Keywords:
Multiple Sclerosis - Neuromyelitis Optica - Myelin-Oligodendrocyte Glycoprotein -
Diagnosis
Palavras-chave:
Esclerose Múltipla - Neuromielite Óptica - Glicoproteína Mielina-Oligodendrócito -
Diagnóstico
INTRODUCTION
Acquired demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica
spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease
(MOGAD) compromise the optic nerves, brain and spinal cord and lead to a range of
clinical symptoms including visual, pyramidal, sensory, autonomic, and cerebellar
deficits. The diseases affect mainly young individuals and may lead to severe disability.
In fact, MS is the second leading cause of disability of young adults in developed
countries[1].
Prompt diagnosis and initiation of treatment are essential towards preventing attacks
and halting the accumulation of disabilities. The ability to perform accurate differential
diagnoses is crucial to the good prognosis of patients, however it can be extremely
challenging, as the field is dynamic and expanding, different disease entities clinically
overlap and access to specific assays is still limited in certain settings.
This paper aims to provide an updated practical approach on how to perform the differential
diagnoses of suspected acquired demyelinating syndromes taking into account the particularities
of the Brazilian population and healthcare system.
METHODS
We performed a targeted literature review pertaining to the diagnosis of MS, NMOSD
and MOGAD. Resulting evidence was jointly critically appraised by a junior and a senior
neuroimmunologist.
Epidemiological/demographic update: prevalence of ADS in Brazil
Estimating the prevalence of demyelinating disorders in Brazil is challenging due
to the absence of representative country-wide prevalence studies, heterogeneous access
to qualified health systems and the ethnically diverse population. Nonetheless, a
metanalysis described a national MS prevalence of 8.69/100,000 (95% CI: 6.0-12.6),
with an association between the prevalence of MS and latitude of study location (OR=1.09;
95% CI: 1.04-1.14), ethnic composition (OR=1.03; 95% CI: 1.01-1.05) and weather. The
authors identified a 9% increase in the prevalence rate of MS for the increase of
each degree in latitude and a 3% raise in the prevalence of MS for every degree increase
in the proportion of white people[2].
The prevalence of NMOSD is also heterogeneous and influenced by the population’s ethnical
background. Different studies report prevalences in Brazil that range from 0.37 to
4.52/100,000 inhabitants with a north-south gradient decrease in the risk of developing
NMOSD[3],[4]. Prevalence and disease phenotypes are influenced by ethnicity, and worse clinical
outcomes are associated with Asian, African and Latin American ancestry[5].
MOGAD incidence rates worldwide range from 0.16 to 1.4 per 100,000[6]. The proportion of MOG-IgG related acquired demyelinating syndromes (ADS) decreases
with age. Higher disease incidences have been reported in pediatric cohorts (39%),
than among mixed cohorts of children and adults (29%) or adults (23%)[6]. Ethnicity initially seemed to not be as important with 78-90% (MOGAD) versus 60-63%
(NMOSD) of Caucasians, however Brazilian data suggests that it may play a role in
the prevalence of the disease[7],[8]. The nationwide estimations of the prevalence of MOGAD have not yet been published.
Diagnosis of demyelinating disorders
Demyelinating disorders lead to overlapping clinical syndromes. A methodical diagnostic
approach, including thorough investigation of the medical history, neurological examination
and complementary tests is helpful towards performing differential diagnoses ([Table 1]). Unfortunately, not all tests are available in the Brazilian public health system,
therefore mindful investigation is suggested to prevent unnecessary financial expenses.
Table 1
Diagnostic workup for demyelinating disorders.
|
Medical history
|
|
Personal history of autoimmunity
|
|
Family history of autoimmunity
|
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Presence of infectious or vaccinal triggers.
|
|
History of previous neurological symptoms.
|
|
Biomedical workup
|
Blood
|
Complete blood count, renal function, liver function, thyroid function
|
|
Serologies (EBV, VZV, CMV, HIV, HTLV I/II, HBC, HCV, Syphillis)
|
|
Rheumatologic profile (ANA, anti-Ro, anti-La, anti-DNA)
|
|
AQP4-IgG
|
|
Anti-MOG IgG
|
|
Metabolic profile (Vitamin B12, Vitamin D, Folic acid)
|
|
CSF
|
Total and differencial cell count
|
|
Biochemical analysis (glucose, protein, lactate)
|
|
Oligoclonal band profile
|
|
Image
|
Brain MRI
|
|
Spinal cord MRI
|
|
Complementary tests
|
OCT
|
|
VEP
|
|
MEP/SEP
|
AQP4-IgG: Anti aquaporin-4 antibody; MOG-IgG: Myelin Oligodendrocyte glycoprotein
antibody.
