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 unavailable is to use a liquid levodopa preparation made by crush- ing levodopa \200\223per ipheral decarboxylase tablets, mixed together with water and ascorbic acid (vitamin C) as a n antioxidant. Th is solution allows for minute dose adjustments and more rapid onset. Th e drawbacks to liquid levodopa include instability; the solution remains stable for less tha n 24 hours and must be refrigerated and kept away from light (32). Making up a new solution every day and storing and carrying it in portable containers can prove onerous. Patients a nd families oft en abandon this strategy soon aft er start- ing. Another rescue agent worth y of consideration is parenteral apomorphine. Th is is a dopamine agonist which has been us ed for many years in Europe for the treatment of ON \200\223OFF fl uctuations and sudden-OF F (33). A single subcutaneous injection can allevi- ate parkinsonian signs within 5 \200 \22315 minutes and last for 1 \200\2231.5 hours (34). Th e dose needs to be determined for an individual patient and ranges from 3 to 10 mg. An open-label follow-up of 546 PD patient s using subcutaneous apomorphine for OFF periods reported the most eff ective average dose to be 4 mg (35). Pre-treatment with oral antiemetics such as trimethobenzamide hydrochlorid e (300 mg tid) or domperidone (20 mg tid) is necessary given the pro-emetic eff ects of apo morphine. For subjects requiring several injections per day with persistent unpredictable O N \200\223OFF fl uctuations, apo- morphine can also be given as a continuous subcutaneous i nfu- sion. Apomorphine infusions may be an alternative for individuals unsuitable for surgi cal treatments (see section below on treatments for unresponsive motor fl uctuations). \227\206 Empty stomach. Patients should also be instructed to take lev- odopa on an empty stomach (at least 30 minutes prior to food or 2 hours aft er) or with a light snack. If nau sea is a problem, patients can be pretreated with an antiemetic agent with promo- tility pr operties, such as domperidone. \227\206 Constipation and anticholinergic s. Treating constipation and reducing or stoppin g anticholinergic treatment can provide improved GI motility and ease patient discomfort. I n our experience, most standard stool soft eners, osmotics, and stimu- lant laxatives are e ff ective in managing constipation in PD. \227\206 Treatment of Helicobacter pylori. infection is thought to cause a gastroduodeniti s which interferes with levodopa absorption. Th ere is recent evidence that eradication of H. pylori infection improves the effi cacy of anti-PD therapy and hence reduces motor fl uc tuations (37, 38). \227\206 Soluble levodopa. Th ese preparations have a more rapid and reli- able onset of action \227\206 Apomorphine. Bypassing the GI system with parenteral apomor- phine can avoid prob lems with levodopa gastrointestinal absorp- tion entirely. Acute deterioration of symptoms or persistence of unexplained dose failures in advanced PD without cause should raise suspicion of co-morbid pathologies (39). It is important to asse ss patients thoroughly for changes in compliance, intercurrent illness, or other factors wh ich may aff ect PD control (Table 10.2). Dose failure: no response to dose, delayed response, partial response In early PD, patients may fi nd that their response to levodopa is not greatly aff ected by diet or the relation ship between meal and medication times. In advanced PD this typically changes, and maximizi ng levodopa absorption can be a key factor in reducing motor complications. Th e disease pr ocesses underlying PD, as well as intake of food per se, can lead to slowed gastric emptyin g with delay of levodopa transit and absorption in the small bowel. Constipation also resul ts in slowed gastric emptying and worsens levodopa absorption. Other medications used in th e treatment of PD, particularly anticholinergic agents, can further slow gastric emptying a nd bowel motility. Additionally, levodopa competes with dietary large amino acids for trans portation into the bloodstream and, in particular, across the blood \200\223brain barrier. Beginning-of-dose worsening and end-of-dose rebound Patients can experience worsening of th eir symptoms soon aft er taking a levodopa dose, called \200\230beginning-of-dose worsenin g \200\231 (40). Th ese symptoms, most commonly tremor, last for a short time (5 \200\22315 min) aft er which a more usual benefi cial response ensues. Similarly, patients may also n ote an exacerbation or rebound of their symptoms as a dose of