Última actualización:
August 16, 2017
Años publicados: 2012, 2017
NORD gratefully acknowledges John F. Kerrigan, MD, Associate Professor of Child Health and Neurology, University of Arizona College of Medicine – Phoenix; Director, Hypothalamic Hamartoma Program, Barrow Neurological Institute at Phoenix Children’s Hospital, for assistance in the preparation of this report.
Hypothalamic hamartomas (HH) are rare, tumor-like malformations that occur during fetal development and are present at birth. They are non-progressive lesions and do not expand, spread or metastasize to other locations. They grow in proportion to normal brain growth, and consequently their relative size to the rest of the brain is the same for the lifetime of the patient. There is tremendous diversity in the type and severity of symptoms from patient to patient. However, symptoms are apparent during childhood in the overwhelming majority of patients. Two clinical phenotypes of HH are recognized: 1) central precocious puberty and 2) epilepsy and related neurobehavioral symptoms.
For those with central precocious puberty only, symptoms may occur as early as 1-3 years of age. These patients present with precocious (abnormally early) development of the physical changes associated with puberty. Neurological problems, such as epilepsy, are usually absent. Magnetic resonance (MR) imaging on patients with central precocious puberty typically shows attachment of the HH lesion in an anterior location in the hypothalamus, in the region of the tuber cinereum or pituitary stalk.
For those with epilepsy, gelastic (laughing) seizures are usually the first symptom, often during infancy. Associated symptoms can include developmental delay, cognitive deterioration, and psychiatric symptoms such as rage behaviors. MR imaging on patients with epilepsy typically shows attachment of the HH in a posterior location in the hypothalamus, in the region of the mammillary bodies. Approximately 40% of HH patients with epilepsy also have precocious puberty. These patients tend to have large lesions, which are broadly attached both anteriorly and posteriorly in the hypothalamus.
Anti-epilepsy medications usually do not control the gelastic seizures associated with HH, and seizures often worsen with additional seizures types that begin around 4-7 years of age. Cognitive deficits and psychiatric symptoms may also present at this time.
For some patients, HH can be a progressively disabling condition. For others, symptoms may be stable and represent little or no disability.
Patients with precocious puberty can usually be treated successfully with medications, specifically with a class of drugs known as gonadotropin-releasing hormone agonists. Medications, specifically anti-epilepsy drugs (AEDs) are less successful for controlling the seizures associated with HH, and therefore surgical treatment is often required. There has been rapid progress over the past 15 years on developing various surgical approaches for treating HH. The selection of the most appropriate surgical technique is individualized to the clinical symptoms and HH anatomy of each patient.
Central precocious puberty (CPP) is one of the hallmark clinical syndromes associated with HH. Puberty is abnormally early if it occurs prior to the age of 8 years in girls or 9 years in boys. “Central” indicates that the disease process responsible for triggering puberty at an abnormally early age involves the brain, with premature pulsatile release of gonadotropin-releasing hormone (GnRH) which in turn signals the ovaries or testes to begin production of sex hormones (estrogen and progesterone in females and testosterone in males).
Central precocious puberty has many causes, and requires evaluation by a pediatric endocrinologist to identify and treat the underlying etiology. Hypothalamic hamartoma is one of the most important causes and is notable in that puberty associated with HH can occur at particularly early ages, even prior to 12 months of age in some patients. The health consequences of abnormally early puberty include short stature and problems with age-appropriate psychosocial adjustment.
For girls, physical signs associated with CPP include breast development and the appearance of mature-appearing pubic and axillary hair. For untreated girls, menses (first menstrual bleeding) will follow. For boys, physical signs begin with testicular growth, followed by enlargement of the penis and maturation of the scrotum, with the development of pubic and axillary hair. Associated features include deepening of the voice and acne.
For patients with epilepsy and neurological symptoms, there is a great deal of variability with respect to the age of onset, severity and changes over time. This clinical diversity must be borne in mind when considering the diagnosis of HH, and are equally important when considering treatment options, including the timing of surgical intervention.
