The relationship between magnetic resonance imaging findings and clinical manifestations of hypothalamic hamartoma

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Object. Hypothalamic hamartoma is generally diagnosed based on its magnetic resonance (MR) imaging characteristics and the patient's clinical symptoms, but the relationship between the neuroradiological findings and clinical presentation has never been fully investigated. In this retrospective study the authors sought to determine this relationship.

Methods. The authors classified 11 cases of hypothalamic hamartoma into two categories based on the MR findings. Seven cases were the “parahypothalamic type,” in which the hamartoma is only attached to the floor of the third ventricle or suspended from the floor by a peduncle. Four cases were the “intrahypothalamic type,” in which the hamartoma involved or was enveloped by the hypothalamus and the tumor distorted the third ventricle.

Six patients with the parahypothalamic type exhibited precocious puberty, which was controlled by a luteinizing hormone—releasing hormone analog, and one patient was asymptomatic. No seizures or mental retardation were observed in this group. All patients with the intrahypothalamic type had medically intractable seizures, and precocious puberty was seen in one. Severe mental retardation and behavioral disorders including aggressiveness were seen in two patients. The seizures were controlled in only one patient, in whom stereotactically targeted irradiation of the lesion was performed.

This topology/symptom relationship was reconfirmed in a review of 61 reported cases of hamartoma, in which the MR findings were clearly described. The parahypothalamic type is generally associated with precocious puberty but is unaccompanied by seizures or developmental delay, whereas the intrahypothalamic type is generally associated with seizures. Two thirds of patients with the latter experience developmental delays, and half also exhibit precocious puberty.

Conclusions. Classification of hypothalamic hamartomas into these two categories based on MR findings resulted in a clear correlation between symptoms and the subsequent clinical course.

Abstract

Object. Hypothalamic hamartoma is generally diagnosed based on its magnetic resonance (MR) imaging characteristics and the patient's clinical symptoms, but the relationship between the neuroradiological findings and clinical presentation has never been fully investigated. In this retrospective study the authors sought to determine this relationship.

Methods. The authors classified 11 cases of hypothalamic hamartoma into two categories based on the MR findings. Seven cases were the “parahypothalamic type,” in which the hamartoma is only attached to the floor of the third ventricle or suspended from the floor by a peduncle. Four cases were the “intrahypothalamic type,” in which the hamartoma involved or was enveloped by the hypothalamus and the tumor distorted the third ventricle.

Six patients with the parahypothalamic type exhibited precocious puberty, which was controlled by a luteinizing hormone—releasing hormone analog, and one patient was asymptomatic. No seizures or mental retardation were observed in this group. All patients with the intrahypothalamic type had medically intractable seizures, and precocious puberty was seen in one. Severe mental retardation and behavioral disorders including aggressiveness were seen in two patients. The seizures were controlled in only one patient, in whom stereotactically targeted irradiation of the lesion was performed.

This topology/symptom relationship was reconfirmed in a review of 61 reported cases of hamartoma, in which the MR findings were clearly described. The parahypothalamic type is generally associated with precocious puberty but is unaccompanied by seizures or developmental delay, whereas the intrahypothalamic type is generally associated with seizures. Two thirds of patients with the latter experience developmental delays, and half also exhibit precocious puberty.

Conclusions. Classification of hypothalamic hamartomas into these two categories based on MR findings resulted in a clear correlation between symptoms and the subsequent clinical course.

Hypothalamic hamartomas are well-known non-neoplastic lesions characterized by the peculiar symptoms patients harboring them manifest, which include precocious puberty and/or gelastic seizures.8,9,53,62 Magnetic resonance (MR) imaging is a major diagnostic tool for identification of hypothalamic hamartoma, because surgical specimens are not easy to obtain. These lesions are uniformly isointense to gray matter on T1-weighted MR images and slightly hyperintense or isointense on T2-weighted images.6,9,10,14,23,36,40 They are not enhanced by gadolinium.9,14,58 Their clinical manifestations, however, are not uniform. We conducted a retrospective analysis in 11 of our patients with hypothalamic hamartoma to determine the correlation between MR findings and clinical presentation. We also reviewed the literature, in which the MR findings and symptoms of hypothalamic hamartoma are well described.

Clinical Material and Methods
Patient Population

The study group consisted of 11 patients (Table 1), including two previously reported cases.3,25 There were seven females and four males with hypothalamic hamartomas that had been diagnosed on the basis of characteristic MR findings, patient symptoms, and results of histological examinations. The mean patient age at the time of the first MR study was 15.5 ± 12.7 years (± standard deviation [SD]) and ranged from 3 months to 76 years. The age at onset of the initial symptoms was 1.7 ± 1.9 years (± SD), ranging from 5 days to 9.4 years.

TABLE 1

Summary of clinical characteristics in 11 patients with hypothalamic hamartoma categorized by MR findings*

  Tumor Size (mm)MR Findings  Follow Up (mos) 
Case No.Age, SexPedNarDisSymptom(s)OnsetTherapyCourse  
parahypothalamic type   
1 9 yrs, F 15+PP 1 yr 72LH-RH well controlled
2 13 yrs, F 9++PP 1.5 yrs 57LH-RH well controlled
3 3 yrs, F 17+PP 3 yrs 24LH-RH well controlled
4 6 yrs, F 7++PP 9 mos 37LH-RH well controlled
5 3 mos, F 15PP 3 mos 48LH-RH well controlled
6 76 yrs, M 13+  26 uneventful
7 10 yrs, M 25PP 9.3 yrs 8LH-RH well controlled
intrahypothalamic type   
8 15 yrs, F 17+GS, SMR, BD 2.7 yrs 40AED intractable
9 11 yrs, F 26+GS, PP, SMR, BD 1 mo 8AED intractable
10 25 yrs, M 10+GS 1 mo 60AED, GK seizure free
11 2 yrs, M 20+GS, MMR 5 days 24AED, GK improved

All tumors were isointense on T1-weighted images and slightly hyperintense on T2-weighted images. None enhanced after gadolinium injection (not performed in Case 9). Ages represent patient's age at diagnosis. Abbreviations: AED = antiepileptic drug; BD = behavioral disorder; dis = distorted IIIrd ventricle; GK = gamma knife; GS = gelastic seizure; MMR = mild mental retardation; nar = narrowing at attachment; ped = peduncle; PP = precocious puberty; SMR = severe mental retardation; + = present; − = absent; — = none.

Neuroradiological Imaging

The type of MR images used in the study varied. High magnetic field strength (1.5 teslas) was used in seven patients (Cases 1–4, 6, 10, and 11), intermediate (0.5 teslas) in three patients (Cases 5, 7, and 8), and low magnetic field strength (0.1 teslas) in one patient (Case 9). Gadolinium contrast material was injected in all but one patient (Case 9). Coronal and sagittal T2-weighted imaging was performed first, followed by coronal and sagittal T1-weighted imaging. The latter studies were performed immediately after intravenous injection of 0.1 mm/kg of gadolinium. Axial imaging was also performed when necessary. The last follow-up MR image was obtained 8 to 72 months (36.8 ± 16.2 months [mean ± SD]) after the initial investigation.

