Clinical, Neurophysiological, and Genetic Predictors of Recovery in Patients With Severe Acquired Brain Injuries (PRABI): A Study Protocol for a Longitudinal Observational Study.

Background: Due to continuous advances in intensive care technology and neurosurgical procedures, the number of survivors from severe acquired brain injuries (sABIs) has increased considerably, raising several delicate ethical issues. The heterogeneity and complex nature of the neurological damage of sABIs make the detection of predictive factors of a better outcome very challenging. Identifying the profile of those patients with better prospects of recovery will facilitate clinical and family choices and allow to personalize rehabilitation. This paper describes a multicenter prospective study protocol, to investigate outcomes and baseline predictors or biomarkers of functional recovery, on a large Italian cohort of sABI survivors undergoing postacute rehabilitation. Methods: All patients with a diagnosis of sABI admitted to four intensive rehabilitation units (IRUs) within 4 months from the acute event, aged above 18, and providing informed consent, will be enrolled. No additional exclusion criteria will be considered. Measures will be taken at admission (T0), at three (T1) and 6 months (T2) from T0, and follow-up at 12 and 24 months from onset, including clinical and functional data, neurophysiological results, and analysis of neurogenetic biomarkers. Statistics: Advanced machine learning algorithms will be cross validated to achieve data-driven prediction models. To assess the clinical applicability of the solutions obtained, the prediction of recovery milestones will be compared to the evaluation of a multiprofessional, interdisciplinary rehabilitation team, performed within 2 weeks from admission. Discussion: Identifying the profiles of patients with a favorable prognosis would allow customization of rehabilitation strategies, to provide accurate information to the caregivers and, possibly, to optimize rehabilitation outcomes. Conclusions: The application and validation of machine learning algorithms on a comprehensive pool of clinical, genetic, and neurophysiological data can pave the way toward the implementation of tools in support of the clinical prognosis for the rehabilitation pathways of patients after sABI.

Efficacy and Safety of the Association of Nimodipine and Choline Alphoscerate in the Treatment of Cognitive Impairment in Patients with Cerebral Small Vessel Disease. The CONIVaD Trial.

BACKGROUND: No approved treatment is available for patients with vascular cognitive impairment (VCI) due to cerebral small vessel disease (SVD). OBJECTIVE: The CONIVaD (Choline Alphoscerate and Nimodipine in Vascular Dementia) study aimed to investigate the feasibility, efficacy, and safety of a combined treatment with choline alphoscerate and nimodipine in patients with SVD and mild-to-moderate cognitive impairment. METHODS: Within this pilot, single-center (university hospital), double-blinded, randomized clinical trial, patients were randomized to two arms: 1-year treatment with nimodipine 30 mg three times a day (TID) plus choline alphoscerate 600 mg twice a day (BID) (arm 1) or nimodipine 30 mg TID plus placebo BID (arm 2). Patients underwent an evaluation at baseline and after 12 months. Cognitive decline, defined as a ≥ 2-point loss on the Montreal Cognitive Assessment, was the primary endpoint. Functional, quality of life, other cognitive measures, and safety were secondary endpoints. Treatment adherence was measured by the count of medicine bottles returned by patients. RESULTS: Sixty-two patients were randomized (31 each arm). Fourteen patients (22%) dropped out for reasons including consent withdrawal (n = 9), adverse reactions (n = 4), and stroke (n = 1). Forty-eight patients (mean ± SD age 75.1 ± 6.8 years), well balanced between arms, completed the study. Regarding adherence, of the prescribed total drug dose, > 75% was taken by 96% of patients for choline alphoscerate, 87.5% for placebo, and 15% for nimodipine. No statistically significant differences were found between the treatment groups for the primary cognitive outcome, nor for the secondary outcomes. Eight patients had non-serious adverse reactions; five presented adverse events. CONCLUSION: Patients' adherence to treatment was low. With this limitation, the combined choline alphoscerate-nimodipine treatment showed no significant effect in our cohort of VCI patients with SVD. The safety profile was good overall. TRIAL REGISTRATION: Clinical Trial NCT03228498. Registered 25 July 2017.

