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.