Disease-Modifying Therapy in Subacute Sclerosing Panencephalitis: An Area of Darkness : Annals of Indian Academy of Neurology

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Disease-Modifying Therapy in Subacute Sclerosing Panencephalitis

An Area of Darkness

Garg, Divyani; Sharma, Suvasini1

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Annals of Indian Academy of Neurology 26(1):p 3-9, Jan–Feb 2023. | DOI: 10.4103/aian.aian_655_22
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Subacute sclerosing panencephalitis (SSPE) was first identified by Dawson on histopathology in 1933, and was referred to by the eponymous “Dawson's encephalitis.”[1] Subsequently, the measles virus was isolated from brain cell cultures of SSPE patients in 1969, unequivocally establishing the link between SSPE and measles.[23] The current dual dose vaccination strategy for measles offers 98% protection against infection. Despite this well-established protection offered by vaccination, SSPE continues to abound in the lower-income regions of the world because of the lack of universal vaccination. In countries that have implemented effective vaccination programs against measles, the incidence remains substantially low. India and adjoining regions continue to report large numbers of SSPE cases.[4] It is nearly always fatal, with some reports of long-term survival or even spontaneous resolution.[5] The slow momentum in the exploration of newer and effective therapies in SSPE is evidenced by a clear lack of recent literature geared towards this very objective. The pathogenesis of this neurodegenerative and usually fatal disease remains underexplored as well.

In this view point, we have synthesized current literature on therapeutic efforts in SSPE, with an aim to critically explore possible disease-modifying strategies that may be offered to patients with SSPE in our setting.


Immune dysfunction, inflammatory mediators, and genetics have been hypothesized to play a role in the pathogenesis of SSPE [Figure 1].

Figure 1:
Factors involved in the pathogenesis of subacute sclerosing panencephalitis

Immune dysfunction

There is some evidence that impaired cell-mediated immunity (CMI) contributes to the pathogenesis of SSPE. In an earlier study, CMI was studied by E-rosette formation, leucocyte migration inhibition factor, and proliferation in response to mitogens.[6] These responses were found to be abnormal in 11 patients, although there was no correlation of these defects with clinical status. There may also be an impaired generation of cytotoxic T lymphocytes, which may explain the persistence of the measles virus in the nervous system.[7] An increase in cerebrospinal fluid (CSF) B-cells has also been reported by some researchers.[89] However, failure of B-cell depleting therapies such as rituximab disfavors the role of humoral immunity in the pathogenesis of SSPE.[10]


The interferon system also seems to be involved in SSPE.[11] In an in vitro study, the production of type 1 interferon when exposed to the measles virus was variable. Of six patients, the production remained unperturbed in two and decreased significantly in four cases, although similar findings were not reported in response to other viruses. In another study among 11 patients with SSPE and matched controls, interferon production failed among patients in response to poly inosinic-cytidilic acid and Polyhydroxybutyrate (I: C and PBH).[12] After isoprinosine exposure for 7 days, interferon production resumed. On interruption of isoprinosine, the production once again declined. Isoprinosine also induces the production of interferon alfa in vitro.[13] In vitro studies have shown abnormal activation of interleukin (IL)-12/interferon gamma and IL-23/IL-17 pathways.[14] Treatment with interferon alfa and isoprinosine was seen to increase all lymphocyte subsets.[15]

It is also known that children who contract measles infection before the age of 2 years are at increased risk of development of SSPE, suggesting that persistent brain infection occurs in these children before the immune system matures fully.


High parental consanguinity has been reported from some regions.[16] Families with more than one child affected in the same sibling group as well as twins with SSPE have been reported.[17] These observations do suggest some genetic influence. Single nucleotide polymorphisms in some genes related to innate immunity, including toll-like receptor (TLR) 3, TLR4, and MxA, and acquired immunity, including IL-28, IL-29, IL-17, IL-18, IL-12, TNF, and PD-1 gene, have been associated with SSPE, but no clear patterns have emerged.[17181920]


Several treatment options have been used among patients with SSPE in the hope of halting the disease [Table 1]. However, most of these attempts emanate from older studies in the 1970s and 80s. Very few agents have been trialed in recent times.

Table 1:
Summary of drugs tried for disease modification in SSPE


Initial reports emerged in the 1980s observing variably beneficial effects of interferon in SSPE.[21222324252627] The important findings are described in the following.

