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·PREDISPOSITION TO POSTVACCINIAL ENCEPHALITIS

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·CONTENTS . 1 3 10 17 Chapter Introduction I Historical Survey. 2 Development of the Vaccination Problem in the Netherlands 3 The Dangers of Vaccination 4 Clinical Aspects of Post-Vaccinal Encephalitis 5 Pathological Anatomy 6 Euology 7 The Constitutional Factor in the Etiology of Post-Vaccinal Encephalitis A Literature Review 8 Constitution and Electivity in Infiammatory Processes of the Central Nervous System 9 Constitution and Predisposition in Post-Vaccinial Encephalitis 10 Prophylaxis and Therapy Summary Bibliography 20 32 46 64 73 84 127 Index 135 141 157

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·INTRODUCTION Of all the preventive measures in the history of Medicine, vaccination has given rise to the most controversy In the beginning the association of variolation with the much-feared small-por led to much dissension concerning the advantages, disadvantages and cien the dangers of varolation Later, once vaccination had been introduced and had proved its value, the battle, at least in medical circles, was restricted to the question of post-vaccinial encephalitis. Outside medical circles, especially in theological groups, the problems concerning vaccination remained very much alive On the one hand special church services were organized in order to celebrate the arrival of the vaccine, on the other hand there were many dissenting and disapproving theological articles and sermons. The dissenting voices became louder and found larger audiences in 1924/5, when Van Bouwdijk Bastiaanse published his first articles concerning post-vaccinial encephalitis Everyone was shocked. Controls were weakened Physicians who had previously considered vaccination a valuable preventive measure became hesitant or even stopped vaccinating completely This marked the birth of the post-vaccinial encephalitis problem A vast number of physicians went to work to clear this means of preventing a recurrence of smallpor' of the charges brought against It In order to find the factors involved in causing this feared complication, there followed a series of investigations and theories which resulted in an unending stream of publications While some people rejected varsolation from the very beginning on the grounds that smallpox was of an endogenous nature, the approach to the problem of post-vaccinial encephalitis was completely different ·2 INTRODUCTION True, vague remarks were made about the possibility of endogenous factors playing a role, but they were generally not followed up. The object of this investigation is to search for this endogenous predisposition in an attempt to bring the problem of post-vacciniual encephalitis closer to a solution, ·CHAPTER 1 HISTORICAL SURVEY On reviewing old East-Asian literature, it appears that the clinical picture of smallpox has been known for some time. How important this disease was in earlier times we do not know but we note that in India there was even a smallpox goddess. The first reports from other places, especially from Europe, came after a considerable lapse of time The increasing traffic and the migrations of whole populations were responsible for the spread of the disease during the years 400-600 A D Consequently, in the 15th century smallpor had become a common disease in Europe. In many places in Europe there appeared foci from which the por flared out to other areas In the 18th century, when the chance of infection was still great, the inoculation with variola vis was developed. This in turn resulted in a spread of infectious material while maintaining it locally in an active form. The universalty of the infection is reflected in the popular saying of the time "von Pocken und Liebe bleiben nur wenige frei" Generally small por was contracted in childhood When he consider that an epidemic had a mortality of approximately 30% and that a twelfth of the people died of smallpor, we can form some idea of what an awful threat this was for the population of that time The many theories concerned with the genesis of smallpox took into consideration this high frequency Some thought of the possibility of hered. stary 'Pox glands' or the spread of infectious material from mother to chud A different approach to the problem became possible through the discovery of bacteria The latter explanation attracted much attention and as a result the idea arose that it was not absolutely inevitable that one should contract smallpox Before this time, just as in the

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·HISTORICAL SURVEY 5 this brought about among the English aristocracy was understandably great. It caused the English King to have inoculated six convicts who had been sentenced to death. Following the success of this copenment, five orphans were also inoculated' When this latter treatment also succeeded inoculation spread like a fire through the English aristocracy but, quickly, there arose Yoices condemning the method. The opponents of variolation were divided into two groups: the physicians, who found it difficult to accept a method which was introduced by old women and other laymen, and the theologians, whose strongest argument was that the method originated in the East. In the beginning it appeared that the opponents of variolation would win unul, in England, a serious smallpox epidemic developed and the weapon of variolation was put to use. One would have expected this to have established the practice but such was not the case. Again there was resistance and rightly so Through the use of improper material and the air of charlatanry about the doctors who practised inoculation, this method once again was discredited Gatte of Pisa (1760) had more success. He introduced the smallpor material into the skin by means of a puncture and this usually lcd to the development of a muld, generalized exanthema. However, the danger of infection of others by the inoculated remained and, in addition, the method was costly and time-consuming. This development in the European countries led to the enforcement, in 1840, in many of these countries of a ban on inoculation Fortunately, other facts which offered more hope had become known From many countries (India, Peru, Mexico, England, France and Germany) came reports of people who remained well during smallpor epidemics and who were known to have been infected eariter with coupor' Hellwag (1801) reported a case of a girl who attempted in 1772 to infect herself by milking anımais with cowpor When this did not succeed, on the advice of a milkmaid she wounded herself and rubbed cowpor in the sound A later inoculation of the same girl with real smallpor material caused no ill effects! Later, several others made use of this same method (the Englishman Jesty in 1774, the Dane Jensen and the German Pleet in 1791) Unfortunately, little value was placed on these facts ·6 HUISTORICAL SURVEY The Englishman Jenner, born on May 17, 1749, knew nothing of these cases. In his youth he had heard from the wife of a farmer that having had cowpor had made her immune to smallpor. This led him to begin in 1775 a series of experiments which isd to the use of human cowpor lymph for vaccination. On May 14, 1796, the lymph was taken from milkmaid Sarah Nelms and administered to 8-)car-old James Phipps. A later inoculation of this boy with vanola produced no effect. Jenner's service was mainly in his prolonged series of experiments stemming from a folktale and his discovery of the vaccination with human lymph. This discovery made it possible to distribute the vaccine. The result of all this work was that in the beginning of the 19th century vaccination laws were passed in several European countries, beginning with the domains Piombino and Lucca, which had been established by Napoleon and were ruled by his brother-in-law. Vaccination also gained acceptance in countries outside Europe and ships carried human lymph ſrom vaccinated children to other parts of the world (The Phillippines, Peru, etc) Special church services were held to welcome those who brought the lymph The church was cven the site for the vaccination in the United States the first vaccination was performed on May 8. 1808, using vaccine from England. Benjaminc Waterhouse performed the vaccination on his own son after having read Jenner's reports. (The antagonism which he stirred up by this act made it necessary for him to resign from his position as professor at Harvard University in 1810.) In opposition to this enthusiasm, there arose antivaccination movements, and, in addition, there were many (among them Jenner) who warned against too great optimism Many of those who protested had already practised inoculation Their warnings about 'Vervichung now seem comical a vaccinated child became four-footed. another mooed like a cow and yet another coughed like a call or developed hair over its entire body! However, the warnings concerning failures in the vaccination were more authentic; it appeared that the lymph was often used without proper foresight, mistakes and carelessness were common, laymen administered vaccinations. Consequently, the results of vaccination fell far short of expectations. This prosed to be the case in England when, during smallpor cpidem- ·HISTORICAL SURVEY 7 ics, vaccinated people also fell 111, this did great harm to the reputation of vaccination. The fanatics defended themselves by placing the blame on the use of "bastard vaccine', but found even better support in the fact that the mortality in the case of vaccinated patients was considerably lower than in the unvaccinated. This is to be seen in the following statistics from the Stoch well Smallpor Hospital, London: Patients Scars Fatales 475% 703 516 632 677 301 259 none one poor one good two good three good four or more 250 5.3% 7.1% 23% 1.1% But this evidence was rejected on the grounds that the vaccinated patients were not recognized as smallpox patients In this battle, neither of the two sides made a systematic study of the problem. Another question was whether the acquired immunity of a vaccination would last a life-time or would disappear after a number of years. Inasmuch as the facts seemed to point towards the latter, Pearson advised revaccination. This was no discredit to vaccination for there were cases of people having had smallpox twice, and why should the immunity of a vaccination not decrease with time? Two things were clear from all of these facts (1) it was possible to contract smallpor after vaccination, even though it was generally in a mulder form (varioloid); (2) acquired immunity was temporary Since the danger of smallpox was (and still is) very great in ammtes the first revaccinations were performed on German military personnel. While previously smallpox had been predominantly a disease of children, the use of vaccination made the second and third decennia the most important and, understandably, the military were the most interested in revaccination. A standardized programme of vaccination of civilians was not yet in force in Germany. England also had difficulties in adopting vaccination regulations Polls were held among governments and physicians and it appeared that the transmission of syphilis was thought to be a great disadvantage, it had ·6 HISTORICAL SURVEY The Englishman Jenner, born on May 17, 1749, Inew nothing of these cases. In his youth he had heard from the wife of a farmer that having had cos por had made her immune to smallpos. This led him to begin in 1775 a series of experiments which led to the use of human cowpor lymph for vaccination. On May 14, 1796, the lymph was taken from milkmaid Sarah Nelms and administered to 8-)car-old James Phipps. A later inoculation of this boy with variola produced no eſſect. Jenner's service was mainly in his prolonged series of experiments stemming from a folktale and his discovery of the vaccination with human lymph This discovery made it possible to distribute the vaccine. The result of all this work was that in the beginning of the 19th century vaccination laws were passed in several European countries. beginning with the domains Piombino and Lucea, which had been established by Napoleon and were ruled by. his brother-in-law. Vaccination also gained acceptance in countries outside Europe and ships carried human lymph from vaccinated children to other parts of the world (The Phillippines, Peru, etc.) Special church services were held to welcome thosc who brought the lymph. The church was even the site for the vaccination. In the United States the first vaccination was performed on May 8, 1808, using vaccinc from England. Benjaminc Waterhouse performed the vaccination on his own son after having read Jenner's reports. (The antagonism which he stirred up by this act made it necessary for him to resign from his position as professor at Harvard University in 1810 ) In opposition to this enthusiasm, there arose antivaccination movements, and, in addition, there were many (among them Jenner) who wamed against too great optimism. Many of those who protested had already practised inoculation Their warnings about 'Vervichung now scem comical a vaccinated child became four.footed, another moocd like a cow and yet another coughed like a calf or developed hair over its entire body' However, the warnings concoming fatures in the vaccination were more authentic; it appeared that the lymph was often used without proper foresight, mistahes and carclessness were common, laymon administered vaccinations. Consequently, the results of vaccination fell far short of expectations. This proved to be the case in England when, during smallpor cpidem- ·HISTORICAL SURVEY 7 ICS, vaccinated people also fell ill, this did great harm to the reputation of vaccination The fanatics defended themselves by placing the blame on the use of 'bastard vaccine, but found even better support in the fact that the mortality in the case of vaccinated patients was considerably lower than in the unvaccinated. This is to be seen in the following statistics from the Stockwell Smallpox Hospital, London. Parents Scars Fatalles none 703 516 632 677 301 259 one poor one good two good three good four or more 47.5% 250% 5.3% 4.1% 2.3% 1.1% But this evidence was rejected on the grounds that the vaccinated pattents were not recognized as smallpor patients. In this battle, neither of the two sides made a systematic study of the problem Another question was whether the acquired immunity of a vaccination would last a life-time or would disappear after a number of years. Inasmuch as the facts seemed to point towards the latter, Pearson advised revaccination This was no discredit to vaccination for there were cases of people having had smallpor twice, and why should the immunity of a vaccination not decrease with time? Two things were clear from all of these facts. (1) it was possible to contract smallpor after Vaccination, even though it was generally in a mulder form (varialord); (2) acquired immunity was temporary Since the danger of smallpor was (and still is) very great in armies the first revaccinations were performed on German milttary personnel While previously smallpor had been predominantly a disease of children, the use of vaccination made the second and third decennia the most important and, understandably, the military were the most Interested in revaccination A standardized programme of vaccination of civilians was not yet in force in Germany England also had difficulties in adopting vaccination regulations Polls were held among governments and physicians and it appeared that the transmission of syphilis was thought to be a great disadvantage, it had ·6 HISTORICAL SURVEY The Englishman Jenner, born on May 17, 1749, knew nothing of these cases. In his youth he had heard from the wife of a farmer that having had cowpor had made her immunc to smallpor. This led him to begin in 1775 a series of experiments which led to the use of human cowpox lymph for vaccination. On May 14, 1796, the lymph was taken from milkmaid Sarah Nelms and administered to 8-year-old James Phipps. A later inoculation of this boy with variola produced no effect. Jenner's service was mainly in his prolonged series of experiments stemming from a folktalc and his discovery of the vaccination with human lymph. This discovery made 11 possible to distribute the vaccine. The result of all this work was that in the beginning of the 19th century vaccination laws were passed in several Europcan countries, beginning with the domains Piombino and Lucca, which had been established by Napoleon and were rul by his brother-in-law. Vaccination also gained acceptance in countries outside Europe and ships carried human lymph from vaccinated children to other parts of the world (The Phillippines, Peru, etc). Special church services were held to welcome those who brought the lymph. The church was cven the site for the vaccination In the United States the first vaccination was performed on May 8, 1808. using vaccine from England. Benjamine Waterhouse performed the vaccination on his own son after having sead Jenner's reports (The antagonism which he stirred up by this act made it necessary for him to resign from his position as professor at Harvard University in 1810) In opposition to this enthusiasm, there arose antivaccination movements, and, in addition, there were many (among them Jenner) who warned against too great optimism Many of those who protested had already practised inoculation. Th warnings about 'Venichunge nou scem comical a vaccinated child became four-footed, another mooed like a cow and yet another coughed irle a call or developed hair over its entire body' lloncver, the warnings concoming futures in the vaccination were more authentic; it appeared that the lymph was often used without proper foresight, mistakes and carelessness were common, laymen administered vaccinations. Consequently, the results of vaccination fell far short of erpectations, This prosed to be the case in England when, during smalipor cpidem- ·TIISTORICAL SURVEY 7 JOS, vaccinated people also fell ill; this did great harm to the reputafion of vaccination. The fanatics defended themselves by placing the blame on the use of bastard vaccine', but found even better support in the fact that the mortality in the case of vaccinated patients was considerably lower than in the unvaccinated. This is to be seen in the following statistics from the Stoch well Smallpor Hospital, London. Patients Scars Faroles 703 516 632 677 301 259 none one poor one good tuo good three good four or more 47.5% 250% 53% 41% 2.3% 1.1% But this evidence was rejected on the grounds that the vaccinated patients were not recognized as smullpor patients. In this battle, neither of the two sides made a systematic study of the problem Another question was whether the acquired immunity of a vaccination would last a life-time or would disappear after a number of years Inasmuch as the facts seemed to point towards the latter, Pearson advised revaccination. This was no discredit to vaccination for there were cases of people having had smallpor twice, and why should the immunity of a vaccination not decrease with time? Two things were clear from all of these facts: (1) it was possible to contract smallpor after vaccination, even though it was generally in a mulder form (varioloid); (2) acquired immunity was temporary Since the danger of smallpox was (and still is) very great in armies the first revaccinations were performed on German military personnel. While previously smallpox had been predominantly a disease of children, the use of vaccination made the second and third decennia the most important and, understandably, the military were the most interested in revaccination A standardized programme of vaccination of civilians was not yet in force in Germany. England also had difficulties in adopting vaccination regulations. Polls were held among governments and physicians and it appeared that the transmission of syphilis was thought to be a great disadvantage, ut had ·8 HISTORICAL SURVEY already occurred that spirochetes were transmitted with the smallpor material. During the 1860's another solution was sought and the possibility of using animal lymph was considered. The state of vaccination was rather poor, Epidemics continued to break out and in 1870 (war!) a veritable explosion of smallpor occurred as a result of the increased movement of the civilian population as well as military personnel. Exact statistics from this time do not exist, but it is thought that the mortality among the unvaccinated was between 30 and 70%. In the case of vaccinated patients, the morbidity and mortality were much louer. This led to the passing, on Apn! I, 1875, of a vaccination and revaccination law for the whole of Germany Originally, use was made of both animal and human lymph but because of the danger of the transmission of syphilis an investigation was carried out by Robert Koch, which led to the use of animal lymph only. This progress continued until almost all countries had regulations governing vaccination. In the 1930's Europe presented the following picture concerning vaccination:- France: mandatory vaccination before the age of one year, revaccination at the ages of 11 and 21. These regulations were icry important because of the close contact with North Africa. Great Britain vaccination was performed under the age of two, but parents were allowed to refuse on religious grounds. The vaccination picture varied from place to place, but was certainly not optimal Russia. had the same rules as France three obligatory vaccinations Italy: three periods during which vaccination was compulsory. 0-6 months, at school age, and during military senice. Germany had the best vaccination regulations. Here too there were certain periods of compulsory vaccination under the age or one, at the age of 12 for schoolchildren, and during military service. The regulations in the smaller countries have not been mentioned but generally follow the pattern of the rest. At present there are still national differences in Great Bntain, there is still a considerable number of unvaccinated are generally so because of religious convictions. The rather frequent occurrence of cerebral conplications of vaccination must also play a part here Turnbull was the first, in 1912, 10 recognize the clinical persons' these ·HISTORICAL SURVEY 9 picture of post-vaccimal encephalitis. In the 20's he wrote a report to the Minister but, before his findings were released to the public, Van Bourdisk Bastiaanse had had his first report published. This led, in Great Britain as well as in the Netherlands, to the establishment of an Encephalitis Committee. In France, even at present, the vaccination situation is more satisfactory; nevertheless, it is not ideal In 1954 there was an eruption of smallpor at Vannes in which a large number of unvaccinated patients, doctors and nurses were infected. In 1946 Great Britain stopped all regulation of vaccination, Through the great increase within the last decennia of continental and inter-continental traffic, the importance of vaccination regulations has assumed an international rather than a national character. We bekese that, because of certain affective reactions vaccination, the Netherlands occupy a more or less unique position in the world picture, as will be explained in the next chapter.

