CHAPTER 9 Parkinson \200\231s Disease: Premotor Features, Diagnosis, and Early Management 7 9 Side eff ects of COMT inhibitors are primarily dopaminergic (nausea, vomiting, increased dy skinesia) and can usually be con- trolled by down-titrating the dose of levodopa by 20 \200 \22330%. Severe diarrhea has been described with tolcapone, and to a lesser degree with ent acapone, which necessitates stopping the medication in 5 \200\22310% of individuals. Cases of fatal hepatic toxicity have been reported with tolcapone, and accordingly periodic monit oring of liver function is required. Th is problem has not been encountered with entacapone . Discoloration of urine can be seen with both COMT inhibitors because of accumulation of a metabolite, but is of no clinical concern. underlying disease state and is not confounded by symptomatic or pharmacological eff ects o f the study intervention. Some studies have had positive results consistent with the pos- sibility that the drug has disease-modifying eff ects. As described above, selegiline delayed the development of disab ility necessitat- ing levodopa in the DATATOP study, but this result could have been due to a previously unappreciated symptomatic eff ect of the drug that masked rather than protect ed against disease progres- sion. Co-enzyme Q10 is thought to enhance mitochondrial func- t ion, and reduced the rate of decline of UPDRS scores in a pilot study. However, the study w as underpowered and a symptomatic confound could not be excluded. Th e dopamine agonists ro pinirole and pramipexole have anti-apoptotic eff ects in the laboratory, and slowed the rat e of decline of a surrogate neuroimaging biomarker of dopamine function in comparison with levodopa. However, a pharmacological eff ect on the biomarker rather than true protec- tion of dopamine neurons could not be excluded. Th ere has been interest in the possibility that initiating levodopa in combination with a COMT inhibitor will increase its half-life and provide more continuous delivery, thereby re ducing the risk of motor complications. No benefi t was detected in early PD patients in th e recently completed STRIDE-PD study, and the main value of COMT inhibitors continues to be in patients who experience motor fl uctuations. To avoid the problem of a confounding symptomatic eff ect, a delayed-start design has been proposed. Th is is a two-period study in which subjects are randomized to receive the activ e drug or placebo in the fi rst period, while subjects in both groups receive the active dr ug in the second period. Benefi ts of the active drug at the end of period one could be due to symptomatic and/or disease-modifying eff ects. However, benefi ts of early treatment at the end of the sec- ond period, when both groups are receiving the same medication, is unl ikely to be due to a symptomatic eff ect alone and is consistent with disease modifi cation . Th is is substantiated by demonstrating that the rates of decline of motor scores in the early and delayed start groups are not converging, indicating that the benefi t of early tr eatment is enduring. In the ADAGIO study, rasagiline 1 mg met all principal endpoints of th e delayed-start study consistent with the possibility that the drug has a disease-modifying eff ect. However, the 2 mg dose failed in this same clinical trial, and the reason for the se disparate eff ects remains to be clarifi ed. Other medical therapies Centrally acting anticholinergic drugs, such as trihexyphenidyl and benztropine, were used historically for the treatment for PD but lost favor with the intro duction of dopaminergic agents. Th eir major clinical benefi t is an eff ect on tremor, alt hough it is not cer- tain that this is superior to that which is obtained with other agents such as levodopa and dopamine agonists. Still, they can be helpful in individual patients. Th eir use is limited, particularly in the eld- erly, by their propensity to induce a vari ety of side eff ects including prostatism, glaucoma, and particularly cognitive impairment. Amantadine has antiparkinsonian eff ects thought to be due to NMDA receptor antagonism. Whi le some physicians use amanta- dine in patients with early disease for its mild symptomatic eff ects, it is most widely used as an anti-dyskinesia agent in