Dr Hussein Hamdi
email: hussein.m.hamdi@gmail.com

Patrizia Ferrante

Giorgio Spatola

Wesley Clawson

Aileen Mcgonigal

Geraldine Daquin

Nathalie Villeneuve

Virginie Laguitton

Fabrice Bartolomei

Jean Regis

EPILEPTIC HYPOTHALAMIC HAMARTOMAS IMPACT OF TOPOGRAPHY ON CLINICAL PRESENTATION, AND RADIOSURGICAL OUTCOME

Keywords: Hypothalamic Hamartoma, Gelastic, Epilepsy, MRI, Topography, Classification Hypothalamic Hamartoma, Gelastic, Epilepsy, Topography, Anatomy, Classification, Radiosurgery, Gamma Knife

INTRODUCTION

Hypothalamic Hamartoma (HH) is a rare congenital disease and when it is in close contact with mammillary bodies (MB), it presents with epilepsy and cognitive comorbidities with or without precocious puberty (PP) [START_REF] Régis | Safety and efficacy of Gamma Knife radiosurgery in hypothalamic hamartomas with severe epilepsies: A prospective trial in 48 patients and review of the literature[END_REF] . Electrophysiological, deep recording, and single photon emission computed tomography (SPECT) studies demonstrated the intrinsic epileptogenic capacity within the HH itself [START_REF] Kahane | From hypothalamic hamartoma to cortex: what can be learnt from depth recordings and stimulation?[END_REF][START_REF] Kameyama | Ictogenesis and symptomatogenesis of gelastic seizures in hypothalamic hamartomas: an ictal SPECT study[END_REF][START_REF] Munari | Role of the hypothalamic hamartoma in the genesis of gelastic fits (a video-stereo-EEG study)[END_REF] . The origin of focal onset impaired awareness seizures (FOIA) and other seizure types are not completely understood.

Surgery decision and clinical prediction is the main concern challenging the neurosurgeon in the management strategy of HH [START_REF] Régis | Gamma knife surgery for epilepsy related to hypothalamic hamartomas[END_REF][START_REF] Régis | Gamma knife surgery for epilepsy related to hypothalamic hamartomas[END_REF] . Some evidence exists for the role of HH topography and relation to hypothalamus as clinical determinants. Accordingly, several protocols have been developed to describe HH neuro-radiological topography [START_REF] Delalande | Disconnecting surgical treatment of hypothalamic hamartoma in children and adults with refractory epilepsy and proposal of a new classification[END_REF][START_REF] Harvey | Epilepsy in hypothalamic hamartoma: clinical and EEG features[END_REF][START_REF] Régis | Gamma knife surgery for epilepsy related to hypothalamic hamartomas[END_REF] .

We published the first prospective trial evaluating a technique treating the epileptic HH using Gamma Knife Radiosurgery (GKS) [START_REF] Régis | Safety and efficacy of Gamma Knife radiosurgery in hypothalamic hamartomas with severe epilepsies: A prospective trial in 48 patients and review of the literature[END_REF] . In this fully investigated cohort, we design a more precise protocol to study if HH fine topography and relation to hypothalamus structures can affect clinical picture before GKS and outcome after GKS.

METHODS

2.1.

SUBJECTS INCLUDED

The study included 48 epileptic patients with HHs (27 male, 21 female) with median age 16.5 (3-50) years. Total seizure frequency (average) was 170 (range 5-12,000) seizures per month within the three-month period before GKS. Gelastic seizures (GS)

and non-gelastic FOIA seizures were analysed in relation to fine HH topography.

Twenty-three patients (47.9%) presented with precocious puberty (PP) at median age of 6 months (1 month -10 years). Thirty-eight (79%) presented with psychiatric comorbidity, 17 (35.4%) with hyperactivity, 34 (70.8%) with hetero-aggressivity, 21

(43.75%) with school difficulties. Twenty-eight (58.3%) HHs were dominantly attached to the left hypothalamus and 20 (41.7%) HHs were dominantly attached to the right hypothalamus. Demographic and clinical data are summarized in Table 1.This study is approved by the Ethics committee (CM1/99/24 IRB 00011687). Informed consent was obtained by parents or patients for all subjects included.

INTERVENTION AND OUTCOME

All patients were treated by GKS (Elekta, Stockholm, Sweden) by the same neurosurgeon (JR) in Timone University Hospital according to our previously published radiosurgery protocol [START_REF] Régis | Gamma knife surgery for epilepsy related to hypothalamic hamartomas[END_REF][START_REF] Régis | Safety and efficacy of Gamma Knife radiosurgery in hypothalamic hamartomas with severe epilepsies: A prospective trial in 48 patients and review of the literature[END_REF][START_REF] Régis | Gamma knife surgery for epilepsy related to hypothalamic hamartomas[END_REF] . The median marginal dose was 17 Gy (14-25) and the median target volume was 398 mm 3 (79.4-1,600 mm 3 ). Engel epilepsy outcome scale was applied for all patients three years after GKS [START_REF] Engel | Outcome with respect to epileptic seizures[END_REF] .

