- Email: [email protected]
Second Case of Neurocysticercosis in a Patient With Liver Transplantation (First Case in Spain): A Case Report
Second Case of Neurocysticercosis in a Patient With Liver Transplantation (First Case in Spain): A Case Report V. Barra Valencia, A. Moreno Elola-Olaso, Y. Fundora Suárez, J.C. Meneu Dı´az, S.F. Jiménez de los Galanes, B. Pérez Saborido, R. San Juan, J. Ruiz Giménez, M. Abradelo Usera, M. Donat Garrido, A. Gimeno Calvo, M.C. Hernández Pérez, C. Jiménez Romero, and E. Moreno González ABSTRACT Background. Neurocysticercosis (NCC) is a disorder caused by the Taenia solium larva. It is the most common parasitosis of the central nervous system (CNS). Its distribution is universal, but it is endemic in many developing countries and in the third world. In Spain most patients come from countries where the condition is endemic. However, sporadic cases occur among the population of rural regions. NCC in transplant recipients is uncommon. One renal transplant recipient developed NCC but responded to treatment with praziquantel. Recently, it has been reported to complicate a liver transplantation. Case report. The patient was a 49-year-old Ecuatorian man who received a cadaveric donor liver graft in June 2001 due to acute liver failure induced by toadstool and was under treatment with FK506. In January 2006, the patient presented with a generalized onset of a tonic-clonic seizure for 1 minute without sphincter incontinence, headache, fever, or previous brain trauma. Neurological evaluation did not show evidence of organic brain dysfunction. The neuroimaging findings (brain) computed tomography scan, magnetic resonance imaging were compatible with NCC: many cystic lesions intra- and extraparenchymatous with a scolex visible in three of them. Serology for cysticercosis in plasma was initially indeterminate but positive afterward. The patient was treated with anticonvulsivants (valproic acid) and albendazole. Systemic steroids were added in order to reduce the edema produced upon death of the cyst. Treatment lasted 3 weeks and it was completed without complications or neurological symptoms. Liver function was not affected. One year later the patient remained asymptomatic. Conclusion. NCC is a condition that must be included in the differential diagnosis of patients with CNS involvement and cystic lesions on neuroimaging investigations in transplant recipients, especially patients originating from or traveling to endemic areas. First-line therapy for active cysts includes antiparasitic drugs (albendazole or praziquantel) as well as steroids and anticonvulsivants. In our patient, this therapy was effective.
C
YSTICERCOSIS IS A infection caused by the Taenia solium larva. It is acquired through ingestion of taenia eggs by fecal-oral contamination,1,2 after which the larva
cysts (cysticerci) cross the gastrointestinal tract and migrate via the vascular system to muscles, subcutaneous tissues, skin, eyes, or central nervous system (CNS). When cystic-
From the General, Digestive and Abdominal Organs Transplantation Surgical Department (V.B.V., A.M.E.-O., Y.F.S., J.C.M.D., S.F.J.D.L.G., B.P.S., M.A.U., M.D.G., A.G.C., M.C.H.P., C.J.R., E.M.G.), Infectious Disease Unit (R.S.J.), and Department of Neurology (J.R.G.), “12 Octubre” Universitary Hospital, Madrid, Spain.
Address reprint requests to Vanessa Barra Valencia, General, Digestive and Abdominal Organs Transplantation Surgical Department, “12 Octubre” Universitary Hospital, Avenida de Córdoba s/n 28041, Madrid, Spain. Telephone: 34649479465; E-mail: [email protected]
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.07.049
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2454
Transplantation Proceedings, 39, 2454 –2457 (2007)
SECOND CASE OF NEUROCYSTICERCOSIS
2455
ercosis involves the CNS, it is called neurocysticercosis (NCC). NCC is the most common parasitosis of the CNS.3,4 Its distribution is universal, but it is endemic in many developing countries, especially Latin America, Africa, and Asia. In Spain, most patients are from countries where the condition is endemic.5 However, sporadic cases still occur among the population of rural regions.6 Infectious diseases are important complications of immunosuppressed patients, but NCC in transplant recipients is uncommon. It has been reported as a complication in renal transplantation (México, 1984) and in liver transplantation (United Kingdom, 2005).7,8 Clinical presentation is pleomorphic, depending on the type, stage, location, size, and number of lesions in the nervous system as well as on the host’s response.9 The most frequent clinical manifestations are epilepsy (70% to 90%),2,3,10 focal deficit, intracranial hypertension, and cognitive impairment. The treatment of symptomatic NCC is controversial but includes antihelminthic therapy in addition to corticosteroids and antiepileptic drugs.11 Medical failures often necessitate surgical treatment. CASE REPORT A 49-year-old Ecuadorian man underwent orthotopic liver transplantation in June 2001 for acute hepatic failure induced by toadstool ingestion. The postoperative course was uncomplicated, he initially received immunosuppression with tacrolimus. Methylprednisolone was added during the first 6 months. Pathology of the
Fig 1. Initial brain CT scan: cystic lesions, intra- and extraparenchymatous without perilesional edema and with nodule in one of them (scolex).
