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Hamartoma of the hypothalamus and tuber cinereum : a brief review of the literature.
The word 'hamartoma' is derived from the Greek word 'hamartion' which means bodily defect. A hamartoma is a focal malformation that resembles a neoplasm but does not show any particular tendency to a neoplastic evolution.[8] It results from faulty development in an organ and is composed of an abnormal mixture of its constituent elements. It develops and grows at virtually the same rate as do the normal components of the organ of its origin. It does not compress adjacent tissues. Hamartoma of the hypothalamus and tuber cinereum represents a midline dysraphic syndrome and presents as an ectopic cerebral grey matter,[19] comprising a mass of normal neuronal tissue,[7],[60] or redundant brain tissue.[19],[24] Microscopically, its gang-lion cells resemble those of hypothalamus and tuber cinereum but are arranged in a somewhat haphazard fashion surrounded by normal glial cells.[7] The neurones may vary in size.[34],[53],[73] Exclusively glial forms of hamartoma have also been described.[49] In no cases have abnormal cells been demonstrated.[1] The neurones contain membrane- bound granules similar in size and character to those described in the hypothalamus and median eminence.[5] Many of the vessels within the hamartoma have characteristics of the median eminence and of neural tissue with an absent blood brain barrier.[30] Their fenestrated vessels permit transport of neurosecretory products directly into the blood stream and direct neuronal connection between hamartoma and brain[53] becomes unnecessary. Access to the pituitary portal system is provided by vessels of the tuber cinereum.[34] The cytoarchitectural normalcy of its individual cells is retained. The composition of the hamartoma resembles that of cerebral grey matter both quantitatively and qualitatively.[63]
Most of these lesions are small with a diameter of a few millimeters to 1.5 cm.[34] Rarely, they may reach a size of 3 to 3.5 cm.[28],[29],[33],[46],[53] They lie in the vicinity of the tuber cinereum and posterior hypothalamus in the subarachnoid space between the optic chiasm and pons, usually in the interpeduncular cistern,[10],[19],[42],[80] and resemble the collar button.[42] They do not distort adjacent tissues. Commonly, they are pedunculated and attached to the ventral surface of the hypothalamus anywhere from the tuber cinereum to mamillary bodies by a distinct, thin or thick, stalk.[10],[19],[22],[42],[43],[60],[68],[70],[78], [80] Occasionally, the hamartoma may have a wide attachment to the ventral surface of the hypothalamus,[42] or lie embedded within the substance of the hypothalamus or may lie free in the inter-peduncular cistern.[53] The location of hamartoma of the hypothalamus and tuber cinereum corresponds to the area where the ventral face of the neuraxis comes close to the anterior tip of the notochord at about the end of the first gestational month.6 At this time, the ventral face of the neuraxis, situated behind the oral hypophysis, undergoes two movements: (i) evagination of infundibulum anterior to the tip of the notochord, and (ii) folding behind the tip of the notochord with the formation of mamillary recess displacing the ventral face of the neuraxis posteriorly.[19] It has been postulated[19] that hamartomas are formed during these displacements: cell tracts interdependent of the notochord are detached from the mamillary region and move posteriorly. The associated cerebral malformations such as a defect in corpus callosum, malformed optic apparatus, as reported in the literature,[19],[39],[65] originate at the same embryonic age. Hamartoma of the hypothalamus and tuber cinereum may be regarded as a midline dysraphism like callosal defects, prosencephaly or septal dysplasia, and they may be associated with various other malformations of cerebral hemisphere.[39],[43],[46],[54],[65]
Hamartoma of the hypothalamus and tuber cinereum is a relatively rare, cerebral malformation and not more than 80 cases have been reported in the literature. Only 46 cases were reported in the literature till June 1978[42] and approximately 70 cases till 1983.[19] New information from computed tomography indicate that this tumour has been underdiagnosed in patients with precocious puberty. According to Diebler and Ponsot,[19] its frequency is equal to that of aneurysms of the vein of Galen and of adrenolukodystrophy. No familial incidence has been reported. Incidence of hamartoma is equal in both sexes. The disease manifests in early life, commonly in the first two years[24] and occasionally immediately after birth.[43],[60] In one series of 18 cases,[19] there was an equal number of boys and girls, 17 of these 18 cases presented before the age of 6 years, 16 before 2 years and 6 before 6 months. In one case, the seizure appeared in the neonatal period.