Tumor Classification

The lesions were classified into two types according to their topology in relation to the hypothalamus as depicted on MR imaging. Seven patients (Cases 1–7) had the “parahypothalamic type,” in which the hamartoma was suspended from the floor of third ventricle by a peduncle (Fig. 1) or only attached to the floor (Figs. 2 and 3), and there was no or minimal displacement of the third ventricle. Four patients (Cases 8–11) had the “intrahypothalamic type,” in which the hamartoma involved the hypothalamus or was enveloped by hypothalamic tissue and distorted the shape of the third ventricle (Figs. 4 and 5). The presentation and clinical course of both types were investigated retrospectively.

Fig. 1.
Fig. 1.

Case 2. Coronal (upper) and sagittal (lower) MR images revealing a parahypothalamic-type hypothalamic hamartoma in a 13-year-old girl with precocious puberty. The lesion is suspended from the mammillary body by a peduncle (arrow).

Fig. 2.
Fig. 2.

Case 3. Coronal (upper) and sagittal (lower) MR images revealing a parahypothalamic-type hypothalamic hamartoma in a 3-year-old girl with precocious puberty. The lesion is attached to the base of the hypothalamus at a narrow interface (arrow), but there is no peduncle.

Fig. 3.
Fig. 3.

Case 7. Coronal (upper) and sagittal (lower) MR images revealing a parahypothalamic-type hypothalamic hamartoma in a 10-year-old boy with precocious puberty. This lesion, which was attached to the base of the hypothalamus with a wide interface (arrows), can be called “sessile.” Involvement of the hypothalamus is minimal.

Fig. 4.
Fig. 4.

Case 11. Coronal (upper) and sagittal (lower) MR images revealing an intrahypothalamic-type large hypothalamic hamartoma in a 2-year-old boy who suffered gelastic and tonic seizures. The lesion extensively involved the hypothalamus. The third ventricle is remarkably distorted (arrows).

Fig. 5.
Fig. 5.

Case 10. Coronal (upper left), sagittal (upper right), and axial (lower left) images revealing a small intrahypothalamic-type hypothalamic hamartoma (arrows) in a 25-year-old man who suffered gelastic and tonic—clonic seizures. The lesion is completely enveloped by hypothalamic tissue. Lower Right: Axial MR image obtained at 12 months after stereotactically targeted radiation treatment, revealing complete disappearance of the lesion.

Statistical Analysis

Statistical analysis of differences between the groups was performed using the Mann—Whitney U-test. Statistical significance was judged to be present at probability values of less than 0.05. The literature was reviewed to assess the correlation between MR findings and clinical presentation. The reported cases were statistically analyzed using multiple regression analysis, with the same level of statistical significance.

All the images, including those obtained in our series, were reviewed by two neuroradiologists who were blinded to the patients' clinical history. Their classifications coincided with the authors', except for an uncertain decision on three reported cases in which displacements of the hypothalamus were minimal, which we classified as the parahypothalamic type.

Results
Common Features

All lesions were isointense on T1-weighted MR images when compared with the cerebral gray matter and slightly hyperintense on T2-weighted images. They were 15.8 ± 4.7 mm (SD) in size, and there was no increase in size during the follow-up period (36.8 ± 16.2 months [SD]). The age at onset of symptoms in patients with the intrahypothalamic type tended to be younger (0.8 ± 1.1 years [SD]) than in those with the parahypothalamic type (2.6 ± 2.7 years [SD]), but the difference was not significant (Mann—Whitney U-test). Histological composition was verified in three patients (Cases 2, 8, and 9) in whom biopsies of the lesions had been obtained at hospitals in which they had been treated previously. Partial removal of the tumor had not improved the symptoms.

Comparison of the Two Types
Topography

Two of the seven parahypothalamic lesions (Cases 2 and 4) were suspended from the base of the hypothalamus by a short peduncle (Fig. 1). In the other five cases, no peduncle was seen and the lesion was attached to the hypothalamus by a narrow (Cases 1, 3, and 6; Fig. 2) or wide base (Cases 5 and 7; Fig. 3). No displacement of the hypothalamus was seen in this type (Figs. 1 and 2) or it was minimal (Fig. 3).

In all four patients with the intrahypothalamic tumor type, the lesions largely involved the hypothalamus and distorted the third ventricle (Figs. 4 and 5). In one patient (Case 10), the lesion was nearly totally enveloped by the hypothalamus (Fig. 5).

Clinical Manifestations

In six patients with the parahypothalamic tumor type (Cases 1–5 and 7), precocious puberty was observed between the ages of 3 months and 9.3 years. In one patient with the parahypothalamic type (Case 6), the lesion was discovered on a brain image obtained when he presented with dizziness. The patient's history did not include any evidence of precocious puberty. No behavioral disorders, mental retardation, seizures of any kind, or other neurological symptoms were observed in patients with this tumor type.

In contrast, in all four cases of the intrahypothalamic type, the patients experienced gelastic attacks and other types of seizure. Two patients (Cases 8 and 9) demonstrated severe mental retardation and behavioral disorders such as aggressiveness. One (Case 11) had mild mental retardation and developmental delay. Precocious puberty was seen in Case 9 alone.

Response to Treatment

Precocious puberty was well managed in six patients (Cases 1–5 and 7) with the parahypothalamic tumor type by treatment with a super long—acting luteinizing hormone—releasing hormone (LH-RH) analog (leuprolide acetate depot, TAP-144-SR; [D-Lieu-[des-Gly10]-NH2-LH-RH ethylamide acetate).30,57 In Case 5, the size of the lesion was considerably diminished by the drug.25 In two patients (Cases 1 and 2), the drug was discontinued because they reached the standard age for normal puberty and skeletal maturation was complete.

None of the seizures exhibited by the patients with the intrahypothalamic tumor type was controlled by any combination of antiepileptic drugs. In two patients (Cases 10 and 11), 36 Gy of stereotactically targeted radiation was administered to the center of the lesion, which appeared to be surgically inaccessible because of the degree of involvement of the hypothalamus. In Case 10 (Fig. 5), gelastic and tonic—clonic seizures that had been medically intractable for 24 years subsided 3 months after the radiation therapy. Follow-up MR imaging performed 12 months postirradiation revealed complete disappearance of the lesion (Fig. 5 lower right). In Case 11, tonic seizures ceased 1 month posttreatment, and the incidence of gelastic attacks has been remarkably reduced since 4 months after the radiation therapy. A follow-up MR image obtained 6 months posttreatment revealed central necrosis of the lesion. Treatment of the precocious puberty in Case 9 was not considered because of the severity of the patient's mental retardation.

