Ferroptosis in Cardiovascular Disease and Cardiomyopathies: Therapeutic Implications of Glutathione and Iron Chelating Agents.

This review explores ferroptosis, a form of regulated cell death reliant on iron-induced phospholipid peroxidation, in diverse physiological and pathological contexts, including neurodegenerative disorders, and ischemia-reperfusion. In the realm of cardiovascular diseases, it significantly contributes to cardiomyopathies, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and restrictive cardiomyopathy. Ferroptosis involves intricate interactions within cellular iron metabolism, lipid peroxidation, and the balance between polyunsaturated and monounsaturated fatty acids. Molecularly, factors like p53 and NRF2 impact cellular susceptibility to ferroptosis under oxidative stress. Understanding ferroptosis is vital in cardiomyopathies, where cardiac myocytes heavily depend on aerobic respiration, with iron playing a pivotal role. Dysregulation of the antioxidant enzyme GPX4 is linked to cardiomyopathies, emphasizing its significance. Ferroptosis's role in myocardial ischemia-reperfusion injury, exacerbated in diabetes, underscores its relevance in cardiovascular conditions. This review explores the connection between ferroptosis, the NRF2 pathway, and atherosclerosis, emphasizing their roles in protecting cells from oxidative stress and maintaining iron balance. It discusses the use of iron chelating agents in managing iron overload conditions, with associated benefits and challenges. Finally, it highlights the importance of exploring therapeutic strategies that enhance the glutathione (GSH) system and the potential of natural compounds like quercetin, terpenoids, and phenolic acids in reducing oxidative stress.

The Role of Oxidative Stress in TB Meningitis and Therapeutic Options.

Meningitis is an inflammatory condition affecting the meninges surrounding the brain and spinal cord. Meningitis can be triggered by various factors, including infectious agents like viruses and bacteria and non-infectious contributors such as cancer or head injuries. The impact of meningitis on the central nervous system involves disruptions in the blood-brain barrier, cellular infiltrations, and structural alterations. The clinical features that differentiate between tuberculous meningitis (TBM) and non-tuberculous meningitis (NTM) are discussed in this review and aid in accurate diagnosis. The intricate interplay of reactive oxygen species, ferroptosis, and reactive nitrogen species within the central nervous system reveals a promising field of research for innovative therapeutic strategies tailored to TBM. This review highlights the alternative treatments targeting oxidative stress-induced TBM and ferroptosis, providing potential avenues for intervention in the pathogenesis of this complex condition.

Association between universal health coverage and the disease burden of acute illness and injury at the global level.

BACKGROUND: This study examines the relationship between universal health coverage (UHC) and the burden of emergency diseases at a global level. METHODS: Data on Disability-Adjusted Life Years (DALYs) from emergency conditions were extracted from the Institute for Health Metrics and Evaluation (IHME) database for the years 2015 and 2019. Data on UHC, measured using two variables 1) coverage of essential health services and 2) proportion of the population spending more than 10% of household income on out-of-pocket health care expenditure, were extracted from the World Bank Database for years preceding our outcome of interest. A linear regression was used to analyze the association between UHC variables and DALYs for emergency diseases, controlling for other variables. RESULTS: A total of 132 countries were included. The median national coverage of essential health services index was 67.5/100, while the median national prevalence of catastrophic spending in the sample was 6.74% of households. There was a strong significant relationship between health service coverage and the burden of emergency diseases, with an 11.5-point reduction in DALYs of emergency medical diseases (95% CI -9.5, -14.8) for every point increase in the coverage of essential health services index. There was no statistically significant relationship between catastrophic expenditures and the burden of emergency diseases, which may be indicative of inelastic demand in seeking services for health emergencies. CONCLUSION: Increasing the coverage of essential health services, as measured by the essential health services index, is strongly correlated with a reduction in the burden of emergency conditions. In addition, data affirms that financial protection remains inadequate in many parts of the globe, with large numbers of households experiencing significant economic duress related to seeking healthcare. This evidence supports a strategy of strengthening UHC as a means of combating death and disability from health emergencies, as well as extending protection against impoverishment related to healthcare expenses.

Sex differences in etiology and short-term outcome in young ischemic stroke patients receiving mechanical thrombectomy.

