What is primary progressive multiple sclerosis (PPMS) and how is it managed?

Primary Progressive Multiple Sclerosis (PPMS): Definition and Management

Primary progressive multiple sclerosis (PPMS) is a distinct form of MS affecting 5-10% of MS patients, characterized by deterioration from disease onset without relapses or remissions, with ocrelizumab being the only FDA-approved disease-modifying therapy for this condition. 1

Definition and Clinical Characteristics

PPMS differs significantly from other MS subtypes:

• Represents 5-10% of all MS cases 1
• Characterized by continuous neurological deterioration from disease onset without relapses or remissions 1, 2
• Typically presents with progressive spastic paraparesis or cerebellar syndrome 1
• Mean onset age of 37-43 years 2
• Common symptoms include:
  • Mobility issues
  • Persistent pain
  • Sensory disturbances
  • Cognitive deficits
  • Bowel and bladder problems that intensify over time 2

Diagnostic Features

PPMS has distinct diagnostic characteristics:

• Neuroimaging shows substantial brain and spinal cord atrophy 2
• Fewer brain lesions but more spinal cord lesions compared to relapsing forms 2
• Only 5% of new lesions show gadolinium enhancement, compared to 80% in relapsing-remitting MS 3
• Requires evidence of dissemination in space (multiple lesions in different CNS locations) and clinical symptoms corresponding to these lesions 1
• Often requires extensive differential diagnosis and long-term follow-up before correct recognition 4

Treatment Options

FDA-Approved Therapy

• Ocrelizumab is the only FDA-approved disease-modifying therapy for PPMS 1, 5
  • Administered as 600 mg IV infusion every 24 weeks 5
  • Has demonstrated significant reduction in disability progression 1
  • First therapy to reach the primary disability endpoint in PPMS clinical trials 6
  • Targets B cells, which have emerged as a promising therapeutic target 6

Investigational Therapies

Several experimental approaches are being investigated:

• High-dose biotin, simvastatin, and coenzyme Q10 2
• Fingolimod, idebenone, and anti-LINGO-1 2
• Neuromodulation and plasmapheresis 2
• Cell metabolism modulation and inflammatory pathway inhibition 6
• Stem cell therapies:
  • Hematopoietic and non-hematopoietic stem cell therapies 2
  • Human fetal neural precursor cells (hfNPCs) 2

Monitoring and Management

Effective management of PPMS requires:

• Annual brain MRI for monitoring disease activity 1
• Regular clinical assessment for new neurological symptoms 1
• Investigation of any new lesions on MRI that weren't present on previous scans 1
• Consideration of treatment change when there is evidence of active disease (clinical or radiological) 1

Challenges in PPMS Management

Several challenges remain in PPMS management:

• Limited therapeutic options compared to relapsing forms of MS 6, 7
• Need for validated outcome measures beyond physical disability alone 6
• Relative lack of inflammation makes traditional MS therapies less effective 7
• Need for neuroprotective agents that target neuronal loss directly 7
• Further investigation into pathogenic mechanisms is required to guide development of future therapies 7

Future Directions

Research is focusing on:

• Gene therapy studies on immune regulation, neuroprotection, and remyelination 2
• Development of reliable biomarkers to assess disease outcomes 4
• Improvement of individualized therapeutic approaches 4
• Identification of novel therapeutic targets relevant for managing progression 4
• Inclusion of efficacy endpoints beyond physical disability, such as cognition, quality of life, advanced MRI measures, and molecular biomarkers 6

PPMS represents a significant challenge in MS management but also offers valuable insights into the mechanisms of disease progression that may benefit our understanding of all forms of MS.