Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). This condition arises when the myelin sheath, crucial for nerve signal transmission, is damaged due to a complex interplay of genetic predispositions and environmental factors (1, 2). Understanding MS pathology has evolved since the initial histopathological observations by Carswell and Cruveilhier in the 19th century (3, 4). Jean-Martin Charcot notably linked clinical manifestations to histopathology in 1868, terming it “la sclerose en plaques”. Charcot’s descriptions of MS lesions, or “plaques,” characterized by focal demyelination, inflammation, gliosis, and varying axonal loss, remain fundamentally accurate today. Early plaques exhibit prominent inflammation and demyelination, whereas later stages are marked by axonal damage and neuronal loss (5).
MS presents in diverse clinical and pathological forms. Relapsing-remitting MS (RRMS), affecting 80–85% of patients, is characterized by attacks (relapses) followed by periods of remission. Primary progressive MS (PPMS), seen in 10–15%, follows a slow, progressive course without distinct relapses (6). Radiologically isolated syndrome (RIS) describes individuals with MS-suggestive MRI findings but lacking clinical symptoms, identified incidentally during imaging for other reasons (7). Clinical isolated syndrome (CIS) represents the first clinical episode suggestive of MS, such as optic neuritis, spinal cord syndromes, or brainstem/hemispheric involvement, often with MRI evidence of MS-like lesions (8). The clinical classifications of MS were formalized by Lublin et al. in 1996 and further refined in 2013 to include active and non-active disease forms (6, 9):
- Clinical isolated syndrome (CIS)
- Relapsing remitting MS (RRMS): Active and non-active RRMS
- Progressive MS (PMS): Active progressive, active non-progressive, non-active progressive, non-active non-progressive (stable) subtypes.
Effective MS management hinges on minimizing inflammation and subsequent neuroaxonal damage to prevent lasting disability. Early and accurate diagnosis is paramount for timely intervention and optimal treatment outcomes. This article will delve into the diagnostic approach for MS, focusing on the Differential Diagnosis For Multiple Sclerosis, and explore current diagnostic algorithms based on the latest MS diagnostic guidelines.
Diagnostic Approach to Multiple Sclerosis
Currently, there are no definitive biomarkers specific to MS. Diagnosis relies heavily on a detailed medical history and thorough neurological examination. Accurate identification of MS attacks is therefore crucial. An attack is defined as the emergence of new neurological deficits lasting over 24 hours, attributable to a specific anatomical location within the CNS, and occurring in the absence of fever or infection. These deficits typically develop subacutely over 2 to 4 weeks and may resolve spontaneously or with corticosteroid treatment over 6 to 8 weeks, either completely or partially. Attacks can be monofocal, affecting a single CNS region, or multifocal, involving multiple regions concurrently (1, 2.
For patients presenting with a suspected MS attack, magnetic resonance imaging (MRI) with intravenous gadolinium contrast is the most critical paraclinical investigation. MRI helps to characterize lesions as inflammatory and demyelinating, aiding in differential diagnosis, and demonstrates lesion dissemination in space (DIS) and time (DIT), essential criteria in current diagnostic frameworks.
Cerebrospinal fluid (CSF) analysis via lumbar puncture is another vital component of MS diagnosis. Standard CSF biochemistry (glucose, protein, albumin, IgG, lactate), microbiological assessments (cell count, and targeted tests as needed), cytopathology (malignancy screening), and evaluation of intrathecal immunoglobulin G (IgG) synthesis (IgG index and oligoclonal band [OCB] analysis) are performed. Electrophysiological tests like visual evoked potentials (VEP) and somatosensory evoked potentials (SEP) may also be used when indicated. Table 1 summarizes the investigations used in the diagnostic workup for suspected MS.
