Influence of Outlet Boundary Conditions on Cerebrovascular Aneurysm Hemodynamics

Computational fluid dynamic (CFD) studies of blood flow in cerebrovascular aneurysms have potential to improve patient treatment planning by enabling clinicians and engineers to model patient-specific geometries and compute predictors and risks prior to neurovascular intervention. However, the use of patient-specific computational models in clinical settings is unfeasible due to their complexity, computationally intensive and time-consuming nature. An important factor contributing to this challenge is the choice of outlet boundary conditions, which often involves a trade-off between physiological accuracy, patient-specificity, simplicity and speed. In this study, we analyze how resistance and impedance outlet boundary conditions affect blood flow velocities, wall shear stresses and pressure distributions in a patient-specific model of a cerebrovascular aneurysm. We also use geometrical manipulation techniques to obtain a model of the patient’s vasculature prior to aneurysm development, and study how forces and stresses may have been involved in the initiation of aneurysm growth. Our CFD results show that the nature of the prescribed outlet boundary conditions is not as important as the relative distributions of blood flow through each outlet branch. As long as the appropriate parameters are chosen to keep these flow distributions consistent with physiology, resistance boundary conditions, which are simpler, easier to use and more practical than their impedance counterparts, are sufficient to study aneurysm pathophysiology, since they predict very similar wall shear stresses, time-averaged wall shear stresses, time-averaged pressures, and blood flow patterns and velocities. The only situations where the use of impedance boundary conditions should be prioritized is if pressure waveforms are being analyzed, or if local pressure distributions are being evaluated at specific time points, especially at peak systole, where the use of resistance boundary conditions leads to unnaturally large pressure pulses. In addition, we show that in this specific patient, the region of the blood vessel where the neck of the aneurysm developed was subject to abnormally high wall shear stresses, and that regions surrounding blebs on the aneurysmal surface were subject to low, oscillatory wall shear stresses. Computational models using resistance outlet boundary conditions may be suitable to study patient-specific aneurysm progression in a clinical setting, although several other challenges must be addressed before these tools can be applied clinically.

Continuity of care in older adults with multiple chronic conditions

Thesis (Ph.D.)--University of Washington, 2016-08

Clinical practice guideline on diagnosis and treatment of hyponatraemia

Hyponatraemia, defined as a serum sodium concentration <135 mmol/l, is the most common disorder of body fuid and electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia in widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution-and speciality-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed the Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice.

Two-year clinical outcome from the Iberian registry patients after left atrial appendage closure

AIMS: The aim of this study was to observe the percentage of thromboembolic and haemorrhagic events over a 2-year follow-up in patients with non-valvular atrial fibrillation (NVAF) undergoing closure of the left atrial appendage (LAA) with an occlusion device. Observed events and CHADS2 (congestive heart failure, hypertension, age, diabetes, stroke history), CHA2DS2-VASc (also adding: vascular disease and sex) and HAS-BLED (hypertension, abnormal liver/renal function, stroke history, bleeding predisposition, labile international normalised ratios, elderly, drugs/alcohol use)-predicted events were compared. METHODS: LAA closure with an occlusion device was performed in 167 NVAF patients contraindicated for oral anticoagulants and recruited from 12 hospitals between 2009 and 2013. At least two transoesophageal echocardiograms were performed in the first 6 months postimplantation. Antithrombotics included clopidogrel and aspirin. Patients were monitored for death, stroke, major and relevant bleeding and hospitalisation for concomitant conditions. Mean age was 74.68±8.58, median follow-up was 24 months, 5.38% had intraoperative complications and implantation was successful in 94.6% of subjects. Mortality during follow-up was 10.8%, mostly (9.5%) non-cardiac related. Bleeding occurred in 10.1% of subjects, 5.7% major and 4.4% minor though relevant, and 4.4% suffered stroke. Major bleeding and stroke/transient ischaemic attack events within 2 years (annual event rates, 290 patients/year) were less frequent than expected from CHADS2 (2.4% vs 9.6%), CHA2DS2-VASc (2.4% vs 8.3%) and HAS-BLED (3.1% vs 6.6%) risk scores (p<0.001, p=0.003, p=0.047, respectively). CONCLUSIONS: LAA closure with an occlusion device in patients contraindicated for oral anticoagulants is a therapeutic option associated with fewer thromboembolic and haemorrhagic events than expected from risk scores, particularly in the second year postimplantation.

