[Hypothalamotomy in patients with treatment-resistant aggressiveness: functional outcomes]. / Hipotalamotomía en pacientes con agresividad refractaria: resultados funcionales.

INTRODUCTION: Aggressiveness is part of the behavioural manifestations associated with some mental disorders; it is a symptom that is difficult to manage and is often resistant to pharmacological measures. Surgery for behavioural disorders emerges as a therapeutic alternative. This procedure consists in performing interventions on different structures of the limbic system in order to correct the alteration of the circuit involved in producing the symptoms. AIM: To describe the clinical outcomes of a posterior hypothalamotomy with gamma knife to control aggressiveness in 20 patients resistant to treatment, who underwent surgery at the Imbanaco Medical Centre between 2013 and 2018. PATIENTS AND METHODS: The severity of the aggressiveness was quantified using the Overt Aggression Scale (OAS) and the Clinical Global Impression Scale (CGI-SI), and its functional impact is evaluated using the Global Assessment of Functioning scale (GAF). RESULTS: Control over aggressiveness was observed in all patients treated by posterior hypothalamotomy with gamma knife, evidenced by a decrease in the scores on the OAS and CGI-SI and an improvement in the GAF. CONCLUSIONS: Posterior hypothalamotomy gives rise to few complications, is a safe procedure and offers good results, suggesting that it could be a good alternative treatment in cases of treatment-resistant aggressiveness where it seems that all the possible pharmacological and therapeutic measures have failed.

TITLE: Hipotalamotomía en pacientes con agresividad refractaria: resultados funcionales.Introducción. La agresividad forma parte de las manifestaciones comportamentales asociadas a algunos trastornos mentales, es un síntoma de difícil manejo y, con frecuencia, es refractaria a las medidas farmacológicas. La cirugía de los trastornos del comportamiento surge como una alternativa terapéutica. Este procedimiento consiste en realizar intervenciones sobre distintas estructuras del sistema límbico, con el fin de corregir la alteración del circuito que estaría implicado en la producción de los síntomas. Objetivo. Describir los resultados clínicos de la hipotalamotomía posterior con gamma knife en el control de la agresividad en 20 pacientes refractarios al tratamiento, intervenidos en el Centro Médico Imbanaco entre 2013 y 2018. Pacientes y métodos. La gravedad de la agresividad se cuantificó mediante la escala de agresividad manifiesta (OAS) y la escala de impresión clínica global (CGI-SI), y su impacto funcional, a través de la escala de evaluación de la actividad global (EEAG). Resultados. El control de la agresividad se observó en todos los pacientes tratados con hipotalamotomía posterior con gamma knife, evidenciado por la disminución en las puntuaciones de la OAS y la CGI-SI y la mejoría en la EEAG. Conclusiones. La hipotalamotomía posterior muestra bajas complicaciones, seguridad en el procedimiento y buenos resultados, lo cual sugiere que podría ser una buena alternativa de tratamiento en los casos de agresividad refractaria donde las medidas farmacológicas y terapéuticas parecen agotarse.

Tratamiento de la agresividad refractaria mediante amigdalotomía e hipotalamotomía posteromedial por radiofrecuencia / Treatment of refractory aggressiveness by amygdalotomy and posteromedial hypothalamotomy by radiofrequency

Introducción. Dado que, en algunas circunstancias, las conductas defensivas o de ataque muestran un patrón de dominancia motora, tal como se observa en los sujetos dedicados a los deportes de contacto o de lucha, se consideró que la conducta agresiva tiene un patrón motor dominante. Con el fin de evitar los problemas funcionales descritos con los procedimientos de lesión bilateral tanto del núcleo central de la amígdala como del hipotálamo posteromedial, se decidió combinarlos; es decir, realizar amigdalotomía del núcleo central de la amígdala e hipotalamotomía posteromedial de manera unilateral y simultánea, basándose en la dominancia motora del paciente mediante la prueba de Edimburgo. Pacientes y métodos. Este estudio muestra la experiencia quirúrgica en una serie de nueve pacientes con el diagnóstico de síndrome neuroagresivo resistente al tratamiento farmacológico. Dentro del protocolo de estudio, se les realizó resonancia magnética cerebral para descartar la presencia de neoplasias, enfermedades vasculares, infecciones y trastornos degenerativos. El grado de agresividad se cuantificó mediante la escala global de agresividad de Yudofsky. Adicionalmente, se determinó la dominancia manual a través de la prueba de Edimburgo. Resultados y conclusiones. El buen control de la agresividad se observó de modo inmediato. En algunos casos fue necesario reducir la medicación de antipsicóticos o benzodiacepinas, ya que aumentaban la agresividad. Sólo un caso requirió una segunda cirugía. Se logró seguimiento del 100% de los casos en 24 meses y del 78% en 36 meses

