Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions.

Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes-DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy.

Subclinical central hypothyroidism in patients with hypothalamic-pituitary disease: does it exist?

Central hypothyroidism (CH) is characterized by decreased thyroid hormone production due to insufficient stimulation of an otherwise normal thyroid gland by TSH. In patients with established hypothalamic-pituitary disease, a low FT4 concentration is considered highly specific, although poorly sensitive, for the diagnosis of CH. That would be comparable to diagnosing primary hypothyroidism in patients at risk only when serum FT4 concentrations are below the reference range, missing all patients with subclinical primary hypothyroidism and preventing proper therapy in patients in which thyroxine replacement is clearly beneficial. Cardiac time intervals, especially the isovolumic contraction time (ICT), have been considered the gold standard of peripheral thyroid hormone action. Using Doppler echocardiography, we have previously shown a very high proportion of prolonged ICT in patients with hypothalamic-pituitary disease and serum FT4 levels indistinguishable from controls. As ICT decreased/normalized after thyroxine-induced increases in FT4 concentrations within the normal reference range, prolonged ICT was considered a bona fide diagnostic biomarker of subclinical CH. Those findings challenge the usual interpretation that FT4 concentrations in the mid-reference range exclude hypothyroidism in patients with hypothalamic-pituitary disease. Rather, subclinical central hypothyroidism, a state analogous to subclinical primary hypothyroidism, seems to be frequent in patients with hypothalamic-pituitary disease and normal FT4 levels. They also challenge the notion that thyroid function is usually the least or the last affected in acquired hypopituitarism. The relevance of Doppler echocardiography to correctly diagnose and monitor replacement therapy in both clinical and subclinical forms of CH should improve quality of life and decrease cardiovascular risk, as already demonstrated in patients with clinical and subclinical primary hypothyroidism.

Acquired hypothalamic obesity: A clinical overview and update.

Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future.

Comprehensive review of status gelasticus: Diagnostic challenges and therapeutic insights.

Status gelasticus is a rare form of status epilepticus characterized by prolonged and/or clustered gelastic seizures. The review encompasses an analysis of cases reported in the literature, focusing on causes, clinical-electroencephalographic features, and therapeutic interventions. The study reveals the challenges in defining and understanding status gelasticus due to its diverse etiologies and limited reported cases. The association with hypothalamic hamartomas and other brain abnormalities underscores the importance of thorough evaluations. The review also discusses new treatments, including medications and less invasive surgeries. While progress has been made, the study points out challenges in diagnosing and managing this complex condition, highlighting the importance of ongoing research.

Body weight variation is not an independent factor in the determination of functional hypothalamic amenorrhea in anorexia nervosa.

OBJECTIVE: Functional hypothalamic amenorrhea (FHA) is one of the foremost manifestations in anorexia nervosa (AN), but a subset of patients have menses despite marked weight loss and underweight. The aim of our study was to investigate parameters potentially influencing FHA in AN. DESIGN AND METHODS: In this observational retrospective study, we selected 114 female patients with AN who completed a 12 months semi-residential rehabilitation program and a subsequent 12 months outpatient follow-up. We divided our sample into three groups: "Group 0" patients who experienced FHA and recovered their menses, "Group 1" persistent FHA, "Group 2" never experienced FHA, and looked for clinical and hormonal correlations. RESULTS: At the enrollment, the BMI was higher in Group 2 than in Group 1 (p = 0.0202), but the last follow-up weight was higher in Group 1 (p < 0.0001) despite persistent amenorrhea. At logistic regression, the higher BMI at which patients experienced amenorrhea was the main prediction factor for persistent FHA. Notwithstanding comparable leptin levels at admission, they improved significantly at discharge only in Groups 0 and 2 (p = 0.0054 and p = 0.0104, respectively). FT3 at admission was significantly higher in Group 2 than in Group 0 (p = 0.0249). CONCLUSIONS: FHA does not correlate strictly with body weight variations in AN patients, indicating a multifactorial origin, likely including an individual predisposition. Higher FT3 levels identify patients who continue having menses at extremely low BMI. AN patients with persistent FHA constitute a subgroup in whom estroprogestins should be considered after significant weight recovery to prevent prolonged tissue hypoestrogenism.

Chorioretinal biomarkers in hypothalamic amenorrhea.

