Adopting the Rumsfeld approach to understanding the action of levodopa and apomorphine in Parkinson's disease.

Dopaminergic therapies dominate the treatment of the motor and non-motor symptoms of Parkinson's disease (PD) but there have been no major advances in therapy in many decades. Two of the oldest drugs used appear more effective than others-levodopa and apomorphine-but the reasons for this are seldom discussed and this may be one cause for a lack of progress. This short review questions current thinking on drug action and looks at whether adopting the philosophy of ex-US Secretary of State Donald Rumsfeld reveals 'unknown' aspects of the actions of levodopa and apomorphine that provide clues for a way forward. It appears that both levodopa and apomorphine have a more complex pharmacology than classical views would suggest. In addition, there are unexpected facets to the mechanisms through which levodopa acts that are either forgotten as 'known unknowns' or ignored as 'unknown unknowns'. The conclusion reached is that we may not know as much as we think about drug action in PD and there is a case for looking beyond the obvious.

Optimised endoscopic access for intrajejunal levodopa application in idiopathic Parkinson's syndrome.

Pump-guided intrajejunal levodopa administration is one of the indispensable forms of therapy in advanced Parkinson's syndrome, along with deep brain stimulation and subcutaneous apomorphine injection. The standard application of levodopa gel via a JET-PEG, i.e. a percutaneous endoscopic gastrostomy (PEG) with an inserted internal catheter into the jejunum, has not been unproblematic due to the restricted absorption area of the drug in the region of the flexura duodenojejunalis and especially due to the sometimes considerable accumulated complication rates of a JET-PEG. Causes of complications are mainly a non-optimal application technique of PEG and internal catheter as well as the often missing adequate follow-up care. This article presents the details of a-compared to the conventional technique-modified and optimised application technique, which has been clinically proven successfully for years. However, many details derived from anatomical, physiological, surgical and endoscopic aspects must be strictly observed during the application to reduce or avoid minor and major complications. Local infections and buried bumper syndrome cause particular problems. The relatively frequent dislocations of the internal catheter (which can ultimately be avoided by clip-fixing the catheter tip) also prove to be particularly troublesome. Finally, using the Hybrid technique, a new combination of an endoscopically controlled gastropexy with 3 sutures and subsequent central thread pull-through (TPT) of the PEG tube, the complication rate can be dramatically reduced and thus a decisive improvement achieved for patients. The aspects discussed here are highly relevant for all those involved in the therapy of advanced Parkinson's syndrome.

Randomized controlled trials on the use of cannabis-based medicines in movement disorders: a systematic review.

Anecdotal references, preclinical, and non-randomized studies support the therapeutic potential of cannabinoids for movement disorders (MD). To create an evidenced-based point of view for patients and physicians, we performed a systematic review of randomized controlled trials (RCT) on the use of cannabinoids in MD. The seven RCTs found on PD used different cannabis formulations. No improvement of motor symptoms was shown in any of the two RCTs with this as primary outcome (PO), but in the nabilone group, an improvement in quality of life was documented. Of the three RCTs having levodopa-induced dyskinesia as PO, only one using nabilone showed a reduction. Anxiety and anxiety-induced tremor could be reduced in the cannabidiol group as well as anxiety and sleeping problems in the nabilone group in another RCT. In two RCTs with Tourette syndrome, an improvement in tics was revealed. From three RCTs on Huntington's disease only one found symptoms relief using nabilone. No reduction of dystonia could be shown in the two included RCTs. The limited number of available but small and inhomogeneous RCTs precludes reliable conclusions. Therefore, more and smartly designed RCTs are urgently needed.

Gastrointestinal involvement in Parkinson's disease: pathophysiology, diagnosis, and management.

