Vertebral artery dissection caused by atlantoaxial dislocation in a patient with Marfan syndrome.

A small number of case reports have documented a link between atlantoaxial dislocation (AAD) and vertebral artery dissection (VAD), but this association has never been described in patients with hereditary connective tissue disorders. We present a case of an 18-year-old female patient, diagnosed with Marfan syndrome since the age of one, who underwent brain MRA for intracranial aneurysm screening revealing tortuosity of the internal carotid and vertebral arteries as well as atlantoaxial dislocation. Since the patient was asymptomatic, a wait-and-see approach was chosen, but a follow-up MRA after 18 months showed the appearance of a dissecting pseudoaneurysm of the V3 segment of the left vertebral artery. Despite the patient being still asymptomatic, it was decided to proceed with C1-C2 stabilization to prevent further vascular complications. Follow-up imaging showed realignment of the atlantoaxial joint and reduction of the dissecting pseudoaneurysm of the left vertebral artery. In our patient, screening MRA has led to the discovery of asymptomatic arterial and skeletal abnormalities which, if left untreated, might have led to severe cerebrovascular complications. Therefore, AAD correction or close monitoring with MRA should be provided to MFS patients with this craniovertebral junction anomaly, even if asymptomatic.

Neurological abnormalities in individuals with Marfan syndrome: results from a genetically confirmed Italian cohort.

BACKGROUND AND AIMS: Neurological abnormalities have been frequently reported in individuals with Marfan Syndrome (MFS). However, available data relies solely on retrospective studies predating current diagnostic criteria. METHODS: Cross-sectional study comprehensively investigating neurological abnormalities within a prospective cohort of adults (≥ 18 years) with genetically confirmed MFS referred to an Italian hub center for heritable connective tissue diseases (Jan. 1st - Nov. 15th, 2021). RESULTS: We included a total of 38 individuals (53% female). The commonest neurological symptom was migraine (58%), usually without aura (73%). Neuropsychological testing was generally unremarkable, whilst anxiety and depression were highly prevalent within our cohort (42% and 34%, respectively). The most frequent brain parenchymal abnormality was the presence of cortico-subcortical hypointense spots on brain MRI T2* Gradient-Echo sequences (39%), which were found only in patients with a prior history of aortic surgery. Migraineurs had a higher frequency of brain vessels tortuosity vs. individuals without migraine (73% vs. 31%; p = 0.027) and showed higher average and maximum tortuosity indexes in both anterior and posterior circulation brain vessels (all p < 0.05). At univariate regression analysis, the presence of brain vessels tortuosity was significantly associated with a higher risk of migraine (OR 5.87, CI 95% 1.42-24.11; p = 0.014). CONCLUSIONS: Our study confirms that neurological abnormalities are frequent in individuals with MFS. While migraine appears to be associated with brain vessels tortuosity, brain parenchymal abnormalities are typical of individuals with a prior history of aortic surgery. Larger prospective studies are needed to understand the relationship between parenchymal abnormalities and long-term cognitive outcomes.

Tacrolimus-associated neurotoxicity isolated to the brainstem: two illustrative cases and a systematic review of the literature.

INTRODUCTION: Tacrolimus-associated neurotoxicity (TAN) manifests with wide clinical spectrum, ranging from mild tremors to severe encephalopathy. The isolated involvement of the brainstem is a rarely documented presentation of TAN, and its clinical and diagnostic characteristics are unclear. METHODS: We report two cases of brainstem-isolated TAN (bi-TAN). Moreover, we performed a systematic review of the literature on bi-TAN and extracted data concerning demographics, clinical characteristics, radiological features, and management. The systematic literature search followed PRISMA guidelines and a pre-defined protocol. RESULTS: Eleven patients, including our two, were identified (mean age: 41.3 years, ± 18.8; five males, 45%). Speech disturbance was the most common clinical presentation (45%). The mean latency from Tacrolimus initiation to bi-TAN onset was 26 days (± 30.8). Tacrolimus serum level tested above the reference range in three patients (mean: 26.83 ± 5.48). Brain MRI showed T2-FLAIR hyperintensities; three showed restricted diffusion on ADC maps. Neurological symptoms resolved completely in seven patients (63%) after Tacrolimus withdrawal or dose reduction. CONCLUSIONS: Our findings suggest that bi-TAN could represent a brainstem variant of posterior reversible encephalopathy syndrome. Recognition of bi-TAN as a potential cause of isolated brainstem lesions is crucial to disentangle the diagnostic work-up and ensure prompt withdrawal or reduction of the offending agent.