Gender differences in post-stroke functional outcome at discharge from an intensive rehabilitation hospital.

BACKGROUND: Gender differences in stroke functional recovery after rehabilitation are poorly investigated. Our aim was to compare functional outcomes at discharge from an intensive rehabilitation hospital after stroke in men and women, and to analyze their prognostic factors. METHODS: Retrospective observational study of consecutive stroke patients discharged from an intensive neurological rehabilitation hospital, from January 2018 to June 2019. Modified Rankin Scale (mRS) at discharge was the main outcome measure. RESULTS: Among the 208 included patients (mean age 73.4 ± 13.6 years), 105 (50.5%) were women. Women were significantly older (75.3 ± 13.8 vs. 71.4 ± 13.2 years, respectively, p = 0.041), and less often had a history of smoking habit (27% vs. 50%, p < 0.001). No gender differences emerged for vascular risk factors and comorbidities, pre-stroke functional status, length of hospital stay, stroke type, and number of clinical deficits. At admission to the rehabilitation hospital, mRS score distributions were not different (p = 0.795). At discharge, mRS score distributions and destinations did not differ between men and women (p = 0.391, p = 0.785, respectively). A significant interaction between gender and the change in mRS score from admission to discharge was found (F = 6.6, p = 0.011) taking into account age, stroke type, and number of initial clinical deficits. Dividing the cohort according to age, elderly women showed a better functional recovery compared to men. CONCLUSIONS: At admission to an intensive rehabilitation hospital, men and women presented a similar functional and clinical status and a substantial overlap of functional recovery after stroke. At higher ages, the potential for recovery appeared better in women compared to men.

Altered Regional Brain Homogeneity of BOLD Signal in CADASIL: A Resting State fMRI Study.

BACKGROUND AND PURPOSE: The cognitive decline in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is assumed to be due to a cortical-subcortical disconnection secondary to damage to the cerebral white matter (WM). Using resting state functional MRI (rsfMRI) and analysis of the regional homogeneity (ReHo), we examined a group of CADASIL patients and a group of healthy subjects in order to: (1) explore possible differences between the two groups; and (2) to assess, in CADASIL patients, whether any ReHo abnormalities correlate with individual burdens of WM T2 -weighted hyperintensity and diffusion tensor imaging (DTI)-derived index of mean diffusivity (MD) of the cerebral WM, an index reflecting microstructural damage in CADASIL. METHODS: Twenty-three paucisymptomatic CADASIL patients (13 females; age mean ± standard deviation = 43.6 ± 11.1 years; three symptomatic and 20 with no or few symptoms) and 16 healthy controls (nine females; age 46.6 ± 11.0 years) were examined with T1 -weighted, T2 -weighted fluid attenuated inversion recovery images, DTI, and rsfMRI. RESULTS: When compared to controls, CADASIL patients showed four clusters of significantly lower ReHo values in cortical areas belonging to networks involved in inhibition and attention, including the right insula, the left superior frontal gyrus, and the bilateral anterior cingulated cortex. ReHo changes did not correlate with an individual patient's lesion burden or MD. CONCLUSIONS: This study reveals decreased ReHo of rsfMRI signals in cortical areas involved in inhibition and attention processes, suggesting a potential role for these functional cortical changes in CADASIL.

Comparison between Ischemic and Hemorrhagic Strokes in Functional Outcome at Discharge from an Intensive Rehabilitation Hospital.

