Induction v escalation therapy in multiple sclerosis

Buron MD, Chalmer TA, Sellbjerg F.  Initial high-efficacy disease-modifying therapy in multiple sclerosis. A nationwide cohort study. Neurology 2020; 9 5e1041-e1051

The initial treatment of MS is at times controversial, with some doctors adocating escalation therapy and others induction therapy or initial treatment with a stronger drug. This Danish study of patients on an MS registry, n= 194 between  2001-2018. Patients were categoroized as taking high efficacy DMT if they took Natalizumab, fingolimod, alemtuzuab, cladribine, daclizumab, or ocrelizumab and low efficacy if they started interferon B, teriflunomide, dimethyl difumarate or glatiramer acetate.   Endpoint was confirmed six month disability score on EDSS, and time to first relapse.  

Not surprisingly, highly effective DMT group had longer time to first relapse and lower rate of confirmed disability. 

Comment- As a cohort study, the paper has significant limitations, but the general idea seems obvious: treat early and hard.   Although entrants had to have an entry EDSS of less than 5.5, it is not known if there are subgroups that do just as well on medium intensity treatments.  

Canadian prednisone protocol oral for relapses

prednisone 50 mg
Number 125 tablets

Each day for five days, crush 25  tablets into powder, mix with orange soda take orally  

Piriformis muscle exercises

https://www.summitmedicalgroup.com/library/adult_health/sma_piriformis_syndrome_exercises/

Optimum study Ponesimod v teriflunomide

Ponesimod won decisively in this phase 2 study in RRMS. 1333 patients were randomized. Ponesimod group had lower ARR,  by 30 percent;  less combined unique active lesions (cual) by 56 percent, and less fatigue

Ofatumumab (Novartis) v. teriflunomide in 2 phase3 trials.  They had a lower ARR and time to confirmed disability. 

Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis

Barkhof F, Kappos L, Wolinsky J.  Neurology; 2019; e1778-1786.

Authors analyzed 163 individuals from partly blinded  phase II trials of ocre and 1656 from double blind phase 3 trials for MS who underwent q 4 week scans, Control group got interferon Beta in phase 3 trials, and 1/3 also got placebo in pahse 2 trials.    Relative to placebo, ocrelizumab produced reduction in MRI activity by week 4.  Relative to interferon beta 1a, there were less ARR by week eight.  

European website for medicines

https://www.ema.europa.eu/en/medicines

Bicams

https://www.bicams.net/

Symptom management in MS

Heat management

1.  cool pool

2,  Avoid hot showers

3. Hydration

4.  cooling vests and packs

5.  Lightweight clothes

6.  Rest after exertion



Spasticity management

1.  Stretching ROM

2.  yoga

3.  orthotics

4. Air splints

5.  relaxation techniques

6.  botox


Fatigue management

1.  Exercise 30 minutes five days per week

2.  Spasticity management-- esp stretching

3.  Postural stability esp truncal and core exercises

4.  Energy conservation-- rest breaks, prioritizing

5.  Mobility devices as appropriate

6.  Sleep management

7.  Healthy lifestyle and diet- low carbs

8.  Heat management

MS clinical resources that are commonly used

http://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-Researchers/Clinical-Study-Measures

Pearls on cognition in MS 2017 Consortium

1.  Ralph Benedict concluded that of all volume measurements the one that correlated best with cognitive deficits was third ventricle enlargement, and by inference thalamic atrophy.

BiCams is available for scoring in his website with normal

thalamic SHAPE also is important not just atrophy

Cognitive rehab works

CN atrophy corresponds with cognitive fatigue

Pearls on non MS demyelinating disease in kids

1.  CRION is rare in children is steroid dependent optic neuritis, relapse off steroids

2.  One presenter stated that ON + TM presentation "Devics presentation" has been MOG in "all cases she has seen"

3.  Pediatric NMO has more brain lesions

4.  4 MOG phenotypes in kids:  a.  Recurrent ADEM   b.  recurrent ON   c.  ADEM followed by ON   d.  NMOSD with MOG positive serology rather than Aquaphorin 4 positive

5.  No cases of simultaneous MOG positive and MS

6.  MOG has female predominance 1.5:1 and mean age of onset of 21

7.  MOG respods best to IVIG not Rituxan; has 20 % rate of relapses but they are bad relapses.

Source 2017 Consortium session on pediatric MS

Pediatric MS pearls

1.  PPMS is very rare before age 18

2. associations include lots EBV, early menarche, obesity, HLA DR1*15

3. Kids with MS look genetically like adults with MS

4.  Kids can have lesion disappearance between attacks that can be confusing

5. Teens have lots of cortical lesions, atrophy, that corresponds with IQ

6.  ADEM kids also have atrophy especially thalamus

7.  Need to be 11 to accurately use McDonald criteria

8.  Incidence is 1:100,000

9. Consider differential diagnosis in  kids including ADEM,NMO, MOG, CRION (see separate post).  Well trained radiologists can be very helpful. In a series of 110 kids with demyelinating disease, 56 had MS,  25 had NMOSD, 12 had ADEM and 5 had RION

10.  RR is 2-3 times higher and disability rate is higher

11.  Don't diagnose with a presentation of encephalopathy

source- lectures at Consortium meeting session on pediatric MS 2017

MS resources

SSD guide MS Society
nationalMSsociety.org/SSDguide

how to guide
checklist of actions to take
legal information

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Practical fitness online MS
range of motion
strength training workouts
designed for you
18.95 per month
20-30 minutes per day
new workouts every Monday
wheelchair and standup
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towel blizzard caps
tag along towels
great for MS patients going into sun
www.capkick.com
www.tagalongtowelblizzardcaps.com
stay cool in 100 degree heat

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www.Steelevest.com
cooling vests
1-888-783-3538

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MRI Funding Assistance
mymsaa.org/mri
or 1-800-532-7667 ext 120

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Dictus band- orthosis for drop foot
less expensive and simpler than AFO

cheaper yet AIDER band for dropfoot 9.99$

https://www.cascade-usa.com/cascade-media/pdfs/salessheets/ortoped_dictusband_salessheet.pdf

please note there are other suppliers, this is just one of them
-

Merry walker

Mary Harroun
21350 South Sylvan Drive
Mendelein IL 60060
ph 847-837-9580
f     847-837-8582

www.merrywalker.com

merrywalker@comcast.net

fingolimod associated peripheral adverse effects

Russo M, Guarneri C, Mazzon E, et al.  Mayo Clin Proc 2015; 90(10)1424-7

 

prurplish acral lesion reappeared with rechallenge four years after disease onset.  Another AE of fingolimod

clemastine for MS

The University of California, San Francisco (UCSF) initiated a clinical trial to evaluate the antihistamine clemastine fumarate, manufactured by Novartis as Tavist, for its efficacy in treating multiple sclerosis patients. The laboratory of Dr. Jonah Chan, a professor of neurology at UCSF, used a high-throughput method to identify Tavist and seven other Food and Drug Administration-approved medicines as potentially efficacious for multiple sclerosis therapy.

