535129
research-article2014
MSJ0010.1177/1352458514535129Multiple Sclerosis JournalS Lattanzi, F Logullo
MULTIPLE SCLEROSIS MSJ JOURNAL
Personal Viewpoint
Multiple sclerosis, solitary sclerosis or something else? Simona Lattanzi, Francesco Logullo, Paolo Di Bella, Mauro Silvestrini and Leandro Provinciali
Multiple Sclerosis Journal 2014, Vol. 20(14) 1819–1824 DOI: 10.1177/ 1352458514535129 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract Background: Inflammatory demyelinating diseases of the central nervous system represent a wide spectrum of entities and their classification cannot currently be regarded complete. Objective: Our aim is to describe a series of patients presenting with progressive myelopathy associated to a single demyelinating lesion of the spinal cord. Methods: We identified the patients affected by chronic progressive spinal cord dysfunction related to a single spinal cord lesion not satisfying the diagnostic criteria for any of the currently defined diseases. Results: Seven females and one male were included. The median age at onset of symptoms was 53 years (range 42–68) and the median follow-up was 8 years (range 5–12). Brain and spinal magnetic resonance imaging (MRI) scans detected only one single, circumscribed, T2 hyperintense, non-longitudinally extensive lesion at level of cervico-medullary junction or cervical cord, in the absence of Gadolinium enhancement or swelling. Cerebrospinal fluid (CSF) examination displayed neither oligoclonal bands nor raised IgG index. A response to immunosuppressive agents was observed in some of the patients. Serial control brain and spinal MRI did not reveal accumulation of new lesions. Conclusion: New entities or variants should be included among the inflammatory demyelinating diseases of the central nervous system, and their characterization may have relevant prognostic and treatment implications.
Keywords: Multiple sclerosis, transverse myelitis Date received: 6 February 2014; revised: 2 April 2014; accepted: 20 April 2014
Introduction The central nervous system (CNS) may be affected by different chronic, relapsing–remitting or progressive, non-infectious idiopathic inflammatory demyelinating disorders (IIDDs); these are heterogeneous conditions with proved or presumed autoimmune pathogenesis which may variably involve, in localized, multifocal or diffuse form, the brain and the spinal cord and whose classification may be not still regarded as definitive.1 The aim of this study was to describe a series of patients affected by progressive myelopathy conducible to a single demyelinating lesion of the spinal cord in absence of spatial dissemination. Methods We identified the patients admitted to the Neurological Clinic of the Ospedali Riuniti of Ancona between
January 2003 and December 2008, prospectively followed-up for at least 5 years and responding to the following criteria: signs and symptoms of spinal cord dysfunction, subacute or insidious onset, chronic progressive course2 and evidence of only one single focal T2 hyperintense, non-longitudinally extensive, lesion of spinal cord at baseline brain and spinal magnetic resonance imaging (MRI) scans. All records of instrumental investigations, laboratory work-up and clinical evaluations of the patients were collected. Exclusion criteria were: infection or vaccination within the 30 days preceding the onset of the neurological symptoms, history of malignancy or spinal cord irradiation, infectious myelitis, spinal cord compression, trauma, arteriovenous malformation, fistula or neoplasia, exposure to toxic agents, fulfilment of the criteria for multiple sclerosis (MS), neuromyelitis optica (NMO) spectrum disorders, primary or secondary vasculitis of the CNS, connective tissue diseases,
