Social cognition in adult survivors of brain tumors: studying the relationship between theory of mind and quality of life.

OBJECTIVE: The present study is the first to examine theory of mind (ToM) sequelae in a sample of adult survivors of primary brain tumors, and to investigate the assumed relationship between ToM and health-related quality of life (HRQoL). METHOD: Participants were 40 long-term adult survivors of primary brain tumors and 40 matched healthy controls. They completed ToM tests (Faux-Pas test and Advanced ToM task) and two questionnaires assessing HRQoL (36-Item Short-Form Health Survey and EORTC QLQ-C30/QLQ-BN20). Their relatives also completed an observer-rated version of the SF-36 questionnaire. RESULTS: Survivors performed worse than controls only on the Advanced ToM task. Overall, patients and caregivers reported more problems than healthy controls and their relatives regarding both global HRQoL and its social/emotional aspects. No relationship was found between ToM and HRQoL scores. CONCLUSION: Adult survivors of primary brain tumors may exhibit ToM deficits several years after treatment and report more problems on social/emotional HRQoL components. Our findings highlight the need to consider these late effects in survivors' long-term follow-up, even if the clinical involvement of ToM deficits still needs to be elucidated. The assessment of ToM deficits and their potential impact on survivors' everyday life is thoroughly discussed.

Natural history of spinal cord metastasis from brain glioblastomas.

BACKGROUND AND OBJECTIVES: Spinal cord metastasis arising from an intracranial glioblastoma is a rare and late event during the natural course of the disease. These pathological entities remain poorly characterized. This study aimed to identify and investigate the timeline, clinical and imaging findings, and prognostic factors of spinal cord metastasis from a glioblastoma. METHODS: Consecutive histopathological cases of spinal cord metastasis from glioblastomas in adults entered in the French nationwide database between January 2004 and 2016 were screened. RESULTS: Overall, 14 adult patients with a brain glioblastoma (median age 55.2 years) and harboring a spinal cord metastasis were included. The median overall survival as 16.0 months (range, 9.8-22.2). The median spinal cord Metastasis Free Survival (time interval between the glioblastoma diagnosis and the spinal cord metastasis diagnosis) was 13.6 months (range, 0.0-27.9). The occurrence of a spinal cord metastasis diagnosis greatly impacted neurological status: 57.2% of patients were not ambulatory, which contributed to dramatically decreased Karnofsky Performance Status (KPS) scores (12/14, 85.7% with a KPS score ≤ 70). The median overall survival following spinal cord metastasis was 3.3 months (range, 1.3-5.3). Patients with a cerebral ventricle effraction during the initial brain surgery had a shorter spinal cord Metastasis Free Survival (6.6 vs 18.3 months, p = 0.023). Out of the 14 patients, eleven (78.6%) had a brain IDH-wildtype glioblastoma. CONCLUSIONS: Spinal cord metastasis from a brain IDH-wildtype glioblastoma has a poor prognosis. Spinal MRI can be proposed during the follow-up of glioblastoma patients especially those who have benefited from cerebral surgical resection with opening of the cerebral ventricles.

Associations between Adult Primary Brain Tumor Survivors' Behavioral Executive Functions, Health Related Quality of Life and their Caregivers' Health Related Quality : A cross-sectional study.

The present study focused on adult primary brain tumor (PBT) survivors' caregivers. The main objective was to study associations between PBT survivors' health-related quality of life (HRQOL), their behavioral executive functions (EF) and their caregivers' HRQOL. Forty PBT survivors of PBT and 37 caregivers (mostly patient's spouses 81.08%; n = 30) participated in the study. PBT survivors completed a cancer related Quality of Life (QOL) questionnaire. Caregivers completed informant rated HRQOL and behavioral EF reports relating to PBT survivors and a self-rated HRQOL questionnaire relating to themselves. Correlational and multiple regression analyses were conducted. No associations were found between caregivers' physical HRQOL and PBT survivors' HRQOL nor behavioral EF. Analyses yielded several significant correlations between caregivers' mental HRQOL and variables pertaining to PBT survivors' HRQOL and behavioral EF. Multiple regression analyses showed that caregivers' mental HRQOL is predicted by PBT survivors' mental HRQOL, global cancer-related QOL scores and global behavioral EF scores. This study provides evidence suggesting that during the survivorship phase, at an average of 3.67 (SD = 2.31) years following treatment for a PBT, caregivers mental HRQOL is linked to PBT survivors' long-term effects. These findings shed some light regarding post-cancer care for both PBT survivors and their caregivers.

