He stressed the point that concomitant mercury treatment caused impairment of renal function , and at any rate a temporary delay in arsenical excretion .sx He stated that by giving these drugs alternately he had only two cases of exfoliative dermatitis in 12,000 injections .sx Stokes ( 15 ) and Strathey , Smith and Hannah ( 16 ) agree with this theory , but do not lay so much stress on it .sx The series of cases quoted by Moore and Keidel ( 17 ) were given no mercury .sx Stokes and Cathcart ( 5 ) found no higher incidence of skin reaction in those cases which were given mercury than in those which were not .sx Out of 33 cases of dermatitis they found that seven of them had had no mercury .sx They also found no evidence of previous renal trouble in any of their cases which developed cutaneous reactions , but they admit that possibly a renal disorder may exist , but not be discovered by the ordinary tests .sx None of my own cases showed any evidence of renal injury , and mercury was given in only two cases .sx Glombitza ( 18 ) thought that perhaps a syphilitic injury to the liver was a basis for a perverted salvarsan metabolism causing arsenic retention .sx Widal ( 19 ) pointed out the effect of damage to the proteopexic function of the liver by salvarasan .sx He thought that this impaired proteopexic function might be the basis of a variety of anaphylactic phenomena .sx Stokes ( 20 ) refers to damage to the liver due to infection during the course of salvarsan treatment .sx Lees ( 3 ) states that two out of his series of ten cases developed icterus during the course of their attack of dermatitis .sx Out of my seven cases , one ( No .sx 2 ) developed dermatitis during the course of an attack of post-arseno-benzene jaundice .sx The amount of the drug administered seems to be of secondary importance in the production of a skin reaction in the bulk of cases .sx Most cases occur after the third or fourth dose , giving a low figure for the total amount of drug given .sx Stokes and Cathcart ( 5 ) found that in the majority of cases the cutaneous reaction came on early in the course of treatment .sx In my own series , in No .sx 3 the eruption developed after the fourth injection of a second course of N.A.B. , in No .sx 4 after six injections of 0.6 grm .sx of N.A.B. , making a total of 3.6 grm .sx In case No .sx 7 the eruption occurred after one injection of 0.6 and six of 0.9 grm .sx of N.A.B. , making a total dosage of 6 grm .sx This is clearly a case of over-dosage .sx In all my other cases the reaction occurred early in the course of treatment .sx It would appear then , that over-dosage with the drug may cause a cutaneous reaction , but that this is not the usual mechanism at work .sx Harrison ( 4 ) thinksthat the erythema developing after the third dose is mild in character , and that the worst cases are those which develop at the end of a course of seven to ten injections , or one month or more later .sx Stokes and Cathcart ( 5 ) have opened up an entirely original aspect of the dermatological reactions to the salvarsan group of drugs , based on a series of cases in which they show that there is a relationship between the eruption and pre-existing foci of sepsis .sx Out of 33 cases of dermatitis they found that 6 had no demonstrable foci of sepsis , and out of these 6 cases , 5 had very mild skin-reaction and 1 a mild exfoliative eruption .sx In the remaining 27 cases varying degrees of focal sepsis were present .sx They were led to believe that a pre-existing focus of sepsis sensitized the skin to the salvarsan compounds .sx Partial removal of foci in 7 cases before treatment was instituted did not reduce the severity of the dermatitis .sx Further , the interference with the focus was found to cause a flare-up of the skin condition in 5 cases .sx They also suggest that acute infections such as sore throat , rhinitis and tonsillitis also play a part in preparing the allergic substrate , but admit that their evidence ( 10 cases ) is not very conclusive .sx Their deductions are that the mechanism of post-arsenobenzene dermatitis is based on a pre-existing idiosyncrasy or allergic instability caused by the absorption of bacterial sensitizing protein from a focus of infection .sx The cells of the skin become particularly hyper-sensitive and the arsenic carried to these cells causes an inflammatory reaction .sx In none of my cases was I able to discover any evidence of focal infection .sx Moore and Keidel ( 17 ) consider that post-salvarsan dermatitis is caused by a local reaction in the skin following sensitization .sx They think that the arseno-benzene itself changes the serum of the patient , so as to induce sensitization in the cells of the skin .sx Further administration of the arsenical compound produces a reaction in these sensitized cells followed by varying degrees of inflammation .sx This theory fits in with the fact that in some cases the eruption commences after the third or fourth dose and in others after intensive dosage .sx Obviously there must be a large personal factor present which decides how much of the drug is required to effect sensitization .sx Lees ( 3 ) has found that in nearly all his cases the patients have shown some degree of seborrhoea or have been of the sebor-rhoeic type .sx This indicates a degree of hypersensitivity of the skin present prior to the commencement of arsenical treatment .sx In my series various skin troubles were present prior to the commencement of .sx treatment .sx No .sx 2 had suffered from slight psoriasis for some years .sx No .sx 4 had an occupational dermatitis on both hands which had been present for a number of years ; he had also suffered from sycosis barbae and cheiropompholyx .sx No .sx 7 had been the subject of furunculosis and developed a crop of boils during his attack of salvarsan dermatitis .sx McDonagh ( 21 ) has stated that dermatitis and other complications of arsenobenzene therapy are due to the metallic arsenic present in the compounds over-oxidizing the tissues of the body .sx Harrison ( 4 ) , as the result of his war experience , stresses the fact that exposure to cold increases the susceptibility to dermatitis and considers that the condition is commoner in winter .sx Other