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Multiple Sclerosis Differential Diagnoses

  • Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD, MBA  more...
 
Updated: Jun 16, 2016
 
 

Diagnostic Considerations

A common misconception is that any attack of CNS demyelination means a diagnosis of acute multiple sclerosis (MS). When a patient has a first attack of demyelination, the physician should not rush to diagnose MS, because the differential diagnosis includes a number of other diseases.

Clinicians who specialize in MS commonly see patients referred for multiple, ill-defined, vague complaints and T2 hyperintense lesions on recent head or spinal magnetic resonance imaging (MRI) scans. Careful questioning in these cases reveals that symptoms have been stereotyped and vague or are consistent with other disorders (eg, scintillating scotomas in a patient with concomitant migraines, or hand symptoms consistent with carpal tunnel syndrome). A history of meningoencephalitis during childhood occasionally emerges.

Another common problem is the presence of small T2 hyperintensities on MRI studies of the CNS, typically referred to as unidentified bright objects (UBOs) by neuroradiologists. These nonspecific lesions are relatively common in the general adult population, and clinical correlation (ie, a high degree of suspicion based on clinical evidence) becomes important in the diagnosis. To confirm MS in these cases, the physician should look for sites of involvement that are rare for UBOs but frequent for MS (eg, the corpus callosum or throughout the spinal cord).

The main differential diagnoses for MS include, but are not limited to, the following:

  • Spinal cord neoplasms (eg, astrocytomas, ependymomas)
  • Acute disseminated encephalomyelitis (ADEM)
  • Schilder disease
  • Baló concentric sclerosis
  • Sarcoidosis
  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
  • Transverse myelitis
  • Infarction of the spinal cord
  • Vasculitis
  • Radiation myelitis
  • Arteriovenous fistula
  • Progressive multifocal leukoencephalitis
  • Subacute combined degeneration of the spinal cord (vitamin B 12 deficiency)
  • Small-vessel ischemic disease (affecting the brain primarily, and caused by diseases with vascular risk factors, such as diabetes, hypertension, hyperlipidemia, old age)

Spinal cord neoplasms

Both primary and metastatic spinal cord neoplasms must be considered in the differential diagnosis of MS. On imaging studies, the presence of cysts and hemorrhage support the diagnosis of neoplasm.

ADEM

ADEM is considered an isolated postinfectious or postvaccination autoimmune attack on the CNS that leads to diffuse demyelination. ADEM is characterized by acute onset of motor, sensory, cerebellar, and cranial nerve dysfunction with encephalopathy, progressing to coma and eventual death in 30% of cases. Occasionally, ADEM has a fulminant hemorrhagic component, in which case it is termed acute hemorrhagic encephalomyelitis or leukoencephalitis of Weston Hurst.

MRI of the brain may be helpful for showing additional lesions in cases of MS or ADEM. This condition usually responds to steroid therapy; therefore, a treatment trial is often considered before proceeding with biopsy. This process is typically monophasic.

Schilder disease

Schilder disease is characterized in children and young adolescents by massive demyelination, presenting often as asymmetrical foci (often the size of an entire lobe) in the white matter on MRI and with a malignant course (ie, deterioration over months or a few years, with cortical blindness, hemiplegia, or paraplegia). Some patients, however, may respond to steroids and immunosuppressive therapy.

Baló concentric sclerosis

Baló concentric sclerosis is considered by some authors to be a variant of Schilder disease, with MRI lesions showing a characteristic alternating pattern of spared and damaged white matter that suggests progression of the disease process from the ventricles outward. Baló concentric sclerosis is often associated with more inflammatory cerebrospinal fluid (CSF) findings and a more fulminant progression than typical MS.

Sarcoidosis

Sarcoidosis involves the CNS in approximately 5% of cases. Concomitant pial involvement is frequently encountered. Gadolinium enhancement of the pia and white matter lesions on MRI is usually the rule.

CADASIL

CADASIL is an autosomal dominant disease affecting small and middle-sized brain blood vessels and characterized by recurrent headaches and strokes or transient ischemic attacks. Mutations in the Notch 3 gene can be demonstrated with current laboratory techniques. In young people with CADASIL who have multiple white matter lesions, CADASIL may be misdiagnosed as MS. Classical CADASIL hyperintense lesion localizations by MRI include frontal and temporal lobes, and deep gray matter (basal ganglia and thalamus). A family history of headaches and strokes should prompt a diagnostic workup for CADASIL.

