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. 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CHAPTER 11 Non-motor Symptom Management in Parkinson \200\231s Disease Eduardo Tolosa, Carl es Gaig, and Lillian Acevedo Introduction Interest in non-motor symptoms (NMS) in Parkinson \200\231s disease (PD) has i ncreased in recent years. Unlike the classic motor symptoms that can respond to dopaminergi c treatment and functional neurosurgery, NMS generally fail to improve with currently avail able treatments. Consequently, they are a major source of disability and frequently impact negatively upon the patient \200\231s quality of life. Interest in NMS in PD has also incre ased aft er it became evident that some NMS antedate the classic motor signs of PD. Informa tion on the nature of NMS in premotor PD may provide information about the causes of PD and in the study of drugs with neuroprotective potential. of NMS in premotor PD is briefl y discussed at the end of the chapter. Sleep disturbances Nocturnal sleep problems such as sleep fragmentation and early awakening , or parasomnias like RBD and EDS, are frequent in PD and may have a major impact on patien ts \200\231 quality of life (1 \200\2235) . Th ey occur more commonly in advanced than in e arly PD, mostly because of a combination of factors which include an increase in dopaminerg ic treatment, worsening of motor performance, and neurodegeneration of systems other than t he nigrostriatal path- way that are important in regulating the sleep \200\223wake cycle (6 , 7). Disturbances such as RBD or EDS can antedate the development of the motor symptoms of PD by several years (5). Many NMS are caused by PD-related lesions in the brain involv- ing non dopaminergic structu res (Table 11.1). Examples of such non-dopaminergic NMS include dementia, fatigue, smell lo ss, constipation, and REM behavior disorder (RBD). Even though most NMS are thought to be p rimarily non-dopaminergic, they may be infl uenced by dopaminergic drugs. Examples of NMS t hat may respond in part to dopaminergic drugs are insomnia and other nocturnal problems, ur inary urgency, depression, and in general NMS occurring during the OFF state. Insomnia Insomnia is present in up to 55% of patients with PD (8 \200\22310). Sleep fragmen tation and early awakening are the most frequent causes of insomnia in PD. Several factors can cause insom- nia in PD, and defining the relevant ones in a given patient may be challe nging (1, 11, 12). Fragmented sleep and early awakening can be related to nocturnal akinesi a (difficulties in turning in bed), but also to bouts of nocturnal tremor and dyskinesias ( OFF-period dystonia). Sensory disturbances such as pain due to immobility or pain related t o OFF periods, as well as restless-leg-like symptoms, may also disturb the patient. Nocturi a can lead to sleep fragmentation (1). Mental depression and anxiety are other frequent con tributory factors (9, 10). In addition, selegiline and amantadine are known to cause insom- nia, and dopaminergic drugs such as the dopamine agonists or levodopa may have an awakenin g effect when administered at night. Fragmented sleep can also be related to obstructive sl eep apnoea (OSA) (13). Several NMS in PD are related to treatment. A number of medica- tions, as well as deep brai n stimulation (DBS), can produce or poten- tiate NMS, and acknowledgement of this is import ant for adequate management. Examples of NMS induced or aggravated by medica- tions in PD a re orthostatic hypotension (OH), hallucinations and excessive daytime sleepiness (EDS) asso ciated with dopaminergic treatment, and memory problems related to anticholinergics. In this chapter emphasis will be placed upon those NMS con- sidered to be an intrinsic part of the PD process, including smell disturbances, dysautonomia, pain and other sensory symp toms, sleep disturbances, apathy and depression, and fatigue. Some less common or less disa bling NMS, such as seborrhoeic dermatitis or hyperhidrosis, and particularly those NMS most ly related to treatment, such as skin erosions or skin nodules associated with DBS or apomo rphine are listed in Table 11.2. Th e occurrence Specifi c measures to treat insomnia include modifi cation of antiparkinsonian treatment, s uch as reduction of selegiline or Oxford Textbook of Movement Disorders 100 possible, and depression and anxiety treated. Adding a hypnotic is another option (16). Table 11.1 Non-motor symptoms and presumed neuropathological substrate Non-motor symptoms S mell loss Underlying brain structures Olfactory bulb; anterior olfactory nucleus; amygdala; perirhina l cortex REM sleep behavior disorder RBD is a parasomnia characterized by recurrent episodes of vig- orous dream-enacting behaviors associated with nightmares and abnormally increased phasic and/or tonic electromyographic (EMG) activity during REM sleep. In these dreams, patients a re usually threatened or attacked by people or animals, and they react verbally or physical ly to the off ender (17). Frequency and intensity of abnormal behaviors and dreams may vary during the night (they are usually worst at the end of the night), between diff erent nigh ts, and from one patient to another. In some patients these abnormal dream-enacting behavio rs can be severe and cause injury to the patient or their bed partner, resulting in fractur es, lacerations, or contusions. In other cases, the RBD is less severe in its expression. I n most instances patients are unaware of these behaviors, which are reported by the bed par tner (18). Autonomic dysfunction Amygdala; dorsal nucleus of the vagus; intermediolateral column of the spinal