"A major unmet need in the development of therapeutics for repair in multiple sclerosis has been the ability to screen compounds in a high-throughput manner," said Dr. Chan in a news report. Along with lead author Feng Mei and collaborators from UCSF, Third Military Medical University in China, University of Cambridge, and Trianja Technologies in Texas, Dr. Chan published the team's research in Nature.

As described in the paper, the research team screened 1,000 bioactive molecules in a unique platform called "binary indicant for myelination using micropillars arrays." Among the molecules, eight had a positive effect on oligodendrocyte precursor cell (the myelinating cells of the brain) differentiation and remyelination. All eight worked through muscarinic receptors on oligodendrocyte precursors, but of the molecules tested, clemastine was the most potent.

After identifying the effects of clemastine on in vitro oligodendrocytes, the team moved on to in vivo studies to treat mice with spinal cord lesions. Just as in multiple sclerosis myelin is damaged, so to in spinal cord injuries is myelin damaged. Clemastine had a remyelinating effect on mice treated with the compound.

To see how clemastine affects multiple sclerosis patients and determine dosing requirements, clinical trials have been initiated, and the current Phase 2 trial is still enrolling patients. Researchers are primarily interested in the effects of clemastine on vision, but tolerability and disability changes are outcome measures, as well.

Outcome measures will be assessed at three and five months after taking a baseline at the beginning of treatment. Fifty patients will be treated for a total of five months in the crossover study. For the first three months, patients will receive either a 4 mg Tavist (clemastine fumarate) tablet or placebo twice daily, and for the following two months, patients will receive the alternate treatment (placebo or Tavist).

In addition to the clinical trial, a company focused on regrowing myelin has started on the basis of Dr. Chan's high-throughput method. Roche, which is the parent company of Genetech, and Versant Ventures, a Menlo Park-based venture capital firm, formed Inception 5 one month ago. Inception 5 is among a number of companies who have begun to focus on remyelination rather than only soothing inflammation and stopping myelin erosion.

Dr. Chan's research was backed by donations to UCSF's MS Research Group, UCSF's Clinical and Translational Science Institute, and the National Multiple Sclerosis Society. Although the study shows promise for Tavist as a  multiple sclerosis treatment, it is only approved as an antihistamine, and multiple sclerosis patients are urged not to self-medicate with Tavist because its effects are unknown for multiple sclerosis.

pacemakers and MRI

http://www.mypacemaker.com/mri-pacemakers/getting-a-pacemaker/index.htm?gclid=CjwKEAjwxMetBRDJx6Sz2p7DsQ0SJADJHAqNfosE_xSHoRpQbsztutw7Z1nEHSnYPjt0h7o7itPhRBoCRsnw_wcB

Is an MRI Compatible Pacemaker Right for You? MyPaceMaker.com Pacemakers with SureScan technology allow the wearer to have MRI scans. If you need a pacemaker and anticipate having MRI scans, learn about your options. Read more...

Fwd: [MP4MS] MRI safe pacers

 

=Basically there newer models of pacemakers that are MRI conditional given less use of ferromagnetic materials and more sophisticated circuitry. 

See this link for a list of those that are MRI conditional vs MRI unsafe (http://www.mrisafety.com/TheList_search.asp?s_list_description=pacemaker&s_ANYwords=&s_object_category=)   

If the patient has a MR conditional model they can undergo a 1.5 T MRI as long as set of very specific procedures are carried out. These procedures vary from manufacturer to manufacturer (most requiring informed consent and the involvement of cardiology assessing patient/pacer before and after the scan) and are available from the manufacturer's website. There are additional safeguards at each institution and in general everyone is very hesitant to do scans in people with pacers but things are changing.  While in the literature with different models patients have undergone scanning safely at 3T I don't believe that any of the models are technically approved at that magnet strength and we don't do them at 3T here.

Here is a nice overview of the issue from mrisafety.com, which is the MR bible on what is allowed into a magnet ( http://www.mrisafety.com/SafetyInfov.asp?SafetyInfoID=167)

 

 

From: seMSc@googlegroups.com [mailto:seMSc@googlegroups.com]
Sent: Tuesday, August 04, 2015 8:30 AM
To: seMSc@googlegroups.com
Subject: [MP4MS] MRI safe pacers

 

 

 

 to group:

 

What is the scoop on MRI safe pacemaker defibrillators?   A patient (daughter, an ER nurse)  told me she got a device that was not MRI safe due to "3 major companies" not offering MRI safe devices except in research, and considering but not getting MRI safe wires in case the safe pacemakers come out later and she changed the device.  Is there a particular company, brand, type of MRI machine that is compatible?    Also, she was told with this device she could get an MRI if absolutely needed if monitored apprpriately.  ???? Thank you.

 

Also, same patient, very interesting, has experienced repeated bouts of flash pulmonary edema/cardiogenic shock from which she recovers to a normal EF over time which may be an MS symptom ("neurocardunculus"). At one point wore a "temporary" life vest for months until improving, then was considered and declined for a cardiac transplant.  Cardiologist is stumped. At one point he thought it might be delayed event due to long ago novantrone, but recoveries and repetitiveness suggests otherwise. 

 

Daniel Jacobs, MD, FAAN

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Fingolimod and LV dysfunction

 

 

Daclizumab induced side effects

Oh J, Saidha S, Cortese I, et al.  Daclizumab induced side effects in multiple organ systems in multiple sclerosis. Neurology 2014; 82:  984-988.

 

Authors at Johns Hopkins MS clinic studied 20 patients on daclizumab.  After 20 months pstients got alopecia, rash, and breast nodules and lymphadenopathy that resolved with discontinuation. 

