Clinical+Symptoms+and+Diagnosis

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 //by Demi Wang// toc

Symptoms of multiple sclerosis (MS) vary from one individual to another depending on the location of demyelination in the brain. However, the majority of patients begin with relapsing remitting multiple sclerosis (RRMS) with 50-60% of these patients progressing on to secondary progressive (SP) disease. Another clinical course is primary progressive multiple sclerosis (PPMS) where it is characterized by continuous worsening without distinct relapse [1]. The mechanisms of PPMS are still not well understood and only 15% of patients take on this course [3]. It is still a debate on whether or not PPMS is a part of the MS disease spectrum or a separate disease by itself. = =

=1.1 Prognosis =

Patients with MS are often exempt from severe disability and can lead a fairly normal life as MS is not a fatal disease and presents itself in a slow clinical evolution fashion. Most patients have a moderately normal lifespan and usually die from the same causes as the general population. 50-60% of individuals evolve from RRMS to SP within a span of 20-25 years [9]. The remaining individuals take on a slightly rarer course called PPMS where there is a progressive accumulation of irreversible neurological symptoms [9]. Factors such as age and prior deficits of motor control and cognitive functioning can all lead to a higher risk of developing a more severe condition of MS. Since there are currently no reliable clinical or biological markers of disease progression, long term prognosis is difficult to predict for individuals [7]. = =

=2.1 Two Major Courses of Multiple Sclerosis =

Approximately 2.5 million people are affected by MS [1]. MS can take on two major courses: relapsing remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). Around 80% of the patients develop RRMS which is characterized by episodes of acute exacerbation followed by complete or partial recovery while PPMS is mostly characterized by continuous worsening without distinct relapses [1]. The current diagnostic tool for MS is known as the McDonald Diagnostic Criteria. Underlying pathogenic mechanisms that causes the two courses are currently unknown. = =

=2.2 Relapse Remitting Multiple Sclerosis =

Around 80% of patients with MS develop RRMS during the early stages of the disease. Younger patients usually have a higher chance of experiencing RRMS than older patients. Similar to how clinical manifestations can be variable, the exact frequency of relapses is hard to define for individual cases. However, relapses are a common event and can occur up to 0.8 relapses/year if the patients are not treated with modifying agents [2]. Though the pathology for relapses are still up in the air, it is believed that relapses are a consequence focal inflammatory demyelinating lesions, which also happens to be the histopathological hallmark in MS [1].

2.2a Clinical Phenotypes
Acute exacerbation gives rise to cognitive dysfunctions and behavioural symptoms each day. Cognitive dysfunctions is documented to occur up to 60% of MS patients [10]. The most common cognitive dysfunctions include impairments in information-processing speed, attention, and memory while some behavioural impairments include depression, personality change, inappropriate social behaviour, and disinhibition [10].

During the early stages, the most common clinical phenotypes of RRMS are sensory disturbances (such as numbness, tingling, and loss of balance), optic neuritis, diplopia, and weakness in one or limbs [5] [10]. In terms of cognitive impairments that occur during this stage of MS, functions such as attention, working memory, information processing speed, memory, inhibition, and conceptualisation are mainly affected [6]. On the other hand, functions like verbal or non-verbal fluency seems to be unaffected at this stage [6]. It has been suggested that these deficits reflect both damage within and outside the location of the lesion [6]. This is important because it may serve as severity markers for early stages of MS. It should also be noted that deficiencies that occur at this stage are probably less severe and may not have significant impact on daily life.

2.2b Diagnostic Criteria
In the past, doctors relied on clinical evidence for dissemination in time and space to diagnose MS [14]. In 2001, the McDonald Criteria was published and allowed for the use of MRI evidence for dissemination in time and space in patients with clinically isolated syndromes (CIS) [11]. CIS is the single acute clinical episode that is caused by inflammation and demyelination of nerve tissues [11]. It has been believed that brain lesions associated with CIS may be indicative of MS. Thus, the McDonald 2001 Criteria allows for early diagnosis of MS to be made after one clinical attack if a patient obtains a positive result on a MRI scan [14]. This can be beneficial because it enables the visualization of lesions in the brain that are clinically silent and allows for a possibility of early treatment [14].

