In Morning Report on Tuesday May 3, 2022, we discussed a case of a new presentation of multiple sclerosis, possible syndromes and patterns of disease, as well as how to differentiate this from other syndromes such as neuromyelitis optica spectrum disorder (NMOSD) and anti-myelin oligodendrocyte glycoprotein (MOG) antibody syndrome.
1. Introduction and MS Syndromes
Multiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system. Some possible syndromes that can occur with multiple sclerosis are:
- Optic neuritis (relative afferent pupillary defect on examination)
- Brainstem syndromes such as internuclear ophthalmoplegia and trigeminal neuralgia
- Internuclear ophthalmoplegia (INO) leads to an inability to perform lateral gaze as there is a lesion in the medial longitudinal fasciculus
- Impaired adduction to the ipsilateral side of the lesion, abduction nystagmus contralateral to the side of the lesion
- Internuclear ophthalmoplegia (INO) leads to an inability to perform lateral gaze as there is a lesion in the medial longitudinal fasciculus
- Cerebellar syndromes
- Transverse myelitis
Other features of MS:
- Lhermitte sign (electric shock sensation down spine)
- Onset between age 15 and 50 years
- Uhthoff phenomenon (heat sensitivity)
- Fatigue
Four disease courses have been identifed:
- If patient does not meet criteria for MS but has a single attack typical for MS demyelination, then this term is called clinically isolated syndrome. This may represent a first attack but does not meet full McDonald criteria for a diagnosis of MS.
- Relapsing-remitting –> Unpredictable attacks which can leave patients with disabilities after attack, followed by episodes of remission
- Primary progressive –> steady increase in disability without attacks
- Secondary progressive MS –> Initial relapsing-remitting then gradual worsening
2. McDonald Criteria – 2017
| Number of clinical attacks (dissemination in time) | Number of lesions with objective clinical evidence (space) | Additional data needed for diagnosis |
| >= 2 | >= 2 | None |
| >= 2 | 1 (as well previous attack involving a lesion in a specific anatomic lesion based on a clear history) | None |
| >= 2 | 1 | Dissemination in space shown by an additional clinical attack involving a different CNS system or MRI |
| 1 | >= 2 | Dissemination in time shown by an additional clinical attack or by MRI or demonstration of CSF-specific oligoclonal bands |
| 1 | 1 | Dissemination in space shown by an additional clinical attack implicating a different CNS site or by MRI and Dissemination in time shown by an additional clinical attack or by MRI or demonstration of CSF-specific oligoclonal bands |
Part of the diagnosis requires that there isn’t another inflammatory condition or myelopathy to explain the presentation or syndrome.
Dissemination in Space
- When it comes to assessing dissemination in space with imaging features, there are four areas in the brain where you can see T2-hyperintense MRI lesions. The presence of one MRI T2-hyperintense lesion in two of these regions is required:
- (1) Periventricular
- (2) Cortical or juxtacortical
- (3) Infratentorial brain regions
- (4) Spinal cord
Dissemination in Time
Other than the history, some features that point to dissemination in time are:
- Single MRI with enhancing and non-enhancing (by gadolinium) on MRI OR
- The appearance of a new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI compared to an initial baseline MRI scan
- Two or more oligoclonal bands can be used instead of clinical or MRI dissemination in time. (Oligoclonal bands: proteins made of immunoglobulin G antibodies – two ways to check which are protein electrophoresis or isoelectric focusing/silver staining)
3. Features Atypical for Multiple Sclerosis
The differential diagnosis for MS may include neuromyelitis optica spectrum disorder (NMOSD), syndromes associated with myelin oligodendrocyte glycoprotein (MOG) antibody, neurosarcoidosis, and CNS manifestations of rheumatologic diseases and oncologic disease.
There are some features that may point towards another disease entity other than multiple sclerosis. The feature are listed below:
- Severe or bilateral optic neuritis –> points more towards NMOSD
- Longitudinally extensive transverse myelitis –> NMOSD, neurosarcoidosis, anti-MOG–associated myelitis, systemic rheumatologic disease, or a paraneoplastic disorder
- Complete spinal cord lesions or intractable vomiting – NMOSD (whereas partial Brown Sequard, which means hemicord, is more typical for MS)
- Transverse myelitis with prodromal symptoms or MRI T2 signal abnormality confined to spinal cord gray matter may suggest anti-MOG–associated myelitis
- Multiple cranial nerves involved –> think about neurosarcoid
- Transverse myelitis or optic neuritis with high CSF pleocytosis –> consider of infectious or inflammatory disorders other than MS.