Introduction. Since, under certain circumstances, defensive or attacking behaviours display a pattern of motor dominance, as observed in subjects who participate in contact or fighting sports, aggressive behaviour was considered to have a dominant motor pattern. With the aim of preventing the functional problems reported with bilateral lesion procedures involving both the central nucleus of the amygdala and the posteromedial hypothalamus, the decision was made to combine them; thus, an amygdalotomy of the central nucleus of the amygdala and a posteromedial hypothalamotomy were to be performed simultaneously and unilaterally, on the basis of the motor dominance of the patient determined by means of the Edinburgh test. Patients and methods. This study describes the surgical experience in a series of nine patients diagnosed with refractory neuroaggressive syndrome. As part of the study protocol, a magnetic resonance brain scan was performed to rule out the presence of neoplasms, vascular diseases, infections and degenerative disorders. The degree of aggressiveness was quantified using Yudofsky's Overt Aggression Scale. Additionally, manual dominance was determined by means of the Edinburgh test. Results and conclusions. Good control of aggressiveness was seen immediately. In some cases it was necessary to reduce the antipsychotic or benzodiazepine medication, as it was seen to increase aggressiveness. Only one case required a second surgical intervention. Follow-up was achieved in 100% of the cases at 24 months and 78% at 36 months

Ablative stereotactic neurosurgery for irreducible neuroaggressive disorder in pediatric patients. / Neurocirugía estereotáctica ablativa para trastorno neuroagresivo irreductible en pediátricos.

INTRODUCTION AND OBJECTIVES: The irreducible neuroaggressive disorder (IND) is a well-described entity known to be associated with impulsive and aggressive behavior. While various studies have assessed available pharmacological and non-pharmacological treatment regimens, patients with IND continue to pose a major threat to themselves and society. While targeted stereotactic therapy for IND has gained traction in recent years, there is a paucity of information describing comparative effectiveness of different validated anatomic regions. In this paper, we discuss the surgical results for patients with IND following targeted lesional therapy with a special focus on selection criteria and operative methods. The objective is to analyze the efficacy and safety of the different described targets for this disorder in pediatric patients. MATERIALS AND METHODS: Eight pediatric patients met strict criteria for IND and were enrolled in this study. Electroencephalography (EEG), video electroencephalography (VEEG) and magnetic resonance imaging (MRI) were performed in all patients prior to surgery. Irreducible neuroagressive symptom was approached by lesional therapy based on most described targets for this disorder and assessed by The Overt Agressive Scale (OAS) pre-operatively and 6 months following surgery, using Wilcoxon test for statistical analysis. RESULTS AND CONCLUSIONS: The average patient age was 13 years 2 months. 7 of the 8 patients enrolled had intellectual disabilities, 1 patient suffered neurologic sequelae referable to Dandy Walker syndrome and 7 patients had no preoperative anatomical alterations. Following surgery, patients with IND noted improvement in their OAS. On average, the OAS improved by 39.29% (P=.0156), a figure similar in comparison to studies assessing treatment of IND in adult patients. The most satisfactory results were achieved in patients whose ablative therapy involved the Amygdala in their targets. There were no deaths or permanent neurological deficits attributable to procedure. To the author's knowledge, this is the largest series described in the literature for pediatric patients with IND treated with lesional stereotactic therapy.

Exploring the brain through posterior hypothalamus surgery for aggressive behavior.

Neurological surgery offers an opportunity to study brain functions, through either resection or implanted neuromodulation devices. Pathological aggressive behavior in patients with intellectual disability is a frequent condition that is difficult to treat using either supportive care or pharmacological therapy. The bulk of the laboratory studies performed throughout the 19th century enabled the formulation of hypotheses on brain circuits involved in the generation of emotions. Aggressive behavior was also studied extensively. Lesional radiofrequency surgery of the posterior hypothalamus, which peaked in the 1970s, was shown to be an effective therapy in many reported series. As with other surgical procedures for the treatment of psychiatric disorders, however, this therapy was abandoned for many reasons, including the risk of its misuse. Deep brain stimulation (DBS) offers the possibility of treating neurological and psychoaffective disorders through relatively reversible and adaptable therapy. Deep brain stimulation of the posterior hypothalamus was proposed and performed successfully in 2005 as a treatment for aggressive behavior. Other groups reported positive outcomes using target and parameter settings similar to those of the original study. Both the lesional and DBS approaches enabled researchers to explore the role of the posterior hypothalamus (or posterior hypothalamic area) in the autonomic and emotional systems.

