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ِArticle Topic: Highly Aggressive Multiple Sclerosis
Author: Abdeljaber Tayyem
Editor: Haneen Al-Abdallat, Haneen A. Banihani
Reviewer:  Lobana Mahdawi

Keywords: Aggressive Multiple Sclerosis, Expanded Disability Status Scale, Humanized Monoclonal Antibodies, Immunosuppressants, Induction therapy, Escalation therapy

Overview

Multiple sclerosis(MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS). It has various clinical presentations according to the site of the central nervous system involved and is categorized according to clinical course into clinically isolated syndrome, relapsing-remitting, secondary progressive, and primary progressive according to 2013 disease course definitions (1). A subset of MS patients experience an aggressive form of the disease where they progress rapidly to a disability or have a higher number of relapses. They need special attention to define this form of the disease to facilitate early identification and intervention to prevent rapid progression to disability (2)(3).

Etiology and pathogenesis

Generally speaking, MS is thought to be caused by the accumulation of genetic and environmental risk factors, which lead to the activation of autoreactive lymphocytes in the CNS, including B lymphocytes which release proinflammatory cytokines, chemokines, and autoantibodies, as well as T lymphocytes which include CD8+ T cells that release perforins and granzymes which will damage the axons and found in vast areas of brain parenchyma as well as CD4+ T cells which are more concentrated in the perivascular cuffs. In addition to glutamatergic excitotoxicity, this inflammatory cascade, hypoxia, and reactive oxygen species lead to calcium influx, thus causing mitochondrial dysfunction, oxidative stress, and cell death, which will cause demyelination and axonal damage. However, aging-related neurodegeneration, meningeal lymphoid-like follicles, and innate immunity involving microglial activation, which is not targeted by current MS therapies, are thought to be the cause of late progression of the disease where there is increased neurodegeneration, axonal damage, and a more indolent form of inflammation are involved. (4)(5)(6)

 The development of permanent disability in MS is related to axonal loss, i.e., a higher rate of axonal loss would relate to a more aggressive disease. Macrophage infiltration contributes to inflammation, and decreased myelin trophic factors increase axons’ vulnerability to inflammation, leading to axonal transection and cortical involvement and causing neuronal death. This leads to a more aggressive and less treatment-responsive form of MS. There is also an association between dysregulated subgroups of T cells and NK cells and decreased diversity of T cell receptors on CD4+ T cells with aggressive MS (2).

Risk factors

Multiple risk factors were associated with aggressive MS, such as Male sex, older age at onset(more than 35), smoking, and non-white ethnicities. Multiple genetic markers are also related to aggressive MS including HLA-DRB1, APOE4, PD-1, MGAT-5, and BDNF. (2)(3)(6)

Clinical presentation

Optic neuritis

Patients present with eye pain and visual blurring or vision loss for hours to days. In a fundoscopic examination, the optic disc appears normal (retrobulbar optic neuritis) in two-thirds of cases or swollen (papillitis) in one-third of patients. Relative afferent pupillary defect (Marcus Gunn pupil) can also be present. (7)

Myelitis

This could be either transverse myelitis, in which sensory, motor, and bladder or bowel spinal cord tracts are involved, or partial myelitis, where one or more spinal cord tracts are involved but not all. However, MS typically presents with partial myelitis. (7)

Brainstem syndromes

Brainstem could be affected in MS by the involvement of cranial nerves (III, IV, and VI), causing diplopia, medial longitudinal fasciculus damage leading to ophthalmoplegia, cranial nerve VII leading to facial palsy, cranial nerve VIII leading to vertigo, cranial nerves (IX, X or XII) causing bulbar symptoms including dysphagia or dysarthria or cranial nerve V leading to sensory impairment in the face. However, facial sensory impairment can also be related to cervical spinal cord lesions. In addition, there might be cerebellar involvement leading to unilateral ataxia, dysdiadochokinesia, dysmetria, or cerebellopontine involvement, causing pendular nystagmus. (7)

Motor symptoms

Since the corticospinal tracts are usually involved, the upper motor neuron syndrome usually presents with hyperreflexia, spasticity, weakness, and positive Babinski sign . (7)