The diagnoses can be obtained through the interpretation of the medical history, neurological
examination, biomedical/imaging tests and application of current diagnostic criteria[9],[10] ([Tables 2], [3] and [4]).
Table 2
Diagnostic criteria for relapsing remitting multiple sclerosis.
|
The 2017 McDonald criteria for diagnosis of multiple sclerosis in patients with an
attack at onset[9]
|
|
Number of attacks
|
Number of lesions with objective clinical evidence
|
Additional data needed for a diagnosis of multiple sclerosis
|
|
≥2 clinical attacks
|
≥2
|
None
|
|
≥2 clinical attacks
|
1 (as well as clear-cut historical evidence of a previous attack involving a lesion
in a distinct anatomical location
|
None
|
|
≥2 clinical attacks
|
1
|
Dissemination in space demonstrated by an additional clinical attack implicating a
different CNS site or by MRI
|
|
1 clinical attack
|
≥2
|
Dissemination in time demonstrated by an additional clinical attack or by MRI OR demonstration
of CSF-specific oligoclonal bands
|
|
1 clinical attack
|
1
|
Dissemination in space demonstrated by an additional clinical attack implicating a
different CNS site or by MRI AND dissemination in time demonstrated by an additional
clinical attack or by MRI OR demonstration of CSF-specific oligoclonal bands
|
Table 3
Diagnostic criteria for primary progressive multiple sclerosis.
|
2017 McDonald criteria for diagnosis of multiple sclerosis in patients with a disease
course characterized by progression from onset (primary progressive multiple sclerosis)[9]
|
|
Primary progressive multiple sclerosis can be diagnosed in patients with:
|
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1 year of disability progression (retrospectively or prospectively determined) independent
of clinical relapse
|
|
Plus two of the following criteria:
|
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One or more T2-hyperintense lesions characteristic of multiple sclerosis in one or
more of the following brain regions: periventricular, cortical or juxtacortical, or
infratentorial
|
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Two or more T2-hyperintense lesions in the spinal cord
|
|
Presence of CSF-specific oligoclonal bands
|
Table 4
Diagnostic criteria for neuromyelitis optica spectrum disorders.
|
International consensus diagnostic criteria for neuromyelitis optica spectrum disorders[10]
|
|
Diagnostic criteria for NMOSD with AQP4-IgG
|
|
1. At least 1 core clinical characteristic
|
|
2. Positive test for AQP4-IgG using best available detection method (cell-based assay
strongly recommended)
|
|
3. Exclusion of alternative diagnoses
|
|
Diagnostic criteria for NMOSD without AQP4-IgG or NMOSD with unknown AQP4-IgG status
|
|
1. At least 2 core clinical characteristics occurring as a result of one or more clinical
attacks and meeting all of the following requirements:
|
|
a. At least 1 core clinical characteristic must be optic neuritis, acute myelitis
with LETM, or area postrema syndrome
|
|
b. Dissemination in space (2 or more different core clinical characteristics)
|
|
c. Fulfillment of additional MRI requirements, as applicable
|
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2. Negative tests for AQP4-IgG using best available detection method, or testing unavailable
|
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3. Exclusion of alternative diagnoses
|
|
Core clinical characteristics
|
|
1. Optic neuritis
|
|
2. Acute myelitis
|
|
3. Area postrema syndrome: episode of otherwise unexplained hiccups or nausea and
vomiting
|
|
4. Acute brainstem syndrome
|
|
5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical
diencephalic MRI lesions
|
|
6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions
|
|
Additional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknown AQP4-IgG
status
|
|
1. Acute optic neuritis: requires brain MRI showing (a) normal findings or only nonspecific
white matter lesions, OR (b) optic nerve MRI with T2-hyperintense lesion or T1-weighted
gadolinium- enhancing lesion extending over .1/2 optic nerve length or involving optic
chiasm
|
|
2. Acute myelitis: requires associated intramedullary MRI lesion extending over 3
contiguous segments (LETM) OR 3 contiguous segments of focal spinal cord atrophy in
patients with history compatible with acute myelitis
|
|
3. Area postrema syndrome: requires associated dorsal medulla/area postrema lesions
|
|
4. Acute brainstem syndrome: requires associated periependymal brainstem lesions
|
To this day, the diagnosis of MOGAD still relies on the identification of the MOG-IgG
antibody in serum. Live cell-based assays are the established gold standard for the
identification of the antibody, due to its superior sensitivity and specificity[11]. Unlike what is observed in MS and NMOSD, a portion of patients with MOGAD present
with monophasic disease and therefore, might have a MOG IgG serostatus switch over
time regardless of immunosuppressive treatment. The final diagnosis of MOGAD should
account for the medical history and clinical phenotype of the patient in addition
to their serostatus, as a percentage of patients with MS may present with low titers
of MOG-IgG, while employed assays may not be adequately sensitive to detect low antibody
titers and clear diagnostic criteria for the disease have not yet been defined.