MR TOPOGRAPHY ANALYSIS

We studied the MR images performed on the day of GKS according to our previously published classification [START_REF] Régis | Gamma knife surgery for epilepsy related to hypothalamic hamartomas[END_REF][START_REF] Régis | Gamma knife surgery for epilepsy related to hypothalamic hamartomas[END_REF] . The hypothalamus was visually inspected between hypothalamus sulcus superiorly, lamina terminalis anteriorly, and a plane passing from posterior commissure until the caudal end of the MB posteriorly [START_REF] Wilkinson | Chapter 8 -Diencephalon and internal capsule[END_REF] while laterally bounded by internal capsule, cerebral peduncle and subthalamus on each side [START_REF] Nauta | Hypothalamic nuclei and fiber connections[END_REF] .

HYPOTHALAMIC REGIONS AND ZONES

On the sagittal plane, along rostral-caudal axis, two planes passing through the pituitary stalk and anterior of MB divided the hypothalamus into three regions from anterior backwards as follow; supra-optic, tuberal and mammillary regions [START_REF] Crosby | Comparative anatomy of the preoptic and hypothalamic areas In: Springfield: Thomas, in The Hypothalamus[END_REF][START_REF] Mai | Atlas of the Human Brain[END_REF][START_REF] Nauta | Hypothalamic nuclei and fiber connections[END_REF] . For each region, the HH involvement could be partial (< 50%, >50%) or total.

On the coronal plane, along the medio-lateral axis, three main zones were considered from the midline of the third ventricle; thin periventricular zone (within 5 mm lateral to center of III ventricle) [START_REF] Mai | Atlas of the Human Brain[END_REF] , medial, and lateral zones. Lateral and medial zones were separated by a sagittal plane passing through the anterior pillar of the fornix [START_REF] Mai | Atlas of the Human Brain[END_REF][START_REF] Truex | The diencephalon and corpus striatum[END_REF] . Each hamartoma could involve one or more of these zones (as shown in Figure 1).

HH DIMENSIONS, VOLUMES AND CONTACT

Fine longest anatomical dimensions of HH were also measured in three planes:

anterior-posterior, vertical, and horizontal (length, height, andwidth). HH volumes;

total volume, intra-hypothalamic volume (intra-HH), and extra-hypothalamic volumes (extra-HH) were precisely measured based on accurate Gamma Plan measuring tools.

The contact to pituitary stalk (PS), tuber cinereum (TC) and MB with the lesion was also considered during analysis.

RESULTS

Main findings are summarized in Table 2 and incidence rate in Table 3.

PRECOCIOUS PUBERTY

23/48 (47.9%) HHs presented PP at time of GKS treatment mainly with larger HH extending in the tuberal region, medial and lateral zone.

Hypothalamic regions and zones involved

Tuberal region involvement was associated with higher PP incidence. The PP incidence was 9 PP/11 HHs (81.8%) with total tuberal involvement, 12 PP/ 27 HHs (44.4%) with more than 50% of tuberal region was involved, and 2 PP/10 HHs (20%) when less than 50% of tuberal region was involved (p=0.016, Chi-square) (as shown Figure 2). The Mammillary region had no measurable effect. Medial and lateral hypothalamus involvement was associated with higher incidence of PP (volume effect). The PP incidence was 9PP/30 HHs (30%) with periventricular zone involvement, 12 PP/ 16 HHs (75%) with medial zone, 2 PP/ 2 HHs (100%) with lateral zone (p=0.002, Fisher's exact) (volume effect). All HHs with PP were in contact with the tuber cinereum.

HH types and measurements

Higher order HH type was associated with higher incidence of PP. PP incidence was 18 PP / 43 HHs (42%) of type I-III presented PP (67% of them type III) while no one cured of psychiatric condition, 7 improved, and 4 remained stable. Mean and range of disease duration was 25 (16-40) years in the stable group and 16 (3-35) in the improved and cured group. Presence or absence of psychiatric comorbidity before GKS did not affect epilepsy outcome after GKS (p>0.05, Chi Square).

Effect of anti-epileptic medications

Anti-epileptic medications (AEDs) and absolute number before and after GKS did not have any effect on the presence of psychiatric comorbidities (yes/no) and psychiatric outcome (cured, improved, stable), but it was clear that the Engel I group (19 patients) had significant lower number of AEDs after GKS rather than others (p=0.002 post-GKS AEDs, p=0.001 ΔAEDs, Mann-Whitney). In the total cohort, pre-GKS AEDs was (1-4), post-GKS AEDs (0-4), and ΔAEDs (-3, +1).

3.4.

HYPERKINESIA

Seventeen HHs (35.4%) presented hyperactivity (hyperkinesia) at time of GKS mainly when HH extended laterally into the hypothalamus and with HHs type III.

Hypothalamic regions and zones involved

Hyperkinesia incidence was 10/18 (55.5%) in medial hypothalamic zone involvement and 7/30 (23.3%) without this involvement (p=0.032, Fisher's exact test).

