New MRI Montalban criteria for diagnosis of multiple sclerosis

Neurology 2010; 74: 427-434.  called MAGNIMS proposal

* An MRI at any time showing dissemination in space (DIS) and showing 1 or more asymptomatic lesions enhancing and nonenhancing thus meeting criteria for dissemination in time (DIT) is sufficient to diagnose MS

*  An MRI showing DIS but without enhancing lesions, or with all lesions enhancing (thus no DIT), would require a new MRI to demonstrate additional lesions

*  An MRI at any time showing lesions but not DIT or DIS requires new MRI's

One DIS criterion: need one or more asymptomatic lesions in 2 of 4 locations considered characteristic for MS: juxtacortical (JC), periventricular (PV), infratentorial (IT), and spinal cord (SC).

Two DIT criteria:  1)  presence of one or more enhancing and nonenhancing lesions irrespective of the time of the scan and 2) presence of a new T2 and/or Gd+ lesion compared to a previous scan, irrespective of the time of the scan

The above apply only to those with CIS, ie symptomatic patients. 

fatigue components

Nocturnal jerks and phasic spasms
Nocturia multiple NGB
Depression
Deconditioning
increased energy requirements to move-- due to spasticity, balance
lots of drugs that contribute to fatigue
anemia
low vitamin levels, b12, D
temperature effects especially perimenstrual
effects of interferons. Try Naprelan, the long acting naprosyn, treximet,or pentoxifylline to prevent AE's before injections.

pearls symptoms management elliott froman

This summary is not available. Please click here to view the post.

differential diagnosis of longitudinally extensive spinal cord lesions

sarcoid
neuromyelitis optica
lupus
Sjogren's
multiple sclerosis
glioma (don't biopsy these patients deteriorate over weeks to months not days)

Pearls

evaluation includes

CSF
ESR
HIV status
CXR
MRI with contrast
B12
copper
Gallium scan for sarcoid
? Ace level
noncontrast CT chest to screen for  neurosarcoid (even in whites)

differential diagnosis of ring enhancing lesions on MRI

h/t Benjamin Greenberg AAN 2010

metastasis
abscess
glioma
lymphoma
infarction
contusion
demyelination
resolving hematoma
radiation necrosis

MS 12 item walking score

• These questions ask about limitations to your walking due to MS during the past 2 weeks.




• For each statement, please circle the one number that best describes your degree of limitation.



• Please answer all questions even if some seem rather similar to others, or seem irrelevant to you.



• If you cannot walk at all, please tick this box.









In the past two weeks, how much has your MS ... Not at all

--------------------------------------------------------------------------------

A little

--------------------------------------------------------------------------------

Moderately

--------------------------------------------------------------------------------

Quite a bit

--------------------------------------------------------------------------------

Extremely

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1. Limited your ability to walk? 1 2 3 4 5

2. Limited your ability to run? 1 2 3 4 5

3. Limited your ability to climb up and down stairs? 1 2 3 4 5

4. Made standing when doing things more difficult? 1 2 3 4 5

5. Limited your balance when standing or walking? 1 2 3 4 5

6. Limited how far you are able to walk? 1 2 3 4 5

7. Increased the effort needed for you to walk? 1 2 3 4 5

8. Made it necessary for you to use support when walking indoors (e.g., holding on to furniture, using a stick, etc.)? 1 2 3 4 5

9. Made it necessary for you to use support when walking outdoors (e.g., using a stick, a frame, etc.)? 1

--------------------------------------------------------------------------------

2 3 4 5

10. Slowed down your walking? 1 2 3 4 5

11. Affected how smoothly you walk? 1 2 3 4 5

12. Made you concentrate on your walking? 1 2 3 4 5



--------------------------------------------------------------------------------



Please check that you have circled ONE number for EACH question

© 2000 Neurological Outcome Measures Unit.

Infliximab and central and peripheral demyelination

Neurology AAN 2010 S47:002.  NozakiN, Judson M. Charleston.  2 cases of suspected sarcoid that became worse (central or peripheral demyeination) due to infliximab,  The case of peripheral demyelination improved with plasma exchanges. 

Radiological isolated syndrome

NEUROLOGY 2009;72:800-805

criteria above

44 patients

mean time for those converting to CDMS was 5.4 years

30 percent converted to CDMS, the majority 8/11 with CSF positive bands. The band positive group also had 10/11 with radiographic progression

the biggest risk factor is gad positive MRI lesions

depression scales other scales for PD, AD and MS

http://www.mhsfopcls.com/downloads/ger_dep_scl.pdf Geriatric Depression scale

 

 

http://www.ibogaine.desk.nl/graphics/3639b1c_23.pdf  Beck Depression inventory- pref in Parkinson's disease

 

http://healthnet.umassmed.edu/mhealth/ZungSelfRatedDepressionScale.pdf  Zung SRDS

 

Other scales

http://www.nysaaaa.org/Caregiver_Forum/CaregiverForumErieHandout09.pdf caregiver burden assessment

 

http://www.nationalmssociety.org/for-professionals/researchers/clinical-study-measures/mfis/index.aspx

MFIS with link to MSQLI (Connie is this different than MSQOL and how?)

 

http://www.nationalmssociety.org/for-professionals/researchers/clinical-study-measures/index.aspx

link to links to many clinical tools in MS research

 

http://www.mdvu.org/library/ratingscales/pd/updrs.pdf  updrs and scwab (parkinson;s)

 

http://www.alegent.com/documents/Sleep_eval.pdf berlin and epworth sleep questionnaire

 

http://www.hospitalmedicine.org/geriresource/toolbox/pdfs/clock_drawing_test.pdf clock drawing and mini cog (= 3 word recall)

 

http://www.hospitalmedicine.org/geriresource/toolbox/pdfs/instrumental_activities.pdf Instrumental activities of daily livving (IADL)

http://www.hospitalmedicine.org/geriresource/toolbox/pdfs/phys_selfmain.pdf physical self maintenance scale

 

http://www.hospitalmedicine.org/geriresource/toolbox/pdfs/function_status_questionnai.pdf (last page is functional activities questionnaire)

 

http://www.hospitalmedicine.org/geriresource/toolbox/pdfs/painscales.pdf pain scale

 

http://www.mocatest.org/  Moca-- has links for multiple languages

 

http://www.neurotransmitter.net/alzheimerscales.html   link to MANY Alz assessment tools, behavior and otherwise a few linked below

 

http://strokecenter.org/trials/scales/blessed_dementia.html blessed dementia scale

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MSQOL link

http://www.nationalmssociety.org/for-professionals/researchers/clinical-study-measures/msqol-54/download.aspx?id=261

More studies of cognitive dysfunction in MS

Prakash RS, Snook EM, Lewis JM, Motl RW, Kramer AF. Cognitive impairments in relapsing-remitting multiple sclerosis: a meta-analysis. Multiple Sclerosis 2008; 00: 1-12.

Used 57 studies with 3891 participants with 755 "effect sizes"
Cognitive deficits are reported in broad domains of memory, attention, executive function, and verbal fluency. One report suggested by subtype that PPMS had more problem with executive control, whereas RRMS had more significant memory related dysfunction.

"With exception of motor functioning and mood status, most effect sizes were in the moderate range" MS patients had more trouble with nonverbal than verbal intellectual deficits.
Attention-- most abnormal was selective / focused attention with SDMT, TMT, Stroop word and color reading more than measures of working memory and short term storage. Categories also included processing speed (abnormal), sustained attention/vigilance, executive control, short term storage capacity.

Memory and learning-- categories
verbal immediate recall
verbal delayed recall* key item that was abnormal among subcategories
verbal recognition-- not enough data, item eventually dropped.
visual immediate recall
visual delayed recall, visual recognition

All other categories were medium

Verbal function- normal
categories-- verbal fluency were more impaired than comprehension, verbal expression and discourse.
Other factors-- age > 40 was very important, females more than males. Education, disease duration, and EDSS not important EXCEPT for memory and learning

Motor tests
grooved pegboard, finger tapping, nine hole peg test

Paper 2: Chiaravalottti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol 2008; 7: 1139-51. review paper. Emphasizes processing speed, attention, executive function and long term memory. Refers to minimal assessment battery (see Benedict RH, Cookfair D , Gavett, R et al. Validity of the minimal assessment of cognitive function in MS. J Int Neuropsychol Soc 2006; 12:549-558. Also refers to re internet based testing, Younes M, Hill J Quinles J, Kilfuss M et al. Internet based cognitive testing in multiple sclerosis. Multiple Sclerosis 2007; 13: 1011-19.
Adds assessment of rudimentary oral motor function, since most tests are done orally.See Arnett et al. JINS 2008; 14: 454-462.

Objective, structured, standardised assessment of functional activity, designed by OT, resulted in executive functions performance test (Baum et al., Cognitive performance in senile dementia of the Alzheimer's type: the kitchen task assessment. Am J Occ Ther 1993; 47; 431-436) found correlation to cognition (Kalmar et al. Neuropsychology 2008; 22: 442-449) whereas subjective assessment of cognitive function correlates with emotional distress. Functional deficits are common including housework, driving, cooking, using public transportation.

