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June 2022; 12 (3) Commentary

Confirming a Historical Diagnosis of Multiple Sclerosis

Challenges and Recommendations

View ORCID ProfileAndrew J. Solomon, View ORCID ProfileGeorgina Arrambide, Wallace Brownlee, View ORCID ProfileAnne H. Cross, María I. Gaitan, Fred D. Lublin, Naila Makhani, Ellen M. Mowry, View ORCID ProfileDaniel S. Reich, Àlex Rovira, View ORCID ProfileBrian G. Weinshenker, Jeffrey A. Cohen
First published January 6, 2022, DOI: https://doi.org/10.1212/CPJ.0000000000001149
Andrew J. Solomon
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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Georgina Arrambide
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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Wallace Brownlee
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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Anne H. Cross
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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María I. Gaitan
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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Fred D. Lublin
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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Naila Makhani
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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Ellen M. Mowry
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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Daniel S. Reich
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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Àlex Rovira
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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Brian G. Weinshenker
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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Jeffrey A. Cohen
Department of Neurological Sciences (AJS), Larner College of Medicine at the University of Vermont, University Health Center - Arnold 2, Burlington, VT; Servei de Neurologia-Neuroimmunologia (GA), Centre d’Esclerosi Múltiple de Catalunya, (Cemcat), Vall d’Hebron Institut de Recerca, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain; National Hospital for Neurology and Neurosurgery (WB), London, United Kingdom; Department of Neurology (AHC), Washington University School of Medicine, St. Louis, MO; Department of Neurology (MIG), Neuroimmunology Section, FLENI, Buenos Aires City, Argentina; The Corinne Goldsmith Dickinson Center for Multiple Sclerosis (FDL), Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pediatrics and Neurology (NM), Yale School of Medicine, New Haven, CT; Multiple Sclerosis Precision Medicine Center of Excellence (EMM), Johns Hopkins University, Baltimore, MD; Translational Neuroradiology Section (DSR), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Section of Neuroradiology (ÀR), Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Department of Neurology (BGW), Mayo Clinic, Rochester, MN; and Mellen Center for MS Treatment and Research (JAC), Neurological Institute, Cleveland Clinic, Cleveland, OH.
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Citation
Confirming a Historical Diagnosis of Multiple Sclerosis
Challenges and Recommendations
Andrew J. Solomon, Georgina Arrambide, Wallace Brownlee, Anne H. Cross, María I. Gaitan, Fred D. Lublin, Naila Makhani, Ellen M. Mowry, Daniel S. Reich, Àlex Rovira, Brian G. Weinshenker, Jeffrey A. Cohen
Neurol Clin Pract Jun 2022, 12 (3) 263-269; DOI: 10.1212/CPJ.0000000000001149

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Abstract

Patients with a historical diagnosis of multiple sclerosis (MS)—a patient presenting with a diagnosis of MS made previously and by a different clinician—present specific diagnostic and therapeutic challenges in clinical practice. Application of the McDonald criteria is most straightforward when applied contemporaneously with a syndrome typical of an MS attack or relapse; however, retrospective application of the criteria in some patients with a historical diagnosis of MS can be problematic. Limited patient recollection of symptoms and evolution of neurologic examination and MRI findings complicate confirmation of an earlier MS diagnosis and assessment of subsequent disease activity or clinical progression. Adequate records for review of prior clinical examinations, laboratory results, and/or MRI scans obtained at the time of diagnosis or during ensuing care may be inadequate or unavailable. This article provides recommendations for a clinical approach to the evaluation of patients with a historical diagnosis of MS to aid diagnostic confirmation, avoid misdiagnosis, and inform therapeutic decision making.

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Patients diagnosed with multiple sclerosis (MS) may transfer care to a new clinician for a variety of reasons. Such patients present with a historical diagnosis of MS—one made previously and by a different clinician. Application of the McDonald criteria1 is often straightforward when applied contemporaneously with a clinical syndrome typical of an MS attack or relapse. Retrospective application of the criteria in routine care is feasible and has been successfully applied to longitudinal research cohorts. Yet in some patients, assessment of a previous diagnosis of MS can be challenging.

A clinical approach to historical diagnosis of MS should consider several interrelated clinical questions beyond reevaluation of a remote diagnosis. Have the clinical and imaging characteristics remained consistent with MS? What were the characteristics and frequency of disease activity over time? Are current symptoms and disability the result of MS or a comorbid condition? Were there disease-modifying therapy (DMT) changes in the past, and, if so, what was the rationale? Does available clinical and paraclinical information justify the risks and benefits of continuing DMT initiated by a previous clinician?