Sensory symptoms

Sensory symptoms include numbness, paresthesia, pain, and Lhermitte sign in which neck flexion causes an electric shock-like sensation running through the spine, indicating cervical or upper thoracic dorsal column involvement. (7)

Imbalance

It is caused by cerebellar involvement, vestibular dysfunction, or sensory impairment (sensory ataxia). (7)

Cognitive, psychological, and functional symptoms

The most common cognitive symptoms of MS are mental slowing, executive function impairment, or long-term verbal and visual memory. Less commonly, MS patients can have dementia. However, cognitive impairment indicates white matter, cortical involvement, and brain atrophy. Depression is present in some patients of MS as well as fatigue which is a highly prevalent presentation of MS and is related to depression or even diseases other than MS, warranting further investigations. (7)

Uthoff’s phenomenon

Patients experience heat sensitivity in which symptoms are exacerbated by heat due to higher temperatures causing less efficient conduction in demyelinated fibers (7).

Bladder and bowel dysfunction

Bladder involvement is manifested in a neurogenic bladder, leading to patients experiencing urinary retention, urinary frequency, difficulty initiating urine stream, or urinary incontinence. MS can also lead to bowel involvement, which is less common than bladder involvement, and usually presents as constipation and less commonly as incontinence, where a severe spinal cord injury could be related (7).

Sexual dysfunction

Erectile dysfunction is the most common symptom in men, and fatigue or loss of libido is common in women (7).

Headaches

Migraine is the most common type of headache. However, MS is not related to an increased risk of migraines, but migraines are linked to an increased risk of MS.(7)

MS  exhibits multiple disease courses. These include clinically isolated syndrome, where patients have an initial attack of MS but need additional attacks to prove the diagnosis of MS, and relapsing-remitting form, in which patients suffer from multiple attacks with periods of recovery that could be partial or complete without progression of the disease during recovery periods. Such disease courses also include a secondary progressive form in which relapsing-remitting disease becomes progressive with worsening disability and is associated with relapses, as well as a primary advanced form in which the disability progresses at disease onset without early relapses or remissions. (1)

The expanded disability status scale (EDSS) can be used to define aggressive MS and predict the risk of progression to aggressive MS.(2) The EDSS scale was established in 1983 and is still used to describe the degree of disability and response to therapy in MS using multiple functional systems (Table 1). (8) Initially, EDSS was named the Disability status scale (DSS), which included the same functional systems but differed in the number of steps on the scale, which were ten steps on DSS and became 20 in EDSS (Table 2). (9)

Table 1: functional systems, reprinted from Piri Çınar B, Güven Yorgun Y(9):

Table 2: EDSS, reprinted from Piri Çınar B, Güven Yorgun Y(9)

Diagnosis

In general, the primary investigations used to diagnose multiple sclerosis include Magnetic Resonance Imaging (MRI), cerebrospinal fluid (CSF) analysis, visual evoked potential (VEP), and blood tests including hemogram, renal and liver function tests, lipid profile, vitamins and electrolytes levels, viral serology and autoantibodies present in other autoimmune diseases such as lupus.(10)Investigations and clinical findings are integrated within the 2017 McDonald criteria (Table 3), which should be used with caution, especially in patients with an atypical presentation, such as initial presentation of progressive form, in children and elderly, or other patients with high suspicion of other differential diagnoses. (11)

Table 3: McDonald 2017 criteria, reprinted from Alan J Thompson et al. (11).

Aggressive MS 

Aggressive MS can exhibit any of the clinical features and courses of MS(2)(3)(6), some clinical characteristics are related to aggressive MS including:

Frequent attacks and shorter inter-attack intervals

Shorter inter-attack intervals correlate with faster progression to disability, walking difficulty, and need for a cane. Unresponsiveness to treatment and frequent attacks, especially within the first year of therapy, correlate with poor prognosis. Each episode in the early few years increases the risk of reaching disability milestones, including limited walking distance, need for a cane, and single neurological system moderate disability.(3)

Incomplete recovery after attacks

Incomplete recovery after MS exacerbations were associated with reaching disability milestones more quickly. A ten-fold increase in reaching the milestones was shown in patients with incomplete recovery. The strongest predictor of walking disability after ten years was a higher EDSS score after exacerbations. (3)

