Non-motor symptoms in Parkinson's disease

The thesis “Non-motor symptoms in Parkinson’s disease” is part of the PROPARK study, a longitudinal cohort study of approximately 400 patients with Parkinson’s disease (PD), who are profiled on genotype, phenotype, disability, and global outcomes of health, using valid and reliable assessment instruments for PD. The aims of this thesis were to characterize the non-motor domains important in PD such as olfactory, autonomic, sleep, cognitive, and psychiatric problems. Additionally, their relations with other domains of the disease were evaluated on a cross-sectional level, as well as their impact on disability and health-related quality of life. Furthermore, the phenotypic characteristics of mutation carriers in the cohort were evaluated. The most important conclusions from this thesis are: 1. Non-motor symptoms are frequently present in patients with PD 2. Non-motor symptoms are related to each other 3. Non-motor symptoms greatly influence quality of life in patients with PD The results as described in this thesis will serve as guideline for future research which will be aimed at underlying disease mechanisms.Van Alkemade-Keuls Fonds, Parkinson Patiënten Vereniging, Stichting het Remmert Adriaan Laan FondsLUMC / Geneeskund

The effect of dopamine agonists on adaptive and aberrant salience in Parkinson's disease

Clinical evidence suggests that after initiation of dopaminergic medications some patients with Parkinson's disease (PD) develop psychotic symptoms, such as hallucinations and delusions. Here, we tested the hypothesis that the neurocognitive basis of this phenomenon can be defined as the formation of arbitrary and illusory associations between conditioned stimuli and reward signals, called aberrant salience. Young, never-medicated PD patients and matched controls were assessed on a speeded reaction time task in which the probe stimulus was preceded by conditioned stimuli that could signal monetary reward by color or shape. The patients and controls were re-evaluated after 12 weeks during which the patients received a dopamine agonist (pramipexole or ropinirole). Results indicated that dopamine agonists increased both adaptive and aberrant salience in PD patients, that is, formation of real and illusory associations between conditioned stimuli and reward, respectively. This effect was present when associations were assessed by means of faster responding after conditioned stimuli signaling reward (implicit salience) and overt rating of stimulus-reward links (explicit salience). However, unusual feelings and experiences, which are subclinical manifestations of psychotic-like symptoms, were specifically related to irrelevant and illusory stimulus-reward associations (aberrant salience) in PD patients receiving dopamine agonists. The learning of relevant and real stimulus-reward associations (adaptive salience) was not related to unusual experiences. These results suggest that dopamine agonists may increase psychotic-like experiences in young patients with PD, possibly by facilitating dopaminergic transmission in the ventral striatum, which results in aberrant associations between conditioned stimuli and reward

Success of conservative therapy for chronic subdural hematoma patients: a systematic review

BackgroundConservative therapy for chronic subdural hematoma (cSDH) is an option for patients who express no, or only mild symptoms, thereby preventing surgery in some. Because it is not clear for whom conservative therapy is successful, we aimed to estimate the success rate of conservative therapy and to identify which factors might influence success.MethodsWe systematically searched MEDLINE and EMBASE databases to identify all available publications reporting outcome of conservative therapy for cSDH patients. Studies containing >10 patients were included. The primary outcome was the success rate of conservative therapy, defined as “no crossover to surgery” during follow-up. In addition, factors possibly associated with success of conservative therapy were explored. Bias assessment was performed with the Newcastle Ottowa Scale and the Cochrane risk-of-bias tool. We calculated pooled incidence and mean estimates, along with their 95% confidence intervals (CIs), using OpenMeta[Analyst] software.ResultsThe search yielded 1,570 articles, of which 11 were included in this study, describing 1,019 conservatively treated patients. The pooled success rate of conservative therapy was 66% (95% CI: 50–82%). One study (n = 98) reported smaller hematoma volume to be associated with success, whilst another study (n = 53) reported low hematoma density and absence of paresis at diagnosis to be associated with success.ConclusionConservative therapy is reported to be successful in the majority of cSDH patients who have either no, or only mild symptoms. Hematoma volume, low hematoma density and absence of paresis could be factors associated with success. However, further research is warranted in order to establish factors consistently associated with a successful conservative therapy.OtherNo funding was acquired for this study. The study was not registered nor was a study protocol prepared

