Subacute Sclerosing Panencephalitis (SSPE)
This 25 year-old Hispanic woman with a recent history of undiagnosed, partially resolved monocular blindness, presented with a progressive dystonia accompanied by cognitive decline and personality change. Her dystonic presentation was characterized by periodic, stereotyped movements of the neck, arms, and legs. Imaging of the head and cervical spine revealed no abnormalities, and routine laboratory studies were essentially unremarkable. The most striking part of her evaluation was the EEG, which showed periodic episodes of high-amplitude delta-frequency activity associated with the involuntary movements, superimposed on relatively normal background activity. The periodicity of these complexes as well as their morphology and association with dystonic movements was highly suggestive of a diagnosis of subacute sclerosing panencephalitis (SSPE). CSF studies were also highly consistent with SSPE, showing a markedly elevated intrathecal IgG synthesis rate and multiple oligoclonal bands on high-resolution electrophoresis, without a cellular reaction. High titers of Rubeola IgG were demonstrated in the CSF, further supporting the diagnosis. Even in retrospect, no history of clinically apparent measles infection was ever elicited from the patient or her family.
Subacute sclerosing panencephalitis (SSPE) is a subacute inflammatory and neurodegenerative encephalitis related to the measles (rubeola) virus, and usually affecting children and young adults. The diagnosis of SSPE can be made if three of the following five criteria are fulfilled (Dyken 1985, Santoshkumar and Radhakrishnan 1998):
The clinical course of SSPE is variable, but affected individuals generally progress through four loosely defined stages. The first stage is characterized primarily by behavioral and personality changes, and may be heralded by a change in school or work performance. The second stage involves continued cognitive decline as well as myoclonus, seizures, choreoathetosis, apraxia, and visual changes. Features of the third stage include the development of autonomic instability, rigidity, and decreasing levels of consciousness often with decorticate/decerebrate posturing. In the final stage, the patient demonstrates quadraparesis, akinetic mutism, active startle responses and coma. The myoclonus and rigidity is usually less prominent at this point. The overwhelming majority of cases follow a progressive downhill course leading to death; although there have been a few case reports of patients who have apparently gone into remission (Dyken 1985, Santoshkumar and Radhakrishnan 1998). Five percent of patients survive three months or less and 20% survive four or more years, with a mean survival of only 18 months (Singer et al. 1997).
Singer et al. (1997) report that adult-onset patients are more likely than children to present with purely ophthalmologic complaints rather than the classical personality changes as their first symptom of disease. A wide variety of visual disorders have been associated with SSPE, including papilledema, retinitis, chorioretinitis, optic nerve pallor, homonymous visual field deficits, and cortical blindness. For this reason, and because of the presence of oligoclonal banding on CSF electrophoretic studies, a diagnosis of multiple sclerosis may sometimes be considered in the early stages of SSPE.
The pathognomonic EEG findings in SSPE are periodic complexes with generalized bilateral, usually synchronous and symmetrical slow waves of high amplitude, classically occurring every 5-10 seconds (Dogulu et al. 1995, Gokcil et al. 1998). These periodic complexes are usually associated with clinically evident myoclonic or dystonic activity (Singer et al. 1997). Early in the course of SSPE, the EEG may show normal background activity, even in the presence of the periodic complexes. However, as the disease progresses, the background activity eventually becomes progressively slower, with the emergence of bifrontal slow activity.
Magnetic resonance imaging may be relatively normal, or may show early changes of increased signal on T2-weighted sequences, frequently involving the periventricular or subcortical white matter. Later in the disease, MRI may show diffuse cerebral atrophy. Other findings, less commonly encountered, may include pial and parenchymal contrast enhancement, local mass effect of parenchymal lesions, and involvement of the splenium of the corpus callosum. Discrete basal ganglia and brainstem lesions have also been reported. The extent of MRI findings does not correlate well with the clinical neurologic status of the patients (Anlar et al. 1996, Brismar et al. 1996).
Histopathologic findings in SSPE consist of a pattern of gliosis, foamy macrophages in the white matter, perivascular and periventricular inflammatory changes, and Cowdry-A inclusion bodies. Usually, demyelination is symmetric, progressing from the occipital region and extending anteriorly, and involving the thalamus, putamen, and brainstem nuclei as well (Gascon 1996, Singer et al. 1997).
