Clin Neuroradiol DOI 10.1007/s00062-015-0384-0
Correspondence
Hypertrophic Olivary Degeneration Secondary to Neuro-Behçet’s Disease W.A. Martins · L.P. Schilling · F.K. Neto · J. Becker
Received: 17 October 2014 / Accepted: 4 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Introduction
Case Report
Behçet’s disease (BD) is a multisystem inflammatory disease of unknown etiology, characterized by intense inflammatory perivasculitis [1]. It mainly affects the skin and mucous membranes, leading to recurrent oral and genital ulcers, skin lesions, and uveitis [1–3]. Neurological involvement in BD is rare and occurs most often in the set of systemic disease [1–5]. Several neurological syndromes may ensue, but meningoencephalitis is the most common, representing 75 % of central nervous system lesions [1]. Rhombencephalitis is usually the main clinical picture, but there is also inflammatory damage to the thalamus, basal ganglia, cerebellum and cerebral cortex, a combination known as brainstem-plus sign [6]. Hypertrophic olivary degeneration (HOD) is a known complication of brainstem injuries [7]. HOD is a trans-synaptic degeneration, in which a lesion in the dentate-rubroolivary pathway leads to neuron loss, increase in glial cells, and demyelination, appearing as a tumor-like lesion in the medulla oblongata [8, 9]. Although rhombencephalitis is a frequent presentation of neuro-Behçet’s disease (NBD), HOD had not yet been reported in these patients. We describe a patient with NBD who developed a tumor-like lesion in his brainstem 4 months after clinical improvement. Timing, location, and clinical stability indicated a benign residual lesion.
A 22-year-old man presented with an acute altered mental status, left third cranial nerve palsy, ataxia, and right side weakness, all of which suggestive of brainstem encephalitis. Six months earlier, he had persistent fever, myalgia, and weight loss. Soon after fever resolution, oral and scrotal ulcers, usually painless, appeared accompanied by acneiform skin lesions in the chest and arms. At the time, antibiotic treatment led to partial regression of the lesions. Brain magnetic resonance imaging (MRI) showed hyperintense lesions on left midbrain, thalamus, and subcortical regions (Fig. 1). Cerebrospinal fluid analysis showed only mild lymphocytic pleocytosis. Pulse therapy with methylprednisolone 1 g/day for 7 days followed outstanding clinical improvement, although residual right hemiparesis and kinetic tremor remained. At discharge, he was on prednisone 20 mg/day and azathioprine 150 mg/day. Four months after therapy onset, a control brain MRI demonstrated resolution of most lesions along with signal alteration and enlargement of the olivary nuclei in the left medulla (Fig. 2a). At the time, he presented only minor oculopalatal myoclonus. Clinical stability and imaging pattern of the lesion suggested a benign finding, and no further investigation was pursued. Six years later, brain MRI showed an atrophic left midbrain peduncle with less evident olivary degeneration. In addition, there was significant atrophy of right cerebellar hemisphere (Fig. 2b) and shrinkage of midbrain (Fig. 2c, d). At that point, the patient had only mild right hemiparesis and oculopalatal myoclonus. Azathioprine 150 mg/day was his only medication, and he remains stable until this moment.
W.A. Martins, MD () · L.P. Schilling, MD · F.K. Neto, MD · J. Becker, MD, PhD Department of Neurology, Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida ipiranga 6690, 90610-000 Porto Alegre, RS, Brazil e-mail: [email protected]
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2
Fig. 1 a, b Axial fluid-attenuated inversion recovery magnetic resonance imaging (MRI) showing hyperintense lesions in the thalamus and mesodienFig. 2 a Axial T2-weighted magnetic resonance imaging (MRI) a month after presentation showing left hypertrophic olivary degeneration (red arrow); b 6 years later, coronal T2-weighted image displayed right cerebellar hemisphere atrophy (white arrow); c, d axial fluid-attenuated inversion recovery and sagittal T1-weighted image, respectively, demonstrating significant midbrain atrophy (yellow arrow)
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W.A. Martins et al.