patients with advanced PD. Indeed, it is the only oral agent that has been dem- onstrated in controlled studies to re duce dyskinesia while improv- ing parkinsonian features, and this eff ect can be sustained in many patients. Side eff ects include livedo reticularis, weight gain, and, most importan tly, dose-related impairment in cognitive function. Amantadine should always be discontinue d gradually as patients can experience withdrawal symptoms. Th e importance of the delayed-start design is its potential to detect benefi ts of a putat ive neuroprotective agent that are not due to an early symptomatic eff ect and therefore mu st be due to disease modifi cation. However, long-term studies are required to deter- mine the clinical signifi cance of the drug and assess its eff ect on cumulative disability. Management of early PD Th e management of PD should be tailored to the needs of the individ ual patient, and there is no single approach that is univer- sally accepted (79, 80). Clear ly, if an agent was demonstrated to have disease-modifying eff ects it would be initiated a t the time of diagnosis. Several studies now suggest that it may be best to initi- ate symp tomatic therapy early aft er diagnosis in order to main- tain quality of life and to preser ve compensatory mechanisms and provide benefi ts even in early disease. Levodopa remains th e most eff ective symptomatic therapy for PD, and some recommend start- ing therapy early b ut with relatively low doses to minimize the risk of motor complications. Alternatively, ma ny physicians select an alternative strategy in early patients, especially if they are youn ger, in order to reduce the risk of motor complications. A compromise is to begin with an M AO-B inhibitor or a dopamine agonist and reserve levodopa for when these drugs can no longe r provide sat- isfactory control. In patients with more severe disability, in the eld- erly , where there is cognitive impairment, or where the diagnosis is Neuroprotection Despite the many therapeutic agents available for the treatment of PD, pati ents still experience intolerable disability due to dis- ease progression and the emergence of features such as falling and dementia that are not controlled with dopaminergic therapi es. Th e development of a therapy that slows or stops disease progression is the most impor tant need in PD therapeutics. Towards this end, there are many promising candidate agents b ased on targeting fac- tors implicated in the pathogenesis of PD. However, no agent which u nequivocally has a disease-modifying eff ect in PD has been deter- mined. Obstacles to defi ning a disease-modifying drug include uncertainty as to the precise cause of the disease, and exactly what to target, and a relevant animal model that refl ects the aetiopatho- gene sis of the disease in which to test promising compounds. With the identifi cation of genes and proteins associated with familial PD, it is anticipated that there will be important pr ogress in these areas in the near future. Equally challenging will be the develop- ment of an endpoint for clinical trials that provides a measure of the Oxford Textbook of Movement Disorders 80 uncertain, most physicians would elect to initiate therapy directly with levodopa. It is im portant not to deny patients levodopa in scenarios where they are not adequately controlled by alternative medications. 11. Neumann J, Bras J, Deas E, et al . Glucocerebrosidase mutations in clinical and patholo gically proven Parkinson \200\231s disease. Brain 2009; 132 : 1783 \200\2239 4 . 12. Schapira AH . Etiology of Parkinson \200\231s disease. Neurology 2006; 66 (Suppl 4): S10 \200\2232 3 . If motor complications develop, they can be treated by manipu- lating the frequency and dos e of levodopa, or by combining lower doses of levodopa with a dopamine agonist, a COMT inhi bitor, or an MAO-B inhibitor. Amantadine is the only drug that has been demonstrated to tre at dyskinesia without worsening parkinson- ism, but the benefi ts are not permanent. Eff or ts are being aimed at developing a long-acting continuous delivery oral or transdermal form ulation of levodopa that mirrors the pharmacokinetic proper- ties of a levodopa infusion. S uch a formulation might provide all the benefi ts of levodopa without motor complications a nd avoid the need for polypharmacy and surgical interventions. 