Neurol Sci DOI 10.1007/s10072-014-1694-8
HISTORY OF NEUROLOGY
Pseudobulbar paralysis in the Renaissance: Cosimo I de’ Medici case F. Arba • D. Inzitari • D. Lippi
Received: 14 February 2014 / Accepted: 15 February 2014 Ó Springer-Verlag Italia 2014
Abstract Cosimo I de’ Medici (1519–1574) was the first Grand Duke of Tuscany. He was one of the most important members of the Medici family. He was an excellent conqueror and a good politician. Moreover, he was able to attract and encourage artists, scientists and architects to promote Florence as the cultural capital of the Italian Renaissance. Historical chronicles report that he suffered from a stroke when he was 49 years old. Together with the acute manifestation of stroke, he displayed peculiar symptoms. He had gait disturbances and sphincter dysfunctions. His language became poor and hard to understand. His mood was very fluctuating and in the last years of his life he was a short-tempered man. In addition, he had a characteristic symptom, so-called pathological laughing and crying. The course of his disease was slow and stuttering. Taken together, these data seem to be one of the first reports of pseudobulbar paralysis. The disease of Cosimo I was probably due to a chronic cerebral vasculopathy, known as small vessels disease. We discuss this hypothesis regarding an ancient clinical case, with the support of current studies. Keywords Stroke Disability Small vessel disease Renaissance
F. Arba (&) D. Inzitari NEUROFARBA Department, University of Florence, Largo Brambilla 3, 50134 Florence, Italy e-mail: [email protected] D. Lippi Department of Anatomy, Histology and Legal Medicine, University of Florence, Viale Morgagni 85, 50134 Florence, Italy
Cosimo de’ Medici, 1st Grad Duke of Tuscany Son of Giovanni de’ Medici, of the Black Bands, and Maria Salviati, Cosimo belonged to the younger branch of the Medici family, descending from Lorenzo the Elder [1]. In 1537, Cosimo was 17 years old and the Emperor Charles V recognized his legitimacy as Duke. From the very beginning of his government, Cosimo took steps to lay the foundations of the Grand Duchy, progressively destroying the olden structures of the commune in an absolutist sense. He was astute and unscrupulous, and, with Florence under his control, he turned his ambition to territorial enlargement, bringing nearly all Tuscany under his power. Cosimo was also an important patron of the arts: he embellished and improved the City of Florence to a significant degree, founding the Uffizi complex to establish a seat of government, which later become a museum. Cosimo supported some of the leading painters of the day and in the late 1530s he summoned Bronzino to enter his service as official painter. In 1539, Cosimo married Eleonora di Toledo, daughter of the vice king of Neaples. The couple had 11 children. Two years later, Cosimo delegated the actual government of his dominions to his eldest son, Francesco, though he retained his ducal title. In 1569 Pope Pius V conferred him the title of Grand Duke of Tuscany, 5 years before his death.
Cosimo’s iconography Cosimo was a politician of great ability, lucidity and tenacity. He was a pragmatic and clear-sighted man, who managed to keep a strict control over culture, bending it to an extensive and single-minded program of personal and dynastic consolidation.
123
Neurol Sci
Fig. 1 Bronzino. Cosimo I in Armour, ca.1545. Oil on panel, 71 9 57 cm. Florence, Galleria degli Uffizi. Inv. No. 28. Copyright free
However, his despotism provoked many enemies, who defamed him, raising the suspicion he had murdered his son Garzia (1547–1562) and his daughter Maria. In response to these accusations, it was necessary for Cosimo to develop an iconography that could rehabilitate him. Therefore, Bronzino executed a first portrait of the Duke in armor, which would function as a tool of political propaganda: from this portrait, numerous later versions were produced (Fig. 1). This type of all’antica portrait is also to be found in a series of bust-length sculptures Cosimo commissioned from the principal sculptors of the time. Cosimo’s imperial imagery is confirmed by the sculptural program of the Uffizi fac¸ade and by the central tondo of the ceiling in the Sala Grande in Palazzo Vecchio, with his apotheosis.