Comparison studies on recovery outcomes in ischemic (IS) and hemorrhagic strokes (HS) have yielded mixed results. In this retrospective observational study of consecutive IS and HS patients, we aimed at evaluating functional outcomes at discharge from an intensive rehabilitation hospital, comparing IS vs. HS, analyzing possible predictors. Modified Rankin Scale (mRS) at discharge was the main outcome. Out of the 229 patients included (mean age 72.9 ± 13.9 years, 48% males), 81 had HS (35%). Compared with IS (n = 148), HS patients were significantly younger (75 ± 12.5 vs. 68.8 ± 15.4 years, p = 0.002), required longer hospitalizations both in acute (23.9 ± 36.7 vs. 35.2 ± 29.9 days, p = 0.019) and rehabilitation hospitals (41.5 ± 31.8 vs. 77.2 ± 51.6 days, p = 0.001), and had more severe initial clinical deficit (mean number of neurological impairments: 2.0 ± 1.1 vs. 2.6 ± 1.4, p = 0.001) and mRS scores at admission (p = 0.046). At discharge, functional status change, expressed as mRS, was not significantly different between IS and HS (F = 0.01, p = 0.902), nor was the discharge destination (p = 0.428). Age and clinical severity were predictors of functional outcome in both stroke types. On admission in an intensive rehabilitation hospital, HS patients presented a worse functional and clinical status compared to IS. Despite this initial gap, the two stroke types showed an overlapped trajectory of functional recovery, with age and initial stroke severity as the main prognostic factors.

Association of nimodipine and choline alphoscerate in the treatment of cognitive impairment in patients with cerebral small vessel disease: study protocol for a randomized placebo-controlled trial-the CONIVaD trial.

BACKGROUND: Vascular cognitive impairment (VCI) is an extremely disabling condition that includes post-stroke dementia and VCI caused by cerebral small vessel disease (SVD). Currently, there is no approved treatment for this condition. Drugs active on the cholinergic pathway have been tested in VCI patients showing positive but limited efficacy. The calcium-antagonist nimodipine also showed some moderate positive effects in VCI patients. AIMS: CONIVaD (choline alphoscerate and nimodipine in vascular dementia) is a pilot, single-center, double-blinded, randomized trial aimed to assess whether the association of choline alphoscerate and nimodipine is more effective than nimodipine alone in reducing cognitive decline in patients with SVD and mild-to-moderate cognitive impairment. METHODS: All patients are evaluated at baseline and after 12 months with: (1) clinical, daily functions, quality of life, and mood assessment and (2) extensive neuropsychological evaluation. After the baseline evaluation, patients are randomly assigned to one of the two arms of treatment: (1) nimodipine 90 mg/die t.i.d plus placebo b.i.d and (2) nimodipine 90 mg t.i.d plus choline alphoscerate 1200 mg/die b.i.d. for a total of 12 months. The primary endpoint is cognitive decline, expressed as the loss of at least two points on the Montreal Cognitive Assessment at 12 months. Secondary endpoints include safety and tolerability, functional, quality of life, and neuropsychological measures. DISCUSSION: CONIVaD study is the first randomized controlled trial to examine the cognitive efficacy of combined choline alphoscerate-nimodipine treatment in VCI patients. Results of this pilot study will serve as a methodological basis for other clinical controlled, multicentric, double-blinded, and randomized trials. TRIAL REGISTRATION: Clinical Trial NCT03228498. Registered 25 July 2017.

Functional Magnetic Resonance Imaging of Inhibitory Control Reveals Decreased Blood Oxygen Level Dependent Effect in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Background and Purpose- Small-vessel damage in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is associated with impaired vascular constriction and dilation. We used a functional magnetic resonance imaging task with an event-related design of stimulus to explore the anticipated abnormally decreased blood oxygen level dependent effect in CADASIL. Methods- Twenty-one CADASIL patients and 16 healthy controls performed a Go/No-go task exploring reactive and proactive phases of inhibition control in a 3-T magnet. Results- Error number and reaction times were not different between patients and controls. Analysis of the reactive inhibition (No-go/baseline contrast) did not show clusters of lower or higher blood oxygen level dependent effect in patients or controls. Analysis of the proactive inhibition (alertness contrast) in CADASIL patients revealed a lower blood oxygen level dependent effect in the alerting network (anterior cingulate cortex and insula, thalamus), lower brain stem and left cerebellar hemisphere (crus I) that is involved in executive functions. Conclusions- In CADASIL patients, an event-related Go/No-go task reveals a lower blood oxygen level dependent effect in the alerting network and areas involved in executive functions possibly reflecting the altered hemodynamic response secondary to small-vessel changes. Our observation extends the role of MR in demonstrating one of the fundamental pathophysiological changes of CADASIL.