Fingolimod and MS: Four cautionary tales

editorial:  Bourdette D, Gilden D.  Neurology 2012; 79: 1942-3

 

This editorial goes with four case reports in same journal about fingolimod, One case report indicates a patient who developed tumefactive MS six months after starting fingolimod (Visser F. et al.).  Centonze et al. reported three patients who stopped natalizumab, three months later began fingolimod, and several weeks later experienced severe exacerbations.   Gross et al. describes marked exacerbations of MS that occur after stopping therapy with fingolimod (rebound type activity)/  Ratchford et al. described VZV encephalitis in a patient who was taking fingolimod. 

pearls on vaccines in MS patients

1.  Standard guidelines indicate use of a killed and not inactivated vaccine v. influenzae is safe, but it should not be given during a relapse.

 

2.  Response to vaccines is high in standard therapies, but two new oral vaccines have a slightly lower response:  teriflunomide in the 14 mg dose is effective in only 76 %  of one particular strain (v.about 90 %)

 

3.  Fingolimod was effective in only 54 % with weakness v. certain strains such as California strain.  However the incidence of influenza was comparable in patients and controls in this 2015 study published in Neurology.

Imaging characteristics of NMO-SD esp in brain; update

Kim et al.  MRI characteristics of neuromyelitis optica spectrum disorder: an international update.Neurology 2015; 84: 1165-1173

 

While the findings below are not considered pathognomonic, and do not even construe the "main" elements of the disease, they can be considered imaging pearls for NMO that may help differentiate it from  MS.

 

1.  Up to 46 % have involvement of the area postrema, which has been postulated as the port of entry in the CNS

 

2.  Callosal lesions occur in NMO SD but rather than being ovoid,  perpendicular, "Dawson's fingers" as in MS, have unique characteristics.  They are more likely periependymal, following the ependymal lining; they may be edematous and heterogenous forming a "marbled pattern,"; and may involve the whole thickness of the splenium in an "arch bridge " pattern. Clinical symptoms of callosal lesions have not been well described.

 

3.  Lesions involving the corticospinal tracts, unilateral or bilateral, that may be contigious and longitudinally extensive may occur, curiously, since the area is not rich in aquaphorin 4 receptor.

 

4.  Contrast enhancement in a marginated, subtle, multiple "cloudlike" pattern may appear.

 

5.  Optic nerve involvement tends to be more posterior, to involve chiasm and be bilateral

 

6. On MRS, myo-inositol is reduced compared to NAA in MS

More on risk of PML Annals article

The only published data on indices that I am aware of, is in the Annals publication ("Anti–JC Virus Antibody Levels in Serum or Plasma Further Define Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy", ANN NEUROL 2014;76:802–812). A couple of quotes that may be relevant to this discussion are pasted below. If anyone has information on PML in 'low titer positives' (index <0.9), I would appreciate receiving it. The official Biogen website, that gives updates on PML cases (https://medinfo.biogenidec.com/, accessed today) has this to say: "As of Mar 3, 2015, there are 278 natalizumab-treated MS PML patients with pre-PML samples collected at least 6 months prior to PML diagnosis. Of these 278 patients, 275 (99%) tested anti-JCV antibody positive prior to diagnosis and 3 (1%) tested anti-JCV antibody negative." However, there is no information on PML in low-positives.

Quotes from Annals article:

"Using the predicted probabilities from the combined data sets, PML risk estimates were generated for anti-JCV antibody index thresholds of 0.9 to 1.5 (Table 2). For anti-JCV antibody–positive patients with no prior immunosuppressant use and an anti-JCV antibody index at or below thresholds of 0.9 to 1.5, the risk of PML was approximately 0.1 per 1,000 patients during the first 2 years of natalizumab treatment, and it ranged from 0.3 to 1.3 per 1,000 patients from month 25 to 48 and from month 49 to 72. For patients with no prior immunosuppressant use and an anti-JCV antibody index > 1.5, the risk of PML was approximately 1 per 1,000 patients during the first 2 years of natalizumab treatment, and ranged from 8.1 to 8.5 per 1,000 patients from month 25 to 48 and from month 49 to 72.
...
Twenty-five natalizumab-treated MS patients with no prior immunosuppressant use who developed PML had at least 2 pre-PML samples. For 24 of these patients (96%), all samples had an anti-JCV antibody index- > 0.9, and for 21 of 25 patients (84%), all samples had an anti-JCV antibody index > 1.5 (Fig 5). In 1 patient, 3 of 4 available samples had an anti-JCV antibody index- 0.9, 2 of which were collected within 12 months of PML diagnosis."

PLEX for central demyelination

Magana SM, Keegan M, Weinshenker BG, et al.,Beneficial plasma exchange response in central nervous sytem inflammatory demyelination.  Arch Neurol 2011; 68: 870-878

 

Authors from Mayo Clinic reviewed clinical documentation for PLEX for 153 patients in inflammatory CNS demyelination seen over 2 year period.  Diagnoses included NMOSD, probable or definite MS, monophasic ON, ADEM, shorrt segment TM, and CIS.

 

 

Ninety patients (59%) showed moderate or substantial clinical improvement at six months. 

 

Patients with preserve deep tendon reflexes had a fourfold chance of positive response to PLEX

 

Plex responders had a shorter median diseae duration but not affected by gender, EDSS at time of initial attack, or time from index event to initiation of PLEX.

 

Most patients responded quickly, with a median response noted byt he third exchange.  A small subset,six percent, responded late by day 60.  Patients with RRMS had highest PLEX response of any of diagnostic categories (75 %, p<.008).  Progressive MS patients had a lower response rate (30 %).

 

Radiographic features associated with response were ring enhancement of lesions(82 v. 54 % response for non ring enhancement) and mass effect (75 % v. 50 % for non masss effect MRI's).These two patterns had four fold and three fold,respecctive increased chance of respone over patients lacking these features.

 

NMO serologic status was not important in this study for PLEX response.

 

Comment

see also Llufriu , Castillo J, Blanco Y, Neurology 2009; 73:949=953 for another clinical trial supportig use of PLEX is certain patients with MS.

 

Also note that the average EDSS of the patients in this study, both responders and nonresponders was 8.

Bowel regiment in MS

Bowel incontinence in MS occurs in two principal situations…(1) an augmented gastrocolic reflex (colonic motility with gastric distention) with postprandial urgency (may or may not sense the colonic movements) and (2) reflex bowel emptying when the rectum becomes full.

 

Getting the bowel to empty regularly and predictably  is the best prevention for reflexive incontinence. Using a pad is important for smaller episodes and confidence. Carrying a change of underclothes/pants is important.

 

First, parous women may have pelvic floor abnormalities which increase the likelihood of incompetence of the sphincter and urology or gynecology should evaluate.