13. Ross GW, Petrovitch H, Abbott RD, et al . Association of olfactory dys- function with r isk for future Parkinson \200\231s disease. Ann Neurol 2008; 63 : 167 \200\2237 3 . 14. Ponsen MM, Stoff ers D, Booij J, van Eck-Smit BL, Wolters EC, Berendse HW . Idiopathic hyposmia as a preclinical sign of Parkinson \200\231s disease. Ann Neurol 2004; 56 : 173 \200\2238 1 . 15. Sommer U, Hummel T, Cormann K, et al . Detection of presymptomatic Parkinson \200\231s disease: combining smell tests, transcranial sonography, and SPECT. Mov Disord 2004; 19 : 1 196 \200\22320 2 . 16. Siderowf A, Newberg A, Chou KL, et al . (99mTc)TRODAT- 1 SPECT imaging correlates with odor identifi cation in early Parkinson disease. Neurology 2005; 64 : 1716 \200\2232 0 . Th e non-dopaminergic features of PD remain an important target for future therapies. Agent s that target non-dopaminergic systems, such as A2a antagonists, glutamate antagonists, cho linergic agents, and trophic factors, are all being actively investigated, but it is by no means clear that they will meaningfully infl uence non-dopaminergic symptoms. Th e best pro spect is a neuroprotective therapy which might slow disease progression. While this has pro ved diffi cult to achieve with currently available drugs and clinical designs, there have b een great advances that create opportunities for the future. Advances in genetics have defi ned new candidate targets. Transgenic animals which carry mutations associated with PD are likely to provide animal models for testing candidate neuropro- tective agents that are mo re reliable than those which have been employed to date. Finally, it is hoped that new clin ical trial designs will the delineation of disease-modifying eff ects and their clinical si gnifi cance. 17. Katzenschlager R, Zijlmans J, Evans A, Watt H, Lees AJ . Olfactory func- tion distingui shes vascular parkinsonism from Parkinson \200\231s disease. J Neurol Neurosurg Psychiatry 2004; 75 : 1749 \200\2235 2 . 18. Wenning GK, Shephard B, Hawkes C, Petruckevitch A, Lees A, Quinn N . 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Eur J Neurol 2011; 18 (Suppl 1): 16 \200\2232 1 . 79. Schapira AH . Treatment options in the modern management of 54. Hilker R, Schweitzer K, Coburger S, et al . Nonlinear progression of Parkinson disease as determined by serial positron emission tomo- graphic imaging of striatal fl uorodopa F18 activity. Arch Neurol 2005; 62 : 378 \200\2238 2 . Parkinson disease. Arch Neurol 2007; 64 : 1083 \200\2238 . 55. Schrag A, Dodel R, Spottke A, Bornschein B, Siebert U, Quinn NP . Rate of clinical prog ression in Parkinson \200\231s disease. A prospective study. Mov Disord 2007; 22 : 938 \200 \2234 5 . 80. Schapira AH, Olanow CW . Drug selection and timing of initiation of treatment in early Parkinson \200\231s disease. Ann Neurol 2008; 64 (Suppl 2): S47 \200\2235 5 . This page intentionally left blank CHAPTER 10 Parkinson \200\231s Disease: Advanced Disease, Motor Complications, and Manageme nt Susan H. Fox , Binit Shah, Richard Walsh , and Anthony Lang Introduction Th e early stages of Parkinson \200\231s disease (PD) can be well managed with medical therapy. However, as the disease progresses, motor complications make it diffi cul t to maintain adequate control of par- kinsonian symptoms. Motor complications can broadly be divided into those which are amenable to dopaminergic therapies and those which tend to be refractory (see Table 10.1). Th e two main catego- ries of levodopa-responsive motor com plications are motor fl uctu- ations and dyskinesia. Motor complications that are less resp onsive and oft en refractory to dopaminergic therapy include drug-resistant tremor, postura l instability, freezing of gait, postural deformity, and speech problems. Th is chapter des cribes these motor complications and provides practical approaches to treatment and managem ent. levodopa, whereas the LDR refers to maintained benefi t of levo- dopa therapy beyond the no rmal half-life of an individual dose. Th e LDR is dominant in early PD, where patients with mild early disease are adequately controlled with only two to three daily doses of levodop a. Patients tend to note no temporal response to their