Exposure to topiramate and acetazolamide causes endocrine disrupting effects in female rats during estrus.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues. METHODS: Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA. RESULTS: Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands. CONCLUSION: These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.

Antibiotics-Induced Intracranial Hypertension: A Case Report With Literature Review.

Idiopathic intracranial hypertension (IIH) is a rare condition characterized by increased intracranial pressure, with an unknown cause. However, the pathophysiology of antibiotic-induced IIH remains unclear. The clinical symptoms include headache, visual disturbances, and vomiting. The diagnosis is confirmed by an elevated intracranial pressure (ICP) with normal CSF study and cerebral imaging. Management includes discontinuing the offending antibiotic and reducing ICP with medications such as acetazolamide or diuretics. Therefore, surgical intervention may be necessary in severe cases. In this article, we report the case of a 19-year-old patient, admitted with symptoms of intracranial hypertension syndrome, occurring three days after receiving antibiotics (gentamicin, penicillin). Physical examination revealed bilateral optic disc edema. Cerebral magnetic resonance imaging (MRI) revealed indirect signs of intracranial hypertension. The CSF pressure measurement was approximately 290 mmHg, while CSF and other laboratory blood tests were normal. The patient received methylprednisolone bolus and topiramate (50 mg/day). A month later, the clinical outcome showed regression of headaches and regression of the papilledema.

Idiopathic Intracranial Hypertension After Abrupt Cessation of Medication: A Case Report of Abrupt Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist Cessation and Review of the Literature.

PURPOSE OF REVIEW: The purpose of this review is two-fold: (1) to discuss a case report of idiopathic intracranial hypertension (IIH) after abrupt cessation of a glucagon-like peptide-1 (GLP-1) receptor agonist with resultant rapid weight gain and (2) to review the literature regarding the potential role of GLP-1 receptor agonists in the treatment of IIH as well as potential pitfalls. RECENT FINDINGS: GLP-1 receptor agonists have become widely used to treat obesity. Obesity is a known risk factor for the development of IIH, though the precise pathophysiology is unclear. GLP-1 receptor agonists may help treat IIH by promoting weight loss, lipolysis of adipose tissue, and potentially decreasing the secretion of CSF, as was seen in rat models. Abrupt cessation of GLP-1 receptor agonists can result in regaining lost weight rapidly. In the case that we present, the patient stopped duraglutide abruptly due to lack of insurance coverage and regained the weight she had lost within a month. She subsequently developed IIH. GLP-1 receptor agonists have the potential to help treat IIH; however, this class of medication needs to be used carefully, as cessation of the medication and resultant rapid weight gain can result in IIH.

The Pseudotumor Cerebri Syndrome.

Pseudotumor cerebri syndrome is a syndrome of increased cerebrospinal fluid pressure without ventriculomegaly, mass lesion, or meningeal abnormality. It is either primary (idiopathic intracranial hypertension, IIH) or secondary. A secondary cause is unlikely when adhering to the diagnostic criteria. Permanent visual loss occurs if undetected or untreated, and the associated headaches may be debilitating. Fulminant disease may result in blindness despite aggressive treatment. This study addresses the diagnosis and management of IIH including new insights into the pathobiology of IIH, updates in therapeutics and causes of overdiagnosis.

Longitudinal optical coherence tomography indices in idiopathic intracranial hypertension.

Idiopathic intracranial hypertension (IIH) may result in optic nerve fiber loss and even atrophy. The timing of the optical coherence tomography (OCT) indices reaching the lowest point (nadir) and the factors that predict the patient's anatomical outcome are not known. We aimed to determine the timing and the factors that affect nadir retinal nerve fiber layer (RNFL) thickness. The medical records of 99 IIH patients who were treated from December 2009 to January 2020 were retrospectively reviewed. The mean RNFL thickness at presentation was 263.5 ± 106.4 µm. The mean time to nadir was 7.9 ± 6.3 months. The average RNFL and ganglion cell complex (GCC) thickness at the nadir were 92.6 ± 14.5 µm (47% showed thinning) and 77.9 ± 27.8 µm (70% showed thinning), respectively. The Frisén disc edema stage and average RNFL thickness at baseline correlated with a longer time to nadir, (r = 0.28 P = 0.003 and r = 0.24, P = 0.012, respectively). The nadir average RNFL thickness and the nadir average GCC thickness (r = 0.32, P = 0.001, r = 0.29, P = 0.002, respectively) correlated with the baseline visual field mean deviation. The final anatomical outcome of IIH episodes in this study resulted in RNFL and GCC thinning. The time to RNFL nadir and its values correlated with IIH severity at presentation.

