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

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. 

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

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

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 

Saturday, August 10, 2013

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. 

Thursday, July 04, 2013

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.

Monday, June 17, 2013

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.
 
 

Sunday, February 10, 2013

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.

Friday, October 05, 2012

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. 

Saturday, September 29, 2012

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.

Saturday, September 08, 2012

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.

Tuesday, September 04, 2012

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

Sunday, September 02, 2012

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.

Tuesday, May 15, 2012

Drugs that affect or may affect qt interval

Biggest problem is the proven drugs to cause torsades (drugs we see a lot)
Citalopram Celexa® Anti-depressant / depression
Erythromycin E.E.S.® Antibiotic;GI stimulant / bacterial infection; increase GI motility
Haloperidol Haldol® Anti-psychotic / schizophrenia, agitation When given intravenously or at higher-than- recommended doses, 
Methadone Dolophine® Opiate agonist / pain control, narcotic dependence
Quinidine Nuedexta® for PBA
 
The possible list to cause torsades, which is in my mind, the same risk as those above (drugs we use a lot):
Amantadine Symmetrel® Dopaminergic/Anti-viral / Anti-infective/ Parkinson's Disease
Dolasetron Anzemet® Anti-nausea / nausea, vomiting
Escitalopram Lexapro® Anti-depressant / Major depression/ Anxiety disorders
Famotidine Pepcid® H2-receptor antagonist / Peptic ulcer/ GERD
Fosphenytoin Cerebyx® Anti-convulsant / seizure
Granisetron Kytril® Anti-nausea
Levofloxacin Levaquin® Antibiotic / bacterial infection
Quetiapine Seroquel® Anti-psychotic / schizophrenia
Risperidone Risperdal® Anti-psychotic / schizophrenia
Tizanidine Zanaflex® Muscle relaxant
Venlafaxine Effexor® Anti-depressant / depression
Ziprasidone Geodon® Anti-psychotic / schizophrenia
 
The conditional ones (which we see used sometimes) which given the right circumstances (OD, drug interactions) cause torsades
All tricyclics (amitriptyline, doxepin, despipramine, imipramine, nortriptyline, trazodone among others).
Cyclobenzaprine is a tricyclic.
All other SSRI paroxetine, fluoxetine (not enough data on duloxetine milnacipran)
All fluoroquinolone antibiotics and TMP SMX
And azole antifungal agents
 
So ALL antidepressants, ALL antipsychotics, most muscle relaxants, most antibiotics. Don't forget Pepcid! As well as beta blockers, clonidine, calcium channel blockers (verapamil, diltaizem and a few others), quinine, quinidine, amiodarone.
 
THE GOOD NEWS IS THAT XANAX ISN'T ON THE LIST – I THINK I NEED SOME.
 
We

Wednesday, April 11, 2012

ordering free jcv antibody test through quest

90257
jc virus antibodywith reflex to inhibition assay
1 866 my quest call to get order sheet for test

Saturday, February 11, 2012

Risk factors for multiple Sclerosis

D'hooge MB, Nagels G, Bissay V, De Keyser J .  Modifiable factors influencing relapses and disability in multiple sclerosis. Modifiable facors influencing  relapses and disability in multiple sclerosis.  Multiple Sclerosis 2010; 16: 773-785.

Review paper.
Strong evidence suggest relapses can be triggered by infections, the postpartum period and stressful life events.  Hormone fertility treatment may trigger relapses.

Disease progression may occur due to stressful life events,radiotherapy to the head, low levels of physical activity and low vitamin D levels.  Smoking affects disease progression clinically and by MRI.  TNF inhibitors induce exacerbation.  GCF colony stimulator factor for stem cells induces worsening in 4/10 patients. Add on statin to Betaseron may trigger relapses, larger trial is underway.

Vaccinations against influenza, tetanus and hepatitis B appear safe as are surgery, general and epidural anesthesia, and physical trauma. 

