Adult-Onset Subacute Sclerosing Panencephalitis: Exploring A Potential Cure
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.344671
Source of Support: None, Conflict of Interest: None
Keywords: Adult-onset, immunomodulation, levamisole, remission, subacute sclerosing panencephalitis
Subacute sclerosing panencephalitis (SSPE) or Dawson's disease, a devastating slow viral infection of the central nervous system caused by mutated measles virus, is still quite prevalent in developing nations such as India and Pakistan despite worldwide decline in prevalence to one per 100,000 cases of measles due to better immunization coverage in developed countries., As per WHO surveillance data, India had 10761 and 3178 cases in 2019 and 2020, respectively [Figure 1]. However, updated data on current incidence and prevalence of SSPE is not available. As per the last available literature, reported incidence rates were 21 cases per million population in India, 11 per million in Japan, and 0.06 per million in Canada. Further, the true magnitude of the existing problem may be underestimated due to variability in physician seeking practices, misdiagnosis, inadequate follow-up, and premature death.
SSPE, manifested by diffuse chronic encephalopathy with a progressive stereotypic decline in cognitive function, quasiperiodic myoclonus, psychiatric, visual, and gait abnormalities culminating in a quadriparetic vegetative state, and premature death, has again been generating interest recently. Pathogenesis of SSPE and its predisposing factors are under rigorous evaluation with genetic studies demonstrating point mutations in matrix (M) and fusion (F) protein genes. Unfortunately, therapeutics have been dismal and various medications tried such as isoprinosine, interferons, and ribavirin have been unsuccessful till date., With this background of apparent hopelessness, a case of adult-onset SSPE, who is in complete remission after treatment, is highlighted with a brief review of previous therapeutic attempts at cure.
A 21-year-old woman presented with recurrent myoclonic jerks and generalized tonic clonic seizures for 6 months with one episode of convulsive status epilepticus with cardiorespiratory arrest. She was on anti-seizure medications in addition to aripiprazole for psychosis. Cognitive decline and slowness of gait requiring two-person support for activities of daily living were noted. She was cachexic, drooling saliva, and irritable with low volume and dysarthric speech, generalized lead-pipe rigidity, and bradykinesia. Quasiperiodic negative myoclonus was noted every 10–14 s, persisting throughout the day which would subside during sleep with frequent major jerks causing her to fall. She had contracted measles between 6 and 8 years of age.
Hematological and biochemical investigations were unremarkable. MRI brain showed mild diffuse cerebral and cerebellar atrophy [Figure 2]a,[Figure 2]b,[Figure 2]c. EEG showed generalized slowing of background activity with quasiperiodic long duration long interval generalized sharp and slow wave Radermecker complexes [Figure 3]a. Cerebrospinal fluid (CSF) was clear, under normal pressure, and paucicellular with normal protein and sugar. IgG antibody by ELISA was positive for measles in the CSF (>250 U/mL; ref: <8 U/mL) while IgM was 2.05 U/mL. Based on Dyken's criteria, diagnosis of SSPE (modified Risk and Haddad Stage 2c) was made.
As the patient was resistant to multiple anti-seizure medications (levetiracetam, clobazam, and sodium valproate) and unable to afford immunomodulatory medications generally recommended for SSPE, a trial of levamisole was given with gradual dose escalation (cost of 150 mg tablet being INR 15.70). No adverse hematological or biochemical effects were noted after initiation. Though there was no immediate clinical change, a subtle decrease in frequency of major jerks was noted after 2 months. By 3–6 months of therapy, major jerks had reduced to once in 4–5 h and periodic myoclonus to once in 20 s. After 8 months, EEG showed periodic complexes at intervals of 15–20 s [Figure 3]b. At this time, levamisole was stopped due to transient thrombocytopenia which recovered [platelet count: 64000/mm3 (before) and 1.97 lac/mm3 (after stopping)]. However, the patient continued to improve and at 18 months, jerk frequency had reduced to once in 5–10 min. Gait and speech had improved. By 20 months, rare myoclonus in 8–10 h and progressive gain of weight and independent functions were observed. The jerks completely subsided by 21 months and at 2 years after starting treatment with levamisole, she was able to walk unsupported and erect, talked more fluently while making eye contact. EEG was normal [Figure 3]c with later persistence of normalcy [Figure 3]d. MRI brain after 24 months of remission showed no new lesions or progression of cortical atrophy [Figure 2]d,[Figure 2]e,[Figure 2]f. CSF examination at 24 months was unremarkable. IgG antibody by ELISA was positive for measles in serum (28251.5 U/mL; ref: <8 U/mL) while it was 635.2 U/mL in CSF and CSF/serum quotient was 0.05 (<1.3 normal). At 36 months, patient was normally conversant, interactive, and expressed her desire to continue improving and come off medications entirely (modified Risk and Haddad Stage 4c).
