Subacute Sclerosing Panencephalitis (SSPE)
When evaluating children with intellectual difficulties, one must first distinguish between developmental delay (slowed progression in achieving developmental milestones) and psychomotor regression (loss of previously attained milestones). In children with psychomotor regression (as in this case), one must further consider four basic questions:
Patient #24 presented at age 9 with progressive encephalopathy and seizures (myoclonic and complex partial) accompanied by retinal, extrapyramidal, pyramidal, and cerebellar degeneration. The pattern of CNS involvement, with prominent personality changes, seizures, and dementia suggests gray matter involvement (processes that primarily affect white matter generally present with focal neurological deficits, marked spasticity, and blindness). There was no hepatosplenomegaly, and peripheral nerves were not involved clinically. This limits the possibilities to a subgroup of the large differential diagnoses that comprise progressive encephalopathy in childhood.
After two years of age children with progressive dementia may suffer from any of a number of metabolic, toxic, or infectious abnormalities. A short differential in patients with hepatomegaly includes the mucopolysaccharidoses, disorders of glycoprotein synthesis, Wilson's disease, Neimann-Pick disease, and Gaucher's disease, type II. The absence of visceromegaly in this patient essentially precludes these diagnoses, so further evaluation was not performed. Patients presenting with white matter involvement may have adrenoleukodystrophy, juvenile Krabbe's disease, juvenile sulfatide lipidosis, or metachromatic leukodystrophy. These conditions were not strongly considered in this patient because of the symptom pattern suggesting gray matter involvement. However, because of the overlap in presentation between white and gray matter diseases, laboratory investigation to exclude adrenoleukodystrophy and metachromatic leukodystrophy was performed. Leukocyte arylsulfatase A activity was normal, excluding metachromatic leukodystrophy; and essentially normal very long chain fatty acids, the absence of typical white matter involvement, clinical presentation, and EEG findings characteristic of SSPE excluded the diagnosis of adrenoleukodystrophy. Onset at age 8-9 would be unusual for the juvenile form of Krabbe disease, but onset as late as adolescence has been reported. The initial manifestation is generally progressive spasticity rather than dementia; unlike the infantile form, peripheral nerve involvement is not common. The lack of significant white matter involvement and prominent gray matter involvement clinically essentially excluded this as a possible diagnosis.
Patients presenting in childhood without hepatomegaly and with primarily gray matter involvement (as in this case), may have neuronal ceroid lipofuscinosis, one of the mitochondrial encephalomyopathies, juvenile Tay-Sachs disease, Wilson's disease, juvenile Huntington's disease, Heller syndrome, heavy metal exposure, or an infectious cause (SSPE, congenital rubella infection, HIV). Choosing amongst these possibilities on pure clinical grounds is somewhat difficult, but a few distinctions can be drawn. The juvenile form of neuronal ceroid lipofuscinosis, Spielmeyer-Vogt syndrome, is characterized by visual and intellectual deterioration associated with frequent seizures, as in this case. Fundoscopic examination shows abnormal retinal pigmentation and optic atrophy, as in this case as well. However, the EEG does not show periodic complexes occurring every 7-14 seconds and there is no evidence of elevated IgG in the CSF. Heller syndrome is characterized by progressive intellectual deterioration without motor involvement and marked autistic features (not seen in this case). Wilson's disease may present with progressive intellectual decline and a movement disorder (myoclonus, etc.), but does not typically include seizures or retinal deterioration. Kayser-Flescher rings and hepatic involvement are usually present. Juvenile Huntington's disease presents with progressive intellectual decline, extrapyramidal involvement (rigidity and parkinsonism are common in the juvenile form of this disorder), and seizures (approximately 50% of juvenile cases). Retinal degeneration is not present and the EEG does not show a periodic pattern. Exposure to heavy metals, such as lead may cause a progressive encephalopathy in childhood associated, at times, with seizures, but the other features seen in this case are generally not present. Juvenile Tay-Sachs disease generally begins earlier (around age 3), though it consists of intellectual decline, gait disturbance, and seizures seen in this case. As opposed to the infantile form of the disorder, there is no ethnic predilection. Of the infectious causes, HIV generally causes encephalopathy in infancy. It would be highly unusual for a congenital HIV infection to result in this constellation of findings in a child this age. There was no history to suggest post-natal exposure. Progressive rubella encephalitis, on the other hand, may occur after congenital or acquired infection, appears between 4-14 years of age, and is characterized by progressive dementia associated with pyramidal and extrapyramidal deficits. Truncal ataxia and myoclonic seizures are prominent. The EEG, however, does not usually show a periodic pattern. Creutzfeldt-Jakob disease presents with progressive dementia, pyramidal and extrapyramidal involvement, and myoclonus; however, this disease has never been seen in this age group (described as early as 16).