cephalic region, consistent with brainstem-plus sign; c coronal T1-weighted MRI with gadolinium, showing partial lesion enhancement (white arrow)
Hypertrophic Olivary Degeneration Secondary to Neuro-Behçet’s Disease
3
Discussion In 1931, Guillain and Mollaret described HOD in a patient with oculopalatal myoclonus and a lesion on the inferior olivary nuclei (ION) [7]. HOD is a multisynaptic degeneration, occurring due to lesions between the connections of the dentate nucleus, red nucleus, and ION, also known as the triangle of Guillain and Mollaret [7–9]. Anatomic knowledge of this pathway is important to comprehend this unique synaptic degeneration (Fig. 3). First, fibers from dentate nucleus of cerebellum pass through the superior cerebellar peduncle and decussate in the brachium conjuntivum into the contralateral red nucleus. Second, central tegmental tract connects the red nucleus to ipsilateral ION at the medulla. Last, ION sends efferents through the inferior cerebellar peduncle, terminating at the contralateral dentate nucleus, which ends up forming the dentate-rubral-olivary circuitry [9–14]. A lesion in any part of this synaptic pathway may result in HOD and is accompanied, due to deafferentation, by atrophy of ipsilateral midbrain and contralateral cerebellar hemisphere, exactly as our patient. Lesions in this axonal pathway usually lead to unilateral HOD, but cases of bilateral HOD have been exceptions to this rule. The main pathologic findings in HOD involve proliferation of glial cells, vacuolation of neurons, cell death, and demyelination, but the exact mechanism is not fully understood [8, 9]. Palatal myoclonus or tremor is often the clinical expression, but ocular myoclonus may also be seen, depending on which brainstem nuclei had been injured [7–9]. Although symptomatic and essential palatal myoclonuses are clinically identical, other features may be present in symptomatic disease and help in the differential diagnosis, such as cerebellar or extrapyramidal disorders [8, 9]. Vascular lesions [8, 10] are the most common etiology of HOD. Other causes include neoplasm, iatrogenic injury [11], cerebral trauma [12], and degenerative diseases [14]. Despite the intense inflammatory response triggered in the brainstem by NBD, HOD has not yet been reported in this context. In NBD, the most common manifestation is an asymmetric lesion in the mesodiencephalic junction along long fiber tracts with sparing of the red nucleus [15], similar to our patient (Fig. 1). Hemispheric lesions are exceedingly rare, but up to 71 % may fulfill MRI diagnostic criteria for multiple sclerosis [16]. Progressive infratentorial atrophy, tumor-like lesions in the brainstem, and preservation of corpus callosum help in the differential diagnosis [5, 15, 16]. Temporal evolution in our patient consisted only of an acute phase, and treatment may have halted a relapsing-remitting course [1]. Although NBD can present with tumor-like lesions in the central nervous system, involvement [1–3], pattern, and location of the medullary lesion in our patient strongly pointed to HOD, in particular because of progressive clini-
Fig. 3 Illustration of the Guillain–Mollaret triangle. A lesion in any part of this synaptic pathway may lead to HOD
cal improvement. Some cases of chronic progressive NBD with extreme atrophy of the brainstem and cerebellum have been reported [4, 5]. Pathological alterations typically follow clinical worsening, which did not occur in our patient, suggesting it was rather a sequel of prior brainstem involvement and axonal damage, especially at midbrain. In addition, secondary demyelination occurs in NBD, especially at the corticospinal tract, sometimes extending to cervical spinal cord [15]. Therefore, in our patient, imaging patterns and clinical evolution strongly suggested a benign residual lesion. Conclusion In summary, this is the first time that HOD is reported secondary to BD. As NBD may have clinical–radiological exacerbations in the central nervous system [1], awareness of patterns of residual injury is essential to avoid unnecessary treatment and provide adequate management. Disclosure This article is in accord with all coauthors, and its manuscript has not been submitted in any other medical journal. Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
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4 Conflict of Interest There are no conflicts of interest regarding this article.
References 1. Al-Araji A, Kidd DP. Neuro-Behçet’s disease: epidemiology, clinical characteristics, and management. Lancet Neurol. 2009;8(2):192–204. 2. Dutra LA, Gonçalves CR, Braga-Neto P, Pedroso JL, Gabbai AA, Barsottini OG, de Souza AW. Atypical manifestations in Brazilian patients with neuro-Behçet’s disease. J Neurol. 2012;259(6):1159–65. 3. Mirsattari SM, McGinn GJ, Halliday WC. Neuro-Behcet disease with predominant involvement of the brainstem. Neurology. 2004;63(2):382–4. 4. Taskapilioglu O, Seferoglu M, Akkaya C, Hakyemez B, Yusufoglu C, Basak AN, Gundogdu A, Bora I. Delayed diagnosis of a neuro-Behçet patient with only brainstem and cerebellar atrophy: literature review. J Neurol Sci. 2009;277(1–2):160–3. 5. Kanoto M, Hosoya T, Toyoguchi Y, Oda A. Brain stem and cerebellar atrophy in chronic progressive neuro-Behçet’s disease. Eur J Radiol. 2013;82(1):146–50. 6. Liewluck T. A brainstem plus sign in neuro-Behçet disease. Intern Med. 2009;48(16):1483–4. 7. Guillain G, Mollaret P. Deux-cas de myoclonies synchrones et rhythmes velopharyngo-laringo-oculo-diaphragmatiques. Rev Neurol. 1931;2:545–66.
