SSPE

Introduction

Subacute Sclerosing Panencephalitis (SSPE), historically known as Dawson's encephalitis, is a rare, chronic, progressive, and almost invariably fatal neurodegenerative disorder of the central nervous system (CNS) caused by a persistent infection with a defective measles virus. It is classified as a "slow virus infection" because of the long latency period between the primary measles infection and the onset of neurological symptoms.

While the successful implementation of measles vaccination has dramatically reduced the incidence of SSPE in developed nations, it remains a significant public health challenge in developing countries like India, where measles is still endemic.

Epidemiology

1. Incidence

• Pre-vaccine Era: The estimated incidence was approximately 1 case per 100,000 cases of natural measles.
• Developing Countries: The incidence is significantly higher. In southern India, the incidence has been reported as high as 21 per 100,000 population, and in Pakistan, estimates have reached 100 per 100,000.
• Post-vaccine Era: Widespread immunization has led to a profound decline in SSPE cases in developed nations. However, in regions with suboptimal vaccine coverage or frequent outbreaks, SSPE rates remain concerning.

2. Risk Factors

• Age at Primary Infection: This is the most critical risk factor. The risk of developing SSPE is significantly higher if the primary measles infection occurs early in life. Approximately 50% of patients with SSPE acquired measles before the age of 2 years, and 75% before the age of 4 years. The immature immune system of infants is thought to predispose them to persistent infection.
• Gender: There is a consistent male preponderance, with boys affected 2 to 3 times more frequently than girls.
• Geography: A higher incidence is often observed in rural areas compared to urban populations, potentially linked to environmental cofactors or animal exposure, though this association is not fully understood.
• Ethnicity: Some registries have noted a higher prevalence among children of Hispanic origin.

Etiology and Microbiology

The causative agent is a defective variant of the wild-type measles virus. Studies analyzing viral material from the brains of SSPE patients have consistently revealed sequences of wild-type virus, never vaccine virus. There is no evidence that the measles vaccine itself causes SSPE; rather, it protects against it by preventing the primary infection.

Viral Defects

The SSPE virus differs from the acute wild-type measles virus in critical ways that allow it to persist in the CNS without being cleared by the immune system:

1. M Protein Defect: The most characteristic defect is in the Matrix (M) protein, which is essential for the alignment and budding of the virus. In SSPE, the M protein is often absent or non-functional due to mutations (often hypermutations) in the M gene.
2. Defective Replication: Because of the M protein defect, the virus cannot assemble complete virions and bud out of the cell. Instead, it spreads directly from cell to cell via fusion, protecting it from circulating antibodies.
3. Hypermutation: The viral genome in SSPE often shows "biased hypermutation" (U-to-C transitions), particularly in the M gene, leading to the production of defective proteins.

Pathogenesis

The pathogenesis of SSPE involves a complex interplay between the defective virus and the host's immune system.

1. Primary Infection & Persistence: following acute measles, the virus likely enters the CNS. In most individuals, it is cleared. In those who develop SSPE, the virus establishes a persistent, non-productive infection, likely facilitated by the immaturity of the cellular immune response in young infants.
2. Latency: The virus remains dormant or replicates slowly for a period ranging from 7 to 13 years (average 7–10 years). During this time, the virus spreads slowly across neurons and glial cells using ribonucleoprotein (RNP) complexes, evading immune surveillance.
3. Reactivation and Inflammation: Eventually, the virus triggers an inflammatory response. The host mounts a massive humoral immune response, leading to extremely high titers of anti-measles antibodies in both serum and cerebrospinal fluid (CSF). However, because the virus is intracellular and spreads by cell fusion, these antibodies are ineffective at clearing the infection ("anergic" state).
4. Neurodegeneration: The inflammatory process leads to demyelination, gliosis, and neuronal death, resulting in the clinical features of the disease.

Pathology

1. Macroscopic Findings

The brain may appear normal in the early stages. As the disease progresses, there is marked cortical atrophy, particularly in the occipital and parietal lobes, and ventriculomegaly. The brain consistency may be firm due to gliosis.