levodopa wears off , called \200\230end-of-dose rebound \200\231 (41). Th ese rebounds can result in a phenomenon known as \200\230super-OFFs \200\231 where, as a dose of levodopa wears off , symptom severity is notably worse than in the early morning when the long- est time has passed between levod opa doses. Fluctuating non-mo- tor symptoms or non-motor fl uctuations (e.g. pain, akathisi a, behavioral changes) oft en complicate these super-OFFs, adding considerably to the patie nt \200\231s disability. Treating these symptoms is diffi cult. Adding a dose of levodopa w hile still in the ON state can help to avoid problematic wearing-off , but it oft en does s o at the cost of increasing dyskinesia. Other approaches to treating motor fl uctuations ou tlined above can all be tried with varying success. Referral for deep brain stimulation (DB S) should be considered when medication changes are unsuccessful for all the above motor co mplications. A delayed ON is an increase in latency between taking a dose of levodopa and experiencing b enefi t from it (36). A partial response or entirely absent response to a dose of levodopa are called partial ON or dose failure (no-ON), respectively. Th ese problems are oft en cau sed by defi cient or delayed levodopa absorption in the GI tract. Delay in the action of on e dose can sometimes result in simultanous onset of eff ect with a subsequent dose, resulti ng in marked dyskine- sias, further contributing to the wide variation in levodopa response . Th is eff ect can be further exacerbated by patients taking additional doses when they ar e concerned that a delay in onset means that a tablet has \200\230not worked \200\231. A n umber of strategies can be tried in the hope of making the response to treatment more predi ctable: OFF-period freezing Freezing represents a transient inability to initiate or continue volun tary movement, usually lasting several seconds. Freezing is common in advanced PD but can o ccur at any stage. Early freez- ing should prompt consideration of an alternative diagnosis , such as progressive supranuclear palsy or vascular parkinsonism. Freezing can disrupt mov ement in any muscle group, but \200\230freez- ing of gait \200\231 (FoG) is the most commo n form observed and is an important contributor to the risk of falling. Freezing of gait ca n occur on initiation of gait (start hesitation), when turning, or \227\206 Dietary protein intake. Protein intake should be adjusted in such a way as to red uce interference with levodopa absorption. Th is can be accomplished by directing patients to avoid large protein loads at the morning meal and spread protein intake throughout the d ay. CHAPTER 10 Parkinson \200\231s Disease: Advanced Disease, Motor Complications, and Manageme nt 87 Table 10.2 Management of acute deterioration in advanced PD 1. Check for missed doses or in appropriate administration of dopamine receptor antagonists. Th is is most common in the pe rioperative setting. 2. A change of levodopa formulation between generic and proprietary brands can sometimes ca use a change in clinical response, although this is uncommon and generally mild. A planned or inadvertent change from intermediate to controlled release formulation will reduce the b ioavailability of administered levodopa by approximately 30%. 3. Constipation can a \200 ect absorption of levodopa and hence result in apparent worseni ng of underlying PD. A plain \201 lm of abdomen can help diagnose constipation, but this is usually clear from the history. Resolution can sometimes consider ably improve individual dose responses. 4. If the pattern of lower limb weakness appears pyramidal or there is an unexplained deter ioration of gait that is unresponsive to levodopa, always consider a cervical spine problem, particularly in the age group with advanced disease. Be particularl y suspicious when dyskinesias below the neck resolve in the setting of new gait impairment. 