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. Technical consideration and cost may preclude widespread uptake in this treatment. However, infusional levodopa may be use- ful in advanced PD subjects intolerant of apomorphine beca use of confusion, hallucinations, intolerable infusion site complications, or hypotension, or for subjects who are considered poor surgical candidates because of age constraints or c ognitive \200\223behavioral concerns (78). Despite concerns in relation to potential tolera nce and neuropsychiatric complications of continuous dopaminer- gic stimulation, infusional levodopa therapy appears to be well tolerated (79). In the recently reported experience of the French DUODOPA study group, over 50% of the study participants had cognitive impairmen t suggestive of PD dementia; however, the procedure was tolerated and no patient experienci ng hallucina- tions prior to infusional therapy reported a worsening of this side eff ect ( 77). On the other hand, management of this form of therapy is very complex, and patients wi th moderate to severe dementia should probably not be considered as candidates. Subthalamotomy and subthalamic nucleus stimulation Th e subthalamic nucleus (STN) is of int erest as a target for sur- gical treatment given our knowledge of pathologically increased neuronal fi ring within it that may drive excessive inhibitory out- puts via the indirect c ortico-striato-pallido-thalamo-cortical path- way. However, although the STN was fi rst cho sen because it was believed that DBS has a lesion-like inhibitory eff ect on its target, th e eff ects of DBS are clearly much more complicated than this and it must be acknowledged t hat there is still great uncertainty as to exactly how it works and whether its mechanism o f action is the same in diff erent anatomical targets. Subthalamotomy is rarely per- formed now because of the risk of producing contralateral hemibal- lism. Th is risk does not appe ar to be present with stimulation of the same target. Th ere has previously been little evi dence to guide the choice between the STN or the globus pallidus internus (GPi) as the prim e surgical target in PD, although the STN is currently the more commonly chosen target. Th e recently reported Co-op Study of 299 patients randomized to either STN or GPi DBS found s imilar motor benefi t in both groups at 24 months (84). Analysis of sec- ondary endpoints s uggested that patients with depression may ben- efi t more from GPi DBS. Worsening verbal f l uency and executive Surgical options in advanced Parkinson \200\231s disease Despite being developed as early a s the 1940s, surgical therapy for PD faded from prominence aft er the advent of levodopa th erapy. However, in the last two decades it has again emerged as a viable Oxford Textbook of Movement Disorders 92 dysfunction have been reported following STN DBS, but these parameters were not evaluated i n the Co-op Study (85). Th erefore, it seems that, with all else being equal, individualiza tion of the tar- get for particular patients may depend on a number of non-motor features t hat should be evaluated prior to a fi nal choice being made. Long-term follow-up will be cr itical in helping to resolve this debate as there is some evidence that patients with GPi s timulation may lose benefi t aft er a period of two or more years, and such patients have r esponded to subsequent STN stimulation (86). and 50% were experiencing choking episodes (94). Th ese non-dopa-responsive features were d eemed to be more disabling than the motor fl uctuations that were also extremely common in this cohort. Measures to help management of these late motor fea- tures, typically resistan t to levodopa, are discussed below. Falls and postural instability Th e impact of falling in PD can be huge, not only in terms of immediate risk of fractures and their associated complications but also on the psycholog ical outlook of the patient. It is important to recognize that falls are commonly multifact orial in patients with long-standing disease, making both their management and the study of novel therapies diffi cult. Careful history taking with a reliable informant is, as always , important. Consideration should be given to the possibility that orthostatic hypotension may con- tribute to some falls and can be eff ectively managed by a reduc- tion in hypotens ive agents (including dopamine agonists) or the addition of drugs that increase vasomotor t one or circulating blood volume. Cognitive issues are also likely to play a signifi cant ro le. Anecdotally, patients will oft en report a fall occurring when trying to perform two ta sks at once (dual