Transverse myelitis

Transverse myelitis is the term usually used for idiopathic inflammatory myelopathy. Swelling and enhancement of the spinal cord may be evident on MRI, often affecting a longer segment than the typical involvement seen with partial myelitis in MS. This also needs to be distinguished from the longitudinally extensive transverse myelitis seen in Devic disease, classically involving multiple spinal cord levels with a linear trajectory.

Infarction of the spinal cord

Infarction of the spinal cord is more common at the thoracic level. Usually, only a single lesion is present. Contrast may be present, although this is not the dominant feature. Signal alteration usually and initially involves the anterior gray matter (anterior spinal artery distribution). The patient's clinical presentation will be acute. Particularly consider this entity if the patient is older and/or has a history of aortic/vascular surgery.

Vasculitic processes

Vasculitic processes such as systemic lupus erythematosus can result in spinal lesions that mimic MS. Often, multiple lesions are present. However, the clinical history is often known and helps to establish the correct diagnosis.

Radiation myelitis

Radiation myelitis generally occurs only in patients who have received doses higher than 4000 cGy. However, chemotherapy may be synergistic (ie, may lead to radiosensitization, triggering myelitis at lower radiation doses). The latency period is 1-3 years. Images may show some peripheral enhancement.

Arteriovenous fistula

Arteriovenous fistula usually occurs at the thoracolumbar level, and patients are usually older than 50 years, with a long history of back pain. The cord signal abnormality can involve a very long segment. Look for a serpiginous flow void along the cord surface.

Differential Diagnoses

 
 
Contributor Information and Disclosures
Author

Christopher Luzzio, MD Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison School of Medicine and Public Health

Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Coauthor(s)

Fernando Dangond, MD, FAAN Head of US Medical Affairs, Neurodegenerative Diseases, EMD Serono, Inc

Fernando Dangond, MD, FAAN is a member of the following medical societies: American Academy of Neurology, American Medical Association

Disclosure: Received salary from EMD Serono, Inc. for employment.

Chief Editor

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association

Disclosure: Nothing to disclose.

Acknowledgements

Martin K Childers, DO, PhD Professor, Department of Neurology, Wake Forest University School of Medicine; Professor, Rehabilitation Program, Institute for Regenerative Medicine, Wake Forest Baptist Medical Center

Martin K Childers, DO, PhD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Congress of Rehabilitation Medicine, American Osteopathic Association, Christian Medical & Dental Society, and Federation of American Societies for Experimental Biology

Disclosure: Allergan pharma Consulting fee Consulting

Edmond A Hooker II, MD, DrPH, FAAEM Assistant Professor, Department of Emergency Medicine, University of Cincinnati College of Medicine

Edmond A Hooker II, MD, DrPH, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American Public Health Association, Society for Academic Emergency Medicine, and Southern Medical Association

Disclosure: Nothing to disclose.

J Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Marjorie Lazoff, MD Editor-in-Chief, Medical Computing Review

Marjorie Lazoff, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, American Medical Informatics Association, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Consuelo T Lorenzo, MD Physiatrist, Department of Physical Medicine and Rehabilitation, Alegent Health, Immanuel Rehabilitation Center

Consuelo T Lorenzo, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation

Disclosure: Nothing to disclose.

William J Nowack, MD Associate Professor, Epilepsy Center, Department of Neurology, University of Kansas Medical Center

William J Nowack, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Electroencephalographic Association, American Medical Informatics Association, and Biomedical Engineering Society

Disclosure: Nothing to disclose.

Richard Salcido, MD Chairman, Erdman Professor of Rehabilitation, Department of Physical Medicine and Rehabilitation, University of Pennsylvania School of Medicine

Richard Salcido, MD is a member of the following medical societies: American Academy of Pain Medicine, American Academy of Physical Medicine and Rehabilitation, American College of Physician Executives, American Medical Association, and American Paraplegia Society

Disclosure: Nothing to disclose.

Daniel D Scott, MD, MA Associate Professor, Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine; Attending Physician, Department of Physical Medicine and Rehabilitation, Denver Veterans Affairs Medical Center, Eastern Colorado Health Care System

Daniel D Scott, MD, MA is a member of the following medical societies: Alpha Omega Alpha, American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, Association of Academic Physiatrists, National Multiple Sclerosis Society, and Physiatric Association of Spine, Sports and Occupational Rehabilitation

Disclosure: Nothing to disclose.

