Neurologists have by tradition separated disorders of the central nervous system from those affecting the peripheral nervous system. Arguments for this distinction have noted the role of the blood-brain-barrier as protective to the CNS by preventing ingress of toxins, poisons, and impacts of metabolic disorders such as diabetes and uremia – whose effects are felt primarily in the PNS. Demyelinative disorders such as multiple sclerosis affect the CNS and those of acute polyradiculitis- Guillain-Barre syndrome - primarily involve the PNS. Many genetic disorders of neurological function are defined by molecular pathologies that impact one site or the other- leukodystrophies and Pelizaeus-Merzbacher disease affecting the CNS and Charcot-Marie-Tooth the PNS.
This concept has been breaking down in recent years. In the case of the neurodegenerative disorders such as Parkinson’s disease (PD) recent clinical and pathological studies point to defects in function of the peripheral nervous system and autonomic nervous system as well as the clearly defined changes that occur in the central dopaminergic pathway- loss of neurons in the substantia nigra, decrease in dopamine levels in the striatum and appearance of Lewy bodies that stain immunocytochemically for the protein alpha-synuclein. In PD, disturbances in gastrointestinal function with constipation and abdominal discomfort, are now recognized to occur early in the disorder. Moreover according to the Braak hypothesis, PD progresses from involvement of peripheral afferent inputs to brain stem and eventually to abnormalities in the cortex that cause dementia.
That the distinction between CNS and PNS neurodegenerative changes may not be precise is further emphasized in a recent review on pain (Reichling and Levine, 2011). The authors reference two recent reports on the common occurrence of pain syndromes in patients with PD (Beiske et al., 2009 and Ford, 2009).
Reichling and Levine emphasize that disorders of a neurodegenerative nature such as PD, amyotrophic lateral sclerosis, multiple system atrophy, and a variety of ‘tauopathies’ may exhibit a combination of peripheral afferent abnormalities with central pathological changes resulting in neuropathic pain. They hypothesize that “primary neuropathic pain, is not merely an eventual consequence of an overall deterioration of the nervous system and functional impairment of the body in neurodegenerative diseases. Instead, we suggest that it is the result of the very same cellular processes that underlie neurodegenerative disease itself, but occurring in the peripheral nervous system.”
They argue that a variety of cell biological processes may be compromised in the process of neurodegeneration and that afferents from the periphery show aberrancies that have not previously been appreciated fully. Examples include defects in mitochondrial mechanisms and cytoskeleton defects. They point to the appearance of protein aggregates, for example as not being restricted to central neurons. Examples are provided by Reichling and Levine to suggest that such changes are the source of a ‘primary’ rather than a secondary neuropathic pain disturbance.
What do you think? We’d like to hear your thoughts on this paper.
- If you see patients with Parkinson’s, do they often complain of pain that is not easily explained by their movement limitations or tremor?
- Do you think existing evidence supports the hypothesis of neuropathic pain in Parkinson disease as proposed by Reichling and Levine?
- What is your view of the evolution of the disorder (from peripheral to central) as outlined by the Braak hypothesis?
- Are there new directions of experimental inquiry that might clarify or rule out the hypothesis of Reichling and Levine?
Beiske AG, Loge JH, Ronningen A, Svensson E. Pain in Parkinson's disease: Prevalence and characteristics. Pain. 2009 Jan; 141(1-2):173-7. Epub 2008 Dec 18.
Ford B. Parkinson disease: Pain in Parkinson disease: The hidden epidemic. Nat Rev Neurol. 2009 May; 5(5):242-3.
Reichling DB, Levine JD. Pain and death: Neurodegenerative disease mechanisms in the nociceptor. Ann Neurol. 2011 Jan; 69(1):13-21.