Plasma Biomarkers of Inflammation Reflect Seizures and Hemorrhagic Activity of Cerebral Cavernous Malformations.

The clinical course of cerebral cavernous malformations (CCMs) is highly variable. Based on recent discoveries implicating angiogenic and inflammatory mechanisms, we hypothesized that serum biomarkers might reflect chronic or acute disease activity. This single-site prospective observational cohort study included 85 CCM patients, in whom 24 a priori chosen plasma biomarkers were quantified and analyzed in relation to established clinical and imaging parameters of disease categorization and severity. We subsequently validated the positive correlations in longitudinal follow-up of 49 subjects. Plasma levels of matrix metalloproteinase-2 and intercellular adhesion molecule 1 were significantly higher (P = 0.02 and P = 0.04, respectively, FDR corrected), and matrix metalloproteinase-9 was lower (P = 0.04, FDR corrected) in patients with seizure activity at any time in the past. Vascular endothelial growth factor and endoglin (both P = 0.04, FDR corrected) plasma levels were lower in patients who had suffered a symptomatic bleed in the prior 3 months. The hierarchical clustering analysis revealed a cluster of four plasma inflammatory cytokines (interleukin 2, interferon gamma, tumor necrosis factor alpha, and interleukin 1 beta) separating patients into what we designated "high" and "low" inflammatory states. The "high" inflammatory state was associated with seizure activity (P = 0.02) and more than one hemorrhagic event during a patient's lifetime (P = 0.04) and with a higher rate of new hemorrhage, lesion growth, or new lesion formation (P < 0.05) during prospective follow-up. Peripheral plasma biomarkers reflect seizure and recent hemorrhagic activity in CCM patients. In addition, four clustered inflammatory biomarkers correlate with cumulative disease aggressiveness and predict future clinical activity.

CSF inflammatory response after intraventricular hemorrhage.

OBJECTIVE: To investigate the temporal pattern and relevant associations of CSF inflammatory measures after intraventricular hemorrhage (IVH). METHODS: We analyzed prospectively collected CSF cell counts and protein and glucose levels from participants in the Clot Lysis Evaluation of Accelerated Resolution of IVH phase III (CLEAR III) trial. Corrected leukocyte count and cell index were calculated to adjust for CSF leukocytes attributable to circulating blood. Data were chronologically plotted. CSF inflammatory measures (daily, mean, median, maximum, and cases with highest quartile response) were correlated with initial IVH volume, IVH clearance rate, thrombolytic treatment, bacterial infection, and adjudicated clinical outcome at 30 and 180 days. RESULTS: A total of 11,376 data points of CSF results from 464 trial participants were analyzed. Measures of CSF inflammatory response evolved during the resolution of IVH. This was significantly more pronounced with initial IVH volume exceeding 20 mL. Intraventricular alteplase was associated with a significantly augmented inflammatory response compared to saline, even after correcting for initial IVH volume. There was an association but nonpredictive correlation of CSF inflammation measures with culture-positive CSF bacterial infection. None of the CSF inflammatory measures, including cases with upper quartile inflammatory response, was associated with a significant detrimental effect on 30 or 180 days functional outcome or mortality after multivariate adjustment for measures of disease severity. CONCLUSIONS: Aseptic CSF inflammation after IVH is primarily dependent on the volume of initial bleed. Thrombolysis intensifies the inflammatory response, with no apparent detrimental effect on clinical outcome. CLINICALTRIALSGOV IDENTIFIER: NCT00784134.

Surgical Performance in Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation Phase III Clinical Trial.

BACKGROUND: Minimally invasive thrombolytic evacuation of intracerebral hematoma is being investigated in the ongoing phase III clinical trial of Minimally Invasive Surgery plus recombinant Tissue plasminogen activator for Intracerebral hemorrhage Evacuation (MISTIE III). OBJECTIVE: To assess the accuracy of catheter placement and efficacy of hematoma evacuation in relation to surgical approach and surgeon experience. METHODS: We performed a trial midpoint interim assessment of 123 cases that underwent the surgical procedure. Accuracy of catheter placement was prospectively assessed by the trial Surgical Center based on prearticulated criteria. Hematoma evacuation efficacy was evaluated based on absolute volume reduction, percentage hematoma evacuation, and reaching the target end-of-treatment volume of <15 mL. One of 3 surgical trajectories was used: anterior (A), posterior (B), and lobar (C). Surgeons were classified based on experience with the MISTIE procedure as prequalified, qualified with probation, and fully qualified. RESULTS: The average hematoma volume was 49.7 mL (range 20.0-124), and the mean evacuation rate was 71% (range 18.4%-99.8%). First placed catheters were 58% in good position, 28% suboptimal (but suitable to dose), and 14% poor (requiring repositioning). Posterior trajectory (B) was associated with significantly higher rates of poor placement (35%, P = .01). There was no significant difference in catheter placement accuracy among surgeons of varying experience. Hematoma evacuation efficacy was not significantly different among the 3 surgical approaches or different surgeons' experience. CONCLUSION: Ongoing surgical education and quality monitoring in MISTIE III have resulted in consistent rates of hematoma evacuation despite technical challenges with the surgical approaches and among surgeons of varying experience.