Aside from MRI evidence, evidences of white matter lesions in the central nervous system (CNS) disseminated in both time and space is an essential diagnostic criteria for MS [11]. This means patients should experience two attacks of neurological dysfunctions and these neurological dysfunctions cannot be attributed to a single lesion [14]. Examples of neurological dyfunctions include optic neuritis, sensory disturbances, and double vision. It should be noted that patients who experience an initial attack may not develop MS and the time of relapse between first and second attacks may take up to a year.

2.2c Progression to secondary progressive disease
Within 10-15 years of diagnosis, more than two-thirds of RRMS patients develop SPMS, a progressive disease stage where patients are susceptible to increased risk of accumulating irreversible tissue damage [12]. This phase is characterized by an accumulation of neurological disabilities that is frequently manifested as paraparesis, hemiparesis, sensory loss, ataxia, and dementia [12]. Once a patient hit the secondary progressive phase, the rate of progression varies widely among individuals [12].

=<span style="font-family: Arial,Helvetica,sans-serif; font-size: 18px;">2.3 Primary progressive Multiple Sclerosis =

PPMS is the rarer course of MS. Only 15% of patients develop PPMS and the disease course varies very widely for individual cases [4]. PPMS is characterized by gradual continuous worsening of MS symptoms without distinct relapses. The onset of PPMS is usually 10 years after the onset of RRMS, but at a similar time during the conversion from RRMS to SPMS. Thus, patients are usually diagnosed with PPMS in their forties or fifties [1].

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 16px;">2.3a Clinical Phenotypes
PPMS is commonly characterized by spastic paraparesis (83% of cases) and compressive lesions like bone compression, tumors, and vascular anomalies [1]. Other characteristics include cerebellar dysfunction (8%), hemiplegia (6%), brain stem syndromes (1%), and visual loss (1%) [1]. Cognitive dysfunctions has presented itself in 30% of all patients, affecting memory, attention/speed of informational processing, and executive functioning [13]. White matter and grey matter lesions are said to have a role in determining cognitive dysfunctions in specific domains [13].

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 16px;">2.3b Diagnostic Criteria
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">In 1997, emerging paraclinical technologies such as CSF evaluation, evoked responses, and MRI evidences were required to be taken into consideration for PPMS diagnosis [1]. In a PPMS patient, if CSF is positive then there should be an increase in immunoglobulin levels and oligoclonal bands, his/her visual evoked responses should be delayed, and MRI evidence (which is based on the number of lesions) should be positive [1]. In 2005, the revised version of McDonald Criteria added that MRI brain or spinal cord lesions should indicate dissemination of disease in time and space and there should be positive spinal fluids.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">The most recent diagnostic update (in 2011) maintained previous proposed criteria and emphasized on spinal cord lesions [1]. This is because for PPMS cases, nonspecific age-related signals cannot be detected by MRI of the spinal cord [1].

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Emerging studies are starting to show a strong correlation between T2 and T1 lesion loads with poor performance on memory and attention tasks [13]. Other current studies have also highlighted the interhemispheric callosal pathway as a potential determinant for physical and cognitive disabilities in PPMS [4]. Damage to this pathway, which serves to interconnect motor and cognitive networks between two hemispheres, may result in a disconnective syndrome that contributes to long-term physical and cognitive disability [4].

Diagnosis for PPMS is usually very hard because of various factors like age. Since the onset of PPMS is usually in patients around their forties, people at this age are more likely to have conditions affecting their motor control. Thus, it makes it hard for one to diagnose a patient for PPMS. One potential markers that clinicians look for is cord atrophy as it is only present in PPMS and not RRMS.