Differential diagnosis
The careful interpretation of medical history, physical examination and additional
investigation allows the distinction between the various acquired demyelinating syndromes
([Table 5]). It is important to highlight that the criteria currently used for the diagnosis
of MS and NMOSD were developed and validated in populations with ethnic and environmental
backgrounds distinct from what is observed in the Brazilian population, which might
compromise the sensitivity and specificity of the criteria. Brazilian neurologists
ought to be mindful to identify “red-flags” for atypical demyelinating syndromes and
systematically rule out differential diagnoses, including endemic infectious diseases
such as HLTV I/II and schistosomiasis.
Table 5
Demographic, clinical, MRI and CSF features of demyelinating diseases of the central
nervous system.
|
Demographic, clinical, MRI and CSF features of MS, AQP4-IgG positive NMOSD and MOG-IgG
associated disease. (Adapted from Hegen et al. Ther Adv Neurol Disord. 2020.)
[6]
|
|
Disease
|
|
|
MOGAD
|
AQP4-IgG positive NMOSD
|
MS
|
|
Epidemiology
|
|
|
|
|
Brazilian prevalence (per 100,000)
|
Unknown
|
0.37- 4.52
|
8.69
|
|
Demographics
|
|
|
|
|
Female:male ratio
|
1-2/1
|
8-9/1
|
3/1
|
|
Age at onset
|
More often in childhood than adulthood
|
>40 years
|
20-30 years
|
|
Clinical presentation
|
|
|
|
|
Clinical presentation
|
ADEM-like (ADEM, MDEM, ADEM-optic neuritis, encephalitis) or opticospinal (optic neuritis,
myelitis) or brainstem encephalitis
|
Optic neuritis, myelitis, area postrema syndrome, brainstem syndrome, narcolepsy or
acute diencephalic syndrome, cerebral syndrome with NMOSD-typical brain lesions
|
Optic neuritis, myelitis, brainstem or cerebellar syndrome, cognitive dysfunction
and symptoms caused by involvement of other MS-typical brain regions
|
|
Disease course
|
Monophasic and recurrent (recurrence often presents as optic neuritis)
|
More often recurrent than monophasic
|
Relapsing-remitting or chronic progressive
|
|
Magnetic resonance imaging
|
|
|
|
|
Brain MRI
|
ADEM-like, atypical for MS (fluffy lesions or three lesions or fewer) or no brain
lesions
|
Atypical for MS and/or lesions in the brainstem; or no brain lesions
|
Multiple focal white matter lesions, ovoid lesions adjacent to the lateral ventricles,
Dawson fingers, U-fibre subcortical lesions, T1 hypointense lesions
|
|
Frequency of normal brain MRI at disease onset
|
Up to 50% (depending on type of manifestation; normal brain MRI often seen in optic
neuritis)
|
Up 50%
|
NA
|
|
Spinal MRI
|
Long-segment lesions (>3 vertebral segments); typically involving thoracolumbar segment
and conus; confined to grey matter (H sign); contrast-enhancement infrequent
|
Long-segment lesions (>3 vertebral segments); typically involving cervicothoracic
segment; central cord predominance; contrast-enhancement frequent
|
Short-segment lesions (<3 vertebral segments); axial peripheral (dorsal/lateral column);
contrast-enhancement frequent
|
|
Optic neuritis
|
Bilateral more often than unilateral, often anterior optic pathway, long lesion, often
recurrent, severe, good recovery
|
Bilateral more often than unilateral, often posterior optic pathway, involvement of
optic chiasma, long lesion, often recurrent, severe, often residual deficits
|
Unilateral more often than bilateral; short lesion, good recovery
|
|
Cerebrospinal fluid
|
|
|
|
|
Pleocytosis
|
Common (>70% of patients)
|
Common (>70% of patients)
|
Moderate (<50% of patients)
|
|
Cytology
|
Mononuclear, but neutrophils can occur (in up to ~50% of samples)
|
Mononuclear, but neutrophils can occur (in up to ~50% of samples)
|
Mononuclear
|
|
OCBs
|
Rare (<10-20% of patients)
|
Rare (<10% of patients)
|
Common (>90% of patients)
|
|
Optical coherence tomography
|
|
|
|
|
Axonal damage (assessed, e.g., by pRNFL decrease)
|
Moderate (per optic neuritis attack)
|