Table 1. Investigations for the Diagnosis of MS
| Primary Tests |
|---|
| 1. Blood tests: Hemogram, renal and liver function tests, electrolytes, sedimentation rate, CRP, B12, folate, vitamin D, thyroid function tests, lipid panel, viral serology (HIV, HCV, HbsAg, anti-Hbs), VDRL-RPR, ANA (titer and patterns), ENA profile (if ANA positive), antiphospholipid antibodies, anti-ds DNA. 2. MRI: Cranial, cervical, and thoracic spine. 3. CSF analyses: CSF protein, CSF and serum glucose, CSF and serum albumin and IgG, CSF lactate, CSF IgG index, CSF OCB analysis (isoelectric focusing). 4. In patients with optic neuritis: VEP and optic coherence tomography. |
| Secondary Tests |
| 1. Evoked potentials: VEP and SEP. 2. Optic coherence tomography. 3. Urodynamic testing. 4. Cognitive testing. |
| Other tests for differential diagnosis |
| 1. Further biochemical tests: Vasculitis panel (autoantibodies), 24-hour urine analysis, GFR, rheumatological disorders (anti-CCP, complement levels), lymphoma (serum beta2 microglobulin), sarcoidosis (serum and CSF ACE levels), adrenoleukodystrophy (adrenal hormones, long/very long chain fatty acids), mitochondrial diseases (serum pyruvate, lactate), neuromyelitis optica (anti-aquaporin 4 and anti-MOG). 2. Specific tests for infectious etiologies: Lyme disease and Brucellosis antibodies, PPD and QuantiFERON for tuberculosis. 3. Angiography: Cerebral, fluorescein, MRA. 4. Biopsy: Skin, lymph node, brain/leptomeninges, peripheral nerve, other. 5. Eye examination: Retina (metabolic disorders), uvea (sarcoidosis, Behçet’s disease). 6. Hearing tests: Susac syndrome. 7. Electrophysiology: Nerve conduction studies, EMG. 8. Chest X-ray: Chronic/sequel lung infections, hilar adenopathy. 9. Cardiac examination: Echocardiography (SLE, mitochondriopathies). 10. Others: Schirmer test/salivary gland scintigraphy (Sjögren’s disease), SPECT/PET (malignancies, metabolic disorders). |
Since the 1950s, numerous diagnostic criteria for MS have been proposed to enhance diagnostic accuracy by demonstrating lesion dissemination in time and space within the CNS, and to differentiate MS from conditions that mimic it both clinically and radiologically. While MS diagnosis is straightforward in many cases based on clinical and laboratory findings, challenges arise in early stages or in patients with atypical presentations. A thorough differential diagnosis process is essential, particularly in these complex scenarios.
The earliest comprehensive clinical criteria were established by Schumacher et al. in 1965 (10). These criteria required exclusion of other diagnoses and defined “probable MS” based on: (1) two or more attacks at least one month apart, each lasting at least 24 hours (dissemination in time), and (2) evidence of involvement in more than one CNS region (dissemination in space).
Poser et al. incorporated paraclinical tests in 1983, categorizing diagnoses as “clinically definite” or “laboratory supported definite” MS, improving diagnostic reliability (11). Evoked potentials and CSF analysis were then recognized as supportive paraclinical findings. MRI criteria were subsequently developed and have been continuously refined Table 2.
Table 2. MRI Criteria for MS Diagnosis Over Time
| Criteria Set | MRI Criteria |
|---|---|
| Paty, 1988 | >4 T2 hyperintense lesions or >3 T2 hyperintense lesions, at least one periventricular (PV) |
| Fazekas et al., 1988 | >3 T2 hyperintense lesions with: >1 infratentorial, >1 PV, >1 lesion >6 mm |
| Barkhof et al., 1997 | At least 3 of: (1) >1 Gd-enhancing lesion, (2) >1 juxtacortical lesion, (3) >1 infratentorial lesion, (4) >3 PV lesions |
| Barkhof & Tintore, 2000 | Modified Barkhof 1997 criterion (1): >1 Gd-enhancing lesion or >9 T2 hyperintense lesions |
The McDonald criteria, first introduced in 2001 and revised in 2005, 2010, and 2017 (12–15), marked significant advancements. The 2001 criteria integrated radiological evidence and redefined dissemination in time, enabling a diagnosis of “definite MS” at the first attack if dissemination in space criteria were met. CSF OCB positivity and elevated IgG index, along with VEP findings, were also included. The 2001 criteria classified MS as “definite MS”, “suspected MS”, and “non-MS” (12). The 2005 revision refined MRI and CSF criteria for clarity and introduced criteria for PPMS Tables 3 and 4. Comparing the 2001 and 2005 criteria showed similar diagnostic sensitivity (91% vs. 88%) but increased specificity (50% to 60%) (13). The 2010 McDonald criteria simplified dissemination in space criteria and removed OCB positivity and VEP from the main criteria Table 3. However, these simplifications were criticized for being overly inclusive, and the exclusion of CSF analysis made diagnosis challenging in atypical cases (14).
Table 3. McDonald 2010 Criteria and MRI Criteria for DIS and DIT
| McDonald 2010 Criteria |
|---|
| Clinical Finding |
| >2 attacks, >2 objective clinical lesions |
| >2 attacks, 1 objective clinical lesion |
| 1 attack, >2 objective clinical lesions |
| 1 attack, 1 objective clinical lesion |
| MRI Criteria for Dissemination in Space and Time |
| Dissemination in Space |
| At least 3 of: (1) 1 Gd(+) lesion or 9 T2 hyperintense lesions, (2) 1 infratentorial* lesion, (3) 1 juxtacortical lesion, (4) 3 periventricular lesions |
* Spinal cord lesions are considered equivalent to infratentorial lesions.
