EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson's disease.

OBJECTIVE: Real-life observational report of clinical efficacy of bilateral subthalamic stimulation (STN-DBS), apomorphine (APO), and intrajejunal levodopa infusion (IJLI) on quality of life, motor, and nonmotor symptoms (NMS) in Parkinson's disease (PD). METHODS: In this prospective, multicenter, international, real-life cohort observation study of 173 PD patients undergoing STN-DBS (n = 101), IJLI (n = 33), or APO (n = 39) were followed-up using PDQuestionnaire-8, NMSScale (NMSS), Unified PD Rating Scale (UPDRS)-III, UPDRS-IV, and levodopa equivalent daily dose (LEDD) before and 6 months after intervention. Outcome changes were analyzed with Wilcoxon signed-rank or paired t test when parametric tests were applicable. Multiple comparisons were corrected (multiple treatments/scales). Effect strengths were quantified with relative changes, effect size, and number needed to treat. Analyses were computed before and after propensity score matching, balancing demographic and clinical characteristics. RESULTS: In all groups, PDQuestionnaire-8, UPDRS-IV, and NMSS total scores improved significantly at follow-up. Levodopa equivalent daily dose was significantly reduced after STN-DBS. Explorative NMSS domain analyses resulted in distinct profiles: STN-DBS improved urinary/sexual functions, mood/cognition, sleep/fatigue, and the miscellaneous domain. IJLI improved the 3 latter domains and gastrointestinal symptoms. APO improved mood/cognition, perceptual problems/hallucinations, attention/memory, and the miscellaneous domain. Overall, STN-DBS and IJLI seemed favorable for NMSS total score, and APO favorable for neuropsychological/neuropsychiatric NMS and PDQuestionnaire-8 outcome. CONCLUSIONS: This is the first comparison of quality of life, nonmotor. and motor outcomes in PD patients undergoing STN-DBS, IJLI, and APO in a real-life cohort. Distinct effect profiles were identified for each treatment option. Our results highlight the importance of holistic nonmotor and motor symptoms assessments to personalize treatment choices. © 2019 International Parkinson and Movement Disorder Society.

Subthalamic Stimulation Improves Quality of Life of Patients Aged 61 Years or Older With Short Duration of Parkinson's Disease.

OBJECTIVE: The optimal timing of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) is a topic of ongoing debate. In patients with short disease duration an improvement of quality of life (QoL) has been demonstrated for patients aged younger than 61 years. However, this has not been systematically investigated in older patients yet. We hypothesized that patients aged 61 years or older experience a significant QoL improvement after STN-DBS with no difference in effect sizes for groups of patients with short and longer disease duration. MATERIALS AND METHODS: From four centers (Cologne, London, Manchester, Venice) we identified "older patients" aged 61 years or older with short (≤8 years) or longer disease duration and compared QoL, motor impairment, complications, medication requirements, and Mini-Mental State Examination (MMSE) on baseline and five months after surgery. RESULTS: Mean age/disease duration in 21 subjects with shorter disease duration were 65.5/6.3 years compared to 66.8/14.6 in 33 subjects with longer disease duration. The short disease duration group was affected by less baseline motor complications (p = 0.002). QoL in the short/longer disease duration group improved by 35/20% (p = 0.010/p = 0.006), motor complications by 40/44% (p = 0.018/p < 0.001), and medication requirements by 51/49% (both p < 0.001). MMSE remained unchanged in both groups. CONCLUSION: Patients aged 61 years or older benefited from STN-DBS regardless of short (≤8 years) or longer (>8 years) disease duration. Our results contribute to the debate about DBS selection criteria and timing and call for prospective confirmation in a larger cohort.

EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson's disease.

