The neuroparalytic accidents of antirabies vaccination

372 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. Vol. 47. No. 5. September,1953.

THE NEUROPARALYTIC ACCIDENTS OF ANTIRABIES VACCINATION BY

A. J. S. McFADZEAN*

Professor, University of Hong Kong AND

G. H. CHOA

Lecturer, University of Hong Kong From the Department of Medicine Prior to the introduction of antirabies vaccine by PASTEUR in 1885, both furious and paralytic rabies had been described as occurring in man. T h e latter was apparently rare, and, although described by van SWEITEN in 1753, its occurrence was not widely known. Shortly after the introduction of the vaccine, fatal cases of paralysis, occurring during or after treatment, were recorded. These were ascribed by PASTEUR and his supporters to the street virus producing " dumb " rabies; in other words, the vaccine had failed to protect. T h e y insisted that the fixed virus of the vaccine was harmless. PASTEUR'Santagonists were quick to draw a parallel between the fatal paralysis and the state of rabbits infected with fixed virus, and claimed that the fixed virus of the vaccine was responsible. T h e condition was somewhat caustically termed by PETER, PASTEUR'Schief antagonist, " rage de laboratoire." T h e hypothesis that the fixed virus was innocuous was rendered untenable when persons, treated with the vaccine after being bitten by dogs subsequently shown to be non-rabid were proved to have rabies by histological observations at autopsy and by transmission experiments. It must be appreciated, therefore, that during or after treatment with rabies vaccine, paralytic rabies, due either to the street virus or to the fixed virus, may well be encountered. Both these conditions are accepted as fatal. Some three years after the introduction of the vaccine there were reported cases of a condition considered to be paralytic rabies which was not necessarily fatal. According to STUARTand KRIKORIAN (1928), GONZALESdescribed three such cases in 1888, and LAVERAN (1891) described a case of transient paralysis of the legs commencing 8 days after the start of treatment. Within a short time a n u m b e r of cases were reported, and it would appear that the authors considered that the condition was due to modification of the street virus. This hypothesis was no longer tenable when paralysis occurred in persons bitten by healthy dogs. For example, TONNIN (1901) reported such a case and concluded that the causal factor was present in the vaccine. By 1905 REMLINGER (1905) had collected records of 40 cases occurring among 107,712 persons treated. T o this condition the term " paralytic * We would express our thanks to Drs. A. H. R. COOMBES, J. M. PARKand T. Y. LI, who afforded us access to the clinical records of Cases 4, 8 and 12, respectively, and to Dr. E. F. DUCK who provided some of the statistical details set out in Table II.

373

A. J. S. MCFADZEAN AND G. H. CHOA

accident of Pasteur treatment " has been given. This designation does not include paralytic rabies due to street virus or fixed virus; it is reserved for paralytic conditions resulting from the action upon the brain, spinal cord, or peripheral nerves of some as yet undetermined substance contained in the vaccine. MATERIAL

In the years 1949 to 1952 we have encountered 14 cases of neuroparalytic accidents of rabies vaccination and our attention has been drawn to three other cases in this period. All patients had received the Semple vaccine, a killed phenolized vaccine. Data in the 17 cases, of interest from the point of view of incidence, are set out in Table I and the total number given the vaccine in Hong Kong in the period under review together with the age, sex and race distribution are shown in Table II. INCIDENCE GREENWOOD (1945-46) in the period covered by the League of Nations 10th Report, recorded 13 accidents in 88,459 patients receiving killed phenol vaccine, and incidence of 1 : 6,805. T h e incidence for all vaccines for this period was 1 : 5,562. In the period covered by all 10 League of Nations Reports there were 68 accidents in 579,129 patients receiving killed phenol vaccine an incidence of 1:8,517. T h e incidence for all vaccines was 1 : 5 , 8 1 4 . T h e s e figures suggest that neuroparalytic accidents are rare and are less frequent w h e n killed phenol vaccine is used. Statistics from the U n i t e d States, however, indicate that the incidence of neuroparalytic accidents may well be m u c h higher. REDEWILL and UNDERWOOD (1947) reported an incidence of 1 : 1,194 and an incidence of 1 : 600 was reported by PAIT and PEARSON ( 1 9 4 9 ) i n the C o u n t y of Los Angeles in the years 1940-46 and also by KOPROWSKI and Le BELL (1950) in Manhattan in the years 1946-49. PHILIPS, BERRY and SNOOK (1921) reported an incidence of 1 : 280 in a small series of 1,680 cases.