Beatty et al. found five variables correlate with 49 % of variance in employment status in MS , 3 of which are cognitive (J Neurol Rehab 1995; 9: 167-173). Benedict found poor cognitiion especially on processing efficiency, verbal memory and executive function predicted vocational status (op cit).

Neuropscch screening test key: Benedict RH , Zivadinov R. Reliability and validty of neuropsychological screening and assessment strategies in MS J Neurol 2007; May 254: s 2 1122-1125.
Amato MP et al. The Rao's BRB and Stroop Test ; nornative values with age, education and gender corrections in an Italian population. Mult Scler. Dec 2006 12: 787-793.
Parmenter BA. Screening for cognitive impairment in multiple sclerosis using the Symbol Digit Modalities Test. Mult Scler Jan 2007 13: 52-57.


Components of BRB-- SRT
10/36 spatial recall test
SDMT
PASAT
Word list generation (20 minutes)

MACFIMS-- takes 90 minutes
COWAS
JLO
CVLT 2d edition
Brief visuospatial memory test
SDMT
PASAT
Delis-Kaplan executive function system scoring test

MS Cognitive Impairment

Possible Panel for Study

MSQOL
Beck or Hamilton Depression Scale
Fatigue Impact Scale
Cognition
Med list
Sexual dysfunction

Test Batteries
*Rao's BRB Brief Repeatable Battery (Neurology 1991; 41:685-691)
Above plus Stroop Color Word Test
MS Neuropsychological Screening Questionnaire
Minimal Assessment of cognitive function in MS

Individual tests
PASAT
Symbol Digit Modalities Test (adapted for use in MS)
California Verbal Learning Test
Brief Visuospatial Memory Test (revised)
Delis-Kaplan Executive Function Symptom, Sorting Test
Controlled Oral Word Association Test
Judgment of Line Orientation Test
Auditory Consonant Trigrams
WCST
Trails A/B
WMS Revised
Rey COmplex Figure
EDSS


Published studies
Aricept Christodoulou et al. CNS Drugs 2008; 22:87-97 and J Neurol Sci 2006; 245: 127-136.
Avonex-- benefit after two years see Fischer et al. Ann Neurol 2000; 48:885-892.
Betaseron-- small group study Barak et al. Eur Neurol 2002
Copaxone-- open label ext trial (Schwid et al. J Neurol Sci 2007) suggestive of benefit
COGIMUS (Cog in MS) Italian study prospective Italian study with cognition measured annually using BRB and Stroop

Post optic neuritis (Nilsson P, Rorsman I, Larrson EM, Norving B, Sandberg-Wollheim M. Cognitive dysfunction 24-31 years after isolated optic neuritis. Multiple Sclerosis 2008; 14:913-918. was case ascertainment study of 110 individuals, 86 of whom consented to followup 22 who did not have MS and who were alive underwent further testing. Most common abnormalities were WCST (exec function) and Trails A (attention) and Rey Figure. Less affected, BNT, verbal learning, verbal memory or verbal comprehension (Token Test). There was not much correlation with MRI findings.

Sources for MS Cognitive Screens

Computerized testing
Wilken JA, Kane R, Sullivan CL et al. The utility of computerized neuropsychological assessment in patients with relapsing-remitting multiple sclerosis. Mult Scler. 2003;9:119-127.

brief screening
Parmenter BA, Weinstock-Guttman B, Garg N, Munschauer F, Benedict RHB. Screening for cognitive impairment in MS using the Symbol Digit Modalities Test. Mult Scler 2007; 13:52-57.

also see
Benedict RHB, Cox D, Thompson LL, Foley FW, Weinstock-Guttman B, Munschauer F . Reliable screening for neuropsychological impairment in MS. Mult Scler 2004; 10: 675-678.

Suggest use of above with concurrent measures for depression and fatigue for minimal cost.

Once cognitive impairment is identified, can then use other measures to follow it These include The Brief Repeatable Neuropsychological Battery for MS (BRNB) see Rao SM. A Manual for the BRNB in MS. New York, National MS Society, 1991.

Or, The Minimal Assessment of Cognitive Function in MS (MACFIMS). JINS 200612: 549-558.

Former has more non English assessments

Purpose to detect worsening MS or non benign MS.

Possible Journal Club article: Portaccio E. et al. Neuropsychological and MRI measures predict short term evolution in benign MS. Neurology 2009; 73:498-503.

PML A Stochastic event before brain infection

per Dr Joe Berger's talk at AAN. A number of necessary events must occur

1. 80 % of individuals are infected with JC virus, virtually all by age 20.

2. Latent primary viral infection must occur, involving spleen, kidney, bone marrow, tonsil, oropharyngeal lymph nodes and other tissues. Controversial whether it is latent in brain. Virus appears incapable of replicating in brain. Must have receptor to allow virus to bind.

3. Infected cell must have NF 1X to allow virus to replicate

4. 98 base pair tandem repeat within nucleus probably within B cells must allow insertion to allow replication of virus within brain (b cells must activate)

5. Failure of immunosuppression in periphery and allow detectable JC virus in blood (see IgG antibody in blood suggesting its reactivated infection)

6. Periodic reexpression of JC virus in PBMC

7. Entry of JC virus into brain and allowance of productive oligodendrocyte function

8. Failure of immunoregulatory function in the brain

Natalizumab-- may cause release of B cells and ciruculate, premature and mature B cells and increased transcription factors resulting in a productive infection. Decreased immunosurveillance in brain. JC toxic circulating t lymphocytes are important. Also loss dendritic cells responsible for antigen presentation.

Rebif site reaction

Memantine transiently worsens MS

Villoslada P et al. Memantine induces reversible neurologic impairment in patients with MS.
30 patients underwent a one year randomized crossover trial with 30 mg memantine. Patients had poor cognitive scores and MS . The trial was halted after 9 patients due to blurred vision, fatigue, headache, increased muscle weakness, trouble walking/gait. Symptoms only occurred at maximum dose.

Early MRI in ON" Risk for disability

Swanton et al. Neurology 2009; 72: 542-550. (Queen's Square)
106/143 patients reached scheduled five year followup after being diagnosed with ON. 100 were evaluated clinically. At median 6 years, 48 % converted to CDMS 52 % did not. At baseline, the presence and number of spinal cord lesions and new T2 lesions at followup (odds ratio, respectively of 3.3, 1.94, 7.12) predicted higher disability. Also Gd+ lesions and number of infratentotial lesions at baseline were predictive.

Many factors were not predictive including age, gender, baseline EDSS, spectros/MTR measures, NOT baseline lesion number although lesion load at 5 years and increase from baseline was predictive.

ACT trial negative

Cohen et al. Neurology 2009: 72:535-541.

There were 313 subjects, no benefit of adding IVMP or MTX to interferon beta one alpha. Trend to less NABs. It was safe and well tolerated. There was a trend to benefit in the IVMP group.

ECTRIMS 2007 Therapy papers

QD v QOD GA suggests possible role of qod therapy. Khan plans 3 arm study multicenter randomized of daily v qod v weekly.

Perfumal et al. Uses IIS (intense immunosuppression) as inital therapy in active rrms patients. In active patients used 6 months of monthly cytoxan before beginning DMT first line, with good results on clinical and MRI outcomes.

Mancuso et al. JC virus has 9.8 % prevalence in CSF,mostly asymptomatic.

Imaging studies at ECTRIMS 2007

Calabrese et al. Used double inversion recovery (DIR) sequences to assess cortical lesions over 24 months in rrms, found more cortical lesions in untreated patients.

Haacke et al. SWI (susceptibility weighted imaging) to detect/quantify tissue iron; on 1.5 T machine, 78/141 lesions were seen on SWI only in gray and white matter; on 3 T machine, 20 lesions were seen on SWI only (our of 90 lesions); on 4 T machine 45/116 lesions were seen on SWI only. Iron content found 47 ug.gm higher than normal.

Kahn O. et al. B Cell response (CSF IgG index) correlates with gray matter atrophy in clinically aggressive disease.

Complications after 5 years of DMT in MS

Caon C. et al
Copaxone-- 89 % had local injection site reactions and 78 % had lipoatrophy. No other complications were significant.

SQ IFN B- 38 % flu like reactions, 68 % local injection site reactions, 11 % injection site necrosis, 41 % lipoatrophy, 8 % abnl LFT and 8 % abnl CBC, 25 % headache

IM IFN B-- 22 % flu like 18 % local injection site reaction, 24 % severe post injection reaction, 6 % abnl LFt, 9 % headache.

Injection compliance five years into continuous therapy:
taking 90% or more scheduled injections per month: SC IFn >70, im IFN 58, GA 20 %
taking 70-90 % of scheduled injections per month: all 3 around 20 %
taking <70% of injections: GA around 60, IM IFN about 25, SQ IFN <10 %

Hits Ectrims 2007 HHV6, Vit D, Rebound

Marmocets who were injected with HHV6 got subpial inflammation and parenchymal demyelination, those who did not get injected did not get it. The suggested causal mechanism is CNS persistence of HHV6A and direct toxicity to cells, with resultant apoptosis.

