MS for Medical Students (PDF)

# Multiple Sclerosis and related disorders ## Dr Majed Habahbeh MBBS FRCP FRCS ## Multiple (Disseminated) Sclerosis - Pathology - Pathogenesis - Epidemiology/Etiology - Clinical course and stages / Prognosis - Diagnosis/ Differential diagnosis - Approach to treatment/ Disease-modifying therapy/ P...

# Multiple Sclerosis and related disorders ## Dr Majed Habahbeh MBBS FRCP FRCS ## Multiple (Disseminated) Sclerosis - Pathology - Pathogenesis - Epidemiology/Etiology - Clinical course and stages / Prognosis - Diagnosis/ Differential diagnosis - Approach to treatment/ Disease-modifying therapy/ Prognostication ## Pathology * Unique Dual pathology- Inflammation and degeneration * MS is a chronic inflammatory disease of the CNS that leads to focal destruction of myelin, axonal damage and reactive gliosis of astrocytes in the white and grey matter. * MS is characterised by multifocal demyelinating lesions or 'plaques' * Plaques are most commonly seen in the spinal cord, optic nerves, brainstem/cerebellum and periventricular white matter. ## Pathophysiology Multiple sclerosis is an autoimmune disease in which lymphocytes migrate out of lymph nodes into the circulation, cross the blood-brain barrier, and aggressively target putative myelin antigens in the CNS, causing inflammation, demyelination, neuroaxonal injury, astrogliosis, and ultimately neurodegeneration - It is considered an immune-mediated disease in genetically susceptible individuals. - The immune attack is triggered by an environmental agent that is acquired in childhood (<15 yrs). ## Epidemiology - MS is the most common inflammatory demyelinating disease of the CNS and is the most common disabling neurological disease to afflict young adults - The mean age of onset is approximately 30 years. - Almost 70% of patients manifest symptoms between ages 20 and 40. - Disease onset rarely occurs prior to 10 or after 60 years of age. However, patients as young as 3 and as old as 67 years of age have been described - There is clear gender difference with females being more frequently affected than men (2.5:1) ## MS Epidemiology - There is a clear trend towards increased prevalence over the last few decades- according to the MSIF, the global median prevalence of MS increased by 10% in the last 5 years (from 1.8 million in 2008 to 2.5 million in 2017) - This increase is quite gender-specific, and seen mostly in females. - Increasing prevalence is multifactorial.. ## MS Epidemiology- Geographical distribution A world map showing prevalence of MS by country in 2013. The prevalence per 100,000 is shown in the following categories: - **>100** - **60.01-100** - **20.01-60** - **5.01-20** - **0-5** - **Data not provided** ## Factors explaining the rise in MS prevalence - Longer survival - Better/earlier diagnosis due to improved imaging and more sensitive diagnostic criteria - But, there is also an actual increase in incidence of the disease ## Etiology of MS A cartoon displaying a hand holding a gun with the caption "Genetics loads the gun and environment pulls the trigger". To the right is a Venn Diagram showing "Genes", "Environment" and "You" overlapping, and the intersection labelled "Phenotype". ## Genetic factors The incidence of MS in first-degree relatives is 20-40 times higher than in the general population, suggesting the influence of genetic factors on the disease. - Monozygotic twins: 25% concordance - Dizygotic twins: 5% concordance - 1 parent has MS: 2%-4% - Second-degree relative: 1% - Lifetime risk of developing MS: 0.1%-0.2% A graph showing the concordance of MS in identical twins, first-degree relative, second-degree relative, and the general population. ## Triggers of MS - Epstein-Barr virus (EBV) infection - Decreased sun exposure/vitamin D deficiency - Smoking (Active and passive) - High salt intake - High BMI (Diet) - Increased physical and emotional stress? - Improved hygiene - Other viral infections (HPV) "Urbanization and western life-style" ## EBV theory - Exposure to EBV at an early age in children has been linked to reduced incidence of MS, while exposure in the form of infectious mononucleosis later in life (late adolescence) is linked to an increased risk. - EBV prevalence