Objective
To compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese ...Val30Met FAP.
Methods
We compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies, and muscle biopsies are reported. We also conducted a comprehensive literature review to further determine the range of phenotypic expression.
Results
By comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr, and LateVal30Met FAP showed more rapid and severe disease progression; onset of gait disorders was 3 times more rapid (p < 0.0001) and the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p < 0.0001). Median survival was much shorter in Ile107Val and in Val30Met mutation with late onset (>50 years; LateMet30) FAP (p = 0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p = 0.0005), and difficult identification of amyloid deposits in nerve and muscle biopsies.
Interpretation
Ile107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by frequent large‐fiber involvement and associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing). Ann Neurol 2015;78:901–916
•Failure of Phase 3 ProTECT III and SyNAPSE, testing progesterone protection after TBI.•Neuroprotection by progesterone: evidences and limitations of preclinical studies.•The integration of ...preclinical data into the design of ProTECT III and SyNAPSE.•Lack of sensitive and reliable biomarkers for clinical TBI trials.•High pressure on researchers and clinicians contribute to translational failure.
Since the first pioneering studies in the 1990s, a large number of experimental animal studies have demonstrated the neuroprotective efficacy of progesterone for brain disorders, including traumatic brain injury (TBI). In addition, this steroid has major assets: it easily crosses the blood–brain-barrier, rapidly diffuses throughout the brain and exerts multiple beneficial effects by acting on many molecular and cellular targets. Moreover, progesterone therapies are well tolerated. Notably, increased brain levels of progesterone are part of endogenous neuroprotective responses to injury. The hormone thus emerged as a particularly promising protective candidate for TBI and stroke patients. The positive outcomes of small Phase 2 trials aimed at testing the safety and potential protective efficacy of progesterone in TBI patients then provided support and guidance for two large, multicenter, randomized and placebo-controlled Phase 3 trials, with more than 2000 TBI patients enrolled. The negative outcomes of both trials, named ProTECT III and SyNAPSE, came as a big disappointment. If these trials were successful, progesterone would have become the first efficient neuroprotective drug for brain-injured patients. Thus, progesterone has joined the numerous neuroprotective candidates that have failed in clinical trials. The aim of this review is a reappraisal of the preclinical animal studies, which provided the proof of concept for the clinical trials, and we critically examine the design of the clinical studies. We made efforts to present a balanced view of the strengths and limitations of the translational studies and of some serious issues with the clinical trials. We place particular emphasis on the translational value of animal studies and the relevance of TBI biomarkers. The probability of failure of ProTECT III and SyNAPSE was very high, and we present them within the broader context of other unsuccessful trials.
Summary Cerebral cavernous malformations (CCM) are vascular malformations that can occur as a sporadic or a familial autosomal dominant disorder. Clinical and cerebral MRI data on large series of ...patients with a genetic form of the disease are now available. In addition, three CCM genes have been identified: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 . These recent developments in clinical and molecular genetics have given us useful information about clinical care and genetic counselling and have broadened our understanding of the mechanisms of this disorder.
Objective
To compare clinical features of CCM1, CCM2, and CCM3 mutation carriers.
Methods
A detailed clinical and molecular analysis of 163 consecutive cerebral cavernous malformation (CCM) families ...was performed.
Results
A deleterious mutation was detected in 128 probands. Three hundred thirty‐three mutation carriers were identified (238 CCM1, 67 CCM2, and 28 CCM3). Ninety‐four percent of the probands with an affected relative had a mutation compared with 57% of the probands with multiple lesions but no affected relative (p < 0.001). The number of affected individuals per family was lower in CCM3 families (p < 0.05). The proportion of patients with onset of symptoms before 15 years of age was higher in the CCM3 group (p < 0.0025). Cerebral hemorrhage was the most common initial presentation in CCM3 patients. The average number of T2‐weighted imaging lesions was similar in the three groups, in contrast with a significantly lower number of gradient‐echo sequence lesions in CCM2 patients (p < 0.05). The number of gradient‐echo sequence lesions increased more rapidly with age in CCM1 than in CCM2 patients (p < 0.05).
