Continuing Education Activity

Subacute sclerosing panencephalitis (SSPE) is a devastating complication of the measles virus. Although it is a rare complication and the measles virus is preventable with vaccination, healthcare systems may see more cases given the re-emergence of measles in many countries in the last few years. High mortality rates are associated with SSPE, and there is no known cure at this time. This activity outlines the evaluation and management of subacute sclerosing panencephalitis and reviews the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Summarize the epidemiology of subacute sclerosing panencephalitis.
• Describe the presentation of a patient with subacute sclerosing panencephalitis.
• Outline the treatment considerations for patients with subacute sclerosing panencephalitis.

Introduction

Subacute Sclerosing Panencephalitis (SSPE) is a rare complication due to persistent measles infection. This neurological sequela typically presents in early adolescence and has a progressive course with a high mortality rate.[1] Vaccination implementation has been effective in reducing the number of Measles cases, thereby reducing cases of SSPE. However, measles remains endemic in many countries with poor access to vaccinations. Also, there has been a re-emergence of measles in industrialized countries due to vaccination refusal.[2]

Etiology

Subacute sclerosing panencephalitis is caused by the measles virus, which is a single-stranded RNA virus of the Paramyxoviridae family. As one of the most contagious diseases, measles can be transmitted to 12 to 18 persons from one infected individual. Transmission occurs through aerosols from person to person. Many complications can occur both acutely and chronically, some of which are neurological complications, like SSPE. Children less than five and adults over the age of 20 are at higher risk of death.[2][3]

Epidemiology

Subacute sclerosing panencephalitis cases have seen a steady decline since vaccination for measles has been introduced. It appears that the number of reported SSPE cases has an inverse relationship with the number of reported measles cases. In the United States, there are usually 4 to 5 cases of SSPE per year.[4] However, this number may see an increase in the future, given the decline in vaccination secondary to vaccination hesitancy, which has led to decreased herd immunity. In 2019, there was a 300% increase in reported measles cases compared to the previous year. The measles virus has killed more than 100,000 people per year since 2010, most of whom were less than 5.[2] Measles is still endemic in many developing countries within Africa and Asia due to poor access to vaccines.[5] Generally, 4 to 11 per 100,000 cases of measles result in SSPE. This number goes up to 18 per 100,000 cases if the child was less than five years old when primarily infected with measles. It appears to have a higher prevalence in males, with later onset and increased latency in females.

Risk factors for SSPE include being from a rural area or poverty-stricken area, overcrowding, multiple siblings, or higher birth order due to an increased chance of exposure and infection at a younger age (less than 5). SSPE tends to have an earlier onset and a more fulminant course in individuals with acquired immunodeficiency syndrome, children whose mothers had measles during pregnancy, or if there was an incomplete transfer of measles antibodies during gestation.

There is no possibility of contracting SSPE after vaccination. It has been proven that to occur, there must be a direct measles infection. Also, no tissue specimens obtained from patients with SSPE have been positive for vaccine strains of the virus. By far, the risk of measles infection outweighs any risk posed by vaccination.[4]

Pathophysiology

A person must be directly infected with the measles virus to cause subacute sclerosing panencephalitis. It has been found that wild strains causing measles have a tri-residue motif, which infers an increased ability to spread, which is not present in lab-adapted strains used for vaccines. Thus, SSPE remains solely a complication of the wild-type measles infection. The latency period varies from 7-10 years, with shorter latency periods observed with children infected with the measles virus under the age of 2 or intrafamilial measles cases.

The measles virus has a tropism for lymphocytes in the lower respiratory tract and epithelial cells in the upper respiratory tract.[3] The measles virus initially infects immune cells within the respiratory tract, which carry the infection to local lymph nodes. From the lymphatic system, various organs and tissues are infected through cellular fusion, causing syncytium formation, also known as Warthin-Finkeldey cells. As epithelial cells are destroyed secondary to the infection, the cells slough off and are expelled via coughing and sneezing. This allows for the airborne transmission of the measles virus to another host.[6]

With initial infection, the measles virus causes heavy immunosuppression that can continue for a considerable amount of months. This results in many secondary infections.[2] SSPE is a more prevalent complication in younger patients exposed to the measles virus, likely secondary to their immature immune systems. The typical immune response to infection starts with T-helper 1 cells that release interferon-alpha and IL-2. These cytokines help to eliminate the viral infection from cells. The humoral response then plays a role in making antibodies for long term protection from the virus. These antibodies will trigger T-helper 2 cells that release large amounts of IL-4 and a small amount of IL-2 and interferon-alpha. It is a possibility that SSPE is the result of a poor cellular immune response. There is evidence to suggest that patients who go on to develop SSPE have a reduced cellular immune response and an elevated humoral immune response, which would prevent the patient from completely eradicating the virus.[4]

