The development of motor complications is a major limitation to the long-term benefit from chronic levodopa treament of PD, affecting a majority of patients with Parkinson's disease (PD) after 5 to 10 years of exposure.1 Levodopa-induced dyskinesias (LID) are present in at least 55% of patients after 10 years.2 While multiple pharmacological approaches have been shown to reduce motor fluctuations, amantadine is the only widely used oral drug with established efficacy to treat LIDs.1, 3 However, even when exploiting the diversified portfolio of drug options, a proportion of patients will not be sufficiently controlled and suffer from “refractory” motor complications (RMC). National and international guidelines list deep brain stimulation (DBS) or infusion therapies as therapeutic options to regain control of fluctuations and dyskinesias in RMC.4, 5 While the terms “refractory fluctuations/dyskinesias” and “optimized oral medication” are frequently used, there is a lack of operational definitions in current guidelines. Here we suggest a pragmatic algorithm to operationalize the definition of “refractory motor complications (RMC).” This algorithm allows to evaluate the potential of oral/transdermal drug treatment to satisfactorily control response fluctuations and / or dyskinesias in an individual PD-patient within a time-span of a few months. Treatment of tremor not responding to dopaminergic medication requires specific pharmacotherapy which is beyond the scope of the present proposal. Since availability of different drugs varies between countries this algorithm needs to be adapted to local circumstances. Wearing-off type response fluctuations usually respond to increases in levodopa dosing frequency with reduced interdose intervals, although this increases both the demand on dosing compliance and total daily dose with an associated risk of LIDs.1, 3 The need for total daily doses of levodopa up to 1000 mg therefore has to be balanced against the individual LID risk. The individual dose requirements to achieve optimal motor control vary over a wide range and may even exceed 1000 mg levodopa if necessary and tolerated. Dose restriction to an arbitrary maximum daily dose in younger patients based on risk perception for future side effects, contradicts the principle of “best medical management” requirement for “optimized medication.” Even if higher doses of levodopa are associated with an increased risk for LID these are often non-troublesome and affected patients perceive dyskinesias as less disabling compared to OFF-states.6, 7 In principle, all available dopaminergic drug classes act synergistically on the motor symptoms of PD. Pragmatically, response fluctuations can be classified as “refractory” when they are not sufficiently controlled by a four-drug combination of levodopa preparations, COMT inhibitors, MAO-B inhibitors and dopamine agonists (see3 for comprehensive review of the effects on response fluctuations). For the latter three substance classes, study data on combination therapy with L-dopa demonstrate an additive effect3, 8-10 and the combined use of levodopa with enzyme inhibitors and dopamine agonists may indeed provide the best continuity of striatal dopamine substitution that is possible with oral drug regimens. The increased risk of impulse control disorders must be considered when using higher doses of dopamine agonists. At least in its controlled release formulation (available in the USA) amantadine has also been shown to reduce response fluctuations. In addition, extended release levodopa/carbidopa formulations (IPX 066, and, more recent, IPX203) were found to be effective in reducing OFF-time compared to immediate release levodopa/carbidopa.11, 12 On-demand dopaminergic therapies (apomorphine pen/sublingual, levodopa dissolved/inhaled) can be used in addition to an optimized stable drug regimen to overcome OFF periods. On demand medication may have to be restricted or avoided in patients with dopamine dysregulation syndrome. If dyskinesias cannot be controlled by adapting dopaminergic medication without loss of efficacy, adjunct amantadine is an well-established option, but tolerability issues may arise in a proportion of patients, particularly mental status changes in elderly subjects or those with cognitive impairment. These recommendations are largely in line with the standards defined for “best medical treatment” in the EARLYSTIM-study.13 Best management of response fluctuations also includes proper patient education, such as taking medication on time, avoiding interference with food intake, maintaining an effective exercise protocol, and sleep hygiene. Dose above response threshold and—if possible—below dyskinesisa threshold. Dose frequency according to individual need. If needed/available: use of soluble formulations for rapid onset eg, in early morning-OFF or delayed ON. Levodopa controlled release for nocturnal symptoms. Consider advanced extended release formulations (eg, IPX) if available. Against