Section 3 Diagnosis

*Multiple Sclerosis*

[181] Planas R, Jelcic I, Schippling S, Martin R, Sospedra M. Natalizumab treatment perturbs memory- and marginal zone-like B-cell homing in secondary lymphoid organs in multiple sclerosis. European Journal of Immunology. 2012;**42**(3):790-798

[188] Greenfield AL, Hauser SL. B-cell

Entering an era. Annals of Neurology.

[189] Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. The New England Journal of Medicine.

therapy for multiple sclerosis:

2018;**83**(1):13-26

2017;**376**(3):209-220

[190] Li R, Rezk A, Miyazaki Y, Hilgenberg E, Touil H, Shen P, et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Science Translational

Medicine. 2015;**7**(310):310ra166

[191] Rao SP, Sancho J, Campos-Rivera J, Boutin PM, Severy PB, Weeden T, et al. Human peripheral blood mononuclear cells exhibit heterogeneous CD52 expression levels and show differential sensitivity to alemtuzumab mediated cytolysis. PLoS One. 2012;**7**(6):e39416

[192] Ambrose LR, Morel AS, Warrens AN. Neutrophils express CD52 and exhibit complement-mediated lysis in the presence of alemtuzumab. Blood.

[193] Baker D, Giovannoni G, Schmierer K. Marked neutropenia: Significant but rare in people with multiple sclerosis after alemtuzumab treatment. Multiple

Sclerosis and Related Disorders.

2009;**114**(14):3052-3055

2017;**18**:181-183

[182] Metz I, Radue EW, Oterino A, Kumpfel T, Wiendl H, Schippling S,

[183] Kivisakk P, Francois K, Mbianda J, Gandhi R, Weiner HL, Khoury SJ. Effect of natalizumab treatment on circulating plasmacytoid dendritic cells: A crosssectional observational study in patients with multiple sclerosis. PLoS One.

[184] Painter MM, Atagi Y, Liu CC, Rademakers R, Xu H, Fryer JD, et al. TREM2 in CNS homeostasis and neurodegenerative disease. Molecular Neurodegeneration. 2015;**10**:43

[185] Kleinberger G, Yamanishi Y, Suarez-Calvet M, Czirr E, Lohmann E, Cuyvers E, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis.

Science Translational Medicine.

[186] Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, et al. Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain. 2008;**131**

2014;**6**(243):243ra86

(Pt 11):3081-3091

[187] Ohrfelt A, Axelsson M,

Malmestrom C, Novakova L, Heslegrave A, Blennow K, et al. Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. Multiple Sclerosis. 2016;**22**(12):1587-1595

et al. Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy. Acta Neuropathologica. 2012;**123**(2):235-245

2014;**9**(7):e103716

**38**

Chapter 3

Abstract

Joyce Pauline Joseph

to the clinical features.

dissemination in space

1. Introduction

41

Diagnosis of Multiple Sclerosis

Keywords: multiple sclerosis, diagnosis, criteria, dissemination in time,

Multiple sclerosis is an immune-mediated disease involving the central nervous system predominantly affecting the brain, spinal cord, and optic nerves. There is no gold standard or pathognomonic features that can distinguish MS from other neurological conditions with multiple anatomical site involvement. A comprehensive history obtained from the patient, clinical examination with the support of laboratory investigations with is required to assist in the diagnosis of MS. The key to diagnosis has always been dissemination in time, which translates into different time interval of clinical relapse, and dissemination of space, which is a variable anatomical site in the central nervous system. Hence difference in time and neuroanatomical site is essential. Several criteria have been created over the last several decades such as Schumacher criteria, [1], Poser criteria [2], and McDonald criteria [3–5]. McDonald criteria has been first established in 2001 and revised in 2005, 2010, and 2017. Revisions are necessary due to evolving research and advances in the field of demyelinating diseases. Researchers in neuroimmunology diseases concurred the diagnosis of MS could be made earlier and can be used for paediatric population and Asian patients [5]. Investigations are done for diagnosis of MS to ensure there are no other possible explanations for the clinical and radiological presentation. As the patient can be subjected to lifelong immune modulators and immunosuppressant, it is highly essential to ensure diagnosis is made accurately and possible differentials are monitored during follow-up. A clinician's job does not end with establishing diagnosis and instituting treatment. Careful surveillance is necessary to ensure we are in the right track as regards to the diagnosis. Misdiagnosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system. Although there are no pathognomonic features to confirm the diagnosis of this immune-mediated disease, a constellation of clinical, radiological, and immune studies can ensure the clinician gets a more definitive diagnosis. Criteria have been made every few years based on research to clinch the diagnosis. The most recent criteria which are the McDonald criteria have been formed in 2001 and revised in 2005, 2010, and 2017. Most criteria are to be used only as a guide to facilitate the diagnosis of multiple sclerosis. Advances in demyelinating disorders will require diagnostic criteria to be revised every few years with scientists hoping for a more definitive and confirmative diagnosis. The cardinal features for diagnosis are dissemination in time and space. There should be no other possible explanation

## Chapter 3 Diagnosis of Multiple Sclerosis

Joyce Pauline Joseph

## Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system. Although there are no pathognomonic features to confirm the diagnosis of this immune-mediated disease, a constellation of clinical, radiological, and immune studies can ensure the clinician gets a more definitive diagnosis. Criteria have been made every few years based on research to clinch the diagnosis. The most recent criteria which are the McDonald criteria have been formed in 2001 and revised in 2005, 2010, and 2017. Most criteria are to be used only as a guide to facilitate the diagnosis of multiple sclerosis. Advances in demyelinating disorders will require diagnostic criteria to be revised every few years with scientists hoping for a more definitive and confirmative diagnosis. The cardinal features for diagnosis are dissemination in time and space. There should be no other possible explanation to the clinical features.

