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NEUROCYSTICERCOSIS
Osvaldo M. Takayanagui
Departamento de NeurologiaFaculdade de Medicina de Ribeirão Preto - USP
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
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
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
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
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
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
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
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)