Subcutaneous apomorphine infusion (Apo) and intrajejunal levodopa infusion (IJLI) are two treatment options for patients with advanced Parkinson's disease (PD) and refractory motor complications, with varying cost of treatment. There are no multicenter studies comparing the effects of the two strategies. This open-label, prospective, observational, 6-month, multicenter study compared 43 patients on Apo (48.8% males, age 62.3 ± 10.6 years; disease duration: 14 ± 4.4 years; median H & Y stage 3; interquartile range [IQR]: 3-4) and 44 on IJLI (56.8% males, age 62.7 ± 9.1 years; disease duration: 16.1 ± 6.7 years; median H & Y stage 4; IQR, 3-4). Cohen's effect sizes (≥0.8 considered as large) were "large" with both therapies with respect to total motor, nonmotor, and quality-of-life scores. The Non-Motor Symptoms Scale (NMSS) with Apo showed moderate improvement, whereas sleep/fatigue, gastrointestinal, urinary, and sexual dimensions of the NMSS showed significantly higher improvement with IJLI. Seventy-five percent on IJLI improved in their quality-of-life and nonmotor symptoms (NMS), whereas in the Apo group, a similar proportion improved in quality of life, but 40% in NMS. Adverse effects included peritonitis with IJLI and skin nodules on Apo. Based on this open-label, nonrandomized, comparative study, we report that, in advanced Parkinson's patients, both IJLI and Apo infusion therapy appear to provide a robust improvement in motor symptoms, motor complications, quality-of-life, and some NMS. Controlled, randomized studies are required.

Perceptions of symptoms and expectations of advanced therapy for Parkinson's disease: preliminary report of a Patient-Reported Outcome tool for Advanced Parkinson's disease (PRO-APD).

BACKGROUND: What do patients expect from a treatment? A patient-centred approach to treatment is becoming necessary given the choices for invasive treatments for Parkinson's disease. Patient's perceptions of severity and expectations from complex therapies have not been studied. We describe the rationale and concept of developing a Patient-Reported Outcome (PRO) tool to assess perceptions of symptom severity and expectations of therapy. We report preliminary findings from use of the tool, association with clinical factors, and illustrate the potential use in individual patients awaiting therapy. METHODS: Patient symptoms were grouped into four domains, with 8 motor, 7 non-motor, 7 psychological and 4 social questions. For each question, symptom severity was rated on a Likert scale scoring from 0 (no problem) to 7 (perceived as a severe problem). Similarly, the expectation for each symptom to change after therapy was rated on a Likert scale: score -3 (expected to be very much worse) to + 3 (expected to be very much improved). RESULTS: 22 consecutive patients, routinely planned to receive one of Deep Brain Stimulation/Intrajejunal Levodopa Infusion/Apomorphine Infusion therapies, were recruited: 13 male, mean (+/-sd) age: 65.6 (+/-9.5) years, mean (+/-sd) disease duration: 14.3 (+/-5.7) years. Subjective severity scores are reported as mean (+/-sd) / maximum possible score: (i) motor 23.5 (+/-7.5) / 56, (ii) non-motor 15.5 (+/-5.6) / 49, (iii) cognitive - psychological 12.4 (+/-5.8) / 49, (iv) social 9.3 (+/-4.1) / 28. Expectation of change (improvement) scores are reported as mean (+/-sd) / maximum possible score of: (i) motor 14.0 (+/-5.6) / 24, (ii) non-motor 8.5 (+/-4.1) / 21, (iii) cognitive - psychological 7.4 (+/-4.4)/ 21, and (iv) social 5.5 (+/-2.8) / 12. For each domain, Spearman correlation coefficient showed significant associations between severity and expectation within-domain. CONCLUSION: This tool (PRO-APD) provides a description of perceived problem severity and expectation of treatments encompassing a holistic patient-driven view of care. PD patients about to receive complex therapy have moderately high perception of symptom load in multiple domains, and expect substantial improvements in multiple domains. These preliminary findings may be useful in documenting multi-domain symptoms, as well as counseling patients to help them reach realistic expectations and reduce potential dissatisfaction following therapy.

Addressing Comorbidities in People with Parkinson's Disease: Considerations From An Expert Panel.