Growing evidence suggests an increasing significance for the extent of gastrointestinal tract (GIT) dysfunction in Parkinson's disease (PD). Most patients suffer from GIT symptoms, including dysphagia, sialorrhea, bloating, nausea, vomiting, gastroparesis, and constipation during the disease course. The underlying pathomechanisms of this α-synucleinopathy play an important role in disease development and progression, i.e., early accumulation of Lewy pathology in the enteric and central nervous systems is implicated in pharyngeal discoordination, esophageal and gastric motility/peristalsis impairment, chronic pain, altered intestinal permeability and autonomic dysfunction of the colon, with subsequent constipation. Severe complications, including malnutrition, dehydration, insufficient drug effects, aspiration pneumonia, intestinal obstruction, and megacolon, frequently result in hospitalization. Sophisticated diagnostic tools are now available that permit more detailed examination of specific GIT impairment patterns. Furthermore, novel treatment approaches have been evaluated, although high-level evidence trials are often missing. Finally, the burgeoning literature devoted to the GIT microbiome reveals its importance for neurologists. We review current knowledge about GIT pathoanatomy, pathophysiology, diagnosis, and treatment in PD and provide recommendations for management in daily practice.

Implications of dopaminergic medication withdrawal in Parkinson's disease.

The trajectory of the use of dopamine replacement therapy (DRT) in Parkinson's disease (PD) is variable and doses may need to be increased, but also tapered. The plan for dose adjustment is usually done as per drug information recommendations from the licensing bodies, but there are no clear guidelines with regards to the best practice regarding the tapering off schedule given sudden dose reductions of drugs such as dopamine agonists may have serious adverse consequences. A systematic literature search was, therefore, performed to derive recommendations and the data show that there are no controlled studies or evidence-based recommendations how to taper or discontinue PD medication in a systematic manner. Most of the data were available on the dopamine agonist withdrawal syndrome (DAWS) and we found only two instructions on how to reduce pramipexole and rotigotine published by the EMA. We suggest that based on the available data, levodopa, dopamine agonists (DA), and amantadine should not be discontinued abruptly. Abrupt or sudden reduction of DA or amantadine in particular can lead to severe life-threatening withdrawal symptoms. Tapering off levodopa, COMT inhibitors, and MAO-B inhibitors may worsen motor and non-motor symptoms. Based on our clinical experience, we have proposed how to reduce PD medication and this work will form the basis of a future Delphi panel to define the recommendations in a consensus.

An updated calculator for determining levodopa-equivalent dose.

Calculation of levodopa-equivalent dose in Parkinson's disease has become common in research, but is also a useful tool in clinical practice, especially when initiating device-aided treatments (deep brain stimulation, apomorphine and levodopa infusions). The aim with the present calculator is to provide an updated conversion table, including dose calculation of the recently developed levodopa/entacapone/carbidopa intestinal gel infusion. Future versions of the calculator should be made conducive to learning by means of artificial intelligence.

[Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest) for assessment of non-motor symptoms in dystonia : Intercultural adaptation in the German language]. / Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest) zur Erhebung nichtmotorischer Symptome bei Dystonie : Interkulturelle Adaptation in deutscher Sprache.

BACKGROUND: Non-motor symptoms (NMS) in patients with dystonia have a relevant impact on health-related quality of life; however, a comprehensive easy to use NMS assessment tool for clinical bedside use is currently not available. OBJECTIVE: The validated German version of the dystonia non-motor symptoms questionnaire (DNMSQuest) for assessing NMS in craniocervical dystonia is presented. METHODS: The DNMSQuest in the German language was developed based on internationally recognized standards for intercultural adaptation of self-completed patient questionnaires. Translation of the original English questionnaire into the German language as well as back translation to English was carried out independently by four bilingual specialists in neurological movement disorders. In each case a consensus version accepted by each translator was created by another neurologist. The back translated English version was compared with the original English questionnaire for relevant linguistic and content discrepancies by a neurologist who was significantly involved in the development of the original questionnaire. The final German version was used in 130 patients with cervical dystonia and 48 healthy controls in an international, multicenter validation study. RESULTS: An interculturally adapted validated version of the DNMSQuest in the German and English languages was developed for rapid bedside assessment and evaluation of NMS in cervical dystonia. CONCLUSION: The DNMSQuest successfully bridges the current gap of a validated disease-specific, patient self-administered, short, comprehensive questionnaire for NMS assessment in routine clinical practice in craniocervical dystonia. It is envisaged that this tool will be useful for the clinical practice and trials.

Bypassing pan-enterovirus host factor PLA2G16.

