Fulminant adult-onset subacute sclerosing panencephalitis: a case report

Abstract

We present the case of a young adult who developed acute encephalopathy with severe status epilepticus and rapid deterioration to vegetative state and death within 6 weeks. Although the clinical picture, MRI and EEG findings were atypical, the hypothesis of subacute sclerosing panencephalitis (SSPE) was suggested by markedly increased intrathecal IgG synthesis in the cerebrospinal fluid, and diagnosis was confirmed by the presence of high antimeasles antibodies in cerebrospinal fluid and brain biopsy findings. Acute SSPE is an exceptionally rare and little-known form of SSPE with protean symptomatology, and this case is to our knowledge the first observation of SSPE presenting with status epilepticus in adults. Our case reinforces the need to include, even in developed countries, SSPE as a diagnostic possibility in unexplained acute encephalopathies.

BACKGROUND

Subacute sclerosing panencephalitis (SSPE) is a rare, progressive, inflammatory and neurodegenerative disease caused by persistent measles infection. It was first described by Dawson in 1933.¹ SSPE is a slow infection caused by a defective measles virus that escapes the host immune response, but the exact pathogenesis remains uncertain.² Since measles vaccination became available, SSPE has been virtually eliminated in developed countries, but the incidence is still high in developing countries such as India.³ SSPE usually affects children and is characterised by progressive mental deterioration associated with motor decline and myoclonic jerks. Although several studies suggest that immunomodulatory molecules and antiviral agents can be useful in SSPE, it remains a fatal disease that culminates in neurovegetative state followed by death.⁴

This report describes a young French man who developed a fulminant SSPE with severe status epilepticus and rapid neurological deterioration and death within 6 weeks. Acute SSPE is an exceptionally rare form of the disease and this case is to our knowledge the first observation of SSPE presenting with status epilepticus in an adult.

CASE PRESENTATION

A previously healthy student in his 20s presented in January 2007 with a 2-day history of behavioural disturbances. On admission, he was alert but disoriented to time, place and person. Neurological examination demonstrated only hyperactive deep tendon reflexes on the right side. He had no fever and the findings of the general physical examination were unremarkable. A CT scan of the brain was normal. Findings on routine laboratory studies were normal. The cerebrospinal fluid (CSF) was clear and acellular, with a normal glucose concentration and a mildly raised protein count (70 mg/dl). No organisms were seen on Gram stain and no bacteria were cultured from CSF. One day after admission, he had right partial motor seizures. An EEG showed rhythmic epileptic discharges in the left frontal area. Cerebral MRI showed a small left frontal cortical hyperintensity on fluid-attenuated inversion recovery (FLAIR) images (fig 1) without gadolinium enhancement. Intravenous treatment with aciclovir (3 g/day), amoxicillin (12 g/day) and phenytoin (600 mg/day) was started, but the patient deteriorated rapidly and developed complete right hemiplegia and nonconvulsive status epilepticus. He was admitted to the intensive care unit. He presented refractory generalised convulsive status epilepticus requiring assisted ventilation and treatment with thiopental. Despite suppression of epileptic activity, he remained comatose, and right-sided spasticity increased. MRI showed progression of the left frontal lesion (fig 2). The second lumbar puncture (20 days after admission) revealed clear CSF with 4 lymphocytes per microlitre, a mild rise in protein count (52 mg/l) with an elevated Ig level (66% of total CSF protein) and an IgG index of 4.86 (normal value, <0.65). On the basis of an analysis developed by Reiber,⁴ this patient’s results indicated increased intrathecal IgG synthesis without evidence of dysfunction of the blood–brain barrier. Viral PCR studies for herpes simplex and zoster virus, cytomegalovirus and West Nile virus were negative. Bacterial and fungal microscopy and culture were also negative. General toxic and autoimmune screens were negative. Cerebral angiography was normal. The hypothesis of postinfectious encephalitis was proposed and methylprednisolone (1 g/day) was administered intravenously for 5 days, without improvement. The third MRI (20 days after admission) (fig 3) demonstrated extension of the lesion to involve both hemispheres. At 35 days after admission, a brain biopsy was performed. This showed mild inflammation of the brain involving cortical and subcortical grey matter as well as white matter. Light microscopy revealed massive neuronal loss, reactive gliosis, perivascular cuffing (fig 4) and inclusions in neurons and glial cells (fig 5). The reactive glial cells were positive for glial fibrillar acidic protein (GFAP). Within 5 weeks, the patient reached a state of deep coma and showed signs of brainstem disturbance. An EEG showed marked slowing of the background rhythm with intermittent pseudoperiodic complexes consisting of low-voltage bursts of delta waves at 4 s intervals. This pattern suggested SSPE. The patient’s parents noted that he had never received measles immunisation and had developed clinically diagnosed measles at 8 years of age. The diagnosis of SSPE was confirmed by a high antimeasles antibodies titre in the CSF (1/14000), and RNA of the measles virus was detected by PCR in a frozen brain specimen. Measles virus strain was analysed with reverse transcriptase PCR and the genotype C2 was identified. The fourth MRI (45 days after admission) demonstrated extension of the lesion to involve the whole brain and brainstem (fig 6).

