Annals of the Royal College of Surgeons of England (1978) vol 6o
        James Reilly and the autonomic nervous system
         A prophet unheeded?
         D A Buxton Hopkin MD FFARCS
         Honorary Consulting Anaesthetist, Charing Cross and St Thomas's Hospitals, London
         Robert Laplane MD
            Chaire d'Hygie'ne et Clinique de la Premiere Enfance, Ho'pital Trousseau, Paris
         Biographical note                                                       asked where he got his idea that nervous irritation
         Sometimes modesty and self-effacement, especially                       played a part in pathology. In reply he quoted an
         in scientific research, can hinder progress as much                     obscure paper published in a foreign specialised
         as over-anxious seeking of publicity can do by mak-                     joumnal in I894, when he was seven years old.
         ing    premature       claims    which     subsequently       prove         His method of research was a combination oif
         false.   Certainly this is true of the late Dr James                     intuition   and deduction. By intuitive processcs he
         Reilly, who for over 40 years conducted research                         would formulate a hypothesis and then prepare a
         in   Paris    into   the   physiopathological        processes    of     very carefully thought out programme of research
          disease    with    results   which,     although      challenging       with the aim of either confirming and substantiat-
          the basic principles of conventional teaching, remain                   ing his hypothesis or showing it to be false. He was
          unknown outside Europe. There are several reasons                       an extremely severe critic of his own and other
          for this apparent neglect, but most of them can                         people's work and never accepted questionable find-
          be found in the character of the man himself.                           ings   or made unjustified claims
             Bom in I887, Reilly was descended from an Irish
          rebel who, condemned to death, was subsequently
          pardoned and banished to France. Both his parents
          died when he was three to four years old and he
          passed into the care of some rather cold and tight-
          fisted near relatives. Apparently they never ceased
          to remind him of his impecunious state so that he
          became consumed with an obsession about poverty.
          He lived alone in sparsely furnished rooms in the
          Rue de Vaugirard in conditions approaching mon-
          astic   simplicity    and travelled across Paris second
          class in the Metro to reach his hospital. When his
          friends    reproached      him and encouraged him to
          take better care of himself he always replied, 'But
          you do not understand, I have always been poor'.
             Through the generosity of another female relative
          he was able to study medicine in Paris. After gradu-
          ation and serving in the French Army during the
          First   World War he had an appointment at the
          Pasteur Institute, where he designed a method of
          culturing anaerobic bacteria known to this day as
          Reilly's tubes. In 1922 he was appointed director
          of   the newly created Central Laboratory of the
          Claude Bernard Hospital for Fevers in Paris, a
          position he was to occupy for over 40 years. He died
          in 1974. was a clinician as well as a
             Reilly                                  of           laboratory
          worker. He had good powers                      observation and
          the    gift  of   selecting     significant    features    from a
          confused mass of symptoms presented by a patient.
          He had an excellent and a selective memory which
          allowed him to use isolated facts read and remem-                                      James Reilly (I887-I974)
          bered many years before. For example, once he was
                                                                                    Reilly and the autonomic nervous system
                                                                         James                                                                                lOg
                  As a person Reilly was unpredictable and very                                It   is  impossible to condense the work of
               difficult to approach. On some days he would appear                         40 years into a short paper. The best one can
               taciturn and hostile but on others a brilliant and                          achieve is to indicate the general lines of
               humorously ironic conversationalist, covering a great                       investigation which he undertook. These can
               \ariety of topics and revealing a wide knowledge of                         broadly be divided into three sections-the
               literature (he was a great admirer of James Joyce),
               music, and the arts in general. He had very few                             part played by the autonomic nervous system
               intimate friends but in those he had he inspired the                        in (i) inflammatory processes and immunity;
                deepest affection.        publicity was almost pathological.                (2) the physiopathology of infectious diseases,
                  His avoidance of          be proposed a member of the                    especially typhoid fever; and (3) other patho-
                He only agreed to de Medecine provided he could                            logical processes.