Interferon alfa

In an initial study, intraventricular interferon alfa was administered in 22 patients between 1986 and 1991.[28] Follow-up at 56–108 months demonstrated a higher survival rate in patients who received interferon compared to those who did not. However, most of these patients deteriorated after a follow-up of 6–90 months. The combinational use of isoprinosine did not influence the outcome.

In one patient, intrathecal interferon achieved disease remission for nearly 7–8 years.[29]

A continuous lumbar infusion device for continued intrathecal interferon alfa led to improvement in a patient who was deteriorating on subcutaneous interferon injections.[30] Transient stabilization using continuous intrathecal infusion has also been achieved in a few patients, using a reservoir placed in the subcutaneous abdominal space.[3132]

A combination of intravenous and intrathecal interferon alfa-2a used concurrently has also been used (dose varied from 15 to 60 million units).[33] Among 12 patients, improvement occurred in three and deaths in three. No significant change was noted in six patients. This combination was, hence, not found to be effective.

The various regimens used have been summarized in Table 2.

Table 2:
Regimens used in intraventricular/intrathecal interferon alfa

Interferon beta

Compared to interferon alfa, the use of interferon beta in the treatment of SSPE has been considerably less. Small case series reported the potential benefit of the combination of isoprinosine (50–100 mg per kg per day) with subcutaneous twice or thrice weekly interferon beta.[38] Two different regimens of interferon beta were compared in a retrospective review: 60 mcg intramuscular once weekly or 22 mcg subcutaneously thrice weekly, along with oral isoprinosine 50–100 mg/kg per day.[39] Patients who were followed up for at least 3 months and had follow-up data for at least 1 year were assessed. The patients on thrice-weekly doses had longer survival time and better clinical response, measured in terms of stabilization or improvement in scores on the Neurological Disability Index.


Isoprinosine or inosine pranobexor methisonprinol refers to a synthetic combination of p-acetamido-benzoatesaltof N-dimethylaminoisopropanol and inosine in a 3:1 ratio. It exerts multimodal actions, including antiviral and immunostimulatory properties.[40]

In a 1979 open-label study among 15 patients, isoprinosine led to improvement in 33%, which was sustained for at least 2 years. Isoprinosine was well tolerated, except for mild hyperuricemia.[41] Improvement or stabilization was observed in five patients (33%). Variable effects have been observed in other older studies.[4243] In 1980, it was administered to 18 patients at doses of 50–100 mg/kg based on weight for a few months (range 2–27 weeks), but no improvement was noted compared to 96 unmatched historical controls.[44] A criticism of this study was the relatively short duration of treatment with isoprinosine.[45] Another study showed slowing of progression in patients with chronic forms of SSPE, but not in rapidly progressing forms.[46] It was tried in another study among 15 patients, with post-treatment follow-up ranging from 2 to 144 months, with favorable effects in morbidity and mortality in 10 (66%).[47] Another earlier study showed no effect on survival.[48] In another large study, 89 patients treated with isoprinosine were compared to 62 untreated cases.[49] Slower progression and increased survival was reported in the treatment group.

In the largest study of isoprinosine therapy by the International Consortium on SSPE, it was administered among 98 patients with SSPE, at multiple centers in the United States of America and Canada, with a duration up to 9.5 years.[50] The actuarial probability of survival compared to control at 2, 4, 6, and 8 years was 78, 69, 65, and 61% (compared to 38, 20, 14, and 8%), respectively.


Ribavirin is a nucleic acid analog. Oral ribavirin was tried in SSPE from the 1980s onwards.[51] In 1989, Ogle et al.[51] used it in the oral form but did not observe any beneficial effects. One reason may have been lack of penetration of the drug into the CSF space, which was seen in in vitro studies. In animal studies in hamsters, however, intracerebral administration of ribavirin was shown to exert anti-SSPE effects and improve survival.[5253] The challenge with ribavirin was its narrow therapeutic window in the CSF. Hence, CSF levels may need to be monitored (target 50–200 μg/L). Consequently, intravenous ribavirin administration was also attempted, in combination with intraventricular interferon therapy. Although studies were small, symptomatology improved, accompanied by reduction in anti-measles antibody titres. However, extensive systemic side effects including hemolytic anemia led to discontinuation.[5455]

Intraventricular ribavirin using an Ommaya reservoir was shown to have clinical improvement in patients in whom CSF ribavirin concentrations could be maintained at a high level.[5455] Doses used included 1–3 mg/kg, 1–3 times per day. Hosoya et al.[54] used daily intraventricular ribavirin in five patients, of which four showed improvement. Tomoda et al.[55] used 5–10 days of daily administration followed by a gap of 10–20 days. Of 10 patients in which this regimen was used, seven showed improvement. Problems related to this route were inability to achieve therapeutic levels in some patients. Furthermore, repeated taps through the Ommaya reservoir predispose to meningitis.

