An Unusual Cluster of An Unusual Cluster of Epilepsia Partialis Continua in Epilepsia Partialis Continua in

a Pediatric AIDS Cohorta Pediatric AIDS Cohort

Authors: Authors: D Duiculescu¹, E Major², HV Vinters³, E Ungureanu¹, M D Duiculescu¹, E Major², HV Vinters³, E Ungureanu¹, M Barcau¹, L Ene¹, A ZamfirescuBarcau¹, L Ene¹, A Zamfirescu44, T Ciprut, T Ciprut55,,

P Ionescu¹, P Calistru¹ , CL AchimP Ionescu¹, P Calistru¹ , CL Achim66

1 “Dr. Victor Babes” Hospital for Infectious and Tropical Diseases Bucharest , Romania1 “Dr. Victor Babes” Hospital for Infectious and Tropical Diseases Bucharest , Romania2 NINDS, NIH, Bethesda, Maryland, USA2 NINDS, NIH, Bethesda, Maryland, USA3 UCLA, Los Angeles, California, USA3 UCLA, Los Angeles, California, USA4 “Dr. Victor Gomoiu” Hospital for Children, Bucharest, Romania4 “Dr. Victor Gomoiu” Hospital for Children, Bucharest, Romania5“ELIAS” Hospital – Department of Radiology, Bucharest, Romania5“ELIAS” Hospital – Department of Radiology, Bucharest, Romania6 University of Pittsburgh, Pittsburgh, Pennsylvania6 University of Pittsburgh, Pittsburgh, Pennsylvania , , USAUSA

Background/Objectives:Background/Objectives:

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

MethodsMethods

Retrospective, single-center study, between Retrospective, single-center study, between October 1997 – December 1998, based on a October 1997 – December 1998, based on a comprehensive protocol, including:comprehensive protocol, including:– epidemiologicepidemiologic– clinicalclinical– laboratorylaboratory– neuroimaging neuroimaging

data analysis, of all HIV-1 infected children with data analysis, of all HIV-1 infected children with EPC, admitted at “Dr. Victor Babes” Hospital EPC, admitted at “Dr. Victor Babes” Hospital

Distribution in time of EPC casesDistribution in time of EPC cases

DMCFNETCTGBL

LDCKM

VIMMSMTJCANLNSDI

CAATFANHMADMGSG

pa

tie

nts

Oct.

97

Nov.97

Dec.97

Ian.98

Feb.

98

Mar.98

Apr.98

May98

Jun.

.98

Jul.

98

Aug.98

Sep.98

Oct.

98

Nov.

98

Dec.

98

Ian.99

Patient profile (n=23)Patient profile (n=23)Boys: girls ratioBoys: girls ratio 13/1013/10

age in years (mean +/-SD) 9.29.2 +/- 0.9 +/- 0.9

HIV infection route Parenteral (all)Parenteral (all)

CDC clinical classification before neurological complication diagnosis

cl.B:16cl.B:16

cl.C:7cl.C:7

CDC immunological classification before neurological complication diagnosis

Cl 3: 17 patientsCl 3: 17 patients

Cl 2: 5 patientsCl 2: 5 patients

Cl 1: 1 patientCl 1: 1 patient

median, range 114.5114.5, 15-599, 15-599

HIV infection diagnosed concomitant with EPC

44

Time from HIV diagnosis to EPCTime from HIV diagnosis to EPC <1 yr : <1 yr : 66

1 – 5 yrs: 61 – 5 yrs: 6

> 5 yrs: 7> 5 yrs: 7

AIDS defining diseases before the AIDS defining diseases before the EPC diagnosisEPC diagnosis

Tuberculosis* (11)Tuberculosis* (11)

Recurrent bacterial pneumonia (4)Recurrent bacterial pneumonia (4)

HIV Encephalopathy (2)HIV Encephalopathy (2)

Cryptococcus meningitis (2)Cryptococcus meningitis (2)

Kaposi Sarcoma (1)Kaposi Sarcoma (1)

* Not included as AIDS disease in pediatric CDC classification

Clinical history Clinical history withinwithin 6 months 6 months preceding the EPC diagnosis (n=23)preceding the EPC diagnosis (n=23)

Respiratory infections (all)Respiratory infections (all)

Herpes (VZV, HSV) infections (6)Herpes (VZV, HSV) infections (6)

Diarrhea (5)Diarrhea (5)

Strongyloidiasis (2)Strongyloidiasis (2)

Crypto meningitis (2)Crypto meningitis (2)

Presumptive diagnosis of measles (2)Presumptive diagnosis of measles (2)

Kaposi Sarcoma (1)Kaposi Sarcoma (1)

Clinical presentation (1)Clinical presentation (1)

