Abstract

Background:Giuseppe Gradenigo (1859–1926), a legendary figure of Otology, was born in Venice, Italy. He soon became a pupil to Adam Politzer and Samuel Leopold Schenk in Vienna, demonstrating genuine interest in the embryology, morphology, physiopathology, as well as the clinical manifestations of ear diseases. In this paper, the authors attempt to highlight the major landmarks during Gradenigo's career and outline his contributions to neurosciences, which have been viewed as looking forward to the 20^th century rather than awkward missteps at the end of the 19^th.

Methods:Several rare photographs along with many non-English, more than a century old articles have been meticulously selected to enrich this historical journey in time.

Results:It was after Gradenigo that the well-known syndrome consisting of diplopia and facial pain due to a middle ear infection was named. However, Gradenigo was much more than a syndrome. Surprisingly, despite the fact that he is considered a pioneer of the Italian Otology of the late 19^th and early 20^th century, little is written of his life and his notable achievements in the English literature.

Conclusions:Even though his name lives on nowadays only in the eponym “Gradenigo's syndrome,” his accomplishments are much wider and cast him among the emblematic figures of science. His inherent tendency for discovering the underlying mechanisms of diseases and his vision of guaranteeing quality of services, professional proficiency, respect, and dedication toward the patients is in fact what constitutes his true legacy to the next generations.

Keywords: Audiology, Giacomo Puccini, Giuseppe Gradenigo, Otology, Primo Dorello, syndrome

THE BEGINNING

On Thursday, September 29th, 1859, Giuseppe Gradenigo (1859–1926) [ Figure 1 ] was born in Venice (Italy).[ 4 7 8 37 40 ] Gradenigo descended from a long line of powerful Venetians, numbering 14 procurators, 3 Doges, 2 cardinals, and several diplomats.[ 8 37 ] In fact, Pietro Gradenigo (1251–1311) was a Doge (1289–1311) when Marco Polo returned from the Orient in 1294.[ 37 ] Giuseppe Gradenigo's family roots can be traced back to the 7^th century with the most acceptable region of origin being the area between Grado and Aquileia in the northwestern Italy.[ 37 ]

Figure 1

Photographs of Count Giuseppe Gradenigo, MD (1859– 1926). (a) Gradenigo in his middle age (Reprinted with permission from Felisati D, Sperati G: Italian ORL Society. Past and Present. Genova: Tipografia Mengotti Carlo & c. snc, 2005).[ 7 ] (b) Gradenigo in his later years (Reprinted with permission from Felisati D, Sperati G: Gradenigo's syndrome and Dorello's canal. Acta Otorhinolaryngol Ital 29:169-172, 2009)[ 8]

He was the eldest child of Ernesta Conto and Pietro Gradenigo (1831–1904) who was an influential Professor of Clinical Ophthalmology at the University of Padova.[ 4 8 37 ] Pietro Gradenigo had served in the rebellion against the Austrian-ruled kingdom of Lombardy-Venice, during which his brother (Giuseppe) had died.[ 37 ]

MEDICAL TRAINING

At the age of 18 (1877), Gradenigo was admitted to the University of Padova, from where he graduated in 1883.[ 4 7 ] Considering his father's advice, he turned to Otology, working in Vienna under Adam Politzer (1835–1920),[ 35 40 ] and Samuel Leopold Schenk (1840–1902) on the embryology of the ear.[ 40 ] Actually, his very first research was devoted to this topic.[ 2 37 ] While in Vienna, Gradenigo met the Hungarian-Austrian anatomist Emil Zuckerkandl (1849–1910) who at that time was appointed assistant professor at the local university, and maintained correspondence with him for more than 20 years.[ 7 ]

APPOINTMENTS

After his studies in Vienna, Gradenigo returned to Padova where in 1888 he was nominated Libero Docente (private professor).[ 4 35 37 ] One year later, on 1 June 1889, he became Head of the Department of Otolaryngology of the Turin's Polyclinic and subsequently (1890)[ 4 40 ] founded the University Clinic in the same town. It was in that clinic that Gradenigo established a training program, one of the firsts in Italy, in Otolaryngology and insisted on integrating this program in the formal university curriculum. In 1908, he wrote: “Diseases of organs as important as ears, nose and throat are still not included in the compulsory teaching program… continuing to consider the study of a Specialty as an optional, is the equivalent of recognizing that it is of limited value.”[ 7 ] Yet, only in 1929, Otorhinolaryngology (ORL) was finally assigned to the 4th year of medical studies as an obligatory course.[ 35 ]

