By Irving M. Asher, MD
Published in Missouri Medicine, the journal of the Missouri State Medical Association, July/August 2012
Parkinson's disease (PD) is the second most common neurodegenerative disorder. Since the initial description of PD, clinical evaluation and management has focused on the motor signs and symptoms. Recent advances in our knowledge of neurologic involvement has led to a new emphasis on a broad spectrum of clinical features prompting the development of guidelines by the American Academy of Neurology for ongoing care of patients with PD. This review will touch on the historical aspects and traditional management of PD and discuss the latest recommendations for evaluation and care of PD patients. A broadened understanding of the multisystem nature of PD will enable physicians to improve the care and quality of life of their patients.
James Parkinson published his treatise on the Shaking Palsy in 1817.1 His description of a progressive disorder in which, eventually… “the submission of the limbs to the directions of the will can hardly ever be obtained in the performance of the most ordinary offices of life,” remains poignant. In 2000, Arvid Carlsson was awarded the Nobel Prize2 for work he and his Swedish colleagues began in the mid 1950s, that demonstrated dopamine (DA) to be a neurotransmitter, present in discreet neural pathways within the brain, one of which is from the substantia nigra to the caudate and putamen. They showed that the depletion of DA in the brains of rodents causes symptoms similar to those of PD that can be reversed by its repletion (See Figure 1). Oleh Hornekiewcz demonstrated DA deficiency in the striatum of patients with PD in 1960, and soon thereafter, following the lead of Carlsson, Birkmeyer, and Cotzias, administered the DA precursor L-Dopa to PD patients, which lead to the improvement of motor signs and symptoms.3 The twentieth century revolution of neuropharmacology and neuro-psychopharmacology had begun.
Figure 1. Dopamine is a neurotransmitter, present in discreet neural pathways within the brain, one of which is from the substantia nigra to the caudate and putamen. The depletion of DA in the brains of rodents causes symptoms similar to those of PD.
Our ability to improve the cardinal manifestations of PD, bradykinesia, rigidity, and resting tremor, by the administration of dopaminergic agents, has been the central focus of the therapeutic intervention since its importance and availability were established in the 1960s and early 70s. This allowed for a dramatic improvement in the lives of those suffering from PD and soon led to the appearance of previously unseen motor abnormalities – fluctuations in response to L-Dopa and dyskinesias (hyperkinetic, involuntary, choreic movements). Dopamine agonists, COMT inhibitors and MAOB inhibitors came in to use to aid in management of Parkinsonian symptoms and strategies were developed to reduce and attempt to delay the onset of motor fluctuations and dyskinesias.
Amongst the strategies used to delay onset of motor fluctuations and dyskinesias was the preferential early administration of a dopamine agonist rather than L-dopa. A series of studies were performed with multiple such agents (bromocriptine, permax, requip, pramipexole) all of which demonstrated that indeed such a delay could be achieved.4 The utility of this delay was, however, debated, as these agents provide less symptomatic benefit and a less favorable side effect profile than does L-Dopa.
In 2005 Hely et al.5 published the results of a 15-year follow up from one of the first of these studies, the multi-center Sydney study. The major impediments to life on long-term follow up were shown to be cognitive decline 84%, dementia 48%, daytime sleepiness 79%, depression 50%, hallucination 21%, falls 81%, fractures 23%, dysphagia 50%, urinary incontinence 41%, and symptomatic orthostatic hypotension 35%. These non-motor problems were unaffected by the choice of early drug.
Though central nervous system (CNS) pathology outside the substantia nigra was already known, through the late 90s and early decade of this century neuropathologic studies revealed an even greater diversity of CNS involvement than the dopaminergic loss upon which physicians had become fixated by their therapeutic success. Braak6 in 2002 published his hypothesis suggesting a progression of CNS involvement beginning in the olfactory tubercle and dorsal motor nucleus of the vagus in the medulla, and then ascending the brainstem and finally progressing into limbic and neocortical regions. This schema provided possible anatomic explanation for the appearance of anosmia and REM sleep behavior disorder (RSBD) as presymptomatic findings in PD as well as the later appearance of dementia. Anosmia and RSBD are now being looked at as potential presymptomatic screens for PD.7 In addition to involvement of nondopaminergic CNS regions, pathology of the autonomic nervous system outside the CNS has been identified in PD. This includes both cardiac sympathetic denervation demonstrated by single positron emission tomography employing iodine-131-meta-iodobenzylguanadine (MIBG SPECT) as an early finding8, and involvement of the enteric nervous system with Lewy neurites in Auerbach’s plexus and the myenteric plexus.9 Chronic constipation had already been found in the Hawaiian VA study foreshadow a four to five fold increased risk of PD after 12 years, and these patients had a higher incidence of incidental Lewy Bodies at autopsy.10
In addition to the non-dopaminergic problems and involvement noted above, the late 90s and early decade of this century showed increasing awareness of non-motor symptoms as manifestations of fluctuations of dopaminergic state,11 including depression, clouding of consciousness, anxiety and pain as L-dopa wearing off phenomena, as well as the appearance of impulse control disorders, including compulsive gambling, eating, shopping and sexual activity, as side effects of dopaminergic agents, particularly DA agonists.12 These symptoms are now ultimately felt related to changes induced in the mesolimbic, ventral-tegmental( VTA-accumbens) DA pathway involved in reward systems and limbic circuitry as opposed to the nigrostriatal system - A10 rather than A9 per scheme of Carlsson and Ungerstedt.13