Keywords: multiple sclerosis, diagnosis, criteria, dissemination in time, dissemination in space

## 1. Introduction

Multiple sclerosis is an immune-mediated disease involving the central nervous system predominantly affecting the brain, spinal cord, and optic nerves. There is no gold standard or pathognomonic features that can distinguish MS from other neurological conditions with multiple anatomical site involvement. A comprehensive history obtained from the patient, clinical examination with the support of laboratory investigations with is required to assist in the diagnosis of MS. The key to diagnosis has always been dissemination in time, which translates into different time interval of clinical relapse, and dissemination of space, which is a variable anatomical site in the central nervous system. Hence difference in time and neuroanatomical site is essential. Several criteria have been created over the last several decades such as Schumacher criteria, [1], Poser criteria [2], and McDonald criteria [3–5]. McDonald criteria has been first established in 2001 and revised in 2005, 2010, and 2017. Revisions are necessary due to evolving research and advances in the field of demyelinating diseases. Researchers in neuroimmunology diseases concurred the diagnosis of MS could be made earlier and can be used for paediatric population and Asian patients [5]. Investigations are done for diagnosis of MS to ensure there are no other possible explanations for the clinical and radiological presentation. As the patient can be subjected to lifelong immune modulators and immunosuppressant, it is highly essential to ensure diagnosis is made accurately and possible differentials are monitored during follow-up. A clinician's job does not end with establishing diagnosis and instituting treatment. Careful surveillance is necessary to ensure we are in the right track as regards to the diagnosis. Misdiagnosis

could still occur, and therefore it must be addressed, and measures should be undertaken to minimise them.

eye and may worsen till visual acuity is lost. Diminished colour appreciation or dyschromatopsia may be seen. The pain associated with ON tends to progress over days. Visual improvement may occur in 3–8 weeks, and most visual recovery occurs within the first 6 months but can continue for up to 1 year after the acute event [8–12]. However, many patients may experience residual and variable visual complaints and dysfunction after recovery. Examination on optic neuritis could reveal

no abnormalities, and deficits are present; there may be disc selling, fine haemorrhages, impaired visual acuity, central or centrocecal oedema, relative afferent pupillary defect or Marcus Gunn pupil, impaired colour vision, and pale optic discs [11]. Phosphenes, which are an experience of bright flashes of light without light entering the eye, Uhthoff's phenomenon where there is brief blurring

[14]. The clinical diagnosis involving the cord is called myelitis.

Numbness and weakness of upper and or lower limbs are presentations seen in spinal cord lesions in MS [14]. Cord lesions also come with urinary incontinence, frequency, and urinary retention depending on the level and severity involved. Constipation and diarrhoea could relate to bowel dysfunction. The symptoms are of corticospinal tract lesion; a clear sensory level might guide the clinician to focus on a cord lesion rather than a peripheral lesion due to a lower motor neuron lesion. Clinical assessment may reveal increased tone, monoparesis, hemiparesis and quadriparesis, abnormal cutaneous and sensory deficit, and sphincter disturbance

Double vision, speech difficulty, swallowing difficulty, nausea, vomiting, hiccups, vertigo, unsteadiness, and weakness of limbs are symptoms seen in brainstem lesions. Examination would reveal nystagmus, ophthalmoplegia, dysarthria, and facial weakness [14]. Cranial nerve deficits involving III–XII may be seen. Cerebellar connection with the brainstem can cause dysdiadochokinesia, dysmetria, and ataxia [15]. Brainstem lesions could also cause respiratory failure and locked-in syndrome. Localization of the neuroanatomical site can be judged based on the

Unsteadiness involving upper and lower limbs, gait instability, and dysarthria are common symptoms seen in structures involving the cerebellum. Tremors, which are either due to cerebellar or thalamic involvement, could occur, and they result in tremor affecting limbs, trunk, and vocal cord, and head. Types of tremors are intention, postural, rest, and rubral (Alistair [16]). Cerebellar signs will be evident with a significant involvement of the cerebellum. A pure cerebellar syndrome is rare and other causes must be investigated. Tremors in cerebellar involvement affect arms, legs, head, and trunk in descending order of frequency. Face, tongue, and jaw were not affected in a study done by Alusi et al. [17].

Symptoms involving the cerebral hemispheres correlate the site of lesion such

as the parietal, temporal, frontal, and occipital lobes. Symptoms are right- or left-sided hemianaesthesia, hemiparesis, hemiplegia, or monoplegia and visual

of vision during physical exercise [13].

2.2 Spinal cord

Diagnosis of Multiple Sclerosis

DOI: http://dx.doi.org/10.5772/intechopen.85258

2.3 Brainstem

2.4 Cerebellum

2.5 Cerebrum

43

symptoms prior to neuroimaging.

## 2. Making the diagnosis: symptoms and signs

Awareness about MS is crucial for the patient to seek attention, and to ask for a second opinion when necessary is important both for patients and healthcare providers. A good history with a knowledge of common presentations and bearing in mind neuroanatomical sites involved will be valuable in coming to a conclusion, and focused investigations will be needed. Knowledge of subtypes and classification will be helpful to the clinician.

Four subtypes of multiple sclerosis are used [6].

Active or disease activity is measured by clinical relapses and MRI evidence of contrast-enhanced lesion or new or enlarging lesion on T2-weighted images by annual clinical assessment.

Progression-progressive disability by annual clinical assessment If no annual assessment is done, it is called indeterminate.

	- Active
	- Not active
	- Active
	- Not active
	- Active with progression
	- Active but without progression
	- Not active but with progression
	- Not active and without progression
	- Active with progression
	- Active but without progression

#### 2.1 Optic nerve

Optic nerve involvements are common and often the first presentation in multiple sclerosis [7]. The severity can vary from being asymptomatic to severe visual loss, and recovery could be complete, partial, or no resolution. The symptoms could begin as pain behind the eye and evolve into visual impairment in the centre of the

### Diagnosis of Multiple Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.85258

eye and may worsen till visual acuity is lost. Diminished colour appreciation or dyschromatopsia may be seen. The pain associated with ON tends to progress over days. Visual improvement may occur in 3–8 weeks, and most visual recovery occurs within the first 6 months but can continue for up to 1 year after the acute event [8–12]. However, many patients may experience residual and variable visual complaints and dysfunction after recovery. Examination on optic neuritis could reveal no abnormalities, and deficits are present; there may be disc selling, fine haemorrhages, impaired visual acuity, central or centrocecal oedema, relative afferent pupillary defect or Marcus Gunn pupil, impaired colour vision, and pale optic discs [11]. Phosphenes, which are an experience of bright flashes of light without light entering the eye, Uhthoff's phenomenon where there is brief blurring of vision during physical exercise [13].

## 2.2 Spinal cord

could still occur, and therefore it must be addressed, and measures should be

Awareness about MS is crucial for the patient to seek attention, and to ask for a second opinion when necessary is important both for patients and healthcare providers. A good history with a knowledge of common presentations and bearing in mind neuroanatomical sites involved will be valuable in coming to a conclusion, and focused investigations will be needed. Knowledge of subtypes and classification will

Active or disease activity is measured by clinical relapses and MRI evidence of contrast-enhanced lesion or new or enlarging lesion on T2-weighted images by

Optic nerve involvements are common and often the first presentation in multiple sclerosis [7]. The severity can vary from being asymptomatic to severe visual loss, and recovery could be complete, partial, or no resolution. The symptoms could begin as pain behind the eye and evolve into visual impairment in the centre of the

Progression-progressive disability by annual clinical assessment If no annual assessment is done, it is called indeterminate.

undertaken to minimise them.

Multiple Sclerosis

be helpful to the clinician.

annual clinical assessment.