Using EEG total energy as a noninvasively tracking of intracranial (and cerebral perfussion) pressure in an animal model: A pilot study.

PURPOSE: This study aims to describe the total EEG energy during episodes of intracranial hypertension (IH) and evaluate its potential as a classification feature for IH. NEW METHODS: We computed the sample correlation coefficient between intracranial pressure (ICP) and the total EEG energy. Additionally, a generalized additive model was employed to assess the relationship between arterial blood pressure (ABP), total EEG energy, and the odds of IH. RESULTS: The median sample cross-correlation between total EEG energy and ICP was 0.7, and for cerebral perfusion pressure (CPP) was 0.55. Moreover, the proposed model exhibited an accuracy of 0.70, sensitivity of 0.53, specificity of 0.79, precision of 0.54, F1-score of 0.54, and an AUC of 0.7. COMPARISON WITH EXISTING METHODS: The only existing comparable methods, up to our knowledge, use 13 variables as predictor of IH, our model uses only 3, our model, as it is an extension of the generalized model is interpretable and it achieves the same performance. CONCLUSION: These findings hold promise for the advancement of multimodal monitoring systems in neurocritical care and the development of a non-invasive ICP monitoring tool, particularly in resource-constrained environments.

Navigating the Enigma: A Comprehensive Review of Idiopathic Intracranial Hypertension.

An unidentified source of increased intracranial pressure is a hallmark of idiopathic intracranial hypertension (IIH), also referred to as pseudotumor cerebri. It mainly affects young, obese women, yet it can happen to anyone, regardless of age, gender, or weight. IIH presents with symptoms such as headaches, visual disturbances, and pulsatile tinnitus and can lead to severe complications, including vision loss, if left untreated. Diagnosis involves clinical evaluation, neuroimaging, and lumbar puncture, while management options include medical interventions and surgical procedures. This review provides a comprehensive overview of IIH, including its etiology, clinical presentation, epidemiology, complications, management approaches, and challenges. Increased awareness among healthcare professionals, standardized diagnostic criteria, and further research efforts are essential for improving outcomes and quality of life for individuals with IIH.

Idiopathic intracranial hypertension as the initial presenting manifestation of systemic lupus erythematosus in a child.

Idiopathic intracranial hypertension (IIH) is a diagnosis of exclusion characterized by features of raised intracranial pressure (ICP) in the absence of brain parenchymal lesion, vascular malformations, hydrocephalus, or central nervous system (CNS) infection. Commonly used other terms for this entity include benign intracranial hypertension (BIH) or pseudotumor cerebri. Few case reports of systemic lupus erythematosus (SLE) presenting as IIH are available in the literature. We report a 12-year-old girl presented with chronic holocranial headache and occasional episodes of projectile vomiting for the last 6 months and then developed blurring of vision for the last month. She fulfilled the criteria for IIH. Subsequent evaluation revealed a diagnosis of SLE. The occurrence of IIH in SLE is not coincidental and is reported in 1%-5.4% of patients with SLE. Though corticosteroids have not been widely used in IIH, underlying SLE warranted administering corticosteroids with subsequent complete resolution of IIH. Pediatricians, neurologists, intensivists, and ophthalmologists should consider SLE as a differential diagnosis in children presenting with IIH.

Developments in targeting calcitonin gene-related peptide.