Gelastic seizures are the most characteristic symptom associated with HH. Superficially resembling laughter, they have a peculiar appearance that usually differs from true laughter, and most family members can readily distinguish between the two. Not uncommonly, patients may have seizures that more closely resemble crying rather than laughter (known dacrystic seizures). Gelastic seizures can be quite subtle, and may be mistaken for other conditions, particularly during infancy, including colic and gastroesophageal reflux disease (GERD).
They are brief, sometimes just a few seconds, and usually less than 30 seconds in duration. They can be very frequent, however, with multiple seizures per day, and even multiple seizures per hour in more severely affected patients. Gelastic seizures may or may not be associated with altered consciousness (altered awareness of the event). However, making this determination in infants and young children can be challenging.
Gelastic seizures associated with HH usually begin at an early age, and are usually the first seizure type. The correct diagnosis can be delayed by the unusual nature of this seizure. However, in retrospect, parents can identify the onset of these peculiar laughing spells at a very early age. In a series of patients with HH and epilepsy, the mean age of onset for gelastic seizures is 10.8 months, and 75% of all patients had onset before one year of age. Gelastic seizures become less frequent after 10 years of age, and may disappear entirely as other seizure types develop. Uncommonly, patients with HH may not develop gelastic seizures until adolescence or early adulthood.
Other seizure types that are more disabling to the patient develop in approximately 75% of children with HH and gelastic seizures, most commonly between 4-7 years of age. Virtually all possible types of seizures have been reported, and individual patients may have multiple active seizure types, including focal (localization-related) and generalized seizures.
Cognitive deficits are evident in the majority of patients with HH and epilepsy. Difficulties with processing speed and short-term memory are most common. Here again, there is significant diversity from patient to patient. Recent studies with neuropsychological testing in HH patients undergoing evaluation for surgical treatment show approximately 50% have intellectual disability (full-scale intelligence quotient [IQ] less than 70). Factors contributing to a greater degree of cognitive impairment include 1) higher number of anti-epilepsy medications taken at the time of testing, 2) larger HH lesion size, 3) younger age of seizure onset, and 4) higher seizure frequency. Conversely, patients with HH and central precocious puberty without epilepsy typically do not have developmental or cognitive deficits.
Behavioral and psychiatric symptoms are also common in the group of patients with HH and epilepsy. Episodes of behavioral aggression associated with poor frustration tolerance, often described as rage attacks, are particularly problematic and are a hallmark symptom of HH. Rage attacks are usually reactive to external (often minor) stimuli, and consist of explosive anger. These behaviors can be the most disabling feature of the disease for some patients. There is a greater likelihood of rage behaviors with 1) male gender, 2) the presence of intellectual disability, 3) younger age at the time of first seizure, and 4) multiple seizure types (rather than only gelastic seizures).
Psychiatric symptoms are reported in over 80% of children and adults with HH and epilepsy. A wide range of symptom types, symptom severity and psychiatric diagnoses can be involved. In children with HH, these include oppositional-defiant disorder (83%), attention-deficit/hyperactivity disorder (75%), conduct disorder (33%) and mood disorder (17%), which are far more common in affected patients compared to their unaffected siblings.
Roughly half of children with HH and epilepsy experience deterioration (worsening) of their symptoms over time, with a decline in cognitive functioning and worsening of behavioral symptoms. Worsening seizures, cognitive decline, and behavioral deterioration often occur simultaneously, and probably share a biological link. HH appears to be a clinical model for epileptic encephalopathy, although the basic mechanisms responsible for the deterioration experienced by these patients are poorly understood.
The underlying cause for hypothalamic hamartomas remains unknown. Over 95% of cases are sporadic (that is, there is no prior family history and the identified patient remains the only affected individual in the family). A defect in factors that regulate fetal development of the hypothalamus is most likely.
However, HH can also occur in patients with identified genetic disorders. Of these, Pallister-Hall syndrome accounts for the majority. This is a rare dysmorphology syndrome that can include HH, deformities of the hands and feet (postaxial polydactyly and syndactyly), abnormalities of the larynx (bifid epiglottis), imperforate anus, and others. Pallister-Hall syndrome is known to be associated with a genetic mutation in the GLI3 gene, which acts as a transcription factor (a regulator protein for turning on and off gene expression) in the sonic hedgehog intracellular signaling pathway. This is a genomic (or genome-wide) mutation, which is to say, a mutation present in every cell in the body. (For further information, choose “Pallister-Hall” as your search term in the Rare Disease Database.)