Fig 2. Initial brain CT scan: cystic lesions, intra- and extraparenchymatous without perilesional edema and with nodule in one of them (scolex).
explanted liver demonstrated massive hepatocyte necrosis. The patient had resided in Spain since 2000 and traveled to Ecuador in 2003. He denied previous neurological diseases. In January 2006 the patient presented with a generalized onset of a tonic-clonic seizure during 1 minute without sphincter incontinence, headache, fever, or previous brain trauma. Neurological evaluation did not show evidence of organic brain dysfunction or meningeal inflammation. Biochemical studies were normal; serum tacrolimus level was 8.2 ng/mL. Brain computed tomography (CT) scan demonstrated multiple small, cystic, intra and extraparenchymatous lesions without perilesional edema and with a nodule in one of them (scolex) (Figs 1 and 2). MRI identified 12 cystic lesions with signal properties similar to cerebrospinal fluid (CSF) including FLAIR technique and without perilesional edema. Three of them showed visible scolex (Fig 3). Therefore, the neuroimaging findings were compatible with active NCC (colloid vesicular stage). Plasma serology for cysticercosis was initially indeterminate but was positive 10 days after the seizure. With the diagnosis of active disease, the patient was treated with anticonvulsvants (valproic acid, 500 mg/8 hour) and albendazol (400 mg/12 hour) as well as with steroids to reduce the edema produced by the death of the cysts during 3 weeks. The patient did not experience complications or neurological symptoms. Liver function was not affected. Two months later, brain MRI demonstrated partial regression of the cystic lesions. The patient presented a new episode of tonic-clonic seizure without other neurological symptoms 1 month later due to failure of compliance to the antiepileptic drug. After that he has remained asymptomatic through 1 year follow-up with antiseizure medication (valproic acid 500 mg/8 hour).
2456
BARRA VALENCIA, MORENO ELOLA-OLASO, FUNDORA SUÀREZ ET AL
Fig 3. Initial MRI: cystic lesions with signal properties similar to cerebrospinal fluid without perilesional edema and with scolex visible.
DISCUSSION
NCC is the most common helminthic CNS infection. It results from ingestion of eggs from the adult tapeworm Taenia solium.1,2,3,11 When these eggs are exposed to gastric acid in the human stomach, they turn into larval cysts (cysticerci), which penetrate the intestinal mucosa and are hematogenously transported to muscles, subcutaneous tissues, eyes, or the central nervous system.12 Involvement of the CNS is seen in 60% to 90% of patients with cysticercosis.13 NCC is the most common cause of acquired epilepsy in the world.9,14 Infection is endemic in many developing countries (Latin America, Asia, and Africa). Owing to massive emigration from endemic areas, its frequency has increased in developed countries,9 and NCC is currently a growing public health problem in these countries.1,10 The clinical presentation is varied, depending on the number, location, size, and viability of the cysticercal cysts within the CNS13 as well as on the host’s immune response to the parasite. The disease may be classified into three main groups according to its site: parenchymatous, extraparenchymatous, and mixed. Seizures are the most frequent clinical manifestation of parenchyma cysticercosis,2,3,9,10,13 and intracranial hypertension is the most frequent in the extraparenchymatous forms. Acurate diagnosis of NCC is based on the combination of clinical, epidemiological, neuroradiographic, and inmunological information.3,10,13,15 The sensitivity and specificity of inmunological studies to detect anticysticercal antibodies to T solium antigens in the serum and CSF (ELISA, EITB) are limited.13,16 CT scan and MRI provide objective evidence of the number and location of intracranial cysticerci, their viability, and the severity of the host inflammatory reaction against the parasites.17,18 Neuroimaging findings in paren-