Robot-assisted stereotactic multiple brain abscesses' puncture: technical case report.

We report a case of multiple brain abscesses' puncture, employing the ROSA™ Brain surgical robot (Zimmer Biomet) and the O-arm® O2 Imaging System (Medtronic). A 51-year-old man was diagnosed with multiple supratentorial ring enhancing cystic lesions consistent with brain abscesses. A neurological deterioration occurred despite broad spectrum antibiotic therapy, due to mass effect of the abscesses. Stereotactic aspiration was performed using the described technique, allowing a single stage puncture of the cerebral lesions. In this case, the robot-assisted and image-guided procedure permitted an accurate, quick, and efficient targeting of the multiple abscesses for drainage.

Meningiomas and cyproterone acetate: a retrospective, monocentric cohort of 388 patients treated by surgery or radiotherapy for intracranial meningioma.

PURPOSE: Meningiomas are the most common intracranial tumors, accounting for 20-30% of central nervous system tumors. Recently, the European Medicines Agency issued an alert on cyproterone acetate (CPA) based on the results of a study that found an increased risk of meningioma 7 to 20 times higher when a patient is on CPA. The primary objective of this study was to determine the prevalence of CPA exposure in patients who had one or more intracranial meningiomas treated surgically or with radiation therapy. The secondary objectives were to establish a description of the patients who had intracranial meningioma in Nantes and to establish whether there was a difference in the intrinsic and tumoral characteristics of patients exposed to CPA compared with patients who had no hormonal exposure and patients who had been exposed to other hormones. METHODS: Monocentric, retrospective study including all patients treated by surgery or radiotherapy for intracranial meningioma from 2014 to 2017 excluding those with a history of exposure to ionizing radiation or neurofibromatosis type 2. RESULTS: 388 patients were included, 277 were treated by surgery and 111 by radiotherapy. 3.9% of the patients had a history or current use of CPA, 16.2% were taking other hormonal treatment. Compared with the group without hormonal exposure, the CPA-exposed group had significantly an earlier onset of meningiomas at 48.9 vs. 61.9 years (p = 0.0005) and had more multiple meningiomas, 26.7% vs. 6.1% (p = 0.0115). CONCLUSIONS: In our study, patients with a history or current use of CPA had significantly more meningiomas and were significantly younger at the onset.

Subthalamic nucleus stimulation reverses spinal motoneuron activity in parkinsonian patients.

Although a cardinal symptom of Parkinsonian disease, up to now, rigidity has been investigated much less than spasticity in hemiplegic patients. Many pathophysiological mechanisms may at least theoretically contribute to Parkinsonian rigidity, from altered viscoelastic muscle properties to inability of parkinsonian patients to relax. However, as demonstrated many years ago, motoneuron responses to muscle afferent volleys are involved in rigidity since afferent volleys are suppressed after dorsal root section. To our knowledge, homosynaptic depression (i.e. the fact that motoneuron responses to Ia afferent volleys exhibit a frequency-related depression) has not been studied in parkinsonian disease, despite the fact that in spastic patients, changes in homosynaptic depression are significantly correlated at wrist and ankle levels with the severity of spasticity. Thus, in the present series of experiments, we investigated in parkinsonian patients with chronic implantation of both subthalamic motor nuclei, the amount of homosynaptic depression at wrist and ankle levels on and off deep brain stimulation. Off deep brain stimulation, the frequency-related depression disappeared, the patients became rigid and the amount of homosynaptic depression was significantly correlated with the severity of rigidity. On deep brain stimulation, the frequency-related depression was restored and the rigidity suppressed, suggesting that homosynaptic depression is one of the mechanisms underlying rigidity in Parkinson's disease. Moreover, the unexpected finding that changes in the rigidity score and the amount of homosynaptic depression are time-locked to the onset of deep brain stimulation leads us to reconsider the mechanisms underlying changes in homosynaptic depression.

Cognitive tasks and combined statistical methods to evaluate, model, and predict mental workload.