Knowing that Pallister-Hall syndrome is due to a mutation in GLI3, researchers have examined the possibility that a somatic (tumor-only) mutation of GLI3 is responsible for sporadic HH cases. Using tissue removed at surgery, it has been discovered that up to 25% of patients have a somatic mutation of GLI3 in HH tissue. More recently, advanced genotyping has shown that several other genes within the sonic hedgehog pathway can also have somatic mutations that result in HH. With current (2017) genotyping technology, somatic mutations can be identified in approximately 40% of HH lesions. It is also likely that other, as yet unidentified mutations in other genes can be responsible. At this time, mutation analysis (genotyping) of HH lesions is not recommended for routine clinical care of patients with HH.
Hypothalamic hamartomas are relatively rare. Population-based research has shown that HH with epilepsy occurs in 1 of 200,000 children and adolescents. The prevalence of HH with only precocious puberty is unknown. At least for HH with epilepsy, males appear to have a slightly higher risk than females (approximately 1.3 to 1 ratio). HH occurs worldwide, without any obvious geographical concentration of cases. It is currently felt that all ethnic groups are at equal risk. There are no identified maternal risk factors or fetal exposures that increase the risk of HH.
Brain imaging with magnetic resonance (MR) techniques is the single most important diagnostic test. MR imaging is sufficient to establish (or exclude) the diagnosis of HH. However, there are important considerations to imaging for HH. Imaging must be technically adequate to permit detailed visualization of the hypothalamus. Movement artifact resulting from restlessness of the patient within the scanner can obscure small HH lesions. Accordingly, for children or other patients with limited cooperation, a sedated study is recommended. Additionally, the choice of specific MR imaging sequences is also important. A coronal T2 fast spin echo (FSE) sequence is recommended, with thin slices and no gap or space between slices. Lastly, the radiologist should be informed that HH is one of the clinical conditions under consideration, so as to include careful inspection of that region of the brain. Most patients (over 90%) have normal brain findings on MR imaging aside from the HH. A small number of patients may have additional abnormalities, such as malformations of cortical development.
Computed tomography (CT) imaging is not adequate for detecting small HH lesions, and has the added disadvantage of radiation exposure.
Physical signs of precocious puberty require evaluation by an endocrinologist. The hypothalamus and pituitary together produce a number of different hormones, including the reproductive hormones responsible for puberty. Consequently, evaluation of patients with HH should include testing for other factors such as thyroid, adrenal, and growth-related hormones.
Electroencephalography (EEG) testing is routinely performed in patients with epileptic seizures or suspected epileptic seizures, and can be useful in evaluating patients with HH and epilepsy. However, for HH patients the EEG results may be normal, particularly at younger ages when gelastic seizures are the only seizure type. This includes video-EEG monitoring that captures gelastic seizures. That is, the EEG may show no change even during the actual gelastic seizure event. This is due to the fact that gelastic seizures arise in the HH, and as a structure located deep at the base of the brain, it is distant from EEG electrodes on the scalp. This can lead to incorrect diagnoses.
EEG studies can show abnormal results, particularly in older patients who have developed other types of seizures. A wide variety of findings is possible, and can suggest either focal or generalized disturbances. Consultation with a neurologist experienced with evaluating patients with HH and epilepsy is recommended whenever possible. This expertise is usually available at regional epilepsy referral centers.
Neuropsychological testing can be an important tool for patient management, particularly those with HH and epilepsy. These patients are «at-risk» for developmental and cognitive deficits. For some patients, these difficulties may be progressive, with deterioration or worsening in their level of function. Neuropsychological testing can help define the pattern of functioning (i.e., strengths and weaknesses) in the various skills of higher brain functioning (such as memory, language, problem-solving, etc). This can help with adaptive therapies and provides a baseline for those patients who may be declining. Additionally, neuropsychological testing is very important for those undergoing surgical intervention in order to clarify changes (for either the better or worse) that may accompany surgical treatment.
