Внутригиппокампальный нейроцитома, представляющая собой синдром Клейне-Левина: исчезновение после резекции и обзор нейрохирургических состояний, связанных с гиперсексуальностью. Иллюстративный случай.

Kleine-Levin syndrome (KLS) is a rare disorder that predominantly affects adolescent males (prevalence of 3:1 male vs female) but can develop at all ages. KLS is characterized by periods of hypersomnia alternate to apathy, hypersexuality (HS), megaphagia, and derealization/altered perception. 1 Headache and/or vomiting may also precede the onset of hypersomnia. 2 KLS often severely affects patient life, but it has a general favorable evolution with spontaneous resolution of the episodes after 1 or 2 decades. 2 Imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. 3

Most cases are sporadic, and its pathophysiology is still unknown, although genome-wide association studies have indicated a strong association with birth difficulties and variants in the TRANK1 (tetratricopeptide repeat and ankyrin repeat containing 1) gene loci. 4

KLS secondary to definite neurosurgical alterations has been rarely described in the context of traumatic brain injury 5 – 7 or in association with a large hemorrhage into the right lateral and third ventricle, complicating endoscopic surgery for a colloid cyst. 8

Here, we report a case of secondary KLS (sKLS) associated with HS due to an atypical neurocytoma originating from the right septum. The syndrome resolved after surgical removal of the tumor. We also review the existing literature on HS and/or KLS arising in the contest of neurosurgery or neurosurgery-related diseases.

Illustrative Case

Patient Report

A 25-year-old right-handed heterosexual man of North African descent, with no known personal or family history of neuropsychiatric disorders, presented with a 6-month history of hypersomnia and apathy, alternating with periods of hypersexual behavior and hyperphagia.

During the hypersexual episodes, his behavior included multiple instances of sexually inappropriate conduct toward unfamiliar women, as well as frequent autoerotic activity, sometimes occurring in public. His behavior was considered as socially inappropriate by his family and friends, who attempted to restrain or manage his manifestations. On at least one occasions, he was even physically assaulted by bystanders reacting to his behavior; in other instances, he was brought to different hospitals and referred for psychiatric evaluation and treatment that he did not accept. He displayed no remorse and, when questioned, provided no explanation, responding only with a smile or sometimes negating his inappropriate behavior.

Following loss of sphincteric control and increasing walking difficulties, he was brought to the emergency department of our hospital, where he was found to be conscious but apathic, unable to stand alone and with left-sided hemiparesis (Medical Research Council grade 3/5). His BMI was within normal range (22.63).

CT with contrast revealed a large intraventricular mass occupying the right lateral and third ventricles, extending across the midline and compressing the septal region that was stretched from right to left ( Fig. 1A ). After admission, the presence of the tumor was confirmed by MRI with contrast ( Fig. 1B and C ).

A: Preoperative axial, sagittal, and coronal ( left to right ) CT images showing an isodense lesion of the right lateral ventricle with extension in the third ventricle and leftward displacement of the septum. B: Preoperative contrast-enhanced T1-weighted axial MR image ( left ) of the lesion inside the right lateral ventricle and T2-weighted coronal MR image ( right ) of the lesion extending to the third ventricle. Some movement artifacts due to incomplete cooperation of the patient are visible in the T1-weighted image. C: Postoperative contrast-enhanced T1-weighted axial ( left ) and T2-weighted coronal ( right ) MR images obtained after tumor resection and partial opening of the septum.

Basal morning plasma levels of thyroid-stimulating hormone, free thyroxine, free triiodothyronine, adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, growth hormone, prolactin, and cortisol were within the normal range, while insulin-like growth factor 1 was higher (415.0 ng/ml, normal value 117.0–329.0 ng/ml) and total serum testosterone (1.37 ng/ml, normal value 2.70–15.00 ng/ml) and free testosterone (39.3 pg/ml, normal value 50.0–210.0 pg/ml) were lower than the accepted range for adult males.

In the month preceding admission, at least two episodes suggestive of generalized epileptic activity were reported by the family on questioning. In preparation for surgery, the patient was started on levetiracetam (1 g twice a day). No clinical signs of epileptic activity were observed during the hospital stay or the subsequent rehabilitation period.

Surgery was performed after 4 days, during which the patient continued to alternate between periods of drowsiness and apathy, and others in which he exhibited hypersexual behavior, openly engaging in autoerotic practices and sometimes harassing nurses. There was no clinical evidence of further epileptic activity. Hypermetamorphosis, hyperorality, and visual agnosia were neither reported in the months prior to hospitalization nor observed in the days preceding surgery. The tumor was removed through a right frontal transcortical approach; the pathological diagnosis was atypical neurocytoma ( Fig. 2A ).

