Flemming, Kelly D.

BACKGROUND Hypertrophic olivary degeneration (HOD) is a rare form of transsynaptic degeneration caused by disruption of the dentato-rubro-olivary pathway (Guillain-Mollaret triangle). It is most described following surgical intervention or acute hemorrhagic injury affecting that pathway. However, longitudinal imaging documenting the natural progression of HOD in patients with brainstem cerebral cavernous malformations (CCMs) remains sparsely described at the individual patient level. OBSERVATIONS The authors present the case of a 70-year-old woman with a pontine CCM followed longitudinally over 4 years. Initial imaging demonstrated a right-sided pontine lesion with unilateral HOD in the absence of symptoms. Over time, the CCM enlarged and extended across the midline, coinciding with the development of bilateral HOD and delayed onset of gait imbalance and palatal myoclonus. No surgical intervention was performed. LESSONS In this case, the radiographic evolution from unilateral to bilateral involvement occurred concurrently with the delayed clinical manifestation of HOD. https://thejns.org/doi/10.3171/CASE26577

Abstract Background and aims Patient foramen ovale (PFO) is a stroke risk factor evaluated using transthoracic echocardiogram (TTE), transesophageal echocardiogram (TEE), transcranial Doppler ultrasound (TCD), and cardiac computed tomography (CCT). TCD is non-invasive, but its diagnostic performance relative to other modalities is unclear. We hypothesized that TCD has high sensitivity but low specificity for PFO detection. Methods We conducted an IRB-approved, single-center retrospective study of patients undergoing TCD for right-to-left shunt (RLS) detection between January 2024 and April 2025. Patients were identified from the Neurosonology Laboratory Quality Database. Records were reviewed for demographics, comorbidities, and TTE, TEE, and CCT findings. Sensitivity, specificity, and positive and negative predictive values were calculated for TCD, TTE, and CCT relative to TEE, the gold standard. The sensitivity and specificity of TCD versus TTE were compared using McNemar test. Results Ninety-two patients were included. Mean age was 52.66 ± 15.78 years, and 51% were female; qualifying events included ischemic stroke or transient ischemic attack. RLS was detected in 53 patients (57.6%) by TCD, 17 (30%) by TTE, 18 (28.5%) by TEE, and 3 (21%) by CCT. TCD demonstrated 94% sensitivity and 53% specificity, (PPV 66%, NPV 89%). TTE showed 50% sensitivity and 82% specificity (PPV: 75%, NPV 61%), while CCT showed 33% sensitivity and 100% specificity (PPV 100%, NPV 33.3%). TCD had significantly higher sensitivity than TTE for RLS detection (p=0.039) with a non-significant difference in specificity (p=0.062), using TEE as the reference. Conclusions TCD has high sensitivity for RLS detection in patients with ischemic stroke or transient ischemic attack. Conflict of interest Rachel Knopp: nothing to disclose; Kelly Flemming: nothing to disclose; Eugene Scharf: nothing to disclose; Zafer Keser: nothing to disclose; Jessica Prink: nothing to disclose; Shari Johnson: nothing to disclose; Guy Reeder: nothing to disclose; Robert Brown: nothing to disclose; William Harmsen: nothing to disclose; Muhib Khan: nothing to disclose Table 1 - belongs to Results

OBJECTIVE The aim of this study was to elucidate the long-term morbidity associated with untreated cerebral cavernous malformation (CCM). METHODS From a prospectively maintained database of patients with CCM, we assessed functional outcome as measured using the modified Rankin Scale (mRS) score at baseline and the last untreated follow-up evaluation. Disability was defined as an mRS score ≥ 3. Kaplan-Meier curves were used to assess the time to disability, and Cox proportional hazards models were used to determine risk factors for disability. Furthermore, the predictive performance of a previously published nomogram for morbidity in CCM was assessed. RESULTS The cohort consisted of 332 patients (58.4% female, mean age at diagnosis 44.5 years), with 19.8% having the familial form and 28.0% having a CCM located in the brainstem. Of 48 patients who presented with symptomatic hemorrhage (SH) and who did not undergo surgery or have a prospective SH, 27.1% had an mRS score ≥ 3 at diagnosis. By 1 year and 5 years, this improved to 6.2% and 4.7%, respectively. Over a mean follow-up duration of 6.6 years, 103 of 332 patients (31.0%) had one prospective SH and 48 (14.5%) had multiple prospective SHs. Patients with brainstem-located CCM had an 18.8% 5-year and 35.4% 10-year risk of disability compared with 4.1% and 7.5%, respectively, in patients with a nonbrainstem location (p < 0.0001). Multivariate analysis showed that a brainstem location, history of self-reported psychiatric disorder, and ≥ 2 SHs were predictive of disability at the last follow-up. External validation of a published nomogram demonstrated high specificity but limited sensitivity for predicting disability, with an area under the receiver operating curve of 0.687 for mRS scores ≥ 2 and 0.783 for mRS scores ≥ 3. CONCLUSIONS Most patients improved after a first hemorrhage, with the most improvement occurring in year 1. Disability increased with each SH. Disability was associated with 2 or more SHs, a brainstem location, and a self-reported psychiatric diagnosis. Ten-year disability risk with a nonbrainstem CCM location was < 8%.