Associations with lower relapses include pregnancy, exclusive breastfeeding, sunlight and higher vitamin D exposure. 

Childbirth does not increase relapse rate.  Protective effect of ETOH remains to be confirmed. 

Thursday, February 09, 2012

Re: [seMSc] Case - Gilenya

Please be aware of this paper:
 
Espinosa PS, Berger JR.  Delayed fingolimod associated asystole.  Multiple Sclerosis 2011; 17:1387-9.
 
A patient with MS developed asystole and sustatined bradycardia 21 hours after the first dose of fingolimod.  Patient was a 20 yo male with no prior treatment with DMT's, no personal or family history of cardiac disease.He had mild mental retardation and was taking risperidone.  He received IVMP and on day 4 began fingolimod.  The period of asystole lasted only seven seconds, was associated with brief LOC and convulsive like activity and was captured.  He remained bradycardic for two more days.  The f. was discontinued.  Authors suspect a synergistic response between fingolimod and risperidoneand possibly other psychotropic medication.

Early onset natalizumab related PML

Multiple Sclerosis 2011; 17: 1397-98 (letter)
 
23 year old with MS with EDSS of 5, failed GA, then azathioprine, then natalizumab.  After 6 doses he developed ataxia and was diagnosed with PML, confirmed by CSF. 

2 minute walk test in MS

Gijbels D, Eijnde BO, Feys P.  Comparison of the 2 and 6 minute walk test in multiple sclerosis.  Mulitple Sclerosis 17: 1269-72, 2011.
 
Authors state the shorter 2mwt is a practical alternative to the standard 6mwt in a disabled population.  40 subjects with MS, mean EDSS of 3.5, some walking with a cane, and analysis showed 2mwt was within 5 +/- 4 % of 6mwt.  Authors believe can substitute 2mwt for 6mwt based on results.

Components of Rao's brief repeatable battery of Neuropsychological tests

BRBNT
 selective reminding test
Spart- Spatial recall test
PASAT/SDMT
World List Generation
 
multiple forms used
 
also can be used with
Stroop
MADRS (depression scale)
FSS
 

Thursday, December 01, 2011

Tuesday, November 29, 2011

Natalizumab v. Interferon Beta head to head study

Natalizumab vs interferon beta 1a in relapsing-remitting multiple sclerosis: a head-to-head retrospective study; Lanzillo R, Quarantelli M, Bonavita S, Ventrella G, Lus G, Vacca G, Prinster A, Orefice G, Tedeschi G, Brescia Morra V; Acta Neurologica Scandinavica (Nov 2011)

Background -  No head-to-head study has been performed yet to assess whether natalizumab is more effective than classical immunomodulators in multiple sclerosis (MS). Aim -  To retrospectively compare the efficacy of natalizumab vs IFN beta 1a SC (44 μg; Rebif(®) ) on clinical and radiological findings in two matched cohorts of patients with MS. Patients and methods -  We retrospectively enrolled two cohorts of 42 patients (F/M: 35/7) with relapsing-remitting multiple sclerosis treated with natalizumab or IFN beta 1a for at least 12 consecutive months. Outcome measures were annualized relapse rate (ARR), changes in expanded disability status scale (EDSS) score, and number of contrast-enhancing lesions (CELs) at magnetic resonance imaging (MRI). Results -  In both groups, the ARR in the 12 months of treatment was lower than in the 12 months before therapy (0.24 vs 1.50 in natalizumab-treated group, P < 0.0000; 0.55 vs 1.10 in IFN beta 1a-treated group, P = 0.0006), being the effect of natalizumab significantly stronger (P = 0.0125). EDSS reduction was significantly different between the two groups in favor of natalizumab (P = 0.0018). The frequency and number of CELs per patient were decreased in both groups. In the second year, the treatment affected ARR and EDSS progression in the two groups of patients similarly to the first year, whereas number of CELs decreased more significantly in natalizumab group (P = 0.008). Conclusions -  After 12 and 24 months of therapy, natalizumab was more effective than IFN beta 1a SC on both disease activity and disability progression. Prospective head-to-head studies would be helpful to further evaluate the differences observed in the MRI outcomes.

