Smell dysfunction is among the earliest and most salient non-motor signs of Parkinson’s disease (PD), occurring in an estimated 90% of so-called sporadic cases years before the onset of the classic motor symptoms. Until olfaction is tested formally, the vast majority of PD patients are unaware of their loss, which is usually less than total. The smell problem is rarely identified by neurologists, reflecting, in part, their failure to enquire about smell function let alone testing the olfactory nerve formally. The Quality Standards Committee of the American Academy of Neurology has designated olfactory dysfunction as one of the key diagnostic criteria for PD [1] and the Movement Disorder Society has recommended olfactory testing in the diagnosis of PD [2] and in the identification of prodromal PD [3].

Non-motor symptoms (NMS) are a crucial component of Parkinson’s disease (PD) and the burden of the range of NMS that occurs in PD is one of the main determinants of quality of life [1]. In 1817, Dr. James Parkinson already described several NMS in his “shaking palsy,” the condition that would later be named after him, including pain, constipation, and sleep disturbances [2]. Nonetheless, after a long period of inertia, over the last 20 to 25 years, the interest in NMS has increased and evidence suggests that the overall burden of NMS dominates and can influence the risk of developing motor parkinsonism in the premotor stage of PD while being a driving factor for quality of life [3]. The identification of NMS in PD has been greatly aided by the development of specific tools, such as the NMS questionnaire (NMSQ) in 2006 [4] and the NMS Scale (NMSS) in 2007 [5].

Parkinson’s disease (PD) has long been considered as a prototype of a sporadic disorder with little or no involvement of genetic factors. Three to four decades ago, the typical perception of genetics in PD was that “it appears unlikely that heredity is an important determinant in the development of the disorder” [1]. The discovery of SNCA mutations in 1997 [2] started a new era of genetic studies in PD. We now know of at least 90 independent genome-wide association study (GWAS) risk variants in 78 loci that are associated with sporadic PD [3]. Several other genes that are involved in familial, sporadic PD, or atypical forms of familial parkinsonism, have also been identified (Table 18.1).

The non-motor manifestations of Parkinson’s disease have been known since the description of the disease by James Parkinson in 1817. In his ‘Essay of the Shaking Palsy’, he clearly stated ‘sleep becomes much disturbed … .the bowels, which had been all along torpid, in most cases demand stimulating medicines of very considerable power … .sometimes the expulsion of feces requiring mechanical aid’ [1]. However, for years the emphasis has been on the motor features which define the disease, largely by the availability of dopaminergic and other agents which alleviate the bradykinesia and rigidity, and partly also the tremor. In fact, these drugs added new non-motor manifestations.

Late-stage Parkinson’s disease (PD) poses a significant challenge to clinicians. In addition to this, there is a lack of clarity in even its terminology and definition. It has been termed as advanced, late-stage, end-stage, and even palliative PD [1–3]. As the term late-stage PD has become the most widespread, it will be used henceforth. The criteria for diagnosing late-stage PD too has varied, with initial literature using varying cut-offs of the Hoehn and Yahr (H&Y) staging to determine the degree of advancement [1–3]. There has been significant criticism to this approach; it was asserted that while H & Y is heavily weighted towards postural instability and lower limb problems, it may overlook other motor symptoms that contribute to the advancing state, and it excludes non-motor symptoms (NMS). It was also written with the assumption that severity of PD is most related to motor symptoms [4].

Parkinson’s disease (PD) is traditionally characterized by its motor symptoms of tremors, bradykinesia, rigidity, and postural instability [1]. However, it is now recognized that non-motor symptoms including neuropsychiatric manifestations are frequently present in PD, and their onset not only could precede motor symptoms but is also associated with increased dysfunction and reduced quality of life [2–4]. This chapter focuses on depression, the most commonly seen mood disorder in PD, and provides an overview of the epidemiology, clinical symptoms, proposed pathophysiology, diagnostic tools, and treatment options available for depression in PD.

For many years Parkinson’s disease (PD) was regarded primarily as a motor disorder and attempts to discover treatments focused on therapies for rigidity, bradykinesia, and tremor. The brain pathology studies concentrated on the nigrostriatal pathways and dopamine. It was the success of the dopamine replacement therapies which opened the way to discuss the non-motor manifestations of the disease, particularly mental health manifestations and dementia.