Correspondence to: Simona Lattanzi Neurological Clinic, Marche Polytechnic University, Via Conca 71, 60020 Ancona, Italy. alfierelattanzisimona@ gmail.com Simona Lattanzi Francesco Logullo Paolo Di Bella Mauro Silvestrini Leandro Provinciali Neurological Clinic, Marche Polytechnic University, Ancona, Italy
http://msj.sagepub.com 1819
Downloaded from msj.sagepub.com at UNIV NEBRASKA LIBRARIES on April 7, 2015
Multiple Sclerosis Journal 20(14) sarcoidosis, copper deficiency or other alternative diagnosis. Standard protocol approvals and patients consents Institutional review boards approved the study, and written informed consent was obtained from all participating patients. Results Baseline clinical data Eight patients, one male and seven females, were included in the study. Clinical characteristics are summarized in Table 1. All patients came to our attention for progressive motor symptoms (mono-, para- or triparesis) associated with sensory disturbances with impairment of spinothalamic and/or posterior column modalities. All but one of the patients had neurogenic bladder dysfunction. Cerebrospinal fluid and laboratory work-up Cerebrospinal fluid (CSF) exam revealed neither oligoclonal bands nor raised IgG index. The search for NMO-immunoglobulin G was negative in all cases. Other investigations performed in all subjects included: serum levels of Vitamins B12 and E, homocysteine, folate, copper, ceruloplasmin, very long chain fatty acids, lactate, arylsulfatase A, angiotensinconverting enzyme, lysozyme, thyroid-stimulating hormone, anti-phospholipid antibodies, anti-nuclear antibodies, anti-extractable nuclear antigens antibodies, anti-neutrophil cytoplasm antibodies, neoplastic markers, paraneoplastic autoantibody profile, complement fractions, cryoglobulins, Schirmer test, pathergy test, HLA-B*51 allele analysis, serologic investigations for Herpes Simplex Virus (HSV)-1, HSV-2, Varicella Zoster Virus, Cytomegalovirus, Epstein–Barr Virus, Enteroviruses, Hepatitis-B Virus, Hepatitis-C Virus, Human Immunodeficiency Virus, Human T-cell Lymphotrophic Virus type I, Coxsackievirus, Chlamydia, Legionella, Mycoplasma pneumoniae, Borrelia burgdorferi, Treponema pallidum, Tropheryma whipplei. All these studies resulted negative. Magnetic resonance imaging In all patients baseline MRI scans of the brain and cervical and thoracic spine, before and after Gadolinium injection, were acquired at a median time interval from symptoms onset of 2 years (range 1–13);
one single circumscribed T2 hyperintense lesion, non-longitudinally extensive, in the absence of Gadolinium enhancement or swelling, was detected at level of cervico-medullary junction in two subjects and at level of cervical cord in the remaining patients (Figure 1). A series of control MRI studies of both the brain and the entire spinal cord (median 4, range 2–6, for each patient) before and after Gadolinium injection was performed and did not reveal accumulation of new lesions nor Gadolinium enhancement during follow-up. The median time lag between the first and last MRI scans was 6 years (range 4–9). Evoked potentials and other instrumental investigations Visual evoked potentials (VEPs) using pattern-reversal, full-field, checkerboard stimuli, were obtained at baseline and repeated during follow-up. The VEPs were serially performed (median 5, range 2–7, for each patient) and did not demonstrate any abnormality establishing spatial dissemination; the median temporal interval between the first and last