Sunday, June 12, 2011

GLANCE trial

Goodman A et al.  GLANCE : Results of a phase 2 randomized double blind placebo controlled study.  Neurology 2009; 72:806-812.

Study adding Tysabri to glatiramer-- safety trial.  Results showed increased natalizumab antibodies, but safe otherwise.  Efficacy was much better in combination group than in the GA alone group re MRI.  110 patients were randomized, half got GA + placebo, others GA + NAT.  Took patients with active disease year before entry.

NABs and Steroids-- the Mayo Clinic critically appraised

Zarkou S., et al. I Dean Wingerchuk)  Ar corticosteroids efficacious for preventing or treating neutralizaing antibodies in multiple sclerosis patients treated with Beta interferons?  A Critically appraised topic. The Neurologist 2010; 16: 212-214.

Bottom line-- idea of using steroids in any scenario for Nabs is based on dubious evidence.

Outcomes among natalizumab patients acquiring PML

Vermesch P et al.  Clinical outcomes of natalizumab - associated progressive multifocal leukoencephalopathy.  Neurology 2011; 76:1696-1704

Authors analyzed 35 patients with PML related to natalizumab.  25 survived.  Survivors had lower age and EDSS on mean, and shorter time to diagnosis of PML.  86 % had unilobar or multilobar disease on initial PML brain MRI, whereas 70 percent of fatal cases has widespread disease on MRI.  Disability scores (Karnofsky scale) among survivors was highly variable.  16/36/48 % respectively had mild, moderate or severe disability.

Tidbits
Almost all patients withdrawn from natalizumab got IRIS and were treated with i-c corticosteroids, in addition to plasma pheresis to removed natalizumab.  They also received mirtazepine or mefloquine due to in vitro studies showing an effect on replication. 

Tables show much less nonfatal PML in US v. Europe.  Rate of nonfatal to fatal PML was, US: 3:8 in Europe 22:2.  This is not discussed but I wonder if more nonfatal PML slips through cracks in US  and is either not diagnosed or reported. 

Posterior fossa PML was rare.  Most patients had enhancing lesions.

Saturday, June 11, 2011

Vitamin D and African Americans with MS

Gelfand JM, Cree BAC, McElroy J et al.  Vitamin D in African Americans with Multiple Sclerosis.  Neurology 2011; 76:1824-1830. 

339 African American MS patients and 342 controls were compared.  MS patients had lower vitamin D levels than controls, but the lower levels did not affect disease severity.  The differences were explained by geography and climate, as well as ancestry. 

Natural history of MS relapses

Bejaoui K, Rolak L.  What is the risk of permanent disability from an MS relapse?  Neurology  2010: 74: 900-902.

Authors review >2500 relapses and find only 7 with relapse with EDSS >6 that did not recover. 2 of those were on interferons at the time.  Two had a presentation of tumefactive MS.  They concluded that the fear of sudden irreversible disability should not affect treatment decisions. 

Monday, April 25, 2011

4 aminopyridine toxicity mimicking autoimmune limbic encephalitis

Neurology 72; 2009: 1100-1101
A 22 year old man ingested 30 tablets of 4-AP. He was agitated but oriented, flushed, mildly febrile, hypertensive.  EEG showed spikes and polyspikes and waves. CSF was normal.   MRI showed bitemporal hyperintensity on T2 imaging as well as affecting anterior cingulum.  Cardiac EF initially was 24 % but recovered.  He awoke to be mute and amnestic.  He recovered over one year but still had short term memory problems.   