_Genain CP et al.
Blogger note-- HHV6 is so ubiquitous in humans its impossible to study, as almost 95 % prevalence exists in human population

Vitamin D-Correale et al. In vitro, Vitamin D effects are very similar to interferons. 1,25 Vit D inhibits proliferation of CD4+ cells, enhances IL 10, decreases IL 6, increases number of CD4 and CD 25 regulatory cells.
Blogger notes-- amounts being studied in clinical trials are manifold higher than the amount available and are potentially extremely toxic. Also, vitamin d levels are of little use.

Stopping DMT: No rebound Bejaoui et al. Stopping ifn or GA did not result in more relapses than continuing therapy. Blogger notes--only one year followup was offered with no MRI evidence. What happens in year 2?

Campath for multiple sclerosis

Alemtuzumab vs. interferon Beta-1a in early multiple sclerosis. The CAMMS223Trial Investigators. NEJM 2008;359: 1786-1801. (phase 2 trial)

In patients with early RRMS alemtuzumab (Campath 1H) was more effective than interferon-1a but was associated with autoimmunity most seriusly manifesting as immune thrombocytopenic purpura. The study was not powered to detect uncommon adverse effects.

Blogger notes. The investigators deserve credit for going up against Rebif (high bar to hurdle) and then hurdling it. Autoimmune events included in addition to ITP, Graves' disease and Goodpasture's syndrome. The patients studied all had MILD MS (EDSS was less than or equal to 3) in naive patients and no conclusions can be drawn about its use in advancing patients or as switch therapy in patients who have had the disease more than three years. The conundrum in a brand new patient is whether to use the most effective drug when it works (Campath) before they fail Rebif, even though it exposes the patient to the risk of autoimmune disease on Campath, because Campath might not work if given later (see 1999 paper on Campath in 2pms). In addition, it is not clear how many times to dose Campath. In this study, subjects were dosed one, two or three times, with eight protocol changes during the study. One or two times should be enough, but Genzyme wants to try to test using the drug every year. A final issue is the use of concomitant drugs-- once campath is finished. Should none be used (the allure), or copaxone ? Does the risk of adverse effects increase with each dosing? We need more answers before Campath can be widely utilized.

BECOME trial

Betaseron v. Copaxone with triple dose gado and 3T MRI. Head to head trial with combined active lesions as primary endpoint. No difference between 2 groups in 75 randomized patients. In a secondary endpoint, IFN but not GA has a drop in active lesions from pre treatment. Not clear what this means

Combination therapy mitixantrone + copaxone

Journal of Neurology 253 November 2006 Mike Boggild Liverpool Induces the MTX then gives GA. Uses for severe or active disease. Uses MTX 20 mg for 3 months then 2 quarterly doses of 10 mg for total of 80 mg. In fifth month GA is initiated. Data on 60 patients is presented . All patients were in first 3 years since onset. Relapses went from 2/year to none. Suggested synergy.

Khan's five year imaging data

Background--
Rudick showed brain parenchymal fraction declines in MS
Summers showed cognitive impairment is proportional to atrophy (MS 2008)
Khan looked at 5 years of patients treated continuously with one drug (n=608) picked (how?) 275 including 121 GA 101 high dose IFN 57 low dose IFN used SIENA technique updated in 2004 to include voxel based analysis reliable to 5 mm gaps. He threw out the first year due to known problems with "pseudoatrophy" which is due to loss of extracellular fluid. Was interested in changed in atrophy from year 2-5.
.
Note that in BEYOND beta 500 , beta 250, and GA had the following amount of atrophy at year one and two: -.9(second year). I Khan study at 2 years IFN -.64, GA was -.46. In interval to year five, betaseron had -2.2, Avonex had -1.83, and GA had -1.4, controls -3.8.

Predictors of disability in MS

Robust--
Incomplete recovery after first attack
short interval to a second attack
sphincter affected at onset
motor function affected at onset

Others-
increased age
male gender
multifocal onset with cerebellar involvement

PRECISE Comi et al. for CIS using copaxone

481 patients 81 centers 1:1 randomization 3 years then openlabel extension. For entry patients had to have a unifooal attack and more than 2 large MRI lesions and enroll within 90 days . There was a robust effect on MRI and black holes, data on EDSS is pending. There was a 45 % reduction in relapse rate.

Current clinical trials/ recent trials quick hits August 2008

PRECISE Comit et al CIS and copaxone 481 patients 81 centers 1:1 randomization 3 years then open label robust effect on conversion to CDMS, black holes, EDSS data is pending.

 

FORTE study-- dosage study of copaxone 20 v. 40 mg 1155 patients 12 months negative  result

 

CHAMPS   (older study ) best prediictor of relapse is Gd++ lesions

 

BEYOND-- Betaseron 25v. Betaseron50 v. copaxone-- year two brain atrophy data was -.63, -.64 and -.59 respectively, favoring copaxone

 

REGARD  year two atrophy -.6% for rebif,-.5 % for copaxone favors copaxone but beware of pseudoatrophy effect in year one

 

CAREMS1 phase 3 Campath trial for naive early active patients

 

CAREMS2 phase 3 Campath trial for treatment failures on IFN who relapse with rrms 1200 patients

 

Freedoms  fingolimid, 2 doses .5 and 1.25 v placebo

 

Tranforms fingolimid v avonex

 

DEFINE BG12 fumarate dose finding 240 bid v tid

 

CONFIRM  fumarate v. comparator (which one?)

 

CLARITY  cladribine phase 3 pivotal fast track

 

ORACLE  cladribine trial for CIS

 

BRAVO  laquinomodv. placebo for rrms

 

OlympusRituxan v.placebo for PPMS failed trial in press

 

HERMES    Rituxan v. placebo for rrms reported in NEJM 2008

 

CAMMS223 Campath for RRMS phase 2 trial in press NEJM

 

 

 

 

 

 

 

 

 

 

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Infratentorial lesions predict disability in MS

Minneboo A, Barkhod F, Polman CH et al. Infratentorial lesions predict long term disability in patients with initial findings suggestive of multiple sclerosis. Arch Neurol 2004; 61:217-221.

42 patients assessed over 8.7 years. Thos chosen had initial findings c/w MS based on MRI and these patients were followed until they achieved EDSS of 3.0. 26/42 converted to CDMS (clinically definite MS). Gad lesions and hypointense T1 lesions were not predictuive. 2 or more infratentorial lesions best predicted disability.

Sastre-Garriga J, Tintore M, Rovira A et al. Specificity of Barkhod criteria in predicting conversion to multiple sclerosis when applied to clnically isolated brainstem syndromes.
Arch Neurol 2004; 61: 222-224.

51 patients with CISB (clinically isolated brainstem syndromes) and 102 with other CIS (clinically isolated syndromes) were followed for 34, and 40 months respectively. (The CIS had 46 with transverse myelitis and 56 with optic neuritis). The specificity of the Barkhof criteria was less in CISB v other CIS (61 v 73 %), due to infratentoria lesion requirement having less specificity (no dissemination in space). Conclusion-- beware of specificity in CISB

Fatigue in MS

Factors causing/correlating with fatigue in MS
1.Depression
2. Deconditioning
3. hypothyroidism
4. anemia
5. medications
6. ambient temperature
7. relapse/exacerbation
8. psychological concerns
9. N acetylaspartate-creatine ratio in MR spectroscopy (indicates axonal damage)

NOT correlated
1. T2 lesion volume on MRI
2. Gad lesions
3. C reactive protein
4. transcranial magnetic stimulation response (measure of motor conduction) not difference in larger fibers (may not be the ones involved in fatugue)

Source-- editorial Arch Neurol 2004Feb pp.176-177 Michael Racke Kathleen Hawker and Eliot Frohman, Fatigue in multiple Sclerosis: is the picture getting simpler or more complex

The contribution of demyelination to axonal loss in multiple sclerosis

DeLuca GC. Brain 2006; 129: 1507-1516. An autopsy study of 55 patients with MS prior to death age range 25-83 noted no or a weak correlation between MS plaque load and axonal loss. Both were studied and evaluated microscopically. Spinal cord plaque load was also not closely related. The study indicates the need to reconsider the inflammatory hypothesis as the sole basis with which to assess the efficacy of MS treatments, particularly in certain patients.

HERMES trial for relapsing multiple sclerosis NEJM article

Hauser S SL, Waubant W. Arnold DL, Vollmer T, et al for HERMES Trial Group. B Cell Depletion with rituximab in relapsing remitting multiple sclerosis. NEJM 2008; 358: 676-678

and editorial
McFarland HF. Focus on research: the B Cell -- old player, new position on the team. NEJM 2008; 358: 664-666.

The phase 2 trial of Rituxan (Rituximab, Biogen Idex and Genentech) in relapsing remitting multiple sclerosis showed a significant reduction of relapses and of MRI lesions, the primary outcome measure. It was a short trial (48 weeks) and not powered to show an effect on disability. There was a rapid reduction not only of contrast enhancing lesions on MRI but also total lesions, within 4 weeks. McFarland opines that the benefits of led to increased interest in the role of B cells in diseases thought to be mediated by T cells. Some patients may have antibody mediated complement destructive lesions and in others B cells may precede lesion development. However the rapidity of the response suggests another mechanism. Possibly, B cells are involved in antigen presentation to T cells and activation of T cell programming (cites Rock, 1984). They may contribute to T cell priming and lesion formation. Treated patients showed the subsequent development of naive rather than memory B cells.