During this period, for his clinical practice, 10 beds for hospitalization and surgery in a General Surgery Clinic directed by A. Carle were at his disposal.[ 4 ]

On 13 February 1896, Gradenigo was nominated Professore Straordinario (newly appointed professor) of Otology in Turin [ Figure 2 ].[ 4 5 35 ] In 1902, he was ranked first for the Chair of ORL in the University of Rome, but he chose to refuse the new position.[ 4 ] On 24 March 1910, Gradenigo was appointed Professore Ordinario (full professor) in Turin.[ 4 7 37 ] The next year (1911) he declined an invitation extended by the Medical School of Naples to succeed Professor Vincenzo Cozzolino (1853–1911), another student of Politzer.[ 4 ] However, 6 years later (1917), he was appointed Professor of Clinical Otolaryngology in Naples after the death of Ferdinando Massei (1847–1917).[ 4 7 37 40 ]

Figure 2

Photograph of an extract (page 63) from Chironi's Annuario Della R. Università di Torino 1903–1904. Anno 500o dalla fondazione (Yearbook of the R. University of Turin 1903–1904. 500th year from establishment), printed in Turin, 1904. In the first table (number 9), Giuseppe Gradenigo is demonstrated as “Professore Straordinario”[ 5]

With the support of 20 Italian colleagues, Gradenigo founded in 1891 the Italian Society of Laryngology, Otology and Rhinology (La Società Italiana di Laringologia, Otologia e Rinologia – SILOR) [ Figure 3 ].[ 7 35 ] He served as President of this society twice but not in consecutive terms (1897–1900 and 1925-1926).[ 7 37 ] In 1893, Gradenigo together with Professor Emilio De Rossi (1844–1902) launched the journal Italian Archives of Otology, Rhinology and Laryngology (Archivio Italiano di Otologia, Rinologia e Laringologia) [ Figure 4 ],[ 4 7 35 40 ] and in 1902, he founded together with Oskar Brieger (1914†) from Breslau (Germany) the Central Journal for Otology (Zentralblatt für Ohrenheilkunde) in which they were co-editors until the beginning of the First World War.[ 4 37 40 ]

Figure 3

Photograph of Count Giuseppe Gradenigo, taken during the 5^th Congress of the Italian Society of Laryngology, Rhinology and Otology (SILOR), Naples, April 1900 (front row, the second from the right) (Reprinted with permission from Felisati D, Sperati G: Italian ORL Society. Past and Present. Genova: Tipografia Mengotti Carlo & c. snc, 2005)[ 7]

Figure 4

Photograph of the title page of Archivio Italiano di Otologia, Rinologia e Laringologia (Italian Archives of Otology, Rhinology and Laryngology) (Reprinted with permission from the website “Maremagnum.com”)

During this war, he founded together with C. Biaggi and A. Stefanini the Italian Society of Experimental Phonetics (Società Italiana di Fonetica Sperimentale).[ 4 37 ] Gradenigo was actively involved in numerous associations [ Table 1 ] and received several prestigious awards [ Table 2 ].[ 4 7 8 37 ]

Table 1

Gradenigo's membership in medical associations[ 4 7 8 37]

Table 2

Gradenigo's awards[ 4]

THE GRADENIGO HOSPITAL

In 1899, the limited resources of the public hospitals forced Giuseppe Gradenigo to establish in Turin a private Clinic (Ospedale Gradenigo) with 70 beds to provide treatment to the poor ear, nose, and throat (ENT) patients.[ 4 35 ] The official inauguration was held on 29 January 1900.[ 4 37 ] During the First World War, he granted the clinic as well as his villa in Lancenigo (Treviso, Italy) to the Italian army. Along with this clinic, a post-graduate school was also established at that time.[ 4 6 ]