 

Second, most medications with anticholinergic actions depress the forcefulness of the reflexes and help to manage urgency.

 

I don't find a low residue diet helpful. The most helpful is regular BMs. We call this "a bowel regimen." It is similar to what is used for constipation.

 

History should include the number of BMs. If this is infrequent due to constipation, then augmentation with PEG is used in the dose which regularly will produce a daily DM (1/2-2 doses a day).

 

To assure regular emptying, each AM they are instructed to have a hot drink for breakfast, preferably coffee, and go to bathroom to have a BM after. They are to use a glycerin suppository for stimulation if it does not occur in a timely fashion. If this is not routinely successful, a Dulcolax suppository can be used.

 

Those with frequent episodes usually require pharmacotherapy to impair the reflex oxybutynin, hyoscyamine typically. A strong gastrocolic reflex may require using the bathroom on a schedule multiple times a day postprandially.

 

For those with really aggressive hypermotility and more watery stool situations, cholestyramine is the best strategy,  and finding the right dose usually greatly improves the frequency. Loperamide usually is helpful only in the most severe diarrheal cases, but sometimes helps.

 

GI evaluation is often fruitless. After a colonoscopy patients are usually told there is nothing to do. However, bloody or painful stools, or severe constipation or diarrhea, should have GI review.

Active v. progressive classification of MS

Lublin FD, Reingold SC, Cohen JA, et al.  Defining the clinical course of multiple sclerosis: the 2013 revisions.  Neurology 2014; 83:278=286.

 

The new classification supplants the 1996 version by Lublin et al. with four types of MS.  Old system has PPMS, RRMS, @PMS, and progressive relapsing.

 

New classification adds CIS, NOT RIS

deletes progressive relapsing

 

Active MS is those who have clinical relapses or worse MRI's in one year time frame.

worsening MS is impairment due to relapses

progression is progression of disability in a patient with progressive MS independent of relapses

 

Thus patients may have relapsing MS that is active or inactive,  with or without worsening

 

and may have primary or secondary progressive disease that is active or inactive with or without progression

 

Confirmed worsening specifies a time perido and replaces sustained worsening. 

 

Benign and malignant MS are retained but to be used sparingly

Parent of origin effects in inherited MS

Herrera BM, Ramagopalan SV, Lincoln MR, et al.  Parent of origin effects in MS. Observations from avuncular pairs.  Neurology; 2008: 71:799-803.

 

Genetics review of MS.  The risk for a first degree relative of an MS proband of 3-5 % is 30-50 times higher than the general population (0.1%) and vary by relatedness and number of affected individuals in family.  There is agreement that there are a number of genes of small effect interacting with the environment. 

 

This study used avuncular pairs and found a strong predilection for maternal gene of origin in 871 families surveyed.  After removing families where the parent had MS, there were 807 families with 938 avuncular pairs.  There were 526 maternal pairs, and 412 paternal pairs which was highly significant (McNemar test).

 

Moreover, the niece to nephew ratio of 2.67:1 was higher than the aunt/uncle ratio of 1.85.  In paternal families only, the ratio was higher in families with an affected aunt. 

 

Authors note that in Canada the increase is MS is noted to be due to increased number of females. 

 

The gene of locus is not known.

 

Authors also note the May birthday peak and November birthday nadir for MS births.

Dalframpridine and trigeminal neuralgia

Birnbaum G., Iverson J.  Dalfampridine may activate latent trigeminal neuralgia in patients with multiple sclerosis.  Neurology 2014; 83: 1610-12.

Of 71 patients in MS clinic given dalfampridine, 5 had a history either of trigeminal neuralgia (TN) or altered facial sensation.  One with altered facial sensation developed TN after starting dalfampridine x 18 months.  Pain subsided when dalfampridine was stopped.  Three other patients had marked worsening of TN after starting dalfampridine, became refractory to medicinal treatment, and in one case required surgery for pain control

Moral- use dalfampridine with caution in patients with preexisting TN.

Aubagio and birth defects

Annette M. Langer-Gould, Neurology 83; 2014:1685.

response to a letter to editor.

Teriflunamide is the active ingredient of leflunomide.

Published literature has about 100 pregnancies with accidental exposure.  There were 56 live births from 64 women with an average of 3 weeks of postconception leflunomide exposure, of which 95 % underwent rapid elimination.  Three of 56 (5.4 %) had major structural defects , 47 % had 3 or more minor structural anomalies, and 35.7 % were delivered preterm.  Exposed infants were significantly smaller at birth and postnatally. 

Recommendation is that a woman on teriflunomide desiring pregnancy should stop medication untila  safe leflunomide level is reached either by natural elimination (approximately two years) or a rapdi elimination procedure.

based on Langer Gould AM.  The pill x 2: what every woman with multiple sclerosis should know.  Neurology 2014; 82: 654-655

Fingolimod, and macular edema: pathophysiology, diagnosis and management

Cugati S. et al.  Neurology Clinical Practice, October, 2014

Review article

Pearls

1. Mechanism is drug acts of S1P3 receptor as agonist, reducing the tight junction between the endothelial cells of the retinal capillaries. Fluid accumulates in outer plexiform layer and the inner nuclear layer resulting in swelling of the Muller cells of retina.

2.  OCT is recommended at baseline, 3,6, months and then annually.  LATE  onset ME (>12 mo) HAS BEEN REPORTED

3. Risk is increased in  diabetic, h/o uveitis, undergoing surgery eg. cataracts

4. Treatment is stopping drug; anti-inflammatory medications can be used

5.  The BRB (blood retinal barrier) , located in the retinal pigmented epithelium and retinal capillaries, can also be injured by VEGF, angiotensin 2thiazolidinediones (rosiglitazones, pioglitazeones), taxanes (docetaxol, paclitaxel), tamoxifen, niacin, and interferons.  Ocular drugs can cause ME including PG analogues (latanoprost, bimatoprost, travopost), epinephrine, beta blockers (timolol, betaxolol) and mechanical factors such as vitreomacular traction

6.  ME was more common in MS patients with previous optic neuritis

7.  Proposed mechanism is focal intraretinal microglial activation and inflammation resulting in retinal neuronal and axonal injury AND  breakdown of the BRB, which may occur in conjunction with breakdown of the blood brain barrier.