Cosimo’s stroke and neurological history According to literary sources, Cosimo had good health for more than 20 years and the memories of his diseases are very seldom before 1540. The interpretation of the descriptions provided by literary sources (reports of doctors, general histories, memories, private letters) is very difficult and ultra vires, but some details can be positively evaluated. The main episode, which provoked his disability, took place in 1568, when Cosimo was 49 years. At that time, he
123
suffered from an acute stroke. Two different biographers [2, 3] mentioned the event with the words ‘‘a drop of a sick humor fell in his side’’, even if there was no agreement regarding the affected side. Cosimo showed a good functional recovery, and he resumed his daily activities [4], since chronicles reported that ‘‘he walked without restraint, hunted, played board games, read and wrote as usual’’ [5]. Nonetheless, after some years he showed peculiar symptoms, with a stuttering and progressive course. Chronicles describe low intensity of voice (‘‘His majesty got better in his head, in the eyes and in the legs, but not in the voice’’) [6], and his speech was difficult to understand (i.e., dysarthria). After two years he was completely unable to talk. He had gait disturbances and he could not move without a walking stick: his walking was slow, with dragging feet (‘‘he could not move without drag his feet’’) [7]. At the end of his life, he was described as a marble statue because of the lack of spontaneous movements [8]. Interestingly, at the end of his life his writing rapidly worsened and his signature in documents was almost unintelligible. He had urinary incontinence. Besides motor symptoms, he displayed agitation, but the majority of the time he had depressive symptoms (his mood was described as melancholic) and frequently he broke into sudden crying. He was often drowsy. He had mood swings, with colleric behavior, and he became eventually apathic. The clinical picture described so far is suggestive of the clinical diagnosis of vascular cognitive impairment (vMCI), eventually ending with a full-blown vascular dementia picture. Cognitive decline (progressive loss of functional independency), motor and psychiatric symptoms, and sphinteric disfunctions were the prominent clinical manifestations of the disease. The course was stuttering and progressive. Differential diagnosis indicated parkinsonian syndrome, but Cosimo did not show tremor of his hands or extremities. Cognitive domains are not usually affected in parkinsonism syndromes. However, cerebrovascular diseases are responsible of more than 20 % of parkinsonisms [9]. Cosimo died of complications of pneumonia at the age of 55, in 1574, 6 years after the previously reported stroke. Taken together, the history of a previous stroke and Cosimo’s progressive cognitive decline led us advance the hypothesis that a chronic cerebrovascular disease was responsible for the typical clinical picture of signs and symptoms of the Medici Grand Duke (Table 1) [10].
Risk factors Risk factors for cerebrovascular dementia include age, hypertension and diabetes. From iconography one can argue that Cosimo was overweight, whereas historical
Neurol Sci Table 1 Comparison between typical clinical features of cerebral small vessel disease and Cosimo’s disease (modified from Pantoni L, Lancet Neurol 2010)
Cognitive performance
Clinical picture of cerebrovascular dementia
Cosimo’s symptoms and signs
Cognitive impairment/dementia
–
Mood
Depressive symptoms/depression
Melancholic mood, apathy, mood swings
Sphinteric functions
Urinary incontinence
Urinary incontinence
Gait
Slowing, postural instability, apraxic
Gait impairment, slowing, dragging feet, use of walking stick
Pseudobulbar signs
Dysphagia, dysarthria, pathological laughing and crying
Ipophony, dysarthria, pathological crying
Daily living functions
Functional impairment, complete loss of autonomy
Progressive loss of autonomy
reports and paleopathological investigations revealed that Cosimo had at least two cardiovascular risk factors. Cosimo likely suffered from hypertension. In 2004 a paleopathological research was started on the remains of some members of the Medici family (sixteenth–eighteenth centuries) [11]. It was only possible to use the preserved bones to individuate the physical and pathological characteristics of the bodies exhumed. The study of Cosimo’s skeleton revealed that he was arthritic. The doctors of his time interpreted the disease as ‘‘gout’’: they believed in fact that pains were caused by a ‘‘drop’’ (lat. Gutta) of a vicious fluid in the joints. Apart from the diffused ossifications of the articular ligaments caused by an articular disease linked to diabetes and obesity, known as DISH (diffuse idiopathic skeletal hyperostosis), the ossification of the anterior right vertebral ligament at the level of the sixth, seventh and eighth thoracic vertebral bodies provides very important clues to identify his disease: the ossification on the left side was missing, presumably due to increased pulsatility of aorta following hypertension [12], which hampered the formation of the ostheophytes. Hypertension is a pivotal risk factor for cerebrovascular pathologies and stroke [13, 14], and patients with systolic hypertension have from twofold to fourfold increased probability to have a stroke. Hypertension is also a major determinant of white matter changes (WMCs), usually seen on CT or MRI, the socalled leukoaraiosis [15], which is an independent risk factor for stroke [16]. Hypertension and consequent WMCs may have contributed to Cosimo’s pathology.