Motor, sphincter, cognitive or multifocal nature of symptoms

An increased proportion of patients reaching disability milestones in patients with pyramidal, sphincter, cerebellar, or brain stem dysfunction. However, patients with sensory or visual symptoms had a better prognosis, but the effect of visual symptoms on prognosis was modest after controlling for male gender, age, and progressive disease onset. In addition, the relation between motor symptoms and age, gender, and progressive onset are confounding factors in the relationship between motor symptoms and disability progression. Cognitive symptoms also predicted a higher EDSS. Although not found in all studies, an onset of multifocal symptoms was associated with a higher risk of disability in many studies. (3)

Progressive disease onset

Progressive disease onset is strongly related to a more aggressive course of MS in which patients’ risk of disability is two times higher than those with a relapsing-remitting disease course. Patients reach disability milestones one-third to half of the time that patients with relapsing-remitting disease need. (3)

Increased disease severity

Patients with aggressive MS exhibit more severe relapses that can increase EDSS by one or more points, increase any functional system score by two or more points, or increase two or more functional system scores by one or more points. Patients with aggressive disease acquire disability more rapidly and are more prone to reach an EDSS of 3 or more within the first year. (2)

findings associated with aggressive multiple sclerosis,  include the following:

MRI findings

A high number of T2-enhanced lesions (⩾20) 0r gadolinium-enhanced lesions (⩾2), and T1 black holes indicating tissue loss and lesions in the spinal cord can predict increased severity of multiple sclerosis. Furthermore, spinal cord lesions, atrophy, and decreased upper cervical surface area are highly related to higher EDSS scores. The development of more than one gadolinium-enhanced lesion or new T2 lesions at follow-up is associated with a worse disease course. Also, early atrophy in the brain, including the cortex, deep grey matter, thalamus, basal ganglia, or infratentorial regions, is associated with aggressive MS and faster progression to disability. In addition, smoldering lesions indicating delayed recovery, persistent inflammation, and neurodegeneration are used as markers for aggressive MS(2)(3)(5). Figure ( 1 )Figure( 2)

Figure 1: T2 MRI enhanced lesions, Case courtesy of Associate Professor Frank  Gaillard,(12)

Figure 2: T1 black holes, Case courtesy of Dr Ahmed Abdrabou,(13)

Biochemical markers

Presence of IgM oligoclonal bands, B lymphocyte chemoattractant (CXCL13), neurofilament light chain (NFL), or Chitinase-3-like protein 1 (CHI3L1) in CSF,     elevated IgG index and Elevated NFL in serum. (2)(3)(5)

There are many names and definitions used to describe aggressive multiple sclerosis for research or clinical purposes, and still no specific diagnostic criteria are agreed upon(2)(6), definitions include:

– Malignant MS: describes a very rapid progression of the disease, but the term is ambiguous because it is more commonly used to describe an unstoppable form of MS that can result in death within months to a few years, such as the Marburg variant of MS. Some researchers define malignant MS as rapid progression to death or disability. Another definition is the progression of EDSS to a score of 6 points in 5 years which is sometimes called ever malignant MS. Based on whether relapses or sustained progression is present, some research groups classify malignant MS into transient or sustained.(2)(6)

  – Aggressive MS: has various definitions, including reaching an EDSS of 6 within five years, reaching an EDSS of 6 at 40, or transforming to secondary progressive MS within three years since relapsing-remitting MS onset. Other researchers use the definition of reaching an EDSS of 6 within ten years since disease onset. Aggressive MS is also defined as relapsing-remitting MS with one or more of an EDSS score of 4 within the first five years, two or more relapses in the last year with incomplete recovery, presence of more than two new or enlarging T2 or gadolinium-enhanced MRI lesions despite treatment or use of 1 or more disease-modifying therapies (DMTs) for one year with no response.(2)(6)

• Aggressive relapsing-remitting MS: where the baseline EDSS is 2.5-5, one or more gadolinium-enhancing lesions are present on MRI, and two or more relapses or an increase in EDSS of 2 or more points in the last 12 months. (2)(6)

