|Year : 2021 | Volume
| Issue : 1 | Page : 35-42
Subacute sclerosing pan encephalitis: An update
Kumar Saurabh, Varun Kumar Singh, Abhishek Pathak, Rameshwar Nath Chaurasia
Department of Neurology, Institute of Medical Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
|Date of Submission||16-Aug-2020|
|Date of Decision||04-Sep-2020|
|Date of Acceptance||18-Sep-2020|
|Date of Web Publication||4-Mar-2021|
Rameshwar Nath Chaurasia
Professor and Head, Department of Neurology, Institute of Medical Science, Banaras Hindu University, Varanasi 221 005, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Despite increasing immunisation rates, developing countries continue to report subacute sclerosing pan encephalitis (SSPE). The defective measles virus causng SSPE persists in brain cells because of hypermutated M protein and deranged host's immune responses. Patients usually present with cognitive decline and myoclonus. However, atypical presentations such as seizures and visual loss are also quite common, causing wrong or delayed diagnosis in a significant number of cases. Diagnosis is based on suggestive clinical features, electroencephalographic findings and elevated cerebrospinal fluid (CSF) antimeasles antibody titre. Newer methods of reporting antibody levels such as CSF/serum quotient (CSQrel) result in increased specificity, but individual values of serum and CSF antimeasles antibody titres should also be checked if CSQrel is negative or equivocal. In highly suspicious cases with negative CSF antimeasles antibody profile, repeat testing should be done. Combination therapy with interferon-alpha and isoprinosine is the most common starting regimen. Intraventricular administration of interferon-alpha is theoretically the most effective route but requires meticulous hygiene and complications are frequent. Hence, the proper route and frequency of interferon-alpha treatment should be chosen depending on efficacy, affordability, disease stage and parent's expectations. Though treatment has largely remained unsatisfactory, reported rates of improvement or stabilisation (34%–35%) are much better than that for spontaneous remission (5%–10%). Fusion inhibitors and adenovirus-delivered small interfering RNA are being studied as new therapies. However, increasing immunisation rates can be the only long-term answer to tackle the menace of measles and its complications.
Keywords: Cerebrospinal fluid, interferon-alpha, Isoprinosine, subacute sclerosing pan encephalitis
|How to cite this article:|
Saurabh K, Singh VK, Pathak A, Chaurasia RN. Subacute sclerosing pan encephalitis: An update. J Clin Sci Res 2021;10:35-42
| Introduction|| |
Subacute sclerosing pan encephalitis (SSPE) is persistent and chronic encephalitis secondary to measles virus infection that causes widespread demyelination of the central nervous system. It was first described by Dawson in 1934, in an individual with rapidly progressive encephalitis.
| Epidemiology|| |
SSPE incidence parallels that of measles in various parts of the world. Reported incidence rates are 21 cases per million population in India, 2 per million in Turkey and 0.06 per million in Canada.,, Overall, 4–11 cases of SSPE are expected for every 100,000 cases of measles, but the incidence is higher among children aged <5 years (18/100,000). SSPE is more common in males, in those belonging to lower socioeconomic class and in those coming from rural areas. It has been observed that the measles vaccine use was not associated with SSPE according to epidemiological data.
| Pathogenesis|| |
Measles virus belongs to the family Paramyxovirus, a negative-stranded RNA virus with envelope and a nucleocapsid core, having structural and non-structural proteins. After primary infection, virus is rapidly cleared because of host immunity. However, sometimes, due to inherent subtle inadequacies in host immune response due to genetic polymorphism and immaturity of the immune system in the infant and toddler age group, the virus persists in the human body. After gaining entry into brain cells by some yet undeciphered mechanism, hypermutated M protein prevents complete virus formation, budding and spread to other cells. Hence, the virus remains dormant, away from the host's immune surveillance. How the virus becomes activated or the immune response goes out of control, damaging the host himself, is not completely understood. Mutations in F protein render it hyperfusogenic and result in the spread of the virus through syncytium formation even if there is no extracellular spread of the virus.
| Clinical Features|| |
The most common age of onset is 5–15 years, usually 5–8 years after measles infection. Myoclonus, cognitive decline, poor scholastic performances and behavioural abnormalities are the most common presenting features.