measurements was 7 years (range 4–11). Thoracic-abdominalpelvis computed tomography (CT) scans, neurosonological study of extracranial and intracranial vessels, echocardiography, salivary gland scintigraphy and biopsy were unremarkable. Pharmacological treatment and follow-up A progressive neurologic decline was observed in three patients not pharmacologically treated with any immunosuppressor or immunomodulator agent and in one patient who started azathioprine and then shifted to methotrexate. One patient died from bacteria pneumonia while he was taking methotrexate without any benefit on the neurological symptoms. The chronic progressive course stopped during follow-up in three cases: two subjects underwent to a stabilization of their neurological condition when immunosuppressive therapy, respectively with cyclophosphamide and azathioprine, was started, and one patient under methotrexate treatment showed an improvement persisting at 9 years. None of the patients presented symptoms suggestive for acute relapse or involvement of other CNS sites. Discussion Chronic progressive myelopathy presents a major diagnostic challenge since its differential diagnosis includes a wide list of potential mimickers. Clinical history, the involvement of organs other than CNS, laboratory and instrumental findings, and responsiveness to a specific drug regimen may be crucial cues
1820 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV NEBRASKA LIBRARIES on April 7, 2015
Downloaded from msj.sagepub.com at UNIV NEBRASKA LIBRARIES on April 7, 2015
F
F
F
F
F
M
F
F
1
2
3
4
5
6
7
8
57
68
63
45
54
43
42
52
Age at onset (years)
88
76
66
86
58
63
72
92
Initial SNRS score
C1-C2; antero-lateral (left)
C5–C6; lateral (right)
C2–C3; postero-lateral (left)
C2; postero-lateral (right)
Ventral cervico-medullary junction (right)
Ventral cervico-medullary junction (bilateral)
C2–C4; postero-lateral (bilateral) C5–C7; lateral (right)
Lesion location
14
13
15
12
8
11
21
28
Lesion size (mm)*
Corticospinal, anteriorspinothalamic, anteriorcerebrospinal, vestibulospinal, sulcomarginal Corticospinal, anteriorspinothalamic, anteriorcerebrospinal, vestibolospinal Corticospinal, posterior spinothalamic, ventro-dorsal spinocerebellar, lateral cerebrospinal Corticospinal, ventro-dorsal spinocerebellar, lateral cerebrospinal, posterior columns Corticospinal, posterior spinothalamic, ventro-dorsal spinocerebellar, lateral cerebrospinal, posterior columns Corticospinal, spinothalamic, ventro-spincocerebellar, vestibulospinal
Corticospinal, posterior spinothalamic, ventrospinocerebellar, vestibolospinal
Corticospinal, posterior columns
Involved tracts
*Maximum diameter of the lesion was reported. AZT: azathioprine; CYC: cyclophosphamide; MTX: methotrexate; SNRS: Scripps Neurological Rating Scale. NA: not applicable (death of the patient).
Sex
Patient
Table 1. Clinical data.
13
11
54
55
86
NA
76
84
6
5
7
12
9
5
7
11
6
19
15
61
12
10
Disease duration (years)
97
Last SNRS score
9
Follow-up (years)
AZT, MTX
AZT
CYC, MTX
CYC
None
None
None
MTX
Therapy
S Lattanzi, F Logullo et al.
http://msj.sagepub.com 1821
Multiple Sclerosis Journal 20(14)
Figure 1. T2-weighted MRI findings. A (patient 1): hyperintense spinal C2–C4 lesion, sagittal. B (patient 2): right C5–C7 hyperintense lesion, axial. C (patient 3), D (patient 4): hyperintense lesions at ventral cervico-medullary junction, sagittal. E (patient 5): hyperintense lesion of spinal cord at C2 level, sagittal. F (patient 6): hyperintense spinal C2–C3 lesion, sagittal. G (patient 7): right C5–C6 hyperintense lesion, axial. H (patient 8): left antero-lateral hyperintense C1–C2 lesion, axial.