cord; sympath etic ganglia; enteric plexus neurons; autonomic neurons in the thoracic and sacral spinal c ord, heart, and gastrointestinal and genitourinary tracts Sleep disturbances Nucleus subcoeruleus; pedunculopontine nucleus; thalamus; hypothalamus Behavioral/emotional dysfunction Locus coeruleus; raphe nuclei; amygdala; limbic cortex; mesolimbic and mesocortical cortex Hallucinations, psychosis Amygdala; limbic cortex Dementia and cognitive dysfunction Frontal and ventral temporal lobe/neocortex, hippocampus, amygdala, nucleus basalis of Meyn ert, locus coeruleus Polysomnography with audiovisual recording (VPSG), dem- onstrating either abnormal movement s or excessive EMG activ- ity during REM sleep, is needed to confi rm the diagnosis of RBD. VPSG is also helpful in ruling out conditions such as OSA, som- nambulism, nocturnal epile psy, hallucinations, confusional awak- enings, or prominent periodic leg movements, which c an mimic RBD-like behaviors (5, 19). Table 11.2 Pain, cutaneous disturbances, and other less well-known NMS Pain and sensory symptoms \227\206 Non- \202 uctuating: continuous, not related to timing of antiparkinson drugs \227\206 Musculoskeletal or radicular \200\223neuropathic types of neck, lower back, or When diagnosis is based solely on clinical history, RBD fre- quency in PD is 15 \200\22346% (4, 20, 21). If RBD diagnosis is per- formed using VPSG, the frequency is somewhat higher, ranging from 46 to 58% (22 \200\22325). RBD may occur more oft en in the rig- id \200\223a kinetic than in the tremor-predominant subtype of PD (26, 27). Whether RBD is more common i n patients with dementia is unclear, but some studies have suggested that the presence of R BD is associated with cognitive impairment and represents a risk factor for dementia (28). RBD also occurs in patients with PD associated with parkin gene mutations (29). RBD in PD i s probably best explained by dysfunction of the neural systems that regulate REM sleep, par ticularly those located in the brainstem including the locus coeruleus and pedunculopontine tegmental nucleus (17, 30). limb pain \200 Central primary pain in a limb \200 Akathisic discomfort \227\206 Associated with motor \202 uctuations OFF related: central primary pain in limb, low back, unusual body sites; angina-like chest pain; burning mouth syndrome; genital pain; abdominal pain OFF dystonia (usually in the foot) akathisic discomfort RLS-like symptoms ON related: associated to ON-dyskinesias akathisia Cutaneous problems \227\206 Facial seborrhoea (seborrhoeic dermatitis) \227\206 Possible increased risk of skin cancer Most patients with RBD respond to clonazepam at doses of 0.5 \200\2232 mg taken at night in a single dose (17). Th ere is no clear evi- dence that dopaminergic agents infl uence the development, evo- lution, or severity of RBD (26). However, initiation of levodopa has been reported to improve RBD in some patients. In others, reduction of total daily dose of levo dopa or other dopaminergic agents, such as the MAO-B inhibitors, may improve or eliminate t he symptoms. \227\206 Malignant melanoma (unrelated to dopaminergic treatment) \227\206 Keratosis and basal cell carcinoma \227\206 Adverse event of antiparkinsonian therapy \227\206 Amantadine-induced livedo ret icularis \227\206 Leg oedema (dopamine agonists) \227\206 Erythromelalgia-like (dopamine agonists) \227\206 Subcutaneous nodules related to s.c. apomorphine injections \227\206 S kin erosion over implants in deep brain stimulation Excessive daytime sleepiness Th e presence of EDS in PD has been reported to vary from 12 t o 84% of patients (2, 3, 6, 10). Patients may complain of a constant feeling of sleepiness, or describe episodes of sudden, irresistible, and overwhelming sleepiness without awarenes s of falling asleep, which have been labeled sleep \200\230attacks \200\231 or episodes of sudden onset of sleep (31). Sleep attacks have been reported in 0.5 \200\22320% of patient s with PD on a background of EDS (2, 3, 6, 10). A sub- group of patients (15 \200\22339%) w ith somnolence-present sleep-onset REM periods (SOREMPs) on the Multiple Sleep Latency Test (MSLT) and are said to have a narcolepsy-like phenotype (32, 33). Ocular and visual disturbances \227\206 Dry eyes (xerostomia, related to autonomic dysfunc tion) \227\206 Diplopia, blurred vision Other \227\206 Weight loss, weight gain (possibly drug-induced), rhinorrhoea, ageusia amantadine, or optimization of antiparkinsonian treatment at night to minimize nocturnal mo tor or sensory symptoms. Agents with a long half-life or sustained eff ect, such as rotigot ine or ropinirole 24-hour prolonged release, can be useful for attenuating OFF periods duri ng the night (14, 15). Nocturia has to be improved, if CHAPTER 11 Non-motor Symptom Management in Parkinson \200\231s Disease 101 However, in contrast with narcolepsy, hypocretin-1 levels in the cerebrospinal fl uid (CSF) are normal in most PD patients (34 \200\22337). EDS in PD has been attributed to neurodege nerative changes in brain areas that regulate the sleep \200\223wake cycle, including the l ocus coeruleus, the dopaminergic midbrain ventral tegmental area, the pedunculopontine tegm ental nuclei, and the hypocretin-producing neurons in the lateral hypothalamus (38 \200\223 40). Supporting the notion of a \200\230central \200\231 hypersomnia in PD is the fact tha t EDS is more frequent in patients with advanced PD or in those patients in whom the neurop athological process is more extensive, for example PD patients with dementia (6, 7, 37, 41 \200\22342). sodium oxybate, a drug that has been approved for treating nar- colepsy, could improve EDS in PD (53).