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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Interferon beta babies-- Pregnancy on MS treatment

Two articles and editorial. editorial by Waubant E and Sadovnick AD. Neurology 2005; 65:788-789. Articles in same issue editorialized are Sandberg-Wollheim M et al. Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis. Neurology 2005; 65:802-806. Boskovic R et al. The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Neurology 2005; 65: 807-811.

DMT's (Disease modifying therapy) are abortifacient in monkeys, but not known to be so in humans. The first article showed that looking at the published literature cumulatively, patients on interferon do not have trouble getting pregnant. Pregnancy outcomes, defined by pregnancy loss and congenital malformations, were not different compared to placebo. The rate of miscarriage was at the upper limit of normal expected range. The numbers are reassuring and similar to those derived from glatiramer acetate. The women studied may not be representative since they were on clinical trials.

The Boscovic article compares people with MS who conceived on interferon DMT, who conceived after stopping interferons and healthy controls. There was a slight increased risk of miscarriage (spontaneous abortion) and smaller birth weight babies in those conceived while on DMT. There also was a suggestion that the rate of malformation might be higher.

The editorialist writes that "prudence suggests the discontinuation of IFN-1A and any DMT prior to initiating pregnancy whould remain the rule whenever possible."

JC Virus/PML in MS

Khalili K et al. Reactivation of JC virus and development of PML in patients with multiple sclerosis. Neurology 2007;68: 985-990.
This review article of basic science issues is informative about the process of JC virus activation and infection with PML in MS patients. IN order for PML to occur, latent JC virus in kidney or lymphatic system must be activated, and disseminated to the CNS where destructive replication occurs in oligodendrocytes. Pathologically, patients with PML have the triad of demyelination, giant bizarre astrocytes and nuclear inclusions. It continues to occur in HIV patients despite HAART therapy (up to 5 % of patients prior to advent of HAART). It also is reported in leukemia, lymphoma, organ transplantation patients, after treatment of solid tumors, autoimmune disease, granulomatous disorders, agammaglobulinemia, or rarely without an associated disorder. More recently, two patients with MS and one with Crohn's d had exposure to natalizumab/other drugs and another to rituximab. HIV accounts for 80 % of cases.

JC virusAB is seen in 80 % of normals. PCR in urine is seen in 30 % of normals. Quantitative PCR (Q-PCR) can be measured in urine, serum, CSF and biopsy samples. Standardization issues and threshold issues are important. This also has been shown in the related condition, polyoma asociated nephropathy (PVN) in which screening the urine has been important. The authors hypothesize that screening the blood of patients may lessen the risk of PML. JC virus is occassionally seen in CSF of patients with MS. It is unknown if they are at risk of developing PML.

Targets for treatment include nucleoside analogues (cytarabine, cidofavir) cytokines, enzyme inhibitors, and JCV receptor blockers such as 5H2a chlorpromazine, mirtazepine, heparin, Tat inhibitors.

The authors note "Screening blood for JC viremia did not prove useful in the two MS cases and could provide a false level of security." "More MRI screening is needed."

Contraindications of tizanidine (Zanaflex)

based on updated safety printout of Acorda Therapeutics. Beware of other CYP1A2 inhibitors that can cause toxicity. Beware of Ciprofloxacin, , fluvoxamine, other fluoroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone, verapamil) cimetidine, famotidine, oral contraceptives, acyclovir, ticlodipine. The combinations can lead to potentiated sedative and hypotensive effects. tylenol used concomitantly delays t max by about twenty minutes.