5. Where there is also cognitive deterioration, eliminate other common causes of systemic u pset in an elderly population, including electrolyte imbalance, dehydration, new drugs, and infections. Where there is a history of falls consider a CT bra in scan to rule out a subdural haematoma. Long-standing drugs such as amantadine that were previously tolerated may subacutely become toxic due to changes in renal function or age-re lated changes in cerebral tolerance. less commonly on reaching a destination such as approaching a chair to sit down. Another ch aracteristic of freezing is responsive- ness to triggers. Patients will oft en report incre ased incidence of freezing in situations where they must deal with restrictions in time (cr ossing the street with a changing light is oft en cited as an example) or space (a narrow d oorway). A change in sensory inputs such as a transition from one color of fl oor tile to a nother can also trigger freezing. Th e relationship of freezing to levodopa treatment is co mplex. It has been suggested that freezing is a side eff ect of levodopa treatment (42). Lo nger duration of levodopa treatment correlates with freezing, although this association may be more refl ective of an association with greater disease severity rather than with levod opa per se (43). Freezing can be seen in both treated and untreated PD, supporting the noti on that it is a disease-related phenomenon and not necessarily a motor com- plication of le vodopa treatment, although in some patients high doses of levodopa or dopamine agonists cle arly trigger or worsen freezing. Non-dopaminergic pathology may also be important as there appears to be a relationship with the emergence of balance and speech problems, which are t ypically unresponsive to levo- dopa treatment (see later section). Amantadine is another drug with a mild dopaminergic eff ect which may be helpful for freezi ng in some patients, although there is con- fl icting evidence (43, 49). ON period and unpr edictable freezing and non-dopaminergic approaches to their management are dealed with late r in this chapter. OFF dystonia Dystonia can occur during OFF periods or when dopaminergic therapy is wearing off . Th e prototypical time for this is upon awaken- ing in the morning, known as \200 \230early morning OFF dystonia \200\231 or \200\230early morning painful dystonia \200\231 . Th is tends to involve the extremities, particularly the feet, and toe curling or other f i xed dystonic posture is commonly reported (50, 51). Th ese problematic OFF times can be m anaged by having patients take levodopa prophylactically or as soon as symptoms begin. Solu ble levodopa preparations, crushing levodopa tablets, or rescue injections of apomorphine c an provide fast-acting options to reverse OFF symptoms. For early morning dystonia, patient s can be instructed to set an alarm and take a dose of levodopa overnight. Levodopa CR at b edtime can provide ben- efi t by providing some dopaminergic coverage by the time patients wake up. An algorithm for the management of dystonia in PD is reviewed later (see Fig. 10.4 ). Th e underlying pathophysiology of freezing is unclear. Freezing episodes may be the tip of the iceberg, with evidence of sub clinical stride-to-stride variation and progressive shor tening of stride before freezing episodes in aff ected patients (44). Th is would suggest t hat freezing is not a paroxysmal gait disorder but part of a wider dis- order of the timing and scaling of lower limb movements during walking. OFF-period freezing has been linked to abnormalities of temporal discrimination thresholds that normalize with levodopa (45). Cog nitive load appears to be a factor in some cases, raising the possibility that an attentive defi cit contributes to freezing when \200\230dual tasking \200\231 (46). ON state complications Th e long-term eff ectiveness of levodopa can become complicated by the development of involuntary movements \200\224dyskinesia. Less frequently subjects can a lso experience some worsening of certain symptoms with levodopa, including freezing (ON-fre ezing) and increased speed of movements (tachykinesia). Dyskinesia It is important to determine the timing of dyskinesia in relation to the antipar kinsonian action of levodopa as treatment options will vary. In the majority of patients freezing occurs in the OFF state, sug- gesting a relationship w ith low dopamine levels (47). Th is off ers an important therapeutic avenue to begin with w here this relationship can be gleaned from the history. Th erefore management of OFF states can reduce OFF period freezing. Th ere has been interest in the possibility that the MAO-B inhibitor selegiline may have an additional protective eff ect by reducing the risk of fut ure freezing. A double-blind placebo-controlled follow-up of the DATATOP cohort found that fewer patients treated with selegiline went on to develop freezing (48). However, much of t he therapeutic eff ect in patients with OFF period freezing is likely to be due to a sympto matic eff ect. Peak-dose dyskinesia Peak-dose dyskinesia is the most common form of dyskinesia and occurs at the time of the best ON response to levodopa, while less commonly \200\230square-wave \200\231 dyskinesia