Representative histopathological images of the neurocytoma. A: Hematoxylin-eosin. B: Insulinoma-associated protein 1 immunohistochemical reaction. Brown cells are positive for INSM1, which is an accepted marker for neurocytoma. C: Representative neurocytoma section showing the absence of cells immunostained for oxytocin. D: Representative neurocytoma section showing the absence of cells immunostained for tyrosine hydroxylase. We used the following antibodies on formalin-fixed paraffin-embedded 8-µm sections: INSM1 (rabbit anti-INSM1 [SP493] monoclonal antibody, concentration 5 µg/ml, Ventana-Roche), OXT (rabbit anti-oxytocin polyclonal antibody, dilution 1:5000, Merck AB911), and TH (chicken anti–tyrosine hydroxylase polyclonal antibody, dilution 1:1000, Merck AB9702). After immunohistochemical reaction, the sections were lightly counterstained with hematoxylin. Scale bars = 10 µm.

Given prior works showing links between dopamine and oxytocin and HS, 9 , 10 we performed immunohistochemistry for tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine, and for oxytocin on the tumor. We did not detect cells immunoreactive for either marker in the atypical neurocytoma tissue ( Fig. 2B ).

After surgery, there was a transient worsening of left-sided hemiparesis (Medical Research Council grade 2/5), which improved rapidly, allowing the patient to stand and walk within 1 week postoperatively, and resolved completely within 1 month. Immediately after surgery, all symptoms suggestive of sKLS disappeared and did not reappear during 14 months of follow-up.

Review of the Literature

We performed a literature review of the PubMed, Scopus, and Google Scholar databases using the terms “Kleine-Levin” and “hypersexuality” to identify case reports and case series discussing KLS and/or HS in neurosurgical patients.

We did not consider HS arising in parkinsonian patients following deep brain stimulation (DBS). 11 – 13 Although previous reports have suggested that bilateral DBS of the subthalamic nucleus may induce HS as one of several impulse control disorder manifestations, 11 – 13 we excluded this factor because the reported baseline prevalence of HS in patients with Parkinson’s disease is approximately 3%–4%, 14 and the incidence of HS does not differ significantly between patients treated with DBS and those receiving dopaminergic therapy alone. 15 Moreover, HS after DBS device implantation was not reversed by stopping the stimulation and resolved either spontaneously or after a limited treatment with atypical antipsychotics. 11 – 13

We also did not include HS arising after surgery for temporal lobe epilepsy in our analysis, as it is typically regarded within the context of Klüver-Bucy syndrome, which results from either anatomical or functional bitemporal damage. In humans, this syndrome is more commonly associated with changes in sexual preference rather than with HS. 16 , 17

Of the 9 patients who met our search criteria ( Table 1 ), 5 were diagnosed as affected by KLS. Among sKLS patients, 4 developed the syndrome after head trauma and only 1 as a complication of a neurosurgical intervention. In the majority of cases, both sKLS and HS improved either spontaneously or after therapies with lithium or citalopram or sertraline and risperidone. In all cases except one, the right side of the brain of male patients contained the lesion(s). However suggestive these findings are, no conclusion could be made on sex prevalence and lateralization due to the small sample size.

TABLE 1. Literature review Authors & Year KLS/HS Age (yrs) Sex Lesion Type Location Side Resolution Nishikuni et al., 2014 8 KLS 61 M Hemorrhage after colloid cyst removal Lat & 3rd ventricles Rt Spontaneous (6 mos) Pelin et al., 2004 6 KLS 32 M Head trauma Anterior inferior frontal Rt Lithium therapy Kostic et al., 1998 7 KLS 19 M Head trauma Temporal lobe, hypothalamus Rt No Will et al., 1988 5 KLS 17 M Head trauma NA NA Lithium therapy Will et al., 1988 5 KLS 16 M Head trauma NA NA Lithium therapy Malladi & Singh, 2005 24 HS 34 M Hamartoma Hypothalamus NA Citalopram therapy Gorman & Cummings, 1992 33 HS 76 M Injury by ventricular catheter Septum Rt No Gorman & Cummings, 1992 33 HS 75 M Injury by ventricular catheter Septum Lt No Cao et al., 2010 41 HS 35 F Arteriovenous malformation Occipital lobe Lt Sertraline, risperidone NA = not available.

Literature review

NA = not available.

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

Observations

We describe a case of KLS secondary to a large atypical neurocytoma developing from the right septum and filling the right lateral and third ventricles. Characteristic signs of alternating periods of apathy, HS, and increased food intake were present for approximately 6 months before the patient developed focal signs, including left hemiparesis, impaired walking, urinary incontinence, and seizures.

