Aggression In Hypothalamic Hamartoma

Article Author:
Yusra Azhar
Article Editor:
Mohammed Molla
Updated:
9/22/2019 2:38:21 PM
PubMed Link:
Aggression In Hypothalamic Hamartoma

Introduction

Hypothalamic hamartomas are benign congenital tumors that arise from the ventral hypothalamus.[1][2] Research ash identified two clinical phenotypes of hypothalamic hamartoma, namely parahypothalamic and intrahypothalamic hamartoma.[3] Parahypothalmic hamartoma, also known as pedunculated, are attached to the anterior hypothalamus. Parahypothalamic hamartomas are highly associated with central precocious puberty, whereas intrahypothalamic hamartoma attached to the posterior hypothalamus correlates highly with treatment-resistant epilepsy.[4][5] This treatment-resistant epilepsy mainly starts with gelastic (laughing) seizures, which later develops into other resistant seizure types, including localization-related and generalized seizures. Nearly 40% of patients with hypothalamic hamartoma have both central precocious puberty and epilepsy; however, this is more related to larger lesions which arise from anterior and posterior hypothalamus.[4]

The intrahypothalamic subtype of hypothalamic hamartoma, in particular, are also associated with neurobehavioral comorbidity, including cognitive impairment and psychiatric symptoms.[6][7] Cognitive impairment varies in patients, from mild to severe depending on the earlier age of onset of the first seizure, frequency, size, and the number of antiepileptic drugs.[8][9]

Psychiatric symptoms are a common comorbid feature of hypothalamic hamartoma with epilepsy.[10] These are most disabling in patients and are a significant challenge for the patient and their families. Most commonly, psychiatric symptoms present with externalizing behaviors such as aggression and rage attacks. Patients can also have a reduced threshold for frustration, with extensive reactivity to minor stimuli, which can also result in destructive physical features.[3]

Etiology

A hamartoma is a discrete lesion that resembles a neoplasm but often arises from an errant organ and contains atypical portions of tissue elements.[11] Hypothalamic hamartomas are rare congenital benign tumors that contain atypical portions of neuronal tissue elements.[12]

Hypothalamic hamartoma develops in the fifth to sixth week of gestation that appears in and/or around the hypothalamus arising from infundibular recess and mammillary bodies. There is a theory that a defect in the fetal development of hypothalamus results in the development of the tumor. Pathologically hypothalamic hamartoma consists of mature neurons and glial cells with a range in size from 10 to 30 mm.[13]

The cause of hypothalamic hamartoma remains unknown. Cases are usually sporadic with no identified family history, and the patient remains the only affected individual.[14] However, hypothalamic hamartomas are also associated with rare genetic disorders such as Pallister-Hall syndrome. Pallister-Hall syndrome is an autosomal dominant disorder caused by a mutation to the GLI3 gene which classically presents with hypothalamic hamartoma and polydactyly.[15] 

Epidemiology

The estimated prevalence of hypothalamic hamartoma with epilepsy is 1 case per 50000 to 100000 in children and adolescents.[11] The prevalence of hypothalamic hamartoma with only precocious puberty remains unclear. For hypothalamic hamartomas with epilepsy, males are a slightly higher risk than females with a  ratio of 1.3 to 1.[16] Hypothalamic hamartomas occur worldwide with no specific geographic concentration of cases. The current thinking is that all ethnic groups are at equal risk, with no identified maternal risk factor or fetal exposures.

History and Physical

Clinical presentation of hypothalamic hamartomas depends on their region of attachment to the hypothalamus.[12] Clinically hypothalamic hamartomas present as two recognized subtypes, namely parahypothalamic and intrahypothalamic hamartomas.

Parahypothalmic hamartomas, also known as pedunculated occur in the anterior hypothalamus arising from the inferior surface of the hypothalamus, tuber cinereum. This subtype of hypothalamic hamartoma is associated with central precocious puberty.[4] Central precocious puberty associated with hypothalamic hamartomas starts early at an average age of 3.7 years in boys and 2.5 years in girls.[17]