Acute, no feverAcute, no feverMyoclonus Myoclonus – localizationlocalization

initially initially unilateral unilateral (upper limbs, face)(upper limbs, face)Spread Spread initial unilateral then then on the opposite site of the on the opposite site of the bodybody

– particular featuresparticular features Bilaterality of myoclonus Bilaterality of myoclonus (17)(17)

Presence of axial myoclonus in few casesPresence of axial myoclonus in few casesWithout generalized tonic-clonic seizuresWithout generalized tonic-clonic seizures

Motor impairmentMotor impairment– Initial (occasional, few patients)Initial (occasional, few patients)– The strength of the affected parts decreased and the The strength of the affected parts decreased and the

majority of patients progressively became hemi/tetra pareticmajority of patients progressively became hemi/tetra pareticCranial nerve involvement (n=18)Cranial nerve involvement (n=18)

Clinical presentation (2)Clinical presentation (2)

Mental statusMental status– No cognitive deterioration at the onsetNo cognitive deterioration at the onset (7) (7)– Visual and auditory hallucinations (5)Visual and auditory hallucinations (5)– Progression to coma (14) Progression to coma (14) within 2 weekswithin 2 weeks (mean) (mean)

Additional neurological findingsAdditional neurological findings– Visual impairment (14): Visual impairment (14):

blindness (9)blindness (9)limited visual field (5)limited visual field (5)

– Ocular bobbingOcular bobbing– Conjugated eyes deviationConjugated eyes deviation

Keratitis and conjunctivitis (18)Keratitis and conjunctivitis (18)

CSF analysisCSF analysis

Normal values: cells, proteins, glucoseNormal values: cells, proteins, glucose

Cultures negative for all common Cultures negative for all common infectious agents testedinfectious agents tested

Antibodies (by ELISA)Antibodies (by ELISA)– IgG: measles* (3), CMV (2), toxo (3)IgG: measles* (3), CMV (2), toxo (3)– (?) (?) IgM: measles* (2), CMV (1), toxo (1)IgM: measles* (2), CMV (1), toxo (1)

* 12 CSF samples tested* 12 CSF samples tested

Humoral immunity to measles in the Humoral immunity to measles in the VBH cohortVBH cohort

12 of 14 patients had positive serum IgG 12 of 14 patients had positive serum IgG antibodies at diagnosis of EPC antibodies at diagnosis of EPC

11 of 23 patients had 11 of 23 patients had positive serum IgM positive serum IgM antibodiesantibodies at least once within the 5 months at least once within the 5 months period preceding the diagnosis of EPCperiod preceding the diagnosis of EPC

The serum IgM/IgG dynamics, tested in 14 The serum IgM/IgG dynamics, tested in 14 patients suggest patients suggest recent sero-conversion in 6 recent sero-conversion in 6 (43%)(43%) patients patients

LCD, 8 years LCD, 8 years (20/01/1998)(20/01/1998)

FRFR CRCR

CRCR PRPR

PRPR OROR

TARTAR TPRTPR

FLFL CLCL

CLCL PLPL

PLPL OLOL

TALTAL TPLTPL

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

EEG (2)EEG (2)

CT scan patient 1CT scan patient 1

MRI scan – patient 1MRI scan – patient 1

MRI scan – patient 1MRI scan – patient 1

MRI scan- patient 2MRI scan- patient 2

MRI scan patient 3MRI scan patient 3

Histopathologic changes consistent Histopathologic changes consistent with HIVEwith HIVE

Astrogliosis, white matter (GFAP) PV infiltrating macrophages (CD68)

Microglial nodule (CD68) MGN with HIV positive cells (p24)

TreatmentTreatment

Antiretroviral treatment:Antiretroviral treatment:– Before the onset of EPC – 7 childrenBefore the onset of EPC – 7 children– After the onset of EPC – 6 childrenAfter the onset of EPC – 6 children

Antiviral treatment:Antiviral treatment:– Acyclovir 14 patientsAcyclovir 14 patients– Foscavir 4 patientsFoscavir 4 patients– Interferon 2 patientsInterferon 2 patients

Corticotherapy:Corticotherapy: 13 patients 13 patientsIVIGIVIG: 6 patients: 6 patientsAnticonvulsivantsAnticonvulsivants::– Carbamazepine: 14Carbamazepine: 14– Lamotriginum: 12Lamotriginum: 12– Diazepamum: 10Diazepamum: 10– Acidum valproicum: 10Acidum valproicum: 10– Phenytoinum: 3Phenytoinum: 3

Survival curveSurvival curve

Chi-square = 6,5260DF = 1P = 0,01

6

17

2

8

1

16

4 42

15

5

0

5

10

15

20

25

30

35

40

45

50

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

EPC (n=23)measles (n=57)