=<span style="font-family: Arial,Helvetica,sans-serif; font-size: 18px;">3.1 Differences between RRMS & PPMS =

Currently, it has been thought that both RRMS and PPMS are a result of accumulating axonal and neuronal damage triggered by multifocal inflammatory lesions. Epidemiologic, imaging, and pathological studies all seem to point towards PPMS as part of the disease spectrum [1]. According to the McDonald, the author of McDonald Diagnostic Criteria, he suggested that PPMS should be classified as a distinct subgroup that should be further researched [1]. Still, other researchers are willing to go further and hypothesize that PPMS itself, should be a separate disease.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 16px;">3.1a Grey and white matter deficits
Neurodegenerative mechanisms such as axonal loss and acute axonal damage are seen when inflammatory lesions are present [1]. These traits are mostly seen in RRMS rather than PPMS which has a rather low lesion load. Despite having a low lesion load, PPMS patients exhibit severe disabilities earlier on. Compensatory and repair mechanisms such as remyelination are also more present in RRMS than PPMS [1].

The onset of grey matter atrophy is earlier and more frequent in PPMS than in RRMS [1]. Grey matter atrophy has shown to be a better predictor than white matter lesion load and atrophy for disability. When measuring the rate of grey matter and white matter atrophy, it was found that white matter atrophy remained constant in all disease stages while grey matter atrophy increased 14-fold in PPMS patients and 3.4-fold in RRMS when converted from CIS [8].

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 16px;">3.1b Cord Atrophy
As stated in section 2.3a, PPMS is heavily characterized by spastic paraparesis which indicates spinal cord dysfunction. Study shows that three-fourths of PPMS patients were documented to have spinal cord T2 lesions, specifically in the cervical region [1]. While grey and white matter deficits are present in both RRMS and PPMS, cord atrophy is only present in PPMS [3]. This is groundbreaking not only in the fact that it provides clues for researchers on MS biomarkers but it is very clinically relevant when diagnosing for PPMS.

=<span style="font-family: Arial,Helvetica,sans-serif; font-size: 18px;">4.1 Conclusion =

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">With a wide spectrum of symptoms in hand for MS, it is an constant challenge for scientists to come up with a definite model for the disease. The McDonald Criteria is always undergoing revisions and biological markers for MS are still currently unknown. Underlying pathogenesis is unclear but MS is currently accepted as a T cell-mediated autoimmune disease. Many gene expression studies are being undertaken to find candidate genes for MS. Since MS manifests itself in many different forms, it makes MS one of the most common disease diagnosed. Therefore, further research is imperative.

=<span style="font-family: Arial,Helvetica,sans-serif; font-size: 18px;">5.1 References =