Conversely, intrahypothalamic hamartomas also know as ‘sessile’ occur in posterior hypothalamus with an attachment level at mamillary bodies.[2] Intrahypothalamic hamartomas are associated with gelastic seizures, epilepsy, cognitive impairment, and psychiatric symptoms.[3][18] Gelastic seizures are rare forms of seizure characterized by inappropriate smiling, giggling, or laughter associated with EEG changes and unrelated to external or interpersonal stimulation.[19] These seizures classically occur in infancy with increasing frequency and periodicity.[20] The mean age of presentation of gelastic seizures is 2.8 years with the age of onset ranging from 1 month to 15 years. Gelastic seizures can be a precursor to other seizure types, cognitive deterioration, and behavioral abnormalities. The clinical spectrum of hypothalamic hamartoma associated epilepsy ranges from being sporadic and easily controlled partial seizures to seizures partially responsive to epileptic drugs and a catastrophic course which requires surgical intervention.[21][22]

Cognitive impairment can present as language delay with learning disabilities. Behavioral disorders are associated more commonly with hypothalamic hamartomas and gelastic seizures. These include ADHD (75%), aggressiveness, anxiety oppositional defiant disorders (83.3%) and conduct disorders (33.3%).[11] Other behavioral disorders include rage, temper tantrums, and violence. Anxiety and mood disorders ( 8.3 to 25%) can also present as phobias, post-traumatic stress disorder, avoidant disorder, major depression, and dysthymia. 

Patients with gelastic seizures present with affective aggression. The definition of affective aggression is as being out of control, damaging one's property, physical harm to oneself, aggressive without a purpose, aggressive with stronger children when aggressive, and express remorse after aggression. Some children also present with predatory aggression. Predatory aggression includes the ability to control their behavior when aggressive, protects oneself when aggressive, fights with weaker children and tries to get something out from being aggressive. More commonly, patients with hypothalamic hamartomas and gelastic seizures support affective aggression. These aggressive episodes arise quite suddenly and not motivated by ill will towards the victims.[11]

Other predictive factors associated with an increased likelihood of aggression include male gender, the presence of intellectual disability, younger age at the time of first seizure, and multiple seizures. Postulates are that seizure activity in patients with hypothalamic hamartoma is a contributing factor to neurobehavioural deficits. The cause of rage and aggression are poorly understood but is thought to be influenced by gender and hormonal dynamics.[23]

Evaluation

Since hypothalamic hamartomas present with a plethora of psychiatric symptoms, these patients need a thorough neuropsychiatric evaluation process.  Diagnostic tools, including the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) and the Overt Aggression Scale, can be useful.[24] Other aggression scales such as Vitiello Aggression Scale differentiates affective and predatory aggression.[25] Head MRI confirms the presence of hypothalamic hamartoma. MRI is the primary diagnostic tool for hypothalamic hamartomas as surgical specimens are difficult to obtain.[26] Central precocious puberty may be caused by excessive secretion of GnRH from the lesion.[27] 

Child and adolescent psychiatrists frequently have to evaluate youth presenting with rage and anger. Distinguishing between predatory and affective aggression at this time is very important. Also, if the patient presents with a history of inappropriate smiling or giggling, this should alert the psychiatrists that gelastic epilepsy could be present, and the patient should obtain a referral for a thorough neurological assessment. Gelastic seizures fail to demonstrate EEG changes; therefore, a video EEG is the recommended approach.[28] Video EEG captures the gelastic seizure with head deviation and twitching.[29] Further, if the patient presents with findings of aggression and precocious puberty, a complete thorough assessment by an endocrinologist is also required.

Treatment / Management

The gelastic seizures associated with hypothalamic hamartomas are complicated to treat or manage.[30] These seizures are refractory to medical treatment, and reports exist of surgical attempts to control the seizures. However, in some instances, the surrounding hypothalamic tissue interferes with safe surgical access, so alternative modalities include stereotactically targeted radiation therapy or radiofrequency lesioning.[31] Recent studies have reported a complete resection is not necessary and disconnecting the tumor is sufficient for seizure control, therefore less invasive modalities are increasingly being used. The main disadvantage of the non-surgical approach is a delayed effect on seizure control which usually takes about six months, radiation damage to the surrounding vital structures such as the optic tract and lower efficacy of seizure control in contrast to the open surgical approach.[13]

If precocious puberty is the isolated finding with the hamartoma, then medical management is focused on suppressing the pubertal development. An example of this treatment plan would be the administration of gonadotropin-releasing hormone analog.[32] Long-acting LH-RH analogs suppress the gonadotrophin secretion. Therefore treatment with LH-RH analogs is the first choice.[26] However, if this does not help, then surgical removal is recommended. In contrast to the intrahypothalamic hamartomas, parahypothalamic hamartomas are relatively easily accessible for surgical removal.[32]