Many trials have shown a reduction of MRI lesions but not clinical disease activity. Since antibodies maybe involved in repair mechanisms, clinical status of the patients will need to be closely monitored in the phase 3 trial. B cells may alos be important within lesions, as CXCL13 which regulated B cell migration in lymphoid tissue is found within plaques.

The study is a phase 2 trial, which means that unanswered questions include low frequency side effects, duration of oeffect, and effect on disability. The study involves only 104 patients.

Side effects of interferon beta

1. cutaneous reaction
2. hyperthyroidism (Schwid et al. Arch Neurol 1997;54:1165-1190)
3. transvaginal bleeding (Pakulski et al., 1997 Ann Pharmacother311:50-52)/
4. liver carcinoma (Makita et al., Nippon Shokakdyo, Sasshi 1996;93:406-410)
5. psoriasis (Webster et al., J Am Acad Derm 1996; 34:365-367).
6. transitory hearing loss (Kanda et al., Audiology 1995; 34: 98-102)
7. polymyositis
8. intraocular bleeding
9. Severe anaphylaxis-- sudden laryngospasm and shock after taking drug for six months
10. flulike illness, fatigue and headache
11. depression

Consensus statement on CSF standards in diagnosis of MS

Freedman MS, Thompson EJ, Deisenhammer F, et al. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis. A Consensus statement. Arch Neurol 2005; 62:865-870.

general points
1. The IgG index or any other quantitative IgG anaysis is not equivalent to qualitative analysis using isoelectric focusing with immunofixation, as opposed to the previous recommendation that equated the IgG index with qualitative analysis.

There is complete agreement that isoelectric focusing (IEF) on agarose gels followed by immunoblotting should be the gold standard for detecting oligoclonal bands. Other methods such as polyacrylamide gels combined with IEF and silver staining of proteins might have proved useful IN THE PAST but they LACK SPECIFICITY for IgG and are not supported by consensus. Direct silver staining techniques demonstrate reduced sensitivity and specificity.

Some techniques also stain kappa and gamma light chains (both free and bound) that discern faint bands better against polyclonal background. Light chain staining will also be positive in rare cases where OCB's are caused by the presence of IgA or IgM which will not appear on gels stained only for IgG. These add little to routine MS diagnosis.

Serum free chains are usually removed by kidney (free chains). Intrathecal IgG is usuallyy associated with kappa chains.

Sensitivity of using IEF with immunoblotting is in excess of 95 %. A negative test is an indication to rethink the diagnosis. The presence of only one band in CSF not in serum may indicate the need to retest as many patients will convert. There is a high negative predictive power of negative CSF in clinically isolated syndrome (CIS) such that a negative CSF exam indicates a low likelihood of developing MS. There are five patterns accepted (1- no bands in CSF or serum 2- OCB in CSF not in serum 3-- OCBs in CSF, identical bands in serum (still there is CSF IgG synthesis) 4-- same as 3 except with leaky BBB suggesting systemic oligoclonal band production 5-- Monoclonal bands in CSF and sera, suggestive of a monoclonal IgG protein present).

Q albumen (albumen quotient) can be used to assess CSF leakiness. Controls should be run with each sample to make sure that OCB's in positive controls are not overdeveloped and negative controls are not underdeveloped.

Patients deserve to have CSF analyzed at a lab that utilizes accepted standards.

Hematopoeitic stem cell transplantation for multiple sclerosis

Burt RK, Cohen B, Rose J et al. Arch Neurol 2005; 62: 860-864 Neurologic Review.

Authors comment intial attempts by hem-onc specialists used hem-onc protocols targeting SPMS patients. Recent trials from MS specialists with earlier patients are encouraging with less morbidity and mortality and improvement in EDSS. The key factors in success are selecting active patients (active by MRI or clinical criteria), treatment early before progressive disability ensues, and use of safer lymphoablative but not myeloablative HSCT conditioning regimen.

Rationale-- transplant ablates the aberrant disease causing immine cells while transplanted cells regenerate a new and antigen naive immune system.

Animal models -- Theiler murine encephalomyelitis virus (TMEV) in mice is a persistent viral related autoimmune disease, wherease EAE is a relapsing disease like MS. HSCT should be done while still in immune mediated inflammatory process not chronic progressive process.

Mobilizing hematopoietic stem cells (HSC's) from patients with MS-- HSCs are mobilized from peripheral blood from bone marrow with a growth factor such as granulocyte colony stimulating factor or chemotherapy (cyclophosphamide). GCF's can induce worsening of MS sometimes irreversibly and thus are prevented by administering steroids or cyclophosphamide. Ex vivo, lymphoctes and monocytes are purged and stem cells are selected, sometimes with monoclonal antibodies.

Conditioning regimen-- again the goal is lymphoablation not myeloablation. Myeloablative agents anyways will kill stem cells. Total body iradiation has the potential of causing neural stem cell apoptosis. Non myeloablative regiments include fludaribine, cyclophosphamide, Campath 1h, antithymocyte globulin. Fever induced pseudoexacerbations due to conduction blocks in marginally functional demyelinated axons should be avoided. The goals are 1) dose escale agents that work as conventional therapy 2) maximize immune suppression without myeloablation 3) avoid conditioning agents that injure disease affected and damaged CNS tissue 4) minimize the risk of fever 6) design justifiable regimens.

First generation protocols-- were extremely effective on MRI but not clinically due to late stage patients selected. tHERE WERE ALSO TREATMENT RELATED DEATHS.

Second generation therapies: the rationale for autologous HSCT is that MS is an environmentally caused disease, not a genetic stem cell defect. Nonmyeloablative treatments would presume to be more safe, following which HSC are infused to shorten period of cytopenias. Ruled OUT are etoposide, total body irradiation, busulfan, melphalan, and carmustine. Instead, cyclophosphamide and Campath 1H are used. Criteria are active disease despite treatment and EDSS 2.5-6.0, or higher if they have rapid deterioration and activity on MRI. A German protocol uses cyclophosphamide and rabbit antithymocyte globulin. At Northwestern, a regimen of cyclophosphamide and Campath 1H is used. More than half do not requrie a blood transfusion.

Comment-- to my knowledge this therapy is cash on the barrelhead, which has given some serious MS researchers pause in suggesting it.

MRI as a surrogate measure for disease activity in MS

See Neurology suppl. 3 2002 p. S29
Authors note that in the main clinical trials the correlations between relapse rate and EDSS progression with T2 burden are generallyin the range of 0.15 to 0.30. MRI cannot be used to predict EDSS progression or relapse rate. Autors cite the "Prentice criteria" a statistical look at what makes a surrogate marker. (Prentice R. Surrogate markers in clinicl trials: definition and operational criteria. Stat Med 1989; 8:431-440) states the surrogate marker must closely mirror the gold standard which here, is clinical activity.

Rating the main MS studies (the classics)

from Neurology suppl 59;S3 2002
CHAMPS Avonex v. Solumedrol/placebo Outcome point CDMS NOT disability, relapse, brain atrophy. NTT 6.7 to prevent one conversion to CDMS over 3 years. Class I Category A trial

Beta1a v. placebo. Primary endpoint was confimred EDSS progression between treatment group and controls. Relpase rate was a secondary endpoint. EDSS 1-3.5 at entry, 2 relapses in 3 years. Only 57 % of patients completed 2 years. Proportion with a one point increase in EDSS was 21.9 v. 34.9 % in treated/control groups, respectively. (p=0.02). Relapse rate improved by 18 %. Among the subgroup that completed 2 years of treatment there was a 31 % reduction of relapses. There was a 50 % reduction of Gad+ lesions but only 165/301 patients were included in this analysis. There wa no effect on T2 burden. NAbs were seen in 22 % by week 104. NTT to prevent one point increase in EDSS was 7.7. Class I Category A. However, it was short study was stopped early , studied a restricted population (mild entry EDSS 1-3.5) and showed decreased disability but no effect on T2 burden .

ETOMS Rebif 22 sq/per week v. placebo . Unlike CHAMPS, no steroids given in placebo group. No change in EDSS seen. MRI showed a benefit. NTT 9.1 to prevent one CDMS in 2 years. Class I Category A trial

PRISMS patients with 2 relapses in 2 years with EDSS 0-5.0 were reandomized to Rebif 22, Rebif 44 or placebo. Active treatment increased the time to progression of disability and reduced the probability of progression, and reduced the median integrated Disabiliyt status Scale score (area under the curve) mean increase in EDSS and mean increase in Ambulation Index. It reduced relapses, reduced moderate and severe relapses, number of steroid courses, and number of hospitalizations. It increased the number of relapse free patients. T2 burden increased by 10 % inplacebo and decreased with both treatment arms. Number of active lesions also was significantly reduced. 90 % completed 2 years and 95 % were followed for two years. NTT (high and low dose Rebif) to prevent one relapse per year, was 2.4, and 2.7, to render one patient relapse free for one year, 4.3 and 6.7; to render one patient relapse free for two years, 6.3 and 9.1; to prevent one moderate to severe relapse over two years, 2.7 and 3.6; and to prevent onepoint progression in EDSS, 9 and 12. Class I Category A. Rebif prevents progression of disability and reduces relapses in MS.