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W.A. Martins et al. 8. Goyal M, Versnick E, Tuite P, Cyr JS, Kucharczyk W, Montanera W, Willinsky R, Mikulis D. Hypertrophic olivary degeneration: meta-analysis of the temporal evolution of MR findings. AJNR Am J Neuroradiol. 2000;21(6):1073–7. 9. Sánchez Hernández J, Paniagua Escudero JC, Carreño Morán P, Asensio Calle JF. Degeneración hipertrófica de la oliva por lesión del triángulo de Guillain-Mollaret. Presentación de 2 casos. Neurología. 2013;28:59–61. 10. Asal N, Yılmaz O, Turan A, Yiğit H, Duymuş M, Tekin E. Hypertrophic olivary degeneration after pontine hemorrhage. Neuroradiology. 2012;54:413–5. 11. Gatlin JL, Wineman R, Schlakman B, Buciuc R, Khan M. Hypertrophic olivary degeneration after resection of a pontine cavernous malformation: a case report. J Radiol Case Rep. 2011;5(3):24–9. 12. Siebert E, Harms L, Herbst M. Posttraumatic bilateral hypertrophic olivary degeneration. Neurol Sci. 2013;34(10):1829–30. 13. Ogawa K, Mizutani T, Uehara K, Minami M, Suzuki Y, Uchihara T. Pathological study of pseudohypertrophy of the inferior olivary nucleus. Neuropathology. 2010;30(1):15–23. 14. Otto J, Guenther P, Hoffmann KT. Bilateral hypertrophic olivary degeneration in Wilson disease. Korean J Radiol. 2013;14(2):316–20. 15. Koçer N, Islak C, Siva A, Saip S, Akman C, Kantarci O, Hamuryudan V. CNS involvement in neuro-Behçet syndrome: an MR study. AJNR Am J Neuroradiology. 1999;20(6):1015–24. 16. Borhani Haghighi A, Sarhadi S, Farahangiz S. MRI findings of neuro-Behcet’s disease. Clin Rheumatol. 2011;30(6):765–70.
Correspondence
Hypertrophic Olivary Degeneration Secondary to Neuro-Behçet’s Disease W.A. Martins · L.P. Schilling · F.K. Neto · J. Becker
Received: 17 October 2014 / Accepted: 4 March 2015 © Springer-Verlag Berlin Heidelberg 2015
Introduction
Case Report
Behçet’s disease (BD) is a multisystem inflammatory disease of unknown etiology, characterized by intense inflammatory perivasculitis [1]. It mainly affects the skin and mucous membranes, leading to recurrent oral and genital ulcers, skin lesions, and uveitis [1–3]. Neurological involvement in BD is rare and occurs most often in the set of systemic disease [1–5]. Several neurological syndromes may ensue, but meningoencephalitis is the most common, representing 75 % of central nervous system lesions [1]. Rhombencephalitis is usually the main clinical picture, but there is also inflammatory damage to the thalamus, basal ganglia, cerebellum and cerebral cortex, a combination known as brainstem-plus sign [6]. Hypertrophic olivary degeneration (HOD) is a known complication of brainstem injuries [7]. HOD is a trans-synaptic degeneration, in which a lesion in the dentate-rubroolivary pathway leads to neuron loss, increase in glial cells, and demyelination, appearing as a tumor-like lesion in the medulla oblongata [8, 9]. Although rhombencephalitis is a frequent presentation of neuro-Behçet’s disease (NBD), HOD had not yet been reported in these patients. We describe a patient with NBD who developed a tumor-like lesion in his brainstem 4 months after clinical improvement. Timing, location, and clinical stability indicated a benign residual lesion.