8.  Risk of ME is dose dependent; in pivotal trials the  risk on the 1.25 dose was 1- 1.6 %; among those on the 0.5 mg dose it ranged from 0-0.5 %, 

9.  Age > 41 is an additional risk factor. 

10. Clinical presentation can include reduced vision, contrast sensitivity, and altered color vision; occasionally metmorphopsia or micropsia, or relative or absolute scotoma.  Diagnosis without OCT can be made from dilated fundus exam  with slit lamp or contact lens; findings include elevation of retinal, intraretinal cysts as an altered light reflex esp. with green light, and late fluorescein leakage. 

ADEM pearls

old paper, useful insights

Menge T, Hemmer B, Nessler S et al  Acute disseminated encephalomyelitis: an update. Arch Neurol 2005; 62: 1673-1680

 

1.  Consider a temporal relationship to a vaccine or infection.  If vaccine, especially MMR, also polio and European tick borne encephalitis vaccination. Many organisms are related, but temporal relationship is almost always within 3 months.  Average latency however is 4-13 days.

2.  No sex preponderance in ADEM.  Also, although it occurs most in children, adults of any age can ge the disease.

3.  Measles vaccine associated ADEM is 10-20 / 100,000 whereas ADEM after measles encephalitis is 100 per 100,000.

4.  Upper respiratory infections (URI's) with fever occur in 50-75% of cases.


5.  Children present with fever and headaches, adults with motor and sensory deficits.

6.  Bilateral optic neuritis appears to be associated with chicken pox and has a less polysymptomatic course.

7.  12.5 % of kids , and 37-58% of adults may have OCB's, these often are transient. 

8.  apl AB syndrome may mimic ADEM in kids

9.  Flareups while tapering medication eg. steroids should be regarded as flare ups of the initial monophasic courese (multiphasic disseminated encephalomyelitis or MDEM) not as MS which is the chief dDx of ADEM

10. Authors propose pulse iv steroids for 3-5 days, followed by prolonged oral prednisone taper over 3-6 weeks. Second line is plasma exchange, third line is immunosupression, cyclophosphamide or mitoxantrone. 

Alochol protective against MS

Hedstrom AK, Hillert J, Olsson T et al.  Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk.  Jama Neurology 2014; 71: 300-305.

 

2 case control studies were combined looking at , in first, 745 cases and 1761 controls; and in the second 58 74 cases and 5246 controls.  There was a dose dependent inverse association between alocho consumption and risk of developing MS in both sexes.  Women with high etoh consumption had an odds ratio of 0.6, and men, 0.5 in EIMS, and was 0.7 in both sexes in GEMS.  Moreover the detrimental effect of smoking was higher among nondrinkers. 

antiMOG seronegative NMO

Kitley J, Waters P, Woodhall M, et al. Neuromyelitis optica spectrum disorders with aquaphorin-4 and Myelin-oligodendrocyte glycoprotein antibodies: a comparative study.

 

see Levy M. Does aquaphorin-4-seronegative neuromyelitis optica exist? (editorial) JAMA Neurology 2014; 71:271-2.

 

Authors of both studies ferret out a subtype of seronegative NMO that is actually yet another disease.   Anti MOG positve patients with clinical features of NMO have a slightly different phenotype with features of ADEM also.  This group encompasses young males with severe episodes with better recoveries that are more likely to be monophasic, sometimes with simultaneous or rapidly sequential optic neuritis and transverse myelitis.. AntiMOG patients also had more conus involvement on spine MRI and more involvement of deep gray nuclei on brain MRI.  There were no patients with both anti MOG and anti AQU4 antibodies.  anti MOG antibodies are available at Neuroimmunology Testing Service, Oxford, England for 30 pounds).  "n" of the study was 10 aq-4 patients and 9 MOG AB patients. 

 

More clinical information:  4/9 anti MOG and 6/20 AQU$ AB patients had ON as initial invoolvement or part of ; anti MOG had more bilateral ON involvement (75 v. 33 %); both had severe ON when it did happen.  12/20 AQU$ 4 and 9/9 antiMOG had spinal cord involvement initially; Transverse myelitis differed with more bladder involvement in anti MOG patients as iniital symptom (33 v. 0 %) and more late sphincter disturbance in NMO ab patients.  Brain MRI was more likley to be ADEM like in MOG ab patients (44 %) v. 0 % in NMO. 

cog research tidbit on ms

Types of memory loss in ms

Meta memory

Cognitive fatigue

Social emotional function  

Mspt Rudick has iPad based testing self administered

Patients self report of symptoms correlate except for cognition have anosognosia

Social cognition measures WMO nonexistent

Std tests for research discount individual need for test

 

misc adverse effects tysabri and fingolimod

Tysabri

Alopecia

Dermatographia

Bulbous pemphigoid

Liver crisis

Treatment withdrawal a

Relapse on discontinuation

Fingolimod- 

nephrolithiasis

adverse effects tysabri and fingolimod misc

Tysabri

Alopecia

Dermatographia

Bulbous pemphigoid

Liver crisis

Treatment withdrawal a

Relapse on discontinuation

Fingolimod- 

nephrolithiasis

MS Consortium notes 2014 on pathology of MS

Miscellany Consortium 2014

 

MRI pearls

 

1)  T2 much better than flair in post fossa

2)  Black holes can resolve sometimes; these are "active black holes"

3)  Enhancement doesn't equal active lesions;  consider eg. whether used image delay, whether received  recent steroids,  gad dose, fluctuating enhancement

4)  Uspio may be better? Need 24 hour delay to image. Stay positive  longer than gado

 

Pathology types and MRI pearls

 

type 1 associated with macrophages

Type 2 associated with complement deposition and antibodies 

Type 3 associated with apoptosis

type 4 associated with mitochondrial injury

 

MRI correlates

 

Patterns one and 2 sharp border; ring enhancing often is macrophages full of iron patterns; also hypointesne rims; Ring on afc correlates with hypo intense rings but not  with gad ring enhancement

 

Pattern  3 mixed  border, no enhancement

Late progression compartmentaluzed inflamm with no gado enhancement

Includes meningeal inflammation = sub pial and slow progression older lesions these are hard to see even with 8t machines

Some disease is due to mitochondrial activation with oxidative injury

Dir wasn't correlated with path till 2012

 

Patterns of enhancement diffuse modular ring enhancing

Differential diagnosis: 

1,  Adc maps ms v abscess/tumor dark ring arc pattern  V.Isointense ring pattern 

2.  Rapid shifts of adc typical ms not abscess/tumor 

3.  Ring enhancement and rim enhancement and response to plasmapheresis and steroids with type one and two

 

4.  Nmo brain lesions in two and three

 

Concept of heterogeneity across patients and homogeneity within patients key

Also different bio markers

Fingolimod and atrial fibrillation

Rolf et al.  Paroxysmal atrial fibrillation after initiation of fingolimod for multiple sclerosis treatment

 

42 year old male had PAF on initiation, resolution on withdrawal of, recurrence on reinitiation and reresolution permanently on discontinuation of fingolimod.  Extensive cardiac testing was negative.   This is different than the bradycardia that is known to occur with fingolimod which requires initiation with cardiac monitoring. 

