Acute fulminant subacute sclerosing panencephalitis in two patients: Dual viral hit hypothesis


Subacute sclerosing panencephalitis (SSPE) is a rare lethal neurological disorder caused by persistent mutant measles virus (MV) in central nervous system. Usually affected individuals have a positive history of measles infection in infancy phase. The disease is characterized by progressive cognitive decline, deterioration in motor functions, repeated myoclonus finally leading to vegetative state and death. Commonly, SSPE patients manifest clinically after 2-10 years of intervening gap from primary measles infection. In last few years, atypical presentations of subacute sclerosing panencephalitis have been reported, many patients initially presenting with vision loss. Why only some patients developed SSPE after long gap of primary measles infection? Various immunological mechanisms have been hypothesized. It has been proven that subacute sclerosing panencephalitis patients failed to form adequate antibodies to measles virus M (matrix) protein despite an appropriate response to other viral proteins. In this case report, we hypothesized that viral co-infections could lead to immune abnormalities and immunosuppression resulting into acute fulminant subacute sclerosing panencephalitis. We presented two patients of subacute sclerosing panencephalitis, one patient preceded by dengue virus infection and other by varicella zoster infection.

Keywords: Dengue fever, encephalopathy, measles, subacute sclerosing panencephalitis

How to cite this article:
Verma R, Sharma P, Kumar D, Vidhate MR. Acute fulminant subacute sclerosing panencephalitis in two patients: Dual viral hit hypothesis. Ann Trop Med Public Health 2012;5:605-8
How to cite this URL:
Verma R, Sharma P, Kumar D, Vidhate MR. Acute fulminant subacute sclerosing panencephalitis in two patients: Dual viral hit hypothesis. Ann Trop Med Public Health [serial online] 2012 [cited 2016 Aug 14];5:605-8. Available from:

Subacute sclerosing panencephalitis (SSPE) is fatal, progressive neurodegenerative disorder. It is characterized by cognitive decline; myoclonus and extrapyramidal manifestations leading to vegetative state and death within few years of onset. It is attributed to persistent mutant measles virus infection. The diagnosis is based on typical electroencephalographic (EEG) abnormality and the elevated anti-measles antibodies titer in the cerebrospinal fluid in the background of characteristic clinical presentation. [1],[2]

SSPE usually affects children and young adults. Majority of the patients with SSPE have a history of primary measles infection at an early age (<2 years). SSPE can occur from 2 to 10 years after the primary measles infection. It is possible that the measles virus enters the nervous system at the time of the primary measles infection, either by direct infection of endothelial cells or in infected leukocytes. [3] Consequently, the SSPE virus maintains a persistent infection in neuronal cells of the brain, probably in a dormant form as the patients remain asymptomatic during this period. What factors reactivate this virus leading to SSPE is not well known? Here we are describing two patients of SSPE where symptoms developed rapidly after another viral illness, one preceded by Dengue infection and another by varicella zoster.

Case Reports

Case 1

A young girl of 15 years age was apparently alright one month back, when she developed mild to moderate fever. It was associated with severe myalgia and body ache. Her routine blood investigations were normal except thrombocytopenia and leukopenia (platelet count- 80000/mm 3 ; total leukocyte count-2800/mm 3 ). Her dengue serology (Ig M Antibody) was positive. She was managed with antipyretics and fever subsided in 7-8 days. She remained asymptomatic for 10 days when she presented in our hospital with acute onset painless vision loss in both eyes for last 7 days. The vision deteriorated rapidly to such an extent over 2-3 days that she was not able to see the face of a person standing in front of her. There was no history of redness, lacrimation, diplopia, headache, vomiting, seizures, and motor weakness. After 7 days of onset of vision loss, she also developed abnormal behaviour in the form of excessive smile and emotional lability. She started speaking less and also responds slowly and takes more time in replying simple questions. She had a normal birth history and had normal motor and mental development. On neurological examination, she was conscious with a Glasgow Coma Scale of 15/15. Surprisingly, her mini mental status examination was 14/30. Prior to illness, she had been a 10 th standard student with good scholastic performance. She denied perception of light in both eyes and the pupils were normal in size and reacting to light. The spasticity was present in all limbs and deep tendon reflexes were brisk, however planter response was flexor bilaterally. She was admitted in our hospital for evaluation and during the stay in hospital, she started having axial myoclonus. The frequency of myoclonus increased from occasional myoclonus to 2-3/min over 2-3 days. She had history of measles at one and half years of age and she had not received any measles vaccine. The parents were nonconsanguineous and her three siblings were in good health. There were no signs of meningeal involvement. Other neurological and systemic examination was normal.

