Upload
others
View
1
Download
0
Embed Size (px)
Citation preview
Xavier Montalban
University of Toronto
St Michael’s Hospital
Toronto, Canada
Cemcat
Hospital Universitari Vall d’Hebron
Barcelona, Spain
Paris 2017
Teaching Course 6—Current Controversy in
Management: Interactive Case Discussion
Disclaimer
Dr. Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, GSK, Roche, Almirall, NMSS and MSIF. Editor for Clinical Cases for MSJ.
Case report
• 45 year old Caucasian gentleman living in Barcelona
• Smoker of 20 cig/day for the last 20 years
• No history of past neurological symptoms
• In April 2004, he was referred to our MS clinic because of a 6 months history of progressive weakness in his left lower extremity
Case report
Examination:
• Normal general physical examination
• Higher mental functions and cranial nerves were normal
• Moderate weakness in his left lower limb
• Bilateral extensor plantar response
• Bilateral altered touch sensation in his lower limbs specially in his left limb
• A clear sensory level was not found
Which is the right answer?
1. Myelopathy is the most probable cause of the symptoms
2. Several lesions distributed within the CNS can’t be ruled out
3. Although there is no clear sensory level myelopathy can’t be ruled out
4. An spinal MR is the most appropriate test to be performed
5. All answers are correct
Which is the right answer?
• Myelopathy is the most probable cause of the symptoms
• Several lesions distributed within the CNS can’t be ruled out
• Although there is no clear sensory level myelopathy can’t be ruled out
• An spinal MR is the most appropriate test to be performed
• All answers are correct
MR showed several lesions sugestiveof demyelination
A diagnosis of PPMS was suspected
Primary Progresive Multiple Sclerosis
Defined by steady progressive from onset, without distinct relapses, in
neurological function over months to years
Represents 10-15% of all MS cases
Slight gender bias (F/M: 1.1-1.3 to 1)
Greater mean age at onset (40 vs 30 years)
Almost never seen in childhood
Clinical features very different from those of acute relapsing MS
80-85% spastic paraparesis (no clear sensory level)
10-15%: progressive cerebellar ataxia, and cognitive, brainstem
or visual symptoms
Diagnostic challenge
More difficult to achieve (diagnosis of exclusion)
Spinal cord MRI, and CSF analysis highly informative
Which is the right answer?
1. MR is specific enough to be pathognomonic of MS
2. Patient’s clinical history, neurological examination and the results of the MR are diagnostic of MS
3. A CSF tap is not recommended
4. Brain MR is not indicated
5. Other aetiologies should be ruled out
Which is the right answer?
1. MR is specific enough to be pathognomonic of MS
2. Patient’s clinical history, neurological examination and the results of the MR are diagnostic of MS
3. A CSF tap is not recommended
4. Brain MR is not indicated
5. Other aetiologies should be ruled out
Rule out other diagnosisPrimary Progressive MS
Dural fistula
Meningiomatosis
Multifocal white matter lesionsSpecific diagnosis in young adults
SUSACCADASIL Fabry PACNS Neurosarcoidosis
Lyme disease Multiple sclerosisFat embolism
1 2 3 4 5
6 7 8
Rice et al. JNNP 2013
Differential Diagnosis of PP multiple sclerosis
•Degenerative disorders:ALS•Compressive:
•Tumors•Chiari type I
•Hereditary:•HSP, SCA•Leukodystrophies
•Metabolic:•Vitamins B12, E•Copper•Hypothyroidism•Toxic: phenytoin, nitricooxide•Alcohol
•Infective/inflammatory•HIV•Syphilis•Prions•Vasculitis•Sarcoid•Lupus•Brucellosis
•Paraneoplastic•Idiopathic
Diagnostic criteria 2010: PPMS
DIS: ≥ 1 T2 lesion in ≥ 1 topography
juxta infraPV
DIS: ≥ 2 T2 spinal cord lesions
Positive Brain MRI
Positive Spinal cord MRI
1.- Positive CSF evidence
2.- Positive Brain MRI
3.- Positive spinal cord MRI
• Progressive syndrome for > 1 year
• Other progressive conditions excluded
• Two out of three:
This consensus-based recommendation is justifiedby comparing diagnostic criteria for PPMS and bya subsequent reanalysis of these data (X.Montalban, personal communication).