Long-term outcomes of untreated cerebral cavernous malformations: a prospective, population-based cohort study

\ua9 2025 The Authors. Background: Treatment decisions for cerebral cavernous malformations (CCM) currently rely on risk extrapolation from short-term studies, despite potential variations over time. This study aims to quantify the risks and functional outcomes of untreated CCMs during long-term follow-up. Methods: This population-based study included people aged ≥16 years in Scotland who were newly diagnosed with CCM between 1 January 1999 and 31 December 2003 or 1 January 2006 and 31 December 2010, using brain MRI or pathology. We analysed clinical events and functional outcomes using the Oxford Handicap Scale (OHS) during prospective follow-up without CCM intervention until 31 December 2023. The primary outcome was a composite of symptomatic intracranial haemorrhage (ICH) or new, non-haemorrhagic, persistent/progressive focal neurological deficit (FND) definitely or possibly related to CCM (ICH/FND). Findings: Among 300 patients (median age 44 years [IQR 32–57], 159 [53%] female, 48 [16%] brainstem CCM) included during 1999–2003 or 2006–2010, 81 (27%) presented with ICH/FND, 88 (29%) with epileptic seizure(s), and 131 (44%) incidentally. Over 4779 person-years of follow-up (completeness 95%), 44 patients were censored after microsurgical resection (n = 41) and stereotactic radiosurgery (n = 3). During a median untreated follow-up of 15 years (IQR 8–20), 40 (13%) patients experienced ICH/FND, 72 (24%) experienced dependence (OHS score 3–5), and 53 (18%) died (n = 7 [2%] related to CCM). The hazard of recurrent ICH/FND was higher than the first-event hazard (hazard ratio 8.66 [95% CI 4.44–16.90], p < 0.0001). The hazard rate of recurrent ICH/FND declined approximately 50-fold from 0.109 (95% CI 0.074–0.160) over the first five years to 0.002 (0.000–0.015) in the subsequent 20 years (p < 0.0001). Interpretation: The risk of a first ICH/FND from CCM is low, while the risk of recurrence is significantly higher, although the recurrence risk declines dramatically five years after a first ICH/FND. These long-term findings can guide clinical decision-making, and suggest focussing on a 5-year risk horizon rather than extrapolating annual risks to patients\u27 lifetimes. Funding: Medical Research Council, Chief Scientist Office of the Scottish Government, and Stroke Association

Inter-method reliability of the modified Rankin Scale in patients with subarachnoid hemorrhage

BACKGROUND AND OBJECTIVES: The modified Rankin Scale (mRS) is one of the most frequently used outcome measures in trials in patients with an aneurysmal subarachnoid hemorrhage (aSAH). The assessment method of the mRS is often not clearly described in trials, while the method used might influence the mRS score. The aim of this study is to evaluate the inter-method reliability of different assessment methods of the mRS. METHODS: This is a prospective, randomized, multicenter study with follow-up at 6 weeks and 6 months. Patients aged ≥ 18 years with aSAH were randomized to either a structured interview or a self-assessment of the mRS. Patients were seen by a physician who assigned an mRS score, followed by either the structured interview or the self-assessment. Inter-method reliability was assessed with the quadratic weighted kappa score and percentage of agreement. Assessment of feasibility of the self-assessment was done by a feasibility questionnaire. RESULTS: The quadratic weighted kappa was 0.60 between the assessment of the physician and structured interview and 0.56 between assessment of the physician and self-assessment. Percentage agreement was, respectively, 50.8 and 19.6%. The assessment of the mRS through a structured interview and by self-assessment resulted in systematically higher mRS scores than the mRS scored by the physician. Self-assessment of the mRS was proven feasible. DISCUSSION: The mRS scores obtained with different assessment methods differ significantly. The agreement between the scores is low, although the reliability between the assessment methods is good. This should be considered when using the mRS in clinical trials. TRIAL REGISTRATION: www.trialregister.nl; Unique identifier: NL7859. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00415-021-10880-4