 

Authors note that fingolimod is an agonist of S1P-R1,2,3 in cardiovascuklar system.  In atrial myocytes, binding of the receptors causes activation of the potassium channels leading to an inward K current and decreased firing rate.  Therefore drug causes bradycardia or AV conduction blockade.  There is in animal models, S1P induced reperfusion tachyarrythmias. 

Fingolimod and birth defects

Karlsson G, Francis G, Koren G, et al. Pregnancy outcomes in the clinical development of fingolimod in multiple sclerosis.  Neurology 2014; 82: 674-680

 

and editorial Langer-Gould AM.  The pill times 2:  What every woman with multiple sclerosis should know.  Neurology 2914; 82: 654-5.

 

FDA required a pregnancy registry with approval of new MS drugs, including fingolimod.  66 women in clinical trials had unplanned pregnanies.  20 had elective abortions, 41 attempted to carry to term, of which 26 had healthy appearing babies, 9 had spontaneous abortions in first trimester,  4 pregnancies were terminated due to fetal abnormalities and 2 were born with major malformations including tetralogy of Fallot, failure of development and acrania.

 

Authors note that new orals (unlike monoclonals and first generation platform drugs) are small molecules that cross the placenta readily.

anti MOG antibodies phenotype in adults

1. Joanna Kitley, BM, BS*, 
2. Mark Woodhall, PhD*, 
3. Patrick Waters, PhD*, 
4. M. Isabel Leite, DPhil, 
5. Emma Devenney, MB, Bch, BaO, 
6. John Craig, MB, Bch, BaO, 
7. Jacqueline Palace, DM and 
8. Angela Vincent, FRS. 

Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype Neurology September 18, 2012 vol. 79 no. 12 1273-1277

Authors report one group of "seronegative NMO" of four patients with clinical symptoms mimicking NMO (LETM and ON) .  They call this a typically monophasic disorder more akin to Devic's than to NMO.  ON and TM may occur together, patients are more likely to be male and younger and have more favorable outcome.  Additionally, those with seropositive NMO did not have anti MOG.

Differential diagnosis of LETM includes NMO/NMOSD, anti MOG, ADEM and postinfectious.  Elsewhere Weinshenker advocates for cervical spondylosis/spinal stenosis being in differential (think signet ring MRI sign) also see other posts this blog 

EFrohman cocktail for reducing side effects of tecfidera

1. 0.5 to 1 mg of glycopyrrolate (Robinul) for GI

2. Baby ASA + 10mg of Zyrtec for flush, hot, etc. 

Above taken 30-60 minutes before both doses (NOT concomitantly). 

Then take Tecfidera with a cup of applesauce (or more food). 

2-4 weeks of this then attempt to withdraw. Some can, some cannot. 

I will tell you all, the above has been magic in a number of our "ready to jump ship" patients. It's reduced our 30% down to less than 10% withdrawal. Perhaps our percentage of intolerant patients is higher than most, but Bob Lisak told me last night, this was his number as well. 

Pearls on mitoxantrone related leukemia and toxicity

review article  Chan A and LoCoCo F.  MTX related acute leukemia in MS. An open or closed book>
Neurology 2013; 80"1529-33.

Pearls

1. Current therapy related risk is 0.81 % but varies widely among countries.  It still is current therapy in many parts of Europe with different protocols in different countries.

2. Therapy related leukemia is specifically acute promyelocytic leukemia (the "other" PML). This may be due to preferential attachment to DNA breaks at the PML gene site locus.

3.  Genetic variants of dna repair genes  BRCA 2 (rs1801406) and XRCC5 (rs207906) and detoxification enzyme CYP384(rs2740574) may predispose to apml. Combinations of first two lead to 50 fold increase in risk of MTX associated leukemia in MS patients.

4.  Early MTX cardiotoxicity is associated with a rare ABC transporter genotype leading to increased intracellular MTX levels.

5.  aPML is aggressive and often fatal within hours or days if NOT recognized, but a very treatable form of leukemia if recognized and diagnosed promptly.  80 % curable with all trans retinoic acid and arsenic trioxide together with anthracycline chemotherapy, which is true also for MTX related forms.

6.  Presentations of aPML: bruising, petechiae, anemia, thrombocytopenia, infections related to neutropenia and immune dysfunction,  lymphadenopathy and splenomegaly,  and systemic symptoms including fever and weight loss.  Leukocyte nadir occurs 10-14 days after treatment and returns after 21 days, monitoring is crucial.

7.  Other tests that hav potential value in assessing include blood smear, aPTT, fibronogen, d-dimer, LDH, and bone marrow biopsy.

8.  aPML may occur up to five years after therapy so vigilance in surveillance is indicated.

Pearls Frohman's talk on symptom management AAN 2013

1.  70 % of MS patients have impaired sweating, or delayed sweating.  This complicates efforts to manage heat intolerance.

 

2.   Pulfrich's sign after optic neuritis is very common and can present as dizziness or sensation of discomfort with moving cars, roller coasters, etc.  It is easily treatable with tinted lenses.

 

3.   Uhtoff's sign and L;Hermitte's sign each have many and varied analogues in systems throughout the body besides just the visual and c spine areas.

 

4.  Calls "MS hug" the "anaconda sign"

 

5.  Beware of infections in MS patients, compare temperature against their true baseline temp.  If they run 97 degrees, then 98.2 can represent a fever and an infection.

 

6.  Reverse Uhtoff's occurs when MS patients are sensitive to cold temperatures.

 

7.  Bronson's vitamins, available online are effective in some patients with fatigue and contain carnitine

 

8.  Before prescribing anticholinergics, check a PVR if high check for pelvic floor abnormalities, allow patients to double and triple urinate if needed to relax and get the number down.

