Factors predicting protracted improvement after pallidal DBS for primary dystonia: the role of age and disease duration

In many patients, optimal results after pallidal deep brain stimulation (DBS) for primary dystonia may appear over several months, possibly beyond 1 year after implant. In order to elucidate the factors predicting such protracted clinical effect, we retrospectively reviewed the clinical records of 44 patients with primary dystonia and bilateral pallidal DBS implants. Patients with fixed skeletal deformities, as well as those with a history of prior ablative procedures, were excluded. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores at baseline, 1 and 3 years after DBS were used to evaluate clinical outcome. All subjects showed a significant improvement after DBS implants (mean BFMDRS improvement of 74.9% at 1 year and 82.6% at 3 years). Disease duration (DD, median 15 years, range 2-42) and age at surgery (AS, median 31 years, range 10-59) showed a significant negative correlation with DBS outcome at 1 and 3 years. A partition analysis, using DD and AS, clustered subjects into three groups: (1) younger subjects with shorter DD (n = 19, AS < 27, DD ? 17); (2) older subjects with shorter DD (n = 8, DD ? 17, AS ? 27); (3) older subjects with longer DD (n = 17, DD > 17, AS ? 27). Younger patients with short DD benefitted more and faster than older patients, who however continued to improve 10% on average 1 year after DBS implants. Our data suggest that subjects with short DD may expect to achieve a better general outcome than those with longer DD and that AS may influence the time necessary to achieve maximal clinical response.

Reduced muscle mass and bone size in pediatric patients with inflammatory bowel disease

BACKGROUND: Decreased bone mineral density has been reported in children with inflammatory bowel disease (IBD). We used peripheral quantitative computed tomography (pQCT) to assess bone mineralization, geometry, and muscle cross-sectional area (CSA) in pediatric IBD. METHODS: In a cross-sectional study, pQCT of the forearm was applied in 143 IBD patients (mean age 13.9 +/- 3.5 years); 29% were newly diagnosed, 98 had Crohn's disease, and 45 had ulcerative colitis. Auxological data, cumulative glucocorticoid dose, disease activity indices, laboratory markers for inflammation, and bone metabolism were related to the results of pQCT. RESULTS: Patients were compromised in height (-0.82 +/- 1.1 SD), weight (-0.77 +/- 1.0 SD), muscle mass (-1.12 +/- 1.0 SD), and total bone cross-sectional area (-0.79 +/- 1.0 SD) compared to age- and sex-matched healthy controls (z-scores). In newly diagnosed patients, the ratio of bone mineral mass per muscle CSA was higher than in those with longer disease duration (1.00 versus 0.30, P = 0.007). Serum albumin level and disease activity correlated with muscle mass, accounting for 41.0% of variability in muscle mass (P < 0.01). The trabecular bone mineral density z-score was on average at the lower normal level (-0.40 +/- 1.3 SD, P < 0.05). CONCLUSIONS: Reduced bone geometry was explained only in part by reduced height. Bone disease in children with IBD seems to be secondary to muscle wasting, which is already present at diagnosis. With longer disease duration, bone adapts to the lower muscle CSA. Serum albumin concentration is a good marker for muscle wasting and abnormal bone development.

Dorsal rather than ventral visual pathways discriminate freezing status in Parkinson's disease

BACKGROUND: Although visuospatial deficits have been linked with freezing of gait (FOG) in Parkinson's disease (PD), the specific effects of dorsal and ventral visual pathway dysfunction on FOG is not well understood. METHOD: We assessed visuospatial function in FOG using an angle discrimination test (dorsal visual pathway bias) and overlapping figure test (ventral visual pathway bias), and recorded overall response time, mean fixation duration and dwell time. Covariate analysis was conducted controlling for disease duration, motor severity, contrast sensitivity and attention with Bonferroni adjustments for multiple comparisons. RESULTS: Twenty seven people with FOG, 27 people without FOG and 24 controls were assessed. Average fixation duration during angle discrimination distinguished freezing status: [F (1, 43) = 4.77 p < 0.05] (1-way ANCOVA). CONCLUSION: Results indicate a preferential dysfunction of dorsal occipito-parietal pathways in FOG, independent of disease severity, attentional deficit, and contrast sensitivity.