PRISMS 4-- extension of trial to four years. primary endpoint was relapse rate, with main comparison high dose angainst placebo. Original placebo patients were rerandomized to high or low dose. A dose effect relationship for disability was seen in years 3 and 4. Relapse rate was better with treatment but not with high dose treatment. The higher dose was significantly more effective for time to second relapse and the need for steroids. MRI was always better in the earlier treated patients. 20 % + of patients switching from placebo to drug developed NAbs. NTT not calculated. Class I, Category A. The trial established that Rebif 22 or 44 was effective in reducing relapses, delaying disability, improving MRI markers(t2 burden and no of new T2 lesions per scan) but no difference between high and low doses.

Interferon B1b in RRMS EDSS 0-5.5. gave betaseron 1.6 or 8 miu sq qod. Not well blinded, but randomized. No beneficial effect of EDSS found. Significant effect found on time to first relapse, proportion of patients relapse free, relapse rate, , number of moderate or severe relapses, and need for hospitalization over two years. MRI lesion burden increased by 20 % in placebo group, 10.5 % in low dose group, and decreased by 0.1 % in high dose group. NTT was 2.3 patients to prevent one relapse per year in this actively relapsing group. NTT 5.6 patients to keep one patient relapse free for two years, and 4.5 to prevent one moderate or severe relapse in one year. Class I category A

Extension study of Beta ib. Primary outcome measures were time to sustained worsening by one point on EDSS and mean change in each group from baseline. Not blinded. Study showed a trend (p=0.096) on time to sustained disability over five years with NO DATA GIVEN on other stated endpoint of mean change in EDSS. Both doses led to better relapse data for whole five year period. Rate of moderate and severe attacks was lower in both groups. Less patients completed years 3-5. MRI was beneficial for treated group although numbers were small at this point of study. There were 154 dropoutsby then en d of the study. NTT not calculated. Class II Category B, shows an effect for relapses only.

Copolymer (glatiramer acetate) GA v. placebo baseline EDSS of 0-5.5 . There was no effect of EDSS. Relapses were reduced 29 % over two years. MRI data not presented. NTT was 2.7 to prevent one relapse over two years. Class I Category A study for relapses.

Open label extension trial. Disability data gleaned against natural history data. Annual relapse rate of 0.42 over both phases of trial was stated as 72 % reduction over 2 years before study entry is misleading as it only was calculated with 83 patients and no account was made for regression to the mean. No MRI data exist. Injection site reactions were reported as 2.4 %. There was 27 % dropout. Class II Category C.

IVIG-- insufficient quality to be evaluated

Mitoxantrone randomized MRI blinded patients with aggressive MS EDSS <> 1.0. Entry 2 relapses in 2 years. EDSS outcome was better in treatment group (7 % progresses v. 37 % changed by one point over two years; however there was no change in MEAN change in EDSS score. Relapse outcome over 2 years was .89 v. 2.62. Percent relapse free was 63 v. 21 % all significant. NTT was 3.3. Class II/III Category C study due to trouble blinding.

MIMS MTX in SPMS bseline EDSS 4.5-7 with one point deterioration in year prior to entry. Primary endpoint was a composite of EDSS, Ambulation Index, number of relapses requiring steroids, and Standard Neurologic Status. The result was highly significant p<0.0001). There was a difference in groups on EDSS progression, at 6 months, mean number of treated relapses, time to first treated relapse, percentage of patients without a relapse, totoal number of relapses, and number of hospitalizations. Class II Category B. Key point is that it was ana actively relapsing group in the two years before study entry.

Secondary progressive MS:
Interferon B1b (European) entry 3-6.5 EDSS 70 % of patients had relapses in 2 years before study entry. Progression of disability was 49.7 % v. 38.9 % p=0.0048, also less patients became wheelchair bound. Relapses were reduced by about 30 %. No treatment effects in patients with baseline EDSS 6.0 or 6.5. Decreased T2 burden. NTT was 9.2 patients for 3 years to prevent one point EDSS increase. Class I Category A. Difference with SPECTRIMS (North American study) might be due to less pre treatment relapses in N American group.

Head to Head
INCOMIN Beta 1b v. Beta 1a (Betaseron v. Avonex) 2 year trial, primary endpoint was no of relapse free patients, and number of patients with no new T2 lesions on their MRI. Entry 2 relapses in 2 years, EDSS 1-3.5. EDSS progression of one point was 13 % over 2 years with Betaseron, 30 % with Avonex. T2 lesion burden showed o new lesions in 55 %with Betaseron, 26 % of those with placebo. NTT to make a patient relapse free for 2 years was 7 for betaseron v. avonex. Class I for MRI, Class III for clinical outcomes (unblinded)


EVIDENCE Rebif v. Avonex. primary endpoint was proportion of patients who were relapse free at 24 weeks. entry edss 0-5.5, pastients who got Rebif received 44 mcg tiw dose. Evaluating neurologists were blinded. There was no change in disability. Relapse free patients favored Rebif (74.9 v. 63.3 %, odds ratio 1.9, p=0.0005). Combined unique active lesions on MRI favored Rebif. NTT was 9 at 24 weeks and 10 at 48 weeks. Class I study.

Neutralizing Antibodies against Natalizumab

editorial Freedman MS, Pachner AR. Neutralizing antibodies to biological therapies: A "touch of grey" vs. a "black and white" story. Neurology 2007; 69:1386-1388.
based on article Calabresi PA, Giovannoni G, Confavreux C et al. The incidence and significance of antinatilizumab antibodies : results from AFFIRM and SENTINEL. Neurology 2007; 69: 1391-1403.

Cut to the chase:
from the editorial "With natalizumab, NAb's develop quickly, are readily measured, and can be shown to correspond with a loss of activity against a validated disease measure (eg. MR). With IFN B, NAbs develp more slowly, can spontaneously resolve and reappear depedning on titer and are not completely time synchronous with their effect on disease measures. " NAbs correlate (with natalizumab) with new MRI lesions, increased number of relapses, and progression of disability. Editorial notes the gray areas: some patients have NAbs and no re-emergence of disease, relapse rates are only higher inthe persistent NAbs group, and the persistent groups has more infusion reactions early, in the first few months of therapy, before its possible to identify the persistent NAbs group. The lack of persistence in AB might be due to antibodies to the antibodies. NAbs titers are not important.

In the Calabresi article, authors note that 9 % of patients in AFFIRM had NAbs, 3 % transiently and 6 % persistently. SENTINEL results were similar to AFFIRM.

Genome profile in multiple sclerosis

article and editorial
Hafler DA et al. Risk alleles for multiple sclerosis identified by genomewide study. NEJM 2007; 357:851-862.Peltonen L. Old suspects found guilty-- the first genome profile of multiple sclerosis. NEJM; 2007; 357: 927-929.

Editorial comments on use of SNP's (single nucleotide polymorphisms) to define genetic diseases. The technique has localized diseases (DM, Crohn's) to unsuspected pathways, genese without a known function, or to noncoding regions of genes. Identical twins have a 30 % concordance of developing MS; dizygotic twins, 2 %, general population, 0.1 %. Since 1972, there has been an association with HLA-DRB1 gene on chromosome 6p21. Minor loci are seen on 5p, 17q, and 19q. The above study of NS Genetics Consortium supports the prediction of multiple risk alleles.

The test analyzed more than 330,000 SNP's in 931 trios (affected patient and both parents)by monitoring the overtransmission of any SNP to the affected child with transmission dysequilibrium testing. The data support the HLA locus but also 2 interesting genes, IL2RA which encodes the alpha subunit of the IL-2 receptor (also known as CD 21) on chromosome 10p15, and IL7RA which encodes the alpha subunit of the IL-7 receptor on chromosome 5p13. IL2 receptor is critical for the regulation of T Cell responses, and IL-7 for the homeostasis of the memory T cell pool and generation of the autoreactive T cells in MS. These two genes together, though explain only a small portion of the variance (0.2%) in risk of MS.

Author suggests the potential high risk alleles in large study samples should be sequenced, to encounter, probably, rare high impact alleles with critical importance for disease risk in some families or patients (analagous to BRCA1,2 testing). Author believes other genome variants should be sought, terms finding somewhat disappointing.