1822 http://msj.sagepub.com
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S Lattanzi, F Logullo et al. for diagnosis. Greater diagnostic difficulties are often encountered in distinguishing the inflammatory disorders: the IIDDs represent a broad group of CNS diseases with relatively specific characterization but also with considerable similarities and areas of overlap.1 This spectrum includes monophasic, multiphasic and progressive disorders ranging from highly localized forms to multifocal or diffuse variants. MS represents the prototypical IIDD, with the relapsing–remitting and secondary progressive variants the most frequently observed, although other phenotypes such as primary progressive and progressive relapsing should be taken into account. Furthermore, even less common ‘monosymptomatic’ and ‘topographically restricted’ conditions as Devic’s neuromyelitis optica, recurrent optic neuritis or relapsing transverse myelitis belong to the IIDDs. With respect to the isolated involvement of the spinal cord, while consensual diagnostic criteria have been established for acute and relapsing idiopathic myelitis,3,4 even including a distinction between their complete and partial forms because of the different natural history and risk of clinically definite MS, a clear characterization is still lacking for the primary progressive variant. The patients we described did not fulfil the diagnostic criteria for MS5–7 or NMO spectrum disorders,8,9 and alternative diagnoses were not applicable or were ruled out. Evidence of infectious, paraneoplastic, metabolic, or inflammatory connective tissue diseases was not present in any patient, and none had spinal trauma or stenosis; furthermore, the progressive course is not common for ischemia of the spinal cord, patients lacked of significant vascular risk factors and radiological findings were suggestive for an inflammatory demyelinating nature of the lesions. The lesions we described were not only small but also marginally located, a feature supporting the hypothesis that they may correspond to MS-like lesions rather than to those characteristic of NMO, usually more extensive and centrally located. Recently, progressive myelopathy due to a solitary demyelinating lesion of the brainstem or upper cervical cord has been described as solitary sclerosis and considered a subtype of MS, despite the clinical and radiologic absence of spatial dissemination.10 In respect to this newly hypothesized variant and despite the similar radiological findings, the patients we reported differed for distinctive features such as the higher age at onset of symptoms, the absence of CSF findings typically associated with MS such as the oligoclonal bands, the absence of episodic symptoms before onset of the progressive disease, and the inconstant responsiveness to immunosuppressive treatment
with a stabilization or even an improvement of the neurological condition. In view of these discrepant findings, it is reasonable to argue that totally or partially distinct aetiological and pathophysiological immune-mediated mechanisms may be implicated in different inflammatory demyelinating conditions; although to date these biological pathways are not exhaustively known, clinical evidence strongly suggests that the IIDDs represent a continuous spectrum of disorders. To date no studies have systematically addressed the questions of clinical presentation and long-term course of chronic myelitis not associated with spatial dissemination, and it is plausible that it may be conducible to different, and to some extent still neglected, conditions other than MS and its variants. The understanding of the pathogenesis of inflammatory demyelinating diseases of the CNS still remains partial. The available classification may be not currently regarded as definitive, and new entities or variants should be better characterized and included. The accurate systematization may assume great relevance for prognostic and treatment implications since immunosuppressive and immunomodulatory therapies do not alter significantly the ongoing worsening of neurologic deficits in patients affected by progressive MS and solitary sclerosis, but they may be more effective in other inflammatory demyelinating disorders. Furthermore, the selection of patients who might respond to existing and future disease-modifying therapies is expected to become an increasingly unavoidable necessity for physicians in their clinical practice. Conflict of interest None declared. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References 1. Cañellas AR, Gols AR, Izquierdo JR, et al. Idiopathic inflammatory-demyelinating diseases of the central nervous system. Neuroradiology 2007; 49: 393–409. 2. Lublin FD, Reingold SC and National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Defining the clinical course of multiple sclerosis: Results of an international survey. Neurology 1996; 46: 907–911.
http://msj.sagepub.com 1823
Downloaded from msj.sagepub.com at UNIV NEBRASKA LIBRARIES on April 7, 2015
Multiple Sclerosis Journal 20(14) 3. Maria Josè SA. Acute transverse myelitis: A practical reappraisal. Autoimmun Rev 2009; 9: 128–131. 4. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002; 59: 499–505. 5. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127. Visit SAGE journals online http://msj.sagepub.com
SAGE journals
6. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005; 58: 840–846.
7. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292–302. 8. Wingerchuk DM, Lennon VA, Pittock SJ, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006; 66: 1485–1489. 9. Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. The spectrum of neuromyelitis optica. Lancet Neurol 2007; 6: 805–815. 10. Schmalstieg WF, Keegan BM and Weinshenker BG. Solitary sclerosis. Progressive myelopathy from solitary demyelinating lesion. Neurology 2012; 78: 540–544.
