What is the recommended treatment plan for a patient diagnosed with multiple sclerosis, considering disease-modifying therapies and symptomatic treatments?

Diagnosis and Management of Multiple Sclerosis

Diagnosis

Diagnose MS using the 2017 McDonald Criteria, which integrate clinical presentation, MRI findings showing dissemination in space and time, and cerebrospinal fluid oligoclonal bands. 1

• Obtain baseline brain MRI with gadolinium-enhanced T1-weighted and T2/FLAIR sequences to establish lesion burden and focal inflammatory activity 2
• MS typically presents in adults aged 20-30 years with unilateral optic neuritis, partial myelitis, sensory disturbances, or brainstem syndromes developing over several days 1
• Classify the MS subtype immediately as this dictates all therapeutic decisions: relapsing-remitting MS (RR-MS) is most common, followed by secondary progressive MS (SP-MS) and primary progressive MS (PP-MS) 2

Initial Treatment Strategy

Initiate high-efficacy disease-modifying therapies (DMTs) immediately for relapsing-remitting MS rather than using traditional step-up approaches, as this achieves 87% progression-free survival at 10 years. 2

First-Line High-Efficacy DMTs

The most effective first-line options include: 2

• Ocrelizumab (anti-CD20 monoclonal antibody)
• Ofatumumab (anti-CD20 monoclonal antibody)
• Natalizumab (α4-integrin inhibitor)
• Alemtuzumab (anti-CD52 monoclonal antibody)
• Cladribine (purine analog)

Alternative First-Line Options

For patients requiring moderate-efficacy agents due to contraindications or patient preference: 1

• Interferon-β preparations (intramuscular IFNβ-1a, subcutaneous IFNβ-1a, subcutaneous IFNβ-1b)
• Glatiramer acetate 20 mg daily subcutaneously or 40 mg three times weekly 3
• Sphingosine 1-phosphate receptor modulators (fingolimod)
• Fumarates (dimethyl fumarate)
• Teriflunomide

These moderate-efficacy DMTs reduce annualized relapse rates by 29-68% compared to placebo but are inferior to high-efficacy agents for long-term outcomes. 1

Critical Safety Consideration for Natalizumab

Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic JC virus brain infection usually leading to death or severe disability. 4

• Instruct patients to immediately report progressive weakness on one side of the body, clumsiness, vision disturbances, or changes in thinking, memory, and personality 4
• Continue monitoring for PML symptoms for approximately 6 months following natalizumab discontinuation 4

MRI Surveillance Protocol

Perform brain MRI at least annually for stable patients, but increase frequency to every 3-4 months for high-risk patients with highly active disease or recent treatment changes. 2

Required sequences include: 2

• T2-weighted and T2-FLAIR sequences for detecting new or enlarging lesions
• Gadolinium-enhanced T1-weighted sequences to identify active inflammatory lesions

Management of Breakthrough Disease Activity

When breakthrough disease activity occurs on first-line therapy, escalate to natalizumab if JC virus antibody-negative, or consider alemtuzumab, ocrelizumab, or fingolimod. 2

• If breakthrough occurs on high-efficacy DMT, proceed immediately to autologous hematopoietic stem cell transplantation (AHSCT) evaluation 2

AHSCT for Refractory Disease

AHSCT represents the most effective escalation therapy for highly active RR-MS that has failed high-efficacy DMTs, achieving superior disease control compared to continued DMT escalation. 5, 2

Referral Criteria for AHSCT

Refer patients immediately after failure of first high-efficacy DMT if they meet: 2

• Age <45 years
• Disease duration <10 years
• High focal inflammation on MRI with gadolinium-enhancing lesions

AHSCT Conditioning Protocols

For MS treatment, intermediate-intensity conditioning protocols such as BEAM-ATG or cyclophosphamide-ATG are recommended to achieve the best balance of efficacy and risk. 5

• Low-intensity regimens (low-dose cyclophosphamide without serotherapy) are not recommended outside clinical trials due to poor efficacy 5
• High-intensity myeloablative protocols (busulfan-cyclophosphamide-ATG) are not recommended outside clinical trials due to higher toxicity risk 5
• AHSCT involves higher acute risk than approved DMTs, including treatment-related mortality and infections during neutropenia 2

Rehabilitation After AHSCT

Begin intensive rehabilitation immediately after AHSCT to exploit neuroplasticity during complete inflammatory suppression. 5, 2

The rehabilitation phases include: 5

• Pre-habilitation (weeks -4 to 0): Optimize physical, social, and emotional functioning before AHSCT through breathing exercises, cardiovascular training, spasticity management, and cognitive rehabilitation
• Acute rehabilitation (weeks 0-4): Prevent hospitalization-related complications through gentle mobilization adapted to platelet counts
• Subacute rehabilitation (months 1-6): Intensive therapy to maximize functional recovery
• Community rehabilitation (months 6+): Long-term maintenance and optimization

Treatment of Progressive MS

Primary Progressive MS

Ocrelizumab is the only FDA-approved DMT specifically indicated for primary progressive MS, though efficacy is limited to slowing disability progression rather than halting it. 2

Secondary Progressive MS

Consider AHSCT only for young patients (<45 years) with early secondary progressive MS of short duration who have well-documented clinical and radiological evidence of active inflammatory disease. 5, 2

Symptomatic Treatment

Acute Relapses

Treat acute relapses with high-dose corticosteroids: 6

• Intravenous methylprednisolone 1000 mg daily for 3-5 days
• Adverse effects are usually transient and resolve after treatment completion

Common Symptomatic Therapies

Address specific symptoms with targeted interventions: 1

• Spasticity management
• Fatigue management
• Pain control
• Bladder dysfunction treatment
• Cognitive rehabilitation

Special Populations

Pregnancy

Glatiramer acetate is the only MS treatment with FDA pregnancy category B, making it the preferred option for women planning pregnancy or who become pregnant. 4

• Instruct patients to inform their healthcare provider if they become pregnant or plan to become pregnant while taking any DMT 4

Older Patients (>55 years) with Stable Disease

Patients over 55 years with stable disease may be considered for treatment discontinuation, as the benefits of continuing immunosuppressive therapy may be outweighed by increased risks of infections. 7

• Perform brain MRI at least annually after discontinuation, with more frequent monitoring (every 3-4 months) initially 7
• Disease stability off therapy should be confirmed with both clinical and MRI assessments 7

Brain Volume Monitoring

Measure global brain volume to better gauge global disease burden, as brain volume loss is associated with and predicts disability in all clinical MS phenotypes, including the earliest stages. 5

• Measure cervical cord area loss because this measure is associated with and predicts disability in all MS phenotypes 5
• Grey matter volume changes are more pronounced and clinically relevant than white matter changes, even in early MS 5

Common Pitfalls

Avoid traditional step-up approaches starting with moderate-efficacy agents, as early aggressive treatment with high-efficacy DMTs yields superior long-term outcomes. 2

• Do not delay AHSCT referral in eligible patients who fail first high-efficacy DMT, as disease duration <10 years is a critical eligibility criterion 2
• Be aware of pseudoatrophy effect with DMTs, particularly in the first year of treatment with natalizumab or interferons, where brain volume loss may initially increase due to resolution of inflammation and edema before showing treatment benefit 5