Table 4. Evolution of Criteria for Primary Progressive MS
| Criteria Set | PPMS Criteria |
|---|---|
| McDonald 2005 | >1 year progressive course (dissemination in time) and ≥2 of: (1) >9 cranial T2 hyperintense lesions, (2) >4 cranial T2 lesions and positive VEP, (3) >2 spinal cord T2 lesions, (4) Positive CSF* |
| McDonald 2010 | >1 year progressive course (dissemination in time) and ≥2 of: (1) >1 cranial T2 lesion**, (2) >2 spinal T2 lesions***, (3) Positive CSF* |
| McDonald 2017 | >1 year progressive course (PR or PP) (dissemination in time) and ≥2 of: (1) >1 cranial T2 lesion (cortical area added), (2) >2 spinal T2 lesions (with brainstem/spinal cord symptomatic lesions), (3) CSF OCB positivity |
* Increased IgG index or OCB positivity. ** At least one of juxtacortical, periventricular, or infratentorial. *** Symptomatic lesions in brainstem or spinal cord are excluded.
In 2015, the Magnetic Resonance Imaging in MS Study Group (MAGNIMS) standardized MRI protocols, specifying minimum slice thickness, sequence parameters, contrast agent (Gadolinium) dosage, and post-contrast imaging timing. Guidance for follow-up MRI in early stages (RIS, CIS) was also provided (16). MRI’s high sensitivity (up to 95%) makes it a crucial diagnostic tool. However, its negative predictive value increased to 65%, revealing a higher rate of false positives due to conditions like neuromyelitis optica (NMO), systemic connective tissue diseases, vasculitis, and even findings in healthy individuals. This led to the 2017 revision of the McDonald criteria (15).
The 2017 McDonald criteria (Table 5) incorporated three key revisions:
Table 5. Revised 2017 McDonald Criteria for MS Diagnosis
| Clinical Attack | Number of Objective Clinical Lesions | Requirements for MS Diagnosis |
|---|---|---|
| >2 | >2 | None |
| >2 | 1 (lesion in different CNS area indicating prior attack) | None |
| >2 | 1 | Dissemination in space (I): New attack in different CNS region OR DIS on MRI |
| 1 | >2 | Dissemination in time (II): New attack in different CNS region OR OCB (+) in CSF |
| 1 | 1 | Dissemination in space (I) AND time (II): (I) New attack in different CNS region OR DIS on MRI, (II) New attack in different CNS region OR DIT on MRI OR OCB (+) in CSF |
- For CIS patients with clinical or radiological dissemination in space and CSF-specific OCBs, a diagnosis of definite MS can be made without requiring MRI-demonstrated dissemination in time or a second clinical attack.
- Spinal cord lesions, previously excluded from dissemination in space or time criteria in 2010 due to reduced diagnostic sensitivity, were re-included in the 2017 criteria, recognizing their diagnostic value.
- Cortical lesions were added to juxtacortical, periventricular, and infratentorial lesions as evidence of dissemination in space, broadening MRI diagnostic sensitivity.
The Role of CSF Analysis in Differential Diagnosis of MS
CSF analysis is invaluable for differentiating inflammatory CNS disorders, both infectious and non-infectious. CSF findings are particularly beneficial in diagnosing patients with atypical MRI results. Beyond its general differential diagnosis utility, CSF analysis is especially important in early MS stages like RIS and CIS.
Measuring albumin and immunoglobulin levels in CSF and serum distinguishes between increased protein due to blood-brain barrier (BBB) disruption and isolated intrathecal synthesis. The CSF/serum albumin concentration gradient (Qalb) reflects BBB permeability (17. In MS, CSF protein and Qalb levels are usually normal or slightly elevated; mild BBB permeability increase is observed in about 20% of patients. Reiber’s formula quantifies intrathecal IgG synthesis (18. The IgG index, calculated as (CSF IgG/serum IgG)/(CSF albumin/serum albumin), is normally below 0.7. Oligoclonal IgG detection, a qualitative method using isoelectric focusing of serum and CSF, is positive in 80–90% of definite MS cases, though OCB presence is not MS-specific (19. Typical MS CSF is clear, with normal pressure and glucose. Protein may be elevated in about one-third of cases, but levels above 100 mg/dL should raise suspicion for alternative diagnoses. Mild lymphocytic pleocytosis may be present, but cell counts exceeding 50/mm3 warrant consideration of other conditions in the differential diagnosis (18, 19.
Differential Diagnosis Considerations
While the McDonald criteria provide a robust framework for MS diagnosis, it is crucial to consider other conditions that can mimic MS clinically and radiologically. The differential diagnosis for multiple sclerosis is broad and includes:
- Neuromyelitis Optica Spectrum Disorders (NMOSD): Previously considered a variant of MS, NMOSD is now recognized as a distinct astrocytopathy often associated with anti-aquaporin-4 antibodies. NMOSD typically presents with severe optic neuritis and longitudinally extensive transverse myelitis (LETM). Anti-MOG antibody-associated disease is another related entity in the NMOSD spectrum.
