Albert Pitres: Charcot's Brilliant Student - Karger Publishers
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Historical Note Eur Neurol 2022;85:245–251 Received: September 1, 2021 Accepted: December 13, 2021 DOI: 10.1159/000521526 Published online: March 21, 2022 Albert Pitres: Charcot’s Brilliant Student Emmanuel Drouin a Yann Pereon b Marta Pasquini a Patrick Hautecoeur a aService de Neurologie, Groupe Hospitalier de l’Institut Catholique de Lille, GHICL, Lille, France; bCHU Nantes, Centre de Référence Maladies Neuromusculaires Rares Atlantique-Occitanie-Caraïbes – FILNEMUS, Hôtel-Dieu, Nantes, France Keywords Medical Education History of neurology · Albert Pitres · Jean-Martin Charcot · Bordeaux · Cerebral localization · Hypnotism Jean Marie Marcel Albert Pitres was born in Bordeaux on August 26, 1848. He was the son of Jean Adolphe Pi- tres (1804–1880), landowner, and Madeleine Coraly Abstract Rousseille (1820–1892), grocer. He was a college student Albert Pitres (1848–1928) was an internist, neuropsychiatrist, in Bordeaux, and then began his medical studies at Bor- professor of anatomy, pathology, and histology. He never deaux secondary Medical and Pharmaceutical School in really had a biography in English. However, the develop- 1866. At the end of 1866, Pitres received as an end-of-year ment of neurology and neurosciences in Bordeaux owes a excellence prize, the book by Vulpian [1] (1826–1887) lot to him, as to the psychiatrist Emmanuel Régis (1855– published in 1866, “Leçons sur la physiologie générale et 1918). The fact that his career was so closely linked with comparée du système nerveux, faites au Muséum d’Histoire Charcot (1825–1893) should have secured him a more prom- Naturelle” (Lessons on general and comparative physiol- inent place in neurology and the history of aphasiology. Pi- ogy of the nervous system, made at the Natural History tres went on to co-author clinical and experimental research Museum), lessons taught in 1864. Reading this book had papers with Charcot that are considered some of the most a decisive influence on his medical orientation. notable ones among Charcot’s publications. Both carried out He performed his residency at Saint-André Hospital in studies about pathological correlations between cortical le- Bordeaux from 1867 to 1869. Pitres was ranked 95th as sions and hemiplegia, published series of articles and two non-resident student of the hospitals of Paris in 1871, major books about neurophysiology of motor control. To then 8th in the resident contest in 1872. He was then res- convey the atmosphere and the importance of the neuro- ident with Polaillon in 1873 at Cochin (semester 1), with logical clinic of Pitres in the heyday, we illustrate this article Demarquay in 1873 at the Maison de Santé (semester 2), with unpublished photos of him. © 2022 S. Karger AG, Basel Jacques-Joseph Moreau of Tours (1804–1884) in 1874 at the Salpêtrière Hospital, Charles-François Matice at Karger@karger.com © 2022 S. Karger AG, Basel Correspondence to: www.karger.com/ene Emmanuel Drouin, emmanuel.drouin @ univ-catholille.fr
to cerebral histology by Louis Antoine Ranvier (1835– 1922) at the Collège de France as an assistant and to Phys- iology by Etienne Jules Marey (1830–1904) in the com- pany of Charles Emile François (1849–1921), deputy di- rector of Marey. The competition with the German school of neurology following French defeat in 1870, in the race for cerebral localizations, reflects the spiteful spirit that served as a driving force for numerous researches in neurology Pi- tres, who fought in the war of 1870 as an auxiliary doctor, clearly expresses this spirit of revenge which serves as a driving force for much research. Consequently, regarding the defeat in the War of 1870, Pitres declares: “I felt strong- ly how the burden of defeat weighs on a defeated nation. I was repeatedly offended by the judgments I heard about the glory of the mightier Germany and the well-deserved lesson it was openly said that France had just received. I understood then that each young Frenchman should use all the means in his power to restore to his country the consid- eration and the prestige which it had lost and that everyone Fig. 1. Cover page of Albert Pitres’ medical doctorate thesis. had the duty to work, not only for their own well-being but for the recovery of their