History Lectured on Midwifery at St Bartholomew’S Hospital and and Was in Attendance at the Births of All of Her Children

Sir Charles Locock and potassium bromide

MJ Eadie Honorary Research Consultant and Emeritus Professor, Faculty of Health Sciences, University of Queensland, Royal Brisbane and Women’s Hospital, Australia

ABSTRACT On 12 May 1857, Edward Sieveking read a paper on epilepsy to the Correspondence to M Eadie Royal Medical and Chirurgical Society in London. During the discussion that Faculty of Health Sciences, followed Sir Charles Locock, obstetrician to Queen Victoria, was reported to have University of Queensland, Royal Brisbane and Women’s commented that during the past 14 months he had used potassium bromide to Hospital, Herston, successfully stop epileptic seizures in all but one of 14 or 15 women with ‘hysterical’ Brisbane 4029, Australia or catamenial epilepsy. This report of Locock’s comment has generally given him credit for introducing the first reasonably effective antiepileptic drug into medical Tel 61 2 (0)7 38311704 e-mail [email protected] practice. However examination of the original reports raises questions as to how soundly based the accounts of Locock’s comments were. Subsequently, others using the drug to treat epilepsy failed to obtain the degree of benefit that the reports of Locock’s comments would have led them to expect. The drug might not have come into more widespread use as a result, had not Samuel Wilks provided good, independent evidence for the drug’s antiepileptic efficacy in 1861.

Keywords Epilepsy treatment, Charles Locock, potassium bromide, Edward Sieveking, Samuel Wilks

Declarations of Interests No conflicts of interest declared.

Introduction

Potassium bromide was the first even modestly effective agent for preventing epileptic seizures to emerge from a search of more than two thousand years. It is often stated that the drug was introduced into antiepileptic therapeutics by Sir Charles Locock in 1857. Enough detail of the circumstances of Locock’s recognition of the antiepileptic activity of the substance has been published over the years since then1–4 to make any further account unnecessary, had it not been for several peculiar details which seem to have been overlooked.

Sir Charles Locock (1799–1875)

Several accounts of Locock’s life are available.5–8 Charles Locock (Figure 1) was born in Northampton on 21 April 1799 to Henry Locock, a medical practitioner and his first wife Susanna, née Smythe. He studied at St George’s Hospital in London before graduating MD from Edinburgh University in 1821. He became a Licentiate of the Royal College of Physicians of London in 1823 and gained experience at the Westminster Lying-in Hospital Figure 1 Sir Charles Locock. Reproduced with kind in London before commencing consulting practice in permission of the Wellcome Library, London. midwifery in that city. In 1826 Locock married Amelia Lewis, who predeceased him. The couple had five sons. Physicians (RCP). He served as a member of the RCP He built up a very large and successful practice and Council between 1840 and 1842. In 1840 Locock was became Physician to the Westminster Lying-in Hospital, appointed First Physician Accoucheur to Queen Victoria history lectured on midwifery at St Bartholomew’s Hospital and and was in attendance at the births of all of her children. in 1836 was elected Fellow of the Royal College of He retired from practice in 1857, having been created a