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research-article2014
MSJ0010.1177/1352458514535129Multiple Sclerosis JournalS Lattanzi, F Logullo
MULTIPLE SCLEROSIS MSJ JOURNAL
Personal Viewpoint
Multiple sclerosis, solitary sclerosis or something else? Simona Lattanzi, Francesco Logullo, Paolo Di Bella, Mauro Silvestrini and Leandro Provinciali
Multiple Sclerosis Journal 2014, Vol. 20(14) 1819–1824 DOI: 10.1177/ 1352458514535129 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract Background: Inflammatory demyelinating diseases of the central nervous system represent a wide spectrum of entities and their classification cannot currently be regarded complete. Objective: Our aim is to describe a series of patients presenting with progressive myelopathy associated to a single demyelinating lesion of the spinal cord. Methods: We identified the patients affected by chronic progressive spinal cord dysfunction related to a single spinal cord lesion not satisfying the diagnostic criteria for any of the currently defined diseases. Results: Seven females and one male were included. The median age at onset of symptoms was 53 years (range 42–68) and the median follow-up was 8 years (range 5–12). Brain and spinal magnetic resonance imaging (MRI) scans detected only one single, circumscribed, T2 hyperintense, non-longitudinally extensive lesion at level of cervico-medullary junction or cervical cord, in the absence of Gadolinium enhancement or swelling. Cerebrospinal fluid (CSF) examination displayed neither oligoclonal bands nor raised IgG index. A response to immunosuppressive agents was observed in some of the patients. Serial control brain and spinal MRI did not reveal accumulation of new lesions. Conclusion: New entities or variants should be included among the inflammatory demyelinating diseases of the central nervous system, and their characterization may have relevant prognostic and treatment implications.
Keywords: Multiple sclerosis, transverse myelitis Date received: 6 February 2014; revised: 2 April 2014; accepted: 20 April 2014
Introduction The central nervous system (CNS) may be affected by different chronic, relapsing–remitting or progressive, non-infectious idiopathic inflammatory demyelinating disorders (IIDDs); these are heterogeneous conditions with proved or presumed autoimmune pathogenesis which may variably involve, in localized, multifocal or diffuse form, the brain and the spinal cord and whose classification may be not still regarded as definitive.1 The aim of this study was to describe a series of patients affected by progressive myelopathy conducible to a single demyelinating lesion of the spinal cord in absence of spatial dissemination. Methods We identified the patients admitted to the Neurological Clinic of the Ospedali Riuniti of Ancona between
January 2003 and December 2008, prospectively followed-up for at least 5 years and responding to the following criteria: signs and symptoms of spinal cord dysfunction, subacute or insidious onset, chronic progressive course2 and evidence of only one single focal T2 hyperintense, non-longitudinally extensive, lesion of spinal cord at baseline brain and spinal magnetic resonance imaging (MRI) scans. All records of instrumental investigations, laboratory work-up and clinical evaluations of the patients were collected. Exclusion criteria were: infection or vaccination within the 30 days preceding the onset of the neurological symptoms, history of malignancy or spinal cord irradiation, infectious myelitis, spinal cord compression, trauma, arteriovenous malformation, fistula or neoplasia, exposure to toxic agents, fulfilment of the criteria for multiple sclerosis (MS), neuromyelitis optica (NMO) spectrum disorders, primary or secondary vasculitis of the CNS, connective tissue diseases,
