Acta Neurochirurgica 33, 107--112 (1976) 9 by Springer-Verlag 1976
Department of Neurosurgery of Siena Medical School, Siena, Italy
Tabetic Lumbar Osteoarthropathy with Cauda Equina Syndrome Case Report By G. P. eantore and D. Gambaeorta With 2 Figures Summary The ease is described of a 52 year old patient admitted for a cauda equina compression syndrome (flaccid paraplegia of the lower limbs, bilateral lumbar and sciatic pains, urinary incontinence) of rapid onset and due to narrowing of the lumbar canal from tabetic arthropathyl These vertebral manifestations occur in a low percentage of tabetic arthropathies, which are relatively rare, and are not often accompanied by severe neurological disturbances. Decompressive laminectomy afforded rapid and lasting
relief. Arthropathy due to nervous system lesions has been known for a long time (Mitchell 1831). The first to make precise reports were Scott and Allison (1843) on hemiplegia, Blasius (1848) and Sehlesinger (1895) on syringomyelia, Magnier (1859) on transverse myelitis, Packard (1861) and Shands (1930) on the association with traumatic or inflammatory lesions of the peripheral nerves and Jordan (1936) Zueker and Mander (1952) on diabetic neuropathy. Neurogenic arthropathy has also been reported after spinal cord injuries and in cases of eongenitM insensitivity to pain (see in Jaffe 1972). Charter (1868) was the first to suggest a possible relationship between tabes and this kind of arthropathy, which came to be known by his name. The pathogenesis of neurogenie arthropathy is uncertain. In some eases, as in tabes, looseness of the ligaments and museular hypotonia due to proprioeeptive afferent loss with or without a reduced input of pain stimuli induce articular hypermobility and abnormal friction at the joints
108
G . P . Cantore and D. Gambacorta:
causing erosion of c a r t i l a g e a n d m M a l i g n m e n t of t h e joints. L a t e r come d e s t r u c t i o n of t h e u n d e r l y i n g bone (osteoporosis w i t h connective tissue p r o l i f e r a t i o n b e t w e e n t h e d i s o r g a n i s e d lamellae), spinal disc degeneration, a n d s i m u l t a n e o u s bone p r o l i f e r a t i o n w i t h sclerosis of t h e bone ends a n d f o r m a t i o n of spurs (Jaffe 1972). I n t h e m a j o r i t y of eases p r o l i f e r a t i v e p h e n o m e n a p r e v a i l o v e r t h e regressive p h e n o m e n a , b u t in a n y case t h e m o r p h o l o g y a n d s t r u c t u r e of t h e affected j o i n t are a l t e r e d a n d w e a k e n e d so t h a t ankylosis a n d p a t h o l o g i c a l f r a c t u r e s are l i k e l y risks. T h e foregoing suppositions are confirmed b y e x p e r i m e n t a l w o r k (Eloesser 1917; Corbin 1937) and, in t a b e t i c p a t i e n t s , b y t h e r a r i t y of serious m a n i f e s t a t i o n s of m o t o r a t a x i a . T a b e s is r a r e l y seen t o d a y , a n d still more u n u s u a l are t h e a r t h r o p a t h i e s t h a t , according to r e p o r t s (l~{cNeel a n d E n h i 1969, a n d B o u v i e r et al. 1972), occur in 4-21~ of p a t i e n t s w i t h t h e disease. T a b e s nonetheless r a n k s second a f t e r s y r i n g o m y e l i ~ a m o n g t h e causes of neurogenic arthropathy. The following r e p o r t describes a ease of c a u d a e q u i n a s y n d r o m e due to t a b e t i c l u m b a r a r t h r o p a t h y .