Clinical, laboratory, imaging, or health care system barriers complicate the evaluation of a historical diagnosis (Table 1). This commentary highlights these common challenges and important red flags in patients presenting with a historical diagnosis of MS and provides recommendations for clinical approaches.

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Table 1

Common Challenges in Confirming a Historical Diagnosis of Multiple Sclerosis

Challenges in the Evaluation of a Patient With Historical Diagnosis of MS

Confirming Relapse Onset Disease

The McDonald criteria for relapsing-remitting MS (RRMS) require a clinical syndrome typical for MS (e.g., unilateral optic neuritis, partial myelitis, and focal cerebral or brainstem syndromes)1 with corroborating objective evidence by neurologic examination or paraclinical testing.1 Recent data suggest that these concepts are sometimes neglected or misunderstood,2,3 resulting in misapplication of the criteria in patients with atypical syndromes without objective evidence of a CNS lesion and ultimately misdiagnosis.4 In some patients presenting with a historical diagnosis, it may be difficult to determine whether the criteria were previously applied correctly at the time of diagnosis. This situation should prompt reevaluation to prevent diagnosis momentum bias5—the tendency to accept a previous diagnosis that may perpetuate misdiagnosis.

Confirming a remote relapse associated with diagnosis can be challenging. Patients may imprecisely recollect symptoms that occurred years earlier, and contemporaneous health care records may be incomplete or unavailable. Nonspecific descriptions of prior symptoms such as blurry vision, dizziness, and numbness, while compatible with optic nerve, brainstem, or spinal cord demyelinating syndromes, can also occur in alternative disorders frequently referred for MS evaluation, such as migraine.6 In some patients, abnormal neurologic examination findings may have resolved. Limited patient recollection and inadequate documentation are insufficient to conclude a diagnosis of MS is incorrect, but should prompt further investigation for objective evidence of a CNS lesion in a region typical for MS to corroborate a prior reported relapse (Table 2). The McDonald criteria for RRMS were validated in patients with presentations typical for MS—retrospective application in patients lacking convincing evidence of such a syndrome likely diminishes its specificity and raises the risk of misdiagnosis.7

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Table 2

Recommendations for a Clinical Approach to a Historical Diagnosis of Multiple Sclerosis

Assessing Historical Disease Activity

Although a previous syndrome typical of MS and without clinical or radiologic red flags suggesting alternative disorders8 can be confirmed in some patients with a historical diagnosis, an accurate determination of the accumulation and severity of clinical relapses or active (contrast-enhancing or new T2) MRI lesions in the years after diagnosis may also be difficult. Such information is important to inform shared decision making surrounding the risks and benefits of continuing DMT initiated by a prior clinician.

The challenges of MS relapse ascertainment are well recognized.9 The number and characteristics of remote relapses in patients with longstanding MS may be difficult to recall. The term relapse is sometimes misunderstood and ascribed to fluctuating symptoms that are instead the sequelae of prior CNS inflammatory events or pseudorelapses10—reemergence of symptoms attributable to prior relapses in the setting of stressors such as infection. In some patients, these phenomena may have been misinterpreted as evidence of active disease, resulting in DMT escalation.9 Several clinical approaches can be considered (Table 2) when historical disease activity is uncertain.

Evaluating Clinical Progression or Severe Disability

Confirming a progressive MS phenotype11,12 by either patient report or clinical documentation of accumulating disability can be difficult in some patients with a historical diagnosis. Patients may present with a vague history of worsening disability, mild or minimal disability on neurologic examination, and poor documentation of sustained clinical changes. Fluctuation of symptoms due to stressors such as infection, and effects of comorbidities and aging, can confound previous assessments for progression, influence patient perceptions of worsening symptoms, and may make interpretation of previous documentation challenging.

In patients with a history of progressive MS with severe longstanding disability, clinicians may be reluctant to reevaluate diagnosis, disease activity, or clinical progression. Such patients may not be receiving DMT or regular MRIs, with care instead focused on symptom management. In some patients, obtaining a new MRI may reveal MS disease activity that could prompt reconsideration of DMT or a comorbid condition amenable to treatment, such as compressive myelopathy13 or a neoplastic disorder.14 Clinical reassessment may also identify severe optic neuritis or myelitis with marked residual disability without evidence of progression—a phenotype more consistent with neuromyelitis optic spectrum disorder (NMOSD) where diagnosis may alter treatment even in patients with advanced disability.