Literature Review

The results of this study of our 11 cases indicated a strong topology/symptom relationship in hypothalamic hamartomas. To confirm this relationship, we reviewed the literature in which MR findings, especially the extent of hypothalamic involvement, were clearly documented. We found 30 reported cases of the parahypothalamic type of hypothalamic hamartoma,1,7,9,12,13,20,23,24,26,28,36,38,43,50,51,59,63 including our own seven cases (Table 2). No distortion of the base of the third ventricle was seen in any of these cases, and only five lesions had peduncles.1,12,38 Narrowing attachment was seen in 23 lesions, whereas the other seven7,13,20,43,63 did not show narrowing of their attachment to the hypothalamus and could be considered “sessile.” Twenty-five of the 30 patients exhibited precocious puberty alone, and none of these had mental retardation. Two of the remaining five patients did have seizures and mental retardation,20,43 whereas no lesion-related symptoms were found in the other three.13,28

TABLE 2

Literature review of 30 patients with the parahypothalamic type of hypothalamic hamartoma*

 Tumor Size (mm)MR Findings
Authors & YearCase No.Age, SexPedNarDisSymptom(s)
Beningfield, et al., 1988126 mos, M 8+PP
213 mos, M 7PP
Hahn, et al., 198812.5 yrs, M 16+PP
22.5 yrs, F 10+PP
Nishio, et al., 198914 yrs, M 17+PP
22.5 yrs, M 15SZ, MeRe, BD
Boyko, et al., 199116 mos, F 10+PP
Diaz, et al., 19919 yrs, M 12SZ, MeRe
Lona-Soto, et al., 199143 yrs, F 35+PP
51 yr, F 20+PP
Hsiao, et al., 19927 yrs, F 9+PP
Albright, et al., 1993219 mos, M 6+PP
36 mos, F 7++PP
Cheng, et al., 199331 yrs, M 25
Mahachoklertwattana, et al., 199318 mos, F 10++PP
53.8 yrs, F 8+PP
Robben, et al., 199410 mos, F 6+PP
Romner, et al., 19946 mos, F 8+PP
Valdueza, et al., 1994621 mos, F 10+PP
Chamouilli, et al., 19957.5 mos, F 6++PP
Zucchini, et al., 19954.7 yrs, F 10PP
Isaka, et al., 199642 yrs, M 20§§
Hamilton, 19973 yrs, F 13+PP
present study19 yrs, F 15+PP
213 yrs, F 9++PP
33 yrs, F 17+PP
46 yrs, F 7++PP
53 mos, F 15PP
676 yrs, M 13+
710 yrs, M 25PP

Ages represent the patient's age at diagnosis. Abbreviations: MeRe = mental retardation; SZ = seizure; others as in Table 1.

Concomitant external malformations such as syndactyly, polydactyly, and cleft epiglottis were omitted.

Diameter not stated in article but estimated from figures.

Isolated from hypothalamus.

There were 31 reported cases of the intrahypothalamic type of hypothalamic hamartoma,4,8,9,11,16,22,27,31–34,36,37,40,42,59–61 including our own four (Table 3). No peduncles or narrowing at the attachment were seen in any of these, whereas all lesions exhibited considerable degrees of distortion of the third ventricle at the base. Twenty-nine patients suffered seizures: 13 of these 29 also exhibited precocious puberty, and 20 of them also had associated developmental problems, such as mental retardation, behavioral disorders, or speech disturbance. There were no lesion-related symptoms in two patients.33 The intrahypothalamic lesions were significantly larger than the parahypothalamic lesions (p < 0.01, Mann—Whitney U-test).

TABLE 3

Literature review of 31 patients with the intrahypothalamic type of hypothalamic hamartoma*

 Tumor Size (mm)MR Findings
Authors & YearCase No.Age, SexPedNarDisSymptom(s)
Berkovic, et al., 198834 yrs, NM 11+SZ, MeRe, BD
41 yr, M 16+SZ, PP, MeRe, BD
Hubbard & Egelhoff, 1989111 mos, M 30+SZ, MeRe
Boyko, et al., 199125 yrs, M 20+SZ
46 yrs, F 15+SZ
Koelfen & Wentz, 19917 yrs, F 15+SZ, PP, MeRe
Lona-Soto, et al., 199122 yrs, M 38+SZ, PP
Machado, et al., 19911 yr, F 20+SZ, MeRe
Marliani, et al., 199112 yrs, M 20+SZ, PP, MeRe
23.5 yrs, M 8+SZ, PP, MeRe
310 yrs, M 10+SZ, MeRe
41 yr, M 15+SZ, PP, MeRe
Cascino, et al., 199338 yrs, F 12+SZ, PP
Katayama, et al., 19936 mos, M 50+SZ, PP
Wentz, et al., 1993NM, F 15+SZ, PP
Kujat, et al., 1994123 yrs, M 28+
253 yrs, F 25+
Valdueza, et al., 199412.8 yrs, M 15+SZ, SpD, BD
24.7 yrs, M 20+SZ, SpD
44 yrs, M 15+SZ, MeRe
521 mos, F 20+SZ, PP, BD
Asanuma, et al., 199516 mos, M 15+SZ
Commentz & Helmke, 199513 mos, F 20+SZ, PP
Guibaud, et al., 19951 day, F 50+SZ
Munari, et al., 199530 mos, F 18+SZ, MeRe, BD
Kuzniecky, et al., 19972neo, F 14+SZ, PP, MeRe, BD
Watanabe, et al., 19982.5 yrs, F 20+SZ, MD, BD
present study815 yrs, F 17+SZ, MeRe, BD
910 yrs, F 26+SZ, PP, MR
1025 yrs, M 10+SZ, MeRe
112 yrs, M 20+SZ, MeRe

Ages represent the patient's age at diagnosis. Abbreviations: neo = neonate; NM = not mentioned; SpD = speech disturbance.

Concomitant external malformations such as syndactyly, polydactyly, and cleft epiglottis were omitted.

Diameter not stated in article but estimated from figures.

The correlation between topology and symptom in reported hypothalamic hamartoma is summarized in Table 4. The parahypothalamic type, which had peduncles in a few cases, was generally small and associated with precocious puberty but unaccompanied by seizures or developmental delay. The intrahypothalamic type was generally associated with seizures. Two thirds of these patients also had developmental delays, and approximately half of the patients with this type of hamartoma also exhibited precocious puberty. There were occasional asymptomatic cases associated with both types.

TABLE 4

Correlation between type of hypothalamic hamartoma and clinical presentation*

Clinical Presentation
Tumor TypePPSZPP+SZAsympTotal
parahypothalamic25 2 0330
intrahypothalamic016 (12)13 (8)231 (20)
total2518 (12)13 (8)561 (20)

Values in parentheses represent the number of patients with developmental delay. Abbreviation: asymp = asymptomatic.

One tumor was isolated from the hypothalamus.

Multiple regression analysis of the reported cases was performed to identify the factors that influenced the clinical presentation (Table 5). For seizures, the most significant factor was the topological type of lesion (intrahypothalamic, p < 0.0001), followed by the form of attachment (sessile, p = 0.0075). Size or the presence (or absence) of a peduncle was irrelevant to the prediction of seizures. For precocious puberty, the presence of a peduncle was the sole significant factor (p = 0.0001).

TABLE 5

Multiple regression analysis of factors suspected of influencing symptoms in hypothalamic hamartoma

Symptom & Factorp Value
seizure
 tumor size (<10, 10–20, or >20 mm)0.2744
 topological type (parahypothalamic or intrahypothalamic)<0.0001
 peduncle (present or absent)0.3603
 attachment (narrow or sessile)0.0075
precocious puberty
 tumor size (<10, 10–20, or >20 mm)0.5428
 topological type (parahypothalamic or intrahypothalamic)0.9504
 peduncle (present or absent)<0.0001
 attachment (narrow or sessile)0.2414

Discussion

The pathomechanism of the clinical manifestations of hypothalamic hamartoma is still unclear. Several investigators have found LH-RH—secreting cells in hypothalamic hamartomas of patients with precocious puberty.1,17,29,48 This abnormal gonadotropin-releasing hormone (GnRH) may activate gonadotrophs in the pituitary. An abnormal afferent neuronal network originating in hamartomas may stimulate activity in LH-RH cells in the hypothalamus.21,35,39,49,56,62 Some investigators have suggested that mechanical compression by the lesion impairs mechanisms that inhibit gonadotropin-secreting cells.2,5,44

Mechanical compression of the mammillary body and/or the development of pathological neuronal connections between the hypothalamus and the limbic system are considered by some investigators to be important for seizure mechanisms.59 Munari, et al.,42 reported that stereotactically guided electroencephalographic monitoring showed that gelastic seizures were strictly linked to ictal discharges that began in the hamartoma, and atonic seizures might be a demonstration of secondary epileptogenesis. Kuzniecky, et al.,34 reported that single photon emission computerized tomography scanning performed during typical gelastic seizures demonstrated hyperperfusion in hamartomas. These authors also detected focal seizure activities by means of an electrode stereotactically implanted in the lesion and elicited the gelastic seizures by stimulating the lesion through the electrode. Improvement of seizure control by surgical removal of the tumor,59 radiofrequency lesioning,34 or stereotactically targeted radiation therapy3 also corroborates the idea that abnormal epileptogenic neuronal activity in the lesion itself is a primary cause of seizures in these patients.

What causes the variety of symptomatology associated with hypothalamic hamartomas, that is, some patients exhibiting precocious puberty but not seizures and others exhibiting seizures but not precocious puberty?

Boyko, et al.,9 classified hamartomas into two types, pedunculated and sessile, based on their manner of attachment to the hypothalamus. They noted a higher incidence of seizures in children with sessile hamartomas. However, Mahachoklertwattana, et al.,38 denied this correlation, because their three sessiletype cases were associated with precocious puberty alone.38 However, in these authors' representative sessiletype case showing precocious puberty alone the tumor had a very narrow attachment, and it should have been categorized as the pedunculated type according to Boyko, et al. This confusion was caused by the vagueness of the criteria for distinguishing pedunculated from sessile tumors. The sessile label should be applied only to lesions that have a broad and unconstricted interface with the hypothalamus. When these criteria are used, the sessile type has a relatively good correlation with seizure episodes. Despite these restrictions, some patients with lesions of the sessile type, such as our Cases 5 and 6, Case 2 of Beningfield, et al.,7 and the case reported by Zucchini, et al.,63 did not experience seizures, because the lesions did not involve the hypothalamus or displace the third ventricle.

We therefore propose, for the MR imaging era, a new classification of hypothalamic hamartomas into parahypothalamic and intrahypothalamic types, which are well correlated with the clinical presentation and subsequent clinical course. The key point in this classification is whether hypothalamic displacement is clearly present as opposed to absent or minimal. Coronal and sagittal MR images easily display the topographical relationship between the lesion and the hypothalamus. Multiple regression analysis justifies our simplified classification of hypothalamic hamartomas based on the extent of hypothalamic involvement. Even if the lesions were very large, they did not cause seizures if they did not involve the hypothalamus, as in Case 4 of Lona-Soto, et al.,36 and our Case 6. The presence of a peduncle was also a strong influential factor for precocious puberty, but it is rare in hypothalamic hamartomas; it was found in only five of the 61 cases reported. Categorization according to the existence of a peduncle is thus not universally applicable to hypothalamic hamartomas.

Valdueza, et al.,59 classified hypothalamic hamartomas into two categories and four subtypes based on their localization, type of attachment, extent of hypothalamic displacement, and size. In their classification, Type I is a relatively small lesion attached to the tuber cinereum (Type Ia) or mammillary body (Type Ib) with a peduncle, usually presenting with precocious puberty. Type II is a relatively large lesion that displaces the hypothalamus slightly (Type IIa) or markedly (Type IIb) and is associated with gelastic and other types of seizure. The lesions classified as Type I by Valdueza, et al., seem to coincide roughly with our parahypothalamic type, and Type II with our intrahypothalamic type. However, two representative cases of Type I in the article published by Valdueza, et al., (Cases 4 and 6) did not have the peduncle that is described as being present in most lesions in this category. Even in one patient with Type I the tumor had a wide attachment to the hypothalamus. These cases would thus correspond with our parahypothalamic type, because they did not involve the hypothalamus and were not accompanied by seizures.

Our review and analysis of MR imaging findings and the clinical course of reported cases of hypothalamic hamartoma indicate that the major pathomechanism causing symptoms of hypothalamic hamartomas is as follows. The seizures may be caused by epileptogenic neuronal activity propagated in the lesion through ample neuronal networks that appear to exist only in the intrahypothalamic tumor type. Precocious puberty may be caused in these patients by excessive GnRH secreted by the lesion in either the intrahypothalamic or parahypothalamic type. Another plausible mechanism for precocious puberty is that abnormal discharges by the lesion excessively activate relatively well-maintained GnRH neurons, a situation that may be more common in the parahypothalamic type.