Case Report S. t~., a m a n aged 52, who at the age of 24 years had contracted syphilis and was treated with some unspecified drug. A t 39 years of age his gait was somewhat unsteady and he had occasional paraesthesiae in the lower limbs. The diagnosis was tabes dorsalis, and penicillin t r e a t m e n t was given. The symptoms remained stationary for m a n y years b u t then over a period of 4 years the patient was hospitalised several times for attacks of abdominal pain accompanied by violent vomiting which responded to courses of high dose penicillin therapy. He had a 3 year history of mild lumbar pains and an 8 month history of bilateral lumbar and sciatic pains, more m a r k e d on the left side. During the 7 days before admission the pain became more severe with loss of movement in the lower limbs, urinary incontinence, vomiting, and abdominal pain. NeurologicM examination showed: flaccid paraplegia of the lower limbs, pronounced wasting of the lower limb muscles, superficial hypoesthesia at levels L3-$2, loss of vibration sense as far up as the iliae crests, hypotonia and decreased reflexes in the upper limbs, absent pupillary reflexes, optic disc pallor, and urinary incontinence. L u m b a r CSF: albumen 0.50g~o, VDl~L and T I T weakly positive. Serological tests : V D R L and T I T positive (~- @). Vertebral column X - r a y : fusion of L 1 and L 2, m a r k e d reduction of the lumbar disc spaces, massive marginal osteophytosis, narrowing of the spinal canal (Figs. 1 and 2). Positive contrast myelography b y suboceipital route: m a r k e d deformation and irregular reduction of the spinal subarachnoid space, partial arrests and skipping at the levels of the L 3-L 4, L 4 - L 5 and L 5-S 1 spaces, no visualization of the lumbar root pouches.
Tabetic Lumbar Osteoarthropaghy with Cauda Equina Sytldrome
Fig. 1
t09
Fig. 2
Figs. 1 and 2. Lumbar column X-ray in antero-pos~erior (Fig. i) and lateral view (Fig. 2): marked reduction of disk spaces, fusion of L 1 and L 2, massive marginal osteophytosis and narrowing of the spinal canal
Penicillin treatment (up to 2.5 million units daily) was started, and this was followed by relief of abdominal pain and disappearance of vomiting. Four days after admission the patient was subjected to lamincetomy from L 2 to S 1 with bilateral foraminotomies. The dural sac appeared to be squashed in an irregularly narrowed eanal. The bone was considerably increased in thickness but not in eonsisteney. The operation was followed by rapid and spectacular recovery. Pain virtually disappeared, bladder function was regained in a week, and the patient was able to walk without aid after about one month's intensive motor reeducation.
110
G.P. Cantore and D. Gambacorta: Discussion
Knee, hip, elbow, ankle and wrist are, in order of frequency, the joints most often affected by tabetic arthropathy. The lower limbs are affected, either alone or together with other joints, in 75% of cases (Jaffe 1972). Spinal column manifestations, with or without symptoms in other joints, are found in 6-20% of tabetic patients with articular complications (Bouvier et al. 1972). The foatures of our case that tally with those of the majority of the cases in the literature are: a) The lumbar localization. This segment of the column is the most affected. Of over 200 published cases (Serre 1970) only 3 cases of Charcot spine were at cervical level (Cutting 1949; Brain and Wilkinson 1958; Sieard 1959), 2 at dorsal level (Holland 1953; Thuiel et al. !966), and one at sacral level (Garvey and Glass 1927). b) Onset of symptoms in middle life (49 years in our patient. The mean age at onset of articular symptoms according to Bouvier et al. is 55 years). e) Clear history of tubes which, as a rule, is present in vertebral arthropathy, though it is more likely to be missing or missed with arthropathies in other sites (Comte 1964) when a painless joint swelling or a pathological fracture may be the first sign of the disease (Jaffe 1972). d) The long interval between the time of infection and the onset of articular manifestations, which in our case began some 28 years later in the form of lumbar and sciatic pains. e) The mildness of the ataxia. This accords with the pathogenetic role of minor trauma. The uncommon features of the arthropathy in our patient were: a) The presence and the seriousness of the neurological deficits from root compression. According to Bouvier et al. (1972) neurological complications of vertebral tabetic arthropathy are extremely rare. Sieard and Lavagne (1967) suppose that in cases of severe root lesions, and especially when the lesions are bilateral, as in our case, compression takes effect at the level of the spinal canal rather than at that of the conjugate foramina. b) The rapid progression of the cauda equina compression symptoms (under a month). In most cases progression is slow, although it may be accelerated by an injury or pathological fracture (Jaffe 1972). c) Sphincter disturbances, reported as rare by l%amani and Sengupta. This depends, obviously, upon the level and the extent of the lesion.