Vaccines in multiple sclerosis

Guidelines for Administration of Human Papillomavirus (HPV) Vaccine (Gardasil®) to Multiple Sclerosis Patients
(Developed by the Executive Committee of the National Clinical Advisory Board, National MS Society USA)

November 30, 2007—Gardasil® (Merck) is available as a prophylactic vaccine, designed to prevent the following conditions in girls and women 9 to 26 years of age:

HPV 6, 11, 16 and /or 18-related cervical cancer
cervical dysplasias
vulvar and vaginal dysplasias
condyloma acuminata
Gardasil is a vaccine prepared from noninfectious purified virus-like particles of recombinant major capsid (L 1) protein of HPV types 6, 11, 16, and 18. The product information states that individuals with impaired immune responsiveness may have reduced antibody response to active immunization due to:
immunosuppressive therapy
genetic defect
HIV infection
Immune response to vaccines may be reduced due to immunosuppressive therapy, including:
irradiation
antimetabolites
alkylating agents
cytotoxic drugs
corticosteroids (used in greater than physiologic doses)
This vaccine has been tested exclusively in 9 to 26-year-old healthy females (it has not been tested in an MS population):
Safety and efficacy information is available only for healthy girls/women of that age group.
Studies of the vaccine are now being done in boys/men and women older than 26 years of age.
FDA consideration for licensing the vaccine for other groups will take place when there are data to show that it is safe and effective for them.
It is important for girls and women to get HPV vaccine before they become sexually active.
Immunizations and Multiple Sclerosis*, a clinical practice guideline published by the Multiple Sclerosis Council for Clinical Practice Guidelines in 2001, presents conclusions based upon available research data. The expert panel used the recommendations of the Centers for Disease Control and Prevention (CDC) as a foundation for the development of its guideline. The consensus of the panel, based on available research data, was that:

People with MS should not be denied access to health-preserving and potentially-life saving vaccines because of their MS.
Vaccinations that do not contain live viruses can be given to MS patients unless they are currently experiencing an exacerbation.
The immune modulators approved by the FDA for use in MS are not believed to contraindicate vaccination with Gardasil:
Glatiramer acetate (Copaxone® )
Interferon beta1a (Avonex® and Rebif®)
Interferon beta1b (Betaseron®)
Natalizumab (Tysabri®) also should not contraindicate vaccination with Gardasil. Mitoxantrone (Novantrone®), like other immunosuppressive agents, would be likely to interfere with effective immunization by Gardasil.
*Available from the ProfessionalResource Center by calling our toll free number 866-MS-TREAT (866-678-7328) or by emailing: MD_info@nmss.org or healthprof_info@nmss.org.


--The Executive Committee of the National Clinical Advisory Board

Narcolepsy caused by ADEM

Gledhill RF, et al. Arch Neurol 2004; 61: 758-760.

Narcolepsy/cataplexy usually occurs sporadically in patients positive foo HLA DQB1*0602 with a loss of hypocretin/orexin in CSF, and is presumed autoimmune. However, it can also occur secondary to a lesion, in this case due to ADEM and partly responsive to steroids. In this case the lesion surrounded the third ventricle and hypothalamus and extended to the basal forebrain. The patient had sleep onset rem periods (SOREM) and cataplectic attacks.

injection reactions with morning injection

TIMING OF INJECTIONS COULD MINIMIZE SIDE EFFECTS
Individuals on interferon therapy often do their injections at night so that they can sleep through side effects, such as flu-like symptoms. However, a recent study suggests that injecting in the morning may minimize side effects.

German researchers conducted a study with 16 people who were just starting interferon therapy. Half were given injections at 8 a.m. and the other half at 6 p.m. Those who injected in the evening experienced more intense side effects than those who injected in the morning. The evening injectors also had a greater increase of cytokines (a protein involved in the immune response) like IL-6. After six months of treatment, however, all side effects and most of the blood chemistry changes ceased.

Investigators believe that natural fluctuations of hormones and cytokines over the course of the day and night affect the body's response to interferon injections. They suggest that anyone having a problem with side effects consider trying morning injections to see if that proves helpful.

Toxocariasis of CNS simulating ADEM

Marx et al. Toxocariasis of the CNS Simulating ADEM. Neurolgy 2007; 69: 806-807. General notes about the disease: there are two forms, visceral larval migrans (systemic) and disease focused on optic nerves. The hosts are dogs and ADin which adults live in intestine. Humans ingest embryonated eggs fromsoil (geophagia, pica) or through exposure to dirty hands, raw vegetables, larva from undercooked giblets. Case was a 2 year old girl with fever and cough, leukocytosiswith MRI of brain and spinal cord extensively involved mimicking ADEM.

Diagnosis is made by high titers of T. canis with ELISA or Western blot, eosinophils in blood or CSF, demonstration of intrathecal synthesis of anti T Canis antibodies and close contact with dogs. Clinicalnormalization with treatment supports the diagnossi.

Daclizumab in MS

Rose JW, Burns JB et al. Daclizumab phase II trial in relapsing and remitting multiple sclerossi.MRI and clinical results. Neurology 2007; 69:785-789.

Daclizumab binds to the alpha chain (CD25) of interleukin 2 receptor (IL2R) which is involved in activation of T and B cells. Currently its approved for renal allograft rejection.

Subjects had RRMS with EDSS 1-6.5, withone relapse in previous year and failed IFN therapy with at least 2 GD+ lesions on one or more of the baseline scans. 11 patients were studied. AE's included severe UTI's severe relapse at time of infusion, transient thrombocytopenia (while also receiving Bactrim). Study shows promise of daclizumab as monotherapy for MS.

Natalizumab for Multiple Sclerosis

Ransohoff RM. NEJM 2007; 356:2622-9. Clinical Therapeutics. Review article. Introduction cites that 50 % of patients reach the following disability milestones at the following times: loss of employment, 10 years after diagnosis; use of assistive devices to walk (15 years); inability to walk (25 years).The cost of care is about $47,500 per patient per year. Natalizumab contains humanized MAB's against leukocyte alpha 4 integrins, which, together with Beta chain, comprise heterodimeric glycoprotein responsible for trafficking leukocyte entry in to the CNS. In trial one, 942 patients were randomized to infusion v. placebo. Natalizumab decreased cumulative probability of sustained disability progression from 29 to 17 % (p<0.001, NTT=9), and reduced number of enhancing lesions on MRI at year 2 by 92 %. The second study, N was added to interferon beta (or not) in 1171 patients, reduced sustained disability from 29 to 23 %, NTT = 17, increased relapse free patients from 37 to 61 %, NTT=5, 89 % reduction in enhancing lesions. The review article indicates the necessity of a three month hiatus from immunosuppressant medication before starting the drug, and ensuring the diagnosis of MS is secure. TOUCH program mandates assessment of the patient at 4,7,13 and every 6 months therafter.

The fragile benefit of BENEFIT

Coles A. The Lancet Neurology 6: 753-754 2007.
Coles provides a classically British look at the BENEFIT trial noting that the study was a complicated look at Betaseron in CIS looking at disability. The first trial agaist placebo replicated CHAMPS and ETOMS by showing a delay to diagnosis of MS in a two year study of Betaseron. (N=292 on Betaseron, 176 on placebo). He offers that in the treatment arms of CHAMPS, ETOMS and BENEFIT, the conversion rate was 0.35, 0.34, and 0.28 respectively; in the respective placebo arms, the conversion rates were ).5, 045, and 0.45). In the third year everyone got betaseron (some placebo patients got betaseron earlier if they converted to MS earlier) (early treated v. late treated). In the second analysis, Betaseron was associated with less disability (the only interferon with that endpoint). In the third analysis the later treated patients had worse MRI scans. However, Coles notes that only 42/292 early treated patients accumulated disability v. 40/176 delayed treated patients. The Number to treat (NTT) to prevent one additional case of accumulated disability was 11.9. However 68 patients were lost during the trial, suggesting the possibility of statistical blips. Coles believes the trial was too small to draw conclusions and might have been compromised by dropouts or multiple endpoints measured and states another larger trial is needed.

Susac Syndrome-- Pearls

Triad of BRAO (branch retinal artery occlusion), hearing loss, encephalopathy

Demographic age9-70 predominantly young adults 2:1 female

BRAO vision spots, loss eye exam-- infarctions, BRAO, Gass plaques and silver lines. Gass plaques are like Hollenhorst plaques but not necessarily at branch points. Clinical variable-- spots, visual obscurations, blurring, inversion of vision transient. Diagnostic test of choice-- fluorescein angiogram, signature finding in young adult esp.

Hearing loss-- affects apex of cochlea first, low tone hearing loss. Bang bang is one ear then other, rare in MS. If affects semicircular canal may cause vertigo, tinnitus, vomiting,confusion with Meniere's disease

Encephalopathy-- usually strong association with headache. May persist.

MRI callosal lesions "snowball" and "spokes" often in center of corpus callosum rather than on ventricular edge, holes in middle of lesions virtually pathognomonic per Susac. May also have lesions in brain substance and meninges, may enhance. Cranial nerves are spared. Cases may even mimic cancer.

Pathology-- vasculopathy not vasculitis. Small arteriolar occlusion. Inflammation afterwards may mimic encephalitis pathologically. Question of relation to juvenile dermatomyositis, rash, looks like erythema nodosum.

Course-- two types: two year type and long term type.

Therapy-- Big sledgehammer and little sledgehammer. protocols in J Neurol Sci? 2007. Include initial Solumedrol and IVIG then Cell Cept, or cytoxan or rituxan.

Notes on extension trials GA v. interferons

Again, Noseworthy's comment that they are more useful for safety than efficacy needs to be considered. Or is that true?

Natural history trials suggest that at 11-15 years, in three trials (lyon, London Ontario, and Olmstead County) 48 % reached EDSS of 4 at eleven years (Lyon), half reached EDSS of 6 at 15 years (London), and 28 percent reached an EDSS of 6 at ten years (olmstead County). IN addition, 10 and 7 percent, respectively, reached an EDSS of 8 (london and Olstead Cty).