 

 

IRIS and Tysabri related PML

Tan IL, McArthur JC, Clifford DB, et al.  Immune reconstitution syndrome (IRIS) in natalizumab associated PML.  Neurology 2011; 77: 1061-1067

Patients in literature (42) were generally managed with discontinuation and PLEX/IA.   17 patients had contrast enhancement at time of discontinuation (early PML-IRIS) and 20 developed it later(late PML-IRIS).  load All patients developed IRIS.  Among early IRIS patients, JC virus load increased tenfold, among late IRIS patients, load increased  lesthan two fold.  All patients had worsening EDSS after discontinuation of natalizumab, but early IRIS patients did far worse. Mortality was about the same in early IRIS and late IRIS groups  20-30 %, slightly worse in early group.  Corticosteroid therapy was associated with better EDSS outcome/score.  

Conclusion:  PLEX may accelerate IRIS, corticosteroids may be beneficial and may require a larger study to confirm.

Notes
there are also 2 forms of IRIS in HIV literature
there is no effect of prior immunosuppression

mefloquine and mirtazepine did not seem to help although this was not purpose of study
adjuvant steroids help another iris like syndrome, TB meningitis in HIV negative patients that helps survival.

Two new studies on BG 12 a new oral for MS

Gold R et al. Define Investigators.  Placebo-controlled phase 3 study of oral BG12 for relapsing multiple sclerosis. NEJM 367:1098-1107 , 2012

Fox et al.  CONFIRM investigators.  Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.  NEJM 2012; 367: 1087-1097.

DEFINE  1234 patients were randomized and received at least one dose of meds (BG 12 , 240 bid, BG 12 240 tid, or placebo), about 400 per group.  Primary endpoint was number with relapse at 2 years.  Secondary endpoints were ANNUALIZED RELAPSE RATE, TIME TO CONFIRMED PROGRESSION OF DISABILITY, AND MRI FINDINGS. 

Results favored BG-12. Percent with relapses were 27 and 26 % in two BG 12 groups and 46 % with placebo, p<.001 for both.   ARR was .17, .19, and .36 again favoring BG 12. Percent with confirmed disability was 16 %, 18 %, and 27 % respectively favoring BG 12.  MRI  was also better. 

Patient selection:  age 18-55, EDSS ranging from 0-5, one relapse clinically or by MRI in period before entry into study.  198 sites in 28 countries participated with 1:`1:1 randomization. Baseline characteristics were similar in patients.  Patients could switch therapy if they completed 48 weeks of study or developed confirmed worse disability.Half in MRI study.  78 % completed study with similar rates of withdrawal in the 3 groups.  Time to first relapse was 37 weeks (placebo), 87 and 91 weeks in 2 BG 12 groups. 
Safety: key events were nausea, vomiting, abdominal pain, pruritus, flushing, and PROTEINURIA ( 12 %).  3 % had elevated LFT's esp first six months.

CONFIRM
1430 patients were randomized, and patient 18-55, EDSS 0-5, one relapse or MRI change before initiation into study. 1:1:1:1 groups including bid and tid BG 12, placebo and  glatiramer.  Study went 96 weeks.  Primary endpoint was ARR, secondary endpoints were (in an MRI subcohort) new and enlarging lesions, enlarging T1 black holes, proportion of patients with relapse, and proportion with disability progression at two years. Dropout rates were higher in placebo group. 
ARR was 0.22, 0.2 and 0.44 favoring BG12 against placebo, and rate was .29 for glatiramer. 
Study was not powered to compare BG 12 and glatiramer.  Disability was not affected significantly in any group at 24 weeks.  All three non placebo groups had better outcome on MRI for new T1 black holes, number of new and enlarging lesions, and gado enhancing lesions. 

Comments:
Exciting data.  CANNOT compare BG 12 and glatiramer.  Define but not Confirm showed benefit for disability.  Both studies showed benefit on relapse rates, and MRI although MRI was subgroup analysis in both studies. 

Signals for many immunosuppressant drugs and PML

Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS); Schmedt N, Andersohn F, Garbe E; Pharmacoepidemiology and Drug Safety (Jul 2012)

 

PURPOSE: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system that has been reported as rare adverse drug reaction (ADR) of immunosuppressive drugs. We aimed to study signals of PML for immunosuppressants using a disproportionality analysis of spontaneous adverse event reports. METHODS: Within the US Adverse Event Reporting System, we analyzed all reports of ADRs submitted to the US Food and Drug Administration between January 1, 2004 and September 30, 2010. We used univariate and multivariate logistic regression analysis to calculate reporting odds ratios with 95% confidence intervals of PML for immunosuppressants according to the Anatomical Therapeutic Chemical classification system (L04), rituximab and cyclophosphamide compared to all other drugs. RESULTS: We identified 635 PML cases in a total of 1 978 706 patients eligible for analysis. Altogether, 21 out of 36 analyzed immunosuppressants were reported at least once with PML. In the univariate analyses, we found a signal for 11 of these drugs (azathioprine, cyclosporine, cyclophosphamide, efalizumab, leflunomide, methotrexate, mycophenolate mofetil, natalizumab, rituximab, tacrolimus and sirolimus). In the multivariate analysis, the signal was no longer present for sirolimus, leflunomide and methotrexate. DISCUSSION: Our study revealed signals of PML for a substantial number of immunosuppressants, including some drugs less considered so far as a risk factor of PML, especially when used for the treatment of autoimmune disorders. These drugs and possible interactions between different immunosuppressants should be studied more closely in future studies. Copyright © 2012 John Wiley&Sons, Ltd.

Interferon B for SPMS: a systematic review

La Mantia L, Vacchi L, Rovaris M et al.  JNNP 2012

Cochrane analysis of placebo controlled trials 1995-2012. 5 trials, 3082 patients. IFN did not reduce disability progression, there was small decrease in relapses, cognition not studied.  More treated than placebo patients dropped out.  Conclusion: Only use IFN in selected patients with active disease to reduce risk of disabling superimposed relapses.

Comment (blogger).  If patients are relapsing they have RRMS.  SPMS is diagnosed and differentiated from RRMS as an art form.

Emerging therapies in MS AAN 2012 Mark Freedman

Random Notes

 

1.  Tereflunomide- blocks de novo synthesis of pyrimidine synthesis

 

"Nobody has a clue how these things really work"

 

2. TEMSO  2 doses used 7 and 14 mg decreased RR, time to attack, and EDSS progression at 2 years and disease activity free measure increased by 60 percent  with higher dose, decreased Gd+ lesions

 

3. Minor safety issues minor GI , hair thinning (reversible) ; decreased pain (???)

 

4.  TENERE  -- primary point not efficacy but effectiveness which comparator Rebif.  looked at time to treatment failure due to relapse or AE's leading to stop drug.  RR similar except low dose, but effectiveness was better with tereflunomide.LFT's only thing seen reliably.