The course is one of subacute or gradual downhill, that can be stratified in four stages (Jabbour staging). In stage 1, there will be behavioural changes and cognitive decline leading to poor scholastic performances. Myoclonus heralds the onset of stage 2. It gradually becomes more frequent and violent, resulting in repeated falls. In stage 3, patients develop various combinations of pyramidal and extrapyramidal features such as rigidity, dystonia, tremor, spasticity and hemiparesis. Stage 4 is characterised by an akinetic-mute state with episodes of drenching sweats, blood pressure fluctuation and respiratory rate abnormalities.
Myoclonus in SSPE is usually slow, axial and generalised owing to the predominant subcortical nature of the disease. Subtle myoclonus in early stages can be made prominent by making the patient stand with feet close together and arms outstretched in front.
Seizures are common in SSPE patients. They can be either disease revealing or sequellar. Disease-revealing seizures are most commonly focal due to the localised nature of brain lesions in early disease. Sequellar seizures are more likely to be generalised due to the widespread nature of lesions in advanced disease.
Visual involvement can be there in as many as 50% of patients. Rarely, it may be present at disease onset. There can be many causes of vision loss in SSPE patients, as structures from the retina to cortex can be involved. Neuroretinits, chorioretinitis, papillitis, papillo-oedema and optic atrophy are amongst the common ophthalmoscopic findings. Cortical blindness can be present in SSPE due to its predilection for parieto-occipital region, sometimes also resulting in Anton and Balint syndrome. Other forms of ocular involvement include nystagmus, gaze palsies and ptosis. While central causes of vision loss are often referred to a neurologist, who on performing timely investigations such as electroencephalography (EEG) and cerebrospinal fluid (CSF) studies can diagnose the disease at an early stage, those confined to the eye such as neuroretinitis or retinochoroiditis can remain undiagnosed for long times before neurological involvement occurs. A high index of suspicion for SSPE is required for cases presenting with primary macular pathology. These are frequently misdiagnosed with more common aetiologies such as toxoplasmosis. Ocular involvement can sometimes precede neurological symptoms by months or even years.,
Some previous studies showed that adult-onset disease had a higher percentage of cases presenting with visual symptoms. In one series, 8 of the 13 cases presented with visual symptoms. However, more recently, in a major series of adult-onset SSPE comprising 39 patients, adult-onset patients had a similar clinical profile as compared to their juvenile counterparts. Visual symptoms were presenting features in only 2 out of 39 patients. SSPE in pregnancy can be fulminant, with a significant number of cases presenting as visual loss due to cortical blindness.
Atypical presentations are quite common in SSPE. Diagnosis of SSPE can be very challenging particularly in atypical cases when myoclonus is absent or subtle. One large study put figures of misdiagnosis as high as 78.8%, with an interval between accurate diagnosis and presentation being 6.2 ± 11.3 months (range 0.2–96 months).
| Diagnosis|| |
Dyken's criteria is used for diagnosis, which include two major and four minor criteria. Major criteria include elevated anti-measles antibody titres in CSF ≥1:4 or ratio ≥1:256 in serum and typical (acute or rapidly progressive, subacute progressive, chronic progressive and chronic relapsing–remitting) or atypical (seizures, prolonged stage I and unusual age of presentation like infancy or adulthood) clinical history.
Minor criteria include the following: [i] characteristic electroencephalogram (EEG) findings of periodic, generalised, symmetrical and bilateral synchronous high-amplitude slow waves, also known as 'Radermecker' complexes; [ii] CSF globulin levels >20% of the total CSF protein; [iii] brain biopsy showing typical histopathological findings such as inflammatory changes in the meninges and brain parenchyma; necrotising leucoencephalitis with diffuse demyelination; viral inclusion bodies in neurons, oligodendrocytes and astrocytes; neuronal loss; and astrocytosis; and [iv] molecular diagnostic test showing identified mutations of wild-type measles virus. Two major criteria plus one minor criterion are required. In cases with atypical features, histopathological or molecular evidence may be required.