HH types and measurements

Hyperkinesia incidence increased progressively from type I to type III as follows 2/11(18%, type I), 4/15 (26%, type II), 11/17 (64%, type III) (p=0.02, Pearson Chi-Square, type I-III). Heteroaggression incidence was higher with presence of hyperkinesia 16/17 (94%) in HHs with hyperkinesia and 18/31 (58%) in HHs without hyperkinesia (p=0.009, Fisher's Exact).

HETERO-AGGRESSION

Thirty four patients (70.8%) presented hetero-aggression. Incidence was 16/18 (88.9%) of HHs involving medial and lateral hypothalamus and 18/30 (60%) of HHs involving the periventricular hypothalamus alone (p=0.03, Pearson Chi-Square).

Hyperkinesia incidence was higher in presence of heteroaggreion; 16/34 (47%) in HHs with heteroaggression and 1/14 (7%) in HHs without heteroaggression (p=0.009, Fisher's Exact). Furthermore; the epileptic hamartoma of the hypothalamus offers a new fundamental model of sub-cortical origin of the epileptic zone [START_REF] Kerrigan | The hypothalamic hamartoma: a model of subcortical epileptogenesis and encephalopathy[END_REF] . Through its clinical uniqueness and intrinsic epileptogenic capacity [START_REF] Kahane | From hypothalamic hamartoma to cortex: what can be learnt from depth recordings and stimulation?[END_REF][START_REF] Kameyama | Ictogenesis and symptomatogenesis of gelastic seizures in hypothalamic hamartomas: an ictal SPECT study[END_REF][START_REF] Munari | Role of the hypothalamic hamartoma in the genesis of gelastic fits (a video-stereo-EEG study)[END_REF] , it is a turning point in our understanding of the epilepsy since mid-1990s [START_REF] Andermann | Hypothalamic hamartoma and epilepsy: the pathway of discovery[END_REF] .

RADIOSURGERY EPILEPSY OUTCOME

Radiological topography of the lesion is always well informative and helpful for clinical prediction and management decisions. An agreement exists that hamartomas associated with epilepsy have sessile displacing attachment to the hypothalamus, whereas those associated with precocious puberty alone are pedunculated [START_REF] Debeneix | Hypothalamic hamartoma: comparison of clinical presentation and magnetic resonance images[END_REF] . The intra-ventricular versus inter-cisterna lesions can reflect its cellular and neuroendocrine potential [START_REF] Freeman | MR Imaging and Spectroscopic Study of Epileptogenic Hypothalamic Hamartomas: Analysis of 72 Cases[END_REF] . The importance of the intra-hypothalamic part associated with seizures is a subject of great interest [START_REF] Arita | The relationship between magnetic resonance imaging findings and clinical manifestations of hypothalamic hamartoma[END_REF] . Close relation to fornix, mammilothalamic tract, and MB was a clear observation in epileptic hamartoma [START_REF] Freeman | MR Imaging and Spectroscopic Study of Epileptogenic Hypothalamic Hamartomas: Analysis of 72 Cases[END_REF] . The surgical strategy must be based on both the topographic type of the lesion and the clinical severity [START_REF] Régis | Gamma knife surgery for epilepsy related to hypothalamic hamartomas[END_REF][START_REF] Régis | Gamma knife surgery for epilepsy related to hypothalamic hamartomas[END_REF] . Further studies are required to investigate this anatomical correlation in detail.

RELATION TO HYPOTHALAMIC COMPLEX

Several studies separately investigated the role of different hypothalamic areas in the field of epilepsy, PP, psychiatric diseases and aggression. MB and lateral hypothalamus were studied for the possible propagation pathways from the epileptic HH. Each group of Kahane et al. [START_REF] Kahane | From hypothalamic hamartoma to cortex: what can be learnt from depth recordings and stimulation?[END_REF] and Kameyama et al [START_REF] Kameyama | Ictogenesis and symptomatogenesis of gelastic seizures in hypothalamic hamartomas: an ictal SPECT study[END_REF] proposed two different pathways for HH epilepsy and cognitive presentation [START_REF] Prigatano | Intellectual functioning in presurgical patients with hypothalamic hamartoma and refractory epilepsy[END_REF] ; "mamillo-thalamo-cingulate" and "thalamoponto-cerebellar", respectively. The former pathway included the "MB", while the latter pathway included "lateral hypothalamus", tegmentum, and mediodorsal nucleus of thalamus [START_REF] Kameyama | Ictogenesis and symptomatogenesis of gelastic seizures in hypothalamic hamartomas: an ictal SPECT study[END_REF] . However, in the current study, contact of MB was always present, and higher seizures frequency was found in HHs extending towards lateral hypothalamus and eventually linked to mediodorsal nucleus of thalamus, these findings could support both pathways.

Tuberal region and TC involvement were always important for PP. The mechanism of PP is either by being autonomous-heterotopic pulsatile GnRH cells in HH or disinhibition by compression of inhibitory impulse of hypothalamus. Both require close location toward the pituitary stalk and especially, the median eminence containing the axons of GnRH neurons [START_REF] Harrison | Hypothalamic hamartoma with epilepsy: Review of endocrine comorbidity[END_REF] . In the current study, tuberal region and TC were clearly associated with PP.