Since then, the Sisters of Charity (Figlie della Carità) of San Vincenzo de’ Paoli have been the cornerstone of the hospital management “with generosity, passion, and far-sightedness.” It was for this reason that Gradenigo wanted them to inherit the hospital after his death.[ 6 37 ]

Nowadays, the Gradenigo Hospital has become much larger. Over the course of time, a unit of general medicine, a surgical unit, and an emergency ward have been added to the initial ENT unit.[ 6 ]

GRADENIGO AND GIACOMO PUCCINI

Gradenigo had the unfortunate privilege to meet Giacomo Puccini (1858–1924), the Italian composer of various famous operas such as La bohème (1896), Tosca (1900), and Turandot (1924).[ 30 ] In February 1924, the composer began suffering from hoarseness, difficulty in swallowing, persistent cough, and cervical swelling. After having consulted many famous professors of his time at Florence, among whom were Camillo Torrigiani (1881–1946) and Addeo Toti (1861–1935), he finally turned to Gradenigo who was then a professor at the University of Naples.[ 30 ] Puccini wrote to his good friend and also general director of his publisher (BMG Ricordi) Carlo Clausetti: “il mio male è papilloma, non grave, ma bisogna levarselo e presto; è situato sotto l’ epiglottide. Ho telegrafato al Prof. Gradenigo… vedremo il responso del Gradenigo” (my bad papilloma is not serious, but we must get rid of it and immediately as it is located below the epiglottis. I telegraphed to Professor Gradenigo… we will see the response of Gradenigo).[ 31 ]

Indeed, on 2 November 1924, Professors Gradenigo, Torrigiani, and Toti visited Puccini and performed a laryngeal biopsy. Gradenigo promptly suggested that he should go to Dr. Louis Ledoux's Clinic in Brussels, where laryngeal cancer was treated by radium therapy. In the words of Gradenigo: “…macché Firenze! Vada a Bruxelles. Lì il radium fa miracoli. Le darò io una lettera per il Prof. Ledoux. Un tumoretto… Andrà via tutto” (…not in Florence! Go to Brussels. There, radium makes miracles. I’ll give you a letter for Professor Ledoux. A little tumor… It will all go away).[ 31 ]

Unfortunately, Puccini prophetically anticipated the end; just a few days before leaving for Brussels, in a discussion with the conductor Arturo Toscanini (1867–1957), he stated concerning his unfinished opera Turandot: “L’ opera verrà rappresentata incompleta, e poi qualcuno uscirà alla ribalta e dirà al pubblico: ‘A questo punto il maestro è morto’” (the opera will be presented incompletely, and then somebody will come before the audience and say: ‘at this point the maestro is dead’”).[ 31 ] At 11:30 a.m. of 29 November, Puccini passed away.

SCIENTIFIC CONTRIBUTIONS

Gradenigo occupies a unique position in the world of medicine and his work reflects a wide spectrum of physiological and clinical research.[ 7 8 37 ] Besides History of Medicine,[ 4 27 ] his publications concern the microbiology,[ 4 ] embryology,[ 4 9 28 38 ] morphology,[ 4 9 28 ] physiopathology,[ 4 11 ] as well as the clinical entities of the ear and pharynx.[ 3 4 15 18 – 21 23 40 ] He studied tinnitus, abnormal adaptation (tone decay) in patients with retrocochlear lesions, hysterical hearing loss [ Figure 5 ], genetic hearing impairment, experimental phonetics, and audiological rehabilitation.[ 2 3 12 36 37 ] He devoted much of his time on Acoumetry, working with Aristide Stefanini (1846–1925).[ 3 ] Among others, he developed a variety of audiometers including the first bone conduction device and performed several vestibular tests.[ 37 ]

Figure 5

Photograph of the title page of Ueber die Manifestationen der Hysterie am Gehörorgan (On the manifestations of hysteria on the hearing organ) by Giuseppe Gradenigo