chymal NCC depend on the stage of development of the parasites: vesicular (living cysticerci), colloid-vesicular, granular-nodular, and nodular calcified stage.18 Only cystic lesions with scolex are specific.2 Definitive diagnosis is pathological. The treatment of NCC has been marked by intense controversy. It depends on the number, location, and viability of parasites in CNS.19 All patients require adequate symptomatic therapy with antiepileptic drugs.2 In parenchymal disease with viable cysts, anticysticercal therapy with albendazole (15 mg/kg/d for 7 days or longer) is administered simultaneously with steroids.20 Albendazol has been shown to enhance radiological resolution and also seems to suggest an improvement in the prognosis of associated seizures.18 There is no reason to use antiparasitic drugs to treat dead calcified cysts. Given the efficacy of medical treatment, surgery is reserved as a second-line therapy for parenchymal disease. However, the benefit of conservative management for extraparenchymal and intraventricular cysticercosis is less clear and surgery may be required.13 In immunosuppressed patients, there is no evidence to indicate the best therapy. Our patient presented with a generalized onset of tonicclonic seizures without organic brain dysfunction or previous neurological diseases. The diagnosis of active neurocysticercosis was made based upon the clinical presentation, CT scan, and MRI findings (multiple cysts, intra- and extraparenchymatous lesions with scolex visible in three of them) and plasma serology for the parasite. The patient was treated with anticonvulsivants (valproic acid 500 mg/8 hour) and albendazol (400 mg/12 hour) with steroids for 3 weeks. This therapy was effective, and 1 year later he remains asymptomatic. NCC is a condition that must be included in the differential diagnosis of patients with CNS involvement and cystic
SECOND CASE OF NEUROCYSTICERCOSIS
lesions included in neuroimaging investigations of transplant recipients, especially patients originating from or traveling to endemic areas. This case represents the second report of NCC in a liver transplant recipient.
REFERENCES 1. Garcı´a HH, Del Brutto OH: Neurocysticercosis: updated concepts about an old disease. Lancet Neurol 4:653, 2005 2. Carpio A: Neurocysticercosis: an update. Lancet Infect Dis 2:751, 2002 3. Garcı´a HH, Del Brutto OH: Taenia solium cysticercosis. Infect Dis Clin North Am 14:97, 2000 4. Garcı´a HH, Gonzáles AE, Evans CAW, et al: Taenia solium cysticercosis. Lancet 362:547, 2003 5. Manzano-Blanco S, Gutierrez-Solana LG, Garcı´a Peñas JJ, et al: A case of mixed (parenchymatous meningo-basal) neurocysticercosis. Rev Neurol 25:1585, 1997 6. Rodrı´guez-Sánchez G, Castellanos-Pinedo F, Jiménez-Pando J, et al: Hydrocepahlia and subarachnoid cyst due to neurocysticercosis. A new case from rural Extremadura. Rev Neurol 34:348, 2002 7. Gordillo-Paniagua G, Muñoz-Arizpe R, Ponsa-Molina R: Unusual complication in a patient with renal transplantation: cerebral cysticercosis. Nephron 45:65, 1987 8. Hore M, Gelson WT, Antoun N, et al: Early recurrence of neurocysticercosis after orthotopic liver transplant. Liver Transpl 12:490, 2006
