Devic’s Syndrome: Close to a Cure?

Wise Young, PhD MD

Devic’s syndrome was first described in 1870 by Sir Thomas Allbutt (what a name to have had as a kid!) who pointed out an association between myelitis and optic nerve disorder.  In 1894, Eugene Devic and his student Fernand Gault described 16 patients who had lost vision in one or both eyes and developed spastic weakness, sensory loss, and incontinence.  For many years, Devic’s syndrome was just one of several variants of multiple sclerosis that presented with relapsing optic neuritis followed by spastic weakness and sensory loss.  The other name of the condition was neuromyelitis optica (NMO).

A major breakthrough came in 2004 when a specific marker NMO-IgG was found for the disorder [1].  IgG stands for immunoglobulin (a kind of antibody).   NMO-IgG is a autoantibody (an antibody against a protein in one’s own body) and turned out to target aquaporin-4 (a protein that is responsible for water channels in cells).  The identification of NMO-IgG as a marker for Devic’s syndrome allows the disease to be distinguished from other autoimmune diseases, i.e. myasthenia gravis [2], systemic lupus erythematosus [3], necrotizing myelopathy [4], paraneoplastic myelopathy [5].  More important, it has allowed the creation of animal models and the study of the mechanisms of the disease [6].

Aquaporin-4 is a water channel that plays an important role in the blood brain barrier and astrocytic function.  Devic’s disease is now classified as an “autoimmune channelopathy” disease [7].  With that recognition, the treatment of the disease has become more rational.  While intravenous high-dose glucocorticoids is recommended for acute relapses of the condition, clinicians are using rescue plasmapheresis for severe, progressive, and steroid-resistant cases.  In between attacks, immunosuppression with azathioprine or mycophenolate mofetil is recommended for mild conditions and rituximab for those with more recent severe attacks [8].

Much progress has been made in immunoablative therapies.  In Hong Kong, Mok, et al. [9] recently described the use of immunoablative cyclophosphamide to treat refractory lupus-related neuromyeltis optica.  This approach uses a chemotherapeutic agent (cyclophosphamide) to kill a significant part of the immune system, in the hopes that it will eliminate those cells in the immune system that are producing the particular antibodies.  When the immune system reconstitutes itself from the remaining cells, the auto-antibodies are sometimes eliminated.

An alternative approach may be immunoablation followed by umbilical cord blood transplants.  This approach will replace the immune system with normal hematopoeitic cells from cord blood.  This would allow more intensive immunoablation and increase the probability of ablating the auto-immune cells.  If autologous cord blood is available, this would be the least risky.  Haller, et al. [10] used autologous umbilical cord blood infusions to treat type 1 diabetes, another autoimmune diseases.  However, heterologous cord blood can also be used.

Use of cord blood or bone marrow transplants have now been successfully to treat many patient with autoimmune diseases.  According to Burt, et al. [11], 26 reports from 1997-2007 indicated that 854 patients treated with immune-ablation and transplantation had less than 1% treatment related mortality (2/220 patients for nonmyeloablative, 3/197 for dose-reduced myeloablative, and 13% for intensive myeloablative regimens).  While no randomized trials have been performed, all the trials indicate potent disease-remitting effects.

In summary, for sufferers of Devic’s syndrome, effective treatments are becoming available.  The identification of a specific marker NMO-IgG has not only eased the diagnosis of the condition but also provide a rational approach to therapy of the condition.  Not only are there therapies that can reduce the impact of relapsing attacks and prevent attacks but a cure may be possible by myeloablation and hematopoietic cell replacement.  For a long time, myeloablation had an unacceptable mortality of >10%.  However, with reduced-dose myeloablative regimens, the morality is now approaching 1%, less than the mortality of the diseases themselves.  Of course, eliminating the autoimmune disease does not necessarily restore function that has been lost, but regenerative therapies are being worked on.

References

1. Wingerchuk DM and Weinshenker BG (2005).  Neuromyelitis Optica.  Curr Treat Options Neurol.  7: 173-182.  Link
2. Furukawa Y, Yoshikawa H, Yachie A and Yamada M (2006).  Neuromyelitis optica associated with myasthenia gravis: characteristic phenotype in Japanese population.  Eur J Neurol.  13: 655-8. Link
3. Jacobi C, Stingele K, Kretz R, Hartmann M, Storch-Hagenlocher B, Breitbart A and Wildemann B (2006).  Neuromyelitis optica (Devic’s syndrome) as first manifestation of systemic lupus erythematosus.  Lupus.  15: 107-9.  Link
4. Okai AF, Muppidi S, Bagla R and Leist TP (2006).  Progressive necrotizing myelopathy: part of the spectrum of neuromyelitis optica?  Neurol Res 28: 354-9.  Link
5. Jacob A, Matiello M, Wingerchuk DM, Lucchinetti CF, Pittock SJ and Weinshenker BG (2007).  Neuromyelitis optica: changing concepts.  J Neuroimmunol 187: 126-38.  Link
6. Mueller S, Dubal DB and Josephson SA (2008).  A case of paraneoplastic myelopathy associated with the neuromyelitis optica antibody.  Nat Clin Pract Neurol 4: 284-8.  Link
7. Lalive PH, Perrin L and Chofflon M (2007).  [Neuromyelitis optica/Devic's syndrome: new perspectives].  Rev Med Suisse 3: 950-5.  Link
8. Wingerchuk DM and Weinshenker BG (2008).  Neuromyelitis optica.  Curr Treat Options Neurol 10: 55-66. Link
9. Mok CC, To CH, Mak A and Poon WL (2008).  Immunoablative cyclophosphamide for refractory lupus-related neuromyelitis optica.  J Rheumatol 35: 172-4.  Link
10. Haller MJ, Viener HL, Wasserfall C, Brusko T, Atkinson MA and Schatz DA (2008).  Autologous umbilical cord blood infusion for type 1 diabetes.  Exp Hematol 36: 710-5.  Link
11. Burt RK, Loh Y, Pearce W, Beohar N, Barr WG, Craig R, Wen Y, Rapp JA and Kessler J (2008). Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases. Jama 299: 925-36. Link

Recommended Reading

Devic’s disease - Wikipedia, the free encyclopedia