In the UK, guidance exists to aid clinicians and patients deciding when treatment for Parkinson's disease (PD) should be initiated and which therapies to consider. National Institute for Health and Care Excellence (NICE) guidance recommends that before starting PD treatment clinicians should discuss the following: the patient's individual clinical circumstances; lifestyle; preferences; needs and goals; as well as the potential benefits and harms of the different drug classes. Individualization of medicines and management in PD significantly improves patients' outcomes and quality of life. This article aims to provide simple and practical guidance to help clinicians address common, but often overlooked, co-morbidities. A multi-disciplinary group of PD experts discussed areas where clinical care can be improved by addressing commonly found co-morbidities in people with Parkinson's (PwP) based on clinical experience and existing literature, in a roundtable meeting organized and funded by Bial Pharma UK Ltd. The experts identified four core areas (bone health, cardiovascular risk, anticholinergic burden, and sleep quality) that, if further standardized may improve treatment outcomes for PwP patients. Focusing on anticholinergic burden, cardiac risk, sleep, and bone health could offer a significant contribution to personalizing regimes for PwP and improving overall patient outcomes. Within this opinion-based paper, the experts offer a list of guiding factors to help practitioners in the management of PwP.

The impact of deep brain stimulation on the nonmotor symptoms of Parkinson's disease.

Deep brain stimulation (DBS) is a well-established therapy for patients with advanced Parkinson's disease (PD) with clear benefits on many of the motor symptoms. The effects of DBS on the nonmotor symptoms are less well examined. Emergence of tools to measure the nonmotor burden in PD is now allowing a more objective assessment of impact of DBS on such symptoms. Here we review the pertinent evidence and conclude that, as a therapy, DBS has a major potential to contribute towards the holistic care of PD patients.

Mechanical thrombectomy through a 'carotid-carotid bypass'.

An elderly patient presented with acute-onset right-sided weakness and aphasia. A large penumbra was noted in the left middle cerebral artery (MCA) territory without any infarct core. The patient was noted to have a carotid-carotid bypass. This posed certain technical challenge in accessing the intracranial circulation across the carotid bypass; however, the guiding catheter with soft distal segment was successfully navigated coaxially over the aspiration catheter across the bypass and intracranial circulation was accessed for mechanical thrombectomy. Complete recanalisation and reperfusion were achieved with significant neurological recovery of the patient post-thrombectomy. The aim of this report is to emphasise on this rarely encountered situation in thrombectomy and its successful management. The procedure should not be delayed or deferred due to lack of operator experience.

An endobronchial lipoma mimicking asthma and malignancy.

Endobronchial lipomas are rare benign tumours of the lung. Bronchial occlusion may lead to a misdiagnosis of asthma or malignancy. We describe a 52-year-old man treated for asthma for several years, who presented with non-resolving right upper lobe pneumonia. Bronchoscopy proved to be diagnostic and therapeutic. Clinical characteristics of this unique entity are discussed.

Noninvasive options for 'wearing-off' in Parkinson's disease: a clinical consensus from a panel of UK Parkinson's disease specialists.

In the past 4 years, two adjunctive treatment options to levodopa have been licensed for use in the UK in patients with Parkinson's disease (PD) and motor fluctuations: opicapone, a third-generation catechol-O-methyl transferase inhibitor, and safinamide, a monoamine oxidase B inhibitor. This clinical consensus outlines the practical considerations relating to motor fluctuations and managing wearing-off in patients with PD, and provides a clinical insight to adjunctive treatment options, including opicapone and safinamide. Practice-based opinion was provided from a multidisciplinary steering Group of eight UK-based movement disorder and PD specialists, including neurologists, geriatricians and a nurse specialist, from England, Scotland and Wales.

Short-term quality of life after subthalamic stimulation depends on non-motor symptoms in Parkinson's disease.

