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Radicular dysfunction due to spinal deformities in Marfan syndrome at older age: Three case reports
European Journal of Medical Genetics 53 (2010) 35e39
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short report
Radicular dysfunction due to spinal deformities in Marfan syndrome at older age: Three case reportsq,qq N.C. Voermans a, *, A.J. Hosman b, N. van Alfen a, c, R.H. Bartels d, M. de Kleuver e, J.W. op den Akker f, g, B.G. van Engelen a a
Donders Centre for Neuroscience, Department of Neurology, Radboud University Nijmegen Medical Centre, The Netherlands Department of Orthopedic Surgery, Radboud University Nijmegen Medical Centre, The Netherlands Department of Clinical Neurophysiology, Radboud University Nijmegen Medical Centre, The Netherlands d Department of Neurosurgery, Radboud University Nijmegen Medical Centre, The Netherlands e Department of Orthopedic Surgery, Sint Maartenskliniek Nijmegen, The Netherlands f Department of Radiology, Radboud University Nijmegen Medical Centre, The Netherlands g Department of Radiology, ZGT Almelo, The Netherlands b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 August 2009 Accepted 22 October 2009 Available online 30 October 2009
Marfan syndrome is a inherited connective tissue disorder due to mutations in fibrillin-1. It presents with cardiovascular, ocular, skeletal, pulmonary and dural signs and symptoms. Some of the symptoms of later onset are those associated with scoliosis and dural ectasia. This is the enlargement of the neural canal especially in the lower lumbar and sacral region and occurs in over 90% of Marfan patients. We here report three patients with lumbar and/or sacral radiculopathy due to (kypho)scoliosis and dural ectasia with spinal meningeal cysts. The pain, muscle weakness, muscle atrophy, and sensory disturbances illustrate the severe neurological complications which may occur in Marfan syndrome, especially at later age. Awareness of these complications and development of management protocols is essential since life expectancy of Marfan patients has increased. Marfan syndrome might gradually become recognized as an inherited connective tissue disorder with potentially severe neurological complications during ageing. Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords: Marfan syndrome Radiculopathy Muscle weakness Sensory disturbances Ageing Spinal meningeal cyst (Kypho)scoliosis
1. Introduction Marfan syndrome is an autosomally dominant inherited disorder of the connective tissue with an estimated prevalence of 1 in 5000. Phenotypic expression is variable and mutations in fibrillin-1 on chromosome 15 are detected in 66e91% of cases, of which 27% are de novo [8]. Clinical presentation includes cardiovascular, ocular, skeletal, dermal, pulmonary, and dural signs and
q Financial disclosure: We certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on us or on any organisation with which we are associated AND, if applicable, we certify that all financial and material support for this research (NIH or NHS grants) and work are clearly identified in the title page of the manuscript: N.V. was supported by a grant of the NWO (Netherlands Organisation for Scientific Research). qq Device status statement: The manuscript submitted does not contain information about medical device(s). * Corresponding author at: Donders Centre for Neuroscience, Department of Neurology, 935, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: þ31 24 3615202; fax: þ31 24 3541122. E-mail address: [email protected] (N.C. Voermans). 1769-7212/$ e see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2009.10.006
symptoms. Many symptoms present during puberty or later and severe complications (e.g. severe scoliosis and pectus excavatum, spontaneous pneumothorax, retinal detachment or sight-threatening glaucoma resulting from a dislocated lens) rarely develop before adulthood. With the availability of elective cardiac surgery and management by expert centers, the mean life expectancy of Marfan patients has increased from 32 years in 1972 to 41 years in 1993, and probably even much further since then [2,9,13,17, 19,21,27,30]. This increased life expectancy may be accompanied by increase of spinal and neurological complications. Some of the symptoms of later onset are those associated with scoliosis and dural ectasia [4]. Scoliosis affects around 60% of Marfan patients and may rapidly progress during growth spurts, leading to marked deformity, back pain, and restricted ventilation [2,16]. Dural ectasia is the enlargement of the neural canal especially in the lower lumbar and sacral region, which occurs in over 90% of Marfan patients [6], and less frequently in EhlerseDanlos syndrome or neurofibromatosis type I [3,26]. It is probably caused by ongoing hydrostatic pressure and transmitted pulsation of cerebrospinal fluid, which progressively dilates the dural sac since the elastin
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N.C. Voermans et al. / European Journal of Medical Genetics 53 (2010) 35e39
composition of the dura mater is altered due to fibrillin deficiency [6,13]. It can present as thinning of the cortex of the vertebral bodies, pedicles, and laminae of the vertebrae, as widening of the neural foraminae, or as an anterior (sacral) meningocele [4]. The diameter of dural ectasia seems to be related to age, and dural ectasia can be present for a long time without producing any noticeable symptoms [6,29]. Symptoms can include leg pain, abdominal pain, lower back pain, or postural headaches [16]. When the dilated part of the dura protrudes through the neural foramina, arachnoid cysts may develop either outside or inside the dura, which are respectively referred to as extradural cysts: type IeII and intradural cysts: type III [6,11,14,15]. Since classification based on imaging studies is difficult, these arachnoid cysts might better be described as spinal meningeal cysts. They have been associated with additional neurological symptoms, including sphincter disturbance and radicular compression with neurological deficits, especially in the elder patients [2,5,6,11,12,13,16,20,24]. Studies on treatment of symptomatic dural ectasia with or without spinal meningeal cysts are not available. We here report three patients with lumbar or sacral radiculopathy due to (kypho)scoliosis and dural ectasia with spinal meningeal cysts. The pain, muscle weakness, muscle atrophy, and sensory disturbances illustrate the severe neurological complications which may occur in Marfan syndrome, especially at later age. 2. Case reports The patients were referred to the neuromuscular outpatients department