·DEVELOPMENT OF THE VACCINATION PROBLEM IN THE NETHERLANDS As was mentioned at the end of the last chapter, the Netherlars have been, and remain, in an unusual situation with regard to the problem of vaccination. While the arguments againse vaccination in Other countries were principally medical, those in our country were mainly of a theological or political nature. The Dutch tend to theologize. With this background of theology the problem of sacennatics became so affect-ioaded that it was often impossible to obtain an etjosa Inve, sober analysis or judgement. The objections to vaccination fase usually been voiced by members of the orthodor Protestant groups. These groups held the opinion that everything that happened was God's Will, and that if He ordained that we should fall ill it was mot proper that we should attempt ta thware the illness by taking precava vions such as vaccination They also quoted from the Bible saying that a healthy man needs no physician (see below) It is casily understood ihat such a point of vicw can lead to serious consequences The situation became even more complex when religion and politics became linked by the establishment of political parties with religious foundations This resulted in the colouring of parliamentary debates by the religious convictions of the various groups. In order to understand fully the difficulties which surrounded the problem of vaccination regulations we must always bear in mind the theological-political situation, The physician Abraham Capadose was closely involved in the derclopment of the problems concerned with vaccination. This physician, who had become conserted from Sudaism to Christianity, considered vaccination as he did magnetism He was among those who reasoned from Luke S 37 They that are whole need not 1 physician Furthes, reasoned Capadose, the number of desits within a certain period was predetermined, and those lives which might ·DEVELOPMENT OF THE VACCINATION PROBLEM be saved by vaccination would certainly be lost by other means! For a physician, a dangerous point of view! Capadose taught his followers that the ability to heal was a great gift but that one should not attempt to prevent disease because in doing so one tries to be greater than one's Creator, who called Himself merely a healer. There were some in the camp of the vaccination adherents who performed, often reprehensible, crperiments, frequently on foundlings and orphans. Capadose used these as the basis for his attacks on Vaccination, and not without reason. But when he states that because of the vaccination the children look miserable and that the human race suffers because the normal development is disturbed, it becomes difficult for a present-day physician to follow him It becomes more difficult when, after making the above statement, he later comes to the conclusion that no effect can be ctpected from vaccination since susceptibility to disease is a result of the Fall from grace and therefore, unalterable. Nevertheless, the influence of Capadose was considerable. Remarks of some politicians are in the same vern. Keuchenius, at the time one of the leaders of the Anti-Revolutionary Party said: “The Gospel is God's path towards salvation the vaccine is Jenner's way towards purification and health of the cow. Instead of the eternal Gospel of God's grace in Christ, the enlightened of this century have found a new Gospel, that of Jenner's cow's love for mankind, which speaks of sin and redemption, but the sin is only by smallpox, and the redemption, only from the taint of pox" Having indicated the atmosphere surrounding the vaccination question, we should like to follow the development of vaccination regulations in the Netherlands The translation of Jenner's work in 1801 was a signal for many to intensify their fight against vaccination. Prior to this, when only the inoculation method was used, there might only be carried out with the consent of the 'Magistrate' and only at times when small-por had been diagnosed in that locality By 1825, vaccination had practically replaced inoculation with smallpor virus, so that the battle was concerned solely with vaccination ·12 DEVELOPMENT OF THE VACCINATION PROBLEN This battle was not in the beginning an official one (sec above). Under the influence of the development of vaccination regulations in other countries it probably became increasingly clear that something along these lines was needed in the Netherlands, On December 4th, 1872, under the guidance of Minister Thorbecke, the first vaccination law became a fact. Vaccination was declared compulsory for pupils and teachers in primary schools, for volunteers in charitable institutions, prisons and for Army and Navy personnel. In some places pro-vaccination propaganda took the form of premiums, etc. In spite of the protests from those whose religious and moral principles were in conflict with vaccination, the law remained in force until 1929. This is not to say that there were not many attempts to change the course of events, among others by the proposed law of 1903 (Kuyper). This was intended to reduce the number of children absent from school because of non-compliance with the law of 1872 by making it possiblc to receive a certificate of exemption from vaccination because of religious convictions. This was to be coupled with a declaration that the person was not insured against the effects of a disaster (fire, Storm, etc.), These certificates were to be requested orally from the Mayor in the presence of two witnesses. The eremption was valid for one year. At the same time it was strongly advised that school personnel and children above the age of eleven should be revaccinated. The above became law on July 17th, 1911. In 1924 a new law was proposed by Aalbersc, suggesting that denominational and non-denominational schools be treated alike, that the validity of exemptions be crtended to three years, and that the requirement of two witnesses be replaced by the sucaning of an oath. This law was never passed oning to the change of Ministries in 1925. Meanwhile, the first reports of post-saccipial encephalitis had been published (Van Boundijk Bastiaanse et al.). This gave risc to a new problem Laymen and physicians airke became hesitant and this resulted in the law valid at that time becoming completely inciTectual. In February, 1927, the Afinisters proclaimed that the proposed changes cacceded the limits sei by the Cabinct. This fired the situation ·DEVELOPMENT OF THE VACCINATION PROBLEM 13 of vaccination at the 1872 level, but it was not to remain there for long. On March 9th, Byleveld proposed an amendment granting eremption from vaccination on the ground of conflicting principles, and with terms similar to those suggested by Aalberse but with the following changes. The exemption would be permanent and the limitation on the total number of eremptions would be eliminated The revaccination regulations were to remain unchanged The amendment was defeated, changed and re-submitted in its new form. After fierce opposition the amendment was passed on June 8th, 1927. In February, 1928, enforcement of the indirect compulsion was postponed until January 1st, 1930, and because of the threat of postvaccinial encephalitis repeatedly postponed, each time for the period of one year. In 1938 a committee (the second) was formed to investigate whether the law of 1928 should be enforced or changed and, if changed, in what manner. This led to the drawing up of a new law which was passed on December 22nd, 1939, and became effective as of January Ist, 1940. This law stated that all children should be vaccinated before reaching the age of one year. The parents would be warned by the Mayor of their community when a child reached the age of four months. Exemptions were to be obtainable on application; a physician had to be consulted and the reasons, medical and otherwise, given The penalty for failure to comply with this order was a ferm of imprisonment and a maximum fine of 100 guilders Thus, this law utilized the means of individual legal persuasion. The result has been that since that time the majority of the inhabitants of the Netherlands have been vaccinated between the ages of six and twelve months A weak spot in our vaccination condition arose in the years preceeding 1939. parents did not have their children vaccinated, and physicians, recognizing the risks involved, hesitated to take the initiative As a result, a considerable group of persons now aged 20-35 years have never been vaccinated, Since it is largely from this age group that both the mıhtary recruits and emigrants come, the risk involved in vaccination (In this case primary vaccination) was considerably increased, a fact that is reflected in the statistics of the last few years ·14 DEVELOPMENT OF THE VACCINATION PROBLEM TABLE 1 UNIRER OF CASES OF AND FATALITIES TROY VARIOLA MAJOR (VARIOLA MINOR) IN ADDITION TO THE AUMBER VACCINATED AGAINST SMALLPO SINCE 1900 Number of coses Yurtola major Total frariola mimor) number of Carer Death racei RS Awal l'emise of variouflantol Carltren of Alberner Aldren of 0-5 years Per lom Inhabitants 109) Year واموره مردم 6 8 5 22 12 13 6 6 1 4 1900 68 1901 40 1903 56 1903 150 1904 106 1905 64 1906 43 1907 43 1908 7 1909 17 1910 7 1911 4 1912 8 1913 37 1914 2 1915 7 1916 85 1917 1918 1919 1920 SO 1921 1922 1923 1924 1925 2 1926 3 1927 1928 1929 2(449) 1930 1931 1932 1933 1934 8 129021 127217 142189 137500 130159 133357 154749 135387 738634 140589 143836 142213 142913 185423 161665 153463 163-402 1386-45 142728 147128 149392 1409-19 145370 159063 162328 165386 174847 150653 52757 1469914 2713) 28528 26338 35096 21940 25.27 786933 24.56 79-4787 26 57 804097 25.74 813918 23 80 824306 24.03 835136 27.47 847019 23 71 858248 23.96 861961 23 99 871576 24 37 879344 23 76 880785 23.55 884168 30.08 893726 26 02 903670 24 00 909566 25 08 914189 20 87 923787 21.29 921993 21 59 911029 21.95 914573 20,20 935758 20 51 9553-49 22 25 974523 22.35 998008 22 48 1018639 23 71 1021838 20.01 1011831 692 1007409 190.14 1003340 346 999330 360 1000723 327 1003035 307 1001333 3.63 1001830 118308 116473 115615 19825 119458 120983 136419 124742 127579 129242 133703 131351 131660 138-499 137631 137244 141672 125627 131787 13.1171 133991 127467 132580 145927 149646 133028 157412 140414 49873 104140 33417 26667 24416 22899 19132 150,34 146 55 14378 147.22 14492 1.4787 161.05 14534 147.50 148 29 152 OS 149 36 149 91 15497 12.30 150 89 15497 135 99 142.78 147.57 146 31 138 22 138.78 149 74 149.94 15023 ISOS 138.77 49 S1 10) 83 25 42 2661 5 3 21 1 Il 32 $0 19 10 ·DEVELOPMENT OF THE VACCINATION PROBLEM 15 Amber of cars ratidla major $varkide Cases Degek Yatal Number of taimeriont Per JAN Inhabitants Awinder of Number of vaccinations of children of Chiwen of 0-5 years 0-5 years PT 1000 caluron a 0-5 years I'rar 1 1935 1936 1931 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 19.48 1949 1950 1951 1952 17682 2.09 997882 15069 15 10 21061 2,48 992868 18562 18.29 25485 2.95 987584 21630 21 90 30969 3.56 986096 28272 28,76 40984 4 67 992696 37638 37.91 61840 6,98 1488-46) 48327 324 63 94058 10 49 181959 80996 47513 92846 10 31 189975 87689 456 74 88148 969 209379 85623 408.90 Because of the war, figures are not reliable. 79988 8 49 284456 75437 265 20 174158 1809 267348 13530 SOS 45 155699 1589 247923 150774 607 06 220122 22 11 236177 171572 726 99 109730) 10.85 ) 229369 107299 ) 467 80 ) 641379) 6249) 228631 14$858) 638 00 *) 144829 ) 1395) 232557 141540"> 608 62) $2 2 > In connection with the vaccination law of 1939, the figures for the cars following 1939 refer to the number of five births and to the number of vaccinations performed under the age of 2 years ) Provisional statistics In addition to the above-mentioned circumstances, the danger of an insufficiently vaccinated population was demonstrated when it became necessary to perform mass vaccination in the southern part of our country because that area was exposed to the very real threat of an epidemic. This applies particularly to Tilburg Fortunately, vaccination has been gaimng ground in the Netherlands (cf. Table 1) We are becoming convinced that vaccination of an entire population must not be neglected, especially in view of the recent threats (1947 and 1951 in Tilburg. 1953-54 in The Hague) Nevertheless, the problem of post-vaccinial complications of the central nervous system remains And this is a very real danger' in 1954 compulsory vaccination of recruts became law. Those refusing ·18 THE DANGERS OF VACCINATION an unvaccinated person. In our Out-Patient Department, we $21 child with posi-vaccinial encephalitis who had transmitied the sac to her mother, with the result that the latter contracted a vacci gencralisata. After this, a condition descloped which we shall cal *dienecphalosis' (Sillevis Smitt) This is probably a case of a coret reaction to a vaccini infection, (3) Eczema vaccinatum: This can be caused by (unu isely) vaccinat a child suffering from eczema, or by infection of the child through means discussed under (A). (C) Neuralgia: especially after revaccination (Wayenburg, Bouudijk Bastiaanse). (D) Vaccinia: gencralized syndrome such as we also scc with ou contagious diseases and which appears during the development of i por.pustules. See Chapter 4 (Sissingh) (C) Convulsions in children: Report of the Netherlands Society 1 the Advancement of Medicine. (F) Increased retal mortality in the second and third months pregnancy The possibility of this was established by MacArthur in 1952 duri an investigation concerning the elect on fctal mortality of vaccinatı This raises the question whether there is trans-placental infection the fetus, it is more or less to be ctpected considering its occurren in other virus discases such as German measles Greenberg and othe on the other hand, believe that there is no connection between accer tion during pregnancy and increased fetal mortality. (G) Glomerulonephritis after succination Recently, Koster h brought forth neu euidence concerning this danger. He advises agair the Vaccination of cases of chronic nephritis because of the danger cute cracerbations The author has seen a case of post-vaccini encephalitis which was concomitant with a nephritis (H) Vaccina generaliszła the development of pustulos all over 1 body (1) Vaccination cranthema' this cranthema, seen following a vaccin tion, ethibits great Fanation it can look like measles, scarlet fosc or even crythema crudativum muluforme Most of the above skin changes desclop approumately onc Hee alter vaccination, therefore at about the same time as thc pustu ·THE DANGERS OF VACCINATION 19 reaches its maximum deselopment. In addition, there are other shin conditions which occur later and are seen especially after revaccination Here the incubation period varies between 16 and 21 days. We can dillerentiate between two groups (Alalie et al.); (1) Very diffuse rapulovesicular cranthema in addition to forms which are primarily papular, we also see vesicular forms, and others consisting of very small rapules. (2) Solitary erythemato-resicular spots which correspond with "Exanthèmes fires'. These conditions generally disappear spontaneously. No virus or other pathogenic organism has yet been isolated The possibility of an allergic reaction must be considered. (J) On rare occasions we may see a haemorrhagic deathesis, with bleeding into the skin, mucosae, and even kidneys. Similar conditions are also seen in other virus discases (Veldkamp, Keyzer). (K) Positive Wassermann reaction following vaccination: this was originally described by Bellow et al, and more recently confirmed by Winser) (111) Late complications (A) Post-vaccinal pustulcs. occasionally, a second set of pustules appears 4 or 5 weeks after the vaccination, thus after the healing of the first set. (B) Kelord formation in the scar this is very resistant to therapy; we often see recurrence even after wide ercision (C) Post-accoual encephato-nyelites This important complication will now be considered ·22 CLINICAL ASPECTS The first step uc took was to separate thc encephahtides after revaccination. The total of the dates after primary vaccination is represented in Fig. 2. We see here a peak at 7 and one at 12 days. This could mean that we are dealing with a curve that is an expression of two factors, ie. the incubation period for young children and the incubation period for older children and adults. If we separate these results into two groups, one under two years (where we see clinically very little post-vacciniat cncephalitis) and one above tho years, we obtain the picture rep resented in Fig 3. We see that both diagrams tend to follow a regular curve. The first diagram shous a peah at 12-13 days, which is the incubation period that is generally seen in post-vaccinial encephalitis The second shows a peak at 7 days but also shows a morc irregular picture and the spread is large. Our findings have been checked by the Statistics Department of the TNO by means of Student's test The ascrage incubation period of cuses of post-vaccinal encephalitis in children over the age of two was 11 57 day's In the group from 0-2 years it was 9 days. The difference between the averages (2.57 days) is very strongly signifcant (p < 00001) In addition, it appeared that the spread of incub.llion penods in the two groups was significantly different; it was much greater in the 0-2 group than in the group over two (P -- 003) The standard deviations were found to be respectively 3.4 and 2 6 days Although the / test can theoretically only be used if the spreading usthin both groups is the same, the statistician believes the significance of the difference between the two averages to be so great that the difference in spread within the groups has no influence on the con. clusion Since sonic boitere that post-vaccinal cncephalitis in young children is based on a chance coincidence of a vaccination and an encephalitis, uc had our statistics ctamined as to the probability of such an occurrence If it were true that the chance of encephalus .35 independent of the cime, 18, that this chance was equally great for cicry child every day, then we should (if indeed the occurrence of cncephalitis had nothing to do with vaccination) ctpect 10 sec a regular (rectangular) distribution Buching. through the use of the ( 13)

·CLINICAL ASPECTS
23
Number of cases
will.
10
20
15
Incubation period in doys
Number of cases
ul.la
20
Incubation periods in days
Number of coses
10
15
Incubation periods in days
Fig 3 (A), Cases Over 2 years of age. (B), Cases under 2 years of age;
(C) Cases after revaccination

·24 CLINICAL ASPECTS table showed, however, that there was a significant deviation (P = 0.001) from the rectangular distribution. There must therefore be a relationship between the vaccination and the encephalıuides which follow them Exactly what this relationship is must be further investigated. The onset of the disease is generally acute or subacuts. One oflen finds that during the development of the pot pustule the patient gexs through a period where he feels sick and has a high temperature, with or without cephalalgia. This is the picture of the vaccinia. One or more days later the disease symptoms can break out again, this time mere abruptly; these are the first symptoms of post-vaccinal cncephalitis. The most striking symptoms in the beginning are: (1) Fever. Often extremely high. (2) Mental conſusion. The intensity varies from patient to patient, not only as an early symptom but also during the course of the discase. and ranges from slight disturbances in the level of consciousness ut here the patient cxhibits amentia, to cases where patients are in a coma (3) Headache. This is generally throughout the whole head, especially in the occipital region. Often there is vomiting and signs of meningea! stimulation, e.g rigidity of the neck, sign of Kernig. Brudzinsky (4) Convulsions. Seen especially in children in the early stages but occasionally in adults also. Very young children often have lengthy spasms of their extremities with or without trismus With this general syndrome we also see other symptoms that have a focal character. In a large group of cases there are signs that point to pyramid tract involvement. We can find un or bi-lateral pathological reflexes with or without paretic symptoms Symptoms pointing to involvement of the extra-pyramid system are scen occasionally. In 1954 we saw a patient with post-vaccinial encephalitis who did not show any parcsis but who was unable to perform the finger-nose test correctly The movement was one betucen a cerebellar atatia and a rough tremmer such as is seen in damage of the basal ganglions. In the arms there was cogwheel rigidity The cranud nentes may be affected, the motor-cranial nenes usually being the most involcd ·CLINICAL ASPECTS 25 In the group of families that he investigated we found a probable abortive case that expressed itself two weeks after vaccination by ocular muscle paresis (musc.rect ext) Occasionally during the course of the disease optic nerve neuritis was observed An almost constant symptom is mucturition disturbance: incontinence as well as retention. Sometimes signs of medulla oblongata involvement are seen; these include disturbances of respiration, swallowing and speech Investigators who describe hyperalgesia point out the possibility of spinal nerve involvement. This is usually in the background, however, and does not serve as an important diagnostic aid. In addition to the lowered level of consciousness, there are other psychic symptoms We have, for instance, noticed (patient p. 75) a negativism. This has been described by other investigators Delirium and agrypnia appeared occasionally. The laboratory findings of patients with post-vaccinial encephalitis vary widely. The blood sedimentation rate can be greatly increased but is often normal The cerebrospinal fluid shows changes that vary from one patient to the other One patient may have a normal cell value and another patient definite pathological changes in regard to cells The cell reaction varies from a slightly to a greatly increased number of lymphocytes The protein content of the cerebrospinal fluid is very often raised, extreme readings, however, are seldom seen The Mastix-sol and Gold curves are often pathological The changes are usually in the first part of the curve, resembling changes seen when there is rapid destruction of parenchyma The sugar content of the cerebrospinal fluid is a point of discussion Sometimes in postvaccinial encephalitis we find an increased sugar content but usually the findings are normal There is little support for the theory that the sugar level must be pathological, as in the cases of epidemic encephalatis After looking at the complete picture we can conclude that in post- -accinial encephalitis it is the cerebral symptoms that dominate, with Minor changes taking place in the myelum Occasionally the myelum changes dominate the picture In 1952 saw a young man of 20 who, 12 days after vaccination, showed syndrome of a transverse lesion of the spinal cord After several onths the condition cleared up without leaving any trace The case ·26 CLINICAL ASPECTS 1135 diagnosed as post-vaccinial transscrse mychtis at the level of DIV. Changes in the peripheral nenous system (neuralgia, peripheral paralysis) are seldom described in the literature. Neuralgia has been obscrved after re-vaccination (Van Wayenburg. Turnbull. Report of the Encephohns Commission, 1932, Silleus Smitt, Meunier, Van Bogaert). Viberall has described two cases of post-vacchial polyncurits during the vaccination of the population of Santiago di Chili. The course of post-vaccinial encephalitis varies. In the literature. therefore, one finds varying figures as regards mortality. Bcfore the second world war the following figures were gren (after Meunier), Tyrol 71.4% Belgium 31.6% Netherlands 31% Germany 35% England 40%. in 1947 Keyzer reported the epidemic in Tilburg as having a mortality of 2 per 27 patients. The course of the disease is usually tuo ucces. Sometimes the disease lasts but a few hours. These quick and usually scrious cases often cnd fatally. In the course of time the medical world began to accept the fact that post-vaccinial encephalitis cnded in one of tuo ways; cither death or recovery without any trace of the discase. Sillers Smit and Biemond, however, pointed out that recovery could occur with permanent damage to the nervous system In carrying out our family investigation uc unquired as to permanent damage. The findings were as follows Complete recovery. 48 patients, Fatalitics, 23 patients Incomplete recoscry 38 patients 3/46 Institutionalized for epilepy Imbecile. 7446 Epilepsy for two years following vaccination 2/47 Personality changes. 5,47 Cephalalgia 647 Personality changes 1647 Personality change's Intolerance for alcohol 19 47 Incontinentia urinac. Irritable Right-sided ratesis Pathological reflexos. (207 Patient's brother developed a strabismus following Vaccination ) ·CLINICAL ASPECTS 27 21/47 Derealization Incontinentia urinae. Same family. 22/47 Incontinentia urinae 27/47 Right leg paretic Right and left foot-sole refferes with dorsal flexion 29/47 Cephalalgia, 37/47 Incontinentia urinae. Walks with difficulty (anamnestic) 43747 Cephalalgia Has become \cry nenous. Cousin of 42/47. 44447 Left foot-sole reflex: dorsal flexion 33/47 Cephalalgia 59447 Incontinenti alyi et urinac 61/47 Patellar refer more active right than left Lelt foot-sole reller dorsal ferion. 1/48 Right hemiparesis Motor aphasia and alexia. 2/48 Mentally retarded. 8/48 Malaise in the afternoons 10/48 Epilepsy Plantar refleres dorsal flexion, 15/48 Cephalalgia Attacks similar to Menière 17/48 Plantar reflexes: night, dorsal flexion, left, uncertain 18/48 Easily tired Pain in left arm. Strabismus 12/49 Mentally retarded 14/49 Right plantar reflex, dubrous dorsal flexion 2/50 Ataria Epilepsy Right facial paresis 1/51 Cephalalgia Disturbed power of concentration 2/51 Spastic paraparesis of legs and paresis of left arm Scapulac alatae 4/51 Greatly increased need for sleep 15/51 Cephalalgia 19/51 Cephalalgia 22/51 Slight encephalopathic syndrome 31/51 Cephalalgia Depressive 36/51 Cephalalgia 45/51 Cephalalgia 54/51 Encephalopathic syndrome with pathological rage 59/51 Cephalalgia. (This table shows almost the same relations as found by Puntigam and Berger, 1936), An important point is the question of recurrences This was mentioned in the '1932 Report and later described by other writers (Rigotti, Hausmann) in connection with the evology (compared with the "Schube'in multiple sclerosis) we consider it undesirable to neglect this Point To the question What are the chances of getting post-vaccinta ·28 CLINICAL ASPECTS cncephalo-myelitis after vaccination? we find oursekos unable to give a clear-cut ansuer owing to the great variety of statistics. In the Netherlands during the years 1924-1934, there was one casc per 22,000 saccinations in one- and two-ycar-old patients. Mortality was 0. Amongst the sest of the population there was one casc per 3,600 vaccinations. For every 13,000 vaccinations one death was recorded. These figures are stated simply to gise the reader an idea as to the frequency of the disease; the figures has little value further. There are patients regularly attending our Neurological Out-Patients Department with symptoms that can be regarded as symptoms of previous post-vaccinal encephalitis. In many cases the diagnosis is made at the clinic for the first time. Therefore these are cases that have never found their way into the statistics. Even if the diagnosis had been made carlier we have no assurance that the case was registered with the Chief Medical Officer. This appeared not so cry long ago in an article concerning a number of cases in which the diagnosis of post-vaccinal cncephalo-myelitis was probably certain, On further investigation, the Chief Medical Officer appcared to inow nothing concerning these cases If we are to become better onented in the prevention of this syndrome, casc reports will have to be more complete Perhaps we can get a clearer picture of the incidence by reporting the results of the mass vaccination at Tilburg. 1,206 children or 0-6 years were vaccinated without a single case of post-vacciniai encephalitis resulting Following 14,792 vaccinations of children from 7-17 cars old, there were 27 cases in which the diag. nosis of post-vaccinial encephalitis was practically certain, which means that there was one case per 650 vaccinations (primary and revaccination together), which was to be expected (Terburgh) No cascs of post-vaccinial encephalitis were observed following the Vaccination of 758 persons older than 18 Nevertheless, the total number of encephaltides was rather large, comparablc only with the 1944-45 results of vaccinations in Basel, Switzerland, where there was a morbidity of 1-2", The Medical Officer (1952, p 161) reported 31 cases in five million vaccinations, 13 of which were fatal. or 750.000 vaccinations in Glasgow and Edinburgh in 1943 therr #cre 18 cases. 4 of which were fatal ·CLINICAL ASPECTS 29 In 1950 there were no new cases seen in 162,000 vaccinations The same holds for Brighton, where 90,000 vaccinations were performed. The question whether post-vaceisial encephalitis us encountered in children under the age of one year has received and continues to recene much attention We need only refer to articles by Jutrus and by Peters and Neurdenburg. Clinically, there have certainly been cases in which the diagnosis has been justified That the picture is very much altered when the patsent is a very young child may be seen in the different incubation periods and from the pathological anatomy, which we shall discuss presently Another very important question is that of the post-revaccinal encephalitis, which does occur, although much less frequently (Van Bouwdijk Bastiaanse) The morbidity of encephalitis after revaccination hes in the neighbourhood of 1:50.000 The Report of the Encephalitis Commission, 1932 mentions 26 cases occurring after revaccination. The cutaneous reaction was accelerated in seven cases the interval between primary vaccination and revaccination varied from 14 to 40 years, while the oldest patient was a man of 76 The mortality was 26.9%. We have already mentioned the occurrence of neuralgiform pain after revaccination According to correspondence from other authors and our own ctperience in the Utrecht clinic, this also occurs following primary vaccination The statistics published several years ago in Austria agree, to a large erlent, with the above For more information concerning postsevaccinal encephalitis see Chapter 5 After reading the above sketch of the many possibilities involved, it will become clear to the reader that the warnings at the beginning of this chapter were not without foundation. We can trace following series of post-accination events. The development of the pustules may be accompanied by fever, which may be extreme. The cephalalgia with or without signs of meningeal irritation and the lowering of the level of consciousness that often Accompany the fever make it difficult to differentiate between 'vaccinua' and post-vaccinal encephalius. In 1949, Sissingh found that of 570 vaccinations 119 people were found to have suffered from vaccinia, for an average of 4 days, and were unable to work We often see the same picture in oiber infectious diseases Comelia de Lange (1943) mentions the frequent occurrence of these symptoms ·30 CLINICAL ASPECTS in measles. They are so common in typhoid fever that they forman important aspect of the clinical picture Histologically, these conditions are characterized by a slight meningeal crudate (meningitis serosa) and a few lymphocytes around the parenchymal scssels (De l'ries) The difficulties of the differential diagnosis have stimulated a few workers to attempt to clarify the situation. Baumann suggested dividing the clinical pictures as follows: (A) Morbus postvaccinalis per se. Here we seconly general symptoms; there are no neurological or psychiatric changes. (B) Encephalopathia postiaccinalis. General neuropsychiatric symp toms without any signs of cerebral damage. (C) Encephalitis postiaccinalis. Neurological and/or cerebrospinal fluid changes. This classification docs not help us towards an casier and sharper differential diagnosis. Should sc classify a case of high fever plus slight lowering of the level of consciousness under (A) or under (13)? Obviously, these are symptoms of an infectious disease and, as such, fall under (A), but if we consider the psychiatric aspect (the louening of the level of consciousness) they can also be classified under (?) in addition, what exactly are se to understand by "general neuropsychiatric symptoms"? In 1932 the Encephalitis Commission attempted to set up a more practicable classification based on clinical findings plus any available pathological-anatomical evidence, It distinguished: (1) Cascs wluch, on the basis of the available cvidence, could be considered as being definitely post-vaccinal encephalitis. (11) Somcuhat doubtful cases which were in all probability postvaccinal encephalus (UIT Doubtful cases in which it was just as probable that they were not post-succinial encephalitis as that they use. (IV) Casos concerning which fittic more was known other than that vaccination was followed by illness or death, and where case reports Mere incomplete The commission did not think it justified to disregard these cascs completely if the period between accination and illness or death seemed to indicate a connection This classification is also far from perfect, especially when uc consider that the pathological anatomy must also be taken into ·CLINICAL ASPECTS 31 account. Thus ke see cerebral complications following vaccination which fall cimically more or less under the above classification, but which are anatomically quite different. Since we are neter aware of the pathological-anatomical picture at the bedside we might do well to ask whether it is even possible to make the diagnosis of postvaccinal encephalitis with certainty The pathological-anatomical changes which we shall discuss presently and which have been so often described as classical (ie the perivenous demyelinating microgła encephalus) must always be considered an addition 13 the chinical course. It is our opinion that by the diagnosis "post-vaccinial encephalıtıs' is meant the postvaccinial appearance of cerebral reactions which may be of infectious nature, In the majority of the cases and especially of the incubation period agrees with that outlined above, this reaction will be definitely connected with a vaccination and the anatomical changes will agree with the classical picture of the microglia encephalitis We must, however, make some reservations for the other possibihties.

·CHAPTERS PATHOLOGICAL ANATOMY We have been very fortunate in that. since 1925, the pathologicalanatomical investigation of cases of post-vaccinial encephalitis in the Netherlands has been largely carried out at the Utrecht Neurological Clinic (Van Bouw dijk Bastiaanse, L. Bouman, De Vries); this has led to the collection of a vast amount of material. Here we have come into close contact with the many problems concerning the anatomical background of this condition. Is there a specific histological picture to be seen in all cases in which the clinical diagnosis of post-vaccinial encephalitis has been made? In other words, is the more or less typical clinical picture accompanied by a specific anatomical background? Originally, this was thought to be so A series of investigators, many of them Dutch (Van Boundijk Bastiaanse, Cornelia de Lange, Brouwer, Sillevis Smull, Bouman. Bok, and others), described the picture which De Vries called, 'perivenous demyelınızıng microglia encephalitis' (abbreviated: 'microglia cnccphalıtıs') This was thought to be specific. In this condition, cry diffuse peri-senous or sometimes peri-arterial (but never porta capillary) masses of microglia cells are to be seen in the parenchyma (Fig. 4), and these microglial collections generally show more or less dilTuse demyelinization (Fig 5 and 6) Small collections of lymphocytes and mononuclear cells may also be present in the Virchou- Robin spaces (Perdrau, Comelia de Lange, Van Gehuchten and Falcon) The arons in these arcas of demyelinization remain largely intact, so that there is a discrepancy between the condition of the arons and the related myclin sheaths Also noteworthy is the fact that the ganghon cells in these arcas are completely unaffected This may be significant in considering the etiology (De Vries, Koklon). which will be discussed in a separate chapter.

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·duration of the clinical symptoms In cases of longer duration, the the connection of the clinical picture with the anatomical background 34 We should nou like to consider the problem already mentioned of PATHOLOGICAL ANATOMY This demyelinization and microglial grouth may also ha son ependymal and sub-pial, the so-called 'edge gliosis' (Wohlull. C... Lange, De Vries) seen with a slight meningeal reaction (Fig. 7). In the spinal cord, increases of glia can be observed along t: radiations of the posterior roots, the efferent veins, and the afferen! arteries. The affected areas of the cerebrum as well as the cerebemus are generally localized in the white matter, hence the inclusion of te condition under the group 'leuco-encephalstis' (Pette) This loca???" tion in the white matter becomes less and less clear the more caudal one makes sections (Van Bouw dıjk Bastiaansc, Turnbull and ... Intosh, Pette, Leiffer, Oesch, Finley and others). This means that in the brain stem (thalamic nuclei, globus pallidus, nucleus caudales substantia nigra) and in the spinal cord ke shall find affected areas in the grey matter. Here, there is very often a neuronophagia (De Vries, Van Bouwdigh Bastiaanse, Querida, Wiersma) Suppan reported that the incidence of localizations in the mid-brain and surrounding the fourth ventricle is higher in children under the age of S than in adults. Perdrau described early lymphocytic and plasma cell in&&- tration of the spinal ganglia. This changing of the histological picture at different levels is not an isolated phenomenon: in acute anterior poliomyelitis we often see that the bulbar reactions are more beniga and transient (the localization is more dangerous!) than the spiral oces The meningeal reaction shows itself as an infiltration of lympha ocytes and large mononuclear cells; we never sec plasma cells. The vascular reactions and haemorrhages are of an unknown narium (Lumsden, Van Gehuchten, Falcon). The parenchyma is normal around the infected areas, i.e. there is neither a diffuse oligoghaar increase nor an infiltration about the small vessels. According to De Vries the histological picture in the affected areas is fully developed by the lith day after vaccination, regardless of the vasculas filtration, which means that the greatest degree of anffarcas may become confluent through a more diffuse microglial pesia tration was not immediately around the vessel. In adduion, we may sec fat-granule cells in areas of greater necrosis.