– Aggressive onset MS is also used to describe patients having two or more relapses and two or more gadolinium-enhancing MRI lesions or having one relapse in the last year that results in a sustained increase of EDSS of 3 with two or more gadolinium-enhancing MRI lesions.(2)(6)

–Highly active MS is used to identify patients eligible for immunoablative therapy with homologous stem cell transplant and indicates a poor prognosis. It is defined as conventional treatment failure with one or more relapsed and incomplete recovery, MRI with one or more gadolinium-enhancing lesions of 3mm diameter or more, or an increase in T2 lesion of 0.3 or more per month in two consecutive MRI 6-12 months apart.(2)(6)

Multiple criteria are used to identify aggressive MS(3), as shown in Table 4, Table 5, and Table 6 below:

Table 4: Canadian working group assessment, reprinted from Dr James D. Bowen(3)

Table 5: modified Rio score, reprinted from Dr James D. Bowen(3)

Table 6: MS decision model, reprinted from Dr James D. Bowen (3). HADS: hospital anxiety and depression scale. If the color green was found on interpretation in all domains no change in therapy is needed, while patients with one yellow domain should be reassessed in three months and patients with two yellow domains or one red domain should have their therapies changed.

An EDSS of 6 or more was associated with a secondary progressive disease which is of unfavorable response to aggressive treatment and hence can be used as a good criterion to identify aggressive MS.(6)

Differential diagnoses of MS that could also have aggressive presentation

Other inflammatory demyelinating diseases, some of which can be considered atypical forms of MS, such as Acute disseminated encephalomyelitis (ADEM) or acute hemorrhagic leukoencephalitis, Shidler disease, Balo concentric sclerosis, Marburg variant of MS, Tumefactive demyelination, Solitary sclerosis and Cavitary MS.(10)(14)

-Balo concentric sclerosis: Is a monophasic acute demyelinating disease most frequently affecting Asian women. Patients usually present with encephalopathy, headache, cognitive impairment, or seizures which are atypical of classical MS and might help differentiate the disease (10). Antibodies are usually negative, and patients are negative for oligoclonal bands. T2 enhanced MRI shows hyperintense alternating with a hypointense lamella,, which is related to regions of preserved myelin alternating with legions of severe demyelination. The disease is treated with corticosteroids and other immunosuppressants. The disease can be identified in patients with previous MS diagnoses, other atypical forms of MS,, or previously healthy patients. On pathology oligodendrocytes, loss and MS immune pattern III are seen (14). Figure (3)

Figure 3: Balo concentric sclerosis on axial T2 enhanced MRI, Case courtesy of Austin Neuropathology(15)

– Tumefactive demyelination:  patients usually present with atypical MS symptoms such as lethargy, headaches, and seizures. On MRI patients who have>2 cm well-defined demyelinating lesions (Figure 4) that can be isolated, multiple, or associated with other MS lesions. The lesions are ring-like or of infiltrative pattern and are in supratentorial areas. The oligoclonal band is an inconsistent finding in CSF analysis, but patients usually have higher CSF interleukin (IL)-6 and similar CSF IL-10 compared to MS. On histopathology, patients exhibit more Creutzfeldt Peter cells and dystrophic astrocytes, displayed in fewer numbers in typical MS (14). However, patients with tumefactive lesions have a favorable prognosis compared to other MS patients and are usually treated with corticosteroids or DMTS(16).

Figure 4: Tumefactive demyelinating lesion on MRI, Case courtesy of Dr Hani Makky Al Salam, (17)

-Schiller’s disease: Is another severe atypical MS variant that can be misdiagnosed as MS in the early stages because of the presence of white matter lesions. However, the disease progresses more rapidly and presents with impaired consciousness. On MRI, Schidler’s disease lesions are similar to tumefactive lesions. The disease affects children more frequently than adults .(10)

-Marburg variant of MS: This is a deadly atypical variant presenting with loss of consciousness, coma, and death within weeks. On MRI, supratentorial, infratentorial, and spinal cord lesions are present and progress rapidly. (Figure 5)