Interpretation of Cosimo’s disease Cosimo had a stroke at the beginning of his pathology. He did not show cortical symptoms, so he likely had a lacunar stroke, a stroke subtype which is strongly associated with WMCs [15]. WMCs underline the presence of small vessels disease [10], a wide range of alterations in the
microcirculation of the brain that recognize a number of etiologies. Small vessels disease drives the pathological process that leads to ischemic vascular disease and to cognitive impairment [17, 18] with a progressive loss of activities in daily living, as Cosimo definetely had. A recent multicenter, prospective, observational study in Europe between 1998 and 2002 (Leukoaraiosis And DISability Study, LADIS) aimed to evaluate the effect of WMCs (or leukoaraiosis) detected with CT or MRI scan on disability [19]. The results from the LADIS study showed that severe WMCs independently predicted global functional decline, gait difficulties, depression and urinary incontinence [20]. The observation period in the study cohort was 3 years. One can argue that Cosimo showed depressive symptoms because of his progressive loss of autonomy. However, deep white matter lesions are independently associated with depressive symptoms and cognitive status [21, 22] after correcting for confounding factors such as age and hypertension. Cosimo showed also sudden crying, another peculiar neurological symptom. Traditionally, this symptom is associated with laughing, named pathological laughing and crying [23], which is recognized to have a vascular origin. As shown in the Table 1, Cosimo’s disturbances were consistent with the clinical picture of cerebrovascular dementia. Balance disturbances and falls are associated with frontal deep WMCs [24], supposed to damage corticosubcortical circuits involved in balance and gait control. The severity of WMCs compromises gait and motor effectiveness [25], pointing out that the degree of clinical symptoms is correlated with the extent of such alterations. Regarding sphincter symptoms, it has been demonstrated that WMCs are independently related to urinary incontinence [26], as described for Cosimo. Other classical pseudobulbar signs of the Cosimo’s pathology were slow intensity of voice and dysarthria, reported in chronicles. It is unknown whether Cosimo suffered from dysphagia, a typical sign of pseudobulbar paralysis. We cannot rule out
123
Neurol Sci
that Cosimo died of ab-ingestis pneumonia, one of the most frequent complications of dysphagia. Taken together, these symptoms and signs are consistent with a diagnosis of cerebrovascular dementia resulting from a cerebral small vessel disease. NINDS-AIREN [27] clinical features for vascular dementia include the following: (1) early presence of gait disturbance (small-step gait or magnetic, apraxic–ataxic or parkinsonian gait); (2) history of unsteadiness and frequent, unprovoked falls; (3) early urinary frequency, urgency, and other urinary symptoms not explained by urologic disease; (4) pseudobulbar palsy; and (5) personality and mood changes, abulia, depression, emotional incontinence, or other subcortical deficits including psychomotor retardation and abnormal executive function. Diagnosis of probable vascular dementia is by neuroimaging (CT or RMN). We cannot demonstrate the presence of small vessel disease, although clinical features are highly suggestive of such pathology. The NINDS-AIREN criteria for probable vascular dementia include: (1) diagnosis of dementia; (2) diagnosis of cerebrovascular disease; (3) a relationship between the above two disorders. In our case there is a clear temporal correlation between the occurrence of the reported stroke and the manifestations of progressive cognitive impairment, resulting in a clinical picture of dementia with a stepwise progression. Conclusions Evaluation of Cosimo’s clinical history through the study of his remains let us interpret his progressive disability as resulting from a chronic cerebral vascular pathology with a stepwise progression, consistent with cerebral small vessel disease. Consequent neurological disability may have conditioned Cosimo’s life and behavior. Also Francesco, his eldest son, had likely suffered from a stroke consequent to neurosyphilis [28]. However, Francesco’s stroke was concealed from chronicles and pictures of his time, whereas Cosimo’s stroke and course of the pathology were well described in historical reports. Cosimo’s pathology may represent an emblematic clinical picture of cerebral small vessel disease in Renaissance. Acknowledgments suggestions. Conflict of interest interests.