In Hong Kong in the years 1949-52, 17 cases are known to have occurred among 14,119 patients given the vaccine, a known-case incidence of 1 : 831. It is highly improbable that we have seen or have had brought to our notice all cases. There is no doubt that many Chinese patients who develop untoward reactions during treatment by " western medicine will promptly seek assistance from traditional Chinese medicine. This is especially true of neuroparalytic accidents since traditional medicine has the reputation of curing rabies with which the patient and his relatives readily confuse the accident of vaccine treatment. We have been told of one practitioner of traditional Chinese medicine who, in the period under review, cured two cases of " rabies which was not prevented by antirabies vaccination. A similar argument might well apply to many of the areas from which the League of Nations obtained their figures and account for the low incidence of accidents reported by them. "

"

AGE INCIDENCE

In a series of 149 cases cited by STUART and KRIKORIAN(1928) 135 of the subjects were over 15 years. The age incidence in our series is set out in Table I from which it will be seen that 15 of the 17 cases were in persons over 20 years of age, yet of the 14,119 patients given the vaccine in the period under consideration 56 per cent. were under 20. It would appear, therefore, that while children and young adults constitute the majority of patients attending for antirabies vaccination they are much less prone to paralytic accidents. SEX INCIDENCE

Available records, according to STUARTand KRIKORIAN(1928), permit of analysis of the absolute but not the relative sex incidence. In four series cited by these authors the ratio

374

NEUROPARALYTIC ACCIDENTS OF ANTIRABIE$ VACCINATION

TABLE I.

Certain data of interest in 17 cases of neuroparalytic accident of antirabies vaccination occurring in Hong Kong in the years 1949-52. Extraneural reactions

Neuroparatytic accident

Total Day T y p e Day Case Age Sex Race number of of (Horack of No. injections onset (1939)) onset

Syndrome

1

37

M

C

9

5

Type 2 10

Transverse myelitis

2

41

M

C

14

12

Type 2 20

,,

3

32

M

C

14

4

25

M

C

14

5

43

M

C

6

39

M

7

35

8

Negative

Biting animal Unknown

28

,,

9

Type 2 37

,,

Not done

12

9

Type 2

19

,,

Positive (negative Non-rabid after 6 months)

C

6

6

Type 2

12

Ascending myelitis

Negative

F

C

11

11

Type 2

11

Encephalomyelitis

Positive

Unknown

32

M

E

12.

Nil

14

,,

Negative

Non-rabid

9

27

F

C

9

Type 2

9

,,

10

18

M

C

3

Nil

17

11

11

M

C

11

Nil

8

Encephalitis

12

8

M

C

8

Nil

14

,,

13

30

M

C

14

9

Type 2 14

Polyneuritis

14

29

M

C

14

12

T y p e 3 28

,,

15

25

M

C

14

16

34

M

C

11

17

36

M

C

14

TABLE II.

Nil

Intradermal reaction (1/50; 1/100 dilution of vaccine)

7

Positive (negative Unknown after 6 months) Negative 1 year after

Non-rabid

Negative

Unknown

18

,,

,,

Non-rabid

4

T y p e 3 12

,,

,,

Unknown

3

Type 3 15

,,

Nil

T h e age, sex and race distribution of patients receiving antirabies vaccine in Hong Kong in the years 1949-52.

Total number given vaccine 1949-52 14,119

Sex

Age

Race

Below 20

Above 20

Male

Female

Chinese

European

7,981 (57%)

6,138 (43%)

7,898 (56%)

6,221 (44%)

12,861 (91%)

1,258 (9%)

A. J. S. MCFADZEAN AND G. H. CHOA

375

of males to females was 60 : 10, 73 : 14, 32 : 10, and 179 : 49. In our series the absolute and relative sex incidences are available. Fifty-six per cent. of the patients receiving the vaccine were males and 44 per cent. females. Since only two of our 17 cases were in females and since 61 per cent. of the females receiving the vaccine were over 20 years of age, it would appear that they are less prone to develop neuroparalytic accidents. RACE Van GENDEREN (1926) reported 21 cases from Java and of these 19 were in Europeans although in the period under review twice as many natives had been given the vaccine. Since that time many observers have considered that there is a higher incidence in European stock. JORDAN, according to STUARTand KRIKORIAN(1928), found the converse to obtain in Shanghai. Of our 17 cases, 16 occurred in Chinese who in turn constituted 91 per cent. of the patients receiving the vaccine. Thesefigures are consistent with an equal incidence in both native and foreign population.