The characteristic presenting clinical features, [11],[12],[13],[14],[19],[23],[24],[26],[28],[29],[31],[36],[39],[42],[43],[44],[47],[49],[64],[66],[70],[71],[72],[74] both endocrinological and neurological, are as follows: (1) iso-sexual precocious puberty of central origin (this is the commonest presentation), (2) seizure disorders, gelastic epilepsy and partial complex seizures; (3) mental changes, intellectual and behavioural disorders. These clinical features are noted commonly in early life and may occur as early as in the neonatal period. In 1983, Diebler and Ponsot[19] reviewed the literature (52 published observations) and reported personal experience of 18 cases. Amongst their 18 cases, true iso-sexual precocious puberty was the most frequent clinical sign, and was observed in 14 cases. Four of these 14 cases, in addition, had neurological signs as well. Another 4 of the total 18 cases presented with neurological deficits only. In these 8 patients with neurological signs, all suffered seizures in addition. In 7 cases, gelastic epilepsy was noted and in one, partial complex seizure. Permanent neurological deficits were observed in only 2 cases-one had hemiparesis and the other congenital nystagmus with partial unilateral third nerve paresis. In some cases diencephalic symptoms have been reported.[42] Lin et al[42] reported an interesting patient who had persistent hyponatremia, seizures and growth failure rather than precocity and the hamartoma was found within the substance of the hypothalamus at autopsy. Absence of any specific neurological and endocrinological signs has been reported only in three cases in the literature.[46],[65] Gross et al[27] reported a case of carcinoma of breast in a young woman with a hamartoma found at autopsy. Similarly, Bedwell and Lindenbarg[4] reported a young patient who died after head injury in whom a hamartoma, 1 cm in diameter, was detected at autopsy. Most patients with such a hamartoma die by the early half of the second decade.[41]
Till June 1978, 41 of the reported 46 cases had presented with true precocious puberty.[42] True isosexual precocious puberty is twice as common in females as in males but the idiopathic variety is common in the former and is secondary to mass lesions in the latter.[15],[35] As many as 20-40% of male patients harbour mass lesions. The diagnosis of precocious puberty is considered only if it manifests before the age of 8 years in females and 10 years in males. Isosexual true precocious puberty of central origin due to hamartoma indicates abnormal early activation of hypothalmic-pituitary-gonadal axis[35],[37],[42] due to early elaboration of gonadotropin. It is associated with increased growth rate, advanced bone age and development of appropriate iso-sexual, secondary sexual characteristics[35],[42] i.e. growth of pubic hairs, acne, enlargement of penis and testis in male, development of breasts in females, and changes in voice. As a result, androgen secretion and spermatogenesis occur in boys and estrogen secretion and cystic ovarian activity are prompted in girls.[34],[35] Spermatogenesis and cyclic ovarian activity are absent in pseudo-precocious puberty caused by adrenal or gonadal lesions.[34],[35],[42] Mass lesions involving posterior hypothalamus i.e. craniopharyngioma, hypothalamic tumors (glioma, ganglioglioma, germinoma, etc.), ectopic pineal tumors, parasellar arachnoid cyst, may cause precocious puberty but the hypothalamic hamartoma is the most frequent cause.[19],[32],[33],[35],[52],[53],[63],[67],[75],[76] These mass lesions progressively destroy the posterior hypothalamus and eliminate its suppressive control on pituitary gonadotropin secretion by elaboration of LH-RH from median eminence in pre-pubertal age.