occurs throughout the entire duration of levodopa eff ect (52). Peak-do se dyskinetic movements are typically choreiform, oft en of the neck and limbs, but dystoni c posturing is also common (53). Ballistic movements and myoclonus are rare. Dyskinesia oft en begins with limb and neck involvement on the side most aff ected by PD (54). As the dis ease progresses and Oxford Textbook of Movement Disorders 88 dyskinesia becomes more prominent, facial dyskinesia and even diaphragmatic dyskinesia can be seen. tachyphylaxis can limit long-term use of amantadine. However, a recent study suggested ongo ing benefi t of amantadine for dyski- nesia aft er a mean use of 4.8 years (59). Treatment of peak-dose dyskinesia begins with fi rst identifying the degree to which dyskin esias are problematic. Most patients on levo- dopa therapy will develop dyskinesias as some point (55); however, these dyskinesias are oft en not troublesome (56). Where dyskinesia i s either physically limiting for patients, or presents unacceptable social embarrassment, t reatment is required. A practical approach to managing dyskinesia is shown in Fig. 10.3. Fi rst, reducing the dose of levodopa should be attempted with close observation of the patien t to assess for worsening parkinsonian disability. Along with decreasing individual doses o f levodopa, increasing dose frequency may be required to avoid wearing-off . Using frequent small doses of levodopa runs the risk of causing a very unpredictable fl uctuating motor s tate with multiple dose failures. Dopamine agonists may be used to enable a reduction in le vodopa without worsening of dyski- nesia. Another option is to reduce or discontinue the us e of COMT inhibitors and MAO-B inhibitors. As PD advances and motor fl uctuations are more problematic, these adjuvant agents provide less benefi t than in earlier disease, they are more likely to induce dyskinesia, and stopping them may not adversely aff ect overall PD sy mptom control (12). Clozapine is an atypical antipsychotic agent with a reduced propensity to worsen parkinsoni an symptoms because it has less affi nity for striatal dopamine D2 receptors than standard neu- roleptics and non-dopaminergic properties (60). Th ese properties have enabled clozapi ne to be safely used to treat PD psychosis. A single RCT demonstrated that clozapine reduce d dyskinesia by 30%, although the eff ect was largely on resting and not activated dyskines ia (61). Th e possible adverse eff ect of agranulocytosis warrants frequent blood monitorin g and thus can limit its con- venience and use. Botulinum toxin injections can be used for problematic or dis- abling focal dystonic dyskin esias. Th ese are best used when there is a more fi xed posture (especially accompanied by pain) where targeted injections can provide signifi cant benefi t without risk of bothersom e weakness (62). Th e management of dystonia (both ON and OFF period) is summarized in Fig. 10.4. Diphasic dyskinesia Diphasic, or \200\230beginning-of-dose/end-of-dose \200\231, dyskinesi a involves predominant lower extremity stereotypical alternating, jerking, dystonic, or bal listic kicking movements (53). Th ese symptoms occur at low or intermediate levels of levod opa (i.e. when dopamin- ergic tone is increasing soon aft er a dose is given or decreasing as a dose is wearing off ). Managing these symptoms can be challen ging. Clinical experienc e suggests that the most eff ective option is to add a dopamine agonist to provide longer-a cting dopamine receptor stimulation. To date, no RCTs have been performed to fully evalu- a te this approach. Agents used for predictable wearing-off typically do not work well for di phasic dyskinesia. Shortening the levodopa interval may work temporarily; however, the timi ng oft en quickly If the above steps fail to reduce problematic dyskinesia or lead to unacceptable worsening of PD symptoms, introducing a specifi c antidyskinesia agent should be considered. Th e mos t commonly used agent for this purpose is the non-selective N -methyl- d -aspartate (NMDA) receptor antagonist amantadine (100 \200\223400 mg/day), which has been shown to reduce dys kinesia without worsening parkinsonian symptoms (57, 58). Waning of benefi t and Decrease individual levodopa doses Dystonia Shorten levodopa dose intervals Add or increase long- acting dopamine agonist ON dystonia OFF dystonia Early morning dystonia Change levodopa CR to regular levodopa Management of peak-dose dyskinesia (See Fig. 10.3) Minimize OFF time (See Fig. 10.2) Add bedtime dose of levodopa CR OR Overnight dose of regular levodopa