H.R.Ghalyanchi
MS fellow
Sina MS Research Center,TUMS
Definition Primary progressive multiple sclerosis (PPMS) is
characterized by :
Progressive accumulation of disability from disease onset with
occasional plateaus,
temporary minor improvements, or
acute relapses still consistent with the definition
Two other classifications, no longer in use Progressive relapsing MS (PRMS) is characterized by progressive
disease from onset, with superimposed relapses
Transitional progressive MS (TPMS) defined as a single relapse before or after the onset of disease progression.
Over a quarter of patients with PPMS have been reported to experience a relapse even two or three decades after onset, although the relapse is usually mild
An acute attack in a patient with progressive disease from onset is now considered to be PPMS with active disease, whereas those with progressive disease from onset without acute attacks (relapses) are considered to have PPMS, not active but with progression
2010 McDonald Criteria for Diagnosis ofMS in Disease with Progression from OnsetPPMS May Be Diagnosed in Subjects With:1. One year of disease progression (retrospectively or prospectively determined)2. Plus
2 of the 3 following criteria:A. Evidence for DIS in the brain based on ≥1 T2 lesions in at least1 area characteristic for MS(periventricular, juxtacortical, or infratentorial)B. Evidence for DIS in the spinal cord basedon ≥2 T2 lesions in the cordC. Positive CSF (isoelectric focusing evidence ofoligoclonal bands and/or elevated IgG index)
If a subject has a brainstem or spinal cord syndrome, all symptomatic lesions are excluded from the Criteria.Gadolinium enhancement of lesions is not required
Characteristics of PPMS vs. RRMSPPMS RRMS
Prevalence 10-15% 85%
Gender Men=women Women > men
Clincal Presentation more Motor- progressive spastic paraparesis with probable bowel,urinary or sexual problems
More sensory or visual
Cognition relatively spared Usually involved
Prognosis for ultimate disability
worse better
Age of onset 10 years later
PPMS vs. SPMS
PPMS SPMS
Age of onset earlier later
Rate of progression similar
Differential diagnosis of PPMSCategories Diseases
Infections HTLV-1 associated myelopathy (TSP)HIV, syphilis, lyme
Hereditary, genetic, congenital
Hereditary Spastic Paraplegia (HSP)AdrenoleukodystrophyCerebrotendinous XantomatosisPhenylketonuriaChiari Malformation
Inflammatory Neurosarcoidosis
Vascular Spinal dural AVM
Neurodegenerative MND: ALS, PLS
Toxic, Metabolic B12 deficiency (SCD)Copper deficienceyNitrous oxide related myelopathy
Tumors Spinal cord compression, paraneoplastic
Spinal degenerative Cervical spondylotic myelopathy
MRI in PPMS
A paucity of focal lesions
Less Gd- enhancing lesion
Fewer new lesions over time
The smaller lesions may be more destructive
More diffuse signal abnormalities
More lesions in spinal cord than brain
Enhancement may be present particularly early on the disease
T2 lesion load correlate with the evolution of disability
T1 lesions and cord ones do not correlate with disability in PPMS.
MRI measures to quantify changes in NABT: Magnetization Transfer Ratio imaging (MTR), 1H (MRS),and diffusion MRI
Pathological examination
Less inflammation,
Less numerous white matter lesions than SPMS
Less acute axonal injury
More nerve degeneration
Unique oligodendrocyte degeneration
Cortical demyelination is a characteristic feature
Measures of clinical disease progression
Expanded Disability Status Scale (EDSS ): is not linear
Multiple Sclerosis Functional Composite (MSFC): more sensitive
T25WT: more useful in PPMS
Combining EDSS and T25WT improve responsiveness
Therapeutics for PPMS
Failed treatments
Partially or Probably effective treatments
Future Trials
Symptomatic managements
Rehabilitation
Failed therapiesDrugs Effects No Effect
Cladribine (S.C. form) Reduce Gd enhancing lesion (RRMS)
Progression, brain atrophy
Interferon β1-a T2 lesion load, 9-hole peg test
EDSS
Interferon β-1b T2,T1 lesion load Progression
Mitoxantrone 2 of 61 patients (Gd +) (progression)
Riluzole Spinal cord atrophyT1 lesion accrual
Tetrahydrocannabinol(Dronabinol)(neuroprotective?)
Inhibit Ca influx (axon)Activate K channel (dendritic)Spasticity, walking speed
Progression
Cyclophosphamide <40 y and <1 year progression in SPMS
Ineffective for PPMS
Flecainide, Phenytoin Na channel blockade
Lamotrigine Neuroprotective agent?
Partially Effective Treatments Glatiramer Acetate: The PROMiSe trial
Interim analysis : No significant effect on progression
Post-hoc subgroup analysis : Significant delay in progression treated male patients due to a faster background progression rate in males.
Cochrane Systematic review, concluded that the “GA is not suitable for progressive MS”
Partially effective Rituximab:The OLYMPUS Study: four two-week
cycles of intravenous rituximab at a dose of 1 g, or placebo, over 96 weeks
Time to confirmed disease progression was increased only in two subsets of patients:
Those aged less than 51,
Those with Gd-enhancing lesions identified at baseline
T2 lesion load and mobility decline on TWT was significantly lower in treated
MTX Methotrexate, oral or subcutaneous, 7.5 to 20 mg per week, with or
without monthly glucocorticoid pulses alters the disease course in patients with SPMS and PPMS (AAN guidelines)
Methotrexate positively affected measures of upper extremity function such as the 9-Hole Peg Test .