2. Microscopic Findings

The hallmark of SSPE pathology is panencephalitis involving both grey and white matter. Key findings include:

• Inclusion Bodies: Eosinophilic intranuclear and intracytoplasmic inclusion bodies (Cowdry type A) are characteristic. These are aggregates of viral nucleocapsids found in neurons and oligodendrocytes.
• Inflammation: Perivascular cuffing with lymphocytes and plasma cells.
• Demyelination: Extensive demyelination occurs in the white matter, secondary to the loss of oligodendrocytes.
• Gliosis: Prominent astrocytic and microglial proliferation.

Clinical Manifestations

The onset is insidious, usually occurring in children and adolescents between 5 and 15 years of age. The clinical course is classically described in four stages (Jabbour stages), although the progression can be variable.

Stage I: Psychointellectual and Behavioral Changes

• Duration: Weeks to months.
• Symptoms: This stage is subtle and often overlooked. It manifests as a decline in school performance, forgetfulness, distractibility, and behavioral changes such as irritability, temper tantrums, or lethargy.
• Neurology: Overt neurological signs are usually absent, making diagnosis difficult at this stage.

Stage II: The Myoclonic Stage

• Duration: 3–12 months.
• Hallmark: The defining feature is myoclonus.
• Characteristics: These are massive, repetitive, synchronous myoclonic jerks involving the head, trunk, and limbs. They typically occur every 5–10 seconds and disappear during sleep.
• Motor Dysfunction: The child develops clumsiness, ataxia, dysarthria, and eventually movement disorders like dystonia or choreoathetosis. Seizures (generalized tonic-clonic or partial) may also occur.

Stage III: Extrapyramidal and Autonomic Dysfunction

• Duration: Variable.
• Symptoms: Myoclonus gradually disappears and is replaced by severe rigidity (decorticate or decerebrate posturing).
• Motor: The patient becomes bedridden with lead-pipe rigidity, dystonia, and inability to swallow (dysphagia).
• Mental Status: Progressive dementia leads to stupor and unresponsiveness.
• Autonomic: Autonomic instability manifested by hyperthermia, sweating, and unstable blood pressure becomes prominent.

Stage IV: Vegetative State

• Symptoms: The patient enters a akinetic mutism or vegetative state.
• Loss of Function: There is a loss of cortical function, causing loss of breathing control and other vital centers.
• Outcome: Death usually results from intercurrent infections (pneumonia), bulbar palsy, or autonomic failure.

Ocular Manifestations

Visual disturbances occur in 10–50% of patients and may precede other symptoms.

• Chorioretinitis: Macular pigmentary changes are classic (necrotizing retinitis).
• Others: Cortical blindness, optic atrophy, and papilledema.

Diagnosis

The diagnosis is based on a characteristic clinical history in a young patient combined with specific laboratory and electrophysiological findings.

1. Diagnostic Criteria (Dyken’s Criteria)

Diagnosis requires three of the following five criteria:

1. Typical clinical presentation (progressive cognitive decline and myoclonus).
2. Characteristic EEG changes.
3. Elevated cerebrospinal fluid (CSF) globulin levels.
4. Elevated measles antibody titers in serum and CSF.
5. Brain biopsy consistent with SSPE.

2. Electroencephalogram (EEG)

The EEG findings are virtually pathognomonic, especially in Stage II.

• Radermecker Complexes: These are periodic, synchronous, high-voltage (200–500 µV), bilaterally symmetrical, polyphasic slow-wave bursts (delta waves).
• Interval: They occur at regular intervals of 4–10 seconds and typically have a 1:1 relationship with myoclonic jerks.
• Background: The background activity is often suppressed (burst-suppression pattern).

3. Cerebrospinal Fluid (CSF) Analysis

• Routine Analysis: Usually normal cell count (acellular) and normal glucose. Protein may be normal or slightly elevated.
• Immunology: The hallmark is a markedly elevated titer of anti-measles IgG antibody.
• Oligoclonal Bands: CSF electrophoresis reveals oligoclonal IgG bands that are specific to measles virus antigens. This indicates intrathecal synthesis of antibodies. A reduced Serum:CSF measles antibody ratio (<40:1) confirms local production in the brain.

