Long-term follow-up of patients with subacute sclerosing panencephalitis treated with intraventricular alpha-interferon

Subacute sclerosing panencephalitis (SSPE) has an invariably fatal course, although transient improvements or plateaus may occur and 20% of patients can survive 4 or more years. ^[1] We reported remission in 50% and stabilization in 22% of patients treated with intraventricular alpha-interferon (alpha-IFN) and oral inosiplex. ^[2] Others obtained similar results with this combination given in a different dose regimen. ^[3]

Spontaneous remissions are rare in SSPE. They may last 7 to 10 years. ^[4] The duration of remissions or improvements induced by alpha-IFN is unknown. We present the long-term follow-up of the first 22 patients treated with alpha-IFN and reported in 1992. ^[2]

Patients and methods.

The original group of 22 SSPE patients (15 boys, seven girls, aged 8-17 years, mean 12.5 +/- 2.6) treated with intraventricular alpha-IFN and oral inosiplex was followed up by neurologic examination, neurologic disability index (NDI), EEG, and psychometric tests done at various intervals for 54 more months after the initial report, total 56 to 108 months. Patients whose follow-up was incomplete were contacted by phone. The clinical staging system of Risk and Haddad ^[1] was used. The treatment regimen consisted of 6-week courses of natural alpha-IFN, started as 100,000 units/m sup 2 and increased to 1 million units/m² body surface area per day, 5 days/week, given through an Ommaya reservoir. Courses were repeated up to six times, at 2 to 6-month intervals. Patients were also given oral inosiplex 50 to 100 mg/kg daily. ^[2]

The survival rate of the group taking alpha-IFN was compared with that of 35 other SSPE patients diagnosed during the same period (1986-1992) who did not receive alpha-IFN for various causes but did receive inosiplex or symptomatic treatment only. The age and sex distribution of the control group was similar to the treatment group: 25 boys and 10 girls, age 3 to 20, mean 11.2 +/- 3.9. The control group was followed up for 48 to 110 months.

Results.

Improvement or stabilization was observed in 16 patients initially (Table 1). In all patients whose NDI decreased with treatment (n = 11) the condition became stable in 3 to 12 months. Three remain in stable condition, with a follow-up of 56 to 104 months. The condition of the others (n = 8) began to deteriorate 12 to 84 months after treatment, and three of them died 20 to 90 months after treatment. One of these patients (case 15) was re-treated with the same regimen 1 year after deterioration started, but did not have a response. In the five patients in whom the condition initially stabilized, the disease also returned and progressed 6 to 60 months after treatment, and four died 8 to 66 months after treatment (Table 2). Clinical stage, age, duration of disease before alpha-IFN treatment, and inosiplex therapy did not influence the time and probability of later deterioration.

The disease continued its progressive course after alpha-IFN treatment in six patients, although at a slower rate in three of them. Two patients who had the slowly progressive disease reached a stable condition 1 year after treatment and are still being followed up (56 and 90 months). The other patient with the slowly progressive disease died of meningitis while he was not receiving IFN, 14 months after treatment. Three patients in this group who died 3 to 12 months after treatment were included in the first report. ^[2]

The higher survival rate of IFN-treated patients compared with the control group persisted during 9 years of follow-up; however, the difference was smaller after 8 years (Figure 1). The use of inosiplex was not significantly different between the two groups: 13 patients in the alpha-IFN and 16 in the control group had received inosiplex for at least 6 months.

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Figure 1. Survival curves of patients treated with alpha-IFN and control cases.

Discussion.

Intraventricular alpha-IFN combined with oral inosiplex slowed or stopped the progressive course of SSPE, with a markedly increased chance of survival during the first 2 years after treatment. ^[2] This effect continued for several years, but at 9 years, the survival rate of patients treated with alpha-IFN was closer to that of untreated controls. Longer follow-up demonstrated that some remissions induced by alpha-IFN could be temporary, like spontaneous remissions. The recurrences were not influenced by inosiplex therapy. They tended to be more frequent and earlier among patients whose condition stabilized rather than improved after alpha-IFN, but the difference was not statistically significant. On the other hand, in two patients whose disease was slowly progressing after treatment, the disease became stable in one year; late remissions, although rare, seem possible.

The pathophysiology of remissions and relapses in SSPE is unknown. The stable state may depend on a balance between viral replication and immune response, and the immune system possibly has a role in remissions. CSF interferon levels were low in patients with SSPE ^[5] and their peripheral mononuclear cells failed to produce IFN in response to stimulation in in vitro experiments. ^[6] These findings suggest a deficient IFN system in SSPE. There may also be a relative resistance of the SSPE virus to IFN. ^[7] The effect of alpha-IFN treatment in SSPE may be mediated through these mechanisms. After a period of antiviral state induced by exogenous alpha-IFN, viral replication and propagation may increase due to acquired higher resistance, or to the presence of antibodies to IFN. The lack of response to re-treatment with alpha-IFN in one of our patients supports this possibility. We readministered alpha-IFN 1 year after she began to show late deterioration; we might have obtained better response with earlier treatment. The resistance to alpha-IFN might be overcome by higher doses given longer; two patients whose condition was deteriorating with alpha-IFN treatment became stabilized when the drug was given at higher doses and shorter intervals. ^[8]

Treatment in SSPE still requires further research, possibly including combinations of alpha-IFN with other agents. Among several immune modulators tested, Sobzyck et al. ^[9] observed the best results with Propionobacterium granulosum. ^[9] A single case report ^[10] suggested the efficacy of immune globulins, but our experience with immune globulins did not show any significant benefit (unpublished observations). Preliminary trials with beta-IFN are under way. Although its effect is limited, intraventricular alpha-IFN appears to be the most efficient therapeutic agent in the treatment of SSPE at present.

Acknowledgments

We thank Mehmet Okan, MD, and Bulent Coskun, MD, for their assistance in the follow-up of the patients and for their contribution to this study.