The clinical and laboratory evidence supports a diagnosis of subacute sclerosing panencephalitis (SSPE). This disorder, caused by a slow virus infection with the measles virus, is characterized by personality change, intellectual deterioration, and myoclonic seizures (especially of the head, trunk, and limbs) indicating gray matter involvement. The myoclonic jerks are associated with characteristic EEG discharges (usually generalized high voltage di-, tri-, or multiphasic sharp waves) that are virtually diagnostic. The discharges may rarely be lateralized, but are more often bilaterally synchronous. At the onset of the disease, the EEG background activity may be normal; but, with progression of the disease, the background activity becomes increasingly slower with much bifrontal slow activity. Clinically, speech and spontaneous movements slow and patients develop progressive spasticity and extrapyramidal dyskinesias. Visual loss due to chorioretinitis and optic atrophy is universally present. Diagnosis, as in this case, is suggested by the clinical presentation and EEG findings and confirmed by the presence of elevated levels of measles antibodies in the serum and CSF.
Patients with SSPE progress inexorably to a vegetative state and death. There is no effective treatment for the condition. The patient was started on anti-epileptic medications for seizure control and oral Inosoplex in order to slow the progression of the disease. He was then transferred to a local care facility near his home.
Subacute sclerosing panencephalitis (Dawson's encephalitis) is a neurodegenerative disease due to persistent rubeola infection that affects children and young adults. Onset of the disease is insidious and often only recognized after significant neurologic deficits occur. Affected individuals progress through four loosely defined clinical stages at differing rates. Diagnosis of subscute sclerosing panencephalitis (SSPE) is based upon clinical presentation, a characteristic EEG, and abnormal CSF studies. Worldwide, the incidence of infection varies and is linked to implementation of early childhood rubeola vaccination. No proven effective treatment is currently available, although several medication trials are underway.
Symptoms of subacute sclerosing panencephalitis (SSPE) vary widely among patients depending on the stage of illness (Dyken, 1985; Gascon, 1996; Risk & Haddad, 1979). Stage I is characterized by subtle behavioral changes, cognitive decline, emotional lability, lethargy, and nonspecific neurologic symptoms. This stage may last for weeks to months. Stage II includes continued intellectual decline, dysarthria, visual changes with optic atrophy (secondary to chorioretinitis), apraxia, tremors, sinuous myoclonus, and focal seizures with secondary generalization. This stage may last three months or less. Neurologic decline persists in Stage III (decreased level of consciousness, autonomic instability, dystonia and rigidity, decorticate/decerebrate posturing), but the pace slackens, and symptoms may stabilize for 1-2 years. Features of Stage IV include active startle reflex, flexor limb positioning, and wandering eye movements. At this time, myoclonus, seizures, and rigidity are less frequent than in prior stages. Death occurs in Stage IV, often the result of intercurrent illnesses such as pneumonia.