BACKGROUND: Although there are well known sex differences in older patients with ischemic stroke receiving acute reperfusion treatments, there is paucity of data in younger patients. METHODS: We investigated sex-related differences in clinical presentation, stroke etiology and short-term outcomes in consecutive young patients with acute ischemic stroke (AIS) below the age of 50 years receiving mechanical thrombectomy (MT) between January 2011 and May 2021 in a tertiary stroke center. RESULTS: We identified a total of 202 young ischemic stroke patients with MT, with 51% being female. Young female AIS patients were significantly younger (39 ± 8 vs. 43 ± 7 years, p < 0.001), and presented with a trend for more severe stroke on admission (median NIHSS 12 vs. 9, p = 0.065), compared to males, respectively. Young female AIS patients had higher rates of embolic strokes of determined or undetermined sources in the anterior circulation, while young male AIS patients suffered more often strokes of arterio-arterial embolism. Complete reperfusion (TICI score 3) was achieved significantly less often in young female AIS patients (69% vs. 83%, p = 0.006), and in-hospital mortality was 2-times higher (5% vs. 2%, p = 0.271) compared to males. CONCLUSIONS: Young female AIS patients receiving MT have higher rates of severe embolic strokes and less often complete reperfusion due to different occlusion sites and stroke etiology compared to males.

The prevalence of bacteremia in out of hospital cardiac arrest patients presenting to the emergency department of a tertiary care hospital.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) remains one of the most common causes of death. There is a scarcity of evidence concerning the prevalence of bacteraemia in cardiac arrest patients presenting to the Emergency Department (ED). We aimed to determine the prevalence of bacteraemia in OHCA patients presenting to the ED, as well as study the association between bacteraemia and in-hospital mortality in OHCA patients. In addition, the association between antibiotic use during resuscitation and in-hospital mortality was examined. METHODS AND RESULTS: This was a study of 200 adult OHCA patients who presented to the ED between 2015 and 2019. Bacteraemia was confirmed if at least one of the blood culture bottles grew a non-skin flora pathogen or if two blood culture bottles grew a skin flora pathogen from two different sites. The prevalence of bacteraemia was 46.5%. Gram positive bacteria, specifically Staphylococcus species, were the most common pathogens isolated from the bacteremic group. 42 patients survived to hospital admission. The multivariate analysis revealed that there was no association between bacteraemia and hospital mortality in OHCA patients (OR = 1.3, 95% CI= 0.2-9.2) with a p-value of .8. There was no association between antibiotic administration during resuscitation and hospital mortality (OR = 0.6, 95% CI= 0.1 - 3.8) with a p-value of .6. CONCLUSION: In our study, the prevalence of bacteraemia among OHCA patients presenting to the ED was found to be 46.5%. Bacteremic and non-bacteremic OHCA patients had similar initial baseline characteristics and laboratory parameters except for higher serum creatinine and BUN in the bacteremic group. In OHCA patients who survived their ED stay there was no association between hospital mortality and bacteraemia or antibiotic administration during resuscitation. There is a need for randomised controlled trials with a strong patient oriented primary outcome to better understand the association between in-hospital mortality and bacteraemia or antibiotic administration in OHCA patients.KEY MESSAGESWe aimed to determine the prevalence of bacteraemia in OHCA patients presenting to the Emergency Department. In our study, we found that 46.5% of patients presenting to our ED with OHCA were bacteremic.Bacteremic and non-bacteremic OHCA patients had similar initial baseline characteristics and laboratory parameters except for higher serum creatinine and BUN in the bacteremic group.We found no association between bacteraemia and hospital mortality. There was no association between antibiotic administration during resuscitation and hospital mortality.There is a need for randomised controlled trials with a strong patient oriented primary outcome to better understand the association between in-hospital mortality and bacteraemia or antibiotic administration in OHCA patients.

Regional variation in outcomes and healthcare resources utilization in, emergency department visits for syncope.