Severe (per optic neuritis attack)
|
Moderate (per optic neuritis attack)
|
Role of novel biomarkers
Optical coherence tomography (OCT) is an imaging technique which uses infrared light
in a similar manner to that of the ultrasound to measure different biological tissue's
backscatter, getting micrometer-resolution images. When used in the retina, it allows
the reconstruction of tomographic maps and quantification of axons of the retinal
nerve fiber layer (RNFL) and neurons of the macular ganglion cell layer (mGCL)[12]. OCT has consistently been used to screen for subclinical optical abnormalities
in patients with demyelinating disorders, however data shows associations between
reduced RNFL/mGCL and neurodegeneration with correlations to types of MS, disability
and cognitive impairment[12]-[15]. In addition, distinct OCT patterns can be used as diagnostic biomarkers aiding
in the differential diagnosis of MOGAD from other demyelinating disorders[16],[17].
Neurofilaments (Nf) are structural proteins involved in the radial growth and stability
of neurons. Studies have demonstrated that Nf-l has a value as a scientifically useful
biomarker of disease activity and therapy effectiveness of groups of patients with
inflammatory diseases of the CNS, such as multiple sclerosis and clinically isolated
syndrome[18]-[22]. It is currently not commonly used in clinical practice, as its measure is modulated
by body-mass index (BMI), age, and comorbidities which compromise the definition of
fixed cutoffs and individually pathological levels of Nf-l[23]. Recent data has shown that Nf-l levels can be clinically employed to predict disease
activity and disease-modifying therapy effectiveness in the real world setting on
an individual level if percentiles and Nf-l Z scores are used[23]. Nonetheless, the description is new and the practice still not widespread.
Glial fibrillary acidic protein (GFAP) is a principal intermediate filament that forms
the astrocyte cytoskeleton and is regarded as a biomarker of astrocyte injury[24]. Evidence describes its role as a potential diagnostic and prognostic biomarker
in NMOSD, a known astrocytopathy, however its use is still currently limited to scientific
purposes[25],[26].
DISCUSSION
Acquired demyelinating disorders lead to a plethora of clinical syndromes which are
common among distinct nosologies. In the past 20 years, anti-aquaporin 4 antibodies
(AQP4-IgG), anti-MOG antibodies (MOG- IgG) and their associated disease entities,
AQP-4 IgG NMOSD and MOGAD, were described. Since then, making a differential diagnosis
between the most prevalent acquired demyelinating disorders has become more challenging,
especially in places where environmental and genetic conditions are distinct to those
of the settings where studies guiding diagnostic criteria were carried out.
A methodical approach to the diagnostic process can aid in achieving timely accurate
diagnoses. In addition to a thorough medical history and neurological examination,
biomedical and imaging data can provide crucial information to aid in identifying
each disease. Although clinical phenotypes often overlap, integrated analysis of demographic,
clinical, biomedical, and imaging data is particular to each disease and therefore
should be interpreted together.
As the field further develops, new technologies and biomarkers are systematically
being studied and translated from the bench to the bedside. For now, it is suggested
that neurologists examine the validity, specificity, and sensitivity for individual
use of each new diagnostic tool before applying it in their routine diagnostic practice.
In conclusion, a comprehensive analysis of the diagnostic workup should be performed
to obtain a differential diagnosis of an acquired demyelinating disorder. Diagnostic
criteria should be mindfully employed considering ethnic and environmental particularities
of each patient.
