Epilepsia Partialis in Pediatric AIDS Cohort

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Epilepsia Partialis in Pediatric AIDS Cohort

  1. 1. An Unusual Cluster of Epilepsia Partialis Continua in a Pediatric AIDS Cohort Authors: D Duiculescu¹, E Major², HV Vinters³, E Ungureanu¹, M Barcau¹, L Ene¹, A Zamfirescu 4 , T Ciprut 5 , P Ionescu¹, P Calistru¹ , CL Achim 6 1 “Dr. Victor Babes” Hospital for Infectious and Tropical Diseases Bucharest , Romania 2 NINDS, NIH, Bethesda, Maryland, USA 3 UCLA, Los Angeles, California, USA 4 “Dr. Victor Gomoiu” Hospital for Children, Bucharest, Romania 5“ELIAS” Hospital – Department of Radiology, Bucharest, Romania 6 University of Pittsburgh, Pittsburgh, Pennsylvania , USA
  2. 2. Background/Objectives: <ul><li>Epilepsia partialis continua (EPC) is a rare condition usually reported without any epidemiologic correlations. </li></ul><ul><li>In HIV-1 infected patients only a few cases were described. </li></ul><ul><li>During a short time period, we noticed an unusual cluster of EPC in the pediatric HIV-1 infected population. </li></ul><ul><li>The overall objective of the study is to describe the clinical entity, its particular outcome and pathologic correlates. </li></ul><ul><li>The ultimate goal is to identify potential co-factors that may indicate its etiology and mechanism of disease. </li></ul>
  3. 3. Methods <ul><li>Retrospective, single-center study, between October 1997 – December 1998, based on a comprehensive protocol, including: </li></ul><ul><ul><li>epidemiologic </li></ul></ul><ul><ul><li>clinical </li></ul></ul><ul><ul><li>laboratory </li></ul></ul><ul><ul><li>neuroimaging </li></ul></ul><ul><li>data analysis, of all HIV-1 infected children with EPC, admitted at “Dr. Victor Babes” Hospital </li></ul>
  4. 4. Distribution in time of EPC cases Ian.99 Dec. 98 Nov. 98 Oct. 98 Sep.98 Aug.98 Jul. 98 Jun. .98 May98 Apr.98 Mar.98 Feb. 98 Ian.98 Dec.97 Nov.97 Oct. 97
  5. 5. Patient profile (n=23) <1 yr : 6 1 – 5 yrs: 6 > 5 yrs: 7 Time from HIV diagnosis to EPC 4 HIV infection diagnosed concomitant with EPC 114.5 , 15-599 median, range Cl 3: 17 patients Cl 2: 5 patients Cl 1: 1 patient CDC immunological classification before neurological complication diagnosis cl.B:16 cl.C:7 CDC clinical classification before neurological complication diagnosis Parenteral (all) HIV infection route 9.2 +/- 0.9 age in years (mean +/-SD) 13/10 Boys: girls ratio
  6. 6. AIDS defining diseases before the EPC diagnosis <ul><li>Tuberculosis* (11) </li></ul><ul><li>Recurrent bacterial pneumonia (4) </li></ul><ul><li>HIV Encephalopathy (2) </li></ul><ul><li>Cryptococcus meningitis (2) </li></ul><ul><li>Kaposi Sarcoma (1) </li></ul>* Not included as AIDS disease in pediatric CDC classification
  7. 7. Clinical history within 6 months preceding the EPC diagnosis (n=23) <ul><li>Respiratory infections (all) </li></ul><ul><li>Herpes (VZV, HSV) infections (6) </li></ul><ul><li>Diarrhea (5) </li></ul><ul><li>Strongyloidiasis (2) </li></ul><ul><li>Crypto meningitis (2) </li></ul><ul><li>Presumptive diagnosis of measles (2) </li></ul><ul><li>Kaposi Sarcoma (1) </li></ul>
  8. 8. Clinical presentation (1) <ul><li>Acute, no fever </li></ul><ul><li>Myoclonus </li></ul><ul><ul><li>localization </li></ul></ul><ul><ul><ul><li>initially unilateral (upper limbs, face) </li></ul></ul></ul><ul><ul><ul><li>Spread initial unilateral then on the opposite site of the body </li></ul></ul></ul><ul><ul><li>particular features </li></ul></ul><ul><ul><ul><li>Bilaterality of myoclonus (17) </li></ul></ul></ul><ul><ul><ul><li>Presence of axial myoclonus in few cases </li></ul></ul></ul><ul><ul><ul><li>Without generalized tonic-clonic seizures </li></ul></ul></ul><ul><li>Motor impairment </li></ul><ul><ul><li>Initial (occasional, few patients) </li></ul></ul><ul><ul><li>The strength of the affected parts decreased and the majority of patients progressively became hemi/tetra paretic </li></ul></ul><ul><li>Cranial nerve involvement (n=18) </li></ul>
