Multiple Sclerosis: Understanding Disease Progression, Pain, and Function
A Clinical Primer

Multiple Sclerosis Diagnosis and Comorbidities

How to make an accurate MS diagnosis, including a look at overlapping disorders and current assessment tools.



When making a diagnosis of multiple sclerosis (MS), it is crucial to rule out other conditions that could explain the patient’s presenting symptoms. Otherwise, a misdiagnosis may be made, in particular, in cases where an individual has an atypical presentation.1 In addition to meeting the criteria for dissemination in space (ie, clinical evidence of two or more demyelinating episodes with two or more lesions) and time (ie, clinical evidence of lesions occurring in different locations of the central nervous system),2 several recommended diagnostic tests can help clinicians rule out other possible underlying etiologies. A thorough history and physical examination are also important components of the assessment protocol, as certain clinical signs can be “red flags” for other conditions besides MS.

This paper reviews medical conditions that may be misdiagnosed as – or overlap with – multiple sclerosis, as well as the assessment tools and diagnostic tests that can help clinicians make an accurate differential diagnosis.

Multiple Sclerosis and Differential Diagnoses

Many medical conditions besides multiple sclerosis can result in the neurological symptoms commonly observed in persons with MS. While these disorders can include other demyelinating disorders such as neuromyelitis optica (NMO) and acute disseminated encephalomyelitis (ADEM),3 they also can be other underlying etiologies that produce symptoms similar to MS. For example, migraine headaches and fibromyalgia were the two most common misdiagnoses observed in a study involving four academic medical centers.1 Part of the diagnostic workup for MS involves ruling out other conditions, such as those highlighted below.3

Inflammatory Central Nervous System (CNS) Disorders

Several autoimmune or immune-mediated conditions can cause an inflammatory response in the CNS, which can result in symptoms such as fatigue, pain, and neuropathy – all common symptoms in MS. Examples include:

  • Sarcoidosis
  • Sjogren’s syndrome
  • Systemic lupus erythematosus (SLE)
  • Behçet’s disease
  • Vasculitis  

CNS Infections

Infections that affect the CNS can cause symptoms similar to MS, such as fatigue, weakness, pain, and dysesthesias. Examples include:

  • Lyme disease
  • Progressive multifocal leukoencephalopathy (PML)
  • Human T-cell lymphotropic virus-1 or -2 (HTLV-I/II)
  • Human immunodeficiency virus (HIV)
  • Syphilis

Vitamin Deficiencies

Several deficiencies can result in neurological symptoms that compare to MS, which can be identified by blood work. Examples include:

  • Vitamin B-12 deficiency
  • Copper deficiency

Vascular and Coagulation Disorders

Several vascular conditions can produce MRI changes and neurological deficits that mimic MS.  Examples include:

  • Antiphospholipid syndrome
  • Anterior ischemic optic neuropathy
  • Atypical MRI lesions associated with hypertension and hyperlipidemia

Genetic Disorders

Certain genetic disorders can affect the CNS, causing symptoms such as balance difficulties and cognitive impairment. Examples include:

  • Mitochondrial disease
  • Leukodystrophies
  • Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
  • Hereditary cerebellar degeneration
  • Hereditary myelopathies

Tumors and Structural Damage

Tumors infiltrating the CNS or conditions that cause structural damage to the brain or spinal cord can result in symptoms similar to MS. Examples include:

  • Lymphoma
  • Metastases
  • Syringomyelia (with or without Chiari’s malformation)
  • Cervical spondylosis
  • Herniated disk

Other Disorders that May Mimic MS

These conditions may mimic the clinical symptoms of MS and should be ruled out when making an MS diagnosis. Examples include:

  • Migraine headaches
  • Fibromyalgia
  • Functional neurological disorders


Multiple Sclerosis Diagnostic Tools

As part of the diagnostic process, several paraclinical tests are used to help identify MS and/or differentiate from other conditions. See also, a Scripted conversation below on how to talk to patients about undergoing MS diagnostic tests.