Quantitative measurement of dural ectasia: associations with clinical and genetic characteristics in Marfan syndrome.

PURPOSE: Dural ectasia (DE) may significantly impact Marfan syndrome (MFS) patients' quality of life due to chronic lower back pain, postural headache and urinary disorders. We aimed to evaluate the association of quantitative measurements of DE, and their evolution over time, with demographic, clinical and genetic characteristics in a cohort of MFS patients. METHODS: We retrospectively included 88 consecutive patients (39% females, mean age 37.1 ± 14.2 years) with genetically confirmed MFS who underwent at least one MRI or CT examination of the lumbosacral spine. Vertebral scalloping (VS) and dural sac ratio (DSR) were calculated from L3 to S3. Likely pathogenic or pathogenic FBN1 variants were categorized as either protein-truncating or in-frame. The latter were further classified according to their impact on the cysteine content of fibrillin-1. RESULTS: Higher values of the systemic score (revised Ghent criteria) were associated with greater DSR at lumbar (p < 0.001) and sacral (p = 0.021) levels. Patients with protein-truncating variants exhibited a greater annual increase in lumbar (p = 0.039) and sacral (p = 0.048) DSR. Mutations affecting fibrillin-1 cysteine content were linked to higher VS (p = 0.009) and DSR (p = 0.038) at S1, along with a faster increase in VS (p = 0.032) and DSR (p = 0.001) in the lumbar region. CONCLUSION: Our study shed further light on the relationship between genotype, dural pathology, and the overall clinical spectrum of MFS. The identification of protein-truncating variants and those impacting cysteine content may therefore suggest closer patient monitoring, in order to address potential complications associated with DE.

Capsular Warning Syndrome: Features, Risk Profile, and Prognosis in a Large Prospective TIA Cohort.

INTRODUCTION: Features and prognosis of capsular warning syndrome (CWS) have been poorly investigated prospectively. AIMS: The study aimed to characterize CWS clinical features, risk profile, short- and long-term prognosis, among a large TIA cohort. METHODS: Prospective cohort study of consecutive TIAs was conducted from August 1, 2010, to December 31, 2017. Demographic and clinical characteristics, risk profile, primary (stroke and composite outcome) and secondary (TIA recurrence, cerebral hemorrhage, new onset atrial fibrillation) outcomes were compared between CWS, lacunar (L), and nonlacunar (NL) TIAs. RESULTS: 1,035 patients (33 CWS, 189 L-TIAs, 813 NL-TIAs) were enrolled. Newly diagnosed (ND) hypertension, hypercholesterolemia, cigarette smoking, and leukoaraiosis were independent risk factors of CWS (p < 0.05). CWS showed the highest stroke (30.3% vs. 0.5% and 1.5% for L-TIAs and NL-TIAs, respectively) and composite outcome risk at follow-up (p < 0.001), but better 3-month post-stroke prognosis (mRS 0-2 90.0% vs. 36.8%; p = 0.002). CWS-related stroke mostly occurred <48 h (80.0%) and had a small vessel occlusion etiology (100%), affecting more often the internal capsule (60.0%). Dual antiplatelet therapy (DAPT) versus single antiplatelet therapy was associated with lower 3-month cumulative stroke incidence (12.5% vs. 57.1%; p = 0.010). Intravenous thrombolysis (IVT) showed similar 3-month efficacy and safety in strokes after TIAs groups (median mRS 0, IQR 0-1; p = 0.323). CONCLUSIONS: CWS is associated with higher stroke risk and better functional prognosis than L- and NL-TIAs. CWS risk profile is consistent with severe small vessel disease, and ND hypertension could represent a major risk factor. DAPT and IVT seem effective and safe in preventing and treating stroke following CWS.