Drug-resistant cluster headache: long-term evaluation of pain control by posterior hypothalamic deep-brain stimulation.

OBJECTIVE: On the basis of recent findings about the pathophysiology of cluster headache and through the experience reported in recent literature, we have reviewed the outcome of four patients affected by drug-resistant cluster headache treated in our department by posterior hypothalamic deep brain stimulation with a follow-up of more than 5 years. METHODS: Between 2004 and 2006, we selected four patients affected by cluster headache. The diagnosis was based on the International Classification of Headache Disorders II criteria, and all patients were refractory to drug therapy. Under local anesthesia they underwent stereotactic positioning of a stimulation electrode within the posterior hypothalamus, ipsilateral to the site of pain. An intraoperative neurophysiological test stimulation was performed to assess possible side effects and symptoms related to hypothalamic neuronal activity. A second surgery was then performed with the patient under general anesthesia to implant the extension cable and the implantable pulse generator. RESULTS: After 5 years of follow up, all patients had a valuable benefit with a reduction in episode frequency from 90% to 50% associated with a decrease in pain intensity perception. CONCLUSION: The long-lasting pain reduction and the improvement in the patients' symptoms should be considered a real positive prospective, not only because there was uncertainty about the persistence of the beneficial effects at a long-term follow-up, but also for the improvement of the quality of life. The stimulation can restore important aspects concerning the psychic condition that very often constitutes an important limiting factor in normal daily life for this type of patient.

Electrical stimulation of the mesencephalic ventral tegmental area evokes skeletal muscle vasodilatation in the cat and rat.

To test the hypothesis that the mesencephalic ventral tegmental area (VTA) plays a role in autonomic control of the cardiovascular system, we examined the cardiovascular effects of electrical stimulation of the mesencephalic ventral areas in anesthetized, paralyzed cats and rats. Electrical stimulation of the VTA for 30 s (100-µA current intensity; 40-50-Hz pulse frequency; 0.5-1-ms pulse duration) increased femoral blood flow by 130-162% in anesthetized cats and rats, whereas the identical stimulation of the substantial nigra (SN) failed to increase femoral blood flow. Electrical stimulation of the VTA also increased the arterial blood pressure and heart rate in anesthetized rats, but did not alter them in anesthetized cats. Accordingly, femoral vascular conductance was increased by 102-134% in both cats and rats. Atropine methyl nitrate (0.1 mg/kg) injected intravenously in the cats markedly attenuated the increases in femoral blood flow and vascular conductance. VTA stimulation was able to produce substantial increases in femoral blood flow and vascular conductance following a decerebration procedure performed at the premammillary and precollicular level in the cats, although their responses tended to attenuate to 55-69% of the control before the decerebration. Thus, it is likely that electrical stimulation of the VTA, but not the SN, is capable of evoking skeletal muscle vasodilatation, particularly via a sympathetically mediated cholinergic mechanism in the cat, and that the ascending projection from the VTA to the forebrain may not be responsible for the muscle vasodilatation.

[Review of the target for the deep brain stimulation of chronic cluster headache]. / Revision de la diana para la estimulacion cerebral profunda de la cefalea en racimos cronica.

Cluster headache is included in the group of trigeminal autonomic cephalalgias. Although the pathophysiology of cluster headache has not yet been sufficiently established, the theory of a central origin tells us that this headache is produced by hypothalamic dysfunction. More than 50 patients have been treated with deep brain stimulation of the posterior nucleus of the hypothalamus from 2001. The results show clinical improvement in more than 60% of the cases, opening a promising issue for the treatment of the cluster headache persistent after medical treatment. The surgical target that have been used until now is based on the origin of the cluster headache in the hypothalamic dysfunction. Nevertheless, It has still some open questions as the lack of proving the posterior nucleus of the hypothalamus is the real origin of the cluster headache, the lack of consensus about the anatomy of the surgical target and the variability of the structures stimulated with the surgery. The aim of this article is a review of the target used and propose another surgical target based on physiopathological concepts to explain the improvement with the deep brain stimulation in these patients.

