Objective:

To investigate the effect of immunosuppression with cyclophosphamide (CTX) in reducing brain atrophy in refractory RRMS not responsing to interferon beta (IFNB) or glatiramer acetate (GA).

Background: Immunosuppression with CTX is often used as a therapeutic intervention in refractory RRMS not responding to therapy with IFNB or GA. Previous studies have identified young age and clinically active disease as two important factors in predicting a favorable response to CTX. It is unclear if treatment with CTX has a long-term effect on reducing brain atrophy.

Methods:

We treated 31 RRMS patients with intravenous CTX who failed therapy with IFNB or GA defined as two relapses in the prior year despite therapy. Brain MRI scans were obtained prior to IV CTX which was given monthly for 6 months at a dose of 1000 mg/m2 of BSA. Doses of CTX were adjusted to achieve a two-week WBC nadir of 2000 to 2500. All patients resumed therapy with IFNB or GA after 6 months. In 4 cases, IV CTX was continued on alternate months for an additional 6 months. Brain MRI scans with an identical protocol were obtained 3 years after stopping CTX. Patients were examined every 3 to 6 months during this period. 40 RRMS patients who received either IFNB or GA with monthly steroids for 6 to 12 months and declined treatment with CTX were also imaged over a 3 year period avoiding MRI scans within 6 weeks of steroid administration. 12 healthy volunteers were also imaged to check reproducibility of imaging technique.

Results:

Using SIENAX, cross sectional normalized brain volume was 1512.4 + 76 ml in the CTX-treated group and 1487.4 + 86 ml in the non-CTX treated group. Percent change measured with SIENA versus baseline scan was -1.3% in the CTX-treated group and -2.7 % in the non-CTX treated group (p<0.01). High lesion load at baseline showed a trend in correlating with brain volume change.

Conclusions:

Short-term exposure to intense immunosuppression with CTX may lead to long-term reduction of brain atrophy. Long-term studies may provide the best opportunity to study loss of brain volume.