Demographic Risk Factors for Vascular Lesions as Etiology of Intraventricular Hemorrhage in Prospectively Screened Cases.

BACKGROUND: Spontaneous intraventricular hemorrhage (IVH) is associated with high rates of morbidity and mortality despite critical care and other advances. An important step in clinical management is to confirm/rule out an underlying vascular lesion, which influences further treatment, potential for further bleeding, and prognosis. Our aim is to compare demographic and clinical characteristics between IVH patients with and without an underlying vascular lesion, and among cohorts with different vascular lesions. METHODS: We analyzed prospectively collected data of IVH patients screened for eligibility as part of the Clot Lysis: Evaluation Accelerated Resolution of IVH Phase III (CLEAR III) clinical trial. The trial adopted a structured screening process to systematically exclude patients with an underlying vascular lesion as the etiology of IVH. We collected age, sex, ethnicity, and primary diagnosis on these cases and vascular lesions were categorized prospectively as aneurysm, vascular malformation (arteriovenous malformation, dural arteriovenous fistula, and cavernoma), Moyamoya disease, or other vascular lesion. We excluded cases <18 or >80 years of age. Baseline characteristics were compared between the CLEAR group (IVH screened without vascular lesion) and the group of IVH patients screened and excluded from CLEAR because of an identified vascular lesion. We further analyzed the differential demographic and clinical characteristics among subcohorts with different vascular lesions. RESULTS: A total of 10,538 consecutive IVH cases were prospectively screened for the trial between 2011 and 2015. Out of these, 496 cases (4.7%) screened negative for underlying vascular lesion, met the inclusion criteria, and were enrolled in the trial (no vascular etiology group); and 1,205 cases (11.4%) were concurrently screened and excluded from the trial because of a demonstrated underlying vascular lesion (vascular etiology group). Cases with vascular lesion were less likely to be >45 years of age (OR 0.28, 95% CI 0.20-0.40), African-American (OR 0.23, 95% CI 0.18-0.31), or male gender (OR 0.48, 95% CI 0.38-0.60), and more likely to present with primary IVH (OR 1.85, 95% CI 1.37-2.51) compared to those with no vascular etiology (p < 0.001). Other demographic factors were associated with specific vascular lesion etiologies. A combination of demographic features increases the association with the absence of vascular lesion, but not with absolute reliability (OR 0.1, 95% CI 0.06-0.17, p < 0.001). CONCLUSION: An underlying vascular lesion as etiology of IVH cannot be excluded solely by demographic parameters in any patient. Some form of vascular imaging is necessary in screening patients before contemplating interventions like intraventricular fibrinolysis, where safety may be impacted by the presence of vascular lesion.

Vascular permeability and iron deposition biomarkers in longitudinal follow-up of cerebral cavernous malformations.