Magnetic resonance imaging (MRI) is one of the gold standards in diagnosing MS. The 2017 McDonald criteria specify counting the lesions in the brain that are periventricular, cortical or juxtacortical, infratentorial, optic nerve, or spinal cord to meet specific criteria.2 The lesions can be symptomatic or asymptomatic.2 Evidence of an abnormal brain MRI with clinically isolated syndrome (ie, the first relapse) can be used to demonstrate dissemination in space and time and make a diagnosis of MS. In addition, the 2017 McDonald criteria include cortical and juxtacortical lesions as fulfilling dissemination in space criteria.2

One longitudinal study noted that 88% of individuals with clinically isolated syndrome who had an initial abnormal MRI went on to develop MS.4 About 95% of persons with MS have an abnormal brain MRI.5 Persons with MS who have normal brain MRIs typically have other abnormal tests, such as a lesion on a spinal cord MRI, evidence of oligoclonal bands, or abnormal evoked potentials.5

To streamline the diagnostic process, add consistency between scans and different MRI scanners a standard protocol should be utilized. A consortium group recently updated MRI consensus recommendations, including: the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS), Consortium of Multiple Sclerosis Centers (CMSC), and North American Imaging in Multiple Sclerosis Cooperative (NAIMS).6 For a brain MRI, at least a 1.5 T field strength is recommended, although a 3 T is preferred.6 The imaging should cover the whole brain, with as much of the cervical spinal cord as possible. In terms of the slice thickness, it is dependent on whether 3D (preferable) or 2D techniques are used. A 1 mm thickness is preferred with 3D (not over 1.5 mm if contiguous), while the slice thickness should be 3 mm or less with no gaps if using 2D.

MRI Brain Diagnostic Sequences for MS

The core MRI brain diagnostic sequences include:6  

  1. Axial T2-weighted (T2-w) turbo spin echo (TSE) or fast spin echo (FSE)
  2. Sagittal 3D T2-w Fluid Attenuated Inversion Recovery Sequence (fat suppression is optional)
  3. Axial T2-w FLAIR (not necessary if a sagittal 3D with multiplanar reconstruction is obtained)
  4. Axial (or 3D sagittal) T1-w post-contrast sequence

MRI Contrast for MS

The use of a gadolinium contrast is recommended, as it can assist with meeting the dissemination in time criteria of the McDonald criteria (ie, if the lesion is acute or chronic).6 For instance, gadolinium enhancement is suggestive of an acute lesion as it is a result of an inflammatory response.

Spinal cord lesions are considered in the 2017 McDonald criteria,2 making spinal MRIs an important component of the diagnostic workup. They can also be useful in ruling out other etiologies.6 At least a 1.5 T field strength MRI is currently recommended.6 The required sequences include:6

  1. At least two of: sagittal T2-w TSE and FSE, proton density FSE or TSE, or short tau inversion recovery (STIR)
  2. Sagittal T1-w post-contrast sequence

Interpreting MRI Results for MS

When interpreting the MRI, it is crucial that the clinician understand how MS lesions present, as several of the differential diagnoses can result in lesion formation and other findings on MRI. For instance, persistent gadolinium enhancement should be a red flag for other conditions, such as sarcoidosis or vasculitis.7 In addition, MS-related lesions are expected in certain regions of the CNS. T2-hyperintensities noted in regions such as the basal ganglia, hypothalamus, or thalamus may signify the presence of conditions such as Behçet’s disease or ADEM.7

Cerebrospinal Fluid (CSF) Analysis

In addition to evidence of MS disease activity on MRI, positive findings of oligoclonal bands in the CSF can substitute for demonstration of dissemination of lesions in time in some settings.2 CSF testing is recommended when:2

  • The patient presents with a progressive course at onset
  • There is insufficient evidence from other sources (ie, MRI and clinical examination) to diagnose MS
  • The patient presents with atypical features
  • he patient belongs to a population where MS is less common

CSF analysis for MS primarily looks at oligoclonal banding and immunoglobulin G (IgG) index;8 however, other aspects of the report can be useful for clinicians when ruling out other causes of inflammation.9 It should be noted that CSF analysis alone should not be used to diagnose MS. According to the National MS Society,10 up to 10% of persons with clinically definite MS do not have CSF abnormalities. That said, positive CSF findings can speed up the appropriate diagnosis of MS in the setting of acute onset of optic neuritis without other history, examination, or other MRI findings.