Mental workload (MWL) is a concept that is used as a reference for assessing the mental cost of activities. In recent times, challenges related to user experience are determining the expected MWL value for a given activity and real-time adaptation of task complexity level to achieve or maintain desired MWL. As a consequence, it is important to have at least one task that can reliably predict the MWL level associated with a given complexity level. In this study, we used several cognitive tasks to meet this need, including the N-Back task, the commonly used reference test in the MWL literature, and the Corsi test. Tasks were adapted to generate different MWL classes measured via NASA-TLX and Workload Profile questionnaires. Our first objective was to identify which tasks had the most distinct MWL classes based on combined statistical methods. Our results indicated that the Corsi test satisfied our first objective, obtaining three distinct MWL classes associated with three complexity levels offering therefore a reliable model (about 80% accuracy) to predicted MWL classes. Our second objective was to achieve or maintain the desired MWL, which entailed the use of an algorithm to adapt the MWL class based on an accurate prediction model. This model needed to be based on an objective and real-time indicator of MWL. For this purpose, we identified different performance criteria for each task. The classification models obtained indicated that only the Corsi test would be a good candidate for this aim (more than 50% accuracy compared to a chance level of 33%) but performances were not sufficient to consider identifying and adapting the MWL class online with sufficient accuracy during a task. Thus, performance indicators require to be complemented by other types of measures like physiological ones. Our study also highlights the limitations of the N-back task in favor of the Corsi test which turned out to be the best candidate to model and predict the MWL among several cognitive tasks.

Natural Course and Prognosis of Primary Spinal Glioblastoma: A Nationwide Study.

BACKGROUND AND OBJECTIVES: Primary spinal glioblastoma (PsGBM) is extremely rare. The dramatic neurologic deterioration and unresectability of PsGBM makes it a particularly disabling malignant neoplasm. Because it is a rare and heterogeneous disease, the assessment of prognostic factors remains limited. METHODS: PsGBMs were identified from the French Brain Tumor Database and the Club de Neuro-Oncologie of the Société Française de Neurochirurgie retrospectively. Inclusion criteria were age 18 years or older at diagnosis, spinal location, histopathologic diagnosis of newly glioblastoma according to the 2016 World Health Organization classification, and surgical management between 2004 and 2016. Diagnosis was confirmed by a centralized neuropathologic review. The primary outcome was overall survival (OS). Therapeutic interventions and neurologic outcomes were also collected. RESULTS: Thirty-three patients with a histopathologically confirmed PsGBM (median age 50.9 years) were included (27 centers). The median OS was 13.1 months (range 2.5-23.7), and the median progression-free survival was 5.9 months (range 1.6-10.2). In multivariable analyses using Cox model, Eastern Cooperative Oncology Group (ECOG) performance status at 0-1 was the only independent predictor of longer OS (hazard ratio [HR] 0.13, 95% CI 0.02-0.801; p = 0.02), whereas a Karnofsky performance status (KPS) score <60 (HR 2.89, 95% CI 1.05-7.92; p = 0.03) and a cervical anatomical location (HR 4.14, 95% CI 1.32-12.98; p = 0.01) were independent predictors of shorter OS. The ambulatory status (Frankel D-E) (HR 0.38, 95% CI 0.07-1.985; p = 0.250) was not an independent prognostic factor, while the concomitant standard radiochemotherapy with temozolomide (Stupp protocol) (HR 0.35, 95% CI 0.118-1.05; p = 0.06) was at the limit of significance. DISCUSSION: Preoperative ECOG performance status, KPS score, and the location are independent predictors of OS of PsGBMs in adults. Further analyses are required to capture the survival benefit of concomitant standard radiochemotherapy with temozolomide.

Idiopathic normal pressure hydrocephalus and frontotemporal dementia: an unexpected association.

Idiopathic normal pressure hydrocephalus has a complex multifactorial pathogenesis and is associated with Alzheimer's disease in many patients. To date, it is not well known if a similar association exists with behavioural variant of frontotemporal lobar degeneration. In a first step, we compare the prevalence of idiopathic normal pressure hydrocephalus in two groups of patients, one with behavioural variant of frontotemporal lobar degeneration (n = 69) and the other with Alzheimer's disease (n = 178). In the second step, we describe more precisely the phenotype of patients with the association of idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration. Firstly, we report that the prevalence of idiopathic normal pressure hydrocephalus was far higher in the group of patients with behavioural variant of frontotemporal lobar degeneration than in the group of patients with Alzheimer's disease (7.25% and 1.1%, respectively, P = 0.02). Secondly, we show that patients with the double diagnosis share common clinical and para-clinical features of both idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration patients, including CSF shunting efficacy in real-life experience. Overall, our results suggest a link between these two conditions and should encourage neurologists to look for idiopathic normal pressure hydrocephalus in their behavioural variant of frontotemporal lobar degeneration patients in the event of gait disturbances; the benefit/risk balance could indeed be in favour of shunt surgery for selected patients with this newly described entity.

