Journal of the Neurological Sciences 345 (2014) 262–264
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Uhthoff's phenomena and brain MRI suggesting demyelinating lesions: RIS or CIS? A case report
1. Introduction Uhthoff's phenomenon (UP) is a stereotyped, brief disturbance in neurological functioning triggered by any increase in core body temperature (CBT) [1]. It is related to recurrent fluctuations in neuronal conduction of demyelinated axons, being a feature of multiple sclerosis (MS) [1]. Radiologically isolated syndrome (RIS) has been defined by Okuda [2] as an incidental MRI finding of central nervous system (CNS) white matter anomalies suggestive of MS (according to Barkhof's criteria for dissemination in space), with no historical accounts of remitting neurological symptoms, no related-disability and no other better explanation (e.g. substance abuse, medical condition, cerebrovascular disease). We describe a case with transient and recurrent oscillopsia, interpreted as UP, with MRI suggesting demyelinating lesions.
2. Case report A seventeen-year-old man, with a family history of MS (mother) and a congenital moderate hearing loss (DFNB1/GJB2 mutation), had three episodes of oscillopsia (an illusory side-to-side movement of the seen environment) during intense sport performance in summer. His past medical history was unremarkable. In all occasions, circumstances and symptoms were highly stereotyped: while he was running during a cycling race, after a sudden turn of his head to look at the opponents during overtaking he experienced oscillating vision lasting few seconds. He presented the first two episodes in September 2012. Medical tests (brain CT, EEG, ECG) were normal. In June 2013 another episode occurred, with a violent fall to the ground conditioning a mild traumatic brain injury. His primary care physician sent him to brain MRI scan which revealed a right middle cerebellar peduncle (MCP) lesion in the context of disseminated T2-hyperintense white matter anomalies (no gadolinium enhancement), suggestive of inflammatory demyelinating origin (Fig. 1, a–f) [2]. He was then admitted to our department for assessment: neurological exam, spinal-cord MRI, visual, sensory and motor evoked potentials were unremarkable. Auditory event-related potentials showed an increased stimulation threshold (right side) and a slight increase of I–V interpeak latency (left side). Cerebrospinal fluid (CSF) analysis revealed intrathecal synthesis of oligoclonal IgG bands. Aetiological mimics were excluded [3]. A brain MRI-scan performed four months later showed a new T2-lesion in lateral mid-pons (Fig. 1, g), without any related symptom. Otovestibular tests and videonistagmography showed only qualitative alterations (irregular and arrhythmic eye-movement pattern), consistent with cerebellumbrainstem impairment [4]. Currently, the patient is under close clinical and radiological monitoring.
http://dx.doi.org/10.1016/j.jns.2014.07.020 0022-510X/© 2014 Elsevier B.V. All rights reserved.
3. Discussion A family history of MS, brain MRI findings and CSF intrathecal IgG synthesis all supported an inflammatory demyelinating disease of the CNS. As a consequence, we interpreted the episodes of oscillopsia as recurrent UP. loss of myelin sheath is the main cause of UP: elevation in CBT in the context of axonal demyelination results in pore closure of voltage-gated sodium channels, thereby compromising action potential depolarization [1]. Heat stressors are variable (fever, pre-menstrual period, physical exercise, etc.) such as clinical manifestations of UP which depend on where demyelinating plaques are localized [1]. In our patient rise of CBT during physical exercise could have unmasked the MCP lesion impairing the vestibuloocular reflex (VOR) after rapid head turns, generating oscillopsia [4]. Ponto-cerebellar projections pass through the MCP and are pivotal in the modulation of VOR, especially when cerebellum has to process a high number of sensory inputs [4]. Despite DFNB1/GJB2 mutation is generally associated only with hearing loss [5], some authors have recently discovered a vestibular impairment too [6]. Oscillopsia is not uncommon in MS and is widely described in literature; however, the location of related brainstem/cerebellar lesions is often undefined. Our neurophysiopathological considerations are therefore speculative, but they are supported by anatomical and neurophysiological evidence [4]. Nonetheless, videonistagmography findings in our patient pointed out a dysfunction of the central neural integrator. This patient presents some peculiar diagnostic aspects: strictly adhering to Okuda's definition, UP represents a remitting neurological symptom consistent with neurological dysfunction, excluding this subject from RIS diagnosis [2]. Further, he did not fulfill the McDonald criteria for MS as paroxysmal disorders can be considered an attack of MS if consisting of multiple episodes occurring over not less than 24 h. [7]. However, original Okuda criteria [2], especially B criterion “no historical accounts of remitting clinical