·PATHOLOGICAL ANATOMY 35 called by De Vries peri-venous demyelinating microglial encephalitis. In 1939, Comby pointed out the various reaction patterns of the nervous system following vaccination, and Hans Jacob, in 1948, emphasized them further. In 1950, in an article entitled “Post-infectious encephalo-myelitis and multiple sclerosis", Ludo van Bogaert described several possibilities of cerebral reaction following infectious diseases. In addition to the peri-venous encephalitis, he differentiated. (1) nonsuppurative lymphocytic meningo-encephalitis, and (2) haemorrhagic pseudo-encephalitis. Constitutional factors were considered to decide which reaction would follow a given agent (see Hans Jacob) It is our opinion that post-vaccinal encephalitis may be similarly considered De Vries goes more deeply into the histological picture and sees several other possibilities. (A) Toxic encephalopathy After every vaccination there is a viremia and often a septicemia. Thus, there is always a varied amount of intoxication of the entire body which can lead to malaise, reaching its peak at the 4th or 5th day post-vaccination The malaise and fever may force the patient to cease work (Sissingh, see page 29) On rare occasions we may see a case in which these symptoms are very much intensified, headache, dullness and meningism may be accompanied by convulsions. If the patient succumbs and the cerebrum is examined, we see: (1) a slight meningeal exudate If this is increased we speak of ‘meningitis serosa'; (2) hyperemic meninges containing small amounts of lymphocytes and polymorphonuclear leucocytes, (3) lymphocytic infiltration of the parenchyma surrounding some of the vessels This more or less corresponds to the non-suppurative meningoencephalitis of Van Bogaert De Vnes classifies the following case as belonging to this group Child P, was born blind The mother had had German measles during the first trimester of pregnancy (We were unable, even after lengthy ques. tioning, to obtain full particulars concerning the mother's illness ) The primary vaccination took place at the age of 34 Six days later, the child became histless and the temperature rose to 40°C, at which point she suffered [text contrawed P 33

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·ETIOLOGY I' (B) The actuation theory has always had its supporters, cient me present day In 1949, Pison pointed to the activation of a latent visu 25 a causatne agent for post-vaccinal encephalitis. We are confron'! therefore with a condition Anoun as commensal infection to Loghem) In this regard we consider the lowered reststance it's patent as a primary factor and the actuating etiological ag: secondary factor. We know from the literature and also from personal ep. that in the genesis of infectious diseases conditions that lower res play a role (trzums, malnutrition, distus basices in the central segus 3 of various vital functions whether organic or functional) As . of this lowered resistance the infectious agent gets its chance It no way strange, therefore, that in the genesis of posz-usccomunal encephalitis consideration should be given to the possibility that the Vaccination itself is responsible for lowered resistance This would Mave the way for a latent encephalitogenic ur This reaso ing » supported by the fact that previously we never, or scurcly ever. Encountered encephalitis after vaccination After the first world - 3r there were many cases of epidemic encepha- Inis This served as a possible solucion to the problem since we then had a combination of the vaccine and an encephalitogenic virus (Stensers). As an argument for this theory, use has been made of the sporadic quality of post-ractinial encephalitis as regards ime assed place. This would fit in with the presence or adsencc at the ime of vaccination of the agent causiog encephalus In this light the strange occurrence of three cases of post-vacciual encephalitis after 36 vaccinations performed on the island of Marken can be viched in the lighs of this theory. It also might be used to explain the occurrence of several cases in one family. Recently the local occurrence of cases of encephalsts was used as the starting point for a study. Special attention was paid to the possibility of the occurrence of In addition to this the local occur- ? cceive atten- Tence, we have to consider tos when he discuss er A point in favour of the C virus in animals sicur tence at different ages.

·34 PATHOLOGICAL ANATOMY This demyelinization and microglial growth may also do Sul cpendymal and sub-pial, the so-called 'edge gliosis (Woh}ull, 6 d: Lange, De Vries) seen with a slight meningeal reaction (Fig. 7) in the spinal cord, increases of glis can be obsen ed along the radiations of the posterior roots, the efferent veins, and the allerede arteries. The affected areas of the cerebrum as well as the cerebelum are generally localized in the white matter, hence the inclusion of the condition under the group 'leuco-encephalitis' (Pette) This localization in the white matter becomes less and less clear the more caudillo one makes sections (Van Bouwdijk Bastiaanse, Tumbull und Mö Intosh, Pette, Leiffer, Oesch, Finley and others). This means that so the brain stem (thalamic nuclei, globus pallidus, nucleus caudatus, substantia nigra) and in the spinal cord ue shall find affected areas in the grey matter. Here, there is very often a neuronophagia ID: Vries, Van Bouw dijk Bastiaanse, Querido, Wiersma) Suppan reporish that the incidence of localizations in the mid-brain and surround.no the fourth ventricle is higher in children under the age of 5 than in adults Perdrau described early lymphocytic and plasma cell infiltration of the spinal ganglia. This changing of the histological picture at different levels is not an isolated phenomenon: in acute anterior poliomyelitis we often see that the bulbar reactions are more benign and transient (the localization is more dangerous!) than the spinat oncs The meningeal reaction shows itself as an infiltration of lymphocytes and large mononuclear cells; we never see plasma cehs. The vascular reactions and haemorrhages are of an unknown nature (Lumsden, Van Gchuchten, Falcon) The parenchyma is norms! around the infected areas, ie, there is neither a diffuse oligog!:! increasc nor an infiltration about the small vessels According to De Vries the histological picture in the affected areas is fully descioped by the 11th day after vaccination, regardless of the duration of the clinical symptoms in cases of longer duration, the areas may become confluent through a more diffuse microglial perta vascular infiltration, which means that the greatest degree of filtration us not immediately around the vessel. In addition, we may see fut-grumul cells in arcas of greater necrosis. We should nou like to consider the problem already mentioned or ihe connection of the clinical picture with the anatomical background ·PATHOLOGICAL ANATOMY 35 called by De Vries: peri-venous demyelinating microglial encephalitis. In 1939, Comby pointed out the various reaction patterns of the nervous system following vaccination, and Hans Jacob, in 1948, emphasized them further. In 1950, in an article entitled “Post-infectious encephalo-myelitis and multiple sclerosis", Ludo van Bogaert described several possibilities of cerebral reaction following infectious diseases. In addition to the peri-venous encephalitis, he differentiated. (1) nonsuppurative lymphocytic meningoencephalitis, and (2) haemorrhagic pseudo-encephalitis. Constitutional factors were considered to decide which reaction would follow a given agent (sce Hans Jacob). It is our opinion that post-vaccinal encephalitis may be similarly considered De Vries goes more deeply into the histological picture and sees several other possibilities. (A) Toxic encephalopathy After every vaccination there is a viremia and often a septicem. Thus, there is always a varied amount of intoxication of the entire body which can lead to malaise, reaching its peak at the 4th or 5th day post-vaccination. The malaise and fever may force the patient to cease work (Sissingh, see page 29) On rare occasions we may see a case in which these symptoms are very much intensified, headache, dullness and meningtsm may be accompanied by convulsions. If the patient succumbs and the cerebrum is examined, we see: (1) a slight meningeal exudate. If this is increased we speak of 'meningitis serosa'; (2) hyperemic meninges containing small amounts of lymphocytes and polymorphonuclear leucocytes, (3) lymphocytic infiltration of the parenchyma surrounding some of the vessels This more or less corresponds to the non-suppurative meningoencephalitis of Van Bogaert De Vries classifies the following case as belonging to this group. Child P, was born blind The mother had had German measles during the first trimester of pregnancy (We ucre unable, even after lengthy questioning. to obtain full particulars concerning the mother's illness.) The primary vaccination took place at the age of 54 Sut days later, the child became listless and the temperature rose to 40° C, at #huch point she suffered text onimned P 33) ·344 PATHOLOGICAL ANATOMY This demyelinization and microglial growth may also be se's ependymal and sub-pial, the so-called 'edge gliosis' (Wohlul, C.d: Lange, De Vries) seen with a slight meningeal reaction (Fig 7) In the spinal cord, increases of gira can be obsen ed along the radiations of the posterior roots, the efferent veins, and the afferere arteries The affected areas of the cerebrum as well as the cerebellum are generally localized in the white matter, hence the inclusion of the condition under the group 'leuco-encephalıtıs* (Pette) Thus localization in the white matter becomes less and less clear the more caudal one makes sections (Van Bouwdijk Bastiaanse, Turnbull und Mi- Intosh, Pette, Leiſler, Oesch, Finley and others). This means that in the brain stem (thalamıc nuclei. globus pallidus, nucleus caudatus. substantia nigra) and in the spinal cord wc shall find affected areas in the grey matter. Here, there is very often a neuronophagia (De Vries, Van Bouudijk Bastiaanse, Querido, Wiersma) Suppan reported that the incidence of localizations in the mid-brain and surrounding the fourth ventricle is higher in children under the age of 5 than in adults Perdrau described carly lymphocytic and plasma cell infile fration of the spinal ganglia. This changing of the histological picture at different levels is not an isolated phenomenon in acute anterior poliomyelitis we often see that the bulbar reactions are more benign and transient (the localization is more dangerous') than the spinalones. The meningeal reaction shows itself as an infiltration of lymph+ ocytes and large mononuclear cells; we neier sec plasma cells The Vascular reactions and haemorrhages are of an unknown nature (Lumsden, Van Gehuchten, Falcon). The parenchyma is norma around the infected arcas, le there is neither a diffuse oligoglia] increase nor an infiltration about the small vessels According to De Vries the histological picture in the affected 3re38 ts fully descioped by the 11th day after vaccination, regard’ess of the duration of the clinical symptoms in cases of longer ducation, the Jrous may become confluent through a more diffuse microglial pone suscular infiltration, which means that the greatese degree of an filffafton was not immediatcly around the sesscl. In addition, he may see fat-gunul cells in arcas of greater necrosis We should fou like to consider the problem already mentioned of the connectwn of the clinical picture with the anatomical background 7 ·PATHOLOGICAL ANATOMY 35 called by De Vriesperl-1cnous demyelinating microglial encephalitis. In 1939, Comby pointed out the various reaction patterns of the nervous system following vaccination, and Hans Jacob, in 1948, emphasized them further. In 1950, in an article entitled “Post-infectious encephalo-myelitis and multiple sclerosis", Ludo van Bogaert described several possibilities of cerebral reaction following infectious diseases, In addition to the peri-venous encephalius, he differentiated. (1) nonsuppurative lymphocytic meningo-encephalitis, and (2) haemorrhagic pseudo-encephalitis. Constitutional factors were considered to decide which reaction would follow a given agent (see Hans Jacob) It is our opinion that post-vaccinal encephalitis may be similarly considered De Vries goes more deeply into the histological picture and sees several other possibilities, (A) Toxic encephalopathy After every vaccination there is a viremia and often a septicemia Thus, there is always a varied amount of intovication of the entire body which can lead to malaise, reaching its peak at the 4th or 5th day post-vaccination. The malaise and ſever may force the patient to cease work (Sissingh, see page 29) On rare occasions we may see a case in which these symptoms are very much intensified headache. dullness and meningism may be accompanied by convulsions. If the patient succumbs and the cerebrum is examined, we see (1) a slight meningeal exudate. If this is increased we speak of 'meningitis serosa', (2) hyperemuc meninges containing small amounts of lymphocytes and polymorphonuclear leucocytes, (3) lymphocytic infiltration of the parenchyma surrounding some of the ressels. This more or less corresponds to the non-suppurative meningoencephalitis of Van Bogaert De Vries classifies the following case as belonging to this group Child P, was born blind The mother had had German measles during the first trimester of pregnancy (We were unable, even after lengthy questioning, to obtain full particulars concerning the mother's illness ) The primary vaccination took place at the age of St Six days later, the child became listless and the temperature rose to 40°C, at which point she suffered eos continued P 381 ·38 PATHOLOGICAL ANATOMY a convulsion She remained comstous and dıcd after 10 hours Cerebrospinal fluid: cells 7/3, total protein 14 mg7. Cornelia de Lange cramined the brain and diagnosed the case as a fulminating post-vaccinial encephalitis. D: Vries fater examined the same cerebrum and reported the following. The brain, as well as the internal organs, is Sery hyperemic, the pia capillaries are especially so. There is no clear suelling of the cerebrum. The sections show, in addition to a slight meningeal infiltration, a difTuse slight glial increase which is not peri-venous. Most of the round nuclci of the oligogla lie in rows along the vessels, mostly capillarics or pre-capillaries. Many of these glial cells contain protoplasm which can be coloured with Nissi's stain but which does not form a syncytrum with that of other cells as is the case with collections of microglia cells. No changes are observable in the myelin sheaths. As a curiosity, we may also mention the calcium-like concrements present in the walls of the vessels in the caudate nucleus and heterotopic grey matter in the occipital ventricular wall (a remainder of the intra-uterine rubella?) Fig 8 js reproduction of the genealogical trec of the patient's family. To sum up the findings. (1) The child had obviously degenerative stigmata (among others, the cerebral heterotopia). (2) It is very probable that the mother had rubella during her pregnancy. (3) There are vascular conditions in the family which give rise to symptoms at an early age (calcium in the vessel walls!). (4) We sec degenerative sugmata in the family. (5) The child died of a cerebral disorder following a vaccination. It is cry possible that it was because of this predisposed cerchrum that the reaction was so crplosne We wonder whether the vascular anomalies may not themselves have been responsible for the type of the histo-pathological picture, altering it so that it no longer fits into our scheme As we have already mentioned, the non-suppurainc meningocncephalitis of Van Bogaert belongs to this group. (B) Sometimes the faccinia is followed by an actual encephalitis, ·PATHOLOGICAL ANATOMY 39 which is clinically a post-vaccinal encephalitis, but which may show different pathological-anatomical pictures De Vries does not consider it justified to regard this as a cerebral aggraverion or condensation of the vaccinia septicaemia. He considers it very probable that there is a totin-antitovin reaction present. (C) A cute haemorrhagic encephalopathy (probably corresponding to the 'haemorrhagic pseudo-encephalitis' of Van Bogaert) De Vries describes the following casc. Puuent de G, aged 13 Successful primary vaccination at the age of it. Epileptic fits since her third year. At the age of 13 she was an imbecile cpilepuc, Six days after revaccination (without any visible results) she became sick, listless and showed muscular spasms. The next day she had an epileptic fit followed by a progressive coma Bronchitis developed and she died on the ninth day after the revaccination The brain showed much ocdema and hyperemia, many areas of subcortical demyelinization and gltal increases with central or ring-shaped haemorrhages The demyelinized areas were round and transversed by many myelinated strands. The masses of microglial cells were found only in the softened, necrotic centres This case was considered by Van Bouwdyk Bastiaanse and Querido as a typical post-vaccinial encephalitis but De Vries wonders whether this may not be Hurst's acute haemorrhagic leuco-encephalitis, which he (Hurst) considered one of the typical cerebral allergic reactions We also se: such a picture in experimental encephalitis (Wolf, see Page 58). (D) Complications after revaccination Van Bouwdijk Bastiaanse stated that the encephalus seen following revaccination (with a resulting reaction of immunity) differs from the typical microglta encephalitis. We do, however, see this typical picture when the revaccination shows a primary reaction In cases of postrevaccinial encephalo-myelitis we see round areas of demyelinization which look Itke of stains There are little or no peri-vascular microglia masses, but there is pseudo-neuronophagia and degeneration of nerve cells The histological pictures seen following revaccination vary so widely that De Vries does not consider it possible to classify ·40 PATHOLOGICAL ANATOMY these rare cases of post-revaccinial encephalitis until we have gained more experience. (E) Pjenuc-septicaemic encephaltis Here we are probably dealing with a cerebral inflammation caused by secondary infection. We sec small multiple arcas, sometimes with 1 central group of bacteria Here and there are small arcas crowded with polymorphonuclear leucocytes: the precursors of abscesses. Not in quently, all we see are small necrotic spots with collections of glial cells The patient described by De Vries was a diabetic. He became ill on the sixth day post-vaccination and died on the ninth day. This condibonpro bably developed from the viremic-septicaemic stage and had a shorter incubation period than is generally seen in post-vaccinial encephaltıs. (F) Acule anterior poliomyelitis has been reported sevcral times in connection with vaccination (Heidema, Burgerhout, Verjaal). (6) Panencephalitis has also (although rarely) been seen. This has been verified by patho-histological investigation. (H) Epidemic encephalitis was seen once by De Vries in an infant, On surveying the pathological anatomy, the value of the 'classical pern enous demyelinizing microglia encephalitis becomes somewhat less than absolute Corncha de Lange drew attention to this problem when she wrote in 1948. “neben klypersemie kann mann auch Orden finden. Nchrosen, Blutungen, beginnende Thrombosen und Aus. schutzung von Plasma Jus den Gerassen". De Vries also speaks of our sometimes finding things whose significance is not clear 10 us The degree of perriscular lymphocytic infiltration vanes greatly De Vries describes the case of a young man of 19, who succumbedd I dass after a vaccination, he found a degeneration of the substantia rigidshowing many suotten (sometimes pigment-free) cells or cellshadows without any infiltration This picture was quite different from what we generally cancet in a microgla encephalitis. The diagnosis of scuie anterior poliomyelitis could not be considered brosuse in ·PATHOLOGICAL ANATONY that condition kc always see the progression: cellular disease, neuronophagia, und inflammation. We must mention, however, that this cerebrum showed several old scars. In a child of 3) years De Vries found many oligogla nuclet in the peri-vascular arca. During the period of vaccination this child had been treated with scrum for pertussis. On reviewing all of the above, we can say that if the earlier reports (Van Boundyk Bastiaanse, Bouman and Bok, Van Hasselt, Bijl, Terburgh, Turnbull and McIntosh) on the pathological anatomy of post-vaccinial encephamis mere monotonous, this is certainly no longer the case! This devergence from the classical' picture, houcier, does not seem so senous when we consider that all the unusual vanations described by De Vries were found in cases whose histories revealed, in addition to vaccination, other occurrences which may very well have modificd the histological picture The future will hure 10 prove the accuracy of this hypothesis It remains difficult to draw any far-reaching conclusions from the pathological-anatomical picture, partly because the central nervous system is very limited in its means of reaction (Spielmeyer, De Lange, Report of the Encephalus Commission, 1932) We should now like to turn our attention to the question of whether or not post-vaccinial encephalitis is ever seen in young children. In 1938, Julius attempted to show by statistical means that encephalitis following the vaccination of young children must be considered as a coincidental occurrence. He found the same incidence of encephalitis in vaccinated and non-vaccinated chsldren of this age Peeters and Neurdenburg protested strongly against this pomt of view they constdered nothing proved one way or another concerning either the toincidental or the causal theories of post-vaccinal' encephalis in young children Some time ago, under the auspices of the TNO, a statistical analysis was carried out which shoued that the coincidence found by Julius was impossible De Vries examined the cerebra of 20 children under the age of 14 who died shortly after vaccination, 5 clear-cut cases of other diseases (embolus, meningococci. poliomyelitis, sinus chrombosis, epidemic encephalitis, and found:

·42 PATHOLOGICAL ANATOMY 3 cases of toric conditions (eczema vaccinatoria, enteritis, pneumonia) in addition to vaccinia; 4 cases of cerebral oedema; 11 cases of a toric picture, of which 5 had showni convulsions; and 1 case in which the cause of death was probably not cerebral. Why was he unable to find the picture of a microglia cncephalitis in children under the age of 1j? Not because of an absence of myelin, for there was sufficient myelin present. According to Flechsig. the association centra are myelinated after birth, at which time the projection centra are already myelinated. At birth, myelination of the brain stem, medulla oblongata and spinal cord has alrcady begun and is practically complete by the age of 1j. Let us follow D: Vnes's arguments still further. Microglia is also present at the age of 1); according to Hortega these cells penetrate the nervous tissue from the meninges during the prenatal period and have completed their migration after a period ranging from several days to several wechs. Evidence for this is the microglial collection seen in infants suffering from other diseases (e.g. poliomyelitis) The absencc of the microglial character in the encephalitis seen in (other) cranthematous discuses is also a problem: Dagnélie and Dubois described four cases of measles encephalitis and (like Musser and Hauser) found no microglia encephalitis. They also reported a case of encephalitis following varicella: some degree of demyelinization, but no microglia encef halitis. Zimmermann and Yanet described the case of a baby girl of 13 months who died 4 days after a varicella eruption; they found some demyelinization but no increase of microglia. Dubois, Ley and Dagnélie mention seven cases of encephalitis following pertussis, none of which showed the picture of a nucroglia cncephalitis. A great difficulty in the assessment of the value of the presence or absence of demyelinization is that we know nothing concerning the nature of the process itself. We see it in so many varied conditions. fat embolia, pinpoint haemorrhages, bacterial embolt (Woll) Here We are tempted to regard the vascular occlusion or changes as the cause, but why are the arons undamaged? They are known to be very sensitive 10 an oxygen deficiency. Krogh and Eppinger consider it possible that the demyelinization is brought about substance formed in the tissue itself. This would then secondanlı sore ·PATIIOLOGICAL ANATOMY cause the demyelinization. We can then hypothesize that the abnormal metabolism caused by vascular occlusion forms a substance having a demyelinating effect. In support of this theory is the fact that demycunization is absent in the very early stages (Graffar) We can cttend the theory still further: the touc ageat enters the arterial blood stream and reaches the parenchym.), where it causes tissuc damage, with or without a seaction, leading to the liberation of a demyelinating substance ((phosphatase?) Verlinde, Kret and De Vries) This substance us spread diffusely throughout the parenchyma and is not sufficsently concentrated to do serious damage. It then flows towards the venous system, with the result that the concentranon is increased and concomitantly the touc (c. demyelinating) clicct also. This may also serve to explain why the demyelinization is perivenous. If we assume that the substance passes through the venous wall, we arrive at a retrograde spread in regard to the normal flow. There is little support for Jacob's theory that the demyelmization is caused by a diffusion of plasma (a hyperergic inflammation), Alter this discussion of the nature of demyelinization we proceed Further with our problem. The other types of viral encephalus poliomyelitis, epidemic encephalitis, herpes encephalitis) scere in children of one year or younger show the same histopathological picture as in the adult cases De Vries can give no explanation for the fact that these viral encephalstdes show the same picture in adults and infants, whereas in the case of the para-infectious and postraccinial encephalitis the duergence is so great in 1949, Brante rummed up the various changes which the composition of myelin undergoes during life Edgar found significant differences between the chemical composition of myelin in young and adult rabbits. It is very possible that there is a connection between this difference in chemical composition and the means whereby the myelın reacts In Ifying to compare encephalins of various etiologies, we must never forget the warning by Rivers, “no known virus acting directly on the central nesvous system produces a perivascular demyelinating type ofencephalitis", which may mean that here we are confronted with an entirely different sort of process We should now like to consider whether or not we may class:fy the ·PATHOLOGICAL ANATOMY changes seen in children as belonging to the fulminating microglia encephalus. Unfortunately, it is not possible to compare the rapidly fatal cases in infants with those having had a longer course because the latter are not available. Thus, we have to compare fulminating and slower adult cases. First of all, we should like to go back to the case of child P, described on page 35. De Vries wonders whether this case might not be more suitably considered as a toxic vaccinia: in encephalitis we should expect a much longer incubation period Doring describes two cases, one of which, a man of 27, had an incubation period of 13 days in such cases uc generally find a typical microglia encephalus, but here this was not found. De Vries mentions the possibility of this being a case of slowly-developing microglia encephalitis in which death was caused by a rapid formation of cerebral oedema. This would also send to explain the acute clinical course, Pette (1947) divides the course of the microglia cncephalıs into two stages. Firstly, vascular dilatation with slight infiltrations and perivascular gla (oligoglia?), Secondly, the appearance of demyehnszation with pronounced collections of micro- and oligo-glia and of fat-granule cells surrounding the vessels Is it possible when we are unable to find the picture of a microglia encephalitis of post-mortem cxamination that convulsions have caused an carly death? Cornelia de Lange rightly warns of the danger of postulating organic cerebral damage when dealing with convulsions in children. It would scarcely appear justified to say (as does Gorter) that no encephalitis following the vaccination of young children is a real post-vaccinal encephalitis (sce Julius). Gorter believes that the appearance of con ulsions in a child depends more on the constitution of the child than on the acquired illness. This may be true in some Cuscs but it is definitely not valid as a generalization. The possibility is not excluded that the same constitutional factor may cause a predisposition not only to the reaction with convulsions but also to the cerebral reaction in the organic sense This, however, does not bring us any closer to a solution of the problem We do not behese that He can say any more than that the possibility ctists that consulsions occur without any ccrebral damage csen though the two generally no hand in hand, ·PATHOLOGICAL ANATOMY 45 De Vries describes two cases in which after an illness of one day, the patients dicd 11 and 13 days after vaccination Histologically, there was a clear microglia encephalitis. Since the cases described as fulminating show ohgogira reactions and areas of infiltration around the cortical vessels (arterioles as well as veins), De Vries finds it difficult to consider these as early stages of microgha encephalitis. He has seen the 'toric encephalopathy' cleven times in children of one year and younger, but has never seen a more advanced stage. Thus, he lacks the trait d'union with the microglia encephalitis. He suggests, therefore, that as long as we are unable to prove that the vaccinia virus is the cause of the encephalnis, we should consider the 'loxic encephalopathy as being connected with the vaccinia rather than the post-vaccinal encephalitis. From our point of view, it has hitherto not been desproved that reactions in children are different from those in adults. We do sce different pictures but may these not be caused by other properties of the terrain" (Comby) We see a parallel when we consider skın reactions. how often do we not see eczema infantum disappear as the child becomes older? The manner of reacting changes with age And who is surprised when this child, now older, suddenly begins to have attacks of asthma" Another example of differences in reaction is seen in the vaccination itself very young infants do not react to vaccination by developing a good immunity. It is also known that young animals do not readily produce antibodies. Doorschods showed that the titer of anti-vacciniahaemaglutination (an index of the immunity) is proporvonal 10 the age. The above are all separate stemts which (at present) we are unable to integrate.