OBJECTIVE Vascular permeability and iron leakage are central features of cerebral cavernous malformation (CCM) pathogenesis. The authors aimed to correlate prospective clinical behavior of CCM lesions with longitudinal changes in biomarkers of dynamic contrast-enhanced quantitative permeability (DCEQP) and quantitative susceptibility mapping (QSM) assessed by MRI. METHODS Forty-six patients with CCMs underwent 2 or more permeability and/or susceptibility studies in conjunction with baseline and follow-up imaging and clinical surveillance during a mean 12.05 months of follow-up (range 2.4-31.27 months). Based on clinical and imaging features, cases/lesions were classified as stable, unstable, or recovering. Associated and predictive changes in quantitative permeability and susceptibility were investigated. RESULTS Lesional mean permeability and QSM values were not significantly different in stable versus unstable lesions at baseline. Mean lesional permeability in unstable CCMs with lesional bleeding or growth increased significantly (+85.9% change; p = 0.005), while mean permeability in stable and recovering lesions did not significantly change. Mean lesional QSM values significantly increased in unstable lesions (+44.1% change; p = 0.01), decreased slightly with statistical significance in stable lesions (-3.2% change; p = 0.003), and did not significantly change in recovering lesions. Familial cases developing new lesions during the follow-up period showed a higher background brain permeability at baseline (p = 0.001), as well as higher regional permeability (p = 0.003) in the area that would later develop a new lesion as compared with the homologous contralateral brain region. CONCLUSIONS In vivo assessment of vascular permeability and iron deposition on MRI can serve as objective and quantifiable biomarkers of disease activity in CCMs. This may be applied in natural history studies and may help calibrate clinical trials. The 2 techniques are likely applicable in other disorders of vascular integrity and iron leakage such as aging, hemorrhagic microangiopathy, and traumatic brain injury.

Peripheral plasma vitamin D and non-HDL cholesterol reflect the severity of cerebral cavernous malformation disease.

AIM: To correlate cerebral cavernous malformations (CCMs) disease aggressiveness with peripheral blood biomarkers hypothesized mechanistically. PATIENTS & METHODS: A prospective case-control study enrolled 43 CCM patients, where 25-(OH) vitamin D, HDL and non-HDL cholesterol, CRP plasma levels and leukocyte ROCK activity were correlated with parameters of disease aggressiveness reflecting chronic and acute domains. RESULTS: Patients with one or more features of chronically aggressive disease (early age at symptom onset, two or more symptomatic bleeds, high lesion burden) had significantly lower 25-(OH) vitamin D and non-HDL cholesterol levels in comparison to patients without these features. CONCLUSION: Validation of these biomarkers and their potential treatment modulation may influence the clinical care of patients with CCM disease.

Cross-Sectional Study of Bowel Symptoms in Adults With Cerebral Palsy: Prevalence and Impact on Quality of Life.

OBJECTIVES: To determine the prevalence and type of bowel symptoms, and their impact on health-related quality of life (HRQOL) in adults with cerebral palsy (CP). DESIGN: Prospective cross-sectional study. SETTING: Urban, outpatient rehabilitation facility. PARTICIPANTS: Adults with CP (N=91; 46 men, 45 women; mean age, 36y; age range, 18-79y). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Participants were interviewed using standardized instruments to assess the frequency and types of bowel dysfunction. The International Consultation of Incontinence Questionnaire-Bowel was used to assess bowel incontinence and impact on quality of life, and constipation presence was determined using the Rome III criteria for constipation. Constipation symptoms were rated by the Patient Assessment of Constipation-Symptom Scale. Participants' mobility status was classified using the Gross Motor Function Classification System (GMFCS). Interactions between mobility measures, anthropometric measures, and bowel symptoms were assessed. RESULTS: Of the 91 participants enrolled, 62.6% were GMFCS IV or V. Twenty-eight participants (30.8%) reported severe difficulty with control of liquid stool (rating never or rarely); these participants were more likely to have a greater GMFCS level (P=.0004). Twenty-six participants (28.6%) reported that bowel function caused embarrassment some/most/all of the time. Fifty-nine participants (64.8%) met criteria for chronic constipation, which did not differ by GMFCS levels. Overall, 57.1% of participants reported that bowel symptoms interfered with life; 40.7% reported moderate to severe interference. CONCLUSIONS: Bowel symptoms were frequent, a source of embarrassment, and impacted HRQOL in these adults with CP. Addressing bowel-related symptoms has the potential to improve HRQOL in these adults.

Lubiprostone vs Senna in postoperative orthopedic surgery patients with opioid-induced constipation: a double-blind, active-comparator trial.