by the cardiologist at the multidisciplinary outpatients department for Marfan patients in one of the three specialized Marfan centers in The Netherlands Marfan syndrome was diagnosed based on the clinical diagnostic criteria [3] and confirmed by FBN1 mutation analysis in all three patients. Patient 2 has previously been reported in our systematic study on neuromuscular features in ten Marfan syndrome patients (F59) [29]. Patient 1 This 64-year year-old male patient suffered from severe pain for four years, radiating from his lower back to his left upper leg during walking or standing upright. Lower back pain had been present for longer, but was never as severe. The current pain had a burning character with a Visual Analogous Score of 9/10 when upright, completely disappearing after lying down. Pain severity had gradually increased and the pain also radiated to his right leg since one year. He was severely limited in his daily activities since he could not stand or walk longer than ten minutes because of the severe pain. He had also noticed numbness of the ventral and medial side of his lower leg. Erections had disappeared ten years ago, and the patient suffered from urinary hesitation, which was ameliorated by tamsulosin. Defecation was normal. Transdermal opiod patches and gabapentin had only resulted in partial pain reduction. Physical examination showed typical signs of Marfan syndrome, with mild weakness of hip flexion and of the ankle dorsiflexors bilaterally (MRC 4). Vibration sense was reduced in both feet, and pain and touch sensation were reduced in dermatomes L2eL4 on the left. Knee reflexes were normal, and ankle jerks were absent bilaterally. Nerve conduction studies revealed an axonal polyneuropathy, with neurogenic changes in the tibialis anterior muscle on needle EMG examination. Neurogenic changes were also found in both rectus femoris muscles, with denervation in the L4 paraspinal muscles on both sides, indicating bilateral L4 radiculopathy. Neurogenic changes of an older date were also observed in the gastrocnemius muscle on the left side (right side not tested), compatible with previous S1 radiculopathy or axonal polyneuropathy. Sagittal MRI
imaging of the lumbosacral spine revealed a kyphosis of segments L3eL5, with extensive degenerative changes (irregular superior and inferior endplates, osteophytes, bulging discs). The body of L3 was mildly laterally displaced to the left in relation to the body of L4, in combination with a right sided discus protrusion at this level. These findings resulted in bilateral narrowing of the foramina. Radices S1 were compressed along their course due to large bilateral sacral dural ectasia (Fig. 1). Neurosurgical intervention was not considered beneficial due to high risk of dural tears. A selective locoregional anesthetic block of the left L4 nerve root resulted in mild reduction of the radiating pain. Patient 2 A 58-year female patient suffered from progressive scoliosis, for which a thoracolumbal spondylodesis (anterior fusion and anterior single rod instrumention Th9eL2 through a left sided thoracoabdominal approach) was performed at the age of 33 years. At the age of 49, she reported symptoms of spinal stenosis. She developed a paresis of the right ankle and toe dorsiflexors, for which an orthesis was prescribed. Three years later she experienced numbness of the left foot and ankle. At the age of 56 years weakness of her right foot increased, and the quadriceps and hamstring muscles also became weak. She started using knee braces. One year later, paresis of the gluteal muscles occurred, which further impaired walking. With help of a walking aid she could walk a maximum of 2 km, needing several pauses. Gradually she developed urine retention and constipation for which she started intermittent bladder catheterization and had to remove feces manually. Physical examination at the age of 51 years revealed typical signs of Marfan syndrome, including severe kyphoscoliosis of the thoracolumbar spine after surgical correction. Strength, sensation, and reflexes of her arms, hands, and left leg were normal, but a mild paresis of her right leg MRC grade 4.5 was found. Examination at the age of 58 years showed progressive weakness of her right more than left leg and foot (MRC scores: Right: distally 0; hip flexion 3, hip extension 0; hip adduction 4, hip abduction 1, knee extension 3; Left: distally 3, proximally 4). Deep tendon reflexes were reduced in the left leg and absent on the right, and vibration sense was reduced in both feet. Muscle atrophy was most pronounced in her right leg, and she had bilateral claw feet (left more than right). Nerve conduction studies indicated an axonal polyneuropathy. Repeated needle electromyography revealed denervation in several leg muscles (rectus femoris, tibialis anterior, and gastrocnemius bilaterally; right extensor hallucis longus and right gluteus medius), with marked progression of neurogenic changes over the course of seven years. These findings were compatible with progressive radiculopathy at multiple lumbosacral levels. Sagittal MRI revealed dural ectasia and extensive spinal meningeal cysts at the sacral level. Transverse imaging showed a close relationship of the radices S1 and S2 with the spinal meningeal cysts. Furthermore, sagittal imaging showed severe thoracolumbar kyphoscoliosis, with an elongated aspect of the spinal cord, (epic)conus and cauda at these levels. Furthermore, the body of L2 showed a large bony defect of the posterior surface, partially surrounding the conus. The conus seemed to be stretched out at this level (Fig. 2). The patient participated in a clinical rehabilitation program to increase physical condition and to limit impairments. This program consisted of: pelvic floor therapy to improve control of defecation; training with a hand bike to improve outdoor mobility; provision of new orthopedic shoes; physical therapy including hydrotherapy, focusing on walking and improvement of muscle strength and cardiorespiratory fitness; occupational therapy for adaptive equipment recommendations and usage training, and environmental
N.C. Voermans et al. / European Journal of Medical Genetics 53 (2010) 35e39
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Fig. 1. Patient 1: T2 weighted MRI at the age of 64 years: Sagittal MRI imaging of the lumbosacral spine revealed a kyphosis of segments L3eL5, with extensive degenerative changes (irregular superior and inferior endplates, osteophytes, bulging of discs), dural ectasia and extensive sacral spinal meningeal cysts (left image). The right S1 root is compressed by large spinal meningeal cysts and no longer completely surrounded by fat.
