Multiple Sclerosis Management Concepts

Multiple Sclerosis: Concepts and Update on Management

• Multiple Sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system (CNS)
• Etiology is unknown, characterized by demyelination and axonal loss
• Age of onset is typically 20-40
• Females are affected 1.5-3 times more often than males
• MS is the second most common disabling disease in the USA
• Globally, 2.8 million are affected (underestimate)
• Costs range from 9,000to9,000 to 9,000to50,000 USD per patient annually
• High rate of unemployment as disease progresses
• Etiology: Multifactorial, involving genetics, infection, geography, climate, environment, nutrition, and smoking

Geography and Climate

• Increased prevalence away from the equator
• Exceptions exist
• Critical migration age is 14-15
• Those born in November are less affected than those born in May

Epidemiology

• Age 20-40.
• Female:Male is 1.5-3:1

Etiology

• Multifactorial
• Interplay of Genetics-Infection-Geography-Climate-Environmental-Nutrition-Smoking

Genetics

• Susceptibility and protective genes are related to HLA
• Monozygotic twins have a 30% concordance rate
• Dizygotic twins have a 5% concordance rate
• Non-twin siblings have a 2.5% concordance rate
• Treatment response genes and genotype-phenotype relation are mentioned but not detailed

Epstein-Barr Virus Infection

• A longitudinal analysis reveals a high prevalence of Epstein-Barr virus (EBV) associated with multiple sclerosis
• Risk of MS increased 32-fold after EBV infection
• There is not an increased risk after other infections such as cytomegalovirus
• Neurofilament light chain biomarker elevated after EBV seroconversion

EBV Virus Mechanism

• Uncontrolled latency and inflammatory cascade
• Inflammatory B cell and EBNA1 peptides
• CNS trafficking and autoreactivity
• Molecular mimicry

EBV Critical Points

• Infection timing is critical in genetically susceptible individuals
• Age at infection impacts risk

Vitamin D and Multiple Sclerosis

• Vitamin D is an immune modulator and gene regulator
• Supplements are mandatory for MS patients by most experts
• High-dose Vitamin D is safe in certain trials
• Relationship between low Vitamin D levels, increasing lesions, and disability progression is confirmed

Immune-Pathogenesis in MS

• Characterized by an imbalance between immunoregulatory and proinflammatory immune cells

Pathology

• MS starts peripherally, then resides centrally and disables the blood-brain barrier (BBB), starting its destruction

Post-Mortem MS Brain

• MS causes more extensive demyelination of the grey matter than the white matter

MS Plaques

• Occur around veins in the brain and contain both lymphocytes and macrophages

MS Results in Demyelination

• Demyelination occurs in both the brain and spinal cord

Clinical Presentation

• Central: Fatigue, Cognitive Impairment, Depression, Unstable mood
• Visual: Nystagmus, Optic neuritis, Diplopia
• Speech: Dysarthria
• Throat: Dysphagia
• Musculoskeletal: Weakness, Spasms, Ataxia
• Sensation: Pain, Hypoesthesias, Paraesthesias
• Bowel: Incontinence, Diarrhea, Constipation
• Urinary: Incontinence, Frequency, Retention

Optic Neuritis

• Unilateral visual loss
• Red vision affected first
• Pain on eye movement
• Pain typically doesn't last more than two weeks
• Acute Optic Disc Swelling is a sign
• Chronic Optic Disc Pallor is a sign

Brainstem/Cerebellar

• Facial Palsy
• Ataxia
• Diplopia
• Trigeminal neuralgia

Signs in Brain Stem Syndrome

• Nystagmus: Description of eye movement
• One-and-a-half syndrome: Description of eye movement
• Ataxia: Description of body movement

Symptoms - Spinal Cord

• Lhermitte's symptom
• Numbness
• Urinary Urgency
• Faecal Incontinence
• Sexual Dysfunction
• Spastic paraplegia

Signs in Spinal Cord Syndrome

• Weakness
• Increased tone +/- clonus
• Brisk reflexes
• Upgoing plantar response

Signs in Spinal Cord Syndrome (Acute Transverse Myelitis)

• Acute transverse myelitis in MS is usually partial
• Involves more than three adjacent cord segments
• Brown Sequard syndrome is a type of manifestation