BACKGROUND: Management of patients with syncope lacks standardization. We sought to assess regional variation in hospitalization rates and resource utilization of patients with syncope. METHODS: We identified adults with syncope using the Nationwide Emergency Department Sample from years 2006 to 2014. Demographics and comorbidity characteristics were compared across geographic regions in the US. Multiple regression was conducted to compare outcomes. RESULTS: 9,132,176 adults presented with syncope. Syncope in the Northeast (n = 1,831,889) accounted for 20.1% of visits; 22.6% in the Midwest (n = 2,060,940), 38.5% in the South (n = 3,527,814) and 18.7% in the West (n = 1,711,533). Mean age was 56 years with 57.7% being female. The Northeast had the highest risk-adjusted hospitalization rate (24.5%) followed by the South (18.6%, ORadj 0.58; 95% CI 0.52-0.65, p < 0.001), the Midwest (17.2%, ORadj 0.51; 95% CI 0.46-0.58, p < 0.001) and West (15.8%, ORadj 0.45; 95% CI 0.39-0.51, p < 0.001). Risk-adjusted rates of syncope hospitalizations significantly declined from 25.8% (95% CI 24.8%-26.7%) in 2006 to 11.7% (95% CI 11.0%-12.5%) in 2014 (Ptrend < 0.001). The Northeast had the lowest risk-adjusted ED (Emergency Department) service charges per visit ($3320) followed by the Midwest ($4675, IRRadj 1.41; 95% CI 1.30-1.52, p < 0.001), the West ($4814, IRRadj 1.45; 95% CI 1.31-1.60, p < 0.001) and South ($4969, IRRadj 1.50; 95% CI 1.38-1.62, p < 0.001). Service charges increased from $3047/visit (95% CI $2912-$3182) in 2006 to $6267/visit (95% CI $5947-$6586) in 2014 (Ptrend < 0.001). CONCLUSIONS: Significant regional variability in hospitalization rates and ED service charges exist among patients with syncope. Standardizing practices may be needed to reduce variability.

Accurate prediction of clinical stroke scales and improved biomarkers of motor impairment from robotic measurements.

OBJECTIVE: One of the greatest challenges in clinical trial design is dealing with the subjectivity and variability introduced by human raters when measuring clinical end-points. We hypothesized that robotic measures that capture the kinematics of human movements collected longitudinally in patients after stroke would bear a significant relationship to the ordinal clinical scales and potentially lead to the development of more sensitive motor biomarkers that could improve the efficiency and cost of clinical trials. MATERIALS AND METHODS: We used clinical scales and a robotic assay to measure arm movement in 208 patients 7, 14, 21, 30 and 90 days after acute ischemic stroke at two separate clinical sites. The robots are low impedance and low friction interactive devices that precisely measure speed, position and force, so that even a hemiparetic patient can generate a complete measurement profile. These profiles were used to develop predictive models of the clinical assessments employing a combination of artificial ant colonies and neural network ensembles. RESULTS: The resulting models replicated commonly used clinical scales to a cross-validated R2 of 0.73, 0.75, 0.63 and 0.60 for the Fugl-Meyer, Motor Power, NIH stroke and modified Rankin scales, respectively. Moreover, when suitably scaled and combined, the robotic measures demonstrated a significant increase in effect size from day 7 to 90 over historical data (1.47 versus 0.67). DISCUSSION AND CONCLUSION: These results suggest that it is possible to derive surrogate biomarkers that can significantly reduce the sample size required to power future stroke clinical trials.

Characteristics and Outcomes of Pediatric Septic Patients With Cancer: A Retrospective Cohort Study.

BACKGROUND: Pediatric oncology patients may be at a higher risk of complications and mortality from sepsis compared with their nononcology counterpart. OBJECTIVES: The aim of this study is to compare characteristics, treatment, and sepsis-related mortality between oncology and nononcology patients presenting to the emergency department (ED). METHODS: This is a retrospective single-center cohort study including patients <18 years old with a diagnosis of sepsis, severe sepsis, septic shock, or bacteremia presenting to an academic ED between January 2009 and January 2015. A total of 158 patients were included with 53.8% having an underlying malignancy. The primary outcome of the study was in-hospital mortality. Secondary outcomes included ED vital signs, resuscitation parameters, laboratory work, infection site, general practitioner unit, intensive care unit length of stay, and hospital length of stay. RESULTS: Oncology patients had a higher in-hospital mortality (5.9% vs. 2.7%), however, it did not meet statistical significance (p = 0.45). On presentation, oncology patients had a lower respiratory rate (24.33 ± 9.48 vs. 27.45 ± 7.88; p = 0.04). There was a significant increase in the white blood count in oncology patients (4.011 ± 4.965 vs. 17.092 ± 12.806; p < 0.001) with this cohort receiving more intravenous fluids. In the first 6 hours (33.0 ± 27.7 mL/kg vs. 24.9 ± 16.1 mL/kg; p = 0.029) as well as having a higher percentage of vasopressor administration (15.3% vs. 1.4%; p = 0.002). Antibiotics were initiated at an earlier stage in the oncology cohort (1.25 ± 1.95 vs. 3.33 ± 1.97 hours; p < 0.0001). Cancer-free patients had a significantly higher rate of lung infections compared with cancer patients (68.5% vs. 32.9%; p < 0.0001). In terms of infection characteristics, cancer patients had a higher percentage of bacteremia (27.1% vs. 4.1%; p < 0.001). CONCLUSION: There was no statistical significance regarding mortality between the 2 cohorts. Pediatric cancer patients were found to have a higher incidence of bacteremia and received more aggressive treatment.