Gradenigo's publications exceed 400 (with 9 books included).[ 3 4 40 ] Four of the books and 87 articles were focused on Audiology.[ 3 37 ] He made substantial contributions to this scientific domain.[ 4 7 10 – 14 16 17 22 24 – 27 34 37 39 ] For example, in 1899, he presented a device to vary the oscillations of the tuning fork. It was composed of two metal bands inserted in the tips of the prongs of the instrument. This invention instantly met with success.[ 7 37 ] In the next century, many series of tuning forks were used among which the most popular were the series of Gradenigo and Hartmann composed of seven elements with a frequency varying from 64 to 4096 Hz.[ 7 37 ] In 1904, during an Otology Congress, Professors Gradenigo, Deleaux, and Politzer classified the acoumetric tests by integrating them to an Acoustic Schema in order to achieve uniform diagnostic criteria for hypoacousia.[ 7 13 34 37 ]

However, his favorite topic was by far otitis media;[ 1 17 ] the study of its complications led to the description of the so-called “Gradenigo's syndrome,”[ 17 18 23 37 40 ] which will be presented more thoroughly later in this vignette. Moreover, he exhibited special interest in the embryology of the ear.[ 4 9 28 38 ] Concerning the double origin of stapes, he wrote: “The human and mammalian stapes arises from two elements, which are embryologically and morphologically completely different. First from the annulus stapedis, which is formed by the second gill arch. Secondly, by the lamina stapedis stemming from the wall of the labyrinth capsule.”[ 28 ] In his study Gradenigo used cat, dog, pig, and rabbit embryos for the earlier stages and human embryos for the later stages, studying them histologically.[ 37 ]

During the First World War, he held the rank of lieutenant colonel.[ 2 4 ] He had the opportunity to focus on the pathology of war and, in collaboration with the physiologist Amedeo Herlitzka (1872–1949), created a psycho-physiological laboratory to study several methods for selecting air pilots.[ 2 4 40 ]

As already mentioned, Gradenigo wrote many monographs and books. One of his most influential ones, perhaps the epitome of his accumulated experience, was Patologia e Terapia Dell’ Orecchio e Delle Prime Vie Aeree (Otologia, Rinologia, Laringologia) (Pathology and Therapeutics of the Ear and Upper Respiratory Passages (Otology, Rhinology, Laryngology) which instantly attracted the attention of the readership in 1903 [ Figure 6 ].[ 17 40 ] One year after its publication, an anonymous book critic wrote: “The general textbook of diseases of the ear and upper air passages which he has now published ought to command the attention of a large circle of readers. It combines many of the excellences both of the German and of the French schools, and it will be found clear and thorough without being laboured.”[ 1 ] It is in this book that a very touching dedication to his father can be found: “a mio padre Conte Piero Gradenigo tempra geniale di scienziato e di artista nelle discipline optalmologiche versatissimo clinico ed operatore mirabile con affetto e riconoscenza perenni questo libro dedico” (to my father, Conte Pietro Gradenigo, a brilliant scientist and artist of clinical ophthalmology and wonderful surgeon, with affection and everlasting gratitude I dedicate this book).[ 17 ]

Figure 6

Photograph of the title page of Gradenigo's Patologia e Terapia Dell’ Orecchio e Delle Prime Vie Aeree (Pathology and Therapeutics of the Ear and Upper Respiratory Passages) printed in Firenze, Italy, 1903[ 17]

Of more limited interest, yet of great value for the field of Audiology, was the book entitled Sulla Acumetria. Proposta di Nuovi Metodi Acumetrici (On Acoumetry. Proposal for New Acoumetric Methods) [ Figure 7 ].[ 4 25 37 ]

Figure 7

Photograph of the title page of Sulla Acumetria. Proposta di Nuovi Metodi Acumetrici (On Acoumetry. Proposal for New Acoumetric Methods) by Giuseppe Gradenigo, printed in Siena, Italy, 1908[ 25]

Some of the numerous publications of Gradenigo are summarized in Table 3 .[ 3 4 9 – 28 34 37 – 40 ]

Table 3

Some publications of Giuseppe Gradenigo in chronological order (title, year, and type of publication)[ 3 4 9 – 28 34 37 – 39]