tasking) such as turning to pick up something from a worktop in the kitch en. Reduced attention to the act of maintaining an upright posture may be responsible when the automatic motor programs that maintain postural control cannot be relied upon. Th ere i s limited evidence to support a trial of acetylcholinesterase inhibitors \200\224drugs whic h may improve cogni- tion or attention (95). Pallidotomy and pallidal stimulation Th is target is chosen because it receives glutaminerg ic neurons from the STN which is overactive in PD. Lesioning or stimulation of the GPi is s ometimes chosen for its particular benefi t in managing contralateral dyskinesia or dystoni a. It can also be helpful for con- tralateral rigidity and tremor (87). As indicated above, it is unclear why lesioning and stimulation can produce similar results. Bilateral pallido tomy is associated with increased risk of cognitive dysfunc- tion, dysarthria, and dysphagi a (88, 89). As with thalamotomy, the propensity of bilateral lesioning to produce intolerab le side eff ects has pushed bilateral GPi stimulation to the forefront. Th e GPi and STN ar e the two main targets for the management of motor fl uctua- tions in advanced PD with no c lear benefi t of one over the other in terms of change in UPDRS motor scores (see below). Th alamotomy and thalamic stimulation Unilateral thalamotomy of the ventralis intermediate (VIM) nucleus has potent anti-tremor eff ects on the contralateral side and produces a redu ction in contralateral rigidity. Th e latter eff ect is less impressive than the tremor res ponse with reported improvements from 45.8 to 92% (90, 91) Bilateral thalamotomy is associa ted with an increased risk of irreversible dysarthria and dysphagia. Given this risk, bilat eral thalamotomies are not commonly performed since DBS has become the standard of practice . DBS for PD tremor should not be restricted to patients with advanced disease, as younger patients with a shorter duration of disease but intractable drug-resistant tremor may also benefi t greatly. Th e majority of falls in advanced PD are due to postural instabil- ity, a primary disorder of balance that becomes increasingly com- mon with advancing disease duration. Freezing of gait will oft en accompany postural instability but can occur independently. It is likely that involvement of non-dopaminergic neurons projecting to and from the basal ganglia contr ibute to the instability. Th e struc- tural correlates of gait dysfunction in PD are poorly understood but there has been interest in pursuing alternative targets for DBS, in particu lar the PPN area. Th is is a poorly defi ned structure ana- tomically, made up predominantl y of cholinergic neurons that are known to be destroyed in PD. Th e PPN has a number of eff erent and aff erent connections with the basal ganglia and surrounding brainstem nuclei. B linded evaluations of stimulation, possibly infl u- encing an excess of descending inhibito ry control from the basal ganglia, have suggested limited benefi t (93) and, clearly, furth er well-designed trials are needed before this target can be accepted for treatment-resista nt axial features. Th e current mainstay of man- aging postural instability is physiotherap y and gait training. Oft en the very process of addressing postural instability in the clin ic can lead to a reduction in falling frequency, as both patients and fam- ily become incre asingly cautious. Input from physiotherapists with experience in managing PD can be particu larly helpful as patients will learn adaptive mechanisms to prevent falls and can be traine d to concentrate on maintaining stride length (96). Over time, how- ever, the cognitive imp airment that oft en accompanies the onset of axial motor symptoms can limit the benefi t pa tients obtain from such training. Treatment to prevent osteoporosis is important to limit t he consequences of falls in PD. Other targets Recently, novel target sites for DBS have been investigated. Th ese include b ilateral stimulation of the caudal zona incerta (cZI) and pedunculopontine nucleus (PPN). A study evaluating cZI in PD tremor, along with other tremor types, found marked reduction p rimarily in PD tremor, but also in bradykinesia and rigidity (92). However, it is unclear w hether this eff ect was due to stimulation of the STN, given its proximity to the cZI. PPN stimulation is dis- cussed later in this chapter. It may have a role in controlling axial s ymptoms and improving postural instability in PD (93). Drug-resistant motor complications Th e gratifying response of most symptoms to treatment i n early PD is oft en in stark contrast to the predominance of symptoms