adaptation including provision of equipment; and psychological assessment and counseling. Based on reduction of her impairments and on the general satisfaction of this patient, this program was considered successful. Operative intervention including multiple osteotomies of the lumbar spine and instrumentation over a long segment was considered but not performed since its outcome was deemed too unpredictable in relation to the possible complications of the procedure. Patient 3 This 51-year-old male patient suffered from a ruptured aneurysm of the abdominal aorta at the age of 49 years, which resulted in spinal cord ischemia with paraparesis, impotence and urinary retention for which he performed intermittent bladder catheterization. He had gradually regained mobility after rehabilitation, but
in spite of the improvement of muscle strength and mobility he experienced progressive pain, radiating from his lower back to both legs and the sacral dermatomes. At rest the pain consisted of a cold burning sensation exacerbated by touch. Walking of short distances (20e100 m) caused a feeling of stiffness in his lower legs that would gradually turn in to severe pain. If he continued walking he would fall because of muscle weakness and pain. Physical examination showed typical signs of Marfan syndrome. Muscle strength was normal in his arms and reduced in the legs (MRC scores: proximally 4; distally 2e3). Sensation was reduced below the 12th thoracic dermatome. Pain sense and vibration sense were absent in his feet. Touch of the sacral region was very painful locally. Although the knee jerks were increased, his ankle jerks were absent bilaterally. Nerve conduction studies showed an axonal polyneuropathy. Needle electromyography showed neurogenic changes in the
Fig. 2. Patient 2: T2 weighted MRI at the age of 58 years: Dural ectasia and extensive spinal meningeal cysts at the level of L5eS1. Transverse images showed a close relationship of the radices S1 and S2 with the dural ectasia and spinal meningeal cysts (left image). Sagittal MRI images further showed a severe thoracolumbar kyphoscoliosis, along which the spinal cord, (epi)conus and cauda were extended. No signs of root compression were found at these levels. However, the posterior surface of the L2 body revealed a large bony defect partially surrounding the conus and seemingly stretching it (right image). Just above that level, susceptibility artifacts due to a ferromagnetic metal implant were observed.
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Fig. 3. Patient 3: T2 weighted MRI at the age of 51 years: MRI studies of the thoracic, lumbal and sacral spine showed an anterolisthesis of L5eS1, thoracic scoliosis, and lumbosacral dural ectasia and spinal meningeal cysts with severe scalloping of the posterior cortex S1 and S2 (left image). Both S1 roots are in close contact with the dural ectasia and bilateral spinal meningeal cysts (right image).
extensor hallucis, tibialis anterior, and gluteus medius muscles on the left, and of the gastrocnemius and gluteus maximus on the right, with signs of reinnervation in the right gluteus maximus. Findings were compatible with longer lasting radiculopathy of the L5eS2 levels on the left and S1eS2 levels on the right. No EMG abnormalities were found in the hands. T2 weighted MRI studies of the thoracic, lumbal and sacral spine showed thoracic scoliosis, an anterolisthesis of L5eS1, and lumbosacral dural ectasia and spinal meningeal cysts with severe scalloping of the posterior surface of S1 and S2, suggestive of longer lasting compression by the dural ectasia. Both S1 roots were in close contact with the dural ectasia and spinal meningeal cysts. No signs of syringomyely were seen (Fig. 3). Neurosurgical intervention was again not considered beneficial due to the multifactorial origin of the pain and the high risk of perioperative dural tears. 3. Discussion We here report three genetically confirmed older Marfan patients with pain in the lower back and legs and neurological impairment due to progressive lumbosacral radiculopathy at multiple levels. In all patients symptoms occurred predominantly while standing upright or walking, which suggests a role of the hydrostatic pressure of the cerebrospinal fluid within the dural ectasia and/or meningeal cyst in the progression of radicular compression. A concomitant axonal polyneuropathy was detected in all patients, which concurs with our previous findings in ten Marfan patients [29]. Spinal cord ischemia may have contributed to severity of neurological features in patient 3. Imaging studies revealed (kypho)scoliosis, anterolisthesis, degenerative changes, and sacral root compression by dural ectasia with spinal meningeal cysts in all three patients. Surgical options were considered limited due to the high risk of occurrence of dural tears and osseous complications. Neurological impairment secondary to spinal abnormalities in Marfan syndrome has occasionally been reported. Hoshino reported a Marfan patient with dysesthesia of dermatome S2 and sacral pain due to S2 root compression by an arachnoid mass [11]. Furthermore,
