Tuesday, December 02, 2014

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

Thursday, November 13, 2014

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.

Tuesday, November 04, 2014

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

Monday, October 27, 2014

Fingolimod, and macular edema: pathophysiology, diagnosis and management

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

Review article


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. 

Wednesday, June 04, 2014

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. 

Monday, June 02, 2014

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




Bulbous pemphigoid

Liver crisis

Treatment withdrawal a

Relapse on discontinuation



adverse effects tysabri and fingolimod misc




Bulbous pemphigoid

Liver crisis

Treatment withdrawal a

Relapse on discontinuation



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

Saturday, May 17, 2014

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. 

Thursday, April 17, 2014

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.

Monday, January 06, 2014

anti MOG antibodies phenotype in adults

  1. Angela Vincent, FRS. 
Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype Neurologyvol. 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