Fu-Dong Shi, MD, PhD Director of Neuroimmunology Laboratory, Barrow Neurological Institute, St Joseph's Hospital and Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Florian P Thomas, MD, MA, PhD, Drmed Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Timothy Vollmer, MD Consulting Staff, Department of Emergency Medicine, Geisinger Medical Center

Disclosure: Nothing to disclose.

Sandra F Williamson, MS, ANP-C, CRRN Clinic Coordinator, Department of Rehabilitation Medicine, Denver Veterans Affairs Medical Center

Sandra F Williamson, MS, ANP-C, CRRN is a member of the following medical societies: Phi Beta Kappa, Phi Kappa Phi, and Sigma Theta Tau International

Disclosure: Nothing to disclose.

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The mechanism of demyelination in multiple sclerosis may be activation of myelin-reactive T cells in the periphery, which then express adhesion molecules, allowing their entry through the blood-brain barrier (BBB). T cells are activated following antigen presentation by antigen-presenting cells such as macrophages and microglia, or B cells. Perivascular T cells can secrete proinflammatory cytokines, including interferon gamma and tumor necrosis factor alpha. Antibodies against myelin also may be generated in the periphery or intrathecally. Ongoing inflammation leads to epitope spread and recruitment of other inflammatory cells (ie, bystander activation). The T cell receptor recognizes antigen in the context of human leukocyte antigen molecule presentation and also requires a second event (ie, co-stimulatory signal via the B7-CD28 pathway, not shown) for T cell activation to occur. Activated microglia may release free radicals, nitric oxide, and proteases that may contribute to tissue damage.
MRI of the head of a 35-year-old man with relapsing-remitting multiple sclerosis. MRI reveals multiple lesions with high T2 signal intensity and one large white matter lesion. These demyelinating lesions may sometimes mimic brain tumors because of the associated edema and inflammation.
MRI of the head of a 35-year-old man with relapsing-remitting multiple sclerosis. This MRI, performed 3 months after the one in the related image, shows a dramatic decrease in the size of lesions.
Inflammation in multiple sclerosis. Hematoxylin and eosin (H&E) stain shows perivascular infiltration of inflammatory cells. These infiltrates are composed of activated T cells, B cells, and macrophages.
Demyelination in multiple sclerosis. Luxol fast blue (LFB)/periodic acid-Schiff (PAS) stain confers an intense blue to myelin. Loss of myelin is demonstrated in this chronic plaque. Note that absence of inflammation may be demonstrated at the edge of chronic lesions.
Gadolinium-enhanced, T1-weighted image showing enhancement of the left optic nerve (arrow).
Corresponding axial images of the spinal cord showing enhancing plaque (arrow). The combination of optic neuritis and longitudinally extensive spinal cord lesions constitutes Devic neuromyelitis optica.
Table 1. 2010 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis [53]
Clinical Presentation Additional Data Needed for MS Diagnosis
  • Two or more attacks
  • Objective clinical evidence of 2 or more lesions with reasonable historical evidence of a prior attack
None; clinical evidence will suffice. Additional evidence (eg, brain MRI) desirable,



but must be consistent with MS



  • Two or more attacks
  • Objective clinical evidence of 1 lesion
Dissemination in space demonstrated by MRI or



Await further clinical attack implicating a different site



  • One attack
  • Objective clinical evidence of 2 or more lesions
Dissemination in time demonstrated by



MRI or second clinical attack



  • One attack
  • Objective clinical evidence of 1 lesion (clinically isolated syndrome)
Dissemination in space demonstrated by



MRI or await a second clinical attack implicating a different CNS site



and



Dissemination in time, demonstrated by MRI or second clinical attack



· Insidious neurologic progression suggestive of MS One year of disease progression and dissemination in space, demonstrated by 2 of the following:
  • One or more T2 lesions in brain, in regions characteristic of MS
  • Two or more T2 focal lesions in spinal cord
  • Positive CSF
Notes: An attack is defined as a neurologic disturbance of the kind seen in MS. It can be documented by subjective report or by objective observation, but it must last for at least 24 hours. Pseudoattacks and single paroxysmal episodes must be excluded. To be considered separate attacks, at least 30 days must elapse between onset of one event and onset of another event.
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