Because the parahypothalamic type of lesion is relatively safely accessible, precocious puberty unaccompanied by seizures can be well managed by surgical removal.1,2,17,48,51,55 Central precocious puberty is also well controlled by LH-RH analogs, which suppresses gonadotropin secretion.15 Mahachoklertwattana, et al.,38 found that nine patients with hypothalamic hamartomas showed excellent responses to LH-RH agents. The super long—acting LH-RH analog used in our cases released LH-RH continuously for 4 weeks.30,56 In a dose-finding study in 36 patients with central precocious puberty, subcutaneous injection of LH-RH at levels greater than 30 µg/kg every 4 weeks normalized serum basal and peak LH and follicle-stimulating hormone levels on an LH-RH stimulation test, and significantly suppressed urinary excretion of follicle-stimulating hormone and estradiol.56 Thus the clinical course of the parahypothalamic tumor type, which usually is accompanied by precocious puberty alone, can be expected to be amenable to treatment, with administration of an LH-RH analog as a first choice and surgery as an alternative.

Seizures caused by the intrahypothalamic type are usually medically intractable.8,18,19,41 Some attempts to control seizures surgically have been reported,37,43–47,52,54,56,59,60 and these occasionally result in substantial improvement. In some instances, however, the surrounding hypothalamic tissue interferes with safe surgical access to the lesion.46,47 Stereotactically targeted radiation therapy3 or radiofrequency lesioning34 may be alternative modalities. However, the lack of long-term follow up restricts the use of these modalities to truly intractable and surgically inaccessible lesions.

Conclusions

We classified hypothalamic hamartomas into two categories, parahypothalamic and intrahypothalamic types, based on the tumor topology in relation to the hypothalamus as demonstrated on MR imaging. This classification demonstrated a useful correlation with the clinical manifestations and outcome.

Acknowledgment

We thank Prof. Paul D. Andrew for his valuable advice and for reviewing the manuscript.

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  • 12.

    Chamouilli JMRazafimahefa BPierron H: Puberté précocissime et hamartome hypothalamique: traitement par triptoréline durant 8 ans. Arch Pediatr 2:4384411995Arch Pediatr 2:

  • 13.

    Cheng KSawamura YYamauchi Tet al: Asymptomatic large hypothalamic hamartoma associated with polydactyly in an adult. Neurosurgery 32:4584601993Neurosurgery 32:

  • 14.

    Chong BWNewton TH: Hypothalamic and pituitary pathology. Radiol Clin North Am 31:114711831993Radiol Clin North Am 31:

  • 15.

    Comite FPescovitz OHRieth KGet al: Luteinizing hormonereleasing hormone analog treatment of boys with hypothalamic hamartoma and true precocious puberty. J Clin Endocrinol Metab 59:8888921984J Clin Endocrinol Metab 59:

  • 16.

    Commentz JCHelmke K: Precocious puberty and decreased melatonin secretion due to a hypothalamic hamartoma. Horm Res 44:2712751995Horm Res 44:

  • 17.

    Culler FLJames HESimon MLet al: Identication of gonadotropin-releasing hormone in neurons of a hypothalamic hamartoma in a boy with precocious puberty. Neurosurgery 17:4084121985Neurosurgery 17:

  • 18.

    Curatolo PCusmai R: Gelastic seizures, precocious puberty, and hypothalamic hamartomas. Neurology 36:4434441986Neurology 36:

  • 19.

    Curatolo PCusmai RFinocchi Get al: Gelastic epilepsy and true precocious puberty due to hypothalamic hamartomas. Dev Med Child Neurol 26:5095271984Dev Med Child Neurol 26:

  • 20.

    Diaz LLGrech KFPrados MD: Hypothalamic hamartoma associated with Laurence-Moon-Biedl syndrome. Case report and review of the literature. Pediatr Neurosurg 17:30331991Pediatr Neurosurg 17:

  • 21.

    Driggs MSpatz H: Pubertas praecox bei einer hyperplastischen Missbildung des Tuber cinereum. Virchows Arch Pathol Anat 305:5675921939Virchows Arch Pathol Anat 305:

  • 22.

    Guibaud LRode VSaint-Pierre Get al: Giant hypothalamic hamartoma: an unusual neonatal tumor. Pediatr Radiol 25:17181995Pediatr Radiol 25:

  • 23.

    Hahn FJLeibrock LGHuseman CAet al: The MR appearance of hypothalamic hamartoma. Neuroradiology 30:65681988Neuroradiology 30:

  • 24.

    Hamilton RL: Case of the month. July 1996—precocious puberty. Brain Pathol 7:7117121997Hamilton RL: Case of the month. July 1996—precocious puberty. Brain Pathol 7:

  • 25.

    Harada KYoshida JWakabayashi Tet al: A super long-acting LH-RH analogue induces regression of hypothalamic hamartoma associated with precocious puberty. Acta Neurochir 137:1021051995Acta Neurochir 137:

  • 26.

    Hsiao PHTsai WYLee JSet al: Hypothalamic hamartoma and precocious puberty: report of a case. J Formos Med Assoc 91:101710201992J Formos Med Assoc 91:

  • 27.

    Hubbard AMEgelhoff JC: MR imaging of large hypothalamic hamartomas in two infants. AJNR 10:12771989AJNR 10:

  • 28.

    Isaka TNakatani SYoshimine Tet al: Asymptomatic hypothalamic hamartoma associated with an arachnoid cyst—case report. Neurol Med Chir 36:7257281996Neurol Med Chir 36:

  • 29.

    Judge DMKulin HEPage Ret al: Hypothalamic hamartoma: a source of luteinizing-hormone-releasing factor in precocious puberty. N Engl J Med 296:7101977N Engl J Med 296:

  • 30.

    Kappy MStuart TPerelman Aet al: Suppression of gonadotropin secretion by a long-acting gonadotropin-releasing hormone analog (leuprolide acetate, Lupron Depot) in children with precocious puberty. J Clin Endocrinol Metab 69:108710891989J Clin Endocrinol Metab 69:

  • 31.

    Katayama HMiyao MKobayashi Set al: [A case of hypothalamic hamartoma with gelastic seizures, precocious puberty, poly- and syndactyly.] No To Hattatsu 25:3413461993 (Jpn)No To Hattatsu 25:

  • 32.

    Koelfen WWentz J: Pubertas praecox und Lachanfälle. Monatsschr Kinderheilkd 139:4794811991Monatsschr Kinderheilkd 139:

  • 33.

    Kujat CMoringlane JRLöw Met al: Familiäre Assoziation von Hypothalamushamartom und Polysyndaktylie. Radiologe 34:6626651994Radiologe 34:

  • 34.

    Kuzniecky RGuthrie BMountz Jet al: Intrinsic epileptogenesis of hypothalamic hamartomas in gelastic epilepsy. Ann Neurol 42:60671997Ann Neurol 42:

  • 35.

    List CFDowman CEBagchi BKet al: Posterior hypothalamic hamartomas and gangliogliomas causing precocious puberty. Neurology 8:1641741958Neurology 8:

  • 36.

    Lona-Soto ATakahashi MYamashita Yet al: MRI findings of hypothalamic hamartoma: report of five cases and review of the literature. Comput Med Imaging Graph 15:4154211991Comput Med Imaging Graph 15:

  • 37.

    Machado HRHoffman HJHwang PA: Gelastic seizures treated by resection of a hypothalamic hamartoma. Childs Nerv Syst 7:4624651991Childs Nerv Syst 7:

  • 38.

    Mahachoklertwattana PKaplan SLGrumbach MM: The luteinizing hormone-releasing hormone-secreting hypothalamic hamartoma is a congenital malformation: natural history. J Clin Endocrinol Metab 77:1181241993J Clin Endocrinol Metab 77:

  • 39.

    Marcuse PMBurger RASalmon GW: Hamartoma of the hypothalamus. Report of two cases with associated developmental defects. J Pediatr 43:3013071953J Pediatr 43:

  • 40.

    Marliani AFTampieri DMelançon Det al: Magnetic resonance imaging of hypothalamic hamartomas causing gelastic epilepsy. Can Assoc Radiol J 42:3353391991Can Assoc Radiol J 42:

  • 41.

    Matustik MCEisenberg HMMeyer WJ III: Gelastic (laughing) seizures and precocious puberty. Am J Dis Child 135:8378381981Am J Dis Child 135:

  • 42.

    Munari CKahane PFrancione Set al: Role of the hypothalamic hamartoma in the genesis of gelastic fits (a video-stereo-EEG study). Electroencephalogr Clin Neurophysiol 95:1541601995Electroencephalogr Clin Neurophysiol 95:

  • 43.

    Nishio SFujiwara SAiko Yet al: Hypothalamic hamartoma. Report of two cases. J Neurosurg 70:6406451989J Neurosurg 70:

  • 44.

    Northfield DWCRussell DS: Pubertas praecox due to hypothalamic hamartoma: report of two cases surviving surgical removal of the tumour. J Neurol Neurosurg Psychiatry 30:1661731967J Neurol Neurosurg Psychiatry 30:

  • 45.

    Paillas JERoger JToga Met al: Hamartome de l'hypothalamus. Etude clinique, radiologique, histologique. Resultats de l'exérèse. Rev Neurol (Paris) 120:1771941969Rev Neurol (Paris) 120:

  • 46.

    Pendl G: Gelastic epilepsy in tumours of the hypothalamic region. Adv Neurosurg 3:4424491975Pendl G: Gelastic epilepsy in tumours of the hypothalamic region. Adv Neurosurg 3:

  • 47.

    Ponsot GDiebler CPlouin Pet al: Hamartomes hypothalamiques et crises de rire. A propos de 7 observations. Arch Fr Pediatr 40:7577611983Arch Fr Pediatr 40:

  • 48.

    Price RALee PAAlbright ALet al: Treatment of sexual precocity by removal of a luteinizing hormone-releasing hormone secreting hamartoma. JAMA 251:224722491984JAMA 251:

  • 49.

    Richter RB: True hamartoma of hypothalamus associated with pubertas praecox. J Neuropathol Exp Neurol 10:3683831951Richter RB: True hamartoma of hypothalamus associated with pubertas praecox. J Neuropathol Exp Neurol 10:

  • 50.

    Robben SGTanghe HLDrop SL: Hypothalamic hamartoma. J Belge Radiol 77:2211994J Belge Radiol 77:

  • 51.

    Romner BTrumpy JHMarhaug Get al: Hypothalamic hamartoma causing precocious puberty treated by surgery: case report. Surg Neurol 41:3063091994Surg Neurol 41:

  • 52.

    Sato MUshio YArita Net al: Hypothalamic hamartoma: report of two cases. Neurosurgery 16:1982061985Neurosurgery 16:

  • 53.

    Schmidt EHallervorden JSpatz H: Die Entstehung der Hamartome am Hypothalamus mit und ohne Pubertas Praecox. Dtsch Z Nervenheilk 177:2352621958Dtsch Z Nervenheilk 177:

  • 54.

    Sher PKBrown SB: Gelastic epilepsy, onset in neonatal period. Am J Dis Child 130:112611311976Am J Dis Child 130:

  • 55.

    Starceski PJLee PAAlbright ALet al: Hypothalamic hamartomas and sexual precocity. Evaluation of treatment options. Am J Dis Child 144:2252281990Am J Dis Child 144:

  • 56.

    Takeuchi JHanda H: Pubertas praecox and hypothalamic hamartoma. Neurosurg Rev 8:2252311985Neurosurg Rev 8:

  • 57.

    Tanaka THibi IKato Ket al: A dose finding study of a super long-acting luteinizing hormone-releasing hormone analog (leuprolide acetate depot, TAP-144-SR) in the treatment of central precocious puberty. The TAP-144-SR CPP Study Group. Endocrinol Jpn 38:3693761991Endocrinol Jpn 38:

  • 58.

    Turjman FXavier JLFroment JCet al: Late MR follow-up of hypothalamic hamartomas. Childs Nerv Syst 12:63681996Childs Nerv Syst 12:

  • 59.

    Valdueza JMCristante LDammann Oet al: Hypothalamic hamartomas: with special reference to gelastic epilepsy and surgery. Neurosurgery 34:9499581994Neurosurgery 34:

  • 60.

    Watanabe TEnomoto TUemura Ket al: [Gelastic seizure treated by partial resection of a hypothalamic hamartoma.] No Shinkei Geka 26:9239281998 (Jpn)No Shinkei Geka 26:

  • 61.

    Wentz KUKölfen WSuchalla R: Pubertas praecox und gelastische Epilepsie bei einem Hamartom des Tuber cinereum. ROFO Fortschr Reb Roentgenstr Neuen Bildgeb Verfahr 158:2802821993ROFO Fortschr Reb Roentgenstr Neuen Bildgeb Verfahr 158:

  • 62.

    Wolman LBalmforth GV: Precocious puberty due to hypothalamic hamartoma in a patient surviving to late middle age. J Neurol Neurosurg Psychiatry 26:2752801963J Neurol Neurosurg Psychiatry 26:

  • 63.

    Zucchini Sdi Natale BAmbrosetto Pet al: Role of magnetic resonance imaging in hypothalamic-pituitary disorders. Horm Res 44 (Suppl 3):8141995Horm Res 44 (Suppl 3):

Article Information

Address reprint requests to: Kazunori Arita, M.D., Ph.D., Department of Neurosurgery, Hiroshima University School of Medicine, 1–2–3, Kasumi, Minami-ku, Hiroshima 734–855, Japan. email:karita@mcai.med.hiroshima-u.ac.jp.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Case 2. Coronal (upper) and sagittal (lower) MR images revealing a parahypothalamic-type hypothalamic hamartoma in a 13-year-old girl with precocious puberty. The lesion is suspended from the mammillary body by a peduncle (arrow).

  • View in gallery

    Case 3. Coronal (upper) and sagittal (lower) MR images revealing a parahypothalamic-type hypothalamic hamartoma in a 3-year-old girl with precocious puberty. The lesion is attached to the base of the hypothalamus at a narrow interface (arrow), but there is no peduncle.

  • View in gallery

    Case 7. Coronal (upper) and sagittal (lower) MR images revealing a parahypothalamic-type hypothalamic hamartoma in a 10-year-old boy with precocious puberty. This lesion, which was attached to the base of the hypothalamus with a wide interface (arrows), can be called “sessile.” Involvement of the hypothalamus is minimal.

  • View in gallery

    Case 11. Coronal (upper) and sagittal (lower) MR images revealing an intrahypothalamic-type large hypothalamic hamartoma in a 2-year-old boy who suffered gelastic and tonic seizures. The lesion extensively involved the hypothalamus. The third ventricle is remarkably distorted (arrows).

  • View in gallery

    Case 10. Coronal (upper left), sagittal (upper right), and axial (lower left) images revealing a small intrahypothalamic-type hypothalamic hamartoma (arrows) in a 25-year-old man who suffered gelastic and tonic—clonic seizures. The lesion is completely enveloped by hypothalamic tissue. Lower Right: Axial MR image obtained at 12 months after stereotactically targeted radiation treatment, revealing complete disappearance of the lesion.

References

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Albright ALLee PA: Neurosurgical treatment of hypothalamic hamartomas causing precocious puberty. J Neurosurg 78:77821993J Neurosurg 78:

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Alvarez-Garijo JAAlbiach VJVila MMet al: Precocious puberty and hypothalamic hamartoma with total recovery after surgical treatment. Case report. J Neurosurg 58:5835851983J Neurosurg 58:

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Arita KKurisu KIida Ket al: Subsidence of seizure induced by stereotactic radiation in a patient with hypothalamic hamartoma. Case report. J Neurosurg 89:6456481998J Neurosurg 89:

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Berkovic SFAndermann FMelanson Det al: Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging. Ann Neurol 23:4294391988Ann Neurol 23:

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Boyko OBCurnes JTOakes WJet al: Hamartomas of the tuber cinereum: CT, MR, and pathologic findings. AJNR 12:3093141991AJNR 12:

10.

Burton EMBall WS JrCrone Ket al: Hamartoma of the tuber cinereum: a comparison of MR and CT findings in four cases. AJNR 10:4975011989AJNR 10:

11.

Cascino GDAndermann FBerkovic SFet al: Gelastic seizures and hypothalamic hamartomas: evaluation of patients undergoing chronic intracranial EEG monitoring and outcome of surgical treatment. Neurology 43:7477501993Neurology 43:

12.

Chamouilli JMRazafimahefa BPierron H: Puberté précocissime et hamartome hypothalamique: traitement par triptoréline durant 8 ans. Arch Pediatr 2:4384411995Arch Pediatr 2:

13.

Cheng KSawamura YYamauchi Tet al: Asymptomatic large hypothalamic hamartoma associated with polydactyly in an adult. Neurosurgery 32:4584601993Neurosurgery 32:

14.

Chong BWNewton TH: Hypothalamic and pituitary pathology. Radiol Clin North Am 31:114711831993Radiol Clin North Am 31:

15.

Comite FPescovitz OHRieth KGet al: Luteinizing hormonereleasing hormone analog treatment of boys with hypothalamic hamartoma and true precocious puberty. J Clin Endocrinol Metab 59:8888921984J Clin Endocrinol Metab 59:

16.

Commentz JCHelmke K: Precocious puberty and decreased melatonin secretion due to a hypothalamic hamartoma. Horm Res 44:2712751995Horm Res 44:

17.

Culler FLJames HESimon MLet al: Identication of gonadotropin-releasing hormone in neurons of a hypothalamic hamartoma in a boy with precocious puberty. Neurosurgery 17:4084121985Neurosurgery 17:

18.

Curatolo PCusmai R: Gelastic seizures, precocious puberty, and hypothalamic hamartomas. Neurology 36:4434441986Neurology 36:

19.

Curatolo PCusmai RFinocchi Get al: Gelastic epilepsy and true precocious puberty due to hypothalamic hamartomas. Dev Med Child Neurol 26:5095271984Dev Med Child Neurol 26:

20.

Diaz LLGrech KFPrados MD: Hypothalamic hamartoma associated with Laurence-Moon-Biedl syndrome. Case report and review of the literature. Pediatr Neurosurg 17:30331991Pediatr Neurosurg 17:

21.

Driggs MSpatz H: Pubertas praecox bei einer hyperplastischen Missbildung des Tuber cinereum. Virchows Arch Pathol Anat 305:5675921939Virchows Arch Pathol Anat 305:

22.

Guibaud LRode VSaint-Pierre Get al: Giant hypothalamic hamartoma: an unusual neonatal tumor. Pediatr Radiol 25:17181995Pediatr Radiol 25:

23.

Hahn FJLeibrock LGHuseman CAet al: The MR appearance of hypothalamic hamartoma. Neuroradiology 30:65681988Neuroradiology 30:

24.

Hamilton RL: Case of the month. July 1996—precocious puberty. Brain Pathol 7:7117121997Hamilton RL: Case of the month. July 1996—precocious puberty. Brain Pathol 7:

25.

Harada KYoshida JWakabayashi Tet al: A super long-acting LH-RH analogue induces regression of hypothalamic hamartoma associated with precocious puberty. Acta Neurochir 137:1021051995Acta Neurochir 137:

26.

Hsiao PHTsai WYLee JSet al: Hypothalamic hamartoma and precocious puberty: report of a case. J Formos Med Assoc 91:101710201992J Formos Med Assoc 91:

27.

Hubbard AMEgelhoff JC: MR imaging of large hypothalamic hamartomas in two infants. AJNR 10:12771989AJNR 10:

28.

Isaka TNakatani SYoshimine Tet al: Asymptomatic hypothalamic hamartoma associated with an arachnoid cyst—case report. Neurol Med Chir 36:7257281996Neurol Med Chir 36:

29.

Judge DMKulin HEPage Ret al: Hypothalamic hamartoma: a source of luteinizing-hormone-releasing factor in precocious puberty. N Engl J Med 296:7101977N Engl J Med 296:

30.

Kappy MStuart TPerelman Aet al: Suppression of gonadotropin secretion by a long-acting gonadotropin-releasing hormone analog (leuprolide acetate, Lupron Depot) in children with precocious puberty. J Clin Endocrinol Metab 69:108710891989J Clin Endocrinol Metab 69:

31.

Katayama HMiyao MKobayashi Set al: [A case of hypothalamic hamartoma with gelastic seizures, precocious puberty, poly- and syndactyly.] No To Hattatsu 25:3413461993 (Jpn)No To Hattatsu 25:

32.