AAN position conclusions on Nabs

Treatment of MS with IFNß (Avonex, Betaseron, or Rebif) is associated with the production of NAbs to the IFNß molecule (Level A).
It is probable that the presence of NAbs, especially in persistently high titers, is associated with a reduction in the radiographic and clinical effectiveness of IFNß treatment (Level B).
It is probable that the rate of NAb production is less with IFNß-1a treatment compared to IFNß-1b treatment (Level B). However, because of the variability of the prevalence data, and because NAbs disappear in the majority of patients even with continued treatment (especially in those with low-titer NAbs), the magnitude and persistence of any difference in seroprevalence between these forms of IFNß is difficult to determine.
It is probable that the seroprevalence of NAbs to IFNß is affected by one or more of the following: its formulation, dose, route of administration, or frequency of administration (Level B). Regardless of the explanation, it seems clear that IFNß-1a (as it is currently formulated for IM injection) is less immunogenic than the current IFNß preparations (either IFNß-1a or IFNß-1b) given multiple times per week subcutaneously (Level A). Because NAbs may disappear in many patients with continued therapy, the persistence of this difference is difficult to determine (Level B).
Although the finding of sustained high-titer NAbs (>100 to 200 NU/mL) has been associated with a reduction in the therapeutic effects of IFNß on radiographic and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, and which cutoff titer to apply (Level U).

Tysabri Notes

Based on a teleconference witrh Carlo Tornatore, MD (Georgetown). He has experience with many patients with Tysabri and MS and has NIH research experience working with PML.
1. All patients have JC virus in their bone marrow. However, JC virus in the blood is abnormal and suggests an immunosuppressed state. (Test PCR either Athena or Mayo can be done at Quest labs). Patients with a negative JC virus may be eligible for Tysabri if they meet other criteria.
2. JC virus in blood along with MRI is repeated every six months. If postive, Tysabri is stopped. CSF can be checked and there "are no false positives in the CSF." If the PCR is positve they have PML. Generally CSF is checked if there is any question about a new lesion being PML.
3. PML (unlike NMO) does not affect optic nerves or spinal cord. Hypothesizes the oligodendrocytes are different.
4. Different cocktails for treating PML have been tried. Ara C is too toxic but a combination of alpha interferon, and sodafavir? is OK. The main thing is to stop the tysabri to reconstitute the immune system. To do so fully, he also phereses for 5 days followed by IVIG for five days.
5. He has 3 exacerbations in over 100 patients each treated for ?18 months. He used steroids for exacerbations.
6. Pretreat claritin and tylenol
7. jc virus pcr in blood helps if positive not if negative
8. take off tysabri if new lesions or if antibody positive
9. discounts rebound except after short term use
10. clinical trials good data both for newly diagnosed as well as breaking through
11. Work coming off on MR metrics, spectro, atrophy, vision
12. 9 % develop nabs but only 6 % have persistent ab's if persistent then stop drug (usually test after 6 months). Won't check again unless a clinical problem. Usually develop early. Athena or Focus labs. If someone is doing well with ab's.???
13. risk benefit is good in scenario of breakthrough disease
14. takes off platform therapy drugs for one month, 3 mo for other imm supp drugs prior to starting tysabri. Pulse steroids not a problem.
15. slightly increased infusion reactions in patients previously treated. NABs unknown

High dose copaxone

Randomized, double blind dose comparison study of glatiramer acetate in relapsing-remitting MS . Cohen JA et al. Neurology 2007; 68:939-944. The study screened treatment naive patients EDSS 1-5, one relapse in prior year, about 45 patients in each group. Compared 20 v 40 mg. Trend towards less relapses in higher dose group. More injection reactions in higher dose group. MRI scores showed a trend favoring the higher dose group.

predictors of disability in MS

Langer-Gould A, Popat RA, Huang SM, Cobb K, et al. Clinical and demographic predictors of long-term disability inpatients with relapsing remitting multiple sclerosis. A systematic review. Arch Neurol 63: 1686-91 2006

Study based on meta-analysis, including studies in the literature since 1966 that met preselected criteria, including differentiation of RRMS, enrollment of greater than 40 patients, observation > 5 years, and followup collection exceeding 80 percent.

The most important predictors were sphincter symptoms at onset and early disease course outcomes. Age at onset, sex, were weak factors.

High dose cytoxan for multiple sclerosis

Gladstone DE et al. High dose cyclophosphamide for moderate to severe refractory multiple sclerosis. Arch Neurol 2006; 63:1388-1393.

The authors studied refractory MS, defined as EDSS scores of 3.5 or higher after 2 or more FDA approved DMD's. 12 patients received 200 mg/kg over four days. No patients increased EDSS by more than one point. Five decreased by one or more points. Patients reported improvement in ll QOL measures.