Continuous subcutaneous infusion systems for ribavirin administration, using a pump which has been used for baclofen pump, has been shown to maintain adequate CSF levels in three patients although safety and efficacy are unknown.[56] This was used in combination with interferon and isoprinosine. Among three patients in which it was tried, one discontinued therapy because of exacerbation of symptoms. The other two remained in stage III and survived for more than 5 years.


Lamivudine is a nucleoside analogue. Lamivudine has been used in patients with SSPE in one trial. Nineteen patients who received treatment were compared with 13 patients who received no treatment.[57] The protocol for treatment, delivered during 6 months, included oral lamivudine (10 mg/kg per day), oral isoprinosine (100 mg/kg/day), and subcutaneous interferon alfa-2a, 10 million units/m2 thrice weekly. Although there was no difference in mortality between the two groups, remission rates were higher in the treatment group (36.8% vs. none), which was higher than the spontaneous remission rate of 5%.


Favipiravir is an anti-influenza drug. In vitro study to examine the effect of favipiravir against measles virus (Edmonston strain) and SSPE virus (Yamagata strain) demonstrated some effect against the virus, comparable to ribavirin.[58]


Amantadine was used initially for SSPE in a preliminary report in 1969.[59] In a study of 38 patients with SSPE in 1980, longer survival was associated with the use of amantadine.[60] In an in vitro study in 1989, amantadine was found to exhibit no anti-SSPE properties. No further studies were conducted using this antiviral agent.


Aprepitant is an anti-nausea medication used for patients on chemotherapy. It is a neurokinin-1 receptor antagonist. In a randomized trial in Turkey, aprepitant (n = 31, dose = 250 mg orally daily) was compared with placebo (n = 31), given for 15 days, and a repeat of this cycle was performed after 2 months.[61] Eighteen patients left the study over the ensuing year. There was no difference in clinical status between the groups at 6 and 12 months, although mild improvement was noted in EEG scores.


Oral isoprinosine with intraventricular interferon has been tried as a combination from the 1980s.[62] In an older case series of 18 patients, oral isoprinosine (100 mg/kg/day) was combined with intraventricular interferon alfa 2b. Eight patients had remission, four worsened, and six died.[36]

In another older case series among eight patients, four were managed with oral isoprinosine and four with combined intraventricular interferon alfa and oral Isoprinosine.[34] Of the latter group, three progressed and one died. In the combined group, one patient showed mild progression, one showed remission and the remaining two had stabilization of the disease. Similar results were also reported by Yalaz et al.[63]

Oral Isoprinosine was compared to combined isoprinosine and intraventricular interferon alfa 2b. There was no significant difference in clinical outcomes between the groups.[64]

Intravenous ribavirin and intrathecal interferon alfa combination was also attempted in two patients, with some improvement.[65] Lamivudine has been combined with subcutaneous interferon alfa and oral ribavirin with some benefit, as detailed above.[57]

Other combinations of intraventricular interferon alfa, ribavirin, and isoprinosine have been attempted without success.[66]


In 1973, infusion of leukocyte transfer factor, collected from donors with demonstrable antibodies to measles virus, was employed in one patient with success, based on a presumed defect in T-cell mediated immunity.[67]

Rituximab therapy was attempted in one patient, based on the increase in CSF B-cells reported by some authors, but without success (dose: 375 mg/m2 per week for four doses, combined with 2 weeks of intravenous ribavirin).[10]

Intravenous immunoglobulin

An initial case report in 1996 described the use of intravenous immunoglobulin (IVIg) (dose 400 mg/kg/day for 5 days) in combination with ribavirin (100 mg/kg/day) in a patient with stage 3 SSPE.[68] This patient showed rapid improvement at 1 month of initiation of therapy. Another course of IVIg was repeated on recurrence of myoclonic jerks.


Oral steroids have also been used in one patient.[69] This patient presented with progressive cognitive impairment, myoclonic jerks, and motor abnormalities. He was treated with valproate and clonazepam. As the patient continued to have myoclonic jerks, oral steroids (prednisolone dose 40 mg per day) were added and tapered gradually over 3 months. Myoclonic jerks subsided and cognition also improved. However, the possibility of spontaneous improvement, well known in SSPE, cannot be discounted.