AIM: To investigate the efficacy of lubiprostone compared to Senna on bowel symptoms and constipation in post-operative orthopedic patients treated with opioids. METHODS: In this double blind, randomized, active comparator trial, adults who required opioids for analgesia following orthopedic procedures and who were admitted in inpatient rehabilitation were randomized following baseline assessments to lubiprostone (Amitza(®)), orally twice a day or Senna (generic) two capsules administered daily for six days. Subjects were assessed using the patient assessment of constipation (PAC)-symptoms (PAC-SYM) and the PAC-quality of life (PAC-QOL) scales measured at baseline and Day 7; Subjects were assessed daily for secondary measures included the Bristol stool scale bowel consistency, specific bowel symptom score (Nausea, cramping, straining, completeness, abdominal pain, time per lavatory attempt, assistance needed), adverse events and rescue medications required. Function was measured using the functional independence measure (FIM) at admission and discharge; length of stay (LOS) and missed treatments due to gastrointestinal symptoms were also assessed. RESULTS: 64 adults were enrolled; 56 participants (28 in each group) had baseline and follow up measures and were included in the intention to treat (ITT) analyses. 43 participants completed the study, 21 in the active lubiprostone and 22 in the active Senna group. The mean age of the participants was 71.5 years (SD = 11.4 years, range: 28-96 years). In the ITT analyses, participants showed significant improvement in bowel symptoms as measured by the PAC-SYM (mean ± SD, -0.28 ± 0.60, range: -1-2.33) and PAC-QOL (mean ± SD, 0.33 ± 0.81, range: -1.5-2.0) over time, but there were no significant differences between the lubiprostone and Senna groups in mean change in the PAC-SYM (-0.20 ± 0.60 vs -0.36 ± 0.61, P = 0.61 respectively) or the PAC-QOL (0.29 ± 0.76 vs 0.37 ± 0.87, P = 0.61 respectively). The mean change in each bowel symptom also did not significantly differ between treatment groups on ITT analyses, except for completeness of bowel movement, with the Senna group showing greater negative mean change in bowel movement completeness (-0.56 ± 1.01 vs -2.00 ± 1.41, P = 0.03) and for reduction of abdominal pain, favoring Senna (-0.14 ± 0.73 vs -0.73 ± 1.08, P = 0.04). Fifteen (75%) participants in the lubiprostone and in the Senna group requested rescue treatments. Participants made significant functional improvement from admission to discharge over a median LOS of 12 d, with a mean FIM change of 29.13 ± 13.58 and no significant between group differences (27.0 ± 9.2 vs 31.5 ± 16.6, P = 0.27). CONCLUSION: Both lubiprostone and Senna improved constipation-related symptoms and QOL in opioid-induced constipation, with no significant between-group differences.

Urinary incontinence in adults with cerebral palsy: prevalence, type, and effects on participation.

OBJECTIVE: To assess the prevalence, type, and impact of urinary problems in adults with cerebral palsy and their relation with the Gross Motor Function Classification System for cerebral palsy. DESIGN: A cross-sectional prospective survey study. SETTING: An outpatient, urban, academic rehabilitation clinic. PARTICIPANTS: Ninety-one adults with cerebral palsy (45 women, 46 men). INTERVENTIONS: Subjects were approached at clinic presentation and were interviewed regarding current function, type and incidence of bladder issues, and concerns with bladder problems. MAIN OUTCOME MEASURES: The International Consultation on Incontinence Questionnaire-Female, or the International Consultation on Incontinence Questionnaire-Male Lower Urinary Tract Symptoms Module, Gross Motor Function Classification System, employment, and type of residence. RESULTS: The mean age for both women and men was 36 years (range, 18-79 years). The subjects were currently assessed with the Gross Motor Function Classification System scales I-V: I, 4.4%; II, 19.8%; III, 13.2%; IV, 40.7%; and V, 22.0%. 95.6% of females and 84.7% of males were living at home. Twenty-three percent were currently employed. Twenty percent of the women indicated that they had bladder urgency most to all of the time and 46.7% of the women had leakage that occurred 2-3 times per week to several times per day. In men, urgency that occurred more often than "occasionally" was reported by 45.7%, and 19.6% reported this occurred "most to all of the time." Multivariable analyses found that obesity compared with normal weight was significantly related to leaking before reaching a toilet (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.3-14.7), to leaking with cough, exercise, or sneeze (OR 5.6, 95% CI 1.3-23.1), and to nocturia (OR 5.4, 95% CI 1.2-25.1). Women were more likely to leak with cough, exercise, or sneeze (OR 5.5, 95% CI 1.5-20.0). On scales that indicate symptom interference with life, high levels of interference were reported for women with symptoms of leaking and for men with urgency and leaking. No significant differences in living situation or employment were related to incontinence scores for women or men. CONCLUSION: There are high levels of incontinence in adults with cerebral palsy, and these individuals report interference with quality of life. Despite these issues, most participants were living in the community, and incontinence scores were not related to employment.