Tools and Tests for Multiple Sclerosis






9


Tools and Tests for Multiple Sclerosis


Robert A. Bermel







KEY POINTS FOR CLINICIANS


         Blood tests play an important role in excluding mimics of multiple sclerosis (MS).


         Spinal fluid analysis can help establish an inflammatory basis for abnormal imaging findings and help exclude mimics of MS in atypical situations, but is only occasionally required to make the diagnosis of MS.


         Evoked potentials can help to establish dissemination in space consistent with the diagnosis of MS, but are not specific for MS.


         Biomarker blood tests exist to help establish the diagnosis of neuromyelitis optica and assess individual risk for complications associated with natalizumab.


         Biomarkers are not yet available to predict an individual patient’s response to a specific therapy.


         Optical coherence tomography is a newer technology that can track retinal neurodegeneration and monitor for macular edema in patients on fingolimod therapy for MS.






The diagnosis of MS is made clinically on the basis of a synthesis of the history, examination, imaging, and paraclinical testing where necessary (1). No single paraclinical test can confirm or exclude MS with certainty. The brain MRI has emerged as the foremost test suggesting the diagnosis of MS if abnormal with typical features, or excluding the diagnosis of MS if normal. Paraclinical testing can be used to support the diagnosis of MS by fulfilling the criteria for dissemination in space (usually, evoked potentials [EPs] or optical coherence tomography [OCT]) and verifying an inflammatory etiology for the neurological disorder (spinal fluid analysis). The ubiquitous availability of MRI and its utility in diagnosing MS makes it a test that is now commonly performed early in the course of neurological symptoms. When the brain MRI is definitively abnormal but not classic for MS, it raises the possibility of an alternative neurological diagnosis, and blood and spinal fluid tests can be used to exclude “mimics” of MS at the time of diagnosis. When the brain MRI is mildly abnormal and the clinician views the diagnosis of MS as unlikely, testing such as EPs and spinal fluid analysis can be utilized to show a lack of central nervous system (CNS) pathology, in order to more definitively exclude the diagnosis of MS.


BLOOD TESTS


The differential diagnosis of MS (discussed in detail in Chapter 10) is broad, and multiple alternative disease entities can cause similar symptoms and a similar imaging appearance to MS. When atypical clinical features make the exclusion of mimics essential, blood tests play a key role (2). Even when the diagnosis of MS is secure, blood tests are indicated in order to exclude the presence of comorbid conditions, which can occur at high frequency. Finally, there are also blood tests which can be used to help guide therapeutic decision making.



 





When atypical clinical features make the exclusion of mimics essential, blood tests play a key role.






Testing to exclude mimics of MS is performed if prompted by red flags on the history or exam (see Chapter 10). The specific tests sent are guided by the specific clinical scenario. Some of the most commonly ordered tests are for 80rheumatological or autoimmune diseases, which can cause CNS demyelination (Table 9.1). Many of these possibilities can be reliably distinguished from MS on the basis of clinical features, imaging findings, or lab results. Other organ-specific autoimmune diseases, such as thyroid autoimmunity and pernicious anemia, occur with higher frequency in patients with MS, have some symptomatic overlap with MS, and therefore justify screening (Table 9.1). Antinuclear antibody (ANA) is commonly positive in MS at low or moderate titres and if present in isolation without clinical signs does not indicate systemic lupus erythematosus and typically needs no further evaluation. Prior to initiating disease-modifying therapy for MS, it is often prudent to send tests of liver and kidney function, given the effect of some MS treatments on these organs. With the growing emphasis on vitamin D supplementation in patients with MS, some clinicians choose to check vitamin D levels to guide the dosage of vitamin D (3). Immunity to varicella zoster virus is required (whether by exposure or vaccination) prior to utilizing some immunosuppressive therapies to treat MS, so this status is also often evaluated.


There are reports that antiglycan antibodies occur with increased frequency in MS, and serological tests for those have been proposed as a tool aiding in the diagnosis of MS at early stages or to help distinguish patients who are more likely to experience disability progression (4). Although these serological tests are commercially available, they have limited specificity and sensitivity and have not been independently replicated. At this point, they are not commonly utilized in clinical practice. MRI and in some cases spinal fluid results are used preferentially to inform diagnosis and prognosis in MS, and it is not clear that antiglycan antibody testing would significantly affect treatment decisions even in cases where the MRI and other testing are equivocal.


