An Unusual Cluster of Epilepsia Partialis Continua in a Pediatric AIDS Cohort

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 Zamfirescu4, T
  Ciprut5,
• P Ionescu¹, P Calistru¹ , CL Achim6
• 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
• 5ELIAS Hospital Department of Radiology,
  Bucharest, Romania
• 6 University of Pittsburgh, Pittsburgh,
  Pennsylvania, USA

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Background/Objectives

• Epilepsia partialis continua (EPC) is a rare
  condition usually reported without any
  epidemiologic correlations.
• In HIV-1 infected patients only a few cases were
  described.
• During a short time period, we noticed an unusual
  cluster of EPC in the pediatric HIV-1 infected
  population.
• The overall objective of the study is to describe
  the clinical entity, its particular outcome and
  pathologic correlates.
• The ultimate goal is to identify potential
  co-factors that may indicate its etiology and
  mechanism of disease.

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Methods

• Retrospective, single-center study, between
  October 1997 December 1998, based on a
  comprehensive protocol, including
• epidemiologic
• clinical
• laboratory
• neuroimaging
• data analysis, of all HIV-1 infected children
  with EPC, admitted at Dr. Victor Babes Hospital

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Distribution in time of EPC cases
5
Patient profile (n23)
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AIDS defining diseases before the EPC diagnosis

• Tuberculosis (11)
• Recurrent bacterial pneumonia (4)
• HIV Encephalopathy (2)
• Cryptococcus meningitis (2)
• Kaposi Sarcoma (1)

Not included as AIDS disease in pediatric CDC
classification
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Clinical history within 6 months preceding the
EPC diagnosis (n23)

• Respiratory infections (all)
• Herpes (VZV, HSV) infections (6)
• Diarrhea (5)
• Strongyloidiasis (2)
• Crypto meningitis (2)
• Presumptive diagnosis of measles (2)
• Kaposi Sarcoma (1)

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Clinical presentation (1)

• Acute, no fever
• Myoclonus
• localization
• initially unilateral (upper limbs, face)
• Spread initial unilateral then on the opposite
  site of the body
• particular features
• Bilaterality of myoclonus (17)
• Presence of axial myoclonus in few cases
• Without generalized tonic-clonic seizures
• Motor impairment
• Initial (occasional, few patients)
• The strength of the affected parts decreased and
  the majority of patients progressively became
  hemi/tetra paretic
• Cranial nerve involvement (n18)

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Clinical presentation (2)

• Mental status
• No cognitive deterioration at the onset (7)
• Visual and auditory hallucinations (5)
• Progression to coma (14) within 2 weeks (mean)
• Additional neurological findings
• Visual impairment (14)
• blindness (9)
• limited visual field (5)
• Ocular bobbing
• Conjugated eyes deviation
• Keratitis and conjunctivitis (18)

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CSF analysis

• Normal values cells, proteins, glucose
• Cultures negative for all common infectious
  agents tested
• Antibodies (by ELISA)
• IgG measles (3), CMV (2), toxo (3)
• (?) IgM measles (2), CMV (1), toxo (1)

12 CSF samples tested
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Humoral immunity to measles in the VBH cohort

• 12 of 14 patients had positive serum IgG
  antibodies at diagnosis of EPC
• 11 of 23 patients had positive serum IgM
  antibodies at least once within the 5 months
  period preceding the diagnosis of EPC
• The serum IgM/IgG dynamics, tested in 14 patients
  suggest recent sero-conversion in 6 (43)
  patients

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Seroconversion e.g. in 3 patients
14
CA, 10 years
EEG (1)
Tri-phase waves frontal-central-parietal right
15
LCD, 8 years (20/01/1998)
EEG (2)

• wave-spike complex frontal-central left,
• slow waves

16
LCD, 8 years (6/05/1998)
EEG (3)

• Polispike-waves in
• frontal-central left right

17
Neuroimaging CT scan (n11)

• Neuroimaging revealed subcortical hipodense
  lesions
• 5 parietal
• 1 temporal
• 1 occipital
• Apparently without modifications 3 patients

