Hypothalamic hamartomas in adulthood: Clinical spectrum and treatment outcome—A unicenter experience (2024)

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Data Availability Statement

Abstract

Keywords: adult, epilepsy, hypothalamic hamartoma, radiosurgery, seizures, treatment, vagus nerve stimulation

1. INTRODUCTION

Hypothalamic hamartomas (HH) are composed of ectopic neural and glial tissue and represent a notable etiology of treatment‐resistant epilepsy. Two different clinical phenotypes are described depending on the location of the hamartoma. Those HH that invade mainly the anterior hypothalamus may develop endocrinological disturbances such as central precocious puberty (CPP) and those HH affecting the posterior hypothalamus and the mammillary bodies associate drug‐resistant seizures that usually start in the early childhood as gelastic seizures (GS) (Harrison, Oatman, & Kerrigan, 2017; Kerrigan et al., 2017).However, HH have a wide clinical expression spectrum (Mullatti et al., 2003; Striano & Striano, 2017) that ranges from a few seizures with normal cognitive development to a catastrophic epileptic encephalopathy (EE) resembling a Lennox‐Gastaut‐like syndrome with cognitive impairment and severe behavioral disturbances (Cross & Spoudeas, 2017; Scheffer et al., 2016). We present the clinical features, electroencephalographic (EEG) recordings, imaging findings, and therapeutic options in a series of adult patients with epilepsy due to hypothalamic hamartoma.

2. MATERIAL AND METHODS

We reviewed all patients with epilepsy and HH referred to the Epilepsy Unit of Hospital Clínic (Barcelona, Spain) between 2003 and 2018. We included those patients with history of seizure and magnetic resonance imaging (MRI) evidence of an HH defined by a T2‐weighted image hyperintense and T1‐weighted image hypointense lesion, that involves the hypothalamus, mammillary regions, tuber cinereum, and/or third ventricle floor. Patients with dual pathology were also included.

Evaluation included a detailed clinical history and examination. We analyzed treatment choices, age at evaluation and seizure onset, sex, type of seizures according to the International League Against Epilepsy (ILAE) classification (Delalande & Fohlen, 2003), frequency of seizures, scalp EEG or video‐EEG recordings, MRI findings according to the Delalande and Fohlen classification (Palmini, Paglioli‐Neto, Montes, & Farmer, 2003), endocrine disturbances, psychiatric comorbidities, cognitive status, current antiepileptic drug (AED) therapy, and nonpharmacological treatment of the HH. We report single photon emission computed tomography (SPECT) and subtraction ictal SPECT coregistered to MRI (SISCOM) results, when obtained during admission in patients who went through presurgical evaluation. Nonpharmacological treatment is discussed. The study was approved by the Healthcare Ethics Committee of the Hospital Clínic de Barcelona.

3. RESULTS

4. DISCUSSION

Our series is a good example of the variable clinical expression of HH in the adult age and its low prevalence. HH is a rare condition, with an estimated prevalence of 1–2 cases per 100,000 population (Striano et al., 2012). We practice at a referral center in Spain for drug‐resistant epilepsy, and we identified eight patients in our database. We could not find any patients with frank GS in the context of frontal or temporal lobe epilepsy, without associated HH. HH is usually sporadic, but in 5% of cases can be associated with the Pallister‐Hall syndrome (Georgakoulias, Vize, Jenkins, & Singounas, 1998; Scheffer et al., 2016). The initial presentation in the sporadic cases usually occurs in the first months of life as GS. In 50% of the cases, it may progress to a disabling epileptic syndrome with multiple types of seizures typically refractory to antiepileptic therapy resembling a severe encephalopathy with possible additional features such as endocrinological and psychiatric disturbances (Kerrigan et al., 2017; Ng et al., 2006; Oehl et al., 2010; Striano et al., 2012).