Correspondence to: Simona Lattanzi Neurological Clinic, Marche Polytechnic University, Via Conca 71, 60020 Ancona, Italy. alfierelattanzisimona@ gmail.com Simona Lattanzi Francesco Logullo Paolo Di Bella Mauro Silvestrini Leandro Provinciali Neurological Clinic, Marche Polytechnic University, Ancona, Italy
http://msj.sagepub.com 1819
Downloaded from msj.sagepub.com at UNIV NEBRASKA LIBRARIES on April 7, 2015
Multiple Sclerosis Journal 20(14) sarcoidosis, copper deficiency or other alternative diagnosis. Standard protocol approvals and patients consents Institutional review boards approved the study, and written informed consent was obtained from all participating patients. Results Baseline clinical data Eight patients, one male and seven females, were included in the study. Clinical characteristics are summarized in Table 1. All patients came to our attention for progressive motor symptoms (mono-, para- or triparesis) associated with sensory disturbances with impairment of spinothalamic and/or posterior column modalities. All but one of the patients had neurogenic bladder dysfunction. Cerebrospinal fluid and laboratory work-up Cerebrospinal fluid (CSF) exam revealed neither oligoclonal bands nor raised IgG index. The search for NMO-immunoglobulin G was negative in all cases. Other investigations performed in all subjects included: serum levels of Vitamins B12 and E, homocysteine, folate, copper, ceruloplasmin, very long chain fatty acids, lactate, arylsulfatase A, angiotensinconverting enzyme, lysozyme, thyroid-stimulating hormone, anti-phospholipid antibodies, anti-nuclear antibodies, anti-extractable nuclear antigens antibodies, anti-neutrophil cytoplasm antibodies, neoplastic markers, paraneoplastic autoantibody profile, complement fractions, cryoglobulins, Schirmer test, pathergy test, HLA-B*51 allele analysis, serologic investigations for Herpes Simplex Virus (HSV)-1, HSV-2, Varicella Zoster Virus, Cytomegalovirus, Epstein–Barr Virus, Enteroviruses, Hepatitis-B Virus, Hepatitis-C Virus, Human Immunodeficiency Virus, Human T-cell Lymphotrophic Virus type I, Coxsackievirus, Chlamydia, Legionella, Mycoplasma pneumoniae, Borrelia burgdorferi, Treponema pallidum, Tropheryma whipplei. All these studies resulted negative. Magnetic resonance imaging In all patients baseline MRI scans of the brain and cervical and thoracic spine, before and after Gadolinium injection, were acquired at a median time interval from symptoms onset of 2 years (range 1–13);
one single circumscribed T2 hyperintense lesion, non-longitudinally extensive, in the absence of Gadolinium enhancement or swelling, was detected at level of cervico-medullary junction in two subjects and at level of cervical cord in the remaining patients (Figure 1). A series of control MRI studies of both the brain and the entire spinal cord (median 4, range 2–6, for each patient) before and after Gadolinium injection was performed and did not reveal accumulation of new lesions nor Gadolinium enhancement during follow-up. The median time lag between the first and last MRI scans was 6 years (range 4–9). Evoked potentials and other instrumental investigations Visual evoked potentials (VEPs) using pattern-reversal, full-field, checkerboard stimuli, were obtained at baseline and repeated during follow-up. The VEPs were serially performed (median 5, range 2–7, for each patient) and did not demonstrate any abnormality establishing spatial dissemination; the median temporal interval between the first and