Background A recent randomized prospective controlled trial demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter rebleeding in cerebral cavernous malformations. However, any consequences of discontinuing atorvastatin remain unknown. We hypothesized that symptomatic hemorrhage (SH) recurs more frequently in cerebral cavernous malformations after discontinuation of atorvastatin than placebo. Methods We conducted a 12‐month posttreatment follow‐up of patients enrolled in the Atorvastatin Therapy in Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) trial (41 randomized to atorvastatin, 39 to placebo) to identify potential recurrent SH after trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded from follow‐up for <90% compliance with study drug, for its discontinuation <3 months after trial enrollment, for statin reinitiation <3 months after discontinuation, or for lack of follow‐up. Cases were censored during follow‐up upon cerebral cavernous malformation resection/radiation or later statin reinitiation. Results Follow‐up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin. Four SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and 1 SH at 395 days after discontinuing placebo. There was significantly lower symptomatic hemorrhage‐free survival in the atorvastatin‐discontinuation group (log‐rank χ 2 =4.136, P =0.042). The hazard ratio was 0.162 (95% CI, 0.027–0.977) for placebo versus atorvastatin discontinuation. Conclusions Discontinuation of atorvastatin was associated with a higher risk of recurrent SH compared with placebo discontinuation. Additional studies are warranted to confirm this hypothesis‐generating observation, examine potential mechanisms, and how best to mitigate this risk. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02603328.

Background: There is much interest in drug development to prevent rebleeding after symptomatic hemorrhage (SH) in cerebral cavernous malformations (CCM) and its neurologic sequelae. A recent randomized prospective controlled trial (AT CASH EPOC clinicaltrials.gov NCT02603328) demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter CCM iron deposition or SH rates. However, the consequences of discontinuing atorvastatin in CCM patients remain unknown. Given reports of rebound effects with discontinuation of statins, we here hypothesize that SH recurs more frequently in hemorrhagic CCMs after discontinuation of atorvastatin than placebo. Methods: We conducted 12-month (±1 month) post-treatment follow-up of all 80 patients randomized in the AT CASH EPOC trial (41 atorvastatin, 39 placebo) to identify potential recurrent SH from the date of trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded for < 90% compliance with study drug or its discontinuation <3 months during the trial, and for lack of follow-up. Cases were censored during follow-up upon CCM resection/radiation or atorvastatin initiation/re-initiation. Results: Follow-up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin.During follow-up, 4 SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and only 1 SH 395 days after discontinuing placebo. Kaplan–Meier curves demonstrated significantly lower symptomatic hemorrhage-free survival in the atorvastatin-discontinuation group (log-rank chi=4.136, p=0.042). The Gehan–Breslow–Wilcoxon test (chi=4.080, p=0.043) highlighted early divergence in recurrent SH risk. The hazard ratio was 0.162 (95% CI 0.027–0.977) for placebo vs. atorvastatin discontinuation. Conclusion: While there was no difference in SH rates during 2 years of treatment with atorvastatin versus placebo in randomized clinical trial, discontinuation of atorvastatin was associated with a significantly higher and earlier risk of recurrent SH compared with placebo discontinuation. This raises concern for a rebound effect during the year after statin withdrawal in hemorrhagic CCM patients, potentially mediated by reactivation of Rho-associated kinase. Additional studies are warranted to confirm these observations and to assess whether statin tapering or maintenance therapy can mitigate the risk of discontinuation in hemorrhagic CCM.