symptoms consistent with neurologic dysfunction”, could lead to ambiguous interpretation: Grandberg et al. [8] highlighted that about 50% of subjects diagnosed as RIS received a brain MRI scan due to headache. Although this neurological symptom is not typical of CNS demyelination, the authors raised some doubts about the concept of “asymptomatic” [8]. Finally, a newly published article by Okuda's group clarifies that subjects included in RIS follow-up study must not have “history of remitting clinical symptoms…lasting N 24 h prior to CNS imaging…suggestive of MS” [9]. This elucidation would therefore make us consider our case as a RIS. Another important aspect to consider is the prognostic value of UP. In the general population the prevalence of RIS ranges 0.06–0.7% [8], while in people with at least one relative affected by MS it rises from 2.9% (RIS-Okuda criteria) to 10.3% (RIS-Swanton criteria) [10]. About 1/3 of RIS will develop neurological symptoms during mean follow-up time of 5 years, converting to CIS or definite MS [8,9], suggesting the opportunity of a close follow-up. Among the factors related to the risk of
Letter to the Editor
263
Fig. 1. Brain MRI scans (T2 and FLAIR sequences) of June 2013 (a–f) showing lesions in right middle cerebellar peduncle (a, d), corpus callosum (b), internal capsule bilaterally (c, e) and periventricular (c, f, e). Brain MRI scan (FLAIR sequence) of October 2013 (g) showing a new lesion in right lateral mid-pons.
conversion to CIS/MS, the following have been identified: cervical/ thoracic spinal cord lesions, male sex, infratentorial lesions, young age, intrathecal IgG synthesis, and familiarity for MS [8,9]. Our patient presented many of these negative prognostic factors; indeed 4 months after he developed a new brainstem lesion. UP could represent an additional risk factor, supporting a demyelinating nature of brain MRI anomalies. Concluding, this case highlights a gap of current diagnostic criteria for RIS and MS. Patients with a transient neurological dysfunction such as UP and a family history of MS should be submitted to brain MRI-scan to unveil a possible RIS.
Disclosures Dr. Baroncini reports no disclosures. Dr. Zaffaroni has served on scientific advisory boards for Teva, Medtronics, Merck Serono and Novartis, and served as a consultant for Biogen Idec. Prof. Minonzio reports no disclosures. Dr. Annovazzi has served as a consultant to Biogen Idec, Teva Pharmaceuticals and Novartis and received speakers' bureaus for Biogen Idec and Teva Pharmaceuticals. Dr. Baldini reports no disclosures. Prof. Comi has served on scientific advisory boards for Bayer Schering Pharma, Merck Serono, Teva Pharmaceutical, Sanofi-Aventis, Novartis and Biogen Idec; has received speaker honoraria from Teva Pharmaceuticals, Sanofi-Aventis, Serono Symposia International Foundation, Biogen Idec, Merck Serono, Novartis and Bayer Schering Pharma. Dr. Ghezzi has served on scientific advisory boards for Merck Serono, Biogen Idec, Teva Pharmaceutical Industries Ltd.; has received speaker honoraria from Merck Serono, Biogen Idec, Bayer Schering Pharma, and Novartis, Serono Symposia International; served as a consultant for Novartis; and receives research support from Sanofi-Aventis, Biogen Idec, and Merck Serono. All human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
References [1] Frohman TC, Davis SL, Beh S, Greenberg BM, Remington G, Frohman EM. Uhthoff's phenomena in MS—clinical features and pathophysiology. Nat Rev Neurol 2013 Sep;9(9):535–40. [2] Okuda DT, Mowry EM, Beheshtian A, Waubant E, Baranzini SE, Goodin DS, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology 2009; 72: 800–805. Erratum. Neurology 2009;73:1714. [3] Charil A, Yousry TA, Rovaris M, Barkhof F, De Stefano N, Fazekas F, et al. MRI and the diagnosis of multiple sclerosis: expanding the concept of “no better explanation”. Lancet Neurol 2006;5:841–52. [4] Leigh RJ, Zee DS. The neurology of eye movements. 3rd ed. Oxford University Press; 1999 410 [479–482]. [5] Cohn ES, Kelley PM. Clinical phenotype and mutations in connexin 26 (DFNB1/ GJB2), the most common cause of childhood hearing loss. Am J Med Genet 1999;89(3):130–6. [6] Dodson KM, Blanton SH, Welch KO. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A 2011 May;155(5):993–1000. [7] Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011 February;69(2):292–302. [8] Granberg T, Martola J, Kristoffersen-Wiberg M, Aspelin P, Fredrikson S. Radiologically isolated syndrome: incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review. Mult Scler 2013;19:271–80. [9] Okuda DT, Siva A, Kantarci O, Inglese M, Katz I, Tutuncu M, et al. Radiologically Isolated Syndrome Consortium (RISC); Club Francophone de la Sclérose en Plaques (CFSEP). Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLoS One Mar 5 2014;9(3):e90509. [10] Gabelic T, Ramasamy DP, Weinstock-Guttman B. Prevalence of radiologically isolated syndrome and white matter signal abnormalities in healthy relatives of multiple sclerosis patients. AJNR Am J Neuroradiol Jul 25 2013. http://dx.doi.org/ 10.3174/ajnr.A3653.
