Clinical manifestations

Presentation and course

In the central nervous system, measles virus infection can manifest itself as 4 distinct syndromes: primary measles encephalitis, acute post-measles encephalomyelitis, measles inclusion body encephalitis, and perhaps the best known to the reader, subacute sclerosing panencephalitis.

Patients with primary measles encephalitis present with fever, headache, alteration of consciousness, motor deficits, and seizures. In this syndrome, the virus invades and replicates in the brain cells. Subsequent chemokine induction and lymphocytic infiltration may result in significant brain edema, leading to the development of increased intracranial pressure (42). This syndrome typically develops during the exanthema stage of the infection (Fisher et al 2015), although cases preceding the rash have rarely been described (31). Detection of measles virus RNA in the CSF can help establish the diagnosis. The virus can also be isolated from the brain cell cultures (08).

Acute postinfectious measles encephalomyelitis is the most frequent central nervous system complication of measles infection (40) and typically occurs closer toward the resolution phase of the infection or days to months after the infection has cleared. Acute post-measles encephalomyelitis may also rarely occur as a result of vaccination (1 to 2 cases per million) (15; Tenembaum et all 2007).

Unlike primary measles encephalitis, acute post-measles encephalomyelitis is immune-mediated and does not involve invasion of the brain parenchyma by the virus. Symptoms of acute post-measles encephalomyelitis arise secondary to diffuse demyelination. Patients present with altered mental status, motor or sensory deficits, or ataxia. Those with significant spinal cord involvement may have back pain as well as bowel and bladder dysfunction (38). In the very rare instances when acute post-measles encephalomyelitis presents after a measles vaccination, its course is typically less aggressive (09).

Postinfectious measles encephalomyelitis may relapse in one third of patients (35). Because the syndrome is immune mediated, viral RNA typically cannot be isolated from the CSF (20; 27). Magnetic resonance imaging can be used to demonstrate disseminated white matter lesions in the brain and spinal cord (09; 23).

Measles inclusion body encephalitis, also known as immunosuppressive measles encephalitis, subacute measles encephalitis, or acute measles encephalitis of the delayed type, is a syndrome that typically affects immunocompromised children within 1 year of the primary measles infection. This syndrome occurs due to persistent measles infection in the CNS. Cases have been described in association with HIV, autoimmune disorders, and solid organ and stem cell transplantation.

Patients typically present with mental status changes, motor abnormalities, or seizures. Dysarthria and visual disturbances, including cortical blindness, have rarely been described as well (39). Less often, patients present with fever, nausea, vomiting, and emotional lability. In some instances, hypertension and other symptoms of autonomic instability may be seen. Seizures are often refractory to multiple antiepileptic medications (39). Course of the disease is that of progressive neurologic dysfunction over days to weeks, frequently resulting in coma and death (05; 37; 28).

It must be noted that some cases of measles inclusion body encephalitis have been reported in children with no known primary measles infection (28). This is likely due to the fact that the classical morbilliform rash seen in primary measles infection is a result of T-cell-mediated hypersensitivity reaction to the virus, whereas in the immunompromised patients, the typical viral exanthem may be nearly absent, making the correct diagnosis difficult.

Subacute sclerosing panencephalitis predominantly occurs in patients who acquired primary measles infection before the age of 2 years (46). Average delay between primary measles infection and subacute sclerosing panencephalitis is 6 to 15 years (Buchanan and Bonthius 2012). Clinical manifestations are insidious and involve cognitive and behavioral changes in the first stage of the syndrome. Children may present with deterioration in their school performance, whereas adults may develop difficulties at work. Ocular involvement is common and occurs in nearly 50% of cases. Patients present with necrotizing retinitis and in some cases with optic neuritis. Ocular manifestations may precede the onset of symptoms by several years (01). In the second stage of subacute sclerosing panencephalitis, patients develop myoclonus, abnormal movements and postures, and ataxia as well as seizures. Progression into the third stage of the disease is manifested by progressive rigidity and akinetic mutism, culminating in stage 4, which is coma (36; 30). A case of subacute sclerosing panencephalitis, presenting with myoclonic astatic epilepsy, has been described (32).

Prognosis and complications

Primary measles encephalitis carries 10% to 15% mortality, with about 25% of surviving patients developing permanent neurologic sequelae, such as seizures or cognitive deficits (Buchanan and Bonthius 2012).

Prognosis of patients with acute postinfectious measles encephalomyelitis is overall better than of those with primary measles encephalitis. Estimated mortality is 5% in children and 25% in adults. Some patients may fully recover, whereas others may be left with permanent neurologic sequelae.

A 3-year follow-up study of patients with acute postinfectious measles encephalomyelitis suggested that some children, despite appearing fully recovered, may go on to have long-term behavioral or cognitive deficits (49).

Relapses can be seen in up to one third of patients (35).

Measles inclusion body encephalitis is associated with high mortality, which is estimated at 75% (47), with death ensuing within several weeks of the first symptoms. Treatment is mainly supportive and focuses on cessation of immunosuppressive agents and seizure control. No effective treatment currently exists. Antiviral agents, such as intravenous ribavirin, have been attempted in a few cases, but their efficacy has been limited (39; 17).