Neurophysiological Testing (Evoked Potentials)

In some situations, neurophysiological testing (ie, evoked potentials) may be done as part of an MS assessment. These tests can provide evidence that there is demyelination through slowed electrical conduction. For instance, visual evoked potentials may be used to detect optic nerve involvement,2 which can be helpful in individuals where there is difficulty detecting clear evidence of impairment above the foramen magnum.8 Between 42% and 100% of persons with MS exhibit abnormal visual evoked potentials.5

While visual evoked potentials and other evoked potentials, such as somatosensory, can provide valuable information, further research is needed to support their usage in fulfilling the McDonald criteria.2

Blood Work

Blood work is often ordered as part of the diagnostic protocol to rule out other conditions when determining an MS diagnosis.8 These can include tests to rule out nutritional deficiencies such as vitamin B12, folate, and copper. Infectious conditions such as HTLV-I/II and HIV can be ruled out with their respective blood tests. Thyroid functioning may be evaluated, as abnormal thyroid functioning can cause symptoms such as fatigue. Other commonly ordered blood tests include:8

  • Antinuclear antibody test (ANA) for autoimmune disorders like SLE and Sjogren’s syndrome
  • Erythrocyte sedimentation rate (ESR) for inflammatory responses, like vasculitis
  • Rheumatoid factor (RF) test for autoimmune disorders such as rheumatoid arthritis and Sjogren’s syndrome

Clinical Examination

While imaging and laboratory tests are an important part of the diagnostic process for multiple sclerosis, a thorough history and clinical examination are crucial components. Lhermitte’s sign, spinal cord sensory levels, and heat-related symptoms are common and helpful signs to look for in the clinical evaluation. In addition, the year of disability progression for primary progressive MS (PPMS) can be determined retrospectively.2

Furthermore, symptom presentation and their timeline can help establish that the criteria for dissemination in time and space have been met.2 The clinical examination can also reveal red flags indicative of other conditions. For instance, if a patient presents with peripheral neuropathy, there is a high likelihood that their presentation is due to another etiology such as Lyme disease or a vitamin B12 deficiency.7 Other potential flags that can be observed on clinical examination include rashes, amyotrophy, isolated progressive ataxia, and mucosal ulcers.7


Figure 1. How to talk to patients about undergoing diagnostic tests for Multiple Sclerosis. Download a PDF.



Differentiating between Multiple Sclerosis Relapses and Progression

As described in Part I of this Clinical Primer, persons with MS experiencing a relapse have new or worsening symptoms that last over 24 hours, followed by a partial or full recovery, and then periods of neurological stability.2,11 Often, new MRI activity is noted when a relapse occurs. Progression, on the other hand, is defined as an accumulation of disability.2 MS progression may or may not coincide with new MRI activity (ie, active disease). Gathering a comprehensive history of the patient’s symptoms and their changes over time is a key component to differentiating between a relapse and disease progression. Clinicians should also consider using measures such as the Kurtzke Expanded Disability Status Scale (EDSS)12 to track patients’ disability over time.


Multiple Sclerosis Comorbidities

While clinicians need to consider other etiologies that may better explain an individual’s clinical presentation while assessing for MS, they also need to be aware that a patient may present with both MS and another condition, which may complicate the diagnostic process. For instance, persons with MS and a comorbidity experience a longer delay in getting a diagnosis.13 Some of the differential diagnoses for MS can also be present in persons with MS as comorbidities. For instance, during the diagnostic workup, clinicians need to consider whether a patient’s symptoms are due to a vascular condition.7 However, vascular comorbidities are not uncommon in MS,13,14 and they are associated with a greater risk of disability progression.14 As such, clinicians will need to consider the patient’s medical history, including the timeline of symptom presentation in relation to their pre-existing symptoms, and evaluate whether their new symptoms are due to MS or another etiology.


Diagnosing MS: Clinical Takeaways

When diagnosing MS, clinicians need to consider a person’s medical history, clinical examination, and the results on diagnostic tests. MS remains a clinical diagnosis with support from paraclinical tests. While MRIs can help provide the necessary data to meet the criteria for dissemination in time and space, clinicians may need to consider other measures if the results are inconclusive or the presentation is atypical.2 The assessment protocol should include procedures such as blood work8 and observations of unusual signs that may be indicative of other conditions.7 Finally, clinicians should be aware that a patient may present with both MS and a comorbid condition, which could complicate the diagnostic process.13

Back to the full Clinical Primer on MS.

Last updated on: September 13, 2021
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