Chronic high frequency stimulation of the posteromedial hypothalamus in facial pain syndromes and behaviour disorders.

Chronic high frequency stimulation (HFS) of the posteromedial hypothalamus (PMH) has been the first direct therapeutic application of functional neuroimaging data in a restorative reversible procedure for the treatment of an otherwise refractory neurological condition; in fact, the target coordinates for the stereotactic implantation of the electrodes have been provided by positron emission tomography (PET) studies, which were performed during cluster headache attacks. HFS of PMH produced a significant and marked reduction of pain attacks in patients with chronic cluster headache (CCH) and in one patient with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). The episodes of violent behaviour and psychomotor agitation during the attacks of CCH supported the idea that the posteromedial hypothalamus could be also involved in the control of aggressiveness; this has been previously suggested, in the seventies, by the results obtained in Sano's hypothalamotomies for the treatment of abnormal aggression and disruptive behaviour. On the basis of these considerations, we have performed HFS of the PMH and controlled successfully violent and disruptive behaviour in patients refractory to the conventional sedative drugs. Finally, we also tested the same procedure in three patients with refractory atypical facial pain, but unfortunately, they did not respond to this treatment.

Update on neurosurgical treatment of chronic trigeminal autonomic cephalalgias and atypical facial pain with deep brain stimulation of posterior hypothalamus: results and comments.

The objective of this study is to describe the therapeutic effect and the technical and surgical problems of deep brain stimulation (DBS) of the posterior hypothalamus over seven years, for treatment of chronic trigeminal autonomic cephalalgias and atypical facial pain. We report a surgical series of 20 patients that underwent DBS of the posterior hypothalamus. This series includes 16 patients with chronic cluster headache (CH), one patient with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and three patients with atypical facial pain. All patients of this series were resistant to any pharmacological and conservative treatment. The stimulated target was the same in the whole series even though stereotactic coordinates of the target referred to the midcommissural point differ slight in the Y anteroposterior value due to individual anatomical variability. The commissures based reference system was adapted to individual anatomical landmarks of the brainstem adding to the registration a third reference point below the commissural plane. The stimulation parameters of unipolar stimulation were similar in the whole series: 180 Hz, 60 mus, 1-3 V. In the CH series, at five years follow-up the percentage of total number of days free from pain attacks improved from 1%-2% to 71%. Ten patients of this series had a complete and persistent pain-free state at 18 months follow-up and the patient with SUNCT has complete pain relief. In the three patients with atypical facial pain, the neurostimulation procedure was absolutely unsuccessful. DBS of the posterior hypothalamus produced a significant and marked reduction of pain bouts in CH patients and in the SUNCT patient. The attempts to treat atypical facial pain in three patients failed.

Deep brain stimulation in craniofacial pain: seven years' experience.

Cluster headache (CH) is a primary headache with excruciatingly painful attacks that are strictly unilateral. About 10% of cases experience no significant remission, and about 15% of these do not respond to medication, so surgery is considered. Neuroimaging studies show that the posterior inferior hypothalamus is activated during CH attacks and is plausibly the CH generator. We report on 16 chronic CH patients, with headaches refractory to all medication, who received long-term hypothalamic stimulation following electrode implant to the posterior inferior hypothalamus. After a mean follow-up of 23 months, a persistent pain-free to almost pain-free state was achieved in 13/16 patients (15/18 implants; 83.3%) a mean of 42 days (range 1-86 days) after monopolar stimulation initiation. Ten patients (11 implants) are completely pain-free. A common side effect was transient diplopia, which limited stimulation amplitude. In one patient, a small non-symptomatic haemorrhage into the 3rd ventricle occurred following implant, but regressed 24 h later. Persistent side effects are absent except in one patient with bilateral stimulation, in whom stimulation was stopped to resolve vertigo and worsened bradycardia, but was resumed later without further problems. Hypothalamic stimulation is an effective, safe and well tolerated treatment for chronic drug-refractory CH. It appears as a valid alternative to destructive surgical modalities, and has the additional advantage of being reversible.

Stress-induced release of anterior pituitary hormones: effect of H3 receptor-mediated inhibition of histaminergic activity or posterior hypothalamic lesion.