Our series also illustrates that diagnosis may be challenging specially in the most benign cases. Patient No. 4 had very short focal seizures with consciousness impairment and mild GS, that he defined as mirth or “pressure to laugh” and which had a minor impact in his quality of life. He was diagnosed of HH in our Unit, 25years after seizure onset at 27years of age. This case represents a mild end to the clinical spectrum and reminds us of the fact that cognitive or behavioral disturbances may not always be present as previously stated (Striano et al., 2002).

Children with HH‐epilepsy usually have no cognitive impairment prior epilepsy onset; however, after seizures begin, especially if this happens at an early age, patients develop progressively behavioral deterioration and developmental delay, such as oppositional defiant disorder (83%), attention deficit/hyperactivity (75%), aggression (89%), behavioral disorder (33%), speech disorder/learning impairment (33%) and anxiety and mood disorders (17%) (Cross & Spoudeas, 2017). The deterioration seems more obvious in those patients who develop an EE and not only GS. Patients without cognitive and behavioral deterioration present minor attacks, mild GS and often smaller lesions that did not protrude into the lumen of the third ventricle (Striano, Striano, Sarappa, & Boccella, 2005).

Most of the patients in our series had 1 or 2 seizure types starting at the age of 2years or afterward, presented type II HH in MRI and had no psychiatric disorders. Patients with the most severe behavioral alterations and neurodevelopmental delay (patients No. 3 and No. 8) presented daily, different seizure types since early childhood and displayed lesions invading the third ventricle. Size was variable and patients with longer epilepsy duration had smaller median size than those with less duration of the disease with a negative correlation coefficient (r: −.4751) not statistically significant (p: .19) due to the low sample number.

There is not a definitive predictor of evolution patterns and clinical variability in HH patients but it is known that clinical expression and syndrome severity are related to the dimension, location, and attachment of the HH (Georgakoulias et al., 1998). Often the sessile masses associate epilepsy and the pedunculated ones may be related to endocrinological disturbances and/or to visual impairment (Kameyama, Masuda, & Murakami, 2010). Some authors suggest that larger hamartomas are frequently associated with higher seizure severity, cognitive impairment, and behavioral disorder as signs of EE probably due to hypothalamic‐thalamic‐mammillary connections dysfunction (Deonna & Ziegler, 2000; Frattali et al., 2001; Prigatano, 2007; Tezer, Pektezel, Gocmen, & Saygi, 2014). In our experience, the most severe cases with pronounced cognitive decline were the ones that started earlier with GS, suggesting that age of onset may also play a predictor role in HH‐ES outcome. Severity may be also related to duration of epilepsy, the cases who started earlier and did not achieve seizure freedom may progress to an EE. However, patient No. 5 presented a giant hamartoma and early onset of GS but showed no developmental delay, behavioral or psychiatric problems. This raises the question of whether location and invasion of close structures may be the most important factors related to epilepsy severity.

The hamartoma location influences the regulation of hormone release. Pedunculated HH occupying the anterior hypothalamus (Type I) may cause endocrinological disturbances, being the CPP the most frequent one, probably because of a premature pulsatile release of gonadotropin‐releasing hormone (GnRH) from the hypothalamus (Harrison et al., 2017; Striano & Striano, 2017). CPP and epilepsy coexist in up to 45% of the patients undergoing surgical treatment for epilepsy (Oehl et al., 2010). Other disturbances include secondary or tertiary hypothyroidism and weight gain with obesity. Infrequent comorbidities are Addisonian crisis and central diabetes. Sleep disturbances like hypersomnia (Dunn, Deroo, & Rivara, 2001) and reduction in REM sleep have been described and may worsen seizure severity (Cross & Spoudeas, 2017; Troester et al., 2011). None of the patients in our series had history of CPP, even when masses were large enough to invade the anterior hypothalamus. Two patients presented hypothyroidism and another one severe central obesity and dyslipidemia.