differential diagnosis of long segment myelopathy suggesting NMO

Compression/ spondylitic myelopathy-- pearl- check enhancing scan for signet ring sign 

zoster myelitis-- history of shingles

paraneoplastic-- history of cancer

infective-helminth-- prior "Wells" syndrome, with eosiniphilia

cord AVM- history of worsening with Vasalva, singing, defecation, also check blood sensitive sequences and MRA cord

Sjogren's-- controversial, check CSF NMO as well as serum

B12 deficiency-- posterior cord

copper deficiency-- also posterior cord

stroke-- can affect almost any part of cord

multiple sclerosis/transverse myelitis-- check brain MRI

GBS/CIDP-- may be difficult to differentiate clinically, check nerve roots for radiculitis on MRI

CMV radiculitis -- in immunocompromised

Behcet's



Sunday, April 03, 2011

Thursday, January 06, 2011

Pearls about natalizumab and PML

1.  PML appearance in natalizumab cases may include enhanced lesions and even ring enhancing lesions unlike HIV associated PML
 
2.  JC virus must be ordered as ultrasensitive assay as routine assay limit of sensitivity is around the fifty percentile of the (low) number of copies seen in some cases of Tysabri associated PML
 
3.  PML presentation can be any type of new neuro abnormality including aphasia, heimparesis, hemisensory loss and others.
 
4.  PML cases increase with Tysabri exposure up to two years but is not clear about more than two years.  Prior immunosuppressive therapy increases the risk of PML
 
5.  IRIS occurs after removal of natalizumab with sometimes precipitous decline in patient's status and even death.MRI usually shows GD+ enhancement, within 1-6 weeks after removing natalizumab.
 
6.  IRIS prevention is reason for using Solumedrol one gram iv per day for five days followed by long taper

Sunday, November 07, 2010

Simvastatin for SPMS is recruiting

The MS-STAT trial: a phase II trial of high-dose simvastatin for secondary progressive multiple sclerosis: baseline trial profile; Chataway J, Anderson V, Chan D, Frost C, Hunter K, Kallis C, Greenwood J, Schuerer N, Alsanousi A, Nicholas R; Journal of Neurology, Neurosurgery, & Psychiatry (JNNP Online) 81 (11), e55 (Nov 2010)

Background Therapeutic options for secondary progressive MS (SPMS) are very limited. Simvastatin is an attractive drug with potentially anti-inflammatory (e.g., reducing leukocyte migration) and neuro-protective effects (e.g., up-regulation of the major cell survival protein bcl-2), in addition to being well tolerated. In trials of early stage MS it is undergoing trials as a single agent or in combination therapy with standard disease modifying treatments. This is the first trial in SPMS. Trial Overview Double-blinded/placebo-controlled (1:1) with 80 mg of simvastatin. Two-year follow-up. Entry EDSS 4.0-6.5. Brain atrophy rate as determined from T1-weighted volumetric MRI using the brain boundary shift integral is the primary outcome measure. Secondary outcomes include disability scores, neuropsychological assessments and immunological profiling. Results 408 patients were referred, 203 screen failures, 140/140 patients were randomised. Age 52 years (range 35-65), 68% female, MS duration 21 years (8) with a secondary progressive phase of 13 years (7). Median EDSS 6.0 (IQR 0.5). MSFC 10 m walk/s 23.6 (25.6); Nine-hole peg test/s 34.6 (13.2); PASAT/60 35.3 (14.2). MSIS-29ver 2.0 scores: physical 49/80 (11), psychological 20/36 (8), total 69/116 (14). All data as mean (SD) unless stated. Conclusion This trial is fully recruited and will report in late 2011. ClinicalTrials.gov, number NCT00647348.

Sunday, August 15, 2010

Testing for Vitamin D Pearls

Kennel KA et al. Vitamin D deficiency in adults : when to test and how to treat.  may Clin Proc 2010: 85; 753-758

1.  Terminology:  D2 = ergocalciferol is obtained from vegetables and oral supplements.  D3= cholecalciferol is obtained from UVB sunlight, oily fish and some fortified foods such as milk and bread.  25 (OH) D= calidiol, contains D2 and D3.  1,25 (OH)2D= calcitriol and is converted in kidney and other tissues by the one alpha hydroxylase gene. 