Interpretation
Despite similarities among the three groups, there is a significantly lower number of affected individuals in CCM3 pedigrees, CCM3 mutations may confer a higher risk for cerebral hemorrhage, particularly during childhood, and the increment of gradient‐echo sequence lesions with age differs between CCM1 and CCM2 patients. Ann Neurol 2006
Endovascular treatment (EVT) for basilar artery occlusions (BAO) is associated with a higher rate of futile recanalization compared with anterior circulation procedures. We aimed to identify the ...incidence and predictors of poor clinical outcome despite successful reperfusion in current clinical practice.
We used data from the ETIS (Endovascular Treatment in Ischemic Stroke) registry, a prospective multicenter observational registry of stroke treated with EVT in France. Patients undergoing EVT for acute BAO from January 2014 to May 2019 successfully treated within 8 hours from onset were included. Predictors of 90-day poor outcome (modified Rankin Scale (mRS) 4-6) were researched within patients with successful (modified Thrombolysis In Cerebral Infarction (mTICI 2b-3)) and excellent (mTICI 2c-3) reperfusion.
Among 242 patients treated within 8 hours, successful reperfusion was achieved in 195 (80.5%) and excellent reperfusion in 120 (49.5%). Poor outcome was observed in 107 (54.8%) and 60 (50%) patients, respectively. In patients with successful early reperfusion, age, higher initial National Institutes of Health Stroke Scale (NIHSS) score, lower posterior circulation Alberta Stroke Programme Early CT Score (pc-ASPECTS), and absence of prior intravenous thrombolysis were independent predictors of poor outcome. The only treatment factor with an independent predictive value was first-pass mTICI 2b-3 reperfusion (adjusted OR 0.13, 95% CI 0.05 to 0.37, p<0.001). In patients with excellent early reperfusion, independent predictors were age, initial NIHSS score, first-pass mTICI 2c-3 reperfusion, and hemorrhagic transformation on post-interventional imaging.
Early successful reperfusion with EVT occurred in 80.5% of patients, and the only treatment-related factor predictive of clinical outcome was first pass mTICI 2b-3 reperfusion. Further research is warranted to identify the optimal techniques and devices associated with first pass reperfusion in the posterior circulation.
Objective
The stroke risk for persons living with human immunodeficiency virus (PLHIVs) doubled compared to uninfected individuals. Stroke‐unit (SU)—access, acute reperfusion therapy—use and outcome ...data on PLHIVs admitted for acute ischemic stroke (AIS) are scarce.
Methods
AIS patients admitted (01 January 2017 to 31 January 2021) to 10 representative Paris‐area SUs were screened retrospectively from the National Hospitalization Database. PLHIVs were compared to age‐, initial NIHSS‐ and sex‐matched HIV‐uninfected controls (HUCs). Outcome was the 90‐day modified Rankin Scale score.
Results
Among 126 PLHIVs with confirmed first‐ever AIS, ~80% were admitted outside the thrombolysis‐administration window. Despite antiretrovirals, uncontrolled plasma HIV loads exceeded 50 copies/mL (26% of all PLHIVs; 38% of those ≤55 years). PLHIVs' stroke causes by decreasing frequency were large artery atherosclerosis (LAA), undetermined, other cause, cerebral small‐vessel disease (CSVD) or cardioembolism. No stroke etiology was associated with HIV duration or detectable HIVemia. MRI revealed previously unknown AIS in one in three PLHIVs, twice the HUC rate (p = 0.006). Neither group had optimally controlled modifiable cardiovascular risk factors (CVRFs): 20%–30% without specific hypertension, diabetes, and/or dyslipidemia treatments. Their stroke outcomes were comparable. Multivariable analyses retained good prognosis associated solely with initial NIHSS or reperfusion therapy. Older age and hypertension were associated with CSVD/LAA for all PLHIVs. Standard neurovascular care and reperfusion therapy were well‐tolerated.