medication doses and no \200\230wea ring off \200\231, even if a dose is taken late or missed entirely. In advanced PD, the SD R is the more typical response to levodopa doses. In this case, PD patients are much more a ware of the timing of individual levodopa doses. Th e maxi- mum benefi t of levodopa on PD symptoms may remain robust, but the duration of the eff ect shortens and the benefi t is le ss consistent. Peripheral pharmacokinetics of levodopa in relation to absorption via the ga strointestinal (GI) tract can also play a signifi cant role in the development of motor com plications and will be discussed further below. Th e cause of drug-resistant motor complica tions in advanced PD is less clear, although progressive degenerative changes beyond the do paminergic nigrostriatal system (e.g. within brainstem and cerebral cortex) are likely to b e important. Full dis- cussion of the pathophysiological changes that may occur in all form s of motor complications is beyond the scope of this chapter. Th e pathophysiology of motor complications Th e development of drug-responsive motor compl ications occurs as a result of a combination of disease progression and chronic levodopa th erapy. Th e plasma half-life of levodopa is short ( 90 min); early in the disease this is b uff ered by the storage capabili- ties of remaining nigrostriatal neurons. Over time there is loss of presynaptic nigrostriatal dopaminergic input with more pulsatile stimulation of dopamine receptors. Th e consequent loss of the nor- mal tonic stimulation of postsynaptic dopamine receptors results in pharmacodynamic changes in basal ganglia signaling pathways. In addition, there are peripheral and central pharmacokinetic factors that contribute furth er to the fl uctuant response to levodopa (1). One means of defi ning the development of mo tor complications over time is the duration of antiparkinsonian response to levodopa. Th us , the antiparkinsonian response can be divided into what is termed the \200\230short-durat ion response \200\231 (SDR) and the \200\230long-duration response \200\231 (LDR) (2, 3). Th e SDR refers to levodopa benefi t on PD symptoms which occurs in response to each indivi dual dose of Drug-responsive motor complications OFF state complications Predictable wearing-o \200 Th e earliest encountered fl uctuation in advancing PD is predictable wearing-off . As describ ed above, the LDR eff ect begins to wane and the duration of benefi t of each dose of levod opa becomes shorter. Akinesia on awakening in the morning may be the fi rst sign of this th at patients notice. Additionally, patients who forget doses or take them late will begin to recognize a re-emergence of problematic symptoms. Patients inevitably become more dependen t on the need to rigidly adhere to their dose schedules. For some patients, factors such as exercise can further accelerate the wearing-off of Oxford Textbook of Movement Disorders 84 time (4, 5). Th e bioavailability of these longer acting preparations is 20 \200\22330% les s than standard release preparations and patients require higher daily doses of levodopa, w ith a greater risk of dys- kinesia (6). In addition, these preparations typically have a lo nger latency from drug intake to benefi t, so patients may experience \200\230delayed-ON \200\231 problems. Table 10.1 Motor complications of advanced PD OFF-state complications On-state complications Transitional state complications Drug-responsive Predictable wearing-o \200 Peak-dose dyskinesia Beginning-of-dose worsening and end-of- dose rebound Adding an inhibitor of catechol- O -methyltransferase (COMT), an enzyme involved in the bre akdown of levodopa and dopamine, can help prolong the duration of action of levodopa and re duce OFF time. Th e peripheral COMT inhibitor entacapone has been demonstrated to reduce OF F time by an average of 1 hour per day (7). Retrospective analysis of four phase III RCTs ( pooled n = 977) comparing RCTs of levodopa and entacapone with levodopa for 6 months follow ed by open-label addition of entacapone for up to 5 years showed maintained improvement in ON time (as meas- ured by duration of action of fi rst dose of the day) above baseline. How ever, 28% discontinued due to side eff ects including worsening of PD and dyskinesia (8). A