                Academic Nationale                       courtesy visits to the
                dispense with the customarystrong persuasion from
                other members. In spite of he steadfastly refused                           I)    INFLAMMATORY PROCESSES AND IMMUNITY
                his   friends    aind   colleaguesCollege de France once
                to accept a chair in the                    When some people               Inflammation             The autonomic nervous system
                occupied by Claude Bernard.                    for a Nobel Prize            is concerned in two aspects of tissue inflamma-
                suggestec    he should be nominated It is said that he                     tion: (i) vasomotor and (2) reticuloendothelial.
                he strongly opposed such action.                     of   his   death                                                                  outlined
                requestcd      that   no acknowledgment                                        The experimental protocol briefly
                should he made until after his funeral. the Societe                         above (that is, irritation of peripheral sym-
                   Apart from a few contributions to                             in   a     pathetic nerves) results in an intense vasormotor
                de Biologie all his major papers appeared                                   reaction in the digestive tract evidenced by
                much respected journal, the Annales de medecine,                            vasodilatation and hyperaemia together with
                which was little read outside France and ceased
                publicatiotn soon after the Second World War. He                            an increase of capillary permeability with
                prefcrrcdl    this   journal because the editors I)ut Ino                   serous or haemorrhagic exudate. Within a
                limit   to the lenigth of his papers. The clisappear-                       few hours the reticuloendothelial system begins
                ance of this periodical and the fact that many of                           to participate,          as evidenced by swelling of
                his conitributions appeared during the German oc-                           endothelial cells with enhanced ingestive ca-
                cupation of France account for the lack of knowledge
                about his work amongst Anglo-Saxon readers.                                 pacity, seen particularly in the Kupffer cells of
                The Reilly phenomena                                                        the liver. The reticular cells of the spileen and
                                                                                            the lymphoid formations of the intestinal tract
                Certain clinical            and experimental observa-                       undergo hyperplasia, eventually being trans-
                tions had convinced Reilly that the autonomic                               formed into macrophages with, in places, syn-
                nervous system was far more closely concerned                               cytial formation.                             that the tonicity
                in infectious diseases than had hitherto been                                   All these changes suggestreticuloendothelial
                thought. To test this hypothesis he devised in                              and the vitality of the                      dependent on re-
                 I932' a highly original experimental technique                             tissues are to a large extentautonomic nervous
                which consisted in applying a stimulus to a                                 flexly induced activity in the
                segment of the peripheral sympathetic nervous                               system.
                system (for example, the splanchnic nerve or                                                                         also affects the pro-
                coeliac ganglion) either by depositing on it                                Immunity Inflammation autonomic nervous
                a bacterial toxin or a chemical irritant sub-                               cesses of immunity. The                        on the progress
                stance or by physical means such as faradisa-                               system, through its influencein local defence
                tion. He applied this technique to a variety                                of infection,         is   concerned been known that
                of    animals        (rats,    guineapigs,        rabbits,      dogs,       mechanisms. It has long to immunity by
                cats, monkeys), exploring all the main visceral                             vasodilatation          contributes                          Reilly's
                territories. Over the course of time he improved                            promoting diapedesis of leucocytes. nervous
                the conditions of his experiments and as they                               experiments proved that the autonomic
                 developed the wide extent of their potential                               system also acts by increasing the phagocytic
                 field of application became more and more                                  properties of reticuloendothelial tissue. as the
                 evident. Briefly, the acute results of irritation                              A process devised by Reilly known
                 of   abdomninal sympathetic nerves appeared                                'sac    jugulaire'2        demonstrates this particular
                 as    an     intense       vasomotor          reaction        visible      point and several other aspects iof the effects
                 as gastrointestinal haemorrhage and prolifer-                              of autonomic irritation. A segment of rabbit's
                 ation of lymphoid tissue.                                                  jugular vein is tied off at both ends. When a
         iio       D A Buxton Hopkin and Robert Laplane
        chemical or bacterial irritant is placed in this              creased    and ultimately led to death froTn
        segment the effects of irritation are evident not             septicaemia.