The effect of stress- or lipopolysaccharide (LPS) endotoxin-induced release of ACTH, beta-endorphin (beta-END) and prolactin (PRL) was investigated in two groups of conscious male rats: (1) Rats pretreated with different H3 receptor agonists, which inhibit neuronal histamine (HA) synthesis and release, and (2) rats with bilateral posterior hypothalamic lesion, which destroys the histaminergic perikarya exclusively localized in the mammillary nuclei. The H3 receptor agonists R(alpha)methyl-HA, BP 2-94 or imetit injected intraperitoneally (ip) had no effect on basal secretion of ACTH or PRL but inhibited the ACTH and PRL responses to restraint stress and the ACTH response to LPS endotoxin. LPS had no effect on PRL secretion. The inhibitory effect of the agonists was prevented by prior ip administration of the H3 receptor antagonist thioperamide. Bilateral lesion of the posterior hypothalamus inhibited the ACTH, beta-END and PRL responses to restraint stress, ether stress and LPS endotoxin, whereas sham operation had no effect compared to nonoperated control rats. In addition, posterior hypothalamic lesion inhibited the PRL response but not the ACTH and beta-END responses to activation of serotonergic neurons induced by ip administration of the 5-HT precusor 5-hydroxytryptophan in combination with the 5-HT re-uptake inhibitor fluoxetine. Thus, serotonergic pathways were not damaged by the lesions. The present results support our previous findings that inhibition of neuronal HA synthesis by alpha-fluoromethylhistidine as well as blockade of H1 or H2 receptors inhibit the ACTH, beta-END and PRL responses to stress and LPS endotoxin and further substantiate an important role of histaminergic neurons in the mediation of the stress-induced release of pituitary stress hormones. Furthermore, in accordance with our previous findings, the lesion experiments indicated the existence of an interaction between the histaminergic and serotonergic system in regulation of the stress- and LPS-induced PRL release.

Air-ventriculography provokes an anterior displacement of the third ventricle during functional stereotactic procedures.

The width of the third ventricle, the length of the anterior commissure-posterior commissure line (AC-PC line), the spatial position of the midplane of the third ventricle, and the co-ordinates of the AC, the PC, and of 17 brain targets in the thalamus, hypothalamus and pallidum, were assessed on a pre-operative stereotactic computed-tomography (CT) study and compared to measurements on intra-operative air-ventriculography, using a non-invasive relocatable stereotactic frame. There were no significant differences in the length of the AC-PC line, in the position of the midsagittal plane of the third ventricle, or in the vertical or lateral co-ordinates of the AC, the PC and the cerebral targets, between measurements on CT and on air-ventriculography. However, the width of the third ventricle was significantly larger, and the spatial positions of both AC and PC were significantly more anterior on air-ventriculography than on the CT study. This anterior dislocation of the commissures was presumably due to the insufflation of air into the ventricles of patients being in the supine position during surgery.

[Hypothalamic hamartoma with precocious puberty--a case report].

A case of hypothalamic hamartoma with precocious puberty is presented and the literature of reported cases is reviewed. An 8-year-old boy was admitted to our hospital because of precocious puberty and mental retardation. His genital development was Tanner's stage 4 and pubic hair was Tanner's stage 3. Bone age was 11 years. Plain CT showed an isodense mass in the suprasellar cistern which was not enhanced following contrast administration. Metrizamide CT cisternography showed a filling defect in the suprasellar cistern. Endocrinological evaluation revealed high levels of serum luteinizing hormone (LH) and testosterone with a marked response of LH to LH-RH injection. A left frontotemporal craniotomy was performed and the tumor was partially removed. The tumor was gray, firm and well-circumscribed with poor vascularity. Postoperatively, a right oculomotor palsy and transient diabetes insipidus developed. He was discharged ambulatory one month later. Serum LH and testosterone returned to normal and the response of LH to LH-RH injection became normal. Hamartoma was diagnosed on histological examination. Electron micrographic study showed numerous dense granules with approximately 0.1 mu in diameter, in which Judge proved LH-RH by immunofluorescent study in 1977. Our case supports the hypothesis that hypothalamic hamartoma may cause precocious puberty by autonomous secretion of LH-RH and we consider that neurosurgical treatment is recommended.

The posteromedial hypothalamus and pain, behavior, with special reference to endocrinological findings.

Stereotactic intervention into the posterior hypothalamus gives satisfactory results for controlling both aggressive, violent behavioral disorders and intractable pain. From the endocrinological point of view, this procedure activates the hypothalamic-hypophyseal axis only temporarily, without causing any serious dysfunctions.