New Developments in Transplantation Medicine

Summer 1996

Volume 3, Number 1

NEUROLOGY

Bone Marrow Transplantation for Multiple Sclerosis?

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system. The initial event that triggers the disease is unknown, but once started, MS is an immune-mediated disease that involves both lymphocyte- and macrophage-mediated destruction of myelin. Approximately 1 in 1000 individuals are affected, with the peak age of onset at 20-30 years.1 Because any central neurologic pathway may be affected, the clinical manifestations are diverse. The clinical course is equally variable:

For most patients, life expectancy is similar to that of the age-matched general population, but the tempo of disease progression varies. Some patients progress rapidly to a completely bedridden state or death within 10 years.1-3 This subset has been termed malignant or rapidly progressive MS. Causes of death include suicide (three consecutive Kevorkian patients who underwent assisted suicide had MS), urosepsis from indwelling catheters, aspiration pneumonia, pulmonary emboli, and arrhythmia.1-3

For mild disease, a watch and wait approach without therapeutic intervention is appropriate. For more debilitating or aggressive disease, therapy is directed towards modulating or suppressing the immune system. Such treatment has included steroids, cyclophosphamide, azathioprine, antilymphocyte antibodies, cladribine (2-chloroadenosine), total nodal irradiation, craniospinal irradiation, and ß-interferon.4-11 Although improvement has been reported with these approaches, no current therapy is curative.

The philosophy behind these therapies is suppression or modulation of the immune system. Since immune regulatory cells (ie, lymphocytes and macrophages) arise from the hematopoietic compartment, an alternative approach would be complete ablation of the hematopoietic/immune compartments. Hematopoiesis and lymphopoiesis could then be reconstituted with hematopoietic stem cell rescue, either with lymphocyte-depleted (ie, purged) autologous stem cells or a genotypically matched allograft.

Extrapolating from BMT results in patients with leukemia, early mortality for allografts is 20-30%, compared with a 5% mortality for autografts. This difference is predominately due to graft-versus-host-disease (GVHD) and infections. It would, therefore, be safer to use autologous stem cells for a controversial concept like treatment of MS with bone marrow transplantation. In reality, autologous marrow transplantation is simply immune ablation and hematopoietic stem cell rescue. To be a candidate for an unproven therapy with an anticipated mortality of 5%, patients need to be identified before they become completely or irreversibly disabled and should have rapidly progressive disease.

Survival of patients with MS correlates best with the level of disability. Less than 6% of patients with an unrestricted activity level are dead within 10 years compared with a 10-year mortality of 70% for patients confined to a wheelchair. Factors predictive for a rapidly deteriorating clinical course are prior course (ie, rapid deterioration from onset) and possibly the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI).1-3,12,13 Neurologic disability is quantified with scales such as the Kurtzke expanded disability status scale (Kurtzke EDSS).14 Scores range from 0 (no disability) to 10.0 (death due to MS). We consider patients with Kurtzke EDSS between 4.5 and 7.5 (limited ambulation to reliance on a cane, walker, or wheelchair) to be potential immune ablation candidates. In addition, candidates must have a rapid clinical course (ie, deterioration of 2 Kurtzke points within 12 months).

To be a candidate for an unproven therapy with an anticipated mortality of 5%, patients need to be identified before they become completely or irreversibly disabled and should have rapidly progressive disease.

Lesions that enhance within gadolinium contrast on MRI indicate inflammation and breakdown in the blood brain barrier.12,13,15 Nevertheless, severe neurologic deficits may be present with only minimal MRI activity. Conversely, large numbers of plaques may be detected in patients with minimal clinical disability. Therefore, the number of gadolinium-enhancing lesions does not correlate with severity of clinical symptoms. However, gadolinium enhancement identifies patients with active immune pathology. The total area or volume of CNS with enhanced gadolinium activity may also predict the rate of deterioration.13 We therefore consider gadolinium-enhancing MRI activity a requirement for immune ablative therapy.