Sleepwalking in Parkinson's disease: a questionnaire-based survey

Sleepwalking (SW) corresponds to a complex sleep-associated behavior that includes locomotion, mental confusion, and amnesia. SW is present in about 10% of children and 2-3% of adults. In a retrospective series of 165 patients with Parkinson's disease (PD), we found adult-onset ("de novo") SW "de novo" in six (4%) of them. The aim of this study was to assess prospectively and systematically the frequency and characteristics of SW in PD patients. A questionnaire including items on sleep quality, sleep disorders, and specifically also SW and REM sleep behavior disorder (RBD), PD characteristics and severity, was sent to the members of the national PD patients organization in Switzerland. In the study, 36/417 patients (9%) reported SW, of which 22 (5%) had adult-onset SW. Patients with SW had significantly longer disease duration (p = 0.035), they reported more often hallucinations (p = 0.004) and nightmares (p = 0.003), and they had higher scores, suggestive for RBD in a validated questionnaire (p = 0.001). Patients with SW were also sleepier (trend to a higher Epworth Sleepiness Scale score, p = 0.055). Our data suggest that SW in PD patients is (1) more common than in the general population, and (2) is associated with RBD, nightmares, and hallucinations. Further studies including polysomnographic recordings are needed to confirm the results of this questionnaire-based analysis, to understand the relationship between SW and other nighttime wandering behaviors in PD, and to clarify the underlying mechanisms.

Low Mannan-binding lectin serum levels are associated with complicated Crohn's disease and reactivity to oligomannan (ASCA)

OBJECTIVES: Mannan-binding lectin (MBL) acts as a pattern-recognition molecule directed against oligomannan, which is part of the cell wall of yeasts and various bacteria. We have previously shown an association between MBL deficiency and anti-Saccharomyces cerevisiae mannan antibody (ASCA) positivity. This study aims at evaluating whether MBL deficiency is associated with distinct Crohn's disease (CD) phenotypes. METHODS: Serum concentrations of MBL and ASCA were measured using ELISA (enzyme-linked immunosorbent assay) in 427 patients with CD, 70 with ulcerative colitis, and 76 healthy controls. CD phenotypes were grouped according to the Montreal Classification as follows: non-stricturing, non-penetrating (B1, n=182), stricturing (B2, n=113), penetrating (B3, n=67), and perianal disease (p, n=65). MBL was classified as deficient (<100 ng/ml), low (100-500 ng/ml), and normal (500 ng/ml). RESULTS: Mean MBL was lower in B2 and B3 CD patients (1,503+/-1,358 ng/ml) compared with that in B1 phenotypes (1,909+/-1,392 ng/ml, P=0.013). B2 and B3 patients more frequently had low or deficient MBL and ASCA positivity compared with B1 patients (P=0.004 and P<0.001). Mean MBL was lower in ASCA-positive CD patients (1,562+/-1,319 ng/ml) compared with that in ASCA-negative CD patients (1,871+/-1,320 ng/ml, P=0.038). In multivariate logistic regression modeling, low or deficient MBL was associated significantly with B1 (negative association), complicated disease (B2+B3), and ASCA. MBL levels did not correlate with disease duration. CONCLUSIONS: Low or deficient MBL serum levels are significantly associated with complicated (stricturing and penetrating) CD phenotypes but are negatively associated with the non-stricturing, non-penetrating group. Furthermore, CD patients with low or deficient MBL are significantly more often ASCA positive, possibly reflecting delayed clearance of oligomannan-containing microorganisms by the innate immune system in the absence of MBL.

Diagnostic delay in Crohn's disease is associated with a complicated disease course and increased operation rate

OBJECTIVES The impact of diagnostic delay (a period from appearance of first symptoms to diagnosis) on the clinical course of Crohn's disease (CD) is unknown. We examined whether length of diagnostic delay affects disease outcomes. METHODS Data from the Swiss IBD cohort study were analyzed. Patients were recruited from university centers (68%), regional hospitals (14%), and private practices (18%). The frequencies of occurrence of bowel stenoses, internal fistulas, perianal fistulas, and CD-related surgery (intestinal and perianal) were analyzed. RESULTS A total of 905 CD patients (53.4% female, median age at diagnosis 26 (20-36) years) were stratified into four groups according to the quartiles of diagnostic delay (0-3, 4-9, 10-24, and ≥25 months, respectively). Median diagnostic delay was 9 (3-24) months. The frequency of immunomodulator and/or antitumor necrosis factor drug use did not differ among the four groups. The length of diagnostic delay was positively correlated with the occurrence of bowel stenosis (odds ratio (OR) 1.76, P=0.011 for delay of ≥25 months) and intestinal surgery (OR 1.76, P=0.014 for delay of 10-24 months and OR 2.03, P=0.003 for delay of ≥25 months). Disease duration was positively associated and non-ileal disease location was negatively associated with bowel stenosis (OR 1.07, P<0.001, and OR 0.41, P=0.005, respectively) and intestinal surgery (OR 1.14, P<0.001, and OR 0.23, P<0.001, respectively). CONCLUSIONS The length of diagnostic delay is correlated with an increased risk of bowel stenosis and CD-related intestinal surgery. Efforts should be undertaken to shorten the diagnostic delay.

