Subacute sclerosing panencephalitis in children.pptx

SSPE is a rare complication of measles virus infection. Here a defective measles virus persists in the central nervous system, causing demyelination and neurodegenerative changes, which is almost always fatal. This presentation emphasis on the pathophysiology & clinical presentations of SSPE for early diagnosis, as well as to mention the available treatment options to slow down the progression of this condition.

1. Subacute sclerosing panencephalitis in children Presented by Dr. Nishat Tasnim FCPS Part 2 trainee, Dept of paediatrics Comilla medical college hospital

2. Introduction SSPE is a chronic encephalitis & progressive neurodegenerative disorder caused by persistence of a defective measles virus in CNS. First described by Dawson on 1933, as subacute inclusion body encephalitis. Also known as Dawson disease, V an Bogaert’s encephalitis & subacute sclerosing leukoencephalitis .

3. Epidemiology SSPE is the most common chronic encephalitis. Incidence quite high in developing countries. Occurs in 6.5 to 11 cases per 100,000 measles cases. Age of onset: <1 yr to <30 yrs. More than 80% cases onset within 5-15 yrs of age. Male:female is about 2 :1. Latent period is approx. 7-10 yrs.

4. Risk factors 50% of SSPE - measles <2 yrs 75% of SSPE - measles <4 yrs Measles <1 yr carries risk of 16 times greater than those infected at age 5 yrs or older. Higher among rural children, living in overcrowded areas, with 2 or more siblings, higher birth order & older age of mother . Lack of measles vaccination.

5. Structure of Measles virus

6. Viral replication cycle

7. Pathophysiology

8. Pathophysiology cont.

9. Course of MeV infection

10. Pathology Early stages : Mild inflammation of meninges & brain parenchyma involving cortical, subcortical gray & white matter, neuronal degeneration, necrosis, gliosis , astrocyte proliferation, periventricular cuffing, lymphocyte and plasma cell infiltration & demyelination .

11. Pathology cont. Later stages : Cerebral cortical atrophy, parieto -occipital region most severely affected. Then whole brain affected including subcortical structures, brainstem & spinal cord. Inclusion body : Both in nucleus & cytoplasm of neurons & glial cells. Cowdry type A- In neurons & oligodendroglia Cowdry type B- In brainstem

12. Clinical manifestation Occurs in 4 stages: Stage I: Subtle change in behavior or school performance Reduced attention span or irritability Temper outburst Altered sleep pattern Personality change Impaired cognitive function Fever, headache & other signs of encephalitis absent.

13. Clinical manifestation cont. Stage II: Hallmark is massive myoclonus . Involuntary movement & repetitive myoclonic jerks at 5-10 sec interval, involving both axial & appendicular muscles . Consciousness is maintained . Marked disturbance in co-ordination, motor function, behavior & vision.

14. Clinical manifestation cont. Stage III: Involuntary movements disappear, replaced by extrapyramidal involvements: Chorioathetosis , dystonia, lead pipe rigidity Myoclonus followed by progressive walking difficulty & frequent falls Sensorium deterioration into dementia, stupor, coma The course is relatively rapid. All cognitive, interactional ability & sphincter function lost.

15. Clinical manifestation cont. Stage IV: Akinetic mutism (coma or persistent vegetative state) Loss of c ritical centers (respiration, heart rate, BP) Death due to CVS collapse, hyperthermia or hypothermia.

16. Visual manifestation May occur in 50% cases. It may precede neurological manifestations by few weeks or months. Most characteristic is necrotizing retinitis. Other findings include- Papillitis , papilloedema , ptosis, nystagmus, optic atrophy, macular degeneration, cortical blindness, Anton and Balint syndrome.

17. Diagnosis Diagnosis can be established through documentation of a compatible clinical course & at least 1 of following supportive findings- Measles antibody in CSF Characteristic EEG findings Typical histologic findings in and/or isolation of virus or viral antigen from brain tissue obtained by biopsy or postmortem examination.

18. Modified Dyken’s criteria

19. Investigations Measles antibody titre in CSF & blood : CSF reveals normal cells but raised IgG and IgM antibody titres >1: 4 . CSF globulin is >20% of total CSF protein. An oligoclonal band of immunoglobulin is also found. Detection of antimeasles antibody (IgG &M) in serum >256. Ratio o f CSF to serum measles specific antibody titre is <200.

20. Investigations cont. EEG : Characteristic abnormality in about 65-83% cases. Typical myoclonic phase: Bilaterally symmetrical, synchronous, high voltage burst of stereotyped slow delta wave , also known as ' Radermecker ' complexes, interspersed with normal background, with constant periodicity. Usually at 4-10 sec interval. Late stage: Disorganized & background activity becomes progressively slower.

21. Periodic EEG complexes consist of generalized and synchronous bursts of sharp-slow wave discharges occurring every 3 seconds in patient with SSPE.