        only locally but also elsewhere in the body,
        taking the form firstly of albuminuria and                    2)   TYPHOID FEVER AND OTHER INFECTIOUS
        subsequently of congestion and gastrointestinal               DISEASES
        haemorrhage.        Reilly's    observations     of   the    Systemic manifestations          In the course of his
        effects of a lycopodium emulsion when placed                  work at the Claude Bernard Hospital in Paris
        in such a sac are noteworthy. After a week                    Reilly had to undertake the postmortem ex-
        histological examination of the carotid artery                amination of patients dying of typhoid fever.
        showed diffuse swelling of the vascular endo-                 His early work on the effects of autonomic
        thelium due to stimulation of the sensory                    irritation, combined with his observations of
        sympathetic fibres of the blood vessel. A week                the constant finding of enlarged lymph nodes
        later a streptococcal culture which previously                in the mesentery, led him to build up the
        had without fail produced a fatal septicaemia                 following hypothesis: Typhoid fever follows
        in control animals was injected intravenously.               the ingestion of typhoid bacilli which, instead
        All the prepared animals survived. Some ran                   of setting up inflammation in the wall of the
        a mild temperature and some developed mono-                  intestine, immediately move through it to reach
        arthritis,  but in none did a positive blood                 the    mesenteric      lymph nodes, where they
        culture occur. The conclusion from this ex-                  multiply during the incubation period, being
        periment was that prolonged stimulation of                   responsible foir an essential morbid character-
        the sensory nerve fibres of the walls of blood               istic of the disease-swelling of the mesenteric
        vessels can, through a reflex mechanism, confer              lymph nodes. The appearance of clinical
        some degree of immunity and arrest infection.                symptoms coincides with (i) systemic spread
           A similar finding followed irritation                of   of   the bacilli     evidenced by positive blood
        lymphoid structures. Reilly found that inocula-              culture and (2) lysis of the bacilli in situ with
        tion of typhoid or paratyphoid bacilli into,                 release of endotoxin.
        the mesenteric lymph nodes of rabbits or                        Reilly confirmed this thesis by producing
        guineapigs invariably led to death from septi-               typhoid fever in animals after placing living
        caemia3. Although this was not prevented by                  bacilli in the lymph nodes of the mesentery3.
        previous     vaccination,     it  was prevented by           He was the first person to do this. His technique
        moderate faradisation of the splanchnic nerve                reproduced all the main clinical and patho-
        half an hour before the inoculation4. Histo-                 logical features of the human disease-that is,
        logical examination of the mesenteric lymph                  an    incubation      period     followed     by fever,
        nodes revealed the protective mechanism. In                  diarrhoea, prostration, positive blood culture,
        the control animals no appreciable histological              and a positive agglutination test. Autopsy
        changes were noted during the first few days.                showed congestive or haemorrhagic swelling
        In the faradised animals, on the other hand,                 of the mesenteric lymph nodes and swelling,
        gross structural changes were seen in lymph                  haemorrhagic        congestion,      and necrosis       of
        nodes in less than 24 hours, taking the form                 Peyer's lymphoid patches in the small intestine.
        of   congestion,     vasodilatation,     exudation of           He next proceeded to establish that these
        fibrin, hyperplasia of reticular cells, and an               pathological changes were the result not of
        increase of polymorphonuclear cells followed                 any action of the living bacilli but of the
        by the appearance of necrotic foci and finally               endotoxin liberated by dead organisms. Ex-
        sclerosis. Thus the autonomic stimulation had                actly the same changes occurred after the
        led to lymphoid reaction which prevented the                 inoculation of endotoxin into the heart or
        multiplication and spread of bacteria and the                lymph nodes of a guineapig.
        release of endotoxin, so that the disease was                   These observations convinced Reilly that
        in fact limited to a lymphoid infection.                     endotoxin released in the mesenteric lymph
           It  is  worth noting, however, that if the                nodes had a selective affinity for sympathetic
        experimental procedure was changed and in-                   nervous tissue. To test this idea he injected a
        tense rather than mild faradisation applied,                 very small quantity of typhoid antigen close
        diffusion    of  bacteria was paradoxically in-              to the splanchnic nerve or coeliac ganglion of
                                                               Reilly and the autonomic nervous system                I I I
                                                      James
           a guineapig. The effect was dramatic: in-                changes are probably the result of histotoxic
           testinal lesions typical of typhoid followed a           or stagnant anoxia leading to local release of
           very small dose which was harmless when                  active but harmful biochemical substances.