CSF analysis shows normal cells or mild pleocytosis, normal glucose and a normal or elevated total protein count. The main findings useful for diagnosis are: [i] demonstration of increased CSF immunoglobulin G [IgG] synthesis; and [ii] elevated antimeasles antibody in CSF.
To demonstrate increased CSF globulin production, its ratio of >0.2 with total CSF protein is taken to be significant. Oligoclonal bands in CSF are also a frequent finding, said to be present in 90% of SSPE patients.
Enzyme linked immunosorbent assay (ELISA) has shown good sensitivity (100%), specificity (93.3%) and a positive predictive value of 100% for demonstrating elevated antimeasles antibody titres. However, several issues need clarification, which has been discussed in subsequent sections.
What is the role of relative cerebrospinal fluid/serum quotient
CSF/serum quotient (CSQrel) can be more specific in demonstrating intrathecal antibody production than the mere elevation of immunoglobulins in CSF. However, an elevated antimeasles antibody in CSF in the absence of elevated CSQrel still fulfils Dyken's criteria for SSPE diagnosis. There is a need for updated criteria set incorporating the utility of CSQrel. In one large study, CSQrel was positive in 15 of 80 suspected SSPE patients. In the case of negative or equivocal results of CSQrel, individual values for CSF and serum antimeasles antibody should also be checked.
Can a one-time negative result for cerebrospinal fluid antimeasles antibody is enough to rule out subacute sclerosing pan encephalitis in highly suspicious cases?
Elevated antimeasles antibody titres in CSF is a compulsory criterion for SSPE diagnosis in the modified version of Dyken criteria. Sometimes, in SSPE cases, antibody level can be elevated in serum only. Few studies have shown that CSF antimeasles antibody titres in SSPE patients can fluctuate over time and can sometimes be normal., Hence, a one-time absence of elevated antibodies in CSF cannot be taken as proof of the absence of infection. Cases having a high suspicion of SSPE but negative antimeasles antibody studies in CSF should be followed with repeat testing of antibody profile.
A biopsy may be undertaken in highly atypical cases with doubtful serology and electroencephalogram(EEG). The sensitivity of measles ribonucleic acid (RNA) demonstration in CSF by real time polymerase chain reaction (RT-PCR) is not known, but probably low due to the impaired extracellular spread of mutated measles virus.
The characteristic EEG abnormality present in 65%–83% of patients is periodic complex (Radermecker complex). These are usually bilaterally symmetrical and synchronous, having high amplitude (300–1500 μv), polyphasic, lasting 1–2 Sec and occurring every 4–20 s intervals. In the early stages, they may occur at prolonged intervals and sometimes maybe even absent. However, as the disease progresses, they become prominent, their interval shortens and they coincide with clinical myoclonic jerks. Diazepam injection can make them more prominent, helping in diagnosis. In later stages, rhythmic discharges may become disorganised and background activity becomes progressively slower. Epileptiform discharges are also common (83%). Generalised periodic epileptiform discharges can also be found in anoxia, metabolic derangements and Creutzfeldt–Jakob disease (CJD). However, these conditions can be excluded based on the clinical scenario.
Magnetic resonance imaging (MRI) findings in SSPE patients are not specific and may be normal in the early stage. In the early stages, parieto-occipital and frontal involvement are more common. The involvement of the thalamus, basal ganglia and the corpus callosum is present in a significant number of patients. The cerebellum and brainstem are rarely involved. With disease advancement, widespread white matter changes together with cortical atrophy ensue. Their utility in following disease progression is also controversial, as they are known to poorly correlate with disease stage and progression. However, newer MRI sequences have shown promise in this regard. Studies have shown that diffusion tensor imaging is abnormal, even when conventional MRI shows no abnormality. Apparent diffusion coefficient values can significantly increase with disease progression., Magnetic resonance spectroscopy was also found to correlate with disease progression, with stage 2 patients having markers of inflammation and stage 3 patients having markers related to neuronal loss.
| Differential Diagnosis|| |
Nearest differentials in children and adolescents are progressive myoclonic epilepsy spectrum disorders namely Unverricht–Lundborg disease, myoclonic epilepsy with ragged red fibres, neuronal ceroid lipofuscinosis and sialidosis. These usually have a history of consanguinity or sometimes a positive family history too and a cortical type of stimulus sensitive and fragmentary myoclonus.