Introduction: Functional outcome scales are commonly used in neurological clinical trials. Prior studies suggested that these scales may reflect symptomatic hemorrhage (SH), but their performance in detecting treatment effects has not been assessed in clinical trials of cerebral cavernous malformations (CCM). And they have not been correlated with CCM bleeding as reflected by lesional iron content assessed by quantitative susceptibility mapping (QSM) MRI. Hypothesis: We hypothesized that functional outcome measures would detect differences between treatment arms in a randomized clinical trial of hemorrhagic CCM, and reflect new SH or a ≥6% increase in mean lesional QSM reflective of CCM bleeding. Methods: Eighty adults with CCM-related SH in the prior 12 months of enrollment were randomized 1:1 to atorvastatin 80 mg/day or placebo for 2 years. Functional outcomes, including mRS, EQ-5D index, EQ-VAS, and PROMIS-29 domains, were collected at baseline, Year 1, and Year 2. Analyses were conducted in 63 participants (32 atorvastatin, 31 placebo) in the modified intention-to-treat trial cohort who had contributed at least one paired annual clinical and imaging assessment. Results: No significant differences were found between atorvastatin and placebo groups in any functional outcome measure across timepoints. Rates of functional decline and improvement were comparable, except for PROMIS Fatigue which improved more in the atorvastatin than placebo patients from baseline to Year 1 (p=0.019). Pooled analyses showed that several functional domains had strong specificity for identifying SH. PROMIS Sleep Disturbance decline from baseline to Year 2 was associated with SH (p=0.0045; specificity 92.3%, sensitivity 57.1%). A ≥10-point drop in EQ-VAS from baseline to Year 1 identified all SH cases during that interval (p=0.007; sensitivity 100%, specificity 83.6%). Functional decline had low sensitivity in detecting CCM bleeding on QSM, though specificity was high (>75%) across domains. Conclusions: Atorvastatin did not influence functional change over 2 years by any measure. PROMIS Sleep Disturbance and EQ-VAS demonstrated high specificity, and in the case of EQ-VAS also a high sensitivity for identifying SH. Functional outcomes across domains also had high specificity for occult bleeding in CCMs as measured by QSM. Poor sensitivity and consistent improvements over time demonstrate the limitations of functional outcome measures as endpoints of drug effects on CCM bleeding.

Background: It is not clear if changes in lesion volume might represent a clinically relevant and statistically advantageous outcome parameter in early phase trials of novel drugs aimed at preventing bleeding in cerebral cavernous malformations (CCM). Methods: We analyzed the modified intention to treat cohort (33 patients receiving atorvastatin and 31 placebo) who contributed at least one paired imaging biomarker in the recently completed double-blinded randomized controlled AT CASH EPOC trial (clinicaltrials.gov NCT02603328). We examined prospective changes in CCM lesion volume and correlated these with symptomatic hemorrhage (SH) events. We contemporaneously assessed changes in lesional iron content by quantitative susceptibility mapping (QSM) on MRI, and objective (mRS) and subjective (EQ-VAS) functional status. We also simulated sample sizes needed to detect potential effects of a drug on lesion volume. Results: There was excellent correlation between independently assessed maximum lesion diameter and CCM lesion volume (R 2 = 0.68, P<0.0001). The mean (SD) percentage change in lesion volume per year was +6 (65) and +18 (94) in atorvastatin and placebo patients, respectively (P= 0.43). All cases with SH had increases in lesion volume as well as increases in mean lesional iron content by QSM, and most had declines in functional status on mRS and EQ-VAS. But there were many cases with increases in lesion volume with improved functional status or decreased mean lesional QSM, and other cases with worsening in function or increased lesional QSM and decreased lesion volume. There were no significant correlations of changes in lesion volume with concomitant changes in mean lesional QSM, mRS or EQ-VAS (all R/R 2 <0.5 and Bonferroni corrected P>0.05), including in brainstem lesions analyzed separately. Sample size simulations indicate larger numbers of cases needed to demonstrate a drug effect on changes in lesion volume than those needed to detect an effect on QSM change with a=0.05 and b=0.8, and even larger samples to detect effects on the proportion of cases with increased or decreased lesion volume. Conclusion: Changes in lesion volume occur frequently in CCM lesions after recent SH, but do not correlate with measures of bleeding in the lesions, nor appear to reflect functional changes. And they are not statistically advantageous in comparison to QSM measures for detecting potential drug effects.

