Current therapies and future perspectives in subacute sclerosing panencephalitis

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Background & pathogenesisSubacute sclerosing panencephalitis (SSPE) is a chronic, persistent encephalitis secondary to a measles infection that causes widespread demyelination of the CNS [1]. In the develop-ing world, the incidence of measles has steadily declined since the introduction of population-wide measles vaccination programs [2]. In 2007 and 2008, the overall measles incidence in European countries declined to a historic low of less than ten cases per 1 million popula-tion, with the majority of cases reported from Western Europe [3]. However, since late 2009, measles virus (MV) outbreaks have become widespread; in 2011, such outbreaks have been reported among older children and young adults who had not been vaccinated in 36 out of 53 the European countries [4]. In the USA, during 2001–2008, a median of 56 cases were reported to the Centers for Disease Control, but recent cases that imported from endemic countries has changed the incidence [5]. Analysis of the 1989–1991 measles epidemic in the USA revealed the risk of developing SSPE after measles was 22 out of 100,000 cases [6]. This risk was much higher than earlier US estimates [7], suggesting previous under-reporting of SSPE. Reported rates in Israel have been even higher, reaching 23.2–27.9 cases of SSPE per 100,000 cases of measles between 1964 and 1969, with rates in those infected under 1 year of age cited as

360.3–375.6 cases out of 100,000 [8]. In a recent study from Madang Province in Papua New Guinea, a rate of 54 cases out of 100,000 was found among individuals younger than 20 years of age during 2007–2009 [9].

The average period between the initial measles infection and the onset of SSPE symptoms has been reported to be between 4 and 10 years. The incidence of SSPE has been shown to be higher in male patients. Other reported risk factors associated with the disease are poverty, living in rural overcrowded areas or countries with few cultural events, parental lack of education, older mothers, higher number of siblings and higher birth order [10].

The measles viruses recovered from SSPE patients have been found to differ from wild-type viruses in the number of mutations that affect the hemagglutinin, matrix, fusion and nucleocapsid genes [11]. After entering the upper respiratory tract, the virus exhibits a tropism for monocytes and lymphocytic cells. Following replication in lymphoid tissue, the virus spreads to the CNS via transmigration of infected leukocytes across the blood–brain barrier, migration through the choroid plexus, infection of microvascular endo-thelial cells or basolateral virus release [12]. An unbalanced immune response may be crucial in the early establishment of a persistent measles infection, for example in children under 2 years of age who have insufficient or absent residual

Burak Tatlı, Barış Ekici* and Meral ÖzmenDepartment of Pediatric Neurology, Istanbul Medical Faculty, Istanbul, Turkey *Author for correspondence: Tel.: +90 505 739 6812 Fax: +90 212 414 2224 [email protected]

Subacute sclerosing panencephalitis is a progressive neurological disorder of children and young adults caused by a measles virus that became defective by persisting in the host. According to the results of clinical trials, antiviral and/or immunomodulatory therapy can slow the progression of the disease and improve life expectancy in patients. However, its long-term effects and eventual outcome remain debatable due to conflicting results and its lack of effect on the rapidly progressive form of the disease. Possible future therapies for subacute sclerosing panencephalitis are RNAi and antiapoptotic agents, which are currently in the hypothetical and experimental stages of research.

Keywords: carbamazepine • flupirtine • interferon • isoprinosine • myoclonic jerks • RNAi • subacute sclerosing panencephalitis • treatment • vitamin A

Current therapies and future perspectives in subacute sclerosing panencephalitisExpert Rev. Neurother. 12(4), 485–492 (2012)

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maternal antibodies and lack the mature immune system neces-sary for complete virus neutralization [13]. Individuals with SSPE demonstrate an altered cellular response to the standard antigens by producing low levels of IFN-a and IL-2, leading to the eradica-tion of the invasive particle from infected cells [14]. Furthermore, unimmunized patients who receive intensive immunosuppressive therapy are more susceptible to SSPE than immunocompetent individuals infected with MV [15].