- Systemic Lupus Erythematosus (SLE) and other Connective Tissue Diseases: These autoimmune disorders can affect the CNS, causing neurological symptoms and MRI lesions that can resemble MS. Presence of systemic symptoms, specific autoantibodies (ANA, anti-dsDNA, etc.), and patterns of lesion distribution can aid in differentiation.
- Vasculitis: Inflammatory conditions affecting blood vessels in the CNS can lead to neurological deficits and white matter lesions. Clinical context, angiographic findings, and sometimes biopsy are needed for diagnosis.
- Sarcoidosis: This systemic granulomatous disease can involve the CNS, causing optic neuritis, myelopathy, and brain lesions mimicking MS. Chest X-ray, serum ACE levels, and biopsy of affected tissues can assist in diagnosis.
- Infections: Lyme disease, syphilis, HTLV-1, and progressive multifocal leukoencephalopathy (PML) can present with neurological symptoms and CNS lesions that may resemble MS. Specific serological tests and CSF analysis are crucial for excluding infections.
- Adrenoleukodystrophy (ALD) and other Leukodystrophies: These genetic disorders affect myelin and can present with progressive neurological deficits and white matter abnormalities on MRI. Family history, age of onset, and specific biochemical or genetic testing are important.
- Mitochondrial Diseases: These disorders of cellular energy production can affect the CNS and mimic MS, particularly in progressive forms. Lactate levels, muscle biopsy, and genetic testing may be necessary.
- Stroke and Vascular Events: Acute onset of neurological deficits and characteristic vascular lesion patterns on MRI usually differentiate stroke from MS, but atypical presentations may require careful consideration.
- Functional Neurological Disorder (FND): Also known as conversion disorder, FND can present with neurological symptoms that mimic MS attacks, but are not explained by organic neurological disease. Careful neurological examination, exclusion of organic causes, and psychological assessment are key to diagnosis.
- Migraine with Aura: Migraine aura can sometimes mimic MS symptoms, but is typically transient and recurrent. Detailed history and neurological exam help differentiate.
Conclusion
Diagnosing MS requires a comprehensive approach that integrates clinical findings, MRI evidence of dissemination in space and time, and often CSF analysis. The McDonald criteria provide a standardized framework, but a thorough understanding of the differential diagnosis for multiple sclerosis is essential to avoid misdiagnosis and ensure appropriate patient management. Careful consideration of alternative conditions, particularly in atypical presentations or early stages of the disease, is crucial for optimal clinical outcomes.
References
1 Compston A, Coles A. Multiple sclerosis. Lancet. 2008 Oct 25;372(9648):1502-17.
2 Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000 Sep 28;343(13):938-52.
3 Carswell R. Pathological anatomy: Illustrations of the elementary forms of disease. Longman, Orme, Brown, Green, and Longmans; 1838.
4 Cruveilhier J. Anatomie pathologique du corps humain, ou, Descriptions, avec figures lithographiées et coloriées, des diverses affections morbides dont le corps humain est susceptible. Baillière; 1829.
5 Charcot JM. Leçons sur les maladies du système nerveux faites à la Salpêtrière. Delahaye; 1873.
6 Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996 May;46(4):907-11.
7 Okuda DT, Mowry EM, Beheshti A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009 Sep 15;73(10):770-5.
8 Miller DH, Weinshenker BG, Filippi M, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler. 2008 Jan;14(1):110-24.
9 Lublin FD, Reingold SC, Cohen JA, et al. New diagnostic criteria for multiple sclerosis: revisions to McDonald criteria. Ann Neurol. 2011 Feb;69(2):183-92.
10 Schumacher GA, Beebe GW, Kibler RF, et al. Problems of experimental trials of therapy in multiple sclerosis. Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci. 1965 Mar 30;122(3):552-68.
11 Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983 May;13(5):227-31.
12 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 Jul;50(1):121-7.
13 Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005 Dec;58(6):840-6.
14 Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb;69(2):292-302.
15 Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-173.
16 Filippi M, Rocca MA, Ciccarelli O, et al. MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol. 2016 Mar;15(3):292-303.
17 Reiber H, Peter JB. Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci. 2001 Oct 15;184(2):101-27.
18 Andersson M, Alvarez-Cermeño J, Bernardi G, et al. Cerebrospinal fluid in the diagnosis of relapsing-remitting multiple sclerosis: A consensus report. J Neurol Neurosurg Psychiatry. 1994 Dec;57(12):897-902.
19 Keir G, Thompson EJ. Intrathecal synthesis of IgG in multiple sclerosis. J Neurol Sci. 1983 Feb;58(2-3):305-22.