·CHAPTER 6 ETIOLOGY We have seen in the preceding chapters that the post-haccınia! encephalitis is a clear-cut entity in which uc can cephekt various histological pictures (after the elimination of coincidental discases of the central nervous system occurring after vaccination) The arguments for uniform histological changes described by carlier investigators have been considerably wcalencd. We now have to consider the factors that play a role in postvaccinial encephalitis. We shall see at the end of the discussion that a definite solution has not been found. If we return once more to the Report of the Encephalins Cominussion, 1932, page 195, se read: “The chapter concerning etiology is a painful chapter After working on the problem for five years, the commission is as far from the solution as it was in 1925, when the question first Now, many years later, se read this passage again and realize that we have little to add We have learnt through the almost constant length of the incubation period that there is a connection betueen vaccination and the following cncephalitis. Alost probably, the incubation period for small children is different from that for adults (De Vries has recently pointed this out) and the pathological-anatomical changes in children are of another type than are seen in the majority of adults. We cannot agree with those investigators who consider encephalitis after vaccination of veryoung children coincidental (Julius, Pecters and Neurdenburg) If there is a relationship between the introduction of the vaccine into the body and inception of post-saccinal encephalisis, uhat are the possibilities? (1) The theory of superinfection Under this theory uc accept the fact that the cou por matenal is the carrier of 11 arose ·ETIOLOGY theory. Gorter, Blum and Boutier pointed out that previously encephalitis 47 (1) Bacteral contamination. This would serve as the causatic agent for the encephalıtıs (?) Non-bacterial contamination due to a concealed virus in the cowpor matenal which causes the post-saccinial encephalitis. (3) Touns (3) The coupor material activates a circulating virus. li could do this by maling the sinus pathogenic or by lowering the resistance of the patient, thereby giving the virus its chance. This is the commensal (C) The cowpor material causes the encephahtis (1) The virus itself is 'encephalitogenic'. (2) The virus gives off, via a certain change, an intermediate substance that has an encephalitogenic action (3) The encephalitis is an allergic reaction to the presence of the virus (A, 1) The possibility of bacterial infection caused by the vaccination was described in 1927 by Aldershoff. He, as well as Pette, was able to cause septicaenua in rabbits by vaccinating them with coupot material containing the otherwise innocuous Bacteriun bipolaris Pondman came to the conclusion that vaccinated rabbits died after the vaccination because of pasteurellosis The assumption that Pasteurella had anything to do with post-vaccinal encephalitis was not substantiated Control vaccinations with neurolapine, in which sterility may be assumed, were also followed by clear-cut cases or post-vaccinal encephalitis Convincing evidence has never buen found for bacterial contamination as a cause of post-vaccrmal encephalisis (A, 2) The possibilty that a virus is brought in with the vaccine and 15 the cause of the encephalitis, has never been proved It was Bijl who worked on this theory His work, especially in regard to the herpes Sirus as a cause, never produced any conclusive findings. Levaditi, among others, suggested the possibility of contamination of the vaccine with herpes virus He received the support of Gridemeister, Herzberg and Heuer, demonstrated immunological relationship berween the herpes and vaccine xirus Positive findings in support of the herpes contamination theory have never been found. following vaccination never appeared At that time the vaccine did ·50 ETIOLOGY circulating encephalitogenic virus. More convincing is the fact that post-raccinial encephalitis also occurs when different coupor materia! is used. Experiments with animais have not yielded satisfactory results. It has not been possible to culture an encephalitogenic sirus from organs of patients who died of post-accinial encephalitis. Using cerebral tissue of the same patients, it was only occasionally possible to culture the cowpor virus. Verlinde, honeser, by vaccinating a cynomolgus ape with a combination of cowpor virus and Columbia SK. virus, succeeded in producing an encephalitis which in part showed the histo-pathological picture similar to that of a microglia encephalitis with demyelinization. In his dissertation, Hoclen discussed success in culturing a virus from the naso-pharynt of patients with post-vaccinial encephalitis that was similar to the herpes and cncephalitis lethargica virus. Upon reviewing the above we can say: there are many arguments in favour of the activation theory but no conclusive proof. There are many infectious discases to which the above remarks could apply and yet we cannot consider that activation plays a role in them. As an example let us consider acute anterior poliomychtis. We know that during epidemics many people come in intimate contact with the poliomyelitis virus (Bicmond). Yet so few show clenical symptoms! Nevertheless, very few clinicians doubt the ctiology of the discase, regardless of its clectic nature. The mechanism of activation can sometimes play a role and this uc accept (See the chapter on pathological anatomy in which us described changes after vaccination that were different from the usual picture. Here we could have activation and loucring resistance playing a sôle ) Usberall belleses he has desproved any relationship with the polio myelitis virus During an epidemuc of poliomychtis a icry large group was saccinated and not a singic case of post-vikinial encephalis was observed Puntigam and Berger insestigated all cases of pohomyelitis in Vienna from 1957 until 1956 to find out if there was sy difference in occurrence of paralytic forms of poliomielius beineen two groups The first group was saccinated against smutſpor, she ·ETIOLOGY 51 second was not. They could not find any influence of vaccination in this respect The virus of lethargicencephalitis gives a different histo-pathological picture, which makes it very improbable that there is any connection betueen it and post-vaccinial encephalitis. From the point of view of epidemiology even less relationship can be found between post-vaccinial and lethargic encephalitis. (France had many cases of encephalitis lethargica without any increase in the number of cases of post-vaccinial encephalitis) De Vries once encountered a case of encephalitis lethargica after vaccination Since this is so rare we cannot consider it the rule, The description given above concerning the pathology of lethargic encephalitis also holds true for acute anterior poliomyelitis. The latter particularly affects the ganglion cells, whereas in post-vaccinal encephalitis the ganglion cells are often the only normal patches in an area of destruction Epidemiologically there is no relationship between the two (see above, Uiberall) In experimental work with animals we do not meet with any convincing arguments for the connection between the virus of pohomyelitis and post-vaccinial encephalitis In conclusion we should like to say that up to the present time it has not been possible to show a relationship between any virus, other than the vaccinia virus, and post-vaccinial encephalitis This is true for the so-called neurotropic viruses as well as for unknown encephalitogenic viruses. This does not mean that no work as being done in this field Nanning, in particular, is working on the problem. He sees a possible connection between the occurrence of post-vaccinjal encephalitis and the presence of the encephalitogenic virus in domestic animals. His finding of the Columbia S K virus in the faeces of a patient, although demonstrated only once, was the foundation for Verlinde's experiments (C) The cowpox virus as etiologic agent The argument that before 1924 no cases, or only sporadıc cases, of post-vaccinal encephalitis were seen has been used to refute the abovementioned hypothesis One does see in the literature, however, descriptions of complications after vaccination which suggest the ·$2 ETIOLOGY posibility of post-accinial encephalitis but this is by no means conclusive (Kaiser, 1803; de Caro, 1801; Freud, 1897; Comb). 1907; Turnbull, 1912). The following extract from the Report of the Encephalitis Comenis sion, 1932, can serve as our point of reference: When a patient in the course of typhoid fever develops osteomyelitis, or at the end of tobar pneumonia a meningitis, no one would consider the activation of an unknown virus as the most plausible explanation. The same report continues: One would think in the first case of typhoid bacilli and in the second case of pneumococci. If no typhoid bacilli and no pneumococci were found and if no other pathological microorganism were found, one would still not assume that an unknown virus was activated. One would, however, ash: Why were no typhus bacilli or pneumococci found? So much for the report. Why special complications occur in these cases still remains a mystery. This same applies to post-vaccinal encephalitis The difficulty in finding a solution is for a great part due to the caution which is needed in considering citological possibilities. Every neurologist knows of a case in which the parents tell of their child falling and thereafter showing signs of cerebral concussion, After the accident the child is never the same again. Walling 15 unsure and there are complaints of headache, with or withour vomit. ing. On exinuination we find an atara, and cyc examination shows choked discs. We find other symptoms indicating increased intracranial pressure. The accepted story of events of trauma capitis – intracranial haematoma - neurological picture is often a misunderstanding The cause of the fall appears, on further questioning, to be insufficient. The child has recently been a little unsure in walking and as result had fallen. A tumour in the posterior cranial fossa sencs to crplain the entire scquence of events. This crample shows us how caufious we must be in draming con clusions on the basis of signs and symploms seen in purricular sequence. In the above crampic a solution was found Hou different in the case of post-accrual encephalitis! If we do not accept the virus siself as being the causalic agent have ne another ciplanation? We have tried to showin the above that support in other darretions is lacking.

·ETIOLOGY 53 Is it possible to demonstrate the vaccinia virus in post-vaccinal encephalitis? After vaccination the pox pustule makes its appearance, it reaches its maximum between the eighth and twelfth day. This is about the same as the incubation period for the encephalitis and vaccinia generalısata After the fifth day antibodies are produced After the eighth day it is possible to demonstrate the specific precipitation reaction (Knor, Finley) In an accelerated local reaction we have seen an 'accelerated cerebral reaction (Comby, Querido) According to Eckstein the virus circulates in the blood from the third to the tenth day, From this we can consider the possibility of the vaccinia virus causing a cerebral reaction during the period of viraemia. This possibility is very slight since we have seen that it has never been possible to cause a picture of post-vaccinual encephalttis after the injection of the virus. It is true that after introducing a large quantity of the virus directly into animal cerebri encephalitis can be seen Here, however, the technique used is so far from the natural course of infection in post-vaccinial encephalitis that little information can be hoped for by further experimentation in this direction. Rivers has pointed out that no known virus that works directly upon the cerebral tissue can produce a microglia encephalitis. Occasionally, it has been possible to demonstrate the virus in the cerebrospinal fluid and the brain tissue of patients who died of post-vaccinial encephalitis The fact that this is not always possible is an argument against the virus as the encephalitogenic factor. An argument for the virus as causative agent is the fact that it has only once been possible to demonstrate a virus other than the vaccinia virus (Echo-virus by Verlinde) Positive findings on patients who died after vaccination due to other causes have never been described The frequent occurrence of negative findings led to a belief that there might be a connection with what Levadıtı called the 'neuroinfections mortelles autostérilisables' in which, in the course of the infectious process, all viruses are destroyed. This is supported by the fact that the cerebral tissue of patients who died of post-vaccinial encephalitis was able to inactivate the vaccinia virus ·54 ETIOLOGY Another possibility is that the virus is destroyed in the cerebral tissue and that the products of this destruction, being carried on towards the Senous system, give the picture of a microglia encephafilis (scc page 43). Whether libsrated phosphatase (Verlinde, Kret. De Vries) or some other demyelinating material (Yoll) plays a role here has yet to be proved. This might act as a starting point for an eoplanstion of the appearance of identical cerebral lesions in the sanious exanthematous diseases: we could postulate a substance 'Xwhich is liberated in the destruction of various viruses and which is responsible for the histological picture. Whether, in addition to 'X', other sub stances are liberated which, in the case of different viruses, are not identical has nothing to do with the matter under consideration. There are many attractive aspects to this line of reasoning, but more facts will have 10 become Anown before it gains support. Since nonc of the above theories are conclusive, other cuplanations were soughi. A good one was thought to have been found in the conception: allergy. This was first pointed out in 1927 by Glanzmann and later by Van Bogaert. The 'allergic reaction of the central nenous system' is, however, a difficult concept to understand and much has still to be learned about it. We are thinking in particular about the pictures called allergic reaction, in which demyelinization is the foremost phenomenon. However, there are other pictures described: Van der Horst describes the symptomatic psychosis and allergic reaction following pertussis vaccination; Hurst, what he calls the acute haemorrhagic icuco-encephalits; and Jacob, many types of possible allergic cerebral reactions. An allergic reaction takes place by the sudden rcaction befucen antigen und anubody, whereby the intensity of the reaction need not parallel that of the immunity reaction Fincy defines the latter as a specific biochemical reaction. brought about in the body by a foreign body, which gives rise to a specific immunity or hypersensie fivity of the body for that agent. Apart from this vague description. fe says nothing concerning what may take place in the cerebrumi. Hansen, in his book on allergy, characterizes the allergic 103fion by three points: (1) Sudden, paroxysmal beginning (2) Relatncly transiton character ·ETIOLOGY 55 (3) Usually rapid and complete regression. The basis for the above are smooth muscle spasms, vascular spasm, serous exudation and especially eosinophile infiltration The latter is seen where there is an intensive antigen contact with a sensitized tissue In cerebral reactions we are generally confronted with haematogenous spread, which raises problems which do not occur where the antigen comes into direct contact with the reacting organ Hansen wonders whether other factors (trauma, infections) may not have formed a locus minoris resistentiae (see page 61). Here again we see no sharp definition of cerebral allergy'. Peers, in his description of allergic encephalomyelitis, mentions only the means by which this picture is produced, considering it a priori allergic. He does not elaborate on the essence of the production of this picture, but says 'allergic encephalitis is an inftanımatory and degenerative disorder of the central nervous system of certain susceptible animals, which is produced by the parenteral injections of sterile emulsion of brain tissue'. This sounds rather decisive but actually does not help us much Pette classifies all the diseases in which demyelinization is seen under one heading He considers the demyelinization the common and most important sign His classification is as follows. Demyelinization encephalomyelius Disseminated Acute multiple sclerosis 2 Chronic multiple sclerosis Para-pfectious encephalomyelitis Diffuse Acute and chronic diffuse sclerosis To what extent this grouping together of these diseases on the basis of a pathological-anatomical symptom is valid remains to be seen We see demyelinization in so many different, and probably unconnected, conditions Some believe that the areas of demyelinization are brought about via the vascular system The walls of the vessels (especially the veins) are supposed to assume a looser structure during this initial stage, and plasma exudes through the wall, which is then ·56 ETIOLOGY more or less infiltrated by lymphocytes and plasma cells At the same time we see inflammatory and reparatory growth of the gla. The vascular dilatation is believed to indicate an carly involvement of the vasomotor apparatus, which may actually be the initial stage of the entire process. After the above stages, we see the appearance of demyelinization, which may or may not be accompanied by damage to the arons and pronounced growth of microglia, oligoglia and fat-granule cells surrounding the vessels (see below). In some of the acute cases death occurs so early that we see no demyelinization. (De Vries believes that these cases represent an entirely different condition. He has seen this picture often in young children, but has never seen demyelinization.) Pette considers scicral factors important in deciding whether or not this picture will develop: in some demyelinating disorders the endog factors are most important, while in others (e.g. para-infectious encephalitides) it is the exogenic factors which are outstanding Other factors such as chimals, frauma, etc., also play a rôle. Pette also attempts to describe a common mechanism for the development of the demyelinization encephalomyelmdes. In order for a reaction to take place, not only is the stimulus important, but also the 'Reaktionsbereitschaft' of the organism or tissue, which ebbs once the reaction has begun, only to flame up again in response to a new and perhaps non-specific stimulus. The reaction is hyper-, hypo or an-ergic, depending on the constitution The stronger the antigen. antibody reaction and the Realttonsbereitschaft', the more intensive will be the morphological answer (the allergic reaction). The 'Read fionsbereitschaft' depends on hereditary factors, age, hormonal balance, etc., and these also determine the tissue specificity. To what extent an antigen determines the localization and type of the drsorder is not known, bu uc do know that different allergens can gic identical reactions and that the same allergen may give rise to varying reactions Klinge has pointed out that the conception of allergy means breaking away from the old ideas concerning cusation and Hiness, which, as the response of a loving organism to 3 nouoss arcnt. constitutes the essence of the patholog) Pette divides the demyelinization encephalo-mycludes, which he considers to be hyperergic reactions, into four stages (1) Vascular dilatation causing slowing or stasis of the circulation, ·ETIOLOGY 57 This is accompanied by a looser structure of the vascular endothelium and a change in capillary permeability. (2) Plasma exudation, (3) Damage of the surrounding parenchyma (necrosis, haemorrhage, infiltration) (4) Organization of the products of destruction and reaction: walling. off. He points out that the changes develop from the vascular system and are of an explosive nature. He regards the reaction of the connective tissue as secondary Here the reaction of the glia is more evident than that of the mesodermal elements. If the patients do not die, demyelinization develops and, in very serious cases, axondestruction The picture described above does not appear to us to be completely applicable to post-vaccimal encephalitis The changes in capillary permeability would lead us to expect reactions in the areas around the capillanes, this we do not see. Necrosis and haemorrhage are also rare findings Very striking is the finding of intact ganglion cells in the middle of damaged areas; this is difficult to explain on the basis of the above theory. Whether it is permissible to group together all the demyelinating disorders in order to arrive at an explanation of the etiology remains, as we have previously mentioned, debatable We do find in the literature, however, descriptions of cases of post-vaccinial encephalitis in which remissions and exacerbations were seen (Hausmann, Stromgren), but does this justify classification with multiple sclerosis? This problem has recently been studied by Greenfield In considering the disorders which are grouped under the heading diffuse sclerosis, he differentiates three forms of demyelinization (1) The 'inflammatory' type, familial and non-familial (2) The 'metachromatic degenerative type, familial and non-famihal (3) With 'epithelord' or globoid" cells, familial. Here again we see the division into obviously different pictures despite the common symptom of demyelinization (see De Vries) It is simpler from the point of view of clinical course and pathological-anatomical changes to group the para-infectious and postvaccinal encephalitdes together ·58 ETIOLOGY We have seen that there is still much uncertainty concerning the quesa tion of allergy and that a convincing explanation of cerebral allergy reaction has still not been arrived at. This is not to deny that many colleagues, especially those in the experimental field, have attempted to reproduce a demyelinization cncephalomyelitis by means of 'allergy In 1901, Heller and Bertarell discovered that repeated injection of a filtered brain ettract caused loss of ucight and sometimes paralysis and death in guinca-pigs Unfortunately, the pathological-anatomical changes were not investigated. In 1925, Koritschoner and Schucinburg repeated these experiments, using rabbits, and on cxamining the tissues microscopically found congestion, oedema and nerve-cell degeneration, but no demyelinization. The above was completely restricted to the spinal cord. There was no cerebral damage. Raven, Sprunt and Berry, in 1933, repeatedly injected rabbits with watery cerebral emulsions or alcohol-ether extracts and produced what they called 'an allergic encephalus. The experiments of Louis and Loomis (1924) revealed that the antibody production of guinea- Pigs with active tuberculosis was greater than that of healthy animals. In 1929, this was supported by experiments with protein and horse scrum (Diem and Schoenheit), they found that they could artificially raise the antibody production by the injection of dead iuberculosis bacılı In 1942, Freund published hes findings on the powerful effect of the injection of tuberculosis bacilli combined with stenle lanolin and liquid paraffin. Kopeloff and Kopeloll ucre the first to use the so-called Freund's adjuvans with cerebral extracts in crpenments on apes and rabbits. In the latter animals they saw the production of paralysis, but un. fortunately did not investigate the anatomical changes. More recently, there has been an increase in the number of publicstions concerning the so-called allergic checphalitis (Kabat, Wolf, Bezer, Olitsky, Cazullo. Ferrara, and many others). Lo all these ciferiments thc encephalitis is seen most clearly in the ape. We see the following picture (1) Foci around the cins and renules.

·ETIOLOGY 59 (2) These are clearest in the white matter, but also demonstrable in the grey matter of the brain-stem and the basal gangha, less so in the corter cerebri (3) The larger veins are dilated (through paralysis of the wall or congestion) (4) Thrombosis is rarely seen. (5) The endothelium is sometimes swollen (6) The perivascular spaces are wide and contain monocytes and, less frequently, polymorphonuclear leucocytes and a few cosinophyl cells The number of cells increases later, at which time we see more lymphocytes and monocytes. (7) In some areas we see narrow vessels (through pressure"). (8) There are foci of demyelinization. (9) Gliosis is seen in some areas (10) Meningeal reactions are seen Although there are points of agreement with post-vaccinal encephalitis, on closer examination there are obvious differences (see Chapter 5) The supporters of this comparison may put forward as an argument the possibility of a róle being played by the previous cerebral traumatism in post-vaccinal encephalitis This might, by destruction of cerebral tissue, sensitize the cerebrum. This was hinted at in 1923, by Levaditi and Nicolau Other authors too (De Vries, Van Bogaert, Bickers, Peust) consider previous cerebral traumatism as a possible important etiological factor. It is not yet certain which substances are involved in the production of these experimental encephalıtıdes Most investigators believe the white matter to be the most active, but Lumsden points out that in the cavia, human grey matter is the most active. An attempt has been made using fractionation, to isolate the active principle Halpern and others consider it to be myelın, but which constituent of the latter is most active is still not known Mornson and others have experimented with lecithinase (prepared from Clostridium welchu), which produces hydrolysis of lecithin No conclusions could be drawn from this concerning the mechanism of demyelinization Verlinde and others were able to produce demyelinzation by means of phosphatase, but the areas were not perivascular No demyelinization was caused by the intravenous injection of ·ETIOLOGY phosphatase in apes. Phosphatase kas, honcier, found to be present in the vaccinia virus and in staphylococci. Olitsly and Tal showed that the substance which produced a disseminated encephalomyelitis in mice may have been a lipoprotein (prololipid A and B). Colouer administered dead tuberculosis bacith in addition 10 fractionated cerebral extracts. With some of the fractions he was able to produce an allergic cnccphalo-myelitis. His opinion is that 3 non-lipoid fraction of the tuberculosis bacillus and a prolcolipid of the cerebral substance (probably a haptene) together form the anugen. In 1954, Wolf surveyed the many materials which were able to prod. uce demyelinization. He placed great emphasis on the dificules of judging the results produced by these substances, We have 35 yet no answer to this difficult but interesting problem. The question arises whether we must accept a relationship between allergic' and post-vaccinial encephalitis despite the differences in pathological anatomy and means of provocation. Ferraro and others believe that it is not necessary to deny a relationship on the grounds of the differences, as long as sc are aware of being on dangerous ground. It seems advisable to us to delay making a definite statement unui more is known concoming the allergic reactions of the central nervous system. We should now like to move on to the question of whether factors other than those aiready mentioned play a rôlc in the production of post-vacciniai encephalitis First of all, is the type of succinc a factor? There has been no satisfactory proof of this perhaps a more complerc investigation might prove profitable, but this is made difficult by the very sporadic appearance of the cnccphalitis. An attempt has been made to restrict the number of cuscs by importing come from countries not having complications after saccinations, but this has proved to be of no help in the Netherlands se hare seen cases of encephalous following the use of this so-called ron-encephalitogenic virus Van Roundh Bastszansc, Heinsius van den Berg and others) During the vaccinations of 1951. stolen skin reactions were frequently seen Some 5.34 this Js an indication that the virulence of the virus might be a factor, but ·ETIOLOGY 61 in judging the skin reaction we must not draw conclusions concerning other reacting parts of the body By this we mean the general immunity and possibly the cerebral reaction Doorschodt pointed this out in judging skin reactions following revaccination. In England (David) an attempt was made to prevent post-vaccinial encephalitis by dilution of the vaccine, but this proved unsuccessful, In general it is accepted that there is no sexual predisposition for post-vaccinial encephalitis (Van Bouwdijk Bastiaanse, Meunier) Falk is one of the very few who believe it to be more common in women than in men. The geographical occurrence shows a very scattered picture. If we consider very large areas, it is observed that post-vaccinial encephalitis is seen mostly in Western Europe, but there are also reports of cases from many other European and non-European (Davies. Africa) countries. Heinsius van den Berg considers the appearance in northern countries more frequent than in southern countries, If we survey the spread within one country, the findings become less conclusive. Van Bouudijk Bastiaanse points out that in the 1920's small communines were harder hit than the larger ones, while in Germany Eckstein reports that the larger communities suffered more. The significance of these facts has yet to be discovered In 1950, Hemmes pointed out the grouping of cases in regard to both location and time He wondered whether some factor may affect a group of the population in such a manner as to lead to the development of post-vaccinial encephalitis, but was unable to explain how thus would come about Several investigators (Knöpfelmacher, Keyzer) report a higher incidence in the school years, but we must not forget that the frequency of vaccination in this age group is a confusing factor We may accept as provea that the risk is much less in the lowest age-group (less than 2 years). Van Bouwdijk Bastiaanse reports a peak of posi-vaccinal encephalitis dunng the months February and March, but this was refuted by other investigators (Heinsius van den Berg, Meunier) The cases we have studied have been spread over the year as shown in Fig 9. Several times cases of post-vaccinial encephalitis have been reported as having been preceded by head injuries (Schachter, brrth trauma, Levaditi and Nicolau, Bickers, Van Bogaert, De Vrics) In cases of ·62 ETIOLOGY COL sa 45 OST 40F 35 25 20- 15- 1947 ICK Fig 9. Spreading of our 109 cases of post-vaccinal cncephalitus over the year. recent traumata, ne might be able to think in the terms of (to put it very vaguely) a lack of defensive resenc. Another possibility has aircady been mentioned; that of the sensitization of the cerebrum by the destroyed brain tissue This may offer an crplanation as to the pathological-anatomical differences between cases in children and adults. The younger the child, the greater the chance that it has suffered (as yet) no cerebral damage (sce Chapter 3) Sull another possibility is that we see the roaction of an organ having a lacus minorus resistentiae. The theory of an insufficiency of defensive resene may well receive support from the fact that post-accinial encephalitis is also described following other resistance-louening circumstances Mage reports a case of post-vaccinal encephalitis seen in a soldier who, after having been to a party, took part in a track meet. In the Netherlands the following obsen ation was made in to Army battalions The first has given regular duty following usccination, while the second was restricted to light duty, all other circumstances remaining the same The first battalion showed a definitely higher ·ETIOLOGY 63 rate of reactions, with an increase in the number of neurological symptoms. Jacobs et al. saw a case of post-vaccintal encephalitis following a tooth extraction This was also seen in our material. In thc Utrecht Clinic a case was seen following appendectomy which was performed one week after vaccination. The patient recovered completely The above data serve to suggest that vaccination should be followed by a period of relative rest. In this way the patient's reserves are not wasted on mechanisms other than those that are connected with the production of a successful vaccination. We have purposely omitted, until now, to mention a phenomenon which is repeatedly reported in the literature: the appearance of more than one case of post-vaccinial encephalitis in the same family. This curious, and not so very uncommon, phenomenon has given us food for thought, especially when one considers the relative ranty of the disorder. It was this ph omenon, among ters, hich led us to undertake the following investigation, ·CHAPTER 7 THE CONSTITUTIONAL FACTOR IN THE ETIOLOGY OF POST-VACCINIAL ENCEPHALITIS: A LITERATURE REVIEW We examined a number of families in which one or more cases of post-vaccinal cncephalitis occurred. (For description, see Chapter 9 ) The purpose of our investigation was to discover whether or not the occurrence of post-vaccinial encephalitis was determined solely by exogenous factors, and, if this were not the case, what other factors play a rôle. We were curious as to what rôle, if any, the constitution played in the genesis of post-vacciniai encephalitis. This line of thought was not original. Earlier reports had pointed in this direction. In reviewing the Interature we see that in the twenties, Eckstein suicc reported the occurrence of two cases of post-vaccinial encephalitis in a single family. It seemed strange to him that a relatively uncommon disease should appear in members of the same family and he therefore published the cases. Netter (1929) did not feel that the invasion of the central nervous system by a virus was the only factor to be considered in the etiology of post-vaccinal encephalitis. If the central nervous system reacts, there must be a certain amount of susceptibility This susceptibility would be related to phenomena such as intellectual precocity, surmenage and heredity. In actual face he pointed in the direction of a constitutional element in the origin of post-vaccinial encephalitis. In 1929, Brouwer garc a lesture for the 'Aledical Circle of Amster dam. He discussed the above-mentioned views of Netics and was not enthusiastic about this line of thought. He especied more results from crperiments with various inoculating material followed by pathological anatomical control. Luksch, the same year, stated that in addition to the vaccine the disposition of the patient cannot be neglected.