  9. 9. Clinical presentation (2) <ul><li>Mental status </li></ul><ul><ul><li>No cognitive deterioration at the onset (7) </li></ul></ul><ul><ul><li>Visual and auditory hallucinations (5) </li></ul></ul><ul><ul><li>Progression to coma (14) within 2 weeks (mean) </li></ul></ul><ul><li>Additional neurological findings </li></ul><ul><ul><li>Visual impairment (14): </li></ul></ul><ul><ul><ul><li>blindness (9) </li></ul></ul></ul><ul><ul><ul><li>limited visual field (5) </li></ul></ul></ul><ul><ul><li>Ocular bobbing </li></ul></ul><ul><ul><li>Conjugated eyes deviation </li></ul></ul><ul><li>Keratitis and conjunctivitis (18) </li></ul>
  10. 10. Monopalsy Hemi palsy Tetra palsy No motor impairment <ul><li>Face </li></ul><ul><li>Upper limbs </li></ul><ul><li>Lower limbs </li></ul>20 5 Cranial nerve palsy 0 15 5 3 3 6 0 14 Motor impairment 10 11 11 7 11 2 Myoclonus Progression At onset
  11. 11. CSF analysis <ul><li>Normal values: cells, proteins, glucose </li></ul><ul><li>Cultures negative for all common infectious agents tested </li></ul><ul><li>Antibodies (by ELISA) </li></ul><ul><ul><li>IgG: measles* (3), CMV (2), toxo (3) </li></ul></ul><ul><ul><li>(?) IgM: measles* (2), CMV (1), toxo (1) </li></ul></ul>* 12 CSF samples tested
  12. 12. Humoral immunity to measles in the VBH cohort <ul><li>12 of 14 patients had positive serum IgG antibodies at diagnosis of EPC </li></ul><ul><li>11 of 23 patients had positive serum IgM antibodies at least once within the 5 months period preceding the diagnosis of EPC </li></ul><ul><li>The serum IgM/IgG dynamics, tested in 14 patients suggest recent sero-conversion in 6 (43%) patients </li></ul>
  13. 13. Seroconversion e.g. in 3 patients IgG CSF EPC pos pos after EPC 1 mo. pos neg EPC neg before EPC 1 mo. IgG serum IgM CSF EPC after EPC before EPC pos 1 mo. EPC 1 mo. 2 mo. 3 mo. 4 mo. neg pos neg TC neg neg pos neg LCD pos pos pos neg CA IgM serum Patient
  14. 14. CA, 10 years Tri-phase waves frontal-central-parietal right EEG (1) TPR TAR CL FL PL CL OL PL TPL TAL OR PR PR CR CR FR
  15. 15. LCD, 8 years (20/01/1998) <ul><li>wave-spike complex frontal-central left, </li></ul><ul><li>slow waves </li></ul>EEG (2) TPR TAR CL FL PL CL OL PL TPL TAL OR PR PR CR CR FR
  16. 16. LCD, 8 years (6/05/1998) <ul><li>Polispike-waves in </li></ul><ul><li>frontal-central left + right </li></ul>EEG (3) TPR TAR CL FL PL CL OL PL TPL TAL OR PR PR CR CR FR
  17. 17. Neuroimaging CT scan (n=11) <ul><li>Neuroimaging revealed subcortical hipodense lesions: </li></ul><ul><ul><li>5 parietal </li></ul></ul><ul><ul><li>1 temporal </li></ul></ul><ul><ul><li>1 occipital </li></ul></ul><ul><li>Apparently without modifications: 3 patients </li></ul>
  18. 18. CT scan patient 1
  19. 19. MRI scan – patient 1
  20. 20. MRI scan – patient 1
  21. 21. MRI scan- patient 2
  22. 22. MRI scan patient 3
  23. 24. Histopathologic changes consistent with HIVE Astrogliosis, white matter (GFAP) PV infiltrating macrophages (CD68) Microglial nodule (CD68) MGN with HIV positive cells (p24)
  24. 27. Opportunistic brain pathology in HIV patients with seizures <ul><li>One of the cases studied, in addition to the typical signs of PML (flares of infiltrating macrophages and bizarre astrocytes) had evidence of HIVE (A, multinucleated giant cells) and toxoplasma encephalitis (B). H&E staining, 40X original magnification) </li></ul>A B
  25. 28. Treatment <ul><li>Antiretroviral treatment: </li></ul><ul><ul><li>Before the onset of EPC – 7 children </li></ul></ul><ul><ul><li>After the onset of EPC – 6 children </li></ul></ul><ul><li>Antiviral treatment: </li></ul><ul><ul><li>Acyclovir 14 patients </li></ul></ul><ul><ul><li>Foscavir 4 patients </li></ul></ul><ul><ul><li>Interferon 2 patients </li></ul></ul><ul><li>Corticotherapy: 13 patients </li></ul><ul><li>IVIG : 6 patients </li></ul><ul><li>Anticonvulsivants : </li></ul><ul><ul><li>Carbamazepine: 14 </li></ul></ul><ul><ul><li>Lamotriginum: 12 </li></ul></ul><ul><ul><li>Diazepamum: 10 </li></ul></ul><ul><ul><li>Acidum valproicum: 10 </li></ul></ul><ul><ul><li>Phenytoinum: 3 </li></ul></ul>
  26. 29. Survival curve Median survival time: 18 days from the onset of EPC
  27. 30. Survival curve Chi-square = 6,5260 DF = 1 P = 0,01
  28. 31. Incidence of new diagnosed measles cases in Romania National vaccination programme Source WHO