The fate of some patients with MS has propelled us to consider more aggressive intervention. Immune ablation with hematopoietic stem cell rescue for these patients is no longer a theoretical or academic discussion.15 Three institutions (Northwestern University, Medical College of Wisconsin, and the University of Indiana) have IRB-approved protocols to perform immune ablation and T-cell depleted autologous hematopoietic stem cell rescue in patients with rapidly progressive MS. Even if clinically unsuccessful, these studies should help to better define the role of the immune system in multiple sclerosis.

Richard K. Burt, MD
Director, Allogeneic Bone Marrow Transplantation
Northwestern University Medical School
Chicago, Illinois

Ann Traynor, MD
Assistant Professor of Medicine
Northwestern University Medical School
Chicago, Illinois

REFERENCES

  1. Matthews WB, ed. Course and prognosis. McAlpine's Multiple Sclerosis (second edition). London, Churchill Livingstone. 1991, pp 139-163.
  2. Phadke JG. Survival pattern and cause of death in patients with multiple sclerosis: Results from an epidemiological survey in north east Scotland. Journal of Neurology, Neurosurg Psych 1987;50:523-531.
  3. Minderhoud JM, Van-der Hoeven JH, Prange AJA. Course and prognosis of chronic progressive multiple sclerosis. Acta Neurologica Scandinavica 1988;78:10-15.
  4. Rose AS, Kuzma JW, Kurtzke JF, Namerow NS, Sibley WA, Tourtellotte WW. Co-operative study in the evolution of multiple sclerosis: ACTH vs placebo. Neurology 1970;5(2):1-59.
  5. Goas JY, Marion JL, Missoum A. High dose intravenous methylprednisolone in acute exacerbation of multiple sclerosis. J Neurol Neurosurg Psychiatr 1983;46:99.
  6. Carter JL, Hafler DA, Dawson DM, Orav J, Weiner HL. Immunosuppression with high-dose IV cyclophosphamide and ACTH in progressive multiple sclerosis: Cumulative 6 year experience in 164 patients. Neurology 1988;38(suppl 2):9-14.
  7. Hauser SL, Dawson DM, Lehrich JR, Beal MF, Kevy SV, Propper RD, et al. Intensive immunosuppression in multiple sclerosis: A randomized three arm study of high dose intravenous cyclophosphamide, plasma exchange and ACTH. N Engl J Med 1983;308:173-180.
  8. Cook SD, Troiano R, Zito G, Lavenhar M, Devereux C, Hafstein MP, et al. Effect of total lymphoid irradiation in chronic progressive multiple sclerosis. Lancet 1986;1:1405-1409.
  9. Cook SD, Devereux C, Troiano R, Zito G, Hafstein M, Lavenhar M, et al. Total lymphoid irradiation in multiple sclerosis: Blood lymphocytes and clinical course. Ann Neurol 1987;22:634-638.
  10. Devereux CK, Vidaver R, Hafstein MP, Zito G, Troiano R, Dowling PC, Cook SD. Total lymphoid irradiation for multiple sclerosis. Int J Rad Onc Biol Phys 1988;14:197-202.
  11. Devereux C, Troiano R, Zito G, Devereux RB, Kopecky KJ, Friedman R, et al. Effect of total lymphoid irradiation on functional status in chronic multiple sclerosis: Importance of lymphopenia early after treatment--the pros. Neurology 1988;38(suppl 2):32-37.
  12. Smith ME, Stone LA, Albert PS, Frank JA, Martin R, Armstrong M, et al. Clinical worsening in multiple sclerosis is associated with increased frequency and area of gadopentetate dimeglumine-enhancing magnetic resonance imaging lesions. Ann Neurol 1993;33: 480-489.
  13. McFarland HF, Frank JA, Albert PS, Smith ME, Martin R, Harris JO, et al. Using gadolinium-enhanced magnetic resonance imaging lesions to monitor disease activity in multiple sclerosis. Ann Neurol 1992; 32:758-766.
  14. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 1983;33:1444-1452.
  15. Burt RK, Burns W, Hess A. Bone marrow transplantation for multiple sclerosis (editorial). Bone Marrow Transplantation 1995;16:1-6.

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