The authors thank Dr. George Weisz for helpful
The authors do not have any conflict of
References 1. Hale JR (2001) Florence and the Medici. Phoenix Press, London 2. Lapini A (1900) Diario fiorentino
123
3. Corazzini O (1899) Sommario di storia fiorentina 4. Archivio di Stato di Firenze, Mediceo del Principato, Fil. 358 bis, c. 764 bis 5. Archivio di Stato di Firenze, Mediceo del Principato, Fil. 642, c. 5,6,7 6. Vasari, Carteggio inedito d’artisti, Firenze, 1839–40, vol. III, p 329 7. Archivio di Stato di Firenze, Mediceo del Principato, Fil. 5784, c. 95 8. Cini GB, Op cit, p 517 9. Mehanna R, Jankovic J (2013) Movement disorders in cerebrovascular disease. Lancet Neurol 12(6):597–608 10. Pantoni L (2010) Cerebral small vessels disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9(7):689–701 11. Weisz GM, Matucci-Cerinic M, Albury WR, Lippi D (2010) The Medici syndrome: a medico-historical puzzle. Int J Rheumatic Dis 13:125–131 12. Giuffra V, Giusiani S, Fornaciari A et al (2010) Diffuse idiopathic skeletal hyperostosis in the Medici, Grand Dukes of Florence (XVI century). Eur Spine J 19(Suppl 2):S103–S107 13. Kannel WB (1995) Framingham study insights into hypertensive risk of cardiovascular disease. Hypertens Res 18(3):181–196 14. Kannel WB, Wolf PA, McGee DL et al (1981) Systolic blood pressure, arterial rigidity, and risk of stroke. The Framingham study. JAMA 245(12):1225–1229 15. Basile AM, Pantoni L, Pracucci G et al (2006) LADIS group. Age, hypertension, and lacunar stroke are the major determinants of the severity of age-related white matter changes. The LADIS (leukoaraiosis and disability in the elderly) study. Cerebrovasc Dis 21(5–6):315–322 16. Inzitari D (2003) Leukoaraiosis: an independent risk factor for stroke? Stroke 34(8):2067–2071 17. Jokinen H, Kalska H, Ylikoski R et al (2009) Longitudinal cognitive decline in subcortical ischemic vascular disease. The LADIS study. Cerebrovasc Dis 27(4):384–391 18. Erkinjutti T (2002) Subcortical vascular dementia. Cerebrovasc Dis 13(Suppl 2):58–60 19. Pantoni L, Basile AM, Pracucci G et al (2005) Impact of agerelated cerebral white matter changes on the transition to disability. The LADIS study: rationale, design and methodology. Neuroepidemiology 24(1–2):51–62 20. Inzitari D, Pracucci G, Poggesi A et al (2009) LADIS study group. Changes in white matter as determinant of global functional decline in older independent outpatients: three year followup of LADIS (leukoaraiosis and disability) study cohort. BMJ 6(339):b2477 21. Krishnan MS, O’Brien JT, Firbank MJ et al (2006) LADIS group. Relationship between periventricular and deep white matter lesions and depressive symptoms in older people. The LADIS study. Int J Geriatr Psychiatry 21(10):983–989 22. Teodorczuk A, O’Brien JT, Firbank MJ et al (2007) LADIS group. White matter changes and late-life depressive symptoms: longitudinal study. Br J Psychiatry 191:212–217 23. Altschuler EL, Wisdom S (1999) An old case of pathological laughing and crying. Lancet 354(9191):1736 24. Blahak C, Baezner H, Pantoni L et al (2009) Deep frontal and periventricular age related white matter changes but not basal ganglia and infratentorial hyperintensities are associated with falls: cross sectional results from the LADIS study. J Neurol Neurosurg Psychiatry 80(6):608–613 25. Baezner H, Blahak C, Poggesi A et al (2008) LADIS study group. Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology 70(12):935–942 26. Poggesi A, Pracucci G, Chabriat H et al (2008) LADIS study group. Urinary complaints in nondisabled elderly people with
Neurol Sci age-related white matter changes: the leukoaraiosis and dISability (LADIS) study. J Am Geriatr Soc 56(9):1638–1643 27. Roma´n GC, Tatemichi TK, Erkinjuntti T et al (1993) Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN international workshop. Neurology 43(2): 250–260
28. Arba F, Inzitari D, Barnett HJ et al (2012) Stroke in Renaissance time: the case of Francesco I de’ Medici. Cerebrovasc Dis 33(6): 589–593
123
HISTORY OF NEUROLOGY
Pseudobulbar paralysis in the Renaissance: Cosimo I de’ Medici case F. Arba • D. Inzitari • D. Lippi
