NEUROCYSTICERCOSIS

Osvaldo M. Takayanagui

Departamento de NeurologiaFaculdade de Medicina de Ribeirão Preto - USP

Neurocysticercosis

50,000,000 people

50,000 die annually

WHO - 1993

Taeniasis/Cysticercosis Complex

Neurocysticercosis

High or moderate prevalence

Low or sporadic prevalence Schantz, 2002

Neurocysticercosis

Latin America

75 million live in endemic areas

400,000 symptomatic form

Bern et al. - CID, 1999

Neurocysticercosis

Prevalence rateRibeirão Preto, Brazil

1992 - 2003

72 cases/100,000 inhabitants

Compulsory Notification

Neurocysticercosis

Cysticercosis

Taeniasis

Life cycle of T. solium

Neurocysticercosis

Subcutaneous cysticercosis

Neurocysticercosis

Lingual cysticercosis

Neurocysticercosis

Ocular cysticercosis

Neurocysticercosis

Muscle cysticercosis

Neurocysticercosis

Pulmonary cysticercosis

CT MRIMamere et al. - 2004

Neurocysticercosis

Del Brutto et al. - 1998

Neurocysticercosis

Neurocysticercosis

1 - Type of cysticerci - vesicular cyst - racemose form2 - Stage of development3 - Number4 - Localization5 - Host immune response

Clinical Features

Neurocysticercosis

There are no

pathognomonic clinical features or

a typical NCC syndrome.

Clinical Features

Neurocysticercosis

651 cases

Epilepsy 62 Intracr. hypertension 34 Meningitis 29 Mental disorders 11 Vasculitis 2 Spinal 0.5 Combined 37

Clinical forms %

Clinical Features

Neurocysticercosis

1- Serologic testing

2- Cerebrospinal fluid

3- Neuroimaging

CT

MRI

4- Surgical detection

Diagnosis

Neurocysticercosis

EITBEnzyme-linked immunoelectrotransfer blot

Tsang et al. (J Infect Dis 159:50, 1989)

2 or more cysts in the CNS Sensitivity: 94% - 98%Specificity: ~ 100%

Richards et al. (Clin Lab Med 11:1011, 1991)Garcia et al. (Lancet 338:549, 1991)

Single cyst or calcificationsLow level of sensitivity and specificity

Garcia et al. (J Infect Dis 175:486, 1997)

Neurocysticercosis

EITB

Systemic cysticercosis

Taeniasis

Other enteroparasitosis

LIMITATIONS

Neurocysticercosis

CSF syndrome

- Pleocytosis

- Eosinophils

- Complement Fixation Test

Lange (Rev Neurol Psiquiat São Paulo, 1940)

Neurocysticercosis

Immunological CSF tests

Indirect imunofluorescence

Passive hemagglutination

Particle agglutination

Western blot

ELISA

EITB

Recombinant antigens

Neurocysticercosis

Sensitivity (%)

Specificity (%)

Serum

41.0

95.7

CSF

71.0

95.7

Serum

86.0

92.8

CSF

86.0

92.8

ELISA EITB

ELISA x EITBNCC - 100 patients Control -70 patients

Proaño-Narvaez et al. (J Clin Microbiol 40: 2115, 2002)

Neurocysticercosis

CT findings

Multiple cysts

Single cyst

Calcifications

Serum

51.6

36.7

0.0

n

64

30

6

CSF

78.1

63.3

33.3

Serum

92.2

83.3

33.3

CSF

92.2

80.0

50.0

ELISA EITBPositive samples (%)

ELISA x EITB

Proaño-Narvaez et al. (J Clin Microbiol 40: 2115, 2002)

Neurocysticercosis

Pardini et al (J Clin Microbiol 39: 3368, 2001)

Immunological detection of antigens SerumT.solium T. crassiceps

CSF T. solium T. crassicepsNCC control NCC control

Neurocysticercosis

Polymerase Chain Reaction

González et al (J Clin Microbiol 38:737, 2000; Diag Microbiol Infect Dis, 42:243, 2002)

170 bp

Neurocysticercosis

Neuroimaging

Neurocysticercosis

Neuroimaging

Neurocysticercosis

Neuroimaging

Neurocysticercosis

Neuroimaging

Neurocysticercosis

ExpertExpert Meeting in Cysticercosis - Lima, Peru, 2000 Meeting in Cysticercosis - Lima, Peru, 2000

