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Recurrent Ischemic Stroke in an Adult with Cystinosis: A Clinical–Pathological Case
Case Report
Recurrent Ischemic Stroke in an Adult with Cystinosis: A Clinical–Pathological Case Dulce Neutel, MD,* Ruth Geraldes, MD,* Pedro Pereira, MSc,† Ant onio Gomes da Costa, MD,‡ Jose Pimentel, PhD,†x and Teresa Pinho e Melo, MD*
A 32-year-old woman with infantile nephropathic cystinosis presented with cystinosis and recurrent ischemic stroke. The neuropathological description demonstrates that recurrent stroke was caused by intracranial stenosis and showed evidence of cystinosis brain involvement. There are few reports of cerebrovascular disease in patients with longstanding nephropathic cystinosis. This case reinforces that cerebrovascular disease can be a cause of neurological impairment and disability in patients with longstanding nephropathic cystinosis, with implications on primary stroke prevention strategies in these patients. Key Words: Cystinosis—genetics— stroke—neuropathology. Ó 2013 by National Stroke Association
Case Report A 32-year-old woman with infantile nephropathic cystinosis presented with sudden onset of speech and gait disturbance. She had renal transplant when she was 12 years; she was on cyclosporine for 17 years and then on hemodialysis in the past 3 years and under cysteamine, levothyroxine, calcium, and folic acid. There were no vascular risk factors, except a systolic blood pressure of 160 mm Hg at admission. Neurologic examination showed severe bilateral visual loss, pendular nystagmus, right central facial
From the *Stroke Unit, Neurosciences Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon; †Laboratory of Neuropathology, Neurosciences Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon; ‡Department of Nephrology, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon; and xInstituto de Medicina Molecular, Lisbon Medical School, Lisbon, Portugal. Received April 18, 2013; revision received June 6, 2013; accepted June 10, 2013. Address correspondence to Dulce Neutel, Laborat orio de Farmacologia Clınica e Terap^eutica, Faculdade de Medicina Lisboa, 1649-028 Lisboa, Portugal. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.06.021
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palsy, and ipsilateral crural palsy. Brain magnetic resonance imaging (MRI) (Fig 1, A) disclosed acute left anterior cerebral artery ischemia and cerebral atrophy. Cervical ultrasonography, transcranial Doppler, and MRI angiography (time-of-flight sequences only) (Fig 1, B) showed a distal right internal carotid artery stenosis and right middle cerebral artery (MCA) stenosis; there was no flow in the right A1 anterior cerebral artery and filiform vertebral and basilar arteries. Cardiac evaluation was unremarkable. She had a normal lipid profile. She started aspirin 100 mg/day and atorvastatine 20 mg/daily and was discharged. She was readmitted 3 months later with global aphasia and right hemiparesis. New brain MRI showed left posterotemporal acute ischemia in the MCA territory (Fig 1, C). One week after readmission, she suddenly died for unknown reason. General autopsy showed splenomegaly, atrophic kidneys, left and right heart ventricular hypertrophy, and a nodular mass of the left lung, corresponding to cystine crystals, also present in the spleen, para-aortic lymph nodes, and bone marrow (Fig 1, D). There was severe generalized atherosclerotic disease. Kidneys and thyroid were atrophic with calcifications (no crystals). Neuropathological examination disclosed generalized atrophic brain and cortical, left frontal, and parietal, subacute, ischemic infarctions. Perivascular
Journal of Stroke and Cerebrovascular Diseases, Vol. 22, No. 8 (November), 2013: pp e674-e675
RECURRENT ISCHEMIC STROKE IN AN ADULT WITH CYSTINOSIS
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Figure 1. MR imaging, MR angiography, and pathologic data. (A) The first brain MRI (DWI)—acute left ACA ischemia and diffuse cerebral atrophy; (B) MR cerebral angiograms— right ICA stenosis (distal to anterior choroidal artery emergence) and right MCA stenosis; no flow was visible in the right A1 ACA; filiform vertebral and basilar arteries; (C) Brain MRI (DWI) at stroke recurrence—left posterotemporal ischemia in MCA territory; (D) cystine crystal deposits in the bone marrow (H&E 340); (E) subcortical perivascular mononuclear inflammatory infiltrates (H&E 3100); (F) narrowing of the arterial lumen of the left ACA and MCA arteries (Verhoeff 3100). Abbreviations: DWI, diffusion-weighted imaging; H&E, hematoxylin and eosin; ICA, internal carotid artery; MCA, middle cerebral artery; MR, magnetic resonance.
inflammatory mononuclear infiltrate (Fig 1, E), patchy cortical spongiform change, and dysplastic focal calcifications were also elicited. MCAs and ACAs presented segmentar subintimal thickening suggesting early atheromatous plaques (Fig 1, F), but small vessels were unremarkable. Rare crystal deposits were found in the cerebral parenchyma under polarized light.