Received: 14 February 2014 / Accepted: 15 February 2014 Ó Springer-Verlag Italia 2014
Abstract Cosimo I de’ Medici (1519–1574) was the first Grand Duke of Tuscany. He was one of the most important members of the Medici family. He was an excellent conqueror and a good politician. Moreover, he was able to attract and encourage artists, scientists and architects to promote Florence as the cultural capital of the Italian Renaissance. Historical chronicles report that he suffered from a stroke when he was 49 years old. Together with the acute manifestation of stroke, he displayed peculiar symptoms. He had gait disturbances and sphincter dysfunctions. His language became poor and hard to understand. His mood was very fluctuating and in the last years of his life he was a short-tempered man. In addition, he had a characteristic symptom, so-called pathological laughing and crying. The course of his disease was slow and stuttering. Taken together, these data seem to be one of the first reports of pseudobulbar paralysis. The disease of Cosimo I was probably due to a chronic cerebral vasculopathy, known as small vessels disease. We discuss this hypothesis regarding an ancient clinical case, with the support of current studies. Keywords Stroke Disability Small vessel disease Renaissance
F. Arba (&) D. Inzitari NEUROFARBA Department, University of Florence, Largo Brambilla 3, 50134 Florence, Italy e-mail: [email protected] D. Lippi Department of Anatomy, Histology and Legal Medicine, University of Florence, Viale Morgagni 85, 50134 Florence, Italy
Cosimo de’ Medici, 1st Grad Duke of Tuscany Son of Giovanni de’ Medici, of the Black Bands, and Maria Salviati, Cosimo belonged to the younger branch of the Medici family, descending from Lorenzo the Elder [1]. In 1537, Cosimo was 17 years old and the Emperor Charles V recognized his legitimacy as Duke. From the very beginning of his government, Cosimo took steps to lay the foundations of the Grand Duchy, progressively destroying the olden structures of the commune in an absolutist sense. He was astute and unscrupulous, and, with Florence under his control, he turned his ambition to territorial enlargement, bringing nearly all Tuscany under his power. Cosimo was also an important patron of the arts: he embellished and improved the City of Florence to a significant degree, founding the Uffizi complex to establish a seat of government, which later become a museum. Cosimo supported some of the leading painters of the day and in the late 1530s he summoned Bronzino to enter his service as official painter. In 1539, Cosimo married Eleonora di Toledo, daughter of the vice king of Neaples. The couple had 11 children. Two years later, Cosimo delegated the actual government of his dominions to his eldest son, Francesco, though he retained his ducal title. In 1569 Pope Pius V conferred him the title of Grand Duke of Tuscany, 5 years before his death.
Cosimo’s iconography Cosimo was a politician of great ability, lucidity and tenacity. He was a pragmatic and clear-sighted man, who managed to keep a strict control over culture, bending it to an extensive and single-minded program of personal and dynastic consolidation.
123
Neurol Sci
Fig. 1 Bronzino. Cosimo I in Armour, ca.1545. Oil on panel, 71 9 57 cm. Florence, Galleria degli Uffizi. Inv. No. 28. Copyright free
However, his despotism provoked many enemies, who defamed him, raising the suspicion he had murdered his son Garzia (1547–1562) and his daughter Maria. In response to these accusations, it was necessary for Cosimo to develop an iconography that could rehabilitate him. Therefore, Bronzino executed a first portrait of the Duke in armor, which would function as a tool of political propaganda: from this portrait, numerous later versions were produced (Fig. 1). This type of all’antica portrait is also to be found in a series of bust-length sculptures Cosimo commissioned from the principal sculptors of the time. Cosimo’s imperial imagery is confirmed by the sculptural program of the Uffizi fac¸ade and by the central tondo of the ceiling in the Sala Grande in Palazzo Vecchio, with his apotheosis.