There are no proposed treatment algorithms for behavioral and psychiatric symptoms in patients with hypothalamic hamartoma.[12] There is also as yet no documented, specific pharmacotherapy for psychiatric symptoms in patients with hypothalamic hamartomas.[3] Behavioral difficulties are addressable through parent management training (PMT). This training involves teaching parents strategies to increase prosocial skills and decrease disruptive behaviors in children. An example of PMT is a brief behavioral intervention program. This program demonstrates successful results in treating symptoms of ADHD and disruptive behaviors in children with parahypothalamic hamartomas.[33]

Behavioral symptoms are common in children with epilepsy. Often parents report their children being more restless and irritable before seizure onset. Controlling seizures ultimately controls aggressive behavior in children. The literature describes this phenomenon in several places. Surgical removal of hypothalamic hamartoma is the more definitive treatment in controlling seizures. After surgical removal, three patients became seizure-free, eight had over 90% reduction in seizures, and all of these eleven patients experienced a dramatic improvement in behavior and cognition.[21]

Differential Diagnosis

Hypothalamic hamartomas are unique in their presentation with gelastic seizures. Other tumors arising from the ventral hypothalamus such as craniopharyngiomas, astrocytomas, optic nerve gliomas do not usually present with gelastic seizures. However, these tumors can be associated with endocrine dysfunction and very rarely associated with central precocious puberty. The differential diagnosis for incessant laughter is broad; however, a thorough history and physical exam along with neuroimaging, video EEG, and psychiatric screening can aid in the diagnosis of gelastic seizures with hypothalamic hamartomas.[29]

Prognosis

Prognosis is dependent on numerous factors such as the size, location, early manifestations of gelastic seizures, behavioral, cognitive impairment, and central precocious puberty. Large sessile hypothalamic hamartomas are likely to present with all of the above features.

The success rate for gonadotropin-releasing hormone agonist therapy is high in treating central precocious puberty.[34] Monitoring pubertal progression is all that is required, however regular testing for LH and sex-steroids can further confirm treatment efficacy.[17] When puberty is desirable, the clinician can discontinue hormone therapy.[34] Long term outcomes of girls and boys treated with GnRH therapy appear favorable.[35][36]

Gelastic seizures are quite distressing for the patient and the family. As they tend to be refractory to antiepileptic drugs, surgery is the predominant treatment choice. Neurosurgical techniques tend to resolve the symptoms rapidly in these patients. Early intervention is quite critical as this condition is progressive with worsening cognitive and behavioral issues over time. Often lesion is inaccessible through an open approach; therefore, minimally invasive surgical or radiosurgical therapies are options, but with variable result outcomes. Only 50% of the patients achieved cure by endoscopic disconnection of hypothalamic hamartomas.[37] This partial improvement with the persistence of seizures in patients suggests that overtime a secondary independent epileptogenic area develops in the cortex.[38] A short window of under 10 years has been proposed from epilepsy onset to surgical treatment in hypothalamic hamartoma to prevent the development of independent stage and cure epilepsy.[39]

Complications

Complications with open surgical procedures are high.[13] Various minimally invasive and non-surgical methods have been in use for the treatment of hypothalamic hamartoma. The main disadvantage of non-surgical methods such as gamma knife radiation is the delayed effect on seizure control, which can take six months or longer. A recent trial reported that 37% of patients’ were seizure-free after gamma knife radiation therapy, and 60% had a dramatic improvement in symptoms.[31] Radiation damage can also occur to the surrounding vital structures such as optic tract. Possible complications associated with surgical resection include pituitary endocrinopathies and hypothalamic obesity syndrome.[17] As hypothalamic hamartoma is a rare disease disorder, complications and adverse effects remain unknown.

Deterrence and Patient Education

Patients and families require education regarding gelastic seizures as these can be quite challenging to manage. Parents should understand the potential for rage behaviors, mood disorders, aggression in patients with hypothalamic hamartoma, and epilepsy — approximately 43% of patients present with significant aggression.[3] Parents should also receive counsel on the progressive nature of the disease with worsening of seizures, cognitive decline, and behavioral deterioration.[12] Regular follow up by an interprofessional team of professionals is necessary for successful management of this disease.