The lateral hypothalamus has an important role in hypothalamic aggression area and sends fibers to mediodorsal nucleus of thalamus [START_REF] Groenewegen | Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography[END_REF][START_REF] Roeling | Efferent connections of the hypothalamic "aggression area" in the rat[END_REF] and medial forebrain bundle in defensive and predatory aggression, which became a target for deep brain stimulation to treat aggression [START_REF] Torres | Deep brain stimulation for aggressiveness: long-term follow-up and tractography study of the stimulated brain areas[END_REF] . Our series demonstrated a direct relation between heteroaggression, psychiatric and school impairment, and lateral hypothalamus involvement and HH width. Hyperkinesia and heteroaggression were related to medial hypothalamic lesions [START_REF] Wiener | Acute hyperkinesia after hypothalamic lesions: A comparison of the time course, level, and type of hyperkinesia induced by ventromedial and lateral hypothalamic lesions in rats[END_REF] , while in current study we found it higher in HHs involving the medial hypothalamus.

HH topography (lateral extension) was the main factor in the presence of psychiatric and behavioral comorbidities before GKS. Furthermore, presence of these psychiatric comorbidities did not affect the epilepsy outcome after GKS. However, better epilepsy outcome (Engel I, II) was associated with higher incidence of psychiatric improvement after GKS.

Current study analysed the presence of psychiatric and behavioral abnormalities as a categorical variable (yes/no) which requires further studies with more comprehensive objective test and scales. Complexity variation of HH presentation and necessary longterm evaluation are common limitations. Accordingly, very few reports succeeded to study the psychiatric [START_REF] Arocho-Quinones | Improvement of Hypothalamic Hamartoma-Related Psychiatric Disorder After Stereotactic Laser Ablation: Case Report and Review of Literature[END_REF][START_REF] Killeen | Psychiatric comorbidity with hypothalamic hamartoma: Systematic review for predictive clinical features[END_REF] and cognitive [START_REF] Wagner | Cognition in epilepsy patients with hypothalamic hamartomas[END_REF][START_REF] Wethe | Cognitive functioning before and after surgical resection for hypothalamic hamartoma and epilepsy[END_REF] condition with detailed comprehensive analysis.

NON-LESIONAL GS AND NON-HYPOTHALAMIC EPILEPTIC HAMARTOMA

Recently, Iapadre et. al. 2020 [START_REF] Harvey | Epilepsy in hypothalamic hamartoma: clinical and EEG features[END_REF] Presence of the hamartoma at hypothalamus makes epilepsy more complex.Presence of HH and other brain abnormalities in epileptic patients could make the disease more severe and complex for management in terms of earlier onset and less favorable outcome because of additional epileptogenic capacity. 4) Type I-III and combined approach for others [START_REF] Régis | Gamma knife surgery for epilepsy related to hypothalamic hamartomas[END_REF][START_REF] Régis | Achieving a cure for hypothalamic hamartomas: a Sisyphean quest?[END_REF][START_REF] Régis | Safety and efficacy of Gamma Knife radiosurgery in hypothalamic hamartomas with severe epilepsies: A prospective trial in 48 patients and review of the literature[END_REF][START_REF] Régis | Gamma knife surgery for epilepsy related to hypothalamic hamartomas[END_REF] . The current study confirmed that intra-ventricular HH types I-III have a very high incidence to respond well after GKS (74% Engel I-II) rather than other HH types. Seizures and cognitive comorbidities were more common in the sessile hamartomas either non-displacing the hypothalamus (Type IIa) or distorting the ventricle (Type IIb) [START_REF] Valdueza | Hypothalamic hamartomas: with special reference to gelastic epilepsy and surgery[END_REF] . In the current study, quantitative measurement demonstrated that larger total HH volume, extra-HH volume, and more anterior involvement of tubular region and tuber cinereum were associated with higher incidence of PP. and 18 years old) with unusually small HH (5 mm diameter), with unusual symptom of daily "pressure to laugh with mirth", refractory to anti-convulsant medications, and often without actual laughter which could be dismissed as psychogenic [START_REF] Sturm | Pressure to laugh": an unusual epileptic symptom associated with small hypothalamic hamartomas[END_REF] . In the current study, two patients clearly reported "pressure to laugh" short time before being seizure free and they had small intra-hypothalamic HH. They found that the bigger size of the HH was associated with greater number of seizures and earlier-age at seizures onset [START_REF] Mullatti | The clinical spectrum of epilepsy in children and adults with hypothalamic hamartoma[END_REF] . The current study demonstrates that the more involvement of HH deeply within the hypothalamus, the more the frequency of total seizures per month and more psychiatric comorbidities. Larger HH volumes and dimensions were associated with earlier age at FOIA onset. Intra-hypothalamic types (I-III) had lower incidence of PP than other types (IV-VI) as in Mullati study. Again, the total seizures frequency is affected more by the direction of HH extension into the hypothalamus rather than the absolute HH volume.