Tabetic Lumbar
Osteoar~hropathy with Cauda Equina Syndrome
iII
Treatment of these tabetic lmnbar arthropathies depends on the severity of the symptoms. Mild arthropathy with incomplete loss of joint movement and slight clinical symptoms may benefit from a rigid support (MeNeel and Enhi 1969; Sicard 1967; Bouvier et al. 1972) or from spinal fusion (Storey 1964). When the spinal canal and foramina are markedly narrowed with severe neurological irritation with or without deficit there is no alternative to decompressive lamineetomy, with or without foraminotomy. In our case the patient is well 4 years after operation. At all events, high doses (up to 2-2.5 million units daily) of penicillin, in annual courses repeated at intervals of 1 to 1 89 months, starting with 100,000 units and increasing by 100,000 units daily up to the maximum dose, are extremely helpful. Penicillin permits better control of the disease and more lasting surgical results (Bouvier st al. 1972).
References
Bouvier, M., Lejeune, E., Boequet, B., Queneau, P., Langue, J. P., Syndrome de la queu de eheval par osteo-arthropathie vertebrale tabetique. (Revue g6ndrate h propos d'une observation personelle). Lyon Med. 227 (1972), 1 1 1 7 - - 1 1 2 7 . Brain, 1~., Wilkinson, M., Cervical arthropathy in syringomyelia, tabes dorsalis and diabetes. Brain 81 (1958), 275--289. Chareot, J. M., Sur quelques artbx'opathies qui paraissent d@endre d'une 16sion du eerveau ou de la moelle @inigre. Archs. Physiol. Norm. Path. 1 (1868), 171--178. Comte, J. P., La forme pseudo-Pottique de l'ost6o-arthropathie vert~brale tabdtique. These de Mddeeine, Lyon 1964. Cutting, P. E. J., A case of Chareot's disease of the cervical spine. Brit. Mcd. J. 1 (1949), 311. Eloesser, L., On the nature of neuropathie affections of joints. Ann. Surg. 66 (1917), 201--207. Delano, P. J., The pathogcnesis of Chareot's joint. Am. J. Roentgen. 56 (194~6), 189--200. Garvey, J. L., Glass, R. L., Tabetic spinal osteo-arthropathy: with report of four cases. Radiology 8 (1927), 133--139. Holland, I-I. W., Tabetic spinal arthropathy. Proc. 1%. Soe. Med. g6 (1953), 747--752. Jaffe, It. L., Metabolic, degenerative and inflammatory diseases of bones and joints, Chap. 27, p. 847--874. M/inehen-Berlin-Wien: Urban and Schwarzenberg. 1972. Jordan, W. R., Neuritic manifestations in diabetes mellitus. Arehs. Int. Med. 87 (1936), 307--366. NcNeel, D. P., Ehni, G., Chareot joint of the lumbar spine. J. Neurosurg. 30 (1969), 55--61. Ramani, P. S., Sengupta, 1R. P., Cauda equina compression due to tabetic arthropathy of the spine. J. Neurol. Neurosurg. Psyehiat. 36 (1973), 260--264.
112
G . P . Cantore et al. : Tabe~ie Lumbar Osteoarthropathy
Serre, H., Gros, C., Simon, L., Baumelou, It., Lamboley, C., Los compressions radiculaires par arthropathie vert~brale tab6tique, l~ev. ~ h u m . Mal. Ost6o-artic. 37 (1970), 525--533. Shands, A. R. jr., Neuropathies of the bones and joints. Report of a case of an arthropathy of the ankle duo to a peripheral nerve lesion. Arch. Surg. 20 (1930), 614---619. Sicard, A., Chirurgie du rachis. Paris : Masson et Cie. 1959 (rep. by Sicard, A., and Lavarde, G., 1967). - - Lavarde, G., Les ]gsions radiculaires au curs des arthropathies tab6tique du rachis lombaire. Presse Med. 75 (1967), 2209--2212. Storey, G., Charcot joints. Brit. J. Ven. Dis. 40 (1964), 109--116. Thurel, 1%, RTehlil, J., Lazar, L., Complications radiculaires e~ m6dullaires dos osl0eo-ar~hropathies vert6brales tab6tiques. Rev. :Neurol. 114 (1966), 62--65. Zucker, G., Marder, M. J., Charcot spine due ~0o diabetic neuropathy. Am. J. Med. 12 (1952), 118--124. Authors' address: Prof. Dr. G. P. Cantore and Dr. D. Gambacorta, Department of Neurosurgery of Siena, Medical School, Piazza Duomo 2, 1-53100 Siena, Italy.