Infectious Diseases Society of America guidelines on the treatment of encephalitis state that in measles encephalitis, empiric treatment with ribavirin can be considered (50).

Subacute sclerosing panencephalitis overall has poor prognosis. Most patients survive for only 1 to 3 years after the onset of symptoms. With good supportive measures, some patients have been known to experience remissions lasting weeks to years. A clinical course ranging from 10 to 15 years has been reported (12).

Clinical vignette

An internationally adopted 13-year-old boy presented to his primary care provider with progressive difficulty with his school work over the past month as well as gait ataxia, poor vision in the left eye, and left-sided hemiparesis. The patient’s MRI revealed multifocal hyperintensities. He was initially diagnosed with acute disseminated encephalomyelitis, and high-dose intravenous steroids were initiated. Subsequently, CSF showed a high titer of anti-measles IgG antibodies. EEG was pathognomonic for subacute sclerosing panencephalitis showing Rademecker complexes (generalized periodic discharges). Patient went on to develop myoclonic jerks and within 3 weeks progressed to coma and died. Biopsy of his brain was consistent with subacute sclerosing panencephalitis. Later obtained detailed history revealed an episode of rash, followed by a fever, around the age of 2 years. History of vaccinations was known.

Biological basis

Etiology and pathogenesis

Primary measles encephalitis is caused by the measles virus directly invading the cells of the central nervous system (neurons, oligodendroglia, and astrocytes). The mechanism of this is unclear as nerve cells do not have the CD150 receptor the virus uses peripherally (45). Because a specific receptor for the viral entry into the CNS has not been discovered, it has been suggested that the virus may gain entry to the central nervous system either via endothelial cells or infected monocytes (48).

Unlike its predecessor, acute postinfectious measles encephalomyelitis does not involve direct invasion of the brain cells by the measles virus and, instead, is immune-mediated. Molecular mimicry results in damage to the myelin basic protein and causes diffuse demyelination (18).

Measles inclusion body encephalitis occurs in immunocompromised patients and is thought to be the consequence of their inability to clear the infection. The virus is readily detectable in neurons, oligodendroglia, and astrocytes. Neuropathology shows glial cell proliferation with areas of focal necrosis and perivascular inflammation. Electron microscopy of tissue reveals intracytoplasmic and intranuclear inclusion bodies, consistent with paramyxovirus nucleocapsids (39).

Subacute sclerosing panencephalitis is thought to occur due to viral persistence, and with time, mutation after the primary infection (typically before the age of 2 years) that could not be successfully cleared by the immune system (19).

The fact that children who become infected with measles virus before age 1 are at highest risk for developing subacute sclerosing panencephalitis suggests that the immaturity of the immune system during primary infection is at least in part responsible for the pathogenesis of this disease (21). Analysis of the viral RNA from the infected cells confirms the same lineage as the virus that caused primary measles infection, but with changes in the M, F, and H proteins (51; Mawrin et all 2002).

Nuclear and cytoplasmic viral inclusion bodies can be detected in both neurons and oligodendrocytes. Grey matter is typically affected more profoundly than the white matter. Extensive mononuclear inflammation can be detected in the parenchyma (10).

Gradual nature of spread occurs over years (as can be suggested by serial MRIs), and eventually clinical manifestations become evident (34).

Epidemiology

Primary measles encephalitis occurs in 1 to 3 of 1000 patients with measles infection (39).

Acute postinfectious measles encephalomyelitis affects approximately 1 in 1000 of children affected with measles (Buchanan and Bonthius 2012) and only 1 to 2 of 1,000,000 of the patients who receive live attenuated measles vaccination (03).

It occurs most frequently in children but has also been described in adults and infants (Kenko et al 2002; 46).

Measles inclusion body encephalitis predominantly occurs in immunocompromised children exposed to the measles virus in the year preceding the onset of symptoms, but it can occur at any age. The incidence is approximately 1 in 10 cases of immunocompromised children with measles. In year 2009 to 2010, during a major measles epidemic in South Africa, more than 18,000 laboratory-confirmed cases of measles occurred, and at least 8 cases of inclusion body encephalitis were detected in immunocompromised children with HIV (25). Three reports of this disorder have been published in patients who received MMR vaccination. In these cases, symptoms developed between 4 and 9 months after the vaccination (22).

Subacute sclerosing panencephalitis occurs in immunologically intact patients who had measles infection commonly prior to the age of 2 years, with its clinical signs many years later. According to the CDC, overall incidence of subacute sclerosing panencephalitis is about 10 per million patients with measles.

Prevention

The Advisory Committee on Immunization Practices (ACIP) recommends vaccination against measles at the age of 12 to 15 months, followed by a second dose not earlier than 28 days after the first dose (typically around the ages of 4 to 6, preceding school/kindergarten entry).

Postexposure prophylaxis is indicated in people without known acquired immunity to measles. Within 72 hours of exposure, patients should receive the measles vaccine, or alternatively, immunoglobulin infusion within 6 days of exposure. These 2 strategies may prevent, attenuate, or significantly alter the course of the symptomatic infection.