Circulating Biomarkers in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Patients.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microangiopathy presenting with variable features, including migraine, psychiatric disorders, stroke, and cognitive decline and variable disability. On neuroimaging, CADASIL is characterized by leukoencephalopathy, multiple lacunar infarcts, and microbleeds. Previous studies suggest a possible role of endothelial impairment in the pathogenesis of the disease. METHODS: We assessed plasma levels of von Willebrand factor (vWF) and thrombomodulin (TM) and the blood levels of endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) in 49 CADASIL patients and 49 age-matched controls and their association with clinical/functional and neuroimaging features. RESULTS: In multivariate analysis, CADASIL patients had significantly higher vWF and lower EPC levels. TM levels were similar in the 2 groups. CADASIL patients with a more severe clinical phenotype (history of stroke or dementia) presented lower CPC levels in comparison with patients with a milder phenotype. On correlation analysis, lower CPC levels were associated with worse performances on neuropsychological, motor and functional tests, and with higher lesion load on brain magnetic resonance imaging (degree of leukoencephalopathy and number of lacunar infarcts). CONCLUSIONS: This is the first CADASIL series in which multiple circulating biomarkers have been studied. Our findings support previous studies on the presence and the possible modulating effect of endothelial impairment in the disease. Furthermore, our research data suggest that blood CPCs may be markers of disease severity.

Inherited leukoencephalopathies with clinical onset in middle and old age.

The currently widespread use of neuroimaging has led neurologists to often face the problem of the differential diagnosis of white matter diseases. There are various forms of leukoencephalopathies (vascular, inflammatory and immunomediated, infectious, metabolic, neoplastic) and sometimes white matter lesions are expression of a genetic disease. While many inherited leukoencephalopathies fall in the child neurologist's interest, others may have a delayed or even a typical onset in the middle or old age. This field is rapidly growing and, in the last few years, many new inherited white matter diseases have been described and genetically defined. A non-delayed recognition of middle and old age inherited leukoencephalopathies appears important to avoid unnecessary tests and therapies in the patient and to possibly anticipate the diagnosis in relatives. The aim of this review is to provide a guide to direct the diagnostic process when facing a patient with a suspicion of an inherited form of leukoencephalopathy and with clinical onset in middle or old age. Based on a MEDLINE search from 1990 to 2013, we identified 24 middle and old age onset inherited leukoencephalopathies and reviewed in this relation the most recent findings focusing on their differential diagnosis. We provide summary tables to use as a check list of clinical and neuroimaging findings that are most commonly associated with these forms of leukoencephalopathies. When present, we reported specific characteristics of single diseases. Several genetic diseases may be suspected in patients with middle or old age and white matter abnormalities. In only few instances, pathognomonic clinical or associated neuroimaging features help identifying a specific disease. Therefore, a comprehensive knowledge of the characteristics of these inherited white matter diseases appears important to improve the diagnostic work-up, optimize the choice of genetic tests, increase the number of diagnosed patients, and stimulate the research interest in this field.

The Florence VAS-COG clinic: a model for the care of patients with cognitive and behavioral disturbances consequent to cerebrovascular diseases.