country” [5]. Having been deputy assistant at the Medical School of Paris in 1877 and 1878, Pitres [6] was accepted for the Beaujon in 1875 and Charcot again at the Salpêtrière Hos- agrégation in the competitive examination in 1878, the pital in 1876. He was tutor at the École Pratique des year of the founding of Bordeaux Medical School on the Hautes Études from 1877 to 1878. topic: “Des hypertrophies et des dilatations cardiaques, in- Charcot and Pitres worked on cerebral localizations dépendantes des lésions valvulaires” (Independent heart from 1876. A that time, scientific study of cerebral loca- enlargement and dilations of valvular lesions) (Fig. 2). tions was recent with Paul Broca (1824–1880) in 1861 and In 1878, Henri Gintrac (1820–1878), dean of the Med- David Ferrier (1843–1928) in 1879 “De la localisation des ical School, asked the young associate professor, who had maladies cérébrales” (On the localization of brain diseas- been his pupil and resident at the Saint-André Hospital es). Earlier, in 1870, Gustav Theodor Fritsch (1838–1927) in 1869, to return to Bordeaux. But Pitres was very reluc- and Eduard Hitzig (1838–1907), had provided experi- tant to leave Paris and to return to the banks of the Gi- mental support for John Hughlings Jackson’s (1835– ronde. Indeed, his father had died young, and his mother 1911) hypothesized motor area in the cortex. Their origi- had limited resources. The young Pitres had to support nal experiments would later be replicated by the English- his brothers’ education through a “very enviable” career man David Ferrier (1843–1928). Charcot and Pitres in Bordeaux. He therefore left for Bordeaux. expanded these results and this led to Pitres’ [2] doctoral In 1879, Pitres (Fig. 3) was nominated to the chair of thesis entitled “Recherches sur les lésions du centre ovale pathological anatomy and histology at Bordeaux Medi- des hémisphères cérébraux, au point de vue des localisa- cal School. He was in charge of the course of general tions cérébrales” (Research on lesions of the oval centre of Anatomy and Histology. He was a doctor at Bordeaux the cerebral hemispheres studied from the point of view hospitals in the 1878 competition, then professor of of cerebral localizations) (Fig. 1). For review, see [3, 4]. medical clinic in Bordeaux, succeeding Professor Jules Pitres [2] defended his doctoral thesis in May 1877, Mabit (1809–1881), on March 10, 1881, where he re- under the supervision of Charcot. In his work, he at- mained until 1919. tempted to clarify the role of the ovale centrum. It was on In 1885, at the age of 37, Rector François Ouvre (1824– this occasion that he made serial frontal cuts of the brain, 1890) called on Pitres to take charge of the deanery of “Coupes de Pitres” (Pitres cuts), where centrum ovale le- Bordeaux Medical School. He was elected dean, “almost sions can be identified. In parallel, Pitres was introduced in spite of himself,” replacing Paul Denucé (who had re- 246 Eur Neurol 2022;85:245–251 Drouin/Pereon/Pasquini/Hautecoeur DOI: 10.1159/000521526
3 2 Fig. 2. Cover page of the aggregation in the competitive examination of 1878. Fig. 3. Portrait of Prof. Albert Pitres. tired from active life for health reasons) and would re- the crust of the hemispheres of the brain) performed with main so for a little over 20 years. As dean, Pitres saw high Charcot and Pitres [10]. and far. He was keen to create teaching of medical speci- In 1883, based on 200 cortical lesions in humans col- alities, in the form of complementary courses. lected from 1879 to 1882, Pitres and Charcot [11] pub- lished a 120 pages thesis entitled “Critical and clinical study of the doctrine of motor localizations in the cerebral Scientific Contribution hemispheres of man” to convince the last “hesitators.” Pi- tres and Charcot emphasized the function of the grey and At the time of Pitres and Charcot, two important ques- white matter, the geographical distribution of the areas of tions regarding central nervous system physiology and the cerebral mantle that serve to control the muscles of pathology preoccupied the scientific world. Firstly, the the life of relationship. They were the first to conclusively use of cerebral localization doctrine in clinical routine show that damage to the human motor cortex causes de- was urgently needed [7, 8]. Then, neurologists