2.   Deficiency is caused by lack of exposure to sunlight, dietary deficiency or malabsorption.  Measuring calcidiol is best measurement of body stores of 25 (OH) D total vitamin D and is best test for deficiency, whereas 25 (OH)  D  D2 and D3 is useful for monitoring to detect noncompliance, or malabsorption. In general the D content of food is low, and D levels come from sunlight and supplements.

3.  1,25 (OH)D can be falsely normal in vitamin D deficient patients due to hyperparathyroidism and thus should not be measured.

4.  Reference ranges may vary based on geographic location, season, ethnic background, age. 

5.  Vitamin D toxicity has never been reported with a level less than 80, and usually requires over 140.   Fear of toxicity is overblown.  This is because calcitriol, the renal 1,25 OH D, feedbacks directly limiting its production via 24 hydroxylase gene.  Calcitriol also feeds back on the PTH gene.  The alternative result is inert metabolites of Vit D, including 24,25 calcidiol and 1,24,25 calcitriol.

6.  Used but not clinically validated for severe Vitamin D Deficiency:  loading dose of 50,000 weekly for 2-3 months, or tiw for one month.  A minimum total dose of 600,000 iu predicts increasing the level to normal (>30).  A lower dose is used for moderate deficiency.  Maintenance of 800-2000 iu is needed to prevent slideback. 

7.  Powder D3 does NOT clog feeding tubes unlike D2. 

Tuesday, August 10, 2010

Motor cortex stimulation for pain in multiple sclerosis

Motor cortex stimulation for intractable neuropathic facial pain related to multiple sclerosis; Tanei T, Kajita Y, Wakabayashi T; Neurologia Medico-Chirurgica (Tokyo) 50 (7), 604-7 (2010)

A 33-year-old man presented with ongoing severe right facial pain and sensory disturbances caused by multiple sclerosis (MS). Neuroimaging demonstrated demyelinating lesions in the right dorsal pons and medulla oblongata. The pain was refractory to carbamazepine at 800 mg/day, gabapentin at 1800 mg/day, morphine at 30 mg/day, amitriptyline at 60 mg/day, and diazepam at 4 mg/day, along with twice-monthly ketamine (60 mg) drip infusions. The patient underwent motor cortex stimulation (MCS), resulting in>60% pain relief, reduction in the required doses of pain medications, and discontinuation of ketamine administration. MCS is effective for MS-related neuropathic facial pain.

 

Tuesday, July 20, 2010

Successful Management of Natalizumab-Associated Progressive Multifocal Leukoence

Schröder A, Lee DH, Hellwig K, Lukas C, Linker RA, Gold R; Archives of Neurology (Jul 2010)OBJECTIVE: To describe a case of successful clinical management of natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution syndrome (IRIS) in a patient with multiple sclerosis. DESIGN: Case report. SETTING: University hospital. Patient A 41-year-old woman with relapsing-remitting multiple sclerosis developed PML after 29 natalizumab infusions. INTERVENTIONS: Immediate plasma exchange was combined for removal of natalizumab with application of mefloquine and mirtazapine to limit viral replication and oligodendrocyte infection. A subsequent IRIS was treated with glucocorticosteroids. RESULTS: After 3 months of treatment, cerebrospinal fluid tested negative for JC virus. There was a favorable outcome, and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML. CONCLUSIONS: In the setting of early diagnosis and consequent treatment, natalizumab-associated PML can be well managed in some cases. This situation differs from the course of PML in other conditions, eg, after the application of depleting monoclonal antibodies, in which irreversible cellular effects are associated with very high mortality.

Friday, July 02, 2010

MACFIMS- cognitive assessment for multiple sclerosis

Benedict R.  Minimal neuropsychological assessment of MS patients.  The Clinical Neuropsychologist 2002; 16:381-397.