MV can remain dormant in cells for years before clinically manifesting itself. It bypasses the acute immunological response, replicates inside cells and only causes damage at a later stage [16]. However, greater MV loads have been linked to the rapidly pro-gressing form of the disease [17]. The acute inflammatory phase of the disease is reportedly characterized by the cortical and subcorti-cal perivascular infiltration of inflammatory cells, spongiosis and demyelination, which are followed by neuronal loss as the disease progresses [18].

Early symptoms of SSPE, such as intellectual decline and behavior change, are usually subtle and may only be recognized as symptoms in retrospect. As the disease progresses these nonspecific signs evolve into motor function disorders and periodic stereotyped myoclonus, shortly followed by ataxia, dyskinesia and dystonia. Typical symp-toms of the advanced stage of the disease are increased spasticity, quadriparesis and deterioration into a comatose state [19]. A modifi-cation of the classifications proposed by Jabbour et al. [20] and Risk et al. [21] is used here to describe the clinical features of SSPE (Box 1).

In a survey recently performed among 410 regional cases diag-nosed between 2000 and 2008 (data of the Ministry of Health, Turkey), those who had at least 2 years of follow-up were analyzed (n = 340). Anlar et al. found that only 60 out of 340 patients (17%) had died within 2 years after diagnosis [22]. However, in 10% of patients, the disease followed a fulminant course, with a fatal outcome occurring within 3 months or less, and the diagno-sis only being made during the autopsy in some cases [23]. Possible risk factors for the fulminant course of SSPE are previous history of measles prior to vaccination and younger age at onset of the disease [24,25], while cortical blindness as a presenting sign is a possible risk factor for the rapidly progressing form of SSPE [26].

TreatmentImmunomodulating agentsIsoprinosine (inosiplex)Isoprinosine is a complex of inosine and 2-hydroxypropyl-dimethyl ammonium-4-benzoate. It has been shown to enhance

the function of various cells of the immune system, an effect explained by improved production of IL-1, IL-2 and modulation of T-helper cell subsets [27,28]. According to case reports and sev-eral uncontrolled studies that have been carried out since the end of the 1970s, isoprinosine prolongs life expectancy in slowly pro-gressing SSPE and leads to clinical improvement in some patients [29–31]. Isoprinosine trials have shown that the drug is beneficial in up to 30–34% of SSPE cases, but ineffective in the rapidly progressing form of the disease (TaBle 1) [32–34] .

Isoprinosine is administered daily in doses of 100 mg/kg/day. No major side effects have been reported; however, recurrence of symptoms is common and treatment needs to be continued even after remission, possibly on a lifelong basis. As isoprino-sine can cause temporary hyperuricemia, uric acid levels need be monitored.

InterferonsInterferons are proteins that play a role in cell growth regula-tion, antiviral defense and immune activation. Type I IFNs are released in response to viral infections and consist of products of the IFN-a multigene family, which are primarily synthesized by leukocytes, and the product of the IFN-b gene, synthesized by fibroblasts and many other cell types [35]. A number of publica-tions in the late 1980s described intrathecal and intraventricular use of interferon [36,37]. Yalaz et al. reported clinical remission in 50% of 22 patients treated with oral isoprinosine and intra-ventricular human-derived IFN-a, which is the best result to date [38]. Interferon was given at daily doses of 100,000 units/m2, increasing to 1 million units/m2 for 5 days a week, 6 weeks at a time and repeated at 2–6 month intervals. No details about the untreated control group were provided and it was unclear why the control subjects did not receive isoprinosine and/or IFN-a. Half of the study group saw improvement and showed a better survival profile during the 8-year follow-up period (TaBle 1) [39]. However, there have also been numerous case reports that describe a poor outcome. In the only randomized con-trolled interferon trial that was conducted by the International Consortium on SSPE and enrolled 121 patients between 1996 and 2000 [34], the first group received isoprinosine and intra-ventricular recombinant IFN-a2b twice a week for 6 months, while the second group only received isoprinosine. Data from 67 patients who stayed adherent to study protocol were analyz-able. No significant difference in mortality was found between groups. Satisfactory outcomes, defined as those whose courses stabilized or improved with treatment, were higher than the reported spontaneous remission rates (5–10%), but there was also no statistically significant difference between the first group (35%) and the second group (34%). The authors concluded that treatment was preferable to no treatment.