◦ Active

◦ Active

◦ Not active

• Primary progressive disease

◦ Active with progression

• Secondary progressive disease

◦ Active with progression

2.1 Optic nerve

42

◦ Active but without progression

◦ Active but without progression

◦ Not active but with progression

◦ Not active and without progression

◦ Not active

• Clinically isolated syndrome

• Relapsing-remitting multiple sclerosis

2. Making the diagnosis: symptoms and signs

Four subtypes of multiple sclerosis are used [6].

Numbness and weakness of upper and or lower limbs are presentations seen in spinal cord lesions in MS [14]. Cord lesions also come with urinary incontinence, frequency, and urinary retention depending on the level and severity involved. Constipation and diarrhoea could relate to bowel dysfunction. The symptoms are of corticospinal tract lesion; a clear sensory level might guide the clinician to focus on a cord lesion rather than a peripheral lesion due to a lower motor neuron lesion. Clinical assessment may reveal increased tone, monoparesis, hemiparesis and quadriparesis, abnormal cutaneous and sensory deficit, and sphincter disturbance [14]. The clinical diagnosis involving the cord is called myelitis.

## 2.3 Brainstem

Double vision, speech difficulty, swallowing difficulty, nausea, vomiting, hiccups, vertigo, unsteadiness, and weakness of limbs are symptoms seen in brainstem lesions. Examination would reveal nystagmus, ophthalmoplegia, dysarthria, and facial weakness [14]. Cranial nerve deficits involving III–XII may be seen. Cerebellar connection with the brainstem can cause dysdiadochokinesia, dysmetria, and ataxia [15]. Brainstem lesions could also cause respiratory failure and locked-in syndrome. Localization of the neuroanatomical site can be judged based on the symptoms prior to neuroimaging.

## 2.4 Cerebellum

Unsteadiness involving upper and lower limbs, gait instability, and dysarthria are common symptoms seen in structures involving the cerebellum. Tremors, which are either due to cerebellar or thalamic involvement, could occur, and they result in tremor affecting limbs, trunk, and vocal cord, and head. Types of tremors are intention, postural, rest, and rubral (Alistair [16]). Cerebellar signs will be evident with a significant involvement of the cerebellum. A pure cerebellar syndrome is rare and other causes must be investigated. Tremors in cerebellar involvement affect arms, legs, head, and trunk in descending order of frequency. Face, tongue, and jaw were not affected in a study done by Alusi et al. [17].

#### 2.5 Cerebrum

Symptoms involving the cerebral hemispheres correlate the site of lesion such as the parietal, temporal, frontal, and occipital lobes. Symptoms are right- or left-sided hemianaesthesia, hemiparesis, hemiplegia, or monoplegia and visual

symptoms due to visual field defect. Aphasia or dysphasia and epilepsy are rare symptoms noted in MS [13].

nervous system pathway can be detected even when there are no obvious clinical features seen. Visual evoked potentials are visual stimulation, which consists high contrast black and white checkerboard where these squares, are changed places and response to this reversal is recorded. Delayed waveform depicts an optic nerve lesion. Brainstem evoked potentials are when auditory stimulations in the form of clicks are given for a response obtained from the brainstem. It assesses lower brainstem auditory pathway. The BAEP are abnormal when demyelination involves brainstem. Somatosensory evoked potentials are obtained when stimulation from the peripheral nerves in the upper limbs produces a response. An abnormal response could translate to demyelination within the central fibres of dorsal column-medial lemniscal pathways. Evoked potentials may not be useful with advances in MRI techniques and oligoclonal band, and they have not been included

Magnetic resonance imaging (MRI) is a neuroimaging of choice for diagnosis of

Baseline studies for patients with a clinically isolated syndrome (CIS) and/or

• Brain MRI protocol with gadolinium at baseline and to establish dissemination

• Spinal cord MRI if myelitis, insufficient features on brain MRI to support diagnosis, or age > 40 years with nonspecific brain MRI findings

• A cervical cord MRI performed simultaneously with the brain MRI could

and would reduce the number of patients requiring a subsequent MRI

suspected MS to look for evidence of dissemination in time (i.e. new T2 lesions or

• 12–24 months for low-risk CIS (i.e. normal brain MRI) and/or uncertain clinical syndrome with suspicious brain MRI features (e.g. radiologic isolated

have prognostic value in the evaluation of CIS patients with or without myelitis

MS and plays a key role in research, surveillance, and treatment. Although the McDonald criteria denote that two clinical attacks depicting dissemination in time and space are sufficient to make a diagnosis, neurologists and neurologist with interest in MS would require a baseline MRI to confirm diagnosis and for surveillance. White matter lesions in the MRI are characteristic with typical juxtacortical, cortical; periventricular, brainstem and spinal cord lesions are required. MRI protocols used in MS are spin echo T2 weighted, fluid-attenuated inversion recovery. The Consortium of MS Centres revised and updated guidelines for MRI

3.4.1 MRI protocols adapted from the Consortium of MS Centers

• Orbital MRI if severe optic neuritis with poor recovery

Timing of a follow-up brain MRI protocol for patients with a CIS and/or

• 6–12 months for high-risk CIS (e.g. ≥ 2 ovoid lesions on first MRI)

in McDonald criteria 2017.

Diagnosis of Multiple Sclerosis

DOI: http://dx.doi.org/10.5772/intechopen.85258

([24], ww.mscare.org/mri).

suspected MS:

in time

appointment

gadolinium-enhancing lesions):

syndrome [RIS])

45

3.4 Magnetic resonance imaging

## 2.6 Symptoms of multiple sclerosis in chronic disease

Spasticity, cognitive dysfunction, fatigue, affective disorders, and sexual dysfunction are normally seen in chronic disease [13]. An in-depth history during the first clinical assessment is a valuable asset to establishing the diagnosis.

## 3. Investigations in MS

## 3.1 Blood investigations

There are no blood investigations that are pathognomonic for the diagnosis of multiple sclerosis. However, in order to rule out other neurological conditions that can mimic MS, a complete workout is necessary. Screening for connective tissue diseases such as Systemic Lupus Erythematosus, antiphospholipid antibody, retroviral screen, other autoimmune condition such as thyroid disease, infectious diseases, Lyme disease and angiotensin converting enzyme are necessary [18].

## 3.2 Lumbar puncture

Lumbar puncture for CSF analysis is required as it can further assist in the diagnosis as its presence reveals a risk of developing MS in patients with clinically isolated syndrome [3, 5, 19]. In 2017, cerebrospinal fluid (CSF) is done to look for oligoclonal band and immunoglobulin G (IgG), and a parallel serum sample need to be taken as no OCB production is noted in the blood in multiple sclerosis. Oligoclonal band and immunoglobulin G are indicative of intrathecal inflammation which is B cell modulated from plasma cells seen in CNS inflammatory disease [20]. Distinctive CSF analysis will disclose slightly raised leucocyte count, B cells, or plasma cells in cytological analysis and raised IgG synthesis [21]. Oligoclonal band will be highly helpful in the event of other clinical features that are not diagnostic, and furthermore it depicts dissemination in space. Lumbar puncture is recommended in the following situations [5]:


The Panel on Diagnosis of Multiple Sclerosis [5] cautions diagnosis of multiple sclerosis early on in the disease and in children when OCB is negative in atypical clinical, radiological, or OCB findings.