Contains tests with alternate forms and test-retest capability. 

Processing speed/Working memory

PASAT
Symbol Digit Modality Test (SDMT)  equally good as PASAT as standalone

Learning and Memory

CVLT-II
Brief Visuospatia Memory Test- Revised

Executive Functions

D- Kefs Sorting Test- sorting cards, Trails, Tower, Design Fluency, Stroop

Visual perception/Spatial Processing

Judgment of Line Orientation

"Language"

Verbal Fluency (COWAT)

Non Macfims-- office assessment
Attention:
1 trial PASAT
Trails (public domain)
Mental control (days forward, backwards, serial 7's)
Cancellation test (public domain)

Memory:
list learning, 10 common, easy, unrelated words, 3 trials, 20 minute delay with recognition trials (yes/no)

Language:

5-10 pictures use for each patient
COWAT equivalents (CFL, PRW, FAS)
semantic category fluency

Motor coordination/processing speed:
9 hole peg
Trails A
SDMT written and oral (public domain)

Subjective:

Multiple sclerosis neuropsychological questionnaire (Benedikt et al., 2004)
15 items, MSNQ

Thursday, July 01, 2010

Benign MS and cognition

Portaccio E, Stromillo ML, Goretti B, et al (last author Stefano) .  Neuropsychological and MRI measures predict short term evolution in benign multiple sclerosis.

Consensus for definition of b-MS is those who are fully functional after ten years.  Different systems are used to classify patients.  Authors defined as EDSS < 3 after 15 years of disease duration. 

Authors used Rao BRB and added Stroop test, using a cutoff as 2 SD's below Italian normals.  Patients with 3 or more test failures were classified as cognitively impaired.  Tests included SRT, SPART (spatial recall, 10/36 cutoff), PASAT, SDMT, WLG, Stroop. 

Authors followed patients at a mean of five years, using "still benign" measure.  Disability was EDSS>4, or increase of 1.5 if starting EDSS was zero, or increase of >1 point if starting EDSS was > 1 confirmed at six months.  31.8 percent of patients with "b-MS" were impaired at baseline cognitively.  Additional 16 % failed one test and 19 % failed 2 cognitive tests at baseline.  At followup, 43 % had EDSS progression of one or more points, confirmed.  18 % became "no longer benign," or "NLB."  NLB subjects had more relapses during followup period, but not in year before, and related to male gender and number of tests failed. Also baseline T1 lesion volume was predictive. 

editorial
Benedict RHB, Fazekas F.  Beningn or not benign MS: a role for routine neuropsychological assessment?  Neurology 2009; 73: 494-495.  Authors mention BRB and MacFims, each having alternate forms that permit repeat testing every 2-3 years. 

Wednesday, June 30, 2010

Cortical lesions and atrophy associated with cognitive impairment in RRMS

Calabrese M, Agosta F, Rinaldi F, et al. (last author Filippi).  Arch Neurol 2009; 66:1144-1150.

Authors studied 70 patients with multiple sclerosis and 22 normal controls .  They used the Rao BRB and used a cutoff of 2 SD's below mean on at least one test of, version A of BRB to define cognitive impairment.  They also looked at T2 lesion volume, contrast enahncing lesion number, cortical lesions using double inversion recovery sequences, volume, and normalized grey matter volume.  Finding was that T2 lesion number and enahncing lesions were not important, but that cortical lesions, cortical and brain volume and gray matter involvement predicted cognitive impairment. 

Tests used in BRB were"  SRT and delayed recall, spatial and delayed recall (10/36 cutoff), PASAT 3 and SDMT, and word list generation.  See Camp et al, Brain, 1999 for normative values. (see article anyway). 

24 patients were listed as cognitively impaired.  The rate of impairment was, for SRT delayed, 12.9%; PASAT and word generation 10 %, SDMT 8.6 %, EDSS also predicted. 