TIME RELATIONSHIP TO TREATMENT

TUMSKAYA (1931) reviewed the time relationship between onset of symptoms and commencement of treatment, and concluded that the accident occurred in 25 per cent. of cases in the first 10 days, in 62 per cent. during the 3rd week and later in the remaining 13 per cent. STUART and KRIKORIAN (1928) considered that the accident occurred within 35 days in practically 100 per cent. of cases. Longer periods have been recorded, for example IMRIE (1944) reported the onset of the complication 45 days after starting treatment. T h e time between starting treatment and onset of the accident in our cases is shown in Table I. It will be seen that nine cases occurred in the 2nd week, five cases in the 3rd week, two cases in the 4th week, and one case in the 6th week. T h e shortest interval was 8 days and the longest 37 days. PATHOLOGY Since death from neuroparalytic accidents are infrequent there is a paucity of autopsy reportsFurther, many of the reports are inadequate, for example BAREGGI(1889) reported five cases and mens tioned only hyperaemia of the nervous tissue. The earliest adequate description was that of BABE. and MIRONESeO (1908) who described a pathological picture of encephalomyelitis with prominent perivascular demyelination. GLASERand SMITH (1951) reviewed the pathological findings in 48 fatal cases reported in the literature, and found described in 30 a histological picture of acute myelitis or encephalomyelitis. Many of the remaining reports were inadequate. It is manifest, therefore, that most fatal neuroparalytic accidents of rabies vaccination belong to this category. The histological picture is one of perivascular demyelination, variable perivascular cuffing and microgliosis, the " acute perivascular myelinoclasis " of MARSDEN and HURST (1932). There may be attendant changes in ganglion cells varying from simple swelling and early nuclear changes to karyolysis and karyorrhexis. BASSOE and GRINKER (1930) emphasized the occurrence of capillary damage with swelling of the endothelium, including complete obstruction. It is well recognized that this histological picture is remarkably similar to that of encephalomyelitis following vaccinia, small-pox, measles and chicken-pox. Indeed GRINKER and BASSOE (1931) in a suggested classification of non-suppurative forms of encephalitis, grouped all five conditions with certain cases of disseminated encephalomyelitis as showing focal perivascular incomplete softenings, microgliosis, mild lymphocytic reaction and secondary gliosis. One feature distinguishes the encephalomyelitis of antirabies vaccination from that following vaccinia and the eruptive fevers. In the former, the pathological changes predominate in the spinal cord and not in the brain whereas in the latter the reverse obtains. A second histological picture has been reported and that is one of a polyradiculoneuronitis. As far as we are aware this has been described on only three occasions, two cases by GETZOWA, STUART and KRIKOmAN (1933) and one case by GLASER and SMITH (1951). T h e rarity of the description does

376

N E U R O P A R A L Y T I C ACCIDENTS OF ANTIRABIES V A C C I N A T I O N

not relegate it to a position of purely academic interest for, in our opinion, it would appear to be the pathology of many of the non-fatal neuroparalytic accidents. I n the case reported by GLASER and SMITH (1951) the lesions were found mainly in cranial and peripheral nerves and i n the spinal ganglia. I n the cranial and peripheral nerves there were areas of perivascular infiltration with lymphocytes and spaces filled with granular eosinophilic material were found between nerve bundles. These latter, because of their number, distribution and content of precipitated protein, were interpreted as evidence of actual oedema of the nerve. The neurons of the dorsal ganglia showed nuclear changes and increased numbers of satellite ceils around the ganglion cells. No significant changes were encountered in the cell bodies of the central nervous system but the axons of these cells in several sites, especially in the thoracic and lumbar region, were thicker, tortuous and folded acutely at many points along their course. I n the two cases described by GETZOWA,STUARTand KRIKORIAN(1933) no description of the histology of peripheral nerves is given, but the changes seen in the spinal ganglion cells, both motor and sensory alike, were advanced. These were dominantly nuclear, proceeding often to complete karyolysis and final cytolysis. Oedema of the gray substance of the cord, enlargement of perivascular and pericellular lymph spaces and oedema of glia were also described. The findings reported by these two groups of observers are consistent with the changes found in sporadic fatal cases of the Guillain-Barrd syndrome. In existing classifications of the neuroparalytic accidents no effort is made to distinguish between an ascending myelitis and the Guillain-Barr~ syndrome, both being grouped together as " Landry's paralysis." We would suggest the following classification based on the pathologies which have been described. Group

Pathology

Clinical Syndrome

1

Perivascular myelinoclasis

1. Dorsolumbar myelitis which may be ascending 2. Encephalomyelitis (Gordon's syndrome) 3. Encephalitis without paralysis

2

Polyradiculoneuronitis

Neuritis ranging from isolated 7th nerve palsies to extensive involvement causing death. (GuillainBarr4 syndrome)

It should be noted that combined syndromes have been recorded.