also appears to correlate with the observed differences in MS based on latitude and socioeconomic structure ## MS disease continuum A graph showing a line representing disability progression over time. The y-axis represents disability progression, and the x-axis is years. The line climbs steadily over time forming a plateau at roughly 10 years, before continuing to increase in disability. The different types of MS are shown at the bottom. - **~90%** of patients have relapsing-remitting onset of MS - **~10%** of patients have primary progressive onset of MS - **Relapsing-remitting MS (RRMS)** - **Secondary progressive MS (SPMS) with relapses** - **SPMS without relapses** - **Primary progressive MS (PPMS)** ## Establishing a diagnosis of Relapsing MS - Classically, a diagnosis of relapsing MS is made when a patient exhibits typical inflammatory neurologic episodes (relapses) disseminated in time and space. - Relapses are defined as new or worsening neurologic symptoms that occur in the absence of fever or infection, last over 24 hours, and are preceded by 30 days of relative neurologic stability - No alternative explanation for the episodes A picture of Jean Martin Charcot, 1825-1893, with the quote "To learn how to treat disease, one must learn how to recognize it. The diagnosis is the best trump in the scheme of treatment". ## Clinically Isolated Syndrome - The first clinical presentation of MS. Usually - optic neuritis, or - partial myelitis, or - a brain stem syndrome. - Less commonly a hemispheric presentation or multifocal. ## Common Relapses | Part of CNS affected | Clinical Presentations | |---|---| | Optic nerve | Optic neuritis | | Spinal cord | Numbness/tingling (partial myelitis) <br> Hemi or paraparesis <br> Bowel/bladder dysfunction <br> Lhermitte's sign | | Brain stem | Diplopia/ Internuclear ophthalmoplegia <br> Dizziness/vertigo <br> Trigeminal neuralgia | ## Typical MS-related Acute Optic Neuritis - Unilateral - Onset over few days to 2 weeks - Classic triad of visual loss, periocular pain esp. on moving the eye and dyschromatopsia, - Visual acuity- variable (not very severe) - Relative Afferent Pupillary Defect (RAPD) - Red desaturation - Central visual loss (scotoma) - Good recovery >90% starting within 2-3 weeks - Normal OD in 70% A diagram showing a swinging flashlight test and how to elicit RAPD. ## Brainstem/Cerebellar | MS | Less common | Atypical | |---|---|---| | Internuclear ophthalmoplegia | Facial palsy, facial myokymia | Vascular territory syndrome, e.g., lateral medullary | | Ataxia and multidirectional nystagmus | Deafness | Third nerve palsy | | Sixth nerve palsy | One-and-a-half syndrome | INTERNUCLEAR OPHTHALMOPLEGIA (INO) GAZE TO LEFT SHOWN <br> Right Adduction paresis. <br> Left Abduction nystagmus on left gaze. <br> Anatomic Location: Medial longitudinal fasciculus (MLF) <br> Etiology: Young patient - Multiple Sclerosis <br> Older patient - Ischemia | | Facial numbness | Trigeminal neuralgia | Progressive trigeminal sensory neuropathy | | Paroxysmal tonic spasms | Focal dystonia, torticollis | A labeled diagram showing eyes with Internuclear Ophthalmoplegia. ## William Osler A picture of William Osler, 1825-1893, with the quotes: - To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all - The value of experience is not in seeing much, but in seeing wisely ## Video-24-year-old girl 1 week hx of double vision A close-up picture of a young woman's eyes, showing a slight widening of the palpebral fissure and a subtle divergence of the eyes to the left. ## 3 weeks later after IV Methylprednisolone A close-up picture of the same young woman's eyes, showing her eyes are now straight. ## MS symptoms (not relapses) Residual symptoms from previous relapses or non-relapse-related symptoms: - Fatigue - Pain, spasticity, spasms, Ataxia - Uhthoff's phenomenon- Pseudorelapses - Depression, anxiety, rarely psychosis - Bladder dysfunction - Seizures - Memory problems, cognitive issues ## Para-clinical tests | | Blood tests to exclude other diseases |---|---| | MRI | Normal systemic inflammatory markers (ESR, CRP). | | CSF | Autoantibodies (Low-titre ANA may occur) | | Visual-evoked potentials | | | Other evoked potential (Brainstem,auditory, somato-sens