Laboratory findings reveal increased serum and CSF rubeola IgG titers with normal IgM titers. Serum and CSF oligoclonal banding are also detected in the gamma region (Mehta, et al., 1994). The electroencephalogram (EEG) exhibits a characteristic periodic (4-12 second interval) high voltage (greater than 500 uV), sharp and slow wave complexes (Markland and Panszi, 1975). Early in the course of the disease these periodic discharges may occur on a normal background but later the background becomes increasingly slower and disrupted. Magnetic resonance imaging (MRI) shows early changes consisting of increased signal on the T2 sequence in the frontal, temporal, and occipital white matter; late changes include significant white matter loss (Brismar, et al., 1996). Approximately 30% of patients show basal ganglia changes, while 25% have cortical changes.
Subacute sclerosing panencephalitis is the result of a persistent central nervous system (CNS) infection. During an acute rubeola infection, the virus and infected cells are quickly recognized and cleared from the body by the immune system. Several theories exist as to why rubeola persists as a latent infection in the CNS in some patients. One theory holds that affected patients have a hyperimmune response (Mehta, et al., 1994) resulting in antibodies masking the infected cell surface antigens and making them unrecognizable to cytotoxic T-cells (Gascon, 1996). In this process, complement is required for antibody mediated lysis of infected cells; since the level of complement is low in the CNS/CSF in comparison to other areas, the quantity of infected tissue may outstrip the CNS complement supply (Oldstone, et al., 1975). Another theory suggests that neurons and glia fail to envelope and transport the antigen to the membrane, leading to an inability by the immune system to recognize infected cells (Billeter, et al., 1994).
The CNS pathology of SSPE exhibits a pattern of viral encephalitis, consisting of neuronal cell loss, gliosis, foamy macrophages in white matter, and perivascular/periventricular inflammatory changes (Gascon, 1996; Ohya, et al., 1974). Other features seen include Cowdry A nuclear inclusions and symmetric demyelination progressing in an occipital to frontal pattern. Viral antigen localizes immunogistochemical to dendrites and axons. Neurofibrillary tanges are seen late in symptomatic patients.
Fifty percent of patients who develop SSPE had measles (rubeola) before two years of age, and 80% before age four years (Halsey, et al., 1980). A small number of patients have no clinical history of either measles or reaction to a rubeola immunization (Zilber, et al., 1983). Approximately 80% of individuals have a clinical course spanning one to three years. Ten percent have a course lasting 10 years, while another 10% are fulminant, with the process lasting less than three months (Dyken, 1985). Some patients' symptoms stabilize in Stage III for up to two years. Nonetheless, almost all patients die within 10 years of the initial symptoms.
The incidence of SSPE varies throughout the world. Incidence of SSPE is 1:1,000,000 per year worldwide, with greater rates in Eastern Europe, Middle East, and on the Indian subcontinent. In the United States, the incidence is 0.06:1,000,000 per year, with greater occurrence in the southern states and Ohio River Valley (Dyken, 1985). Regional disparity is most likely due to variable early childhood rubeola immunization. Increased exposure to birds by affected individuals is reported, while an association with dog or farm animal exposure has not been supported (Halsey, et al., 1980; Modlin, et al., 1979). The majority of symptomatic patients present between 5-15 years of age (Modlin, et al., 1979). Disease occurrence is approximately three times greater in males than females (Dyken, 1985; Modlin, et al., 1979).
While no proven effective therapy is available (IVIgG, plasmapheresis, cytarabine, amantidine, beta interferon), a combination of oral inosiplex and intraventricular/intrathecal alpha interferon may delay disease progression (Yalaz, et al., 1992). To evaluate efficacy of these medications, a multicenter study outside the United States is currently underway (Gascon, 1997). Antiepileptic mediation for symptomatic seizures is recommended, and in the case of carbamazepine, may help behavioral and emotional lability (Gascon, 1996). Still, early childhood immunization against rubeola remains the only truly effective means of limiting the incidence of SSPE.
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