[34],[35],[53] The pathogenesis of the true isosexual precocious puberty of central origin due to hamartoma is still uncertain. Postulated mechanisms are: 1. Mechanical action: Theoretically, mild pressure/compression may cause stimulation of posterior hypothalamus,[30],[53] and impede the physiological inhibition of gonadotropin production,[69] thus resulting in growth failure. But a similar mechanism acting on the median eminence (site of LHRH production) would, in turn, stimulate pituitary gonadotropin production.[69] Some investigators,[1],[14],[18],[22],[42],[49],[54] believe that these lesions in some manner suppress the function of a posterior hypothalamic centre whose role is that of inhibiting the release of gonadotropin releasing factors (LH-RH) from the median eminence. With removal of this inhibitory function, gonadotropin releasing factors would be elaborated by the median eminence and transported via the hypothalamic-pituitary portal system to the pituitary. At the pituitary, these factors would, in turn, stimulate the gonadotrophs, and release gonadotropin and thus initiate pubescent changes. 2. Neuronal inter-connections: Recent histological studies have suggested that neurons within the hamartoma may stimulate the median eminence by direct neural transmittance.[41],[53],[60] 3. Independent neuroendocrine unit: Some investigators,[34],[38],[45],[72],[80] have demonstrated that hypothalamic hamartoma acted as an independently functioning neuro endocrine unit. The features in support of this are as follows: (i) Though releasing hormones are so far reported to be present widely in the brain, the amount of LH-RH in the hamartoma as estimated by immunofluorescence is much greater than in the central brain tissue.[34],[69] (ii) Immunofluorescent studies using specific antibody to LH-RH showed antigenicity to the factor in the hamartoma.[77] (iii) Bierich,[7] detected unusually high levels of LH-RH in the CSF of 3 patients, (iv) Judge et al,[34] reported a prompt decline in serum testosterone in their patient on medroxy-progesterone therapy but levels of F.S.H. and L.H. remained elevated. They concluded that the resistance of gonadotropin suppression by medroxy-progesterone acetate suggested secretory autonomy by the hamartoma. (v) Abnormal response to LH-RH stimulation. Kammer et al[35] reported a 15 month old boy with hamartoma who exhibited a pubertal response of pituitary gonadotropin secretion to a 50 µg LH-RH stimulation. They commented that the normal juvenile pituitary does not have the capacity to respond with more than a fourfold rise to an initial infusion of LH-RH. When the gland has been previously exposed to autogenous LH-RH secretion, as in true precocious puberty, then a pubertal type response is obtained. Kyuma et al[38] reported higher basal levels of LH, FSH and testosterone as well as abnormal response to LH-RH stimulation in their patient pre-operatively while post- operatively, the LH, FSH and testosterone levels returned to normal and no abnormal response to LH-RH was elicited. Curatolo et al[17] also reported elevated plasma testosterone levels and abnormal LH-RH stimulation in their case. Absence of precocious puberty in cases of hamartoma of the hypothalamus and tuber cinereum is attributed to the young age at death, or pressure atrophy of hypothalamus (medial eminence),[49] or a lack of neuronal connection between hamartoma and brain.[4],[10],[22],[60] However precocious puberty has been described in one case where careful examination failed to reveal any connection between the hamartoma and brain.[53]
It has been postulated that the convulsions and mental changes in cases of hamartoma of the hypothalamus and tuber cinereum are of focal hypothalamic origin.[43] Mental changes consists of behavioural disorders, abnormal affective responses and intellectual deterioration.[19],[43] The convulsive disorders occur early in life and may even begin shortly after birth. Both petitmal and subcortical tonic seizures with occasional signs of lateralization can occur,[43] but gelastic epilepsy is a typical presentation of hamartoma.