·THE CONSTITUTIONAL FACTOR 65 Van Bous dijk Bastiaanse reported the familial occurrence of postvaccinal encephalitis. In 1930, Hutter described various possibilities connected with the problem of the etiology of post-vaccinal encephalitis. Ir, in one family, He sce several cases of post-vaccinial encephalitis within a period of two to three years, then the following possibilities exist: (1) There is a virus circulating in the family. (2) There is a familial predisposition, He claimed that it is the kind of immunity that is important and that this is predetermined and hereditary. It is possible that at the present time weaker constitutional types may be able to live longer and therefore increase the chances of developing post-vaccinal encephalitis. Secondly, that the 'dystrophic diathesis" (intestinal complaints, mucous membrane secretion, serious dermatological conditions) may play a rôle. Al of the above must be studied more intensively. paying special attention to exudative diathesis, lymphatic disposition, neuropathy, rachitic drathesis, spasmophilia, convulsions and persistent enuresis. This, however, cannot be done by one investigator. In 1932, the Report of the Encephalitis Commission appeared. On page 31 we find reference to the occurrence of post-vaccinial encephalitis in grandchildren of two sisters, in one case two brothers and in two other cases two sisters. They also mention that in the Rolleston Report this coincidence is recorded four times They make no definite statement, however, as to whether or not a familial predisposition plays a role, Van Bogaert sees the predisposition in a different light than Hutter. He assumes that if the skin is not able to block the antigen the central nervous system takes up the task This may lead to an encephantis, but that depends on whether or not there is a congenital or acquired weaktiess of the hematocerebral barrier (Désensibilisation neurale). In 1937, there was a congress Belgium which delved into the problem of post-vaccinial encephalitis. Meunier, in his paper, rejected all suggestion of familial or heredttary predisposition Van Bogaert pointed to several other possibilities He considered the possibility of the existence of a variation of allergic disposition, synchronous with the change of seasons This, in addition ·66 THE CONSTITUTIONAL FACTOR 10 the individual, famihal and racial factor, may give us a berende understanding of the problem. As an illustration of possible comastutional factors he cited a case of Couvreur. Coutreur had secs ? patient who had exhibited a temporary decline in scholastic ability During this decline the patient was vaccinated and reacted with a post-vaccinial encephalitis. Van Bogaert advises that in children special attention should be f: 10 neuropathy; convulsions, eczema, status thymo-lymphatice tuberculosis and asthma, Drogendijk, in his book Encephalitis Post-vaccinalis, points out is possibility of a 'certain familial predisposition. In the same you Comby claimed to see a relationship between nevropathic hcred.lt and possible vascular disturbances. We also see a change of thoughs in Brouwer, who now says that the vaccinc damages the brain only of an endogenous predisposition exists. Kokken, in 1940, shared this opinion when he said: "e virus de la vaccin n'est pas le seul facteur en jeu mais le terrain joue une role primordiale si non unique, Wigand, in 1942, in an article on encephalomyelitis following German measles, said the following "Da ja in jedem Fall son posla infektiosen Encephalitis das Verhalten des Organismus für die Entstehung des Prozesses von wesentlicher Mitbedeutung ist, ucrden wir jeder Anomalie des Gesammtkörpers zu beachten haben" Biemond (1946), in his textbook, described the importance of heredity in post-vaccinal encephalitis and emphasized the importance of rccording a detailed familial case history In 1947, mass vaccination was started in the south of the Nethcslands. This appeared necessary owing to the spread of smallpor from Belgium. The result was an increase in the number of cases of postvaccinial encephalitis. Later, Keyzer and Nicuwenhuis published an article in which stics inice described the occurrence of two cases in the same family. They ucrc, houeter, sull sceptical with regard to predisposition They defended this standpoint by stating that the vaccination of 200 Cecble-minded patients did not produce a single case of encepha- Stuart (1917-18) recapitulated the theory of an individual farailea!

·TIE CONSTITUTIONAL FACTOR 67 's R > -- and regional predisposition without throwing any more light on the subject In 1948, Cornelia de Lange reported a case of post-vacciniai encephalitis in a patient with clubſeet A brother of the patient died of a spina bifida aperta. Gorter, in 1949, told of a patient whose brother was a mongoloid idiot. He accepted a certain sensitivity in the etiology of post-vacciniai encephalitis but he did not go on to explain this sensitivity. Doetsch (1949) reported an interesting observation Uniovular twins, 64 years old, who had previously demonstrated the same reactionpattern for infections, were vaccinated simultaneously with a younger brother After 13 days one of the twins reacted with an encephalıtıs. On the grounds of this observation Doctsch tends to accept the theory of a neurotropic virus. In the same year Hofbauer published his experiences with subcutaneous vaccination. Only once did he see encephalitis The child came from a family with many cases of alcoholism and feeble-mindedness According to this author we should accept an hereditary predisposition in diseases of the central nervous system. During the discussion that followed the Congress to Combat Smallpox and Post-vaccintal Encephalitis (Hemmes, Kramer, 1950) Kramer reported two cases of post-vaccinial encephalites in a brother and sister who had been vaccinated, the one two years after the other He considered the possibility of predisposition playing a rôle (see further) In 1950, Van Bogaert once again discussed predisposition in an article concerning the para-infectious encephalomyelitis in one of a set of twins The twin sister suffered a meningitis 9 days after simultaneous vaccination. During the period 1948/49 there were 15 cases of post-vaccinual encephalitis in Stiermarken. Falk (1950) put this sudden increase down to a special neural predisposition of the inhabitants. In 1952, Hutter repeated his defence for the constitutional factors and pointed to the importance of examining the constitution. In 1953, André-Balsaur gave a detailed review of the 'facteurs préparants' the gist of which is as follows: He asks whether we should consider post-vaccinial encephaltus as the activation of an already manifest process in cerebro which is slow ·68 TITE CONSTITUTIONAL FACTOR and insidious in growth. He cites cerebral complications follows measles and vaccination in patients who were already suffering from diseases of the central nervous system. Or is the problem ore di *fragilité neurale? He gathered the following material from 1: existing literature. Benvenuti: Patient with post-vaccinial encephalitis. Age 25 months. Se was nervous and irritable. Congenital paralysis of the palate and paraha of the N. Facials. Grandfather was an alcoholic and mentally strane Father was a sleep-walker. Brother was an epileptic. The second case was that of a feeble-minded child suffering from Luck's disease. The symptoms of the latter became more severe after vaccinasc". Taccone: Family of 12 children. Parents are healthy. Two children de very young. They exhibited premortal convulsions. The patient was the Uith child. At the age of 3 he had convulsions and was mentally retarded At the age of 13 he was revaccinated and a post-vaccinal encephalitos followed which had a fatal issue The author suggests that attention the paid to familial constitutional factors as well as to previous persona! disorders. Rigota: Woman, 38 years old. Grandfather on the father's side was placed in a psychiatric institution. Brother extrebsted periods of melancholy. The first vaccination took place at a young age During this same period se had measles. At the age of 24: psychiatric treatment; 37: cholecystitis and colitis, 38: after sccond vaccination the patient suffered an encephald's which loh lasting cuphoria and neurologic symptoms Duken Girl, aged 18 months Nine days after vaccination the paucot received a frontal contusio cerebri. The next day she went into a comis, and devclared fever and a right-sided hemiplegia. Her father exhibited convulstons after vaccination (at the age of 1). Besta p 10 years old with post-vaccinial encephalitis. Grandfather ca father side alcoholic Father is Scry nervous suffers from chronic headache Mother is an alcoholic. The patient was vaccinated at the age of 2. TWO days afterwards fever and consulsions developed. Encephalus pashtaccinalis (?) Frutepsy as permanent complication. Rigotto Woman. uged 42. Botuccn the ages of 20 and 23 articular rheuma. tism. After pregnancy in 1947 patient suficred phlebites During this SKRY she was succinated Six days after vaccination an encephalitis declared Pemarent complications de cloped in the left arm.

·THE CONSTITUTIONAL FACTOR Meyer: (1930) Young girl with glomerulo-nephritis was vaccinated. Ten days after vaccination an encephalitis developed. Da Villa In three cases of post-accinjal encephalitis the patients were of the tall slender Type Two of the patients had an hereditary taint (tuberculosis and alcoholism in the family). 69 Alberto Mfugio (1925). Two children suffering from spasmophyla developed encephalitis post-vaccinals, Da Villa Boy, 8 years old Father suffered from delirium tremens with suicidal tendencies Patient; asthenic, adenopathy, trachco-bronchitis, Micro-polyadenitis and laryngospasm. Following vaccination an encephalus developed with hallucinations. Healed completely André-Bafisaur writes “Certaines déterminations Theumatismales, vasculares, renales dorvent être retenues, comme elles l'ont été par Van Bogaert dans ses recherches sur les déterminations encéphalttiques des exanthemes et de certaines encéphafites dites allergiques, sans qu'on puisse encore actuellement se prononcer sur la valeur de leur incidence. On peut évidemment contester statistiquement leur signification nous les invoquons ici dans l'ignorance ou nous sommes encore d'un méchanisme physio-pathologique de ses accidents sans plus" Daser Brother and sister vaccinated simultanicously Both children died, 12 and 14 days later. Kramer (1925/26) A family with three children. In 1923, a girl died of a tubercular meningitis following vaccination This could very possibly have been an encephalitis post-vaccinalis In 1925, ber 6-year-old brother died of post-vaccinial encephalitis Fanconi Eight-year-old boy At the age of 4 months the infant had chickenpox and a commotio cerebri Twelve days after vaccination an encephalitis developed A brother, age 12), who had suffered from enuresis nocturna until his 12th year, Has vaccinated three days later with a different vaccine On the 14th day he developed an encephalitis Both children recovered. According to the author, the commotio cerebri sensitized the vasculovegetative system in this regard he said "on sait combien les énuresies sont frequemment les femoins d'une épilepsie infraclinique ou non reconnue" This may hold true for some patients but certainly not for all ·70 THE CONSTITUTIONAL FACTOR The material insestigated by André-Balisaur himself wis as follows: Family van G. The eldest child, a 13-year-old boy; cncephalitis font Vaccinialis. As a permanent complication there were disturbances in the electro-encephalogram. The second patient was a boy of 10. After vaccinial encephalitis he too showed changes in the electro-encephalogy The third boy was not vaccinated. He had a normal encephalogen Father: healthy, Mother: fragile, nervous, with tendencies to anach. Family G. Eldest child. Male, 30 Congenital bilateral deafness. Second: Female, 29. Normal Third: Male, 28. Pleuritis. Fourth: Male, 22. Post-vaccinial encephalus. Fifth: Male, 20. Right-sided deafness. The first, third and fourth were vaccinated at an carly age The fourt' developed an encephalitis following revaccination. The following is his personal history: Three months old: chickenpox. Seven years old: nephritis following scarlet fever, Healed. At the age of 22 he was revaccinated and developed an cncephalitis which left permanent electro-encephalogram changes. The third and fifth had electro-encephalograms that bordered on the abnorms! Andre-Balisaur thinks it possible that before the fourth uk vaccinated, slight changes had already cuisted in the electroencephalogram as an expression of neural sensitivity; thc encephalitis accentuated the changes. The following conclusions were draun from the above (!) The patients did not cxhibit & more than normal allergie es vascular disposition. (2) Predisposing factors are: (a) Somatic trauma. (b) Psychic trauma (probably originating as a result of vascular changes or changes in the cquilibrium between the endocrine and Autonomic system) (c) Toric-infectious conditions Under (a) are taken into account factors such as cooling. Olet heating, etc Ouing to changes brought about in the permeability of the vascular system, these factors can be fatal during emical periods. (3) Owing to the simultaneous Acurrence of the predisposing and preparatory factors, sensitization of the central or peripheral ·TITE CONSTITUTIONAL FACTOR 71 nervous system arises This paves the way for the so-called 'neuroallergic reaction (4) Recurrences are very rarely or never seen, thus a very strong immunity must exist. This last conclusion is difficult to support. Once a patient has suffered an encephalitis post-vaccinialis a revaccination is generally not indicated (sce page 127). (5) It is strange that other processes play a role in the sensitization of the cerebrum The author (A-B) of the opinion that an infection can bring about two separate conditions. The first is a specific 1mmunity. The second, a 'parallergic', which carries the reaction possibility in it for diseases in the same group (6) The electro-encephalogram may be able to tell us something of the future reactions. The degree to which the observations of André-Balısaur support the above remains to be seen The description of the clinical phenomena, especially if one examines the incubation periods, indicates that care must be taken in many cases before drawing concrete conclusions. If these investigations are to be valid we must be strict in our choice of material. We feel that a more complete examination is necessary. Without this an accurate evaluation is, in our opinion, impossible. In reviewing the literature we found an article by De Morsier (1955) that reported an observation made by Guttmann A 5-year-old child suffered an encephalitis post-vaccinialis that was followed by a hemiparesis It also became subject to epilepuc fits As treatment for this complication an operation was performed which proved fatal. At autopsy the corpus callosum and the vermis cerebelle were absent. Both of these defects are classified under the heading of cranioencephalic dysraphia. In reviewing all of the material in the literature we are struck by the frequent reference to constitutional factors, which may play a rôle in the etiology of post-vaccinial encephalitis In our clinic we also observed tendencies in this direction in our out-patient department we saw a case in which a child has secondarly infected her mother with vaccinia virus Both mother and child suffered a post. vackin;al encephalitis The mother retained symptoms of diencephalic ·72 THE CONSTITUTIONAL FACTOR disregulation as a permanent complication. The family history showed the following peculiarities: SINI: aged four, profuse bleeding from nose and kidneys S2 M, S3 M and FM: enuresis nocturna, J. enuresis nocturna until the age of 10. Spina bifida occulta. SP: Bilateral clinodactyly of the Sth digits and sacral hairgronis A second case was as follows: Family v. d. V. Parents and seven children wanted to emigrate to Canada. Vaccination of the entire family was necessary. The parents had been vaccinated previously but not so the children. The oldest child, a boy of was admitted to our clinic. On the 12th day after vaccination he developed an encephalitis. We found that, in addition to the encephalitis, the ch!! had glomerulo-nephritis. Both conditions disappeared completely on the 15th day after vaccination we examined the entire family. P. On the 8th day after vaccination had a headache and temperature of 406°C. Emotional fability followed, Felt apathetic. During crammation the patient impressed us as being feeble-minded. The patient had a right-sided Babinsk-rel'ct and dubious Gordon and Oppenheim rellexes M: No complaints following vaccination. Examination: slight funnel chest and clinodactyly, Fl. Aga 12 years. Ten days after vaccination had fever. Examination: Therar "en Batcau". High right shoulder. Positive Oppenheim and Gordon rellexes on the left si. Age 9 Seventh day after vaccination had a terminers. turc and headache. Examination: slight funnel chest. High palate. Riste shoulder higher than the left. No neurological symptoms. F2. Age Seventh day after vaccination fever. Examination: Slight funnel chese. No neurological symptoms. Patient is most probably feeble-minded Cannot attend normal school. S 2. Age 6. Was ill from the Sth to the 7th day following vaccination. Telt better for two days but on the 9th day in becamc 1 High temperature and headache. Examination Bilateral clinodactyly No neurological symptoms S3 Age S. Cranky and Irsties after vaccination Examination Impressed us as being fecble-minded Specch retarded Enuresis nocturna No neurological symptoms P.Al died at the age of €6, of a heart attack ASM died at the age of 55. Aroplety was clinically diagnosed Suffered frequent nenous break-downs FIN and F Pucre both in psychiatric institutions. F2P. hydrocephalus Conclusion in the family of a patient with post-vaccinial encephalitis "e sere able to find neurological symptoms in members other than the patient This cramination took place 15 days after vaccination The family exhibited a familial burden in the form of signs of ite status dysraphicus and psychiatric disturbances.

·CHAPTER 8 CONSTITUTION AND ELECTIVITY IN INFLAMMATORY PROCESSES OF THE CENTRAL NERVOUS SYSTEM In 1952, Sillevis Smitt published his article "The prevention of postvaccinal encephalitis". He discussed whether one could prevent a large number of post-vaccinial complications by carefully selecting patients for vaccination, In view of the fact that so little concrete information has been obtained after all these years of investigating the erogenous factors, Sillevis Smitt suggests further study in the direction of the endogenous factors He writes: “From everyday Clinical experiences it appears that all inflammatory processes of the central nervous system under which falls encephalitis are actually Auslese Krankheiten'. The frequency is determined by the concept of 'electivity', since we see only a small percentage of those exposed to the infection actually falling ill." We see very few cases of encephalitis following measles just as we see very few cases of chorea minor following rheumatic fever This makes us feel that in addition to the erogenous factor an endogenous predisposition plays a role. We see this in the literature and it is more or less evident in our own experience. It is, therefore, probable that this predisposition determines whether the nervous system wul be involved in the disease process. This view was also expressed by Pette in 1929. He pointed out that investigation of acute infectious diseases of the central nervous system has yielded results with regard to the causative agents, yet the roblem of the pathoge has not been solved He feels it to be necessary to consider the endogenous influences in order to gain further insight into this problem He stressed this when he discussed post-vaccinial encephalitis In 1933, Curtius published Multiple Sklerose und Erbanlage In this work he discussed the genesis of multiple sclerosis from the endogenous point of view, eg.