Timing of surgery in traumatic spinal cord injury: a national, multidisciplinary survey

Purpose: The optimal surgical timeframe for neurological recovery in traumatic spinal cord injury (tSCI) still remains unknown. Recent guidelines have recommended performing surgery within 24 h for all patients with tSCI regardless of initial neurological deficit. It remains unclear whether patients with complete, incomplete tSCI, or traumatic central cord injury (TCCI) will experience the same degree of improvement after urgent surgical intervention. We investigated if the severity of initial neurological injury influenced surgeons on their decision-making of surgical timing in tSCI. Methods: With a web-based survey, we investigated the current opinion in The Netherlands on timing of surgical decompression and stabilization, depending on the initial degree of neurological injury. Results: Surgeons prefer to perform more urgent surgery for incomplete tSCI compared to complete tSCI. In addition, 43% of patients with complete tSCI are not preferably operated within the recommended 24 h. Even though TCCI is the most common form of incomplete tSCI, these patients are preferably managed less urgently than patients with other types of incomplete tSCI. Conclusion: The severity of initial neurological injury seems to play an important role in the urgency of surgical timing for tSCI. A substantial number of patients with complete tSCI are not preferably treated within the recommended surgical timeframe, while patients with incomplete tSCI are preferably operated far more urgent than recommended in the current guidelines. Graphical abstract: These slides can be retrieved under Electronic Supplementary Material.[Figure not available: see fulltext.]

Prevalence and definition of drooling in Parkinson’s disease: a systematic review

Drooling (saliva loss) is a frequently reported symptom in patients with Parkinson’s disease (PD), but an accurate estimate of the prevalence of drooling is lacking. The aim of this study was to systematically review the prevalence of drooling in published research papers. A systematic PubMed and CINAHL search was done, including studies published until January 2009. Eight studies were found, presenting prevalence rates of drooling based on responses of PD patients to questionnaires. The statistical heterogeneity was highly significant (P < 0.0001), with prevalence rates ranging from 32 to 74%. The pooled prevalence estimate with random effect analysis was of 56% (95% CI 44–67) for PD patients and 14% (95% CI 3–25) for healthy controls; the pooled relative risk (RR) with random effect analysis was 5.5 (95% CI 2.1–14.4). All studies reported data of community dwelling idiopathic PD patients, with a mean age around 65 years and mild PD in 50–60% of the cases. Heterogeneity was mainly caused by differences in definition or frequency of drooling. The highest prevalence rates included nocturnal drooling where others noted only diurnal drooling. Analysis of the data of two studies showed that drooling is reported frequently by 22–26% of the patients. Prevalence rates were lower in milder PD patients. The summarized findings demonstrate that drooling can be present in half of all PD patients. In about a quarter of PD patients, drooling appears to be a frequently occurring problem. We recommend to report drooling in future studies with more detailed consideration of severity, frequency and nocturnal versus diurnal complaints

Diurnal and nocturnal drooling in Parkinson’s disease

Drooling as symptom of Parkinson’s disease (PD) has thus far been poorly defined. This uncertainty is reflected by high variations in published prevalence rates. The aim of this study was to investigate the prevalence of saliva loss versus accumulation of saliva as a possible preliminary stage, and diurnal drooling versus nocturnal drooling. In addition, we evaluated the association between drooling severity and the severity of facial and oral motor disorders. We collected age, disease duration, UPDRS III and Hoehn & Yahr stage from 104 consecutive outpatients with PD. Diurnal and nocturnal drooling was evaluated with a validated questionnaire (ROMP-saliva). A speech pathologist, blinded for drooling severity, rated facial expression, involuntary mouth opening and difficulty with nose breathing and also interviewed patients about sleeping position and nose-breathing during the night. Thirty patients (29%) had no complaints with saliva control (‘non-droolers’), 45 patients (43%) experienced accumulation of saliva or only nocturnal drooling (‘pre-droolers’), and 29 (28%) had diurnal drooling (24 of which also drooled during the night; ‘droolers’). The droolers had longer disease duration (10 vs. 7 years, p = 0.01) and drooling was independently associated with involuntary mouth opening (OR = 2.0; 95% CI 1.02–3.99) and swallowing complaints (OR = 1.2; 95% CI 1.03–1.31). Diurnal drooling—defined as dribbling of saliva while awake—is present in about 28% of PD patients. This is less than usually reported. Diurnal drooling typically appeared later in the disease course. The association with oral motor behavior should encourage the development of behavioral treatment approaches