However, the actual mechanism of CNS infection by the measles virus is unknown. CD46 and protein F likely play a role in viral entry into neurons. Once inside, the measles virus undergoes mutations that allow for evasion of the host immune response and continuous viral production without damaging neuronal cells. The nucleocapsid and hemagglutinin genes appear to remain conserved, while the matrix gene is heavily mutated.[4] Neurovirulence of SSPE strains of the measles virus is likely due to the impaired expression of the M protein. The formation of syncytium in SLAM and nectin-4  negative cells has been attributed to the mutations contained in the F protein gene of SSPE strains. In vitro studies have shown that the spread of the virus from neuron to neuron is through their axonal connections. However, it has been hypothesized that there is another cell receptor, heavily concentrated at the synapses, that the measles virus acts upon to gain entry to neurons.[7]

One of the proposed mechanisms of neuronal spread is via neurokinin-1, while substance P and fusion inhibitory peptide block viral transmission. The virus typically remains dormant for some time before triggering an inflammatory response resulting in neuronal destruction, which presents as SSPE.[4] However, the exact pathogenesis of this complication is still not known, given that neurons do not express either target cell receptors, SLAM, and nectin-4.[2][3] It has been proposed that SSPE occurs as a result of antigenic drift. However, an in vitro study found that both SSPE and wild strains of the measles virus behave in similar manners and can be neutralized in the same capacity, thus disproving the antigenic drift theory.[6]

Histopathology

Between 1933 and 1934, Dawson investigated cerebral lesions of patients who had died from subacute sclerosing panencephalitis. He found several cellular inclusions, which caused the original name to be Dawson’s inclusion body encephalitis. In the 1960s, electron microscopy allowed the discovery of a paramyxovirus found within brain lesions from SSPE patients. Some distinctive histopathology of the disease includes inflammation to both the meninges and cerebral tissue, necrotizing leukoencephalitis with scattered demyelination, neurons and support cells containing viral inclusion bodies, loss of neurons, and astrocytosis.[3] The measles virus has not been found within the extracellular space in this particular CNS infection.[2]

Early stages of CNS infection cause cellular swelling and oxidative damage to genetic material. It is thought that lipid peroxidation causes demyelination in the early course of the disease. This is followed by an acute inflammatory phase where nucleocapsids are evident in oligodendrocytes and neurons, while granulofilamentous inclusions within nuclear bodies are present in astrocytes. Inflammatory cells can be found in perivascular regions along with scattered areas of demyelination and spongiosis.[4][5][8] Neurofibrillary tangles have been found in some cases of SSPE.[9] 

As the disease progresses, there is increased neuronal loss. Evidence of inflammatory changes typically starts in the posterior areas of the cerebrum, then proceeds to spread to the anterior portions while sparing the cerebellum. Brain biopsies from SSPE patients typically show positive measles staining within neurons, neuron support cells, and lymphocytes. RNA from the measles virus has been isolated in the brain, eyes, and spinal cord in patients with SSPE.[5]

History and Physical

Subacute sclerosing panencephalitis is characterized by progressive cognitive decline. Symptoms typically present about 8 to 11 years of post-measles infection. Initially, personality or behavior changes are present, in addition to poor school performance and intellectual deterioration. There is a steady decline in motor function with myoclonus in most cases, autonomic dysfunction, and focal paralysis. Some patients have seizures, either focal or generalized, and about one-third of patients with SSPE develop epilepsy. Patients eventually fall into a vegetative state or akinetic mutism, which is shortly followed by death.[4][3][2]

The course of SSPE has been divided into stages, each of which describes a certain phase of the disease. Stage I includes many personality or behavioral changes, such as irritability, dementia, lethargy, social withdrawal, or speech regression. Stage II is made up of the progressive decline in motor function, including myoclonus, dyskinesia, and dystonia. Stage III consists of patients who have progressed to extrapyramidal symptoms, posturing, and spasticity. Lastly, stage IV occurs when patients develop akinetic mutism, autonomic failure, or enter a vegetative state.[3]

Visual symptoms sometimes precede disease onset by about 2 years, with the most classic lesion being focal necrotizing macular retinitis. Ocular symptoms can range from retinal hemorrhages to papilledema to complete vision loss. Most structures of the eye can be affected, but there is never vitreal inflammation.[4][3][5]

Atypical presentations of SSPE can include psychiatric symptoms, seizure disorders poorly controlled with medication or solely extrapyramidal symptoms. When atypical symptoms are present, SSPE tends to have a fulminant course with neurological deficits occurring in the first 3 months or death within 6 months in about two-thirds of cases. Having the measles virus before the age of 2, increased viral virulence and coinfection with other viruses are risk factors for a more fulminant, atypical course.[4][3]