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and non-motor symptoms (NMS) in advanced Parkinson's disease (PD). However, considerable inter-individual variability has been observed for QoL outcome. HYPOTHESIS: We hypothesized that demographic and preoperative NMS characteristics can predict postoperative QoL outcome. METHODS: In this ongoing, prospective, multicenter study (Cologne, Manchester, London) including 88 patients, we collected the following scales preoperatively and on follow-up 6 months postoperatively: PDQuestionnaire-8 (PDQ-8), NMSScale (NMSS), NMSQuestionnaire (NMSQ), Scales for Outcomes in PD (SCOPA)-motor examination, -complications, and -activities of daily living, levodopa equivalent daily dose. We dichotomized patients into "QoL responders"/"non-responders" and screened for factors associated with QoL improvement with (1) Spearman-correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions using aforementioned "responders/non-responders" as dependent variable. RESULTS: All outcomes improved significantly on follow-up. However, approximately 44% of patients were categorized as "QoL non-responders". Spearman-correlations, linear and logistic regression analyses were significant for NMSS and NMSQ but not for SCOPA-motor examination. Post-hoc, we identified specific NMS (flat moods, difficulties experiencing pleasure, pain, bladder voiding) as significant contributors to QoL outcome. CONCLUSIONS: Our results provide evidence that QoL improvement after STN-DBS depends on preoperative NMS characteristics. These findings are important in the advising and selection of individuals for DBS therapy. Future studies investigating motor and non-motor PD clusters may enable stratifying QoL outcomes and help predict patients' individual prospects of benefiting from DBS.

Beneficial Effects of Bilateral Subthalamic Stimulation on Non-Motor Symptoms in Parkinson's Disease.

BACKGROUND: STN-DBS is well established to improve motor symptoms and quality of life in patients with PD. While non-motor symptoms are crucial for quality of life in these patients, only neuropsychiatric and neuropsychological symptoms have been systematically studied in a longitudinal design so far. However, these are only a part of the non-motor symptoms spectrum. HYPOTHESIS: We hypothesized that STN-DBS is associated with a beneficial effect on a range of non-motor symptoms. METHODS: In this multicenter, open, prospective, international study (EuroInf-study, UKCRN10084/DRKS00006735) we investigated non-motor effects of STN-DBS in "real-life" use. We evaluated Non-motor Symptom Scale, and Questionnaire, PD Questionnaire-8, Scales for Outcomes of PD motor examination and complications, and activities of daily living preoperatively and at 6 months follow-up in 60 consecutive patients (35 male, mean age: 61.6 ± 7.8 years, mean disease duration: 10.4 ± 4.2 years). RESULTS: All outcomes improved significantly at 6 months follow-up (PD Questionaire-8, p = 0.006; activities of daily living, p = 0.012; all others, p < 0.001; Wilcoxon signed-rank, respectively paired t-test; Bonferroni-correction). Post-hoc analyses of Non-motor Symptom Scale domains showed a significant reduction of sleep/fatigue and miscellaneous domains (p ≤ 0.001), perceptual problems/hallucinations (p = 0.036), and urinary (p = 0.018) scores. Effect sizes were "moderate" for Non-motor Symptom Scale, and motor complications, "large" for motor examination, and "small" for other outcomes. CONCLUSIONS: This study provides evidence that bilateral STN-DBS improves non-motor burden in patients with PD and opens the door to a more balanced evaluation of DBS outcomes. Further randomized studies are needed to confirm these findings and compare DBS non-motor effects to other invasive therapies of advanced PD.

Intrajejunal levodopa versus conventional therapy in Parkinson disease: motor and nonmotor effects.

