Approximately 30 years passed between the first description of a paraneoplastic neurologic disorder and the demonstration of an immunologic pathogenesis for one of these syndromes. In the almost 4 decades since, the paraneoplastic neurologic disorders have been subjected to study far out of proportion to their clinical prevalence. These disorders stimulate clinical research because (1) paraneoplastic neurologic syndromes are frequently the presentation of a malignancy, (2) they may bode well for a more favorable tumor prognosis,[3,4] and most importantly, (3) they yield insight into the workings of malignancy and the pathogenesis of neurologic disorders, particularly neurologic degenerations.
The review of the current state of knowledge by Lieberman and Schold nicely summarizes the advances made in the study of paraneoplastic neurologic disorders, amply justifying this interest. Syndromes have been identified with specific antibodies, and the evolving nosology has yielded therapeutic direction. Not surprisingly, the pathogenesis of these disorders depends largely on immune mechanisms, and research on these rare conditions has advanced our understanding of how the two great reactive systems in the body interact in the setting of disease. Doubtless the greatest contribution of such exhaustive study has been the light shed on our understanding of fundamental neurobiologic mechanisms.
Generalizations from observations of the paraneoplastic disorders, which might be considered natural experiments, have served to advance our knowledge of important neurologic, physiologic, and pathogenetic principles. For example, much of our knowledge of neuromuscular physiology and pathophysiology stems from studies of the Lambert-Eaton myasthenic syndrome and other paraneoplastic neuromuscular disorders. The search for the target of Lambert-Eaton syndrome antibodies revealed the importance of the voltage-gated calcium channel and the critical role of the surface membrane protein synaptotagmin in the synaptic terminal exocytosis of acetylcholine quanta. Although much work remains in fully understanding the pathogenesis of this syndrome, it is the best understood of the paraneoplastic disorders.
The discovery of onconeural antigens and the unraveling of their pathogenetic mechanisms should help advance our understanding of not only the immunology of cancer, but also the mechanisms of developmental neurobiology and the pathogenesis of the neurodegenerations. These mysterious disorders, such as amyotrophic lateral sclerosis, Alzheimer’s disease, and spinocerebellar degenerations, have mechanisms that remain elusive. Although each disorder has its own distinct clinical pattern, each pathologically demonstrates spontaneous and premature apoptosis in the absence of overt inflammation.
At first consideration, these disorders may seem the antithesis of the oncology problem, but the mechanisms at hand are likely closely related. Cancer cells do not age appropriately; in neurologic degenerations, senescence is premature. These seemingly opposing processes are probably different faces of the same coin, with the paraneoplastic disorders providing important insight into the workings of both major classes of disease.
Novel mechanisms should not be overlooked. Even cancer-related antibodies do not always cause their neuropathologic mischief through conventional immunologic means. Multiple myeloma, for example, causes peripheral neuropathy by a number of different mechanismscryoglobulins produce sludging in the vasa nervorum, and amyloid protein formed by the crystallization of M protein infiltrates the perineum and damages axons by direct compression and disturbance of the microvascular circulation.
Other novel neuropathologic mechanisms may also lead to paraneoplastic disorders. In early descriptions, diseases with mechanisms as diverse as those of progressive multifocal leukoencephalopathy and central pontine myelinolysis were thought to be of paraneoplastic origin. Viruses and metabolic stresses doubtless play a role in other paraneoplastic phenomenon as well.
Identification of an antibody associated with a neurologic disorder in a cancer patient does not guarantee that the antibody causes the disorder and is not merely an epiphenomenon. Remarkably, many of the characterized paraneoplastic antibodies play a critical role in the pathogenesis of the disorders with which they are associated. Recent demonstrations of the molecular mechanisms by which some of these antibodies cause illness have been a triumph of their intensive study over the past 2 decades.[7-9] These mysterious conditions emphasize the systemic nature of cancer and the complex homeostatic interactions of the nervous and immune systems.
In the next decade, we will almost certainly see the identification of new paraneoplastic antibodies and, more importantly, further understanding of the processes by which these antibodies cause neurologic disease. Although the well-characterized paraneoplastic immune disorders are rare, these mechanisms will likely be shown to play a key role in more commonly occurring oncologic phenomena such as cognitive difficulties and the chronic fatigue syndrome. Unraveling the pathogenesis of these widespread, debilitating clinical conditions may well rest with the study of the extraordinary paraneoplastic neurologic disorders.