Nineteen cases of gelastic epilepsy[2],[7],[16],[19],[21],[43],[48],[51],[55],[79] have been reported in the literature in association with hypothalamic hamartoma. Other lesions[20],[25],[62] extending upto the floor of the third ventricle i.e. gliomas, meningioma, hypophyseal tumours, suprasellar tumours, basilar artery aneurysms, may also cause gelastic epilepsy, but the frequency of gelastic epilepsy is extremely low with other mass lesions as compared to that with hamartoma.[19] Peroperative stimulation of the floor of the third ventricle has been shown to initiate spasmodic laughter.[62] In a typical attack, the child stops his activity and makes several bubbling, laughing noises followed by unilateral or bilateral clonic movements of the buccal, palpebral and ocular muscles producing a grimacing appearance for a short duration. These episodes are rarely followed by generalized seizure.[19] In two cases, the type of seizure was so characteristic that diagnosis of hemartoma was advanced before the neuroradiological examination.[19] The frequency of such fits is as high as 20-30/day. In general, laughter is a complex phenomenon which involves several neuronal structures and gelastic seizures may occur with both hypothalamic and fronto-temporal lesions. The relationship of gelastic epilepsy with a hypothalamic hamartoma has not been clearly defined. Such lesions can cause excitation of the medio-basal temporal structures by way of the limbic system.[57] Various hypotheses have been put forward to explain its pathophysiology: (i) Mechanical action Gelastic epilepsy is common with large tumours; and compression of mamillary region by these may initiate specific seizures.[19] The argument against this hypothesis is the extreme rarity of gelastic epilepsy in other mass lesions of the mamillary region and in at least two patients with small hypothalamic hamartomas, gelastic epilepsy was recorded.[19],[48],[72] (ii) Neural interconnections[19],[54],[65] Interconnections of the neurones of large hamartoma and limbic system could easily explain the seizures, especially when one considers the epileptic potential of small cerebral heterotopias. (iii) Associated cerebral malformations[19],[35],[39] These may be responsible for the seizures and mental changes. (iv) Electrophysiological support Electro-encephalography supports the classification of this disorder as epilepsy.[25] Interictal electro-encephalographies show localized abnormalities, predominantly in the temporal or fronto-temporal areas. During drowsiness or sleeping, bilateral generalized spike and wave activity have been recorded in the majority of cases. Ictal electro-encephalography findings include discharges originating in the frontal[43] or fronto-temporal[21] regions or bilateral synchronous generalized slow waves.[48]
Although the attacks of laughter might be confused with behavioural or emotional disorders, the diagnosis of gelastic epilepsy can be based on their stereotyped recurrences, the absence of any precipitating factor and other manifestations of epilepsy (generalized, myoclonic, temporal lobe and psychomotor seizures), and no other obvious cause for the pathological laughter.[17] However high the dosage of different anticonvulsive drugs employed, the treatment is ineffective.[19]
Plain X-rays of the skull are usually normal except for the tip of the dorsum sella which may show local erosion.[42] In one case reported by Diebler and Ponsot,[19] the tip of the dorsum sella was detached, displaced anteriorly, mimicking a supra-sellar calcification. Lin et al[42] reported suprasellar calcification in a patient with hypothalamic hamartoma who did not have precocious puberty and was felt to have a calcified suprasellar craniopharyngioma. Plain X-ray study should be followed by pneumoencephalography,[24],[42],[44] or computed tomography,[3],[19],[35],[72] or both.[42] According to Lin et al,[42] a computed tomographic scan should be the next investigation not only because of its simplicity but also to rule out other lesions. Obliteration of the suprasellar cistern and anterior third ventricle may be seen.[42] There is usually no enhancement of the lesion following contrast administration.[19],[42] The CT findings are primarily size dependent.[42] The spatial resolution of the newer scanners have rendered possible the detection of hamartomas as small as 4 mm in diameter.[18] Pneumo-encephalography (PEG) with mid- sagittal tomography in particular is also a sensitive study in demonstrating these lesions.[42],[44] The typical findings of hamartoma of the tuber cinereum is a well-circumscribed, collarbutton shaped, soft tissue mass, projecting into the region of the post-chiasmatic, interpeduncular and pre-pontine cistern.[42] Rarely, it is large enough to distort the anterior third ventricle. When the lesion is in the substance of the hypothalamus it then resembles any other hypothalamic lesion.[42] Some cases have been reported where PEG yielded false negative results.