Treatment
Central precocious puberty (CPP) can usually be treated successfully with medication. Surgery is not required for most patients with CPP. Effective treatment consists of administration of gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide acetate [Lupron], which have the effect of feedback inhibition of the pulsatile (pulse-like) release of GnRH that is required to trigger puberty. Leuprolide acetate is customarily administered as a once-monthly intramuscular injection for the duration of time that puberty needs to be suppressed. Once discontinued, puberty occurs normally. Long-term follow-up studies for HH patients with a history of successfully treated CPP show that normal adult height and normal reproductive function are expected.
Treatment options that avoid once-monthly injections have also been developed. Consultation with a pediatric endocrinologist experienced in the treatment of CPP is important to review the treatment options and for discussion of possible side effects.
Gelastic seizures usually do not respond to anti-epilepsy drugs (AEDs). Exceptions to this appear to be rare. Additionally, while the other seizure types that occur later in childhood may be helped with AED therapy, it is unlikely that these seizures will be completely controlled with AEDs («treatment-resistant»). Consequently, surgical treatment is usually required, as discussed below.
The timing of surgical intervention (including gamma knife radiosurgery) is a major decision point facing the patient, family and doctor. Surgical intervention carries the risk of complications and should not be performed until the degree of clinical severity calls for it. For example, relatively brief and infrequent gelastic seizures are usually not significantly disabling. If the child is making good developmental progress, a decision to withhold surgical intervention may be appropriate. However, under these circumstances, the clinical course needs to be observed carefully for any adverse changes in symptoms, such as worsening of seizures, slowing of developmental progress, or emergence of psychiatric symptoms.
However, our current understanding of epilepsy associated with HH also argues against excessive delay in surgical treatment, since it appears that some patients undergo a process known as secondary epileptogenesis, in which uncontrolled seizures from the original location can provoke a process by which seizures begin to arise from a second, distant location elsewhere in the brain. When this occurs (a process that is likely to occur over a period of years rather than months) then surgery removing the HH lesion may be less successful for completely controlling seizures. Outcome studies of surgery for HH associated with epilepsy have shown that success in controlling seizures is inversely related to the patent’s age. That is, older patients are less likely to gain complete seizure control. A recent research study on HH patients undergoing surgery has also shown that a higher likelihood of cognitive improvement after surgery correlates with younger age at the time of surgery.
Gelastic seizures begin in the HH lesion and removing (or otherwise damaging or ablating) the HH can cure seizures. Until recently, HH with epilepsy was considered not treatable, since surgery on the hypothalamus was too dangerous. However, since 2000, several different treatment approaches have been developed that are recognized as effective and safe. These treatment decisions (selecting one of several surgical options including radiosurgery) are highly individualized to the unique circumstances of each patient. This includes an assessment of their clinical course and symptoms, but also the exact anatomy of their HH lesion. Consequently, consultation at a referral center that specializes in the treatment of HH is highly recommended.
A brief discussion of each of these treatment modalities follows. The relative merits of any of these therapies for an individual patient require consultation with a specialist in the field of HH treatment.
Gamma Knife Radiosurgery. Gamma Knife Radiosurgery (GKR) is a relatively non-invasive radiosurgical technique in which a stereotactic frame is temporarily attached to the patient’s head along with a helmet-like device with multiple radiation entry ports. These ports are aligned (targeted) so that multiple beams of radiation are delivered to converge upon the selected target, injuring this tissue, but delivering doses well below the threshold for tissue injury to the rest of the brain. The safety profile for GKR is excellent relative to surgical resection. A small number of patients have transient temperature irregularities following treatment or experience a temporary increase in seizure frequency several weeks after treatment. The biggest disadvantage to GKR is that the therapeutic effect is delayed, typically 6-18 months, but sometimes up to 2-3 years following treatment. This therapy is most appropriate for patients who are clinically stable with respect to their seizures and other symptoms, and can tolerate waiting for effectiveness. Currently published data suggests that 40% of patients treated with GKR will be completely free of seizures upon long-term follow-up.