Numerical investigations on the strain-adaptive bone remodelling in the periprosthetic femur: Influence of the boundary conditions

Background: There are several numerical investigations on bone remodelling after total hip arthroplasty (THA) on the basis of the finite element analysis (FEA). For such computations certain boundary conditions have to be defined. The authors chose a maximum of three static load situations, usually taken from the gait cycle because this is the most frequent dynamic activity of a patient after THA. Materials and methods: The numerical study presented here investigates whether it is useful to consider only one static load situation of the gait cycle in the FE calculation of the bone remodelling. For this purpose, 5 different loading cases were examined in order to determine their influence on the change in the physiological load distribution within the femur and on the resulting strain-adaptive bone remodelling. First, four different static loading cases at 25%, 45%, 65% and 85% of the gait cycle, respectively, and then the whole gait cycle in a loading regime were examined in order to regard all the different loadings of the cycle in the simulation. Results: The computed evolution of the apparent bone density (ABD) and the calculated mass losses in the periprosthetic femur show that the simulation results are highly dependent on the chosen boundary conditions. Conclusion: These numerical investigations prove that a static load situation is insufficient for representing the whole gait cycle. This causes severe deviations in the FE calculation of the bone remodelling. However, accompanying clinical examinations are necessary to calibrate the bone adaptation law and thus to validate the FE calculations.

Effect of remote ischaemic preconditioning in cardiac dysfunction and end-organ injury following cardiac surgery with cardiopulmonary bypass in children: A translational approach investigating clinical outcome and myocardial molecular biology

Congenital heart disease (CHD) is the most common birth defect, causing an important rate of morbidity and mortality. Treatment of CHD requires surgical correction in a significant percentage of cases which exposes patients to cardiac and end organ injury. Cardiac surgical procedures often require the utilisation of cardiopulmonary bypass (CPB), a system that replaces heart and lungs function by diverting circulation into an external circuit. The use of CPB can initiate potent inflammatory responses, in addition a proportion of procedures require a period of aortic cross clamp during which the heart is rendered ischaemic and is exposed to injury. High O2 concentrations are used during cardiac procedures and when circulation is re-established to the heart which had adjusted metabolically to ischaemia, further injury is caused in a process known as ischaemic reperfusion injury (IRI). Several strategies are in place in order to protect the heart during surgery, however injury is still caused, having detrimental effects in patients at short and long term. Remote ischaemic preconditioning (RIPC) is a technique proposed as a potential cardioprotective measure. It consists of exposing a remote tissue bed to brief episodes of ischaemia prior to surgery in order to activate protective pathways that would act during CPB, ischaemia and reperfusion. This study aimed to assess RIPC in paediatric patients requiring CHD surgical correction with a translational approach, integrating clinical outcome, marker analysis, cardiac function parameters and molecular mechanisms within the cardiac tissue. A prospective, single blinded, randomized, controlled trial was conducted applying a RIPC protocol to randomised patients through episodes of limb ischaemia on the day before surgery which was repeated right before the surgery started, after anaesthesia induction. Blood samples were obtained before surgery and at three post-operative time points from venous lines, additional pre and post-bypass blood samples were obtained from the right atrium. Myocardial tissue was resected during the ischaemic period of surgery. Echocardiographic images were obtained before the surgery started after anaesthetic induction and the day after surgery, images were stored for later off line analysis. PICU surveillance data was collected including ventilation parameters, inotrope use, standard laboratory analysis and six hourly blood gas analysis. Pre and post-operative quantitation of markers in blood specimens included cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP), inflammatory mediators including interleukins IL-6, IL-8, IL-10, tumour necrosis factor (TNF-α), and the adhesion molecules ICAM-1 and VCAM-1; the renal marker Cystatin C and the cardiovascular markers asymmetric dymethylarginine (ADMA) and symmetric dymethylarginine (SDMA). Nitric oxide (NO) metabolites and cyclic guanosine monophosphate (cGMP) were measured before and after bypass. Myocardial tissue was processed at baseline and after incubation at hyperoxic concentration during four hours in order to mimic surgical conditions. Expression of genes involved in IRI and RIPC pathways was analysed including heat shock proteins (HSPs), toll like receptors (TLRs), transcription factors nuclear factor κ-B (NF- κ-B) and hypoxia inducible factor 1 (HIF-1). The participation of hydrogen sulfide enzymatic genes, apelin and its receptor were explored. There was no significant difference according to group allocation in any of the echocardiographic parameters. There was a tendency for higher cTnI values and inotropic score in control patients post-operatively, however this was not statistically significant. BNP presented no significant difference according to group allocation. Inflammatory parameters tended to be higher in the control group, however only TNF- α was significantly higher. There was no difference in levels of Cystatin C, NO metabolites, cGMP, ADMA or SDMA. RIPC patients required shorter PICU stay, all other clinical and laboratory analysis presented no difference related to the intervention. Gene expression analysis revealed interesting patterns before and after incubation. HSP-60 presented a lower expression at baseline in tissue corresponding to RIPC patients, no other differences were found. This study provided with valuable descriptive information on previously known and newly explored parameters in the study population. Demographic characteristics and the presence of cyanosis before surgery influenced patterns of activity in several parameters, numerous indicators were linked to the degree of injury suffered by the myocardium. RIPC did not reduce markers of cardiac injury or improved echocardiographic parameters and it did not have an effect on end organ function; some effects were seen in inflammatory responses and gene expression analysis. Nevertheless, an important clinical outcome indicator, PICU length of stay was reduced suggesting benefit from the intervention. Larger studies with more statistical power could determine if the tendency of lower injury and inflammatory markers linked to RIPC is real. The present results mostly support findings of larger multicentre trials which have reported no cardiac benefit from RIPC in paediatric cardiac surgery.