PATHOGENESIS

The theories which have been advanced as to the cause of the paralytic accidents are of two main types. The first postulates a virus origin and the second incriminates the nerve tissue contained in the vaccine. The hypothesis that the street virus, modified by the vaccine, is responsible, is untenable, provided it is accepted that naturally occuring rabies in animals is invariably fatal. As in seven of our cases, the biting animal has been proved frequently to be non-rabid. Many investigators in the past have subscribed to the belief that the accidents are the result of infection with the fixed virus of the vaccine. In this connection, it should be remembered that KELSER(1940), while filtering phenolized vaccine through wire gauze, recovered coarse particles which contained live virus capable of producing fixed virus rabies in rabbits. " Killed " vaccines in which phenol is employed, such as the Semple vaccine, cannot therefore be assumed to be free of living vaccine. REMLINGER (1905) considered that a rabies toxin, together with the fixed virus, was responsible. T h i s view has received little s u p p o r t . P e r h a p s the m o s t attractive of the infective theories is t h a t w h i c h postulates activation of a latent virus. GREENFIELD (1929) in discussing e n c e p h a l o m y e l i t i s following vaccine a n d e r u p t i v e fevers, states, Both the post-vaccinal and other forms of encephalitis which follow eruptive fever are not directly due to the virus of the preceding fever but to another virus which is either stimulated to activity or is directed against the nervous system by the exanthem.

A. ~. S. M C F A D Z E A N A N D G. H . C H O A

377

Advocates of this view would include the encephalomyelitis of rabies vaccination. This concept has been discussed by MARSDEN and HURST (1932) who believe that the encephalomyelitis of vaccinia, eruptive fevers, and antirabies vaccination is an independent exanthem. It should be noted that BABONNEIX and SIGWALD (1929) expressed the view that fixed virus of the vaccine activated a latent virus in the central nervous system. ! STUART and KRIKORIAN (1928) concluded from observations on experimental animals that the neuroparalytic accidents resulted from a constituent of normal nerve substance, which is toxic and capable of producing paralysis. T h e y considered, however, since they could establish no relation between the dose and the occurrence of paralysis, that there was strong evidence in favour of individual hypersentiveness to the cytotoxin. T h e most popularly supported hypothesis is that the neuroparalytic accidents of rabies vaccination is an expression of a sensitization reaction to the nerve substance contained in the vaccine. This view was first advanced by HARVEY and MCKENDRICK (1907) and subsequent experimental observations strongly support it. Adverse effects resulting from the injection of a saline suspension of brain were first reported by CENTANNI (1898). HURST(1932) observed paralysis in rabbits following repeated subcutaneous injection of a saline suspension of human brain but he could detect no microscopic lesions. RIVERS,SPRUNT and BERRY(1933) produced evidence of neurological disease in monkeys by injection of saline suspensions of rabbit brain. The histological picture was that of encephalomyelitis showing perivascular myelinoclasis. RIVERSand SCHWENTKER(1935) elaborated on this work and reported the histological picture in detail, and FERRAROand JERVlS (1940) confirmed their findings. MORGAN(1946) and KABAT,WOLF and BEZER(1947) by using adjuvants succeeded in reducing the time required to produce encephalomyelitis in monkeys with homologous and heterologous brain respectively. A similar result in rabbits was reported by MORRISON (1947). SCHWENTKERand RIVERS (1934) showed that homologous brain tissue injected into rabbits was definitely antigenic, and KOPELOFFand KOPELOFF(1944) employing heterologous brain and adjuvants demonstrated the presence of antibrain-antibodies in the serum of monkeys. Applying these observations to rabies-vaccine encephalomyelitis in man, KIRK and ECKER (1949) described an increased antibrain-antibody titre in the serum of such patients. It should be noted that the lesion experimentally produced is invariably a perivascular myelinoclasis and the hypothesis of sensitization to brain tissue contained in the vaccine can only apply to Group 1 syndromes. Further evidence suggesting that experimentally produced encephalomyelitis and Group 1 neuroparalytic accidents have the same pathogenesis is afforded by the similarity of their responses to A C T H and cortisone. This is discussed later. T h e pathological changes found in Group 2 neuroparalytic accidents are those typically found in sporadic fatal cases of the Guillain-Barr6 syndrome. T h e clinical picture and the elevation of the cerebrospinal fluid protein in the absence of pleocytosis, described below as occurring in members of this group, are consistent with this syndrome. T h e pathogenesis of the syndrome is unknown. BRADFORD,BASHEORD and WILSON (1918) considered that it was due to a specific virus. Hypothetical toxins have been implicated. Recently, however, PULLEN and SODEMAN (1946) and IVERSEN (1949) have drawn attention to similarities between this syndrome and other " allergic " diseases which follow infections, for example, acute rheumatism. Indeed, it has been described as " a hive of the central nervous system." In this connection recent work on the pathology of the condition emphasizes the possible part played b y oedema of the nerve roots. ROSEMAN and ARING (1941) and SCHEINKER (1949) considered that the sequence of events is an initial oedema of the nerve roots as they leave the spinal canal. T h e relatively inelastic dural sheath and, in the case of the 7th nerve, the facial canal, prevent expansion and this results in axon compression which in turn produces myelin degeneration and beading of the axons. This view regards the changes which occur in the ventral horn cells as secondary. Because of the conflicting views as to the patho-