In our patient, basal morning plasma levels of testosterone were below normal. In men showing HS due to multiple etiologies, testosterone levels are usually not increased compared to unaffected individuals; 18 also, HS has been described in some individuals affected by Klineferter syndrome with androgen deficiency from progressive testicular failure. 19 Moreover, in patients with prolactinoma receiving dopamine agonists who developed HS, the change in testosterone levels before and after therapy (rather than the absolute testosterone level) was associated with hypersexual behavior. 20 In our patient, symptoms of KLS disappeared quickly after surgery for tumor removal and did not come back.

If apathy and alternating periods of hypersomnia, two of the symptoms demonstrated by our patient, may also be interpreted as secondary to a fluctuating hydrocephalus linked to the intraventricular mass, the same cannot be said of HS and increased food intake. Altogether, these symptoms are suggestive of sKLS.

The insurgence of sKLS was previously described after endoscopic treatment of a hemoventricle occurring as an early complication of the endoscopic removal of a colloid cyst in a 61-year-old male patient. 8 Similarly to the intraventricular tumor in our patient, in that patient the clot was located in the right lateral and third ventricles, which were acutely enlarged by the bleeding. According to the authors, after endoscopic removal of the clot, scar tissue was concentrated in the right thalamus. 8 In their case, the manifestations of sKLS, which included HS, were not immediately relieved by clot removal but spontaneously resolved 6 months after surgery. 8 In our case, sKLS preceded surgery by 6 months and resolved after surgery resulting in endoventricular tumor removal.

HS, one of the main symptoms of KLS, is rarely reported in association with neurosurgery. Although HS as a separate category is not present in the current edition of the Diagnostic and Statistical Manual of Mental Disorders , the International Classification of Diseases, 11th Revision includes HS in the diagnostic category “compulsive sexual behavior disorder.” 21 Moreover, HS is a recognized symptom associated with multiple neurological conditions from frontotemporal dementia 22 to temporal lobe epilepsy. 23

An important distinction we need to make when considering HS secondary to a neurological or neurosurgical condition is that between disinhibited sexual behavior occurring as part of a profound generalized behavioral alteration, such as in frontotemporal dementia, 22 and HS, occurring in relative isolation, as in patients treated with dopamine agonists for prolactinoma. 9 HS behavior in subjects affected by genetic frontotemporal dementia is associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum, 22 a large network that is also implicated in many other functions than HS.

HS has been rarely linked to brain tumors affecting the diencephalon and the hypothalamus. We are aware of a single case report of a third ventricular hamartoma 24 leading to HS that was apparently solved by the administration of citalopram. Citalopram, like other selective serotonin reuptake inhibitors, decreases the level of extracellular dopamine in the mesolimbic system by direct and indirect effects of the increase in serotonin on the dopaminergic neurons of the ventral tegmental area projecting to the striatum, septal nuclei, and nucleus accumbens. 25

HS is also one of the impulse control disorders that may affect patients assuming dopamine agonists for the treatment of prolactin adenoma. 9 The percentage of patients assuming dopamine agonists for prolactin adenomas reported to develop HS is variable according to the population considered, spanning from 3.9% in China 26 and 6.5% in Turkey 20 to 24.5% in Saudi Arabia. 27

However important are the effects of increased dopamine in inducing HS, alternative pathways must also exist since, in patients affected by KLS, levels of molecules linked to dopamine and serotonin metabolism are usually not increased in the CSF, 28 and amantadine, a molecule known to enhance dopaminergic transmission, has been used successfully for therapy of KLS. 29

Our patient did not assume drugs with a dopaminergic effect or substances of abuse, and in line with the literature on neurocytomas, we did not observe any tyrosine hydroxylase–positive dopamine-producing cells in his neurocytoma ( Fig. 2B ). Increased oxytocin has been described in male patients affected by HS disorders. 10 Increased oxytocin levels impact on attachment in pair partners, eating behavior, and empathy behavior. 30 Furthermore, in many circuits there are reciprocal positive interactions between dopamine and oxytocin. 31 , 32 However, in the neurocytoma affecting our patient, we did not detect cells immunopositive for oxytocin ( Fig. 2B ).

In our patient, the septal region was compressed and displaced from right to left. Two cases of HS have been reported in association with iatrogenic damage of the septum secondary to ventriculoperitoneal shunting. 33 However, inadvertent positioning of the catheter tip in the septum pellucidum or in the septal area is relatively common, 34 , 35 and it is associated with a higher rate of shunt malfunction compared to intraventricular placements 34 , 35 but no additional cases of hypersexual behavior have been reported.