There are two methods of analysing the CSF for oligoclonal band agarose gel electrophoresis/Coomasie Blue Staining and isoelectric focus/silver staining [22]. Oligoclonal bands are positive in up to 95% of patients with clinically definite multiple sclerosis.

## 3.3 Evoked potentials

Evoked potentials are electrophysiological tests done to look for evidence of silent lesions [23]. Abnormal or slowing of electrical conduction along the central

## Diagnosis of Multiple Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.85258

symptoms due to visual field defect. Aphasia or dysphasia and epilepsy are rare

Spasticity, cognitive dysfunction, fatigue, affective disorders, and sexual dysfunction are normally seen in chronic disease [13]. An in-depth history during the

There are no blood investigations that are pathognomonic for the diagnosis of multiple sclerosis. However, in order to rule out other neurological conditions that can mimic MS, a complete workout is necessary. Screening for connective tissue diseases such as Systemic Lupus Erythematosus, antiphospholipid antibody, retroviral screen, other autoimmune condition such as thyroid disease, infectious diseases, Lyme disease

Lumbar puncture for CSF analysis is required as it can further assist in the diagnosis as its presence reveals a risk of developing MS in patients with clinically isolated syndrome [3, 5, 19]. In 2017, cerebrospinal fluid (CSF) is done to look for oligoclonal band and immunoglobulin G (IgG), and a parallel serum sample need to

Oligoclonal band and immunoglobulin G are indicative of intrathecal inflammation which is B cell modulated from plasma cells seen in CNS inflammatory disease [20]. Distinctive CSF analysis will disclose slightly raised leucocyte count, B cells, or plasma cells in cytological analysis and raised IgG synthesis [21]. Oligoclonal band will be highly helpful in the event of other clinical features that are not diagnostic,

• When clinical and MRI evidence is inadequate to make diagnosis of multiple

The Panel on Diagnosis of Multiple Sclerosis [5] cautions diagnosis of multiple sclerosis early on in the disease and in children when OCB is negative in atypical

There are two methods of analysing the CSF for oligoclonal band agarose gel electrophoresis/Coomasie Blue Staining and isoelectric focus/silver staining [22]. Oligoclonal bands are positive in up to 95% of patients with clinically definite

Evoked potentials are electrophysiological tests done to look for evidence of silent lesions [23]. Abnormal or slowing of electrical conduction along the central

• When there are atypical features of clinically isolated syndrome and in population where MS is less common such as children, older individuals, or

be taken as no OCB production is noted in the blood in multiple sclerosis.

and furthermore it depicts dissemination in space. Lumbar puncture is

first clinical assessment is a valuable asset to establishing the diagnosis.

2.6 Symptoms of multiple sclerosis in chronic disease

and angiotensin converting enzyme are necessary [18].

recommended in the following situations [5]:

non-white populations

multiple sclerosis.

44

3.3 Evoked potentials

clinical, radiological, or OCB findings.

sclerosis, especially if treatment is considered

symptoms noted in MS [13].

Multiple Sclerosis

3. Investigations in MS

3.1 Blood investigations

3.2 Lumbar puncture

nervous system pathway can be detected even when there are no obvious clinical features seen. Visual evoked potentials are visual stimulation, which consists high contrast black and white checkerboard where these squares, are changed places and response to this reversal is recorded. Delayed waveform depicts an optic nerve lesion. Brainstem evoked potentials are when auditory stimulations in the form of clicks are given for a response obtained from the brainstem. It assesses lower brainstem auditory pathway. The BAEP are abnormal when demyelination involves brainstem. Somatosensory evoked potentials are obtained when stimulation from the peripheral nerves in the upper limbs produces a response. An abnormal response could translate to demyelination within the central fibres of dorsal column-medial lemniscal pathways. Evoked potentials may not be useful with advances in MRI techniques and oligoclonal band, and they have not been included in McDonald criteria 2017.

## 3.4 Magnetic resonance imaging

Magnetic resonance imaging (MRI) is a neuroimaging of choice for diagnosis of MS and plays a key role in research, surveillance, and treatment. Although the McDonald criteria denote that two clinical attacks depicting dissemination in time and space are sufficient to make a diagnosis, neurologists and neurologist with interest in MS would require a baseline MRI to confirm diagnosis and for surveillance. White matter lesions in the MRI are characteristic with typical juxtacortical, cortical; periventricular, brainstem and spinal cord lesions are required. MRI protocols used in MS are spin echo T2 weighted, fluid-attenuated inversion recovery. The Consortium of MS Centres revised and updated guidelines for MRI ([24], ww.mscare.org/mri).

## 3.4.1 MRI protocols adapted from the Consortium of MS Centers

Baseline studies for patients with a clinically isolated syndrome (CIS) and/or suspected MS:


Timing of a follow-up brain MRI protocol for patients with a CIS and/or suspected MS to look for evidence of dissemination in time (i.e. new T2 lesions or gadolinium-enhancing lesions):


## Multiple Sclerosis

Timing of brain MRI protocol for patients with an established diagnosis of MS:

• No recent prior imaging available (e.g. patient with established diagnosis of MS and new to your clinical practice)

5.1 Neuromyelitis optica spectrum disorder

DOI: http://dx.doi.org/10.5772/intechopen.85258

Diagnosis of Multiple Sclerosis

Diagnostic criteria for NMOSD[30].

1. At least one core clinical characteristic

assay strongly recommended)

3. Exclusion of alternative diagnoses

with LETM, or area postrema syndrome

testing unavailable

1. Optic neuritis

2. Acute myelitis

and vomiting

AQP4-IgG status:

47

6.Exclusion of alternative diagnoses

Core clinical characteristics:

4.Acute brainstem syndrome

NMOSD-typical diencephalic MRI lesions

Diagnostic criteria for NMOSD with AQP4-IgG

harmful.