were inter- generation of the pyramidal tracts and lateral columns of ested in the precise detailed, scientific description of hys- the spinal cord. teria and hypnotism. His publications on hysteria and Pitres’ [12] “ Leçons sur l’hystérie et l’hypnotisme faites hypnotism marked a moment in the history of neurology. à l’hôpital Saint-André de Bordeaux” (Clinical lessons on As early as 1877, in collaboration with Charcot, Char- hysteria and hypnotism given at Saint-André Hospital in cot and Pitres [9] published a new study on “Contribution Bordeaux), published in 1891, were given from 1884 to à l’étude des localisations dans l’écorce des hémisphères du 1890 and had legitimate impact in France and abroad. cerveau” (Contribution to the study of localizations in the These lessons were prefaced by Charcot, who found there crust of the hemispheres of the brain) in the monthly an opportunity to justify his quarrel with the Nancy Journal of Medicine and Surgery. The file of cerebral lo- School of Hippolyte Bernheim (1840–1919). Moreover, calizations increased with new studies in 1878 and 1879 Charcot was pleased that “the hysteria observed in Paris with the “Nouvelles contributions à l’étude des localisa- was of the same nature as in the provinces.” In fact, Bern tions motrices dans l’écorce des hémisphères du cerveau” heim set up the School of Nancy, or School of Suggestion, (New contributions to the study of motor localizations in as opposed to the Charcot’ School of Salpêtrière. Bern- Albert Pitres: Charcot’s Brilliant Student Eur Neurol 2022;85:245–251 247 DOI: 10.1159/000521526
image putative centres. Thus, according to Pitres [17], amnesic aphasia can exist without lesion in Broca’s area: it is caused by the loss of evocation of words and could be less serious than motor aphasia. Coming from Paris, Emmanuel Régis (1855–1918) gave lectures on mental diseases in Bordeaux. He can be considered as the founder of the Bordeaux neuropsychi- atric school. He began his studies in Toulouse, then in Paris, where he was an intern and Clinical head at Saint Anne Hospital with Benjamin Ball (1833–1893). In 1894, he proposed the term “dreamlike” to account for acute hallucinatory states, including mental confusion. Pitres and Régis [18] published “Obsessions et impulsions” in Fig. 4. Facade of the Holy André hospital in Bordeaux at the time 1902. They defined obsessions as “a morbid syndrome of Pitres. characterized by the anxious experience of parasitical thoughts and feelings, and leading to some psychical dis- sociation whose final stage is a splitting of the conscious personality” (p. 16). They defended this emotivist view at heim defined hypnosis as simple sleep produced by sug- the 12th International Congress of Medicine in Moscow gestion and susceptible to therapeutic applications. In in 1897. At the request of Pitres, Régis was appointed this, he disagreed with Charcot who considered hypnosis holder of the Bordeaux chair in mental pathology from as a pathological state specific to hysterics. 1913 to 1918 at the Saint-André hospital. Régis was in- Neurological patients were sent from all over the world creasingly close associate of Pitres. Régis published the to Pitres’ department at the Saint-André Hospital in Bor- “Practical manual of mental medicine” in 1885, consid- deaux. On each occasion, he led his students to publica- ered a reference manual in France. tions of which he left the honour but of which he was the Pitres had already taken part in the France-Prussia inspiration. Pitres carried out his scientific research, his 1870 war. He was particularly interested in the stumps of clinical work, and his administrative work at the deanship amputees [19], having already tried to assess pathophysi- at the same time. At that time, Bordeaux Medical School ology of soldier phantom limbs. Pitres [20] chose a pe- (Fig. 4) was the second largest in the province in terms of ripheral explanation linked to the abnormal excitability number of students. Pitres also created outpatient clinics, of the nerve endings of the stump (1897), very close to the research laboratories in the hospital, and new chairs of actual mechanisms. Another later explanation referred to medical clinics. the spontaneous stimulation of cortical areas representa- Many of his lessons in amphitheatre have been gath- tive of the lost