dyskinesias, possibly also useful for response fluctuations. Maximum dose 600 mg/d (Amantadine-hemisulfate) or 300 mg (Amantadine-HCl) Consider controlled release formulations if available. If specific substance classes are not tolerated by an individual patient, the applied drug combination may consist of less than four substance classes with or without amantadine. Doses need to be adapted to the individual limit of tolerability. All drug therapies listed in Table 1 have solid evidence from carefully conducted randomized controlled trials regarding their efficacy in reducing response fluctuations or drug-induced dyskinesias.3 The same is true for currently available device-aided therapies (DAT). Compared to conventional treatment DBS and intrajejunal infusions have surgical risks and all infusion therapies carry the burden of handling and wearing equipment. Subcutaneous and intrajejunal infusion therapies have high direct costs which are particularly striking for levodopa infusions.14, 15 Surgical risks, handling issues and costs are reasons to avoid premature use of DAT in patients for whom “best medical treatment” may enable satisfactory motor control. Over the past years several expert groups and Delphi Panels have produced consensus papers to more closely define the criteria of eligibility of a given patient for any of the available DATs and also the timing of these treatments.16-18 While providing useful guidance, they lack definitions of what treatments at which dose should be employed for how long before concluding on someone being “refractory” to “best medical management.” The most recent example is the “Manage PD Tool” promoted by AbbVie that is built around a simple rule of thumb previously suggested by a group of experts following a Delphi-type procedure.16, 17, 19, 20 Time to consider DATs is anchored on the presence of at least 2 h of OFF-time, at least 1 h of troublesome dyskinesia and need of at least five doses of levodopa. Yet, these approaches have generally not addressed the question which of the numerous options of adjunctive therapies to treat levodopa-related motor complications should be tried before resorting to one of the DAT approaches. In recent years there have been calls for an earlier use of DAT.21, 22 The European Academy of Neurology (EAN) in collaboration with the European section of the MDS (MDS-ES) has recently published the first chapter of a set of guidelines for the treatment of PD, which deals with interventions requiring surgery, invasive medication delivery and lesional therapies. The guideline task force concluded that DBS of the subthalamic nucleus (STN) should be offered to eligible patients with PD with “medically resistant fluctuations” and that STN-DBS can be offered to people with early PD and early fluctuations who fulfill the inclusion and exclusion criteria for DBS. Again a definition of “medically resistant” is lacking and optional DBS in patients with “early fluctuations” is recommended based on the 2-year results of the EARLYSTIM study13 that had randomized patients with no more than a 3 year history of motor complications to receive STN-DBS or standardized “best-medical treatment” (BMT) and found a significant benefit of DBS on quality of life, ON-time and dyskinesia severity. Yet, it is not clear from the published data what proportion of participants had undergone medication optimization prior to randomization that met the RMC criteria presented here. Structured “best medical treatment” did not occur until after randomization, so it can be assumed that at the start of the study, the conservatively treated group included both patients with RMC and those still having potential for improvement under BMT. Since this cannot be differentiated from the overall group mean values, we argue that the EARLYSTIM study provides strong evidence to not delay DBS when BMT has failed but cannot be used to infer whether and which drug treatment options are dispensable before surgery. With respect to infusion therapies, there has been no study to date that has investigated whether earlier use in the course of the disease would have (cost-effective) medium- or long-term benefits for patients compared with adaptations of oral or transdermal therapy. While self-scoring motor diaries are an established means to quantify ON- and OFF-time and time spent with troublesome dyskinesias, they cannot capture the impact on individual well-being and the degree of subjective suffering, which may vary among patients with similar diary patterns. Health-related quality of life instruments (eg, PDQ-39) may be more informative in this regard but generally do not allow conclusions on the cause of decreased well-being. A post hoc analysis of the EARLY-Stim study has shown that low pre-surgery QoL is related to a high probability of improved PDQ-39-scores after DBS.23 Whether RMC should actually be a reason for recommending DAT in an individual patient depends not only on the extent of suffering, but also on how much relief can be