274 history

13 13 275 In London after 16 reported that he had he that reported 14 The element bromine was The element bromine 11,12 ely ely omide immediat Locock omide before 15 Todd’s patient had gout secondarygout patient had to lead- Todd’s 17 ium br tass ium br tass There is no evidence that Locock did further with is no evidence work There years few next the Over 1857. after bromide potassium London colleagues indicated that they some of Locock’s mentioned and drug the of use reported his of knew his monograph in the first edition of In 1858, their own. prescribed he had mentioned that Sieveking epilepsy, on to results enough but did not have bromide potassium Potassium bromide was listed in the Britishwas Pharmacopoeia bromide Potassium for as a treatment curiously 1835 and 1851, between to lack efficacy. but was found splenomegaly, Po Po least two France contains at from The literature history early the of accounts potassium of use the of in medicine. bromide In his 1842 thesis, Otto Graf Otto thesis, 1842 his In of the substance local applications Thielman employed priapism. treat to Robert Bentley Todd employed it in a patient with it in a employed Todd Robert Bentley Locock before years several in 1852, epileptic seizures it. used induced nephropathy, was in terminal renal failure and failure renal was in terminal induced nephropathy, to intake bromide commencing after soon too died did not Todd its efficacy. permit conclusions regarding the drug. using indicate his rationale for a bromide potassium used Locock before even Thus been had already amount of scientific work reasonable and it Graf and Huette. not least by done with the drug, various indications, for therapeutically had been employed on at least one occasion. including epileptic seizures, isolated from salt water by the Marseille chemist chemist Marseille the by water salt from isolated was potassium bromide in 1826 and Antoine Balard it tried Puche and Ricord afterwards. soon synthesised potassium iodide in treating to as an alternative secondarytertiary and syphilis but it was not successful. become impotent while taking 600 milligrams (mg) of 600 impotent while taking become recovered and weeks two for day a times three drug the was report This ended. intake drug after function sexual induced that report journal the origin of the probably Charles Huette noted drug. the Locock to prescribe less or more produced intake bromide potassium that and insensitivity complete torpor of the genital organs general stupefaction. as well as pharynx, of the palate and control rate) which strongly suggested that a new highly highly new a that suggested which strongly rate) control discovered. been have might agent antiepileptic effective (or the Sieveking by omission a strange This seems ‘expressed earlier he had minutes reporter) when only epilepsy existed’. for treatment his belief that no specific Locock

10 . omide in Medical Times and Gazette Times Medical ium br tass 2012; 42:274–9 2012; and the and 9 J R Coll Physicians Edinb Coll Physicians J R © 2012 RCPE epilepsy Curiously, Locock never published his own account of own published his Locock never Curiously, his discovery of the antiepileptic efficacy of potassium in effectiveness the drug’s about His statement bromide. a meeting of the in reports of epilepsy appeared treating Medical and Chirurgical held in London on Society Royal on 23 published The reports were 1857. 12 May Tuesday in The Lancet May Locock’s use of po baronet in that year when he also became President of President became also when he year in that baronet 1863 he In Society. and Chirurgical Medical the Royal and Society of London of the Obstetrical was President Society. of the Royal to Fellowship in 1864 was elected to attempted unsuccessfully he retirement his During enter politics. to the medical literature contributions Locock made a few but otherwise was notable career, in his professional early expertise his obstetric for his and mainly lifetime in his Family. to the British Royal in relation role Locock had chaired the meeting at which Dr (later Sir) which Dr the meeting at chaired had Locock of analysis an (1816–1904) presented Sieveking Edward presentation Sieveking’s Following of epilepsy. 52 cases audience, the of members three from comments and his made Sieveking the chair before from Locock spoke was reported to have Locock concluding response. failed to mention two had pointed out that Sieveking to infantile epilepsy related epilepsy, of causes frequent indulgence, sexual to due epilepsy and dentition of He then spoke masturbation. i.e. ‘onanism’ particularly in to women limited a disorder epilepsy’, ‘hysterical at exclusively and consistently occurred which seizures of instances in (except menstruation of time the that he had stated Locock mental excitement’). ‘extreme of a German Medical Review in the British and read Foreign reversibly others himself and rendered who had worker This report bromide. impotent when taking potassium who women it for prescribe to Locock prompted had deal of sexual excitement and ‘a great experienced he and their times of menstruation disturbance’ around calming. very marked observedproduced drug the that also 1857 he had May prior to 14 months About nine- with a woman a for bromide potassium prescribed ceased seizures Her epilepsy’. ‘hysterical history year of the while continuing seizure-free she remained and 13 or in another the drug used then Locock treatment. ‘fits’ whose in a woman one failure, with only 14 cases, The menstrual in their timing. not exclusively were about the sole this information Lancet account lacked failure. treatment concluding Sieveking’s that Neither journal reported extraordinarily Locock’s mentioned had response seizure 93% than (a greater result therapeutic successful MJ Eadie

