NEUROCYSTICERCOSIS Osvaldo M. Takayanagui Departamento de Neurologia Faculdade de Medicina de Ribeirão Preto - USP
Taeniasis/Cysticercosis Complex 50,000,000 people 50,000 die annually WHO - 1993
High or moderate prevalence Low or sporadic prevalence Schantz, 2002
Latin America 75 million live in endemic areas 400,000 symptomatic form Bern et al. - CID, 1999
Compulsory Notification Prevalence rate Ribeirão Preto, Brazil 1992-2003 72 cases/100,000 inhabitants
Life cycle of T. solium Taeniasis Cysticercosis
Subcutaneous cysticercosis Neurocysticercosis
Lingual cysticercosis Neurocysticercosis
Ocular cysticercosis Neurocysticercosis
Muscle cysticercosis Neurocysticercosis
Pulmonary cysticercosis CT MRI Mamere et al. - 2004
Neurocysticercosis Del Brutto et al. - 1998
Clinical Features 1 - Type of cysticerci - vesicular cyst - racemose form 2 - Stage of development 3 - Number 4 - Localization 5 - Host immune response
Clinical Features There are no pathognomonic clinical features or a typical NCC syndrome.
Clinical Features 651 cases Clinical forms % Epilepsy 62 Intracr. hypertension 34 Meningitis 29 Mental disorders 11 Vasculitis 2 Spinal 0.5 Combined 37
Diagnosis 1- Serologic testing 2- Cerebrospinal fluid 3- Neuroimaging CT MRI 4- Surgical detection
EITB Enzyme-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 calcifications Low level of sensitivity and specificity Garcia et al. (J Infect Dis 175:486, 1997)
EITB LIMITATIONS Systemic cysticercosis Taeniasis Other enteroparasitosis
CSF syndrome - Pleocytosis - Eosinophils - Complement Fixation Test Lange (Rev Neurol Psiquiat São Paulo, 1940)
Immunological CSF tests Indirect imunofluorescence Passive hemagglutination Particle agglutination Western blot ELISA EITB Recombinant antigens
ELISA x EITB NCC - 100 patients Control -70 patients Serum ELISA EITB CSF Serum CSF Sensitivity (%) 41.0 71.0 86.0 86.0 Specificity (%) 95.7 95.7 92.8 92.8 Proaño-Narvaez et al. (J Clin Microbiol 40: 2115, 2002)
ELISA x EITB CT findings Multiple cysts Single cyst Calcifications n 64 30 6 Positive samples (%) ELISA EITB Serum CSF Serum CSF 51.6 36.7 0.0 78.1 63.3 33.3 92.2 83.3 33.3 92.2 80.0 50.0 Proaño-Narvaez et al. (J Clin Microbiol 40: 2115, 2002)
Immunological detection of antigens Serum T.solium T. crassiceps CSF T. solium T. crassiceps NCC control NCC control Pardini et al (J Clin Microbiol 39: 3368, 2001)
González et al (J Clin Microbiol 38:737, 2000; Diag Microbiol Infect Dis, 42:243, 2002) Polymerase Chain Reaction 170 bp
Neuroimaging Neurocysticercosis
Neuroimaging Neurocysticercosis
Neuroimaging Neurocysticercosis
Neuroimaging Neurocysticercosis
Expert Meeting in Cysticercosis - Lima, Peru, 2000 Allan J, UK Belloto A, USA Botero D, Colombia Correa D, Mexico Del Brutto OH, Equador Evans C, UK Flisser A, Mexico Garcia HH, Peru Gilman R, USA Nash T, USA Rajshekhar V, India Sarti E, Mexico Schantz P, USA Takayanagui OM, Brazil Tsang V, USA White AC Jr, USA
Absolute 1- Histologic demonstration 2- Cysts with scolex (CT or MRI) 3- Fundoscopic visualization Major 1- Suggestive lesions (CT or MRI) 2- Serum EITB 3- Resolution after ALB or PZQ 4- Spontaneous resolution Minor 1- Compatible lesions (CT or MRI) 2- Compatible symptoms 3- Positive CSF ELISA 4- Cysticercosis outside CNS Epidemiologic Diagnostic Criteria DIAGNOSIS Definitive - 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)
Neuroimaging & CSF Neurocysticercosis
Neuroimaging & CSF Neurocysticercosis
Neuroimaging & CSF Neurocysticercosis
Therapy for NCC 1- Palliative measures 2- Etiological - Albendazole - Praziquantel - Surgical removal
Pharmacologic Therapy Goal - Simultaneous destruction of multiple cysts - Controlling inflammatory reaction with steroids - Better clinical evolution
Evolution of Epilepsy after ALB Double 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)