combined formulation of levodopa \200\223 carbidopa and entacapone is also available and c an help reduce the number of tablets patients take while achieving the same benefi t as ent acapone taken separately (9). Sudden/unpredictable OFF ON freezing Diphasic dyskinesia OFF freezing Delayed ON OFF dystonia Tachykinesia Dose failure/partial response Drug-resistant Gait and balance ON-period freezing Speech problems Refractory tremor Dysarthria and dysphagia Postural deformity Tolcapone is another COMT inhibitor that has both central and peripheral actions and, becau se it has a longer half-life than entaca- pone, can be given three times daily regardless o f levodopa timing (10). Tolcapone may be more effi cacious than entacapone although no dire ct comparison has been performed. A meta-analysis of 14 studies with 2566 patients showed t hat tolcapone-treated patients had superior improvements in placebo-corrected ON time and O FF time compared with entacapone-treated patients (11). Tolcapone was withdrawn because of concerns related to liver toxicity in unmonitored patients. However, it has been reintroduc ed in several European countries and the US Food and Drug Administration (FDA) has modifi e d monitoring requirements such that liver func- tion testing is required every 2 \200\2234 weeks for 6 months and at the physician \200\231s discretion thereaft er. the levodopa dose. A suggested algorithm for treating predictable wearing-off is shown in F ig. 10.1. Th e treatment of predictable wearing-off involves maintaining a minimum eff ective level o f levodopa throughout the day. Simply decreasing the dose interval to around 4 hours may be suffi cient when wearing-off fi rst begins. Alternatively, maintaining dose tim- ings but increasing individual doses can also serve to increase the duration of action for levodopa, but with the risk of inducing dys- kinesia. Th ere may be an attraction to using a long-ac ting form of levodopa such as levodopa CR; however, double-blind rand- omized controlled tr ials (RCTs) comparing CR with standard lev- odopa have shown no benefi t of such a strategy in reducing OFF Monoamine oxidase B (MAO-B) is an enzyme which catalyzes the oxidation and inactivation of monoamines, including dopamine. MAO-B inhibitors block this action and therefore prolong th e eff ect of levodopa. Th e currently approved agents are selegiline and rasagiline. Selegi line is available in an oral ingestible tablet form and reduces OFF time by 1.6 hours per d ay (12). Concerns related to potential amphetamine metabolites led to development of a zydi s form that disintegrates under the tongue and bypasses hepatic metabolism with reduced amp hetamine metabolite pro- duction (13, 14). Evidence for benefi t using this preparation is con- tradictory, with one study showing a signifi cant eff ect on reducing total daily OFF time in patients with predictable wearing-off com- pared with placebo (15) and a second stu dy showing no eff ect (16). Rasagiline is another MAO-B inhibitor that is not associated wi th the production of amphetamine metabolites (17). It can signifi - cantly reduce total dai ly OFF time by 1.18 \200\2231.8 hours (18, 19). No head-to-head comparison study between se legiline and rasagiline has been conducted. Add additional dose of levodopa OR Decrease interval Watch for problematic peak-dose dyskinesia Increase levodopa dose Mild OFF symptoms Add dopamine agonist Add COMT inhibitor* Dopamine receptor agonists provide reliable long-acting dopamine receptor stimulation and a re options for managing predictable wearing-off . Th e non-ergot agents ropinirole, ropinir ole prolonged release (PR), pramipexole, and rotigotine, and the ergot-derived dopamine ago nists pergolide, cabergoline, and bromocriptine, have all been shown to signifi cantly redu ce OFF time by an average Add MAO-B inhibitor* The order of choosing these could be interchangeable Fig. 10.1 Algorithm for managing predictable OFFs. CHAPTER 10 Parkinson \200\231s Disease: Advanced Disease, Motor Complications, and Manageme nt 85 Unpredictable OFFs, sudden OFFs, and ON \200\223OFF \202 uctuations Patients may experien ce unpredictable wearing-off that is unrelated to medication timing. When this wearing-off is rapid, occurring over seconds or minutes, it