a 25-year-old man with a two-year history of worsening distal sensory and motor deficits of the lower limbs due to a large intraspinal arachnoidal cyst was reported by Lazzaro [5]. A study by Foran et al. showed that dural ectasia is often accompanied by leg pain and sensory deficits in the legs, but this was based on questionnaires and did not include clinical or imaging data [7]. Dural ectasia with or without spinal meningeal cysts may cause symptoms through a variety of mechanisms [7], including direct pressure on the periosteum and erosion of bony elements of the lumbosacral spine [10,25], distortion or traction on neural roots [22], structural thinning and weakening of the sacrum leading to micro-fractures or instability, direct pressure on abdominal organs by anterior meningocele, shifts in cerebrospinal fluid volume, or increased pressure within focal cysts [1,18,23]. In the three patients reported here, both osseous deformities and dural ectasia with spinal meningeal cysts are likely to have contributed to the radicular dysfunction. Increased vulnerability of peripheral and central nervous system to mechanical stress by dural ectasia might predispose to these symptoms in Marfan syndrome, similarly as in other inherited connective tissue disorders [28]. Awareness of these complications and development of management protocols is essential since life expectancy of Marfan patients has increased [9]. Marfan syndrome might become better recognized as an inherited connective tissue disorder with potentially severe neurological complications, also at older age [29]. References [1] N.U. Ahn, P.D. Sponseller, U.M. Ahn, L. Nallamshetty, B.S. Kuszyk, S.J. Zinreich, Dural ectasia is associated with back pain in Marfan syndrome. Spine 25 (2000) 1562e1568. [2] J.C. Dean, Marfan syndrome: clinical diagnosis and management. Eur. J. Hum. Genet. 15 (2007) 724e733. [3] M. de Kleuver, J.P. van Jonbergen, D.D. Langeloo, Asymptomatic massive dural ectasia associated with neurofibromatosis type 1 threatening spinal column support: treatment by anterior vascularized fibula graft. J. Spinal Disord. Tech. 17 (2004) 539e542. [4] A.M. De Paepe, R.B. Devereux, H.C. Dietz, R.C. Hennekam, R.E. Pyeritz, Revised diagnostic criteria for the Marfan syndrome. Am. J. Med. Genet. 62 (1996) 417e426.
N.C. Voermans et al. / European Journal of Medical Genetics 53 (2010) 35e39 [5] V. Di Lazzaro, F. Pilato, M. Dileone, G. Minicuci, P. Profice, C. Colosimo, T. Tartaglione, P.A. Tonali, Extradural arachnoid cyst with lumbosacral cord and root compression in marfan syndrome. Arch. Neurol. 64 (2007) 284e285. [6] R. Fattori, C.A. Nienaber, B. Descovich, P. Ambrosetto, L.B. Reggiani, G. Pepe, U. Kaufmann, E. Negrini, K.Y. von, G.F. Gensini, Importance of dural ectasia in phenotypic assessment of Marfan's syndrome. Lancet 354 (1999) 910e913. [7] J.R. Foran, R.E. Pyeritz, H.C. Dietz, P.D. Sponseller, Characterization of the symptoms associated with dural ectasia in the Marfan patient. Am. J. Med. Genet. A 134A (2005) 58e65. [8] J.R. Gray, A.B. Bridges, R.R. West, L. McLeish, A.G. Stuart, J.C. Dean, M.E. Porteous, M. Boxer, S.J. Davies, Life expectancy in British Marfan syndrome populations. Clin. Genet. 54 (1998) 124e128. [9] A. Hasan, J. Poloniecki, A. Child, Ageing in Marfan syndrome. Int. J. Clin. Pract. 61 (2007) 1308e1320. [10] N.C. Ho, D.W. Hadley, P.K. Jain, C.A. Francomano, Case 47: dural ectasia associated with Marfan syndrome. Radiology 223 (2002) 767e771. [11] Y. Hoshino, H. Edakuni, H. Shimada, S. Hayashi, M. Machida, S. Shimano, T. Taya, I. Ohki, A. Takahashi, T. Kurihara, I. Yamada, T. Arai, Y. Miyamoto, Y. Togo, Sacral arachnoid cyst associated with marfan syndrome. Intern. Med. 44 (2005) 271e273. [12] K.B. Jones, G. Erkula, P.D. Sponseller, J.P. Dormans, Spine deformity correction in Marfan syndrome. Spine 27 (2002) 2003e2012. [13] K.B. Jones, P.D. Sponseller, G. Erkula, L. Sakai, F. Ramirez, H.C. Dietz III, S. KostByerly, K.H. Bridwell, L. Sandell, Symposium on the musculoskeletal aspects of Marfan syndrome: meeting report and state of the science. J. Orthop. Res. 25 (2007) 413e422. [14] M.W. Nabors, T.G. Pait, E.B. Byrd, N.O. Karim, D.O. Davis, A.I. Kobrine, H.V. Rizzoli, Updated assessment and current classification of spinal meningeal cysts. J. Neurosurg. 68 (1988) 366e377. [15] T. Oosterhof, M. Groenink, F.J. Hulsmans, B.J. Mulder, E.E. van der Wall, R. Smit, R.C. Hennekam, Quantitative assessment of dural ectasia as a marker for Marfan syndrome. Radiology 220 (2001) 514e518. [16] R.E. Pyeritz, U. Francke, The Second International Symposium on the marfan syndrome. Am. J. Med. Genet. 47 (1993) 127e135. [17] R.E. Pyeritz, Marfan syndrome: 30 years of research equals 30 years of additional life expectancy. Heart 95 (2009) 173e175.