SSPE tends to vary in presentation, making it very difficult to diagnose. It is important to have SSPE in a differential in many circumstances. SSPE has been diagnosed in elderly patients with predominantly psychiatric features that become progressive dementia.[10] Later onset of SSPE tends to correlate with a more rapid decline and lower mean survival of only a few months.[8] Screening for SSPE should occur in children with acute cognitive decline, myoclonus, or new-onset epileptic syndromes.[11] SSPE can also present during pregnancy with cognitive dysfunction or difficulty with simple tasks. Children born to mothers suffering from SSPE tend to be healthy.[8]

Evaluation

Evaluating for SSPE tends to be multi-faceted. While the gold standard for diagnosis is brain biopsy, clinicians tend to use a set of criteria to diagnose SSPE.  Initially, Dyken criteria were developed to help diagnose SSPE. This consisted of certain symptoms and specific CSF/serum, EEG, and brain biopsy findings, requiring at least 3 of the five criteria for diagnosis. However, due to the variable nature of the SSPE presentation, the second set of criteria was developed in 2010. This proposed SSPE diagnosis criteria include several major and minor criteria, with a diagnosis requiring two major and one minor criterion. If there is insufficient evidence or supporting criteria for diagnosis, but it is still highly likely, histopathological and molecular testing is available.

Major Criteria

• One of the major criteria is having either a typical or atypical presentation. The typical presentation is defined as either acute, rapid, subacute, or chronic progressive or chronic relapsing-remitting.
• The atypical presentation includes seizures, prolonged stage I, or unusual age at presentation. Another major criterion is elevated anti-measles antibodies greater than or equal to 1:4 in the CSF or 1:256 in the serum.

Minor Criteria

• The minor criteria cover supporting evidence of clinical presentation, one of which is EEG findings consistent with high-amplitude slow waves occurring bilaterally and synchronously at fixed and regular intervals. These are called slow-wave complexes or Radermecker complexes.
• Another minor criterion is an elevated level of globulin in the CSF, that makes up more than 20% of the total protein found in CSF.
• Brain biopsy findings consistent with SSPE discussed in the histopathological section is a minor criterion
• Lastly, a molecular test used to identify the genome mutations in the wild strain of the measles virus is a minor criterion.[3][8] The sensitivity and specificity of the newer criteria have yet to be assessed in either the general public or pregnant females.

CSF findings can include pleocytosis and increased immunoglobulins as described in the criteria with normal glucose and protein levels. ELISA of CSF will typically show the presence of the measles virus.[4] The EEG findings described in the criteria for diagnosis are seen in about 65% to 83% of SSPE cases. However, some will have atypical findings, such as a lack of rhythmicity, varying intervals between slow-wave complexes, or occipital spikes before complexes.[4]

Imaging can be used as supportive evidence of a diagnosis, but it does not always have abnormal findings.

Magnetic resonance imaging (MRI) can show decreased gray matter volume, hyperintensities, and atrophy with marked ventriculomegaly.[3] MRI helps clinicians follow disease progression. Initial imaging can be normal, then progress to lesions in the periventricular white matter, followed by spread into deep brain structures and the brainstem. Case reports have shown that some patients with SSPE develop primary brainstem lesions rather than the typical progression described above. Historically, these lesions in the brainstem have been suggestive of autoimmune or metabolic disorders. However, this evidence demonstrates that SSPE must also be considered with primary brainstem lesions on imaging.[1]

Magnetic resonance spectroscopy can also be used to evaluate patients for SSPE. If caught early in the course, there will be a decrease in N-acetyl-aspartate and an increase in choline, which is evidence of inflammation and demyelination.[4] Later on in the disease course, there should be elevated ratios of choline to creatinine or inositol to creatinine with normal N-acetyl-aspartate to choline ratio or decreased N-acetyl-aspartate to creatinine ratio. These findings are suggestive of reduced brain volume.[3]

Treatment / Management

No cure exists for subacute sclerosing panencephalitis. Most treatments are aimed at symptom reduction. However, there is only about a third of patients that benefit from treatments. This benefit is defined as slowing the course of the disease, stabilizing progression, survival prolongation, or clinical improvement (rarely occurs).[4][3] Many supportive measures have been used or tried in cases of SSPE. Although no set guidelines or recommendations exist, several drugs tend to be used in conjunction with each other.