ALB x PZQ ALB 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)
ALB x PZQ COST PZQ (50 mg/kg/d for 21 days) - US$ 502 ALB (15 mg/kg/d for 8 days) - US$ 38
Praziquantel for 1 day PZQ - 75 mg/kg (3 divided doses) Dexamethasone (3 following days) - 10 mg/d IM Resolution of cysts - 80% Corona et al (N Engl J Med 334: 125,1996)
Praziquantel for 1 day Cases 1 2 3 4 5 6 7 8 Viable cysts before after 1 0 1 0 1 0 1 0 1 0 5 5 8 8 43 43 Pretell et al (Clin Neurol Neurosurg 103: 175, 2001)
Albendazole Multiple viable brain parenchymal cysticerci
Albendazole Intraparenchymal viable cysticerci Dose: 15 mg/kg/d, divided in 2 doses Duration: 8 days Dexamethasone: 6 mg/d
Albendazole Sulfoxide C 3 H 7 S N NHCO 2 CH 3 ABZ N H CYP3A4 FMO C 3 H 7 ASOX O S * N N H NHCO 2 CH 3 CYP C 3 H 7 ASON O S O N N H NHCO 2 CH 3
Concentration of ALB sulfoxide ALB sulfoxide Mean SD Minimal Maximal Plasma µg/ml 0.64 0.32 0.16 1.10 CSF µg/ml 0.34 0.16 0.17 0.84 CSF/plasma % 64.3 33.5 30.9 156
Enantiomers of ALB sulfoxide CONCENTRATION ( ng/ml) 250 200 150 100 50 ALB sulfoxide (+) dextro (-) levo 0 0 2 4 6 8 10 12 TIME (h) Marques-Pereira et al. (Chirality 11:218, 1999)
Takayanagui et al. (Ther Drug Monit 19:51,1997) ALB sulfoxide and Dexamethasone ALB sulfoxide (µg/ml) 1,0 0,8 0,6 0,4 0,2 ALB+Dexa+Cimetidine ALB+Dexa ALB 0 2 4 6 8 time (h)
ALB sulfoxide and Antiepileptic Drugs 1000 800 600 400 200 (+)-ASOX plasma concentration (ng/ml) 200 (-)-ASOX 150 100 50 0 0 2 4 6 8 10 12 time (h) 0 0 2 4 6 8 10 12 Control Phenytoin Carbamazepine Phenobarbital time (h) Lanchote et al. (Ther Drug Monit 24: 338, 2002)
Enantiomers of ALB sulfoxide in CSF Enantiomers ALB sulfoxide (+) ALB sulfoxide (-) AUC 0-12 ng.h/ml 1836.1 536.5 Takayanagui et al. (Brit J Clin Pharmacol 54: 125, 2002)
ALB sulfoxide and Resolution of Cysts Enantiomers CSF ASOX (+) ASOX (-) ASOX total Partial ng/ml 58.0* 7.1 65.1* Total ng/ml 145.7 25.5 171.2 Odashima (Thesis, FMRP-USP, 2002)
Encephalitis - Steroids Neurocysticercosis
Intraventricular cyst Neurocysticercosis
Colli et al (Neurosurg Focus 12: 1, 2002) IV ventricle - Surgical removal
Single giant cyst - Surgical removal
Albendazole or Surgery? ALB 30 mg/kg/d for 60 days Agapejev (Arq Neuropsiquiatr, 1996) ALB 15 mg/kg/d for 30 days PZQ 100 mg/kg/d for 30 days Proaño et al (N Engl J Med, 2001)
Albendazole or Surgery? Neurocysticercosis
Racemose NCC: Food and Drug Administration DAY 1 RANDOMIZATION 15 30 45 60 90 MONTH 1 : ALB 15 mg/kg/d MONTH 2 : ALB 15 mg/kg/d MONTH 1 : ALB 15 mg/kg/d MONTH 2 : PLACEBO EFFICACY: REDUCTION OF SIZE OF THE LESIONS ON MRI Lima Ribeirão Preto Guayaquil Medellin Houston NIAID-NIH 180 EFFICACY: DISAPPEARANCE OF LESIONS ON MRI (PRIMARY ENDPOINT) 360 EFFICACY: NO RELAPSE OF LESIONS ON MRI
Consensus guidelines of therapy Expert Meeting in Cysticercosis - Lima, Peru, 2000 Viable cysts 1-5 cysts > 5 cysts > 100 cysts PARENCHYMAL NCC 1- ALB + steroids 2- ALB. Steroids only if side effects 3- No antiparasitic treatment Consensus: ALB + steroids 1- ALB + high-dose steroids 2- Only steroid management Garcia et al (Clin Microbiol Rev, 2002)
Consensus guidelines of therapy PARENCHYMAL NCC Enhacing lesions (degenerating cysts) 1- No antiparasitic treatment Mild to moderate 2- ALB + steroids 3- ALB. Steroids if side effect Encephalitis Consensus: high-dose steroids Calcifications Consensus: no antiparasitic Garcia et al (Clin Microbiol Rev, 2002)
Consensus guidelines of therapy EXTRAPARENCHYMAL NCC Ventricular 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 cysts Consensus: Shunt. No antiparasitic treatment Garcia et al (Clin Microbiol Rev, 2002)
Consensus guidelines of therapy Spinal cysticercosis Consensus: surgical removal Ophthalmic cysticercosis Consensus: surgical resection Garcia et al (Clin Microbiol Rev, 2002)
Challenge! Cysticercosis is a potentially eradicable disease