Symptoms - Cerebral Hemispheres

• Cognitive impairment
• Hemiparesis
• Seizures
• Encephalopathy

Signs in Cerebral Hemisphere Syndrome

• Description of symptoms on each side of the brain

Acute Attack

• Usually more than 24 hours
• Subacute presentation
• Optic neuritis, acute transverse myelitis, brainstem and cerebellar syndromes, and pyramidal syndromes

Course of MS

• Multifocal inflammation of brain and spinal cord
• Neuroaxonal degeneration
• Relapsing-remitting, primary progressive, and secondary progressive

Types of Multiple Sclerosis

• Descriptions of graphs showing progression of symptoms and disability over time for each type

Diagnosis

• No single diagnostic test
• McDonald criteria (2017) combines clinical, MRI, and ancillary tests
• Excludes MS mimics (vasculitis, autoimmune disease), vitamin B12 deficiency, and NMOSD
• Dissemination in time and space is essential

MRI

• Describes different types of lesions seen on brain MRI

2017 McDonald Criteria

• Criteria for diagnosis of MS

Diagnosis of PPMS

• One year of disease progression (retrospectively or prospectively confirmed)
• Plus two of three following: evidence of DIS on brain MRI, evidence of DIS in the cord, positive unmatched OCBs in the CSF

CIS & RIS

• Clinically Isolated Syndrome (CIS) is the initial episode of demyelination
• Radiologically Isolated Syndrome (RIS) is the presence of MRI findings of MS in an asymptomatic patient

Prognosis

• Proportion of wheelchair-bound patients after diagnosis of relapsing-remitting MS (RRMS)
• Dependency projected in RRMS cases after 25 years

MS Progression

• Graph of Expanded Disability Status Scale (EDSS), tracking progression over time from clinical onset

Treatment

• Acute Attack: Methylprednisolone 5-day course +/- plasma exchange
• Maintenance: Disease-specific and symptomatic

Disease-Specific Treatment

• Strategies: Wait and see, Hit early, Shift early, Hit strong from the start
• Describes different philosophies about timing and intensity of treatment
• Techniques such as time-lapse MRI

Treatment Agents

• List of disease-modifying therapies
• Detailed descriptions of how each medication addresses MS

Interferon Beta 1

• Four formulations
• Yearly relapse reduction, disability reduction
• Injectable

Glatiramer Acetate

• Comparable relapse rate (to interferon)
• No effect on disability
• Injectable

Natalizumab

• High reduction of relapse rate and disability
• Injectable every 4 weeks
• Safety issue of PML (Progressive Multifocal Leukoencephalopathy)

Fingolimod

• Oral tablet drug
• Unique mechanism of action
• Reduces annual relapse rate (vs placebo and interferon)
• Improves MRI parameters
• Requires admission for initial dose

Siponimod

• Oral daily S-1-P modulator
• Efficacy and side-effect profile similar to fingolimod, for RRMS and SPMS

Teriflunomide

• Oral
• comparable relapse rate reduction to interferon
• Side effects of alopecia and non-life threatening infection
• Teratogenic in both males and females

Dimethyl Fumarate

• Oral capsule
• Immune modulator and neuroprotective
• Relapse rate reduction 45%
• Positive effects on disability and MRI parameters
• Side effects acceptable, though PML reported

PEG Interferon and High-Dose GA

• Improvements in study design and adherence among patients

Alemtuzumab

• Anti CD52
• Infusion, 5 days, then three days each year
• Side effects include ITP, Thyroid disease, and neoplastic processes.
• Serious infections are another possible complication
• Treatment for severe non-responsive cases of MS

Anti CD20

• Rituximab (off label) or Ocrelizumab (approved) every 6 months for RRMS
• Ofatumumab monthly self-injectable, approved for RRMS & CIS
• Side effect profile includes possible infusion reactions and infections
• Comparative clinical trials (RCT)

Cladribine

• Chemotherapeutic agent
• Immune reconstitution
• Oral 5-day course annually
• Side effects such as cytopenia and infection

Future Treatments

• Intra-thecal anti-CD20 therapy
• Stem cell transplant
• Bruton tyrosine kinase inhibitors
• Anti-CD19 monoclonal antibodies

Once Was a Dream...

• Visual representation of normal and demyelinated nerve function, and remyelination via therapy

COVID and MS

• MS patients are no more likely to get COVID
• COVID prognosis worse in cases with more disability
• Vaccination against Covid safe and can be coordinated with MS medications, where appropriate

Thanks for Listening