Subacute Sclerosing Panencephalitis

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84.1 Clinical Features

and Laboratory Investigations Subacute sclerosing panencephalitis (SSPE) is one of the slow virus infections of the CNS. It is a rare disor- der, but it is the commonest of the chronic virus infections to affect children. It is caused by measles virus and occurs in approximately 4:100,000 cases of measles. SSPE is a disease of childhood and adoles- cence, with an age of onset range of 4–25 years and a peak incidence at 9–17 years. SSPE is rare in adults.

The disease occurs on average 9 years after the initial infection. There is a racial difference in incidence of SSPE: in the United States the incidence is four times higher in whites than in blacks. Boys outnumber girls by 3 or 2 to 1. Children who acquire measles infection under the age of 1 year are more likely to develop SSPE. The mean age at infection is 12–14 months. In exceptional cases SSPE can also occur after live measles immunization, but the incidence is highly reduced after immunization. Since the introduction of measles vaccination, the incidence of SSPE has be- come very low in countries where a high immunization coverage (~ 95%) is achieved.

The clinical syndrome of SSPE is rather variable.

The duration of the disease ranges from 3 months to more than 7 years. Although there is a marked varia- tion in presenting signs and in the sequence of events, four clinical phases can usually be discerned. Stage I is characterized by an insidious deterioration of behavior and intellectual performance. The duration of this stage is usually several months, but the exact time of onset of the disease is often difficult to determine.

Personality changes occur with withdrawn, timid, or aggressive behavior. These changes are followed by lethargy, drooling, slurred speech, and paucity of speech. Soon after the onset of intellectual deterioration, visual disturbances can often be detected. These are either related to progressive chorioretinitis or to lesions of the central visual pathways. In stage II, mas- sive, repetitive, and frequent myoclonic jerking occurs. The myoclonia develops slowly and irregularly, but gradually affects all somatic muscle groups, especially the axial muscles, in a reasonably symmetric fashion and at a regularly repetitive rate. The my- oclonus may be sufficiently severe to throw the child to the floor. The jerking interferes with intentional movements, giving the impression of clumsiness. The jerking is absent during sleep. Seizures of a more conventional type may also occur, such as focal motor,

generalized, and psychomotor convulsions. They may even precede the myoclonic jerking. Mental deterioration becomes progressively more obvious. At this stage, choreoathetosis, ataxia, tremor, and spasticity are common. The duration of stage II varies from 1 month to 1 year or more. In some patients the disease is arrested in stage II and remains in this stage for years. In stage III there is severe dementia. The spasticity increases, and the child becomes bedridden. Ex- trapyramidal dysfunction of the parkinsonian type is frequent. Nasogastric tube feeding is often required at this time because of progressive bulbar palsy. Hyper- thermia may be found without evidence of infection.

It is the rule that the myoclonia diminishes in stage III. Stage IV is the final stage in which the child is in a vegetative state, characterized by mutism and decor- ticate or decerebrate postures. There is no bladder or bowel control. Ophthalmological abnormalities occur in 50% of patients and include optic atrophy and chorioretinitis. The chorioretinitis may be most marked at the maculae, where scars are seen with characteristic pigmentation. There are signs of auto- nomic dysfunction, such as hyperthermia, severe per- spiration, and changes in heart rate and blood pressure. The duration of stage IV varies from 1 to 6 years.

Most patients die during stage III or IV from car- diorespiratory complications related to impaired central mechanisms controlling temperature, cardiac, and respiratory functions. Another common cause of death is infection. Spontaneous long-term remissions are exceedingly rare, but may occur.

The clinical diagnosis of SSPE is confirmed by the finding of increased levels of anti-measles virus antibody in serum and CSF with an elevated CSF-to- serum ratio in antibody level. The CSF is clear, and the pressure and glucose concentration are normal. Mod- erate pleocytosis (5–20 mononuclear cells per milli- liter) is often present. The protein level is usually normal or mildly elevated; a level that exceeds 0.90 g/l is uncommon. The level of IgG as a percentage of total protein is highly increased, and oligoclonal bands are present. Measles-specific IgG antibodies represent nearly 10–20% of total serum IgG and about 75% of the total CSF IgG. There is always an elevated CSF-to- serum ratio of IgG, especially of measles virus antibodies, indicating local production of measles virus antibodies within the CNS.