Neuromyelitis optica spectrum disorder is often considered as a differential of MS. It was considered as a part and spectrum of Multiple sclerosis, till Aquaporin 4 antibody serum antibodies [28, 29] that target the water channel aquaporin 4 was considered in the pathogenesis of NMOSD. It is essential to differentiate multiple sclerosis and NMOSD as the treatment differs in both, and some treatment could be

2. Positive test for AQP4-IgG using best available detection method (cell-based

Diagnostic criteria for NMOSD without AQP4-IgG or unknown AQP4-IgG status:

1. At least two core clinical characteristic occurring as a result of one or more

2. At least one core clinical characteristic must be optic neuritis, acute myelitis

5. Negative test for AQP4-IgG using the best available detection method or

3. Area postrema syndrome: episode of otherwise unexplained hiccups or nausea

5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with

Symptomatic cerebral syndrome with NMOSD-typical brain lesions Additional MRI requirements for NMOSD without AQP4-IgG or unknown

clinical attacks and meeting all of the following requirement:

3. Dissemination in space (two or more core clinical characteristics)

4.Fulfilment of additional MRI requirements, as applicable


## 4. Diagnosis of MS with McDonald criteria

The International Panel on Diagnosis of Multiple Sclerosis consists of 30 members of European, American, and Asian representatives who are experts in their field, met in 2016 and 2017 to revise and formulate a new guideline based on advances on MS. The criteria are to be used only in the setting of clinically isolated syndrome to diagnose MS and progressive MS [5].

#### 4.1 Optical coherence tomography

Optical coherence tomography (OCT) is a noninvasive cross-sectional imaging in biological systems [26]. OCT assesses the peripapillary area of the retina. Retinal nerve fibre layer and ganglion cell layer thickness loss affects visual function, disability, and magnetic resonance imaging. OCT angiography is a new technique under study in MS [27]. Retinal nerve fibre thinning is seen in multiple sclerosis, and OCT is able to measure the loss. Fundoscopy is the clinical parallel of OCT.

## 5. Common differential diagnosis

Clinicians should bear in mind multiple sclerosis mimickers to ensure there is no other possible explanation. Common differentials are connective tissue disease such as systemic lupus erythematosus and antiphospholipid antibody syndrome. Neuromyelitis optical spectrum disorder, which was previously known as Devic's disease, is an immune-mediated disorder that can be distinguished, from MS by typical MRI lesions and/or anti-aquaporin 4 antibody. Other conditions are acute disseminated meningoencephalitis, small vessel disease, and Susac's syndrome.

Timing of brain MRI protocol for patients with an established diagnosis of MS:

• Prior to starting or switching disease-modifying therapy

of MS and new to your clinical practice)

establish a new baseline on the new therapy

(gadolinium-based contrast recommended)

4. Diagnosis of MS with McDonald criteria

syndrome to diagnose MS and progressive MS [5].

4.1 Optical coherence tomography

5. Common differential diagnosis

46

• Postpartum to establish a new baseline

Multiple Sclerosis

• No recent prior imaging available (e.g. patient with established diagnosis

• Approximately 6–12 months after switching disease-modifying therapy to

subclinical disease activity (i.e. new T2 lesions or gadolinium-enhancing lesions). Less frequent MRI scans required in clinically stable patients after 2–3 years of stable treatment (gadolinium-based contrast optional)

• Unexpected clinical deterioration or reassessment of original diagnosis

• The use of gadolinium-based contrast agents is helpful but not essential for detecting subclinical disease activity because new T2 MS lesions can be identified on well-performed standardized MR imaging unless there is a large T2 lesion burden, which may obscure new T2 lesion activity.

The International Panel on Diagnosis of Multiple Sclerosis consists of 30 members of European, American, and Asian representatives who are experts in their field, met in 2016 and 2017 to revise and formulate a new guideline based on advances on MS. The criteria are to be used only in the setting of clinically isolated

Optical coherence tomography (OCT) is a noninvasive cross-sectional imaging in biological systems [26]. OCT assesses the peripapillary area of the retina. Retinal nerve fibre layer and ganglion cell layer thickness loss affects visual function, disability, and magnetic resonance imaging. OCT angiography is a new technique under study in MS [27]. Retinal nerve fibre thinning is seen in multiple sclerosis, and OCT is able to measure the loss. Fundoscopy is the clinical parallel of OCT.

Clinicians should bear in mind multiple sclerosis mimickers to ensure there is no other possible explanation. Common differentials are connective tissue disease such

as systemic lupus erythematosus and antiphospholipid antibody syndrome. Neuromyelitis optical spectrum disorder, which was previously known as Devic's disease, is an immune-mediated disorder that can be distinguished, from MS by typical MRI lesions and/or anti-aquaporin 4 antibody. Other conditions are acute disseminated meningoencephalitis, small vessel disease, and Susac's syndrome.

• Every 1–2 years while on disease-modifying therapy to assess for

## 5.1 Neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder is often considered as a differential of MS. It was considered as a part and spectrum of Multiple sclerosis, till Aquaporin 4 antibody serum antibodies [28, 29] that target the water channel aquaporin 4 was considered in the pathogenesis of NMOSD. It is essential to differentiate multiple sclerosis and NMOSD as the treatment differs in both, and some treatment could be harmful.

Diagnostic criteria for NMOSD[30]. Diagnostic criteria for NMOSD with AQP4-IgG


Diagnostic criteria for NMOSD without AQP4-IgG or unknown AQP4-IgG status:


Symptomatic cerebral syndrome with NMOSD-typical brain lesions Additional MRI requirements for NMOSD without AQP4-IgG or unknown AQP4-IgG status:

	- Requires brain MRI showing
	- Normal findings or only nonspecific white matter lesions, OR
	- Optic nerve MRI with T2-hyperintense lesion, or T1-weighted gadolinium-enhancing lesion extending over 1/2 optic nerve length or involving optic chiasm

## 5.2 MOG antibody disease

Seronegative NMOSD patients have been associated with MOG antibody disease, which is a myelin oligodendrocyte glycoprotein and which is found only in the central nervous system. Myelin oligodendrocyte glycoprotein is a small part of myelin [31]. MOG can be found in extracellular surface of myelin sheaths and oligodendrocytes. MOG antibodies were seen in several demyelinating diseases of the central nervous system disorders [32, 33]. MOG antibody disease tends to favour women, which is one third of patients (Figure 1).

B-cell activation is the strongest element seen in central nervous system of multiple sclerosis patients. Central nervous system-directed antibodies are produced in the periphery in neuromyelitis optica and myelin oligodendrocyte glycoprotein antibody disease. MRZ reaction is antibodies against measles, rubella, and varicella zoster (Tables 1–3).

demyelinating disorders of the CNS to clarify the terminology for demyelination disease, and this was further updated in 2013 [38]. ADEM criteria require the

Biomarkers in Multiple sclerosis, Neuromyelitis Optica Spectrum Disorder and MOG antibody disease. MRZ

ii. Encephalopathy that cannot be explained by fever is present

reaction are antibodies against measles, rubella and varicella zoster. (Adapted from [34]).

i. A first polyfocal clinical neurological event with presumed inflammatory cause

iii. No new clinical or radiological evidence of a new event suggestive of ADEM

i. A new onset of ADEM in 3 or more months after the primary event

ii. A new onset or reappearance of ADEM linked to previous clinical or

ADEM should be a diagnosis of exclusion and should be differentiated from

radiological event involving the central nervous system

multiple sclerosis from its clinical and radiological profile.

iii. Time of symptom onset in relation to steroids has no relevance

following:

49

Figure 1.