Predictors of temporary and permanent work disability in patients with inflammatory bowel disease: results of the swiss inflammatory bowel disease cohort study

BACKGROUND Inflammatory bowel disease can decrease the quality of life and induce work disability. We sought to (1) identify and quantify the predictors of disease-specific work disability in patients with inflammatory bowel disease and (2) assess the suitability of using cross-sectional data to predict future outcomes, using the Swiss Inflammatory Bowel Disease Cohort Study data. METHODS A total of 1187 patients were enrolled and followed up for an average of 13 months. Predictors included patient and disease characteristics and drug utilization. Potential predictors were identified through an expert panel and published literature. We estimated adjusted effect estimates with 95% confidence intervals using logistic and zero-inflated Poisson regression. RESULTS Overall, 699 (58.9%) experienced Crohn's disease and 488 (41.1%) had ulcerative colitis. Most important predictors for temporary work disability in patients with Crohn's disease included gender, disease duration, disease activity, C-reactive protein level, smoking, depressive symptoms, fistulas, extraintestinal manifestations, and the use of immunosuppressants/steroids. Temporary work disability in patients with ulcerative colitis was associated with age, disease duration, disease activity, and the use of steroids/antibiotics. In all patients, disease activity emerged as the only predictor of permanent work disability. Comparing data at enrollment versus follow-up yielded substantial differences regarding disability and predictors, with follow-up data showing greater predictor effects. CONCLUSIONS We identified predictors of work disability in patients with Crohn's disease and ulcerative colitis. Our findings can help in forecasting these disease courses and guide the choice of appropriate measures to prevent adverse outcomes. Comparing cross-sectional and longitudinal data showed that the conduction of cohort studies is inevitable for the examination of disability.

Seizures in patients with Alzheimer's disease or vascular dementia: a population-based nested case-control analysis

PURPOSE Patients with Alzheimer's disease (AD) have an increased risk of developing seizures or epilepsy. Little is known about the role of risk factors and about the risk of developing seizures/epilepsy in patients with vascular dementia (VD). The aim of this study was to assess incidence rates (IRs) of seizures/epilepsy in patients with AD, VD, or without dementia, and to identify potential risk factors of seizures or epilepsy. METHODS We conducted a follow-up study with a nested case-control analysis using the United Kingdom-based General Practice Research Database (GPRD). We identified patients aged ≥65 years with an incident diagnosis of AD or VD between 1998 and 2008 and a matched comparison group of dementia-free patients. Conditional logistic regression was used to estimate the odds ratio (OR) with a 95% confidence interval (CI) of developing seizures/epilepsy in patients with AD or VD, stratified by age at onset and duration of dementia as well as by use of antidementia drugs. KEY FINDINGS Among 7,086 cases with AD, 4,438 with VD, and 11,524 matched dementia-free patients, we identified 180 cases with an incident diagnosis of seizures/epilepsy. The IRs of epilepsy/seizures for patients with AD or VD were 5.6/1,000 person-years (py) (95% CI 4.6-6.9) and 7.5/1,000 py (95% CI 5.7-9.7), respectively, and 0.8/1,000 py (95% CI 0.6-1.1) in the dementia-free group. In the nested case-control analysis, patients with longer standing (≥3 years) AD had a slightly higher risk of developing seizures or epilepsy than those with a shorter disease duration, whereas in patients with VD the contrary was observed. SIGNIFICANCE Seizures or epilepsy were substantially more common in patients with AD and VD than in dementia-free patients. The role of disease duration as a risk factor for seizures/epilepsy seems to differ between AD and VD.

