epilepsy. Neurology Hypothalamic hamartomas and sexual precocity. 58: 1338–1347, 2002 Evaluation of treatment options. Am J Dis Child 144: 56) Parrent AG: Stereotactic radiofrequency ablation for 225–228, 1990 the treatment of gelastic seizures associated with 69) Stewart L, Steinbok P, Daaboul J: Role of surgical hypothalamic hamartoma. Case report. J Neurosurg resection in the treatment of hypothalamic hamarto- 91: 881–884, 1999 mas causing precocious puberty. Report of six cases. 57) Pescovitz OH, Comite F, Hench K, Barnes K, JNeurosurg88: 340–345, 1998 McNemar A, Foster C, Kenigsberg D, Loriaux DL, 70) Sturm JW, Andermann F, Berkovic SF: ``Pressure to Cutler GB Jr: The NIH experience with precocious laugh'': an unusual epileptic symptom associated puberty: diagnostic subgroups and response to short- with small hypothalamic hamartomas. Neurology 54: term luteinizing hormone releasing hormone ana- 971–973, 2000 logue therapy. JPediatr108: 47–54, 1986 71) Unger F, Schrottner O, Haselsberger K, Korner E, 58) Plouin P, Ponsot G, Dulac O, Diebler C, Arthuis M: Ploier R, Pendl G: Gamma knife radiosurgery for [Hypothalamic hamartomas and laughing seizures]. hypothalamic hamartomas in patients with medically Rev Electroencephalogr Neurophysiol Clin 13: intractable epilepsy and precocious puberty. Report 312–316, 1983 (Fre, with Eng abstract) of two cases. JNeurosurg92: 726–731, 2000 59) Polkey CE, Chandler C, Doshi P, Al Sarraj A: Resec- 72) Valdueza JM, Cristante L, Dammann O, Bentele K, tion of hypothalamic hamartoma for intractable Vortmeyer A, Saeger W, Padberg B, Freitag J, epilepsy. Epilepsia 38 Suppl 8: 77, 1997 (abstract) Herrmann HD: Hypothalamic hamartomas: with 60) Price RA, Lee PA, Albright AL, Ronnekleiv OK, Gutai special reference to gelastic epilepsy and surgery. JP: Treatment of sexual precocity by removal of a Neurosurgery 34: 949–958, 1994 luteinizing hormone-releasing hormone secreting 73) Verloes A, David A, Ngo L, Bottani A: Stringent hamartoma. JAMA 251: 2247–2249, 1984 delineation of Pallister-Hall syndrome in two long 61) Reeves AG, Plum F: Hyperphagia, rage and surviving patients: importance of radiological ano- accompanying a ventromedial hypothalamic ne- malies of the hands. JMedGenet32: 605–611, 1995 oplasm. Arch Neurol 20: 616–624, 1969 74) Wolman L, Balmforth GV: Precocious puberty due to 62) Regis J, Bartolomei F, de Toffol B, Genton P, hypothalamic hamartoma in a patient surviving to KobayashiT,MoriY,TakakuraK,HoriT,InoueH, late middle age. J Neurol Neurosurg Psychiat 26: Schrottner O, Pendl G, Wolf A, Arita K, Chauvel P: 275–280, 1963 Gamma knife surgery for epilepsy related to hypotha- 75) Zaatreh M, Tennison M, Greenwood RS: Successful lamic hamartomas. Neurosurgery 47: 1343–1351, treatment of hypothalamic seizures and precocious 2000 puberty with GnRH analogue. Neurology 55: 63) Richter RB: True hamartoma of the hypothalamus 1908–1910, 2000 associated with pubertas praecox. JNeuropatholExp 76) Zuniga OF, Tanner SM, Wild WO, Mosier HD Jr: Neurol 10: 368–383, 1951 Hamartoma of CNS associated with precocious 64) Rosenfeld JV, Harvey AS, Wrennall J, Zacharin M, puberty. Am J Dis Child 137: 127–133, 1983 Berkovic SF: Transcallosal resection of hypothalamic hamartomas, with control of seizures, in children with gelastic epilepsy. Neurosurgery 48: 108–118, 2001 Address reprint requests to:K.Arita,M.D.,Departmentof 65) Scheithauer BW, Kovacs K, Randall RV, Horvath E, Neurosurgery, Graduate School of Biomedical Laws ER Jr: Pathology of excessive production of Science, Hiroshima University, 1–2–3 Kasumi, growth hormone. Clin Endocrinol Metab 15: 655–681, Minami–ku, Hiroshima 734–8551, Japan. 1986 e-mail: karita＠hiroshima-u.ac.jp 66) Sherwin RP, Grassi JE, Sommers SC: Hamartoma-

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