limb. Lhermitte [21] (1877–1959) empha- ered into books. Although Pitres’s activities in the field of sized the role of body image in explaining this phenom- Neurology were far-flung, his favourite subject was apha- enon. During the First World War, despite his age, Pitres sia [13]. In 1884, he published the first detailed clinical was given the task of directing South West neurological case study of pure agraphia [14]. He is mentioned in the centre (XVIIIth military area). Together with the anato- aphasia literature primarily with regard to his 1895 paper mist Léo Testut and Pitres [22] (1849–1925), he wrote a on polyglot aphasia “Étude sur l’aphasie chez les poly- masterly work on “Les nerfs en schémas, Anatomie et glottes” [15]. Ten years after he published his paper on physiopathologie” (The nerves layout. Anatomy and pure agraphia, he gave a talk at the Congrès Français de pathophysiology) and “Peripheral neuritis” in collabora- Médecine Interne in Lyon [16]. At this meeting, he took tion with Louis Vaillard (1850–1935) in 1885 (Félix Al- the opportunity to launch a detailed attack toward the can). In 1895, Charcot and Pitres [23] work on “Centres Holists such as Marie and toward Bernheim who ques- moteurs corticaux chez l’Homme” (Cortical motor centres tioned the existence of focal disorders. His description of in man) was published. agraphia has become famous. Pitres’ observations on amnesic aphasia were also fa- Pitres Got Also Interested in Epilepsy mous. He hypothesized that amnesic aphasia depends on At Bordeaux Medical Congress in 1895, he took up the breakdown of pathways between memory and verbal Charcot’ definition, describing it as “a morbid episode, 248 Eur Neurol 2022;85:245–251 Drouin/Pereon/Pasquini/Hautecoeur DOI: 10.1159/000521526
Fig. 6. The neurological team of Prof. Albert Pitres at the Bordeaux hospital. Fig. 5. The neurological team of Prof. Albert Pitres at the Bordeaux hospital. Pitres reviewed the notion of psychasthenia first de- scribed by Pierre Janet. The latter specified that it is an abulic behaviour (difficulty in acting) associated with ob- sessive ideas and inhibitions. Janet also mentioned “feel- occurring by fits, in which the patient, obeying sudden ings of incompleteness,” manias or phobias. Pitres [27] and irresistible impulse, abruptly leaves the home and specifies that it can indeed be a question of a loss of the wanders around for a longer or shorter time. After the function of the real but also of disturbances related to. In end of the impulse, he returns home and lives there peace- 1883, Charcot came to visit Pitres in Bordeaux. Pitres fully until another attack causes a runaway, as unpredict- having only modest premises to show his professor, Char- able and as irrational as the previous one.” cot replied: “It doesn’t matter about the premises, what Charcot made “automatism” a mechanism common matters is to make pupils.” to many situations, including pre-existing phenomena, Indeed, Pitres succeeded in doing so with great suc- traumatic amnesia, non-convulsive epilepsies, and sleep- cess, constituting a kind of chief-of-staff full of dedication walking. For Charcot, epileptic patients may have auto- (Fig. 5, 6). Pitres regularly asked his students to make clin- matic behaviours after seizures and, “under the influence ical observations and read them at the patient’s bed. of terrible dreams, become violent, break things, destroy Pitres was charged with all kinds of honours. He was everything …” Pitres [24, 25] described the case of a pa- corresponding member (from 1888) and national associ- tient presenting with Jacksonian epilepsy with paroxys- ate member (from 1898) of the French Academy of Med- mal tachycardia of epileptoid nature (1894), ambulatory icine. In addition, he was secretary of the Anatomical So- automatism in relation to epilepsy (1896) and on the se- ciety, correspondent of the Biology Society of Paris in miological value of Jacksonian epilepsy in the topograph- 1878, honorary member of the Anatomical Society of ical diagnosis of brain lesions (1901). Here, Pitres was Paris in 1878, corresponding member of the Medico-Psy- back to motor cortex localization research. chological Society, correspondent of the Academy of In 1889, Charcot entrusted the management of the Moral Sciences for the section of Philosophy. He was psychology laboratory at La Salpêtrière to Pierre Janet elected and introduced as a resident member of the Acad- (1859–1947), one of his students Janet [26] wanted to emy of Sciences, Belles Lettres and Arts1 of Bordeaux dur- combine medical studies with philosophical studies to try ing the session of March 20, 1890, by Mr Berchon (Vice to clinically analyse the mental state of the hysterical pa- President). He succeeded to this title to Henri Gintrac and tient. In her studies on “The Mental State of the Hyster- Paul Denucé. ics,” Janet was largely influenced by the work of Pitres on this subject. 