The CDC recommends vaccinating infants under 12 months of age during an epidemic or when many cases in infants below 12 months of age are reported in the community. Those who were vaccinated prior to the age of 12 months need to be revaccinated between 12 and 15 months of age and again at 4 to 6 years of age.

Life-threatening adverse events related to the MMR vaccine are exceedingly rare and have been associated with rare cases of inborn errors in type I and/or type III interferon pathways (mutations in STAT1, STAT2, and IFNAR2) (26).

If exposed to measles virus, people who are immunocompromised should receive measles immunoglobulin infusion regardless of their vaccination status, as they may not be able to mount an immune response of necessary magnitude and are at increased risk for complications and mortality.

Pregnant women represent another high-risk group for complications, both personal and to the unborn fetus. Pregnant women who have not been previously vaccinated should receive immunoglobulin if exposure occurs. MMR is a live vaccine and is contraindicated in pregnancy.

Differential diagnosis

Depending on the clinical scenario, which may significantly vary in terms of both symptoms and time frame, other viral and immune-mediated entities should be considered.

Viral workup consisting of HSV 1 and 2, VZV, WNV, enterovirus, EBV, CMV, and HHV6 should be considered in the differential diagnosis of acute measles encephalitis, measles inclusion body encephalitis, and postinfectious measles encephalitis. Bacterial and fungal cultures should be obtained. Autoimmune, neoplastic, paraneoplastic, and postinfectious encephalomyelitis; systemic lupus erythematosus; sarcoidosis; multiple sclerosis; neuromyelitis optica; and Behcet disease should be considered depending on the specific symptoms, temporal course, and radiologic abnormalities. For SSPE, the differential diagnosis would include various leukodystrophies, Schilder sclerosis (atypical form of multiple sclerosis), and variant Creutzfeldt-Jakob disease.

Diagnostic workup

The choice of diagnostic workup should be guided by clinical suspicion of a specific measles-associated neurologic syndrome.

Neurologic symptoms associated with the primary measles encephalitis typically develop within 7 days of the systemic infectious prodrome. CSF is usually abnormal with lymphocytic pleocytosis and elevated protein concentration (39). Due to the diffuse inflammatory process, brain edema may ensue, and opening pressure may be significantly elevated. Diagnosis of primary measles encephalitis can be further supported when measles virus RNA is detected in the CSF by polymerase chain reaction (33). CNS symptomatic involvement in a patient with symptoms of measles or with peripheral anti-measles IgM antibodies should raise a strong suspicion of primary measles encephalitis, and CSF diagnostic tests should be performed.

Acute post-measles encephalitis by definition precludes detection of measles virus RNA in the CSF. This syndrome is post-infectious and immune-mediated in nature (27). MRI and CSF are helpful in establishing the diagnosis. Lymphocytic pleocytosis and elevated protein concentration may be present in the CSF. IgG index in the CSF is usually not elevated. MRI shows disseminated white matter lesions in the brain or spine (41; 09).

In measles inclusion body encephalitis, CSF may initially be normal, although mild pleocytosis and an elevated protein concentration may be present (48; 39). With progression of the disease, CSF anti-measles antibody titers rise. In fact, over the course of the disease, in 50% of cases, a 4-fold increase in the CSF antibody titers is expected (39).

Diagnosis is confirmed via biopsy of the brain with detection of viral RNA by PCR or viral antigen via immunohistochemistry specific for measles matrix and hemagglutinin proteins (48). The virus can also be isolated from cerebral tissue and by polymerase chain reaction from CSF (Buchanan and Bonthius 2012; 25).

MRI of the brain is usually normal but occasionally may reveal atrophy, ventriculomegaly, or edema (48).

EEG may be abnormal and may reveal focal or multifocal epileptiform discharges. Focal motor seizures or even epilepsia partialis continua may occur.

Neuropathologic examination may show glial proliferation and areas of necrosis and perivascular inflammation. Electron microscopy may detect intracytoplasmic or intranuclear inclusions consisting of measles virus nucleocapsids (39).

Diagnosis of subacute sclerosing panencephalitis is suspected by the clinical presentation, as discussed in the section above. Titers of anti-measles antibodies in the CSF are typically very high. MRI scans can be used to monitor progression of the disease. Initially, lesions are present in the gray matter, but as the disease progresses, these appear in the periventricular white matter and progressively affect deeper structures as well as brainstem (Fisher et al 2015).

EEG findings may consist of periodic slow-wave complexes, every 4 to 10 seconds, accompanied by myoclonic spasms (04).

Management

No specific antiviral treatment for measles has been proven to be effective. Current treatment strategies focus on supportive measures, prevention, and treatment of secondary bacterial infections.

Vitamin A deficiency is associated with increased measles severity and mortality in children. Acute measles infection increases vitamin A utilization, and those with depletion are at risk for most ocular complications (43). Administration of vitamin A to children with measles reduces both morbidity and mortality (29). The CDC recommends administering 50,000 IU to infants younger than 6 months of age, 100,000 IU to infants younger than 12 months of age, and 200,000 IU for children older than 12 months of age. A second dose should be administered within 24 hours. Both parenteral and oral formulations are available.