2457 9. Alarcón F: Neurocysticercosis: its aetiopathogenesis, clinical manifestations, diagnosis and treatment. Rev Neurol 43(suppl 1): S93, 2006 10. Del Brutto OH: Neurocysticercosis. Semin Neurol 25:243, 2005 11. Sotelo J, Del Brutto OH: Review of neurocysticercosis. Neurosurg Focus 12: 2002 12. DeGiorgio CM, Medina MT, Durón R, et al: Neurocysticercosis. Epilepsy Curr 4:107, 2004 13. Hawk MW, Shahlaie K, Kim KD, et al: Neurocysticercosis: a review. Surg Neurol 63:123, 2005 14. Commission on Tropical Diseases of the International League Against Epilepsy: Relationship between epilepsy and tropical disease. Epilepsy 35:89, 1994 15. Del Brutto OH, Rajshekhar V, White AC Jr, et al: Proposed diagnostic criteria for neurocysticercosis. Neurology 57:177, 2001 16. Feldman M, Plan Carte A, Sandoval M, et al: Comparison of two assays (EIA and EITB) and two samples (saliva and serum) for diagnosis of neurocysticercosis. Trans R Soc Trop Med Hyg 84:559, 1990 17. Garcı´a HH, Del Brutto OH: Imaging findings in neurocysticercosis. Acta Trop 87:71, 2003 18. Garcı´a HH, Del Brutto OH, Nash TE, et al: New Concepts in the diagnosis and management of neurocysticercosis (Taenia Solium). Am J Med Hyg 72:3, 2005 19. Del Brutto OH: Neurocysticercosis: up-dating in diagnosis and treatment. Neurologia 20:412, 2005 20. Garcı´a HH, Gilman RH, Horton J, et al: Albendazole therapy for neurocysticercosis: a prospective double-blind trial comparing 7 to 14 days of treatment. Neurology 48:1421, 1997
C
YSTICERCOSIS IS A infection caused by the Taenia solium larva. It is acquired through ingestion of taenia eggs by fecal-oral contamination,1,2 after which the larva
cysts (cysticerci) cross the gastrointestinal tract and migrate via the vascular system to muscles, subcutaneous tissues, skin, eyes, or central nervous system (CNS). When cystic-
From the General, Digestive and Abdominal Organs Transplantation Surgical Department (V.B.V., A.M.E.-O., Y.F.S., J.C.M.D., S.F.J.D.L.G., B.P.S., M.A.U., M.D.G., A.G.C., M.C.H.P., C.J.R., E.M.G.), Infectious Disease Unit (R.S.J.), and Department of Neurology (J.R.G.), “12 Octubre” Universitary Hospital, Madrid, Spain.
Address reprint requests to Vanessa Barra Valencia, General, Digestive and Abdominal Organs Transplantation Surgical Department, “12 Octubre” Universitary Hospital, Avenida de Córdoba s/n 28041, Madrid, Spain. Telephone: 34649479465; E-mail: [email protected]
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.07.049
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2454
Transplantation Proceedings, 39, 2454 –2457 (2007)
SECOND CASE OF NEUROCYSTICERCOSIS
2455
ercosis involves the CNS, it is called neurocysticercosis (NCC). NCC is the most common parasitosis of the CNS.3,4 Its distribution is universal, but it is endemic in many developing countries, especially Latin America, Africa, and Asia. In Spain, most patients are from countries where the condition is endemic.5 However, sporadic cases still occur among the population of rural regions.6 Infectious diseases are important complications of immunosuppressed patients, but NCC in transplant recipients is uncommon. It has been reported as a complication in renal transplantation (México, 1984) and in liver transplantation (United Kingdom, 2005).7,8 Clinical presentation is pleomorphic, depending on the type, stage, location, size, and number of lesions in the nervous system as well as on the host’s response.9 The most frequent clinical manifestations are epilepsy (70% to 90%),2,3,10 focal deficit, intracranial hypertension, and cognitive impairment. The treatment of symptomatic NCC is controversial but includes antihelminthic therapy in addition to corticosteroids and antiepileptic drugs.11 Medical failures often necessitate surgical treatment. CASE REPORT A 49-year-old Ecuadorian man underwent orthotopic liver transplantation in June 2001 for acute hepatic failure induced by toadstool ingestion. The postoperative course was uncomplicated, he initially received immunosuppression with tacrolimus. Methylprednisolone was added during the first 6 months. Pathology of the
Fig 1. Initial brain CT scan: cystic lesions, intra- and extraparenchymatous without perilesional edema and with nodule in one of them (scolex).