MR showed few lesions sugestive of demyelination
Case report
• CSF analyses showed no cells. Protein and glucose levels were normal. IgG index was 1.2. IgG oligoclonal bands were detected.
• Blood tests showed negative results for Borrelia, Treponema, HIV, toxoplasma and auto-antibodies. B12 levels were normal.
• Normal VEP
Diagnostic criteria 2010: PPMS
DIS: ≥ 1 T2 lesion in ≥ 1 topography
juxta infraPV
DIS: ≥ 2 T2 spinal cord lesions
Positive Brain MRI
Positive Spinal cord MRI
1.- Positive CSF evidence
2.- Positive Brain MRI
3.- Positive spinal cord MRI
Progressive syndrome for > 1 year
Other progressive conditions excluded
Two out of three:
This consensus-based recommendation is justifiedby comparing diagnostic criteria for PPMS and bya subsequent reanalysis of these data (X.Montalban, personal communication).
×
Case report
• CSF analyses showed no cells. Protein and glucose levels were normal. IgG index was 1.2. IgG oligoclonal bands were detected.
• Blood tests showed negative results for Borrelia, Treponema, HIV, toxoplasma and auto-antibodies. B12 levels were normal.
• Normal VEP
• Patient was treated with i.v. steroids for 5 days with some but incomplete recovery of the motor function
Which would you do first?
1. Treat him with alemtuzumab
2. Treat him with siponimod
3. Treat him with fingolimod
4. Recommend giving up smoking
Which would you do first?
1. Treat him with alemtuzumab
2. Treat him with siponimod
3. Treat him with fingolimod
4. Recommend giving up smoking
Healy B Arch Neurol,2009
Smoking: effect on the conversion from relapsing- remitting to secondary progressive MS
Never-smokers
Ex-smokers
Current-smokers
Smoking
Manouchehrinia A Brain 2013
Time of smoking cessation and disability progression
Smoking
Smoking cessation even after the onset of the disease will have a positive impact on disease progression
Case report
• After initial incomplete recovery the motor deficit gradually worsened over 4 years and the patient had difficulties in walking more than 500 m without help or resting
• The patient was seen at our center for a 3 weeks worsening in the difficulty in walking
• A new MR was performed and 2 Gd enhancing lesions were observed (one in the brain and the other in the spinal cord)
Which is the right answer?
1. Patients with PPMS have no attacks during their
follow up
2. Patients with PPMS have no Gd enhancing lesions
3. Patients with PPMS and attacks during the follow
up are classified currently as Progressive Relapsing
MS
4. All the answers are wrong
Which is the right answer?
1. Patients with PPMS have no attacks during their
follow up
2. Patients with PPMS have no Gd enhancing lesions
3. Patients with PPMS and attacks during the follow
up are classified currently as Progressive Relapsing
MS
4. All the answers are wrong
18 out of 42 patients (42%) with early
PPMS had at least one enhancing
lesion on their baseline scan
Enhancing lesion volume and number
of lesions are similar to those seen in
RRMS
Number of enhancing lesions
associated with younger age (r=0.5,
p=0.003) and higher T2 load (r=0.5,
p=0.02) (and higher degree of
disability)
Institute of Neurology, University
College London, UK
Early PPMS study. Brain Enhancement
Ingle, JNNP 2005
Brain 1999
A substantial minority (28%) of the PP-multiplesclerosis cohort had a distinct relapse evendecades after onset of progressive deterioration.
PPMS and inflammation
CIS RRMS
Non active
Active*Non
activeActive
* CIS becomes RRMS if patient experiences subsequentactivity and fulfills current MS diagnostic criteria
Lublin FD, et al. Neurology 2014
PROGRESSIVE DISEASE
Active and with
progression
Active and without
progression
Non active and with
progression
Non active and withoutprogression
PPMS SPMS
2013 clinical phenotypes revisions
Case report
• Different treatment options with DMA were discussed with the patient:
Which is the right answer?
1. Ocrelizumab is approved in US for patients with
PPMS
2. Patients with PPMS must be treated with DMA
3. Most of the trials in patients with PPMS have been
positive
4. There isn’t any hint of efficacy coming from any
PPMS trial
Which is the right answer?
