Neurological complication of antirabies vaccination in São Paulo, Brazil

Journal of the neurological Sciences, 1975, 26:593-598

593

© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands

Neurological Complication of Antirabies Vaccination in Silo Paulo, Brazil Clinical a n d T h e r a p e u t i c a l A s p e c t s

J. LAMARTINE ASSIS Division of Neurology, University of S~o Paulo, School of Medicine, Sg~oPaulo (Brazil) (Received 14 May, 1975)

INTRODUCTION

In S~o Paulo, Brazil, there is a high incidence of infection by rabies virus and a significant number of neuroparalytic accidents following anti-rabies treatment. During the period between 1968 and 1972, 31,060 subjects have been vaccinated every year in S~o Paulo State, and this report details neurological sequelae which have been encountered, and the results of attempts at treatment. MATERIAL AND METHODS

Seventy-three patients with neurological complications of anti-rabies vaccination were studied, 55 due to Semple vaccine and 18 after Fuenzalida. Patients were aged from 5 to 56 years, including 9 children. There were 49 men and 24 women. Eighteen patients were submitted to more than one series of Semple vaccine, due to multiple exposures to rabies at different times: 9 patients had one vaccination, 6 had two, 2 had three, and 1 had 5 revaccinations. Semple vaccine was used until 1967 and Fuenzalida vaccine after 1968. The preventive regime with Fuenzalida vaccine was the following: one i.m. injection per day for 12 days and 2 more each 10 days. A comparative clinical study of the neuroparalytic accidents following administration of both vaccines was made, including analysis of the following data: incubation period, progression and aggravation of the symptoms and clinical picture. The cerebrospinal fluid (CSF) of 57 patients (87~) was studied, 42 treated with Semple vaccine and 15 with Fuenzalida. For estimating treatment, patients were separated into 3 groups for both types of vaccine: Group A, with slight motor disorders in the lower limbs, where it was already known there was a possibility of spontaneous remission in a short time, Read in part before the 10th International Congress of Neurology, 8-15 September, 1973, Barcelona, Spain.

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J. LAMARTINE ASSIS

received symptomatic and maintenance therapy; Group B, with severe forms, almost always acute meningomyelitis or encephalomyelitis quickly progressive with intense and generalized paralytic phenomena more intensely located in the lower limbs, receiving the same treatment as group A, but in addition ACTH and corticoids by oral, intramuscular or intravenous route; Group C, with severe forms similar to group B, receiving the same treatment as group A, but in addition had methylprednisolone* by lumbar intrathecal injection, 20-100 mg weekly. RESULTS

The incubation period, from the time of vaccination to the onset of the clinical signs, ranged from 1 to 60 days. The average for the Semple vaccine was 13 days for a first vaccination and 5 days (between the 2nd and 9th doses) for revaccination. The incubation period was very variable for Fuenzalida vaccine: in about half the cases it lasted about 10 days, but periods of 5 to more than 12 days were encountered. The longest incubation period for either vaccine was 60 days. The average for the period of progression and aggravation of the symptoms was 4 days for the Semple vaccine and ranged in most cases from 1 t'o 3 days with the Fuenzalida vaccine. The clinical pictures can be seen in Table 1. The CSF examination was abnormal in 88~o of a group of 57 patients. Of 42 patients receiving the Semple vaccine, 38 (90~) had an altered CSF. Twelve of the 15 patients vaccinated with Fuenzalida had abnormal CSF (80~). Most of the CSF findings were moderate or slight pleocytosis, especially of mononuclear cells; mildly or moderately increased protein concentration and increased globulin fractions. Only 6 patients had more than 200 cells/mm 3. No eosinophils were found. In 7 cases the protein levels were above 100 mg/100 ml, with a maximum of 260 mg. In most cases the glucose and chloride TABLE 1 CLINICAL FoRMs OF NEUROLOGICALCOMPLICATIONSOF ANTIRAB1ESVACCINATION

Vaccine Clinical forms

Semple

Fuenzalida

number

~

number

Polyneuritis Polyradicul6neuritis Meningitis Meningoradiculitis Myelitis Meningomyelitisa Encephalomyelitis b

1 2 1 2 5 30 14

2 4 2 4 9 55 26

-1 -l 4 4 8

0 6 0 6 22 22 44

Total

55

102

18

100

a Cases with meningomyelitis and meningoradiculomyelitis. b Cases with pure or mixed forms of encephalomyelitis (involving the leptomeninges and/or spinal roots). * Depo-Medrol, Upjohn.