Discussion Cystinosis is an autosomal recessive lysosomal storage disease caused by CTNS gene defect coding for the lysosomal membrane protein cystinosin and leading to intralysosomal cystine accumulation, mainly in the kidney, liver, eye, and thyroid.1 Cystine crystals have been observed in the central nervous system; however, stroke has been rarely reported.2 There are few reports of cerebrovascular disease in patients with longstanding nephropathic cystinosis, the most common reported neurological complications being neurobehavioral abnormalities and progressive motor disturbances.2-4 On brain image and neuropathological examination bases, we could demonstrate that recurrent stroke was caused by intracranial stenosis. A cystine crystal-associated vasculopathy has been described.2,3 However, cardiovascular disease is common in children and young adults with advanced chronic kidney disease, particularly those on longstanding hemodialysis or on cyclosporine because of several mechanisms including accelerated atherosclerosis.5,6 In our case, there was no vessel crystal deposition, and an atherosclerotic vasculopathy with focal vascular calcifications was found. Also, similar to previous descriptions, neuropathology disclosed not only brain calcifications, commonly found
in advanced chronic kidney disease, but also indirect (atrophy and perivascular inflammatory infiltrates) and direct (crystal deposits) evidence of cystinosis brain involvement.3,4 Accumulation of intracellular cystine has been proposed as a risk factor for vascular calcifications, and cysteamine may delay their occurrence.7 This case reinforces that cerebrovascular disease determine neurological impairment and disability in patients with longstanding nephropathic cystinosis, with implications on primary stroke prevention strategies in these patients.8
References 1. Town M, Jean G, Cherqui S, et al. A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet 1998;18:319-324. 2. Vogel DG, Malekzadeh MH, Cornford ME, et al. Central nervous system involvement in nephropathic cystinosis. J Neuropathol Exp Neurol 1990;49:591-599. 3. Berger JR, Dillon DA, Young BA, et al. Cystinosis of the brain and spinal cord with associated vasculopathy. J Neurol Sci 2009;284:182-185. 4. Fink J, Brouwers P, Barton N, et al. Neurologic complications in long-standing nephrophatic cystinosis. Arch Neurol 1989;46:543-548. 5. Mitsnefes MM. Cardiovascular disease in children with chronic kidney disease. J Am Soc Nephrol 2012;23:578-585. 6. Kockx M, Jessup W, Kritharides L. Cyclosporin A and atherosclerosis cellular pathways in atherogenesis. Pharmacol Ther 2010;128:106-118. 7. Ueda M, O’Brien K, Rosing DR, et al. Coronary artery and other vascular calcifications in patients with cystinosis after kidney transplantation. Clin J Am Soc Nephrol 2006;1:555-562. 8. Upadhyay A, Earley A, Lamont JL, et al. Lipid-lowering therapy in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2012;157:251-262.
Recurrent Ischemic Stroke in an Adult with Cystinosis: A Clinical–Pathological Case Dulce Neutel, MD,* Ruth Geraldes, MD,* Pedro Pereira, MSc,† Ant onio Gomes da Costa, MD,‡ Jose Pimentel, PhD,†x and Teresa Pinho e Melo, MD*
A 32-year-old woman with infantile nephropathic cystinosis presented with cystinosis and recurrent ischemic stroke. The neuropathological description demonstrates that recurrent stroke was caused by intracranial stenosis and showed evidence of cystinosis brain involvement. There are few reports of cerebrovascular disease in patients with longstanding nephropathic cystinosis. This case reinforces that cerebrovascular disease can be a cause of neurological impairment and disability in patients with longstanding nephropathic cystinosis, with implications on primary stroke prevention strategies in these patients. Key Words: Cystinosis—genetics— stroke—neuropathology. Ó 2013 by National Stroke Association
Case Report A 32-year-old woman with infantile nephropathic cystinosis presented with sudden onset of speech and gait disturbance. She had renal transplant when she was 12 years; she was on cyclosporine for 17 years and then on hemodialysis in the past 3 years and under cysteamine, levothyroxine, calcium, and folic acid. There were no vascular risk factors, except a systolic blood pressure of 160 mm Hg at admission. Neurologic examination showed severe bilateral visual loss, pendular nystagmus, right central facial
From the *Stroke Unit, Neurosciences Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon; †Laboratory of Neuropathology, Neurosciences Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon; ‡Department of Nephrology, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon; and xInstituto de Medicina Molecular, Lisbon Medical School, Lisbon, Portugal. Received April 18, 2013; revision received June 6, 2013; accepted June 10, 2013. Address correspondence to Dulce Neutel, Laborat orio de Farmacologia Clınica e Terap^eutica, Faculdade de Medicina Lisboa, 1649-028 Lisboa, Portugal. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.06.021
e674