Enhancing Healthcare Team Outcomes

The management of hypothalamic hamartomas is best done with an interprofessional team chiefly because of its rarity and vague symptoms. Clinicians need to be aware that besides seizures, these lesions can present with psychiatric symptoms in the form of rage behaviors, mood disorders, and aggression.[7] There is a general lack of clinical data on such significant comorbidity. Risk factors for psychiatric comorbidity in patients with hypothalamic hamartoma are unknown. Predictors for the increased possibility of aggression are male gender, intellectual disability, early age at the onset of seizure activity, and multiple seizures instead of only gelastic seizure. Atypical presentations of mood or psychiatric symptoms should call for imaging studies of the brain.

Early seizure onset is also associated with cognitive impairment. The neurobiology of rage and aggression is poorly understood but is mostly under the influence of hormonal dynamics such as cortisol and testosterone.[40] Patients with hypothalamic hamartoma present with a broad spectrum of psychiatric symptoms. It is challenging to categorize based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-V)  as virtual symptoms from all categories can be involved. Therefore hypothalamic hamartoma is classified on a purely symptomatic level.

Psychiatric outcomes improve after surgery in patients with hypothalamic hamartoma with epilepsy. There is no current available pharmacotherapy for psychiatric symptoms is recommended at this time needing further clinical trials to explore this possibility.

Despite the absence of a pharmaceutical standard of treatment, when pharmaceutical therapy is the initial treatment option, the pharmacist must have involvement and verify dosing and perform medication reconciliation. Nursing can monitor the effectiveness of treatment, and report any concerns to the treating physician. Nurses are also in the best position to observe for adverse medication effects and will assist in helping if a surgical option is chosen. All providers are responsible for educating and counseling the patient's family regarding gelastic seizures. Only with a full, interprofessional team approach can outcomes be directed optimally. [Level V]