justify an opinion about it.18 In the same year Charles Bland Radcliffe stated that he had used potassium bromide once, in a woman with ‘erotic excitement’ and regularly occurring seizures.19 She went 51 days without seizures before the attacks recurred. In 1861 John Russell Reynolds wrote that he had prescribed potassium bromide perimenstrually in women whose epilepsy worsened at the times of menstruation, without much success.20 However, he had seen no woman with epilepsy that occurred solely at the time of menses in whom he could try the drug. Reynolds was probably unaware that potassium bromide has an elimination half-life of 12 days so it is unlikely that he employed the drug continuously for long enough to achieve adequate steady-state therapeutic conditions in his patients.21 In the same year, in the second edition of his monograph, Sieveking stated that he had used potassium bromide for the same indications as Locock, but without the same degree of success, though he considered the drug ‘decidedly beneficial’. He provided no numerical data to support this opinion.

The outcome of this early British experience of the use of potassium bromide in epilepsy by three London physicians, all shortly to become members of the staff of the recently opened Hospital for the Palsied and Figure 2 Sir Samuel Wilks, from a photograph taken Epileptic at Queen Square, seems not to have been in 1884.45 particularly encouraging. The drug’s use, at least at first, was largely restricted to cases of perimenstrual epilepsy, the disorder that Locock was reported to have treated After Wilks’ publication, reports of the use of potassium so successfully. It seems likely that the drug might have bromide in all varieties of epilepsy appeared in increasing disappeared from use at that stage had it been employed numbers. Charles Radcliffe reported that he had employed solely in these cases. However, beginning probably in the drug in five or six cases where uterine ‘irritation’ was London in 1859 and at first in ignorance of Locock’s prominent, with satisfactory results overall.25 He also reported data,22 Samuel Wilks (Figure 2), physician and mentioned that, at least as early as 1860, he had begun to pathologist to Guy’s Hospital and later President of the use the drug ‘almost promiscuously’ and claimed to have Royal College of Physicians of London, began to use records of 30 cases in whom he had compared the use potassium bromide to treat all forms of epilepsy. He of potassium with iron bromide, preferring the former, published his results in the Medical Times and Gazette on which he considered the best available remedy.26 It is 21 December 1861 in a paper which provided details of difficult to know whether awareness of Wilks’ work his individual patient case records.23 Wilks explained that stimulated Radcliffe’s ‘almost promiscuous’ prescribing of he had been using potassium iodide to treat epilepsy potassium bromide, or whether Radcliffe independently when he thought it might be of syphilitic origin. Since he realised that potassium bromide had a wider spectrum of had difficulty in recognising such instances clinically, he antiepileptic effect than the reports of Locock’s finding began to try the iodide in all cases of epilepsy. He later suggested. As London physicians of the time often tried potassium bromide as an alternative to the iodide attended Wilks’ demonstrations of pathology at Guy’s because it produced better results in treating goitre and Hospital, it is possible that Radcliffe was alerted to the glandular swellings. Wilks observed that the bromide effects of potassium bromide at one of these events. was much more effective than the iodide in controlling epilepsy and concluded that it must possess genuine In 1864 Rogers27 reported using potassium bromide intrinsic antiepileptic rather than simply anti- successfully in two cases of epilepsy (one a male) and in inflammatory properties.22,24 Once he realised this, from the same year M’Donnell28 described only one failure March 1860 onwards he seems to have prospectively when treating five women with perimenstrual epilepsy. A collected case material for future publication. Of his 12 year later, Williams found that fewer seizures occurred reported cases, 11 were treated with potassium bromide. in asylum patients of both sexes over a five-month history In all but one of these, seizures either became less period of potassium bromide intake after an initial five- frequent, or ceased. month baseline period of recording seizure frequency.29