Cosimo’s stroke and neurological history According to literary sources, Cosimo had good health for more than 20 years and the memories of his diseases are very seldom before 1540. The interpretation of the descriptions provided by literary sources (reports of doctors, general histories, memories, private letters) is very difficult and ultra vires, but some details can be positively evaluated. The main episode, which provoked his disability, took place in 1568, when Cosimo was 49 years. At that time, he
123
suffered from an acute stroke. Two different biographers [2, 3] mentioned the event with the words ‘‘a drop of a sick humor fell in his side’’, even if there was no agreement regarding the affected side. Cosimo showed a good functional recovery, and he resumed his daily activities [4], since chronicles reported that ‘‘he walked without restraint, hunted, played board games, read and wrote as usual’’ [5]. Nonetheless, after some years he showed peculiar symptoms, with a stuttering and progressive course. Chronicles describe low intensity of voice (‘‘His majesty got better in his head, in the eyes and in the legs, but not in the voice’’) [6], and his speech was difficult to understand (i.e., dysarthria). After two years he was completely unable to talk. He had gait disturbances and he could not move without a walking stick: his walking was slow, with dragging feet (‘‘he could not move without drag his feet’’) [7]. At the end of his life, he was described as a marble statue because of the lack of spontaneous movements [8]. Interestingly, at the end of his life his writing rapidly worsened and his signature in documents was almost unintelligible. He had urinary incontinence. Besides motor symptoms, he displayed agitation, but the majority of the time he had depressive symptoms (his mood was described as melancholic) and frequently he broke into sudden crying. He was often drowsy. He had mood swings, with colleric behavior, and he became eventually apathic. The clinical picture described so far is suggestive of the clinical diagnosis of vascular cognitive impairment (vMCI), eventually ending with a full-blown vascular dementia picture. Cognitive decline (progressive loss of functional independency), motor and psychiatric symptoms, and sphinteric disfunctions were the prominent clinical manifestations of the disease. The course was stuttering and progressive. Differential diagnosis indicated parkinsonian syndrome, but Cosimo did not show tremor of his hands or extremities. Cognitive domains are not usually affected in parkinsonism syndromes. However, cerebrovascular diseases are responsible of more than 20 % of parkinsonisms [9]. Cosimo died of complications of pneumonia at the age of 55, in 1574, 6 years after the previously reported stroke. Taken together, the history of a previous stroke and Cosimo’s progressive cognitive decline led us advance the hypothesis that a chronic cerebrovascular disease was responsible for the typical clinical picture of signs and symptoms of the Medici Grand Duke (Table 1) [10].
Risk factors Risk factors for cerebrovascular dementia include age, hypertension and diabetes. From iconography one can argue that Cosimo was overweight, whereas historical
Neurol Sci Table 1 Comparison between typical clinical features of cerebral small vessel disease and Cosimo’s disease (modified from Pantoni L, Lancet Neurol 2010)
Cognitive performance
Clinical picture of cerebrovascular dementia
Cosimo’s symptoms and signs
Cognitive impairment/dementia
–
Mood
Depressive symptoms/depression
Melancholic mood, apathy, mood swings
Sphinteric functions
Urinary incontinence
Urinary incontinence
Gait
Slowing, postural instability, apraxic
Gait impairment, slowing, dragging feet, use of walking stick
Pseudobulbar signs
Dysphagia, dysarthria, pathological laughing and crying
Ipophony, dysarthria, pathological crying
Daily living functions
Functional impairment, complete loss of autonomy
Progressive loss of autonomy
reports and paleopathological investigations revealed that Cosimo had at least two cardiovascular risk factors. Cosimo likely suffered from hypertension. In 2004 a paleopathological research was started on the remains of some members of the Medici family (sixteenth–eighteenth centuries) [11]. It was only possible to use the preserved bones to individuate the physical and pathological characteristics of the bodies exhumed. The study of Cosimo’s skeleton revealed that he was arthritic. The doctors of his time interpreted the disease as ‘‘gout’’: they believed in fact that pains were caused by a ‘‘drop’’ (lat. Gutta) of a vicious fluid in the joints. Apart from the diffused ossifications of the articular ligaments caused by an articular disease linked to diabetes and obesity, known as DISH (diffuse idiopathic skeletal hyperostosis), the ossification of the anterior right vertebral ligament at the level of the sixth, seventh and eighth thoracic vertebral bodies provides very important clues to identify his disease: the ossification on the left side was missing, presumably due to increased pulsatility of aorta following hypertension [12], which hampered the formation of the ostheophytes. Hypertension is a pivotal risk factor for cerebrovascular pathologies and stroke [13, 14], and patients with systolic hypertension have from twofold to fourfold increased probability to have a stroke. Hypertension is also a major determinant of white matter changes (WMCs), usually seen on CT or MRI, the socalled leukoaraiosis [15], which is an independent risk factor for stroke [16]. Hypertension and consequent WMCs may have contributed to Cosimo’s pathology.