In the era of DMT for primary progressive MS or secondary progressive MS with potential to result in serious adverse effects, particularly in those who are older and more disabled,15,16 accurately establishing historical progressive disease (Table 2) is a particularly pressing concern.

Challenges With MRI Interpretation in Patients With Historical Diagnoses

MRI may aid or complicate the evaluation of patients with a longstanding diagnosis of MS. Accurate assessment for new T2 lesions from prior MRIs to either support DIT or interval disease activity may be limited by lack of availability of prior scans. Also, differences in pulse sequences, acquisition parameters (e.g., slice thickness), scanning planes, and magnetic field strengths between scanners may complicate comparison.

MRI scans acquired in patients with longstanding MS without the benefit of prior scans for review may also raise questions concerning the accuracy of diagnosis. Coalescence of discrete MS lesions over time may mimic small-vessel vascular disease, leukodystrophies, or toxic/metabolic injury.17 Similarly, coalescence of multiple discrete spinal cord lesions in MS may mimic longitudinally extensive myelitis (LETM) and mistakenly suggest NMOSD or myelin oligodendrocyte glycoprotein antibody–associated disorder (MOGAD). MRI sequelae of age-related comorbidities may also confound retrospective brain MRI assessment for both diagnosis and disease activity. Hypertension and other causes of chronic vascular disease can simulate the appearance of Dawson fingers18 or pontine demyelinating lesions.17 The Figure demonstrates examples of these imaging findings, and Table 2 enumerates clinical approaches.

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Figure Imaging in Patients With Long-Standing MS: Effects of Comorbidity and Disease Duration and Mimics of Clinical Progression

(A) Periventricular and subcortical confluent MRI signal abnormalities mimicking chronic small vessel ischemic disease or leukodystrophy in a patient with longstanding MS without a history of, or risk factors for, vascular disease. (B) Central pontine lesions (solid arrows) suggestive of small vessel ischemic disease in a patient with both MS and vascular disease. (C) A patient with MS and progressive leg weakness due to compressive cervical myelopathy. Images show compression on the spinal cord exerted by intervertebral disc protrusion at the C6-C7 level, associated with central spinal cord signal changes (solid arrow), and lesions from MS seen superiorly (open arrows). (D) A patient with MS who presented with gradually progressive left arm and leg weakness due to an enlarging meningioma. (E) Formerly discrete lesions in a patient with MS, which over time have formed the appearance of longitudinally extensive myelitis (solid arrow). MS = multiple sclerosis.

History of Pediatric-Onset MS

Patients with pediatric-onset MS usually eventually transition care to adult neurologists. These clinicians may at times be less aware of evolving data concerning the differential diagnosis of MS in children.19 Pediatric-onset MS is ultimately diagnosed in only approximately 20% of children presenting with acquired demyelinating syndromes.19MS in children almost never exhibits a progressive course from onset and is associated with higher relapse rates20 and better relapse recovery,21 but earlier age at onset of secondary progression22 compared with adult-onset MS. Contrary to previous literature, contemporary data suggest that pediatric presentations of demyelination with characteristics atypical for adult MS (e.g., severe/bilateral optic neuritis) are more likely to be other demyelinating disorders, rather than pediatric-onset MS.19

Pediatric NMOSD is diagnosed in less than 5% of children with demyelinating syndromes and exhibits clinical features similar to adult NMOSD.19 MOG-IgG is detected in approximately one-third of children with acquired demyelinating syndromes such as optic neuritis and myelitis,19 and MOGAD accounts for a much higher proportion of these syndromes in children (especially those aged <11 years) than in adults.23 Diagnostic reevaluation in patients with a longstanding diagnosis of pediatric-onset MS is often warranted, particularly when either clinical presentation or MRI findings were atypical for adult-onset MS (Table 2).

Evaluation of a patient with a historical diagnosis of MS presents several challenges. The clinical and neuroradiologic evolution of MS with increasing disease duration and age, as well as health care system barriers, may complicate the reassessment of diagnosis, disease activity, and disability needed to guide optimal treatment decisions. Approaches that include retrospective consideration of core elements of the McDonald criteria and vigilance for specific red flags can aid clinicians in the care of such patients.