last measurements was 7 years (range 4–11). Thoracic-abdominalpelvis computed tomography (CT) scans, neurosonological study of extracranial and intracranial vessels, echocardiography, salivary gland scintigraphy and biopsy were unremarkable. Pharmacological treatment and follow-up A progressive neurologic decline was observed in three patients not pharmacologically treated with any immunosuppressor or immunomodulator agent and in one patient who started azathioprine and then shifted to methotrexate. One patient died from bacteria pneumonia while he was taking methotrexate without any benefit on the neurological symptoms. The chronic progressive course stopped during follow-up in three cases: two subjects underwent to a stabilization of their neurological condition when immunosuppressive therapy, respectively with cyclophosphamide and azathioprine, was started, and one patient under methotrexate treatment showed an improvement persisting at 9 years. None of the patients presented symptoms suggestive for acute relapse or involvement of other CNS sites. Discussion Chronic progressive myelopathy presents a major diagnostic challenge since its differential diagnosis includes a wide list of potential mimickers. Clinical history, the involvement of organs other than CNS, laboratory and instrumental findings, and responsiveness to a specific drug regimen may be crucial cues
1820 http://msj.sagepub.com
Downloaded from msj.sagepub.com at UNIV NEBRASKA LIBRARIES on April 7, 2015
Downloaded from msj.sagepub.com at UNIV NEBRASKA LIBRARIES on April 7, 2015
F
F
F
F
F
M
F
F
1
2
3
4
5
6
7
8
57
68
63
45
54
43
42
52
Age at onset (years)
88
76
66
86
58
63
72
92
Initial SNRS score
C1-C2; antero-lateral (left)
C5–C6; lateral (right)
C2–C3; postero-lateral (left)
C2; postero-lateral (right)
Ventral cervico-medullary junction (right)
Ventral cervico-medullary junction (bilateral)
C2–C4; postero-lateral (bilateral) C5–C7; lateral (right)
Lesion location
14
13
15
12
8
11
21
28
Lesion size (mm)*
Corticospinal, anteriorspinothalamic, anteriorcerebrospinal, vestibulospinal, sulcomarginal Corticospinal, anteriorspinothalamic, anteriorcerebrospinal, vestibolospinal Corticospinal, posterior spinothalamic, ventro-dorsal spinocerebellar, lateral cerebrospinal Corticospinal, ventro-dorsal spinocerebellar, lateral cerebrospinal, posterior columns Corticospinal, posterior spinothalamic, ventro-dorsal spinocerebellar, lateral cerebrospinal, posterior columns Corticospinal, spinothalamic, ventro-spincocerebellar, vestibulospinal
Corticospinal, posterior spinothalamic, ventrospinocerebellar, vestibolospinal
Corticospinal, posterior columns
Involved tracts
*Maximum diameter of the lesion was reported. AZT: azathioprine; CYC: cyclophosphamide; MTX: methotrexate; SNRS: Scripps Neurological Rating Scale. NA: not applicable (death of the patient).
Sex
Patient
Table 1. Clinical data.
13
11
54
55
86
NA
76
84
6
5
7
12
9
5
7
11
6
19
15
61
12
10
Disease duration (years)
97
Last SNRS score
9
Follow-up (years)
AZT, MTX
AZT
CYC, MTX
CYC
None
None
None
MTX
Therapy
S Lattanzi, F Logullo et al.
http://msj.sagepub.com 1821
Multiple Sclerosis Journal 20(14)
Figure 1. T2-weighted MRI findings. A (patient 1): hyperintense spinal C2–C4 lesion, sagittal. B (patient 2): right C5–C7 hyperintense lesion, axial. C (patient 3), D (patient 4): hyperintense lesions at ventral cervico-medullary junction, sagittal. E (patient 5): hyperintense lesion of spinal cord at C2 level, sagittal. F (patient 6): hyperintense spinal C2–C3 lesion, sagittal. G (patient 7): right C5–C6 hyperintense lesion, axial. H (patient 8): left antero-lateral hyperintense C1–C2 lesion, axial.