Discontinue COMT inhibitor and MAO-B inhibitor Focal botulinum toxin injections \200 Antidystonia agents (e.g. trihexyphenidyl, benztrop ine) \200 Muscle relaxant agents (e.g. baclofen) \200 Benzodiazepines Treat dyskinesia directly: - Amantadine - Clozapine Reduce levodopa \202uctuations: - Liquid levodopa - Apomorphine infusion - Levodopa \200 \224duodenal infusion Consider deep brain stimulation Consider DBS Fig. 10.3 Algorithm for managing peak-dose levodopa-induced dyskinesia. Fig. 10.4 Management of dystonia in PD. CHAPTER 10 Parkinson \200\231s Disease: Advanced Disease, Motor Complications, and Manageme nt 89 resets with a relapse in symptoms aft er a short hiatus. A fast-acting rescue, in the form of a soluble or crushed levodopa or apomor- phine injection, may shorten or help avoid this phenomenon entirely (63). Some patients will have a mixture of both diphasic and peak-dose dyskinesia, thus making management very diffi - cult. If suitable, patients with diphasic dyskinesia may benefi t from bilateral subthalamic nucleus (STN) DBS (64). If problematic, such symptoms should be managed in the same manner as peak-dose dyskinesia. Additionally, speech and physi- cal therapy, paying particular attention to these issues, may provide some degree of benefi t and should be explored. Currently available agents for the management of drug-responsive motor complications, their adverse eff ects, and conclusions from current evidence based medicine (EBM) reviews from the American Academy of Neurology (AAN) Practice Parameters and Movement Disorder Society E vidence-Based Medicine Updates on Treatments of Motor Symptoms of PD are reviewed in Table 10.3. For recent reviews on new drugs in development for motor complications, see refs 66 a nd 67. Tachykinesia Some patients may experience an increase in speed in speaking (tachyphemia) an d walking (tachyambulia). Th ese are ON-period phenomena usually associated with higher dos es of levodopa (65). Table 10.3 Drug classes used for advanced PD motor symptoms, evidence for their use, and ad verse e \200 ect pro \201 le Motor complication Class of drug Drug(s) AAN Practice Parameter recommendations (68) Mov Disorder Society EBM recommendations 2002, 2005, 2011 Ropinirole, ropinirole ER, pramip exole, pergolide, and rotigotine are e \203 cacious Bromocriptine and cabergoline are prob ably e \203 cacious Side e \200 ects Predictable wearing-o \200 Dopamine receptor agonists Ropinirole (up to 24mg/ day), ropinirole PR Pramipexole (up to 4.5mg/day) Rotigotine patch (up to 6mg/24h) Bromocriptine (up to 100mg/day) Cabergoline (up to 3mg/day) Pergolide (volu ntarily withdrawn) Pergolide, pramipexole, and ropinirole should be considered for treatment of wearing-o \200 (level B) Cabergoline may be considered (level C). Bromocriptine may be disregarded (l evel C) Th ere is no evidence that one DA is superior to another Common: nausea, postural hypotension, somnolence, hallucinations, lower extremity oedema, s leep fragmentation (68) Major: impulse control disorders (ICDs) including excessive or unco ntrollable gambling, shopping, hypersexuality, and hyperphagia (69) COMT inhibitor Entacapone (200mg/ dose of levodopa up to 8 per day) Tolcapone (100mg tid) Entacapone (level A) and tolcapone (level B) are e \200 ective at reducing wearing-o \200 Th ere is no evidence that one COMT inhibitor is superior to another Entacapone and tolcapone are e \203 cacious Common: constipation, nausea/ vomiting, dry mouth, somnolence Major: long-term follow-up of liver monitoring of tolcapone reported that mild increases in transaminases are common, bu t >3 times normal is rare (1 \200\2232%) with no mortality (70) Levodopa Levodopa CR, DDCI controlled release Levodopa \200\223carbidopa CR is not helpful in treating motor \202 uctuations (level C) Insu \203 cient evidence Similar to regular release levodopa \200\223carbidopa MAO-B inhibitor Selegiline (5 \200\22310mg) Rasagiline (1 \200\2232mg) Zydis selegiline (buccal absorption in order to minimize \201 rst-pass metabolism) Rasagiline is e \200 ective at reducing wearing-o \200 (level A) Selegiline (level C) No current evidence that one MAO inhibitor is superior to another Insu \203 cient evidence for selegiline and zydis selegiline in motor \202 uctuations Ra sagiline is e \203 cacious Common: constipation, dizziness, hypotension, emesis Drug interaction: there is a theoretic al risk of serotonin syndrome with MAO-B inhibitors and concurrent use of antidepressants ( tricyclic and serotonin reuptake inhibitors). However, recent RCTs using rasagiline in PD p atients also