Authors discussed the "cognitive impairment index" as discussed in Brain article above.  This is a continuous variable obtained by a grading system applied to each patient's score on each test, depending on number of SD's below mean normal.  Grade 0 means index was above mean for normal controls.  Grade 1 was given for mean to 1 SD below normal.  Grade 2 was 1-2 SD's  below normal.  Grade 3 was given for more than 3 standard deviations below.  The results for all tests were added to give an overlal measure of cognitive dysfunction.

Authors discussed that the CL (cortical lesion) number and volume correlated with CI index score, and deficits in attention, concentration, speed of processing, and memory. 

Saturday, June 26, 2010

Neuropsychological effects of interferons

Fischer JS, Priore RL, Jacobs LD et al.  Neuropsychological effects of interferon B-1a in relapsing multiple sclerosis.  Neurology 2000; 48: 885- 892.

Study looked specifically at Avonex to 166 patients 104 weeks apart.  The neuropsych battery was divided into Set A (information processing and learning/memory) ,  Set B ( visuospatial and problem solving), and Set C (verbal abilities and attention span).  Avonex benefitted A set, with a trend in B set and no effect on C.  Secondary analysis showed a treatment effect on time to worsening with PASAT. 

Subject selection-- disease duration at least one year, at least 2 relapsed in 3 years, and EDSS 1-3.5 inclusive.  age 18-55. Study was placebo controlled.  Actual tests used were , for Set A, signnificant group, CalCap Sequential reaction time (information processing), Ruff Figural Fluency Test error ratio, and CVLT Trials 1-5 (total).

Set B tests were WMS-R Visual Memory Span (forward), WCST perseverative responses, visual search number of trials, TOL % planning time. 

Set C tests were WAIS-R information, and digit span forward.

Secondary outcomes were RFFT error ratios, RFFT unique designs, CVLT trials 1-5 (total), PASAT processing . 

Results-- on set A, the CVLT test was most important.  On Set B, Tower of London was most important.  Set C was negative tests.  In secondary outcomes, slopes were correct direction in all variables, RFFT appeared significant, and  practice effects were noted in all groups. 

Authors contrast to 2 other studies of cognition with treatment for MS.  One was a copaxone study (Weinstein et al, Arch Neurol, 1999) which was negative, and one was for Betaseron, that showed an effect for visual memory  (Pliskin et al, Neurology, 1996).  However, neither of those was as good of a study. 

MIMS Study for Novantrone in MS

Hartung H-P et al.  Mitoxantrone in progressive multiple sclerosis: a placebo controlled, double blind randomised multicentre trial.  The Lancet 2002; 360: 2018-2025.

194 patients with worsening RRMS or SPMS were given MTX or placebo  q 3 months for 24 months (5 mg/meter squared).  at end, the treated group had a benefit in five clinical primary outcome measures:  change in EDSS, change in ambulation index, adjusted total number of treated relapses, time to first treated relapse, and change in standard neurological status. 

Shortened version of PASAT is effective discriminant in MS

Solari A, Motta A, Radice D, Mendozzi L.  A shortened version of the PASAT 3 is feasible.Multiple Sclerosis 2007

Authors studied PASAT in 105 persons with multiple sclerosis and controls using PASAT 3 regular and shorrtened version.  They used the first 20 items.  The first 20, 30 and 50 items of the PASAT 3 retained discriminant value for MS

Notes study did not norm for age (highly sensitive) or practice effect (important). 

Note:  A review of the PASAT Tombaughh TN Arch Clin Neuropsychol 2006; 21:53-76.

Effect of copaxone on fatigue in MS

Metz IM, Patten B, Archibald CJ et al.,The effect of immunomodulatory treatment on multiple sclerossi fatigue.  JNNP 20 04; 75: 1045-7. 