Damiano Baroncini Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, Hospital S. Raffaele, Milan, Italy Multiple Sclerosis Study Center, Sant'Antonio Abate Hospital of Gallarate, Italy Corresponding author at: Multiple Sclerosis Study Center, Sant'Antonio Abate Hospital of Gallarate, Italy. Tel.: +39 331751386; fax: +39 331751385. E-mail address: [email protected]. Mauro Zaffaroni Multiple Sclerosis Study Center, Sant'Antonio Abate Hospital of Gallarate, Italy
264
Letter to the Editor
Giorgio Minonzio Neuroradiology Service, Hospital of Gallarate, Italy Pietro Annovazzi Silvana M. Baldini Multiple Sclerosis Study Center, Sant'Antonio Abate Hospital of Gallarate, Italy Giancarlo Comi Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, Hospital S. Raffaele, Milan, Italy
Angelo Ghezzi Multiple Sclerosis Study Center, Sant'Antonio Abate Hospital of Gallarate, Italy 10 April 2014
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Uhthoff's phenomena and brain MRI suggesting demyelinating lesions: RIS or CIS? A case report
1. Introduction Uhthoff's phenomenon (UP) is a stereotyped, brief disturbance in neurological functioning triggered by any increase in core body temperature (CBT) [1]. It is related to recurrent fluctuations in neuronal conduction of demyelinated axons, being a feature of multiple sclerosis (MS) [1]. Radiologically isolated syndrome (RIS) has been defined by Okuda [2] as an incidental MRI finding of central nervous system (CNS) white matter anomalies suggestive of MS (according to Barkhof's criteria for dissemination in space), with no historical accounts of remitting neurological symptoms, no related-disability and no other better explanation (e.g. substance abuse, medical condition, cerebrovascular disease). We describe a case with transient and recurrent oscillopsia, interpreted as UP, with MRI suggesting demyelinating lesions.
2. Case report A seventeen-year-old man, with a family history of MS (mother) and a congenital moderate hearing loss (DFNB1/GJB2 mutation), had three episodes of oscillopsia (an illusory side-to-side movement of the seen environment) during intense sport performance in summer. His past medical history was unremarkable. In all occasions, circumstances and symptoms were highly stereotyped: while he was running during a cycling race, after a sudden turn of his head to look at the opponents during overtaking he experienced oscillating vision lasting few seconds. He presented the first two episodes in September 2012. Medical tests (brain CT, EEG, ECG) were normal. In June 2013 another episode occurred, with a violent fall to the ground conditioning a mild traumatic brain injury. His primary care physician sent him to brain MRI scan which revealed a right middle cerebellar peduncle (MCP) lesion in the context of disseminated T2-hyperintense white matter anomalies (no gadolinium enhancement), suggestive of inflammatory demyelinating origin (Fig. 1, a–f) [2]. He was then admitted to our department for assessment: neurological exam, spinal-cord MRI, visual, sensory and motor evoked potentials were unremarkable. Auditory event-related potentials showed an increased stimulation threshold (right side) and a slight increase of I–V interpeak latency (left side). Cerebrospinal fluid (CSF) analysis revealed intrathecal synthesis of oligoclonal IgG bands. Aetiological mimics were excluded [3]. A brain MRI-scan performed four months later showed a new T2-lesion in lateral mid-pons (Fig. 1, g), without any related symptom. Otovestibular tests and videonistagmography showed only qualitative alterations (irregular and arrhythmic eye-movement pattern), consistent with cerebellumbrainstem impairment [4]. Currently, the patient is under close clinical and radiological monitoring.
http://dx.doi.org/10.1016/j.jns.2014.07.020 0022-510X/© 2014 Elsevier B.V. All rights reserved.
