Distant Effects of Cancer on the Nervous System

November 1, 2002

Approximately 30 years passed between the first description of a paraneoplastic neurologic disorder[1] and the demonstration of an immunologic pathogenesis for one of these syndromes.[2] 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.

Approximately 30 years passedbetween the first descriptionof a paraneoplastic neurologic disorder[1] and the demonstration of animmunologic pathogenesis for one of these syndromes.[2] In the almost 4 decadessince, the paraneoplastic neurologic disorders have been subjected to study farout of proportion to their clinical prevalence. These disorders stimulateclinical research because (1) paraneoplastic neurologic syndromes are frequentlythe presentation of a malignancy, (2) they may bode well for a more favorabletumor prognosis,[3,4] and most importantly, (3) they yield insight into theworkings of malignancy and the pathogenesis of neurologic disorders,particularly neurologic degenerations.

Research Insights

The review of the current state of knowledge by Lieberman andSchold nicely summarizes the advances made in the study of paraneoplasticneurologic disorders, amply justifying this interest. Syndromes have beenidentified with specific antibodies, and the evolving nosology has yieldedtherapeutic direction. Not surprisingly, the pathogenesis of these disordersdepends largely on immune mechanisms, and research on these rare conditions hasadvanced our understanding of how the two great reactive systems in the bodyinteract in the setting of disease. Doubtless the greatest contribution of suchexhaustive study has been the light shed on our understanding of fundamentalneurobiologic mechanisms.

Generalizations from observations of the paraneoplasticdisorders, which might be considered natural experiments, have served to advanceour knowledge of important neurologic, physiologic, and pathogenetic principles.For example, much of our knowledge of neuromuscular physiology andpathophysiology stems from studies of the Lambert-Eaton myasthenic syndrome andother paraneoplastic neuromuscular disorders.[5] The search for the target ofLambert-Eaton syndrome antibodies revealed the importance of the voltage-gatedcalcium channel and the critical role of the surface membrane proteinsynaptotagmin in the synaptic terminal exocytosis of acetylcholine quanta.[6]Although much work remains in fully understanding the pathogenesis of thissyndrome, it is the best understood of the paraneoplastic disorders.

Mechanistic Elucidations

The discovery of onconeural antigens and the unraveling of theirpathogenetic mechanisms should help advance our understanding of not only theimmunology of cancer, but also the mechanisms of developmental neurobiology andthe pathogenesis of the neurodegenerations. These mysterious disorders, such asamyotrophic lateral sclerosis, Alzheimer’s disease, and spinocerebellardegenerations, have mechanisms that remain elusive. Although each disorder hasits own distinct clinical pattern, each pathologically demonstrates spontaneousand premature apoptosis in the absence of overt inflammation.

At first consideration, these disorders may seem the antithesisof the oncology problem, but the mechanisms at hand are likely closely related.Cancer cells do not age appropriately; in neurologic degenerations, senescenceis premature. These seemingly opposing processes are probably different faces ofthe same coin, with the paraneoplastic disorders providing important insightinto the workings of both major classes of disease.

Novel mechanisms should not be overlooked. Even cancer-relatedantibodies do not always cause their neuropathologic mischief throughconventional immunologic means. Multiple myeloma, for example, causes peripheralneuropathy by a number of different mechanisms—cryoglobulins produce sludgingin the vasa nervorum, and amyloid protein formed by the crystallization of Mprotein infiltrates the perineum and damages axons by direct compression anddisturbance of the microvascular circulation.

Other novel neuropathologic mechanisms may also lead toparaneoplastic disorders. In early descriptions, diseases with mechanisms asdiverse as those of progressive multifocal leukoencephalopathy and centralpontine myelinolysis were thought to be of paraneoplastic origin. Viruses andmetabolic stresses doubtless play a role in other paraneoplastic phenomenon aswell.

Conclusions

Identification of an antibody associated with a neurologicdisorder in a cancer patient does not guarantee that the antibody causes thedisorder and is not merely an epiphenomenon. Remarkably, many of thecharacterized paraneoplastic antibodies play a critical role in the pathogenesisof the disorders with which they are associated. Recent demonstrations of themolecular mechanisms by which some of these antibodies cause illness have been atriumph of their intensive study over the past 2 decades.[7-9] These mysteriousconditions emphasize the systemic nature of cancer and the complex homeostaticinteractions of the nervous and immune systems.

In the next decade, we will almost certainly see theidentification of new paraneoplastic antibodies and, more importantly, furtherunderstanding of the processes by which these antibodies cause neurologicdisease. Although the well-characterized paraneoplastic immune disorders arerare, these mechanisms will likely be shown to play a key role in more commonlyoccurring oncologic phenomena[10] such as cognitive difficulties and the chronicfatigue syndrome. Unraveling the pathogenesis of these widespread, debilitatingclinical conditions may well rest with the study of the extraordinaryparaneoplastic neurologic disorders.

References:

1. Greenfield JG: Subacute spinocerebellar degenerationoccurring in elderly patients. Brain 57:161-176, 1934.

2. Wilkinson PC, Zeromski J: Immunofluorescent detection ofantibodies against neurones in sensory carcinomatous neuropathy. Brain88:529-587, 1965.

3. de la Monte SM, Hutchins GM, Moore GW: Paraneoplasticsyndromes and constitutional symptoms in prediction of metastatic behavior ofsmall cell carcinoma of the lung. Am J Med 77:851-857, 1984.

4. Newsom-Davis J: Paraneoplastic neurological disorders. J RoyColl Physicians Lond 33:225-227, 1999.

5. Skeie GO: Skeletal muscle titin: Physiology andpathophysiology. Cell Mol Life Sci 57:1570-1576, 2000.

6. Martin-Moutot N, el Far O, Leveque C, et al: Synaptotagmin: ALambert-Eaton myasthenic syndrome antigen that associates with presynapticcalcium channels. J Physiol Paris 87:37-41, 1993.

7. Benatar M, Blaes F, Johnston I, et al: Presynaptic neuronalantigens expressed by a small cell lung carcinoma cell line. J Neuroimmunol113:153-162, 2001.

8. Berghs S, Ferracci F, Maksimova E, et al: Autoimmunity tobeta IV spectrin in paraneoplastic lower motor neuron syndrome. Proc Natl AcadSci U S A 98:6945-6950, 2001.

9. Carlson NG, Gahring LC, Rogers SW: Identification of theamino acids on a neuronal glutamate receptor recognized by an autoantibody froma patient with paraneoplastic syndrome. J Neurosci Res 63:480-485, 2001.

10. Shavit YB, Graus F, Probst A, et al: Epilepsia partialiscontinua: A new manifestation of anti-Hu-associated paraneoplasticencephalomyelitis. Ann Neurol 45:255-258, 1999.