ory) | Vasculitis screen, B12, TFT, LFT, serum ACE/CXR | | Specialized blood/CSF biomarkers (Neurofilament Light) | | ## Frequencies of abnormal CSF variables in clinically definite MS - Oligoclonal IgG bands >95% by isoelectric focusing technique - Increased IgG index 75% - Increased WBC count > 5 cells in 1/3 of patients (very rarely > 35) - Mildly increased protein in 1/2 of patients (very rarely> 70) - If protein >100 and/or low glucose unlikely to be MS A diagram showing a protein electrophoresis (immunofixation) for CSF and Plasma in both normal and abnormal cases. The normal CSF shows no oligoclonal bands for IgG, whilst the abnormal sample does show bands. ## MS brain lesion characteristics | | | |---|---| | Lesion configuration | ovoid (round shape) | | Size of lesions | > punctate | | Typical lesion location | periventricular, juxtacortical, infratentorial | | Lesion pattern | random, asymmetric | | Tissue destruction | variable | | Contrast enhancement | frequent | A series of four images showing a coronal MRI of the brain: * The top left image shows a coronal T2-weighted MRI of the brain demonstrating multiple hyperintense lesions in the periventricular white matter. * The top right image is a coronal FLAIR (fluid-attenuated inversion recovery) MRI of the brain showing multiple hyperintense lesions in the periventricular white matter. * The bottom left image is a coronal T1-weighted MRI of the brain, with contrast, showing multiple enhancing lesions in the periventricular white matter. * The bottom right image shows a coronal T2-weighted MRI of the brain demonstrating multiple hyperintense lesions in the periventricular white matter. ## MS spinal cord lesion characteristi - Cigar shaped (in sagittal plane) - Extension < 2 vertebral bodies in length and < 1½ spinal cord diameter - Eccentric location - Mass effect rare - Cervical cord and posterior columns preferentially affected - No incidental age-related / vascular spinal cord lesions Three sagittal images taken at different levels of the cervical and thoracic spinal cord. - The top image shows a sagittal T2-weighted MRI of the cervical spinal cord demonstrating a hyperintense lesion in the posterior portion of the spinal cord. - The middle image shows a sagittal T2-weighted MRI of the thoracic spinal cord demonstrating a hyperintense lesion in the posterior portion of the spinal cord. - The bottom image shows a sagittal T2-weighted MRI of the cervical spinal cord demonstrating a hyperintense lesion in the posterior portion of the spinal cord. ## Differential Diagnosis - Excluding diseases that can mimic MS clinically or radiologically is very important and can be very challenging ## Differential Diagnosis - MS is the most common primary demyelinating disease of the CNS, but other other primary demyelinating disorders should be considered - Acute Disseminated Encephalomyelitis (ADEM) - Neuromyelitis Optica/NMO spectrum disorder (Devic's disease) - Myelin Oligodendrocyte Glycoprotein-associated Demyelination (MOGAD) ## ADEM Six images showing a coronal T2-weighted MRI of the brain demonstrating multiple hyperintense lesions, both in the periventricular and subcortical white matter and the grey matter. - The image is labelled "Acute disseminated encephalomyelitis (ADEM)". ## NMOSD A series of images showing a sagittal T2-weighted MRI of the spine showing multiple hyperintense lesions spanning multiple segments of the spinal cord. The fourth image shows a series of four axial images from the brainstem, demonstrating a hyperintense lesion in the area postrema. The images are labelled: A, B and C for the spine, and D for the brainstem. - The image is labelled "Area Postrema Lesions". ## MOGAD - Optic nerve - Spinal cord - Brain The image shows numerous axial and coronal MRI images of the brain, spinal cord, and optic nerve. - Examples of both contrast and non-contrast T2-weighted images. - Examples of both T1-weighted and post-gadolinium contrast images. ## Demyelination Secondary to systemic disease Ischemic/inflammatory... - Non-specific Age-related WM changes- UBO's ! - Small vessel disease - Migraine - Vasculitis (SLE, APLA syndrome, Sjogren's, Behcet's - Infection (Lyme disease) - Sarcoidosis, Susac's