is termed \200\230sudden-OFF \200\231 (29) . Triggers such as exercise or emotional stress may be present, but there is oft en no iden tifi able cause. Many advanced PD patients also encounter ON \200\223OFF fl uctuations, or \200\230yo-yoing \200\231 (29). Th ese oft en rapid and unpredictable fl uctuations betwee n the ON and OFF states can be very debilitating. of 1 \200\2231.5 hours per day and improve duration of ON time when combined with levodopa (20 \200\22327). To date, studies using once-daily pramipexole extended release (ER) in adv anced PD for wearing-off have not been reported. Dopamine agonists with a longer duration of action and/or once-daily dosing (e.g. cabergoli ne, ropinirole PR, pramipex- ole ER) or the transdermal rotigotine patch would appear to be more attractive options. However, to date, there appears to be no advantage to this strate gy and improvement in OFF time appears comparable with other orally active dopamine agonist s. A recent RCT comparing efficacy of the longer-acting version of ropinirole PR and regula r ropinirole immediate release (IR) reported a significant benefit of ropinirole PR in the propor- tion of patients maintaining \211 20% reduction in OFF time (28), although the fi nal dose of ropinirole was higher in the PR group than in the IR group, thus making compari sons difficult. The relative efficacy of all currently available add-on therapies to levodo pa, including dopamine agonists, COMT inhibitors, or MAO-B inhibitors, is not clear because there is a lack of rand- omized comparator studies. One RCT has shown that rasagiline and entacapone are equally efficacious at reducing wearing-off ( \200\2231.18 hours/day for ras agiline and \200\2231.2 hours/day for entaca- pone compared with \200\2230.4 hours/day fo r placebo (19). A recent meta-analysis evaluating RCTs of add-on therapies using indi- rect comparisons showed that dopamine agonist therapy was more effective and reduced OFF time b y 1.6 hours/day, com- pared with 0.8 hours/day with COMT inhibitors and 0.9 hours/ day with MAO-B inhibitors (12). However, side effects were more frequent with dopamine agonists and COMT inhibitors than with MAO-B inhibitors (12). Treatment of such fl uctuations can be challenging. A practical approach to this problem is outlined in Fig. 10.2. For subjects on levodopa CR, one option is to convert to regular re lease levodopa; this ensures a more consistent onset and duration of eff ect, and allows fo r more precise dose titration. Increasing levodopa dose or frequency can then help to comba t sudden OFFs and unpredictable OFFs, but one must be vigilant about worsening dyskinesia. Adding or increasing the dose of a dopamine agonist allows an increase in overall dopaminer gic treatment with less risk of worsening dyski- nesia. Indeed, adding a dopamine agonist m ay permit a reduction in levodopa dose and may even improve dyskinesia. Practically, howeve r, side eff ects associated with dopamine agonists (see Table 10.3) oft en limit their use in this advanced PD population. Rapid-onset oral forms of levodopa may be useful as \200\230rescue \200\231 for sudden-OFF s. Th ese agents provide a more reliable rapid absorption and onset of eff ect (30). Prepar ations available include orally disin- tegrating levodopa \200\223carbidopa and levodopa \200\223benserazide, levodopa methylester, and levodopa ethylester (31). Th ese levodopa pr epara- tions are not amenable to scheduled dosing because of the short duration of eff ect (1 \200\2231.5 hours) and are best used as intermittent rescue agents. An alternative when such soluble preparations are Sudden OFF OR ON \200\223OFF \202uctuation Dose failure OR Partial response to dose Change levodopa CR to regular release for more reliable e \200ect Optimize levodopa dose and frequency (See Fig. 10.1) Enhance absorption of levodopa: \200 Take on empty stomach \200 Crush tablet; take with carbonated drink \200 Treat constipation \200 Treat H. pylori infection Add dopamine agonist Reduce levodopa \202uctuation: \200 Apomorphine infusion \200 Levodopa \200\224duoden al infusion \200 Deep brain stimulation surgery Rescue agents: \200 Apomorphine injections \200 Soluble levodopa Fig. 10.2 Algorithm for managing unpredictable OFFs. Oxford Textbook of Movement Disorders 86