1 This Academy has always greatly appreciated medical studies. Albert Pitres: Charcot’s Brilliant Student Eur Neurol 2022;85:245–251 249 DOI: 10.1159/000521526
of nervous and mental diseases was transmitted to Jean Abadie (1873–1946), then to Paul Delmas-Marselet (1898–1977). Finally, the sign of Pitres is related to sock hypoesthe- sia observed in tabes dorsalis. This sign was jointly de- scribed by Pitres and Abadie in the “Ostéopathies du tabès.” Jean Abadie (1873–1946), well known in the field of epileptology, became the holder of the clinical chair of mental illnesses after Pitres in 1919. He was, according to Jean Lhermitte who delivered his praise to the Academy of Medicine, one of the most brilliant and illustrious rep- resentatives of French neurology. Later, the chair was transmitted to Paul Delmas-Marselet (1898–1977). In a quite different field, the sign of Pitres penny made pos- sible the diagnosis of pleural effusion, by striking two bronze pennies on the thorax and by placing the ear on the opposite side. Pitres died in Bordeaux, his native city, at the age of 80 (Fig. 7), after falling down a flight of stairs. He remained revered in Bordeaux as a clinical professor but also as Fig. 7. Portrait of Prof. Albert Pitres during his retirement. Dean, the second founder of the Medical School. He had an exceptional capacity for work, no less exceptional teaching qualities, and the art of revealing intelligence. The medal pressed at the request of his students in 1919, The latter recalled that the young Professor Pitres had upon his retirement, was designed by Paul Richer (1849– conquered a high scientific position in the Medical School 1933), another student of Charcot at La Salpêtrière. within the University of Bordeaux. Pitres was one of the Presidents of the Academy of Bordeaux. He was succes- sively elevated to the rank of Knight (April 25, 1888, Min- Acknowledgments istry of Public Instruction), Officer (January 2, 1904, We would like to thank for their help: Mr. Yann Bubien, Gen- Ministry of Public Instruction), and finally Commander eral Director of the Bordeaux University Hospital, Mr. Damien of the Legion of Honour (Pasteur promotion, August 9, Blanchard at the National Academy of Medicine and Mr. Frédéric 1913, Ministry of the Interior). He was made Officer of Laux, Director of the Bordeaux Archives. Special thanks to Pr Public Instruction on January 10, 1892, laureate of the Jacques Poirier for his help. All figures in this article are from the Institute in 1887 (Lallemand Prize) [28]. Pitres loved his own collection of Dr. Emmanuel Drouin. students. He regularly invited them to his home in the presence of his wife. They lived in a beautiful building, Statement of Ethics acquired in 1888, located at 119 Cours d’Alsace-Lorraine in Bordeaux. All his students showed him a grateful affec- This work required no approval from an institutional review tion in all circumstances. From 1881, Pitres had 14 assis- board and was prepared in accordance with ethical guidelines of tants. He was 39 times the President and 25 times member the journal. of MD thesis jury between 1890 and 1897. He would be the President of the Jury for René Cruchet (1875–1959) MD thesis in 1902, which introduced the initial form of Conflict of Interest Statement cognitive behavioural treatments of tics and Tourette’s The author has no conflicts of interest to declare. Syndrome. Cruchet considered tics as a functional disor- der between cortex and basal ganglia with precognition [29]. His therapeutical approach involved conscious Funding Sources mental control upon ventilation in order to inhibit tics with breathing gymnastics. After Albert Pitres, the chair No funding was obtained for this work. 250 Eur Neurol 2022;85:245–251 Drouin/Pereon/Pasquini/Hautecoeur DOI: 10.1159/000521526