that are not respons ive to dopaminergic drugs in advanced disease. Th is is not restricted to the non-motor fea tures that are addressed in Chapter 11. With advancing disease, axial motor features emerge that can be frustratingly refractory to treatment. Such symptoms include postural instabil ity and dysphagia which carry a high morbidity and attributable mortality in advanced disea se. In the Sydney Multicentre Study 81% of patients were experiencing falls at a disease du ration of 15 years, 23% had sustained fractures, Unpredictable or ON-period freezing ON-period freezing occurs when patients otherwise have little bradykinesia, rigidity, or tremor. Most patients with ON-period freezing also experi ence freezing during OFF periods, and this CHAPTER 10 Parkinson \200\231s Disease: Advanced Disease, Motor Complications, and Manageme nt 93 combination results in rather unpredictable freezing. Th ese forms of freezing are particul arly frustrating for both patient and phy- sician to manage, typically being stubbornly unr esponsive to drug treatment. Paradoxically, \200\230high-dose freezing \200\231 or \200 \230hypotonic freezing \200\231 is a phenomenon that was described in some of the fi rst pa tients treated with levodopa. A correlation between serum levo- dopa concentrations and aki nesia was demonstrated (97). Some of these patients would have been treated with doses far higher than those in common usage today and the applicability to current prac- tice is ques tionable. However, when faced with a patient receiving high individual doses of levodopa (o r dopamine agonists), and where all other therapeutic avenues have been exhausted, a trial of lowering dopaminergic medication doses is not unreasonable. However, lowering levodopa m ay lead to worsening of other PD features. Th us a non-dopaminergic approach may be an opti on for ON-period freezing. Several of the non-dopaminergic treatments tried have targeted t he attention defi cits proposed to contribute to some forms of freezing. Others target mono aminergic neuro- transmitters, including noradrenaline and serotonin which are also deplete d in PD and may play a role in brainstem circuits serving gait stability. Non-dopaminergic approaches to freezing of gait include the following. 5. PPN DBS. In a recent study of unilateral DBS of the PPN there was a suggestion that pati ents \200\231 subjective ratings of freezing and postural instability improved (93), but fu rther studies are required to validate this. Refractory tremor Th e management of drug-resistant tremor is not exclusive to advanced PD but may become increasingly problematic and disabling as time progresses. Management can be diffi cult and oft en frustrating as the benefi ts of levodopa in treating bradyki- nesia and rigidity can be overshadowed by a recalcitrant tremor. Maximization of levodopa therapy is typically tried but is limited by dopaminergic side eff ects at higher doses, in partic ular dyski- nesia that becomes ubiquitous in advanced disease. Th e potential benefi t of a n anticholinergic in patients with long-standing PD is oft en limited by the age profi le o f this population in whom toler- ability is an issue. Importantly, unlike all other parkins onian fea- tures, the absence of a levodopa response in the management of tremor does not p redict a poor operative outcome should DBS be considered. However, a number of medical stra tegies can be tried. 1. Dopamine agonists. Th ere is evidence to support the adjunctive use of a dopamine agonis t to provide an additive benefi t for PD tremor, even with concomitant reductions in levodo pa dose (105). Anecdotally, some patients with little or no tremor response to levodopa can experience an improvement on an agonist. 1. Caff eine. A non-selective adenosine receptor antagonist, caff eine has been studied as a non-dopaminergic treatment of freezing in PD. A dose of 100 mg daily improved the \200 \230akinetic \200\231 subtype but tolerance developed (98). Th e mechanism of action is unc lear, but it may be that improved attention is responsible, as opposed to a direct eff ect on basal ganglia as has been proposed for other adenosine antagonists in development for mo tor symptoms of PD (99). 2. Amantadine. Some patients will report improvement with use of this glutamate antagonist, although the mechanism of action is unclear. Th ere is evidence from double-blinded studie s that amantadine is a reasonable choice as a second-line agent in the treatment of parkins onian tremor (106, 107). Antagonism of striatal glutaminergic projections or STN projection s to the GPi, where pathological neuronal oscillations can be recorded, may be responsible. 