Koelfen WWentz J: Pubertas praecox und Lachanfälle. Monatsschr Kinderheilkd 139:4794811991Monatsschr Kinderheilkd 139:

33.

Kujat CMoringlane JRLöw Met al: Familiäre Assoziation von Hypothalamushamartom und Polysyndaktylie. Radiologe 34:6626651994Radiologe 34:

34.

Kuzniecky RGuthrie BMountz Jet al: Intrinsic epileptogenesis of hypothalamic hamartomas in gelastic epilepsy. Ann Neurol 42:60671997Ann Neurol 42:

35.

List CFDowman CEBagchi BKet al: Posterior hypothalamic hamartomas and gangliogliomas causing precocious puberty. Neurology 8:1641741958Neurology 8:

36.

Lona-Soto ATakahashi MYamashita Yet al: MRI findings of hypothalamic hamartoma: report of five cases and review of the literature. Comput Med Imaging Graph 15:4154211991Comput Med Imaging Graph 15:

37.

Machado HRHoffman HJHwang PA: Gelastic seizures treated by resection of a hypothalamic hamartoma. Childs Nerv Syst 7:4624651991Childs Nerv Syst 7:

38.

Mahachoklertwattana PKaplan SLGrumbach MM: The luteinizing hormone-releasing hormone-secreting hypothalamic hamartoma is a congenital malformation: natural history. J Clin Endocrinol Metab 77:1181241993J Clin Endocrinol Metab 77:

39.

Marcuse PMBurger RASalmon GW: Hamartoma of the hypothalamus. Report of two cases with associated developmental defects. J Pediatr 43:3013071953J Pediatr 43:

40.

Marliani AFTampieri DMelançon Det al: Magnetic resonance imaging of hypothalamic hamartomas causing gelastic epilepsy. Can Assoc Radiol J 42:3353391991Can Assoc Radiol J 42:

41.

Matustik MCEisenberg HMMeyer WJ III: Gelastic (laughing) seizures and precocious puberty. Am J Dis Child 135:8378381981Am J Dis Child 135:

42.

Munari CKahane PFrancione Set al: Role of the hypothalamic hamartoma in the genesis of gelastic fits (a video-stereo-EEG study). Electroencephalogr Clin Neurophysiol 95:1541601995Electroencephalogr Clin Neurophysiol 95:

43.

Nishio SFujiwara SAiko Yet al: Hypothalamic hamartoma. Report of two cases. J Neurosurg 70:6406451989J Neurosurg 70:

44.

Northfield DWCRussell DS: Pubertas praecox due to hypothalamic hamartoma: report of two cases surviving surgical removal of the tumour. J Neurol Neurosurg Psychiatry 30:1661731967J Neurol Neurosurg Psychiatry 30:

45.

Paillas JERoger JToga Met al: Hamartome de l'hypothalamus. Etude clinique, radiologique, histologique. Resultats de l'exérèse. Rev Neurol (Paris) 120:1771941969Rev Neurol (Paris) 120:

46.

Pendl G: Gelastic epilepsy in tumours of the hypothalamic region. Adv Neurosurg 3:4424491975Pendl G: Gelastic epilepsy in tumours of the hypothalamic region. Adv Neurosurg 3:

47.

Ponsot GDiebler CPlouin Pet al: Hamartomes hypothalamiques et crises de rire. A propos de 7 observations. Arch Fr Pediatr 40:7577611983Arch Fr Pediatr 40:

48.

Price RALee PAAlbright ALet al: Treatment of sexual precocity by removal of a luteinizing hormone-releasing hormone secreting hamartoma. JAMA 251:224722491984JAMA 251:

49.

Richter RB: True hamartoma of hypothalamus associated with pubertas praecox. J Neuropathol Exp Neurol 10:3683831951Richter RB: True hamartoma of hypothalamus associated with pubertas praecox. J Neuropathol Exp Neurol 10:

50.

Robben SGTanghe HLDrop SL: Hypothalamic hamartoma. J Belge Radiol 77:2211994J Belge Radiol 77:

51.

Romner BTrumpy JHMarhaug Get al: Hypothalamic hamartoma causing precocious puberty treated by surgery: case report. Surg Neurol 41:3063091994Surg Neurol 41:

52.

Sato MUshio YArita Net al: Hypothalamic hamartoma: report of two cases. Neurosurgery 16:1982061985Neurosurgery 16:

53.

Schmidt EHallervorden JSpatz H: Die Entstehung der Hamartome am Hypothalamus mit und ohne Pubertas Praecox. Dtsch Z Nervenheilk 177:2352621958Dtsch Z Nervenheilk 177:

54.

Sher PKBrown SB: Gelastic epilepsy, onset in neonatal period. Am J Dis Child 130:112611311976Am J Dis Child 130:

55.

Starceski PJLee PAAlbright ALet al: Hypothalamic hamartomas and sexual precocity. Evaluation of treatment options. Am J Dis Child 144:2252281990Am J Dis Child 144:

56.

Takeuchi JHanda H: Pubertas praecox and hypothalamic hamartoma. Neurosurg Rev 8:2252311985Neurosurg Rev 8:

57.

Tanaka THibi IKato Ket al: A dose finding study of a super long-acting luteinizing hormone-releasing hormone analog (leuprolide acetate depot, TAP-144-SR) in the treatment of central precocious puberty. The TAP-144-SR CPP Study Group. Endocrinol Jpn 38:3693761991Endocrinol Jpn 38:

58.

Turjman FXavier JLFroment JCet al: Late MR follow-up of hypothalamic hamartomas. Childs Nerv Syst 12:63681996Childs Nerv Syst 12:

59.

Valdueza JMCristante LDammann Oet al: Hypothalamic hamartomas: with special reference to gelastic epilepsy and surgery. Neurosurgery 34:9499581994Neurosurgery 34:

60.

Watanabe TEnomoto TUemura Ket al: [Gelastic seizure treated by partial resection of a hypothalamic hamartoma.] No Shinkei Geka 26:9239281998 (Jpn)No Shinkei Geka 26:

61.

Wentz KUKölfen WSuchalla R: Pubertas praecox und gelastische Epilepsie bei einem Hamartom des Tuber cinereum. ROFO Fortschr Reb Roentgenstr Neuen Bildgeb Verfahr 158:2802821993ROFO Fortschr Reb Roentgenstr Neuen Bildgeb Verfahr 158:

62.

Wolman LBalmforth GV: Precocious puberty due to hypothalamic hamartoma in a patient surviving to late middle age. J Neurol Neurosurg Psychiatry 26:2752801963J Neurol Neurosurg Psychiatry 26:

63.

Zucchini Sdi Natale BAmbrosetto Pet al: Role of magnetic resonance imaging in hypothalamic-pituitary disorders. Horm Res 44 (Suppl 3):8141995Horm Res 44 (Suppl 3):

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