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[18] C. Raftopoulos, F. Delecluse, P. Braude, C. Rodesh, J. Brotchi, Anterior sacral meningocele and Marfan syndrome: a review. Acta Chir Belg 93 (1993) 1e7. [19] F. Ramirez, H.C. Dietz, Marfan syndrome: from molecular pathogenesis to clinical treatment. Curr. Opin. Genet. Dev. 17 (2007) 252e258. [20] L. Robinson, R. Dominguez, J. Cabrera, J.W. Yeakley, M.J. Fenstermacher, M. E. Milner, Multiple meningeal cysts in Marfan syndrome. AJNR Am. J. Neuroradiol 10 (1989) 1275e1276. [21] D.I. Silverman, K.J. Burton, J. Gray, M.S. Bosner, N.T. Kouchoukos, M.J. Roman, M. Boxer, R.B. Devereux, P. Tsipouras, Life expectancy in the Marfan syndrome. Am. J. Cardiol. 75 (1995) 157e160. [22] M.D. Smith, Large sacral dural defect in Marfan syndrome. A case report. J. Bone Jt. Surg. Am. 75 (1993) 1067e1070. [23] C.B. Sonier, T. Buhe, P. Despins, J. Delumeau, A. de Kersaint-Gilly, Sacral pseudomeningocele and Marfan's disease. One case. J. Neuroradiol 20 (1993) 292e296. [24] P.D. Sponseller, M. Shindle, Orthopedic problems in Marfan syndrome. in: P.N. Robinson, M. Godfrey (Eds.), Marfan Syndrome: a Primer for Clinicians and Scientists. Kluwer Academic/ Plenium Publishers, New York, 2004, pp. 24e34. [25] W.E. Stern, Dural ectasia and the Marfan syndrome. J. Neurosurg. 69 (1988) 221e227. [26] G.M. Villeirs, A.J. Van Tongerloo, K.L. Verstraete, M.F. Kunnen, A.M. De Paepe, Widening of the spinal canal and dural ectasia in Marfan's syndrome: assessment by CT. Neuroradiology 41 (1999) 850e854. [27] Y. von Kodolitsch, P.N. Robinson, Marfan syndrome: an update of genetics, medical and surgical management. Heart 93 (2007) 755e760. [28] N.C. Voermans, G. Drost, A. van Kampen, A.A. Gabreels-Festen, M. Lammens, B.C. Hamel, J. Schalkwijk, B.G. van Engelen, Recurrent neuropathy associated with EhlerseDanlos syndrome. J. Neurol. 253 (2006) 670e671. [29] N.C. Voermans, J. Timmermans, N. van Alfen, S. Pillen, J. op den Akker, M. Lammens, M.J. Zwarts, I.A.L.M. van Rooiji, B.C. Hamel, B.G. Engelen, Neuromuscular features in Marfan syndrome. Clin. Genet. 76 (2009) 25e37. [30] N.C. Voermans, N. van Alfen, S. Pillen, M. Lammens, J. Schalkwijk, M.J. Zwarts, I. van Rooij, B.C. Hamel, B.G. van Engelen, Neuromuscular involvement in various types of EhlerseDanlos syndrome. Ann. Neurol. 65 (2009) 687e697.
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short report
Radicular dysfunction due to spinal deformities in Marfan syndrome at older age: Three case reportsq,qq N.C. Voermans a, *, A.J. Hosman b, N. van Alfen a, c, R.H. Bartels d, M. de Kleuver e, J.W. op den Akker f, g, B.G. van Engelen a a
Donders Centre for Neuroscience, Department of Neurology, Radboud University Nijmegen Medical Centre, The Netherlands Department of Orthopedic Surgery, Radboud University Nijmegen Medical Centre, The Netherlands Department of Clinical Neurophysiology, Radboud University Nijmegen Medical Centre, The Netherlands d Department of Neurosurgery, Radboud University Nijmegen Medical Centre, The Netherlands e Department of Orthopedic Surgery, Sint Maartenskliniek Nijmegen, The Netherlands f Department of Radiology, Radboud University Nijmegen Medical Centre, The Netherlands g Department of Radiology, ZGT Almelo, The Netherlands b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 August 2009 Accepted 22 October 2009 Available online 30 October 2009
Marfan syndrome is a inherited connective tissue disorder due to mutations in fibrillin-1. It presents with cardiovascular, ocular, skeletal, pulmonary and dural signs and symptoms. Some of the symptoms of later onset are those associated with scoliosis and dural ectasia. This is the enlargement of the neural canal especially in the lower lumbar and sacral region and occurs in over 90% of Marfan patients. We here report three patients with lumbar and/or sacral radiculopathy due to (kypho)scoliosis and dural ectasia with spinal meningeal cysts. The pain, muscle weakness, muscle atrophy, and sensory disturbances illustrate the severe neurological complications which may occur in Marfan syndrome, especially at later age. Awareness of these complications and development of management protocols is essential since life expectancy of Marfan patients has increased. Marfan syndrome might gradually become recognized as an inherited connective tissue disorder with potentially severe neurological complications during ageing. Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords: Marfan syndrome Radiculopathy Muscle weakness Sensory disturbances Ageing Spinal meningeal cyst (Kypho)scoliosis
1. Introduction Marfan syndrome is an autosomally dominant inherited disorder of the connective tissue with an estimated prevalence of 1 in 5000. Phenotypic expression is variable and mutations in fibrillin-1 on chromosome 15 are detected in 66e91% of cases, of which 27% are de novo [8]. Clinical presentation includes cardiovascular, ocular, skeletal, dermal, pulmonary, and dural signs and
q Financial disclosure: We certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on us or on any organisation with which we are associated AND, if applicable, we certify that all financial and material support for this research (NIH or NHS grants) and work are clearly identified in the title page of the manuscript: N.V. was supported by a grant of the NWO (Netherlands Organisation for Scientific Research). qq Device status statement: The manuscript submitted does not contain information about medical device(s). * Corresponding author at: Donders Centre for Neuroscience, Department of Neurology, 935, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: þ31 24 3615202; fax: þ31 24 3541122. E-mail address: [email protected] (N.C. Voermans). 1769-7212/$ e see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2009.10.006