2. Methylphenidate. Th is amphetamine derivative boosts brain noradrenaline and dopamine le vels by blocking reuptake. In high doses, methylphenidate reduced freezing in patients with advanced disease who had previously undergone bilateral STN DBS (100). However, a recent s tudy using 80 mg/day showed no eff ect on gait, suggesting that subjects with freezing are unlikely to benefi t (101). In a similar manner to selegiline and caff eine, methylphenidat e may be eff ective in part through a direct eff ect on attention (102). 3. Clozapine. Evidence exists for an anti-tremor eff ect of clozapine in PD tremor (108 \200\223110). In keeping with the use of clozapine in dyskinesia, the doses required are ty pically similar to that required for psychosis in PD, and therefore there can be addi- tion al improvement in sleep disturbance, anxiety, and hallucina- tions. A starting dose of 12.5 mg at night alone can be eff ective, and rarely is more than 50 mg daily required. However , manda- tory blood monitoring precludes widespread use of clozapine. 3. Antidepressan t drugs. Anxiety states can provoke freezing in PD. Treatment of anxiety i ntuitively may improve freezing unrespon- sive to dopaminergic drugs. A recent case report identifi ed a patient with primary progressive freezing of gait who had a clear response to the serotonin \200\223noradrenaline reuptake inhibitor (SNRI) anti- depressant duloxetine but not to citalopram (103). Given the action of the former, this raises the question of a more specifi c role for noradrenaline in the mechanism of freezing in PD. 4. -adrenergic antagonists. Consideration of a -adrenergic antag- onist for tremor ma nagement in PD may be an option, especially if there is a postural component and when worse ning with anxi- ety or stress is a major complaint. Despite widespread use, there is a pauc ity of evidence for this approach (111). Long-acting propranolol up to 160 mg daily is gene rally well tolerated, but care should be taken in advanced PD because of the risk of bradyc ardia and signifi cant postural drop in blood pressure. 4. Amantadine. Anecdotally, success with amantadine has been reported where freezing of gai t has been unresponsive to dopaminergic medications. However, there are no data from random ized placebo-controlled trials to support this assertion. A recent open-label non-randomize d study using intravenous amantadine demonstrated a signifi cant improvement in subject- iv e freezing in fi ve of six patients with PD that was unrelated to changes in UPDRS motor sc ores, suggesting a mechanism other than a dopaminergic eff ect (104). Replication in a blin ded study is required. 5. Mirtazapine. Th e antidepressant mirtazapine has anticholin- ergic and antiserotonergic properties that may help reduce tremor, but this has not been demonstrated in a randomized placebo-controlled trial (112, 113). Dysarthria and dysphagia Speech disturbance in PD is characterized by monotony of pitch and volume, loss of prosody, variability of rate, bursts of rapid unin- telligible speech (tac hyphemia), and imprecise consonants (114). Oxford Textbook of Movement Disorders 94 Hypophonia can also be an early symptom when improvement with levodopa treatment suggests a contribution from dopamine defi ciency (115). Levodopa-induced oro-buccal-lingual dyskine- sias in the ON state can also have a detrimental eff ect on speech output in PD. neuroleptic treatment (125). As with camptocormia and head drop, the pathophysiology of lat eral fl exion is poorly understood, with an absence of consistent abnormality on imaging or neurophysi- ology. Tonic activity in paravertebral muscles both ipsilateral and contralate ral to the side of fl exion has been described along with contralateral dystonic activation in six of ten patients in one case series (126). In keeping with this, contralateral hyper trophy has been identifi ed on MRI of paravertebral muscles (127). It is unclear why contra lateral muscle activity should predominate, although pathological dystonic co-contraction h as been proposed. Speech therapy is commonly used in the absence of a demonstra- ble levodopa response. Lee S ilverman Voice Treatment (LSVT) is the only technique that has consistently shown benefi t. Th is method involves an intensive program of frequent training developed to promote an up -scaling of vocal amplitude by improving vocal cord adduction (116, 117). Sustained benefi t on speech volume has been reported for up to two years aft er treatment; however, in clin i- cal practice loss of benefi t is oft en seen before this (118). Variable methodology, la ck of adequate controls, and blinding makes