This chapter deals with the pharmacotherapy of motor clinical hallmarks in Parkinson’s disease (PD), plus other PD and/or its intervention-related signs and symptoms. The treatment of PD-related non-dopaminergic symptoms such as mainly autonomic, neuropsychiatric and sleep–wake disorders are extensively dealt with in other chapters, so the pharmacotherapy of these disorders are only be discussed briefly. Autonomic non-motor fluctuations comprise cardiovascular (orthostatic hypotension), urogenital (detrusor over- and underactivity-related problems, e.g., urgency, frequency, nocturia, hesitation and straining), and gastrointestinal manifestations (sialorrhea, dysphagia, delayed gastric emptying, constipation). Depression and (mild) cognitive impairment are the most important mainly direct PD-related neuropsychiatric disorders, whereas impulse control disorders, as well as dementia and psychosis, are frequently seen as dopaminomimetic adverse events. Sleep–wake disorders with parasomnias are also characteristic non-motor symptoms in PD. The tailored pharmacologic strategies in these non-dopaminergic symptoms are discussed in detail.

Behavior is considered the response to internal and external stimuli. Both the basal ganglia as well as the cerebellum process internal (homeostatic) and external (environmental) cortical information in order to orchestrate adequately adapted behavior and send this processed information via the thalamus back to the cortex for final execution through motor neurons and neuromuscular structures. The basal ganglia arrange for the appropriate selection of behavioral fragments (response selection) out of the available pool of learned standard behaviors, and define their magnitude, while the cerebellum together with the sensory, visual, and vestibular organs deal with their coordination, that is, the exact timing of muscle actions so that the body can move smoothly. The final execution of these movements is enabled by upper/lower motor neurons and neuromuscular structures.

This chapter deals with abnormal, spontaneous and reactive motor behavior as part of the clinical expression of some psychiatric disorders, including abnormal motility, locomotion, gestures, mimic, and speech. Here, the differentiation of the abnormal motor behavior motor dysfunction as an integral part of a psychiatric condition or as a side effect of its treatment is critical for the management but often remains difficult to differentiate. Iatrogenic movement disorders, as might be seen in the treatment of specific psychiatric disorders, for instance with neuroleptics, are discussed in Chapter 51. In this chapter, we focus on the signs and symptoms of movement disorders as an integral, genuine part of the clinical manifestation, sometimes even in prodromal states, in psychiatric diseases, such as in schizophrenia, catatonia, and stereotypies, as well as in major depressive disorders, attention deficit hyperactivity disorders, obsessive-compulsive disorders, and impulse control disorders. Psychogenic (functional or somatoform) motor behavioral abnormalities, the result of conversion, somatization and/or factious disorders (malingering), are described in Chapter 53.

Vascular parkinsonism (VP) is a clinical entity within the broader context of parkinsonian syndromes and usually manifests with an array of clinical features including a mainly lower body motor parkinsonism with a gait disorder, corticospinal and pseudobulbar signs and symptoms, urinary incontinence, dementia, and pyramidal and cerebellar signs. As the name suggests, etiologically VP may be defined as a secondary parkinsonian syndrome occurring in relation to ischemic cerebrovascular disease. Treatment for VP remains challenging as available data on the efficacy of current treatment options are contentious. VP is generally considered to be poorly responsive to levodopa, the most effective of the current treatment modalities for parkinsonism; however, there is evidence that some patients benefit from therapy with levodopa, especially in case of underlying ischemic or hemorrhagic lesions in the substantia nigra, globus pallidus pars externa, thalamic ventral lateral nuclei, or nigrostriatal pathway, leading to presynaptic dopamine transporter deficiency as measured by single photon emission computed tomography.

Parkinson’s disease (PD), a typical Parkinson syndrome, is seen as a progressive multisystem neurodegenerative disease with α-synuclein–containing Lewy bodies and neurites, affecting 1–2 per 1000 of the global population. The prevailing view of PD etiology is that it is the result of cell-autonomous and non-autonomous processes, starting in the olfactory nerve and the autonomous nervous system of the gut, spreading retrogradely through synaptically coupled networks in a topographically predictable sequence to postsynaptic brainstem neurons, affecting the nuclear grays of the basal midbrain and forebrain and finally the neocortex. Cell-autonomous processes (e.g., mitochondrial damage and a defective autophagy by lysosomal and ubiquitin proteasome systems) result in pathologic accumulation of intracellular α-synuclein oligomers and aggregates. Non–cell-autonomous processes comprise the spread of synucleinic pathology in dying neurons to neighboring dopaminergic, cholinergic, serotinergic, and adrenergic neurons and/or to astrocytes, microglia, and lymphocytes across brain regions, plus decreased brain-derived neurotrophic factors and/or microglial-induced inflammatory responses.

Mitochondrial disease presents with a wide, diverse spectrum of clinical manifestations at any age, often characterized by multisystem dysfunction. Movement disorders are a frequent manifestation, and may include ataxia, parkinsonism, myoclonus, dystonia, chorea, tremor. The phenotype of mitochondrial disorders, including the spectrum of movement disorders, may be very variable, even in patients carrying the same genetic mutation. Mitochondrial dysfunction may also play an important role in sporadic neurodegenerative diseases with movement disorders. Identification of a genetic mitochondrial movement disorder is challenging, but has been facilitated by new technologies, such as next-generation sequencing, thus identifying causative genes and eventually expanding the phenotype spectrum in the case of nuclear mitochondrial mutations. Identification of the underlying genetic basis of a mitochondrial movement disorder is crucial for patient management, as potentially mitochondriotoxic agents should be avoided and special precautions taken with anesthesia. This chapter gives a comprehensive overview of the spectrum of movement disorders associated with mitochondrial disease.

Neurodegenerative disorders are complex multisystem disorders mainly characterized by aggregations of misfolded proteins (such as misfolded amyloid-beta protein in Alzheimer’s disease) in select regions in the central, peripheral, and autonomic nervous systems. In this chapter the various proteinopathic neurodegenerative movement disorders will be dealt with: synucleinopathies, tauopathies, frontotemporal lobar degenerations with TAU, TAR DNA binding protein-43 (TDP), and/or fused in sarcoma (FUS) proteinopathies, polyglutamine CAG-repeat disorders, and misfolded prion proteins. Abnormal protein deposits can be visualized post mortem with immunohistochemical methods that define the diseases, allow the staging schemes, and establish correlations between neuropathologic and clinical phenotypes. As neurodegenerative disorders often display comorbidity, immunohistochemistry with antibody panels has to be performed to enable assessment of the specific protein aggregations in various regions.