References

[1] Coons SW,Rekate HL,Prenger EC,Wang N,Drees C,Ng YT,Chung SS,Kerrigan JF, The histopathology of hypothalamic hamartomas: study of 57 cases. Journal of neuropathology and experimental neurology. 2007 Feb;     [PubMed PMID: 17278998]
[2] Parvizi J,Le S,Foster BL,Bourgeois B,Riviello JJ,Prenger E,Saper C,Kerrigan JF, Gelastic epilepsy and hypothalamic hamartomas: neuroanatomical analysis of brain lesions in 100 patients. Brain : a journal of neurology. 2011 Oct;     [PubMed PMID: 21975589]
[3] Killeen Z,Bunch R,Kerrigan JF, Psychiatric comorbidity with hypothalamic hamartoma: Systematic review for predictive clinical features. Epilepsy     [PubMed PMID: 28636978]
[4] Chan YM,Fenoglio-Simeone KA,Paraschos S,Muhammad L,Troester MM,Ng YT,Johnsonbaugh RE,Coons SW,Prenger EC,Kerrigan JF Jr,Seminara SB, Central precocious puberty due to hypothalamic hamartomas correlates with anatomic features but not with expression of GnRH, TGFalpha, or KISS1. Hormone research in paediatrics. 2010;     [PubMed PMID: 20389100]
[5] Valdueza JM,Cristante L,Dammann O,Bentele K,Vortmeyer A,Saeger W,Padberg B,Freitag J,Herrmann HD, Hypothalamic hamartomas: with special reference to gelastic epilepsy and surgery. Neurosurgery. 1994 Jun;     [PubMed PMID: 8084405]
[6] Arzimanoglou AA,Hirsch E,Aicardi J, Hypothalamic hamartoma and epilepsy in children: illustrative cases of possible evolutions. Epileptic disorders : international epilepsy journal with videotape. 2003 Dec;     [PubMed PMID: 14975787]
[7] Berkovic SF,Andermann F,Melanson D,Ethier RE,Feindel W,Gloor P, Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging. Annals of neurology. 1988 May;     [PubMed PMID: 3389755]
[8] Prigatano GP,Wethe JV,Gray JA,Wang N,Chung S,Ng YT,Prenger E,Kerrigan JF, Intellectual functioning in presurgical patients with hypothalamic hamartoma and refractory epilepsy. Epilepsy     [PubMed PMID: 18375185]
[9] Frattali CM,Liow K,Craig GH,Korenman LM,Makhlouf F,Sato S,Biesecker LG,Theodore WH, Cognitive deficits in children with gelastic seizures and hypothalamic hamartoma. Neurology. 2001 Jul 10;     [PubMed PMID: 11445626]
[10] Savard G,Bhanji NH,Dubeau F,Andermann F,Sadikot A, Psychiatric aspects of patients with hypothalamic hamartoma and epilepsy. Epileptic disorders : international epilepsy journal with videotape. 2003 Dec;     [PubMed PMID: 14975791]
[11] Weissenberger AA,Dell ML,Liow K,Theodore W,Frattali CM,Hernandez D,Zametkin AJ, Aggression and psychiatric comorbidity in children with hypothalamic hamartomas and their unaffected siblings. Journal of the American Academy of Child and Adolescent Psychiatry. 2001 Jun;     [PubMed PMID: 11392348]
[12] Veendrick-Meekes MJ,Verhoeven WM,van Erp MG,van Blarikom W,Tuinier S, Neuropsychiatric aspects of patients with hypothalamic hamartomas. Epilepsy     [PubMed PMID: 17606410]
[13] Kumar R,Yadav J,Sahu JK,Tripathi M,Ahuja C,Dayal D, Episodes of prolonged     [PubMed PMID: 30943681]
[14] Kerrigan JF,Parsons A,Tsang C,Simeone K,Coons S,Wu J, Hypothalamic hamartoma: Neuropathology and epileptogenesis. Epilepsia. 2017 Jun;     [PubMed PMID: 28591478]
[15] Mahtabfar A,Buckley N,Murphy S,Danish S,Marshall I, Pallister-Hall Syndrome Presenting in Adolescence. Case reports in genetics. 2019     [PubMed PMID: 31011455]
[16] Zúñiga OF,Tanner SM,Wild WO,Mosier HD Jr, Hamartoma of CNS associated with precocious puberty. American journal of diseases of children (1960). 1983 Feb;     [PubMed PMID: 6336889]
[17] Harrison VS,Oatman O,Kerrigan JF, Hypothalamic hamartoma with epilepsy: Review of endocrine comorbidity. Epilepsia. 2017 Jun;     [PubMed PMID: 28591479]
[18] Debeneix C,Bourgeois M,Trivin C,Sainte-Rose C,Brauner R, Hypothalamic hamartoma: comparison of clinical presentation and magnetic resonance images. Hormone research. 2001;     [PubMed PMID: 11815722]
[19] Go T, ACTH treatment for gelastic seizures. Archives of disease in childhood. 1999 Sep;     [PubMed PMID: 10532927]
[20] Téllez-Zenteno JF,Serrano-Almeida C,Moien-Afshari F, Gelastic seizures associated with hypothalamic hamartomas. An update in the clinical presentation, diagnosis and treatment. Neuropsychiatric disease and treatment. 2008 Dec;     [PubMed PMID: 19337448]
[21] Palmini A,Chandler C,Andermann F,Costa Da Costa J,Paglioli-Neto E,Polkey C,Rosenblatt B,Montes J,Martínez JV,Farmer JP,Sinclair B,Aronyk K,Paglioli E,Coutinho L,Raupp S,Portuguez M, Resection of the lesion in patients with hypothalamic hamartomas and catastrophic epilepsy. Neurology. 2002 May 14;     [PubMed PMID: 12011278]