Autosomal dominant polycystic kidney disease and minimal trauma: medical review and case report.

BACKGROUND: Blunt abdominal trauma in the setting of polycystic kidney disease is still scantly described in the literature and management guidelines of such patients are not well-established. CASE PRESENTATION: The authors herein present a case of hypovolemic shock secondary to segmental renal artery bleed in a 75-year-old man with polycystic kidney disease after minimal blunt abdominal trauma, who underwent successful selective arterial embolization, and provide a thorough review of similar cases in the literature, while shedding the light on important considerations when dealing with such patients. CONCLUSIONS: It is important to suspect renal injury in patients with pre-existing renal lesions irrespective of the mechanism of injury; and, vice-versa to suspect an underlying abnormality in patients with a clinical deterioration that's out of proportion to the mechanism of injury.

Outcomes of patients with systolic heart failure presenting with sepsis to the emergency department of a tertiary hospital: a retrospective chart review study from Lebanon.

OBJECTIVES: Patients with congestive heart failure (CHF) may be at a higher risk of mortality from sepsis than patients without CHF due to insufficient cardiovascular reserves during systemic infections. The aim of this study is to compare sepsis-related mortality between CHF and no CHF in patients presenting to a tertiary medical centre. DESIGN: A single-centre, retrospective, cohort study. SETTING: Conducted in an academic emergency department (ED) between January 2010 and January 2015. Patients' charts were queried via the hospital's electronic system. Patients with a diagnosis of sepsis were included. Descriptive analysis was performed on the demographics, characteristics and outcomes of patients with sepsis of the study population. PARTICIPANTS: A total of 174 patients, of which 87 (50%) were patients with CHF. PRIMARY AND SECONDARY OUTCOMES: The primary outcome of the study was in-hospital mortality. Secondary outcomes included intensive care unit (ICU) and hospital lengths of stay, and differences in interventions between the two groups. RESULTS: Patients with CHF had a higher in-hospital mortality (57.5% vs 34.5%). Patients with sepsis and CHF had higher odds of death compared with the control population (OR 2.45; 95% CI 1.22 to 4.88). Secondary analyses showed that patients with CHF had lower instances of bacteraemia on presentation to the ED (31.8% vs 46.4%). They had less intravenous fluid requirements in first 24 hours (2.75±2.28 L vs 3.67±2.82 L, p =0.038), had a higher rate of intubation in the ED (24.2% vs 10.6%, p=0.025) and required more dobutamine in the first 24 hours (16.1% vs 1.1%, p<0.001). ED length of stay was found to be lower in patients with CHF (15.12±24.45 hours vs 18.17±26.13 hours, p=0.418) and they were more likely to be admitted to the ICU (59.8% vs 48.8%, p=0.149). CONCLUSION: Patients with sepsis and CHF experienced an increased hospital mortality compared with patients without CHF.

Characteristics of patients presenting post-suicide attempt to an Academic Medical Center Emergency Department in Lebanon.