- Systemic symptoms such as joint pain, skin changes, and weight loss might suggest either rheumatologic or paraneoplastic disease
4. Multiple Sclerosis and Associated Disorders
There are certain CNS inflammatory disease syndromes such as neuromyelitis optica spectrum disorder (NMOSD) and anti-myelin oligodendrocyte glycoprotein (MOG) antibody syndrome that can present similarly to MS. Some differences are outlined below:
| Attribute | Multiple Sclerosis | AQP4-IgG | MOG-IgG |
| Age | Any (median age at onset in third decade) | Any (median age onset in fourth decade) | Any (children and young adults) |
| Female:male sex predominance | 2:1 | 9:1 | 1.5:1 |
| Epidemiology | Common in terms of prevalence. Ethnicity: Caucasians more commonly affected | Prevalence is rare, ethnicity: African-Americans and Afro-Caribbeans more predisposed | Unknown prevalence and unknown re: ethnicity predominance |
| Common manifestations | Manifestations can include myelitis, optic neuritis, brainstem, cerebral episodes, myelopathy for progressive multiple sclerosis | NMOSD (single/recurrent myelitis, optic neuritis, area postrema syndrome hiccups, nausea, uncontrollable vomiting) | Initial episode: optic neuritis, acute disseminated encephalomyelitis (ADEM), NMOSD, myelitis. Relapse: optic neuritis |
| Blood biomarker/antibody | None | AQP4-IgG | MOG-IgG |
| CSF | WBC < 50/mm^3 (lymphocytic), can be normal, oligoclonal bands in 85% | WBC variable (usually lymphocytic but can be neutrophilic or eosinophilic), oligoclonal bands in 30% | WBC variable (lymphocytic), oligoclonal bands < 15% |
| Brain MRI | Lesions are ovoid, periventricular (Dawson fingers which are e a radiographic feature of demyelination characterized by periventricular demyelinating plaques along medullary veins), juxtacortical/cortical, infratentorial. Can also be ring/open-ring enhancing | Can be normal or non-specific. If there are lesions: area postrema can be involved (structure in the medulla oblongota and involved in controlling thirst, vomiting, hunger). Also lesions around the third and fourth ventricles, splenium, corpus callosum, pencil thin ependymal or cloud enhancement. | ADEM-like fluffy white matter, deep gray matter, diffuse/confluent brainstem lesions and involving the peduncles of the cerebellum. |
| Optic nerve | Unilateral | Bilateral | Bilateral |
| Spine MRI | Multiple short lesions, periphery of cord | Single spinal cord lesions, 85% longitudinally extensive transverse myelitis | Multiple lesions, 75% are longitudinally extensive; conus involved |
| Acute treatment | IV steroids (Rarely PLEX) | IV steroids Often PLEX | IV steroids Often PLEX IVIG in kids |
| Maintenance | Variety of immunomodulatory drugs | None approved Steroid sparing recommended examples include azathioprine, rituximab among others | None approved None needed if monophasic Steroid sparing-agents if relapsing disease |
| Prognosis | Most can ambulate after 20 years, disability occurs in secondary progressive phase | Accumulation of disability based on attacks | Most disability with first attack Persistent seropositivity and higher titer are predictors of relapse |
5. References
- Solomon A. J. (2019). Diagnosis, Differential Diagnosis, and Misdiagnosis of Multiple Sclerosis. Continuum (Minneapolis, Minn.), 25(3), 611–635. https://doi.org/10.1212/CON.0000000000000728
- Flanagan E. P. (2019). Neuromyelitis Optica Spectrum Disorder and Other Non-Multiple Sclerosis Central Nervous System Inflammatory Diseases. Continuum (Minneapolis, Minn.), 25(3), 815–844. https://doi.org/10.1212/CON.0000000000000742
- Image from Kawachi I, Lassmann H. Neurodegeneration in multiple sclerosis and neuromyelitis optica. Journal of Neurology, Neurosurgery & Psychiatry 2017;88:137-145. Link – https://jnnp.bmj.com/content/88/2/137.citation-tools