 * 1) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Antel, J., Antel, S., Caramanos, Z., Arnold, D.L., Kuhlmann, T. Primary progressive multiple sclerosis part of the MS disease specturm or separate disease entity? //Acta Neuropathol// (2012); DOI: 10.1007/s00401-012-0953-1
 * 2) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Annovazzi, P., Tomassini, V., Bodini, B., Boffa, L., Calabrese, M., Cocco, E., Cordioli, C., De Luca, G., Frisullo, G., Gallo, A., Malucci, S., Paolicelli, D., Pesci, I., Radaelli, M., Ragonese, Roccatagliata, L, Tortorella, C., Vercellino, M., Zipoli, V., Gasperini, C., Rodegher, M., Solaro, C. [|A cross-sectional, multicenter study of the therapeutic management of multiple sclerosis relapses in Italy] //Neurological Sciences// (2012); DOI:10.1007/s10072-012-0981-5
 * 3) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Bieniek, M., Altmann, D.R., Davies, G.R., Ingle, G.T., Rashid, W., Sastre-Garriga, J., Thompson, A.J., Miller, D.H. Cord atrophy separates early primary progressive and relapse remitting multiple sclerosis. //J Neurol Neurosurg Psychiatry// (2006); **77**: 1036-1039
 * 4) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Bodini, B., Cercignani, M., Khaleeli, Z., Miller, D.H., Ron, M., Penny, S., Thompson, A.J., Ciccarelli, O. Corpus callosum damage predicts disability progression and cognitive dysfunction in primary-progressive MS after five years. //Human Brain Mapp// (2012): DOI: 10.1002/hbm.21499
 * 5) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Chan, J.W.Optic neuritis in multiple sclerosis. //Ocular Immunology and Inflammation// (2002); **10**: 161-186
 * 6) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Deloire, M.S.A., Salort, E., Bonnet, M., Arimone, Y., Boudineau, M., Amieva, H., Barroso, B., Ouallet, J.C., Pachai, C., Galliaud, E., Petry, K.G., Dousset,V., Fabrigoule, C., Brochet, B. [|Cognitive impairment as marker of diffuse brain abnormalities in early relapsing remitting multiple sclerosis.] //J Neurol Neurosurg Psychiatry// (2005); **76**: 519-526
 * 7) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Hecker, M., Paap, B.K., Goertsches, R.H., Kandulski, O., Fatum, C., Koczan, D., Hartung, H.P., Thiesen, H.J., Zettl U.K. Reassessment of Blood Gene Expression Markers for the Prognosis of Relapsing-Remitting Multiple Sclerosis //PLoS One// (2011); **6**: e29648
 * 8) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Inglese, M., Oesingmann, N., Casaccia, P., Fleysher, L. PROGRESSIVE MULTIPLE SCLEROSIS AND GRAY MATTER PATHOLOGY: AN MRI PERSPECTIVE //Mt Sinai J Med// (2011); **78**: 258-267
 * 9) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Martinelli-Boneschi, F., Esposito, F., Brambilla, P., Lindstrom, E., Lavorgna, G., Stankovich, J., Rodegher, M., Capra, R., Ghezzi, A., Coniglio, G., Colombo, B., Sorosina, M., Martinelli, V., Booth, D., Oturai, A.B., Stewert, G., Harbo, H.F., Kilpatrick, T.J., Hillert, J., Rubio, J.P., Abderrahim, H., Wojcik, J., Comi, G. A genome-wide association study in progressive multiple sclerosis. //Multiple Sclerosis Journal// (2012); DOI: 10.1177/1352458512439118
 * 10) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Rosti-Otajarvi, E., Hamalainen, P. [|Behavioural symptoms and impairments in multiple sclerosis: a systematic review and meta-analysis.] //Multiple Sclerosis Journal// (2012); DOI:10.1177/1352458512439437
 * 11) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Swanton, J.K., Fernando, K., Dalton, C.M., Miszkiel, K.A., Thompson, A.J., Plant, G.T., Miller, D.H. [|Modification of MRI criteria for multiple sclerosis in patients with clinically isolated syndromes] //J Neurol Neurosurg Psychiatry// (2006); **77**: 830-833
 * 12) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Tian, W., Zhu, T., Zhong, J., Liu, X., Rao, P., Segal, B.M., Ekholm, S. Progressive decline in fractional anisotropy on serial DTI examinations of the corpus callosum: a putative marker of disease activity and progression in SPMS. //Neuroradiology// (2012); **54**: 287-297
 * 13) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Tur, C., Penny, S., Khaleeli, Z., Altmann, D.R., Cipolotti, L., Ron, M., Thompson, A.J., Ciccarelli, O. Grey matter damage and overall cognitive impairment in primary progressive multiple sclerosis. //Multiple Sclerosis Journal// (2011); **17**: 1324-1332
 * 14) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Whiting, P., Harbord, R., Main, C., Deeks, J.J., Filippini, G., Egger, M., Sterne, J.A.C., Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review //BMJ// (2006); **332**: 875-884

Figures Reference
 * 1) http://www.nature.com/aja/journal/vaop/ncurrent/fig_tab/aja2011110f1.html#figure-title
 * 2) http://www.springerlink.com.myaccess.library.utoronto.ca/content/39138506w848v616/
 * 3) http://www.radiologyassistant.nl/en/4556dea65db62
 * 4) http://www.bioscience.org/2004/v9/af/1262/fulltext.asp?bframe=figures.htm&doi=yes

=<span style="font-family: Arial,Helvetica,sans-serif; font-size: 18px;">6.1 See Also =


 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">Multiple Sclerosis, University of Maryland Medical Center
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 13px;">McDonald Diagnostic Criteria