1. Ocrelizumab is approved in US for patients with
PPMS
2. Patients with PPMS must be treated with DMA
3. Most of the trials in patients with PPMS have been
positive
4. There isn’t any hint of efficacy coming from any
PPMS trial
Case report
• Different treatment options with DMA were discussed with the patient:
• One trial with rituximab showed in a subgroup of patients a positive effect
• One trial has been positive (ocrelizumab)
• Ages Eligible for Study: 25 Years to 65 Years• Diagnosis of PPMS (according to the 2005 Revised
McDonald criteria)• Time since first reported symptoms between 2 and 10
years• Evidence of clinical disability progression in the 2
years prior to Screening• Disability status at Screening:
– EDSS score of 3.5-6.0 inclusive– pyramidal functional system score of 2 or more– 25'TWT less than 30 seconds
• 969 patients enrolled
Oral fingolimod (FTY720)
INFORMS® trial - Inclusion criteria
Primary Progressive - INFORMS
Lublin et al. Lancet 2016
Inclusion criteria:Diagnosis of PPMS (McDonald 2005)
≥1 year of disease progression plus two of three criteria: positive brain MRI; positive spinal cord MRI; or positive CSF
Age 25–65 yearsEDSS 3.5–6.0pyramidal FS≥2, 25TWT <30 secDisease duration 2 – 10 years≥0.5 EDSS increase in prior 2 years
Primary outcome: fingolimod vs placebo on delaying time to 3-mo CDP on novel composite endpoint of meeting any of 3 criteria
• Increase from baseline EDSS (if baseline score ≤5.0, or by 0.5 point if baseline score ≥5.5
• ≥20% increase of from baseline 25-Foot-Timed-Walk• ≥20% increase from baseline 9-Hole Peg Test
Primary Progressive - INFORMS
Main secondary outcome: fingolimod vs placebo on delaying time to 3-mo CDP on conventional endpoint of meeting increase from baseline EDSS (if baseline score ≤5.0, or by 0.5 point if baseline score ≥5.5)
Lublin et al. Lancet 2016
CD20 as a Target
• CD20, a phosphorylated protein
(297 amino acids, 33–35 kDa)
– Highly expressed on the
surface of pre-B through
memory B cells, but is not
expressed on stem cells or
plasma cells
– Expressed in B cells in lesions
of acute and progressive forms
of MS (PPMS, SPMS)
– Stable, does not get secreted
or shed, and does not
internalize on antibody binding
PPMS = primary progressive MS; SPMS = secondary progressive MS.
Johnson P, Glennie M. Semin Oncol. 2003;30(1 suppl 2):3–8; Waubant E. Int MS J. 2008;15(1):19–25; Meinl E, et al. Ann Neurol. 2006;59(6):880–92; Magliozzi R, et al. Brain. 2007;130(pt 4):1089–104;
Frischer JM, et al. Brain. 2009;132:1175–896; Magliozzi R, et al. Ann Neurol. 2010;68(4):477–93; Winiarska M, et al. Front Biosci. 2011;16:277–306
CD20
cytoplasm
Confidential — For internal use only. Do not copy, distribute or use without prior written consent
Efficacy And Safety of Ocrelizumab in Primary Progressive Multiple Sclerosis – Results of the Placebo-controlled, Double-blind, Phase III ORATORIO
Study
X Montalban, B Hemmer, K Rammohan, G Giovannoni, J de Seze, A Bar-Or, DL Arnold, A Sauter, A Kakarieka, D Masterman, P Chin, H Garren, J Wolinsky,
on behalf of the ORATORIO clinical investigators
NCT01194570
31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis 2015
Platform presentation number 228
Ocrelizumab
ORATORIO® - Inclusion criteria
Adult patients, 18-55 years of age
Primary Progressive Multiple Sclerosis (according to revised McDonald criteria)
Expanded Disability Status Scale (EDSS) 3 to 6.5 points
Disease duration from onset of MS symptoms < 15 years if EDSS > 5.0, < 10 years if EDSS >/= 5.0
736 patients recruited
ORATORIO: Phase III study in primary progressive MS (PPMS) Study Design
• Diagnosis of PPMS (2005 revised McDonald criteria)1
• Age 18–55 years
• EDSS 3.0–6.5
• CSF: elevated IgG index or >1 oligoclonal bands
• No history of RRMS, SPMS, or PRMS
• No treatment with other MS DMTs at screening 2
:1 R
and
om
isat
ion
#
*Patients received methylprednisolone prior to each ocrelizumab infusion or placebo infusion. †The blinded treatment period may be extended until database lock.#2:1 randomisation stratified by age (≤45 vs >45) and region (US vs ROW).‡Continued monitoring occurs if B cells are not repleted.