The EEG monitoring shows a wide disparity too. Routine (interictal) recordings range from normal EEG results to multiple interictal epileptiform features demonstrating generalized, multifocal, and/or focal discharges and suggesting that EEG is not a specific test for the diagnosis of HH‐epilepsy disorders (Scholly et al., 2013). Ictal recordings may be variable too, though GS show no obvious ictal changes in the majority of events (Gutierrez et al., 2016), non‐GS may show epileptic activity mainly in frontal and temporal lobes (García‐Morales et al., 2007; Scholly et al., 2013).

This lack of electric correlate, especially in patients with subtle GS, makes the diagnosis of HH‐ES challenging in patients with less severe seizures. Scholly et al. introduced the concept of “hypothalamic plus” epilepsy, as a result of secondary epileptogenesis mechanisms referring to the functional involvement of the frontal and temporal lobes in the HH epileptogenic network (Kerrigan, Ng, Chung, & Rekate, 2005; Régis et al., 2017; Striano & Striano, 2017). In our study, one patient showed unilateral HS and another patient had bilateral HS. This findings may relate to potential secondary epileptogenesis which is probably linked to the anatomic and functional connectivity of the hypothalamus with frontal lobes, limbic system, and thalamus (Wu, Gao, Shen, Qiu, & Kerrigan, 2015). HH has been demonstrated to be an intrinsically epileptogenic lesion from stereoelectroencephalography recordings within the lesion (Kahane, Ryvlin, Hoffmann, Minotti, & Benabid, 2003; Munari et al., 1995). Kahane et al. proposed a pathway based on the HH strong connectivity to mammillo‐thalamo‐cingulate tract that could spread epileptic activity to the cingulate and from here to temporal or frontal areas. A secondary “kindling”‐like effect of the primary HH could explain why these interconnected brain areas develop the ability to independently generate seizures (Harvey & Freeman, 2007; Kahane et al., 2003).

Cellular mechanisms responsible for epileptogenesis are unknown but the intrinsic epileptogenicity of HH was explained by the microanatomic organization and electrophysiologic characteristics of HH neurons. The predominant type of neurons are small HH neurons (SHH), they account for approximately 90% of the cells and they have a tendency to cluster (Fenoglio et al., 2007). These SHH appear to have an interneuron‐like phenotype that expresses γ‐aminobutyric acid (GABA) and a tendency for intrinsic pacemaker‐like firing activity. There are also large HH (LHH) neurons which are functionally immature and usually at rest but with paradoxical depolarization and firing in response to GABA ligands. LHH represent around 10% of the neuron population in HH tissue and seem to have a phenotype of excitatory projection‐type neuron by using excitatory glutamate as their primary neurotransmitter (Striano et al., 2002).

Treatment should be individualized depending on the radiological characteristics of the HH, AED response and tolerability, seizure severity, and availability of surgical techniques in each center. Epilepsy associated with HH is known to be in most cases drug‐resistant and there is no data whether medication makes any difference to the natural history of the condition or any longer‐term benefit (Scheffer et al., 2016). Most series however come from surgical centers and this may introduce a significant bias toward more severe cases.

Surgical treatment may have an effect on seizures and additional comorbidities producing a “running‐down‐like” phenomenon, stopping or even reverting the evolution of the HH‐ES and should be performed as early as possible (García‐Morales et al., 2007; Régis et al., 2017; Savard, Bhanji, Dubeau, Andermann, & Sadikot, 2003; Scholly et al., 2013; Striano & Striano, 2017). There is a variety of classical surgical techniques to treat HH including the endoscopic approach such as pterional, orbitozygomatic, or transcallosal interforniceal. However, endocrinological toxicity (malignant obesity, diabetes insipidus, etc.) and neuropsychological deterioration have been reported with these techniques. Radiosurgery with Gamma Knife (GK) was found to be a safe and effective option in the treatment of HH‐ES (Castinetti, Brue, Morange, Carron, & Régis, 2017). Régis et al. published a prospective series of 57 patients with HH treated with GK with a 3‐year follow‐up in 48 of them and a range of age from 3 to 50years. Good result (Engel class I or II) was achieved in 68.8% of the patients in terms of seizure control and none of the patients showed cognitive decline or disabling endocrinological deficits after treatment (Burrows et al., 2016). The latest surgical approach for HH associated with refractory epilepsy is the magnetic resonance imaging‐guided laser interstitial thermal therapy (MRg‐LITT), which offers the advantage of real‐time imaging of direct thermal ablation with minimal major surgical complications (Du, Gandhi, Rekate, & Mehta, 2017).