  29. 32. Incidence of measles cases in VBH in HIV negative population
  30. 33. Measles in HIV infected patients from VBH <ul><li>Median CD4: </li></ul><ul><li>measles patients: 316 (15-1635) n=20 </li></ul><ul><li>EPC patients: 114 (15-599) n=22 </li></ul>
  31. 34. Measles in HIV infected patients during the epidemics 1997-1998 <ul><li>9 children with HIV infection and clinical manifestations of uncomplicated measles infection during 1997-1998 </li></ul><ul><li>Positive IgM antibodies 6 patients out of 7 tested </li></ul><ul><li>Median CD4=416 (range:161-599)lf/mmc </li></ul>
  32. 35. Measles history and vaccination at EPC patients <ul><li>diagnosis of measles in the past </li></ul><ul><ul><li>before 1997: 3 patients </li></ul></ul><ul><ul><li>within 8 months of EPC diagnosis: 3 patients </li></ul></ul><ul><li>Vaccination </li></ul><ul><ul><li>8 received first vaccine within 1 year age </li></ul></ul><ul><ul><li>6 with complete vaccination (revaccinated in 1995-1996) </li></ul></ul><ul><ul><li>1 without vaccination </li></ul></ul><ul><ul><li>2 data not available </li></ul></ul>
  33. 36. Time frame from presumed/certain measles contact to EPC VBH hospitalization Sep 97 Aug. 97 Jul. 97 Jun. 97 Ian. 99 Dec 98 Nov 98 Oct. 98 Sep. 98 Aug98 Jul. 98 Jun. 98 May98 Apr.98 Mar98 Feb. 98 Ian.98 Dec97 Nov. 97 Oct. 97
  34. 37. Measles in the HIV brain <ul><li>Immunocytochemistry with a monoclonal antibody to the measles virus identified many positive cells in the brain of a pediatric HIV infected patient who died with seizures. (Original mag. 20X) </li></ul>
  35. 38. Histo (CD68/ MNGC/ MGN)
  36. 39. Conclusions <ul><li>An EPC cluster (within 15 months) was observed in Romanian HIV positive children </li></ul><ul><li>The clinical features were remarkably similar in all patients </li></ul><ul><ul><li>rapidly progressive neurological deterioration (seizures, coma) resulting in death </li></ul></ul><ul><li>In the cases investigated by neuroimaging the findings were characterized by similarity of the lesions </li></ul><ul><ul><li>Although suggestive of PML, the diagnosis was not confirmed by histology </li></ul></ul><ul><ul><li>The neuropathologic exam (where available) demonstrated abundant macrophage infiltration and microglial activation, accompanied occasionally by demyelization and vasculitis </li></ul></ul>
  37. 40. Discussion <ul><li>Question : could the etiology be related to a subacute form of measles encephalitis or an unusual form of SSPE? </li></ul><ul><ul><li>The timeframe of this EPC cluster, overlapping with a measles epidemic in Romania, suggests a common etiology </li></ul></ul><ul><li>This hypothesis is further supported by the humoral immune response to measles (seroconversion) and by the neuropathologic post-mortem analysis (incomplete) </li></ul><ul><li>The answer may have significant implications for the immunization strategy in HIV infected patients who are at risk in a future measles outbreak </li></ul><ul><ul><li>Current guidelines suggest vaccination only in patients with CD4>200( and passive immunization for the rest) </li></ul></ul>
  38. 42. Case presentation 1 LC 09.01.98 08.01.98 05.01.98 Impaired vision 11.01.98 Visual hallucinations Agitation Myoclonus Plegia Palsy
  39. 43. Exitus 4 month later MSOF Salmonella 05.03.98 Conscious 20.01.98 Conscious Disartria 12.02.98 Conscious Disartria Right hemianopia 06.05.98 Conscious 29.01.98 Conscious Motor aphasia 19.01.98 Comă II 16.01.98 Coma I 15.01.98 Visual hallucinations Psycho-motor agitation
  40. 44. Case presentation 2 SM,10 years 27.02.98 23.02.98 03.03.98 04.03.98 Mixed aphasia Myoclonus Plegia Palsy
  41. 45. 16.03.98 Mixed aphasia 11.03.98 Mixed aphasia 13.03.98 Mixed aphasia 09.03.98 Mixed aphasia Coma I 23.03.98 Coma II 25.03.98 Coma III 28.03.98 EXITUS 29.03.98 18.03.98 No swallow r
  42. 46. Case presentation 3 CA,10 years 17.05.98 Blindness Motor aphasia 19.05.98 seizures 20.05.98 Conscious, blindness, motor aphasia, no swollen r. 21.05.98 Idem + n.III palsy 25.05.98 Conscious, miosis, mixed aphasia EXITUS 26.05.98 Myoclonus Plegia Palsy

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