PURPOSE: The aim of our study was to evaluate changes in the retinal and choriocapillaris circulations in patients with hypothalamic amenorrhea. METHODS: Prospective, cross-sectional observational study on 25 patients (50 eyes) diagnosed with hypothalamic amenorrhea and 25 age-matched healthy women. Optical coherence tomography angiography (OCTA) was used to evaluate the vessel density (VD) of superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris VD layers in whole 6.4 × 6.4-mm image and in fovea grid-based image. In patients' group, systemic parameters were collected: body mass index (BMI), endometrial rhyme thickness, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, insulin, and cortisol. RESULTS: SCP and DCP did not show any statistical difference when comparing patients and controls (all p > 0.05). Differently, choriocapillaris VD in the whole region showed a non-significant tendency toward higher values in the patients group in both eyes (p = 0.038 for right eye [RE], p = 0.044 for left eye [LE]). Foveal choriocapillaris VD was higher in hypothalamic amenorrhea women vs. healthy controls (66.0 ± 2.4 vs. 63.7 ± 6.6%, p = 0.136 for RE; 65.0 ± 2.4 vs. 61.6 ± 7.0%, p = 0.005 for LE). Focusing on correlation with systemic parameters, SCP and DCP foveal density had a medium/high effect size with endometrial rhyme, along with DCP in the fovea area vs. cortisol and SCP in the whole area vs. FSH. CONCLUSION: When comparing hypothalamic amenorrhea patients to healthy subjects, OCTA detected changes in the choriocapillaris layer, showing increased VD in the early stage of the systemic pathology, suggesting that microvascular "compaction" could be a first phase of hypoestrogenism adaptation.

Multimodal Approach for the Treatment of Complex Hypothalamic Hamartomas.

Hypothalamic hamartomas (HHs) are rare congenital lesions formed by heterotopic neuronal and glial cells attached to the mammillary bodies, tuber cinereum, and hypothalamus.They often present with an intractable epilepsy typically characterized by gelastic seizures but commonly associated with other types of refractory seizures. The clinical course is progressive in most of the cases, starting with gelastic seizures in infancy and deteriorating into complex seizure disorders that result in catastrophic epilepsy associated with cognitive decline and behavioral disturbances.Hamartomas are known to be intrinsically epileptogenic and the site of origin for the gelastic seizures. As antiepileptic drugs are typically ineffective in controlling HH-related epilepsy, different surgical options have been proposed as a treatment to achieve seizure control. Resection or complete disconnection of the hamartoma from the mammillothalamic tract has proved to achieve a long-lasting control of the epileptic syndrome.Usually, symptoms and their severity are typically related to the size, localization, and type of attachment. Precocious puberty appears mostly in the pedunculated type, while epileptic syndrome and behavioral decline are frequently related to the sessile type. For this reason, different classifications of HHs have been developed based on their size, extension, and type of attachment to the hypothalamus.The bigger and more complex hypothalamic hamartomas typically present with severe refractory epilepsy, behavioral disturbances, and progressive cognitive decline posing a formidable challenge for the control of these symptoms.We present here our experience with the multimodal treatment for complex hypothalamic hamartomas. After an in-depth review of the literature, we systematize our approach for the different types of hypothalamic hamartomas.

Anti-ZSCAN1 Autoantibodies Are a Feasible Diagnostic Marker for ROHHAD Syndrome Not Associated with a Tumor.

Recent studies have reported the presence of autoantibodies against zinc finger and SCAN domain-containing protein 1 (ZSCAN1) in the sera of patients with rapid-onset obesity with hypoventilation, hypothalamic and autonomic dysregulation (ROHHAD) syndrome associated with neuroendocrine tumors, suggesting immunologic and paraneoplastic processes as the pathologic underpinnings. Moreover, several hypothalamic regions, including the subfornical organ (SFO), were reported to exhibit antibody reactivity in a patient with ROHHAD syndrome not associated with a tumor. Whether ROHHAD syndrome not associated with a tumor is associated with anti-ZSCAN1 autoantibodies remains unclear. We used a comprehensive protein array analysis to identify candidate molecules in the sera of patients with ROHHAD syndrome and identified ZSCAN1 as a target antigen. We also found that ZSCAN1 was co-expressed at the site of antibody reactivity to the IgG in the patient serum observed in mouse SFOs and an enzyme-linked immunosorbent assay showed that >85% of the patients with ROHHAD syndrome were positive for anti-ZSCAN1 autoantibodies. These results suggest anti-ZSCAN1 autoantibodies as a feasible diagnostic marker in ROHHAD syndrome regardless of the presence of a tumor.