INTRODUCTION: Calcitonin Gene-Related Peptide (CGRP)-targeted therapy has revolutionized migraine treatment since its first approval in 2018. CGRP-targeted therapy includes monoclonal antibodies (mAbs) and gepants, which modulate trigeminal nociceptive and inflammatory responses, alleviating pain sensitization involved in migraine pathogenesis. CGRP-targeted therapy is effective not only for migraine but also for other chronic headache disorders that share the CGRP pathway. AREAS COVERED: The authors review the latest developments and evidence for CGRP-targeted therapy for episodic migraine and chronic migraine. In addition, the authors discuss the emerging evidence on response prediction, menstrual migraine, vestibular migraine, idiopathic intracranial hypertension, post-traumatic headache, and the relationship between selected migraine comorbidities and CGRP. EXPERT OPINION: Since the launch of CGRP-targeted therapy, many practical issues have been raised. Generally, it's safe to combine CGRP-targeted mAbs and gepants; this is an excellent option for patients with partial response. When considering stopping CGRP-targeted therapy, although a disease-modifying effect is likely, the optimal time for discontinuation remains unknown. Finally, beyond migraine, CGRP-targeted therapy may be used for other chronic pain disorders and psychological comorbidities.

Subacute Hydrocephalus Revealing a Cryptococcus Infection in a Seven-Year-Old Child.

Cryptococcal meningitis (CM) is the third most common neurological complication in immunocompromised patients and is usually associated with high rates of morbidity and mortality. The most common complication of CM is intracranial hypertension (ICH), and it constitutes a poor prognosis factor. This case report describes a case of subacute onset hydrocephalus revealing a human immunodeficiency virus (HIV)-associated CM in a seven-year-old girl requiring cerebrospinal fluid diversion and fungal treatment with a favorable outcome.

Idiopathic intracranial hypertension associated with SARS-CoV-2 infection in an adult male patient: a case report and review of the literature.

BACKGROUND: Headache is a frequent symptom in coronavirus disease 2019 (COVID-19) patients, and idiopathic intracranial hypertension (pseudotumor cerebri) has been reported among patients who underwent lumbar puncture for persistent headaches. CASE PRESENTATION: A 45-year-old black man presented with dyspnea, cough, fever and headache for 05 days followed by blurring of vision associated with worsening of the headache. Physical examination was significant for tachypnea and oxygen desaturation and there were no abnormal neurologic findings. He tested positive for SARS-CoV-2 with nasopharyngeal swab PCR. His CSF opening pressure appeared high with normal CSF analysis and brain magnetic resonance imaging (MRI) revealed prominent subarachnoid space around the optic nerves and bilateral papilledema. He had significant improvement with medical therapy alone. CONCLUSION: Idiopathic intracranial hypertension (IIH) may occur in association with SARS-CoV-2 infection and should be considered when making a differential diagnosis for headache and blurring of vision. COVID-19 may play a role in the development of intracranial hypertension, even in the absence of known risk factors. Early diagnosis and treatment of IIH has paramount importance to prevent vision loss and other morbidities.

[Acute care of patients with cerebral palsy in neuro-resuscitation surgery]. / La prise en soins des patients cérébrolésés à la phase aiguë en neuroréanimation chirurgicale.

Severe head trauma, with or without polytrauma, subarachnoid haemorrhage due to aneurysm rupture, is an unexpected tragedy for patients and their families. These accidents are likely to result in extremely serious neurological damage, with many of the patients under our care facing a life-threatening prognosis. To protect the brain, one solution is to put the patient into a deep sleep during the so-called "acute" phase, making it impossible to assess the repercussions of the initial injuries at the time: this is what we call "waiting resuscitation".

Foundations of the Diagnosis and Management of Idiopathic Intracranial Hypertension and Pulsatile Tinnitus.