GIUSEPPE GRADENIGO'S SYNDROME AND PRIMO DORELLO

In a communication made to the Royal Academy of Medicine in Turin in the sessions of 29 January, 22 April, and 17 June of 1904, Gradenigo presented for the very first time some cases of paralysis of the abducens nerve of post-otitic origin [ Figure 8 ].[ 21 32 ] These cases formed the basis for the description of a syndrome currently known as Gradenigo's syndrome. In the same year, he published his findings in many journals in Italy,[ 20 ] France [ Figure 9 ],[ 18 ] and Germany[ Figure 10 ].[ 3 19 23 ]

Figure 8

Photograph of an extract (first page) from Gradenigo's Sopra un novo caso di paralisi dell’ abducente di origine otitica: Comunicazione fatta alla R. academia di medicina di Torino nella seduta dei 22 aprile 1904 (On a new case of paralysis of the abducens nerve of post-otitic origin: Communication made to the R. Academy of Medicine in Torino in the session of 22 April 1904), printed in Turin, 1904[ 21]

Figure 9

Photograph of Gradenigo's Sur un syndrome particulier des complications endocraniennes otitiques: paralysie de l’ abducteur d’ origine otitique (On a particular syndrome of intracranial complications concerning the ear: Paralysis of the abducens of post-otitic origin).[ 18] (a) Title page of the journal Annales des maladies de l’ oreille, du larynx, du nez et du pharynx (Annals of diseases of the ear, larynx, nose and pharynx), published in Paris, 1904. (b) An extract (first page) from the article

Figure 10

Photograph of an extract (first page) from Über die Paralyse des Nervus abducens bei Otitis (Abducens nerve palsy originated from otitis) by Giuseppe Gradenigo, published in 1907[ 23]

The syndrome consists of homolateral trigeminal neuralgia and paresis or paralysis of the homolateral abducens nerve in the context of chronic or acute suppuration of the ear after involvement of the apex of the petrous part of the temporal bone.[ 8 17 18 23 33 41 ]

Although everybody agreed with the syndrome's description, the pathogenesis of the sixth cranial nerve involvement was under great debate. Many explanations were formulated. Gradenigo assumed that it was the result of the limited areas of serous and purulent leptomeningitis initiated by the inflammatory process of the tympanic cavity.[ 8 ]

At the age of 33 (1905), Primo Dorello (1872–1963), a young assistant at the University of Rome (Department of Anatomy), postulated that the abducens nerve could only be compressed by the post-otitic edema in a non-extensible canal through which this cranial nerve and inferior petrous sinus pass.[ 41 ] According to Dorello, this canal was formed from a narrowing of the inferior petrous foramen located at the tip of the petrous bone.[ 29 ] This foramen measured 6–12 mm in length and 1–3 mm in width.[ 41 ] He also stated that a thickening of Grüber's petrosphenoidal ligament bordered the superior wall of the canal (since then known as the Dorello's canal).[ 29 41 ] Gradenigo argued this thesis by saying that the veins of the tympanic cavity had no direct relationship with the inferior petrous sinus. This argument in turn was not found persuasive by Dorello who invoked the work of other researchers suggesting that “the inferior petrous sinus receives,” among others, “the internal auditive veins.” It was through these veins, Dorello believed, that the infection was transmitted. On the contrary, Gradenigo thought that “the infectious process through peritubaric pneumatic cells or through those of the carotid canal extends as far as the tip of the pyramid.”[ 17 18 23 ] Yet, this route, according to Dorello would “have given rise to more severe consequences and have required a long period before returning to normal.”[ 8 ]

THE END

Giuseppe Gradenigo died on 15 March 1926, in Treviso, Italy, and was buried with exceptional honors and respect.[ 2 7 37 41 ] Italians and foreigners sent many telegrams, among whom was Benito Mussolini, the Italian Air Force, and the University of Turin.[ 37 ]

According to an obituary of that time, Gradenigo was “the ‘Master’ in the true sense of the word. His words were for the pupils an invitation for pursuit of truth. They stimulated them during their patient and scrupulous researches, which could contribute, in a significant way, to the enrichment of our scientific knowledge.”[ 40 ]