NEUROLOGICAL COMPLICATION OF ANTIRABIES VACCINATION IN S,~O PAULO

595

TABLE 2 NEUROLOGICAL COMPLICATIONSDUE TO SEMPLE VACCINE."THERAPEUTIC RF~ULTS

Evolution Groups recovery

improvement

sequelae

deaths

total

A B C

14 11 10

1 6 2

1 4 1

0 4 1

16 25 14

Total

35

9

6

5

55

TABLE3 NEUROLOGICAL COMPLICATIONSDUE TO FUENZALIDA VACCINE; THERAPEUTIC RESULTSa

Evolution Groups recovery

sequelae

deaths

total

A B C

7 2 3

0 2 0

0 0 0

7 4 3

Total

12

2

0

14

a In 4 cases in extremis treatment was not given.

levels were normal. Six patients showed very low glucose levels and 3 low chloride levels. There was no significant difference between the CSF results of either vaccine group. The results of treatment can be seen in Tables 2 and 3. The statistical analysis was made by the chi-square test (0.05 level being accepted as significant).

DISCUSSION

In S~o Paulo State, the incidence of exposure to rabies virus is high. During the 1968-1972 period, the annual average for contaminated persons was 1.7~o of the population (Saraiva, Assis and Tiriba 1972). The number of neuroparalytic accidents until 1968 was high at 1:2000 vaccinated people with Semple vaccine (Saraiva and Assis 1968). The r9utine use of Fuenzalida vaccine after 1968 reduced the number of neurologic complications (Saraiva et al. 1972). Patients from 18 to 41 years of age seem to be the most susceptiblc, unlikely children aged 5-11 years who are more resistant to the complications of vaccine treatment. Children under 5 seem to be resistant. Exposure to the infection in S~o Paulo is more frequent in the home environment (69~o) (Ribeiro Netto and Machado 1970); younger subjects are at greater risk (50~o were under 15 years of age). These findings support the greater susceptibility to the neurologic complications of vaccination in patients between the 2nd and 4th decades of life since exposure to the infection is the same for all ages in S~o Paulo.

596

J. L A M A R T I N E ASSIS

The slight male preponderance was not significant because 581~',oof patients in the general population attending out-patient clinics are male and 42}o female (Canelas 1962). The incubation period in the accidents due to Fuenzalida was shorter th~tn incubation period for Semple vaccine, except for revaccination. Similarly progression of symptoms was more rapid with the Fuenzalida vaccine. The clinical manifestations depend on the site and extension of the lesions in the nervous system. The type of vaccine does not appear to influence the symptoms (Table 1). Both the central and peripheral nervous system was variably affected. With the Semple vaccine lesions in the central nervous system predominated over those in the peripheral nervous system. These findings confirm the infrequent appearance of peripheral complications with Semple vaccine (Latimer, Webster and Gurdjian 1951; Appelbaum, Greenberg and Nelson 1953; Uchimura and Shiraki 1957; Assis and Duch~ne 1959; Laplane, Graveleau and Pham-Gia-Can 1960; Assis 1963; Saraiva and Assis 1968; Saraiva et al. 1972). The author's results show an identical picture for Fuenzalida, contrary to previous reports (Lopez Adaros 1967; Lopez Adaros and Held 1971). Curiously the incidence of central and peripheral lesions were identical for both vaccines. Table 1 shows the marked involvement of the spinal cord. More cases of pure myelitis and encephalomyelitis were present in the Fuenzalida group than in the Semple group. However, meningomyelitis predominated clearly in the Scruple group. The myelitides and meningomyelitides are almost always of the transverse form, usually at the thoracic or lumbar level. In this group, a case worth mentioning was a patient with an optic nerve lesion and transverse myelitis, presenting a picture of neuromyelitis optica. Previous references to optic nerve involvement in anti-rabies vaccine complications are rare. Pure meningitis is exceptional (1 case with Semple vaccine), and is more commonly associated with the involvement of other structures. Sometimes the meningeal reaction is severe, but it may be mild or asymptomatic, disclosed only by CSF examination. There were 9 cases of acute meningoencephalitis and meningoencephalomyelitis with severe meningeal and encephalitic manifestations, which evolved quite rapidly to death: 5 were secondary to the Semple vaccine and 4 to Fuenzalida. Encephalitis was clinically dominant and most had meningeal manifestations including a turbid CSF. Paretic or paralytic phenomena were present in most cases, being most intense in the lower limbs, and less frequent in the respiratory territory and in the cranial nerves. In t 2 ~o of the cases there was respiratory arrest, which caused 7 deaths~ 4 in the Semple group and 3 in the Fuenzalida group. Since the neurological complications are spontaneously reversible, at least in part, analysis of the therapeutic results is difficult, particularly in the Fuenzalida group, owing to the small number of cases. Assuming the neuroparalytic accidents are the result of a primary immuno-allergic reaction in response to repeated injection of an antigen (the vaccine) (Ferraro and Roizin 1957), then the use of drugs with anti-inflammatory and immunosuppressive activity, such as the glucocorticoid hormones, would appear to be reasonable for severe cases (Ferraro and Roizin 1953; Gammon and Dilsworth 1953; Briggs and Brown 1960; Assis 1963; Assis and Tetner 1968; Saraiva and Assis 1968; Saraiva et al. 1972).