Even after thorough reevaluation, the diagnosis of MS may remain tentative. Sensitive and specific diagnostic and prognostic biomarkers would be helpful. Emerging neuroimaging biomarkers, such as the central vein sign,24 have shown promise in differentiating of MS from common mimics even in longstanding disease and in the presence of comorbid conditions.25 Accumulating data also suggest that serum neurofilament light chain may serve as a sensitive measure of active disease in MS.26 Such progress is encouraging, but the utility of such advances in clinical practice remains to be determined.27

Study Funding

No targeted funding reported.

Disclosure

A.J. Solomon is funded by NIH/NINDS K02NS109340; has received compensation for consulting or advisory boards from EMD Serono, Genentech, Biogen, Alexion, Celgene, Octave Bioscience, and Greenwich Biosciences, compensation for nonpromotional speaking from EMD Serono, and research support from Biogen; and participated in contracted research with Biogen, Novartis, Actelion, and Genentech. G. Arrambide has received compensation for consulting services or participation in advisory boards from Sanofi, Merck, and Roche, research support from Novartis, travel expenses for scientific meetings from Novartis, Roche, Stendhal, and ECTRIMS, and speaking honoraria from Sanofi, Merck, and Roche; is the editor for Europe of: Multiple Sclerosis Journal—Experimental, Translational and Clinical; and is a member of the International Women in Multiple Sclerosis (iWiMS) network executive committee. W. Brownlee has received speaker honoraria for educational activities and/or participation in advisory boards for Biogen, Celgene, Merck, Mylan, Novartis, Roche, and Sanofi Genzyme. Anne H. Cross has received honoraria from: Biogen, Celgene, EMD Serono, Genentech, Greenwich Biosciences, Janssen Pharmaceuticals, Novartis, Roche, and TG Therapeutics and performed contracted research for EMD Serono and Genentech. M.I. Gaitán has received reimbursement for developing educational presentations and/or travel/accommodations stipends from Merck Serono Argentina, Biogen Idec Argentina, Bayer Inc Argentina, Roche Argentina, Genzyme Argentina and Novartis Argentina, and Teva-Tuteur Argentina. F.D. Lublin has participated in consulting, advisory boards, or data safety monitoring boards for Biogen, EMD Serono, Novartis, Teva, Actelion/Janssen, Sanofi/Genzyme, Acorda, Roche/Genentech, MedImmune/Viela Bio, Receptos/Celgene/BMS, TG Therapeutics, MedDay, Atara Biotherapeutics, Mapi Pharma, Innate Immunotherapeutics, Apitope, Orion Biotechnology, Brainstorm Cell Therapeutics, Jazz Pharmaceuticals, GW Pharma, Mylan, Immunic, Population Council, Avotres, and Neurogene, as a speaker for Sanofi (nonpromotional) and EMD Serono (nonpromotional), and has research funding from Novartis, Actelion, Biogen, Sanofi, NMSS, NIH, and Brainstorm Cell Therapeutics. N. Makhani has no financial conflicts related to this work and is funded by the NIH/NINDS (grant number K23NS101099) and the Charles H. Hood Foundation. E.M. Mowry has received free medication for a clinical trial on which she is PI from Teva; is site PI of studies sponsored by Biogen and Genentech; has received funding for investigator-initiated studies from Biogen, Genentech, and Sun Pharma; and has received royalties for editorial duties from UpToDate. D.S. Reich is supported by funding from the NINDS/NIH Intramural Research Program and has received research funding from Vertex Pharmaceuticals. À. Rovira serves/served on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, Roche, Biogen, TensorMedical, and OLEA Medical and has received speaker honoraria from Sanofi-Genzyme, Merck Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, and Biogen. B.G. Weinshenker receives royalties from RSR Ltd, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen GbR for a patent of NMO-IgG as a diagnostic test for neuromyelitis optica spectrum disorders and served on adjudication committee for clinical trials conducted by MedImmune/Viela Bio/Horizon Therapeutics, Alexion, and UCB Biosciences; he consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding a clinical trial for neuromyelitis optica spectrum disorders; he has received honoraria for speaking at internal meetings for Genentech and Novartis and external meetings for Roche. J.A. Cohen received personal compensation for consulting for Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI, speaking for H3 Communications, and serving as an Editor of Multiple Sclerosis Journal. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.

Appendix Authors

Table

Footnotes

  • Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.

  • Received August 12, 2021.
  • Accepted December 14, 2021.
  • © 2022 American Academy of Neurology

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