Cognitive impairment is very frequent in PD and actually may eventually affect all patients if they live long enough [1], causing additional suffering to patients and caregivers. It is not clear what the anatomical basis of cognitive impairment is, but it is thought to reflect α-synuclein deposition in the cortex and particularly in the limbic system, although most PD patients also bear β-amyloid and TDP-43 deposits once they become demented.

Autonomic complications in Parkinsonian syndromes present a considerable cause of reduced quality of life, morbidity, and mortality [1]. Recognition, evaluation, and management are of utmost importance.

The autonomic nervous system is still a field that to many clinicians is obscure or at least its involvement in the clinical course is hard to grasp. This may be based on the considerable widespread knowledge gap and lack of access in electrophysiology evaluation of the autonomic nervous system [2]. However, autonomic syndromes in several autonomic domains are easily evaluable at the bedside, with electrophysiologic autonomic evaluation only necessary in a minority of patients [3]. This chapter will provide a clinical focus on the autonomic cardiovascular, thermoregulatory, urogenital, and gastrointestinal systems.

In neurological clinical practice, Parkinson’s disease (PD) is commonly associated with a variety of dermatological disorders, such as seborrheic dermatitis, rosacea, bullous pemphigoid, skin cancer and melanoma, as well as sweating dysfunction. The recognition, diagnosis, and therapeutic approaches of these characteristic skin disorders affecting PD patients are important for the clinician and may even be life-saving, considering the relatively higher incidence of malignant skin tumors in PD patients.

It is now accepted that Parkinson’s disease (PD) is a multi-system disorder associated not only with progressive assymetric limb bradykinesia, rigidity, rest tremor, and later postural impairment and gait difficulties, but also with dementia, depression, daytime somnolence, REM sleep behavior disorder, and autonomic dysfunction [1]. Pathologically PD is characterized by neuronal inclusions of abnormally aggregated α-synuclein in the form of Lewy bodies and neurites [2]. These target the nigro-striatal and meso-frontal dopaminergic projections impairing limb movement and executive functions, respectively. They also cause cholinergic neuronal loss from the nucleus basalis leading to attentional and memory deficits, serotonergic neuronal loss from the median raphe nuclei leading to affective and sleep disorders, and noradrenergic neuronal loss from the locus ceruleus resulting in REM sleep behavior disorder (RBD), depression, and anxiety.

The syndromes subsumed under the general umbrella term of impulse control disorders (ICDs), punding, compulsive disorders, and the dopamine dysregulation syndrome (DDS), all share the common theme of an overwhelming need to perform some activity. The actions are generally closer in nature to addictive disorders, being ego syntonic, and less like true impulsive disorders which patients may try to resist [1]. Punding represents a need to perform senseless activities repeatedly, such as folding and refolding clothes in a drawer for hours at a time, polishing pennies, or pulling weeds from a lawn or threads from a rug. The more common ICDs include gambling disorder, compulsive sexual disorder, consumerism, and hobbyism, but may include strikingly unusual activities that are extraordinarily narrow in their focus. The DDS seems to be a form of drug addictive behavior, similar to that of the usual addictive drugs.

Lewy body disease, an α-synucleinopathy, is the neuropathological counterpart of idiopathic Parkinson’s disease and one of the most frequent neurodegenerative diseases in humans [1]. Parkinson’s disease features compelling motor symptoms. Parkinson summarized these symptoms under the mixed Greek-Latin term paralysis agitans (shaking palsy) [2], and for decades, these motor symptoms described by Parkinson remained the most studied features of Lewy body disease.

However, autonomic dysfunctions and non-motor symptoms associated with Lewy body disease are frequent and often pre-date the onset of motor diseases [3]. Autonomic dysfunctions comprise constipation, bowel dysfunction, seborrheic face, dysphagia, dysarthria, impotence, urinary frequency, bladder dysfunction, orthostatic hypotension, and increased sweating. Other non-motor symptoms include sleep disorders (REM behavior disorder, vivid dreams, daytime drowsiness, sleep fragmentation cognitive impairment, bradyphrenia, tip-of-the-tongue (word-finding) phenomenon, depression, apathy, anhedonia, fatigue, behavioral and psychiatric problems, sensory symptoms including anosmia, ageusia, pain (shoulder, back), and paresthesias [4].