BACKGROUND: Emergency Department (ED) visits for suicide attempts have been described worldwide; however, the populations studied were predominantly Western European, North American, or East Asian. This study aims to describe the epidemiology of ED patients presenting post-suicide attempt to an academic medical center in Lebanon and to report on factors that affect ED disposition. METHODS: A retrospective cohort study was conducted between 2009 and 2015. Patients of any age group were included if they had presented to the ED after a suicide attempt. Patients with unintentional self-harm were excluded. Descriptive analysis was performed on the demographics and characteristics of suicide attempts of the study population. A bivariate analysis to compare the two groups (hospitalized or discharged) was conducted using Student's t test and Pearson Chi-square where appropriate. A multivariate analysis was then conducted to determine the predictors of hospital admission. RESULTS: One hundred and eight patients were included in the final analysis. Most patients were females (71.4%) and between 22 and 49 years of age. A considerable number of patients were unemployed (43%), unmarried (61.1%), and living with family (86.9%). Most suicide attempts were performed at home (93.5%) and on a weekday (71.3%). The most common mechanisms of injury were overdose with prescription medications (61.3%), overdose with over-the-counter drugs (27.9%), and self-inflicted lacerations (10.1%). The classes of medication most commonly abused were benzodiazepines (39.3%) followed by acetaminophen (27.3%). A large portion of our patients were admitted (70.3%), with the majority going to the psychiatric ward (71.1%). Of note, a quarter (27.5%) of our patients left the ED against medical advice, with 23.5% of admitted patients leaving the hospital before completion of treatment. The main predictors of admission were found to be overdose on prescription medications OR 9.25 (2.12-40.42 CI95%). CONCLUSIONS: The characteristics of our suicide attempters mirror those of international and regional suicide attempters. Further work is required to quantify the effect of voluntary refusal of hospital treatment, the repercussions of family, and financial barriers to healthcare and suicide as a whole in our society.

Dual defibrillation in patients with refractory ventricular fibrillation.

In the setting of cardiac arrest, refractory ventricular fibrillation (VF) is difficult to manage, and mortality rates are high. Double sequential defibrillation (DSD) has been described in the literature as a successful means to terminate this malignant rhythm, after failure of traditional Advanced Cardiac Life Support (ACLS) measures. The authors herein present a case of refractory VF in a patient with cardiac arrest, on whom DSD was successful in reversion to sinus rhythm, and provide a thorough review of similar cases in the literature.

Neuromuscular Disorder as Initial Manifestation of Secondary Hyperparathyroidism - A Case Report.

This case report describes a young woman who presented with slowly progressing weakness of the proximal limb muscles and slight decrease of muscle tone but otherwise unremarkable neurological history. Diagnostic workup revealed fatty degeneration of the girdle muscles and an excessive increase of the parathyroid hormone as a result of severe vitamin D deficiency. Secondary hyperparathyroidism was diagnosed, and neurological deficits resolved after treatment of the underlying endocrinopathy.

Robotic measurement of arm movements after stroke establishes biomarkers of motor recovery.

BACKGROUND AND PURPOSE: Because robotic devices record the kinematics and kinetics of human movements with high resolution, we hypothesized that robotic measures collected longitudinally in patients after stroke would bear a significant relationship to standard clinical outcome measures and, therefore, might provide superior biomarkers. METHODS: In patients with moderate-to-severe acute ischemic stroke, we used clinical scales and robotic devices to measure arm movement 7, 14, 21, 30, and 90 days after the event at 2 clinical sites. The robots are interactive devices that measure speed, position, and force so that calculated kinematic and kinetic parameters could be compared with clinical assessments. RESULTS: Among 208 patients, robotic measures predicted well the clinical measures (cross-validated R(2) of modified Rankin scale=0.60; National Institutes of Health Stroke Scale=0.63; Fugl-Meyer=0.73; Motor Power=0.75). When suitably scaled and combined by an artificial neural network, the robotic measures demonstrated greater sensitivity in measuring the recovery of patients from day 7 to day 90 (increased standardized effect=1.47). CONCLUSIONS: These results demonstrate that robotic measures of motor performance will more than adequately capture outcome, and the altered effect size will reduce the required sample size. Reducing sample size will likely improve study efficiency.

Does the cognitive measure Cog-4 show improvement among patients treated with thrombolysis after acute stroke?

BACKGROUND: Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke (Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale. METHODS: We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran-Mantel-Haenszel test. RESULTS: Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1·56; 95% confidence interval 1·43-1·72; P < 0·001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients (odds ratio 1·31; 95% confidence interval 1·18-1·47; P = 0·006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups (OR 1·01; 95% CI 0·90-1·14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients. CONCLUSION: Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment.

Diagnosis and treatment of cerebral venous thrombosis.