Compare to the Copaxone extension trial. Patients in the MITT (modified intent to treat, based on getting GA either in double blind or open label part of the trial) had 7 years of disease duration at study start and 6.25 or 7.63 mean years of exposure to GA, depending if they ever received placebo. Thus they were ill with for fourteen years, about. The median EDSS at study end increased by 0.5 to 3.53, and was 3.06, mean, and 2.50 median, for subjects who received GA from the beginning. The ongoing (always copaxone group) had 24 % reach EDSS of 4, 8 % reach EDSS of 6, and 1 % reach an EDSS of 8. This is better than Olmstead County, where disease is benign and patients are not treated. At the minimum, one could say that subjects who were able to stay on copaxone were able to do better.

If one uses the MITT, that counts subjects who withdrew but who were followed, the percentages reaching EDSS of 4,6,8 were, respectively, 24,11, and 3, still outstanding. However, there were 74 subjects who withdrew and did not have LTFU. The reasons for withdrawal ranged from inability to comply with protocol (moved, pregnancy, , lack transportation) as well as breaking through. 55 % OF WITHDRAWN PATIENTS WERE STABLE WHILE ON GA. oF THE 50 PATIENTS WHO WITHDREW WITH LTFU, THE MEDIAN EDSS AT 10 YEARS WAS 6.0, WITH 68, 50, AND 10 % REACHING EDSS OF 4,6,8 RESPECTIVELY. That is worse than natural history. What impresses about this study is that almost half of patients were able to complete the full ten years on GA and that of those, the vast majority did well and there were only a few bad outcomes.

Looking at interferons, the data is much sketchier on long term. For interferon ib sc, the study lasted five years and there was a trend to less relapses. However, patients were then contacted periodically thereafter and examined spot check exam, and MRI. Of the patients who were originally in treatment arm, and who were on drug > 80 of 16 years, 45 % reached EDSS 6 and 29 % EDSS 7 (v. 52 and 44 for < 10 % time users) although no data what they took in meantime. 54 % of patients in LTF had NABs. 30 percent of patients were still on Betaseron ten years later (however, no followup study to help them stay on).

They had 19 years of disease on average. No EDSS data are given for Champions (long term Avonex) since the endpoint was conversion to CDMS . 42 % of patients were still on interferon 1a i-m at the end of Champions (5 years after initiation of treatment).

PRISMS 4 measured patients on Rebif 22 and 44 v. placebo for two years, then four more years on either rebif 22 or rebif 44. After 7.4 years, 68 percent were reevaluated once, after 8 years. 20 percent reached EDSS 6. Mean time to progression of one step on EDSS was 5.4 years. Treatment interruptions, co-medication and switches were not documented. No comparative controls.

Caution is indicated since head to head trials were not done, and the respective groups might have been non analagous.

Diseases mimicking MS -- pearls

Five not to miss
1. Clinically isolated syndrome-- CIS-- Repeat MRI in one month to make MS diagnosis
2. Devic's disease(neuromyelitis optica or NMO)-- consider in patients with the combination of ON and transverse myelitis, repeated transverse myelitis, long segment lesions on spinal cord, Asians, patients without bands in CSF, and patients nonresponsive to medication among others. Serum IgG antibody for NMO (new test) segregates fairly reliably from MS. Pearl-- check hepatitis C antibodies. See www.Devicsnotes.blogspot.com for Wingerchuk criteria and more information.
3. Progressive multifocal leukoencephalopathy (PML)-- MRI lesions can mimic MS but they do not enhance. Check PCR to JC virus (papovavirus) in blood and CSF (latter is diagnostic, former is screening, urine is of no value as it is almost always positive). Pearl-- Patients may not have known HIV at time of presentation.
4. Spinal cord tumor-- astrocytoma or ependymoma most common. No brain lesion seen, CSF is negative. Cord may be enlarged. Lesion not necessarily in posterior columns as usual.

MS variants
5.tumefactive MS-- may resemble GBM. May be able to suspect MS with VEP's CSF but may require brain biopsy.
6. Marburg variant-- severe necrotizing rapidly fatal form of MS
7. Balo's concentric sclerosis-- a variant. Concentric rings may be mixed with other MS like MRI lesions.
8. ADEM-- no infallible wayof diagnosing, but ADEM is more common in kids, after vaccinations and infections, may have more gray matter lesions, or LOC or other unusual symptoms.

Ocular presentations/developing countries
9. Subacute myelo-optic neuritis (SMON) common in developing countries. MRI may be abnormal, CSF is not abnormal. May be caused by toxins (cooking oil) or vitamin deficiencies.
10. Eale's disease-- small vessel occlusive disease causing vitreous hemorrhages esp. in India and the Middle East. Opth'y exam and fluorescein angiographyis diagnostic.
11. Behcet's disease-- more common in Asia and Mediterranean. uveitis, MRI changes, CSF pleocytosis without bands, biopsy mucocutaneous ulcers to diagnose.
12. HERNS= hereditary endotheliopathy, retinopathy, nephropathy, and stroke-- aut dom, in Chinese leukoencephalopathy-renal syndrome, prominent dementia.

Systemic disease often cited in differential diagnosis
13. Sarcoid-- 90 % have pulmonary lesions, for biopsy. Meninges may be abnormal. Rarely, oligoclonal bands are positive.
14. Lupus-- Sjogren's-- may affect CNS and mimic MS. If long segment spine lesions are present and if bands are absent, send NMO antibody. For lupus check ANA, ds DNA autoab's and look for kidney/skin involvement. In Sjogren's check SS-A (Ro) and SS-B (La) antibodies.

Retinitis pigmentosa syndromes
15. NARP-- Neuropathy, ataxia, retinitis pigmentosa-- mitchondrial mutation in ATP'ase 6 gene causing visual and motor symptoms in a young person with MRI abnormalities, and sensory PN. Athena has a commercial test.
16. Usher syndrome-- congenital RP, hearing loss, ataxia, sometimes bands.

Other inherited diseases
17. CADASIL-


Infectious


Other ocular syndromes
Inflammatory uveitis/retinitis
AION
Cogan syndrome keratitis and episodes of estibular dysfunction, + hearing loss
Susac syndrome-- relapsing vertigo, vision loss, encephalopathy, abnormal fluorescein angiography and audiograms
Central serous chorioretinopathy-- mimics ON but due to detached retina
Neuroretinitis (stellate retinitis)-- unilateral visual loss, mimics ON due to capillary leak, with macular star formation.


Sneddon syndrome-- usually recurrent strokes, apl ab's, livedo reticularis

Eosinophilia-myalgia syndrome-- hypercoag state can make MRIi abnormal

Differential diagnosis of multiple sclerosis, approach

Rolak LA, Fleming JO. The Differential diagnosis oo multiple sclerosis. The Neurologist 2007;13:57-72.

Below is a brief synopsis of the diseases that can be confused with multiple sclerosis.

Rolak states that 2 factors most reliably identify patients without MS. The first is absence of typical symptoms such as ON, L'Hermitte's sign, sensory level, NGB, etc. The other is normal brain MRI and/or CSF.

Rolak identifies 20 MRI patterns that mimic MS, 15 diseases disseminated in space but not time, 15 disseminated in time but not space, and 20 disseminated in both, all in tables. He suggests against extensive screening for these diseases, arguing that is rarely cost and time productive use of resources and may generate false positives.

Most helpfully, Rolak outlines the seven most common diagnoses for patients without MS. By far, the commonest is psychiatric disease in several large series, including somatization, malingering, hypochondriasis, depression, anxiety. The second most common is everyday sensations that are misconstrued as abnormal, including vision changes, loss of power, and poor balance. Psych symptoms tend to be generalized, such as "weak all over" or "numb everywhere" whereas MS has a clear anatomic localization. The time course of MS symptoms-- onset with regression over days to weeks-- also differs from psychiatric disease. Third most common is migraine. Unilateral numbness and rarely, weakness can mimic MS and MRI shows whitish lesions which can be confused. Other less common causes include peripheral neuropathy, cervical stensosis, and vertigo.

INCOMIN and EVIDENCE

INCOMIN trial Avonex v. Betaseron 188 patients with RRMS , two years study, single blinding (patients were not blinded) 51 % of Betaseron patients were relapse free, v. 36 % of Avonex patients; 55 v. 26 % were free from new T2 lesions (favoring betaseron patients).

EVIDENCE-- Avonex v.Rebif-- 677 patients, outcome at 24 weeks, followed for 48 weeks, single blinded (like INCOMIN). The percentage of relapse free was 74.9 % for Rebif, 63 % for Avonex. There were more NABS in Rebif group and they did worse than the Rebif patients without NABS but better than the Avonex patients.

Copolymer (copaxone) pivotal trial

Studied patients with RRMS, 18-45, EDSS 0-5, 2 exacerbations or more in 2 years, stable for thirty days. 251 patients (73 percent female) with endpoint relapse rate. Exacerbation rate decreased significantly, disability not robust data. Confirmed progression of not close to significance but EDSS was marginally significant.

The followup study with MRI European/Canadian confirmed a 33 % reduction in exacerbations, and a 35 % reduction in enhancing lesions.