Department of Neurosurgery of Siena Medical School, Siena, Italy
Tabetic Lumbar Osteoarthropathy with Cauda Equina Syndrome Case Report By G. P. eantore and D. Gambaeorta With 2 Figures Summary The ease is described of a 52 year old patient admitted for a cauda equina compression syndrome (flaccid paraplegia of the lower limbs, bilateral lumbar and sciatic pains, urinary incontinence) of rapid onset and due to narrowing of the lumbar canal from tabetic arthropathyl These vertebral manifestations occur in a low percentage of tabetic arthropathies, which are relatively rare, and are not often accompanied by severe neurological disturbances. Decompressive laminectomy afforded rapid and lasting
relief. Arthropathy due to nervous system lesions has been known for a long time (Mitchell 1831). The first to make precise reports were Scott and Allison (1843) on hemiplegia, Blasius (1848) and Sehlesinger (1895) on syringomyelia, Magnier (1859) on transverse myelitis, Packard (1861) and Shands (1930) on the association with traumatic or inflammatory lesions of the peripheral nerves and Jordan (1936) Zueker and Mander (1952) on diabetic neuropathy. Neurogenic arthropathy has also been reported after spinal cord injuries and in cases of eongenitM insensitivity to pain (see in Jaffe 1972). Charter (1868) was the first to suggest a possible relationship between tabes and this kind of arthropathy, which came to be known by his name. The pathogenesis of neurogenie arthropathy is uncertain. In some eases, as in tabes, looseness of the ligaments and museular hypotonia due to proprioeeptive afferent loss with or without a reduced input of pain stimuli induce articular hypermobility and abnormal friction at the joints
108
G . P . Cantore and D. Gambacorta:
causing erosion of c a r t i l a g e a n d m M a l i g n m e n t of t h e joints. L a t e r come d e s t r u c t i o n of t h e u n d e r l y i n g bone (osteoporosis w i t h connective tissue p r o l i f e r a t i o n b e t w e e n t h e d i s o r g a n i s e d lamellae), spinal disc degeneration, a n d s i m u l t a n e o u s bone p r o l i f e r a t i o n w i t h sclerosis of t h e bone ends a n d f o r m a t i o n of spurs (Jaffe 1972). I n t h e m a j o r i t y of eases p r o l i f e r a t i v e p h e n o m e n a p r e v a i l o v e r t h e regressive p h e n o m e n a , b u t in a n y case t h e m o r p h o l o g y a n d s t r u c t u r e of t h e affected j o i n t are a l t e r e d a n d w e a k e n e d so t h a t ankylosis a n d p a t h o l o g i c a l f r a c t u r e s are l i k e l y risks. T h e foregoing suppositions are confirmed b y e x p e r i m e n t a l w o r k (Eloesser 1917; Corbin 1937) and, in t a b e t i c p a t i e n t s , b y t h e r a r i t y of serious m a n i f e s t a t i o n s of m o t o r a t a x i a . T a b e s is r a r e l y seen t o d a y , a n d still more u n u s u a l are t h e a r t h r o p a t h i e s t h a t , according to r e p o r t s (l~{cNeel a n d E n h i 1969, a n d B o u v i e r et al. 1972), occur in 4-21~ of p a t i e n t s w i t h t h e disease. T a b e s nonetheless r a n k s second a f t e r s y r i n g o m y e l i ~ a m o n g t h e causes of neurogenic arthropathy. The following r e p o r t describes a ease of c a u d a e q u i n a s y n d r o m e due to t a b e t i c l u m b a r a r t h r o p a t h y .