22. Investigations cont. Imaging : CT scan of brain : May be normal. Later stage s may feature cerebral edema & small ventricles. In very prolonged course there may be cerebral atrophy, ventricular dilatation or prominent sulci . MRI of brain : Hyperintense areas on T2 image, more common on parieto -occipital, subcortical white matter, but also involving gray matter & brainstem.

23. Imaging demonstrate nonspecific atrophy & increased T2 signal in cerebral white matter.

24. Investigations cont. MR spectroscopy : E arly in the course, there will be decrease d N-acetyl-aspartate and i ncrease d choline , indicates inflammation . In l ater stages, elevated ratios of choline to creatinine or inositol to creatinine , suggesting reduced brain volume. Brain biopsy : Seldom required. Cortical & subcortical perivascular cuffing, spongiosis , demyelination, sparing the cerebellum. Inclusion bodies & neurofibrillary tangles .

25. Fig: Postmortem brain microscopy of SSPE. (a). Typical lymphocytic perivascular cuffing within brain parenchyma (b). Cortical neurons with the characteristic intranuclear eosinophilic Cowdry type-A inclusions surrounded by a clear hallo. (c). Profound astrocytic proliferation. (d) . Elecromicrograph of an inclusion body showing curvilinear structures which are most probably viral nucleocapsids .

26. Differential diagnosis 1. Psychiatric manifestations: Depression S chizophrenia M alingering 2. Intracranial space occupying lesions: Pseudotumor cerebri B rain tumor 3. Other encephalopathies: Viral encephalitis Cerebral venous thrombosis Acute disseminating encephalomyelitis Progressive rubella panencephalitis Posterior leukoencephalopathy syndrome 4 . Progressive myoclonic epilepsies : Myoclonic epilepsy with ragged red fibers Lafora's disease Neuronal ceroid lypofuscinoses Sialidoses 5 . Seizure disorders: Absent seizure, Lennox- Gastaut syndrome An tiepileptic drug toxicity 6 . Movement disorders: Rheumatic chorea Wilson’s disease Ce rebral palsy

27. Treatment Mostly supportive. General management: -Psychological support, counseling about the nature & future of disease. Inform that it is progressive toward profound disability & no effective treatment. -Nutritional support -Good nursing care -For seizure: Carbamazepine, Levitiracetam , Sodium valproate, C lonazepam -Spasticity: Baclofen, Physiotherapy

28. Treatment cont. Drugs: Limited efficacy in delaying progression if given in stage 2 or earlier. Isoprinosine ( Inosiplex ) Interferon alpha and beta Ribavirin I VIg Amantadine Cimetidine

29. Treatment cont. Interferon alpha : Suppress viral replication. Initially 1,00,000 unit / m 2 BSA/day . Increase dose everyday upto 1 million unit / m 2 BSA/day at 5th day. Then give 1 million unit/ m 2 / day twice a week over 6 weeks. This cycle is repeated every 6 months. Route: I/V or Intrathecal or intraventricular .

30. Treatment cont. Isoprinosine/ Inosiplex : Increases CD + lymphocyte, augment NK cell function. 50-100mg/kg/day, max 3g/day, orally in 3 divided doses for at least 6 months, or lifelong . Combination of oral isoprinosine with I/V Interferon is the best effective treatment available. Clinical trials using isoprinosine with or without interferon suggest significant benefit (30-34% remission rate).

31. Treatment cont. Ribavirin : It has inhibitory activity against several RNA viruses, including measles viru s . By I/V administration, the ribavirin level in cerebrospinal fluid reaches a concentration at which ribavirin could completely inhibit the replication of SSPE virus. I/V ribavirin (60mg/kg/D) in combination with intraventricular interferon alpha was found effective in recent studies.

32. Novel therapies Fusion inhibitor peptide: It binds to the F protein & suppresses membrane fusion mediated by hyperfusogenic measles virus, thus preventing cell-to-cell spread. Recombinant adenovirus expressing small interfering RNA: Recent studies shows it can inhibit replication of measles virus in a dose-dependent manner.

33. Prognosis Guarded prognosis. Death inevitable within 1-3 yr after diagnosis. 41% patients may survive upto 2 yr. Approximately 5% patients have spontaneous remission. 10% patients have fulminant course & die within few months. Another 10% may survive for prolonged years (4-10 yrs).

34. Prevention A universal vaccination against measles is the only proven way to tackle this menace currently. Live attenuated vaccine: 95-98% immune protection. Patient should be isolated with active measles infection 3 days before & upto 4-6 days after onset of rash.

35. Conclusion SSPE is still common in developing & underdeveloped countries. Difficulty to recognise early symptoms & variable presentation of the disease are the most important limitations in treatment. The treatment available is not curative & unaffordable to the suffering families. Effective measles vaccination seems to be the only solution.