Fig 2. Initial brain CT scan: cystic lesions, intra- and extraparenchymatous without perilesional edema and with nodule in one of them (scolex).
explanted liver demonstrated massive hepatocyte necrosis. The patient had resided in Spain since 2000 and traveled to Ecuador in 2003. He denied previous neurological diseases. In January 2006 the patient presented with a generalized onset of a tonic-clonic seizure during 1 minute without sphincter incontinence, headache, fever, or previous brain trauma. Neurological evaluation did not show evidence of organic brain dysfunction or meningeal inflammation. Biochemical studies were normal; serum tacrolimus level was 8.2 ng/mL. Brain computed tomography (CT) scan demonstrated multiple small, cystic, intra and extraparenchymatous lesions without perilesional edema and with a nodule in one of them (scolex) (Figs 1 and 2). MRI identified 12 cystic lesions with signal properties similar to cerebrospinal fluid (CSF) including FLAIR technique and without perilesional edema. Three of them showed visible scolex (Fig 3). Therefore, the neuroimaging findings were compatible with active NCC (colloid vesicular stage). Plasma serology for cysticercosis was initially indeterminate but was positive 10 days after the seizure. With the diagnosis of active disease, the patient was treated with anticonvulsvants (valproic acid, 500 mg/8 hour) and albendazol (400 mg/12 hour) as well as with steroids to reduce the edema produced by the death of the cysts during 3 weeks. The patient did not experience complications or neurological symptoms. Liver function was not affected. Two months later, brain MRI demonstrated partial regression of the cystic lesions. The patient presented a new episode of tonic-clonic seizure without other neurological symptoms 1 month later due to failure of compliance to the antiepileptic drug. After that he has remained asymptomatic through 1 year follow-up with antiseizure medication (valproic acid 500 mg/8 hour).
2456
BARRA VALENCIA, MORENO ELOLA-OLASO, FUNDORA SUÀREZ ET AL
Fig 3. Initial MRI: cystic lesions with signal properties similar to cerebrospinal fluid without perilesional edema and with scolex visible.
DISCUSSION
NCC is the most common helminthic CNS infection. It results from ingestion of eggs from the adult tapeworm Taenia solium.1,2,3,11 When these eggs are exposed to gastric acid in the human stomach, they turn into larval cysts (cysticerci), which penetrate the intestinal mucosa and are hematogenously transported to muscles, subcutaneous tissues, eyes, or the central nervous system.12 Involvement of the CNS is seen in 60% to 90% of patients with cysticercosis.13 NCC is the most common cause of acquired epilepsy in the world.9,14 Infection is endemic in many developing countries (Latin America, Asia, and Africa). Owing to massive emigration from endemic areas, its frequency has increased in developed countries,9 and NCC is currently a growing public health problem in these countries.1,10 The clinical presentation is varied, depending on the number, location, size, and viability of the cysticercal cysts within the CNS13 as well as on the host’s immune response to the parasite. The disease may be classified into three main groups according to its site: parenchymatous, extraparenchymatous, and mixed. Seizures are the most frequent clinical manifestation of parenchyma cysticercosis,2,3,9,10,13 and intracranial hypertension is the most frequent in the extraparenchymatous forms. Acurate diagnosis of NCC is based on the combination of clinical, epidemiological, neuroradiographic, and inmunological information.3,10,13,15 The sensitivity and specificity of inmunological studies to detect anticysticercal antibodies to T solium antigens in the serum and CSF (ELISA, EITB) are limited.13,16 CT scan and MRI provide objective evidence of the number and location of intracranial cysticerci, their viability, and the severity of the host inflammatory reaction against the parasites.17,18 Neuroimaging findings in paren-
chymal NCC depend on the stage of development of the parasites: vesicular (living cysticerci), colloid-vesicular, granular-nodular, and nodular calcified stage.18 Only cystic lesions with scolex are specific.2 Definitive diagnosis is pathological. The treatment of NCC has been marked by intense controversy. It depends on the number, location, and viability of parasites in CNS.19 All patients require adequate symptomatic therapy with antiepileptic drugs.2 In parenchymal disease with viable cysts, anticysticercal therapy with albendazole (15 mg/kg/d for 7 days or longer) is administered simultaneously with steroids.20 Albendazol has been shown to enhance radiological resolution and also seems to suggest an improvement in the prognosis of associated seizures.18 There is no reason to use antiparasitic drugs to treat dead calcified cysts. Given the efficacy of medical treatment, surgery is reserved as a second-line therapy for parenchymal disease. However, the benefit of conservative management for extraparenchymal and intraventricular cysticercosis is less clear and surgery may be required.13 In immunosuppressed patients, there is no evidence to indicate the best therapy. Our patient presented with a generalized onset of tonicclonic seizures without organic brain dysfunction or previous neurological diseases. The diagnosis of active neurocysticercosis was made based upon the clinical presentation, CT scan, and MRI findings (multiple cysts, intra- and extraparenchymatous lesions with scolex visible in three of them) and plasma serology for the parasite. The patient was treated with anticonvulsivants (valproic acid 500 mg/8 hour) and albendazol (400 mg/12 hour) with steroids for 3 weeks. This therapy was effective, and 1 year later he remains asymptomatic. NCC is a condition that must be included in the differential diagnosis of patients with CNS involvement and cystic
SECOND CASE OF NEUROCYSTICERCOSIS
lesions included in neuroimaging investigations of transplant recipients, especially patients originating from or traveling to endemic areas. This case represents the second report of NCC in a liver transplant recipient.