Case Report S. t~., a m a n aged 52, who at the age of 24 years had contracted syphilis and was treated with some unspecified drug. A t 39 years of age his gait was somewhat unsteady and he had occasional paraesthesiae in the lower limbs. The diagnosis was tabes dorsalis, and penicillin t r e a t m e n t was given. The symptoms remained stationary for m a n y years b u t then over a period of 4 years the patient was hospitalised several times for attacks of abdominal pain accompanied by violent vomiting which responded to courses of high dose penicillin therapy. He had a 3 year history of mild lumbar pains and an 8 month history of bilateral lumbar and sciatic pains, more m a r k e d on the left side. During the 7 days before admission the pain became more severe with loss of movement in the lower limbs, urinary incontinence, vomiting, and abdominal pain. NeurologicM examination showed: flaccid paraplegia of the lower limbs, pronounced wasting of the lower limb muscles, superficial hypoesthesia at levels L3-$2, loss of vibration sense as far up as the iliae crests, hypotonia and decreased reflexes in the upper limbs, absent pupillary reflexes, optic disc pallor, and urinary incontinence. L u m b a r CSF: albumen 0.50g~o, VDl~L and T I T weakly positive. Serological tests : V D R L and T I T positive (~- @). Vertebral column X - r a y : fusion of L 1 and L 2, m a r k e d reduction of the lumbar disc spaces, massive marginal osteophytosis, narrowing of the spinal canal (Figs. 1 and 2). Positive contrast myelography b y suboceipital route: m a r k e d deformation and irregular reduction of the spinal subarachnoid space, partial arrests and skipping at the levels of the L 3-L 4, L 4 - L 5 and L 5-S 1 spaces, no visualization of the lumbar root pouches.
Tabetic Lumbar Osteoarthropaghy with Cauda Equina Sytldrome
Fig. 1
t09
Fig. 2
Figs. 1 and 2. Lumbar column X-ray in antero-pos~erior (Fig. i) and lateral view (Fig. 2): marked reduction of disk spaces, fusion of L 1 and L 2, massive marginal osteophytosis and narrowing of the spinal canal
Penicillin treatment (up to 2.5 million units daily) was started, and this was followed by relief of abdominal pain and disappearance of vomiting. Four days after admission the patient was subjected to lamincetomy from L 2 to S 1 with bilateral foraminotomies. The dural sac appeared to be squashed in an irregularly narrowed eanal. The bone was considerably increased in thickness but not in eonsisteney. The operation was followed by rapid and spectacular recovery. Pain virtually disappeared, bladder function was regained in a week, and the patient was able to walk without aid after about one month's intensive motor reeducation.
110
G.P. Cantore and D. Gambacorta: Discussion
Knee, hip, elbow, ankle and wrist are, in order of frequency, the joints most often affected by tabetic arthropathy. The lower limbs are affected, either alone or together with other joints, in 75% of cases (Jaffe 1972). Spinal column manifestations, with or without symptoms in other joints, are found in 6-20% of tabetic patients with articular complications (Bouvier et al. 1972). The foatures of our case that tally with those of the majority of the cases in the literature are: a) The lumbar localization. This segment of the column is the most affected. Of over 200 published cases (Serre 1970) only 3 cases of Charcot spine were at cervical level (Cutting 1949; Brain and Wilkinson 1958; Sieard 1959), 2 at dorsal level (Holland 1953; Thuiel et al. !966), and one at sacral level (Garvey and Glass 1927). b) Onset of symptoms in middle life (49 years in our patient. The mean age at onset of articular symptoms according to Bouvier et al. is 55 years). e) Clear history of tubes which, as a rule, is present in vertebral arthropathy, though it is more likely to be missing or missed with arthropathies in other sites (Comte 1964) when a painless joint swelling or a pathological fracture may be the first sign of the disease (Jaffe 1972). d) The long interval between the time of infection and the onset of articular manifestations, which in our case began some 28 years later in the form of lumbar and sciatic pains. e) The mildness of the ataxia. This accords with the pathogenetic role of minor trauma. The uncommon features of the arthropathy in our patient were: a) The presence and the seriousness of the neurological deficits from root compression. According to Bouvier et al. (1972) neurological complications of vertebral tabetic arthropathy are extremely rare. Sieard and Lavagne (1967) suppose that in cases of severe root lesions, and especially when the lesions are bilateral, as in our case, compression takes effect at the level of the spinal canal rather than at that of the conjugate foramina. b) The rapid progression of the cauda equina compression symptoms (under a month). In most cases progression is slow, although it may be accelerated by an injury or pathological fracture (Jaffe 1972). c) Sphincter disturbances, reported as rare by l%amani and Sengupta. This depends, obviously, upon the level and the extent of the lesion.