‘Failure to maintain’: care rationing and the clinical and financial burden of nurse sensitive hospital-acquired complications in complex older patients

Background: The ageing population, with concomitant increase in chronic conditions, is increasing the presence of older people with complex needs in hospital. People with dementia are one of these complex populations and are particularly vulnerable to complications in hospital. Registered nurses can offer simultaneous assessment and intervention to prevent or mitigate hospital-acquired complications through their skilled brokerage between patient needs and hospital functions. A range of patient outcome measures that are sensitive to nursing care has been tested in nursing work environments across the world. However, none of these measures have focused on hospitalised older patients. Method: This thesis explores nursing-sensitive complications for older patients with and without dementia using an internationally recognised, risk-adjusted patient outcome approach. Specifically explored are: the differences between rates of complications; the costs of complications; and cost comparisons of patient complexity. A retrospective cohort study of an Australian state’s 2006–07 public hospital discharge data was utilised to identify patient episodes for people over age 50 (N=222,440) where dementia was identified as a primary or secondary diagnosis (N=44,422). Extra costs for patient episodes were estimated based on length of stay (LOS) above the average for each patient’s Diagnosis Related Group (DRG) (N=157,178) and were modelled using linear regression analysis to establish the strongest patient complexity predictors of cost. Results: Hospitalised patients with a primary or secondary diagnosis of dementia had higher rates of complications than did their same-age peers. The highest rates and relative risk for people with dementia were found in four key complications: urinary tract infections; pressure injuries; pneumonia, and delirium. While 21.9% of dementia patients (9,751/44,488, p<0.0001) suffered a complication, only 8.8% of non-dementia patients did so (33,501/381,788, p<0.0001), giving dementia patients a 2.5 relative risk of acquiring a complication (p<0.0001). These four key complications in patients over 50 both with and without dementia were associated with an eightfold increase in length of stay (813%, or 3.6 days/0.4 days) and double the increased estimated mean episode cost (199%, or A$16,403/ A$8,240). These four complications were associated with 24.7% of the estimated cost of additional days spent in hospital in 2006–07 in NSW (A$226million/A$914million). Dementia patients accounted for 22.0% of these costs (A$49million/A$226million) even though they were only 10.4% of the population (44,488/426,276 episodes). Hospital-acquired complications, particularly for people with a comorbidity of dementia, cost more than other kinds of inpatient complexity but admission severity was a better predictor of excess cost. Discussion: Four key complications occur more often in older patients with dementia and the high rate of these complications makes them expensive. These complications are potentially preventable. However, the care that can prevent them (such as mobility, hydration, nutrition and communication) is known to be rationed or left unfinished by nurses. Older hospitalised people who have complex needs, such as those with dementia, are more likely to experience care rationing as their care tends to take longer, be less predictable and less curative in nature. This thesis offers the theoretical proposition that evidence-based nursing practices are rationed for complex older patients and that this rationed care contributes to functional and cognitive decline during hospitalisation. This, in turn, contributes to the high rates of complications observed. Thus four key complications can be seen as a ‘Failure to Maintain’ complex older people in hospital. ‘Failure to Maintain’ is the inadequate delivery of essential functional and cognitive care for a complex older person in hospital resulting in a complication, and is recommended as a useful indicator for hospital quality. Conclusions: When examining extra length of stay in hospital, complications and comorbid dementia are costly. Complications are potentially preventable, and dementia care in hospitals can be improved. Hospitals and governments looking to decrease costs can engage in risk-reduction strategies for common nurse sensitive complications such as healthy nursing work environments that minimise nurses’ rationing of functional and cognitive care. The conceptualisation of complex older patients as ‘business as usual’ rather than a ‘burden’ is likely necessary for sustainable health care services of the future. The use of the ‘Failure to Maintain’ indicators at institution and state levels may aid in embedding this approach for complex older patients into health organisations. Ongoing investigation is warranted into the relationships between the largest health services expense (hospitals), the largest hospital population (complex older patients), and the largest hospital expense (nurses). The ‘Failure to Maintain’ quality indicator makes a useful and substantive contribution to further clinical, administrative and research developments.