A 22-year-old man presented with an acute altered mental status, left third cranial nerve palsy, ataxia, and right side weakness, all of which suggestive of brainstem encephalitis. Six months earlier, he had persistent fever, myalgia, and weight loss. Soon after fever resolution, oral and scrotal ulcers, usually painless, appeared accompanied by acneiform skin lesions in the chest and arms. At the time, antibiotic treatment led to partial regression of the lesions. Brain magnetic resonance imaging (MRI) showed hyperintense lesions on left midbrain, thalamus, and subcortical regions (Fig. 1). Cerebrospinal fluid analysis showed only mild lymphocytic pleocytosis. Pulse therapy with methylprednisolone 1 g/day for 7 days followed outstanding clinical improvement, although residual right hemiparesis and kinetic tremor remained. At discharge, he was on prednisone 20 mg/day and azathioprine 150 mg/day. Four months after therapy onset, a control brain MRI demonstrated resolution of most lesions along with signal alteration and enlargement of the olivary nuclei in the left medulla (Fig. 2a). At the time, he presented only minor oculopalatal myoclonus. Clinical stability and imaging pattern of the lesion suggested a benign finding, and no further investigation was pursued. Six years later, brain MRI showed an atrophic left midbrain peduncle with less evident olivary degeneration. In addition, there was significant atrophy of right cerebellar hemisphere (Fig. 2b) and shrinkage of midbrain (Fig. 2c, d). At that point, the patient had only mild right hemiparesis and oculopalatal myoclonus. Azathioprine 150 mg/day was his only medication, and he remains stable until this moment.
W.A. Martins, MD () · L.P. Schilling, MD · F.K. Neto, MD · J. Becker, MD, PhD Department of Neurology, Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida ipiranga 6690, 90610-000 Porto Alegre, RS, Brazil e-mail: [email protected]
13
2
Fig. 1 a, b Axial fluid-attenuated inversion recovery magnetic resonance imaging (MRI) showing hyperintense lesions in the thalamus and mesodienFig. 2 a Axial T2-weighted magnetic resonance imaging (MRI) a month after presentation showing left hypertrophic olivary degeneration (red arrow); b 6 years later, coronal T2-weighted image displayed right cerebellar hemisphere atrophy (white arrow); c, d axial fluid-attenuated inversion recovery and sagittal T1-weighted image, respectively, demonstrating significant midbrain atrophy (yellow arrow)
13
W.A. Martins et al.
cephalic region, consistent with brainstem-plus sign; c coronal T1-weighted MRI with gadolinium, showing partial lesion enhancement (white arrow)
Hypertrophic Olivary Degeneration Secondary to Neuro-Behçet’s Disease
3
Discussion In 1931, Guillain and Mollaret described HOD in a patient with oculopalatal myoclonus and a lesion on the inferior olivary nuclei (ION) [7]. HOD is a multisynaptic degeneration, occurring due to lesions between the connections of the dentate nucleus, red nucleus, and ION, also known as the triangle of Guillain and Mollaret [7–9]. Anatomic knowledge of this pathway is important to comprehend this unique synaptic degeneration (Fig. 3). First, fibers from dentate nucleus of cerebellum pass through the superior cerebellar peduncle and decussate in the brachium conjuntivum into the contralateral red nucleus. Second, central tegmental tract connects the red nucleus to ipsilateral ION at the medulla. Last, ION sends efferents through the inferior cerebellar peduncle, terminating at the contralateral dentate nucleus, which ends up forming the dentate-rubral-olivary circuitry [9–14]. A lesion in any part of this synaptic pathway may result in HOD and is accompanied, due to deafferentation, by atrophy of ipsilateral midbrain and contralateral cerebellar hemisphere, exactly as our patient. Lesions in this axonal pathway usually lead to unilateral HOD, but cases of bilateral HOD have been exceptions to this rule. The main pathologic findings in HOD involve proliferation of glial cells, vacuolation of neurons, cell death, and demyelination, but the exact mechanism is not fully understood [8, 9]. Palatal myoclonus or tremor is often the clinical expression, but ocular myoclonus may also be seen, depending on which brainstem nuclei had been injured [7–9]. Although symptomatic and essential palatal myoclonuses are clinically identical, other features may be present in symptomatic disease and help in the differential diagnosis, such as cerebellar or extrapyramidal disorders [8, 9]. Vascular lesions [8, 10] are the most common etiology of HOD. Other causes include neoplasm, iatrogenic injury [11], cerebral trauma [12], and degenerative diseases [14]. Despite the intense inflammatory response triggered in the brainstem by NBD, HOD has not yet been reported in this context. In NBD, the most common manifestation is an asymmetric lesion in the mesodiencephalic junction along long fiber tracts with sparing of the red nucleus [15], similar to our patient (Fig. 1). Hemispheric lesions are exceedingly rare, but up to 71 % may fulfill MRI diagnostic criteria for multiple sclerosis [16]. Progressive infratentorial atrophy, tumor-like lesions in the brainstem, and preservation of corpus callosum help in the differential diagnosis [5, 15, 16]. Temporal evolution in our patient consisted only of an acute phase, and treatment may have halted a relapsing-remitting course [1]. Although NBD can present with tumor-like lesions in the central nervous system, involvement [1–3], pattern, and location of the medullary lesion in our patient strongly pointed to HOD, in particular because of progressive clini-
Fig. 3 Illustration of the Guillain–Mollaret triangle. A lesion in any part of this synaptic pathway may lead to HOD
cal improvement. Some cases of chronic progressive NBD with extreme atrophy of the brainstem and cerebellum have been reported [4, 5]. Pathological alterations typically follow clinical worsening, which did not occur in our patient, suggesting it was rather a sequel of prior brainstem involvement and axonal damage, especially at midbrain. In addition, secondary demyelination occurs in NBD, especially at the corticospinal tract, sometimes extending to cervical spinal cord [15]. Therefore, in our patient, imaging patterns and clinical evolution strongly suggested a benign residual lesion. Conclusion In summary, this is the first time that HOD is reported secondary to BD. As NBD may have clinical–radiological exacerbations in the central nervous system [1], awareness of patterns of residual injury is essential to avoid unnecessary treatment and provide adequate management. Disclosure This article is in accord with all coauthors, and its manuscript has not been submitted in any other medical journal. Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