TOPOGRAPHY CLASSIFICATION IN THE LITERATURE (Table

In
Fohlen and Delalande (2003) classified 17 HHs within surgically-oriented classifications according to the plane of insertion to hypothalamus, into"horizontally" inserted hamartoma (Type I, pterional complete disconnection), "vertically" inserted ntraventricular hamartoma (Type II, endoscopic disconnection), "horizontal and vertical" plane of insertion (Type III, combined; endoscopy then pterional), and the "giant" lesion with non-specific surgical rules (Type IV) [START_REF] Delalande | Disconnecting surgical treatment of hypothalamic hamartoma in children and adults with refractory epilepsy and proposal of a new classification[END_REF] . Modified classification was added in 2004 to include other surgical modalities [START_REF] Choi | Endoscopic disconnection for hypothalamic hamartoma with intractable seizure. Report of four cases[END_REF] . In the current study, type I-III (Regis classification) was anatomically consistent with type II (Delalande classification)

and both are good candidates for GKS and endoscopy, respectively. However, the latter carries risks of short term memory worsening, endocrinological disturbance (hyperphagia with obesity, low thyroxine, sodium metabolism disturbance) and thalamic or thalamocapsular infarction have been reported even in the hands of highly skilled neurosurgeons which had never been reported after GKS. Ninety-seven percent had intra-hypothalamic extension displacing the postcommissural fornix, mammillothalamic tract, and hypothalamic gray matter anterolateral. PP were more frequently related with the tuber cinereum [START_REF] Freeman | MR Imaging and Spectroscopic Study of Epileptogenic Hypothalamic Hamartomas: Analysis of 72 Cases[END_REF] . Also, the asymmetry of HH attachment can correlate with asymmetries in clinical seizure characteristics [START_REF] Harvey | Epilepsy in hypothalamic hamartoma: clinical and EEG features[END_REF] . In the current study, HH displacement inside hypothalamus was more detailed in fine topography classification. and slice thickness and interslice distance in each case.PP was associated with larger HH [START_REF] Parvizi | Gelastic epilepsy and hypothalamic hamartomas: neuroanatomical analysis of brain lesions in 100 patients[END_REF] . The current study used the slice by slice drawing tool for volume calculation. Significant prognostic factors for surgical outcome were HH size, surgical approach, and resection level [START_REF] Li | Classification of hypothalamic hamartoma and prognostic factors for surgical outcome[END_REF] . In the current study, HHs type IV-Mx had higher PP incidence than others while smaller HH responded better to GKS as to resection, which may be related to easiness of open total resection in smaller HH but of course with surgical risk.

Most of the patients were type I-III and few patients were IV-Mx. No significant difference was found between two sub-groups (HHs type I-III, HHs type IV-VI) apart from epilepsy outcome and presence of PP. However, further studies may include more patients of type IV-Mx to demonstrate any potential difference

In current study, all fine anatomical patterns and invaded hypothalamic areas did not affect epilepsy outcome after GKS. All these patterns responded well to GKS when HH was smaller (Type I-III). Interaction between the neuromodulatory effect of GKS and HH could be the main factor for epilepsy outcome whatever the invaded hypothalamic area according to cellular mechanism [START_REF] Kerrigan | Hypothalamic hamartomas: neuropathological features with and without prior gamma knife radiosurgery[END_REF] .

CONCLUSION

Clinical presentation of epileptic hypothalamic hamartoma is significantly affected by fine topography patterns and invaded hypothalamic areas. Gamma Knife Radiosurgery effect is better and rapid in smaller hamartoma (Type I-III) and seizure outcome was not affected by the invaded hypothalamic areas.

ACKNOWLEDGEMENT

We would like to thank Wesley Clawson for his valuable scientific contribution and reviewing the manuscript before submission.

CONFLICT OF INTEREST

Authors had nothing to declare regarding any kind of conflict of interest. There are no materials required permission for submission and publications.

FIGURES

DISCUSSION 4 . 1 .

 41 EPILEPTIC HYPOTHALAMIC HAMARTOMAHH has strong anatomical-clinical correlations in the clinical presentation[START_REF] Harrison | Hypothalamic hamartoma with epilepsy: Review of endocrine comorbidity[END_REF] .

Marseille in 1969 ,

 1969 Paillas et al. first demonstrated the epileptic HH with its radiological and histopathological features[START_REF] Paillas | Hamartoma of the hypothalamus. Clinical, radiological and histological study. Results of excision[END_REF] . Regis et al.(2000) considered that HH surgical strategy must be based on topological type and clinical severity. They classified HHs into small inside hypothalamus (Type I), small mainly inside the III ventricle (Type II), essentially on the floor of III ventricle (Type III), sessile in the cistern (Type IV), pedunculated (Type V), and giant (Type VI). They highly recommended GKS for

  Boyka et al. (1991) classified 5 biopsy-proved HHs into epileptic "sessile", with broadbased attachment to hypothalamus, and "pedunculated" type with narrow-based attachment presented with PP 4 . Valdueza et al. (1994) classified 42 HHs according to size (small or large), location (tuber cinereum, MB), displacement (missing or marked), and attachment to hypothalamus (pedicellate or sessile). The PP was associated with the pedunculated HH attached to either the hypothalamus (Type Ia) or MB (Type Ib).