Marburg variant and Shidler’s disease have poor prognoses as corticosteroids or other immunosuppressants are ineffective in stopping disease progression .(14)

Figure 5: Marburg variant MS on MRI, Case courtesy of Dr Mohammad A. ElBeialy,{Formatting Citation}

Acute disseminated encephalomyelitis (ADEM): Is usually present in pediatric patients but rarely in adults. Patients typically present with acute or subacute encephalopathy and can progress to coma, in addition to fever, headache, fatigue, and nausea related to encephalitis. Furthermore, patients can have focal or multifocal symptoms according to sights affected by demyelination. The disease’s cause is idiopathic but related to a recent infection or vaccination. On MRI, multiple T2 hyperintense lesions are present bilaterally and asymmetrically (Figure 6). CSF analysis can show increased lymphocytes, an elevation in CSF pressure, mild protein elevation, normal glucose levels, elevated IgG index, and oligoclonal bands. The disease has a favorable prognosis and is usually monophasic, although some patients can have a non-monophasic presentation mainly related to MS. However, Acute hemorrhagic leukoencephalitis is a rare, severe variant with similar symptoms and a less favorable prognosis. The disease is distinguished by having hemorrhagic lesions . (10)(14)

Figure 6: Axial FLAIR MRI Acute Disseminated Encephalomyelitis, Case courtesy of Assoc Prof Frank Gaillard,(19)

Solitary sclerosis: Is a progressive disease causing spastic paraparesis or hemiparesis. It is caused by an isolated demyelinating lesion in the corticomedullary junction which is found on MRI (Figure 7), through the involvement of other sites of the corticospinal tract. CSF analysis also shows oligoclonal bands. The disease is related to MS and can progress to MS. However, this is yet to be more thoroughly evaluated (14).

Figure 7: Solitary sclerosis on MRI, (A,B) showing lesions on cervicomedullary junction, C and D showing FLAIR hypointensities and hyperintensities respectively, reprinted from X. Ayrignac , C. Carra-Dallie`re and P. Labauge, (14).

Neuromyelitis Optica (Devic’s disease): This is a demyelinating disease that is no longer considered an atypical variant of MS(13). This disease is related to channelopathy due to antibodies against aquaporin-4 in the astrocyte foot processes. It presents with transverse myelitis and optic neuritis that occur simultaneously or separately. The disease is distinguished from MS by aquaporin-4 antibodies or anti-myelin oligodendrocyte glycoproteins. Also, the disease differs from MS by lack of remissions, rapid progression, and unresponsiveness to corticosteroids or other MS therapies; thus, the disease requires different treatments that can be more aggressive such as plasma exchange. (14)

Other non-demyelinating diseases to be considered as differential diagnoses to MS include inflammatory diseases such as systemic lupus erythematosus, Bechet disease, Sjogren syndrome, paraneoplastic syndromes, sarcoidosis and Wegener granulomatosis, infectious disease such Lyme disease, Human T-lymphotropic Virus-1 Associated Myelitis, CNS involvement in Human immunodeficiency virus, progressive multifocal leukoencephalopathy and neurosyphilis, in addition to metabolic disorders such as Adrenoleukodystrophies, Leber’s Hereditary Optic Neuropathy and Subacute Combined Degeneration. Physical examination and investigations are required to differentiate them from aggressive MS.(10)

Treatment

Patients with aggressive MS are unresponsive to conventional first- or second-line treatments of MS; thus, these patients mostly will have tried drugs that either block inflammatory cells’ access to the CNS, such as Natalizumab or that sequester these inflammatory cells in lymph nodes such as fingolimod. Second-line agents such as Natalizumab and fingolimod exert their effect if patients use these drugs.  Natalizumab discontinuation is associated with severe, dangerous rebound disease, and prolonged use is associated with progressive multifocal leukoencephalopathy, although used anecdotally in some aggressive MS patients. On the other hand, fingolimod with a less severe rebound effect after discontinuation is not completely effective for aggressive MS. Therefore, therapies that eliminate immunoreactive cells, including alemtuzumab, rituximab, cladribine, mitoxantrone, cyclophosphamide or the use of immunoablative therapy and homologous stem cell transplant are more effective in aggressive MS . (3)(6)(21)