CONCLUSIONS

Giuseppe Gradenigo made notable contributions to Audiology[ 37 ] and Neurosciences[ 4 ] in general. Even though his name lives on nowadays only in the eponym “Gradenigo's syndrome,” his accomplishments are much wider and cast him among the emblematic figures of science. His inherent tendency for discovering the underlying mechanisms of diseases and his vision of guaranteeing quality of services, professional proficiency, respect, and dedication toward the patients[ 6 ] is in fact what constitutes his true legacy to the next generations. After all, Gradenigo was in complete agreement with Professor De Rossi's statement (1892) that “the scientist should not shrink his brain, by limiting it to a special study, but should continue to cultivate it, and not separate it from the rest of the scientific world which is the basis of medical and surgical culture.”[ 7 ]

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10. Gradenigo G. [Über ein neues elektrishches Akumetermodell – On a new electric acoumetric model.]. Arch Ohrenheilk. 1890. 30: 240-5

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14. Gradenigo G. [New optical methods of Acoumetry – Nuovo metodo ottico di acumetria.]. Arch Ital Otol Rinol Laringol. 1899. 9: 46-8

15. Gradenigo G. [The hypertrophy of the pharyngeal tonsil. One Monography– Die Hypertrophie der Rachentonsille. Eine Monographie.]. Klin Vortr Otol. 1901. 4: 181-392

16. Gradenigo G. [On the decrease in the intensity of the sound of the tuning fork in relation to the duration of vibration – Sul decremente dell’ intensità del suono del diapason in rapporte alla durata di vibrazione.]. G Accad Med Torino. 1903. 9: 622-

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19. Gradenigo G. [On circumscribed leptomeningitis with spinal symptoms and on paralysis of the abducens nerve of post-otitic origin – Über circumscripte Leptomeningitis mit spinalen Symptomen und über Paralyse des N.abducens otitischen Ursprungs.]. Arch Ohrenheilk. 1904. 62: 255-70

20. Gradenigo G. [On circumscribed leptomeningitis and on abducens paralysis of post-otitic origin – Sulla leptomeningite circoscritta e sulla paralisi dell’ abducente di origine otitica.]. G Accad Med Torino. 1904. 10: 59-64

21. Gradenigo G.editors. [On a new case of paralysis of the abducens nerve of post-otitic origin:Communication made to the R. academy of medicine in Torino in the session of April 22, 1904 – Sopra un novo caso di paralisi dell’ abducente di origine otitica: Comunicazione fatta alla R. academia di medicina di Torino nella seduta dei 22 aprile 1904.]. Editrice Torinese. Turin: Stamperia dell’ unione tip; 1904. p. 1-4

22. Gradenigo D. [On the measurement of hearing by means of diapason – Sopra la misurazione dell’ udito col mezzo dei diapason.]. Arch Ital Otol Rinol Laringol. 1905. 16: 265-78

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24. Gradenigo G, Clerici A.editors. [On the diagnostic criteria for the diseases of the auricular labyrinth – Sui criteri diagnostici nelle malattie del labirinto auricolare]. Il Morgagni. Milano: Società Editrice Libraria; 1907. p. 593-624

25. Gradenigo G.editors[On Acoumetry. Proposal for New Acoumetric Methods – Sulla Acumetria. Proposta di Nuovi Metodi Acumetrici.]. Siena: Tip. Editrice S. Bernardino; 1908. p.

26. Gradenigo G. [Simple device to obtain constant and scalable intensity with electricity – Dispositivo Semplice per ottenere Suoni di intensita costante e graduabili colla elettricita]. Arch Ital Otol Rinol Laringol. 1916. 27: 1-4

27. Gradenigo G. [Was Helmholtz really the creator of the hearing theory that bears his name? – Fu Helmholtz veramente l’ ideatore della teoria sulla audizione che porta il suo nome?]. Arch Ital Otol Rinol Laringol. 1917. 64: 10-2

28. Gradenigo G.editors[On the derivation of embryonic stapedius: The homology of auditory ossicles in vertebrates – Sulla derivazione embrionale della staffa: La omologia delle ossicina dell’ udito nei vertebrati.]. Turin: Vincenzo Bona; 1923. p.

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