NEUROLOGICAL COMPLICATION OF ANTIRABIES VACCINATION IN S,~O PAULO

597

In view of the slowness of the recovery processes, in the usual form of thoracolumbar meningomyelitis, the predominance of paralytic phenomena in the lower limbs and the possible benefit of corticoid therapy, the administration of a suspension of methylprednisolone acetate in the subarachnoid space also seems justified. This route allows a direct, immediate and prolonged action on the more directly affected tissues, and it reduces the systemic side-effects. Methylprednisolone acetate suspension maintains reasonably high levels in the CSF for long periods, in contrast to soluble cortico~ls, which rapidly equilibrate with serum levels (Sehgal, Tweed, Gardner and Foote 1963; Fishman and Christy 1965). It is possible to obtain drug diffusion to the upper segments by placing the patient for some minutes in the Trendelenburg position. The response to this method has been surprisingly good, even when it was believed that the disease had become chronic and despite previous conventional treatment. No toxic or irritative effect, either local or systemic, was observed with this technique, the benefit of which had previously been observed (Boines 1961; Gold~tein, McKenzie and McGuckin 1962; Boines 1963; Buskirk, Poffenbarger, Capriles and Idea 1964; Fishman and Christy 1965; Kulick 1965; Baker 1967; Saraiva and Assis 1968; Saraiva et al. 1972). One case at necropsy showed no inflammatory lesion that could be attributed to the drug. No systemic activity of the corticosteroid was observed. Statistical analysis failed to reveal any significant difference between systemic and intrathecal corticosteroids, either in patients with neurological complications from Semple vaccine (Table 2), or from Fuenzalida vaccine (Table 3). ACKNOWLEDGMENTS

We express our thanks to Dr. Thales de Brito, Professor of Pathology from the Medical School and the Tropical Medicine Institute of the University of S~o Paulo, Brazil, for his contribution to the post-mortem study. We thank Drs. P. A. P. Saraiva and A. C. Tiriba from the Emilio Ribas Hospital of S~o Paulo, Brazil, for their assistance. I wish to thank Dr. M. P. Azevedo, Director of the Instituto Pasteur of S~o Paulo, Brazil, for his technical assistance in studying the epidemiological aspects. I also wish to thank Dr. Jos6 Maria Marlet Paretta for his contribution in the statistical analysis. SUMMARY

The author studied especially the clinical aspects and therapeutic results in 73 patients with neurological complications of anti-rabies vaccination. The neuroparalytic accidents and the most constant neurologic signs and symptoms were emphasized. The most common clinical syndrome was thoraco-lumbar meningomyelitis and there were CSF alterations in 88~o of the cases studied. Eighteen patients presented neurologic complications after Fuenzalida vaccine: only 1 of them had Guillain-Barr6 syndrome, 1 had meningoradiculitis, 4 had myelitis and in the other 12 cases there was diffuse involvement of the nervous system especially of the spinal cord and meninges (meningomyelitis and meningoencephalomyelitis).