Currently, there is no cure for SSPE, and eradication by an effective vaccination program is considered to be more beneficial and cost-effective than any other form of control. Despite measles vaccine being part of childhood national vaccination schedules world over and measles elimination goal for year 2020 in six WHO regions, an almost constant number of new patients are diagnosed every year and none of these milestones have been met.,, SSPE is probably a highly preventable illness possible by preventing the inciting measles disease. However, it must be recognized that the translation of good measles control to decline in new SSPE cases occurs only years after decline in incident measles cases. Therefore, a period of at least 5–10 years has to elapse before an impact on SSPE incidence and major decline in SSPE, respectively, is observed after measles control. The further daunting goal is the eradication of SSPE as cases may keep occurring up to 20 to 30 years after elimination of measles due to wide latency period.
SSPE has a high mortality (about 95%) with average life span of 3.8 years (45 days–12 years). Prolonged survival was documented for 3 to 13.8 years from India. While a brief plateau phase or slight improvement may be noted in some patients, long-term stabilization or remission is exceptional. It is clinically difficult to predict which patient will have a substantial remission and “why.” The role of immunological status of host, infection by a wild strain, and altered virulence of measles virus in pathogenesis and outcome of SSPE requires exploration as 5% have substantial spontaneous remissions defined as a bedridden patient, incapable of self-care who becomes ambulatory and able to attend to ones needs. Age of onset of SSPE may prognosticate spontaneous favorable outcome. Adult-onset SSPE appears to have higher rate of spontaneous remission compared to childhood-onset SSPE. Stage of SSPE also contributes as in our case who did not progress beyond modified Risk and Haddad Stage 2c. Similarly, long-term improvement was associated with disappearance of EEG periodic complexes and emergence of normal background activity. However, despite being in remission, they continue to have elevated CSF IgG and measles antibody titers.
While supportive treatment is the mainstay, no standard successful therapeutic protocols have yet evolved. Antiviral drugs and immunomodulators are used in SSPE, specifically isoprinosine, interferon-alfa, ribavirin, and lamivudine., Occasionally amantadine, an anti-RNA agent that retards maturation of viruses by not allowing them to replicate, has been tried., Ketogenic diet, antiapoptotic agents, and RNA inhibitors are also potential candidates. Hence, the search for cure of SSPE is still on.
A review of literature exploring remission-inducing potential of various treatment regimen shows that no drug independently or in combination consistently achieved substantial remission [Table 1]. Of these, isoprinosine alone or in combination with intraventricular interferon has shown greater chance of remissions than spontaneously.,,,, In another series of long-term survival in SSPE, 8 of 19 patients achieved substantial improvement from being bedridden to community ambulant stage, but details of specific treatment had not been documented. Complete clinical, radiological, electrographic, and immunological parameters as well as dynamics of changes in these features during period of remission and degree of clinical recovery have not been consistently documented across all these reports [Table 1]. Some patients have also remained in dependent, vegetative states with persistent features of SSPE. As such, whether these instances may be considered as a legitimate complete remission in SSPE may be debatable.
Levamisole, the levo-isomer of tetramisole, is primarily an immunopotentiating anticarcinogenic agent also used in dermatological disorders. It may stimulate recovery of defective cell-mediated immunity by stimulating lymphocytes, granulocytes, and macrophages. In a series of autoimmune disorders including SSPE, a marked increase in the number of E-rosettes was noted in patients with SSPE suggesting effect on T-cell mediated immunity though it did not clinically translate to improvement in a short period of 4–6 months. Though seldom used in SSPE, our index case demonstrates the potential curative potential of levamisole in SSPE with no major side effects. Addition of levamisole seems to have triggered the positive turn of events leading to clinical, radiological, and electrographic remission which has lasted till time of publication (42 months from treatment and 54 months after onset of SSPE). It will be difficult to postulate a definite cause and effect relationship though a temporal association between initiation of treatment and progressive improvement may suggest a possible effect. The author accepts that a small number of patients may defy the natural course and have variable stabilization and substantial spontaneous remission lasting many years.
As a global community and a relatively resource-poor nation like India, where we are still struggling to eradicate measles and reduce the incidence of SSPE, definitive and effective therapeutic options are still at large. Yet among the dismal performance of other regimes, levamisole may be a potential low-cost candidate demonstrating a curative potential in SSPE.
The authors would like to thank the Departments of Diagnostic and Interventional Radiology and Microbiology, All India Institute of Medical Sciences, Jodhpur for the neuroimaging and serological evaluation of the patient, respectively.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]