TABLE 9.1    Common Blood Tests Sent at the Time of MS Diagnosis





















































TESTS WHICH MAY HELP TO IDENTIFY MIMICS OF MS OR COMORBID CONDITIONS


TESTS WHICH MAY IMPACT OR HELP TO GUIDE MS TREATMENT


Erythrocyte sedimentation rate


Complete blood count


Antinuclear antibodya


Renal and liver function tests


Thyroid stimulating hormone level


JC virus antibody status


Vitamin B12 level


Varicella antibody status


 


Hepatitis remote exposure panel


Tuberculosis screen (Quantiferon)


Copper level


Vitamin D level


Antineutrophil cytoplasmic antibodies


 


Rheumatoid factor


 


SSA/SSB (Sjogren’s antibodies)


 


Extractable nuclear antigen antibodies


 


Antiphospholipid antibodies


 


Aquaporin-4 antibody (neuromyelitis optica IgG)


 


Lyme titers


 






aANA is commonly positive in MS at low or moderate titres and does not typically require further evaluation.


MS, multiple sclerosis.


The neuromyelitis optica IgG antibody (NMO-IgG) is a blood test that has approximately a 76% sensitivity and 94% specificity for neuromyelitis optica (NMO), and is now a key asset in making the diagnosis of NMO (5). NMO-IgG is an autoantibody directed against the aquaporin-4 water channel on astrocyte foot processes, and is now recognized as the pathogenic autoantibody responsible for the manifestations of NMO (6). The discovery of this autoantibody has solidified NMO as a unique pathological entity distinct from MS and requiring a different treatment regimen. NMO-IgG should be tested if inflammatory demyelination is suspected as a mechanism and clinical or imaging features are suggestive of NMO or atypical for MS. Testing in the blood is sufficiently sensitive in most cases, but on rare occasions this test will be positive in the cerebrospinal fluid (CSF) when it is negative in the blood.



 





The neuromyelitis optica IgG antibody is now a key asset in making the diagnosis of NMO.






Although there are not currently any predictive biomarker tests that help to guide choice of therapy on the basis of efficacy in individuals, there are some tests which can guide choice of MS therapy on the basis of risk of a therapeutic complication. A 2-step serological assay for antibodies to the JC virus (JCV) in the blood is currently utilized to help determine risk of progressive multifocal leukoencephalopathy (PML), a complication associated with some MS therapies, particularly natalizumab (7). The pathogenesis of PML is thought to require multiple steps, beginning with acquisition of the JCV and requiring time for the virus harbored in individuals regardless of immune status, to become neurotropic. Only then, in immunocompromised hosts, can the virus cause PML. The prevalence of anti-JCV antibodies is approximately 56% in the MS population (8), and the current recommendation is to check JCV antibody status every 6 months in patients who initially test negative and are being treated with natalizumab. Thus, testing for JCV antibody status allows lower-risk utilization of natalizumab for at least limited and sometimes long periods of time in patients who have not been previously exposed to the virus. Other tests for risk stratification include ECG for cardiac risks and retinal examination for ophthalmological risks related to fingolimod.



 





Testing for JCV antibody status allows lower-risk utilization of natalizumab in patients who have not been previously exposed to the virus.






81Blood tests to either predict the response to therapy (predictive biomarkers) or prognosis in MS (prognostic biomarkers) would be helpful to guide therapeutic decision making, but are not currently available. In their absence, MRI remains the primary means for measuring MS disease burden, degree of disease activity, and assessing response to therapy.



 





Blood tests to either predict the response to therapy or prognosis in MS would be helpful to guide therapeutic decision making, but are not currently available.






LUMBAR PUNCTURE/SPINAL FLUID ANALYSIS


If the clinical history, examination, and imaging are typical for MS, spinal fluid analysis is not a requirement in order to make the diagnosis of MS. Some situations in which spinal fluid analysis is useful in supporting a diagnosis of MS include the following:



 





If the clinical history, examination, and imaging are typical for MS, spinal fluid analysis is not a requirement in order to make the diagnosis of MS.






1.    Exclusion of other alternative etiologies (infectious, inflammatory, granulomatous disorders) if atypical features are present


2.    Diagnosis of some cases of primary progressive MS (PPMS) (especially to distinguish PPMS from neurodegenerative disorders)


3.    Diagnosis of MS in older individuals or those with vascular risk factors, where white matter lesions on MRI may have a vascular or other non-MS etiology


4.    In patients with pacemakers or other reasons precluding MRI, if the diagnosis of MS is suspected


5.    In situations where disease-modifying therapy is being considered (such as after a clinically isolated syndrome) but imaging and EPs alone provide insufficient evidence to support a diagnosis of MS


The brain MRI is the most predictive test for determining the risk of future attacks after a clinically isolated syndrome (9). However, CSF studies do add additional predictive value, with the presence of oligoclonal bands in the CSF conferring almost double the risk of a second attack, independent of brain MRI (10). If CSF analysis is being considered in this situation for risk estimation, it is generally only if the brain MRI is equivocal and the patient or physician would change their decision to start disease-modifying therapy on the basis of the result.


Jan 8, 2020 | Posted by in MUSCULOSKELETAL MEDICINE | Comments Off on Tools and Tests for Multiple Sclerosis
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