Stereotactic Thermoablation (with or without intraoperative MR thermography). Thermoablation involves image-guided stereotactic placement of thin probes into the HH and then heating the lesion to approximately 60°C, injuring the tissue and eradicating its ability to generate seizures. When effective, this therapy works immediately. Multiple passes of the probe into the brain may be required to treat the entire lesion, depending upon its size.
There are two technologies that can be utilized for HH thermoablation treatment. Radiofrequency thermoablation can be successful for complete seizure control in up to 71% of patients (32% of these patients required more than one treatment). The safety profile appears favorable in comparison to open surgery, and outcome with pre- and post-operative neuropsychological testing also shows improvement for most patients.
A newer technology utilizes laser-mediated heating of the stereotactic probe within the HH lesion, and also includes the use of real-time MR thermography (visualizing the heat signature of the treatment in near-real time) to build in safeguards so that the heating is limited at pre-determined safety targets as it spreads to healthy tissue. This approach also appears to be highly effective (67-90% seizure-free outcomes in the reports published to date) and the safety profile has been favorable. However, only a small number of research reports have been published thus far, with relatively small numbers of patients and brief follow-up. Additional studies are anticipated.
Transcallosal Interforniceal Resection. Popularized by Dr. Jeffrey Rosenfeld in Melbourne, Australia, this was the first innovative technique for HH surgery, with an open surgical approach (through a craniotomy) to the HH from above (between the two hemispheres of the brain) rather than below (traversing under the temporal or frontal lobes). Although a longer distance, this approach turns out to be safer and more effective. The HH lesion (and its connection) is directly visualized by the surgeon. This technique is often used in younger patients with large lesions including bilateral connections to the hypothalamus, where surgical visualization is particularly critical. Open resection procedures are favored in circumstances where the child is deteriorating, and the delay in treatment effectiveness inherent with gamma knife radiosurgery is not acceptable. Surgical outcome results from two large series have been published with very similar results (complete seizure control in 52% and 54% of patients, respectively). The potential for surgical complications are important to consider: 8% of patients have residual decrease in short term memory function, for example.
Transventricular Endoscopic Resection. This approach involves placing a small burr hole in the skull and then passing an operating endoscope into the ventricular system, entering the third ventricle (the fluid-filled space between the right and left halves of the hypothalamus). This approach is ideal for those who require prompt intervention and who have relatively small HH lesions with unilateral attachment to the wall of the hypothalamus. The effectiveness is comparable to the transcallosal resection (49% seizure-free after one year), but the procedure is more easily tolerated with a shorter length of stay in the hospital. Short-term memory is still at-risk however, with 8% of patients experiencing a decline in short-term memory function following endoscopic surgery. Recent experience is such that stereotactic thermoablation is now the preferred technique for most patients that would have been candidates for endoscopic resection in the past.
Pterional (Orbitozygomatic) Resection. While surgical approaches from below (under the frontal or temporal lobe) are to be discouraged as a treatment approach for most patients with HH and epilepsy, there are still a substantial number of patients (perhaps 10% of the entire group) where a pterional or orbitozygomatic approach is the most appropriate choice. This approach is chosen for those patients in whom the HH is attached below the hypothalamus and traversing below the brain is therefore the most direct way of getting to the lesion and visualizing its attachment. (Most HH cases with precocious puberty only have this anatomy.)
Combined or Staged Resection for Large (or “Giant”) HH Lesions. Patients with HH and epilepsy associated with giant HH lesions may require two approaches from both above and below to optimize resection and/or disconnection. These HH lesions have complicated planes of attachment within the third ventricle but also below the hypothalamus. It is difficult for the surgeon «to see around corners», and therefore two procedures may be required.
Repeat Surgery in HH Patients with Continued Seizures. Surgical teams that are experienced with HH surgery are conservative with HH resection and treatment. That is, if the precise limits of the HH are unclear, it is preferred to err on the side of removing or destroying less HH and avoiding injury or destruction of normal adjacent brain, rather than undertaking an aggressive approach in which the entire HH is removed along with normal hypothalamus. Therefore, some patients may have residual HH tissue and continued seizures. These patients are candidates for a second surgical treatment, often with a different approach or technique, depending upon the anatomy of the remaining tissue.