expected from a reduction of response fluctuations. If the suffering is not caused by fluctuations or dyskinesias, but by disease aspects independent of these, for which no improvement can be expected from infusion therapies/DBS, therapy escalation is not advisable. The spectrum of such problems ranges from psychological/psychiatric complications to autonomic disturbances and motor symptoms which are unlikely to respond to DBS or infusion therapies such as dysphagia, (ON-)dysarthria, (ON-) freezing and tendency to fall. Individualized consideration is also required with respect to those complications of oral drug therapy for which improvement may be expected from one of the DAT. Thus, in individual cases, the use of DAT may be the best way to manage complications of conventional pharmacotherapy such as excessive daytime sleepiness, hallucinations, or impulse control disorders. In fact, open studies have shown evidence that switching to infusion therapy or DBS can improve such non-motor therapy complications.24-26 Another important aspect of differential indication results from individual patient preference regarding specific forms of therapy. Frequent and timely intake of pills is burdensome and/or not feasible in daily life for some patients, and sometimes acceptance (and compliance) is also affected by the sheer number of pills that need to be taken every day. Just as variable as the attitude towards oral pharmacotherapy is the subjective attitude towards technical therapy procedures. Gender differences in information needs, support, motivating factors, and how patients weigh risks and benefits have recently been described.27 Individual patient preference is a core element of informed shared decision finding. Therefore, the wish of patients to bypass the proposed medical algorithm before starting a DAT should be respected when comprehensive risk–benefit information has been provided and patient expectations of improvement are likely to be met by the selected DAT.27 Given the often dramatic efficacy of DBS or infusion therapies on motor fluctuations, the question arises whether such obviously highly effective procedures should not be used earlier in the course of the disease, that is bypassing bothersome adjustments of conventional pharmacotherapy. Yet, possible benefits of DAT must be weighed against the risk of surgical complications in DBS and the need to continuously rely on an external device in infusion therapies. In addition, especially infusion therapies are associated with high direct costs. We therefore believe that a systematic work-up of non-DAT options needs to be done before escalating to more invasive and costly DATs. Using a pragmatic definition of RMC as a trigger for discussing therapy escalation does not significantly delay decision since the proposed algorithm for optimization of oral pharmacotherapy can be applied in a timely manner. The objective degree of disability and the subjective suffering caused by treatment complications is crucial for the decision to escalate therapy to more invasive procedures. An opportunity/risk assessment that includes these aspects and considers individual preferences, fears and reservations is often not the result of a single educational discussion but rather the end point of a time-consuming decision-making process. A pragmatic definition of RMC as suggested in this article, is not thought to substitute shared informed decision making, but provides methodological guidance for the physician to support this process. Individual medical and personal concerns should always be addressed and may prompt the decision to deviate from the standardized protocol. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. GE: 1A, 3A. TW: 1A, 3B. The authors wish to thank Werner Poewe for his advices and for sharing his thoughts on refractory motor complications. Ethical Compliance Statement: (1) The manuscript contains a review of literature and personal opinion of the authors. Therefore no IRB was involved. (2) Informed patient consent was not necessary for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interesi relevant to this work. Financial Disclosures for the past 12 months: GE has received honoraries for consultancy from AbbVie GmbH, Stada GmbH, BIAL GmbH, Desitin GmbH, Neuraxpharm GmbH, Boehringer GmbH, speaker fees from AbbVie GmbH, BIAL GmbH, Cogitando GmbH, Desitin GmbH, ESTEVE GmbH, Licher GmbH, Milupa GmbH, Stada Pharma GmbH, Zambon GmbH and royalties Kohlhammer Verlag, Springer/Nature-Verlag, Thieme Verlag. TW has received speaker fees/honoraria from Bial, Abbvie, Merz, Desitin, Pfizer, Britannia, Zambon, Neuraxpharm, Esteve, and Licher. He received payment of travel, accommodation, subsistence and conference registration from Abbvie. He received payment for expert advice from Stadapharm, Bial, Merz, Abbvie, and Phagenesis. He received funding for research from Abbvie, and Ever Pharma. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Ebersbach et al. (Fri,) studied this question.