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S t a t i s t i c a l a n a l y s i s failed to s h o w a n y significant difference b e t w e e n s y s t e m i c a n d i n t r a t h e c a l c o r t i c o s t e r o i d t h e r a p y in the s e v e r e l y affected p a t i e n t s , d u e e i t h e r to S e m p l e o r F u e n z a l i d a vaccine. REFERENCES APPELBAUM,E., M. GREENBERGAND J. NELSON(1953) Neurological complications following antirabies vaccination, J. Amer. med. Ass., 151: 188-191. ASSlS, J. L. (1963) Acidentes neuroparalfticos das vacinag6es anti-r~ibicas, Rev. Med. (S. Paulo), 47: 102-108. AssIs, J. L. AND G. H. DUCH~NE(1959) Complica96es neurol6gicas da vacinag~o anti-r~ibica, Arch. N euro-psiquiat. ( S. P aulo ) , 17: 235-250. AssIs, J. L. AND J. TETNER (1968) Corticotrofina e cortic6ides em neurologia: avatiag~io critica dos resultados em 518 pacientes hospitalizados, Arch. Neuro-psiquiat. (S. Paulo), 26: 273-310. BAKER, A. C. (1967) Intrathecal methylprednisolone for multiple sclerosis--Evaluation by a standard neurological rating, Ann. Allergy, 25: 665-672. BOINES, G. J. (1961) Remissions in multiple sclerosis following intrathecal methylprednisolone acetate, Delaware reed. J., 33: 230235. BO~ES, G. J. (1963) Predictable remissions in multiple sclerosis, Delaware reed. J., 35: 200-202. BRINGS,G. W. AND M. W. BROWN(1960) Neurological complications of antirabies vaccine--Treatment with corticosteroids, J. Amer. reed. Ass., 173: 802-804. CANELAS,H. M. (1962) Neurocisticercose--IncidSncia, diagn6stico e formas clinicas, Arch. Neuro-psiquiat. (S. Paulo), 20: 1-16. FERRARO,A. AND L. ROIZIN(1953) Experimental allergic encephalomyelitis during and following cortone acetate treatment, J. Neuropath. exp. Neurol., 12: 373-386. FER~RO, A. AND L. RoIzrN (1957) Hyperergic encephalomyelitides following exanthematic diseases, infectious diseases and vaccination, J. Neuropath. exp. Neurol., 16: 423-445. FlSHMAN,R. A. ANDN. P. CHRISTY(1965) Fate of adrenal cortical steroids following intrathecal injection, Neurology (Minneap.), 15: 1-6. GABON, G. A. AND M. J. DmSWORTH (1953) Effect of corticotropin on paralysis of experimental allergic encephalomyelitis, Arch. Neurol. Psychiat. (Chic.), 69: 649. GOLDSTEIN, N. P., B. F. MCKENZlE AND W. F. McGuCKIN (1962) Changes in the cerebrospinal fluid of patients with multiple sclerosis after treatment with intrathecal methylprednisolone acetate---A preliminary report, Proc. Mayo Clin., 37: 657-668. KULICK,S. A. (1965)The clinical use of intrathecal methylprednisolone acetate following lumbar puncture, J. Mt. Sinai Hosp., 32: 75-78. LAPLANE, R., D. Gm~WLEAUAND PaAM-GIA-CAN(1960) Accidents paralytiques de la vaccination antirabique, Sere. H3p. Paris, 36: 959-962. LATIMER,F. R., J. E. WEBSTERAND E. S. GURDJIAN(1951) Neurological complication of rabies vaccine, Arch. Neurol. Psychiat. (Chic.), 65: 16-28. LOPEZ ADAROS,H. (1967) Complicaciones neuroparalfticas postvacunaci6n antimibica en Venezuela, Rev. Fed. Med. (Venezuela), 17: 34-35. LOPEZ ADAROS,H. ANDJ. R. HELD(1971) Guillain-Barr6 syndrome associated with immunization against rabies--Epidemiological aspects, Res. Publ. Ass. herr. ment. Dis., 49: 178-186. RmEmO NETTO,A. AND C. G. MACn.~DO(1970) Alguns aspectos epidemiol6gicos da exposiq~o humana ao risco da infec~o pelo virus da raiva, na cidade de S~o Paulo, Brasil, Rev. Inst. Med. trop. S. Paulo, 12: 16-30. SARAIVA, P. A. P. AND J. L. ASSlS(1968) Tratamento das complicaq6es neurol6gicas da vacina¢~o anti-r~ibica, Arch. Neuro-psiquiat. (S. Paulo ), 26: 345-350. SARAIVA,P. A. P., J. L. Assls AND A. C. TIRIBA(1972) Acidentes neurol6gicos associados ~ vacinagao anti-rfibica em Sho Pauk>--Aspectos epidemiol6gicos, clinicos, e terap6utieos de 59 casos, Rev. paul. Med., 80: 63-70. SEHGAL, A. D., D. C. TWEED, W. J. GARDNER AND M. K. FOOTE (1963) Laboratory studies after intrathecal corticosteroids--Determination of corticosteroids in plasma and cerebrospinal fluid, Arch. Neurol. Psychiat. (Chic.), 9: 64-68. UCmMURA, I. AND H. SHIRAKI(1957) A contribution to the classification and the pathogenesis of demyelinating encephalomyelitis with special reference to the central nervous system lesions caused by preventive inoculation against rabies, J. Neuropath. exp. Neurol., 16: 139-208. VAN BUSKmK, C., L. A. POFFENaARGER,L. F. CAPRILESAND B. V. IDEA (1964) Treatment of multiple sclerosis with intrathecal steroids, Neurology (Minneap.), 14: 595-597.