Review Introduction James Parkinson 1 accurately described the motor problems of patients but also noted several non-motor features. The motor disorder of Parkinson’s disease has been extensively researched resulting in improved diagnostic accuracy and development of robust rating scales and treatment startegies. 2,3 Despite this emphasis on motor symptomatology, several studies have shown that the non-motor symptoms of Parkinson’s disease, such as depression, psychosis, falls, and sleep disturbance, have greater significance when assessed by quality-of-life measures, institutionalisation rates, or health economics. 4–11 The scale of the problem Non-motor symptoms correlate with advancing age and disease severity, although some non-motor symptoms, such as olfactory problems, constipation, depression, and rapid eye movement disorder, can occur early in the disease (panel 1). 12 As the average age and life expectancy of the population increases, the non-motor features of Parkinson’s disease become increasingly important. 12,13 The prevalence of non-motor symptoms as a whole is inadequately documented because there are insufficient adequately powered, community-based studies on prevalence, effect, and treatment efficacy in relation to non-motor symptoms, and there is a need for large and well-designed prospective studies. The role and effect of the non-motor symptom complex during the disease course is discussed by a prospective study of patients with Parkinson’s disease followed up for 15–18 years, which shows that non-levodopa responsive non-motor symptoms are the most disabling feature of the disease. 13 In the UK, a survey of 163 consecutive symptomatic patients attending a London Parkinson’s disease clinic showed that difficulties with balance, sleep disturbance, memory failure or confusional episodes, and dribbling of saliva were rated as the most disabling symptoms. 14 In recognition of the importance of non-motor symptoms in Parkinson’s disease, the UK government commissioned the National Institute for Clinical Excellence (NICE), which has recommended the gathering of evidence to develop better care for the non- motor aspects of the disease. Pathophysiology of the non-motor symptom complex and the Braak hypothesis Our understanding of the sequence and distribution of pathological changes in Parkinson’s disease continues to evolve with non-dopaminergic-cell dysfunction being thought to play a major part in the development of the non-motor symptom complex. 15,16 The neuroanatomical and neurochemical substrates for much of the non-motor symptom complex in Parkinson’s disease are unknown. A substantial part of the discussion in relation to pathophysiology of non-motor symptoms, therefore, remains speculative. The traditional view that the pathological process in Parkinson’s disease starts by degeneration of dopaminergic neurons in the substantia nigra has been challenged by Braak and colleagues 17,18 who introduced the concept of a six-stage pathological process, beginning at clearly designated induction sites. Braak stage 1 denotes degeneration of the olfactory bulb and the anterior olfactory nucleus, which can clinically manifest as olfactory dysfunction. Braak stage 2 characterises progression of the pathological process to the lower brainstem. These areas, implicated in the preclinical stages 1 and 2 of Parkinson’s disease, are also thought to be key areas that mediate non-motor symptoms such as olfaction, sleep homoeostasis, and other autonomic characteristics. For instance, sleep might be affected by abnormalities in the sleep–wake cycle-related pathway (the flip-flop switch; figure), 19 which mediates thalamocortical arousal, including brainstem nuclei such as the raphe nucleus (serotonin), the locus coeruleus (norepinephrine), and the Lancet Neurol 2006; 5: 235–45 Movement Disorders Unit, Kings College Hospital, Guy’s King’s and St Thomas’ School of Medicine, London, UK (K R Chaudhuri DSc, D G Healy MRCP); University Hospital Lewisham, London, UK (K R Chaudhuri DSc); and Royal Free Hospital Medical School, University College London, London, UK (Prof A H V Schapira FmedSci) Correspondence to: Dr K Ray Chaudhuri, Movement Disorders Unit, King’s College Hospital, Denmark Hill, London SE5 9RS, UK ray.chaudhuri@uhl.nhs.uk http://neurology.thelancet.com Vol 5 March 2006 235 K Ray Chaudhuri, Daniel G Healy, Anthony H V Schapira The clinical diagnosis of Parkinson’s disease rests on the identification of the characteristics related to dopamine deficiency that are a consequence of degeneration of the substantia nigra pars compacta. However, non- dopaminergic and non-motor symptoms are sometimes present before diagnosis and almost inevitably emerge with disease progression. Indeed, non-motor symptoms dominate the clinical picture of advanced Parkinson’s disease and contribute to severe disability, impaired quality of life, and shortened life expectancy. By contrast with the dopaminergic symptoms of the disease, for which treatment is available, non-motor symptoms are often poorly recognised and inadequately treated. However, attention is now being focused on the recognition and quantitation of non-motor symptoms, which will form the basis of improved treatments. Some non-motor symptoms, including depression, constipation, pain, genitourinary problems, and sleep disorders, can be improved with available treatments. Other non-motor symptoms can be more refractory and need the introduction of novel non-dopaminergic drugs. Inevitably, the development of treatments that can slow or prevent the progression of Parkinson’s disease and its multicentric neurodegeneration provides the best hope of curing non-motor symptoms. Non-motor symptoms of Parkinson’s disease: diagnosis and management For The National Institute for Clinical Excellence (NICE) see http://www.nice.org.uk/