4. Neuroimaging

• MRI: More sensitive than CT.
  • Early: High signal intensity on T2-weighted and FLAIR images in the periventricular white matter and subcortical regions, reflecting inflammation and demyelination.
  • Late: Generalized cortical and subcortical atrophy with ventricular dilatation.
• CT Scan: Often normal in early stages; later shows diffuse cerebral atrophy and hypodensities in white matter.

5. Brain Biopsy

Biopsy is rarely indicated today due to the availability of serological and PCR techniques. If performed, it shows perivascular infiltration, viral inclusions (Cowdry A), and gliosis.

Differential Diagnosis

SSPE must be differentiated from other causes of progressive neurodegeneration in children:

1. Viral Encephalitis: (e.g., Herpes Simplex, Japanese Encephalitis). These typically have an acute febrile onset, whereas SSPE is afebrile and insidious.
2. Neuronal Ceroid Lipofuscinosis (Batten Disease): Presents with seizures, vision loss, and cognitive decline but has specific enzymatic/genetic markers.
3. Wilson's Disease: Hepatic involvement, Kayser-Fleischer rings, low ceruloplasmin.
4. Mitochondrial Cytopathies: Elevated lactate, specific MRI features.
5. Progressive Rubella Panencephalitis: Extremely rare, associated with congenital rubella syndrome.
6. Multiple Sclerosis: Relapsing-remitting course, distinct MRI plaques.

Management

There is no curative therapy for SSPE. Treatment is palliative and supportive, although some antiviral and immunomodulatory regimens may slow progression or induce temporary remission.

1. Specific Pharmacotherapy

While no drug is universally effective, combination therapy is often attempted.

• Inosiplex (Isoprinosine): An oral immunomodulator.
  • Dosage: 100 mg/kg/day.
  • Mechanism: Enhances natural killer cell activity and T-cell function.
  • Efficacy: Studies suggest it may prolong survival and stabilize the disease in about 30–50% of patients compared to untreated historical controls. It is most beneficial if started in Stage I.
• Interferon-alpha:
  • Route: Since it does not cross the blood-brain barrier well, it is administered via the intrathecal or intraventricular route (Ommaya reservoir).
  • Combined Therapy: Often used in conjunction with oral Isoprinosine. Some studies report stabilization or improvement, but results are variable and relapse is common upon cessation.
• Ribavirin: Broad-spectrum antiviral. Has been tried intravenously or intraventricularly but with limited success.
• Other Agents: Cimetidine, steroids, and intravenous immunoglobulin (IVIG) have been tried without proven benefit.

2. Symptomatic and Supportive Care

• Anticonvulsants: Carbamazepine or Valproate are often effective in controlling the distressing myoclonic jerks, though they do not alter the disease course.
• Nutrition: Nasogastric feeding or gastrostomy (PEG) may be required in later stages due to dysphagia.
• Spasticity Management: Baclofen or physiotherapy to prevent contractures.
• General Care: Prevention of bedsores (decubitus ulcers), management of secondary infections (aspiration pneumonia).

Prognosis

The prognosis is grave.

• Course: The disease is relentlessly progressive.
• Survival: Death usually occurs within 1 to 3 years of diagnosis.
• Variability: Approximately 10% of patients have a fulminant course leading to death within 3 months. Conversely, about 5–10% may experience spontaneous remission or a prolonged course lasting several years.
• Cause of Death: Usually due to superadded infection, autonomic failure, or loss of bulbar function.

Prevention

Since there is no cure, prevention is paramount.

• Measles Vaccination: This is the only effective preventive measure.
  • Widespread immunization has successfully eliminated SSPE in many countries.
  • The live attenuated measles vaccine virus does not cause SSPE. Cases of SSPE in vaccinated children are attributed to unrecognised wild-type measles infection occurring before vaccination (e.g., in infancy).
• Catch-up Campaigns: Ensuring high vaccine coverage (>95%) and second-dose opportunities (as in the Measles-Rubella campaigns) are essential to prevent outbreaks and protect infants who are at highest risk of SSPE.