using antidepressants report no cases of serotonin syndrome (71) Tyramine e \200 ect: unlike MAO-A inhibitors, MAO-B inhibitors have not been shown to augment the hype rtensive e \200 ects of tyramine ingestion (the \200\230cheese e \200 ect \200\231) (72) . Th eoretical risks should be explained to patients, but concerns should be allayed given the current evidence of safety (Continued) Oxford Textbook of Movement Disorders 90 Table 10.3 (Continued) Motor complication Class of drug Drug(s) AAN Practice Parameter recommendations (68) Mov Disorder Society EBM recommendations 2002, 2005, 2011 Insu \203 cient evidence Side e \200 ects Dose failure, no-ON response, sudden-OFFs; ON \200\223OFF \202 uctuations Levodopa Dispersible: levodopa \200\223benserazide Carbidopa: orally disintegrating tablets Levodopa methylester (melevodopa), levodopa ethylester (etilevodopa) Similar to regular release levodopa \200\223carbidopa Stable suspension of levodopa and carbidopa in methyl cellulose by infusion via gastrojejun ostomy Probably e \203 cacious Acute complications include peritonitis, hemorrhage, local wound infection, and perioperati ve delirium in elderly patients Hardware issues are relatively common and include tube kink ing, displacement, and occlusion Case reports of peripheral neuropathy/ GBS with duodenal l evodopa; possibly associated with vitamin B 6 de \201 ciency \200\224 further studies are ongoing (73) Parenteral DA Apomorphine \200\224 intermittent or (3 \200\22310mg) infusion (30 \200\223100mg/ day) s.c. Apomorphine is e \203 cacious Subcutaneous injections Nausea prevented/reduced using trimethobenzamide hydrochloride (300 mg tid) or domperidone (20mg tid) Hypotension, visual hallucinations and worsening psychos is, punding Infusional therapy: side e \200 ects as above plus subcutaneous nodules \200 \224treated with ultrasound and rotation of injection sites; olive-green discoloration of c lothing Dyskinesia Non-subtype selective NMDA-receptor antagonist Amantadine (100 \200\223400mg/d) Amantadine may be e \200 ective (level C) E \203 cacious Psychosis, confusions, hallucinations, painful lower extremity oedema, and livedo reticular is Side e \200 ects: corneal lesions; myoclonus (dose/plasma-level dependent); care with r enal disease Atypical antipsychotic Clozapine (12.5 \200\223100mg/d) Insu \203 cient data to recommend clozapine E \203 cacious Agranulocytosis: required mandatory monitoring Sedation, postural hypotension DA, dopamine agonist; DDCI, dopa decarboxylase inhibitor. Treatment options for \202 uctuations refractory to oral therapies Apomorphine infusion A pomorphine is a potent dopamine agonist that can be admin- istered by either intermittent s ubcutaneous (s.c.) injection for sudden-OFF periods (see above) or infused over 12 \200\223 24 hours as a method of treating motor complications. Th e system requires a portable pump that is connected to a small needle usually inserted into the skin of the thigh or abdomen. Th e injection site is rotated to avoid the development of subcutaneous nodules. Th e main indi- cation for apomorphine infusion would be for subjects with motor complications unsui table for deep brain stimulation (DBS) of the subthalamic nucleus (discussed below). Apomor phine infusion is eff ective at reducing overall OFF time by 60 \200\22370% and can also im prove dyskinesia (by up to 60%) by a mechanism other than simply permitting a reduction in levodopa dose (74). Despite this benefi t, uptake in use o f apomorphine is limited because of cost and practical issues related to skin viability (e. g. nodule forma- tion), the availability of nursing support, and the need for an active car egiver. It is important to emphasize to patients that apomorphine will not improve any symptoms tha t are not already responsive to levo- dopa. Th e total daily dose of levodopa required can be reduced by up to half in some patients, but monotherapy is usually not achiev- able for tolerability reasons. Th e side eff ects of apomorphine are similar to those of other dopam ine agonists, with local eff ects spe- cifi c to the parenteral infusion (Table 10.3). Infusional levodopa \200\223carbidopa intestinal gel Infusional therapies using levodopa ha ve been attempted over many years but have usually failed because of problems with CHAPTER 10 Parkinson \200\231s Disease: Advanced Disease, Motor Complications, and Manageme nt 91 the method of administration and the need for large volumes to dilute levodopa. A recent pr eparation using levodopa \200\223carbidopa (20mg/5mg/ml) in a stable methylcellulose gel ha s overcome