 

5.  Add on therapy to IFN or GA, patients doing well, added on TFN, did not need attack, just stable dose of drug or placebo, added TFN.  Patients doing well, followed with monthly MRI's, half patients had a Gd+ lesions (.57) decreased 80 % when TFN added.  patients doing well were not doing so well, even without relapses.  Keracles is a phase 3 study of combined.  IFN + TFN > GA + IFN

 

6.  BG 12 blocks NF pathway.  - no effect of BG 12 until got to dose of 240 bid.  bid v tid (240 mg) improved RR , EDSS 9by 30-40 %).  Curves for rr split at 6 months, why ph 2 study (6 month trial) failed, but effect persists and sustains. 

 

7.  Confirm:  beats GA for RR and MRI. 

 

8. DEFINE -- 30 % dropout, mostly flushing and nausea.  Used in Germany for years

 

9.  Laquinomid-- Allegro and Bravo.  23 % reduction RR overall, 36 % reduction risk to progression, modest effect on MRI, well tolerated.  Rare LFT elevations.Did not beat avonex for rr.  EDSS progression "barely significant " for laquinomid.

 

10. alemtuzumab. 

 

Care MS I (naive patients).less than 5 years into disease, EDSS < 3. 

.39 RR, much better with alemtuzumab, EDSS progression, only 11 % progressed in IFN arm, not powered to see .  MRI affected positively at 2 years.  AE's: minor infections, infusion reactions. AI disease; Graves, mild to moderate, usually managed effectively with tapazole.  ITP picked up in 4 patients.  May be a biomarkers to predict ITP.

 

Care MS 2- breakthrough patients with activity. EDSS < 5, years of disease < 10.  2+ attacks in 24 months before entry. 1+ attack during therapy with IFN.  Was 49 % reduction in RR, 42 % risk reduction of sustained disability.

 

1. Daclizumab-- anti CD 25 effect-

 

RR

 

Average duration of disease in initial trials was seven years, so there is a huge difference in timing of treatment

 

 

natalizumab Omar Khan AAN 2012 notes

These are random notes of interest

 

1  Natalizumab was originally used for MS relapses in the 1990s, published in Neurology; negative study but a secondary outcome , on gad enhancement was positive.

 

2. A later trial by David Miller, sequential trial was also positive and focus changed.  There also was a resurgence of disease activity noted even then when treatment ceased.

 

3.   Khan open label study sequential failure on GA/IFN then change to NAT with no change with first switch, but dramatic decline in RR after second switch to NAT with significant MRI findings as well. Old study, about to be published.

 

4.  Suggests usefulness in non aggressive "run of mill " disease.  Tissue repair study with voxel wise MTR imaging, tracking lesions longitudinally

 

5. Risk management: usually 5 issues: infusion reactions, NAB's, hepatotoxicity, malignancies, opportunistic infections.  Rare cases of toxo, lymphoma but PML is king

 

PML-- mean duration of dosing was 34.1 months, range 8-67 doses.  Overall incidence is 2.08/1000 (CI 95 % 1.8 to 2.39) 3 risk factors. 

 

42 patients have died, 159 alive (79 %) but 80 % plus have severe disability among survivors.

 

3-4 x rise in risk with prior IS use, even one dose, across board therapies.

 

JCV Ab conversion rate is approximately 2-3 percent per year

 

6.  "Not a clear path" how to treat patients when they come off natalizumab

MS notes AAN meeting Gilenya 2012

Jeffrey Cohen on Gilenya

 

1. O.5 mg daily is only approved dose, lower doses are being tested

2. May take a month or more to completely clear out of system

3. Caution in patients with severe liver disease

4.  Drug interactions occur with inhibitors of liver metabolism, esp ketoconazole; drugs that lower heart rate (beta blockers and calcium channel blockers), drugs that affect QT interval esp amiodarone, other antiarryhtmics which could cause Q onT phenomenon and tachyarrythmias. 

5.  In their center they weight at least three months to switch onto gilenya from natalizumab, etanercept and other antiimmunosuppressants

6.  Freedoms, about 50 % decrease in relapses, slowing brain atrophy, disability v. avonex and placebo

7.  Musculoskeletal side effects including back pain and others is common.

8.  Lymphocyte counts come back within 1-2 months after stopping drugs, although it is longer in some patients.

9.  Relationship between lymphocyte count in blood and infections is tenuous or nonexistant, tend to ignore .

10.  Case of PML reported : details dx ms in 2007, treated with interferon, then natalizumab in 2008, found to be seropositive to JCV antibody in 2011 and changed to Gilenya.  MRI at that time showed one new lesion, which actually was likely first PML episode.  Later treated with steroids for a relapse, no benefit, visual changes led to stopping gilenya after fourteen weeks, PML found, but was there before starting drug.

11.  HR stays abnormal for up to a month and gradually returns to normal.

12.  Holter before hand is useless

13.  Patient death 23 hours after first dose in November 2011: details:  EMA (Europe) and FDA reviewed.  Recommendations are similar.  CHMP recommendations: stronger language for patients with contraindications, including prior cardiac and CVD which require overnight monitoring, not just overnight;caution in patients on certain drugs, liberal use of cardiology consultation.  First dose monitoring should now include VS and EKG prior to dosing, continuous monitoring during dosing.  Extend monitoring until HR has increased at least two consecutive hours, and if concern, monitor overnight. In USA, less tringent changes for first dose monitoring: EKG prior to dosing and prior to discharge; monitor at least six hours, do hourly VS during dosing.  D/C criteria similar to Europe.  Overnight monitoring for those with symptomatic bradycardia, QTc pronlongation or conditions that would predispose to QTc prolongation.

14.  In first two weeks, repeat induction if they skip one day; in second two weeks, if they skip a week; subsequently if they miss two weeks of therapy.

15.  HTN during gilenya beware of.

16.  Macular edema:  half time is symptomatic (blurring), half time asymptomatic.  Usually unilateral, may b bilateral.  Increased in diabetics, (excluded in ph 3 trial), higher dose, and those with uveitis and ? ON.  Reverses within several months if drug is discontinued.

17.  Cases exist of MI, CVA, PRES, others.  HA's seen in trials and is the most frequent reason to discontinue medication:  exacerbation of preexisting migraine.

18.  Sense of SOB or cough

 

Summary-- his opinion-- used in 800 patients.  Check  LFT's no CBCs, OCT repeated after 3 months

Using in RRMS Approved as first line therapy but actually use less often.