378

NEUROPARALYTIC ACCIDENTS OF ANTIRABIES VACCINATION

genesis of the Guillain-Barr6 syndrome it would be idle to speculate as to its production by antirabies vaccination but since the pathology of Group 2 reactions is different from that of Group 1, and since similar lesions have not been described in experimentally produced encephalomyelitis, it would appear that the pathogenesis of Group 2 accidents may well be distinct from that of Group 1. The effect of adjuvants in accelerating the development of sensitization encephalomyelitis in experimental animals may well be of clinical significance. HORACK (1939) reported a personal or family history of allergic disease in 13 of 16 cases, an incidence of 87.5 per cent. as compared with 33 per cent. for a group in which no paralytic accidents occurred. In view of the effects of adjuvants in accelerating the production of encephalomyelitis in experimental animals it appears reasonable to consider that an allergic diathesis might well have an adjuvant-like action thereby explaining the frequency of histories of allergic diathesis among cases reported by HORACK (1939). In our series a history of allergy was not obtained from any of the patients. Six of the subjects, however, had an enlarged spleen and four of these gave a history of malaria. It was considered possible that the hyperplasia of reticulo-endothelial tissue might well result in an increased production of antibody. Preliminary observations, employing tetanus toxoid as the antigen, indicate that the production of antibody is increased in cases of chronic splenomegaly due to malaria. CLINICAL

The clinical details of the 14 cases which were personally observed are set out in Table III, A and B. From a study of the case reports in the literature and of our own material we are satisfied that severe constitutional disturbance is encountered in Group 1 accidents only. They consist of fever of sudden onset frequently associated with shivering and even rigors, head~ ache, severe backache and generalized aching pain, nausea and vomiting. These symptoms commonly anticipate the onset of evidence of involvement of the central nervous system by a significant period. In the present series the duration of prodromal symptoms ranged from 24 to 72 hours. Constitutional disturbance is not invariably present and, as will be seen from Table III A, it was absent in two cases, Nos. 1 and 2, both of which developed incomplete transverse myelitis from which recovery was rapid. In Group 2 accidents constitutional disturbance is minimal or absent and any subjective symptoms usually coincide with the onset of the paralysis and are the result of the pathology in the central nervous system. The most frequently reported syndrome in Group 1 is a dorsolumbar myelitis which varies in severity from a short-lived paresis of both legs, with or without sphincter trouble, to one which rapidly ascends. In many cases of dorso-lumbar myelitis there is co-existing evidence of encephalitis but when this is prominent, Gordon's syndrome, an encephalomyelitis with high mortality, results. A rare syndrome is the occurrence of encephalitis without paralysis. As far as we are aware only five examples have been recorded, one each by HORACK (1939), PICKAR and KRAMER 0949) and by the Massachusetts Department of Health (1947) and two by McFadzean (1952). One of the cases reported by FERNANDEZ, SORA and MACHADO(1951) may be of this category. In Group 2 the clinical pictures described range from an isolated facial paralysis almost invariably bilateral, to a bilateral facial paralysis associated with such extensive involvement