Interpretation of Cosimo’s disease Cosimo had a stroke at the beginning of his pathology. He did not show cortical symptoms, so he likely had a lacunar stroke, a stroke subtype which is strongly associated with WMCs [15]. WMCs underline the presence of small vessels disease [10], a wide range of alterations in the
microcirculation of the brain that recognize a number of etiologies. Small vessels disease drives the pathological process that leads to ischemic vascular disease and to cognitive impairment [17, 18] with a progressive loss of activities in daily living, as Cosimo definetely had. A recent multicenter, prospective, observational study in Europe between 1998 and 2002 (Leukoaraiosis And DISability Study, LADIS) aimed to evaluate the effect of WMCs (or leukoaraiosis) detected with CT or MRI scan on disability [19]. The results from the LADIS study showed that severe WMCs independently predicted global functional decline, gait difficulties, depression and urinary incontinence [20]. The observation period in the study cohort was 3 years. One can argue that Cosimo showed depressive symptoms because of his progressive loss of autonomy. However, deep white matter lesions are independently associated with depressive symptoms and cognitive status [21, 22] after correcting for confounding factors such as age and hypertension. Cosimo showed also sudden crying, another peculiar neurological symptom. Traditionally, this symptom is associated with laughing, named pathological laughing and crying [23], which is recognized to have a vascular origin. As shown in the Table 1, Cosimo’s disturbances were consistent with the clinical picture of cerebrovascular dementia. Balance disturbances and falls are associated with frontal deep WMCs [24], supposed to damage corticosubcortical circuits involved in balance and gait control. The severity of WMCs compromises gait and motor effectiveness [25], pointing out that the degree of clinical symptoms is correlated with the extent of such alterations. Regarding sphincter symptoms, it has been demonstrated that WMCs are independently related to urinary incontinence [26], as described for Cosimo. Other classical pseudobulbar signs of the Cosimo’s pathology were slow intensity of voice and dysarthria, reported in chronicles. It is unknown whether Cosimo suffered from dysphagia, a typical sign of pseudobulbar paralysis. We cannot rule out
123
Neurol Sci
that Cosimo died of ab-ingestis pneumonia, one of the most frequent complications of dysphagia. Taken together, these symptoms and signs are consistent with a diagnosis of cerebrovascular dementia resulting from a cerebral small vessel disease. NINDS-AIREN [27] clinical features for vascular dementia include the following: (1) early presence of gait disturbance (small-step gait or magnetic, apraxic–ataxic or parkinsonian gait); (2) history of unsteadiness and frequent, unprovoked falls; (3) early urinary frequency, urgency, and other urinary symptoms not explained by urologic disease; (4) pseudobulbar palsy; and (5) personality and mood changes, abulia, depression, emotional incontinence, or other subcortical deficits including psychomotor retardation and abnormal executive function. Diagnosis of probable vascular dementia is by neuroimaging (CT or RMN). We cannot demonstrate the presence of small vessel disease, although clinical features are highly suggestive of such pathology. The NINDS-AIREN criteria for probable vascular dementia include: (1) diagnosis of dementia; (2) diagnosis of cerebrovascular disease; (3) a relationship between the above two disorders. In our case there is a clear temporal correlation between the occurrence of the reported stroke and the manifestations of progressive cognitive impairment, resulting in a clinical picture of dementia with a stepwise progression. Conclusions Evaluation of Cosimo’s clinical history through the study of his remains let us interpret his progressive disability as resulting from a chronic cerebral vascular pathology with a stepwise progression, consistent with cerebral small vessel disease. Consequent neurological disability may have conditioned Cosimo’s life and behavior. Also Francesco, his eldest son, had likely suffered from a stroke consequent to neurosyphilis [28]. However, Francesco’s stroke was concealed from chronicles and pictures of his time, whereas Cosimo’s stroke and course of the pathology were well described in historical reports. Cosimo’s pathology may represent an emblematic clinical picture of cerebral small vessel disease in Renaissance. Acknowledgments suggestions. Conflict of interest interests.