Interpretation
The high uncontrolled HIV‐infection rate and suboptimal CVRF treatment support heightened vigilance to counter suboptimal HIV suppression and antiretroviral adherence, and improve CVRF prevention, mainly for younger PLHIVs. Those preventive, routine measures could lower PLHIVs' AIS risk.
Behçet's disease (BD) is a rare form of vasculitis involving both veins and arteries of all calibers. Psychological symptoms and cognitive impairment appear to be frequent, but few data are ...available.
All consecutive patients in our center fulfilling the 2013 BD criteria underwent a psychometric evaluation with auto- (SCL-90-R and Modified Fatigue Index) and hetero-questionnaires (MINI). A standardized test battery assessed cognitive dysfunction. Data were correlated with BD activity as well as quality of life (SF-36).
We included 20 consecutive patients (16 men, four women) with a median IQR age of 38 (30.0-45.5) and a median disease duration of 7 years (1.8-11.0). Five patients had an abnormal brain MRI. The SCL-90-R questionnaire highlighted eight psychopathological profiles (42.1%) that correlated with altered quality of life and more severe fatigue. The most frequent symptoms were anxiety (9/19, 47.4%), somatization (8/19, 42.1%) and phobia (5/19, 26.3%). Psychopathological symptoms appeared to be more severe, but not more frequent, in neuro-Behçet's patients. Based on standardized cognitive evaluation, nine patients had cognitive impairment defined by three or more altered tests. Notably, 6/9 patients did not have any complaint of memory loss and were thus considered ansognostic.
Cognitive involvement was significantly associated with BD activity score (BSAS) but not with brain MRI abnormalities.
Background
While the association between inflammatory bowel diseases and thromboembolic events has long been evident, cerebral venous thrombosis in this context remains rare and underreported.
...Methods
Among 351 consecutive patients with cerebral venous thrombosis collected in two neurology departments between 1997 and 2009, an analysis of patients with inflammatory bowel disease and a review of literature were performed.
Results
Eight patients had inflammatory bowel disease (6/287, 2/64), Crohn's disease in two, and ulcerative colitis in two. The mean age was 30·9 years (18–45). All inflammatory bowel disease-related cerebral venous thrombosis patients had headache, four patients had focal neurological deficits, three had altered consciousness, and two had seizures. Cerebral venous thrombosis occurred between two-months and 17 years after the first inflammatory bowel disease signs. Six patients had other venous prothrombotic risk factors. All patients were treated with heparin or low-molecular-weight heparin. Seven showed a complete recovery (Rankin 0–1) and one a partial recovery (Rankin 2). Compared with the 49 magnetic resonance imaging-confirmed cerebral venous thrombosis patients of the literature, our patients had more frequent associated prothrombotic risk factors. When comparing 57 inflammatory bowel disease-related cerebral venous thrombosis patients with other cerebral venous thrombosis, those with inflammatory bowel disease were younger in age at cerebral venous thrombosis onset, and there was a higher male to female ratio and a lower headache frequency at presentation.
Conclusion
In our cerebral venous thrombosis cohort, inflammatory bowel disease is present in 2·3% of cases. As cerebral venous thrombosis has no specific feature and may reveal inflammatory bowel disease, intestinal signs should be systematically looked for. All physicians caring for inflammatory bowel disease patients must consider cerebral venous thrombosis in cases of unusual headache or focal neurological symptoms. Treatment is based on full anticoagulation and specific inflammatory bowel disease treatment.
Background: KIF1C (Kinesin Family Member 1C) variants have been associated with hereditary spastic paraplegia and spastic ataxia. Case report: We report fraternal twins presenting with cerebellar ...ataxia and dystonic tremor. Their brain MRI showed a hypomyelinating leukoencephalopathy. Whole exome sequencing identified a homozygous KIF1C variant in both patients. Discussion: KIF1C variants can manifest as a complex movement disorder with cerebellar ataxia and dystonic tremor. KIF1C variants may also cause a hypomyelinating leukoencephalopathy.
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