1822 http://msj.sagepub.com
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S Lattanzi, F Logullo et al. for diagnosis. Greater diagnostic difficulties are often encountered in distinguishing the inflammatory disorders: the IIDDs represent a broad group of CNS diseases with relatively specific characterization but also with considerable similarities and areas of overlap.1 This spectrum includes monophasic, multiphasic and progressive disorders ranging from highly localized forms to multifocal or diffuse variants. MS represents the prototypical IIDD, with the relapsing–remitting and secondary progressive variants the most frequently observed, although other phenotypes such as primary progressive and progressive relapsing should be taken into account. Furthermore, even less common ‘monosymptomatic’ and ‘topographically restricted’ conditions as Devic’s neuromyelitis optica, recurrent optic neuritis or relapsing transverse myelitis belong to the IIDDs. With respect to the isolated involvement of the spinal cord, while consensual diagnostic criteria have been established for acute and relapsing idiopathic myelitis,3,4 even including a distinction between their complete and partial forms because of the different natural history and risk of clinically definite MS, a clear characterization is still lacking for the primary progressive variant. The patients we described did not fulfil the diagnostic criteria for MS5–7 or NMO spectrum disorders,8,9 and alternative diagnoses were not applicable or were ruled out. Evidence of infectious, paraneoplastic, metabolic, or inflammatory connective tissue diseases was not present in any patient, and none had spinal trauma or stenosis; furthermore, the progressive course is not common for ischemia of the spinal cord, patients lacked of significant vascular risk factors and radiological findings were suggestive for an inflammatory demyelinating nature of the lesions. The lesions we described were not only small but also marginally located, a feature supporting the hypothesis that they may correspond to MS-like lesions rather than to those characteristic of NMO, usually more extensive and centrally located. Recently, progressive myelopathy due to a solitary demyelinating lesion of the brainstem or upper cervical cord has been described as solitary sclerosis and considered a subtype of MS, despite the clinical and radiologic absence of spatial dissemination.10 In respect to this newly hypothesized variant and despite the similar radiological findings, the patients we reported differed for distinctive features such as the higher age at onset of symptoms, the absence of CSF findings typically associated with MS such as the oligoclonal bands, the absence of episodic symptoms before onset of the progressive disease, and the inconstant responsiveness to immunosuppressive treatment
with a stabilization or even an improvement of the neurological condition. In view of these discrepant findings, it is reasonable to argue that totally or partially distinct aetiological and pathophysiological immune-mediated mechanisms may be implicated in different inflammatory demyelinating conditions; although to date these biological pathways are not exhaustively known, clinical evidence strongly suggests that the IIDDs represent a continuous spectrum of disorders. To date no studies have systematically addressed the questions of clinical presentation and long-term course of chronic myelitis not associated with spatial dissemination, and it is plausible that it may be conducible to different, and to some extent still neglected, conditions other than MS and its variants. The understanding of the pathogenesis of inflammatory demyelinating diseases of the CNS still remains partial. The available classification may be not currently regarded as definitive, and new entities or variants should be better characterized and included. The accurate systematization may assume great relevance for prognostic and treatment implications since immunosuppressive and immunomodulatory therapies do not alter significantly the ongoing worsening of neurologic deficits in patients affected by progressive MS and solitary sclerosis, but they may be more effective in other inflammatory demyelinating disorders. Furthermore, the selection of patients who might respond to existing and future disease-modifying therapies is expected to become an increasingly unavoidable necessity for physicians in their clinical practice. Conflict of interest None declared. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References 1. Cañellas AR, Gols AR, Izquierdo JR, et al. Idiopathic inflammatory-demyelinating diseases of the central nervous system. Neuroradiology 2007; 49: 393–409. 2. Lublin FD, Reingold SC and National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Defining the clinical course of multiple sclerosis: Results of an international survey. Neurology 1996; 46: 907–911.
http://msj.sagepub.com 1823
Downloaded from msj.sagepub.com at UNIV NEBRASKA LIBRARIES on April 7, 2015
Multiple Sclerosis Journal 20(14) 3. Maria Josè SA. Acute transverse myelitis: A practical reappraisal. Autoimmun Rev 2009; 9: 128–131. 4. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002; 59: 499–505. 5. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127. Visit SAGE journals online http://msj.sagepub.com
SAGE journals
6. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005; 58: 840–846.
7. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292–302. 8. Wingerchuk DM, Lennon VA, Pittock SJ, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006; 66: 1485–1489. 9. Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. The spectrum of neuromyelitis optica. Lancet Neurol 2007; 6: 805–815. 10. Schmalstieg WF, Keegan BM and Weinshenker BG. Solitary sclerosis. Progressive myelopathy from solitary demyelinating lesion. Neurology 2012; 78: 540–544.
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