symptoms. Many symptoms present during puberty or later and severe complications (e.g. severe scoliosis and pectus excavatum, spontaneous pneumothorax, retinal detachment or sight-threatening glaucoma resulting from a dislocated lens) rarely develop before adulthood. With the availability of elective cardiac surgery and management by expert centers, the mean life expectancy of Marfan patients has increased from 32 years in 1972 to 41 years in 1993, and probably even much further since then [2,9,13,17, 19,21,27,30]. This increased life expectancy may be accompanied by increase of spinal and neurological complications. Some of the symptoms of later onset are those associated with scoliosis and dural ectasia [4]. Scoliosis affects around 60% of Marfan patients and may rapidly progress during growth spurts, leading to marked deformity, back pain, and restricted ventilation [2,16]. Dural ectasia is the enlargement of the neural canal especially in the lower lumbar and sacral region, which occurs in over 90% of Marfan patients [6], and less frequently in EhlerseDanlos syndrome or neurofibromatosis type I [3,26]. It is probably caused by ongoing hydrostatic pressure and transmitted pulsation of cerebrospinal fluid, which progressively dilates the dural sac since the elastin
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composition of the dura mater is altered due to fibrillin deficiency [6,13]. It can present as thinning of the cortex of the vertebral bodies, pedicles, and laminae of the vertebrae, as widening of the neural foraminae, or as an anterior (sacral) meningocele [4]. The diameter of dural ectasia seems to be related to age, and dural ectasia can be present for a long time without producing any noticeable symptoms [6,29]. Symptoms can include leg pain, abdominal pain, lower back pain, or postural headaches [16]. When the dilated part of the dura protrudes through the neural foramina, arachnoid cysts may develop either outside or inside the dura, which are respectively referred to as extradural cysts: type IeII and intradural cysts: type III [6,11,14,15]. Since classification based on imaging studies is difficult, these arachnoid cysts might better be described as spinal meningeal cysts. They have been associated with additional neurological symptoms, including sphincter disturbance and radicular compression with neurological deficits, especially in the elder patients [2,5,6,11,12,13,16,20,24]. Studies on treatment of symptomatic dural ectasia with or without spinal meningeal cysts are not available. We here report three patients with lumbar or sacral radiculopathy due to (kypho)scoliosis and dural ectasia with spinal meningeal cysts. The pain, muscle weakness, muscle atrophy, and sensory disturbances illustrate the severe neurological complications which may occur in Marfan syndrome, especially at later age. 2. Case reports The patients were referred to the neuromuscular outpatients department by the cardiologist at the multidisciplinary outpatients department for Marfan patients in one of the three specialized Marfan centers in The Netherlands Marfan syndrome was diagnosed based on the clinical diagnostic criteria [3] and confirmed by FBN1 mutation analysis in all three patients. Patient 2 has previously been reported in our systematic study on neuromuscular features in ten Marfan syndrome patients (F59) [29]. Patient 1 This 64-year year-old male patient suffered from severe pain for four years, radiating from his lower back to his left upper leg during walking or standing upright. Lower back pain had been present for longer, but was never as severe. The current pain had a burning character with a Visual Analogous Score of 9/10 when upright, completely disappearing after lying down. Pain severity had gradually increased and the pain also radiated to his right leg since one year. He was severely limited in his daily activities since he could not stand or walk longer than ten minutes because of the severe pain. He had also noticed numbness of the ventral and medial side of his lower leg. Erections had disappeared ten years ago, and the patient suffered from urinary hesitation, which was ameliorated by tamsulosin. Defecation was normal. Transdermal opiod patches and gabapentin had only resulted in partial pain reduction. Physical examination showed typical signs of Marfan syndrome, with mild weakness of hip flexion and of the ankle dorsiflexors bilaterally (MRC 4). Vibration sense was reduced in both feet, and pain and touch sensation were reduced in dermatomes L2eL4 on the left. Knee reflexes were normal, and ankle jerks were absent bilaterally. Nerve conduction studies revealed an axonal polyneuropathy, with neurogenic changes in the tibialis anterior muscle on needle EMG examination. Neurogenic changes were also found in both rectus femoris muscles, with denervation in the L4 paraspinal muscles on both sides, indicating bilateral L4 radiculopathy. Neurogenic changes of an older date were also observed in the gastrocnemius muscle on the left side (right side not tested), compatible with previous S1 radiculopathy or axonal polyneuropathy. Sagittal MRI
imaging of the lumbosacral spine revealed a kyphosis of segments L3eL5, with extensive degenerative changes (irregular superior and inferior endplates, osteophytes, bulging discs). The body of L3 was mildly laterally displaced to the left in relation to the body of L4, in combination with a right sided discus protrusion at this level. These findings resulted in bilateral narrowing of the foramina. Radices S1 were compressed along their course due to large bilateral sacral dural ectasia (Fig. 1). Neurosurgical intervention was not considered beneficial due to high risk of dural tears. A selective locoregional anesthetic block of the left L4 nerve root resulted in mild reduction of the radiating pain. Patient 2 A 58-year female patient suffered from progressive scoliosis, for which a thoracolumbal spondylodesis (anterior fusion and anterior single rod instrumention Th9eL2 through a left sided thoracoabdominal approach) was performed at the age of 33 