34 indicated Medical Times and In all probability, In all probability, 35 Perhaps Locock had used had Locock Perhaps John Russell Reynolds, with a Russell Reynolds, John 19 23 Duncan et al. found that 78% of 40 of 78% that found al. et Duncan 36 and the and Lancet The Sir Charles LocockCharles Sir bromide potassium and However, the seizure diaries of these the seizure However, 37 women with refractory of most that epilepsy reported women of times their around occurred seizures their menstruation. predominantly neurological practice in London did not did in London practice neurological predominantly epilepsy menstrual exclusively of single instance find a half about that fact the despite 1861, and 1857 between one about and disease convulsive his practice involved of idiopathic epilepsy. third, Locock had seen the abstract and perhaps the text of perhaps and seen the abstract had Locock have would This meeting. the before paper full the his comments. prepare him to enabled in accounts The Sieveking’s followed that discussion the of Gazette but the details, minor in and in wording differ lecture concluding Sieveking’s However, similar. are facts major It is quite different. journals are comments in the two lecture Sieveking’s possible that one reporter attended the for discussion the of versions different prepared but reporters independent two Alternatively journals. two be confirmed. This can’t been involved. have could of cases collect so many did Locock How epilepsy’? ‘hysterical to that Locock appears agree Both journal accounts cases 15 or either 14 in collect data to able been have May and 1856 March epilepsy’ between ‘hysterical of of effects the evaluate to time had have to also and 1857 This suggests in all of them. therapy bromide potassium The month. per case one over just of rate recruitment a be questioned. must occurrences these plausibility of Times and Gazette The account in the Medical epilepsy in which to epilepsy’ referred ‘hysterical that at the time of the menstrual exclusively occurred seizures mental excitement’). ‘great of period (except in the case of catamenial rates reported prevalence modern More epilepsy varywidely. women showed that only 12.5% had at least three at least three 12.5% had that only showed women quarters during their ten perimenstrual seizures of their of frequency the on information published Much days. an Locock, suspect. is probably epilepsy catamenial or 14 accumulated physician, a than rather obstetrician catamenial and with epilepsy patients of 15 instances three Only a year. in a little over epilepsy in particular, and pathologist the scientific physician later, years 11 cases could collect only also in London, Wilks, Samuel for 18 months over of epilepsy (six female) of all forms with bromide. treatment two referees. If they recommended acceptance of the of acceptance recommended If they referees. two medical various to available made was the abstract paper, after the only but in their pages, publication for journals and on condition to the Society read had been paper unaltered. printed was full abstract the that published a more extensive extensive published a more Chirurgical Transactions in which appeared that than paper Sieveking’s of account medical journals. the other two 16 But it could however be however But it could 30–33 2012; 42:274–9 2012; . The accounts of Sieveking’s paper paper Sieveking’s of The accounts . would suffice to establish his achievement. In establish his achievement. to suffice would J R Coll Physicians Edinb Coll Physicians J R © 2012 RCPE Thus Wilks’ Wilks’ after an initial was published 1861 report Thus short fell the of bromide which potassium period in remarks of Locock’s the reports by raised expectations found period in which the drug a subsequent before and all types of epilepsy. a very useful place in treating as to testify to its usefulness began Medical authorities agent. antiepileptic an were identical in each journal. The explanation for these for The explanation identical in each journal. were paper a after that, is probably accounts matching two Medical and Chirurgical was submitted to the Royal Secretary was the Society’s publication, Society for After the paper. of abstract an prepare to required to submitted was abstract this President, the by approval Sir Charles Locock undeniably played the leading role in role the leading played undeniably Sir Charles Locock chemical antiepileptic effective the first recognising peculiar several However to medicine. known agent of the reports of his account of the matter features explained. be to remain of his account his own Locock publish didn’t Why discovery? without omission this noted have authors Previous of the been aware have Locock must explanation. have not importancemay he though finding his of he Moments before its fullpotential. appreciated specific no that say Sieveking heard had he it, announced reported If what was known. epilepsy was for treatment that he had realised have Locock must was correct, only applied benefits if its even treatment, a such found he Perhaps in a particular variety of the disorder. what that proved) events as (correctly felt subsequently Medical Times the was in print in The Lancet and and Gazette bringing his professional 1857 he was deliberately and his secure with his reputation activities to an end, Royal and baronetcy with a acknowledged achievements been waning. have in medicine may His interest favour. for He had not contributed to the medical literature not it was that concluded have may he and years many his a report setting down worth his while to prepare were others by provided findings when brief versions in print. already reported correct? data Locock’s Were of what and paper Sieveking’s reports of were There Medical and to the members of the Royal Locock said the Medical Chirurgical Society in both The Lancet and Times and Gazette DISCUSSION addictive; by the end of the nineteenth century the end of by the addictive; was in London Epileptic and the Palsied for Hospital annually. the chemical of tons two buying nearly MJ Eadie