IFN-b is structurally and biologically similar to IFN-a while being easier to administer and more widely available. While it does not cross the blood–brain barrier, it may modulate inflamma-tory events in the cerebral endothelium by reducing peri vascular infiltrates, decreasing the expression of adhesion molecules and monocyte extravasation, enhancing the expression of molecules

Box 1. Clinical stages of subacute sclerosing panencephalitis.

Stage 1. Behavioral, cognitive and personality changesStage 2. Myoclonic spasms. Apraxias, agnosias and language difficulties. Motor signs: spasticity, ataxia. Ambulatory with assistanceStage 3. Loss of ambulation, extrapyramidal symptoms with limited responsivenessStage 4. No myoclonus. Autonomic failure and neurovegetative state

Tatlı, Ekici & Özmen

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involved in antigen presentation and altering the production of cytokines [40,41]. In their nonrandomized retrospective study, Anlar et al. reported that IFN-b administered subcutaneously three times a week combined with isoprinosine had a significant effect on survival and the progression rate of the disease, com-pared with IFN-b administered once a week [42]. However, the authors noted that the effect of isoprinosine in this combination should be analyzed separately.

Vitamin AVitamin A and its natural and synthetic derivatives are collectively known as retinoids. After entering the nucleus, active ligands of retinoids bind to retinoid receptors. Activated by ligand binding, the nuclear retinoid receptors recruit coactivators to retinoic acid response elements, initiating transcription of retinoid-responsive genes [43]. Retinoids increase STAT1 expression, which binds to interferon-stimulated response elements and triggers the tran-scription of interferon-stimulated genes. These genes play a role in preventing viral replication. Vitamin A can inhibit MV through upregulation of the Type I interferon response, effectively pre-venting the virus from escaping the host innate immune response [44]. A meta-ana lysis of vitamin A use in measles has found a link between receiving two doses of vitamin A and reduced risk of

pneumonia-specific and total mortality in children under 2 years of age [45]. Gungor et al. reported reduced b-carotene levels in SSPE patients [46]; however, the effect of vitamin A supplementation on the course of the disease has not yet been studied.

Intravenous immunoglobulinThe use of intravenous immunoglobulin in SSPE patients has only been mentioned in a single case report. Gürer et al. report a 10-year-old boy treated with intravenous immunoglobulin and inosiplex for 18 months [47]. Clinical improvement from stage 3 to stage 1 was observed and demonstrated by decreasing scores on the Neurological Disability Index.

SteroidsThe use of intravenous immunoglobulin in SSPE patients has only been mentioned in a single case report. Serdaroglu et al. reported on a 24-month-old boy who developed a rapidly progressing dis-ease course after adrenocorticotropic hormone was added to the therapy for infantile spasms [48]. The authors attributed this to the immunosuppressive effects of glucocorticoid therapy. With our unpublished experience of rapid deterioration in a 9-year-old boy after pulse steroid therapy, immunosuppression should be avoided over the course of SSPE.

Table 1. Studies of the effectiveness of isoprinosin and interferon at treating subacute sclerosing panencephalitis.

Study Patients (n) Method Follow-up period

Results Ref.

Anlar et al. (2004)

38 vs 19 im. IFN-b1a weekly + isoprinosine vs im. IFN-b1a 3 times a week + isoprinosine

12 months Three times a week IFN-b1a combined with isoprinosine had a significant effect on survival and the progression rate of the disease, as opposed to IFN-b1a being administered once a week

[42]

Gascon et al. (2003)

67 at Stage 2 or less

Isoprinosine vs isoprinosine + it. recombinant IFN-a2b

2 years No statistically significant differences in improvement rates and mortality between the groups, but stabilization or improvement rates with treatment were higher than spontaneous remission rates

[34]

Gökçil et al. (1999)

8 adults at Stage 2 or less

Isoprinosine (4 patients) vs isoprinosine + it. recombinant IFN-a2b (4 patients)

3–4 years 1 patient died and 3 patients deteriorated with isoprinosine; with combination therapy, 1 patient showed mild deteriorization and 1 patient remission, 2 patients stabilized

[81]

Gascon et al. (1993)