[22] Striano S,Striano P,Sarappa C,Boccella P, The clinical spectrum and natural history of gelastic epilepsy-hypothalamic hamartoma syndrome. Seizure. 2005 Jun;     [PubMed PMID: 15911357]
[23] Cleverley K,Szatmari P,Vaillancourt T,Boyle M,Lipman E, Developmental trajectories of physical and indirect aggression from late childhood to adolescence: sex differences and outcomes in emerging adulthood. Journal of the American Academy of Child and Adolescent Psychiatry. 2012 Oct;     [PubMed PMID: 23021479]
[24] Knoedler DW, The Modified Overt Aggression Scale. The American journal of psychiatry. 1989 Aug;     [PubMed PMID: 2750991]
[25] Vitiello B,Behar D,Hunt J,Stoff D,Ricciuti A, Subtyping aggression in children and adolescents. The Journal of neuropsychiatry and clinical neurosciences. 1990 Spring;     [PubMed PMID: 2136074]
[26] Arita K,Ikawa F,Kurisu K,Sumida M,Harada K,Uozumi T,Monden S,Yoshida J,Nishi Y, The relationship between magnetic resonance imaging findings and clinical manifestations of hypothalamic hamartoma. Journal of neurosurgery. 1999 Aug;     [PubMed PMID: 10433309]
[27] Jung H,Parent AS,Ojeda SR, Hypothalamic hamartoma: a paradigm/model for studying the onset of puberty. Endocrine development. 2005     [PubMed PMID: 15722619]
[28] Troester M,Haine-Schlagel R,Ng YT,Chapman K,Chung S,Drees C,Prenger E,Rekate H,Kerrigan JF, EEG and video-EEG seizure monitoring has limited utility in patients with hypothalamic hamartoma and epilepsy. Epilepsia. 2011 Jun;     [PubMed PMID: 21569021]
[29] Beckwith NL,Khil JC,Teng J,Liow KK,Smith A,Luna J, Inappropriate Laughter and Behaviours: How, What, and Why? Case of an Adult with Undiagnosed Gelastic Seizure with Hypothalamic Hamartoma. Hawai'i journal of medicine     [PubMed PMID: 30533284]
[30] Parrent AG, Stereotactic radiofrequency ablation for the treatment of gelastic seizures associated with hypothalamic hamartoma. Case report. Journal of neurosurgery. 1999 Nov;     [PubMed PMID: 10541251]
[31] Régis J,Scavarda D,Tamura M,Nagayi M,Villeneuve N,Bartolomei F,Brue T,Dafonseca D,Chauvel P, Epilepsy related to hypothalamic hamartomas: surgical management with special reference to gamma knife surgery. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2006 Aug;     [PubMed PMID: 16807727]
[32] Starceski PJ,Lee PA,Albright AL,Migeon CJ, Hypothalamic hamartomas and sexual precocity. Evaluation of treatment options. American journal of diseases of children (1960). 1990 Feb;     [PubMed PMID: 2105631]
[33] Fein RH,Banks GG,Gragert MN,Axelrad ME, Brief Behavioral Intervention for Disruptive Behavior in a Child with a Hypothalamic Hamartoma: A Case Report. Journal of clinical psychology in medical settings. 2018 Nov 23;     [PubMed PMID: 30470962]
[34] Mahachoklertwattana P,Kaplan SL,Grumbach MM, The luteinizing hormone-releasing hormone-secreting hypothalamic hamartoma is a congenital malformation: natural history. The Journal of clinical endocrinology and metabolism. 1993 Jul;     [PubMed PMID: 8325933]
[35] Feuillan PP,Jones JV,Barnes KM,Oerter-Klein K,Cutler GB Jr, Boys with precocious puberty due to hypothalamic hamartoma: reproductive axis after discontinuation of gonadotropin-releasing hormone analog therapy. The Journal of clinical endocrinology and metabolism. 2000 Nov;     [PubMed PMID: 11095429]
[36] Feuillan PP,Jones JV,Barnes K,Oerter-Klein K,Cutler GB Jr, Reproductive axis after discontinuation of gonadotropin-releasing hormone analog treatment of girls with precocious puberty: long term follow-up comparing girls with hypothalamic hamartoma to those with idiopathic precocious puberty. The Journal of clinical endocrinology and metabolism. 1999 Jan;     [PubMed PMID: 9920060]
[37] Schwartz TH, Treatment options for hypothalamic hamartomas--no laughing matter. Epilepsy currents. 2007 May-Jun;     [PubMed PMID: 17520079]
[38] Régis J,Carron R,Bartolomei F,Chauvel P, Seeking new paradigms in epilepsy: stereotactic radiosurgery. Clinical neurosurgery. 2012;     [PubMed PMID: 22960514]
[39] Scholly J,Staack AM,Kahane P,Scavarda D,Régis J,Hirsch E,Bartolomei F, Hypothalamic hamartoma: Epileptogenesis beyond the lesion? Epilepsia. 2017 Jun;     [PubMed PMID: 28591482]
[40] Rosell DR,Siever LJ, The neurobiology of aggression and violence. CNS spectrums. 2015 Jun;     [PubMed PMID: 25936249]