High-Titer Anti-ZSCAN1 Antibodies in a Toddler Clinically Diagnosed with Apparent Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Syndrome.

Severe obesity in young children prompts for a differential diagnosis that includes syndromic conditions. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) syndrome is a potentially fatal disorder characterized by rapid-onset obesity associated with hypoventilation, neural crest tumors, and endocrine and behavioral abnormalities. The etiology of ROHHAD syndrome remains to be established, but recent research has been focusing on autoimmunity. We report on a 2-year-old girl with rapid-onset obesity during the first year of life who progressed to hypoventilation and encephalitis in less than four months since the start of accelerated weight gain. The patient had a high titer of anti-ZSCAN1 antibodies (348; reference range < 40), and the increased values did not decline after acute phase treatment. Other encephalitis-related antibodies, such as the anti-NDMA antibody, were not detected. The rapid progression from obesity onset to central hypoventilation with encephalitis warns about the severe consequences of early-onset ROHHAD syndrome. These data indicate that serial measurements of anti-ZSCAN1 antibodies might be useful for the diagnosis and estimation of disease severity. Further research is needed to determine whether it can predict the clinical course of ROHHAD syndrome and whether there is any difference in antibody production between patients with and without tumors.

[Hypothalamic hamartoma dissection using focused ultrasound under MRI control. The first successful experience in Russia]. / Pervyi uspeshnyi opyt dissektsii gamartomy gipotalamusa metodom fokusirovannogo ul'trazvuka pod kontrolem MRT v Rossii.

Treatment of motor disorders by MRI-guided focused ultrasound is an alternative to neuro- and radiosurgery such as stereotactic radiofrequency ablation and thalamotomy with a gamma knife. However, safety, efficacy and feasibility of this technology for intracranial neoplasms are still unclear. The authors report successful hypothalamic hamartoma dissection by MRI-guided focused ultrasound in a 32-year-old woman with drug-resistant gelastic epilepsy and violent laughter and crying attacks. Magnetic resonance imaging revealed type II hypothalamic hamartoma. The last one was detached from surrounding brain tissue by MRI-guided focused ultrasound without side effects. Symptoms regressed immediately after surgery. No laughter and crying attacks were observed throughout 6-month follow-up.

ZSCAN1 Autoantibodies Are Associated with Pediatric Paraneoplastic ROHHAD.

OBJECTIVE: Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting in hypothalamic dysfunction and frequent sudden death. Frequent co-occurrence of neuroblastic tumors have fueled suspicion of an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Our objective is to determine if an autoimmune paraneoplastic etiology underlies ROHHAD. METHODS: Immunoglobulin G (IgG) from pediatric ROHHAD patients (n = 9), non-inflammatory individuals (n = 100) and relevant pediatric controls (n = 25) was screened using a programmable phage display of the human peptidome (PhIP-Seq). Putative ROHHAD-specific autoantibodies were orthogonally validated using radioactive ligand binding and cell-based assays. Expression of autoantibody targets in ROHHAD tumor and healthy brain tissue was assessed with immunohistochemistry and mass spectrometry, respectively. RESULTS: Autoantibodies to ZSCAN1 were detected in ROHHAD patients by PhIP-Seq and orthogonally validated in 7/9 ROHHAD patients and 0/125 controls using radioactive ligand binding and cell-based assays. Expression of ZSCAN1 in ROHHAD tumor and healthy human brain tissue was confirmed. INTERPRETATION: Our results support the notion that tumor-associated ROHHAD syndrome is a pediatric PNS, potentially initiated by an immune response to peripheral neuroblastic tumor. ZSCAN1 autoantibodies may aid in earlier, accurate diagnosis of ROHHAD syndrome, thus providing a means toward early detection and treatment. This work warrants follow-up studies to test sensitivity and specificity of a novel diagnostic test. Last, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches for detecting novel PNS subtypes. ANN NEUROL 2022;92:279-291.

Clinical and molecular heterogeneity of syndromic hypothalamic hamartoma.