Among brain structures other than the septal nuclei compressed by the atypical neurocytoma in our patient were the right thalamus, fornix, and hypothalamus. Early workers ascribed the insurgence of KLS to a hypothalamic disfunction. 36 However, more recent functional neuroimaging studies have indicated that a broader network is involved in KLS. 37 Prevalent hypoactivation of the hypotalamus and of right structures like the right posterior thalamus, right dorsomedial prefrontal cortex, and right parieto-temporal junction was found in symptomatic periods of KLS. 3

Unilateral or bilateral lesions of the fornix alone do not give rise to HS, 38 even if the fornix is the principal output of the hippocampus, one of the structures damaged in patients who develop Klüver-Bucy syndrome. Moreover, HS associated with Klüver-Bucy syndrome secondary to bilateral lesions of temporal lobes comprehensive of the amygdala and hippocampus in humans is indiscriminate in sexual preference or is associated with changes in premorbid sexual preference, 16 , 17 while our patient was heterosexual and maintained his sexual orientation during the periods of HS. Bilateral and unilateral right thalamic lesions have been associated with HS, although this symptom is rare, and when present, the thalamic lesion is usually limited in its extent. 39 Hypoactivity of the thalamus during symptomatic periods of KLS has also been repeatedly demonstrated by functional imaging studies. 37

Altogether, in our case it is impossible to pinpoint a specific structure whose functional alteration due to the presence of the atypical neurocytoma was responsible for the insurgence of the sKLS. However, as in other KLS patients, functional alterations in a network comprehensive of the structures of the hypothalamus, limbic lobe, and right thalamus were present and likely contributed to the sKLS in our patient. Similarly, in mice, the transition from the appetitive to the consummatory phases of mating is tightly regulated by an extensive neural network that, starting from the medial preoptic area (MPOA) of the hypothalamus, converges on the parathyroid hormone 2 (PTH2) containing neurons of the subparafascicular (SPF) thalamic nucleus (the posterior intralaminar nucleus of humans). 40 In mice, functional perturbation of that network by blocking the tonic inhibition exerted by neurons in the MPOA, together with mechanical stimulation mimicking social contacts, activates PTH2 neurons in the SPF thalamic nucleus, resulting in inappropriate mating behavior. 40

Our case, together with all other cases reported in the literature except one, 41 suggests that KLS and HS are more common in males than females. Interestingly, women affected by primary KLS are less prone than males to develop HS. 37 We also notice that, as in the present case, the vast majority of the lesions of neurosurgical interest associated with HS affect the right hemisphere. HS secondary to seizures arising in the temporal lobes is also more often associated with right temporal foci. 42 However, transient HS has also been described once as arising after removal of a left occipital lobe arteriovenous malformation in a female patient, but even in this case a PET study with F18-FDG indicated an unbalanced metabolic activity with higher metabolism in the left frontal and temporal (posterior hippocampus) lobes compared to the contralateral side. 41 Nevertheless, the number of reported cases is too low for a definitive conclusion and further studies are necessary.

Perhaps, as suggested by the present case, in which tumor removal quickly led to the resolution of HS and the other symptoms associated with KPS, KLS originates from a functional imbalance in the activity of the hypothalamus, septal nuclei, and thalami of the right and left hemispheres, rather than from a complete loss of function. Another strong indication of the temporary nature of the causative alterations comes from the benign course of KLS in the majority of patients without obvious lesions or masses in the brain.

Lessons

KLS or isolated HS secondary to an intraventricular tumor has been rarely reported, and an increased awareness of this condition may avoid unnecessary delay in diagnosis and treatment.

Our report may also encourage careful consideration if similar but less obvious symptoms are present in other patients affected by intraventricular tumors.

In our case and in the majority of other neurosurgical cases of sKLS with behavioral manifestations comprehensive of HS, 6 – 8 the lesion affected the right hemisphere, but the number of cases reported is insufficient to reach a definitive conclusion and further observations are needed.

Acknowledgments

We thank Prof. Annalisa Buffo and Prof. Stefano Gotti, both from the University of Turin, for their generous gifts of the anti–tyrosine hydroxylase antibody and the anti-oxytocin antibody, respectively. We also thank Marco Marchionni, MD, for critically reading the manuscript.

L.M. and A.S. were partially funded by the Scuola di Specializzazione in Neurochirurgia, Università degli Studi di Pavia Research fund.

ChatGPT 4o (OpenAI) was used sparingly to check grammar and improve language clarity.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Magrassi. Acquisition of data: all authors. Analysis and interpretation of data: Magrassi, Scravaglieri, Viglio. Drafting the article: Magrassi. Critically revising the article: Magrassi, Scravaglieri. Reviewed submitted version of manuscript: Magrassi, Scravaglieri. Approved the final version of the manuscript on behalf of all authors: Magrassi. Administrative/technical/material support: Albergati. Study supervision: Magrassi, Albergati.

Correspondence

Lorenzo Magrassi: Università di Pavia and Neurochirurgia Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy. lorenzo.magrassi@unipv.it .

References