Predicting Failure to Recover Swallowing in Patients with Severe Post-stroke Dysphagia: The DIsPHAGIc Score.

In post-stroke dysphagia, early identification of patients at highest risk of failing swallowing recovery (SR) would be useful to decide which of them should undergo percutaneous endoscopic gastrostomy. The studies on this subject were numerous but generally based on small statistical samples. In this retrospective study, 1232 patients with ischemic or hemorrhagic stroke (73.7 ± 13.0 years, 51% men) were assessed: 593 non-dysphagic, 351 partially dysphagic and 288 totally dysphagic. Among the latter, 45.1% could not recover oral intake. A score to assess the risk of failing SR was obtained from the group with total dysphagia, and further 210 patients with total post-stroke dysphagia were utilized for validation. A regular progression of stroke severity markers, complications and mortality was observed from non-dysphagic, to partially dysphagic, up to totally dysphagic patients. Among the latter, seven variables were independently associated with failure of SR, and formed the "DIsPHAGIc score": cerebral lesion Diameter ≥ 6 cm (+ 1), left frontal Ischemia (- 1), Partial anterior circulation syndrome (- 1), Hypoxia (+ 1), Antiplatelet drug (+ 1), GCS verbal reaction < 4 (+ 1), Internal capsule ischemia (- 1). The area under the ROC curve was 0.79 (95% CI 0.74-0.85). For total scores ≥ 2 there was a high risk of failing SR, with specificity 76.9%, sensitivity 72.1% and accuracy 74.7%. The application of the DIsPHAGIc score to the validation sample provided almost identical results. The evolution of post-stroke dysphagia towards irreversibility can be predicted by a simple, reproducible and robust scoring system based on 7 variables commonly available during hospitalization.

Chronic acquired hepatocerebral degeneration presenting with Meige's syndrome and behavioral symptoms fully reversed by liver transplantation.

Chronic acquired hepatocerebral degeneration (CAHD) is a rare neurologic syndrome occurring in patients with chronic liver disease, resulting in the combination of movement disorders and cognitive\behavioral changes. Its pathogenesis is debated and the symptoms are poorly responsive to medical therapy. Meige's syndrome is a form of cranial dystonia, considered an idiopathic form of adult onset dystonia. We report a 60-year-old man with HCV-related liver cirrhosis and hepatocarcinoma who developed Meige's syndrome associated with cognitive and behavioral manifestations, unrelated to acute metabolic derangement. CAHD was diagnosed. Liver transplantation reversed the clinical picture and MR abnormalities, reinforcing the idea that CAHD is a potentially reversible syndrome, which may be healed by liver transplantation and should not be considered a contraindication for this operation.

Association of Left Ventricular Hypertrophy and Atrial Fibrillation with Hemorrhagic Evolution of Small Vessel Disease.

OBJECTIVES: Cerebral small vessel disease (SVD) is often associated with hypertension and may evolve towards intracerebral hemorrhage (ICH) or lacunar ischemic stroke. However, the factors favoring the evolution towards ICH or lacunar stroke are not well understood. MATERIALS AND METHODS: This retrospective study included 326 consecutive patients (71.1±13.2 years, 38% women): 143 with deep ICH and 183 with lacunar lesions (LL) <2 cm, which were visible in a deep location on brain CT scan. Among LL patients, 143 had a small-artery occlusion (SAO) stroke according to the TOAST classification. Clinical characteristics plus laboratory and neuroradiological variables of these patients had been prospectively collected and a subgroup underwent echocardiography. RESULTS: In multivariate analysis, ICH patients (97% hypertensive), compared to SAO patients (89% hypertensive), had greater left ventricular wall thickness (LVWT; OR 4.15, 95%CI 1.64-10.53, for those with LVWT ≥ 1.4 cm, 70% of whom were hemorrhagic) and lower prevalence of white matter lesions (OR 0.30, 95%CI 0.13-0.70), ever smokers (OR 0.39, 95%CI 0.18-0.82) and diabetics (OR 0.29, 95% CI 0.10-0.84). Moreover, ICH patients had a greater prevalence of atrial fibrillation than LL patients (OR 3.14, 95%CI 1.11-8.93), and so they were more often anticoagulated. CONCLUSIONS: Most SVD patients were hypertensive, but those evolving towards ICH were characterized by organ damage at the cardiac level (increase in LVWT and atrial fibrillation), while those evolving towards lacunar stroke were characterized by a higher prevalence of smokers and diabetics, and by organ damage at the cerebral level (white matter lesions).