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CT scan patient 1
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MRI scan patient 1
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MRI scan patient 1
21
MRI scan- patient 2
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MRI scan patient 3
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Histopathologic changes consistent with HIVE
Astrogliosis, white matter (GFAP)
PV infiltrating macrophages (CD68)
Microglial nodule (CD68)
MGN with HIV positive cells (p24)
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Opportunistic brain pathology in HIV patients
with seizures
A
B

• 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). HE staining, 40X
  original magnification)

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Treatment

• Antiretroviral treatment
• Before the onset of EPC 7 children
• After the onset of EPC 6 children
• Antiviral treatment
• Acyclovir 14 patients
• Foscavir 4 patients
• Interferon 2 patients
• Corticotherapy 13 patients
• IVIG 6 patients
• Anticonvulsivants
• Carbamazepine 14
• Lamotriginum 12
• Diazepamum 10
• Acidum valproicum 10
• Phenytoinum 3

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Survival curve
Median survival time 18 days from the onset of
EPC
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Survival curve
Chi-square 6,5260 DF 1 P 0,01
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Incidence of new diagnosed measles cases in
Romania
National vaccination programme
Source WHO
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Incidence of measles cases in VBH in HIV
negative population
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Measles in HIV infected patients from VBH

• Median CD4
• measles patients 316 (15-1635) n20
• EPC patients 114 (15-599) n22

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Measles in HIV infected patients during the
epidemics 1997-1998

• 9 children with HIV infection and clinical
  manifestations of uncomplicated measles infection
  during 1997-1998
• Positive IgM antibodies 6 patients out of 7
  tested
• Median CD4416 (range161-599)lf/mmc

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Measles history and vaccination at EPC patients

• diagnosis of measles in the past
• before 1997 3 patients
• within 8 months of EPC diagnosis 3 patients
• Vaccination
• 8 received first vaccine within 1 year age
• 6 with complete vaccination (revaccinated in
  1995-1996)
• 1 without vaccination
• 2 data not available

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Time frame from presumed/certain measles contact
to EPC
VBH hospitalization
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Measles in the HIV brain

• 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)

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Histo (CD68/ MNGC/ MGN)
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Conclusions

• An EPC cluster (within 15 months) was observed in
  Romanian HIV positive children
• The clinical features were remarkably similar in
  all patients
• rapidly progressive neurological deterioration
  (seizures, coma) resulting in death
• In the cases investigated by neuroimaging the
  findings were characterized by similarity of the
  lesions
• Although suggestive of PML, the diagnosis was not
  confirmed by histology
• The neuropathologic exam (where available)
  demonstrated abundant macrophage infiltration and
  microglial activation, accompanied occasionally
  by demyelization and vasculitis

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Discussion

• Question could the etiology be related to a
  subacute form of measles encephalitis or an
  unusual form of SSPE?
• The timeframe of this EPC cluster, overlapping
  with a measles epidemic in Romania, suggests a
  common etiology
• This hypothesis is further supported by the
  humoral immune response to measles
  (seroconversion) and by the neuropathologic
  post-mortem analysis (incomplete)
• The answer may have significant implications for
  the immunization strategy in HIV infected
  patients who are at risk in a future measles
  outbreak
• Current guidelines suggest vaccination only in
  patients with CD4200( and passive immunization
  for the rest)

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Case presentation 1 LC
11.01.98 Visual hallucinations Agitation
09.01.98
08.01.98
05.01.98 Impaired vision
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29.01.98 Conscious Motor aphasia
15.01.98 Visual hallucinations Psycho-motor
agitation
19.01.98 Coma II
16.01.98 Coma I
Exitus 4 month later MSOF Salmonella
12.02.98 Conscious Disartria Right hemianopia
05.03.98 Conscious
20.01.98 Conscious Disartria
06.05.98 Conscious
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Case presentation 2 SM,10 years
27.02.98
23.02.98
03.03.98
04.03.98 Mixed aphasia
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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
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Case presentation 3 CA,10 years
EXITUS 26.05.98
20.05.98 Conscious, blindness, motor aphasia, no
swollen r.
17.05.98 Blindness Motor aphasia
19.05.98 seizures
21.05.98 Idem n.III palsy
25.05.98 Conscious, miosis, mixed aphasia