SSPE is quite rare in the United States, having decreased dramatically since the 1960s, when the measles vaccination was first introduced. On average, only 4-5 new cases are registered in the entire U.S. each year (Singer et al. 1997). The incidence of SSPE is significantly higher in non-immunized populations, with an annual incidence of 5 or 6 per million people. In their analysis of National Registry data over a 30-year period (1956-1986), covering nearly 570 cases of SSPE, Dyken et al. (1989) reported that 19% had no available measles history, 4% reported no history of measles infection or vaccination, and 77% had suffered measles infection. By comparison, Singer et al. (1997) reported a much lower proportion of a known history of measles infection in patients with adult-onset SSPE. The issue of whether measles vaccination can induce SSPE has been a topic of debate. Severe measles infections have followed the use of live-attenuated virus vaccines in immunocompromised patients, indicating that measles virus from these vaccines can reach the CNS in some cases. However, given that measles infection is not always accompanied by clinical symptoms or signs, it is also possible that cases of SSPE reported following measles vaccination may have resulted from subclinical infection occurring before the administration of vaccine.
The risk of developing SSPE has been found to be higher if measles infection occurs early in life, particularly in the first two years (Zilber et al. 1983, Bradley 2000). The median latency period from the acute measles infection to the onset of clinical signs of SSPE is about eight years, but latencies of up to 25 years are reported in some adult-onset cases (Singer et al. 1997, Bradley 2000). SSPE has consistently been shown to occur more frequently in males by a 2- to 3-fold margin (e.g., Dyken 1985).
SSPE is caused by a persistent CNS infection by the rubeola virus, affecting neurons and glia. The pathogenesis is related to defective maturation of the virus in neural cells with aberrant M (matrix) proteins as well as other envelope proteins such that the virus remains in an intracellular form and spreads by cell to cell contact (Lin and Thormar 1980, Billeter et al. 1994; reviewed in Bradley 2000). The intrathecally synthesized IgG oligoclonal bands in SSPE have been shown in multiple studies to represent an antibody response to fragments of the nucleocapsid protein of measles virus. It has also been suggested that some antibodies mask the surface antigens of infected cells, so that cytotoxic T-cells are unable to recognize them (Gascon, 1996).
There remains no proven effective therapy for SSPE. Various treatment regimens have been tried in the past with little success including intravenous IgG, plasma exchange, cytarabine, amantadine, and beta-interferon. The most promising results to date have used a combination of inosiplex, an antiviral agent, and intraventricular or intrathecal alpha-interferon as an immunomodulator, with stabilization or improvement in some SSPE patients (Yalaz et al. 1992, Gokcil et al. 1999). Long-term follow-up of these patients suggest that the remissions induced by this treatment may be temporary, somewhat like spontaneous remissions (Anlar et al. 1997). Further studies are necessary to study the efficacy of these, and other medications, in the treatment of SSPE. Antiepileptic medications for the symptomatic treatment of the associated seizures and myoclonus have been recommended and have been reported to help the emotional lability and behavioral problems to some degree (Gascon 1996). Early childhood measles vaccinations remain critical in limiting the incidence of SSPE.
This young woman met four of five criteria for the diagnosis of SSPE. She was treated with low doses of prednisone and carbamazepine, with initial modest improvement in her behavior and myoclonus. However, she continued to decline, and was admitted to the hospital one month later for a trial of high-dose steroids and antiviral therapy. Following this therapeutic endeavor, she continued to deteriorate and eventually developed decerebrate posturing and cranial nerve dysfunction. At this time, she showed autonomic dysregulation with a variable heart rate and widely fluctuating temperatures and blood pressures, without evidence for sepsis. She died only two months following her diagnosis, and six months following the apparent onset of her symptoms.
We acknowledge the assistance of William G. Ondo, M.D., of the Movement Disorders Clinic at Baylor College of Medicine, and Amit Verma, M.D., of the Division of Neurophysiology.
-- Dennis R. Mosier, M.D., Ph.D.
Email comments: