revue neurologique 171 (2015) 5–15

Available online at

ScienceDirect www.sciencedirect.com

History of Neurology

The Madrid School of Neurology (1885–1939) L’e´cole de neurologie de Madrid (1885–1939) S. Gime´nez-Rolda´n * Department of Neurology, Hospital General Universitario Gregorio Maran˜o´n, Calle Doctor Esquerdo, 46, 28007 Madrid, Spain

info article

abstract

Article history:

The emergence of neurology in Madrid between 1885 and 1939 had well-defined characte-

Received 30 April 2014

ristics. On foundations laid by Cajal and Rı´o-Hortega, pioneers combined clinical practice

Received in revised form

with cutting-edge neurohistology and neuropathology research. Luis Simarro, trained in

8 June 2014

Paris, taught many talented students including Gayarre, Achu´carro and Lafora. The unti-

Accepted 8 August 2014

mely death of Nicola´s Achu´carro curtailed his promising career, but he still completed the

Available online 13 October 2014

clinicopathological study of the first American case of Alzheimer’s disease. On returning to

Keywords:

myoclonus epilepsy and completed experimental studies of corpus callosum lesions and

Spain, he studied glial cells, including rod cells. Rodrı´guez Lafora described progressive History

clinical and neuropathology studies of senile dementia. He fled to Mexico at the end of the

Madrid

Spanish Civil War (1936–1939). Sanchı´s Banu´s, a sterling clinical neurologist, described the

Neurology

first cluster of Huntington’s disease in Spain, and he and Rı´o-Hortega joined efforts to

Neuropsychiatry

determine that pallidal degeneration underlies rigidity in advanced stages of the disease.

Neuroscience

Just after the war, Alberca Llorente eruditely described inflammatory diseases of the

Mots cle´s :

the siege of Madrid. Dionisio Nieto, like many exiled intellectuals, settled in Mexico DF,

Histoire

where he taught neurohistological methods and neuropsychiatry in the tradition of the

Madrid

Madrid School of Neurology.

neuraxis. Manuel Peraita studied ‘‘the neurology of hunger’’ with data collected during

# 2014 Elsevier Masson SAS. All rights reserved.

Neurologie Neuropsychiatrie Neurosciences

r e´ s u m e´ Lors de son de´but a` Madrid (1885–1939), la neurologie pre´sente des caracte´ristiques bien de´finies. Avec les figures fondamentales de Cajal et de Del Rı´o-Hortega, ses repre´sentants ont combine´ une excellente approche clinique dans le vieux Hospital General avec une recherche pointue en neurohistologie et neuropathologie. Luis Simarro (1851–1921), forme´ aux coˆte´s de Charcot, Magnan et Ranvier a` Paris, a e´te´ suivi par des e´le`ves de haut niveau comme Gayarre, Achu´carro et Lafora qui joueront plus tard un roˆle cle´ dans le de´veloppement de la neurologie madrile`ne. Soutenus par la Junta de Ampliacio´n de Estudios, un programme national de bourses pre´side´ longtemps par Cajal, ils ont fait des voyages d’e´tude en Allemagne et en France pour comple´ter leur formation. La mort pre´mature´e de Nicolas

* Correspondence at: Fuencarral, 126, 28010 Madrid, Spain. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.neurol.2014.08.002 0035-3787/# 2014 Elsevier Masson SAS. All rights reserved.

6

revue neurologique 171 (2015) 5–15

Achu´carro (1880–1918) a frustre´ un futur prometteur comme clinicien de ce dernier. Il a ne´anmoins re´alise´ l’e´tude clinique-pathologique du premier cas ame´ricain de maladie d’Alzheimer au Government Hospital for the Insane a` Washington. De retour en Espagne, ses e´tudes sur l’arquitectonie et les fonctions de la glie ont e´te´ remarquables, ainsi que celles sur les « cellules en baˆtonnets » (rod cells) en neurosyphilis. Outre la description de l’e´pilepsie myoclonique progressive (PME2A), Gonzalo Rodrı´guez Lafora (1888–1971) a e´te´ remarque´ pour ses e´tudes expe´rimentales sur les blessures du corps calleux, la neuropa` thologie de la de´mence se´nile et pour ses nombreuses publications en neurologie clinique. A la fin de la Guerre Civile espagnole (1936–1939), il partit en exil au Mexique, ne revenant en Espagne qu’a` l’approche de sa retraite. Sanchı´s Banu´s (1893–1932) n’a pas eu de formation neurohistologique mais il a, par contre, prouve´ a` de nombreuses fois ses grandes capacite´s en tant que neurologue clinicien. Il a de´crit le premier foyer de maladie de Huntington en Espagne (1923) et, avec Del Rı´o-Hortega, la relation entre la rigidite´ dans les e´tats avance´s de cette maladie et la de´ge´ne´ration pallidale. On doit e´galement remarquer pendant la Guerre Civile Alberca Llorente (1903–1968) pour sa remarquable e´tude sur les affections inflammatoires du neuroaxe, ainsi que Manuel Peraita (1908–1950) pour ses observations sur la « neurologie de la faim » durant le sie`ge de Madrid. Dionisio Nieto (1908–1985) est un excellent exemple de ces nombreux intellectuels partis en exil au Mexique, transmettant dans ce pays les connaissances de la Escuela Madrilen˜a de Neurologı´a. # 2014 Elsevier Masson SAS. Tous droits re´serve´s.

1.

Introduction

In his opening address before both the Spanish and the French societies of neurology in 1967, Jean Sigwald stated that the discipline of neurology in Spain had developed in two cities, Madrid and Barcelona [1]. While there were some exceptions, he was basically correct [2]. The Barcelona School was launched in 1882 by Barraquer-Roviralta (1855–1928) [3]. Another important event in the rise of neurology was the creation, in 1933, of a neurology chair and department under Belarmino Rodrı´guez Arias (1895–1997) [4]. The Barcelona School made significant contributions, mainly to the semiology of nervous diseases. However, the Barcelona and Madrid Schools of Neurology differed broadly in their approaches to brain disorders. This review describes the scientific setting in which the Madrid School of Neurology and its pioneers flourished in the last two decades of the nineteenth century, including biographical notes that help us understand their circumstances and their most relevant contributions. We conclude our review in 1939, the year which heralded the end of the Spanish civil war and the extinction of the original Madrid School of Neurology.

2.

Background

The Madrid School of Neurology had its own distinctive traits:  with Ramo´n y Cajal in the background and Luis Simarro as a father figure, a younger group of doctors successfully combined clinical medicine with research in normal and pathological nervous system histology; nearly all worked at Hospital General in Madrid. All were excellent clinical

neurologists and motivated psychiatrists with a sense of the social implications involved, regardless of any personal preferences for one discipline or the other;  another colossal figure was Pı´o del Rı´o-Hortega (1882–1945), one of Achu´carro’s followers. It is to Rı´o-Hortega that we owe the discovery of microglia and oligodendroglia [5,6];  thanks to the scholarships organized between 1907 and 1936 by the Board for Advanced Studies, a national initiative which Cajal himself directed for years, most of these doctors completed their training in the most advanced schools in Europe. Many of these schools were in Germany, while others were in France; a few students even studied in other countries [7,8].

3.

Madrid’s Hospital General

The great writer and endocrinologist Gregorio Maran˜o´n (1887– 1960) – whose name replaced ‘‘Hospital General’’ on that institution’s new facilities – was known to say that ‘‘to evoke Hospital General in Madrid is to contemplate nearly all of five centuries of Spanish medicine’’ [9,10]. The hospital building was finished in 1781, but the sumptuous original design never materialized due to lack of funds (Fig. 1) [11]. This building currently houses Museo Reina Sofı´a, the art museum. Following Spain’s so-called Glorious Revolution, Jose´ Marı´a Esquerdo y Zaragoza (1842–1912) was given the task of organizing a ‘‘Department for the Surveillance of the Insane’’ for patients with acute mental illness (Fig. 2). Perhaps, the most significant contribution by this romantic and somewhat eccentric figure was his campaign for changes in care for lunatics, who until then had been confined to dark cells. This step meant recognition of mental illnesses as entities treatable

revue neurologique 171 (2015) 5–15

7

Fig. 1 – Hospital General de Madrid (currently the Museo Reina Sofı´a), taken in the early 20th century.

in a general hospital environment, rather than the alienist approach applied in insane asylums [12]. Philippe Pinel (1745–1826) expressed his admiration after a visit to Hospital General in Madrid: ‘‘Spain has taken only a few steps towards this great goal, as I showed a few years ago in a periodic publication: the inmates of a public asylum dedicated to their custody are managed with the greatest gentleness and assigned to regular work, which has served to cure most of them’’ [13]. In turn, surgeon and anatomist Pedro Gonza´lezVelasco (1815–1882), one of Esquerdo’s friends, visited Salpeˆtrie`re Hospital in 1860 to study its organizational structure. He was enraptured by what he considered ‘‘luxurious facilities’’, at least compared to conditions in the old Hospital General in Madrid [14].

Fig. 2 – Jose´ Marı´a Esquerdo: positivist ideals and humane treatment for insane patients at Hospital General.

4.

Luis Simarro, the founder

As some have said of Luis Simarro Lacabra (1851–1921), ‘‘he was steeped in legend from his earliest days’’ (Fig. 3). This much is true; his traumatic childhood could well explain his rebelliousness in the face of injustice and his struggle to defend human liberty without regards for countries and borders [15]. However, his causes took up a great deal of his time and chiselled away at his tremendous intellectual potential. As chance would have it, Simarro was born in Rome; his entire family had moved to that city so that his father could pursue his studies as a painter. They were forced to make a hurried return to Xa`tiva in Valencia province when his father’s tuberculosis grew worse. The day after he died, the desperate mother of his children threw herself off a balcony. Young Luis was handed over to an orphanage at the age of three [16,17]. At

Fig. 3 – Portrait of Simarro by Joaquı´n Sorolla-Bastida (1896); oil on canvas, 46 T 53 cm. Simarro Legacy Trust, Complutense University.

8

revue neurologique 171 (2015) 5–15

the age of 26, Simarro became the director of Santa Isabel asylum, an institution near Madrid known at that time as the ‘‘House of Lunatics’’. He wished to implement the humanist reforms recommended by Pinel and Esquirol but was not permitted to do so [18]. He also wanted to perform autopsies – an unheard-of initiative for an asylum at the time – but this was vetoed by the Church who claimed ‘‘not to have any area properly equipped for this very commendable interest in experimental studies’’ [19]. His patience at an end, he left Spain for a change of scene. Between 1880 and 1885, Simarro’s years in Paris, Salpeˆtrie`re Hospital was rapidly expanding. Microscopes had been introduced, the hospital had acquired an extensive histological collection, and numerous foreign doctors flocked to study under Charcot [20]. Most of Simarro’s library is now conserved as the Fondo Simarro (FS) by the Faculty of Psychology at the Autonomous University of Madrid. It includes Charcot’s lec¸ons sur les localisations dans les maladies du cerveau faites a la faculte´ de Me´decine de Paris, written in 1875 (FS 738). Simarro’s own studies, published after his return to Madrid, were in line with those of Charcot (and Hughlings Jackson) regarding the anatomical and physiological organization of the nervous system [21–25]. He was without doubt the first scholar in Spain to address cerebral localizations [25] and to compile a treatment handbook [24]. However, Charcot’s influence on Simarro’s medical training was perhaps best seen in the Marquis de Larios case, a dispute involving a rich aristocrat whose second marriage had been contracted in secret. He was accused of behavioural problems supposedly caused by general paralysis of the insane. If this were true, his second marriage would be declared invalid, and his beneficiaries would lose their claim to a substantial inheritance. In 1880, at the age of 60, Charcot travelled to Madrid and Ma´laga, accompanied by Alfred Hardy, to give his views on the case. The investigation that Simarro completed in partnership with two colleagues (Jaime Vera and Jose´ Marı´a Escuder) refuted the conclusions of the French team. This study provides a fine example of the thoroughness of these doctors’ understanding of neurology [26]. While working with alienist Valentin Magnan (1835–1916) at Hoˆpital Saint-Anne, Simarro absorbed the evolutionist concept of degeneration. Magnan’s Les de´ge´ne´re´s (e´tat mental et syndromes e´pisodiques), written in 1895, is among the more than 4000 volumes from Simarro’s private collection, the Fondo Simarro mentioned before, which he donated to the University. He also attended Mathias Duval’s classes on embryology, Darwinism, and evolution; these lectures are summarized in Atlas d’embryologie (1889, FS 2684). Simarro always mentioned his Parisian professors in his lectures in the Athenaeum of Madrid [22,23]. Nevertheless, Louis Antoine Ranvier was without a doubt the researcher who most influenced Simarro’s work (1880– 1881). Ranvier worked closely with Claude Bernard, and their objective was to link morphological findings to function [27,28]. The idea would prove fascinating to this ‘‘occasional histologist’’, as Simarro considered himself; ‘‘neurohistology represented a positivist current that would let him understand the mind and its deviations while avoiding the problem of the soul’’ [29]. While following that current, he sketched the

structural basis of mental symptoms in his rather infrequent articles [21]. What he learned in Ranvier’s laboratory would have monumental consequences. Take, for example, the reazione nera used to impregnate nervous tissue with silver chromate. Camillo Golgi published his method in Gazzeta Medica Italiana-Lombardia, a journal with limited circulation. In 1877, Cajal was passing through Madrid and felt an urge to visit his old colleague and catch up with any new advances brought from Europe. The ever-generous Simarro welcomed Cajal to his home, where he showed him the Golgi method and how it reveals the silhouettes of nerve cells.‘‘Just one chance moment was enough to herald the start of the Spanish school of histology’’, was one description of that magical encounter [29]. His fascination was such that Cajal, once back in Valencia, decided to focus all his efforts on nervous system histology. This decision would lead him to the Nobel Prize in 1906 [30]. As he wrote in his memoirs, ‘‘I owe to Luis Simarro, the famous psychiatrist and neurologist of Valencia, the unforgettable favour. . .’’[31]. Cajal often called Le traite´ technique d’histologie de Ranvier (FS 603) ‘‘my histology bible’’.

5. 1885: the birth of the Madrid School of Neurology Upon Simarro’s return to Madrid, he opened a private clinic for patients with nervous system diseases. Just as Ranvier had done in Paris, he set up a small laboratory in his home where he could perform histological studies on the brain. Enthusiastic followers soon joined him, almost all of them doctors from Hospital General: Garcı´a del Real, Garcı´a del Mazo, Sama, Botella, Cejudo, and Sandoval. Miguel Gayarre was responsible for providing autopsy specimens from the internal medicine department run by Madinaveita, another disciple [18]. The painting by his artist friend Joaquı´n Sorolla (1897) shows them expectantly peering over the master’s head as he concentrates on dissecting an embryo with the aid of a Leitz microtome (Fig. 4). Among the array of devices and bottles scattered across his workbench, we find a gleaming bottle of the potassium bichromate used to prepare Golgi’s chromesilver stain. Some have speculated about the identities of the scientists surrounding Simarro: Madinaveita? Sandoval? San Martı´n? [32]. In a telephone call, the grand-daughter of Miguel Gayarre y Espinal (1866–1936) positively assured me that her grandfather was the figure farthest to the right. Gayarre had returned from Berlin in about 1895. He had been training as a neurologist under Hermann Oppenheim [33] presumably in his private clinic; Oppenheim had been denied the position of department head at Hospital de la Charite´ because he was Jewish [34]. All of these pioneering figures in the clinical and pathological study of nervous diseases were raised on the teachings of Simarro and Ramo´n y Cajal (Fig. 5). In the 1960s, Lafora was fond of telling young neurologists, including this writer, that the first scientist to describe senile plaques in Alzheimer’s disease had been Simarro, ‘‘and not Fischer’’, as he reiterated [18]. Czech neuropathologist Oskar Fischer referred to drusige Entartung, ‘‘druse necrosis’’, in 1907, four years before Alois Alzheimer published his famous case report on Auguste D. In truth, however, they had already

revue neurologique 171 (2015) 5–15

9

the ‘‘organicist approach’’ to the cause of mental illness and the and the close links between neurology and psychiatry [38].

6. The tragic loss of Nicola´s Achu´carro Lund (1880–1918)

Fig. 4 – ‘‘An investigation’’ by Joaquı´n Sorolla-Bastida (1897), Madrid, Museo Sorolla (00417). #Fundacio´n Museo Sorolla. Reproduced with kind permission.

Achu´carro was a typical member of the Madrid school of Neurology. He conducted histopathological research as well as practicing clinical neurology and psychiatry, exactly as Professor Simarro had recommended to his 17-year-old student. He possessed a first-rate education, intelligence – Ortega y Gasset (1833–1955) ranked him among the ‘‘ten to twelve Spaniards of the highest intellectual level’’ [39] – and irresistible personal warmth which would have taken him far (Fig. 6). Although all the signs pointed to a brilliant future, Achu´carro died at the age of 38, his influence marked the lives of many excellent students. His followers included eminent histologists such as Pı´o del Rı´o-Hortega (1882–1945) and Cajal’s youngest student Fernando de Castro (1896–1967). Achu´carro learned German during a year spent in Wiesbaden and also had a good command of French and Italian, and to a lesser extent, of English. He studied medicine in Madrid, where he heard Cajal’s lectures [40]. After graduating, he travelled to Paris to study under Pierre-Marie and attend Babinski’s lectures (Fig. 7). At a later date, he trained in psychiatric clinics in Florence under Eugenio Tanzi and Ernesto Lugaro, staunch organicists and supporters of Cajal’s neuron doctrine. Later still, in Munich, he found himself in Alois Alzheimer’s laboratory at the German Institute for Psychiatric Research,

Fig. 5 – Cajal presenting a lecture. Here, we observe a very young Lafora (1), the biologist and naturalist Domingo Sa´nchez (2), J.M. Sacrista´n, (3), M. Gayarre (4), and ´ carro (5). N. Achu

been described by numerous authors [35]. It is entirely possible that Figure 310 in Cajal’s anatomical pathology textbook [36] – labelled as showing Fischer’s plaques – was provided by Simarro, who never published his observations. Among Spanish psychologists, Simarro is well-known for having been made Spain’s first Chair of Experimental Psychology in 1902; his lectures were mainly attended by medical students [37]. Simarro’s biographers highlight his immense intellectual capabilities, cultural level, and generosity. Regrettably, his scientific talents did not reach their full potential since he was active on so many different fronts, and yet he knew how to transmit to outstanding students his enthusiasm and ideas:

´ carro. Fig. 6 – Nicola´s Achu

10

revue neurologique 171 (2015) 5–15

neurosyphilis in 1898, but he did not know how they developed. Ramo´n y Cajal welcomed Achu´carro back from the United States by granting him a Laboratory for Nervous System Histopathology next to his own and naming him the deputy department chair. We know that most of the patients treated by Achu´carro at Hospital General had neurological illnesses although there was probably no specific name for his service [44]. As he grew old, Lafora often shared his recollections of his friend and mentor’s final years [45]. After suffering persistent abdominal pain supposedly due to Hodgkin’s disease, Achu´carro developed paraplegia and died on 23 April 1918. None other than Ramo´n y Cajal and De Castro [31–46] provided the best summaries of Achu´carro’s contributions to neurohistology, some 40 publications. The most important of all are listed here: ´ carro (1) with Pierre-Marie (2) and a group of Fig. 7 – Achu disciples.

´ carro (1) in the laboratory headed by Alzheimer Fig. 8 – Achu (2) with a group of followers, including Salomon Fuller (3) from the United States.

directed at that time by Emil Krapelin. A well-known photograph (Fig. 8) shows him with Alzheimer and a select group of researchers; in the background, a chalkboard displays Achu´carro’s inventive sketches of neurons. Achu´carro’s stay coincided with a visit by an American named Smith Elly Jelliffe, who had been sent by William A. White, the director of the Government Hospital for the Insane in Washington, D.C. (later known as St. Elizabeths Hospital). The director was seeking a neuropathologist to advance his centre’s scientific capabilities, and Alzheimer recommended Achu´carro. Achu´carro worked in Washington for almost two full years between 1908 and 1909, and no grass grew under his feet. In the hospital’s bulletin (1910–1911), he described the neuropathological features of the first known case of Alzheimer’s disease in the United States, and the sixth case in the world. In addition to ‘‘miliary plaques’’, he mentioned glial changes and peculiar structures in pyramidal cells which Simchowicz would describe a year later [41,42]. Upon returning to Madrid, he published new observations on senile dementia [43]. Other important contributions include his suggestions regarding the mesodermal origin and functional significance of Sta¨bchenzellen or rod cells. Nissl had described these cells in

 development of the tannin and ammoniacal silver oxide stain revealing the organelles within neurons;  his postulate that neuroglia were ‘‘an active component and not mere passive insulation’’ and the description of glial architecture (gliotectonia) in Ammon’s horn and stratum radiatum, with the suggestion that glial organization was similar to that of neurons;  his demonstration of how microglia were transformed into Sta¨bchenzellen or rod cells in general paralysis of the insane and in rabies, and his suggestion that their shape was related to local anatomical conditions. It is impossible to imagine how else he would have contributed to clinical neurology if he had only lived longer. Santiago Ramo´n y Cajal (1852–1934), who was by then elderly and ill, would call ‘‘wise Dr Achu´carro’’ to sit by his bedside and give his opinions, which was no small measure of the wise doctor’s prestige [47]. In the 1970s, Gonzalo Moya (1931– 1984) contrived to organize a neurology department in Gran Hospital de la Beneficencia General del Estado (now known as Hospital de la Princesa) [48]. He dedicated it to Nicola´s Achu´carro in 1966 (Fig. 9). A bas-relief portrait of Achu´carro, now displayed in the Spanish Society of Neurology’s historical museum, once presided over the department’s entrance hall, where this writer took his first steps into neurology.

7.

The atypical case of Sanchı´s Banu´s

Jose´ Sanchı´s Banu´s (1893–1932) came to Madrid in 1916 with the idea of studying legal medicine, but his career took a different turn when he met Achu´carro (Fig. 10). After overcoming the difficult competitive exams thanks to his excellent memory and fine verbal skills, he was assigned to the old Department for the Observation of the Insane which had been limping along without a capable director. After Achu´carro’s death in 1918, Sanchı´s Banu´s managed to transform it into the Department of Neurology and Psychiatry, as he usually called it in his publications [49]. Sanchı´s Banu´s certainly cut an atypical figure in the Madrid school of neurology because of his lack of histological studies. However, his intellectual prowess and unequalled working capacity

revue neurologique 171 (2015) 5–15

Fig. 9 – Invitation to the unveiling of the bas-relief portrait ´ carro (1967), Department of Neurology, Gran of Achu Hospital de la Beneficencia General del Estado (now known as Hospital de la Princesa).

11

was only the beginning of a long series of articles on such neurological topics as trichinosis, the palmomental reflex, myasthenia gravis, and the risks of lumbar puncture in brain tumour cases. He kept abreast of the latest advances. In 1922, the same year in which Ramsay Hunt published his observations on dyssynergia cerebellaris myoclonica in Brain, Sanchı´s Banu´s and Gonza´lez-Pa´ez [51] used the same name to describe a case in a girl who manifested cerebellar ataxia and multifocal muscular jerks (today, this syndrome would be considered multicausal). In his second case, he described the uncommon finding of severe action myoclonus in Friedreich’s ataxia, which is identified by the combination of areflexia, pes cavus, and deep sensory deficits. He also wrote original articles on psychiatric topics, such as his description of ‘‘paranoid delusion of the blind’’ or Sanchı´s Banu´s syndrome [52]. What was perhaps Sanchı´s Banu´s’s most historically important contribution was mapping the first cluster of cases of Huntington disease in Spain; it was in Berlanga de Duero, in Soria province [53,54]. The index case had been admitted for symptoms of aggressiveness and agitation after a long history of choreic movements. Strangely enough for that time, the patient displayed ‘‘pronounced hypertonia’’ instead of the expected hypotonia. Doctors speculated whether the presence of parkinsonism could point to a new type of neurodegenerative disease. Pı´o del Rı´o-Hortega carried out an exhaustive neuropathological study of that patient’s brain. In addition to the typical changes in the disease, with which he was very familiar, he was surprised to find swollen oligodendrocytes, and above all, degeneration in the globus pallidus, putamen, and caudate nucleus. This was probably the first published description of pallidal degeneration and muscular hypertonia seen in advanced stages of the disease. Sanchı´s Banu´s was a prominent member of the Socialist Party and his political influence enabled him to build a large psychiatric ward in 1933 at Hospital General [49,55]. While this initiative resulted in undeniable improvements in care for patients with mental illnesses, neurological patients remained in an undefined limbo under the care of general practitioners or psychiatrists who were increasingly swayed by psychodynamic theories; by the 1970s, neurosurgeons had also entered the fray. In 1933, E. Ferna´ndez-Sanz (1872–1950), an internist with substantial contributions to neurology, proposed separating the two specialties and creating a specific neurology department. His initiative was delayed for about forty years.

8. Gonzalo Rodrı´guez Lafora: the man behind the disease

´ s. Fig. 10 – Jose´ Sanchı´s-Banu

‘‘drove him onwards to an almost meteoric career’’, as recalled by Gregorio Maran˜o´n (1887–1960) [10]. A study on climacteric epilepsy, in which he highlighted etiological differences between late-onset forms of epilepsy, confirmed his reputation as an excellent neurologist [50]. This

Lafora disease or PME2 is a type of progressive myoclonic epilepsy characterized by intracellular polyglucosan deposition in multiple organs. Eighty per cent of all cases are due to mutations or deletions in the PME2 gene, which encodes laforin, named in honour of Lafora [56]. Aside from this significant contribution, Gonzalo Rodrı´guez Lafora (1886–1971) is considered the pivotal figure in the history of the Madrid School of Neurology due to his intelligence, honesty, and work ethic (Fig. 11). Born in Madrid to a high-ranking military family, he spent some time in Puerto Rico after a bout of polio had already

12

revue neurologique 171 (2015) 5–15

Fig. 11 – Gonzalo Rodrı´guez Lafora in his later years.

taken its toll. While still in medical school, and working in Simarro’s laboratory (he divided his time between that laboratory and one in the Cajal Institute), he completed his first study on the nervous system of fish. He travelled to Berlin with Theodor Ziehen, Hermann Oppenheim, and Oskar and Ce´cile Vogt. A few months later, he visited Alzheimer’s laboratory in the Nervenklinik in Munich. It was in Paris (1910) while he was working as an assistant in Pierre-Marie’s clinic that he received a letter from Washington, D.C. In it, Achu´carro asked him to take over as head of the neuropathology department at the Government Hospital for the Insane. Lafora did just that, and remained in the United States from 11 May 1910 to September 1912 [15,57]. It was in Washington that Lafora completed his clinicopathological study of the type of progressive myoclonic epilepsy that bears his name. He highlighted its recessive inheritance pattern and the probable metabolic origin of inclusion bodies [58]. Lafora described neuropathological findings in the third case of Alzheimer disease reported in America, in a war veteran who had been committed to an asylum at the age of 58. His report identified the associated endothelial lesions [42] a year before Salomon Fuller, an African-American doctor he had met in Munich, published his own description [59]. Lafora returned to Madrid and Cajal assigned him a workplace in the Cajal Institute, which was housed by the Anthropological Museum in those years. Lafora converted the small third-floor garret into his Laboratory of Nervous System Physiology. He complemented his research with a private practice that grew until he became the most sought-after

specialist in the country. A prolific writer, he published a total of 81 studies on very different aspects of the nervous system between 1912 and 1922. Perhaps, his favourite topics were histopathology in senile dementia, intraspinal treatment for general paralysis [18], manifestations of experimental severing of the corpus callosum, and clinical findings in tumours in that localization [60,61]. His presentation of slides showing corpus callosum lesions in monkeys at the 1921 International Congress of Physiology was publicly praised by Sherrington. In fact, Lafora never headed a public hospital department until 1933. He completed most of his observations in the Neuropathic Sanatorium in Carabanchel, a model private centre he had founded in 1925. Numerous disciples flocked to his laboratory, and many went on to important careers: D. Nieto, L. Valenciano Gaya´, R. Alberca Llorente, J. Germain, J. Gonzalo, and others. An admirer of Karl Kleist (1879–1960), Lafora maintained a staunchly organicist view of psychiatry and always thought of himself as more of a neurologist than a psychiatrist, as he wrote in his later years [45]. His interest in science never waned; he published his last study at the age of 82, on the first reported case of tardive dyskinesia in Spain [62]. One of his most appreciated initiatives was the launch in 1920 of the journal Archivos de Neurobiologı´a in partnership with psychiatrist Jose´ Miguel Sacrista´n (1887–1957) and renowned philosopher Jose´ Ortega y Gasset. His editorial piece in the first issue stated that the journal’s purpose was to foster the development of neurology, psychiatry, and psychology from a non-university perspective, given that universities ‘‘showed no interest in these disciplines’’. This journal would present such important contributions as Cajal’s definitive version of Neuronismo o Reticularismo [Neuron or reticular theory] and Rı´oHortega’s first observations on oligodendroglia and microglia. I for one will never forget seeing him, then a very elderly man, seated in the first row and taking in lectures with a hand cupped to his ear; he was growing deaf, but his passion for learning never wavered. He was also incorrigibly confrontational. In a session of the Spanish Academy of Medicine and Surgery, Sixto Obrador, an influential neurosurgeon with no interest in furthering the rise of neurology as a discipline, was holding forth on cervical myelopathy. His speech was interrupted unexpectedly by a powerful voice from the back of the auditorium, and a venerable figure was seen making his way down the aisle, cane in hand, his uneven gait caused years before by polio: ‘‘Sixto, that is not true, and you know it!’’ The astonished crowd murmured ‘‘It’s Lafora!’’. Obrador condescendingly paused, and a deafening round of applause recognized the upstanding man and model scientist determined to defend the truth at all costs. Jose´ Marı´a Villaverde y Larraz (1888–1936) (Fig. 12), Lafora’s greatest opponent when it came to competitive exams and academic honours, was only two years younger than himself. They also disagreed in certain clinical areas, notably on intraspinal treatment for neurosyphilis, which Lafora defended fiercely, and on the pathogenesis of tabetic ataxia [18]. Like so many others from the Madrid school of neurology, Villaverde was active in histopathological research, first under Cajal and later under Rı´o-Hortega, and he had benefited from a long stay in Germany under Eugen Bleuler. Cajal’s secretary recalled Villaverde as the one who would return after the summer holidays with amusing tales of the liaisons

revue neurologique 171 (2015) 5–15

Fig. 12 – Jose´ Marı´a Villaverde.

dangereuses among the old guard of the Spanish aristocracy [63]. As he was disappointed with psychoanalysis, he practiced organicist psychiatry and neurology, showing a firm interest in epilepsy [64] and toxic neuropathies. He used a typewriter to prepare detailed medical histories and meticulous genetic data [65]. We know very little about him as a person, but one of his contemporaries described him as ‘‘clever and intrusive’’, which might paint him as somewhat opportunistic. In any case, Lafora held liberal and republican views, whereas Villaverde was on the extremist fringe of the monarchist party. The Spanish Civil War (1936–1939) brought it all to an end. Lafora, intrigued by the outbreak of epidemic encephalitis in Spain [66], published an indiscreet comment in a newspaper (El Sol) in which he blamed the army for spreading the disease across the country by fast-tracking the discharges of infected recruits. In June 1938, Lafora made a hurried escape to France before crossing the ocean to Mexico. He returned, however, in 1947 and after his political responsibilities had been thoroughly scrutinized, he was allowed to occupy his former position at Hospital General, albeit just before his time to retire. He was not even allowed to stay on as a volunteer assistant. Villaverde, on the other hand, disappeared in the tragic days that followed the military uprising. His body was never found [67].

9.

13

fates. Roma´n Alberca Llorente (1903–1968), described himself as a follower of Sanchı´s Banu´s and Rı´o-Hortega. His path led him to l’Institut Pasteur in Paris with Constantine Levaditi [68]. He demonstrated the early activation of microglia in experimental lesions in rabbits (1926) and nervous system regeneration after inoculation with aphthous viruses (1927). He wrote a monumental treatise, titled Neuroaxitis ectotropas (1942), on neurological disorders with associated inflammatory signs of various aetiologies, including viruses [69]. He completed his later works in the city of Murcia, where he proved himself a dedicated and capable psychiatrist. Manuel Peraita-Peraita (1908–1950), returned to Madrid after studying with Otfrid Foerster and Altenburger in Breslau (now Wrocław, Poland). Peraita had been among those who suffered severe famine during the siege of Madrid during the Spanish Civil War. His area of expertise was ‘‘the neurology of hunger’’, which he studied in partnership with nutritionist F. Grande-Covia´n and internist B. Llopis [70,71]. Manuel Peraita (not to be confused with his brother Pablo, a distinguished neurosurgeon) revealed his capabilities as a top neurologist in his articles on ‘‘Madrid symptomatic complex’’ and ‘‘paraesthetic-causalgic symptoms’’ (the latter phenomenon was also described in the British Medical Journal) [72]. He also described sensory ataxia and myelopathies related to nutritional deficiency [72]. Peraita assumed the directorship of the Santa Isabel asylum in Legane´s in 1944 and retained that position until shortly before his untimely death. Dionisio Nieto-Go´mez (1908–1985) (Fig. 13) followed the route typically taken by members of the Madrid school of neurology. After an initial period in Rı´o-Hortega’s laboratory in 1929 and additional studies in Munich from 1931 to 1933, he completed his clinical training in nervous system diseases with Sanchı´s Banu´s in Hospital General. For Nieto and a

The last generation

The Spanish Civil War (1936–1939) dismantled the Madrid school of neurology, and its members met with very different

Fig. 13 – Dionisio Nieto, taken during his years in Mexico City.

14

revue neurologique 171 (2015) 5–15

growing number of Spaniards with a university education, the end of the Civil War meant exile and the search for a new life in Mexico, where they were given a warm welcome. Another staunch organicist, Nieto introduced the Cajal school’s techniques to the Castan˜eda asylum and the Laboratory of Medical and Biological Studies, which he set up in Mexico City. Fortunately, his legacy lives on in Mexico today thanks to the efforts of Dionisio Nieto [73]. This exceptionally creative man devised a laboratory method for diagnosing neurocysticercosis in cerebrospinal fluid and modified Rı´o-Hortega’s technique for visualizing T. pallidum in nervous tissue. He also did ground-breaking work in demonstrating the neuropathological changes in schizophrenia, as we read in Minckler’s 1972 Pathology of the Nervous System. Nieto visited Spain towards the end of his life. He spent his last evening in his native land in my home. During a long postprandial chat, I greatly enjoyed his stories, one of which described a secret Republican government mission at the very end of the war [74]. Several excellent hospitals were built in Madrid in the 1970s, and each one boasted a well-equipped neurology department. The Spanish Society of Neurology currently includes 2203 full members, in addition to residents, associate members, and corresponding members. Today, all of Spain’s provincial capitals and major cities provide quality neurological care.

[10] Maran˜o´n G. La medicina hace veinte an˜os. Obras completes (IV). S.A. Madrid: Editorial Calpe; 1974: 231–3. ´ lvarez Sierra J. Los hospitales de Madrid de ayer y de hoy, [11] A 3. Madrid: Publicaciones de la Beneficencia Provincial; 1952. [12] Bogousslavsky J, Moulin T. From alienism to the birth of modern psychiatry: a neurological story? Eur Neurol 2009;62:257–63. [13] Weiner DB. Philippe Pinel’s ‘‘Memoir of Madness’’ of December 11, 1794: a fundamental text of modern psychiatry. Am J Psychiatry 1992;146:725–32. [14] Gime´nez-Rolda´n S. La Salpeˆtrie`re hospital before Charcot: a visit described by Pedro Gonza´lez Velasco. Neurologı´a 2013;28:52–6. [15] Valenciano Gaya´ L. El doctor Lafora y su e´poca. S.A., Madrid: Ediciones Morata; 1977. [16] Salcedo Ginestal E. El doctor Luis Simarro Lacabra. Teodoro, Madrid: Imprenta E; 1926. [17] Carpintero H, Campos JJ, Bandre´s J. Luis Simarro y la Psicologı´a cientı´fica en Espan˜a. Cien an˜os de la Ca´tedra de Psicologı´a Experimental en la Universidad de Madrid. Madrid: Universidad Complutense de Madrid; 2002. [18] Rodrı´guez Lafora G. El profesor Simarro. Arch Neurobiol 1921;2:209–11. [19] Moro A, Villasante O. La etapa de Luis Simarro en el Manicomio de Legane´s, 1. Frenia; 2001. p. 97–120. [20] Micale MS. The Salpeˆtrie`re in the age of Charcot: an institutional perspective on medical history in the late nineteenth century. J Contemp Hist 1985;20:703–31. [21] Simarro Lacabra L. Bosquejo de anatomı´a y fisiologı´a del sistema nervioso, 2. Boletı´n de la Institucio´n Libre de Ensen˜anza (BILE); 1878. p. 167–8 [176-177; 1879 3 19-26, 31-32,

Disclosure of interest

[22] Simarro Lacabra L. Fisiologı´a general del sistema nervioso. El curso de Mr. Ranvier, 4. Boletı´n de la Institucio´n Libre de Ensen˜anza (BILE); 1880. p. 190–1 [1881; 5: 5-7]. [23] Simarro Lacabra L. La ensen˜anza superior en Paris. Escuela de Antropologı´a. Curso de Mr. Matı´as Duval, 4. Boletı´n de la Institucio´n Libre de Ensen˜anza (BILE); 1880. p. 173–4. [24] Simarro L, Gayarre L, Madinaveitia J, Sandoval FR, Cisneros J, Azua J. Vademe´cum clı´nico-terape´utico. Madrid: Romo y Fu¨ssel; 1898: 465–573. [25] Simarro Lacabra L. Estado actual de las localizaciones cerebrales. Lecture presented at Instituto Rubio, 9 July 1910. Arch Esp Neurol, Psiquiatr Fisiotera´pia 1910;1:321–43. [26] Corral Corral I, Corral Corral C. El asunto Martı´n Larios y los inicios de la neurologı´a en Espan˜a: charcot refutado por Escuder. Vera y Simarro. Neurologı´a 2000;15:231–41. [27] Barbara JG. Louis Antoine Ranvier (1835–1922). J Neurol 2006;399–400. [28] Barbara JG. Louis Ranvier (1835–1922): the contribution of microscopy to physiology and the renewal of French general anatomy. J Hist Neurosci 2007;16:414–31. [29] Albarracı´n A. El Dr. Simarro y la escuela histolo´gica espan˜ola. Investigaciones Psicolo´gicas, 4. El Dr. Simarro; 1987. p. 91–113. [30] Ferna´ndez N, Breathnach CS. Luis Simarro Lacabra (1851– 1921): from Golgi to Cajal through Simarro, via Ranvier? J Hist Neurosci 2001;10:19–26. [31] Ramo´n, Cajal S. Oracio´n fu´nebre. Nicola´s Achu´carro (1880– 1918). In: Ramo´n y C, et al., editors. Nicola´s Achu´carro (1880–1918), su vida y su obra.. S,A., Madrid: Taurus Ediciones; 1968 [Reproduced from a speech given on 26 April, 1918, before the Spanish Society of Biology]. [32] Campos-Bueno JJ. Art and Science in Sorolla’s painting A research in Dr. Simarro’s lab. Psychologia Latina 2010;1:9– 26. [33] Gime´nez-Rolda´n S. Miguel Gayarre (1866–1936) y la neurologı´a madrilen˜a: contribucio´n a su biografı´a. Neurologı´a 2002;17:624–7.

37-38, 46-47, 53-54, 61-62, 79 127-127].

The author declares that he has no conflicts of interest concerning this article.

references

[1] Sigwald J. Re´union commune de la sociedad espan˜ola de neurologı´a et de la Socie´te´ franc¸aise de neurologie. Rev Neurol (Paris) 1967;117:541–7. [2] Izquierdo Rojo JM. Historia de la neurologı´a clı´nica espan˜ola (1882–1936). Universidad complutense, Ca´tedra de historia. Oviedo: Gra´ficas Summa; 1978. [3] Barraquer Bordas L. The history of Spanish clinical neurology in Barcelona 1882–1949. J Hist Neurosci 1993;2:203–15. [4] Rodrı´guez Arias B. Historia de la neurologı´a espan˜ola. Arch Neurobiol 1961;24:181–96. [5] Penfield W. Obituaries. Arch Neurol Psychiatr 1945;54:413– 4. [6] De Castro F. Pı´o Del Rı´o-Hortega (1882–1945). In: Universidad Complutense, editor. Cajal y la escuela neurolo´gica espan˜ola. S.A., Madrid: Graficas Cinco; 1981. p. 95–106. [7] Gime´nez-Rolda´n S. La escuela madrilen˜a de neurologı´a en el antiguo Hospital General de Madrid. Neurologı´a 1992;7:102–8. ´ lava A. La escuela madrilen˜a de neurologı´a. In: [8] Gimeno A Historia de la Neurologı´a en Espan˜a. Madrid & Barcelona: A. Martı´n Araguz, Saned; 2002: 139–51. [9] Maran˜o´n G. El pasado, presente y futuro del Hospital General de Madrid. Obras completas (IV). S.A., Madrid: Editorial Calpe; 1974: 287–302.

revue neurologique 171 (2015) 5–15

[34] Pearce JM. Hermann Oppenheim (1858–1916). J Neurol Neurosurg Psychiatr 2003;74:569. [35] Castellani RJ, Lee H-g, Zhu X, Perru G, Smith MA. Alzheimer’s disease pathology as a host response. J Neuropathol Exp Neurol 2008;67:523–31. [36] Ramo´n, Cajal S. Manual de anatomı´a patolo´gica general. Madrid: Librerı´a Moya; 1905. [37] Bandre´s J. Simarro, catedra´tico de la universidad. In: Luis Simarro y la psicologı´a cientı´fica en Espan˜a. Cien an˜os de la ca´tedra de psicologı´a experimental en la Universidad de Madrid. Madrid: Universidad Complutense de Madrid; 2002: 27–38. [38] Poirier J, Clarac F, Barbara J-G, Brousollle E. Figures and institutions of the neurological sciences in Paris from 1800 to 1950: part IV: psychiatry and psychology. Rev Neurol 2012;168:389–402. [39] Ortega, Gasset J. Una pe´rdida nacional: Nicola´s Achu´carro (El Sol, April 26th, 1918). Reproduced in: Nicola´s Achu´carro (1880–1918), su vida y su obra. S,A., Madrid: Taurus Ediciones; 1968: 39–41. [40] Vitoria Ortiz M. Vida y obra de Nicola´s Achu´carro. In: Coleccio´n ‘‘Biografı´as de vascos ce´lebres’’. Bilbao: La Gran Enciclopedia Vasca; 1977. [41] Achu´carro N. Some pathological findings in the neuroglia and in the ganglion cells of the cortex in senile conditions. Bull Gov Hosp Insane (Washington) 1910;2:81–90. [42] Garcı´a-Albea E, Pe´rez Trullen JM. The Spanish school of Neurology and the first American cases of Alzheimer’s disease. J Hist Neurosci 2003;12:437–45. [43] Achu´carro N, Gayarre M. Contribucio´n al estudio de la neuroglia en la corteza de la demencia senil y su participacio´n en la alteracio´n celular de Alzheimer. Trab Lab Invest Biol Univ Madrid 1914;12:67–83. [44] Prados Such M. Nicola´s Achu´carro (1880–1918), su vida y su obra. S, A., Madrid: Taurus Ediciones; 1968: 107–19. [45] Rodrı´guez Lafora G. Reflexiones de un viejo especialista sobre la neurologı´a en el primer tercio del siglo XX. Arch Neurobiol 1969;32:7–21. [46] De Castro F. La obra cientı´fica histopatolo´gica de Nicola´s Achu´carro. In: Cajal y la escuela neurolo´gica espan˜ola. Madrid: Universidad Complutense, Graficas Cinco; 1981: 71–94. [47] Ramo´n Cajal S. Recuerdos de mi vida. 3 edicio´n. Madrid: Imprenta de Juan Pueyo; 1923. [48] Gime´nez-Rolda´n S, Martı´nez-Fuertes L. Gonzalo Moya (1931–1984): a unique neurology department. Neurosci Hist 2014 [In Press]. [49] Pe´rez Salmo´n C. La obra psicolo´gica de Jose´ Sanchı´s Banu´s (1893–1932). Tesis: Universidad Complutense de Madrid; 2009. [50] Sanchı´s Banu´s J. Epilepsia climate´rica. Arch Neurobiol 1920;1:274–80. [51] Sanchı´s Banu´s J, Gonza´lez Paez S. Dissinergia cerebellaris progressiva (enfermedad de Ramsay Hunt). Estudio clı´nico de dos casos de temblor cerebeloso cro´nico progresivo con asociacio´n en uno de ellos de ataxia de Friedreich. Arch Neurobiol 1922;3:43–5. [52] Carrio´n-Expo´sito L, Bancalero-Romero C, Hans-Chacon A, Gonza´lez-Moreno JM, Baena- Baldomero A, Ruı´z-Doblado S.

[53]

[54] [55]

[56] [57]

[58]

[59]

[60] [61]

[62]

[63] [64] [65] [66] [67] [68] [69]

[70]

[71] [72]

[73] [74]

15

Delirio paranoide de los ciegos (sı´ndrome de Sanchı´sBanu´s). Psiquiatr Biol 2012;19:95–8. Sanchı´s Banu´s J. Contribucio´n al estudio del ‘‘corea cro´nico hereditario’’ de Huntington. Resumen general con motivo de los primeros casos espan˜oles. Los Progresos Clı´n 1923;25:221–42. Gime´nez, -Rolda´n S. The history of Huntington disease in Spain: first observations. Neurosci Hist 2013;1:71–9. Ferna´ndez Sanz E. La instalacio´n de departamentos neuropsiquia´tricos en los Hospitales Generales. Arch Med, Cir Especialidades 1933;8:237–9. Genton P. Lafora’s disease (EPM2A). Rev Neurol 2007;163:47– 53. Moya G, Gonzalo R. Lafora: medicina y cultura en una Espan˜a en crisis. Cantoblanco, Madrid: Ediciones de la Universidad Auto´noma de Madrid; 1986. Rodrı´guez Lafora G, Glueck B. Beitrag zur Histopathologie der myoclonischen Epilepsie. Zeitscrift fu¨r die gesamte der Neurol Psychiatr 1911;6:1–15. Kaplan M, Henderson AR, Solomon Carter Fuller MD. (1872– 1953) American pioneer in Alzheimer’s disease research. J Hist Neurosci 2000;9:250–61. Rodrı´guez Lafora G. Un caso de tumor del cuerpo calloso sin dispraxia izquierda. Arch Neurobiol 1920;1:45–9. Rodrı´guez Lafora G, Prados M. Investigaciones experimentales sobre la funcio´n del cuerpo calloso. Arch Neurobiol 1921;2:363–83. Rodrı´guez Lafora G. Sı´ndrome aparentemente ‘‘irreversible’’ de diskinesias consecutivas al uso prolongado de preparados fenotiacinicos. Arch Neurobiol 1968;31:3–20. Lewy Rodrı´guez E. Ası´ era Cajal. Coleccio´n Austral. S.A., Madrid: Espasa Calpe; 1977: 133. Villaverde (De) JM. La epilepsia. Biblioteca de El Siglo Me´dico. Madrid: Monografı´as VIII; 1930. Lo´pez Zano´n A. La historia de un Servicio. Cuadernos Madrilen˜os Psiquiatr 1971;11:1–51. Rodrı´guez Lafora G. La encefalitis leta´rgica en Espan˜a. Arch Neurobiol 1920;1:209–25. Villasante Armas O, Rey Gonza´lez A, Martı´ Bosca` JA. Jose´ M Villaverde: retrato de un desconocido. Med Hist 2008;1:1–15. Rodrı´guez Arias B. R. Alberca Llorente, ‘‘In memoriam’’. An Med Cir 1968;48:105–11. Alberca R, Neuraxitis ectotropas. Estudio clı´nico, etiopatoge´nico, histopatolo´gico y terape´utico. Madrid: Ediciones Morata, Ciencias Biolo´gicas; 1943. Huertas R, Del Cura MI. Deficiency neuropathy in wartime: the ‘‘paraesthetic-causalgic syndrome’’ described by Manuel Peraita during the Spasnish Civil War. J Hist Neurosci 2010;19:173–81. Peraita M. Deficiency neuropathies observed in Madrid during Civil War (1936–1939). Brit Med J 1946;2(4481):784. Peraita M. Las mielopatı´as funiculares carenciales (grupo de la pelagra). Madrid: Consejo Superior de Investigaciones Cientı´ficas; 1949. Dı´az JL. El legado Cajal en Me´xico. Rev Neurol (Barc) 2009;48:207–15. Gime´nez-Rolda´n S. Dionisio Nieto (1908–1985). Arch Neurobiol 1985;48(49):99–112.