REFERENCES 1. Garcı´a HH, Del Brutto OH: Neurocysticercosis: updated concepts about an old disease. Lancet Neurol 4:653, 2005 2. Carpio A: Neurocysticercosis: an update. Lancet Infect Dis 2:751, 2002 3. Garcı´a HH, Del Brutto OH: Taenia solium cysticercosis. Infect Dis Clin North Am 14:97, 2000 4. Garcı´a HH, Gonzáles AE, Evans CAW, et al: Taenia solium cysticercosis. Lancet 362:547, 2003 5. Manzano-Blanco S, Gutierrez-Solana LG, Garcı´a Peñas JJ, et al: A case of mixed (parenchymatous meningo-basal) neurocysticercosis. Rev Neurol 25:1585, 1997 6. Rodrı´guez-Sánchez G, Castellanos-Pinedo F, Jiménez-Pando J, et al: Hydrocepahlia and subarachnoid cyst due to neurocysticercosis. A new case from rural Extremadura. Rev Neurol 34:348, 2002 7. Gordillo-Paniagua G, Muñoz-Arizpe R, Ponsa-Molina R: Unusual complication in a patient with renal transplantation: cerebral cysticercosis. Nephron 45:65, 1987 8. Hore M, Gelson WT, Antoun N, et al: Early recurrence of neurocysticercosis after orthotopic liver transplant. Liver Transpl 12:490, 2006
2457 9. Alarcón F: Neurocysticercosis: its aetiopathogenesis, clinical manifestations, diagnosis and treatment. Rev Neurol 43(suppl 1): S93, 2006 10. Del Brutto OH: Neurocysticercosis. Semin Neurol 25:243, 2005 11. Sotelo J, Del Brutto OH: Review of neurocysticercosis. Neurosurg Focus 12: 2002 12. DeGiorgio CM, Medina MT, Durón R, et al: Neurocysticercosis. Epilepsy Curr 4:107, 2004 13. Hawk MW, Shahlaie K, Kim KD, et al: Neurocysticercosis: a review. Surg Neurol 63:123, 2005 14. Commission on Tropical Diseases of the International League Against Epilepsy: Relationship between epilepsy and tropical disease. Epilepsy 35:89, 1994 15. Del Brutto OH, Rajshekhar V, White AC Jr, et al: Proposed diagnostic criteria for neurocysticercosis. Neurology 57:177, 2001 16. Feldman M, Plan Carte A, Sandoval M, et al: Comparison of two assays (EIA and EITB) and two samples (saliva and serum) for diagnosis of neurocysticercosis. Trans R Soc Trop Med Hyg 84:559, 1990 17. Garcı´a HH, Del Brutto OH: Imaging findings in neurocysticercosis. Acta Trop 87:71, 2003 18. Garcı´a HH, Del Brutto OH, Nash TE, et al: New Concepts in the diagnosis and management of neurocysticercosis (Taenia Solium). Am J Med Hyg 72:3, 2005 19. Del Brutto OH: Neurocysticercosis: up-dating in diagnosis and treatment. Neurologia 20:412, 2005 20. Garcı´a HH, Gilman RH, Horton J, et al: Albendazole therapy for neurocysticercosis: a prospective double-blind trial comparing 7 to 14 days of treatment. Neurology 48:1421, 1997