writers , notably Lees ( 3 ) , find that neither exposure nor season play any part .sx I do not think any one of these theories entirely explains the causation of post-arsenobenzene dermatitis , but consider that several factors are at work .sx Certainly over-dosage , as in my case No .sx 7 , is quite enough in itself to cause a severe eruption .sx From personal experience I consider that in the majority of cases it is a question of sensitization of the skin cells by the drug .sx The amount required to cause sensitization varies in different individuals .sx When sensitization has occurred , whether it be after the first or second dose or after a complete course , the next dose will bring about a reaction in the skin .sx Whether this reaction is mild or severe is either a matter of personal idiosyncrasy or degree of sensitization .sx There is no doubt that patients with pre-existing skin-lesions such as those present in my cases ( Nos .sx 2 , 4 and 7 ) are more susceptible to a cutaneous reaction .sx In some cases the patients are sensitized by the arsenobenzenes and react at a later date to some constitutional upset .sx This would account for those cases in which a reaction occurs several weeks after the completion of a course .sx That this sensitization may be of long duration is shown by my case No .sx 1 , who did not react until after the first injection of a second course of novarsenobillon .sx CLINICAL SIGNS AND SYMPTOMS .sx The clinical signs and symptoms of post-salvarsan dermatitis , although of a fairly constant character , vary considerably in severity , ranging from a mild erythema with no constitutional upset to a severe exfoliative eruption with marked general disturbance .sx Patients who develop a cutaneous reaction often show signs of intolerance to the drug some time during the course of treatment before the eruption occurs .sx Thus in myseries case No .sx 3 , after the second injection of his second course of N.A.B. , fainted and had a series of clonic contractions of the limbs lasting about thirty seconds .sx No .sx 4 , after the second injection of 0.6 grm .sx of N.A.B. , developed a faint erythema with itching over his chest an hour or two after the injection .sx This lasted two days and disappeared quite suddenly .sx He did not mention this at the time , but disclosed the fact when carefully questioned later after he had developed an exfoliative dermatitis .sx No .sx 7 complained of nausea after the first .sx injection , and twelve hours later developed a punctate erythema starting at the site of injection and spreading all over the body .sx In this case there was no itching and the condition cleared up in two to three hours .sx This patient was subsequently given six injections of 0.9 grm .sx of N.A.B. and developed a very severe exfoliative dermatitis .sx It is important to look for such prodromal signs as those given above , because if treatment is instituted at this point more serious results may be averted .sx Patients showing a Herxheimer reaction after the first injection should be carefully watched during treatment .sx That these premonitory signs are not well known and sometimes over-looked may be seen from the following case quoted from the Indian Medical-Gazette ( 22) .sx An otherwise healthy patient was being treated for syphilis .sx In the first four weeks he had been given injections of 0.3 , 0.45 , 0.6 and 0.9 grm .sx of N.A.B. weekly .sx After the fourth injection there was a rigor , temperature of 103 F. , headache and nausea .sx This lasted for two days .sx The writer says , " Up to this date the patient had shown no signs of intolerance of arsenic , " and gave a further injection of 0.9 grm .sx of N.A.B. Three days later he was surprised to find that his patient had developed a maculo-papular rash all over his body , intensely irritating , accompanied by nausea , vomiting and loss of sleep and appetite .sx These prodromal signs are numerous and varied in character , but they occur in such a large number of cases that they should not be neglected .sx Post-salvarsan dermatitis usually follows a definite clinical course .sx The first stage is a generalized punctate erythema , similar to that of scarlet fever but of a lighter colour .sx This , as a rule , is first seen on the backs of the hands and forearms , on the legs and on the chest ; from these parts it spreads and soon covers the whole body .sx Then small papules , usually not bigger than a split-pea , appear on the oldest parts of the erythematous rash and rapidly spread to the rest of the body .sx These papules become vesicular , then quickly dry and desquamate .sx These stages are of short duration , so that desquamation has generally .sx commenced by the second day .sx Occasionally pustules are formed and give rise to a good deal of constitutional trouble .sx Sometimes the skin becomes oedematous , and extensive exuding areas are formed from which the skin peels in large flakes .sx The stage of desquamation continues for a long time , and varies a good deal in character , from the fine branny type described in most of my cases to the large flakes typical of general exfoliative dermatitis .sx As the condition progresses the scales tend to become larger .sx Peeling commences on the parts where the eruption first appeared .sx As a rule the last parts to shed their skin are the palms of the hands and the soles of the feet , where the skin is thrown off in large keratotic plaques .sx Lees ( 3 ) has known the hair and nails to be shed .sx Early in the exfoliative stage there may be some exudation but the fluid is very thin and does not tend to crust .sx At first there is not much irritation although there may be formication round the mouth .sx As the eruption develops the itching becomes intense and is the most intractable symptom .sx The face generally swells , and the conjunctivae and the mucous membranes of the mouth and throat become involved in the inflammatory process , giving rise to lacrymation , photophobia , thirst and laryngitis .sx Bronchitis may occur .sx Although the patient is very miserable he seldom feels ill .sx The temperature sometimes rises to 1000 F. or more .sx The pulse is good and there is little effect on the general health .sx