Gastrointestinal complaints are the most frequent autonomic symptoms in Parkinson’s disease (PD) and affect almost all patients over the course of time [1, 2, 3]. The causes are not clear. It is likely to be a multifactorial event in which both central and peripheral degenerative processes play a role [4, 5]. In addition, influences from the medication have to be considered, which are certainly not predominant. The central degenerative process involving the dorsal vagal nucleus is certainly significant, but it does not explain the range of symptoms. Involvement of the enteric nervous system is likely to be more crucial, with PD typical changes involving the presence of Lewy bodies extending from the upper esophagus down to the rectum in the Plexus myentericus Auerbach and the Plexus submucosus Meissner [4, 6, 7, 8, 9, 10]. The functional disturbance can therefore affect the entire gastrointestinal tract [5]. Thus dysphagia can occur in addition to delayed gastric emptying and extended intestinal transit.

Parkinson’s disease (PD) in pregnancy is a rare occurrence. PD presents before the age of 40 in only 5% of cases and less than 400 women less than 50 years of age are diagnosed with PD each year in the United States [1]. However, as the average maternal age is increasing, it may become more common. Incidence of pregnancy in PD is unknown and knowledge is limited to case reports.

Animal models suggest estrogen has a neuroprotective effect on dopaminergic neurons by influencing anti-oxidative, anti-inflammatory, and anti-apoptotic pathways with studies showing cell death can be significantly decreased by administration of estrogen [2]. Other animal studies showed estrogen has dopaminergic effect by inhibiting catechol-O-methyltransferase (COMT) and striatal dopamine transporter activity as well as enhancing tyrosine hydroxylase [3, 4]. Incidence of PD is less in women, yet after menopause risk of PD increases [5]. Women tend to have less severe disease but more dyskinesia [6, 7].

In 1817, the English surgeon Dr James Parkinson penned his now classic work, “An Essay on the Shaking Palsy.” He describes the condition as, “an involuntary tremulous motion, with lessened muscular power, in parts not in action, and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace; the senses and intellects being uninjured” [1].

The description of this paralysis agitans (later renamed as Parkinson’s disease by Jean Marie Charcot) has largely remained unchanged today over 200 years later. However, we now realize that the latter part, that the senses and intellect being uninjured, is incorrect. This chapter will summarize the prevalence, incidence, pathophysiology, and the scope of the cognitive changes that are seen in this disease.

Musculoskeletal disorders and pain in Parkinson’s disease (PD) are two complex clinically and pathophysiologically distinct problems, but a high degree of overlap exists between the pathogenesis and understanding of these two types of clinical manifestations. Although not commonly recognized as such these non-motor symptoms are quite frequent, impacting patients’ qualify of life. . Early clinical observations [1] have noticed that both musculoskeletal disorders and pain related to these appear even in the prodromal phase, but also during definite PD manifestation, mainly by different algic syndromes determined by so-called fibromyalgia (fibrositis, tendinitis, myalgia), shoulder pain, cervicobrachialgia, ischialgia, lower back pain, and arthralgia. These probably appear indirectly as a component of PD, and seem to be significantly improved by the administration of levodopa. In PD patients with motor fluctuations, musculoskeletal pain tends to occur more often when parkinsonian disability is maximal and less frequently when disability is minimal [2].

In this chapter we will describe how Parkinson’s disease (PD) affects patients’ eye movements, both bedside and laboratory, preceded by brief review of the anatomo-physiological substrate of eye movements. We will provide a practical summary of how to use the eye movement examination to aid the differential diagnosis of the parkinsonian syndromes, in particular idiopathic PD from multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). A sub-section will describe how deep brain stimulation (DBS) also influences eye movements in PD. Despite a plethora of eye movement laboratory studies in PD it is still relatively unknown what the eye movements of these patients are like in real life. Given that the eyes move in order to see better, does the akinesia of PD impose visual deprivation or delays during ecological whole-body movements?.