Parkinsonism is a clinical syndrome characterized by tremor at rest, bradykinesia and hypokinesia and cogwheel rigidity. There are many causes or etiologies of parkinsonism, but the most common is Parkinson's disease (PD). PD has long been considered a clinical–pathologic entity defined clinically by parkinsonism and pathologically by depigmentation of the substantia nigra with the appearance of Lewy bodies: eosinophilic, intraneuronal, cytoplasmic inclusion bodies that contain high concentrations of ubiquitinated α-synuclein. Recent discoveries suggest, however, that the clinical phenotype of PD is much more heterogenous than originally conceived and strains the concept of a clinical entity. At the same time, doubt has been raised about the requirement for the presence of Lewy bodies in PD by the apparent absence of these inclusions from the brains of patients with some of the recently described autosomal dominant and recessive genetic mutations causing clinically typical PD. In addition, there is now an impressive body of evidence emerging that identifies a variety of clinical conditions that cluster in patients destined to develop PD before any of the classical features of parkinsonism are present. These include gastrointestinal dysfunction,1 sleep disorders,2 and anosmia.3 Braak and colleagues have suggested that these “premonitory symptoms” are associated with Lewy body pathology in lower brain stem nuclei preceding the development of such pathology in dopaminergic neurons of the substantia nigra.4 Further complicating the simplistic concept of a clinical–pathologic entity is the emerging evidence that many patients with the clinical features of PD will develop freezing and imbalance, depression, apathy, fatigue, psychosis, and dementia in the later clinical stages of their disease.5 These typically late-emerging features are not particularly responsive to dopaminergic therapies and are unlikely to develop as a consequence of the death of dopamine neurons in the nigrostriatal pathway, per se.
Thus, according to the Braak hypothesis, one may identify three clinical phases of PD as the Lewy body pathology marches inexorably rostrally (see Fig. 11–1). (1) A predopamine phase would be characterized by some combination of gastrointestinal dysfunction, sleep disorders, anosmia, and restless leg syndrome; (2) a dopamine deficiency phase would be heralded by the onset of tremor, bradykinesia, and rigidity; and (3) a postdopamine deficiency phase would subsequently develop consisting of imbalance, freezing, falls, depression, apathy, fatigue, psychosis, and dementia. Although this is a useful structure for considering the various features associated with Lewy body pathology, experienced clinicians, however, recognize numerous exceptions to this “typical” sequence of symptom evolution. Recently, Burke and colleagues have critically reviewed the Braak staging scheme and raised a number of issues as to its validity.6 Nevertheless, the defining clinical features of what we today call PD (tremor, bradykinesia, and rigidity) may now properly be viewed as merely a stage or phase of a more pervasive pathologic process with clinical features ranging from constipation to dementia.7
Clinical phases of Parkinson's disease and relationship to disability ...