some of these issues. Th e levodopa gel is delivered through a gastrostomy tube with a jejunal extension by a pump carried by the patient. Th e gastrostomy is endoscopical ly placed, usually aft er a trial period of nasojejunal delivery, and can typically be init iated during a sin- gle hospital admission. A small study evaluated the effi cacy of this p reparation over 3 weeks when compared with conventional oral therapy, reporting a signifi c ant improvement in ON time without troublesome dyskinesia (75). A retrospective review of 6 4 patients with mean follow-up of 3.7 years (maximum 10.7 years) reported ongoing benefi t (76). Although levodopa \200\223carbidopa gel infusion is available in many countries, its effi cacy has not been reported in an RCT; a large multi-center double-blind double-placebo -controlled trial is ongoing in North America. management option in PD. Better imaging techniques have allowed stereotactic targeting of d eep brain structures and non-destructive stimulation has largely replaced irreversible lesi oning. DBS has the added advantage of allowing postsurgical modifi cation through adjustmen t of stimulation settings, and this is now accepted as being superior to the best medical t herapy for the management of fl uctuations and dyskinesias in advanced PD (80, 81). Stereot actic lesioning is still used in certain clinical scenarios, such as elderly patients in wh om DBS is considered too high risk, and therefore will be addressed briefl y below. Patient selection is of paramount importance. Apart from tremor, DBS will provide no additi onal symptom relief over lev- odopa, but reducing the variability of this response (i.e. mo tor fl uctuations) is the main target of this treatment. Th ere is no absolute age cut-off for consideration of surgery, although many centers do not pursue surgical options in patie nts above the age of 70. Advancing age increases the probability of cognitive impair- ment, surgical co morbidities, and non-levodopa-responsive PD symptoms, such as postural impairm ent. Because of the risk of postoperative deterioration, cognitive impairment is the most c om- mon exclusion factor cited, although a recent report from a con- sortium of experts in the fi eld failed to reach a consensus on the most appropriate measurement tools and exclus ion criteria, and there is increasing interest in applying surgical treatment earlier in th e course of the disease before patients are severely disabled by the symptoms known to be m ost responsive (82). As with much of the decision-making process, the timing of surgery nee ds to be individ- ualized. Most patients undergoing DBS will have had over 10 years of dise ase by virtue of the natural history of evolving motor fl uctua- tions. Early surgical inte rvention may provide better outcomes in terms of quality of life measures (83). A multidisc iplinary approach to patient selection, including input from neurosurgery, neurology, neuro psychology, and psychiatry, is vital before a fi nal decision on suitability is made. Th e large size of the pump required to infuse the viscous gel con- taining levodopa in sus pension is a potential inconvenience and may deter some patients. Most patients start with the infusion run- ning during waking hours only, but continuous infusion overnight can be u sed for troublesome nocturnal symptoms. Additional bolus doses can be given at any time of the day as required. Th e total daily dose of levodopa required can be reduced by 20 \200 \22330% by the addi- tion of a COMT inhibitor if not already being used. Ideally, patients are weaned off dopamine agonists as their long half-life is no longer of benefi t in the se tting of continuous levodopa delivery. Complications associated with gastrostomy tube placement and its chronic use are not uncomm on (Table 10.3). Acute medical problems associated with any surgery will be encountered in this patient group, many of whom will be elderly and considered unfi t for DBS. With contin uous use up to 63% of patients will experience technical hardware problems such as tube kin king, occlusion, or displacement (77). More recently, there have been reports of devel- opm ent of a subacute neuropathy in patients receiving jejunal levo- dopa infusion (73). Th is appears to be associated with biochemical disturbances in B vitamins and associated co-fact ors, although fur- ther clarifi cation on the exact pathogenesis is required. Structures targeted in the management of PD and the rationale and evidence for targeting ea ch will be discussed below along with guidelines for patient selection.