[10],[26],[29],[50],[65] Besides the detection of the hamartoma, neuroradiological examinations may reveal associated malformations as seen in 3 cases out of 18 studied by Diebler and Ponsot.[19] In one case, hamartoma was associated with a complex cerebral malformation, including a cystic dilatation of the cisterna magna, tentorialhypoplasia, a complete callosal defect, and dysplasia of the left cerebral hemisphere containing multiple non-communicating cysts. In the second case, there was a marked unilateral ventricular enlargement. In the third case, there was unilate-ralmicro-ophthalmia with calcified eye. According to Lin et al,[42] the decision on whether to proceed to angiography depends upon the results of the other tests. A small lesion of 1 cm does not require angiography unless there is some concern by its position that it could be an aneurysm missed on CT. If the lesion is larger or unusual, then angiography is indicated.[42] The angiogram may show posterior displacement of the distal basilar artery and anterior ponto-mesencephalic vein, or a slight lateral displacement of the posterior communicating arteries. Abnormal tumour vessels or tumour blush is not expected.[42] According to Frank et al ,[24] angiographic study of the Willis' vessels is the rule when surgery is being considered, but it is of little or no value for the diagnosis. A few suprasellar mass lesions that may occur in children should be included in the differential diagnosis. In general, most of these lesions are more anteriorly located than the tuber cinereum hamartomas. If they extend into post-chiasmatic and interpeduncular cisterns, the suprasellar components usually are so large that structural changes warrant a diagnosis of suprasellar lesions with posterior extension, rather than tuber cinereum hamartomas. Examples are craniopharyngioma, optic chiasm gliomas, hypothalamic gliomas, infundibulomas, pituitary adenomas, ectopic pinealomas, suprasellar dermoid or teratomas, chordomas and arachnoid cysts.[42] Lin et al,[42] emphasized that when a patient presents with precocious puberty and a lesion is demonstrated in the basal cistern between the chiasm and pons with a "collar button" appearance, this is typical of a hamartoma of the hypothalamus and tuber cinereum. Hamartoma should also be considered in the differential diagnosis when the lesion is in the hypothalamus, even in the absence of pubertas praecox. While dense calcification may be seen in the hamartoma, it may also resemble a glioma on radiologic studies and biopsy may be necessary to confirm the diagnosis.
Management of the mass effect of hamartoma of the hypothalamus and its endocrine abnormalities and seizure disorders remains a therapeutic challenge.[55] According to Kammer et al,[35] the purposes in treating hypothalamic hamartoma causing precocious puberty are twofold: (i) to arrest or reverse the prematurely rapid course of skeletal growth with its accompanying early closure of the epiphyses and ultimate short stature, and (ii) to allow the very young child to assume a more normal habitus with disappearance of secondary sexual characteristics. Presently both medical and surgical therapies[1],[3],[7],[19],[23],[30],[35],[38],[40],[53],[56],[59],[61],[72],[80] can variably influence these goals. Some authors recommend surgical removal while others recommend medical therapy. Some authors consider hamartoma to be an ectopic cerebral greymatter with no tendency for neoplastic evolution. They advocate abstention from surgery with close observation of the size of the tumour by means of computed tomography and medical therapy to decelerate the precocious sexual development. Others feel that increase in the size of the hamartoma can result in damage to the surrounding tissues. In such cases surgery is the therapy of choice. The choice between surgery and medical treatment must be made for each individual patient. Medical treatment of precocious puberty includes gestagenic drugs, commonly medroxy progesterone acetate and cyproterone acetate to inhibit gonadotropin production.[9],[58] Medroxy-progesterone acetate has been found to reduce gonadotropin and/or testosterone secretion but is not necessarily effective in slowing the progressive skeletal maturation with early epiphyseal closure and ultimate short stature.[34],[37] Cyproterone acetate has been effective in delaying sexual changes and has question able effect on skeletal growth. Piccolo et al[56] reported 2 patients with true precocious puberty due to hamartoma of the tuber cinereum. Diagnosis was established by the presence of accelerated puberty, elevated blood gonadotropins (without neurological dysfuctions) and positive computed tomography scans. These patients were treated with cyproterone acetate and abstention from surgery was achieved with close observation of the tumour's size by computed tomography. Cyproterone acetate therapy had decelerated growth and bone maturation, and decreased the FSH and LH levels and improved secondary sexual characteristics (more in their female patients than in males). They commented that cyproterone acetate inhibits gonadotropins independent of the site of their production, therefore could be successfully used in patients affected by precocious puberty due to hamartoma without neurological symptoms. When the sexual precocity was the only symptom, Bierich,[7] advised against surgical therapy as an initial treatment and proposed that a clinical trial with gestagenic drugs be completed first. Failure of surgical therapy as an initial treatment and good results later with medical therapy prompted some investigators to advocate the latter. Bossi et al,[9] reported lack of therapeutic effect with surgery in a 3 year old boy who later was treated with cyproterone acetate with good results. However, details of the surgery and completeness of tumour removal in their case are not available.