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“Multiple system degeneration” in hereditary hemorrhagic telangiectasia: The hepatic connection
Journal of the Neurological Sciences 346 (2014) 339–340
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor “Multiple system degeneration” in hereditary hemorrhagic telangiectasia: The hepatic connection Keywords: Multiple system degeneration Hereditary hemorrhagic telangiectasia Hyperammonemia Hepatic vascular malformations
Dear Sirs,
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder of vasculature development characterized by telangiectases and arteriovenous malformations. Although the central nervous system (CNS) lesions such as intracranial arteriovenous malformations, ischemic strokes and brain abscesses are not uncommon [1], the multiple system degeneration mimicking manifestation in HHT is rare. We report a patient who presented with multiple lesions in brain due to hyperammonemia induced by hepatic portal vein to hepatic vein shunts. A 65-year-old man was admitted to our department because of progressive difficulty in repetitive movements for 15 months, recurrent episodes of psychiatric disorders for 6 months, and aggravated gait ataxia for 1 month. He as well as his mother had episodes of recurrent epistaxia and anemia. On neurological examination, he was alert with slightly impaired general cognition. Muscle tone was increased with lead pipe rigidity in both upper extremities, while with clasp-knife sign in lower ones. The deep tendon reflexes were increased with positive Babinski's sign bilaterally. Finger–nose testing was inaccurate and dysdiadochokinesis was detected. Sensation was normal in pinprick test, while the vibratory sense was impaired in both lower extremities and Romberg's sign was positive. Laboratory studies showed normal liver function and hyperammonemia at 205 umol/L (normal: 18–72 umol/L). Brain magnetic resonance imaging (MRI) showed symmetrical lesions involving bilateral cerebral cortex, basal ganglia, brainstem and cerebellar hemispheres. Contrast-enhanced computed tomography (CT) and CT portography of the liver showed early filling of hepatic vein suggesting shunts between the peripheral parts of the hepatic veins and portal veins. (Fig. 1). Based on the clinical manifestations and the Curacao criteria [2], he was diagnosed with portosystemic-venous shunts caused by HHT. Treatments with branched-chain-amino-acid and transcatheter embolization were administered to reduce serum ammonia and to close the portosystemic-venous shunts. Two weeks later, patient's neurological symptoms and signs improved dramatically, and follow-up serum ammonia level was decreased to 35umol/L.HHT, or Rendu–Osler–Weber syndrome, is an autosomal dominant vascular disease characterized by localized angiodysplasia [3]. Telangiectases in the nasal and gastrointestinal mucosa generally present with hemorrhage. While complications of vascular malformations in
http://dx.doi.org/10.1016/j.jns.2014.08.013 0022-510X/© 2014 Elsevier B.V. All rights reserved.
the liver, typically high-output heart failure, portal hypertension with bleeding gastrointestinal varices and encephalopathy, are generally the consequence of blood shunting through these abnormal blood vessels, which lack a capillary bed and thus result in a direct vascular connection. HHT is associated with a variety of neurologic complications, among which acute cerebral hemorrhage from arteriovenous malformations, brain abscess and ischemic stroke secondary to right-to-left shunting associated with pulmonary arteriovenous malformations are most in common. On the contrary, the central nervous system involvements with insidious, progressive presentations mimicking degenerative diseases are very rare. Since Yoshikawa et al. reported a case presenting with levodopa-resistant manganese-induced parkinsonism, assumed as “a new type of neurological complication” [4], only few cases sharing similar toxic mechanism in HHT have been described [5,6]. To the best of our knowledge, “multiple system degeneration” due to hyperammonemia, which is induced by hepatic portal vein to hepatic vein shunts, has never been reported. More importantly, these revisable symptoms paralleled to serum ammonia level are of significance in clinical management. As to the mechanisms of central nervous system involvements in our patient, one explanation is that the direct connections between portal and hepatic veins cause blood in the gastrointestinal track to be diverted past the liver, thereby limiting the liver's vital functions in metabolism and detoxification of ammonia and leading to the neurological system impairments. It may seem paradoxical that the neurological complications related to HHT, a hereditary disease, manifests in the patient's sixties. As a matter of fact, whether and when a patient exhibits symptoms depends on the shunt ratio and the sensitivity of the brain to ammonia as well as the liver function. As the central nervous system tolerance and/or liver function for ammonia decrease gradually with age, these patients' risk for neurological complications will increase compared to when they were young [7]. Blood shunting through the hepatic vascular malformations, which lack a capillary bed is likely to be the reason for “multiple system degeneration” in HHT, warning neurologists about considering HHT in the differential diagnosis of progressive neurological symptoms with hyperammonemia or multiple vascular malformations. Conflict of interest The authors declare that there are no conflicts of interest. The authors are fully responsible for the content and writing of the paper. References [1] McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med 2011;7: 607–16. [2] Shovlin CL, Guttmacher AE, Buscarin E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu–Osler–Weber syndrome). Am J Med Genet 2000;1:66–7. [3] Fernandez-L A, Sanz-Rodriguez F, Blanco FJ, Bernabeu C, Botella LM. Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-beta signaling pathway. Clin Med Res 2006;1:66–78.