Relationships between executive functioning and health-related quality of life in adult survivors of brain tumor and matched healthy controls.

INTRODUCTION: Few studies have considered health-related quality of life (HRQOL) as a primary outcome measure in adult survivors of primary brain tumor (PBT), and fewer still have studied the cognitive factors that may influence it. Research suggests that executive functions (EFs) are associated with HRQOL, but there is scant evidence to support this. The present study was conducted to (1) extend prior findings about HRQOL limitations in a sample of stable, long-term adult survivors of PBT, (2) investigate the associations between objective/reported EFs and HRQOL, and (3) identify the EFs that contribute most to HRQOL. METHOD: We recruited 40 survivors of PBT (> 2 years post-treatment) and 40 matched healthy controls. Participants completed an objective EF assessment (inhibition, working memory, shifting, and rule detection) and two self-report questionnaires probing EFs (Behavior Rating Inventory of Executive Function-Adult) and HRQOL (Medical Outcomes Study Short-Form 36). Participants' relatives completed observer-rated versions of these questionnaires. RESULTS: Patients' objective EF performances were relatively intact. However, patients and caregivers reported significantly more problems than healthy controls and their relatives, for both EFs and HRQOL. There were only negligible links between objective EFs and HRQOL, whereas numerous associations were found between reported EFs and HRQOL components. ANCOVA models revealed that specific reported EF processes contributed to both the physical and mental components of HRQOL, regardless of group. CONCLUSIONS: From a clinical point of view, this study demonstrates that even several years after end of treatment, adult PBT survivors experience substantial problems across different HRQOL domains. HRQOL assessment should therefore be part of the long-term follow-up of PBT survivors, and clinicians should consider EF limitations when designing appropriate survivorship care plans. These findings indicate that cognitive interventions targeting EFs could improve HRQOL.

Patient-reported functional executive challenges and caregiver confirmation in adult brain tumor survivors.

PURPOSE: The main objective of this study was to provide further information concerning the validity of patient-reported executive function (EF) in survivors of primary brain tumor (PBT) compared with a report provided by each patient's caregiver. METHODS: Forty survivors of PBT, 40 non-cancer controls and their proxies completed an assessment of functional executive disorders (e.g., planning, inhibition, shifting, action initiation). Comparisons of self and informant EF reports were examined, for both patients and non-cancer controls. The extent of the concordance between patients' reports and their caregivers' reports was also determined. RESULTS: PBT survivors and their caregivers reported more problems related to EF in contrast with the non-cancer comparison group (significant differences). There was a high level of agreement between patients' and caregivers' ratings within the patient group. CONCLUSIONS: This study provides evidence suggesting that at an average of 3.67 (SD = 2.31) years following treatment for a PBT, EF difficulties are reported by patients and their caregivers. This study establishes a consistency between what is reported by survivors and what is reported by those who frequently interact with them. Further research investigating the link between these ratings and quality of life as well as other functions is encouraged. IMPLICATIONS FOR CANCER SURVIVORS: This study's results demonstrate the importance of listening to PBT survivors' perception of EF difficulties. While not confirmed by neuropsychological evaluations, the functional executive challenges reported by these survivors' close relatives reflect what PBT survivors themselves report. Specialists should pay close attention to these difficulties to guarantee optimal post-cancer care.

Standard 6-week chemoradiation for elderly patients with newly diagnosed glioblastoma.