3. Discussion A family history of MS, brain MRI findings and CSF intrathecal IgG synthesis all supported an inflammatory demyelinating disease of the CNS. As a consequence, we interpreted the episodes of oscillopsia as recurrent UP. loss of myelin sheath is the main cause of UP: elevation in CBT in the context of axonal demyelination results in pore closure of voltage-gated sodium channels, thereby compromising action potential depolarization [1]. Heat stressors are variable (fever, pre-menstrual period, physical exercise, etc.) such as clinical manifestations of UP which depend on where demyelinating plaques are localized [1]. In our patient rise of CBT during physical exercise could have unmasked the MCP lesion impairing the vestibuloocular reflex (VOR) after rapid head turns, generating oscillopsia [4]. Ponto-cerebellar projections pass through the MCP and are pivotal in the modulation of VOR, especially when cerebellum has to process a high number of sensory inputs [4]. Despite DFNB1/GJB2 mutation is generally associated only with hearing loss [5], some authors have recently discovered a vestibular impairment too [6]. Oscillopsia is not uncommon in MS and is widely described in literature; however, the location of related brainstem/cerebellar lesions is often undefined. Our neurophysiopathological considerations are therefore speculative, but they are supported by anatomical and neurophysiological evidence [4]. Nonetheless, videonistagmography findings in our patient pointed out a dysfunction of the central neural integrator. This patient presents some peculiar diagnostic aspects: strictly adhering to Okuda's definition, UP represents a remitting neurological symptom consistent with neurological dysfunction, excluding this subject from RIS diagnosis [2]. Further, he did not fulfill the McDonald criteria for MS as paroxysmal disorders can be considered an attack of MS if consisting of multiple episodes occurring over not less than 24 h. [7]. However, original Okuda criteria [2], especially B criterion “no historical accounts of remitting clinical symptoms consistent with neurologic dysfunction”, could lead to ambiguous interpretation: Grandberg et al. [8] highlighted that about 50% of subjects diagnosed as RIS received a brain MRI scan due to headache. Although this neurological symptom is not typical of CNS demyelination, the authors raised some doubts about the concept of “asymptomatic” [8]. Finally, a newly published article by Okuda's group clarifies that subjects included in RIS follow-up study must not have “history of remitting clinical symptoms…lasting N 24 h prior to CNS imaging…suggestive of MS” [9]. This elucidation would therefore make us consider our case as a RIS. Another important aspect to consider is the prognostic value of UP. In the general population the prevalence of RIS ranges 0.06–0.7% [8], while in people with at least one relative affected by MS it rises from 2.9% (RIS-Okuda criteria) to 10.3% (RIS-Swanton criteria) [10]. About 1/3 of RIS will develop neurological symptoms during mean follow-up time of 5 years, converting to CIS or definite MS [8,9], suggesting the opportunity of a close follow-up. Among the factors related to the risk of
Letter to the Editor
263
Fig. 1. Brain MRI scans (T2 and FLAIR sequences) of June 2013 (a–f) showing lesions in right middle cerebellar peduncle (a, d), corpus callosum (b), internal capsule bilaterally (c, e) and periventricular (c, f, e). Brain MRI scan (FLAIR sequence) of October 2013 (g) showing a new lesion in right lateral mid-pons.
conversion to CIS/MS, the following have been identified: cervical/ thoracic spinal cord lesions, male sex, infratentorial lesions, young age, intrathecal IgG synthesis, and familiarity for MS [8,9]. Our patient presented many of these negative prognostic factors; indeed 4 months after he developed a new brainstem lesion. UP could represent an additional risk factor, supporting a demyelinating nature of brain MRI anomalies. Concluding, this case highlights a gap of current diagnostic criteria for RIS and MS. Patients with a transient neurological dysfunction such as UP and a family history of MS should be submitted to brain MRI-scan to unveil a possible RIS.