syndrome - B12 deficiency/ Hyperhomocystine A coronal T2-weighted MRI image is shown, with evidence of numerous periventricular hyperintensities at the level of the thalamus. A second image, labeled "A", shows a coronal FLAIR image, with slightly more subcortical lesions than the T2-weighted image. ## Behcet's Disease - A multi-system recurrent inflammatory disorder of unknown etiology - strongly associated with HLA-B51 haplotype - Variable vessel vasculitis (VVV) - Can affect vessels of any size (small, medium, and large) - Any type (arteries, veins, and capillaries). - Also called the "Silk Road Disease" A coronal T2-weighted MRI image is shown, with evidence of numerous hyperintense lesions and infarction, consistent with multifocal infarction. A second image, labeled "b", shows a photo of Hulusi Behcet 1889-1948. ## Silk Trading Routes A map of the world showing routes consistent with the silk trading routes, with the highlighted areas showing the distribution of the HLA-B51 gene. The caption below reads “Homo sapiens sapiens migrated to the inhabited world between 300,000 and 30,000 years ago. HLA-B51 gene frequency in controls: >15% 10-15% 5-10% <5% 0%”. ## Frequency Comments A table showing the frequency and comments for various clinical manifestations of Behçet's disease. It shows frequencies for: - Oral ulcers - Genital ulcers - Genital scar - Papulopustular lesions - Erythema nodosum - Pathergy reaction - Uveitis - Arthritis - Subcutaneous thrombophlebitis - Deep vein thrombosis - Arterial occlusion (aneurysm) - Epididymitis - Gastrointestinal lesions A photo is also shown of the mouth of a patient with Behçet's disease, showing a small ulcer on the lower lip. ## Video A short video showcasing a young woman with internuclear ophthalmoplegia. ## Management - Treatment of relapses - Prevention of relapses / disability (Disease-Modifying Therapy) - Symptomatic treatment. - Rehabilitation A picture of a couple, one old man and one old woman, sat outside drinking tea together. ## Relapses - New focal neurological symptoms/signs lasting >24 hrs after at least 1 month of neurological stability - Consider "pseudo-relapses" due to fever, infection, hot weather, emotional stress? (But stress may also trigger true relapses) ## Relapse treatment Faster recovery but no evidence of decreasing residual disability - High-dose steroids - IV/oral Methylprednisolone 1 g daily for 3-5 days - 30-50 % do not respond adequately - ACTH gel (IM or SC) 80 u daily for 5-15 days- more potent immunomodulatory effect but expensive and not available. - Plasma exchange for refractory relapses - IV Immunoglobulins? ## Choosing a Disease-Modifying Drug Moderate-efficacy vs. High-efficacy Therapies A timeline showing the arrival of different MS drugs and therapies, showing: - **1993-2021** - The year of drug approval. The timeline is labelled: “The available treatment arsenal now contains up to 18 drugs. Decades of MS Drug Development” ## The Burden of MS-without treatment Three images are shown of patients with MS, along with a bar graph representing disability progression. - **10 Years*:** An axial T2-weighted MRI of the brain demonstrating multiple hyperintense lesions, both in the periventricular and subcortical white matter and the grey matter. The bar graph shows the average disability progression over 10 years in untreated patients, ending with moderate disability. - **15 Years*:** An elderly man sat in a chair, holding a walking stick. The bar graph shows the average disability progression over 15 years, showing the onset of severe disability. - **25 Years*:** An elderly woman sat in a wheelchair. The bar graph shows the average disability progression over 25 years, showing a steep increase in disability as the patient becomes confined to a wheelchair. The caption below the images reads: (*mean time for development*) ## MS and Pregnancy A picture of a camel and its calf. ## Register your attendance A QR code is shown. A bullet points list of instructions below the code reads “Register your attendance with your university number. Make sure that the settings of your phone allow tracking location. Go to settings > privacy> location> services> make sure that location services is ON”