table 1 Response of epileptic seizures to bromide therapy reported in various published case series. Prior to 1870 the only bromide used in these series was that of potassium.

Author Number of Female (%) Seizure With fewer Not Follow-up subjects free (%) seizures (%) improved (%) duration Locock 18579,10 14 or 15 100 93 0 7 <14 months Wilks 186123 11 55 55 36 9 <20 months M’Donnell 186428 5 80 – – 20 ? Williams 186529 37 49 – – 35 5 months Radcliffe 186625 5 or 6 100 33 or 40 – – ? Clouston 186839 29 0 0 83 17 38 weeks Echeverria 187040 416 ? – – 24 ? Hammond 187141 286 ? 31.4 53 15 ? Voisin 187312 96 ? 21 56 23 6–9 years Otto 187542 33 3 or 6 48 – – 8 months* Bennett 188443 300 ? 12 83 5 ? Turner 190344 147 ? 26 29 45 9 years *mean duration

potassium bromide to treat 14 or 15 women with Considering the above points and Sieveking’s apparent menstruation-related emotional disturbance, at least failure to comment immediately on Locock’s therapeutic two of whom also had epilepsy (and with failure to result (or the reporter[s] failure to mention such achieve seizure control in one of them) and he was comments), Sieveking probably either suspected Locock’s either misunderstood by the reporters, or somehow reported result or interpreted it differently to the misled them in the way he stated his results. Or perhaps reporters. Locock was responsible for making the the reporter(s) imposed a more restrictive interpretation medical profession aware of the antiepileptic efficacy of of ‘hysterical epilepsy’ than Locock intended. potassium bromide through the probable agency of some anonymous reporter(s). The critical issue is if his How did Locock obtain such a high control rate for data really were as reported and that they may have led seizures? to unrealistic expectations in the medical profession. From the point of view of his future reputation, Locock Table 1 shows published data on seizure control rates may have been fortunate in announcing his results when associated with bromide use during the half-century he did, in the way he did, never committing them to print following 1857. After 1870, the figures include patients and in having Wilks provide good quality supporting treated with bromide salts with bases other than evidence. Wilks was never eager to claim the original potassium, including sodium, lithium and ammonium. In medical discovery for himself, though he zealously no series was the seizure control rate as high as the 93% claimed it for an earlier generation of Guy’s Hospital reportedly obtained by Locock. Wilks recognised that men, in particular Bright, Addison and Hodgkin.38 Perhaps short-term follow-up might allow treatments that failed Wilks was being unduly modest when he observed that in the longer term to be regarded as successful because his 1861 paper had merely increased the medical they were associated with apparent early stage seizure profession’s use of potassium bromide.24 It continued to control.23 Locock’s treatment failure rate might have be used for more than 150 years. been the result of short periods of follow-up. history

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