Signals for many immunosuppressant drugs and PML

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

 

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

Interferon B for SPMS: a systematic review

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

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

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

Emerging therapies in MS AAN 2012 Mark Freedman

Random Notes

 

1.  Tereflunomide- blocks de novo synthesis of pyrimidine synthesis

 

"Nobody has a clue how these things really work"

 

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

 

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

 

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

 

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

 

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

 

7.  Confirm:  beats GA for RR and MRI. 

 

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

 

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

 

10. alemtuzumab. 

 

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

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

 

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

 

1. Daclizumab-- anti CD 25 effect-

 

RR

 

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

 

 

natalizumab Omar Khan AAN 2012 notes

These are random notes of interest

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

MS notes AAN meeting Gilenya 2012

Jeffrey Cohen on Gilenya

 

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

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

3. Caution in patients with severe liver disease

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

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

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

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

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

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

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

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

12.  Holter before hand is useless

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

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

15.  HTN during gilenya beware of.

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

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

18.  Sense of SOB or cough

 

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

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

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

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

EPO and MS

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. 

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

 

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.

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.

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. 

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

betaseron pregnancy registry

www.betaseronpregnancyregistry.com

 

phone 800-478-7049

 

less than 100 people enrolled, 85 births

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

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.

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. 

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.

 

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.

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

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. 

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. 

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.   

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.

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.

Weinshenker on Acute Myelopathies from AAN 2010 pearls

1.  Most myelopathies are undetermined cause at initial diagnosis, then infectious, then CVA, then systemic disease eg. lupus

2. NMO may have a central cord syndrome

3.  Initial functinal score and a central lesion on MRI are predictors at outcome, as is systemic disease or NMO at outcome.

4.  Paraneoplastic case with CRMP 5 in a 42 year old man with positive vep, cigar shaped faintly enhanicng lesions improved with removal of papillary thyroid cancer.  One radiographic sign not well known is owl eye sign with 2 "eyes"  suggests cancer or paraneoplastic.

5.  Cord compression can produce abnormal signal mimicking transverse myelitis clue check axials, and clinically symptoms did not progress over 3 weeks. Signet ring pattern of enhancing signal is c/w compression

6.  Case zoster leading to myelitis indistinguishable from NMO by MRI abnormalities.  Infections that cause acute myelopathy include:  Schistosomiasis (esp in Mideasterners), rabies virus, TB, lyme, syphilis, HSV, VZV, West Nile Virus, dengue, polio, coxsackie and Echovirus, actinomyces, blastomyces, >50 % none found, MAY HAVE OCB's

7. 71 yo woman with recurrent TM after 6 months, then paratonic spasms, TPO antibodies, letm, was NMO

8.  ADEM can be NMO positive and turn out to be NMO


Summary- conclusions  Algorithm: 1) is it compressive (subtle types included such as lipomatosis, spondylosis)  2)  is it really a myelopathy (parasagittal meningioma, CIDP)  3)  is it an acute presentation of a metabolic disorder (eg. B12 deficient patient exposed to nitrous oxide)  4) Is image quality and timing adequate?  (too early, too late)   5)  Is it functional?

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

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



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?