Dural sinus or cerebral venous thrombosis (CVT) is a frequently unrecognized cause of stroke affecting predominantly young women. Typical clinical signs include headache, visual problems and seizures. Both computed tomography and magnetic resonance venous angiography are suitable for the detection of CVT, although magnetic resonance angiography is more sensitive to detect small cortical venous thrombosis. Evidence for efficacy of initial treatment with heparin in acute CVT comes from two randomized placebo-controlled studies that together included 79 patients. Although not evidence-based, postacute treatment with oral anticoagulation is recommended for up to 12 months after CVT. Long-term anticoagulation is recommended only in patients suffering from a severe coagulopathy or with recurrent CVT.

Thrombolysis for acute ischemic stroke.

Thrombolysis with intravenous alteplase is the primary therapy for acute ischemic stroke, and is approved in most countries. Early administration improves functional outcome though benefit and risk depend on the time elapsed between stroke onset and initiation of treatment. Randomized controlled trials demonstrated benefit from intravenous thrombolysis when initiated up to 4.5 hours after symptom onset, and pooled analysis of all trials indicates that the sooner that alteplase is given, the greater is the benefit. Treatment carries a risk of bleeding, with symptomatic intracranial hemorrhage (SICH) of around 3%. Initiating treatment after 4.5 hours increases mortality and reverses the risk-benefit balance. Baseline stroke severity, age, diabetes and concomitant stroke are associated with poorer outcome from acute stroke; but secondary analyses and controlled registry data suggest that intravenous alteplase remains effective in most subgroups. Intra-arterial thrombolysis has a less extensive evidence base and is mostly unapproved for acute stroke. Access to thrombolysis remains patchy and involves unacceptable delays: greater awareness of the benefits and time dependency are crucial.

Extinction of conditioned eyeblink responses in patients with cerebellar disorders.

Extinction of conditioned eyeblink responses (CRs) was analyzed in sixteen patients with pure cortical cerebellar degeneration, 14 patients with lesions within the territory of the superior cerebellar artery (SCA), 13 patients with infarctions within the territory of the posterior inferior cerebellar artery (PICA) and 45 age-matched controls. Three-dimensional (3D) magnetic resonance (MRI) data sets were acquired in patients with focal lesions to identify affected cerebellar lobules and possible involvement of nuclei. Eyeblink conditioning was performed using a standard delay protocol. At the end of the experiment 10 CS-alone trials were presented as extinction trials. Controls showed significant effects of extinction that is a significant decline comparing CR-incidences in the extinction trials and the last block of 10 trials of the paired trials. In the group of all cerebellar patients, however, no significant effects of extinction were observed. In patients with unilateral lesions effects of extinction were present on the unaffected, but not on the affected side. Deficits of extinction were observed in PICA and SCA patients both with and without involvement of cerebellar nuclei. Extending previous reports in cerebellar patients the present findings show that the ipsilateral cerebellar hemisphere contributes to extinction of conditioned eyeblink responses in humans. It cannot be ruled out, however, that impaired acquisition affected the extinction results.

Timing of conditioned eyeblink responses is impaired in cerebellar patients.

In the present study, timing of conditioned eyeblink responses (CRs) was investigated in cerebellar patients and age-matched controls using a standard delay paradigm. Findings were compared with previously published data of CR incidences in the same patient population (Gerwig et al., 2003; Timmann et al., 2005). Sixteen patients with pure cortical cerebellar degeneration (spinocerebellar ataxia type 6 and idiopathic cerebellar ataxia), 14 patients with lesions within the territory of the superior cerebellar artery, and 13 patients with infarctions within the territory of the posterior inferior cerebellar artery were included. The affected cerebellar lobules and possible involvement of cerebellar nuclei were determined by three-dimensional magnetic resonance imaging (MRI) in patients with focal lesions (n = 27). Based on a voxel-by-voxel analysis, MRI lesion data were related to eyeblink conditioning data. CR incidence was significantly reduced, and CRs occurred significantly earlier in patients with cortical cerebellar degeneration and lesions of the superior cerebellum compared with controls. Incidence and timing of CRs was not impaired in patients with lesions restricted to the posterior and inferior cerebellum. Voxel-based MRI analysis revealed that cortical areas within the anterior lobe (Larsell lobule HV) were most significantly related to timing deficits, whereas reduced CR incidences were related to more caudal parts (lobule HVI) of the superior cerebellar cortex. The present data suggest that different parts of the superior cerebellar cortex may be involved in the formation of the stimulus association and appropriate timing of conditioned eyeblink responses in humans. Extracerebellar premotoneuronal disinhibition, however, is another possible explanation for changes in CR timing.