Allan J, UKAllan J, UKBellotoBelloto A, USA A, USABoteroBotero D, D, ColombiaColombiaCorrea D, Correa D, MexicoMexicoDel Del BruttoBrutto OH, Equador OH, EquadorEvans C, UKEvans C, UKFlisserFlisser A, A, MexicoMexicoGarcia HH, PeruGarcia HH, Peru

GilmanGilman R, USA R, USANashNash T, USA T, USARajshekharRajshekhar V, V, IndiaIndiaSartiSarti E, E, MexicoMexicoSchantzSchantz P, USA P, USATakayanagui OM, Takayanagui OM, BrazilBrazilTsangTsang V, USA V, USAWhite AC Jr, USAWhite AC Jr, USA

Neurocysticercosis

Diagnostic CriteriaAbsolute1- Histologic demonstration2- Cysts with scolex (CT or MRI)3- Fundoscopic visualizationMajor1- Suggestive lesions (CT or MRI)2- Serum EITB3- Resolution after ALB or PZQ4- Spontaneous resolutionMinor1- Compatible lesions (CT or MRI)2- Compatible symptoms3- Positive CSF ELISA4- Cysticercosis outside CNSEpidemiologic

DIAGNOSISDefinitive- 1 absolute- 2 major + 1 minor + Epid.

Probable- 1 major + 2 minor- 1 major + 1 minor + Epid.- 3 minor + Epid.

Del Bruto et al (Neurology 57: 177, 2001)

Neurocysticercosis

Neuroimaging & CSF

Neurocysticercosis

Neuroimaging & CSF

Neurocysticercosis

Neuroimaging & CSF

Neurocysticercosis

Neurocysticercosis

1- Palliative measures

2- Etiological- Albendazole- Praziquantel- Surgical removal

Therapy for NCC

Neurocysticercosis

- Simultaneous destruction of multiple cysts

- Controlling inflammatory reaction with steroids

- Better clinical evolution

Goal

Pharmacologic Therapy

Neurocysticercosis

Evolution of Epilepsy after ALBDouble blind, randomized, placebo-controlled trial

Albendazole (60 cases) X Placebo (60 cases)

ALB group

Faster resolution of cysts

Similar proportion of partial seizures

Reduction in the rate of seizures with generalization

Garcia et al. (N. Engl. J. Med. 350: 249, 2004)

Neurocysticercosis

ALB x PZQALB more effective than PZQ Sotelo et al. (Arch Neurol - 1988) Sotelo et al. (J Neurol - 1990) Cruz et al. (Trans R Soc Trop Med Hyg - 1991) Takayanagui et al. (Arch Neurol - 1992)

Both drugs are ineffective Carpio et al (Arch Intern Med - 1995)

Neurocysticercosis

COST

PZQ (50 mg/kg/d for 21 days) - US$ 502

ALB (15 mg/kg/d for 8 days) - US$ 38

ALB x PZQ

Neurocysticercosis

PZQ - 75 mg/kg (3 divided doses)

Dexamethasone (3 following days) - 10 mg/d IM

Resolution of cysts - 80%

Praziquantel for 1 day

CoronaCorona et et al (N al (N Engl Engl J J Med Med 334: 125,1996)334: 125,1996)

Neurocysticercosis

Cases12345678

Viable cystsbefore

1111158

43

after0000058

43

Pretell et al (Clin Neurol Neurosurg 103: 175, 2001)

Praziquantel for 1 day

Neurocysticercosis

Multiple viable brain parenchymal cysticerciAlbendazole

Neurocysticercosis

Intraparenchymal viable cysticerci

Dose: 15 mg/kg/d, divided in 2 doses

Duration: 8 days

Dexamethasone: 6 mg/d

Albendazole

Neurocysticercosis

Albendazole Sulfoxide

NH

N

NHCO2CH3

SC3H7

*

ABZ

NH

N

NHCO2CH3

SC3H7

O

ASOX

NH

N

NHCO2CH3

SC3H7

O

O

ASON

CYP

CYP3A4FMO

Neurocysticercosis

Concentration of ALB sulfoxide

ALB sulfoxideMeanSDMinimalMaximal

Plasmaµg/ml0.640.320.161.10

CSFµg/ml0.340.160.170.84

CSF/plasma%

64.333.530.9156

Neurocysticercosis

ALB sulfoxide (+) dextro (-) levo

Enantiomers of ALB sulfoxide

0 2 4 6 8 10 120

50

100

150

200

250

CO

NC

EN

TRA

TIO

N (

ng/m

L)

TIME (h)

Marques-Pereira et al. (Chirality 11:218, 1999)