BACKGROUND AND OBJECTIVE: Services dedicated to patients with cognitive and behavioral consequences of cerebrovascular diseases are not well established. In this paper, we report on the general organization of such a service (the Florence VAS-COG Clinic) after 9 years of activity, updating a previous work related to the first 5 years. METHODS: The Florence VAS-COG clinic, started in 2006, is an outpatient service dedicated to the assessment and follow-up of patients with cerebrovascular diseases and related cognitive, psychiatric, and behavioral disturbances. The staff involved in the clinic is composed of certified neurologists, one neuropsychologist, and neurology residents. The diagnostic protocol includes detailed personal and family history, general and neurologic examinations, and functional, neuropsychological, and neuroimaging assessment. After this work-up, comprehensive diagnoses are made. RESULTS: From January 2006 to March 2014, 600 patients (mean age 67.3 years ± 13.9; 52% females) have been evaluated in the clinic. Cognitive impairment, including mild cognitive impairment and dementia, mainly of vascular origin, was the most common (36.4%) diagnostic category, followed by suspected or confirmed familial micro-angiopathy (35.8%). Compared to the first years of activity, we are now facing the need of augmenting the number of visits due to increasing request and to better implement the multidisciplinarity of the team. Efforts are currently directed towards the definition of management protocols in pharmacological and non-pharmacological strategies. CONCLUSIONS: The establishment of a VAS-COG clinic represents an important step for the appreciation of the patient clinical needs and for the implementation of screening, diagnostic, and treatment options in the field of the neuropsychiatric consequences of cerebrovascular diseases.

Cerebral hemorrhages in CADASIL: report of four cases and a brief review.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease, clinically characterized by migraine, recurrent transient ischemic attacks or strokes, psychiatric disorders and cognitive decline. Strokes are typically ischemic, while hemorrhagic events have been only sporadically described. However, cerebral microbleeds have been found in 31-69% of CADASIL patients. METHODS: We describe four unrelated CADASIL patients who had hemorrhagic strokes. We also briefly review the literature on intracerebral hemorrhage (ICH) in CADASIL. RESULTS: Three patients had a thalamo-capsular hemorrhage (age at onset: 54, 67, 77) and one of these had a second hemispheric cerebellar hemorrhage. Another patient experienced an interpeduncular cistern subarachnoid hemorrhage when he was 39. None of these patients was receiving antiplatelets, anticoagulants or statins at the time of hemorrhage; all were hypertensive. NOTCH3 gene analysis revealed mutations on exons 14, 22 (two patients presenting the same mutation), and 24. MRI signs of previous hemorrhages were present in all these patients. CONCLUSIONS: Hemorrhagic stroke can occur in CADASIL similarly to sporadic cerebral small vessel diseases; this finding expands the phenotype of the disease. A diagnosis of CADASIL should probably be considered also in patients with ICH. These data bear potential implications in terms of need of better control of risk factors, particularly hypertension, and raise relevant questions about the use of antiplatelets as prevention measures in CADASIL patients.

Acetazolamide for the prophylaxis of migraine in CADASIL: a preliminary experience.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by NOTCH3 mutations. It is characterized by migraine, with or without aura, ischemic events, psychiatric and cognitive disturbances. There is no approved treatment for migraine prophylaxis in CADASIL, but acetazolamide has been anecdotally reported to be effective. We retrospectively reviewed our database of patients with a genetic diagnosis of CADASIL to identify how many of them were treated with acetazolamide for the prophylaxis of migraine. The efficacy and the tolerability of this treatment were checked looking at the clinic reports. Acetazolamide was prescribed in seven patients; the mean duration of treatment was 6 months, and the daily dose ranged from 125 to 500 mg. Three patients had a total and sustained remission, while in two patients a reduction in attacks and an improvement of the headache intensity were recorded. In one of these, acetazolamide was deliberately taken only during the migraine attack and the beneficial effect started 1 h after administration. In two patients, the drug did not produce any beneficial effect. Mild side effects were recorded in two patients. Our preliminary experience expands previous reports and confirms the possible efficacy of acetazolamide in CADASIL migraine. Based on these data, a randomized controlled trial seems worthy to be carried out to test the efficacy and safety of this drug.