Does therapeutic writing help people with long-term conditions? Systematic review, realist synthesis and economic considerations

Background Writing therapy to improve physical or mental health can take many forms. The most researched model of therapeutic writing (TW) is unfacilitated, individual expressive writing (written emotional disclosure). Facilitated writing activities are less widely researched. Data sources Databases including: MEDLINE, EMBASE, PsychINFO, Linguistics and Language Behavior Abstracts, AMED, and CINHAL were searched from inception to March 2013. Review methods Four TW practitioners provided expert advice. Study procedures were conducted by one reviewer and checked by a second. Randomised controlled trials (RCTs) and non-randomised comparative studies were included. Quality was appraised using the Cochrane risk of bias tool. Unfacilitated and facilitated TW studies were analysed separately under ICD-10 chapter headings. Meta-analyses were performed where possible using Revman 5.2. Costs were estimated from an NHS perspective and three cost-consequence case studies were prepared. Realist synthesis followed RAMESES guidelines. Objectives To review the clinical and cost-effectiveness of TW for people with long-term health conditions (LTCs) compared to no writing, or other controls, reporting any relevant clinical outcomes. To conduct a realist synthesis to understand how TW might work, and for whom. Results From 14,658 unique citations, 284 full text papers were reviewed and 64 studies (58 RCTs) were included in the final effectiveness reviews. Five studies examined facilitated TW, these were extremely heterogeneous with unclear or high risk of bias, but suggested that facilitated TW interventions may be beneficial in individual LTCs. Unfacilitated expressive writing was examined in 59 studies of variable, or unreported, quality. Overall there was very little or no evidence of any benefit reported in the following conditions (number of studies): HIV (six); breast cancer (eight); gynaecological and genitourinary cancers (five); mental health (five); asthma (four); psoriasis (three); chronic pain (four). In inflammatory arthropathies (six) there was a reduction in disease severity (n= 191, standardised mean difference (SMD) - 0.61 [95% confidence intervals (95% CI) -0.96, -0.26]) in the short term on meta-analysis of four studies. For all other LTCs there was either no, or sparse, data with no, or inconsistent, evidence of benefit. Meta-analyses conducted across all the LTCs provided no evidence that unfacilitated EW had any effect on depression at short term (n= 1,563, SMD -0.06, 95% CI -0.29 to 0.17, substantial heterogeneity), or long term (n= 778, SMD-0.04 95% CI -0.18 to 0.10, little heterogeneity) follow up, or on anxiety, physiological or biomarker-based outcomes. One study reported costs, none reported cost-effectiveness, twelve reported resource use; meta-analysis suggested reduced medication use but no impact on health centre visits. Estimated costs of intervention were low, but there was insufficient evidence to judge cost-effectiveness. Realist review findings suggested that facilitated TW is a complex intervention and group interaction contributes to the perception of benefit. It was unclear from the available data who might benefit most from facilitated TW. Limitations Difficulties with developing realist review programme theory meant that mechanisms operating during TW remain obscure. Conclusions Overall there is little evidence to support the effectiveness or cost-effectiveness of unfacilitated expressive writing interventions in people with LTCs. Further research focussed on facilitated TW in people with LTCs could be informative.