Two children are presented who have a distinct syndrome of multiple buccolingual frenula, a stiff and short fifth finger with small nails, a hypothalamic hamartoma, mild to moderate neurological impairment, and mild endocrinological symptoms. No variant assessed to be pathogenic or likely pathogenic was detected in the GLI3 gene in either child. This syndrome appears to be distinct from the inherited Pallister-Hall syndrome associated with GLI3 variants, which is characterized by hypothalamic hamartoma, mesoaxial polydactyly, and other anomalies. In the individuals described here, manifestations outside of the central nervous system were milder and the mesoaxial polydactyly, which is common in individuals with Pallister-Hall syndrome, was absent. Instead, these children had multiple buccolingual frenula together with the unusual appearance of the fifth digit. It remains unclear whether these two individuals represent a separate nosologic entity or if they represent a milder manifestation of one of the more severe syndromes associated with a hypothalamic hamartoma.

Diagnosis and Management of Idiopathic Hypothalamic Dysfunction: A Case Series and Systematic Review.

INTRODUCTION: Idiopathic hypothalamic dysfunction (IHD) is a rare syndrome with heterogeneous clinical symptoms. This study aimed to systematically review the clinical features and potential treatment of IHD based on our case series and literature. METHODS: We analysed six recently diagnosed cases of IHD in Peking Union Medical College Hospital and conducted a systematic review of IHD case studies published before August 25, 2021, using the PubMed/Medline database. All 12 articles that met the definition of IHD and provided individual clinical data were reviewed. RESULTS: Of the 19 cases reviewed (13 from the literature and 6 from our centre), the median age at onset was 6 years. Obesity/weight gain (n = 14, 73.7%) and electrolyte abnormalities (n = 14, 73.7%) were the most common hypothalamic physiological dysfunction, followed by autonomic dysregulation (n = 13, 68.4%) and adipsia (n = 13, 68.4%). The most common initial symptom of young patients was obesity/weight gain, whereas the initial symptoms of the three adult patients were hypothalamic amenorrhoea, delayed sexual development, and polydipsia. 11 (57.9%) patients had obesity, and three of our patients were diagnosed with metabolic syndrome in late adolescence or early adulthood. Three of our cases diagnosed with growth hormone deficiency received growth hormone therapy, which exerted positive effects on growth promotion and weight stabilization. CONCLUSION: Although obesity/weight gain was the most common symptom of IHD, uncommon initial symptoms such as electrolyte abnormalities and sexual disorders also require attention, especially in patients with late childhood- or adult-onset IHD. Consistent monitoring of metabolic profiles is recommended. Positive effects of growth hormone replacement therapy on growth and weight were observed, but more extensive cohort studies are required to confirm its efficacy and safety.

Ictal semiology of gelastic seizures.

Gelastic seizures are rare epileptic manifestations characterized by laughter or a smile. The main etiology is represented by hypothalamic hamartoma, but also focal localization of the epileptogenic zone is described. We reviewed a group of patients with gelastic seizures to describe the semiology and to establish any difference related to diverse epilepsy etiologies. Thirty-five seizures from 16 patients (6 females) were reviewed. The study confirms that hypothalamic hamartoma is the more frequent etiology associated with gelastic seizures. Laughter represented the majority of gelastic ictal signs, while the ictal smile was less frequent. In 87.5% of patients, the manifestation of laughter or smile was the only ictal phenomenon, or the first and the most important clinical sign. Interestingly, it has been observed that patients with a lesion localized in the hypothalamic region had more frequently laughter with emotional involvement and that laughter was the only manifestation of the seizure. On the contrary, patients with lesions localized outside the hypothalamic region had more often seizures with laugh without emotional involvement, resembling a more mechanical action, and associated with other semeiological signs. It, therefore, seems possible to assume that the emotional involvement and the expression of mirth during the seizure, especially in children, are more frequently associated with hypothalamic hamartoma. On the contrary, when the semiology includes less conveyed emotion similar to a mechanical action and other symptoms, an extra hypothalamic localization should be considered.

Posterior hypothalamic involvement on pre-operative MRI predicts hypothalamic obesity in craniopharyngiomas.

PURPOSE: Hypothalamic obesity (HO) is a complication associated with craniopharyngioma (CP). Attempts have been made to perioperatively predict the development of this complication, which can be severe and difficult to treat. METHODS: Patients who underwent first transsphenoidal surgical resection in a single center between February 2005 and March 2019 were screened; those who have had prior surgery or radiation, were aged below 18 years, or did not have follow up body mass index (BMI) after surgery were excluded. Primary end point was BMI within 2 years post-surgery. Hypothalamic involvement (HI) was graded based on preoperative and postoperative imaging with regards to anterior, posterior, left and right involvement. Data on baseline demographics, pre-operative and post-operative MRI, and endocrine function were collected. RESULTS: 45 patients met the inclusion and exclusion criteria. Most patients in our cohort underwent gross total resection (n = 35 patients). 13 patients were from no HI or anterior HI only group and 22 patients were classified as both anterior (ant) and posterior (post) HI group. There was no significant difference between the two groups in the gross total, subtotal or near total resection. Pre-operative BMI and post-operative BMI were significantly higher in patients who had ant and post HI on pre-operative MRI (p < 0.05 and p < 0.01, respectively). Similarly, post-operative BMI at 13-24 months was also significantly higher in the ant and post HI group on post-op MRI (p < 0.01). There was no significant difference between the two groups in terms of baseline adrenal insufficiency, thyroid insufficiency, gonadal insufficiency, IGF-1 levels, hyperprolactinemia, and diabetes insipidus. Diabetes insipidus was more common following surgery among those who had anterior and posterior involvement on pre-operative MRI (p < 0.05). CONCLUSIONS: HO appears to be predetermined by tumor involvement in the posterior hypothalamus observed on pre-operative MRI. Posterior HI on pre-operative MRI was also associated with the development of diabetes insipidus after surgery.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): a collaborative review of the current understanding.

PURPOSE: To provide an overview of the discovery, presentation, and management of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD). To discuss a search for causative etiology spanning multiple disciplines and continents. METHODS: The literature (1965-2022) on the diagnosis, management, pathophysiology, and potential etiology of ROHHAD was methodically reviewed. The experience of several academic centers with expertise in ROHHAD is presented, along with a detailed discussion of scientific discovery in the search for a cause. RESULTS: ROHHAD is an ultra-rare syndrome with fewer than 200 known cases. Although variations occur, the acronym ROHHAD is intended to alert physicians to the usual sequence or unfolding of the phenotypic presentation, including the full phenotype. Nearly 60 years after its first description, more is known about the pathophysiology of ROHHAD, but the etiology remains enigmatic. The search for a genetic mutation common to patients with ROHHAD has not, to date, demonstrated a disease-defining gene. Similarly, a search for the autoimmune basis of ROHHAD has not resulted in a definitive answer. This review summarizes current knowledge and potential future directions. CONCLUSION: ROHHAD is a poorly understood, complex, and potentially devastating disorder. The search for its cause intertwines with the search for causes of obesity and autonomic dysregulation. The care for the patient with ROHHAD necessitates collaborative international efforts to advance our knowledge and, thereby, treatment, to decrease the disease burden and eventually to stop, and/or reverse the unfolding of the phenotype.

Diencephalic syndrome-like presentation of brainstem tumor: a series case-based review.

PURPOSE: Russel described a rare clinical entity known as diencephalic syndrome (DS) in 1951, which was traditionally caused by a neoplasm in the hypothalamic-optic chiasmatic region. DS is characterized by severe emaciation despite adequate or slightly reduced caloric intake, locomotor hyperactivity, euphoria and other minor features. Current evidence suggests that a rare population of children with a similar phenotype may have their tumor located in the posterior fossa instead, defining the DS-like presentation, a rare entity with few cases reported in the literature. METHODS: A thorough search of three databases (PubMed, Ovid Medline, and Ovid Embase) was conducted to identify relevant papers reporting children with DS associated with brainstem tumors. To our knowledge, only seven cases have been documented in the literature. Moreover, we present four of our own cases, focusing on the unusual clinical presentation, the diagnosis process, and the lag time between the initial symptoms and the definitive diagnosis. RESULTS: In this review, the mean lag time between the onset of symptoms and diagnosis was 20.9 months (median: 16 months; range: 1.5-72 months), whereas in our series of cases, the time was 32.5 months (median: 33 months; range: 7-57 months). CONCLUSION: Despite recent significant advances in neuro-oncology diagnostic tools, this mean lag time did not improve when compared with the previous literature review from 1976. Throughout these data, we aim to raise awareness in the hopes of detecting intracranial neoplasms earlier in cases of children with profound emaciation of unknown cause.