Schizophrenia and mania can be the primary consideration in patients presenting with prominent behavioural symptoms. Diagnosis can remain elusive for a long time before the appearance of typical features such as myoclonus.
Absence of typical features especially myoclonus will bring other childhood neurodegenerative diseases into consideration, priority being given to those having a predominant manifestation of cognitive decline such as GM2 gangliosidosis or those having parieto-occipital distribution on imaging such as adrenoleukodystrophy. Myoclonus is not usually a prominent feature in these disorders.
An acute fulminant presentation can confuse with acute encephalitis; Acute disseminated encephalomyelitis (ADEM); autoimmune encephalitis and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS).,
Presentation with cortical blindness usually leads us to suspect entities such as stroke, posterior reversible encephalopathy syndrome, hypoglycaemia, MELAS, CJD and metachromatic leucodystrophy. However, in almost all these scenarios, antimeasles antibody testing and EEG will settle the issue.
| Treatment|| |
There is no cure for SSPE. Treatment can be divided into that targeting virus and immune mechanisms to alter disease course, symptomatic and palliative care. Treatment trials for SSPE gained momentum in the 1970s after it was proven that SSPE is caused by the measles virus. After initial failure with amantadine, the focus shifted to isoprinosine, which was shown to be effective. Few studies showed that a combination of intraventricular interferon-alpha and oral isoprinosine was very effective. However, a large multicentric trial failed to show any benefit of combination therapy over isoprinosine monotherapy. However, it showed that treatment benefit (slowed progression, stabilisation or improvement) can be much more (34%–35% vs. 5%–10%) than that due to spontaneous remission. Then came the period of trials with ribavirin after it showed effectivity against hepatitis C virus and its beneficial effect was shown in various trials. Intravenous immunoglobulin had shown some benefit in case reports, whereas plasmapheresis and rituximab did not. The current focus is on research targeting molecular mechanisms such as fusion inhibitors and those hindering viral RNA through adenovirus delivered small interfering RNA (siRNA)., However, the treatment of choice remains a combination of interferon-alpha and oral isoprinosine.
Many questions need to be answered regarding the best treatment approach, which should be primarily based on the patient's clinical stage and rate of disease progression [Figure 1]. However, in a developing country like India, efforts should be made to find a proper balance between effectivity and feasibility. Some most important questions are:
|Figure 1: Approach to a case of subacute sclerosing pan encephalitis patients SSPE = subacute sclerosing pan encephalitis; CSF = cerebrospinal fluid; EEG = electrencephalogram; RTPCR = reverse transcriptase polymerase chain reaction|
Click here to view
What should be the first-line treatment approach?
In the light of findings which showed marked benefit of combined interferon-alpha and oral isoprinosine, combined therapy has been considered to be the way forward. However, a large multicentric trial failed to show any benefit of combined therapy over isolated isoprinosine treatment. It is reasonable to start with combination therapy to garner any theoretical advantage of simultaneously using drugs having different mechanisms of action in the initial stages of the disease, when a patient may be most responsive to therapy. However, if there are issues with affordability or disease has progressed to the terminal stage, then consideration should be given to the continuation of therapy with isolated oral isoprinosine.
What is the best route to give interferon-alpha?
There is no head-to-head trial comparing the efficacy, feasibility and safety of different routes. Theoretically intraventricular route with the Ommaya reservoir can be the most effective route, as it provides high sustained CSF levels of interferon. Some of the biggest trials concerning interferon alpha have also been carried out using this route. However, it is invasive, costly and requires meticulous maintenance of hygiene. Some studies have shown the effectiveness of the intrathecal route as well, with more robust evidence with high-dose intrathecal interferon or using a reservoir providing a continuous source, though some others have also come up with contradictory results.,, One study showed that interferon administered via the intrathecal route can maintain CSF levels for 24–48 h. Few studies have also shown the effectiveness of intravenous and subcutaneous routes. The subcutaneous route is particularly tempting as it gives freedom of home-based treatment to attendants. However, according to some studies, systemically administered interferon does not maintain CSF concentration for long. Hence, the trade-off remains between ease and efficacy. A useful sequence of preferred options based on efficacy can be intraventricular, continuous intrathecal, intermittent intrathecal (alternate day or bi-weekly), subcutaneous. However, the final decision should take parent's wishes into considerations regarding their expectations and affordability as trials have shown that benefit of interferon-alpha added to isoprinosine seems to be modest if any. For clinical use, drug doses used in various successful trials can be used as a guide [Table 1].