Clinical Practice Guideline: irritable bowel syndrome with constipation and functional constipation in the adult

In this Clinical Practice Guideline we discuss the diagnostic and therapeutic approach of adult patients with constipation and abdominal complaints at the confluence of the irritable bowel syndrome spectrum and functional constipation. Both conditions are included among the functional bowel disorders, and have a significant personal, healthcare, and social impact, affecting the quality of life of the patients who suffer from them. The first one is the irritable bowel syndrome subtype, where constipation represents the predominant complaint, in association with recurrent abdominal pain, bloating, and abdominal distension. Constipation is characterized by difficulties with or low frequency of bowel movements, often accompanied by straining during defecation or a feeling of incomplete evacuation. Most cases have no underlying medical cause, and are therefore considered as a functional bowel disorder. There are many clinical and pathophysiological similarities between both disorders, and both respond similarly to commonly used drugs, their primary difference being the presence or absence of pain, albeit not in an "all or nothing" manner. Severity depends not only upon bowel symptom intensity but also upon other biopsychosocial factors (association of gastrointestinal and extraintestinal symptoms, grade of involvement, and perception and behavior variants). Functional bowel disorders are diagnosed using the Rome criteria. This Clinical Practice Guideline has been made consistent with the Rome IV criteria, which were published late in May 2016, and discuss alarm criteria, diagnostic tests, and referral criteria between Primary Care and gastroenterology settings. Furthermore, all the available treatment options (exercise, fluid ingestion, diet with soluble fiber-rich foods, fiber supplementation, other dietary components, osmotic or stimulating laxatives, probiotics, antibiotics, spasmolytics, peppermint essence, prucalopride, linaclotide, lubiprostone, biofeedback, antidepressants, psychological therapy, acupuncture, enemas, sacral root neurostimulation, surgery) are discussed, and practical recommendations are made regarding each of them.

Clinical aspects associated with syndromic forms of Orofacial Clefts in a Colombian population

Objectives: To present descriptive epidemiology of Orofacial Clefts and to determine the association of syndromic forms with antenatal high-risk conditions, preterm birth, and comorbidities among nestedseries of cases. Methods: A study of nested-series of cases was conducted. Frequencies of cleft type, associated congenital anomalies, syndromic, non-syndromic and multiple malformation forms, and distribution of Orofacial Clefts according to sex and affected-side were determined. Odds ratios were calculated as measures of association between syndromic forms and antenatal high-risk conditions, preterm birth and comorbidities. A total of three hundred and eleven patients with Orofacial Clefts were assessed in a 12-month period. Results: The most frequent type of Orofacial Clefts was cleft lip and palate, this type of cleft was more frequent in males, whereas cleft palate occurred more often in females. The most common cases occurred as non-syndromic forms. Aarskog-Scott syndrome showed the highest frequency amongst syndromic forms. Hypertensive disorders in pregnancy, developmental dysplasia of the hip, central nervous diseases and respiratory failure showed significant statistical associations (p <0.05) with syndromic forms. Conclusions: These data provide an epidemiological reference of Orofacial Clefts in Colombia. Novel associations between syndromic forms and clinical variables are determined. In order to investigate causality relationships between these variables further studies must be carried out.

Clinical aspects associated with syndromic forms of Orofacial Clefts in a Colombian population

Objectives: To present descriptive epidemiology of Orofacial Clefts and to determine the association of syndromic forms with antenatal high-risk conditions, preterm birth, and comorbidities among nested-series of cases. Methods: A study of nested-series of cases was conducted. Frequencies of cleft type, associated congenital anomalies, syndromic, non-syndromic and multiple malformation forms, and distribution of Orofacial Clefts according to sex and affected-side were determined. Odds ratios were calculated as measures of association between syndromic forms and antenatal high-risk conditions, preterm birth and comorbidities. A total of three hundred and eleven patients with Orofacial Clefts were assessed in a 12-month period. Results: The most frequent type of Orofacial Clefts was cleft lip and palate, this type of cleft was more frequent in males, whereas cleft palate occurred more often in females. The most common cases occurred as non-syndromic forms. Aarskog-Scott syndrome showed the highest frequency amongst syndromic forms. Hypertensive disorders in pregnancy, developmental dysplasia of the hip, central nervous diseases and respiratory failure showed significant statistical associations (p <0.05) with syndromic forms. Conclusions: These data provide an epidemiological reference of Orofacial Clefts in Colombia. Novel associations between syndromic forms and clinical variables are determined. In order to investigate causality relationships between these variables further studies must be carried out.