Figure 1.

MRI. Initial fluid-attenuated inversion recovery (FLAIR) images showed left frontal cortical high signal change (arrow).

Figure 2.

MRI. 5 days after admission, fluid-attenuated inversion recovery (FLAIR) images revealed extension of the frontal lesion (arrow).

Figure 3.

MRI. MRI. 20 days after admission, fluid-attenuated inversion recovery (FLAIR) images revealed bilateral frontal hyperintensities.

Figure 4.

Brain biopsy. Blood vessel showed prominent perivascular cuffing by plasma cells and lymphocytes (arrows) (H&E ×400).

Figure 5.

Brain biopsy. Numerous Cowdry type A intranuclear inclusions in neurons and glial cells with some crescent-shaped intracytoplasmic inclusions (HES X600). (arrows).

Figure 6.

MRI. 45 days after admission, coronal T2-weighted MRI showed pathological signal hyperintensities involving both hemispheres, basal ganglia and brainstem.

OUTCOME AND FOLLOW-UP

The patient’s condition deteriorated dramatically and he died 6 weeks after the initial symptoms.

DISCUSSION

SSPE is usually a chronic disease and runs a stereotypic four-stage protracted course defined using Jabbour’s classification, causing death within 2 to 4 years and with a median survival of about 18 months.^3,5,6 However, acute or fulminant SSPE has also been reported, defined as development of at least two-thirds of neurologic disability within 3 months and death within 6 months of onset of disease. In 1977, Haddad and colleagues estimated that 10% of patients had such a fulminant course.⁷ Nevertheless, this proportion is credibly overestimated, and fewer than 30 well-described cases of acute SSPE have been reported since 1953.^8,9

Classic SSPE most commonly appears in childhood, whereas fulminant cases seem to be more frequent in adults.³ It has already been reported that patients with adult-onset SSPE may have had measles at either an unusually early age (under 3 years) or an unusually late age (after 8 years), as in our patient.¹⁰ Further hypotheses have been put forward to explain the fulminant course of SSPE, including localisation of the infection in the brain at the start of symptoms, impaired host defence mechanisms and genomic variation of the virus,^2,9 but the exact mechanism is not known. No correlation is established between measles genotype and acute course of SSPE, especially with the genotype C2 found in our patient, which is widespread in southern Europe.¹¹

Previous reports have already noted that clinical features of SSPE differ in acute and chronic disease. Typical features such as myoclonic jerks might be absent or too transient to be detected in the acute form. Unusual signs are more frequent, especially visual symptoms, described in half of acute SSPE cases.^8,9 Partial or generalised seizures have been observed in SSPE, but status epilepticus has been reported only once, in a child, as a nonconvulsive status epilepticus.^12,13 Its origin is unclear but might be explained by the fulgurant progression of cortical lesions. Furthermore, localisation of early changes on MRI in the frontal cortex might explain such epileptic activity, whereas initial lesions in SSPE are more commonly seen in the subcortical white matter.³ Characteristic EEG findings in SSPE are symmetrical, synchronous high-amplitude slow-wave complexes with a one-to-one relationship of the jerk to EEG complexes.⁴ The origin of these periodic complexes is unknown, but they might be generated in subcortical areas close to the thalamus.¹⁴ Nevertheless, great variability of EEG patterns in SSPE is recognised, especially for the acute form, in which periodic complexes are lacking in half of cases.^8,9 The absence of myoclonic jerks and atypical EEG patterns in our case support these findings. Precocity of cortical involvement in acute SSPE might account for these variations, because study of brain biopsy specimens has shown that relative integrity of the cortex is necessary for the presence of myoclonic jerks and periodic complexes.⁸

In our patient, CSF analysis indicated markedly increased intrathecal IgG synthesis, with an elevated mass ratio of IgG to total protein (66%). Only a few diseases can elicit an intrathecal response of this magnitude: syphilis, chronic rubella panencephalitis and SSPE.⁴ An increased antimeasles antibody titre in the CSF confirmed the diagnosis of SSPE in our patient. Although one case of acute SSPE without antimeasles-antibody in the CSF has been reported,¹⁵ this simple laboratory analysis is still the best way to confirm the diagnosis, even in the acute form. Brain biopsy in our case revealed features usually seen in SSPE: diffuse perivascular infiltrates of plasmacytes and viral intranuclear inclusions in neurons. Nevertheless, the marked neuronal loss, profusion of viral inclusions and their localisation in cells that stained with GFAP resembled the findings in subacute measles encephalitis (SME). SSPE is clearly distinct from SME, which usually affects immunocompromised patients within months of acute measles, with absence of an antibody and inflammatory response. However, our case highlights that fulminant SSPE can have a peculiar neuropathological presentation, with a histopathological pattern intermediate between those of SME and of chronic SSPE, as has already been reported.¹⁶

LEARNING POINTS

• SSPE can take the form of an acute encephalopathy with severe status epilepticus.

• When faced with a young patient with unexplained encephalopathy and increased intrathecal IgG synthesis, SSPE that should always be excluded with a simple test for measles antibody in an aliquot of CSF.