Focused Ultrasound. This is an investigational non-invasive technique in which multiple highly focused beams of ultrasound energy are brought together at the selected target with destruction of the HH lesion (or other kinds of tumors) with heat energy. If successful, the effectiveness is immediate. This approach is currently under study, and no results have reached publication as of the time of this writing (August 2017).
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Contact for additional information about hypothalamic hamartoma:
John F. Kerrigan, M.D.
Director, Hypothalamic Hamartoma Program
Maggie Bobrowitz, R.N., M.B.A.
Program Coordinator, Hypothalamic Hamartoma Program
Barrow Neurological Institute at Phoenix Children’s Hospital
1919 East Thomas Road, Ambulatory Building B, Third Floor
Phoenix, Arizona 85016
Phone: 602-933-0686
E-Mail: [email protected]
TEXTBOOK CHAPTERS
Kerrigan JF, Kahane P, Fohlen M, Arzimanoglou A. Hypothalamic hamartoma. In: Arzimanoglou A, Cross H, Gaillard WD, Holtshausen H, Jayakar P, Kahane P, Mathern G, eds. Pediatric Epilepsy Surgery. John Libbey Eurotext, Surrey, United Kingdom, 2016.
SELECTED JOURNAL ARTICLES
Du VX, Gandhi SV, Rekate HL, Mehta AD. Laser interstitial thermal therapy: a first line treatment for seizures due to hypothalamic hamartoma? Epilepsia 2017;58(Suppl 2):77-84.
Kerrigan JF, Parsons A, Tsang C, Simeone K, Coons S, Wu J. Hypothalamic hamartoma: neuropathology and epileptogenesis. Epilepsia 2017;58(Suppl 2):22-31.
Regis J, Lagmari M, Carron R, Hayashi M, McGonigal A, Daquin G, Villeneuve N, Laguitton V, Bartolomei F, Chauvel P. Safety and efficacy of Gamma Knife radiosurgery in hypothalamic hamaertomas with severe epilepsies: a prospective trial in 48 patients and review of the literature. Epilepsia 2017;58(Suppl 2):60-71.
Sonoda M, Masuda H, Shirozu H, Ito Y, Akazawa K, Asano E, Kameyama S. Predictors of cognitive function in patients with hypothalamic hamaertoma following stereotactic radiofrequency thermocoagulation surgery. Epilepsia 2017 DOI: 10.1111/epi.13838.
Harrison VS, Oatman O, Kerrigan JF. Hypothalamic hamartoma with epilepsy: review of endocrine comorbidity. Epilepsia 2017;58(suppl 2):50-59.
Hildebrand MS, Griffin NG, Damiano JA, Cops EJ, Burgess R, Ozturk E, Jones NC, Leventer RJ, Freeman JL, Harvey AS, Sadleir LG, Scheffer IE, Major H, Darbro BW, Allen AS, Goldstein DB, Kerrigan JF, Berkovic SF, Heinzen EL. Mutations of the sonic hedgehog pathway underlie hypothalamic hamartoma with gelastic epilepsy. Am J Hum Genet 2016;99:423-429.
Kameyama S, Shirozu H, Masuda H, Ito Y, Sonada M, Akezawa K. MRI-guided stereotactic radiofrequency thermocoagulation for 100 hypothalamic hamartomas. J Neurosurg 2016;124:1503-1512.
Mittal S, Mittal M, Montes JL, Farmer JP, Andermann F. Hypothalamic hamartomas. Part 1. Clinical, neuroimaging, and neurophysiological characteristics. Neurosurg Focus 2013;34(6):E6.
Mittal S, Mittal M, Montes JL, Farmer JP, Andermann F. Hypothalamic hamartomas. Part 2. Surgical considerations and outcome. Neurosurg Focus 2013;34(6):E7.
Wilfong AA, Curry DJ. Hypothalamic hamartomas: optimal approach to clinical evaluation and diagnosis. Epilepsia 2013;54(Suppl 9):109-114.
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