340
Letter to the Editor
Fig. 1. A–D T2-weighted MRI showing symmetrical lesions involving bilateral cerebral cortex, basal ganglia, brainstem and cerebellar hemispheres (white arrow); E Contrast-enhanced CT of the liver showing early filling of hepatic vein (black arrow); F CT portography showing shunts between the peripheral parts of the hepatic veins and portal veins (black arrow).
[4] Yoshikawa K, Matsumoto M, Hamanaka M, Nakagawa M. A case of manganese induced parkinsonism in hereditary haemorrhagic telangiectasia. J Neurol Neurosurg Psychiatry 2003;9:1312–4. [5] Kumar N, Boeve BF, Cowl CT, Ellison JW, Kamath PS, Swanson KL. Hypermanganesemia, hereditary hemorrhagic telangiectasia, brain abscess: the hepatic connection. Neurology 2008;14:1118–9. [6] Oikonomou A, Chatzistefanou A, Zezos P, Mintzopoulou P, Vadikolias K, Prassopoulos P. Basal ganglia hyperintensity on T1-weighted MRI in Rendu–Osler–Weber disease. J Magn Reson Imaging 2012;2:426–30. [7] Alonso-Gamarra E, Parron M, Perez A, Prieto C, Hierro L, Lopez-Santamaria M. Clinical and radiologic manifestations of congenital extrahepatic portosystemic shunts: a comprehensive review. Radiographics 2011;31:707–22. 1
Zhu Zhu Xiang Han Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China Feng Qian Department of Health Policy, Management, and Behavior, School of Public Health, University at Albany – State University of New York, United States
1
Common First Authors: These authors contributed equally to the manuscript.
Wei Shi Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China Weijun Tang Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China Qiang Dong Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China Corresponding author at: No.12 Middle Urumqi Road, Shanghai, China, 200040. Tel.: +86 21 52887145. E-mail address: [email protected].
11 June 2014
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor “Multiple system degeneration” in hereditary hemorrhagic telangiectasia: The hepatic connection Keywords: Multiple system degeneration Hereditary hemorrhagic telangiectasia Hyperammonemia Hepatic vascular malformations
Dear Sirs,
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder of vasculature development characterized by telangiectases and arteriovenous malformations. Although the central nervous system (CNS) lesions such as intracranial arteriovenous malformations, ischemic strokes and brain abscesses are not uncommon [1], the multiple system degeneration mimicking manifestation in HHT is rare. We report a patient who presented with multiple lesions in brain due to hyperammonemia induced by hepatic portal vein to hepatic vein shunts. A 65-year-old man was admitted to our department because of progressive difficulty in repetitive movements for 15 months, recurrent episodes of psychiatric disorders for 6 months, and aggravated gait ataxia for 1 month. He as well as his mother had episodes of recurrent epistaxia and anemia. On neurological examination, he was alert with slightly impaired general cognition. Muscle tone was increased with lead pipe rigidity in both upper extremities, while with clasp-knife sign in lower ones. The deep tendon reflexes were increased with positive Babinski's sign bilaterally. Finger–nose testing was inaccurate and dysdiadochokinesis was detected. Sensation was normal in pinprick test, while the vibratory sense was impaired in both lower extremities and Romberg's sign was positive. Laboratory studies showed normal liver function and hyperammonemia at 205 umol/L (normal: 18–72 umol/L). Brain magnetic resonance imaging (MRI) showed symmetrical lesions involving bilateral cerebral cortex, basal ganglia, brainstem and cerebellar hemispheres. Contrast-enhanced computed tomography (CT) and CT portography of the liver showed early filling of hepatic vein suggesting shunts between the peripheral parts of the hepatic veins and portal veins. (Fig. 1). Based on the clinical manifestations and the Curacao criteria [2], he was diagnosed with portosystemic-venous shunts caused by HHT. Treatments with branched-chain-amino-acid and transcatheter embolization were administered to reduce serum ammonia and to close the portosystemic-venous shunts. Two weeks later, patient's neurological symptoms and signs improved dramatically, and follow-up serum ammonia level was decreased to 35umol/L.HHT, or Rendu–Osler–Weber syndrome, is an autosomal dominant vascular disease characterized by localized angiodysplasia [3]. Telangiectases in the nasal and gastrointestinal mucosa generally present with hemorrhage. While complications of vascular malformations in
http://dx.doi.org/10.1016/j.jns.2014.08.013 0022-510X/© 2014 Elsevier B.V. All rights reserved.
