Monday, October 26, 2015

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

Wednesday, September 09, 2015

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.

Saturday, August 22, 2015

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.

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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This e-mail message, and any attachments, is intended only for the use of individual members of the Medical Partnership 4 MS (MP4MS) and should not be included into any medical records, notes or charts, and may contain information that is confidential, privileged and subject to legal restrictions and penalties regarding its unauthorized disclosure and use. Any unauthorized review, copying, disclosure, use or distribution is strictly prohibited. If you have received this e-mail message in error (or via forwarding), please notify the sender immediately by reply e-mail and delete this message, and any attachments, from your system. Thank you.
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Saturday, April 18, 2015

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. 

Wednesday, April 01, 2015

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. 

Saturday, March 28, 2015

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."

Friday, March 13, 2015

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.

Sunday, March 08, 2015

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.