Efficacy and Safety of Natalizumab in Crohn’s Disease Patients Treated at 6 Boston Academic Hospitals

BACKGROUND: Despite trials demonstrating its efficacy, many physicians harbor concerns regarding the use of natalizumab in the treatment of patients with refractory Crohn's disease (CD). The purpose of this study was to perform a descriptive analysis of a series of CD patients not currently enrolled in a clinical trial. METHODS: A retrospective case review of patients treated with natalizumab at 6 sites in Massachusetts: Boston Medical Center, Beth Israel Deaconess Medical Center, Brigham & Women's Hospital, Lahey Clinic, Massachusetts General Hospital, and UMass Medical Center. RESULTS: Data on 69 CD patients on natalizumab were collected. At the start of treatment, patients' disease duration was 12 years. A high proportion of patients were women (68%), presented with perianal disease (65%) and upper gastrointestinal tract involvement (14%). Prior nonbiologic therapies were steroids (96%), thiopurines (94%), antibiotics (74%), methotrexate (58%), and at least two anti-tumor necrosis factor agent failures (81%). Sixty-nine percent (44 of 64 patients) with available medical evaluation had a partial or complete clinical response. Loss of response was 13% after an average of 1 year of treatment. Adverse events were infusion reactions, headaches, fever, and infections. No case of progressive multifocal leukoencephalopathy was observed. CONCLUSIONS: In our clinical experience outside the context of a clinical trial, natalizumab is largely reserved for CD patients with extensive ileocolonic disease who have failed conventional immunosuppressants and of at least 2 anti-tumor necrosis factor agents. This drug is, however, well tolerated and offers significant clinical improvement for more than a year in one-third of these difficult-to-treat CD patients.

Optimal target localization for subthalamic stimulation in patients with Parkinson disease

OBJECTIVE To further determine the causes of variable outcome from deep brain stimulation of the subthalamic nucleus (DBS-STN) in patients with Parkinson disease (PD). METHODS Data were obtained from our cohort of 309 patients with PD who underwent DBS-STN between 1996 and 2009. We examined the relationship between the 1-year motor, cognitive, and psychiatric outcomes and (1) preoperative PD clinical features, (2) MRI measures, (3) surgical procedure, and (4) locations of therapeutic contacts. RESULTS Pre- and postoperative results were obtained in 262 patients with PD. The best motor outcome was obtained when stimulating contacts were located within the STN as compared with the zona incerta (64% vs 49% improvement). Eighteen percent of the patients presented a postoperative cognitive decline, which was found to be principally related to the surgical procedure. Other factors predictive of poor cognitive outcome were perioperative confusion and psychosis. Nineteen patients showed a stimulation-induced hypomania, which was related to both the form of the disease (younger age, shorter disease duration, higher levodopa responsiveness) and the ventral contact location. Postoperative depression was more frequent in patients already showing preoperative depressive and/or residual axial motor symptoms. CONCLUSION In this homogeneous cohort of patients with PD, we showed that (1) the STN is the best target to improve motor symptoms, (2) postoperative cognitive deficit is mainly related to the surgery itself, and (3) stimulation-induced hypomania is related to a combination of both the disease characteristics and a more ventral STN location.

Suicidal ideation in a European Huntington's disease population.

BACKGROUND Previous studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntington's disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD. METHODS The study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntington's Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntington's Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis. RESULTS At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9-1.0), anxiety (OR=2.14; 95%CI: 1.4-3.3), aggression (OR=2.41; 95%CI: 1.5-3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4-6.6), and a depressed mood (OR=13.71; 95%CI: 6.7-28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1-4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2-5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive. LIMITATIONS As suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated. CONCLUSIONS Suicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines.

Analysis of TNF-antagonist switch over time and associated risk factors in the Swiss Inflammatory Bowel Disease Cohort

BACKGROUND AND AIMS Limited data from large cohorts are available on tumor necrosis factor (TNF) antagonists (infliximab, adalimumab, certolizumab pegol) switch over time. We aimed to evaluate the prevalence of switching from one TNF antagonist to another and to identify associated risk factors. METHODS Data from the Swiss Inflammatory Bowel Diseases Cohort Study (SIBDCS) were analyzed. RESULTS Of 1731 patients included into the SIBDCS (956 with Crohn's disease [CD] and 775 with ulcerative colitis [UC]), 347 CD patients (36.3%) and 129 UC patients (16.6%) were treated with at least one TNF antagonist. A total of 53/347 (15.3%) CD patients (median disease duration 9 years) and 20/129 (15.5%) of UC patients (median disease duration 7 years) needed to switch to a second and/or a third TNF antagonist, respectively. Median treatment duration was longest for the first TNF antagonist used (CD 25 months; UC 14 months), followed by the second (CD 13 months; UC 4 months) and third TNF antagonist (CD 11 months; UC 15 months). Primary nonresponse, loss of response and side effects were the major reasons to stop and/or switch TNF antagonist therapy. A low body mass index, a short diagnostic delay and extraintestinal manifestations at inclusion were identified as risk factors for a switch of the first used TNF antagonist within 24 months of its use in CD patients. CONCLUSION Switching of the TNF antagonist over time is a common issue. The median treatment duration with a specific TNF antagonist is diminishing with an increasing number of TNF antagonists being used.