Rebif pivotal trial

560 patients RRMS 18-50 >= 2 exacerbations over 2 years, EDSS 0-5, no exacerbations for two months prior to study entry, 3 arms, placebo, 22 and 44 ug three times a week, two year followup. All four outcome measures, exacerbation rate, percentage of exacerbation free patients, MRI attack rate, and confirmed progression of disability were helped (confirmed progression was marginal). Higher dose suggestedmore efficacy but the data was not significantly robust on that point.

Avonex pivotal trial

301 patients with rrms 18-55, >2 exacerbations over three years, EDSS 0-3.5, none within two months, placebo v. 1 treatment dose, followed for two years. Result was a decreased exacerbation rate, slightly less than betaseron, decreased progression and attack rate, but burden of disease on MRI was not significant. Barry Arnason called these results "marginal." However, he stated it was the first independent confirmation of the betaseron trial.

Betaseron trials-- four main ones

Pivotal trial-- placebo 123, .05 mcg B 125, .25 mg 125. Primary endpoints were exacerbation rate and % of exacerbation free patients. 72/372 failed to complete their assigned treatment (19%). Exacerbation rates was 1.31, 1.14, and 0.9 respectively in the three groups favoring .25 dose. The % exacerbation free was 16, 18, and 25 respectively.

Two secondary progressive trials, European and North American. In European trial the primary outcome variable was disability, a one point increase on EDSS or 0.5 increase if the EDSS was greater than 6. Patients with CDMS or SPMS were enrolled, 360 patients with MS and 358 with placebo. Patients needed to sustain EDSS for six months prior to study entry. One dose of Betaseron was used. The time to increased EDSS was greater in patients receiving Betaseron. There was less MRI activity in the betaseron group. The relapse rate was .42 in the betaseron group, .63 in the placebo group. These results were highly significant the trial was stopped in the middle and led to approval of Betaseron for SPMS.

In the North American trial for MS, there was no significant difference between the groups.

Natalizumab v. interferons with cost measure

NEW YORK (Reuters Health) May 11 - Natalizumab is comparable to interferon beta-1a in the net health benefits it provides for relapsing multiple sclerosis, an analysis of published data suggests. Previous reports have shown natalizumab to be effective in preventing relapsing and slowing disease progression, but the drug has also been linked to an increased risk of progressive multifocal leukoencephalopathy (PML), which often proves fatal. Whether the benefits of natalizumab provides offsets this risk is unclear. In the current study, Dr. Ray Dorsey, from the University of Rochester Medical Center in New York, and colleagues analyzed published data to assess the quality-adjusted life years (QALYs) gained with natalizumab. A comparison was then made with interferon beta-1a. Data for the natalizumab analysis was drawn from the Natalizumab Safety and Efficacy in Relapsing Multiple Sclerosis (AFFIRM) trial, while the interferon data came from the Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study. Each study lasted roughly 2 years. The investigators report their findings in the May 1st issue of Neurology. The authors found that in terms of the effect on QALYs, natalizumab was minimally more effective than interferon at reducing disease relapses. The agents were comparable in their ability to slow disease progression. Because natalizumab did carry a slight risk of PML, the final net health effect of the drugs was nearly identical - 0.033 QALYs gained. 'Over the first 2 years of therapy, the health effect of natalizumab for the treatment of relapsing multiple sclerosis is much greater than the expected harm from PML,' the authors conclude. Still, they write, long-term observational studies are needed to fully characterize the risk of PML with this drug. Neurology 2007;68:1524-1528. Multiple Sclerosis (MS) Reuters Health Information 2007. 2007 Reuters Ltd.

Sleep Disturbance and fatigue in Multiple Sclerosis

Attarian HP et al. Arch Neurol 2004;61:525-528. (Wash U). Authors uued a case control format to compare 15 patients with MS anf fatigue, 15 MS patients without fatigue and 15 age/sex matched healthy controls. Tools were Fatigue Descriptive Scale, Epworth Sleepiness Scale. The MS patients with fatigue included 2 with delayed sleep phase, 10 with disrupted sleep, and 3 with normal sleep. 12/15 MS patients had normal sleep. The healthy controls had normal sleep.

laquimod at AAN

The oral immunomodulatory agent laquinimod significantly reduces MRI-measured disease activity in relapsing–remitting multiple sclerosis (RRMS) patients, according to results from a phase IIb study in humans. Laquinimod appears to act by modulating the Th1/Th2 balance and inducing the Th3 cytokine transforming growth factor (TGF)-ß. The efficacy of this agent at a dose of 0.3 mg/d was previously established in a 24-week phase II trial in RRMS patients. To assess the effects of 2 different doses of this agent on MRI-monitored disease activity, Giancarlo Comi, University Hospital San Raffaele, Milan, Italy, and colleagues randomized 306 RRMS patients to daily placebo (n=102) or daily doses of laquinimod 0.3 mg/d (n=98) or 0.6 mg/d (n=106) over a period of 36 weeks. All patients were required to have had 1 or more relapses in the year prior to study entry and at least 1 enhancing lesion at screening. Baseline demographic, clinical, and MRI characteristics were comparable for all patient groups. No significant treatment differences were seen for the 0.3 mg dose, reported Dr. Comi. However, significant differences in favor of the 0.6 mg dose over placebo were found for the cumulative number of enhancing lesions/scan in the last 4 scans (2.6±5.3 vs 4.2±9.2; P=0.0048) and for most secondary and exploratory MRI-based outcome measures. In addition, trends in favor of the 0.6 mg dose over placebo were demonstrated for annual relapse rate (0.52±0.92 vs 0.77±1.25; P=0.21), relapse-free patients (70.8% vs 62.7%; P=0.33), and time to first relapse ( P=0.14). Both doses of laquinimod were well tolerated, with only some transient and dose-dependent increases in liver enzymes. Overall, these results support the continued study of the 0.6 mg dose of laquinimod for the treatment of RRMS, concluded Dr. Comi.

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Daclizumab in multiple sclerosis

The monoclonal antibody daclizumab, which is currently used to prevent rejection in organ transplantion recipients, also shows efficacy in the treatment of multiple sclerosis (MS) patients, reported Eman Ali, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, and colleagues. Almost two-thirds of patients who received this agent in a recent clinical trial experienced an improvement or stabilization in Expanded Disability Status Scale (EDSS) scores. Daclizumab is a humanized monoclonal antibody directed against the interleukin (IL)-2 receptor a subunit that is expressed on activated T cells. According to Dr. Ali, daclizumab may be efficacious in MS because of its ability to block this receptor subunit, thereby inhibiting IL-2 signaling, limiting T-cell expansion, and reducing brain inflammation. Dr. Ali and colleagues conducted a retrospective study of this agent in 40 relapsing–remitting MS (RRMS) patients and 15 secondary–progressive MS (SPMS) patients for a mean period of 13 months, most of whom were also receiving ß-interferon treatment. The investigators found that EDSS scores improved in 20% of patients, stabilized in 40%, and worsened in 40%. Treatment effects were more favorable in RRMS patients, with about 63% showing improvement or stabilization. In SPMS patients, improvement or stabilization was seen in about 53% of patients. In a subgroup of 28 patients, the tolerability of the drug was evaluated by a 0–10 visual analogue scale (0=very well tolerated, 10=not tolerated), and the average score was shown to be 1.87. Fatigue and nausea were the most common side effects followed by skin rash.

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AAN 2007 BENEFIT STUDY

Three-year data from the BENEFIT study suggest that, in patients with clinically isolated syndrome (CIS), immediate treatment with interferon (IFN) ß-1b significantly delays progression to clinically definite multiple sclerosis (CDMS). These findings provide further evidence that early treatment, even when administered at the first event suggestive of MS, provides long-term benefits for patients. In the BENEFIT study, 468 CIS patients with MRI findings suggestive of MS were treated with subcutaneous IFN ß-1b (250 µg; n=292) or placebo (n=176) every other day until either a diagnosis of CDMS was attained or they reached 2 years of evaluation. Patients were then eligible to receive open-label IFN ß-1b for up to 5 years after start of double-blind treatment. According to Mark Freedman, University of Ottawa, Ottawa, Canada, this is the first prospectively planned, controlled, multicenter trial to address the impact of randomly assigned immediate vs later initiation of IFN ß-1b (250 µg) therapy at the time of CIS on the further evolution to MS. A total of 418 patients have enrolled in the open-label phase of the study, 261 of whom were previously treated with IFN ß-1b (96%); 157 of whom were previously treated with placebo. Three years after the start of the double-blind study, 37% of those who had received IFN ß-1b from the start and 51% of those who originally received placebo had fulfilled the criteria for CDMS, reported Dr. Freedman. In addition, confirmed Expanded Disability Status Scale (EDSS) progression was seen in 16% of early treatment patients, compared with 24% of delayed treatment patients; this corresponded to a 40% risk reduction after 3 years ( P=0.0218). Differences in EDSS scores did not appear to be affected by changes in relapse rates between the 2 groups.

Comment-- this study has the same pitfalll as the other extension studies in multiple sclerosis with a biased sample for inclusion in the extension trial. Biases include selection bias and others.   

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