Primary endpoint: Significant reduction in 12-week CDP
24% reduction in risk of CDP
HR (95% CI): 0.76 (0.59, 0.98); p=0.0321
Time to 12-week Confirmed Disability Progression
n
Placebo 244 232 212 199 189 180 172 162 153 145 136 120 85 66 46 30 20 7 2
Ocrelizumab 487 462 450 431 414 391 376 355 338 319 304 281 207 166 136 80 47 20 7
Montalban X, et al. ECTRIMS 2015. Platform presentation 228.
Secondary endpoint: Significant reduction in the rate of whole brain volume loss
n
Placebo 203 200 150
Ocrelizumab 407 403 325
17.5% reduction vs placebo
p=0.0206*
Percent Change of Whole Brain Volume from Week 24 to Week 120
-1.1%
-0.90%
Montalban X, et al. ECTRIMS 2015. Platform presentation 228.
Significant reduction in risk of 12-week confirmed disability progression
Overall Study Population
Placebo(N=244)
Ocrelizumab(N=488)
HazardRatio
95% CI
n Events n Events
Overallpopulation
244 96 487 160 0.76 (0.59, 0.98)
≥T1 Gd+
lesions 60 27 133 43 0.65 (0.40, 1.06)
No T1 Gd+
lesions183 68 350 115 0.84 (0.62, 1.13)
24% reduction in risk of CDP
HR (95% CI): 0.76 (0.59, 0.98);
p-value (log rank)=0.0321*
(n=488)
7
Inflammation is a common and frequent phenomenon even in clinically “pure” progressive patients
Neuroprotective plus anti-inflammatory strategies seem to be necessary which means adding more difficulties to trials
Recruitment in phase 3 PC trials in progressive MS increasingly difficult in western countries
Biomarker (probably MR) for phase 2 trials is desperately needed
New trial designs
Something escapes from our understanding (INFORMS)
Conclusions
Case report
• The patient decided not to be treated and continue to progressively worsening over the following 4 years.
• Patient needed two canes to walk 200 meters with difficulty, spasticity was a problem due to painful spasms of the extremities and also contributed to walking problems
• The patient reports that he smokes marihuana occasionally to ameliorate spasticity symptoms with irregular results
1. Treat patient with nabiximols
2. Treat patient with fampridine
3. Treat patient with oral baclofen and/or tizanidine
4. Recommend to continue with smoking cannabinoids
Which is the wrong answer?
1. Treat patient with nabiximols
2. Treat patient with fampridine
3. Treat patient with oral baclofen and/or tizanidine
4. Recommend to continue with smoking cannabinoids
Which is the wrong answer?
Smoking cannabis is not a good option
• Herbs: Smoked Cannabis
– Insufficient evidence
– Data are inadequate to support or refute use of smoked cannabis for spasticity, pain, balance/posture, or cognition in MS (Level U).
• A population-based cohort study examined men (n = 49,321)
• cannabis smoking was significantly associated with more than a twofold risk (hazard ratio 2.12, 95 % CI 1.08-4.14) of developing lung cancer over the 40-year follow-up period, even after statistical adjustment for baseline tobacco use, alcohol use, respiratory conditions, and socioeconomic status
Calleghan RC et al. Cancer C Control 2013
Smoking cannabis is not a good option
Spasticity management. Team approach
PT
Standing, Positioning, Stretching,
exercise programme, Splinting,
FES, Monitoring treatment
PWS / Carer
Monitor aggravating factors
Exercise / stretching
Monitor drug effectiveness
DR
Timing of assessments
& treatments
Drug prescribing & evaluating
OT
Adaptations
Wheelchair
Positioning
Splinting
Role / function
Nurses
Skin, Bladder, Bowel
Education
Positioning
LOW quality
Imprecision of results
Problems in randomization
Lost to follow-up of an important proportion of patients
No safety issues evaluated
From evidence to recommendations
Physiotherapy based in active and passive exercises with stretching, used alone or in combination with other antispastic treatments can help management of the patients symptoms.