Freeman et al. ( 2004 )

 2004 studied72 epileptic HHs and illustrated that epileptic HH were always involving the mammillary region and attached to MB unilaterally or bilaterally.

  Parvizi et al. (2011) examined 100 epileptic HHs at level of posterior hypothalamus and MB. The volume of lesions and the proximity to the MB were not different between the patients with gelastic seizures only and patients with other seizures types. Larger HH volume was correlated with presence of precocious puberty, cognitive comorbidity, and developmental delay. An equation was used for volume measurement (W*H*L)/6

  Li et al. (2014) reviewed 214 surgically-resected HHs and classified them into "extraventricular" HH attached to the floor of III ventricle with narrow (Type I, highest percentage of PP 81.8%) or broad (Type II) attachment. HH extending in the ventricle and the interpeduncular cistern "'straddling" was (Type III), and HH located totally within the third ventricle was (Type IV, highest percentage of gelastic seizures, 91.7%).

Figure 1 :Figure 2 :Figure 3 :Figure 4 :Figure 5 :

 12345 Figure 1: Diagram shows the hypothalamic three sagittally-oriented regions (right) and three coronally-oriented zones (left). The three regions are divided by two planes crossing the anterior end of mammilary body and pituitray stalk. The three zones are divided by the sagittal plane crossing the antierior pillar of the fornix, while the peri-ventricular zone arround the ventricle is limited within 5mm interval from the midline of the third ventrcile.

Figure 3). HH length, height, and width were

		Total and extra-HH volume (not intra-HH) was significantly larger in PP sub-group Mann-Whitney) and average total frequency and range was 655 (6-12000) and 15 (5-
		22), while average GS frequency was 114 (8-6000) and 10 (5-16), respectively. (p=0.01, p=0.03, p=0.06, Mann-Whitney, respectively) (as shown in higher in patients with PP (p=0.04, p=0.02, p=0.01, HHs not contacting PS required larger volume then HHs volume not in contact to PS
		respectively, Mann-Whitney). Earlier age of onset of PP was correlated with larger (p=0.03, Mann-Whitney test) average volume and range was 1406 (1312-1500) and
		total volume (p=0.05, r= -0.48, Spearman's Rho). 498 (28-1600).
	3.1.3. Clinical Presentation 3.2.2. HH types and measurements
		Due to volume effect, an earlier age of onset for FOIA was observed in PP Age of onset of FOIA was 69 (1-207) months. The earlier age of onset of FOIA was
		subgroup than in those without PP (p=0.001, Mann-Whitney) as mean age and correlated with larger HH; in term of volume (p= 0.02, rs-0.73) and width (p=0.008,
		range was 3.7(0-10) and 8 (1.7-17.25) years, respectively. rs -0.43), length (p= 0.018, rs -0.38), height (p= 0.04, rs-0.34) (as shown in Figure 4).
	3.1.4 Outcome Presence of the "Status Epilepticus" (SE) during disease duration (N=15, mean age
		HHs without PP had a trend to respond well 20/25 (80% Engel I-II) than HH with of onset was 138 months, range 16-257) was associated with larger HH width
		PP 13/23 (57% Engel III-IV) (p=0.07, Fisher's exact) which might be due to (p=0.04, Mann-Whitney) and HHs width with SE; mean 9.3 (5-19), HHs width
		volume effect. without SE; mean 7.5 (3.7-22.5) mm.
	3.2.	SEIZURES SEMIOLOGY BEFORE GKS
	3.3.	More severe epilepsy and higher seizure frequency were observed when HH PSYCHIATRIC COMORBIDITIES
		extended laterally into the hypothalamus and not towards the PS. Early onset FOIA 3.3.1. Hypothalamic regions and zones involved
		was observed in larger HHs. Before GKS, 38 (79%) patients had psychiatric and behavioral comorbidities. Lateral
	3.2.1. Hypothalamic regions and zones involved extension of HH inside the hypothalamus was the main factor for presence of
		Total seizure frequency before GKS was 107.3 (5-12,000) seizures per month while psychiatric comorbidities. 14 (77.8%) patients out of 18 HHs involving the medial
		GS frequency was 62 (1-1100) seizures per month.. HHs involving medial and lateral hypothalamus had severe psychiatric comorbidities while only 9 (30%) patients out
		hypothalamus presented higher total seizure frequency (average per month) than of 30 HHs without this involvement had severe psychiatric comorbidities (p=0.01,
		HHs involving periventricular zone alone (p=0.03, Mann-Whitney) and average Fisher's exact test).
	5 PP / 5 HHs (100%) of type IV-VI-Mixed (p=0.01, Chi-square). Total HH volume frequency and range was 1226 (5-12000) and 207 (5-1520) seizure per month, 3.3.2. HH types and measurements
		correlated with extra-HH volume (p=1.5X10 -28 , rs +0.97, Spearman Rho) more than respectively. Regions involved had no effect (p>0.05, Kruskal test).
		The patients with a normal school performance have a less HH width on average
		All the epileptic HHs had MB contact. HH not contacting PS (N=45) presented
		than the patients with impaired school performance (p=0.04).
		higher seizure frequency per month than HHs contacting PS (N=3) (p=0.039, p=0.03,

intra-HH volume (p=0.009, rs +0.39, Spearman Rho).