Tabetic Lumbar
Osteoar~hropathy with Cauda Equina Syndrome
iII
Treatment of these tabetic lmnbar arthropathies depends on the severity of the symptoms. Mild arthropathy with incomplete loss of joint movement and slight clinical symptoms may benefit from a rigid support (MeNeel and Enhi 1969; Sicard 1967; Bouvier et al. 1972) or from spinal fusion (Storey 1964). When the spinal canal and foramina are markedly narrowed with severe neurological irritation with or without deficit there is no alternative to decompressive lamineetomy, with or without foraminotomy. In our case the patient is well 4 years after operation. At all events, high doses (up to 2-2.5 million units daily) of penicillin, in annual courses repeated at intervals of 1 to 1 89 months, starting with 100,000 units and increasing by 100,000 units daily up to the maximum dose, are extremely helpful. Penicillin permits better control of the disease and more lasting surgical results (Bouvier st al. 1972).
References
Bouvier, M., Lejeune, E., Boequet, B., Queneau, P., Langue, J. P., Syndrome de la queu de eheval par osteo-arthropathie vertebrale tabetique. (Revue g6ndrate h propos d'une observation personelle). Lyon Med. 227 (1972), 1 1 1 7 - - 1 1 2 7 . Brain, 1~., Wilkinson, M., Cervical arthropathy in syringomyelia, tabes dorsalis and diabetes. Brain 81 (1958), 275--289. Chareot, J. M., Sur quelques artbx'opathies qui paraissent d@endre d'une 16sion du eerveau ou de la moelle @inigre. Archs. Physiol. Norm. Path. 1 (1868), 171--178. Comte, J. P., La forme pseudo-Pottique de l'ost6o-arthropathie vert~brale tabdtique. These de Mddeeine, Lyon 1964. Cutting, P. E. J., A case of Chareot's disease of the cervical spine. Brit. Mcd. J. 1 (1949), 311. Eloesser, L., On the nature of neuropathie affections of joints. Ann. Surg. 66 (1917), 201--207. Delano, P. J., The pathogcnesis of Chareot's joint. Am. J. Roentgen. 56 (194~6), 189--200. Garvey, J. L., Glass, R. L., Tabetic spinal osteo-arthropathy: with report of four cases. Radiology 8 (1927), 133--139. Holland, I-I. W., Tabetic spinal arthropathy. Proc. 1%. Soe. Med. g6 (1953), 747--752. Jaffe, It. L., Metabolic, degenerative and inflammatory diseases of bones and joints, Chap. 27, p. 847--874. M/inehen-Berlin-Wien: Urban and Schwarzenberg. 1972. Jordan, W. R., Neuritic manifestations in diabetes mellitus. Arehs. Int. Med. 87 (1936), 307--366. NcNeel, D. P., Ehni, G., Chareot joint of the lumbar spine. J. Neurosurg. 30 (1969), 55--61. Ramani, P. S., Sengupta, 1R. P., Cauda equina compression due to tabetic arthropathy of the spine. J. Neurol. Neurosurg. Psyehiat. 36 (1973), 260--264.
112
G . P . Cantore et al. : Tabe~ie Lumbar Osteoarthropathy
Serre, H., Gros, C., Simon, L., Baumelou, It., Lamboley, C., Los compressions radiculaires par arthropathie vert~brale tab6tique, l~ev. ~ h u m . Mal. Ost6o-artic. 37 (1970), 525--533. Shands, A. R. jr., Neuropathies of the bones and joints. Report of a case of an arthropathy of the ankle duo to a peripheral nerve lesion. Arch. Surg. 20 (1930), 614---619. Sicard, A., Chirurgie du rachis. Paris : Masson et Cie. 1959 (rep. by Sicard, A., and Lavarde, G., 1967). - - Lavarde, G., Les ]gsions radiculaires au curs des arthropathies tab6tique du rachis lombaire. Presse Med. 75 (1967), 2209--2212. Storey, G., Charcot joints. Brit. J. Ven. Dis. 40 (1964), 109--116. Thurel, 1%, RTehlil, J., Lazar, L., Complications radiculaires e~ m6dullaires dos osl0eo-ar~hropathies vert6brales tab6tiques. Rev. :Neurol. 114 (1966), 62--65. Zucker, G., Marder, M. J., Charcot spine due ~0o diabetic neuropathy. Am. J. Med. 12 (1952), 118--124. Authors' address: Prof. Dr. G. P. Cantore and Dr. D. Gambacorta, Department of Neurosurgery of Siena, Medical School, Piazza Duomo 2, 1-53100 Siena, Italy.