·24 CONSTITUTION AND ELECTIVITY the hereditary factors. In this way he drew a parallel berucat pathogenesis of multiple sclerosis and post-vaccinis encephalitis Tas approach involves the constitution and on this subject an extens. : mass of literature erists. It does not lie within the scope of the present work to go into this in detail (see the work of Stllesis Smilt 27:/ Kuiper). However, in order to understand the concept we are dis. cussing we shall try to define it in brief. The idea of constitution is very old. At first it was a very stal: concept in which every individual possessed a definire constitution With Hypocrates we see the concept of constitution acquiring a more dynamic aspect. Through the mixing of the four body fluids, Jellow and black bile, mucus and blood, the health of the individual is determined. If the correct ratio exists between these substances uc speak of eucrasia. If this is not the case then we speak of dyscrasia We do not intend to follow the complete devclopment of the constitutional way of thinking. One thing is certain and that is that the more 'causes' of diseases were discovered, the less importance was attached to the constitution. In the past several years the laboratory diagnosis has made such enormous advances that the concept of constitution is no longer considered when searching for a diagnosis. What do we now understand by constitution? Every individual originates through the union of two ser cells The fertilized ccg that results carries with it a certain number of chromosomes. These are the material carriers of properties and form the 'basic material from which is determined what potentials thic developing individual will possess. They form what is generally call:d the genotype. As soon as the individual begins to develop there appcar, besides the hereditary factors, the crogenous factors These will determine which of the hereditarily acquired factors will become manifest, ie what will become of the phenotype. These influences, also called the 'miticu', determine how the indusidual will present itself The milieu docs not begin after birth; it has an imporiant role in the embryonic stage Wortman gives the following description: "The more that life advances the more the phenotype takes over the genotype until death mukes of the genotype an absolute phenotype." in a series of ·CONSTITUTION AND ELECTIVITY 75 development Stockard comes to the following concluston: "Without a genetic basis there is no individual and without a suitably arranged complexity of environment the complete genetic basis is unable to produce the normal individual". if we regard the adult individual according to his appearance and his reaction possibilities then we are forced to consider both components separately If we consider the constitution we encounter the same problem The outward reaction of an individual to stimuli is determined by the genetic make-up and the changes made by the milieu There are two alternatives (1) These reaction possibilities, determined by endogenous genetic and milieu factors, are called constitution. (2) The concept constitution is reserved for the part of the genotype. Julius Bauer described this as "the sum total of an individual's characteristics as they are potentially determined at the moment of fertilization". Peust described the constitution as "der Ausdruck ſur die spezifische Art der biologischen Beschaffenheit seines Trägers, mit dem Leben, seinen Widerstanden und Schädlichkeiten fertig zu werden und bildet damit zugleich den konkreten Ausdruck fur die korperliche, geistige und seelische Erhaltungsfähigkeit Ihres Tragers". If we take into account the changes of the reaction pattern as brought about by the milieu then we speak of the 'condition'. In this last case we can also speak of pheno-constitution' We can then consider the concept constitution' as described by Peust, by the word geno-constitution. The pheno-constitution is partly expressed by the morphological appearance and also by the reaction pattern of the individual In this respect we have to keep in mind that every reaction which takes place does so not solely through the condition but that at the same time the reaction changes the condition in a more or less characteristic way In this way the reaction to a diseaseproducing agent will be determined by the pheno-constitution. After this reaction, the individual can react to the identical stimuli in a different manner It is obvious from the above that the whole of the function and form etists in a close harmony This close connection is also expressed in Kretschmer's Körperbau und Charakter He writes: "Das Problem Form und Funktion steht vom ersten Beginn hinter ·76 CONSTITUTION AND ELECTIVITY unseren Untersuchungen uber die korrelativen Zusammenhänge der psycho-physische Persönlichkeit. Form und Funktion sind len: Gegensatze, sondern zwei Aspekte derselben Sachc." In the pheno-constitution or condition we also see an expressio of the basic geno-constitution. We can, therefore, expect that by examining families with regard to constitutional make-up se sha? find many similarities in both form and content. These can be the determining factors in the origin of predisposition in other words, it is this inheritance on the part of an individual that gives a patholin ical process its chance for development. We can theoretically classif pathological reactions as follows (Polman): (1) Reactions principally determined by hereditary factors (2) Reactions principally determined by the milieu (3) Reactions determined by the equilibrium between genes and milieu. It is self-evident that transition forms exist. On these grounds, Polman came to the conclusion that it is impossible to make a sharp distinction between hereditary and non-hereditary diseases Every individual reacts to an external agent in a manner characteristic of his particular genetic make-up. This same idea is found in the inaugura! address of Biemond. Even in diseases that are known to be determined principally by heredity we see an equilibrium between genetics and the milieu. In this regard Bremond gave a splendid example He also points out that it is impossible to speak of homology and homotypes in neurology for the following reasons: (1) The geno-type may not be completely des cloped (inadequate expression) (2) Some syndromes need a specific genetic composition. This acts as a source of great variety. (3) A genc can sometimes express itself in many different ways as in Wilson's Disease (central nervous system, liver and cornca) This is the so-called pleiotrophism In this way the homology and homotif are surpassed by the hetcrology and the heterotype. This is cypressed by Kroll when he said "das a-typische wird typisch". Curtius, when considerin the heteropheny in inherited neurological diseases also pointed the impossibilny of a sharp distinction in this area Curtius, we must view the occurrence of real 'Umwelt. Accord ·CONSTITUTION AND ELECTIVITY 77 bedingte* diseases in families with hereditary, organic (neurological) diseases in such a way as to take into account the hereditary disposition. This disposition is closely related to the inhented defect of the “Anlage' of the central nervous system. Biemond points out that all of this lies within the area of preventive medicine. We are concerned with recognizing the basis on which certain norae get their chance to develop Silevis Smitt stressed the importance of the constitution in the genesis of post-vaccinial encephalitis. We have seen that many years of searching for erogenous factors has not yielded the expected results we have no convincing theory Comesting the genesis of the disease. We only know that occasionally after vaccination there is a reaction on the part of the central nervous system and that this nervous system belongs to a reacting individual. Is it surprising therefore that we should approach the problem from a different direction and now ask what constitutional properties are to be observed in a patient with post-vaccitiral encephalitis? This is an attempt to discover the conditions which make one susceptible. We must realize that the constitution is not the only other factor besides the vaccine. The condition of the vaccinated person probably plays an important role (sce Chapter 6). Resistance will be met from those people who feel that trying to approach the problem in a constitutional way will discourage advances in therapeutic directions. This will happen because of the premise: "It is constitutional, thus little can be done". We definitely do not believe this On the contrary, we believe that it our therapy be rattonul then we have to consider the constitution within our fratne of reference If we do not do this our therapeutic results will definitely suffer. The study of the influence of constitutional factors in neurological diseases has previously been carried on in other cases We mentioned the work of Curtius with multiple sclerosis He compared the findings en families of patients with multiple sclerosis with a control group He found significant differences with regard to stigmata in these two groups. If we review the various stigmata in the reported investigation we are impressed by the heterogeneous picture. We find properties whose importance is not fully understood In this regard we should like to point out the danges of putting too much emphasis on symptoms ·78 CONSTITUTION AND ELECTIVITY whose value cannot, at present, be assessed. Wagner von Jaurese fais a warning after the work of Curtius appeared. This was especiais against the exaggerated importance given to heredity ctamination Curtius also reported constitutional factors as playing a role in this dorsalis, The problem of the constitution has also been spoken of in relation to encephalitis epidemica. Stern, however, denies that it plays a role Villinger (1921), Peust (1924) and Klaus Jensch (1939) conducted an investigation and came to the conclusion that before one acquires encephalitis epidemica a predisposition has to exist. Curtius points out that in the examination of the constitutions! factors special attention must be paid to the following points: (I) A special topical disposition. (2) A general neuropathic constitution. (3) An extra-neural disposition. The topical disposition is very often seen in a particular family reaction pattern. We sec families that suffer from a high number of changes in the strio-pallidar system. Curtius reports the predisposition for diseases in the anterior motor cells. He points out the combination of poliomyelitis anterior acuta and Duchenna-Aran's Discasc. llc have seen a patient who during his youth had suffered from polo myelitis anterior acuta and at a later age developed the picture of amyotrophic lateral sclerosis. We have not been ablc to demonstrate from the available information a topical disposition of the unite matter (this is the arca in which the post-vacciniai encephalitis occurs) We have attempted to find a general ncuropathic constitution and, as far as possible, to demonstrate an extra-neural disposition The concept 'neuropathic constitution has grown during the last century in 1857 the work of Morch Traile des Dégénérescences appeared He introduced the concept 'degeneration into the medical fiel. Especially in psychiatry. Féré (1894) then launched the idea of 3 fumille neuropathique le described in various families a high percentage of neurosis, psychopathy and criminality. Ile pointed to the correlation that existed between neurological discases and the 50-called "stigmata degenerations and linked in this way degeneration with neurological changes Looking over the so-called stigmata, which are considered to be ·CONSTITUTION AND ELECTIVITY 79 isdicative of a defective constitution, we are confronted with a strange picture. To get an idea of how the problem of heredity was approached in those days we have only to consider that Féré felt that coitus after a funeral would result in an individual who was basically depressive. A long way had to be travelled before these concepts could be considered in a scientifically responsible manner. It was Bremer and Curtius who succeeded in putting the relationship between the stigmata degenerationis and neurological changes into a systematic order. This line of thought was introduced to the Netherlands mainly by the work of Sillevis Smit. How do these stigmata originate? It is generally accepted that they occur through mutations. These mutations cause the majority of changes in the places where sensitivity is the greatest Since the sensitivity to changes in the milieu is greatest where the differentiation is the furthest, it is not surprising that we can observe the results of the changes so manifold in the area of the central nervous system. The resulting tendencies, being genetically bound, are passed on to the following generations. In this way we can see individual constitutional properties manifesting themselves as familial ones. In our examination we have paid special attention to. (A) Morphological changes. (1) The classical heredo-degenerative disease pictures. These are progressive ducing lifetime. (2) Macro-heredo-degeneration These conditions of prominent degenerative syndromes are constant throughout life. (3) The stigmata degenerationis or micro-degenerations Under this heading fall the stigmata of the status dysraphicus (Bijl) (4) Other neurological pictures (epilepsy, etc.) (B) Endocrine-diencephalic disturbances The endocrine syst is centrally regulated by the hypothalamicpituitary system. This area is functionally and anatomically in tery close contact with the rest of the central nervous system We considered it advisable to give the endocrine system a place when we studied the aberrations of the central nervous system ·80 CONSTITUTION AND ELECTIVITY (C) Vegetatire regulation disturbances. These are difficult to determine by examination at an out-patient clinic. Only with very clear-cut changes and reliable case histories was it possible to evaluate vegetative disturbances. (D) Allergic stigniata. In view of the fact that there are many investigators who accept as allergic genesis of post-vaccinial encephalitis, we considered it desirable to draw special attention to allergic stigmata. This was done in the first place with the goal of finding out whether a correlation exists with the 'allergic predisposition of the nervous system, and secondly because these conditions are a part of the concept 'neuropathic constitution'. If we take groups B, C and D together then we see that disturbances in one of these groups very often coincide with disturbances in the other groups. The function of the endocrine system is very closely tied up with the vegetative nervous system. We see this in everyday physiological mechanisms. The day shythm' shows a very close relationship between the two (Gathier). Also in all of the physiological and pathological changes that take place in the endocrine system ** see changes occurring in the vegetative system. During pregnancy an increased reactibility exists on the part of the vegetatile nervous system The symptoms of vegetative lability during the climacterium are well known, just as we are all familiar with vegctative reactions during hypoglycaemia and thyreotoxicosis Hess demonstrated this relationship experimentally in animals. He made use of electrical stimulation in the area of the tuber cinereum. A relationship is generally accepted between allergic disturbances and the vegetative nervous system. Berger and Hansen unte. Bol dem grossen Anteil, den das Gefässsystem an der Allergisierung nimmt, ist es verstandlich, dass die schon vor dem ersten Allergen kontakt gegebene, crerbte oder erworbene, allgemeine und ortliche Gefassterfassung an der Disposition zur Allergisierung henvorragenden Anteil hat. Es ist in der Tat eine alte ärztliche Beobachtung des Ecrasslabile, gefasscretische, vasomotorische, angioneurotische Alca.

·CONSTITUTION AND ELECTIVITY 81 schen bevorzugt allergisch sind, wenngleich natürlich - auch nach cigener Untersuchungen vber die interkutan prüfbare Gefasserregbarkeit - diese besondere Gefassdisposition nicht obligat ist". We have not grouped migraine under the allergic disturbances because of the doubt that exists regarding its validity. We see various forms of migraine occurring in the same family. Van der Does de Willebois considers the allergic genesis of migraine as probable and believes a special equilibrium condition of the neurovegetative system to be prerequisite for its origin We shall consider it as an accepted fact that changes in the endocrine system exert an influence on migraine. In 1952, Schwartz published a study titled Heredity in Bronchial Asshna. In it correlations are made between different allergic disturbances He found a positive correlation between migraine and vrticaria. Further correlations were not such as would place migraine in the group of allergic diseases From his findings it would appear that there is most probably no direct connection between migraine and bronchial asthma. Other diseases that are considered by many authors to be allergic in origins are discussed separately below. This is done because their allergic origin has not (yet) been proved. The skin diseases ichthyosis and psoriasis fall in this group. Ichthyosis is often seen in patients suffering from Besnier's prurigo and/or bronchial asthma Although the etiology of ichthyosis and its coonection with allergy is still unknown, many attach significance to the fact that it occurs with the above-mentioned diseases. Another point of view is that diseases of the skin, which are seen in families with allergic syndromes, though they in many ways resemble ichthyosis are not identical with 16 In these cases perhaps 11 would be more correct to speak of dry hyperkeratonic skin, Another problem connected with Ichthyosis is the frequent occurrence of neurological, psychiatric and endocrine diseases in the same family Laubenthal points out that, in addition to changes as shown in the above-mentioned conditions, there are also changes in the body structure, la general, the body build of the patient is of the asthenic type Laubenshal points out that changes occur in what he calls the acrale growth By this he means the short fingers (brachydactyly), ·82 CONSTITUTION AND ELECTIVITY excessive growth of the acra in the form of arachnodactyly, to mi?) fingers (polydactyly) or changes in the growth of the jaw, Lauberita considers the essential disturbance to be a change in the pituiwin. diencephalon area The frequent occurrence of neurological diseases in the form of striatum changes would subscribe to this opinion. Psoriasis is sometimes seen in combination with hay-lecr. Schwartz points out that psoriasis is very seldom seen in combination with other allergic diseases and also that the pathological anatomical study of the disease is not such that we can be certain about its allergic oniga. Polyarthritis rheumatica chronica and polyarthritis rheumatica acuta have recently been placed in the group of the allergic diseases. Up till now there is no certainty about whether or not allergy plans a róle. Examination of a large group of patients with the disease Ass not resulted in a correlation between it and the well-known allergic syndrones (Járvinen) There is, according to some, a positive correla tion with migraine (Traut and Vrtiak) In addition to the above-mentioned skin conditions, attention w35 paid to other dermatological changes. We recorded all pigment anomalies such as depigmentation, 'café-au-lait' spots and pigmented naev. These anomalies are well-known in the phacomatoses; however, Me see phenomena that are not connected with these diseases. The pigment-carrying cells are ontogenetically derised from the neural crest. Parts of the vegetative nervous system originare in the samc arca. We can casily imagine that disturbances in the develop ment of the nervous system, such as status dysraphicus (Bryl), may coincide with changes in the pigment distribution of the skin We were also interested in vascular anomalies (haemangiorata) as a form of the stigmata degenerationis. Status dysraphicus plassan important role in our consideration of the constitution As fas as was possible with an out-patient cramination, these constitutional. dysontogenetic factors were recorded. It was not possible to complete our findings by radiological cramination Out findings in this investigation also include individual aberrations that ure due to the so-called phenocopies The effect of the above docs not alter our final conclusions since uc hate concerned oursehes with family histories and therefore the isolated individual stigmata are incorporated in the sum of ite ·CONSTITUTION AND ELECTIVITY 83 genealogical trec Besides, we shall also see the phenocopies in our control group There is no reason to believe that the frequency of phenocopies should be different in both groups. The stigmata of the status dysraphıcus as recorded in our investigation are in accord with the findings of Bij! For an outline of the data compiled by us we refer the reader to the following chapter We emphasized the status dysraphicus because a correlation exists between this constitutional disposition and a greater or lesser inferiority of the central nervous system (Curtius, Sillevis Smitt, Bil) in our consideration it is not possible to draw a sharp line between the status dysraphicus and, on the one hand, the normal condition, and, on the other hand, further abnormal constitutional ypes Sillevis Smitt pointed to the relationship of the status dysraphius and the phenomenon of arachnodactyly. Furthermore, we are aware of the dysraphic stigmata and the diencephalosis (Sillevis Smitt, Kuiper) Here we see a trait d'union between the status dysraphicus and endocrine and vegetative stigmata Other relations can be found in the literature For a more detailed survey we refer the reader to the work of Bis! We should like to point out one such relationship Bremer, Curtius, Kehrer and Sildevis Smitt, from their clinical experience, pointed to the connection of the status dysraphicus and mental instability This was checked statistically in a group of Dutch recruits by Bijl He too found a correlation between the above-mentioned conditions Attention was also pard to fibromata, fibro-lipomata and many other conditions called 'stigmata degenerationis' In addition to the above we recorded, as far as possible, all the peculiarities concerning internal organs as well as causes of death It is not possible to discuss all the implicated symptoms separately, we refer to Chapter 9 containing the results and conclusions of our investigation ·CHAPTER 9 CONSTITUTION AND PREDISPOSITION IN POST-VACCINIAL ENCEPHALITIS The investigation into constitutional factors predisposing to postvaccinial encephalitis was based on the cases reported to the Netherlands Chief Inspectorate of Public Health during the period 1945 through 1951. From this material we selected such cases as could be classified in groups 1 and 2 of the classification given on page 30. Whenever possible, examinations included the patient and his brothers and sisters, the parents and their brothers and sisters, and the grandparents. With regard to the cousins, only anamnestic data mert collected Unfortunately it was impossible to include all the patients registered during the above-mentioned period because some families refused to cooperate. On the other hand, the investigation was facilitated by the following favourable factors; (1) The incidence of post-vaccinial encephalitis in the Netherlands was high in the above mentioned period. (2) Distances in the Netherlands are so limited that it 435 possible to visit nearly all relatives, even when scattered throughout the country. (3) The rate of emigration from the Netherlands is relainely low. The investigation covered 107 famies, including 109 cases of frost vaccinual encephalitis Encephalitis occurred in the same family in two instances. In one instance the diagnosis was made in two cousins (their mothers were sisters) One case of encephalitis was in a chil3 of an unmarried mother The geographic distribution of the 109 patients was as follows Aarle Riste! Apeldoorn Bergenheim Amsterdam Amhem Berkel (ZII) $ 1 2 3 Amersfoort Assen picrick ·CONSTITUTION AND PREDISPOSITION 1 85 N 1 1 2 1 1 1 1 1 2 6 Bloemendaal Breda Cupck Drunen Eindhoven Enschede Fijnaart Geertruidenberg Gemert Gouda Grotebroek Den Haag Haaren Haarlem Halsteren Heemstede Den Helder 1 1 1 Helmond Helvoirt Hilversum Hoeven Kerkrade Kollum Menaldumadeel Moergestel Musselkanaal Naaldwijk Nijeveen Nymegen Oirsbeck Oirschot Oosterbeek Oosterhout Oosterwolde 1 1 1 1 S Oude Pekela Roden Roermond Rotterdam Rijnsburg Schinnen Sevenum Sneek Steenwijk Tilburg Udenhout Utrecht Voorburg Voorhout Zaandam Zeist Zevenaar Zurlen 1 1 2 3 1 23 1 2 1 1 1 3 2 The patients were 70 males and 39 ſemales, with the following age distribution 1 0 2 years 2-5 years 5-10 years 26 u 14 10-20 years 20-30 years 40-50 years 39 23 2 The 107 families included 107 mothers and 106 fathers, 1 e. a total of 213 parents Owing to the above-mentioned facts, the number of grandparents was limited to 424 The total number of subjects (patients and relatives) included in the investigation was 2,484 This group will henceforth be referred to as the encephalitis group The grandparents' generation is referred to as the A-generation, that of the parents as the B-generation and that of the patient as the C-generation The B-generation included a total of 1,449 subjects, and the C-generation 6!! The manner of examination of testees was recorded as (1) Complete The completest possible examination was made in the out-patient clinic (2) Partial These subjects refused to undress completely but consented to an inspection of the head, hands and feet.

·86 CONSTITUTION AND PREDISPOSITION (3) No examination but only collection of anamnestic data, venfied as much as possible via medical agencies. Completely eramined Anamnesis duta only 234 543 A-generation B-generation C-generation Partially (tamined 21 86 32 79 820 438 Venfication of the results of our investigation would actually require comparison with the average values in the Netherlands. Some large-scale investigations into the incidence of various manifestations in the average population have been made abrozu (Luxenburger, Stromgren and others) but no efective data of this type were available for the Netherlands. It was therefore necessary to furnish comparative material which could be regarded as more of less representative of the average Dutch population. In collaboration with Van der Wiel, who made a similar investigation among relatives of patients suffering from a cerebral tumour, 102 families were studjed, again including three generations. Fifty families were investi. gated by Van der Wiel. His starting point for the control group was a random proband who corresponded with the cerebral tumour patient as to age and occupation Our control group was composed in a different manner. We selecteu the first families listed under cach letter of the alphabet in the cul registry of the municipality of Utrecht, Utrecht is a medium-sizc city in the central region of the Netherlands, with an crceedingly mired population, and panmixia can be assumed by approximation These two groups will henceforth be referred to, collectively, as the 'control group', whereas the Utrecht group will be called the 'own control group'. Van der Wiel's control group showed the following composition: Total number Completely cramined Partially eramined Cramine 163 A-generation B-eneration C-generation 200 $26 25 33 3442 214 0 0 0 ·CONSTITUTION AND PREDISPOSITION The distribution in our own control group was as follows 87 Total number Completely cramined A-gencration B-generation C-generation Partially examined 208 558 129 NOI examined 84 335 122 13 0 116 210 7 The control group included a total number of 1,866 subjects, of whom 895 were included in our own control group. The graphs of Fig 10 (p. 88) give an impression of the age distribution in the groups at the time of investigation, according to generation and sex For fatal cases the age at the time of death was recorded This figure shows that the distributions in the A- and B-generations are not widely different. The C-generation, however, shows a more marked difference in that older age is predominant in the control group Our own control group shows a slight shift in favour of younger age Table 2 (p 90) shows a division in the groups according to family size. Family size denotes the total number of subjects in the three generations. This table clearly shows that the encephalitis group includes a larger number of large families than the control group In view of the higher age average in the control group it is possible that symptoms becoming more marked with increasing age are more readily diagnosed In this group because they have had time to develop if a higher frequency is none the less found in the encephalitis group, then this difference is only emphasized by the abovc-mentioned circumstances Since this investigation was instituted in order to detect familial hereditary factors, the familial correlation of individual findings must not be neglected in interpreting results We are concerned with familial features rather than with individual data individual data in both groups can be compared only if the following sequirements (a) Corresponding age distribution, and (b) Corresponding family sizes It is difficult to meet these requirements, particularly in a relatively have been met ·88 CONSTITUTION AND PREDISPOSITION A generation E Encephalitis group Control group sol do Encephalits group Cortrol group 4098 02-02 tee-OC 40-49 50-59 60-691 70-74 G8.08 465-06 16702 30-3219 40-49 50-CS 60-cola no-on LOG Age myeon B generation Encephalitis group Control group Encephalitis group Control group 11 16-0 foi 60-6S 20-29 30-35 50-55 18:00 1606 36-0 CooL Sza SUERE 370-75 ooth ot 500- C generation Encephalitis group a Control group c. Oun control group soon Encephalus group S control group do Own control group sole, 4 - EA 68% SOC 0-13 4044 10- Ye... 60 #sos 1909 0-9 4040 CECI SO Fig 10 Age disinbutron (in percentages) ·CONSTITUTION AND PREDISPOSITION 89 small group such as this. In so far as possible, corrections were applied in the elaboration of results to enable a statistical approach Whenever there was no such possibility, there being a risk of excessive mutilation of the material, the findings obtained were used as an illustration of more or less obvious clinical observations This would seem to us to be preferable to complicated statistical procedures which only seemingly elucidate the subject In the following sections a survey is given of the various deviations and anomalies observed in the course of the investigation or included in the anamnesis. Whenever comparisons are made between percentages of tainted families in distributions according to family size, those percentages that have been derived from groups smaller than 10 families are presented in italcs to denote a higher degree of unreliability Niseases of the central nervous system (including the meninges) A striking feature in the results of this investigation reproduced in Table 3 (p 90) is that the two groups do not differ much in the total number of affections of the CNS When the inflammations and inflammatory disorders (the groups I of the encephalitis and the control group) are separately regarded, however, the encephalitis group is seen to include twice as many families with one or several of such anomalies as the control group This proportion indicates that the families of the encephalitis group have an increased tendency to react by infiammations and inflammatory changes in the CNS. Peripheral neurological disturbances In respect to the figures of Table 4 (p. 92), too, the incidence of disturbances in the encephahtis group is unmistakably higher than that in the control group in the latter group, the data on the own control material are the least unfavourable, even in comparison with these data, however, the figures obtained are as follows Encephalitis group 35 disturbances in 27 out of 107 families Own control group 10 disturbances in 10 out of 52 families ·FO 10 up to 14 13 up to 19 up to 24 Number 25 kp ta 29 • Number : > 30 Number Number Total Lncephalitis group Control group Own control group 2 3 3 I2 20 123 Number Number X 40 19 20 26 33 IO 6 3 107 102 S2 - 2 TABLE 3 DISTASIS OF THE CLNTRAL NERVOUS SYSTTM (INCLUDING THE MENINGES) ENCEPHALITIS GROUP 1. Inflaminations and inflammatory disorders Encephalitis After German measics Von Economo Post-vaccinial Other forms total 9 (in 9 families) Meningitis (non-tuberculous) 15 (in 15 families) Poliomyelitis ant ac. 4 (in 4 families) Myelitis 1 Multiple sclerosis Tahes dorsalis 11. Other disorders Morbus Parkinson Chorea minor Tremorcs: congenital (?) other Tumut cetthet Men hus CONSTITUTION AND PREDISPOSITION S mm Portal total 3 ·es on H) Iesli) while Syringomycha Spastic manifestations cci Congenital encephalopathy Cerebellar ataxia Arachnoid hacmorrhage Total number of anomalies (group I and II) Spread over 36 43 families (group I) 31 29 families ONTROL GROUP Inflammations and inflammatory disorders Encephalitis Von Economo 2(1) Other forms total 3(2) (in 3(2) families) Meningitis Tuberculous 1(0) Other forms 6(S) total 715) (in 6(4) families) Poliomyelitis ant ac 1(0) Multiple sclerosis Cerebral abscess 2(0) or disorders Morbus Parkinson Chorca minor Tumor cerebri Morbus Little 1(0) Spastic manifestations CCI 6(6) Narcolepsy 1(0) Post-traumatic encephalopathy 1(0) Hlereditary spastic spinal paraplegia (in 1 family) 7(7) Total number of anomalies (group I and II) 38(28) (group I) 14(8) Spread over 29(20) families 13(7) families The number in parentheses refers to our own control material CONSTITUTION AND PREDISPOSITION 91 ·TARLE+ TERIPIIRAL NEUROLOGICAL DISTURBANCES 92 ENGALITIS GROUP 1 3 3 1 1 2 1 Trigeminal neuralgsa Bell's palsy Polyneuritis (after diphtheria) Herpes zoster Paresis of the ulnar nerve Scalcnus syndrome Meralgia paraesthetica Torticollis Miyotonic mamfestations Adic's syndrome Arcflexia of the legs Neurogenic dystrophy of the muscles Areneta in the same family Intervencbral disc protrusion (in 11 families) Total number of anomalies Spread over 1 5 CONSTITUTION AND PREDISPOSITION Z 2 4 total 6 12 35 27 families CONTROL GROUP On controls 1 1 - Trigeminal neuralgia Bell's palsy Neuritis of the Ischiadic nerve Nounts of the brachial plenus I ·I 1 Herpes zoster Partial thenar atrophy Areflexia of the legs Intervertebral disc protrusjon Total number of anomalies Spread over 2 2 5 2 10 13 families 10 famulis TABLES PSYCHIATRIC DISTURBANCES Encephabtis group Number of Number familles Control group Number of Number familier On control group Number of Number famillex Institutionalized or been institutionalized Schizophrenia Manic depressive group Other psychoses Intellectual disturbances "Psychopathies 2 2 0 CONSTITUTION AND PREDISPOSITION 0 30 8 4 32 2 of onstitutionalized or been stitutionalized Intellectual disturbances *Psychopathies Other nervous disorders 137 48 231 58 32 75 IS 23 12 48 Total 490 15 6 35 93 33 8 6 21 101 49 66 93 ·Since there was a relatively large number of psychiatric anora's 94 CONSTITUTION AND PREDISPOSITION It is very well possible, therefore, that the constitutional disposilica presupposed by us is partly expressed in a higher incidence of peripheral neurological disturbances. Psychiatric disturbances Psychiatric disorders were divided into two groups, distinguished ca the basis of whether or not they had led to institutionalization Apart from personal observations, hetero-anamnesis and information obtained from the medical authorities in charge were used to ensure as comprehensive a picture as possible. A survey of the incidence of psychiatric disorders is presented in Table 5 (p. 93) In both groups, the number of cases of schizophrenia and marie depressive psychosis is small (and within the same limits) Therc ars more marked differences in psychotic conditions under another diagnosis. In this respect the encephalitis group included more tainted families than the control group. The number of intellectual d turbances necessitating institutionalization was also larger in the encephalitis group. An even more marked difference is seen in the category of inte lectual disturbances not necessitating institutionalization 77 standard used in this group was the repetition of two or more classe at clementary schooi. In 58 out of 107 encephalitis families there was a total of 1 positive findings, as against a total of 23 in 15 out of 102 corte: families Similar figures were found with regard to the psychops:. reaction pattern The category of 'other nervous disorders includes such psychiang conditions as could not be classified under any of the abosc diam. x. headings The relations in this group were similar to those in the premis of intellectual disorders a subdivision was made according to the incidence of the 1139 affections. classified according to family size. The predominance expressed in the overall results of institute. ized patients (Table 6) is less apparent when the families are charm pared according to family size.