18 (one group)

Isoprinosine + it. recombinant IFN-a2b

12–40 months 44% rate of remission/improvement [82]

Yalaz et al. (1992)

Anlar et al. (1997)

22 vs historical controlsLong-term results

Isoprinosine + it. human-derived IFN-a

2–54 months

56–108 months

Decreasing scores on the Neurological Disability Index occurred in 11 out of 22 patients (first study), and 8 out of 11 patients experienced deterioration but demonstrated higher survival rates (second study)

[38]

[39]

Fukuyama et al. (1987)

89 vs 62 Isoprinosine vs no treatment

– Progression through the disease stages was significantly slower and survival rate was significantly higher for the isoprinosine group than for the untreated cases

[32]

Jones et al. (1982)

98 vs historical controls

Isoprinosine vs no treatment

Up to 9.5 years Isoprinosine seems to be able to prolong life in patients with SSPE

[29]

im.: Intramuscular; it.: Intrathecal; SSPE: Subacute sclerosing panencephalitis.

Current therapies & future perspectives in subacute sclerosing panencephalitis

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RituximabRituximab is a chimeric monoclonal antibody against B-cell sur-face protein CD20 that has become part of the standard therapy in autoimmune disorders involving CD20-expressing B cells. Only one case of rituximab use in SSPE has been reported: one of a 10-year-old boy treated with ribavirin and rituximab simul-taneously. The authors based their choice on the possibility of autoimmune pathogenesis, supported by reports of elevated levels of anti-CD9 antibodies in the cerebrospinal fluid of patients with SSPE [49]. B cells had become undetectable in peripheral blood and in cerebrospinal fluid after treatment was started, but the disease progressed rapidly [50].

Propionibacterium granulosumPropionibacteria are among the most potent bacterial immuno-modulators, stimulating cell populations involved in nonspecific antibacterial, antiviral, antiparasitic and anti-tumor resistance. Propionibacterium granulosum KP-45, the protype that was selected for clinical and experimental studies, enhances antiviral resistance by inducing interferon synthesis, activating cytolysis mechanisms (natural killer cell reactivity) and stimulating the monocytic system [51]. P. granulosum KP-45 trials in SSPE patients carried out by Sobcyzk et al. [52] reported improvement of verbal function and emotional status in patients receiving isoprinosine with propionibacterium, compared with patients receiving only isoprinosine or isoprinosine with thymus extract [53]. Another study found that the combination of intraventricular interferon and propionibacterium vaccination showed a similar effect [54].

The most common side effect observed in almost all patients receiving systemic propoinobactrium is fever, as well as sporadic headaches and transient bone and joint pain that subside within 24 h after the infusion [52].

Thymus extract was another immunostimulator studied by Sobcyzk et al. [53,55], but its effect on survival and clinical improvement could not be demonstrated.

Antiviral agentsRibavirinRibavirin is a synthetic nucleoside analogue that exerts its antivi-ral activity by depleting the intracellular pool of nucleotides and blocking the formation of some viral code RNA polymerases. The ability of ribavirin to inhibit the replication of the SSPE virus in vitro was reported by Murphy et al. in the late 1970s [56]. A study in which the symptoms of the disease decreased and the survival rate of hamsters increased in a dose-dependent manner showed the effectiveness of intraventricular ribavirin in animals [57]. The synergistic antiviral effect of ribavirin combined with interferons was initially demonstrated in patients with hepati-tis C virus (HCV), followed by experimental research on SSPE [58,59], but there are still very few reports available on combina-tion therapy and its effectiveness. In the largest studies to date that were composed of ten and five patients, decreased measles antibody titers in the cerebrospinal fluid were demonstrated but clinical improvement remained questionable [60,61]. The weakest aspect of these studies was the involvement of advanced patients

in a nonrandomized fashion. In addition to mild and transient side effects, such as lip and gingival swelling, conjunctival hyper-emia, headache and drowsiness, more serious complications of combined intraventricular IFN-a and ribavirin use, such as septic meningitis and chemical encephalopathy, were recently reported [62].

AmantadineAmantadine prevents the release of influenza A viral nucleic acid into the host cell by disrupting the function of the transmembrane domain of the viral M2 protein. In certain cases, amantadine is also known to interfere with virus assembly during virus repli-cation [63]. The mechanism behind the antimeasles activity of amantadine is not understood clearly. In a retrospective study conducted in the 1980s, Robertson et al. reported a positive effect of amantadine on the natural course of the disease compared with rifampicin [64]. However, results of a recent randomized study from Iran show that isoprinosine is significantly more effective than amantadine [65].

Symptomatic treatment of myoclonic jerksPatients with SSPE usually suffer from involuntary myoclonic movements that interfere with gait. The movements are not typi-cally myoclonic in nature but can be described as a “shock-like abruptness”, followed by momentary arrest of movement and then a gradual returning to the position of rest. There have been several case reports that mention the effect of carbamazepine on myo clonus in SSPE. Hayashi et al. described significant improvement in three patients with myoclonus [66], and Yiğit et al. reported on a 20-year-old woman bedridden because of dystonic posturing and very fre-quent myoclonic involuntary movements, who improved dramati-cally with carbamazepine [67]. Carbamazepine does not generally alter electroencephalogram findings of patients in a significant way; however, Becker et al. have reported that the electroencephalogram pattern of a 12-year-old boy with encephalopathy and myoclonus showed improvement after treatment with levetiracetam [68].

Future perspectivesFlupirtineApoptosis is considered one of the main causes of neuronal death in SSPE. Studies have shown that virus-negative cells can suffer apoptosis and that a lack of bcl-2 expression can lead to DNA fragmentation in SSPE patients [69]. Flupirtine is a triamino-pyridine compound that is commonly used as a centrally act-ing non-opioid analgesic. Upregulation of antiapoptotic bcl-2 protein or an increase in intracellular glutathione levels have been suggested as possible mechanisms behind the additional neuroprotective–antiapoptotic effect of the drug [70].

We have hypothesized that a combination of antiviral ther-apy with flupirtine as an antiapoptotic agent may slow down or altogether halt the progressive course of disease [71].

After the publication of the hypothesis, we had the opportunity to treat four patients with flupirtine and isoprinosine. Four male SSPE patients aged 9, 10, 12 and 16 years had clinical stages 2, 3, 3 and 1 of the disease, respectively. The dose of flupirtine was


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increased from 1 mg/kg/day up to 3 mg/kg/day during a period of 2 weeks. The first reported side effect was temporary deterioration of myoclonus, which led to discontinuation in one patient. During the 9-month follow-up period, the 16-year-old boy with stage 1 SSPE stabilized, while families of the two patients with stage 3 SSPEs reported increased responsiveness. However, our experience in flupirtine is only at the level of clinical observation in a small patient group and randomized studies are necessary in order to reach a definitive conclusion about the effectiveness of the drug.

RNAiRNAi is a natural mechanism that plays an important role in pro-tecting organisms from parasitic genes, including viruses. When viral dsRNA molecules appear in a cell, the cellular enzyme Dicer cleaves them into short segments of nucleotide pairs, known as siRNA. After each siRNA is unwound into a passenger strand and a guide strand, the guide strands are incorporated into the RNA-induced silencing complex, where they bind to their target single-stranded mRNA, which triggers the degradation of mRNA and silences the expression of the viral gene [72].

Synthetic siRNA molecules can be introduced into cells by using reagents to promote uptake across the cell membrane or by using engineered viral vectors to deliver a shRNA that will be processed into a siRNA [73]. Silencing of ribonucleoprotein mRNAs of MV was found to be highly effective in reducing viral messenger and genomic RNA [74]. On the other hand, siRNA-mediated knock-down of the M protein enhances cell–cell fusion and increases the levels of messenger and genomic RNA by 2–2.5 times [75]. Defective M protein in mutant MV contributes to the efficient replication and spread of the virus in neuronal cells.

Recently, permanent expression of antiviral shRNAs delivered by a lentiviral vector against N, P and L mRNAs led to a reduc-tion of viral proteins below detectable levels in a high percent-age of transduced cells and complete virus elimination within 2 weeks [76]. However, two major problems awaiting solution before in vivo application are determining a vector system that would be optimal for the complex structure of neurons and glial

cells, and exact target sequences in spite of the high frequency of mutations in MV.

New viral receptors for MVGenerally, MV infection was considered to be initiated by the attachment of the MV hemagglutinin H, a glycoprotein anchored to the virus envelope, to the host cell receptors CD46 or sign-aling lymphocyte activation molecule. However, recent studies revealed other viral receptors. Watanabe et al. identified CD147/EMMPRIN, a transmembrane glycoprotein, which acts as a recep-tor for MV on signaling lymphocyte activation molecule-negative cells and demonstrated the incorporation of cyclophilin B in virion as a cellular ligand for CD147 [77]. Cyclophilin B is also a positive modulator of the HCV RNA-dependent RNA polymerase in the replication complex. Debio 025, a cyclophilin binding molecule, was found to be effective in decreasing the HCV viral load [78]. Neuron-to-neuron spread of MV occurs exclusively at the syn-apse and does not require hemagglutinin receptor interaction. Makhortova et al. demonstrated that NK-1, a docking receptor for the MV-F protein, plays a crucial role at trans-synaptic transmis-sion of MV [79]. NK-1 antagonists are commercially available and exert an anxyolitic, antidepressant, antiemetic, antimigraine and anti-alcohol addiction effect. Regarding cancer, NK-1 receptor antagonists induce antiangiogenesis and inhibit the migration of tumor cells [80].

To date, no clinical trials have been conducted for the effective-ness of cyclophilin B and NK-1 antagonists at SSPE. However, the major problem awaiting solution is determining the appropriate timing for treatment of an infection with long latency.

In conclusion, there is no cure for SSPE, but isoprinosine can statistically slow the progress of the disease in a third of patients. Our clinical practice is to use a combination of isoprinosine, carbamazepine and vitamin A, due to its low side-effect profile.

Expert commentary & five-year viewSSPE is still an uncurable disease and mainly affects children who had measles 4–10 years earlier. As a result of the strategies

Key issues

• Subacute sclerosing panencephalitis (SSPE) is a persistent chronic encephalitis secondary to a measles infection that can remain dormant in cells for years before manifesting itself clinically.

• The major reported risk factors associated with SSPE are: a previous history of measles infection, male sex, poverty, and living in a rural or overcrowded area.

• Isoprinosine trials have shown that 30–34% of SSPE patients benefit from the drug.

• The only randomized controlled trial that has been conducted to date found no significant difference in outcome between patients on interferon and isoprinosine, versus isoprinosine alone. However, it was found that any treatment would be preferable to no treatment.

• The synergistic antiviral effect of ribavirin combined with interferons was demonstrated in experimental research but the results of clinical trials remain questionable.

• Carbamazepine is the drug of choice in the symptomatic treatment of myoclonic jerks.

• As apoptosis is among the main cause of neuronal death in SSPE, it has been hypothesized that the combination of antiviral therapy with flupirtine as an antiapoptotic agent may halt the progression of the disease.

• Using RNAi to silence ribonucleoprotein mRNAs of the measles virus was found to be highly effective in reducing viral messenger and genomic RNA. However, further research is needed before in vivo application.

• Recent studies revealed other viral receptors, such as CD147 and NK-1. Clinical trials are needed for the effectiveness of available cyclophilin B and NK-1 antagonists in SSPE.


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for global measles control, reported measles cases decreased from 2000 to 2008, remained stable in 2009 and increased in 2010. In the near future, it seems that neurologists will continue to face this problem since by the end of 2010, 40% of countries had still not met the incidence target of <five measles cases per million.

After the 1990s, better supportive care has resulted in increased survival rates. However, overall efficacy of treatment has stayed at a disappointing level. Isoprinosine in combination with intra-ventricular INF-a was considered most beneficial from several studies, but the adverse reactions due to intraventricular admin-istration presented as a major set back. Furthermore, isoprinosine monotherapy had yielded nearly identical outcome measures.

Within the next 5 years, clinical trials and molecular research on measles receptor antagonists and antiapoptotic agents will be active areas in the SSPE struggle.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.


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Current therapies and future perspectives in subacute sclerosing panencephalitis