Venous sinus stenosis has garnered increasing academic attention as a potential etiology of idiopathic intracranial hypertension (IIH) and pulsatile tinnitus (PT). The complex anatomy of the cerebral venous sinuses and veins plays a crucial role in the pathophysiology of these conditions. Venous sinus stenosis, often found in the superior sagittal or transverse sinus, can lead to elevated intracranial pressure (ICP) and characteristic IIH symptoms. Stenosis, variations in dural venous anatomy, and flow dominance patterns contribute to aberrant flow and subsequent PT. Accurate imaging plays a vital role in diagnosis, and magnetic resonance (MR) venography is particularly useful for detecting stenosis. Management strategies for IIH and PT focus on treating the underlying disease, weight management, medical interventions, and, in severe cases, surgical or endovascular procedures. Recently, venous sinus stenting has gained interest as a minimally invasive treatment option for IIH and PT. Stenting addresses venous sinus stenosis, breaking the feedback loop between elevated ICP and stenosis, thus reducing ICP and promoting cerebrospinal fluid outflow. The correction and resolution of flow aberrances can also mitigate or resolve PT symptoms. While venous sinus stenting remains an emerging field, initial results are promising. Further research is needed to refine patient selection criteria and evaluate the long-term efficacy of stenting as compared to traditional treatments.

Challenges in the use of Venous Sinus Stenting in the Treatment of Idiopathic Intracranial Hypertension and Pulsatile Tinnitus.

Although numerous case series and meta-analyses have shown the efficacy of venous sinus stenting (VSS) in the treatment of idiopathic intracranial hypertension and idiopathic intracranial hypertension-associated pulsatile tinnitus, there remain numerous challenges to be resolved. There is no widespread agreement on candidacy; pressure gradient and failed medical treatment are common indications, but not all clinicians require medical refractoriness as a criterion. Venous manometry, venography, and cerebral angiography are essential tools for patient assessment, but again disagreements exist regarding the best, or most appropriate, diagnostic imaging choice. Challenges with the VSS technique also exist, such as stent choice and deployment. There are considerations regarding postprocedural balloon angioplasty and pharmacologic treatment, but there is insufficient evidence to formalize postoperative decision making. Although complications of VSS are relatively rare, they include in-stent stenosis, hemorrhage, and subdural hematoma, and the learning curve for VSS presents specific challenges in navigating venous anatomy, emphasizing the need for wider availability of high-quality training. Recurrence of symptoms, particularly stent-adjacent stenosis, poses challenges, and although restenting and cerebrospinal fluid-diverting procedures are options, there is a need for clearer criteria for retreatment strategies. Despite these challenges, when comparing VSS with traditional cerebrospinal fluid-diverting procedures, VSS emerges as a favorable option, with strong clinical outcomes, lower complication rates, and cost-effectiveness. Further research is necessary to refine techniques and indications and address specific aspects of VSS to overcome these challenges.

Future Directions and Innovations in Venous Sinus Stenting.

This review explores the future role of venous sinus stenting (VSS) in the management of idiopathic intracranial hypertension and pulsatile tinnitus. Despite its favorable safety profile and clinical outcomes compared with traditional treatments, VSS is not yet the standard of care for these conditions, lacking high-level evidence data and guidelines for patient selection and indications. Current and recently completed clinical trials are expected to provide data to support the adoption of VSS as a primary treatment option. Additionally, VSS shows potential in treating other conditions, such as dural arteriovenous fistula and cerebral venous sinus thrombosis, and it is likely that the procedure will continue to see an expansion of its approved indications. The current lack of dedicated venous stenting technology is being addressed with promising advancements, which may improve procedural ease and patient outcomes. VSS also offers potential for expansion into modulation of brain electrophysiology via endovascular routes, offering exciting possibilities for neurodiagnostics and treatment of neurodegenerative disorders.

Cerebral Venous Thrombosis in Patients With Traumatic Brain Injury: Epidemiology and Outcome.