The authors thank Dr. George Weisz for helpful
The authors do not have any conflict of
References 1. Hale JR (2001) Florence and the Medici. Phoenix Press, London 2. Lapini A (1900) Diario fiorentino
123
3. Corazzini O (1899) Sommario di storia fiorentina 4. Archivio di Stato di Firenze, Mediceo del Principato, Fil. 358 bis, c. 764 bis 5. Archivio di Stato di Firenze, Mediceo del Principato, Fil. 642, c. 5,6,7 6. Vasari, Carteggio inedito d’artisti, Firenze, 1839–40, vol. III, p 329 7. Archivio di Stato di Firenze, Mediceo del Principato, Fil. 5784, c. 95 8. Cini GB, Op cit, p 517 9. Mehanna R, Jankovic J (2013) Movement disorders in cerebrovascular disease. Lancet Neurol 12(6):597–608 10. Pantoni L (2010) Cerebral small vessels disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9(7):689–701 11. Weisz GM, Matucci-Cerinic M, Albury WR, Lippi D (2010) The Medici syndrome: a medico-historical puzzle. Int J Rheumatic Dis 13:125–131 12. Giuffra V, Giusiani S, Fornaciari A et al (2010) Diffuse idiopathic skeletal hyperostosis in the Medici, Grand Dukes of Florence (XVI century). Eur Spine J 19(Suppl 2):S103–S107 13. Kannel WB (1995) Framingham study insights into hypertensive risk of cardiovascular disease. Hypertens Res 18(3):181–196 14. Kannel WB, Wolf PA, McGee DL et al (1981) Systolic blood pressure, arterial rigidity, and risk of stroke. The Framingham study. JAMA 245(12):1225–1229 15. Basile AM, Pantoni L, Pracucci G et al (2006) LADIS group. Age, hypertension, and lacunar stroke are the major determinants of the severity of age-related white matter changes. The LADIS (leukoaraiosis and disability in the elderly) study. Cerebrovasc Dis 21(5–6):315–322 16. Inzitari D (2003) Leukoaraiosis: an independent risk factor for stroke? Stroke 34(8):2067–2071 17. Jokinen H, Kalska H, Ylikoski R et al (2009) Longitudinal cognitive decline in subcortical ischemic vascular disease. The LADIS study. Cerebrovasc Dis 27(4):384–391 18. Erkinjutti T (2002) Subcortical vascular dementia. Cerebrovasc Dis 13(Suppl 2):58–60 19. Pantoni L, Basile AM, Pracucci G et al (2005) Impact of agerelated cerebral white matter changes on the transition to disability. The LADIS study: rationale, design and methodology. Neuroepidemiology 24(1–2):51–62 20. Inzitari D, Pracucci G, Poggesi A et al (2009) LADIS study group. Changes in white matter as determinant of global functional decline in older independent outpatients: three year followup of LADIS (leukoaraiosis and disability) study cohort. BMJ 6(339):b2477 21. Krishnan MS, O’Brien JT, Firbank MJ et al (2006) LADIS group. Relationship between periventricular and deep white matter lesions and depressive symptoms in older people. The LADIS study. Int J Geriatr Psychiatry 21(10):983–989 22. Teodorczuk A, O’Brien JT, Firbank MJ et al (2007) LADIS group. White matter changes and late-life depressive symptoms: longitudinal study. Br J Psychiatry 191:212–217 23. Altschuler EL, Wisdom S (1999) An old case of pathological laughing and crying. Lancet 354(9191):1736 24. Blahak C, Baezner H, Pantoni L et al (2009) Deep frontal and periventricular age related white matter changes but not basal ganglia and infratentorial hyperintensities are associated with falls: cross sectional results from the LADIS study. J Neurol Neurosurg Psychiatry 80(6):608–613 25. Baezner H, Blahak C, Poggesi A et al (2008) LADIS study group. Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology 70(12):935–942 26. Poggesi A, Pracucci G, Chabriat H et al (2008) LADIS study group. Urinary complaints in nondisabled elderly people with
Neurol Sci age-related white matter changes: the leukoaraiosis and dISability (LADIS) study. J Am Geriatr Soc 56(9):1638–1643 27. Roma´n GC, Tatemichi TK, Erkinjuntti T et al (1993) Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN international workshop. Neurology 43(2): 250–260
28. Arba F, Inzitari D, Barnett HJ et al (2012) Stroke in Renaissance time: the case of Francesco I de’ Medici. Cerebrovasc Dis 33(6): 589–593
123