Factors Associated with Durable Response to Infliximab in Crohnʼs Disease 5 Years and Beyond: A Multicenter International Cohort

BACKGROUND: Infliximab (IFX) has been used for over a decade worldwide. Less is known about the natural history of IFX use beyond a few years and which patients are more likely to sustain benefits. METHODS: Patients with Crohn's disease (CD) exposed to IFX from Massachusetts General Hospital, Boston, Saint-Antoine Hospital, Paris, and the Swiss IBD Cohort Study were identified through retrospective and prospective data collection, complemented by chart abstraction of electronic medical records. We compared long-term users of IFX (>5 yr of treatment, long-term users of infliximab [LTUI]), with non-LTUI patients to identify prognostic factors. RESULTS: We pooled data on 1014 patients with CD from 3 different databases, of whom 250 were defined as LTUI. The comparison group comprised 290 patients with CD who discontinued IFX: 48 primary nonresponses, 95 loss of responses, and 147 adverse events. Factors associated with LTUI were colonic involvements and an earlier age at the start of IFX. The prevalence of active smokers and obese patients differed markedly, but inversely, between American and European centers but did not impact outcome. The discontinuation rate was stable around 3% to 6%, each year from years 3 to 10. CONCLUSIONS: Young age at start of IFX and colonic CD are factors associated with a beneficial long-term use of IFX. After 5 years of IFX, there is still a 3% to 5% discontinuation rate annually. Several factors associated with a good initial response such as nonsmoker and shorter disease duration at IFX initiation do not seem associated with a longer term response.

Prevalence of vascular disease in systemic lupus erythematosus compared with type-1 diabetes mellitus: a cross-sectional study of two cohorts.

OBJECTIVES Systemic lupus erythematosus (SLE) is associated with considerable cardiovascular morbidity that has not yet been directly compared with other diseases with known cardiovascular risk. METHODS Two hundred and forty-one patients of the multicentre Swiss SLE cohort study (SSCS) were cross-sectionally assessed for coronary heart disease (CHD), cerebrovascular disease (CVD) and peripheral artery disease (PAD). SLE patients were compared with a cohort of 193 patients with type-1 diabetes mellitus being followed at the University Hospital Basel. A subgroup analysis of 50 age- and sex-matched patients from the University Hospital Basel was performed. RESULTS Of patients within the SSCS 13.3% had one or more vascular events: 8.3% CHD, 5% CVD and 1.2% PAD. In type-1 diabetes mellitus patients, 15% had vascular events: 9.3% CHD, 3.1% CVD and 5.6% PAD. In the matched subgroup, 26% of SLE patients had vascular events (14% CHD) compared with 12% in type-1 DM patients (2% CHD). Cardiovascular risk factors were similar in both groups. Vascular events in SLE patients were associated with age, longer disease duration, dyslipidaemia, and hypertension. CONCLUSION Cardiovascular morbidity in SLE is at least as frequent as in age- and sex-matched type-1 diabetes mellitus patients. Therefore, aggressive screening and management of cardiovascular risk factors should be performed.

Is Parkinson's disease of early onset a separate disease entity?

Two groups of patients suffering from Parkinson's disease were studied. The first group consisted of 23 patients with an onset age before 40 years; in the second group of 21 patients the onset was after age 50. The clinical findings and the course of the disease were very similar in each group. In spite of a longer disease duration in the patients with early onset of the disease there was no difference in motor impairment; the younger patients did better in mental testing and they were taking less dopaminergic medication. These differences are thought to be due to the age difference rather than to the existence of different disease entities. In the early onset group more familial cases (mostly affecting siblings) were found than in the older ones. The points in favour of there being a hereditary subgroup of early onset Parkinson's disease or of environmental factors causing the disease are reviewed.