Monophasic ADEM:

Diagnosis of Multiple Sclerosis

DOI: http://dx.doi.org/10.5772/intechopen.85258

after 3 months

Multiphasic ADEM

## 5.3 Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is a central nervous systemdemyelinating disease predominantly involving children and young adults. It has been noted in adults and elderly; it follows vaccination and postinfectious state. It is commonly monophasic and rarely multiphasic in nature, and it can involve the brain, spinal cord, and optic nerves as in multiple sclerosis. Fever, malaise, myalgias, headache, nausea, and vomiting can precede neurological symptoms of ADEM, which can begin 4–21 days after the antecedent event. Clinical features of ADEM are the development of a focal or multifocal neurological disorder which could be encephalopathy, coma, and focal and multifocal neurological signs like hemiparesis, cranial nerve palsies, paraparesis, meningismus, ataxia, movement disorders, and seizure [36]. The International Paediatric Multiple Sclerosis Study Group (IPMSSG) [37] proposed consensus definitions for paediatric-acquired

#### Figure 1.

• Acute optic neuritis

Multiple Sclerosis

acute myelitis

lesions

lesions.

patients (Figure 1).

48

varicella zoster (Tables 1–3).

5.3 Acute disseminated encephalomyelitis

5.2 MOG antibody disease

• Requires brain MRI showing

involving optic chiasm

• Normal findings or only nonspecific white matter lesions, OR

• Optic nerve MRI with T2-hyperintense lesion, or T1-weighted

gadolinium-enhancing lesion extending over 1/2 optic nerve length or

• Acute myelitis: requires associated intramedullary MRI lesion extending over three or more contiguous segments (LETM) OR three or more contiguous segments of focal spinal cord atrophy in patients with history compatible with

• Area postrema syndrome: requires associated dorsal medulla/area postrema

• Acute brainstem syndrome: requires associated periependymal brainstem

Seronegative NMOSD patients have been associated with MOG antibody disease, which is a myelin oligodendrocyte glycoprotein and which is found only in the central nervous system. Myelin oligodendrocyte glycoprotein is a small part of myelin [31]. MOG can be found in extracellular surface of myelin sheaths and oligodendrocytes. MOG antibodies were seen in several demyelinating diseases of the central nervous system disorders [32, 33]. MOG antibody disease tends to favour women, which is one third of

B-cell activation is the strongest element seen in central nervous system of multiple sclerosis patients. Central nervous system-directed antibodies are produced in the periphery in neuromyelitis optica and myelin oligodendrocyte glycoprotein antibody disease. MRZ reaction is antibodies against measles, rubella, and

Acute disseminated encephalomyelitis (ADEM) is a central nervous systemdemyelinating disease predominantly involving children and young adults. It has been noted in adults and elderly; it follows vaccination and postinfectious state. It is commonly monophasic and rarely multiphasic in nature, and it can involve the brain, spinal cord, and optic nerves as in multiple sclerosis. Fever, malaise, myalgias, headache, nausea, and vomiting can precede neurological symptoms of ADEM, which can begin 4–21 days after the antecedent event. Clinical features of ADEM are the development of a focal or multifocal neurological disorder which could be encephalopathy, coma, and focal and multifocal neurological signs like hemiparesis, cranial nerve palsies, paraparesis, meningismus, ataxia, movement disorders, and seizure [36]. The International Paediatric Multiple Sclerosis Study Group (IPMSSG) [37] proposed consensus definitions for paediatric-acquired

Biomarkers in Multiple sclerosis, Neuromyelitis Optica Spectrum Disorder and MOG antibody disease. MRZ reaction are antibodies against measles, rubella and varicella zoster. (Adapted from [34]).

demyelinating disorders of the CNS to clarify the terminology for demyelination disease, and this was further updated in 2013 [38]. ADEM criteria require the following:

Monophasic ADEM:


Multiphasic ADEM


ADEM should be a diagnosis of exclusion and should be differentiated from multiple sclerosis from its clinical and radiological profile.


Proton density STIR2

Axial T2/T2\* through lesions

Post-gad T14 (sag, axial)

acquisition gradient echo or MP-RAGE; turbo field echo or TFE

Sagittal: <3 mm, no gap. Axial: <5 Mm, no gap

Axial T2/T2\* entire cervical cord 3D IR-Prep GE5 T1

4. No additional gadolinium necessary if cord examination immediately follows gadolinium-

5. IR-Prep GE (inversion recovery-prepared gradient echo); magnetization-prepared rapid

• May be clinically indicated to confirm optic neuritis and rule out compressive lesions • Recommended sequences include coronal STIR or fat-suppressed T2 and a post-gadolinium fatsuppressed T1 with a section thickness of ≤2 Mm, with coverage to include the optic chiasm • Optional sequences may include axial/coronal pre-gadolinium fat-sat T1, axial fat-sat T2 or STIR,

The clinician should provide on the request for the standardized MRI brain and/or spinal cord protocol:

1. Thoracic and conus coverage recommended if symptoms localize to this region to rule out an

T1-PSIR3

DOI: http://dx.doi.org/10.5772/intechopen.85258

Slice thickness and

Diagnosis of Multiple Sclerosis

Additional sequences Sagittal T1

alternate diagnosis

enhanced brain MRI

Protocol 4: Orbit MRI protocol

MRI requisition:

MRI report:

Scan

Radiol 2017). Recommendations:

Table 1.

51

Portable digital media

MRI protocols (Adapted from [25]).

and axial post-gad fat-sat T1 Recommendations for communication

\*Monitoring for management decision

1. Description of findings

• Clinical questions to be addressed \*diagnosis

• Relevant clinical history and physical examination findings

Standardised nomenclature/terminology should be used and include:

• If known, date and place of previous examinations

space or dissemination in time criteria

\*Studies should be stored in a DICOM format.

