Multiple Sclerosis Differential Diagnoses

Updated: Jan 03, 2023
  • Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD, MBA  more...
  • Print

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 B12 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 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 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 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