Measles in HIV infected patients Measles in HIV infected patients from VBHfrom VBH

Median CD4:• measles patients: 316 (15-1635) n=20• EPC patients: 114 (15-599) n=22

Measles history and vaccination at Measles history and vaccination at EPC patientsEPC patients

diagnosis of measles in the past diagnosis of measles in the past – before 1997: 3 patientsbefore 1997: 3 patients– within 8 months of EPC diagnosis: 3 patientswithin 8 months of EPC diagnosis: 3 patients

VaccinationVaccination– 8 received first vaccine within 1 year age8 received first vaccine within 1 year age– 6 with complete vaccination (revaccinated in 1995-6 with complete vaccination (revaccinated in 1995-

1996)1996)– 1 without vaccination1 without vaccination– 2 data not available2 data not available

Measles in the HIV brainMeasles in the HIV brain

Immunocytochemistry with a monoclonal antibody to the measles virus Immunocytochemistry with a monoclonal antibody to the measles virus identified many positive cells in the brain of a pediatric HIV infected identified many positive cells in the brain of a pediatric HIV infected patient who died with seizures. (Original mag. 20X)patient who died with seizures. (Original mag. 20X)

ConclusionsConclusionsAn EPC cluster (within 15 months) was observed in An EPC cluster (within 15 months) was observed in Romanian HIV positive childrenRomanian HIV positive childrenThe clinical features were remarkably similar in all The clinical features were remarkably similar in all patientspatients– rapidly progressive neurological deterioration (seizures, rapidly progressive neurological deterioration (seizures,

coma) resulting in deathcoma) resulting in death

In the cases investigated by neuroimaging the findings In the cases investigated by neuroimaging the findings were characterized by similarity of the lesions were characterized by similarity of the lesions – Although suggestive of PML, the diagnosis was not confirmed Although suggestive of PML, the diagnosis was not confirmed

by histologyby histology– The neuropathologic exam (where available) demonstrated The neuropathologic exam (where available) demonstrated

abundant macrophage infiltration and microglial activation, abundant macrophage infiltration and microglial activation, accompanied occasionally by demyelization and vasculitisaccompanied occasionally by demyelization and vasculitis

DiscussionDiscussionQuestionQuestion: could the etiology be related to a subacute : could the etiology be related to a subacute

form of measles encephalitis or an unusual form of form of measles encephalitis or an unusual form of SSPE?SSPE?– The timeframe of this EPC cluster, overlapping with a The timeframe of this EPC cluster, overlapping with a

measles epidemic in Romania, suggests a common etiologymeasles epidemic in Romania, suggests a common etiology

This hypothesis is further supported by the humoral This hypothesis is further supported by the humoral immune response to measles (seroconversion) and by immune response to measles (seroconversion) and by the neuropathologic post-mortem analysis (incomplete)the neuropathologic post-mortem analysis (incomplete)The answer may have significant implications for the The answer may have significant implications for the immunization strategy in HIV infected patients who are immunization strategy in HIV infected patients who are at risk in a future measles outbreakat risk in a future measles outbreak– Current guidelines suggest vaccination only in patients with Current guidelines suggest vaccination only in patients with

CD4>200( and passive immunization for the rest)CD4>200( and passive immunization for the rest)

09.01.9808.01.9805.01.98Impaired vision

11.01.98Visual hallucinations

Agitation

Case presentation 1 LCCase presentation 1 LCPalsyPalsy

PlegiaPlegia

Myoclonus Myoclonus

Exitus 4 month later

MSOF Salmonella

05.03.98Conscious

20.01.98ConsciousDisartria

12.02.98ConsciousDisartria

Right hemianopia

06.05.98Conscious

29.01.98Conscious

Motor aphasia

19.01.98Comă II

16.01.98Coma I

15.01.98Visual hallucinationsPsycho-motor agitation

Case presentation 2 SM,10 yearsCase presentation 2 SM,10 years

PalsyPalsy

PlegiaPlegia

Myoclonus Myoclonus

27.02.9823.02.98 03.03.98 04.03.98Mixed aphasia

16.03.98Mixed aphasia

11.03.98Mixed aphasia

13.03.98Mixed aphasia

09.03.98Mixed aphasia

Coma I23.03.98

Coma II25.03.98

Coma III28.03.98

EXITUS29.03.98

18.03.98No swallow r

Case presentation 3 CA,10 yearsCase presentation 3 CA,10 years

PalsyPalsy

PlegiaPlegia

Myoclonus Myoclonus

17.05.98Blindness

Motor aphasia

19.05.98seizures

20.05.98Conscious, blindness,

motor aphasia, no swollen r.

21.05.98Idem +

n.III palsy

25.05.98Conscious,

miosis, mixed aphasia

EXITUS26.05.98