years. At the age of 49, she reported symptoms of spinal stenosis. She developed a paresis of the right ankle and toe dorsiflexors, for which an orthesis was prescribed. Three years later she experienced numbness of the left foot and ankle. At the age of 56 years weakness of her right foot increased, and the quadriceps and hamstring muscles also became weak. She started using knee braces. One year later, paresis of the gluteal muscles occurred, which further impaired walking. With help of a walking aid she could walk a maximum of 2 km, needing several pauses. Gradually she developed urine retention and constipation for which she started intermittent bladder catheterization and had to remove feces manually. Physical examination at the age of 51 years revealed typical signs of Marfan syndrome, including severe kyphoscoliosis of the thoracolumbar spine after surgical correction. Strength, sensation, and reflexes of her arms, hands, and left leg were normal, but a mild paresis of her right leg MRC grade 4.5 was found. Examination at the age of 58 years showed progressive weakness of her right more than left leg and foot (MRC scores: Right: distally 0; hip flexion 3, hip extension 0; hip adduction 4, hip abduction 1, knee extension 3; Left: distally 3, proximally 4). Deep tendon reflexes were reduced in the left leg and absent on the right, and vibration sense was reduced in both feet. Muscle atrophy was most pronounced in her right leg, and she had bilateral claw feet (left more than right). Nerve conduction studies indicated an axonal polyneuropathy. Repeated needle electromyography revealed denervation in several leg muscles (rectus femoris, tibialis anterior, and gastrocnemius bilaterally; right extensor hallucis longus and right gluteus medius), with marked progression of neurogenic changes over the course of seven years. These findings were compatible with progressive radiculopathy at multiple lumbosacral levels. Sagittal MRI revealed dural ectasia and extensive spinal meningeal cysts at the sacral level. Transverse imaging showed a close relationship of the radices S1 and S2 with the spinal meningeal cysts. Furthermore, sagittal imaging showed severe thoracolumbar kyphoscoliosis, with an elongated aspect of the spinal cord, (epic)conus and cauda at these levels. Furthermore, the body of L2 showed a large bony defect of the posterior surface, partially surrounding the conus. The conus seemed to be stretched out at this level (Fig. 2). The patient participated in a clinical rehabilitation program to increase physical condition and to limit impairments. This program consisted of: pelvic floor therapy to improve control of defecation; training with a hand bike to improve outdoor mobility; provision of new orthopedic shoes; physical therapy including hydrotherapy, focusing on walking and improvement of muscle strength and cardiorespiratory fitness; occupational therapy for adaptive equipment recommendations and usage training, and environmental
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Fig. 1. Patient 1: T2 weighted MRI at the age of 64 years: Sagittal MRI imaging of the lumbosacral spine revealed a kyphosis of segments L3eL5, with extensive degenerative changes (irregular superior and inferior endplates, osteophytes, bulging of discs), dural ectasia and extensive sacral spinal meningeal cysts (left image). The right S1 root is compressed by large spinal meningeal cysts and no longer completely surrounded by fat.
adaptation including provision of equipment; and psychological assessment and counseling. Based on reduction of her impairments and on the general satisfaction of this patient, this program was considered successful. Operative intervention including multiple osteotomies of the lumbar spine and instrumentation over a long segment was considered but not performed since its outcome was deemed too unpredictable in relation to the possible complications of the procedure. Patient 3 This 51-year-old male patient suffered from a ruptured aneurysm of the abdominal aorta at the age of 49 years, which resulted in spinal cord ischemia with paraparesis, impotence and urinary retention for which he performed intermittent bladder catheterization. He had gradually regained mobility after rehabilitation, but
in spite of the improvement of muscle strength and mobility he experienced progressive pain, radiating from his lower back to both legs and the sacral dermatomes. At rest the pain consisted of a cold burning sensation exacerbated by touch. Walking of short distances (20e100 m) caused a feeling of stiffness in his lower legs that would gradually turn in to severe pain. If he continued walking he would fall because of muscle weakness and pain. Physical examination showed typical signs of Marfan syndrome. Muscle strength was normal in his arms and reduced in the legs (MRC scores: proximally 4; distally 2e3). Sensation was reduced below the 12th thoracic dermatome. Pain sense and vibration sense were absent in his feet. Touch of the sacral region was very painful locally. Although the knee jerks were increased, his ankle jerks were absent bilaterally. Nerve conduction studies showed an axonal polyneuropathy. Needle electromyography showed neurogenic changes in the
Fig. 2. Patient 2: T2 weighted MRI at the age of 58 years: Dural ectasia and extensive spinal meningeal cysts at the level of L5eS1. Transverse images showed a close relationship of the radices S1 and S2 with the dural ectasia and spinal meningeal cysts (left image). Sagittal MRI images further showed a severe thoracolumbar kyphoscoliosis, along which the spinal cord, (epi)conus and cauda were extended. No signs of root compression were found at these levels. However, the posterior surface of the L2 body revealed a large bony defect partially surrounding the conus and seemingly stretching it (right image). Just above that level, susceptibility artifacts due to a ferromagnetic metal implant were observed.