appli- cation of trial data to the advanced PD population diffi cult. Th e response of dysarthria to functional neurosurgery is usually ne ga- tive, although this complication is less common with DBS than with bilateral stereotact ic lesions. Patients undergoing DBS should be warned about the possibility of increased spe ech and swallowing dysfunction postoperatively. In some patients this is temporary and can be addressed during postoperative programming. Striatal limb deformity Striatal hand and foot deformities tend to be seen more commonly in advanced disease, but can be an uncommon early or even pre- senting feature (128). Th e st riatal hand deformity is characterized by fl exion at the metacarpophalangeal joints, exten sion at the inter- phalangeal joints, and fl exion at the distal phalangeal joints that can be associated with subluxation. Ulnar deviation can be a feature that may lead to misdiagn osis as rheumatoid arthritis, although pain and swelling are not seen. Th e striatal toe of a PD patient is hyperextended at the hallux and can be part of a \200\230striatal foot \200\231, with fl exion of the other toes and an equinovarus deformity of the ankle. Th e s triatal toe can sometimes be mistaken for a Babinski response, although the absence of toe fanning and parkinsonian rigidity in the same limb can help discriminate. Th e pathophysiol ogy of these deformities is unknown, but they probably represent a form of dystonia. Rigidi ty may contribute, and over time contractures can develop. Dysphagia in PD is increasingly common with longer disease duration. Up to 15% of patients can have silent aspiration in the absence of symptoms (119). Aspiration pneumonia is common in advanced disease, and contributes signifi cantly to hospital admis- sions and the overa ll increased mortality (94). As with dysarthria, dopaminergic drugs and surgery do not prov ide consistent benefi t, and the mainstay of management involves surveillance (includ- ing appropriate use of special swallowing studies by experienced speech pathologists), modifi c ation of diet, and provision of swal- lowing strategies. In some cases, the placement of pe rcutaneous endoscopic gastrostomy may need to be considered. Management Camptocormia is generally unresponsive to levodopa, but improvement in up to 20% of cases has been reported (129). Th ere are reported cases of improvement with botulinum toxin injection to the rectus abdomini muscles (130). Botulinum toxin is also useful for a striatal limb that is causing pain or where a striatal toe makes it diffi cult to wear a sh oe. Camptocormia has been treated using a backpack as a form of sensory trick (131). Concur rent antipsychotic drugs should be withdrawn if possible because of their association with drug-induced axial dystonia. If axial posturing develops aft er the introduction of a dopam ine agonist, discontinuation should also be considered (124). Surgical correction may provi de some benefi t for severe symp- toms, although complications are common in this advanced PD population (132). Postural deformity Camptocormia and head drop Postural deformities, particularly those invo lving the axial skel- eton, can complicate advanced PD and contribute signifi cantly to dis ability. Camptocormia is characterized by extreme fl exion of the thoracolumbar spine, some times up to 90 , that is most promi- nent when walking. It can be corrected by sitting, ly ing supine, or sometimes leaning against a wall (helping to diff erentiate it from fi xed b ony deformities). \200\230Head drop \200\231 is another descriptive term relating to patho logical neck fl exion. It is also seen in PD but, like camptocormia, is not specifi c to it , also being seen in multiple sys- tem atrophy, motor neuron disease, and myopathic disorde rs. Th e mechanism of head drop and camptocormia in PD is uncertain and there is no evidenc e to prove a shared pathogenesis. Some authors have proposed an extensor myopathy as the mo st likely mecha- nism, but others favor a form of dystonia or parkinsonian rigidity (120 \200\223123). Rarely, head drop has been associated with dopamine agonist toxicity (124). Conclusion Motor complications are an inevitable feature of advanced PD. Management strateg ies should focus on the elimination of fl uctua- tions in drug response where possible. As the disease progresses, and with advancing patient age, return from further manipulation of the drug regimen is diminished and marked by complications. In such individuals, bilateral STN DBS is the best therapeutic option, with infusion therapies as possible alternatives. A good knowledge of drug indications and side eff ects as well as