A literature review established that fulminant forms of SSPE were related to the use of corticosteroids.[17]

Plasma exchange

Plasma exchange was tried in three children, twice weekly for 6 weeks, using 5% albumin, but no short-term or long-term effects were observed.[70]

Stem cell transplantation

The mechanism of action is unknown, but probably involves the release of anti-apoptotic and anti-inflammatory mediators. In a trial in Turkey, Mesenchymal stem cells (MSC) transplantation was done among five children with worsening SSPE, without any evidence of benefit.[71]


The ketogenic diet has several properties, including anti-inflammatory, anti-oxidant, and metabolic that may benefit the inflammatory process in SSPE. Three case reports have described improvement with ketogenic diet. In the earliest report, ketogenic diet provided transitory benefit in one 9-year-old boy with SSPE.[72] In one report from India, improvement in one child with SSPE was reported with the ketogenic diet.[73] Myoclonic jerks stopped after 11 months of therapy, and cognitive improvement occurred around 36 months of therapy. In another older patient aged 17 years, ketogenic diet therapy led to significant improvement, after the patient failed to improve on oral isoprinosine and ribavirin therapy.[74]


Disease modification has lagged clinical descriptions in SSPE. Future research must be directed against newer strategies because current strategies, at best, seem to produce variable effects on disease stabilization. It is also challenging to attribute these effects to any particular therapeutic strategy, as there are limited randomized trials, patient numbers remain small in studies, and SSPE is well known to demonstrate spontaneous regression in 5% of the cases. Furthermore, the target population should be in the early inflammatory stages of SSPE, before irrevocable neurodegeneration has set in. Major gaps in understanding of pathogenesis have also contributed to the failure of the disease-modifying approach.

There is limited data on the use of ketogenic dietary strategies, which have found a place in the therapeutic armamentarium in children with drug-resistant epilepsy. An open-label trial to assess the low glycemic index diet in SSPE has been planned in Pakistan (NCT05152771). The ketogenic diet is a demanding therapy that requires close monitoring. A less stringent option may be the modified Atkins diet, which has also found success in the management of refractory epilepsy in children.

There appears to be a relationship between the use of corticosteroids and the development of fulminant forms. This is important to acknowledge, as patients with SSPE may resemble autoimmune encephalitis, in terms of presentation with short-duration cognitive decline and seizures. Empirical therapy is often practiced in autoimmune encephalitis while awaiting the autoimmune antibodies panel. Here, a word of caution is advisable. A baseline EEG and a thorough history must be obtained, specifically with the objective to ascertain if SSPE may be a consideration. It may even be worthwhile to obtain CSF measles antibodies in cases that are clinically equivocal, or in children with partial or incomplete vaccination.

For disease modification, there is some data on the use of interferon alfa albeit multiple protocols have been advocated in the literature. If feasible, we suggest the use of intrathecal interferon via lumbar puncture, as implantation of an Ommaya reservoir may not be pragmatic in our setting. Weekly interferon via the intrathecal route in escalating doses, starting at 1 MU and building up in increments to 6 MU weekly for 2 months and then monthly may be a middle path approach. If available, isoprinosine in doses of 100 mg per kg per day should be combined with interferon therapy. A thorough discussion with the family regarding the modest benefits observed in the literature must be done before embarking on this intensive and invasive therapy. Another important facet is to consider the stage of the disease. Earlier stages are more likely to benefit compared to the later stages, when neurodegeneration has already set in.

Another important consideration to be kept in mind in the use and development of anti-SSPE drugs is that they should penetrate the blood-brain barrier and reach the CSF in adequate amounts.


Despite nearly 90 years since the disease was first described, attempts at disease modification have largely failed in SSPE. Although some evidence supports the use of a combination of intraventricular/intrathecal interferon with isoprinosine, this strategy remains out of reach of most patients in our region. Isoprinosine is an expensive medication and is not available readily. The regimens used for interferon therapy are exhausting and lead to parental fatigue and loss of follow-up. Research on SSPE is mostly limited to the low-income regions where SSPE continues to be a prominent problem, and suffers from resource and manpower limitations, and probably, financial thrust. The solution, hence, seems to lie more in the direction of prevention than cure. SSPE continues to dominate in unvaccinated or partially vaccinated populations. Greater awareness and advocacy for universal vaccination is the only long-term solution for a disease that continues to lie within an area of darkness.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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Interferon; isoprinosine; ketogenic diet; ribavirin; SSPE

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