Author Contributions Data Availability Statement Emmanuel Drouin, Yann Pereon: design. Marta Pasquini: All data generated or analysed during this study are included proofreading and design. Patrick Hautecoeur: supervision. in this article. Further enquiries can be directed to the correspond- ing author. References 1 Vulpian A. Leçons sur la physiologie générale 11 Charcot JM, Pitres A. Etudes critique et cli- 20 Pitres A. Etudes sur les sensations et illusions et comparée du système nerveux, faites au nique de la doctrine des localisations céré- des amputés. Ann Méd Psychol. 1897;4: 542– muséum d’histoire naturelle. Paris: G. Bail- brales dans l'écorce des hémisphères céré- 6. lière; New-York: Baillière Brothers; 1866. braux de l’homme. Germer Baillière; 1883. 21 Lhermitte J. L’image de notre corps. Paris: 2 Pitres A. Recherches sur les lésions du centre 12 Pitres A. Leçons sur l’hystérie et l’hypnotisme Nouvelle Revue Critique; 1939. ovale des hémisphères cérébraux, au point de faites à l’hôpital Saint André de Bordeaux. 22 Pitres A, Testut L. Les nerfs en schémas. Anat- vue des localisations cérébrales. Paris: Bureau Paris chez Octave Doin; 1891. Tome 1, 531 omie et physiopathologie. Doin; 1925. p. 706. du Progrès Médical, Adrien Delahaye; 1877. pages. Tomes 2, 551 pages. 23 Charcot JM, Pitres A. Centres moteurs corti- 3 Walusinski O. Les 33 internes de Charcot à la 13 Pitres A. L’aphasie amnésique et ses variétés caux chez l’Homme. Paris: Rueff; 1895. Salpêtrière de 1862 à 1893. Oscitatio; 2021. cliniques. Le Progrès Médical; 1898. série III 24 Pitres A. L’automatisme ambulatoire dans ses 4 Bogousslavsky J, editor. Following Charcot: a 7: 321–324/337–340/369–371/401–404/série raports avec l’épilepsie : le vagabondage forgotten history of neurology and psychiatry III 8:17–23/65–70. pathologique. Congrès des aliéniste et neurol- (frontiers of neurology and neuroscience, 14 Pitres A. Considérations sur l’agraphie. Revue ogists de Bordeaux; 1895. Vol. 29). Basel: Karger; 2011. p. 9–35. Méd. 1884:855–73. 25 Pitres A. De la valeur sémiologique de 5 Pitres A. Journal de Médecine de Bordeaux. 15 Pitres A. Étude sur l’aphasie chez les poly- l’épilepsie jacksonienne dans le diagnostic 1919 Nov 10. p. 478. glottes. Revue Méd. 1895;15:873–99. topographique des lésions cérébrales. Bor- 6 Pitres A. Des hypertrophies et des dilatations 16 Pitres A. Rapport sur la question des aphasies. deaux: G. Gounouilhou; 1901. cardiaques, indépendantes des lésions valvu- Congrès français de médecine interne, session 26 Janet P. L’État mental des hystériques. Biblio- laires. Paris: Germer-Baillière; 1878. de Lyon; 1894. thèque médicale Charcot-Debove. Paris: 7 Charcot JM. Des localisations dans les mala- 17 Pitres A. L’Aphasie amnésique et ses variétés Rueff et Cie; 1894. Vol. 2. I. Les stigmates dies cérébrales. Progrès Méd. 1875; 3(17): cliniques, leçons faites à l’hôpital St-André de mentaux, 1893. II. Les accidents mentaux, 218–20. Bordeaux par le Pr A. Pitres, et recueillies par 1894. 8 Charcot JM. Leçons sur les localisations dans J. Abadie. Paris: Progrès Médical; 1898. 27 Pitres A. La psychasténie. Ann Psychol. 1903; les maladies du cerveau et de la moelle épin- 18 Pitres A, Régis E. Les obsessions et les impul- 10:284–95. ière. Paris: Adrien Delahaye; 1876. sions. Paris: Octave Doin; 1902. 28 Cérémonie en l’honneur de Mr le Professeur 9 Charcot JM, Pitres A. Contribution à l’étude 19 Pitres A. Étude sur les sensations illusoires des Pitres lors de la remise de la cravate de com- des localisations dans l’écorce des hémi- amputés. Annales Médico-Psychologiques; mandeur de la légion d’honneur. Journal de sphères du cerveau. Paris: Librairie Germer 1897. série VIII 5: 5–19/177–192. Médecine de Bordeaux; 1919 Oct 10. p. 473–8. Baillière et Cie; 1877. 29 Cruchet R. Étude critique sur le tic convulsif 10 Charcot JM, Pitres A. Nouvelle contribution et son traitement gymnastique (méthode de à l’étude des localisations motrices dans Brissaud et méthode de Pitres). Bordeaux: l’écorce des hémisphères du cerveau. Paris: Gounouilhou; 1902. Revue mensuelle de Médecine et de Chirur- gie; 1878. Vol. 23; p. 801–15. Albert Pitres: Charcot’s Brilliant Student Eur Neurol 2022;85:245–251 251 DOI: 10.1159/000521526
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