Another confirmatory finding is a characteristic EEG pattern of periodic complexes consisting of bilateral synchronous, symmetric, 2- to 4-Hz high-am-

Subacute Sclerosing Panencephalitis

Chapter 84

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plitude sharp and slow wave bursts, which may occur every 5–7 s. These periodic complexes occur simulta- neously with the involuntary myoclonic movements.

In stage I the EEG may be normal or show only mild to moderate, nonspecific slowing. Stage II is characterized by the occurrence of the periodic complexes;

the background pattern is still relatively normal. In stage III, the background rhythm slows, and fewer bursts of periodic complexes occur. Stage IV has slow delta activity and rare SSPE complexes. These complexes in association with myoclonic seizures provide strong corroborative evidence of SSPE. However, periodic complexes are also seen in other diffuse cerebral disorders, such as some lysosomal storage disorders, mitochondrial encephalopathy (MERRF), cerebral anoxia, and widespread infections of the brain.

84.2 Pathology

The pathology of SSPE is restricted to the CNS. The leptomeninges are thickened. The brain may show atrophy during the terminal stages of disease but is oth- erwise normal on external examination. On slicing the brain, discolored areas are seen. Microscopically, the disease appears to be multifocal in character and may involve all portions of the CNS, with the excep- tion of the cerebellum, which is rarely affected. The frontal lobes are involved first, followed by the parietal, temporal, and occipital lobes, basal ganglia, brain stem, and spinal cord. The typical pathological findings include perivascular infiltration by mononuclear cells in gray and white matter and proliferation of both macroglia and microglia.Astrocyte proliferation can be particularly pronounced in white matter. Neu- ronal degeneration and neuronal loss may be severe.

Neurofibrillary tangles are seen. Demyelination is focal and not always conspicuous. The subcortical white matter is mainly affected, first with inflammation and then with destruction. In the later stages of the disease both cortical atrophy and demyelination are more pronounced. Intranuclear and intracytoplasmic inclusions are present in neurons, astrocytes, and oligodendrocytes. Immunohistochemistry has re- vealed measles virus antigen in neurons, oligodendrocytes, and inflammatory cells. CD4+ T lymphocytes have been demonstrated in the perivascular areas and CD8+ T lymphocytes in the parenchyma.

Ultrastructural examination shows the presence of paramyxovirus particles. A spectrum of viral inclusions and particles has been reported. Some inclusions fill nuclei, whereas smaller particles, nucleocapsids, and virions of different configurations are found in either the nucleus or the cytoplasm of oligoden- droglial cells and neurons. Nuclear bodies and gran- ulofilamentous inclusions occur in astrocytes.

84.3 Pathogenetic Considerations

Measles virus is a member of the Morbillivirus genus in the Paramyxoviridae family. SSPE is a rare compli- cation of measles infection and differs from the acute measles encephalitis that may occur during or imme- diately after acute measles infection. The main risk factor is acquiring the infection at or before the age of 1 year. The elevated serum and CSF anti-measles virus antibody levels in patients suspected of having SSPE are indicative of an active measles virus infection of the brain. Inclusions with paramyxovirus particles have been demonstrated in neuronal and glial cells in SSPE. The cellular inclusions react with anti- measles virus antibodies. For a long time, however, the virus could not be recovered from brain tissue by conventional methods. Successful isolation of the measles virus was finally accomplished by cocultivat- ing brain cells of SSPE patients with cells known to support measles virus replication. After the isolation of the virus, the agent was studied extensively to determine its structural and biological characteristics.