Glioblastoma (GBM) is frequent in elderly patients, but their frailty provokes debate regarding optimal treatment in general, and the standard 6-week chemoradiation (CRT) in particular, although this is the mainstay for younger patients. All patients with newly diagnosed GBM and age ≥ 70 who were referred to our institution for 6-week CRT were reviewed from 2004 to 2018. MGMT status was not available for treatment decision at that time. The primary endpoint was overall survival (OS). Secondary outcomes were progression-free survival (PFS), early adverse neurological events without neurological progression ≤ 1 month after CRT and temozolomide hematologic toxicity assessed by CTCAE v5. 128 patients were included. The median age was 74.1 (IQR: 72-77). 15% of patients were ≥ 80 years. 62.5% and 37.5% of patients fulfilled the criteria for RPA class I-II and III-IV, respectively. 81% of patients received the entire CRT and 28% completed the maintenance temozolomide. With median follow-up of 11.7 months (IQR: 6.5-17.5), median OS was 11.7 months (CI 95%: 10-13 months). Median PFS was 9.5 months (CI 95%: 9-10.5 months). 8% of patients experienced grade ≥ 3 hematologic events. 52.5% of patients without neurological progression had early adverse neurological events. Post-operative neurological disabilities and age ≥ 80 were not associated with worsened outcomes. 6-week chemoradiation was feasible for "real-life" elderly patients diagnosed with glioblastoma, even in the case of post-operative neurological disabilities. Old does not necessarily mean worse.

Trigeminal Ganglion Metastasis of Renal Clear Cell Carcinoma: Cases Report and Review of the Literature.

BACKGROUND: The trigeminal ganglion is an atypical site for metastasis, especially for renal clear cell carcinoma. CASE DESCRIPTION: We report 2 clinical cases of a 66-year-old man and a 58-year-old man with trigeminal symptoms. Both patients had a history of renal clear cell (RCC) that was considered to be cured at 6 and 9 years, respectively. Brain magnetic resonance imaging (MRI) showed a trigeminal ganglion lesion with increased gadolinium enhancement associated with petrous apex erosion. The main diagnostic hypothesis based on MRI was trigeminal schwannoma for both patients. One patient underwent subtotal removal, the other a biopsy. Histologic examinations resulted in the diagnosis of RCC metastasis. Body computed tomography revealed pancreatic metastasis for both but no renal recurrence. The patients were treated by local radiotherapy, and 1 of the patients had associated chemotherapy. We added to these clinical cases a literature review of skull base metastasis of RCC. Trigeminal ganglion metastasis of RCC is very rare and can persist until 10 years after the first RCC diagnosis. It seems that the best treatment is surgical removal. To date, the role of local radiotherapy is not demonstrated, and the prognosis seems to be poor. CONCLUSIONS: In the case of trigeminal symptoms, rapid tumoral growth on brain MRI, or a history of RCC, we think that a body computed tomography should be performed, and surgery should be considered.

Spinal Dural Arteriovenous Fistulas: Clinical Outcome After Surgery Versus Embolization: A Retrospective Study.

OBJECTIVE: Spinal dural arteriovenous fistulas (SDAVFs) are rare vascular spinal malformations. According to the reported data, surgery seems to result in better occlusion rates than endovascular treatment. However, the post-treatment evolution of neurological symptoms stratified by the treatment remains unknown. The main objective of the present study was to compare the clinical outcomes for patients according to the treatment method. METHODS: The data from 63 patients with SDAVFs from 2000 to 2017 at 4 academic neurosurgical departments were retrospectively analyzed. Preoperative and postoperative examination neurological status was assessed using the Aminoff-Logue scale (ALS), which evaluates gait and micturition disturbances. Initial occlusion, late recurrence, and complications of the 2 techniques were also reviewed. RESULTS: Patients who had undergone surgery and embolization improved clinically on the ALS (P = 0.0009), and no significant differences were found between the 2 techniques. Subgroup analysis using the ALS showed that patients who had undergone surgery and embolization without late recurrence improved (P < 0.0001 and P = 0.0334, respectively) and that patients who had undergone surgery or embolization with late recurrence did not improve. The initial occlusion rate was in favor of surgery, with 91.3% versus 70% for endovascular treatment (P = 0.050). The late recurrence rate was higher for embolization (21.4% vs. 9.1% for surgery; P = 0.28). CONCLUSIONS: Surgery can be proposed as first-line treatment of SDAVFs after multidisciplinary discussion between neurosurgeons and neuroradiologists. The development of late recurrence negatively affects the neurological outcome of patients.

Long-Term Follow-Up Comparative Study of Hydroxyapatite and Autologous Cranioplasties: Complications, Cosmetic Results, Osseointegration.