Aortic arch geometry predicts outcome in patients with Loeys-Dietz syndrome independent of the causative gene.

This study aimed to investigate the potential association between imaging features and cardiovascular outcomes in patients with Loeys­Dietz syndrome (LDS). We performed a retrospective cohort study of 36 patients with LDS and described cardiovascular events and imaging data. We observed different clinical courses in patients with LDS, irrespective of the causative gene. Angular or elongated aortic arch geometry correlated with aortic dissection (R = .39, p = .02), occurrence of the first cardiovascular event before 45 years of age (R = .36, p = .03), and the number of operations (R = 0.47, p = .004), but not with age (R = −.05, p = .79) or the causative gene (R = −0.04, p = .79). Relative absences of cardiovascular events at ages 20, 40, and 60 were 100, 75, and 56%, respectively, in patients with "romanesque" aortic arches, and 74, 39, and 21%, respectively, in patients with "gothic" and "elongated" aortic arches (p = .03). Angular or elongated aortic arch geometry is associated with early­onset of disease and a worse cardiovascular outcome in LDS patients. Large multicenter studies are warranted to elucidate the impact of aortic arch morphology evaluation in clinical practice.

Usefulness of the ACTEL Score to Predict Atrial Fibrillation in Patients with Cryptogenic Stroke.

INTRODUCTION: To assess the probability of undetected atrial fibrillation (AF) in patients with ischemic stroke, we previously compared patients who were first diagnosed with AF with patients with large or small artery disease and obtained the MrWALLETS 8-item scoring system. In the present study, we utilized cryptogenic strokes (CS) as the control group, as AF is normally sought among CS patients. METHODS: We retrospectively examined 191 ischemic stroke patients (72.5 ± 12.6 years), 68 with first diagnosed AF and 123 with CS, who had undergone 2 brain CT scans, echocardiography, carotid/vertebral ultrasound, continuous electrocardiogram monitoring and anamnestic/laboratory search for cardiovascular risk factors. RESULTS: In logistic regression, 5 variables were independently associated with AF, forming the "ACTEL" score: Age ≥75 years (OR 2.42, 95% CI 1.18-4.96, p = 0.02; +1 point); hyperCholesterolemia (OR 0.38, 95% CI 0.18-0.78, p = 0.009; -1 point); Tricuspid regurgitation ≥ mild-to-moderate (OR 4.99, 95% CI 1.63-15.27, p = 0.005; +1 point); left ventricular End-diastolic volume <65 mL (OR 7.43, 95% CI 2.44-22.6, p = 0.0004; +1 point); Left atrium ≥4 cm (OR 4.57, 95% CI 1.97-10.62, p = 0.0004; +1 point). The algebraic sum of these points may range from -1 to +4. For AF identification, the area under the receiver operating characteristic curve was 0.80 (95% CI 0.73-0.87). With a cutoff of ≥2, positive predictive value was 80.8%, specificity 92.7% and sensitivity 55.9%. CONCLUSIONS: The ACTEL score, a simplified and improved version of the MrWALLETS score, allows the identification of patients with first diagnosed AF, in the context of CSs, with a high positive predictive value.