recogniz- ing complicatio ns which could be levodopa-responsive will allow the clinician to make timely and eff ectiv e choices. Lateral \202 exion Th is phenomenon was described as scoliosis of Parkinson \200\231s dis - ease by Duvoisin and Marsden in 1975 and is sometimes referred to as the \200\230Pisa sy ndrome \200\231, although this term was originally coined to describe a similar postural ab normality which can complicate CHAPTER 10 Parkinson \200\231s Disease: Advanced Disease, Motor Complications, and Manageme nt 95 Top clinical tips 7. Parkinson Study Group. Entacapone improves motor fl uctuations in levodopa-treate d Park inson \200\231s disease patients. Ann Neurol 1997; 42 : 747 \200\2235 5 . It is important to distinguish motor complications which are levodopa-responsive from those that are not. Having patients or family members keep a detailed diary of symptoms in rela- tion to their drug doses can provide quite helpful information about this. For those sympt oms which are levodopa-responsive, the aim should be smoothing out the drug response to tar get the therapeutic window. \227\206 8. Brooks DJ, Leinonen M, Kuoppamaki M, Nissinen H. Five-yea r effi cacy and safety of levo dopa/DDCI and entacapone in patients with Parkinson \200\231s disease. J Neural Transm 2008 ; 115 : 843 \200\2239 . 9. Brooks DJ, Agid Y, Eggert K, et al. Treatment of end-of-dos e wearing-off in Parkinson \200\231s disease: Stalevo(R) (levodopa/carbidopa/entacapone) and levodopa/DDCI given in co mbination with Comtess(R)/Comtan(R) (Entacapone) provide equivalent improvements in symptom control superior to that of traditional levodopa/DDCI treatment. Eur Neurol 2005; 53 : 197 \200\22320 2 . Avoid overly aggressive treatment of peak-dose dyskinesia. Focus on disabling or painful dy skinesia, but remember that most patients prefer to have better control of PD symptoms and fi nd dyskinesia less bothersome. Indeed, many advanced PD patients have no useful ON witho ut some degree of dyskinesia. \227\206 10. Factor SA, Molho ES, Feustel PJ, Brown DL, Evans SM. Long-ter m comparative experience with tolcapone and entacapone in advanced Parkinson \200\231s disease. Clin Neuropharmacol 2001; 24 : 295 \200\2239 . 11. Lees AJ. Evidence-base d effi cacy comparison of tolcapone and entaca- pone as adjuncti ve therapy in Parkinson \200\231s disease. CNS Neurosci Th er 2008; 14 : 83 \200\2239 3 . Do not chase non-disabling OFF symptoms. Treatment should be geared towards maximizing func tion. Pursuing mild OFF symptoms with escalating doses of levodopa may lead to more problem atic dyskinesia and fl uctuation without practical improvement. \227\206 12. Stowe R, Ives N, Clarke CE, et al. Meta-analysi s of the comparative effi - cacy and sa fety of adjuvant treatment to levodopa in later Parkinson \200\231s disease. Mov Disord 201 1; 26 : 587 \200\2239 8 . 13. Clarke A, Brewer F, Johnson ES, et al. A new formulation of selegiline: improved bioava ilability and selectivity for MAO- B inhibition. J Neural Transm 2003; 110 : 1241 \200\2235 5 . Less is sometimes more. It is important always to evaluate the effi - cacy of all anti-PD a gents frequently. Adjuvant medications (e.g. dopamine agonists, amantadine, COMT inhibitors , and MAO-B inhibitors) may cause more adverse eff ects than benefi ts. Further simplifying drug regimens allows for fewer adverse eff ects and better patient understanding and compl iance. \227\206 14. Archibald NK, Clarke MP, Mosimann UP, Burn DJ. Th e retina in Parkinson \200\231s disease. Brain 2009; 132 : 1128 \200\2234 5 . 15. Waters CH, Sethi KD, Hauser RA, Molho E, Bertoni JA; Zydis Selegiline Study Group. Zydi s selegiline reduces off time in Parkinson \200\231s disease patients with motor fl uctuati ons: a 3-mont h, randomized, placebo-controlle d study. Mov Disord 2004; 19 : 426 \200\2233 2 . Consideration of deep brain stimulation (DBS) should not be thought of as a last resort. Di scussing this option earlier in the disease course will allow for greater patient understan ding and less resistance when DBS is deemed appropriate. Th is can also expedite surgical m anagement before possible cognitive prob- lems can present a contraindication. \227\206 16. Ondo WG, Sethi KD, Kricorian G. Selegiline orally disintegrating tab- lets in patients with Parkinson disease and \200\230wearing off \200\231 symptoms. Clin Neuropharmacol 200 7; 30 : 295 \200\22330 0 . 17. Finberg JP, Lamensdorf I, Weinstock M, Schwartz M, Youdim MB. Pharmacology of rasagilin e ( N -propargyl-1R-aminoinda n). Adv Neurol 1999; 80 : 495 \200\223 9 . 18. Schwid SR, Shoulson I, Stern M, et al. 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