3.3.3. Effect of GKS

After GKS, 12/38 (31.6%) patients were cured (all of them Engel I+II) and 19/38 (50%) patients showed improvement of psychological condition while 7/38 (18.4%) patients remained stable. Separate statistical analysis for these 38 patients did not show association between HH topography and psychiatric outcome after GKS (p>0.05, Kruskal-Wallis, Chi-Square). However, positive response to GKS (Engel I+II) and shorter disease duration were the main two factors for psychiatric improvement after GKS (p=0.017, Chi-Square, p=0.02, Mann-Whitney).

27

/38 (71.1%) patients were Engel class I+II; 12 cured, 12 improved, and 3 remained stable regarding the psychiatric condition while 11/38 (28.9%) patients were Engel III-IV;

  studied 30 pediatric patients presented with non-HH GS with or without brain abnormalities (N=11, N=19, respectively). Patients without these abnormalities presented late-onset disease (median 4.5 years, range 1 month -12 year) and more favorable outcome in terms of seizure outcome (90% seizure freedom), EEG normalization, and AEDs, in comparison with others.

	Another unique series of 13 patients (age: 6-33 years) presented with non-hypothalamic
	epileptic cerebral hamartomas (totally resected and histopathologically-confirmed),
	studied by Volk et. al. in 1997 35 , showed late-onset disease (mean 11y range 1-22) and
	better reduction of seizures (90%) earlier onset than HH series. All non-hypothalamic

epileptic Hamartomas demonstrated location specific epilepsy with corresponding clinical characteristics (7 temporal, 5 frontal, 1 occipital). They are composed of neurons and astrocytes (Like HH).

Table 1 .

 1 Demographic and clinical characteristics.

	Subjects
	Gender	27 (56.3%) Male / 21 (43.7%) Female
	Age	Median 16.5 years (3-50)
	Total SeizuresFrequency	107.3 s/m (5-12,000)
	ClinicalPresentation
	Age First Gelastic (months)	11.8 (1-182)
	Age First Focal non-aware	69 (1-207)
	PrecociousPuberty	23 (48%)
	PsychiatricComorbidity	38 (79%)
	Hyperactivity	17 (35%)
	Heteroaggression	34 (70.8%)
	Schooldifficulties	21 (41.7%)
	HH Morphology
	HH Volume	398 mm 3 ± 425 (79.4-1,600)
	Intra HH Volume	90 mm 3 ± 98.5 (10-465)
	Extra-HH Volume	282 mm 3 ± 396 (61-1506)
	HH Length	10.1 mm ± 4.1 (4.8-23.1)
	HH Height	9 mm ± 4 (4.3-23.4)
	HH Width	6.9 mm ± 3.9 (3.7-22.5)
	Dominant Attachment	28 left (58.3%) / 20 right (41.7%)
	HH Type I	11 (22.9%)
	HH Type II	15 (31.3%)
	HH Type III	17 (35.4%)
	HH Type IV	1 (2.1%)
	HH Type V	1 (2.1%)
	HH Type VI	1 (2.1%)
	HH Type Mixed	2 (4.2%)
	(Table colours are not required)

Table 2 . Summary of HH topography and morphology correlation with clinical variables.

 2

	Topography / Morphology	Results

Table 3 :