The natural history and epidemiological aspects of traumatic cerebral venous thrombosis (CVT) are not fully understood. Due to the concomitant occurrence with intracranial hemorrhages, guidelines for medical treatment have been highly controversial. In this study, our objective was to carry out an analysis description of the population and to conduct a literature review. A prospectively gathered radiology registry data of patients hospitalized at the tertiary hospital of Centro Hospitalar Universitário do São João, Porto, Portugal, between 2016 and 2021 was carried out. All patients with traumatic brain injury (TBI) and concomitant CVT were identified. CVT was confirmed by CT venogram. Demographic, clinical, and radiological data and their medical management were reported. In-hospital complications and treatment outcomes were compared between patients measured by the Glasgow Outcome Score Extended (GOSE) at discharge and GOSE at three months. There were 41 patients with traumatic CVT admitted to this study. The majority (45.2%) had a hyperdense signal near the lateral sinus at admission, and only 26.2% presented with skull fractures. Of this cohort, 95% had experienced lateral sinus thrombosis. Twenty-five patients (60%) had occlusive venous thrombosis. Venous infarct was the main complication following CVT. Thirty-two patients (78%) were anticoagulated after CVT and four developed complications. At the three-month follow-up after discharge, 28.2% had good recovery (GOSE > 6). This study revealed a higher incidence of CVT in severe TBI and a mild association with skull fractures. There is a higher incidence of CVT in the lateral sinus. Management was inconsistent, with no difference in outcome without or with anticoagulation. Larger, prospective cohort studies are required to better comprehend this condition and determine evidence-based guidelines.

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: A Case Report.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a newly discovered autoimmune demyelinating disorder. The clinical manifestations of MOGAD are divergent but often characterized by inflammatory central nervous system (CNS) deficits such as optic neuritis, encephalitis, or transverse myelitis that predominantly affect the pediatric population. Despite the distinct features often associated with MOGAD, the disease exhibits a diverse range of clinical manifestations, making timely diagnosis and treatment challenging. In particular, distinguishing MOGAD from multiple sclerosis (MS) is important for adequate treatment and the prevention of relapsing disease. In this report, we present a rare case of MOGAD in a 57-year-old male who initially exhibited symptoms of bilateral optic nerve edema and flame hemorrhage. This led to an initial misdiagnosis of pseudotumor cerebri. Serological analysis at a tertiary care center ultimately led to the diagnosis of MOGAD after multiple visits to the ophthalmologist with worsening vision deficits.

Fistula espontánea de LCR como manifestación de la hipertensión intracraneal idiopática / Spontaneous CSF fistula as manifestation of idiopathic intracranial hypertension

Introducción: La fistula espontanea de líquido cefalorraquídeo (LCR) de origen desconocido, es una afección poco frecuente cuya etiología se relaciona cada vez más con la hipertensión intracraneal idiopática (HII). Este estudio trata de concienciar que no deben considerase como 2 procesos distintos, sino que las fistulas pueden ser una forma de inicio, requiriendo un estudio y tratamiento posterior. Se describen las técnicas de reparación, así como el estudio de la HII. Resultados: Se trataron 8 pacientes, 5 mujeres y 3 varones, con edades comprendidas entre 46 y 72 años, con diagnóstico de fistula espontánea de LCR, 4 nasales y 4 óticas a los que se le sometió a tratamiento quirúrgico. Tras la reparación se realizó un estudio diagnóstico para la HII mediante RMN y angio-RM, presentando en todos los casos una estenosis de seno venoso transverso. Los valores de presión intracraneal obtenidos mediante punción lumbar mostraron valores de 20mmHg o superiores. Todos los pacientes fueron diagnosticados de HII. El seguimiento a un año no reveló ninguna recidiva de las fistulas, manteniendo un control de la HII. Conclusión: A pesar de su escasa frecuencia tanto de las fistulas craneales de LCR como de la HII, debe considerarse una asociación de ambas afecciones continuando el estudio y vigilancia de estos pacientes tras el cierre de la fístula.(AU)