Disclosures Dr. Baroncini reports no disclosures. Dr. Zaffaroni has served on scientific advisory boards for Teva, Medtronics, Merck Serono and Novartis, and served as a consultant for Biogen Idec. Prof. Minonzio reports no disclosures. Dr. Annovazzi has served as a consultant to Biogen Idec, Teva Pharmaceuticals and Novartis and received speakers' bureaus for Biogen Idec and Teva Pharmaceuticals. Dr. Baldini reports no disclosures. Prof. Comi has served on scientific advisory boards for Bayer Schering Pharma, Merck Serono, Teva Pharmaceutical, Sanofi-Aventis, Novartis and Biogen Idec; has received speaker honoraria from Teva Pharmaceuticals, Sanofi-Aventis, Serono Symposia International Foundation, Biogen Idec, Merck Serono, Novartis and Bayer Schering Pharma. Dr. Ghezzi has served on scientific advisory boards for Merck Serono, Biogen Idec, Teva Pharmaceutical Industries Ltd.; has received speaker honoraria from Merck Serono, Biogen Idec, Bayer Schering Pharma, and Novartis, Serono Symposia International; served as a consultant for Novartis; and receives research support from Sanofi-Aventis, Biogen Idec, and Merck Serono. All human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
References [1] Frohman TC, Davis SL, Beh S, Greenberg BM, Remington G, Frohman EM. Uhthoff's phenomena in MS—clinical features and pathophysiology. Nat Rev Neurol 2013 Sep;9(9):535–40. [2] Okuda DT, Mowry EM, Beheshtian A, Waubant E, Baranzini SE, Goodin DS, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology 2009; 72: 800–805. Erratum. Neurology 2009;73:1714. [3] Charil A, Yousry TA, Rovaris M, Barkhof F, De Stefano N, Fazekas F, et al. MRI and the diagnosis of multiple sclerosis: expanding the concept of “no better explanation”. Lancet Neurol 2006;5:841–52. [4] Leigh RJ, Zee DS. The neurology of eye movements. 3rd ed. Oxford University Press; 1999 410 [479–482]. [5] Cohn ES, Kelley PM. Clinical phenotype and mutations in connexin 26 (DFNB1/ GJB2), the most common cause of childhood hearing loss. Am J Med Genet 1999;89(3):130–6. [6] Dodson KM, Blanton SH, Welch KO. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A 2011 May;155(5):993–1000. [7] Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011 February;69(2):292–302. [8] Granberg T, Martola J, Kristoffersen-Wiberg M, Aspelin P, Fredrikson S. Radiologically isolated syndrome: incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review. Mult Scler 2013;19:271–80. [9] Okuda DT, Siva A, Kantarci O, Inglese M, Katz I, Tutuncu M, et al. Radiologically Isolated Syndrome Consortium (RISC); Club Francophone de la Sclérose en Plaques (CFSEP). Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLoS One Mar 5 2014;9(3):e90509. [10] Gabelic T, Ramasamy DP, Weinstock-Guttman B. Prevalence of radiologically isolated syndrome and white matter signal abnormalities in healthy relatives of multiple sclerosis patients. AJNR Am J Neuroradiol Jul 25 2013. http://dx.doi.org/ 10.3174/ajnr.A3653.
Damiano Baroncini Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, Hospital S. Raffaele, Milan, Italy Multiple Sclerosis Study Center, Sant'Antonio Abate Hospital of Gallarate, Italy Corresponding author at: Multiple Sclerosis Study Center, Sant'Antonio Abate Hospital of Gallarate, Italy. Tel.: +39 331751386; fax: +39 331751385. E-mail address: [email protected]. Mauro Zaffaroni Multiple Sclerosis Study Center, Sant'Antonio Abate Hospital of Gallarate, Italy
264
Letter to the Editor
Giorgio Minonzio Neuroradiology Service, Hospital of Gallarate, Italy Pietro Annovazzi Silvana M. Baldini Multiple Sclerosis Study Center, Sant'Antonio Abate Hospital of Gallarate, Italy Giancarlo Comi Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, Hospital S. Raffaele, Milan, Italy
Angelo Ghezzi Multiple Sclerosis Study Center, Sant'Antonio Abate Hospital of Gallarate, Italy 10 April 2014