Twenty Years of Hepatitis C in the Treviso District (Local Health Unit 2): Treatments, Clinical Management and Cost Analysis

Chronic hepatitis C virus (HCV) infection is a global health problem, and about 10-30% of patients develop cirrhosis or hepatocellular carcinoma several years after being infected. In past decades, treatment of HCV infection was based on peginterferon and ribavirin, which lead to a sustained virologic response (SVR) in only 50-60% of patients. Since 2014, direct acting antiviral (DAA) agents have been available. Patients administered DAA agents usually reach SVR in 12 weeks. The aim of this study was to estimate the cost analysis of these innovative drugs while also taking into account the total health expenditure for managing HCV infection. The pharmaceutical and hospitalisation databases of the Local Health Unit (ULSS2) of Treviso were retrospectively analysed between 1997 and 2016 for each HCV patient. During this twenty-year period, people affected by HCV totalled 2,949; 277 of these patients were treated with DAA and, of these, only 2% did not reach SVR. The HCV genotype 1b was the most common, accounting for 58% of the total patients. The treatment for HCV genotype 3 was associated with higher costs. The expenses for the new treatments were found to be significantly higher compared to those for the old ones (i.e., peginterferon and ribavirin). The average costs for a cycle of therapy were €8,000 and €24,000 for interferon and DAA therapy, respectively. Total health care costs associated with HCV (excluding DAA treatments) for an individual HCV infection patient were estimated to be €32,000. Our results confirm the high efficacy of DAA therapy. Furthermore, these agents improve the clinical conditions and reduce both the treatment cost and health care in patients with HCV infection

Aneurysm prevalence and quality of life during screening in relatives of patients with unruptured intracranial aneurysms

Background and ObjectivesScreening for unruptured intracranial aneurysms (UIAs) is effective for first-degree relatives(FDRs) of patients with aneurysmal subarachnoid hemorrhage (aSAH). Whether screening isalso effective for FDRs of patients with UIA is unknown. We determined the yield of screening insuch FDRs, assessed rupture risk and treatment decisions of aneurysms that were found, iden-tified potential high-risk subgroups, and studied the effects of screening on quality of life (QoL).MethodsIn this prospective cohort study, we included FDRs, aged 20–70 years, of patients with UIAwithout a family history of aSAH who visited the Neurology outpatient clinic in 1 of 3 partici-pating tertiary referral centers in the Netherlands. FDRs were screened for UIA with magneticresonance angiography between 2017 and 2021. We determined UIA prevalence and developed aprediction model for UIA risk at screening using multivariable logistic regression. QoL wasevaluated with questionnaires 6 times during the first year after screening and assessed with alinear mixed-effects model.ResultsWe detected 24 UIAs in 23 of 461 screened FDRs, resulting in a 5.0% prevalence (95% CI3.2–7.4). The median aneurysm size was 3 mm (interquartile range [IQR] 2–4 mm), and themedian 5-year rupture risk assessed with the PHASES score was 0.7% (IQR 0.4%–0.9%). AllUIAs received follow-up imaging, and none were treated preventively. After a median follow-up of24 months (IQR 13–38 months), no UIA had changed. Predicted UIA risk at screening rangedbetween 2.3% and 14.7% with the highest risk in FDRs who smoke and have excessive alcoholconsumption (c-statistic: 0.76; 95% CI 0.65–0.88). At all survey moments, health-related QoLand emotional functioning were comparable with those in a reference group from the generalpopulation. One FDR with a positive screening result expressed regret about screening.DiscussionBased on the current data, we do not advise screening FDRs of patients with UIA becauseall identified UIAs had a low rupture risk. We observed no negative effect of screening on QoL. Alonger follow-up should determine the risk of aneurysm growth requiring preventive treatment.Paroxysmal Cerebral Disorder