OBJECTIVE: A three-dimensional reconstruction technique using the CustomBone (CB) prosthesis allows custom-made cranioplasty (CP) possessing osseointegration properties owing to its porous hydroxyapatite (HA) composition. This reconstruction technique has replaced less expensive techniques such as subcutaneously preserved autologous bone (SP). Our primary objective was to evaluate complications between CB and SP CP techniques. A secondary objective was to assess cosmetic results and osseointegration of CPs. METHODS: This single-center study comprised patients undergoing delayed CB or SP CP after craniectomy between 2007 and 2014. A prospective interview was conducted to collect all data, including 2-year follow-up clinical and radiologic data. Cosmetic results were assessed by a qualitative score, and osseointegration was assessed by measuring relative fusion at the CP margins. RESULTS: Of 100 patients undergoing CB or SP CP between 2007 and 2014, 92 (CB, n = 44; SP, n = 48) participated in the prospective interview. No significant difference in complication rates was observed between the 2 groups. The main complication specific to the CB group was fracture of the prosthesis observed in 20.8% patients. A higher rate of good cosmetic results was observed in the CB group (92.5% vs. 74.3%, P = 0.031). In the CB group, 51% of patients demonstrated no signs of bone fusion of the CP. CONCLUSIONS: Although the CB prosthesis is associated with cosmetic advantages, the porous hydroxyapatite composition makes it fragile in the short-term and long-term, and effective osseointegration remains uncertain.

Dynamic conformal arc radiosurgery for arteriovenous malformations: Outcome and influence of clinical and dosimetrical data.

PURPOSE: To assess efficacy, toxicity, and their predictive factors for dynamic conformal arc arteriovenous malformations (AVM) stereotactic radiosurgery. METHOD: Data concerning 90 consecutive patients were retrospectively studied. Clinical, radiological, dosimetrical data and quality indexes were computed. RESULTS: AVM median volume was 1.06cc. Median prescribed dose was 22Gy. Total occlusion was obtained for 69% of patients. Post-radiosurgery annual hemorrhage rate was 2.2%. Predictive factor for total occlusion was delivered dose. Undesirable events occurred for 28% of patients. Predictive factors for adverse events were AVM revealing mode with seizure or headache, age≤28, AVM diameter≥3cm Spetzler-Martin score≥4, V12Gy≥2cc, large target volume and low homogeneity index (p<0.05). Brain parenchymal radiological reactions concerned 23% of patients, and their predictive factors were AVM revelation by seizure, deep localization, AVM diameter≥3cm, Spetzler-Martin score≥4, previous radiosurgery, numerous embolization, target volume, V12Gy and low homogeneity index (p<0.05). CONCLUSION: Occlusion rate and toxicities are comparable to other series. Specific attention must be paid on pre-treatment clinical data, and target volume should be as small as possible, without reducing the delivered dose.

Understanding the Pathophysiology of Intracranial Aneurysm: The ICAN Project.

BACKGROUND: Understanding the pathophysiologic mechanism of intracranial aneurysm (IA) formation is a prerequisite to assess the potential risk of rupture. Nowadays, there are neither reliable biomarkers nor diagnostic tools to predict the formation or the evolution of IA. Increasing evidence suggests a genetic component of IA but genetics studies have failed to identify genetic variation causally related to IA. OBJECTIVE: To develop diagnostic and predictive tools for the risk of IA formation and rupture. METHODS: The French ICAN project is a noninterventional nationwide and multicentric research program. Each typical IA of bifurcation will be included. For familial forms, further IA screening will be applied among first-degree relatives. By accurate phenotype description with high-throughput genetic screening, we aim to identify new genes involved in IA. These potential genetic markers will be tested in large groups of patients. Any relevant pathway identified will be further explored in a large cohort of sporadic carriers of IA, which will be well documented with clinical, biological, and imaging data. EXPECTED OUTCOMES: Discovering genetic risk factors, better understanding the pathophysiology, and identifying molecular mechanisms responsible for IA formation will be essential bases for the development of biomarkers and identification of therapeutic targets. DISCUSSION: Our protocol has many assets. A nationwide recruitment allows for the inclusion of large pedigrees with familial forms of IA. It will combine accurate phenotyping and comprehensive imaging with high-throughput genetic screening. Last, it will enable exploiting metadata to explore new pathophysiological pathways of interest by crossing clinical, genetic, biological, and imaging information.