In our sample, only patient 6 was completely seizure‐free 2years after an elective LINAC procedure. This patient had a severe worsening of psychiatric symptoms which was attributed to a possible “forced normalization” process. The patient had a previous history of 2 AEDs‐related psychotic episodes, after trying Topiramate and Levetiracetam, respectively. No memory decline was observed 6years after radiosurgery but the patient still has many obsessive thoughts and excoriation disorder with compulsions of skin scratching. The two remaining patients treated with GK and LINAC did not show either a regression or improvement of the clinical symptoms induced by the HH. In our small series, radiosurgery induced necrosis was associated to a better seizure outcome, although no MRI data from the first surgery was available in patient number 3, who was operated in another country during childhood at 6years of age. The variability of results after radiosurgery may be attributed to several factors. Some studies postulate complete disconnection from mammillary bodies as the target to achieve seizure freedom, while others suggest that disconnection may not be a good option and the lesion should be entirely targeted. The fact that two of the patients displayed no response to this therapeutic option raises the point of the importance of an early treatment.

Only small studies of HH and VNS therapy have been published suggesting that this device could have a very modest effect on seizure control (Brandberg, Raininko, & Eeg‐Olofsson, 2004; Murphy, Wheless, & Schmoll, 2000). We implanted the VNS device in two patients with intractable epilepsy who previously failed to respond to radiosurgery. Output current parameters were modified following absence of response to different duty cycles. In our sample, there was no effect on seizure frequency or severity, and only one of them experienced behavior improvement. As it is known for other therapies, late use of drugs and devices is associated to a worse seizure outcome, due to increased drug resistance.

Hypothalamic hamartomas diagnosed in adulthood may show a poorer prognosis to surgical treatment than during childhood because comorbidity and encephalopathy tend to remain following the intervention. In our sample, out of three patients who began seizures in the first months of life, two progress to a disabling epileptic syndrome with multiple types of seizures refractory to antiepileptic therapy, resembling a severe encephalopathy, with additional cognitive and psychiatric disturbances. Lack of seizure control and impairment of mental development have a direct influence on social adaptation and usually condemn patients to depend on a caregiver. Patients with HH‐ES develop progressively behavioral deterioration and developmental delay. However, there are some patients that may present with early seizure onset but represent a mild end to the clinical spectrum as illustrated by patient No. 4. This fact reminds us that cognitive or behavioral disturbances may not always be present and leads our current of thought to the point that location and connectivity of the HH to close structures may be the most important factors related to epilepsy severity.

5. CONCLUSION

Hypothalamic hamartoma‐epilepsy syndrome is a rare condition. In adult age, it includes a wide variety of clinical, radiological and EEG findings. Clinical manifestations may be influenced by the location of the lesion and age of seizure onset. Diagnosis may be difficult in some patients with subtle seizures and normal cognition. Treatment options should be considered on an individual basis. Pharmacological and nonpharmacological options in our series of adult patients with drug‐resistant epilepsy related to HH often had a poor outcome with psychiatric complications.

CONFLICT OF INTEREST

None of the authors have nothing to disclose.

Notes

Conde Blanco E, Anciones Martín C, Manzanares I, et al. Hypothalamic hamartomas in adulthood: Clinical spectrum and treatment outcome—A unicenter experience. Brain Behav. 2019;9:e01412 10.1002/brb3.1412 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Estefanía Conde Blanco and Carla Anciones Martín contributed equally to this work.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

REFERENCES