OBJECTIVE This study evaluated the utility of routine versus symptom-driven MRI to detect hemorrhage in patients with sporadic cerebral cavernous malformations (CCMs) and assessed associated radiographic changes at the first clinical follow-up. METHODS The authors analyzed a prospective, single-center cohort of patients with sporadic, brain-only CCMs who underwent at least 1 follow-up MRI after diagnosis. Clinical and radiological data were obtained from a longitudinal registry. Follow-up findings included lesion growth (≥ 3 mm), changes in Zabramski classification, persistent T1-weighted hyperintensity, edema, and hemorrhage. MRI indications were categorized as routine surveillance or symptom driven (e.g., new or worsening focal neurological deficit [FND], headache, or seizure). Univariate and multivariate analyses were performed to assess predictors of symptomatic hemmorhage (SH). RESULTS Of 236 included patients, 59.3% were female, and 39.8% initially presented with SH. At the first follow-up MRI, radiographic hemorrhage was observed in 13 of 68 patients (19.1%) imaged for new or worsening neurological symptoms (FND, headaches, or seizures), compared to 2 of 168 patients (1.2%) during routine or non–CCM-related surveillance. Among these 168 patients, 17 (10.1%) showed radiological progression—including lesion growth (n = 11 [6.5%]), a change to a more aggressive Zabramski type (n = 10 [6.0%]), and radiological evidence of acute hemorrhage (n = 2 [1.2%]). Most of these events (88.2%) occurred within 2 years. SH was characterized by lesion growth, moderate-to-severe T1-hyperintensity, and edema. Baseline lesion size and location did not predict hemorrhage. New or worsening FND predicted hemorrhage, whereas seizure and headache alone did not. In the multivariate analysis, only the presence of new or worsening FND remained independently associated with hemorrhage (OR 13.73, p < 0.001). CONCLUSIONS In patients with known CCM, MRI should be performed in case of new or worsening FND, as this was the strongest predictor of hemorrhage. Routine surveillance had limited diagnostic yield in asymptomatic patients but may be appropriate in select cases.

BACKGROUND AND OBJECTIVES: It is not clear whether changes in lesion volume might represent a clinically relevant and statistically advantageous outcome parameter in early phase trials aimed at preventing bleeding in cerebral cavernous malformations (CCM). METHODS: We examined prospective changes in CCM lesion volume in the double-blinded AT CASH EPOC trial (clinicaltrials.gov NCT02603328). We correlated these with symptomatic hemorrhage (SH) events, contemporaneously assessed changes in lesional iron content by quantitative susceptibility mapping (QSM) on MRI, and objective (modified Rankin Scale (mRS)) and subjective (Euro-QoL Visual Analog Scale [EQ-VAS]) functional status. We also simulated sample sizes needed to detect potential effects on lesion volume. RESULTS: There was excellent correlation between independently assessed maximum lesion diameter and CCM lesion volume (R 2 = 0.68, P < .0001). The mean (SD) percentage change in lesion volume per year was +6 (65) and +18 (94) in atorvastatin and placebo patients, respectively ( P = .43). All cases with SH had increases in lesion volume and increases in mean lesional iron content by QSM, and most had declines in functional status on mRS and EQ-VAS, but there were no overall meaningful correlations of changes in lesion volume with concomitant changes in mean lesional QSM, mRS, or EQ-VAS (all R/R 2 < 0.5 and Bonferroni corrected P > .05), including in brainstem lesions analyzed separately. Sample size simulations indicate larger case numbers needed to demonstrate an effect on change in lesion volume than those needed to detect an effect on QSM change with α = 0.05 and β = 0.8, and even larger samples to detect effects on the number of cases with increased or decreased lesion volume. CONCLUSION: Changes in lesion volume occur frequently in CCM lesions after recent SH, but do not correlate with biomarkers of lesional bleeding, nor reflect functional changes, and are not statistically advantageous compared with QSM measures in detecting potential drug effects.