palsy, and ipsilateral crural palsy. Brain magnetic resonance imaging (MRI) (Fig 1, A) disclosed acute left anterior cerebral artery ischemia and cerebral atrophy. Cervical ultrasonography, transcranial Doppler, and MRI angiography (time-of-flight sequences only) (Fig 1, B) showed a distal right internal carotid artery stenosis and right middle cerebral artery (MCA) stenosis; there was no flow in the right A1 anterior cerebral artery and filiform vertebral and basilar arteries. Cardiac evaluation was unremarkable. She had a normal lipid profile. She started aspirin 100 mg/day and atorvastatine 20 mg/daily and was discharged. She was readmitted 3 months later with global aphasia and right hemiparesis. New brain MRI showed left posterotemporal acute ischemia in the MCA territory (Fig 1, C). One week after readmission, she suddenly died for unknown reason. General autopsy showed splenomegaly, atrophic kidneys, left and right heart ventricular hypertrophy, and a nodular mass of the left lung, corresponding to cystine crystals, also present in the spleen, para-aortic lymph nodes, and bone marrow (Fig 1, D). There was severe generalized atherosclerotic disease. Kidneys and thyroid were atrophic with calcifications (no crystals). Neuropathological examination disclosed generalized atrophic brain and cortical, left frontal, and parietal, subacute, ischemic infarctions. Perivascular
Journal of Stroke and Cerebrovascular Diseases, Vol. 22, No. 8 (November), 2013: pp e674-e675
RECURRENT ISCHEMIC STROKE IN AN ADULT WITH CYSTINOSIS
e675
Figure 1. MR imaging, MR angiography, and pathologic data. (A) The first brain MRI (DWI)—acute left ACA ischemia and diffuse cerebral atrophy; (B) MR cerebral angiograms— right ICA stenosis (distal to anterior choroidal artery emergence) and right MCA stenosis; no flow was visible in the right A1 ACA; filiform vertebral and basilar arteries; (C) Brain MRI (DWI) at stroke recurrence—left posterotemporal ischemia in MCA territory; (D) cystine crystal deposits in the bone marrow (H&E 340); (E) subcortical perivascular mononuclear inflammatory infiltrates (H&E 3100); (F) narrowing of the arterial lumen of the left ACA and MCA arteries (Verhoeff 3100). Abbreviations: DWI, diffusion-weighted imaging; H&E, hematoxylin and eosin; ICA, internal carotid artery; MCA, middle cerebral artery; MR, magnetic resonance.
inflammatory mononuclear infiltrate (Fig 1, E), patchy cortical spongiform change, and dysplastic focal calcifications were also elicited. MCAs and ACAs presented segmentar subintimal thickening suggesting early atheromatous plaques (Fig 1, F), but small vessels were unremarkable. Rare crystal deposits were found in the cerebral parenchyma under polarized light.
Discussion Cystinosis is an autosomal recessive lysosomal storage disease caused by CTNS gene defect coding for the lysosomal membrane protein cystinosin and leading to intralysosomal cystine accumulation, mainly in the kidney, liver, eye, and thyroid.1 Cystine crystals have been observed in the central nervous system; however, stroke has been rarely reported.2 There are few reports of cerebrovascular disease in patients with longstanding nephropathic cystinosis, the most common reported neurological complications being neurobehavioral abnormalities and progressive motor disturbances.2-4 On brain image and neuropathological examination bases, we could demonstrate that recurrent stroke was caused by intracranial stenosis. A cystine crystal-associated vasculopathy has been described.2,3 However, cardiovascular disease is common in children and young adults with advanced chronic kidney disease, particularly those on longstanding hemodialysis or on cyclosporine because of several mechanisms including accelerated atherosclerosis.5,6 In our case, there was no vessel crystal deposition, and an atherosclerotic vasculopathy with focal vascular calcifications was found. Also, similar to previous descriptions, neuropathology disclosed not only brain calcifications, commonly found
in advanced chronic kidney disease, but also indirect (atrophy and perivascular inflammatory infiltrates) and direct (crystal deposits) evidence of cystinosis brain involvement.3,4 Accumulation of intracellular cystine has been proposed as a risk factor for vascular calcifications, and cysteamine may delay their occurrence.7 This case reinforces that cerebrovascular disease determine neurological impairment and disability in patients with longstanding nephropathic cystinosis, with implications on primary stroke prevention strategies in these patients.8
References 1. Town M, Jean G, Cherqui S, et al. A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet 1998;18:319-324. 2. Vogel DG, Malekzadeh MH, Cornford ME, et al. Central nervous system involvement in nephropathic cystinosis. J Neuropathol Exp Neurol 1990;49:591-599. 3. Berger JR, Dillon DA, Young BA, et al. Cystinosis of the brain and spinal cord with associated vasculopathy. J Neurol Sci 2009;284:182-185. 4. Fink J, Brouwers P, Barton N, et al. Neurologic complications in long-standing nephrophatic cystinosis. Arch Neurol 1989;46:543-548. 5. Mitsnefes MM. Cardiovascular disease in children with chronic kidney disease. J Am Soc Nephrol 2012;23:578-585. 6. Kockx M, Jessup W, Kritharides L. Cyclosporin A and atherosclerosis cellular pathways in atherogenesis. Pharmacol Ther 2010;128:106-118. 7. Ueda M, O’Brien K, Rosing DR, et al. Coronary artery and other vascular calcifications in patients with cystinosis after kidney transplantation. Clin J Am Soc Nephrol 2006;1:555-562. 8. Upadhyay A, Earley A, Lamont JL, et al. Lipid-lowering therapy in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2012;157:251-262.