In Calgary 218 MS clinic studied patients with initially comparable levels of fatigue who were treated with glatiramer (copaxone) v. interferons using fatigue impact scale.  2x as many started on copaxone and 2x as many reported greater reductions in fatigue.  This was true for all MS patients and RRMS patients.  The difference affected total FIS, the physical and cognitive subscale but not the social subscale.  The authors used one SD as the cutoff. 

Cognitive dysfunction in patients with CIS or newly diagnosed MS

Glanz BI, Holland CM, Gauthier SA et al.  Multiple Sclerosis 2007; 13:   senior author Howard Weiner BWH

Authors studied 92 patients with CIS/new MS and fouund 49 % impaired on one or more tests of the battery.  There was not correlation with MRI measures of disease including T2 lesion volume, NAWM, grey matter volume or brain parenchymal fraction.

Tests given were Rao's brief repeatable battery including SRT, 10/36 Spatial Recall test, SDMT, PASAT, COWAT, CES Depression Scale.  PASAT, SDMT, and SRT were the clear tests that showed abnormalities in MS v healthy controls. 

Authors contrast their results to Achiron and Barak (JNNP 2003) who found visual learning and recall , COWAT and SDMT to be most abnormal tests.  Other studies were Feinstein (Brain, 1992; 115: 1403-15) and Callanan MM et al (Warrington) Brain 1989; 112: 361-74.   

Wednesday, June 16, 2010

main references for Zamboni procedure for MS

• Zamboni P, Menegatti E, Salvi F, et al. Intracranial venous haemodynamics in multiple sclerosis. Curr Neurovasc Res 2007;4:252–258.




• Zamboni P, Galeotti R, Salvi F, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392–399.



• Zamboni P, Galeotti R, Salvi F, et al. Endovascular treatment of chronic cerebrospinal venous insufficiency: A prospective open-label study. J Vasc Surg 2009; 50:1348–1358.



Sunday, May 16, 2010

Q & A AAN 2010

COMMENTS
1.  possible association of seminoma and demyelination disorder
2.  dural av fistula lesions identified by stepwise progression and involvement of conus, angiography can miss it
3.  Rabies case of Weinshenker-- rabies is increasing in bat population, catch the bat, give everyone a shot even if they don't have a bite, only have a week or so to get a shot
4.  NMO CSF may be positive with negative serum studies, but is rare.  Antibody arises in blood and leaks into CSF, does not get produced in CSF.  Could be a question of CSF is cleaner with less noise of other antibodies in blood interfering with test.
5.  Persistent black holes at onset is a good sign of non-ADEM; rarely if ever seen all enhancing lesions with ADEM more common to see none of lesions enhance.

Superficial siderosis

check 2009 article Neurology

check cerebellar folia
do myelogram look for extradural defect
consider fixing it

ADEM and atypical demyelinating disease pearls

1. Occurs more in childhood than adulthood
2.  Occurs post infection, infection may include VZV, EBV, HSV 6, measles, influenza
3.  Acutely, all lesions enhance rather than being of different ages (MAY occur)
4.  Pathologically perivenous inflammation with very little tissue or axonal destruction
5.  Hurst's hemorrhaghic leuokoencephalitis is sometimes considered as part of spectrum of ADEM, with severe course, may be fatal, hemorrhage may be petechial, with pathological and MRI diagnosis and severe demyelination
6.  Marburg's MS -- severe and unrelenting MS even within one year. Otto Marburg, 1906
7.  Tumefactive MS--may be monophasic course or develop into MS, typical or otherwise
8.  Balo's concentric sclerosis with concentric rings of demyelination alternating with remyelination, described 1927, variable course, more common in Southeast Asia, high level if inducible nitrous oxide synthase similar to hypoxia.
9.  Isolated optic neuritis without MS--half may not progress to MS without associated MS lesions
10  CRION chronic relapsing inflammatory optic neuritis disease is restricted to optic nerves
11.  NMO spectrum disease with isolated and recurrent optic neuritis

For above, treatment algorithm is five days of solumedrol, then plasma exchange (at Mayo Clinic) then cytoxan.