Its ultrastructural features are similar to those of measles virus. Further studies of the immune re- sponse in patients demonstrated the absence of serum antibody to the matrix (M) protein of measles virus. The M protein is associated with the inner surface of the viral membrane. It is important in the assembly of the virus particle, which occurs by a budding process from the surface membrane of the in- fected cell. Subsequent studies demonstrated the absence of measles virus M protein in the brain tissue of patients with SSPE. More recent studies have demonstrated that the measles viruses isolated from the CNS of SSPE patients have major mutations in the M protein gene. As a consequence, the budding process is defective.Without budding, the replicating intracellular virus may go into a dormant phase. However, M protein gene mutations thought to be characteristic of SSPE viruses have also been found in measles virus isolated in the acute stage of measles infection and it is therefore unclear whether these mutations are critical for the development of SSPE. Regardless of the precise explanation, the absence of M protein ex- plains many of the virological features of SSPE. Lack of M protein results in a persistent, abortive infection, in which no mature infectious virus is produced in the extracellular space. The internal components of the virus accumulate in the cells. It is thought that in the time between primary measles virus infection and the onset of SSPE symptoms, viral nucleocapsids, RNA, and probably other gene products accumulate in cells of the nervous system and spread from cell to cell through the nervous system. The onset of SSPE symptoms is usually ascribed to altered cell function and cell death, resulting from excessive accumulation of viral products. The intracellular virus is never in

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contact with the extracellular space, as a consequence of the absence of M protein and the resulting inabili- ty of the virus to assemble and bud. Only when cells begin to deteriorate and die does the virus make contact with the immune system, causing a rise in anti- measles antibodies, except antibodies to M protein.

The antibodies produced are ineffective in eradicat- ing the intracellular virus.

Other mutations in the measles virus genome may contribute to the risk of SSPE. Fusion protein (F protein) and hemagglutinin (H protein) are two surface glycoproteins. Truncations in the cytoplasmic do- main of the F protein impede efficient virus assembly and budding. Loss of glycosylation in the H protein leads to inefficient membrane transport. These features lead to reduced amounts of envelope protein on the cell surface and may prevent association with the M protein, which leads to hampered assembly and budding of mature measles virus particles. Mutations in H and F proteins may also lead to enhanced cell- cell fusion and spread of the virus from cell to cell, making it possible for the defective virus to accumulate readily and spread without the need at any stage for viral maturation and budding.

Host factors seem also to be important in predis- posing individuals to SSPE. In human beings the primary infection seems to occur during a critical peri- od in early life when passive maternal immunity has faded, in particular before the age of 1 year. Immatu- rity of the host immune system and CNS has been suggested to contribute to the increased risk for SSPE development among infants. Other genetic factors (male versus female; racial differences) seem to contribute and may determine components of the immune system.

84.4 Therapy

There is no effective treatment for SSPE. The disease leads to death in most cases, but there may be spontaneous temporary improvement or an arrest of further progression for a number of years. Attempts to alter the disease course with antiviral agents, such as amantadine (Symmetrel), 5-bromodeoxyuridine, or inosiplex (Isoprinosine,Viruxan) have failed, which is not surprising in view of the marked cell-associated nature of the virus. Intraventricular interferon-alfa- 2b, usually applied in combination with oral inosiplex, seems to have a higher remission and survival rate. Some patients have been treated with a combination of intraventricular interferon-alfa-2b and rib- avirin. Subcutaneous interferon-beta has been applied in patients who could not receive interferon-alfa and has also demonstrated beneficial effects. Both medications are broad-spectrum antiviral agents with activity against both DNA and RNA viruses. In the case reports of a few patients, the addition of rib-

avirin stopped the progression of brain atrophy and improved the clinical condition.

The problem in trials concerning SSPE is the very small number of patients that can be included in the Western hemisphere, so that multicenter, internation- al collaboration is necessary.

84.5 Magnetic Resonance Imaging

CT is normal during the initial stage of the disease, shows multiple low-density areas in the white matter and basal nuclei in subsequent stages, and shows severe atrophy in the end stage. Low-density areas may show contrast enhancement.