Introduction: Spontaneous cerebrospinal fluid (CSF) fistula, of unknown origin, is a rare condition whose etiology is increasingly related to idiopathic intracranial hypertension (IIH). This study tries to raise awareness that they should not be considered as two different processes, but that fistulas can be a form of debut, requiring a study and subsequent treatment. Repair techniques are described, as well as the study of IIH. Results: We treated eight patients, five women and three men, aged between 46 and 72 years, with a diagnosis of spontaneous CSF fistula, four nasal and four otics who underwent surgical treatment. After repair, a diagnostic study was performed for IIH by MRI and angio-MRI, presenting in all cases a transverse venous sinus stenosis. The intracranial pressure values obtained by lumbar puncture showed values of 20mmHg or higher. All patients were diagnosed with IIH. The one-year follow-up did not reveal any recurrence of the fistulas, maintaining a control of the IIH. Conclusion: Despite their low frequency of both cranial CSF fistula and IIH, an association of both conditions should be considered by continuing the study and surveillance of these patients after fistula closure.(AU)

Idiopathic intracranial hypertension in Omani adults: A tertiary center experience.

BACKGROUND: To evaluate the clinical profile, risk factors, and ophthalmic diagnostic and monitoring tools in Omani patients with idiopathic intracranial hypertension (IIH) using optical coherence tomography (OCT). METHODS: A retrospective single institutional cohort study on Omani patients with a fulfilled diagnosis of IIH from January 1, 2014, to January 1, 2020, was conducted. The data obtained from the neuro-ophthalmic clinic contained age of onset of the disease, gender of patients, body mass index (BMI), presence of other associated conditions, and medication use. RESULTS: Our study group comprised 21 patients with IIH with an annual incidence rate of 2.8 per 100,000 population. Female-to-male ratio was 9.5:1 with a mean age of 27.24 ± 7.1. Headaches appeared to be the most prevalent symptom in 21 (100%) patients, followed by transient obscuration of vision in 9 (42.9%) patients and diplopia in 3 (14.3%) patients, and the least common symptom was pulsatile tinnitus in 2 (9.5%) patients. Increased BMI was seen in 19 (90.5%) patients and noted to be the most prevalent predisposing factor among our study group. The use of oral contraceptive pills was documented in 4 (19%) patients and 1 (4.8%) patient was noted to have polycystic ovary syndrome. All patients (100%) had a best-corrected visual acuity of 1.0 in both eyes pre- and postrecovery and 7 (33.3%) patients had an enlarged blind spot on visual field testing. All patients had papilledema on presentation and an average of 14.1 months to resolve to normal clinically and on OCT monitoring. All patients were treated with medications and only 1 (4.8%) continued to have intractable headaches that did not respond to maximum medical therapy and required surgery. CONCLUSION: The incidence of IIH in the Omani population was found to be less than neighboring countries but comparable worldwide. OCT is considered a useful tool to confirm and document papilledema and more importantly monitor recovery.

A genetic survey of patients with familial idiopathic intracranial hypertension residing in a Middle Eastern village: genetic association study.

BACKGROUND: The aim of this study was to determine whether genetic variants are associated with idiopathic intracranial hypertension (IIH) in a unique village where many of the IIH patients have familial ties, a homogenous population and a high prevalence of consanguinity. Several autosomal recessive disorders are common in this village and its population is considered at a high risk for genetic disorders. METHODS: The samples were genotyped by the Ilumina OmniExpress-24 Kit, and analyzed by the Eagle V2.4 and DASH software package to cluster haplotypes shared between our cohort. Subsequently, we searched for specific haplotypes that were significantly associated with the patient groups. RESULTS: Fourteen patients and 30 controls were included. Samples from 22 female participants (11 patients and 11 controls) were evaluated for haplotype clustering and genome-wide association studies (GWAS). A total of 710,000 single nucleotide polymorphisms (SNPs) were evaluated. Candidate areas positively associated with IIH included genes located on chromosomes 16, 8 (including the CA5A and BANP genes, p < 0.01), and negatively associated with genes located on chromosomes 1 and 6 (including PBX1, LMX1A, ESR1 genes, p < 0.01). CONCLUSIONS: We discovered new loci possibly associated with IIH by employing a GWAS technique to estimate the associations with haplotypes instead of specific SNPs. This method can in all probability be used in cases where there is a limited amount of samples but strong familial connections. Several loci were identified that might be strong candidates for follow-up studies in other well-phenotypes cohorts.