Intrathecal methotrexate : every eight weeks, (Dr. Saud Sadiq) : In one study of 121 patients, disability scores to be stable or improved in 89% of SPMS patients and 82% of PPMS patients one year after their last treatment
A longer-term study found that 48% of patients experienced no increase in disability after 3 to 6 years
Stem cell therapy
Autologous hematopoietic stem cell transplantation :
In a meta-analysis, the estimated rate of progression-free survival for 102 patients receiving intermediate-intensity conditioning regimens (five studies with a median follow up of 39 months) was 79 percent .
In contrast, the estimated rate of progression-free survival for 61 patients receiving high-intensity regimens (three studies with a median follow up of 24 months) was 45 percent .
Among 15 studies that reported adverse events, the most frequent complications occurring within six months of autologous HSCT were fever, engraftment syndrome, enteritis, and transient neurologic deterioration.
Stem cell therapy Among 13 case series with post-treatment follow-up,
seven patients died from treatment-related causes, mainly infection, and six patients died from nontreatment-related causes, mainly disease progression. Overall mortality was approximately 3 percent.
Partially effective
Azathioprine: 51 patients PPMS - demonstrated a small therapeutic effect overall
Intermittent (on and off) intravenous (IV) steroidshave been tried in patients with PPMS (monthly pulses) (typically 1000 mg of methylprednisolone)
IVIG: Beneficial effects were seen in the PPMS subgroup in a double blind, placebo-controlled trial of IVIG in progressive MS.
Probable effective Pirfenidone: TNF-α synthesis inhibitor and TNF-
alpha receptor blocker
A small open-label study: clinical stabilization in progressive MS over one year
Amiloride : A few PPMS patients seem to have responded to the potassium sparing diuretic amiloride.
Targeting acid-sensing ion channel 1 (encoded by the ASIC1 gene), contributes to the excessive intracellular accumulation of injurious Na(+) and Ca(2+) that is over-expressed in acute multiple sclerosis lesions
Probable effective LDN (Low dose naltrexone) :
stops progression of multiple sclerosis disability,
prevents relapses, and
reduces MS symptoms, such as fatigue, spasticity, weakness , cognitive dysfunction, urinary incontinence, depression and even heat intolerance
Increases the body’s sensitivity to its own endorphins, or helps the body make more endorphins
LDN administration Interferons should NOT take with LDN ( interact
with it).However, it is OK to be used in conjunction with GA.
LDN should NEVER be combined with any opiate-based drugs (narcotics). For people with multiple sclerosis, the dosage of LDN ranges from
1.5 to 4.5 mg per day
LDN is taken at night, between 9:00 pm and 12:00 midnight, to work with the body’s natural peak release of endorphins, which occurs sometime between 2:00 and 4:00 am. It can be taken with or without food.
Future Trials Fingolimod (FTY720): Primarily anti-inflammatory agent
in vitro influence CNS remyelinationa double-blind placebo-controlled trial in PPMS is currently recruiting (INFORMS; NCT00731692)
Natalizumab in PPMS and SPMS Oral methylprednisolone, 500 mg monthly in SPMS and PPMS Ocrelizumab in PPMS 2017 Lithium in Progressive Multiple Sclerosis Dec 2016 Hydroxyurea (as an antiviral agent vs. EBV) in PPMS Jul2013 Oral Cladribine; for PPMS Mastinib: improved MSFC- continue 2015 Idebenone, a synthetic form of coenzyme Q10 which is thought to
promote remyelination Minocycline
Future treatments
A Phosphodiesterase inhibitor Ibudilast (PDE-4 subtype inhibitor): Anti inflammatory and neuroprotective and antiplateletagent, in a trial MS-SMART in the United kingdom SPRINT MS ibudilast vs placebo in the United States.
Mesenchymal stem cell therapy for MS is being explored NSCs - neural stem cells : ‘allogenic’ stem cells
NSCs injected intrathecally in a clinical trial (phase I). Simvastatin 80 mg : in SPMS affect on whole-brain
atrophy and some measures of disabilityNo effect on new and enlarging brain lesions or in the relapse rate. On PPMS ???
Symptomatic managements
Multidisciplinary approach: medical, psychological and social
Maintain comfort and productivity, and enhancing quality of life
Treat fatigue, urinary incontinence, spasticity, seizures and paroxysmal symptoms, pain, depression,
Dalfampridine: (4-aminopyridine; fampridine), a potassium channel blocker, may improve walking speed in some patients with MS
REHABILITATION: enhancing mobility and promoting safety and independence
Emotional well-being , can be achieved even in the presence of a chronic illness or disability.
Conclusions: No treatment is yet proven to be effective for PPMS It is still ethical to carry out placebo-controlled trials Therapeutic agents directed at axonal protection or
repair may be particularly useful in PPMS, although inflammation clearly occurs and hence trials of anti-inflammatory agents are also justified
Most trials did not last longer than two or three years and give only hints about long-term results of treatment
Too Big, Too Long, Too Expensive As its relative rarity, we need the involvement of multiple
centers in definitive trials using a combination of MRI parameters to assess outcome
Conclusions
Therapeutics in PPMS can no longer be considered a neglected area
Several randomized controlled trials, including Phase 3 trials of glatiramer acetate and rituximab, have now been completed.
A better understanding of the pathophysiology of PPMS is required to guide the development of therapeutic agents to target specific pathogenic mechanisms.
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