           administered elsewhere. These changes were
           not confined to guineapigs but occurred in a             Central nervous involvement          A relationship
           variety of animals4. of experiments he found             between injury to autonomic centres in the
              In a final series                                     diencephalon and gastrointestinal haemorrhage
           that these lesions were not in fact specific to          has been known for over a century. Gastro-
           the typhoid endotoxin itself but that they               intestinal  haemorrhage is also a terminal
           followed    any irritation    of   the sympathetic       feature not only of typhoid fever but of severe
           nervous system. They could be reproduced by              Gram-negative      infections    in   general.   The
           depositing around the splanchnic nerve very              mental torpor accompanying severe typhoid
           small quantities of various irritant substances          fever also suggests an action by endotoxin on
           such as diphtheritic toxin (0.005 ml in guinea-          the central nervous system, particularly of the
           pigs),  20% ethanol, salts of lead, nickel, or           diencephalon. Professor Guy Tardieu demon-
           cobalt,   oil  of  chloroform,     various   alkaloid    strated such an effect 30 years ago in Reilly's
           substances such as nicotine or chelidonium               laboratory5.    He introduced        a   very   small
            extract, and so on. The same effects were also          quantity, as little as o.ooi mg, of typhoid
            obtained by purely physical means such as               antigen into the third ventricle of a dog by
            faradisation for 30 seconds, ligation with a            means of a puncture of the lateral ventricle.
            linen thread, or irritation with a sterile rose         To use his own words, 'This immediately
            thorn'.      up, the above-mentioned findings           plunged the animal into a catatonic state'.
              To sum                                    changes     This condition, due to deep torpor, lasted for
            led to the idea that the pathological                   several days, during which timle the animal
            of typhoid fever are the result oif a two-fold          became febrile, had looseness of the bolwels,
            affinity, that of bacilli for lymph nodes and           and lost weight. Larger doses induced cardio-
            that   of  endotoxin     for   sympathetic     nerve    vascular collapse and intestinal haemorrhage.
            endings.   Furthermore,      the  susceptibility   of   To obtain the same effect by a systemic
            sympathetic    nervous    tissue   to  irritation   is  administration it would be necessary to use
            evidenced by the production of identical path-          a dose at least 200 times greater.
            ological changes by a wide variety of substances           This experiment surely makes it dear that
            which have a common property                that of     one of the most remarkable attributes of the
            irritation. Thus the irritation of nervous tissue       endotoxin of typhoid fever is its affinity for
            is responsible for the lesions of the lymphoid          peripheral and central sympathetic nervous
            tissue; the effects of typhoid endotoxin are            tissue. Indeed, this is a common property of
            due only to its affinity for sympathetic nerves.        all the endotoxins produced by Gram-negative
            Gastrointestinal haemorrhage       It is not difficult  organisms.
            to  produce gastrointestinal haemorrhage in             Scarlet fever    Reilly's previous work on scarlet
            experimental animals by depositing typhoid              fever led him to believe that this disease would
            endotoxin on abdominal sympathetic nerves,              offer an interesting field of investigation. The
            as one of us (RL) has done many times. The              Dick toxin extracted from the haemolytic
            same result is obtained with many other                 streptococci responsible for scarlet fever is not
            substances. Therefore the mechanism of the              harmful when injected subcutaneously or in-
            intestinal  haemorrhages of typhoid fever is            travenously, but if a very small amount comes
            the same as that of the lymphoid lesions.                into contact with any part of the sympathetic
               The microscopic picture shows the same                nervous system of an experimental animal it
            lymphoid lesions-congestion          amounting in        immediately has rigors, albuminuria (some-
            some instances      to   infarction-and       in  the   times with blood), inreased blood urea con-
            vascular system degenerative or proliferative            centration, congestion and at times purpura
            endotheliitis. Probably the vasodilatation is the        of the abdominal wall, and cardiovascular
            result  of anoxic anoxia secondary to vaso-              collapse   indistinguishable    from bacteraemic
            constriction, while the subsequent endothelial           shock and culminating in death. Postmortem