·TABLE 6 INSTITUTIONALIZED PATIENTS <10 Is up to 19 up to N 25 up to 29 30 Total 10 vp 10 11 Number Number! Aumber Numbee Number Number Nombre 6 10 Encephalitis group Control group Own control group SO 33 33 17 10 14 2 2 3 7 4 13 18 21 30 12 30 40 33 8 0 0 47 0 0 30 17 10 28 17 19 1 1 2 TABLE 7 INTELLECTUAL DISTURBANCES 10 10 wp to I wp10 24 23 Mp 10 29 30 Total 15 kpl 19 Number % Number Number Nuncher * Number Number x CONSTITUTION AND PREDISPOSITION Encephalitis group Control group Own control group 39 23 26 12 4 2 60 15 22 76 33 100 58 15 8 8831313138 TABLE 8 PSYCHOPATHIY 10 10 up to 14 > 30 7 olul 21 up to 24 Number * 15 mp lo 19 Number 9 39 23 up to 29 Number Number Number Number Number % 6 32 30 Encephalitis group Control group Own control group 0 0 0 Z 2 17 10 14 5 30 19 22 10 z 1 30 20 5 0 0 29 0 0 02 5 2 6 12 95 ·TABLE 9 OTILR LRVOL'S DISORDERS 10 96 10 up to 14 Number 15 up to 19 Sumber 2 up to 24 25 up to 29 Aumber > 30 Number Total Number 8 Number Number Encephalitis group Control group Oun control group 0 0 2 67 267 67 30 43 19 12 5 83 30 26 13 7 4 65 27 11 6 24 S 4 73 50 67 65 33 0 75 33 21 70 32 40 0 TABLE 10 PSYCHIATRIC DISTURBANCES 10 10 up to 14 Number 15 up to 19 Aamber up to 20 25 up to 29 umber 30 *** Number Torol Number Number Encephalitis group Control group Oun control group 3 Aumber SO 100 100 9 11 11 75 55 79 21 18 8 91 45 42 16 11 3 80 42 30 9 3 CONSTITUTION AND PREDISPOSITION 91 90 83 16 2 94 67 100 93 SI 32 87 SO 62 1 TABLE II MLEPSY Conruldre eles leix Granmal epilepsy Ordre forms of pilepu Incephalitis group Control group Oun control group Total Number of epileptic mualfestations Number of families 61 14 3 21 10 2 87 25 43 21 6 ·CONSTITUTION AND PREDISPOSITION 97 Whenever the percentage of tainted families in the encephalitis group exceeded that in the control group, the difference was more marked than in the reverse case. Few other conclusions can be derived from this variable aspect of the findings obtained. The marked difference between the various groups in the different columns of Table 7, in addition to the marked difference in overall results, warrants the conclusion that the encephalitis group is more heavily tainted with feeblemindedness than the control group A similar conclusion applies to the group of psychopathic anomalies (Table 8) Although the differences are less striking, the constancy of the deviation in each column would seem to support our view that the number of families in which psychopathic reaction patterns occur is larger in the encephalitis group than in the control group As could be expected from Table 5, the percentages given in Table 9 (with the exception of a small group of families of less than 10 members) reveal a heavier taint in the encephalitis group Table 10 presents a survey of families with one or several psychiatric disorders, regardless of further diagnosis and again taking family size into account. A survey of the various data shows that the picture of the various psychiatric disturbances supports the hypothesis that the neuropathic constitution supposed by us is partly manifested by the increased incidence of labile psychological structures Epilepsy A survey of Table 11 immediately reveals that the number of madifestations in each of the groups separately is larger in the encephalitis group than in the control group The number of families in which epileptic manifestations were recorded proved to be about twice as large as that in the control group The distribution over the groups according to family size is shown in Table 12. This survey likewise shows a heavier taint in the encephalitis group. For grand mal, the figures reproduced in Table 13 were found With the exception of the 2nd and 6th column, the percentages of ·TABLE 12 TPILEPTIC MAVIIESTATIONS 10 98 15 mp la 19 umher 10 kp to 14 Sumber up to 29 . 20 up to 4 Sumber Sumber 30 16 Total Number % Number! 1 + Number 8 -- Incephalitis group Control group Own control group 0 0 0 0 0 0 35 2 8 10 7 10 | 25 8 9 5 0 43 19 0 - 3 SI 20 17 2 1 16 47 67 100 43 21 6 40 20 12 TABLE 13 GRAND MAL EPILEPSY 10 10 up to 14 13 up to 19 20 mp to 2 umber 25 up to 29 % A 30 Number % Aumber Total % Number 0 0 0 Number 6 Encephalitis group Control group Own control group Number 0 0 0 0 S 0 20 3 13 10 51 4 CONSTITUTION AND PREDISPOSITION 29 9 0 0 0 0 0 0 2 1 67 100 15 8 2 13 8 4 TABLE 14 COMU'LSIVT. STATES IN INFANTS < 10 10 up to 14 15 mp lo 19 13 * sumber 20 up to 4 Aumber 30 25 up to 29 Number Total Number Incephalitis group Control group Oun control group 6 6 0 0 0 26 18 0 6 4 0 7 30 15 0 2 1 0 10 0 0 0 29 0 0 32 13 30 13 ·CONSTITUTION AND PREDISPOSITION 99 the encephalitis group are higher. This tendency is even more marked in the data on convulsions in infants (Table 14). In view of the considerable difference between the encephalitis group and the control group in the number of tainted families, and also on the basis of the instructive proportions of the various mantfestations in the different groups, it can be considered highly probable that the epileptic taint in the encephalitis group exceeds that in the control group Migraine The data on incidence provide an equivocal picture In the encephaitus group 17 cases of migraine occurred in 9 families in the control group these figures were 17 in 13 families, in our own control groups in 4 families On the basis of these data, no definite conclusion can be reached at this time as to any taint, in any direction Status dysraplucus The stigmata of status dysraphicus can be divided into three groups, VIS (1) Chief anamnestic characteristics These are characteristics which can be verified with sufficient certainty from the anamnesis (2) Chief characteristics observed. In this category the anamnestic data were not sufficiently reliable, so that only personal observations were taken into account (3) Additional characteristics These were recorded as absent or present only after personal observation In groups 2 and 3, characteristics were classified as unknown when only anamnestic data on the probands were available The following characteristics were found Chief anamnestic characteristics: Anencephalia Hydrocephalus Spina bifida aperta Kyphoscoliosis with unmistakable humpback Enuresis nocturna over the age of 10 ·100 CONSTITUTION AND PREDISPOSITION Chief characteristics observed: Marked or unmistakable unilateral or bilateral pes cavus Kyphoscoliosis but not with unmistakablc humpback Irregular build of vertebral column Vertebral column without the normal kyphosis-lordosis structurc Funnel chest Neurological changes atinbutable to my clodysplasia. Additional characteristics: Mild unilateral or bilateral pes cayus Depressed sternum Pigeon chest Enuresis nocturna over the age of 5 Unilateral or bilateral curvature of the intric finger Acrocyanosis Ogival palate Gnatho-palato-chciloschisis Stigmata of arachnodactyha. In the following, the other dysraphic stigmata arc disregarded i order to facilitate systematic elaboration. The following combination were encountered. Chief andnin3/10 characteristics Chies Addrwonal characteristics characteristobsersed Definitely dysraphic (r) present present present present absent present present absent Unknown present present absent ritsent rraient ment Dubiously dysraphic { :) present present absent absent absent Alxens absent absent abwent prosentt present absent unknown unknown absent unknown abrent unknown risert present unknown Dubrously negatnica } cannels absent absent absent ·TABLE 15 GRADES OF DYSRAPIITSM Definitely dysraphic Dublourly dystephie + Dubioutly negative F Negative Totul numhar of persons Encephalitis group Control group Own control group Control group Van der Wiel 596 103 63 40 1036 583 409 211 198 346 375 269 621 275 358 2484 1866 895 971 TABLE 16 GRADES OF DYSRAPJIISM IN PERSONS OVER 20 YEARS OF AGE CONSTITUTION AND PREDISPOSITION Definitely dysruphic Dublously dysraphic Dublously negative Negative Total number of persone ncephalitis group ontrol group un control group pntrol group Van der Wiel 476 94 57 37 456 351 174 177 770 563 271 292 193 537 219 J18 1895 1545 721 824 TOT ·102 CONSTITUTION AND PREDISPOSITION of age. Using the above classification, we found the figures giion in Table IS in the various groups. Since a number of dysraphic stigmata become more marked as the individual approaches adult proportions, Table 16 gives a suner of the dysraphic taint in subjects over 20 years The reliability of the data collected increases when the probands can be personally examined. The anamnestic data, hou cct us!} collected and regardless of the good cooperation of test subjects, have again and again shown a variety of gaps. A good understanding of the proportions in terms of dysraphic taint, therefore, can be obtained by considering the results of the miestigation in subjects completely or partially cramined. Table 17 gives a survey of the results obtained in this manner. The data hanc been subdivided according to the generation. In the second part of Table 17, a division is given according to the geographic distribution of the test subjects so as to give an impression of possible local factors. Although the interpretation of the proportions of the figures fren here may be subject to some justified criticism, these figures never theless give the impression that the percentage of positive dysraphics among the number of examined subjects in Tilburg erceeds that in the other two geographic groups, whereas the percentages in each of these groups in turn exceed that in the control group. If the encephalitis group has a heavier dysraphic taint, then this should be reflected in the occurrence of fatal dysraphia. Or course no rutal dysraphia occurs in the A-generation. In the B-generation of the cncephalitis group there are 1,449 subjects, including 213 parents. The number of subjects in this generation who may dciclop a $3131 dysraphic affection, therefore, is 1,236. Three instances of fatal dysraphia were recorded in this group. The C-generation of this same group consists of bll subjects, including 109 paticnts with post-vaccinial encephalitis. Among the 502 subjects who could have manifested fatal dysraphia, 4 did desclop this condition. In our own control group there were 15+ possibic subjects in the B-generation No case of fatal dysraphia was reported, and the same holds truc for the C-generation (129 subjects) Corresponding figures in the Van der Wiel control group ucre 426 and 195, without a 110 of fatal dysraphia The Central Burcau of Statistics in the Netherlands, ·HISM OF EXAMINED PERSONS Grnerellan Group Number of perrons Amber of infally a remised persons Dysraphism Nuncher + A Encephalitis Controls of purtfully rrumined persons Dyraphism Number of perts 79 24 28 + F 119(84)') 27 5(4) 21 26(22) 6 15 B 81(54) 8(8) Encephalitis | Controls 820 1(1) 7(7) 360 317 677(335) 143 71(45) 86 246(134) Z 42 42 C 360(156) 13(13) 438 Encephalitis Controls 209 9(9) 150 336(122) 79 A 27(14) 32 121(45) 11 188(63) 21 CONSTITUTION AND PREDISPOSITION n B Tilburg с A Remaining 3 parts of C Brabant 214 94 2 20 3 + 74 13 4 72 120 78 3 62 35 20 178 76 164 110 60 36 30 19 21 Rest of the Netherlands C 442 234 19 171 101 93 6 18 73 32 $7 36 12 35 ) The number in parentheses refers to our ... 21 103 ·104 CONSTITUTION AND PREDISPOSITION reporting on the period 1951 through 1957, recorded about 800 instances of fatal dysraphia in the groups of stillbirths and deaths, at an annual birth rate of about 230,000, i e, about 1 in 300 births Comparing the records of our groups under investigation with the above figures, we find a frequency of about 1 in 400 births in th: B-generation of the encephalitis group, and about 1 in 128 births 1a the C-generation. The last-mentioned rate would seem to indicate a heavier dysraphic taint. The difference between the B-generation and the C-generation is probably partly based on the fact that the average age in the Bgeneration is higher, so that data on perinatal mortality are less rchants in this category. The fact that, in tracing cases of farsi dysraphi). ignorance and positive concealment are of great importancc, is rather obvious. The figures presented, therefore, are likely to be lower than the actual values. The following measures were taken to ensure that the dysraphic faint in the various groups should be approached with optimal mathematical reliability *. We calculated the frequency of occurrence of certain dysraphia' (definitely positie) 'probable dysraphia' (dubiously positive), definitely no dysraphia' (negatne) and the cemaining group of *probably no dysraphia' (dubiously negative) The ascrage frequency of each of the four grades of dysraphism per group, per generation, can be calculated in two ways. sz. by calculating the frequency for an subjects per group, and by averaging the abosc-mentioned frequencies Since the grade of dysraphism per family may differ, and since on the other hand the grade of dysraphism may depend on the family size, uc believe that the second method (arcraging the frequencies) us to be preferred in this manner, the average frequencies indicated in Table 18 (p 107) were obtained. This table furnishes the following information: (1) la tko A-generation, the dubiously negative and the negative • The mathematical laboration was carried out by the Department of Elaboration of Results Ohsene, of the Central Organization for Arried Physical Research INOL.

·CONSTITUTION AND PREDISPOSITION 105 cases in the two control groups were diagnosed to different degrees. (2) In the B-generation, the negative cases in the two control groups mere diagnosed to different degrees. If the frequencies frer family could be regarded as independent, normally distributed varsables, then these differences would be significant at the level. It is an obvious supposition that this difference between the (wo control groups may be correlated either with the choice of material or with differences in diagnosis or interpretation of the changes. Once more this demonstrates the necessity of prudence in dealing with 'objectne figures in medicine. In view of this it would seem to be advisable, for the time being, to compare the encephalitis group exclusively with our own control group, using the Van der Wiel control group only for illustration. Such a comparison leads to the following conclusions (1) In the A-generation there is only an indication that the dysraphism in the encephalıtıs group exceeds that in our own control group; the Van der Wiel group points in the same direction (2) In the B-generation the result is more unequivocal The definitely dysraphic fraction is significantly larger and the definitely negative fraction significantly smaller is the encephalitse group, thc two dubious fractions show about the same frequency in the encephalitis group and in our own control group. The Van der Woct group shows the differences found with regard to the encephalitis group to a more (3) In the C-generation, the difference between thc encephalitis group and our own control group as to the frequency of certain dysraphia is highly significant in negatives, 100, the difference is naturally very significant, but in this respect we are confronted with the complication that the dubious negatsies predamnate in the encephalitis group The data on the C-generation have the disadvantage that this generation is represented by only 1 or 2 subjects in many families, the fractions presented, consequently, are pure estimates of the average dysraphism per family but significance calculations can hardly be For the B-generation, #culso calculated a weighed mean of the fractions found, after transformation by the method of angular transformatwn, which renders variance virtually independent of the marked degree. made.

·106 CONSTITUTION AND PREDISPOSITION frequency. Bartlett's correction was applied, replacing fractiors of 0% and 100%, respectively, in a family of n persons by (100,2n)". and 100%-(100/2n) %, respectively. This correction ensures further stabilization of the variance and, in our cases, has the additional advantage that the observation of 0% (relatively often made in the control groups, particularly with small family size) does not escort 100 marked an influence on the mean frequency. Because in angular transformation the variance is inversely proportional to the number of ob servations, i.e. the family size, this size must be used as weight in calcu lating mean and variance. When this method is applied, therefore, large families evert a more marked influence on the means than the small families. In the B-generation, this was found not to have an important cffect on the mean values (as compared with the method discussed carher) The average percentages in Table 19 shown were obtained by re calculation from the angles Owing to the transformation, the total of re-calculated percentages is no longer exactly 100%. Again, the differences between the cocephal. itis group and the two control groups in dubiously positive and negative results are only small; the difference in definitely positive and definitely negative results are very marked and highly significant The method employed also makes it possible to serify whether the grade of dysraphism differs from family to family. If this is not the casc, then the variance of transformed percentages--after weighing with the aid of family sizc--should thcorctically be 909** -- 8207. We found the values of Tablc 20 for these variances. This table shows that, in both control groups, the variances of the definitely positive and dubiously positive results do not signifie cantly differ from the theoretical variance. The variances of the negalite results, however, do differ significantly from the theoretical variance. A plausiblc explanation of this fact may in our opinion be found in the fact that the separation between negatines and dubious negaties has not been made in the correct place and that, in fact, the dysraphism in cach of the two control groups has a frequency which is the same for the majority of the families, The encephalitis group shows an entirely different picture; the variance found here is ini anably highly significantly larger than the ·TABLE 20 DYSRAPISY (VARIANC15 OF TRANSFORMITI MIRCINIACHES) CONSTITUTION AND PREDISPOSITION TABLE 18 DYSRAPHISY IV PERCENTAGES 107 Definitely Modrive Dublously potitive A-generation Encephalitis group Own control group Van der Wiel group Dublundy marine Aerative 65 19 OS 103 130 40 83.5 59.1 82.0 B-generation incephalitis group un control group in der Wiel group 3 68 26 0 135 254 87 51 25.1 267 224 . C-generation Encephalitis group Oun control group Van der Wiel group 396 359 JUS 99 287 390 310 101 49 30 3 32.3 | 338 258 56 99 129 S18 SIS TABLE 19 DYSRAPHISM (AVERAGE PERCENTAGES) Definitely PONTIC Dubinetly PONIN B-generation Encephalitis group Oun control group Van der Wiel group Dwblowly potre Arpaior 238 91 73 24 5 23 7 207 X34 783 UR 26 R01 Definitely Mellin Bewafy petir Ihlavy AFF Nrrolles B-generaton Encephalitis group Own control group Van der Wirel group 19797 1158 5 61S X 9062 1055 799 $ 26416 11301 25517 1028 2 13-440 1509 5 ·10S CONSTITUTION AND PREDISPOSITION theoretical variance. This may indicate that the dysraphic taint in the encephalitis group differs in the various families. The fact that the most unmistakable picture is found precisely in the B-generation need not surprise us. After all, this is the generation which includes few infants, so that diagnosis of the changes is much less difficult than in the C-generation. Apart from this, a larger percentage of the B-generation than of the A-generation could be examined, as the loss due to death in the latter generation is higher. An overall consideration of these data warrants the conclusion that the dysraphism in the encephalitis group significantly ctceeds that in the control group. Allergic disorders The possibility that post-vaccinial encephaltis might be an allergic reaction of the CNS has been previously discussed in some detail While data on other allergic allections are of interest to us, if merely from the point of view of the problem of neuropathic constitution, they are even more interesting in view of the question of a possible correlation between affections known to be allergic and so-called neuro-allergy. Our investigation was limited to the most widely known syndromes of which Table 21 gives a survey. This table shows that the number of families in which allergic disorders occur is larger in the encephalitis group than in the control group, for all affections crccpt hay fever. The number of families in which any allergic affection occurs is also farger in the encephalitis group, as is shown in Tablc 22. In accordance with family size, expressed in percentages, we fourd the distribution of tainted families for infantile eczema as reproduced in Table 23. Whenever percentages in the control group are higher than those in the encephalitis group, the figures are printed in italics. The more reliable percentages point in the direction of a heasier taint in ito encephalitis group There were cien more marked differences in the families tainty with bronchial asthma (Table 24) With the crception of the second ·TABLE 21 ALLERGIC DISORDERS Gram Eczema Infantum Number Number of families Encephalitis Controls un controls 29 12 10 23 Broncklal asthma Number Nuribm of families 38 27 20 19 b Hay fever Number Number of families L'rtícurla Auniber Others 7 4 ce 4 10 Number 6 Number offumilles 14 18 Number of families Total number of Cate: Familles 4 1 0 0 2484 1866 895 107 102 52 Group TABLE 22 NUMBLR OF FAMILIES WITH ONE OR MORE ALLERGIC STIGMATA Encephalitis Controls Own controls Torar number of families CONSTITUTION AND PREDISPOSITION 33 54 70 37 107 102 52 109 ·TABLC 23 CZIVA INFANTU 110 10 up to 14 15 wp to 19 up to 24 25 ur 1079 > 30 Toral under Number umber Number Aumbre * Number 8 3 17 10 18 [ncophalilis group Control group Own control group 21 50 0 0 0 0 2 2 2 5 2 0 22 5 0 20 12 33 24 10 17 23 9 7 - 3 100 13 TABLE 24 BRONCHIAL ASTHMA 10 15 up to 19 up to 10 up to 1 wher 25 wp lo 29 230 Total Aumber Sumber 14 Number 70 Number :: umber CONSTITUTION AND PREDISPOSITION 7 7 Encephalitis group Control group Own control group 23 0 0 0 3 3 17 25 21 30 23 S 35 IS 7 1 1 21 10 17 27 19 6 25 19 12 1 1 0 0 TABLC 25 JIAY TEVTR 10 JO w to lo 15 up to 19 up to 24 3 pt. 33 Tuta! Sumber wmler umber Vumber *** wher 1 Incephalitis group Control group Oun control group 0 0 0 0 0 0 1 + 3 20 12 2 1 1 10 0 0 0 U + 10 5 0 10 10 ·TABLE 26 URTICARIA <10 Id up to 14 13 up to 19 20 up to 24 25 up fo.39 > 30 Total Number % Number % Number % Number % Number Number * Norther 10 3 1 6 Encephalitus group Control group Own control group 0 0 0 O O 0 3 2 0 29 10 0 3 0 0 13 0 0 Nod IS 10 17 14 3 13 3 2 0 0 0 TABLE 27 ENDOCRINE-DIENCEPHIALIC STIGMATA CONSTITUTION AND PREDISPOSITION Group Goltre Diabeter mellitus Number of cases Number of families Number of cases Obesity Number of Number of caser funities Others Number of Number of cast Sumilars - S3 13 11 25 9 7 I 111 Number of familles 26 25 11 36 29 12 164 62 65 40 24 73 24 15 42 22 13 Group 1. Encephalitis group Group II Control group. Group III. Own control group.

·114 CONSTITUTION AND PREDISPOSITION according to family size and expressed in percentages, the data on the occurrence of one or several endocrine-diencephalic disorders in the family are shown in Table 29. Apart from the first column, the percentages in the encephalitis group are higher than those in the control group. Comparison with our own control group, however, yields less convincing results Table 30 presents a survey of the number of families in which one or seseral cases of goitre occurred, also divided according to family sire. All percentages arc higher in the cnccphalitis group than in the control group, with the exception of the first and fifth column. As could be expected from the above suncy, the distribution of families tainted with diabetes mellitus, according to family sure, revealed so small a difference between the two groups that a heasier taint in the encephalitis group cannot be suggested (Table 31) The data on obesity-so suggestive in the general suney-lose convincing power in view of the figures reproduced in Table 32. Although there are again some arguments in favour of a hcauer tainting of the encephalitis group, reversed proportions are also scen (particularly in the third column). The findings in the area of other endocrinc-diencephalic disorders' are reproduced in Table 33 In this table, we find no positive findings in the first two columns in the encephalitis group. Yet the other findings, 25 in the case of obesity, support the suggestion that these stigmata arc more frequent in the encephalitis group. Shin malformations Anomalies in the skin pigmentation were recorded as: (a) café-av. Part spor, (b) nacvus pigmentosus and (c) depigmentation. Table 34 shows that the frequency of pigmental anomalies in cncephalitis group is about the same as that in the control group The number of families in which these stigmata were found is alw about the same in both groups A heaver taint of the encephalitis group in this respect was not demonstrable. Hlucmangiomata were slightly more frequent in the encephalts group The number of families in which haemangiomata ucre found is about twice as large in the encephalitis group (Table 35).