The routine blood investigations including hemogram and urine analysis were normal. The cerebrospinal fluid (CSF) analysis revealed opening pressure of 10cm of water with 6 lymphocytes, 45 mg/dL proteins and 60 mg/dL sugar (corresponding blood sugar was 92 mg/dL). In cerebrospinal fluid Mycobacterium tuberculosis Polymerase chain reaction, Herpes simplex 1 and 2 polymerase chain reaction and cryptococcal antigen were negative. Cerebrospinal fluid antimeasles antibody titers were elevated (1/512 titer by particle agglutination test, 1/128 titer normal). EEG showed generalized periodic high amplitude sharp and slow wave complexes. [Figure 1] Magnetic resonance imaging (MRI) of the brain revealed subtle hyperintensity in the parieto occipital area. [Figure 2] The patient was treated with intrathecal interferon alpha (IFN-α), sodium valproate and clonazepam. There was no significant change with treatment and she became bed bound and dependent for her daily activities at 2 months follow-up.

Figure 1: EEG showing periodic generalized high amplitude sharp and slow wave discharges lasting for 1 to 2 seconds

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Figure 2: Fluid Attenuated Inversion Recovery axial MRI showing subtle asymmetrical hyperintensities in the parieto-occipital cortex (arrow)

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Case 2

A 16-year-old boy was admitted in our hospital with complaints of poor concentration and forgetfulness resulting in decline in scholastic performance from last 20 days and diminution of vision in both eyes for last three days. He had a history of a febrile exanthematous illness 30 days prior to it. The rash was vesiculopapular and centripetal in distribution which subsided over 1 week period. He remained apparently well for about 15 days after clearing of rash. After 5 days of admission in hospital, he developed recurrent episodes of sudden brief shock like jerky movement of left half of body, suggestive of myoclonus. He developed difficulty in walking over next 2-3 days and became bed bound over 2 week’s period. There was no history of loss of consciousness, headache, vomiting, diplopia or any motor deficits. On examination, his vitals were stable. Nervous system examination revealed conscious, disoriented boy with impaired recent memory. The pupils were normal in size and reactive to light. The signs of right hemispheric involvement were present in the form of dressing apraxia and visuospatial disorientation. The cranial nerve, sensory and cerebellar system examinations were normal. Motor system examination showed spasticity in left upper and lower limb. Myoclonic jerks were present over left side of the body. There was no history of measles and he had not received any measles vaccine. The routine hematological and biochemical test were normal. The cerebrospinal fluid examination showed 5 cells/mm 3 (all lymphocytes), 40 mg/dL proteins and 72 mg/dL sugar (corresponding blood sugar was 112 mg/dL). Cerebrospinal fluid ant measles antibody titers were elevated (1/1024 titer by particle agglutination test, 1/128 titer normal). The anti varicella antibody titers were also elevated in the cerebrospinal fluid. The EEG showed generalized high voltage slow wave periodic complexes every 7-8 seconds, suggesting SSPE. MRI brain revealed T2 hyperintensities in the bilateral occipital region [Figure 3]. He was managed with sodium valproate and clonazepam. The patient succumbed to illness after 6 months.

Figure 3: Fluid Attenuated Inversion Recovery axial MRI showing bilateral parieto-occipital hyperintensities

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SSPE is a progressive neurologic disorder, affecting children and young adolescent. The average age of onset vary from 5 to 15 years. [4] Majority of the patients with SSPE have a history of primary measles infection at an early age (<2 years). Primary measles infection in children under one year of age carries 16 times greater risk of SSPE than that in children over five years of age. [5] Most of the patients with SSPE presents after a latent period of 2-10 years. The SSPE virus or mutant measles virus probably enters in the nervous system at the time of primary measles infection. It has been demonstrated in previous studies that measles virus sequences obtained from brain tissues of SSPE patients are homologous to the genotype circulating at the time of primary exposure to measles virus. [6] Consequently to this primary infection, the SSPE virus is able to maintain a persistent infection in neuronal cells of the brain.