Enteroviruses are a major cause of human disease. Adipose-specific phospholipase A2 (PLA2G16) was recently identified as a pan-enterovirus host factor and potential drug target. In this study, we identify a possible mechanism of PLA2G16 evasion by employing a dual glycan receptor-binding enterovirus D68 (EV-D68) strain. We previously showed that this strain does not strictly require the canonical EV-D68 receptor sialic acid. Here, we employ a haploid screen to identify sulfated glycosaminoglycans (sGAGs) as its second glycan receptor. Remarkably, engagement of sGAGs enables this virus to bypass PLA2G16. Using cryo-EM analysis, we reveal that, in contrast to sialic acid, sGAGs stimulate genome release from virions via structural changes that enlarge the putative openings for genome egress. Together, we describe an enterovirus that can bypass PLA2G16 and identify additional virion destabilization as a potential mechanism to circumvent PLA2G16.

Effectiveness of botulinum neurotoxin type A injections in naïve and previously-treated patients suffering from Torti- or Laterocollis or -caput: Results from a German-Austrian open-label prospective post-marketing surveillance study.

AbobotulinumtoxinA (aboBoNT-A; Dysport®) is an effective treatment for cervical dystonia (CD) with a well-established safety profile. In this prospective, multicentre, non-interventional study (NCT01840462) the primary objective was effectiveness (Tsui score) of aboBoNT-A in botulinum neurotoxin type A (BoNT-A) treatment-naïve and previously-treated (>2 yrs) patients after two injection cycles (at visit 3). Secondary objectives included the effectiveness of aboBoNT-A overall visits and quality of life (CDQ-24) in different CD subtypes. Observation time was 12-16 months, including 5 visits and 4 injection cycles (each 3-4 months). In the analysis population 273 patients from 41 centres across Germany and Austria were included. At baseline, 62.6% were previously-treated with BoNT-A. The major primary components of CD were torticollis (64.5%) and torticaput (17.6%). Previously-treated patients showed a slight reduction of the Tsui scores, whereas BoNT-A-naïve patients had a more severe baseline Tsui score and improved much more over all cycles. Results were similar for CDQ-24. Interestingly, improvements mainly occurred in the Tsui subscore A (amplitude of sustained posture). Marked differences between CD subtypes regarding effectiveness could not be determined. To our knowledge this is the first large multi-centre study investigating the effectiveness of BoNT-A in different primary subtypes of CD over several injection cycles.

[Characteristics and dynamics of inpatient treatment of patients with Parkinson's disease in Germany : Analysis of 1.5 million patient cases from 2010 to 2015]. / Charakteristika und Dynamik der stationären Behandlung von Parkinson-Patienten in Deutschland : Analyse von 1,5 Mio. Patientenfällen aus den Jahren 2010 bis 2015.

BACKGROUND: Parkinson's disease is the most common neurodegenerative movement disorder and the fastest-growing neurological disease in the world. The diagnostic spectrum, demographic characteristics, comorbidities and case number developments of inpatient treatment in Germany with resulting implications for patient care have so far been insufficiently investigated. METHODS: Data from the diagnosis-related groups (DRG) statistics were analyzed in patients with a main and secondary diagnosis of primary Parkinson's syndrome (PS), secondary PS or other degenerative disease of the basal ganglia. For the reporting years 2010-2015, the dataset comprised 1,520,366 patient cases from 413 districts/independent cities throughout Germany. RESULTS: In 2015, mostly patients with moderate and severe primary PS were hospitalized (64.7%) often exhibiting motor fluctuations as well as marked medical and psychiatric comorbidities. Vascular parkinsonism was the most frequent secondary PS (36.6%) and progressive supranuclear palsy was the leading diagnosis in the other disorders of the basal ganglia (51.9%). Primary PS as a secondary diagnosis was found in many internal medicine hospitalizations. The inpatient case numbers for primary PS increased significantly from the years 2010 to 2015 and rural regions were particularly affected. CONCLUSION: The number of inpatient cases of Parkinson's disease is greatly increasing in Germany and mainly affects patients with severe motor complications and secondary parkinsonian syndromes. Particularly in rural areas, there is a risk of overburdening the treatment infrastructure, so that both outpatient and inpatient sectors must be strengthened. A limitation of the study is the analysis of only DRG coded data, whose quality could be improved in subsequent examinations by comparison with the current diagnostic criteria of the specialist societies.