·TABLE 29 ENDOCRINE-DIENCEPHALIC STIGYATA 10 10 up to 16 number 15 up to 10 Amber 25 kp to 29 Number 20 up to 24 Number 30 Total Number % Number % Number Encephalitis group Control group Own control group 3 so 100 100 8 10 17 97 67 So 50 17 26 14 IS 74 65 74 88 17 16 8 90 3 85 62 89 7 S 84 63 73 100 38 TABLE 30 GOITRE "To 1 15 up to 19 10 up to 14 Number 20 up to 24 Numher 30 Muniber 75 up to 9 Number! Number Number Totul Number 0 % 4 Encephalitis group Control group Own control group 17 0 3,3 33 6 8 S 7 1 CONSTITUTION AND PREDISPOSITION 8 - 30 12 33 نما 6 2 2 18 20 33 - 1 25 9 47 33 0 0 3 23 9 13 0 TABLE 31 DIABETES MELLITUS <10 10 up to 14 20 up to 24 Number 13 up to 19 Number 23 up to 29 Number Tolul Aumber 16 Number * Number Number Encephalitis group Control group Own control group 0 0 0 0 o 0 2 4 17 20 7 3 10 25 26 35 27 33 8 4 2 24 40 33 6 0 0 35 0 0 3 26 25 I 24 25 21 115 ·TABLE 32 OBISITY 911 10 10 up to 14 up to 24 29 wr to 29 15 up to 19 Aumber JO Total umber umber Sumber umhari Number Number 30 27 Encephalitis group Control group Oun control group 2 30 67 67 65 S 42 25 29 7 17 9 1S 9 5 75 35 S6 82 SO 50 11 2 66 40 24 62 39 46 3 100 TABLE 33 OTHER ENDOCRINE STIGMATA • 10 13 up to 10 10 up to 14 Number V up to 24 25 kp to 29 30 Totul Aumber Number % umber Number 10 Number % Number 0 Encephalitis group Control group Own control group 8 0 33 ! 33 0 4 3 0 20 21 7 10 7 CONSTITUTION AND PREDISPOSITION 11 30 25 37 40 15 1 16 2 0 48 20 0 65 33 100 42 22 13 39 22 25 TABLE 34 ANOMALIES OF PIGMENTATION + umber of families Caritalar I Nantes Pigmentosa Derimentation Encephalitis group Control group Own control group 67 134 1040 S00 92 92 +1 61 29 21 8 7 33 ·TABLE 35 PAEMANGIOMATA Present Abgend Number of familie Encephalitis group Control group Own control group 16 9 3 1320 1123 538 14 8 3 TABLE 36 OTHER SKIN DISORDERS Present Abrent Number of familers CONSTITUTION AND PREDISPOSITION Encephalılıs group Control group Own control group S7 28 21 1279 1104 $20 35 21 15 TABLE 37 OTHER SKIN DISORDERS Lipometa Psoriasis Ichthyosis Oshers Number Number of families Fibromala Number Number of families Number Number of families Number Number offumhes Number umber of families 18 6 Encephalitis group Control group Own control group 7 O 0 7 0 0 14 3 3 12 4 4 12 i 8 10 7 $ 6 Z Z 6 10 2 6 117 ·controls Controls Total number of Van der Wiel (* n controls necphullis group $1 Tuberwower LABIL 38 INSANAL VIKURIRS DURING LINE 15 15 We' furules 9 6 w fle Acute Rhe MEIS oc Ansbert fumdors Chronic 12 Rheumatoid Arth71813 9 under of furules ܕ 1 Brkice -- Wher of furulact 16 ham Lurdus IS Lumines - Corsenital disorders 1300 612 688 1770 umbrs of prudent's CONSTITUTION AND PREDISPOSITION 11S ·CONSTITUTION AND PREDISPOSITION 119 A division of hacmangioma frequency according to family size is impossible in view of the small number of famihes. This would not gne a better understanding The figures given point in the direction of a heavier taint in the encephalitis group In the survey of other skin changes there were more changes in the encephalitis group (Table 36) Since these phenomena, when divided according to nature, provide a heterogeneous picture, we considered it advisable to present a survey of the skin anomalies included in this group in Table 37 In this respect it can be pointed out that the number of lipomata in the encephalitis group exceeds that in the control group The difference is less obvious for the fibromata. There is indeed a difference between the encephahtis group and the control group, but the figures for our own control group render this difference dubious The incidence of psoriasis shows no marked difference between the two groups The occurrence of ichthyosis may be more significant; 18 cases of this condition were registered in 6 families of the encephalitis group Although these data do not warrant any definite conclusions it can be pointed out that whenever a difference occurred in these groups of skin changes, this difference was invariably in favour of the encephalitis group Disorders in the field of internal medicine In Table 38 a survey is presented of registered changes in the field of internal medicine, as found in the various groups during life The number of families with tuberculosis in the encephalitis group exceeds that in the control group In view of the data on causes of death, this fact is supported only by the proportions of the tuber. culosis figures in the B-generation Yet the figures found are rather strongly suggestive of an increased susceptibility to tuberculosis Nothing can be said of the incidence of carcinomata, particularly if we include the carcinomata recorded as cause of death in the field of rheumatic conditions there are higher frequencies in the encephalitis group again ·120 CONSTITUTION AND PREDISPOSITION A remarkable feature is the marked difference in the number of families having one or seicral cases of organic heart defect Concomitance of congenital cardiopathics and dysraphic stigmatı has been discussed in detail by such investigators as Bijl, who raices the question of a possible predisposition to cardiac affections in general. The data of this table, and the heavier dysraphic taint in the encephalitis group, might tend to confirm this possibility. Other degeneratie stigmata Apart from the above-mentioned changes, such stigmata as could probably be largely attributed to dysontogenesis were also registered; they are generally indicated as 'degenerative stigmala A number of these stigmata listed are closely related with the starus dysraphicus Their occurrence probably depends on a dysraphic condition although, in genetic terms, they are more independent than the dysraphic stigmata listed carlier. The cract nature of these relationships is still obscure. As long as this is the case, it would seem to be advisable to keep these stigmata separated. A survey follows of the anomalies found: ENCETHALITIS GROUP Cramm } 1 3 in 1 Cam. 4 in Alam Orycephalia Bathrocephalia Mandibulofacial dysostosis Hypertelorism Reduced intcrocular distance Internal frontal hyperostosis Prognathism Mandibular hypoplasia 5 in 12m 3 in ) lam. stagmus to left and right Sirbimus Maskad mopia Congenital proses bilateral unilatera) 35 in 35 m 716 61192 6 in 3 fam Sin 2517 ·CONSTITUTION AND PREDISPOSITION 121 Sin 4 fam. 1 12 in 6 fam. 2 in 1 fam Blepharophımosis Congenital bilateral loss of abductor function Simple heterochromia of the iris Early cataract Congenital blindness One amblyopic eye Ears Malformation of the external ear Congenital deafness Deafness 2 in 2 fam 15 in 7 fam Extremities Brachydactylia 11 in 4 farst. Syndictyla 11 in 9 fam Other radial anomalies 3 in 3 fam Excessive flaccidity (Hyperlaxite) 16 10 10 fam Congenital luration of the hip 3 in 3 fam Dupuytren's contracture 318 3 fam. Other stigmata' Abortive form of achondroplasia Sin 4 fam. Anal atresia 1 Hyperthelia 2 in 2 fam. Total number of anomalies 181 in 68 Cam OWN CONTROL GROUP Cranium Prognathism Mandibulae hypoplasia Eyes Nystagmus to both sides Strabismus Marked myopia Marked hypermetropia Early cataract Simple heterochromia of the 1015 Unilateral ptosis Congenital unilateral abductor paresis EOS Dealness 3 in 3 fam 10 in 8 fam 6 in 4 fam. 3 in 3 fam 2 ·130 PROPIYLAXIS AND THERAPY different vaccines gave rise to van ing numbers of cases of vaccina generalisata. This was not the case with posi-vaccinal encephalitis. This would tend to support the theory of there being no (or at least no positive) correlation between the dermal and cerebral phenomena An objection to one scar will be that the number of failures to 'tale in young children will probably increase. Doorschodt has shown thal the number of pock marks is smaller in the case of children whose mothers had been vaccinated a short time previously than in these whose mothers had been vaccinated many years previously, or not at all She further stated that there was a correlation between the immunity and the number of pockmarks (sec page 127). Nevertheless, one pochmark would conform to the requirements of the law, which is An argument stressed by Silles is Smitt. The fact that a new vaccinostyle should be used for cach neu vaccination is obvious. English workers have suggested intra-or even sub-cutaneous vaccination (Stuart). It has yet to be proved that this will improve the prognosis. Paschen believes that the reduction of the skin reactions brings with it no certainty of a reduction in encephalıtıdes. This may also be the explanation of the fact that dilution of the vaccine also has no cffect on encephalitis (David). Nett, uc must consider the question of whether the nature of the vaccinc itself has anything to do with the development of post-vaccinial encephalitis In doing this, we omit all mention of the many theories concerned with the ctiology of encepha. litis postvaccinialis, but refer the reader to the appropriate chapter This is not to deny that there is a connection between the tuo problems. It is obvious that as long as the 'activating theory' is not completely discarded it as wise not to vaccinate at times when virus infections are prevalent. Further, the number of micro-organisms found as impurities in the vaccine must of course be kept as low as possibl: These, however, do not concern us; we are interested in the sacre ‘an sich We are now forced to fall back on cmpiricism. The Encephalitis Report of 1932 denies any connection between the desclopmer! of post-vaccinual encephalitis and the sort of saccine used More recent reports also deny any positive correlation between the two The choice of vaccine therefore probably does not play a role, but it seems uite to continue to collect statistics concerning this matter. Perhaps 3:9 ·PROPHYLAXIS AND THERAPY 131 analysis covering a long period of time may be able to lead to a definitive answer. Frenkel and Kapsenberg have occupied themselves with the pro- Puction of contamination-poor and -free vaccine. Ordinary vaccine, Produced by culture on calves, has several disadvantages The bacterial mpurities are reduced by the addition of glycerol and by storing at - 10 to - 20°C for two years in the Netherlands) This timeconsuming method of production can lead to difficulties, for example Huring times of increased demand In addition to which, the vaccine must be used within one week of delivery, and standardization of he product is not possible. Three methods for the production of a acteria-free vaccine have been mentioned: (a) neurovaccine (Gallard, Levaditi and Nicolau), (b) egg passage and (c) culture. In this last method, Kapsenberg uses the epidermis of cow tongue. The vaccine produced proved to have the same immunizing powers calves as the ordinary vaccine Serum from cows immunized with Amsterdam virus neutralizes the cultured virus It is also possible to utrate the material; the optimal titer is probably in the neighbourhood of 10-6 to 10-7. This vaccine is difficult to use, however It is watery and therefore adheres poorly to the skin Its immunizing powers in uman beings have yet to be determined When it becomes available or large-scale use we shall be able to see whether it offers a possibility of reducing post-vaccinial neurological complications. Nelis proposed using a vaccine prepared with a solution of formol This should diminish the encephalitogenic factors, without influencing The immunization against smallpor The 1954 regulations concerning vaccination of military personnel ere as follows The vaccine used must come from an accredited accine centre The instruments used for the vaccination must be tenle. A sterilized or new sterile vaccinostyle or needle is to be used or each person being vaccinated The vaccinc may be allowed to come into contact only with clean, sterile objects. Thus an object that as been in contact with skin or blood may never be held or dipped onto the vaccine (danger of serum hepatitis) Continuous control is ecessary for the development of an immaculate technique. This echnique will consist of either the multiple pressure method or the Ecratch method, and in both cases there must be an absolute minimum ·132 PROPHYLAXIS AND THERAPY of bleeding. The surface used in the former methout must nou k greater than 0.5 cm", with a diameter of 8 mm. In using the scratch mcthard, 2 scratches are to be made of 0.5 cm long, at at least 2 cm dilance from one another. The vaccination site must be cleaned with either cther or soap and water. After vaccination, the creess of vaccine must be alloued to dry in place, temosed wsth a clean piece of coston, or covered with a clean sauze-pad. It is advisable to Icep the vaccination site dry, In addition to all these measures concerning the vaccine, an attempt has been made to decrease the number of cascs of post-vaccinal encephalitis by means of various chemical-humoral procedures, Wc shall merely mention the abstinence from cating mear following Vaccination rational basis for this has never been demonstrated. Drogendijk has advocated the use of Pernacmon as a prophylactic He has not seen any cncephalusis following vaccination combined with administration of Pernacmon. Many authors (Melville MacKenzie, fyfc, Flemming and others) have reported the falourable results of the use of immune scrum 1 is believed that the anti-bodies here combat the vaccinc virus or some other (encephalitogene) virus, one of these being the cause of you vaccinal cncephalitis. In The Netherlands attempts are also being made to gain more certainty about the use of immune seum. li is probable chat gamma globulin and hyperimmune gamma globulin are even more cffccttle. The skin scaction to the vaccination is not affected. (This, howeier, is not very significant. Sec the above concerning the correlation between dermal and cerebral reactions) The following report by Trostdorf of a case of varicella encephalitis grics us food for thought (at least of wc accept the cristence of parallel mechanisms) Hic describes a girl of 31 years of age who was eru to intermittent cold over a period of sentral months. During this period she suffered from transient attacks of squint. She contacted Waricella, which was followed by an acutc, transient blindness Tuclic days after the onset of the chickenpar, she chibuted a slight snequality of telleres following the administration of reconvalescent scrum, the child descloped an acute tetrapicg., which Trostess constders as supporting the theory of the allergic actiology of the para-infectious encephalıfıdes The author has no crperience in these ·PROPIYLAXIS AND TIIRAPY 133 matters We have been unable to find descriptions of similar C.1625 in the literature, but it seems reasonable to bear this possibility in mind (3) The choice of therapeutic agent (or agents) in cases of encephalo. nijelins post-laccinalis The therapy of this disease must, in view of the meagreness of our knowledge concerning the aetiology, at Icast partly be symptomatic (Govaerts) The part of the therapy that may b: called 'specific varies like the opinion of the physician concerning the actiology We should now like to mention some of these specific therapies Under prophylaxis we mentioned the use of immunc scrum This is also used in established cases Van Bouudijk Bastiaanse was the first to recommend the use of serum from highly-immunized animals At the time no favourable effects were seen, Hekman ircated his cases with the intravenous injection of scrum from patients who had been very recently vaccinated. He reported satisfactory results Others (Gordon, Paschen, Kokken and others) reported a similar success In the Bulletin de Organisation mondiale de la Santé, 1947-43, this serum therapy is mentioned. Verlinde pointed out in his dissertation the possibility that disturbances in hepatic functions may play a rolo in the development of encephalitis. Guanıdınc may be the moxt important factor insolved here. This is the ongin of the Pernarmon. therapy. Kramer has declared that he sees possibilities in this theory and therapy. Statistics concerning this therapy are not yet available so that it is impossible to judge its value. L'sing the allergic genesis of post-vaccinial encephalitis as a startingpoint, Ligterink believes that he has seen good results following the tse of ACTH. Stenczel advises administening calcium. Hyttar gres sul further and recommends the use of anti-h1112m1ret (Sore Americans advise using these in the treatment of «clerosit ruilpler') In all of these therapies we can see ill-concealed hypotheses crtio cerring the aetiology. The rember of pauenti is too small to be able to give each of these rethod's 27 adequate therapeutic trial, of denise a reliable opinion based on facts. We are that loreed, 17 trsaing ases of post-viccirist crcephalitis, to choose from a group of 473- Pentics fose valse has rot yet beers prosed ·136 SUMMARY A review of the clinical manifestations of post-vaccinial encephalitis is presented in Chapter 4. The heterogeneity of the manifestations is pointed out. With reſerence to a statement by De Vries-that no typical (demyelinating) microglial encephalitis is seen under the age of t1o-an attempt is made to elucidate some of the clinical aspects of this difference. The incubation periods in the cases of post-vaccinial encephaltis notified during the period 1945/1951 were divided into two groups, with the age of two as the borderline. Two aspects were thus clearly rescaled, riz: The average period of incubation was 9 days in the younger group (with a peak at 7 days), and 11.57 days (with a peak at 12-13 days) in the older group The difference between the averages proved to be significant, as was the difference in the distribution of data ground the average. In addition it was found, on statistical grounds, that children under two years of age also show a correlation betu.cen the time of vaccination and the subsequent cerebral features. In our opinion, both the pathological-anatomical findings and the above. mentioned clinical data warrant the conclusion that post-vacciniz! cncephalitis in young children is a clinical entity which differs from that in older subjects. Among the 109 cases of post-vaccinial encephalitis studied, there were 23 deaths. 38 subjects showed more or less severe residual symptoms This last-mentioned fact is an argument against the view that there are only two possibilities after posi-vaccinial encephalitis, 1: cure without after-effects or a fatal issue. The classification of post-saccinial cnccphalitis recommended by the above-mentioned Encephalitis Commilice scoms to hase retained practical value this classification is as follows: (1) Cascs which can be interpreted with certainty as post-ractoria) encephalitis Dubious cases, but most likely to be positive. (3) Dubious cases which may he cither positive or negatic. HI Concu in which the clinical course can only be identificd asso Locuinul but showing no changes definitely indicative of the condition under JIVUNMON ·SUMMARY 137 The pathological anatomy (Chapter 5) is described largely on the basis of De Vries's work. Apart from the typical picture of demyelinating perisenous microglial encephalitis previously described by Van Bouwdijk Bastiaanse there are other pathological anatomical pictures which can be interpreted as post-vaccinial cerebral complications Mention is also made of the pathological aspect of encephalitis following revaccinafion, among other things As has been pointed out, De Vries found no microglial encephalitis in children under ino years of age. The processes involved in thesc cases are still obscure. The composition of the cerebral substance may be of importance in this respect (Brante, Edgar). These problems are closely correlated with the etiology, of which a suney is given in Chapter 6 The following etiological theories have so far been forwarded: (A) The theory of superinfection (1) Bacterial pollution. (2) A virus in the vaccine (3) Toxins. (B) The theory of actuation. Activation of a circulating virus is believed to play a rôle (C) The vaccine itself causes the encephalitis (1) By the virus itself (2) By an encephalitogenic intermediary product of the virus (3) As an allergic reaction to the virus. It is particularly the last-mentioned possibility which is discussed, in connection with data obtained in experimental neuroallergic encephalitis (Wolf, Kobat, Bezer and many others) The features seen in these cases are reminiscent of those of microglial encephalitis Data from the literature on possible provoking factors in the pathokeresis of post-vaccinial encephalitts are discussed In Chapter 7, a review is presented of publications in which constitutional factors in the pathogenesis of post-vaccinial encephalitis are taken into account in this respect opinions prove to be very ·138 SUMMARY diverse. Several publications, however, mention occurrence of several cascs of post-accinial encephalitis in one family or the occurrence of degenerative changes in siblings of patients with post-vaccinal cncephalitis. A description is given of some personal observations from the Utrecht University Neurological Clinic. In 1951, Sillevis Smitt orce more emphasized the fact that inflammatory changes in the contra! nervous system are governed by the concepton 'clectivity and that this electivity is correlated with constitutional characteristics. This principle is introduced into the field of post-vaccinial encephalitis. This constitutional approach is further claborated in Chapter 8. Some general considerations regarding constitution are followed by a discussion of the conception 'neuropathic constitution". Mention is made of the work done in this field by Bremer, Curtius and others This line of thought was introduced in the Netherlands by Sillesis Smitt. A more detailed description is given of the fundamental hypothesis underlying this investigation, that constitutional factors in the sense of neuropathic or degenerative stigmata play a role in the pathogenesis of post-vaccinial encephalitis Special reference is made to: (A) Morphological changes. (B) Endocrinc disorders. (C) Vegetarisc dysregulation (D) Allergic stigmata. (E) Psychiatric disturbances, To verify this hypothesis against the facts, an investigation was made in 107 families with a series of 109 diagnosed cases of puses vaccinial encephalitis, the insestigation was as comprchenuse as possible, covering cc generations, 1..' (A) The grandparents' generation. (B) The parents' generation (C) The patient's generation (limited to the immediatc family). The findings obtained were compared with those from a similar miestaglion colering 102 random families (Chapter 9). The format group is referred to as the encephalitis group, and the latter as ife control group The investigation indicated that the families t encephalitis group showed increased susceptibility to ·SUMMARY 139 (1) dysraphic stigmata; (2) neurological changes; (3) psychiatric disturbances; (4) epileptic manifestations; (5) allergic symptoms; (6) endocrine-diencephalic stigmata; (7) some internal anomalies; (8) a variety of other 'degenerative stigmata', The skin changes showed a somewhat irregular pattern, interpretat of which is difficult. Some changes (haemangiomata, lipoma ichthyosis) showed an increased incidence in the encephalitis gro In estimating the risk of a vaccination in terms of post-vaccit encephalomyelitis, the constitutional disposition of the subjects to vaccinated should therefore be taken into account Investigation relatives with regard to the above-mentioned stigmata is often necess. if a well-founded opinion is to be formed The possibilities of prophylaxis and treatment of post-vacci encephalitis are discussed once more in Chapter 10, in which fi chapter the following considerations are presented (1) Selection of subjects to be vaccinated Age is of great importance in this respect It is advisable to inocul children under the age of one year The principles elaborated in course of our investigation also come under this heading Vaccinat of subjects with organic cerebral changes, shortly after injuries of head, etc, should be discouraged (2) Technique of vaccination and choice of vaccine A flawless technique observing all precautions is desirable nature of the vaccine has never been demonstrated to evert an influe in this respect. Admmistration of y-globulin simultaneous # vaccination possibly has a favourable effect (3) The choice of medication in the case of post-vaccinial encephalı Treatment varies according to the therapist's views on the pat genic mechanism The therapeutic results obtained are generi discussed in case reports, so that comparison is exceedingly diffic The majority of therapeutic measures taken are symptomatic.

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D, Encephalitis by den hond Een vergelghchuk-pathologisch onderzoek naar de aetiologie van de 18 post-infectieuse encephaltides Thesis, Uny of Utrecht, 1939 VERLINDE, I D, Encephalitis postvaccinalis Geeft de combmaue van de vaccina-virus en van de activeringstheorie een verklaring voor haar onistaan? Ned T Geneesk. 99 (1955) 1020 VILLINGER, W, Konstitutionelie Disposition zur Encephaltus epidemica Münch med Ischr 68 (1921) 913 VRIES, DE, sec DE VRIES WAGNER-JAUREGG, J, Uber erbliche Belastung en klin Ischr. 4 (1902) 1155 WAYENBURG, VAN, See YAN WAYENYURG ·158 IX DE Dcash, causes of, 123 Dupuytren's contractuse, 12! Dysraphia, scc Status dysraphicus -, cranio-encephalic, 71 Dystrophy, neurogenic muscular, 91 Enuresis nocturna, 99, 100 Crictsy, 97,98,94 -, contulions in infants, 9) grand-mal. 97 Eragination, 85 tar malformation, 121 Echo virus, 53 Eczema infantilis, 108 Encephalnis -, allergic, 57 -, epidemic, 40, 43, 49, 50, 51, 78, 90 -, experimental, 57 -, alter German measles, 90 - herpes, 43 -, microgla, 34, 35 - 2-infec11043, S7 Fat-granule cells, 34 l'ecble mundedness, 94,95 FERRARO, 58 Fibromata, 8), 119 FRIVIL, 131 Tuninc chest, 100 pan, 40 Gamma globuline, 192 Ganglion cells, 32 > Ninal, 34 Gono-constitution, see Constitution Genotyr, 74 Cierman mealcs, see Encephalitis Closis "cura", 34 CHIOT COI, H Glorncruluehty?} }B Gnatho saluto chciloschuss, Joo Goitre. 112.14 Cuanssine, 48, 133 - post-revaccinal, 29, 39 - post-vaccinalis, 20 - age distribution, 61 ---, Cerebrospinal flurd, 25 -,-, classification, 30 -- Ecographical distribution, 61 incubation prio, 20, 22, 23 ,,mortality, 28 - recurrenccs, 37 -,-, sedimentation rate, 25 Sens (u24108, 70 scquels, 26 mpiomatology 24 ) Cmic-serticacmis, 40 -, varicella, 13: Laconhalopathy,90 acute hacmorrhagic, 19 - folic, 35, 45 Tlatit. 78 I ostro-enecphalogram, 70 maciaitu ? Indexrins-dienochalic discrets. 79 12 113 1!3cmagglutination ister, sec Anths +30213-hacmagglutiration ter Bacmangiomata, 82,114 Flacmorrhags, arschnou. 90 Hair growth, anomalies n, 113 {lay fesor, 82, OR, 112 Hicad injuric, 65 ficant defect (see also Cardinas cular) 120 fiems virus (see als Inerthus, +7,90 Siccre chroma midis, 131 Hlectors:ny, 76 Homolon, 76 Hometyje 16 Ilumphacı ise ai hynka matur 31%),99 Isdrocephalu, 93 ·INDEX 159 Hyperlauté, 121, 123 Hypermetropia, 121 Hyperostosis frontalis interna, 120 Hypertelorism, 120 Hyperthelia, 121, 122 Ichthyosis, 81, 119 Immunity, 7 Infantilitas, 113 Internal medicine, 119 Naevus pigmentosus, 114 Narcolepsy, 91 Neuralgia postvaccinalis, 18 Neuralgia, trigeminal, 92 Neuritis, 92 Neuronophagia, 34 Neuropathic constitution, sec Constitution Neutralızıng ability of serum, 127 JENNER, E, 6 KABAT, E A, 58 kelord, 19 KEUCHENIUS, 11 KUIJPER, A, 12 Kyphoscoliosis, 94, 100 Obesity, 112, 114 Ocular anomalies, 122 Ogisal palate, 100 Oxycephalia, 120 LANGE, Cornela de, see De LANGE, Cornelia Lecithinase, 59 Lipomata, J19 Little's disease, 90 Luxation of the hip, 121 Mandibular hypoplasia, 120 Mandibulofacial dysostosis, 120 Manic-depressive psychosis, 94 Meningeal reactions, 34 Meningitis, 90 Mental instability, 83 Meralgia paraesthetica, 92 Migroglia encephalitis, see Encepha- Ixtis Migraine, 81, 99 Mortality, perinatal, 104 Mutations, 79 Myelin, 43 Myelitis, 90 - postvaccinalis, 25 Myelodysplasia, 100 Myopia, 120 Myotonia, 92 Panhypopituitarism, 113 Paraplegia, spastic spinal, 91 Parkinson's disease, 90 Pasteurella, 47 Pernaemon, 49, 132, 133 Pes cavus, 100 PETTE, I, 55 Phacomatosis, 82 Pheno-constitution, see Constitution Phenocopies, 82 Phosphatase, 43, 54, 59 Pleiotrophism, 76 Poliomyelitis anterior acuta, 34, 40, 43, 50, 90 Polyarthritis rheumatica, 82, 119 Polydactyly, 82 Polydipsia, 113 Polyneuritis, 92 postvaccinals, 26 Postvacciniai encephalitis, sec Encephalites Prognathism, 120 Psoriasis, 119 Psychiatric disorders, 93, 94, 95, 96, 97, 125 Psychopathy. 94, 95, 97 Pterygium colli, 122 Plosis, 120 ·160 IDEY Rabbit encephalitis virus, 48 Radial anomalies, II Revaccination, 7 Tuterculosis, 60, 119, 123 Tumor cerebri, 90 Urticaria, 81, 11: Scalenus syndrome, 93 Schuzophrenis, 94 Sclerosis mulupic, 35, 73, 77, 90 SILLVIS SUIT, W. G, 32, 73, 74, 77, 83, 129, 130 Skin mallomations, 114 Skin reactions, 61, 130 Smallo. 3 Spina bifida ancrta, 99 Spondylolisthesis. 122 Sprengel's deformity, 122 Status dysraphicus, 82, 99. 102, 123 Strabismus, 120 Surtrinfection, 46 Syndacty), 121, 122 Syringomycha, 90 Vaccination, anti-moitments, 6.12 - complications, 17, 19 - law, 12 -, technique, 129 Vaccine, 60.129 -, bacteria.frec, 131 Vaccinia, 18 -, Virus, 53 Vaccinostyle, 130 VAN BOGAIRT, L., 35, 39, 59, 65, 12 VA BOUW DIA BASTIAANS, f.s.i. 29, 32, 39, 61, 133 Varicella, sec Encephalitis Variolation, 4 Vascular reactions, 34 Vegetative regulation, 80 Vertctral column, 100 VRIES, Ernst De, sec De VRIES, Ernst Tales dorsalis, 78,90 Thenar atrophy partial, 93 THORBECNE, R.), 12 Torticollis, 92 Trauma cerebrs, 128 Tremor, 90 Wassermann reaction, 19 WOLF, A., 38