• Current MS disease-modifying treatment and JC virus status if on natalizumab

• \*Lesion type, location, size, shape, character, number for diagnostic

• \*CIS diagnostic scan: whether meets current MRI dissemination in

2. MS monitoring or CIS follow-up: comparison with previous studies (new lesions, atrophy) 3. Interpretation (typical for MS, atypical for MS, not MS) and differential diagnosis, if appropriate Note: structured reports can be helpful (Alessandrino et al., Ajr, 2018; Dickerson et al., J Am Coll

• \*Qualitative assessment of T2 and brain volume/atrophy

\*Copies of MRI studies should be retained permanently and be available. \*It is strongly recommended for patients to keep their own studies on

2. Short tau inversion recovery (STIR) 3. Phase-sensitive T1 inversion recovery (PSIR)

gap

Axial proton density

1. 3D acquisition should be isotropic ≤1 1 1 mm



Protocol 1: Standardised brain MRI protocol (diagnosis and routine follow-up of MS)

Scan prescription Use the subcallosal plane to prescribe or reformat axial oblique slices

Additional sequences Susceptibility-weighted imaging (SWI). Pre-gad 2D/3D axial T1

4. Inversion recovery-prepared gradient echo (IR-Prep GE); magnetization-prepared rapid

Field strength Scans should be of good quality, with adequate signal-noise ratio (SNR) and resolution (in-slice pixel resolution of ≤1 1 mm) Scan prescription Use the subcallosal plane to prescribe or reformat axial oblique slices

Pre-gad 2D/3D axial T1. Axial proton density

< 3 mm, no gap (for 2D acquisition or 3D reconstruction)

1. Typical PML lesions may appear hyperintense on FLAIR, hypointense on T1, and high signal

5. Inversion recovery-prepared gradient echo (IR-Prep GE); magnetization-prepared rapid

Field strength Scans should be of good quality, with adequate signal-noise ratio (SNR) and resolution (in-slice pixel resolution of ≤1 1 mm)

5. Single dose of gadolinium-based contrast agent as required (note that the FLAIR Or T2 may be performed during the 5-minute minimum delay after gadolinium injection before acquiring the

Core sequences 2D/3D sagittal and Axial FLAIR1,2. 2D/3D axial T21

Post-gad 2D/3D axial T1

acquisition gradient echo or MP-RAGE; turbo field echo Or TFE

Core sequences1 2D/3D sagittal and axial FLAIR2 axial 2D DWI3

Post-gad 2D/3D axial T1

2D/3D axial T2 3D IR-Prep GE5 T1

2. Fluid attenuated inversion recovery (FLAIR) 3. Diffusion-weighted imaging (DWI)

4. Less than 50% of PML lesions will show contrast enhancement

acquisition gradient echo or MP-RAGE; turbo field echo or TFE

Axial 2D DWI3 3D IR-Prep GE4 T1

1. 3D acquisition should be isotropic ≤1 1 1 mm 2. Fluid attenuated inversion recovery (FLAIR) 3. Diffusion-weighted imaging (DWI)

Protocol 2: PML surveillance brain MRI protocol

Coverage Whole brain coverage

Coverage Whole brain coverage

Slice thickness and

Multiple Sclerosis

Gadolinium5 (as required)

Axial proton density

Gadolinium (can be helpful) 4

Slice thickness and

gap

50

Additional sequences DWI

intensity on DWI

Protocol 3: Spinal cord MRI protocol

Coverage Cervical cord coverage1

Core sequences Two of the following: sagittal T2

post-gadolinium T1)

gap

Field strength Scans should be of good quality, with adequate signal-noise ratio (SNR) and spatial resolution (in-slice pixel resolution of ≤1 1 mm)

≤ 3 mm, no gap (for 2D acquisition Or 3D1 reconstruction)


#### Table 1.

MRI protocols (Adapted from [25]).

6. Conclusion

Diagnosis of Multiple Sclerosis

DOI: http://dx.doi.org/10.5772/intechopen.85258

Table 3.

Author details

53

Joyce Pauline Joseph

Department of Neurology, Hospital Kuala Lumpur, Malaysia

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: jpjmy@yahoo.com

provided the original work is properly cited.

Multiple sclerosis can be challenging to make a diagnosis unless a clinician is familiar with the disease. No better explanation for the condition is essential to come to a conclusion regarding the diagnosis. A good history, elaborate and extensive clinical examination, lumbar puncture, magnetic resonance examination, and blood investigations are required. The McDonald criteria have facilitated the diagnosis of multiple sclerosis for precision and allowing earlier diagnosis.

Features of MOG antibody disease, NMOSD and MS. (Adapted from [34]).


#### Table 2. McDonald criteria 2017.

## 5.4 Antiphospholipid antibody syndrome

The antiphospholipid syndrome (APS) is a systemic autoimmune disorder with arterial and venous thromboses; recurrent foetal loss, often accompanied by thrombocytopenia; raised antiphospholipid antibodies, namely, lupus anticoagulant; and anticardiolipin antibodies [39]. Common presentations that can mimic MS are stroke-like presentations such as transient ischemic attack, ischemic stroke, venous thrombosis, epilepsy, headache, movement disorder, transverse myelitis, cognitive impairment, and other neuropsychiatric manifestations.

## 5.5 Systemic lupus erythematous

Systemic lupus erythematous is an autoimmune condition that is frequency associated with neuropsychiatric manifestations and neurological deficit [13].


#### Table 3.

Features of MOG antibody disease, NMOSD and MS. (Adapted from [34]).

## 6. Conclusion

Multiple sclerosis can be challenging to make a diagnosis unless a clinician is familiar with the disease. No better explanation for the condition is essential to come to a conclusion regarding the diagnosis. A good history, elaborate and extensive clinical examination, lumbar puncture, magnetic resonance examination, and blood investigations are required. The McDonald criteria have facilitated the diagnosis of multiple sclerosis for precision and allowing earlier diagnosis.

## Author details

Joyce Pauline Joseph Department of Neurology, Hospital Kuala Lumpur, Malaysia

\*Address all correspondence to: jpjmy@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

5.4 Antiphospholipid antibody syndrome

5.5 Systemic lupus erythematous

manifestations.

52

Table 2.

McDonald criteria 2017.

Multiple Sclerosis

The antiphospholipid syndrome (APS) is a systemic autoimmune disorder with

that can mimic MS are stroke-like presentations such as transient ischemic attack, ischemic stroke, venous thrombosis, epilepsy, headache, movement disorder, transverse myelitis, cognitive impairment, and other neuropsychiatric

Systemic lupus erythematous is an autoimmune condition that is frequency associated with neuropsychiatric manifestations and neurological deficit [13].

arterial and venous thromboses; recurrent foetal loss, often accompanied by thrombocytopenia; raised antiphospholipid antibodies, namely, lupus anticoagulant; and anticardiolipin antibodies [39]. Common presentations

## References

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[2] Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Annals of Neurology. Mar 1983;13(3):227-231

[3] Polman CH, Reingold SC, Edan G, Filippi M, Hartung H-P, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the 'McDonald criteria. Annals of Neurology. 2005;58(6): 840-846. CiteSeerX 10.1.1.604.2677. DOI: 10.1002/ana.20703. PMID 16283615

[4] Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology. 2011;69(2): 292-302. DOI: 10.1002/ana.22366. PMC: 3084507. PMID: 21387374

[5] Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurology. 2018;17(2):162-173

[6] Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014;83(3):278-286

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[8] Hickman SJ, Dalton CM, Miller DH. Management of acute optic neuritis. Lancet. 2002;360:1953-1962

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disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein. Journal of

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[34] Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, Pitarokoili K, et al.