[King's Parkinson's disease pain scale : Intercultural adaptation in the German language]. / King's Parkinson's Disease Pain Scale : Interkulturelle Adaption in deutscher Sprache.

BACKGROUND: Pain is a frequent symptom of idiopathic Parkinson's disease and has a substantial impact on quality of life. The King's Parkinson's disease pain scale (KPPS) has become internationally established and is an English-language, standardized, reliable and valid scale for evaluation of pain in idiopathic Parkinson's disease. This article presents a validated version in German. METHOD: The German translation was adapted interculturally and developed using an internationally recognized procedure in consultation with the authors of the original publication. The primary text was first translated by two bilingual neuroscientists independently of one another. Thereafter, the two versions were collated to generate a consensus version, which was accepted by the translators and preliminarily trialled with 10 patients. Hereafter, the German version was re-translated back into English by two other neurologists, again independently of one another, and a final consensus was agreed on using these versions. This English version was then compared with the original text by all of the translators, a process which entailed as many linguistic modifications to the German version as the translators considered necessary to generate a linguistically acceptable German version that was as similar as possible to the original English version. After this test text had been subsequently approved by the authors, the German text was applied to 50 patients in two hospitals, and reviewed as to its practicability and comprehensibility. RESULTS: This work led to the successful creation of an inter-culturally adapted and linguistically validated German version of the KPPS. DISCUSSION: The German version presented here is a useful scare for recording and quantifying pain in empirical studies, as well as in clinical practice.

[Nonmotor symptoms in Parkinson's disease]. / Nichtmotorische Symptome beim Morbus Parkinson.

Parkinson's disease is a neurodegenerative disease that affects the peripheral and central nervous system. In addition to the motor symptoms, a large number of nonmotor symptoms, which are of high clinical relevance, occur in all disease stages. Particular attention has been paid to neuropsychiatric and autonomic disorders in recent years. Among the neuropsychiatric disorders are depression, cognitive loss as well as psychoses and impulsive control disorders. Regarding autonomic function, all areas can be affected, with cardiovascular, gastrointestinal and urogenital disorders and symptoms being the most common. Therapy is difficult and requires an interdisciplinary approach. There is a considerable diagnostic and therapeutic need in the field of nonmotor disorders.

[Pharmacological treatment of motor symptoms in Parkinson's diseases]. / Medikamentöse Therapie der motorischen Symptome beim Morbus Parkinson.

Since the 1960s many substance classes have been introduced for treatment of idiopathic Parkinson's disease. The most important and effective medication is levodopa (L-dopa) always in combination with a decarboxylase inhibitor. In addition, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, catechol-o-methyltransferase (COMT) inhibitors, N­methyl-D-aspartate (NMDA) antagonists and very rarely anticholinergics are administered depending on the motor symptoms, age and a multitude of other factors. Fortunately, within the substance classes there are various preparations, which also have different effects. In order that the advantages of the individual medications can be exploited and undesired effects and interactions can be avoided, one must come to terms with the complex data and the pharmacology of the medication. In addition important aspects are interactions and reciprocal actions. In the foreseeable future, different substance classes are to be expected.

Anatomy and cervical dystonia : "Dysfunction follows form".

At first glance, cervical dystonia might be an illustration of the well-known proposition "function follows form". Nevertheless, cervical dystonia is a highly non-physiological condition, which cannot be reproduced by healthy subjects and does not respond to the usual physiological rules. "Dysfunction follows form" might be the most accurate aphorism to define cervical dystonia. Taking into account this situation and recent insights, the anatomic approach needs to be adapted to allow a better understanding of semiology and to improve botulinum toxin therapy. In this review dealing with a new approach to cervical dystonia, we develop some practical anatomical concepts concerning the head and neck complex. Knowledge of cervical spine and muscular dysfunctions in cervical dystonia is an essential stage in treating cervical dystonia patients with botulinum toxin.

[Practical Use of the Levodopa Pump]. / Praktische Anwendung der Levodopa-Pumpe.