FDA-approved aggressive treatments for MS are shown in Table 7:

Table 7: FDA-approved aggressive MS drugs

Non-FDA-approved drugs for aggressive MS are shown in Table 8:

Table 8: Non-FDA approved aggressive MS drugs

Immunoablative therapy with stem cell transplantation

It’s a non-FDA-approved approach used in autoimmune diseases, including MS, and is the most aggressive treatment of MS with high efficacy as there is no evidence of disease activity at 50 years approached 70%, which is twice as effective as other aggressive MS therapies. However, this increased efficacy is at the cost of increased risk of severe side effects, including allergic reactions and anaphylaxis, transplant reactions, myelosuppression, liver toxicity, and gastrointestinal toxicity, all of which depend on the type of therapy used. The more effective the therapy is, the more myelosuppression it will involve.(3)(6)(24)

This therapy involves multiple steps starting with stem cell mobilization using granulocyte colony-stimulating factor or immunosuppressants, leukapheresis to collect stem cells, and a conditioning regimen involving high-dose chemotherapy. Examples are:

Highly myeloablative busulfan plus anti-thymocyte globulin in which the risks of myelosuppression and veno-occlusive liver disease are high;

intermediate myeloablative therapy involving Carmustine, etoposide, cytarabine, and melphalan plus anti-thymocyte globulin (BEAM/ATG), which has an intermediate risk of myelosuppression;

nonmyeloablative therapy involves cyclophosphamide and anti-thymocyte globulin, whose side effects are mainly caused by cyclophosphamide. Finally, stem cell infusion leads to bone marrow reconstitution. This will lead to the elimination of autoreactive cells and a reset of the immune system. Immunoablative therapy with stem cell transplant was primarily effective in relapsing-remitting MS patients younger than 32 who didn’t use more than two other therapies. (3)(6)

Treatment approaches

The escalation approach is the first approach to treating aggressive MS (Figure 8). Treatment starts with less aggressive and effective drugs and escalates to higher efficacy drugs according to disease activity and responsiveness, thus, reducing the risk of unnecessary immunosuppression. The escalation approach is more effective in relapsing-remitting MS, but in aggressive MS, the narrow time window to progress to disability will make this approach less effective. However, replacing monotherapy of low-efficacy drugs with monotherapy of high-efficacy medications is found to be preferable to adding high-efficacy drugs to low-efficacy drugs as no increase in effectiveness was found, in addition to the fact that there is a risk of more side effects. The drug to be used next depends on the patient profile and which drugs were used before(6)(23).

Figure 8: Escalation approach for aggressive MS, reprinted from Robert H. Gross, MD; John R. Corboy, MD, FAAN,(23)

The other approach is the induction approach, in which patients with high-risk features of aggressive MS start directly with high-efficacy treatments. This approach comes at the cost of increased toxicity of high-efficacy treatments. The induction approach can be done either by using an induction treatment for a specific period, such as potent lymphocyte-depleting agents including cyclophosphamide and mitoxantrone, alemtuzumab or hematopoietic stem cell transplant, then using a less aggressive maintenance DMT (Figure 9), or by using long term use of high efficacy treatments such as Natalizumab, or anti-CD-20 drugs without de-escalation(Figure 10). (6)(23)

Figure 9: induction approach followed by maintenance, reprinted from Robert H. Gross, MD; John R. Corboy, MD, FAAN,(23)

Figure 10: maintenance doses of second-line agents, reprinted from Robert H. Gross, MD; John R. Corboy, MD, FAAN,(23)

Recommendations

Future retrospective studies or prospective studies that evaluate patients until fulfilling aggressive MS criteria should focus on arriving at a consensus on aggressive MS definition by confirming the best criteria to define patients early and use more aggressive treatments if needed. Risk factors for aggressive MS must be studied to predict patients requiring aggressive treatment. (2) More randomized controlled trials should be done to compare the effectiveness of different approaches in treating aggressive MS, drugs used within these approaches, and treatment algorithms. (6)(23) Also, an excellent endpoint to monitor patients’ response to aggressive MS treatment must be established. One proposed endpoint is NEDA (no evidence of disease activity), with no disease progression, new MRI lesions or new relapses, or a point close to NEDA. (6)

References...