[35] Judge et al[34] reported a case initially treat- ed by surgery and later with medroxy-progesterone acetate, but both forms of therapies failed. The tumour was incompletely excised since it was not pedunculated but arose from the ventral surface of the hypothalamus. The serum testosterone levels had remained elevated and secondary sexual characteristics progressed. Treatment with medroxy-progesterone acetate resulted in a lowered serum testosterone while gonadotropins remained elevated and both secondary sexual characteristics and somatic growth continued at advanced levels. But the coin has two sides. Some investigators advocate surgery after the failure of initial medical therapy. Curatolo et al,[17] described a patient under medical therapy without observable clinical benefits and advised surgical therapy in hamartomas. Alvarez-Garijo et al[1] reported a patient treated with cyproterone acetate in whom improvement of the serum testosterone level occurred but no change in genital appearance followed. At the age of 18 months, partial intracapsular excision was done through a right pterional approach under microscope. Following surgery, there was prompt improvement in clinical signs and plasma endocrine levels. Two years after surgery the patient was completely normal. A word of caution regarding surgery has been expressed by Balgara et al,[3] as post- operatively, their patient developed diabetes insipidus. They concluded that histological verification although necessary to establish the treatment and prognosis, was not without its dangers. The first successful surgically treated patient was reported by Northfield and Russel.[53] A large part of the hamartoma of 3 cm in diameter was excised and the patient was followed ud for almost 11 years. The child rapidly lost the muscle bulk and his adult habitus but had no change in his fully developed genitalia. Later, his height and weight were within normal limits. In another patient described by the same authors,[53] the hamartoma was almost totally excised. The patient was followed up for 4 years and he attained normal somatic growth but showed no regression of already developed genitalia. He had no abnormal sexual interest. Kammer et al[35] demonstrated regression of secondary sexual characteristics but continued somatic growth in their case treated by surgery. They commented that surgery potentially frees the patient from reliance on long term drug therapy and expressed their presumption that gestagenic drugs will be more effective once LH-RH secretion is reduced. Takeuchi et al[72] reported a series of 19 patients. All four surviving patients were amongst the six treated by surgery. Frank et al,[24] concluded that only surgery can confirm the preoperative diagnosis besides giving good therapeutic results towards the endocrine disorder. In 1985, Kyuma et al[38] reported a case successfully treated by surgery. They excised only the central portion of the tumour via a right pterional approach utilizing the space between the right internal carotid artery and the optic nerve under microscope and within a year after operation the pubic hairs, acne and low voice disappeared. The LH, FSH and testosterone levels returned to normal. No abnormal response to LH- RH was elicited. They justified their subtotal removal (proved on post-operative CT scan) with an argument that total removal may result in hypothalamic injury and the subtotal removal of the tumour had already shown regression of precocious puberty in their patient.
On review of aforementioned experiences, it appears that the low morbidity, and mortality and good clinical improvement in surgically treated patients favour operative treatment of these rare tumours, especially when the planned microneurosurgical approach with gentle and careful microdissection of tumour and protection of nearby delicate and vital neural and vascular structures are carried out under operating microscope by an experienced neurosurgeon.
I gratefully thank Prof. S. K. Pandya, M.S., Head, Department of Neurosurgery, K.E.M. Hospital, Bombay, for his persistent encouragement and guidance as well as invaluable help during preparation of this article. I am truly thankful to Mr. U. M. Godhwani for his secretarial assistance.
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