 3 Incidence rate of the current topography study (N/N*).

	Fine Topography	Clinical Preentation	Psychiatric Comorbidity	Precocious Puberty	Hyperkinesia	H.Aggression	Responders	Non-Responders	Tranisent Increased Seizures
				HH	%	N	%	N	%	N	%	N	%	N	%	N	%	N	%
			N*	48	100%	38	79.2%	23	47.9%	17	35.4%	34	70.8%	33	68.8%	15	31.3%	8	16.7%
		Mammillar.	<50% >50% Total	7 21 20	14.6% 43.8% 41.7%	6 15 17	85.7% 71.4% 85%	2 9 12	28.6% 42.9% 60%	5 5 7	71.4% 23.8% 35%	6 12 16	85.7% 57.1% 80%	6 16 11	85.7% 76.2% 55%	1 5 9	14.3% 23.8% 45%	0 1 7	0% 4.8% 35%
	Region	Tuberal	<50% >50% Total	10 27 11	20.8% 56.3% 22.9%	7 23 8	70% 85.2% 72.7%	2 12 9	20% 44.4% 81.8%	2 12 3	20% 44.4% 27.3%	7 19 8	70% 70.4% 72.7%	8 18 7	80% 66.7% 63.6%	2 9 4	20% 33.3% 36.4%	2 4 2	20% 14.8% 18.2%
		Supraoptic	No Partial Total	43 4 1	89.6% 8.3% 2.1%	34 3 1	79.1% 75% 100%	19 3 1	44.2% 75% 100%	15 2 0	34.9% 50% 0%	30 3 1	69.8% 75% 100%	31 2 0	72.1% 50% 0%	12 2 1	27.9% 50% 100%	8 0 0	18.6% 0% 0%
	Contact		MB TC PS	48 28 3	100% 58.3% 6.3%	38 24 3	79.2% 85.7% 100%	23 23 3	47.9% 82.1% 100%	17 12 1	35.4% 42.9% 33.3%	34 21 3	70.8% 75% 100%	33 18 2	68.8% 64.3% 66.7%	15 10 1	31.3% 35.7% 33.3%	8 4 1	16.7% 14.3% 33.3%
		Peri-ventricular	30	62.5%	20	66.7%	9	30%	7	23.3%	18	60%	22	73.3%	8	26.7%	3	10%
	Zone	Medial Hypoth Lateral Hypoth.	16 2	33.3% 4.2%	16 2	100% 100%	12 2	75% 100%	10 1	62.5% 50%	16 2	100% 100%	11 1	68.8% 50%	7 1	43.8% 50%	5 1	31.3% 50%
			I	11	22.9%	9	81.8%	3	27.3%	2	18.2%	8	72.7%	9	81.8%	2	18.2%	1	9.1%
	HH Type		II III	15 17	31.3% 35.4%	11 14	73.3% 82.4%	3 12	20% 70.6%	4 11	26.7% 64.7%	8 14	53.3% 82.4%	10 13	66.7% 76.5%	5 4	33.3% 23.5%	4 1	26.7% 5.9%
			VI-Mx	5	10.4%	4	80%	5	100%	0	0%	4	80%	1	20%	4	80%	2	40%

(Table colours are not required)

Table 4 .

 4 HH MR-based classificationsin literature for clinical prediction and surgery decision making.

	Authors		Year	HH Type	Type Description			Prediction / Decision
	Boyka 4		1991	Sessile	Broad-based attachment			Epilepsy
				Pedunculated	Narrow-based attachment			Epilepsy and PP
	Valdueza 36		1994	Type Ia	Pedunculated attached to the tuber	Low-risk surgery in
					cinereum,	completely	undistorted	young	patients,
					hypothalamus.			Asymptomatic or PP,
										long-acting	LHRH
										analogues
				Type Ib	Pedunculated attached to the mammillary	High risk surgery, PP,
					body or hypothalamus, completely	medical treatment
					undistorted hypothalamus.
				Type Iia	Sessile non-displacing the hypothalamus,	High risk surgery,
					larger than 1.5 cm.			Epilepsy,	Memory
										problem, Rare PP.
				Type IIb	Sessile distorting the third ventricle,	High risk surgery,
					partially within the hypothalamus and the	Epilepsy, Behavioral
					third ventricle.			disorder, Rare PP.
	Arita 2		1999	Intra-Hypothalamic Distorting the third ventricle			Epilepsy
				Para-Hypothalamic	Attached to the floor of the third ventricle	Epilepsy and PP
	Sturm 33		2000	Very small HH (<5mm) can produce drug-resistant "pressure to laugh" without actual
				seizures
	Striano 32		2002	Direct correlation between HH size and seizure severity
	Mullati 21		2003	Small HH	Less than 10 mm length			Late-onset seizures
				Large HH	More than 10 mm length			Early-onset seizures
	Freeman 10		2004	Epileptic HH	More attached to ventricle and MB
				PP-associated HH	More attached to the tuber cinereum
	Fohlen	and	2003	Type I	HH	is	horizontally	inserted	on	Pterional Approach
	Delalande 8				hypothalamus
				Type II	HH is vertically inserted to hypothalamus	Endoscopic Approach
					and intraventricular
				Type III	HH is horizontally and vertically inserted	Combined Approach
					to hypothalamus
				Type IV	Giant					Combined Approach
	Harvey	and	2007	Symmetrically	Symmetrical Clinical Picture
	Freeman 13			Attached HH
				Asymmetrically	Asymmetrical Clinical Picture
				Attached HH
	Parvizi 25		2011	Posterior HH	Posterior Hypothalamus			Epilepsy
				Anterior HH	Anterior Hypothalamus			PP
	Li 19		2014	Type I	Extending into inter-peduncular cistern	PP
					with narrow base
				Type II	Extending into inter-peduncular cistern	PP
					with broad-base
				Type III	Extending between the ventricle and the	Epilepsy
					cistern "'straddling"
				Type IV	Within the third ventricle			Epilepsy
	Regis 27-30		2000	Type I Type II Type III Type IV Type V	Deeply in the hypothalamus Mainly inside the third ventricle On the floor of third ventricle Sessile, extra-ventricular Pedunculated, extra-ventricular		Type I, II and III are good candidates for GKS, IV and V for combined approach