the liver, typically high-output heart failure, portal hypertension with bleeding gastrointestinal varices and encephalopathy, are generally the consequence of blood shunting through these abnormal blood vessels, which lack a capillary bed and thus result in a direct vascular connection. HHT is associated with a variety of neurologic complications, among which acute cerebral hemorrhage from arteriovenous malformations, brain abscess and ischemic stroke secondary to right-to-left shunting associated with pulmonary arteriovenous malformations are most in common. On the contrary, the central nervous system involvements with insidious, progressive presentations mimicking degenerative diseases are very rare. Since Yoshikawa et al. reported a case presenting with levodopa-resistant manganese-induced parkinsonism, assumed as “a new type of neurological complication” [4], only few cases sharing similar toxic mechanism in HHT have been described [5,6]. To the best of our knowledge, “multiple system degeneration” due to hyperammonemia, which is induced by hepatic portal vein to hepatic vein shunts, has never been reported. More importantly, these revisable symptoms paralleled to serum ammonia level are of significance in clinical management. As to the mechanisms of central nervous system involvements in our patient, one explanation is that the direct connections between portal and hepatic veins cause blood in the gastrointestinal track to be diverted past the liver, thereby limiting the liver's vital functions in metabolism and detoxification of ammonia and leading to the neurological system impairments. It may seem paradoxical that the neurological complications related to HHT, a hereditary disease, manifests in the patient's sixties. As a matter of fact, whether and when a patient exhibits symptoms depends on the shunt ratio and the sensitivity of the brain to ammonia as well as the liver function. As the central nervous system tolerance and/or liver function for ammonia decrease gradually with age, these patients' risk for neurological complications will increase compared to when they were young [7]. Blood shunting through the hepatic vascular malformations, which lack a capillary bed is likely to be the reason for “multiple system degeneration” in HHT, warning neurologists about considering HHT in the differential diagnosis of progressive neurological symptoms with hyperammonemia or multiple vascular malformations. Conflict of interest The authors declare that there are no conflicts of interest. The authors are fully responsible for the content and writing of the paper. References [1] McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med 2011;7: 607–16. [2] Shovlin CL, Guttmacher AE, Buscarin E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu–Osler–Weber syndrome). Am J Med Genet 2000;1:66–7. [3] Fernandez-L A, Sanz-Rodriguez F, Blanco FJ, Bernabeu C, Botella LM. Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-beta signaling pathway. Clin Med Res 2006;1:66–78.
340
Letter to the Editor
Fig. 1. A–D T2-weighted MRI showing symmetrical lesions involving bilateral cerebral cortex, basal ganglia, brainstem and cerebellar hemispheres (white arrow); E Contrast-enhanced CT of the liver showing early filling of hepatic vein (black arrow); F CT portography showing shunts between the peripheral parts of the hepatic veins and portal veins (black arrow).
[4] Yoshikawa K, Matsumoto M, Hamanaka M, Nakagawa M. A case of manganese induced parkinsonism in hereditary haemorrhagic telangiectasia. J Neurol Neurosurg Psychiatry 2003;9:1312–4. [5] Kumar N, Boeve BF, Cowl CT, Ellison JW, Kamath PS, Swanson KL. Hypermanganesemia, hereditary hemorrhagic telangiectasia, brain abscess: the hepatic connection. Neurology 2008;14:1118–9. [6] Oikonomou A, Chatzistefanou A, Zezos P, Mintzopoulou P, Vadikolias K, Prassopoulos P. Basal ganglia hyperintensity on T1-weighted MRI in Rendu–Osler–Weber disease. J Magn Reson Imaging 2012;2:426–30. [7] Alonso-Gamarra E, Parron M, Perez A, Prieto C, Hierro L, Lopez-Santamaria M. Clinical and radiologic manifestations of congenital extrahepatic portosystemic shunts: a comprehensive review. Radiographics 2011;31:707–22. 1
Zhu Zhu Xiang Han Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China Feng Qian Department of Health Policy, Management, and Behavior, School of Public Health, University at Albany – State University of New York, United States
1
Common First Authors: These authors contributed equally to the manuscript.
Wei Shi Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China Weijun Tang Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China Qiang Dong Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China Corresponding author at: No.12 Middle Urumqi Road, Shanghai, China, 200040. Tel.: +86 21 52887145. E-mail address: [email protected].
11 June 2014