A. J. S. MCFADZEAN AND G. H. CHOA

379

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of the limb and trunk musculature that death results. All gradations between these two extremes may be encountered, and this is well illustrated by the five cases in the present series and by the three reported by MclNTYRE and KROUSE (1949). Involvement of the oculomotor nerves and pharyngeal paralysis have been described. Optic neuritis has been reported by KOENmSFELD (1945) and in a footnote to this p a p e r the editor mentioned an unpublished case of optic neuritis ascribed to the effects of antirabies vaccination. T h e muscles are commonly tender but sensory changes are variable. T h e sphincters usually escape and the planter responses remain flexor. T h e incidence of these syndromes cannot be accurately ascertained f r o m the literature because of confusion in terminology. AvEzzu (1923) in his analysis of 140 cases found 35 per cent. to be neuritic, 30 per cent. dorsolumbar myelitis, and paralysis of the L a n d r y type constituted 35 per cent. According to t~ASSOE and GRINKER (1930) of 243 cases with adequate data, 7th nerve palsies occurred in 58, paralysis of the L a n d r y type in 39, paraplegia with involvement of the bladder in 68, paresis of both legs with sphincter troubles in 21 and without t h e m in 33. I n our series five cases were of dorsolumbar myelitis and in one of these it ascended. T h e r e were four cases of encephalomyelitis and two of encephalitis without paralysis. T h e r e were five cases of G r o u p 2 reactions of greatly varying severity. F u r t h e r details are set out in T a b l e I I I , A and B.

W.B.C. Count

Cerebrospinal fluid

Differential Group 1

TABLE IV. The white cell counts and cerebrospinal fluid findings in 14 cases of neuroparalytic accident of antirabies vaccination.

Case Total No. (Thous./c.mm.)

N.P.%

E.%

Cells per . Protein c.mm. mg.%

1

10.1

89

1

17

43

2

11.3

92

--

49

52

3

12.2

82

5

38

51

5

14.2

84

1

65

62

6

16.6

91

--

7

16.8

92

9

9.4

86

10

•4.7

91

11

17.0

80

2

120

100

13

5.4

72

2

4

58

14

7.3

60

1

3

56

15

5.9

74

9

164

16

7.1

61

2

5

194

17

6.8

63

2

10

210

not done 240

1

96

not done not done

382

NEUROPARALYTIC ACCIDENTS OF ANTIRABIE8 VACCINATION LABORATORY FINDINGS

It will be seen from Table IV that all cases in Group 1 showed a leucocytosis. The total count ranged from 9,400 to 17,000 per c.mm., the average being 13,600. T h e differential count showed a predominance of neutrophil polymorphonuclear leucocytes of from 80 to 92 per cent., the average being 88 per cent. Only one case showed a significant increase in eosinophils, Case No. 3, in which they constituted 5 per cent. of a total white cell count of 12,200 per c.mm. Normal total and differential white cells count were encountered in all cases in Group 2. These findings are in agreement with cases reported in the literature. Of 14 cases of Group 1 reactions in which haematological data are available the average total white cell count was 11,300 per c.mm. and the average neutrophil percentage 85, whereas in six cases of Group 2 reactions the total and differential white cell counts were normal. The cerebrospinal fluid findings are available in six of the nine personal cases of Group 1, and in all five cases in Group 2. These are set out in Table IV. The fluid in cases in Group 1 showed a variable increase in cells and in protein, whereas in all cases in Group 2 there was albuminocytological dissociation with an increase in total protein. This finding is that encountered in the Guillain-Barr~ syndrome but as pointed out by MCINTYRE (1934) it has been observed in other forms of neuritis, for example those associated with diabetes, diphtheria, alcohol and periarteritis nodosa. EXTRANEURAL REACTIOI~S

HORACK (1939) classified the extraneura] reactions to antirabies vaccination into the following groups : Group 1. A generalized urticarial rash appearing soon after commencement of treatment and reacting to adrenaline. Group 2. Delayed reactions of the tuberculin type which occur at the site of injection. Group 3. Reactions similar to Group 2 but more severe and each injection may cause reaction at the sites of previous injections. There is frequently fever, headache, nausea and adenopathy, and it is this group which is prone to develop neuropara]ytic accidents.