Seventeen patients with advanced Parkinson disease (PD) were treated with intrajejunal L-dopa infusion (IJL) and compared with a matched group of 9 patients (termed comparator [C]) not given IJL because of funding restriction by primary care trusts (PCTs) in the UK, although considered to be clinically eligible for IJL. Assessments were baseline and follow-up (6 months) with Hoehn and Yahr staging, unified PD rating scale (UPDRS-III and UPDRS-IV), Parkinson disease questionnaire (PDQ-8, quality of life [QoL]) and nonmotor symptom scale (NMSS).Baseline characteristics were comparable between the groups. The IJL-treated group showed highly significant improvements in UPDRS-III (P = 0.005), UPDRS-IV (P = 0.0004), total NMSS score (P = 0.004), and QoL (P = 0.01), whereas the C group showed no change in these parameters. A large effect size of IJL was seen in treated patients for UPDRS-III (1.13), UPDRS-IV (1.52), NMSS score (0.82), and QoL (1.12), whereas continuing conventional treatment registered no effect in C.This study confirms the robust effect of IJL on motor and, in particular, nonmotor symptoms and QoL in advanced PD as described in open-label studies but additionally points to the need for such treatment in those denied this therapy because of centrally dictated funding policies leading to inequalities in health care.

Chronic subcutaneous infusion therapy with apomorphine in advanced Parkinson's disease compared to conventional therapy: a real life study of non motor effect.

BACKGROUND: Apomorphine infusion therapy remains under-used and there are no comparative studies of motor and non-motor effects of apomorphine infusion. METHODS: In this paper we report preliminary results from an ongoing clinical observational "real life" surveillance-based study focused on effects of this therapy on non-motor symptoms and health-related quality of life in a group of patients on apomorphine. RESULTS: Apomorphine infusion led to highly significant improvements in UPDRS 3 (p = 0.0003), UPDRS 4 (p = 0.0003), PDQ-8 (Parkinson's disease questionnaire, p = 0.001) and NMSS total (non motor symptoms scale, p = 0.0003). Furthermore, apomorphine was tolerated in patients with visual hallucinations, illusions and paranoid ideations while significant improvement in specific non-motor symptoms such as hyperhidrosis, nocturia, urgency of micturition, and fatigue was recorded. Levodopa equivalent dose decreased significantly (1077.81 ± 446.26 to 458.75 ± 282.29, p < 0.0001) and a large effect size of intervention was noted. In an untreated group no such improvement was noted. The number needed to treat (NNT) for improvement >1 SEM in the Apo group was calculated and was lower than 2 for >1 SEM improvement of UPDRS 3, NMSS, and PDQ-8 total scores. CONCLUSIONS: This pilot observational study suggests that non-motor effects are evident with apomorphine therapy and patients suitable for apomorphine deteriorate in the absence of therapy.

Narcolepsy in Parkinson's disease.

Non-motor symptoms in Parkinson's disease (PD), such as excessive daytime sleepiness, 'sleep attacks', insomnia, restless legs syndrome and rapid eye movement sleep behavior disorder, are common and provide a challenge to treatment. These sleep symptoms are also described in patients suffering from the sleep/wake disorder, narcolepsy. The International Classification of Sleep Disorders (ICSD-2) narcolepsy criteria uses a number of markers for diagnosis, of which lack or deficiency of cerebrospinal fluid (CSF) hypocretin-1 levels is a key marker. Hypocretin neurons prominently located in the lateral hypothalamus and perifornical nucleus have been proposed to interact with mechanisms involving sleep and arousal. Low hypocretin-1 levels in the CSF have been shown to correlate with hypothalamic hypocretin cell loss in narcolepsy and other forms of hypersomnia; therefore, it has been proposed that degenerative damage to hypocretin neurons (such as in PD) may be detected by low CSF hypocretin-1 concentrations, and may also explain the sleep symptoms experienced by some PD patients. To date, there is mixed conflicting data describing hypocretin-1 levels in the CSF of patients with parkinsonism associated with sleep symptoms, with most studies showing no significant decrease when compared with controls. However, hypocretin-1 CSF deficiency has been shown in some studies to be more prominent in PD patients with sleep symptoms versus those without. Notably, the hypocretin system has been shown not to be selectively disrupted, with one study showing melanin concentrating hormone cell loss in the same patients with hypocretin loss. It is likely that hypocretin deficiency in PD patients occurs secondary to collateral damage caused by the neurodegenerative process involving the hypothalamus. Awareness of narcoleptic events in PD is important for driving related advice, in addition to the possible use of dopamine D3 receptor active agonists.