MOG-IgG in NMO and related

202:473-477

Jun 19

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[23] Walsh P, Kane N, Butler S. The clinical role of evoked potentials. Journal of Neurology, Neurosurgery, and Psychiatry. 2005 Jun;76(Supp. 2):

[24] Traboulsee A, Simon JH, Stone L, et al. Revised recommendations of the consortium of MS centers task force for a standardized MRI protocol and clinical guidelines for the diagnosis and follow-

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[10] Soderstrom M. Optic neuritis and multiple sclerosis. Acta Ophthalmologica Scandinavica. 2001; 79:223-227

[11] Optic Neuritis Study Group. The clinical profile of optic neuritis: Experience of the Optic Neuritis Treatment Trial. Archives of Ophthalmology. 1991;109:1673-1678

[12] Lee AG, Brazis PW. Clinical Pathways in Neuro-Ophthalmology: An Evidence-Based Approach. New York: Thieme Medical Publishers; 2003

[13] Compston A, McDonald I, Noseworthy J, Lassmann H, Miller D, Smith K, et al. McAlpine's Multiple Sclerosis. 4th ed2005

[14] Swingler RJ, Compston DA. The morbidity of multiple sclerosis. The Quarterly Journal of Medicine. 1992; 83(300):325-337

[15] Godin D. Multiple Sclerosis and Related Disorders, 3rd Series. Vol. 1222014. Copyright: © Elsevier 2014. eBook ISBN: 9780444633095

[16] Wilkins A. Cerebellar dysfunction in multiple sclerosis. Frontiers in Neurology. 2017;8:312. DOI: 10.3389/ fneur.2017.00312. Recollection 2017

[17] Alusi SH, Worthington J, Glickman S. Bain PG A study of tremor in multiple sclerosis. Brain. 2001;124(Pt. 4):720-730

[18] nationalmssociety.org

[19] McDonald WI, Compston A, Edan G, Goodkin D, Hartung H-P, Lublin FD, Diagnosis of Multiple Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.85258

et al. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis. Annals of Neurology. 2001;50(1):121-127

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Multiple Sclerosis

552-568

16283615

[1] Schumacher GA, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, McDowell F, et al. Problems of experimental trials of therapy In multiple sclerosis: Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Annals of the New York Academy of Sciences. 1965;122:

[9] Beck RW, Cleary PA, Anderson MM.

corticosteroids in the treatment of acute optic neuritis. The New England Journal

[10] Soderstrom M. Optic neuritis and

Ophthalmologica Scandinavica. 2001;

[11] Optic Neuritis Study Group. The clinical profile of optic neuritis: Experience of the Optic Neuritis Treatment Trial. Archives of

Ophthalmology. 1991;109:1673-1678

Pathways in Neuro-Ophthalmology: An Evidence-Based Approach. New York: Thieme Medical Publishers; 2003

[12] Lee AG, Brazis PW. Clinical

[13] Compston A, McDonald I, Noseworthy J, Lassmann H, Miller D, Smith K, et al. McAlpine's Multiple

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[15] Godin D. Multiple Sclerosis and Related Disorders, 3rd Series. Vol. 1222014. Copyright: © Elsevier 2014.

[16] Wilkins A. Cerebellar dysfunction in multiple sclerosis. Frontiers in Neurology. 2017;8:312. DOI: 10.3389/ fneur.2017.00312. Recollection 2017

[17] Alusi SH, Worthington J, Glickman S. Bain PG A study of tremor in multiple sclerosis. Brain. 2001;124(Pt. 4):720-730

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eBook ISBN: 9780444633095

[18] nationalmssociety.org

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83(300):325-337

A randomized controlled trial of

of Medicine. 1992;326:581-588

multiple sclerosis. Acta

79:223-227

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[4] Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology. 2011;69(2): 292-302. DOI: 10.1002/ana.22366. PMC:

[5] Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurology. 2018;17(2):162-173

[6] Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014;83(3):278-286

[8] Hickman SJ, Dalton CM, Miller DH. Management of acute optic neuritis.

[7] Balcer LJ. Clinical practice. Optic neuritis. The New England Journal of Medicine. 2006;354(12):

Lancet. 2002;360:1953-1962

1273-1280

54

3084507. PMID: 21387374

[20] Gastaldi M. Cerebrospinal fluid analysis and the determination of oligoclonal bands. Neurological Sciences. 2017;38(Supp. 2): 217-224. DOI: 10.1007/s10072-017- 3034-2

[21] Stangel M, Fredrikson S, Meinl E, Petzold A, Stüve O, Tumani H. The utility of cerebrospinal fluid analysis in patients with multiple sclerosis. Nature Reviews. Neurology. 2013;9(5):267-276. DOI: 10.1038/nrneurol.2013.41. Epub 2013 Mar 26

[22] Davenport RD, Keren DF. Oligoclonal bands in cerebrospinal fluids: Significance of corresponding bands in serum for diagnosis of multiple sclerosis. Clinical Chemistry. 1988; 34(4):764-765

[23] Walsh P, Kane N, Butler S. The clinical role of evoked potentials. Journal of Neurology, Neurosurgery, and Psychiatry. 2005 Jun;76(Supp. 2): ii16-ii22

[24] Traboulsee A, Simon JH, Stone L, et al. Revised recommendations of the consortium of MS centers task force for a standardized MRI protocol and clinical guidelines for the diagnosis and followup of multiple sclerosis. AJNR. American Journal of Neuroradiology. 2016;37(3):394-401

[25] Consortium of MS Centers MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-up of MS. 2018. REVISED GUIDELINES. www.mscare. org/mri

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[27] Britze J, Frederiksen JL. Optical coherence tomography in multiple sclerosis. Eye (Lond). 2018;32:884-888. DOI: 10.1038/s41433-017-0010-2

[28] Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet. 2004;364:2106-2112

[29] Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. The Journal of Experimental Medicine. 2005; 202:473-477

[30] Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. DOI: 10.1212/ WNL.0000000000001729. Epub 2015 Jun 19

[31] Johns TG, Bernard CC. The structure and function of myelin oligodendrocyte glycoprotein. Journal of Neurochemistry. 1999;72(1):1-9

[32] Baumann M, Sahin K, Lechner C, et al. Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein. Journal of Neurology, Neurosurgery, and Psychiatry. 2015;86:265-272

[33] Zhou D, Srivastava R, Nessler S, et al. Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:19057-19062. [PMC free article] [PubMed]

[34] Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, Pitarokoili K, et al. MOG-IgG in NMO and related

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Section 4

Mental Decline in MS

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