The division of local reactions into Group 2 and Group 3 is in our view unwarranted since all gradations of severity may be encountered in the absence of significant constitutional symptoms and reactions at the sites of previous injections are commonplace. The occurrence of constitutional symptoms during administration of the vaccine, however, is of importance. Firstly,they cannot be distinguished from prodromal symptoms encountered in Group I. While it is true that many subjects with such symptoms do not develop signs of involvement of the central nervous system, examination of the cerebrospina] fluid may reveal abnormality. Thus in two of five cases, with severe constitutional symptoms but without signs of central nervous system involvement which came under our care, the protein content of the cerebrospinal fluid was raised to 48 and 52 mg. respectively. Secondly, constitutional symptoms may represent the phase of invasion of Group 2 accidents. One of the five cases with severe constitutional symptoms but with a normal cerebrospinal fluid developed, 12 days later, a severe polyneuritis of the Guillain-Barr~ type and is Case 17. Two other patients in Group 2, Cases 15 and 16, gave a history of fever, headache, generalized aching pain associated with nausea and vomiting during the course of administration of the vaccine, 16 and 8 days respectivelybefore the onset of the accident. It is our view that significant constitutional symptoms occurring in the course of antirabies vaccination should be

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regarded either as the prodromal symptoms of Group 1 reactions or as the stage of invasion of Group 2 reactions, In the absence of subsequent evidence of involvement of the central nervous system the attack must be regarded as aborted. HORACK(1934) urged that the sensitivity of patients to the vaccine should be determined before treatment, and if the patient proved to be sensitive, desensitization should be carried out by the graded dose technique. HALLE (1948) and THOMAS (1944) both considered this advisable and the former considered it especially desirable in cases which had been given the vaccine previously since there is a higher incidence of neuroparalytic accidents in these cases. For example, SELLARS (1946) reported a history of previous antirabies vaccination in five of seven cases, and LATIMER,WEBSTER and GURDJIAN(1951) such a history in two additional cases. Fifteen of our 17 cases were given intradermally 0.1 c.c. of 1/100 and 1/50 dilution of the vaccine. In three cases the vaccine employed was from the same batch that had been given to the patient previously. In only three could the reaction be regarded as abnormal, and these three were given vaccine from a different batch from that which had been used in treatment. The intradermal test was repeated 6 months later in two of the subjects showing an abnormal response and in each it had become normal. The intradermal response was negative in Case 12, 12 months after an encephalitis. These findings indicate that the local reactions to the vaccine bear no relationship to the neuroparalytic accidents and that intradermal tests prior to administration of the vaccine are valueless. TREATMENT

PICKAR and KRAMER (1949) and SLIPYAN (1948) considered that the course in their eases was favourably influenced by antihistamine drugs. Four of our patients, Nos. 3, 5, 7, and 16, were given parenteral diphenhydramine (benadryt). Local reactions when present were reduced in intensity but no discernible effect was exerted on the course of the neuroparalytic accidents. HALLE (1948) reported a similar failure in two cases.

KABAT,WOLF and BEZER(1951) and MOYER, JERVIS, BLACK, KOPROWSKIand Cox (1950) have shown that cortisone and A C T H respectively can prevent the development of encephalomyelitis in experimental animals. Cases 5, 9, and 10, with Group 1 reactions (two encephalomyelitis and one ascending myelitis) were treated with ACTH, 20 mg. being given daily intravenously by slow drip over 24 hours. The response of the constitutional symptoms and extraneural reactions was the same in each case. Within 24 hours the fever resolved and local reactions disappeared. Following the institution of the treatment there was no further extension of the lesion. While we are aware that the results of treatment must be interpreted with caution since the condition varies widely in its course, this uniform absence of extension appears to us to be of significance. Especially is this true in Cases 9 and 10 which were treated within 24 hours of the onset of symptoms of central nervous system involvement. Both were regarded as early severe encephalomyelitis which reasonably could be expected to progress if untreated. The response in Case 10 can only be described as dramatic in that a deeply comatose convulsing patient 24 hours after starting treatment had, as the only residue of a severe encephalitis, mild headache, somnolence and a retrograde amnesia. In Case 5 the lesion may well have reached its peak when treatment was started but up to that time the levels had been ascending rapidly. The rapidity of recovery of this patient from an extensive myelitis was outwith our experience. Four weeks after starting treatment, control of the bladder returned and he was able to walk unsupported. He was discharged C