Patients with advanced Parkinson's disease and motor complications undergoing optimized oral therapy can significantly benefit from continuous intrajejunal levodopa/carbidopa infusion applied by means of a medication pump. However, this requires a correctly positioned PEG-J tube and finely adjusted pump settings. Although this method is a routine procedure in specialist centers, no standard procedure has been defined up to now. For this reason, an expert recommendation regarding the practical application has been developed in order to standardize the procedure and facilitate patient access to this treatment option.

[Parkinson's Disease at the Border Between Inpatient and Outpatient Care]. / Das idiopathische Parkinson-Syndrom an der Grenze von ambulanter zu stationärer Versorgung.

Parkinson's disease is characterized by a continuous spectrum of varying severity. The treatment is driven by new and sometimes highly complex therapeutic procedures. These two aspects are responsible for the blurred dividing line between outpatient and inpatient care. The aim of this article is to define criteria that should help determine the indication for inpatient or outpatient treatment. We introduce quality requirements that have already been taken into account in part in therapy modalities such as Parkinson complex treatment. The decision on the appropriate form of care affects the medical freedom of therapy, which must reconcile the legitimate interest of patients to receive optimal care with the given economic conditions. Our aim is to provide guidance on decisions on the best form of treatment in the context of changing framework conditions in the health sector.

[Intercultural adaptation of the AIMS in German language: A scale for abnormal involuntary movements]. / Interkulturelle Adaption der AIMS in deutscher Sprache : Eine Skala für abnorme unwillkürliche Bewegungen.

BACKGROUND: Dyskinesias are abnormal involuntary movements and occur across many movement disorders. In Parkinson's disease dyskinesias can be troublesome and are a determinant of the quality of life throughout the course of the disease. Assessment and rating of dyskinesias is thus important for clinical assessment of patients, as well as for academic studies and clinical trials. The abnormal involuntary movement scale (AIMS) is an English language standardised, reliable and validated scale to evaluate dyskinesias. In this article we present a linguistically validated German version of AIMS. METHODS: The intercultural adaptation of the German translation was performed following an internationally accepted procedure. Firstly, two neurologists independently translated the original into German. Taking both versions into account, a consensus version was agreed on by both translators and was tested on 10 patients. This preliminary German version was then independently translated back into the original language by two different neurologists, and again, a consensus version was agreed on. All translators then compared this English version to the original. Subsequently, the German version was linguistically modified until it resulted in a final German version, which was agreed on by all translators, deemed linguistically acceptable, and the translation back into English was considered to be as unambiguous as possible. This final German version of AIMS was applied to 50 patients in two different hospitals for diagnostic purposes and tested for feasibility and comprehension. RESULTS: In this paper, we present an intercultural adaptation of a linguistically validated German version of AIMS.

Enterovirus D68 receptor requirements unveiled by haploid genetics.

Enterovirus D68 (EV-D68) is an emerging pathogen that can cause severe respiratory disease and is associated with cases of paralysis, especially among children. Heretofore, information on host factor requirements for EV-D68 infection is scarce. Haploid genetic screening is a powerful tool to reveal factors involved in the entry of pathogens. We performed a genome-wide haploid screen with the EV-D68 prototype Fermon strain to obtain a comprehensive overview of cellular factors supporting EV-D68 infection. We identified and confirmed several genes involved in sialic acid (Sia) biosynthesis, transport, and conjugation to be essential for infection. Moreover, by using knockout cell lines and gene reconstitution, we showed that both α2,6- and α2,3-linked Sia can be used as functional cellular EV-D68 receptors. Importantly, the screen did not reveal a specific protein receptor, suggesting that EV-D68 can use multiple redundant sialylated receptors. Upon testing recent clinical strains, we identified strains that showed a similar Sia dependency, whereas others could infect cells lacking surface Sia, indicating they can use an alternative, nonsialylated receptor. Nevertheless, these Sia-independent strains were still able to bind Sia on human erythrocytes, raising the possibility that these viruses can use multiple receptors. Sequence comparison of Sia-dependent and Sia-independent EV-D68 strains showed that many changes occurred near the canyon that might allow alternative receptor binding. Collectively, our findings provide insights into the identity of the EV-D68 receptor and suggest the possible existence of Sia-independent viruses, which are essential for understanding tropism and disease.