Neurocysticercosis

0 2 4 6 8

0,2

0,4

0,6

0,8

1,0

ALB

sul

foxi

de (µ

g/m

l)

time (h)

ALB+Dexa+CimetidineALB+DexaALB

Takayanagui et al. (Ther Drug Monit 19:51,1997)

ALB sulfoxide and Dexamethasone

Neurocysticercosis

0 2 4 6 8 10 120

50

100

150

200 (-)-ASOX

plas

ma

conc

entra

tion

(ng/

ml)

time (h)0 2 4 6 8 10 12

0

200

400

600

800

1000 (+)-ASOX

time (h) ControlPhenytoinCarbamazepinePhenobarbital

Lanchote et al. (Ther Drug Monit 24: 338, 2002)

ALB sulfoxide and Antiepileptic Drugs

Neurocysticercosis

Enantiomers of ALB sulfoxide in CSF

Takayanagui et al. (Brit J Clin Pharmacol 54: 125, 2002)

AUC0-12

ng.h/ml

1836.1

536.5

Enantiomers

ALB sulfoxide (+)

ALB sulfoxide (-)

Neurocysticercosis

Enantiomers

CSF

ASOX (+)

ASOX (-)

ASOX total

Partial

ng/ml

58.0*

7.1

65.1*

Total

ng/ml

145.7

25.5

171.2

ALB sulfoxide and Resolution of Cysts

Odashima (Thesis, FMRP-USP, 2002)

Neurocysticercosis

Encephalitis - Steroids

Neurocysticercosis

Intraventricular cyst

Neurocysticercosis

IV ventricle - Surgical removal

Colli et al (Neurosurg Focus 12: 1, 2002)

Neurocysticercosis

Single giant cyst - Surgical removal

Neurocysticercosis

Albendazole or Surgery?

ALB30 mg/kg/d for 60 days Agapejev (Arq Neuropsiquiatr, 1996)

ALB15 mg/kg/d for 30 daysPZQ100 mg/kg/d for 30 days Proaño et al (N Engl J Med, 2001)

Neurocysticercosis

Albendazole or Surgery?

Neurocysticercosis

DAY1

15

30

45

60

90

180

360

RANDOMIZATION

MONTH 1 :ALB

15 mg/kg/d

MONTH 1 :ALB

15 mg/kg/d

MONTH 2 :ALB

15 mg/kg/d

MONTH 2 :PLACEBO

EFFICACY: REDUCTION OF SIZE OF THELESIONS ON MRI

EFFICACY: DISAPPEARANCE OFLESIONS ON MRI (PRIMARY ENDPOINT)

EFFICACY: NO RELAPSE OF LESIONS ONMRI

Racemose NCC: Food and Drug Administration

•Lima•Ribeirão Preto•Guayaquil•Medellin•Houston•NIAID-NIH

Neurocysticercosis

Consensus guidelines of therapy

Viable cysts

1 - 5 cysts

> 5 cysts> 100 cysts

1- ALB + steroids2- ALB. Steroids only if side effects3- No antiparasitic treatmentConsensus: ALB + steroids1- ALB + high-dose steroids2- Only steroid management

PARENCHYMAL NCC

Expert Meeting in Cysticercosis - Lima, Peru, 2000

Garcia et al (Clin Microbiol Rev, 2002)

Neurocysticercosis

Enhacing lesions (degenerating cysts)

Mild to moderate

Encephalitis

1- No antiparasitic treatment2- ALB + steroids3- ALB. Steroids if side effectConsensus: high-dose steroids

Calcifications Consensus: no antiparasitic

Consensus guidelines of therapy

PARENCHYMAL NCC

Garcia et al (Clin Microbiol Rev, 2002)

Neurocysticercosis

EXTRAPARENCHYMAL NCCVentricular

Consensus: neuroendoscopic removal If not available:

1- Shunt + steroids 2- Open surgery, mainly for ventricle cysts

Subarachnoid cysts, including racemose or giant cysts Consensus: ALB + steroids Shunt if hydrocephalus

Hydrocephalus with no visible cystsConsensus: Shunt. No antiparasitic treatment

Consensus guidelines of therapy

Garcia et al (Clin Microbiol Rev, 2002)

Neurocysticercosis

Spinal cysticercosisConsensus: surgical removal

Ophthalmic cysticercosisConsensus: surgical resection

Consensus guidelines of therapy

Garcia et al (Clin Microbiol Rev, 2002)

Neurocysticercosis

Challenge!Challenge!

Cysticercosis is a potentially

eradicable disease