WEAK
Physiotherapy
Safety
From evidence to recomendations
Oral baclofen
LOW qualityHeterogeneity in patients included
Blinding was not completely effective overestimate treatment effects
No sample size calculations
Side-effects such as drowsiness, weakness, paraesthesiae and dry mouth were common and limit the dose tolerated. Baclofen side effects were fewer and better tolerated than those caused by diazepam.
Safety
In patients with spasticity the treatment with oral baclofen is recommended
WEAK
TizanidineMODERATE quality
Conduct of the studies was robust
No sample size calculations
Well tolerated, most frequent side-effects drowsiness and a dry mouth. No difference between tizanidine and baclofen in terms of frequency and severity of side-effects
Safety
From evidence to recomendations
In patients with spasticity and no improvement or poor tolerance to oral baclofen, it can be replaced by tizanidine
WEAK
Nabiximols
HIGH qualityConduct of the studies was robust
No heterogeneity
Well tolerated, most frequent side-effects were dose-related psichotropic effects of cannabis such as dizziness and administration site reactions
Safety
From evidence to recommendations
In patients with spasticity and lack of clinical improvement or poor tolerance to other medications, treatment with Nabiximols is recommended. If no improvement is achieved in the short term, discontinuation must be considered. STRONG
Management
“Based on this review, we are unable to make any newrecommendations on the use of adrenaline for the treatment ofanaphylaxis.”
...but, please, use it!!!
Case report
• Patient was treated with baclofen starting with 10 mg twice a day and increasing the dose progressively until reaching 25 t.i.d. Some improvement was observed but not to a satisfactory degree .
• Nabiximols was tried for 4-6 weeks increasing the dose progressively up to 6 sprays per day. A further improvement was observed with a decrease in the number and intensity of painful spasms (>20% improvement in a VAS). Gait did not improve
Case report
• Patient continued worsening and referred that reaching the toilette from the living room (just about 10m) was very difficult.
Which would you do?
1. Recommend multidisciplinary approach
2. Continue treatment with antispastic drugs
3. Treat patient with fampridine
4. All the above
Which would you do?
1. Recommend multidisciplinary approach
2. Continue treatment with antispastic drugs
3. Treat patient with fampridine
4. All the above
1. Harris Interactive. Experiences with Multiple Sclerosis (MS): Perspectives of People with MS and MS Care Partners [poll]. March 25, 2008.2. LaRocca NG. Patient 2011; 4: 189–201.
3. van Asch. Eur Neur Rev 2011; 6 (2): 115–120.
Walking impairment in MS
• Walking integrates multiple functional systems, including motor (pyramidal and extra pyramidal), sensory (proprioception), cerebellar and vestibular
• Over 60% of people with MS report difficulty walking 1
• 70% of patients who have walking difficulty say it is the most challenging aspect of their MS 2
• As MS progresses, walking impairments become more severe and may have a greater impact on patients’ lives 3
67
• Treatment with fampridine is restricted toprescription and supervision by physiciansexperienced in the management of MS
• It is indicated for the improvement of walking in adult patients with multiplesclerosis with walking disability (EDSS 4-7)
• Initial prescription should be limited to 2 weeks of therapy as clinical
benefits should generally be identified within 2-weeks after starting
fampridine
• A timed walking test, e.g. the Timed 25 Foot Walk (T25FW), is
recommended to evaluate improvement after two weeks. If no
improvement is observed, the drug should be discontinued
• It should be discontinued if benefit is not reported by patients
Walking impairment in MS
Case report
• Patient continued worsening and referred that reaching the toilette from the living room (just about 10m) was very difficult.
• Fampridine was tried and a significant improvement of the Timed 25 Foot Walk and in the MSWS-12 was observed.
• Patient is now being treated in our centre by a multidisciplinary team
Learning objectives
• To review the current diagnostic criteria of PPMS
• To review the new MS phenotype classification
• To understand the current controversy surrounding management of risk factors
• To review the use of therapies