Selective surgical mamillo-thalamic tract disconnection in hypothalamic hamartoma results in complete disappearance of gelastic seizures.

Hypothalamic hamartoma is a less common condition characterized by the several types of epileptic seizures including the gelastic type. It is reported that gelastic seizures are resistant to medical treatment with anticonvulsants, while stereotactic thermocoagulation or Gamma Knife radiosurgery are effective for seizure control. Here, we report an individual case where direct surgical resection disconnecting hypothalamic hamartoma from mammillothalamic tract resulted in complete disappearance of gelastic seizures without deterioration of cognitive function. A 6-year-old boy developed gelastic seizures at the age of 2 and suffered from precocious puberty. Anticonvulsants including carbamazepine and zonisamide failed to control seizures. The patient underwent direct division of the mammillothalmic tract by removal of hypothalamic hamartoma partially via anterior interhemispheric approach. It was observed that gelastic seizures disappeared completely after the surgical treatment without any endocrine and cognitive dysfunction for a follow-up period of 14 years. The mammillothalamic tract which connects anterior nucleus of thalamus and mammillary bodies plays a key role in gelastic seizures related to hypothalamic hamartoma. In this case, we disconnected the hamartoma specifically from the mammillary bodies and not from the rest of hypothalamus. Effectively, it enabled permanent control of seizures. This result shows that fibers connecting other hypothalamic structures and the dorsomedial nucleus of thalamus are not involved in gelastic seizure propagation from the hypothalamic hamartoma. When surgical treatment of hypothalamic hamartomas is performed it has high morbidity associated with hypothalamic disorders. Therefore, disconnection between hypothalamic hamartoma and mammillary bodies presents a possibility of reducing hypothalamic damage. Surgical disconnection between hamartoma and mammillothalamic tract carries minimal hypothalamic injury risk and our results suggest that it has the potential of seizure control for intractable gelastic seizures with less complications.

Obesity status and obesity-associated gut dysbiosis effects on hypothalamic structural covariance.

BACKGROUND: Functional connectivity alterations in the lateral and medial hypothalamic networks have been associated with the development and maintenance of obesity, but the possible impact on the structural properties of these networks remains largely unexplored. Also, obesity-related gut dysbiosis may delineate specific hypothalamic alterations within obese conditions. We aim to assess the effects of obesity, and obesity and gut-dysbiosis on the structural covariance differences in hypothalamic networks, executive functioning, and depressive symptoms. METHODS: Medial (MH) and lateral (LH) hypothalamic structural covariance alterations were identified in 57 subjects with obesity compared to 47 subjects without obesity. Gut dysbiosis in the subjects with obesity was defined by the presence of high (n = 28) and low (n = 29) values in a BMI-associated microbial signature, and posthoc comparisons between these groups were used as a proxy to explore the role of obesity-related gut dysbiosis on the hypothalamic measurements, executive function, and depressive symptoms. RESULTS: Structural covariance alterations between the MH and the striatum, lateral prefrontal, cingulate, insula, and temporal cortices are congruent with previously functional connectivity disruptions in obesity conditions. MH structural covariance decreases encompassed postcentral parietal cortices in the subjects with obesity and gut-dysbiosis, but increases with subcortical nuclei involved in the coding food-related hedonic information in the subjects with obesity without gut-dysbiosis. Alterations for the structural covariance of the LH in the subjects with obesity and gut-dysbiosis encompassed increases with frontolimbic networks, but decreases with the lateral orbitofrontal cortex in the subjects with obesity without gut-dysbiosis. Subjects with obesity and gut dysbiosis showed higher executive dysfunction and depressive symptoms. CONCLUSIONS: Obesity-related gut dysbiosis is linked to specific structural covariance alterations in hypothalamic networks relevant to the integration of somatic-visceral information, and emotion regulation.

Identification of clinical factors related to antibody-mediated immune response to the subfornical organ.

OBJECTIVE: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic-pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ. DESIGN: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe. METHODS: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic-pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses. RESULTS: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Nax channel. CONCLUSIONS: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.