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Fig. 3. Patient 3: T2 weighted MRI at the age of 51 years: MRI studies of the thoracic, lumbal and sacral spine showed an anterolisthesis of L5eS1, thoracic scoliosis, and lumbosacral dural ectasia and spinal meningeal cysts with severe scalloping of the posterior cortex S1 and S2 (left image). Both S1 roots are in close contact with the dural ectasia and bilateral spinal meningeal cysts (right image).
extensor hallucis, tibialis anterior, and gluteus medius muscles on the left, and of the gastrocnemius and gluteus maximus on the right, with signs of reinnervation in the right gluteus maximus. Findings were compatible with longer lasting radiculopathy of the L5eS2 levels on the left and S1eS2 levels on the right. No EMG abnormalities were found in the hands. T2 weighted MRI studies of the thoracic, lumbal and sacral spine showed thoracic scoliosis, an anterolisthesis of L5eS1, and lumbosacral dural ectasia and spinal meningeal cysts with severe scalloping of the posterior surface of S1 and S2, suggestive of longer lasting compression by the dural ectasia. Both S1 roots were in close contact with the dural ectasia and spinal meningeal cysts. No signs of syringomyely were seen (Fig. 3). Neurosurgical intervention was again not considered beneficial due to the multifactorial origin of the pain and the high risk of perioperative dural tears. 3. Discussion We here report three genetically confirmed older Marfan patients with pain in the lower back and legs and neurological impairment due to progressive lumbosacral radiculopathy at multiple levels. In all patients symptoms occurred predominantly while standing upright or walking, which suggests a role of the hydrostatic pressure of the cerebrospinal fluid within the dural ectasia and/or meningeal cyst in the progression of radicular compression. A concomitant axonal polyneuropathy was detected in all patients, which concurs with our previous findings in ten Marfan patients [29]. Spinal cord ischemia may have contributed to severity of neurological features in patient 3. Imaging studies revealed (kypho)scoliosis, anterolisthesis, degenerative changes, and sacral root compression by dural ectasia with spinal meningeal cysts in all three patients. Surgical options were considered limited due to the high risk of occurrence of dural tears and osseous complications. Neurological impairment secondary to spinal abnormalities in Marfan syndrome has occasionally been reported. Hoshino reported a Marfan patient with dysesthesia of dermatome S2 and sacral pain due to S2 root compression by an arachnoid mass [11]. Furthermore,
a 25-year-old man with a two-year history of worsening distal sensory and motor deficits of the lower limbs due to a large intraspinal arachnoidal cyst was reported by Lazzaro [5]. A study by Foran et al. showed that dural ectasia is often accompanied by leg pain and sensory deficits in the legs, but this was based on questionnaires and did not include clinical or imaging data [7]. Dural ectasia with or without spinal meningeal cysts may cause symptoms through a variety of mechanisms [7], including direct pressure on the periosteum and erosion of bony elements of the lumbosacral spine [10,25], distortion or traction on neural roots [22], structural thinning and weakening of the sacrum leading to micro-fractures or instability, direct pressure on abdominal organs by anterior meningocele, shifts in cerebrospinal fluid volume, or increased pressure within focal cysts [1,18,23]. In the three patients reported here, both osseous deformities and dural ectasia with spinal meningeal cysts are likely to have contributed to the radicular dysfunction. Increased vulnerability of peripheral and central nervous system to mechanical stress by dural ectasia might predispose to these symptoms in Marfan syndrome, similarly as in other inherited connective tissue disorders [28]. Awareness of these complications and development of management protocols is essential since life expectancy of Marfan patients has increased [9]. Marfan syndrome might become better recognized as an inherited connective tissue disorder with potentially severe neurological complications, also at older age [29]. References [1] N.U. Ahn, P.D. Sponseller, U.M. Ahn, L. Nallamshetty, B.S. Kuszyk, S.J. Zinreich, Dural ectasia is associated with back pain in Marfan syndrome. Spine 25 (2000) 1562e1568. [2] J.C. Dean, Marfan syndrome: clinical diagnosis and management. Eur. J. Hum. Genet. 15 (2007) 724e733. [3] M. de Kleuver, J.P. van Jonbergen, D.D. Langeloo, Asymptomatic massive dural ectasia associated with neurofibromatosis type 1 threatening spinal column support: treatment by anterior vascularized fibula graft. J. Spinal Disord. Tech. 17 (2004) 539e542. [4] A.M. De Paepe, R.B. Devereux, H.C. Dietz, R.C. Hennekam, R.E. Pyeritz, Revised diagnostic criteria for the Marfan syndrome. Am. J. Med. Genet. 62 (1996) 417e426.
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