In the earliest stage, MRI may be normal, but it shows abnormalities before CT does. Early changes may involve the basal ganglia (Fig. 84.1), lateral genic- ulate bodies, or the disease may present with multifocal white matter lesions, which have a preference for hemispheric subcortical white matter (Fig. 84.2). In more extensive lesions, the deep and periventricular white matter are involved additionally (Fig. 84.3). The abnormalities are often asymmetrical (Fig. 84.2), but in many cases they are extensive and symmetrical (Fig. 84.3). The overlying cortex is often also affected (Fig. 84.2). Large focal lesions involving white and gray matter, resembling infarctions, may occur. These lesions may enhance initially and subsequently be- come nonenhancing. The white matter changes may decrease or resolve, even in the presence of clinical deterioration. Bilateral striatal lesions (Fig. 84.1), bilateral lesions in the middle cerebellar peduncles, brain stem lesions, and cerebellar abnormalities may occur. In end-stage disease, severe atrophy of cere- brum, basal ganglia, brain stem, and cerebellum is found, often with global and generalized white matter signal abnormality.

MR spectroscopy, either as chemical shift imaging or as single voxel measurements, may help to estimate the stage of the disease. In stage I, MRS findings do not differ significantly from those in normal age-matched volunteers. In stage II, there is still a normal N-acetyl- aspartate/creatine ratio, but an increased choline/

creatine ratio. The myo-inositol/creatine ratio is in- creased in this and the subsequent stages. This would correspond with an early inflammatory reaction. In stage III, MRS shows decreased N-acetylaspartate/

creatine, increased choline/creatine, increased myo- inositol/creatine, and elevated lactate and lipid peaks, suggesting demyelination, gliosis, neuronal loss, and macrophage activation, macrophages being highly dependent on anaerobe glycolysis.

The differential diagnosis includes other causes of multifocal abnormalities of gray and white matter, in- cluding acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy, multiple sclerosis, and vasculitides. In some cases of SSPE,

Chapter 84 Subacute Sclerosing Panencephalitis 642

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Fig. 84.1. In this 9-year-old boy with SSPE, MRI initially showed only a few moderately abnormal white matter lesions in the centrum semiovale. The MRI in this figure was performed 7 months later, when signs of neurological dysfunction were

much more severe, and shows lesions of the body of the cau- date nucleus on the left and in the putamen on both sides.

There is still a somewhat higher signal intensity of the parietal deep white matter

Fig. 84.2. In this 3-year-old boy with SSPE, T2-weighted trans- verse and coronal images show asymmetrical involvement of the subcortical and deep white matter, most severe on the left.

The overlying cortex is also abnormal. Courtesy of Dr. M. Pine- da, Department of Neuropediatrics, Clinic-Hospital Sant Joan de Déu, Barcelona, Spain

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MRI shows symmetrical white matter lesions in the occipital area and splenium of the corpus callosum, simulating X-linked adrenoleukodystrophy. In cases with involvement of the basal nuclei, the differential diagnosis includes Creutzfeldt–Jakob disease, mito-

chondrial disorders, in particular Leigh syndrome, and other neurodegenerative disorders. EEG and laboratory findings help to establish the correct diagnosis.

Chapter 84 Subacute Sclerosing Panencephalitis 644

Fig. 84.3. This 20-year-old man with SSPE is in a far advanced stage of the disease. There are extensive abnormalities in the cerebral white matter, most severe in the posterior region, also involving the splenium of the corpus callosum, reminiscent of the cerebral form of X-linked adrenoleukodystrophy. However, there is no enhancement after contrast (not shown). There are

also extensive signal abnormalities in the brain stem, middle cerebellar peduncles, internal capsule. The basal ganglia dis- play subtle signal abnormalities. There is some atrophy. Cour- tesy of Dr. Z. Patay, Department of Radiology, King Faisal Spe- cialist Hospital and Research Center, Riyadh, Saudi Arabia