What options are there if the patient shows progression on treatment but has still not become moribund or pre-terminal?
Studies with ribavirin have been encouraging, particularly using an intraventricular route, though there are few studies which show no benefit.
If a patient is in remission or has stabilised, up to when treatment should continue
When patients on isoprinosine therapy were followed-up, it was reported that due to low risk–benefit ratio, treatment with isoprinosine should continue for a long time, probably lifelong.
Myoclonus in SSPE is particularly resistant to treatment. As in other types of subcortical myoclonus, clonazepam remains the first choice with the subsequent addition of sodium valproate and levetiracetam. Other options include zonisamide and sodium oxybate.
Some work has been done with adenovirus-delivered siRNA, that target viral genetic material and prohibit replication. Fusion inhibitors targeting F proteins which help in syncytium formation and virus spread between cells through synapses are also being studied.,
| Prognosis|| |
SSPE though having an overall dismal prognosis with death occurring within 1–3 years after onset, can also present in a more fulminant way with death within 6 months of the onset of symptoms or with a protracted course with the survival of >3 years after onset. The reported rates of fulminant and protracted courses are 10% and 5%–6%, respectively.,
Two independent studies found that older age of onset was associated with a better prognosis.[3,11] A study from Pakistan in 57 SSPE patients noted that clinical course cannot be predicted at onset. SSPE in pregnancy appears to be particularly aggressive. Most importantly, early diagnosis and institution of therapy with adherence to the treatment regimen can result in a better prognosis than with no therapy (5% spontaneous remission rate).
| Prevention|| |
Developing countries are still facing the menace of measles and its complications. In Papua New Guinea, a high incidence of SSPE is noted despite increasing immunisation efforts, probably indicating high rates of primary vaccine failure. India is also facing a similar situation. It was one of the last countries to implement World Health Organization's recommendation of double-dose vaccination against measles. Measles vaccine coverage is up from 75% in 2008 to 90% in 2018. However, it is still far from the target level of 95% to stop community transmission. Because of this increasing vaccination coverage and double-dose vaccination, measles incidence has started declining in India. A subsequent decline in SSPE cases will likely follow suit in 5–10 years. Replicating a success like that of the polio eradication programme is not easy because of the injectable nature of the measles vaccine which obviates campaigns like a door-to-door mopping up. Hence, in all probability, measles as well as SSPE will remain with us for some time to come.
SSPE is still common in developing countries owing to poor immunisation coverage. Diagnosis of SSPE can be quite challenging if presenting features are atypical. It is quite common for a significant number of cases to be wrongly diagnosed or diagnosed only at a very late stage. Hence, knowledge of atypical presenting features is important. For diagnosis, overall clinical scenario together with sensitivity and specificity of various antimeasles antibody tests should be kept in mind. The individual measles antibody titre in CSF and serum should be checked if CSQrel is negative or equivocal. In highly suspicious cases with normal CSF antimeasles antibody titre, repeat testing should be performed as antibody rise may be transient. Isoprinosine should be offered to all patients in various stages owing to its proven efficacy in various trials coupled with low side effect profile. Interferon-alpha route and frequency should be discussed with parents and the best plan considering the patient's stage, ease of transportation, affordability and expectations should be formulated. Newer therapies such as fusion inhibitors and adenovirus-delivered siRNA showed promising results. However, the best approach remains increasing immunisation coverage to prevent measles altogether – a world without measles and its complications as envisioned by WHO, the road leading to which is both long and tough.
We acknowledge Dr Prerana Dash for secretarial help.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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