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O F ANTIIRABIES V A C C I N A T I O N

from hospital 39 days after admission when the only subjective handicap was a slightly spastic ataxic gait. On examination at this time there was some residual impairment of muscle joint sense over both lower limbs, the tendon reflexes were increased and the plantar responses were extensor. When examined 4 weeks after discharge the gait was normal, sensation was intact but both plantar responses remained extensor. GARRISON(1952) and FERNANDEZ, SORA and MACHADO (1951) have each reported a case of encephalomyelitis treated with cortisone to which there appeared to be a dramatic response. ACTH was administered to Case 17, a Group 2 accident, less than 24 hours after the onset of paralysis. Twenty-four hours later there was relief of the paraesthesias and muscular pain and control of the bladder sphincter had returned. By the 4th day of treatment facial movements were normal save for some slight restriction of those of the lower face and there was return of sensory function. Strikingly the muscular weakness of the upper limbs and flaccid paralysis of the lower limbs showed no improvement. At the end of 4 weeks the patient discharged himself from hospital against medical advice for traditional Chinese treatment, and all contact with him was lost. If ACTH had an effect it was apparently restricted to resolution of the facial paralysis, the control of paraesthesias and pain, and return of sensory function. It is tempting to suggest that A C T H exerted an influence on the oedema of the nerve roots but that it exerted no apparent effect on the pathological process in the ventral horn cells. It can be stated that in this one case of Group 2 accidents the response following the administration of A C T H was not so favourable as that encountered in the three cases of Group 1 accidents similarly treated. Cortisone failed to prevent a fatal outcome in a severe neuritis complicating antirabies vaccination reported by GLASER and SMITH (1951). On the other hand it should be noted that STILLMANand GANONG (1952) reported a case of Guillain-Barr6 syndrome of undetermined aetiology in which A C T H and cortisone were considered to have produced rapid resolution of facial paralysis, return of sensory function and bladder control, and progressive reduction of muscular weakness. The employment of A C T H and cortisone in the treatment of neuroparalytic accidents raises the nice point of the course to adopt in the event of a neuroparalytic accident arising during treatment of a patient who has been bitten by a known rabid dog. Suppression of the hypersensitivity producing the accident may be associated theoretically with suppression of the immune response to the virus. Available relevant evidence indicates that this suppression of immune response does not occur, thus KASSand FINLAND(1951) reviewing the subject considered that ACTH and cortisone act not on the antibody-antigen unions nor on specific hypersensitivity mechanisms but rather on certain components of the inflammatory response. Under the circumstances outlined above we are of the opinion that A C T H or cortisone should be given to control the hypersensitivity response, and that the administration of the vaccine should be continued.

SUMMARY AND CONCLUSIONS

The reported incidence of neuroparalytic accidents of rabies vaccination is reviewed. In Hong Kong in the years 1949 to 1952, 14,119 patients were given the Semple vaccine and 17 cases of neuroparalytic accidents were known to have occurred, an incidence of 1 : 831. The incidence was higher in males and in those above 20 years of age but there was an equal racial incidence.

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T h e two pathologies reported in the literature are briefly described. M u c h the commoner, at autopsy, is an acute perivascular myelinoclasis. T h e second is one of a polyradiculoneuronitis indistinguishable from that encountered in fatal cases of the Guillain-Barr6 syndrome. T h e pathogenesis of the accidents is discussed. Available evidence suggests strongly that Group 1 accidents with perivascular myelinoclasis as their pathology are the expression of a sensitization reaction to the nerve substance contained in the vaccine. T h e response of this type of accident to A C T H and cortisone strengthens this conception. T h e pathogenesis of Group 2 accidents with polyradiculoneuronitis as their pathology is unknown but it is presumed to be similar to that of the Guillain-Barr6 syndrome. T h e clinical and laboratory findings in 14 personally observed cases of neuroparalytic accidents are briefly described. Nine were of Group 1 accidents (four transverse myelitis, one an ascending myelitis, three encephalomyelitis, one encephalitis without paralysis) and five were Group 2 accidents with polyneuritis of greatly varying severity. Group 1 accidents showed a polymorphonuclear leucocytosis which was not found in Group 2. T h e cerebrospinal fluid in Group 1 accidents showed a variable increase in cells and in protein, while that in Group 2 showed albuminocytological dissociation with a total increase in protein similar to that encountered in the Guillain-Barr6 syndrome. T h e significance of the extraneural reactions is discussed. It is concluded that local reactions are of no significance and intradermal tests are valueless, but that constitutional symptoms occurring during the course of antirabies vaccination Should be regarded as prodromal symptoms of Group 1 accidents or as the invasive phase of Group 2 accidents. T h r e e cases of Group 1 accidents and one case of Group 2 accident were treated with intravenous diphenhydramine without appreciable effect on the central nervous system lesion. T h r e e cases of Group 1 accidents were treated with A C T H and were considered to have responded satisfactorily, In one case the response was regarded as dramatic. One case of Group 2 accident was similarly treated with doubtful effect.

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