Inosine pranobex is an oral antiviral that halts viral replication and immunomodulator. The dosing is 100mg/kg/day divided into three doses throughout the day with a maximal dosage of 3000mg/day. This therapy is known to cause elevated uric acid in urine and serum samples, as well as occasional nausea.[4]

Interferon-alpha (INF-alpha) is another mode of therapy typically used with Isoprinosine. It is an immunomodulator administered via the intrathecal route every week. Maximal efficacy of interferon-alpha can only be achieved with long-term treatments. Some studies have shown that there is no advantage to daily Isoprinosine plus weekly INF-alpha versus Isoprinosine monotherapy.[4]

Ribavirin, a nucleotide analog, has also been tried as a supportive treatment. Little success was noted, and it seemed to only mildly benefit patients when used in conjunction with INF-alpha. Antiepileptics have been used for seizure control as well as myoclonic symptoms and encephalopathy. Other therapies that are currently being studied in vitro include antiapoptotic agents and small interfering RNA. siRNA appears to inhibit viral replication in cells but has not been studied as therapy in humans yet.[4][3] Other studies have recommended the development of therapies that could block membrane fusion, which could potentially stop the progression of CNS infections by the measles virus.[7]

As an alternative treatment, several case reports recommend a ketogenic diet. There has been some variable success with this in reducing myoclonus symptoms in patients with SSPE who have failed other treatment options.[3][9] This particular diet is neuroprotective in that it reduces oxidative stress, improves mitochondrial activity, and suppresses factors that induce apoptosis. In one particular case report, a patient who had failed several antiepileptic treatments saw significant improvement after 11 months of being on a ketogenic diet. Initially, in a vegetative psychomotor state with severe myoclonus, the patient had the return of cognitive and physical abilities with complete suppression of myoclonus. Another case report with the ketogenic diet as therapy observed a temporary improvement in myoclonus that became refractory to treatment later on. Using a ketogenic diet as an adjunct to therapy can prove helpful in symptom control.[9]

Vaccination for Measles

• At this moment, preventing SSPE from developing is the best treatment option. Vaccination for the measles virus is a very safe and effective way to prevent initial infection.
• The vaccination is separated into two doses, one given at 12 to 15 months and the second given between the ages of 3 to 5 years.
• Vaccination cannot be given to anyone who is immunosuppressed because it is a live-attenuated vaccine.
• WHO recommends administering the vaccine to HIV-positive patients in the absence of severe immunosuppression.
• 95% must demonstrate immunity with anti-measles antibodies to completely eradicate the measles virus from a population.
• In the last few years, there has been a re-emergence of the measles virus in industrialized countries. This is largely attributed to reduced vaccination due to vaccine hesitancy.[2]

Differential Diagnosis

Given the variable presentation of SSPE and the clinical findings it is associated with, there are many other differential diagnoses to think of. Although SSPE generally occurs in childhood, it can rarely occur in adults and should not be dismissed if the patient is a pregnant woman. It can be misdiagnosed as sole epilepsy or psychiatric illness in the early stages of the disease. Any patients with acute, progressive myoclonus, dementia, and/or seizures should be evaluated for the following:

• Viral encephalitis
• Autoimmune encephalitis
• Atypical multiple sclerosis
• Creutzfeldt-Jakob disease
• NMDA receptor encephalitis
• Neurometabolic encephalopathies
• Neoplasms
• Paraneoplastic syndromes
• Leukodystrophies

By no means is this list completely inclusive, but it speaks to a vast realm of possibilities that should be considered in addition to SSPE.[3][4][5][10][8]

Prognosis

The mortality rate is exceptionally high in the case of SSPE, about 95%, while the remaining cases undergo spontaneous remission.[9][4] The average life span after the initial presentation is about 3.8 years, with a range of 45 days to 12 years.[3]

Complications

SSPE is a complication of chronic CNS infection by the measles virus. A patient with SSPE experiences a progressive course of neurological deficits, which ultimately results in death. Treatments that attempt to prolong and improve the quality of life can have some side effects/complications. Interferon-alpha can cause flu-like symptoms or produce a clinical relapse secondary to antibodies to the interferon. Ribavirin can produce oral mucositis, headache, fatigue, and reversible anemia.[4]

Deterrence and Patient Education

Families should continue to be educated on vaccination programs, especially the potential consequences of measles virus infection and long-term complications. In this case, the benefits outweigh the risks of vaccination and possibly contracting SSPE.

Pearls and Other Issues

SSPE is a progressive neurological complication of the measles virus with no cure to date. This complication has a very high mortality rate despite available therapies. SSPE typically affects children and adolescents several years after initial infection with measles.

Enhancing Healthcare Team Outcomes

After vaccination was introduced, the prevalence of both the measles virus and SSPE dropped significantly. However, given the recent re-emergence of the measles virus within industrialized countries, it is important that moving forward, SSPE is considered as a differential. Especially with children or adolescents presenting with cognitive decline, myoclonus, and seizures. It is also important to continue to encourage families to vaccinate their children. Vaccination against the measles virus is the safest and most effective way to prevent SSPE.