13
4 Conflict of Interest There are no conflicts of interest regarding this article.
References 1. Al-Araji A, Kidd DP. Neuro-Behçet’s disease: epidemiology, clinical characteristics, and management. Lancet Neurol. 2009;8(2):192–204. 2. Dutra LA, Gonçalves CR, Braga-Neto P, Pedroso JL, Gabbai AA, Barsottini OG, de Souza AW. Atypical manifestations in Brazilian patients with neuro-Behçet’s disease. J Neurol. 2012;259(6):1159–65. 3. Mirsattari SM, McGinn GJ, Halliday WC. Neuro-Behcet disease with predominant involvement of the brainstem. Neurology. 2004;63(2):382–4. 4. Taskapilioglu O, Seferoglu M, Akkaya C, Hakyemez B, Yusufoglu C, Basak AN, Gundogdu A, Bora I. Delayed diagnosis of a neuro-Behçet patient with only brainstem and cerebellar atrophy: literature review. J Neurol Sci. 2009;277(1–2):160–3. 5. Kanoto M, Hosoya T, Toyoguchi Y, Oda A. Brain stem and cerebellar atrophy in chronic progressive neuro-Behçet’s disease. Eur J Radiol. 2013;82(1):146–50. 6. Liewluck T. A brainstem plus sign in neuro-Behçet disease. Intern Med. 2009;48(16):1483–4. 7. Guillain G, Mollaret P. Deux-cas de myoclonies synchrones et rhythmes velopharyngo-laringo-oculo-diaphragmatiques. Rev Neurol. 1931;2:545–66.
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W.A. Martins et al. 8. Goyal M, Versnick E, Tuite P, Cyr JS, Kucharczyk W, Montanera W, Willinsky R, Mikulis D. Hypertrophic olivary degeneration: meta-analysis of the temporal evolution of MR findings. AJNR Am J Neuroradiol. 2000;21(6):1073–7. 9. Sánchez Hernández J, Paniagua Escudero JC, Carreño Morán P, Asensio Calle JF. Degeneración hipertrófica de la oliva por lesión del triángulo de Guillain-Mollaret. Presentación de 2 casos. Neurología. 2013;28:59–61. 10. Asal N, Yılmaz O, Turan A, Yiğit H, Duymuş M, Tekin E. Hypertrophic olivary degeneration after pontine hemorrhage. Neuroradiology. 2012;54:413–5. 11. Gatlin JL, Wineman R, Schlakman B, Buciuc R, Khan M. Hypertrophic olivary degeneration after resection of a pontine cavernous malformation: a case report. J Radiol Case Rep. 2011;5(3):24–9. 12. Siebert E, Harms L, Herbst M. Posttraumatic bilateral hypertrophic olivary degeneration. Neurol Sci. 2013;34(10):1829–30. 13. Ogawa K, Mizutani T, Uehara K, Minami M, Suzuki Y, Uchihara T. Pathological study of pseudohypertrophy of the inferior olivary nucleus. Neuropathology. 2010;30(1):15–23. 14. Otto J, Guenther P, Hoffmann KT. Bilateral hypertrophic olivary degeneration in Wilson disease. Korean J Radiol. 2013;14(2):316–20. 15. Koçer N, Islak C, Siva A, Saip S, Akman C, Kantarci O, Hamuryudan V. CNS involvement in neuro-Behçet syndrome: an MR study. AJNR Am J Neuroradiology. 1999;20(6):1015–24. 16. Borhani Haghighi A, Sarhadi S, Farahangiz S. MRI findings of neuro-Behcet’s disease. Clin Rheumatol. 2011;30(6):765–70.