Percutaneous Cement Discoplasty: Biomechanical and clinical assessment of a minimally invasive treatment of lumbar intervertebral disc disease

With population ageing, spine diseases have an increasing prevalence and induce high economic and social costs. The development of minimally invasive surgeries allows reducing the surgery-associated risks in elderly and polymorbid patients, and save costs by treating more patients in shorter time and reducing the complications. Percutaneous Cement Discoplasty (PCD) is a minimally invasive technique developed to treat highly degenerated intervertebral discs exhibiting a vacuum phenomenon. Filling the disc with bone cement creates a stand-alone spacer which partially restores the disc height and re-opens the foraminal space. PCD has recently been introduced to clinical use. However, the spine biomechanics following this treatment remained unravelled. The aim of this PhD thesis is to bridge the clinical experience with in vitro methodologies, to provide a multilateral evaluation of PCD outcome and a better understanding of its impact on the spine biomechanics, and of its possible contraindications. Firstly, a suitable in vitro porcine model to test the biomechanics of discoplasty by comparing specimens in the preoperative and postoperative conditions was developed. The methodology was then applied to investigate the biomechanics of discoplasty in cadaveric human segments. The in vitro specimens were mechanically investigated in flexion and extension, while a DIC system quantified the range of motion, disc height, and strains on the disc surface. Then, a versatile tool to measure the impact of discoplasty on the foramen space was developed and applied both to clinical and experimental work. The vertebrae reconstructed from CT scans were registered to match the loading configuration, using ex vivo DIC measurements under loading. The foramen volumetric changes caused by PCD was measured using a 3D geometrical method clinically developed by the research group. In conclusion, this project significantly extended the understanding of PCD biomechanics, highlighting its benefits in the treatment of advanced cases of intervertebral disc degeneration.

The Clinical Impact Of Cerebellar Grey Matter Pathology In Multiple Sclerosis.

The cerebellum is an important site for cortical demyelination in multiple sclerosis, but the functional significance of this finding is not fully understood. To evaluate the clinical and cognitive impact of cerebellar grey-matter pathology in multiple sclerosis patients. Forty-two relapsing-remitting multiple sclerosis patients and 30 controls underwent clinical assessment including the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale (EDSS) and cerebellar functional system (FS) score, and cognitive evaluation, including the Paced Auditory Serial Addition Test (PASAT) and the Symbol-Digit Modalities Test (SDMT). Magnetic resonance imaging was performed with a 3T scanner and variables of interest were: brain white-matter and cortical lesion load, cerebellar intracortical and leukocortical lesion volumes, and brain cortical and cerebellar white-matter and grey-matter volumes. After multivariate analysis high burden of cerebellar intracortical lesions was the only predictor for the EDSS (p<0.001), cerebellar FS (p = 0.002), arm function (p = 0.049), and for leg function (p<0.001). Patients with high burden of cerebellar leukocortical lesions had lower PASAT scores (p = 0.013), while patients with greater volumes of cerebellar intracortical lesions had worse SDMT scores (p = 0.015). Cerebellar grey-matter pathology is widely present and contributes to clinical dysfunction in relapsing-remitting multiple sclerosis patients, independently of brain grey-matter damage.

Epilepsies Associated With Hippocampal Sclerosis.

Hippocampal sclerosis (HS) is considered the most frequent neuropathological finding in patients with mesial temporal lobe epilepsy (MTLE). Hippocampal specimens of pharmacoresistant MTLE patients that underwent epilepsy surgery for seizure control reveal the characteristic pattern of segmental neuronal cell loss and concomitant astrogliosis. However, classification issues of hippocampal lesion patterns have been a matter of intense debate. International consensus classification has only recently provided significant progress for comparisons of neurosurgical and clinic-pathological series between different centers. The respective four-tiered classification system of the International League Against Epilepsy subdivides HS into three types and includes a term of gliosis only, no-HS. Future studies will be necessary to investigate whether each of these subtypes of HS may be related to different etiological factors or with postoperative memory and seizure outcome. Molecular studies have provided potential deeper insights into the pathogenesis of HS and MTLE on the basis of epilepsy-surgical hippocampal specimens and corresponding animal models. These include channelopathies, activation of NMDA receptors, and other conditions related to Ca(2+) influx into neurons, the imbalance of Ca(2+)-binding proteins, acquired channelopathies that increase neuronal excitability, paraneoplastic and non-paraneoplastic inflammatory events, and epigenetic regulation promoting or facilitating hippocampal epileptogenesis. Genetic predisposition for HS is clearly suggested by the high incidence of family history in patients with HS, and by familial MTLE with HS. So far, it is clear that HS is multifactorial and there is no individual pathogenic factor either necessary or sufficient to generate this intriguing histopathological condition. The obvious variety of pathogenetic combinations underlying HS may explain the multitude of clinical presentations, different responses to clinical and surgical treatment. We believe that the stratification of neuropathological patterns can help to characterize specific clinic-pathological entities and predict the postsurgical seizure control in an improved fashion.