The development of SSPE in some of these patients may be dependent on the efficiency of their immune system. A genetically determined immune dysfunction specifically against the measles virus may be responsible for development of SSPE in these susceptible individuals. A defective cell-mediated immunity or abnormal inflammatory cytokines responses are suggested to have some pathogenic role in the development of SSPE. Inoue et al. demonstrated the association of three genes, MxA, interleukin-4, and interferon-1 genes with SSPE susceptibility in Japanese patients. MxA protein is an antiviral protein induced by interferon-alpha and interferon-beta which inhibits the replication of single-stranded RNA viruses including measles virus. [7]

Classically, SSPE begins insidiously and progress slowly, leading to death within 1-3 years after the onset of symptoms. About 10% of patients may present with rapid fulminant, progressive course. PeBenito et al. had reported 25 cases with acute, fulminant form of SSPE. [8] Herguner M.O. et al also reported acute fulminant SSPE in their patients. Acute, fulminant course is diagnosed as the patient develops at least 66% neurologic disability (as measured by the neurologic disability index) in the first three months or death within six months. [8] The factors producing an acute fulminant course are not well known. Several factors such as primary measles at an early age, virulence of SSPE virus, impaired host immunity, and concurrent other viral illnesses have been suggested for the development of acute fulminant SSPE. [5]

We describe two patients in whom the symptoms developed rapidly after viral infections. In one patient, the neurological symptoms developed after Dengue infection and in other after varicella zoster. The concurrent viral illness may cause immune dysfunction which may lead to development of symptoms of SSPE. The inflammatory cytokines like interferon produced in the viral illness may play some pathogenic role in the acute presentation. In a recent study, the role of immunization on progression of the disease has been described. They showed that the disease course was more rapid in unimmunized children. [9] Our observations are well substantiated by animal study. The authors mentioned that continuous replication of measles virus stimulates the high antibody response. They described that dual viral hit result from two factors. Firstly, the ability of anti measles virus antibodies has ability to prolong the life span of measles virus infected cells, a phenomenon known as antibody induced antigenic modulation. The second is the enhanced U to C, A to G mutations in the M (Matrix) gene occurring in humans with SSPE. They concluded that first hit of measles viral infection does not result in central nervous system disease. But after second attack by other virus in an individual infected by measles virus could cause subacute sclerosing panencephalitis. [10]

The acute presentation of SSPE after concurrent viral infections has not been well described in the literature. These patients may have atypical presentation of SSPE. In conclusion, SSPE should be considered in patients having unexplained acute neurological presentations such as vision loss, ataxia or difficulty in walking with cognitive decline after a viral illness and co-viral infection might have some pathogenic role in the activation of SSPE virus leading to symptoms of fulminant SSPE. Further studies are required.

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3. Cosby SL, Duprex WP, Hamill LA, Ludlow M, McQuaid S. Approaches in the understanding of morbillivirus neurovirulence. J Neurovirol 2002;8(Suppl 2):85-90.
4. Yilmaz D, Aydin OF, Senbil N, Yuksel D. Subacute sclerosing panencephalitis: Is there something different in the younger children? Brain Dev 2006;28:649-52.
5. Garg RK. Subacute sclerosing panencephalitis. Postgrad Med J 2002;78:63-70.
6. Rima BK, Earle AP, Baczko K, Ter Meulen V, Liebert UG, Carstens C, et al. Sequence divergence of measles virus haemagglutinin during natural evolution and adaptation to cell culture. J Gen Virol 1997;78:97-106.
7. Inoue T, Kira R, Nakao F, Ihara K, Bassuny WM, Kusuhara K, et al. Contribution of the interleukin 4 gene to susceptibility to subacute sclerosing panencephalitis. Arch Neurol 2002;59:822-7.
8. PeBenito R, Naqvi SH, Arca MM, Schubert R. Fulminant subacute sclerosing panencephalitis: Case report and literature review. Clin Pediatr (Phila) 1997;36:149-54.
9. Malik MA, Saeed M, Qureshi AU, Ahmed N, Akram M. Predictors of clinical course of subacute sclerosing panencephalitis: Experience at the Children’s Hospital, Lahore. J Coll Physicians Surg Pak 2010;20:671-4.
10. Oldstone MB, Dales S, Tishon A, Lewicji H, Martin L. A role for dual viral hits in causation of subacute sclerosing panencephalitis. J Exp Med 2005;202:1185-90.

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1755-6783.109300


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