References:

1.       Klineova S, Lublin FD. Clinical Course of Multiple Sclerosis. Cold Spring Harb Perspect Med. 2018 Sep;8(9). 

2. Iacobaeus E, Arrambide G, Amato MP, Derfuss T, Vukusic S, Hemmer B, et al. Aggressive multiple sclerosis (1): Towards a definition of the phenotype. Mult Scler. 2020 Jun;26(9):1352458520925369. 

3.      Bowen JD. Highly Aggressive Multiple Sclerosis. Continuum (Minneap Minn). 2019 Jun;25(3):689–714. 

4. Nourbakhsh B, Mowry EM. Multiple Sclerosis Risk Factors and Pathogenesis. Continuum (Minneap Minn). 2019 Jun;25(3):596–610. 

5.      Díaz C, Zarco LA, Rivera DM. Highly active multiple sclerosis: An update. Mult Scler Relat Disord. 2019 May;30:215–24. 

6.      Rush CA, MacLean HJ, Freedman MS. Aggressive multiple sclerosis: proposed definition and treatment algorithm. Nat Rev Neurol. 2015 Jul;11(7):379–89. 

7.      Gelfand JM. Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. Handb Clin Neurol. 2014;122:269–90. 

8.      Meyer-Moock S, Feng Y-S, Maeurer M, Dippel F-W, Kohlmann T. Systematic literature review and validity evaluation of the Expanded Disability  Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients with multiple sclerosis. BMC Neurol. 2014 Mar;14:58. 

9.      Çinar BP, Yorgun YG. What We Learned from The History of Multiple Sclerosis Measurement: Expanded  Disability Status Scale. Noro Psikiyatr Ars. 2018;55(Suppl 1):S69–75. 

10. Ömerhoca S, Akkaş SY, İçen NK. Multiple Sclerosis: Diagnosis and Differential Diagnosis. Noro Psikiyatr Ars. 2018;55(Suppl 1):S1–9. 

11. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162–73. 

12.    Gaillard PF. t2 lesions. In: radiopedia. 

13. Abdrabou DA. t1 black holes. In: radiopedia. 

14.    Ayrignac X, Carra-Dallière C, Labauge P. Atypical inflammatory demyelinating lesions and atypical multiple sclerosis. Rev Neurol (Paris). 2018 Jun;174(6):408–18. 

15. Neuropathology A. balo concentric sclerosis. In: radiopedia. 

16.    Brod SA, Lindsey JW, Nelson F. Tumefactive demyelination: Clinical outcomes, lesion evolution and treatments. Mult Scler J – Exp Transl Clin. 2019;5(2):2055217319855755. 

17.     Salam DHM Al. tumefactive demeyilnation. In: radiopedia. 

18.    ElBeialy DMA. marburg variant ms. In: radiopedia. 

19.    Gaillard PF. acute dissiminated encephalomyelitis. In: radiopedia. 

20.    Fujihara K. Neuromyelitis optica spectrum disorders: still evolving and broadening. Curr Opin Neurol [Internet]. 2019;32(3). Available from: https://journals.lww.com/co-neurology/Fulltext/2019/06000/Neuromyelitis_optica_spectrum_disorders__still.11.aspx

21. Freedman MS, Rush CA. Severe, Highly Active, or Aggressive Multiple Sclerosis. Continuum (Minneap Minn). 2016 Jun;22(3):761–84. 

22.    Jalkh G, Abi Nahed R, Macaron G, Rensel M. Safety of Newer Disease Modifying Therapies in Multiple Sclerosis. Vaccines. 2020 Dec;9(1). 

23.    Gross RH, Corboy JR. Monitoring, Switching, and Stopping Multiple Sclerosis Disease-Modifying  Therapies. Continuum (Minneap Minn). 2019 Jun;25(3):715–35. 

24.    Kuan TLT, Amini F, Seghayat MS. Feasibility and toxicity of hematopoietic stem cell transplant in multiple  sclerosis. Iran J Basic Med Sci. 2017 Jul;20(7):729–38.