Goal of therapy is to stop disease progression.
Procedure was 200 mg/kg based on IBW over f days. Hemorrhagic cystitis prevention was done with mesna and forced diruresis. Antibacterial, antiviral and antifungal prophylaxis was given. Evaluation included EDSS, neuro-opthalmologic evaluation and MRI and QOL eval using short form 36.

Patients suffered absolute neutropenia for nine days, received a median of i unit prbc's

Alternatives: mitoxantrone, stem cell mobilization (filgastrim)

Tysabri risk and possible interventions

Stuve O et al. Potential risk of PML with natalizumab therapy. Arch Neurol 2007; 64:169-176. Neurological Review. The authors point out that neurologists must be aware of possible therapies because the n of patients studied is likely to be low. Possible treatments include antivirals, immunomodulatory treatments, hematopoietic growth factors, plasma exchange, IVIG, leukopheresis and autotransfusion of leukocytes. Points of note: 1) the risk of developing PML among 3116 patients treated in studies was 0.1 % and the risk of PML among patients treated longer is not known. 2) JC virus is ubiquitous in all people in kidney, peripheral blood cells and normal brain at autopsy. The prevalence of antibodies is around 90 %. 3) The biological half life of natalizumab is around six months , far exceeding its pharmacological half life. Goals of a possible therapy: 1)eliminate JCV; 2) generate new competent WBC's with unbound VLA-4; 3)neutralize free natalizumab, and 4)eliminate free natalizumab. 1)Antivirals help PML in HIV patients. Reconstitution of CD4 and CD* lymphocytes maybe required to ensure a positive outcome in the patients. 2) Natlizumab is present in blood for 3-8 weeks after dosing. Elimination depends upon the interaction with VLA 4 which is reversible bond and follows normal thermodynamic rules. The idea is to change the binding strength and the in vivo binding equilibrium between natalizumab and VLA4. Existing interventions: cytarabine iv and it did not help HIV patients with PML. Cidofovir showed no benefit in one study. Drugs can cause renal failure and myelosuppression. Interferon alpha and beta and IL2 have case reports of improvement. No data exist of their efficacy. Serotonin 2 alpha blockers may prevent JC viral infection of oligodendrocytes. These drugs include olanzepine, ziprasidone, and risperidone. Hematopoeitic growth factors: pros: Theoretically IL7, G CSF, GM-CSF is well tolerated and might produce unbound lymphocytes. In theory it could be used with IVIG or plasma exchange. Cons: see article

Mitoxantrone for Devic's disease

Weinstock-Guttman B et al. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica. Arch Neurol 2006;63:957-963 The authors studied five patients over two years and felt they improved on MRI, edss.

Familial effects of the clinical course of MS

Hensieck AE et al. Neurology 2007; 68:376-383. There is concordance among family members for age at onset, NOT for severity. There are no apparent transmission patterns nor evidence for genetic loading. However, familial factors do affect the probability of an eventual progressive course (either PPMS or after RRMS, SPMS).

Normal appearing white matter (NAWM)& disability

Vrenken H. Altered diffusion tensor in multiple sclerosis normal-appearing brain tissue: cortical diffusion changes seem related to clinical deterioration. Journal of Magnetic Resonance Imaging 2006; 23:628-636.

Prospective controlled study of normal looking white and gray matter. 64 MS patients and 20 healthy controls. The 64 MS patients had 38 RRMS, 14 SPMS, and 12 with PPMS. Whole brain diffusion coefficient (ADC maps) and fractional anisotropy (FA) were obtained. In NAWM, global FA was decreased and global ADC increased in MS patients v. controls. The changes in ADC in NAWM correlated with disability more strongly than T2 lesion load. In gray matter regional analysis, changes in both ADC and FA were significant.
Note the correlation with disability was still "modest at best"

Copaxone and neuroprotection

Kahn O. Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing-remitting multiple sclerosis. Multiple Sclerosis 2005; 11:646-651.

Two year study partly blinded with MR spectroscopy in treatment naive MS patients and controls. GA (Copaxone) reduced NAA, a surrogate of axonal injury. 18 patients who started GA were assessed, and four controls (subjects who elected not to begin therapy). The NAA/Cr increased in both groups. In the VOI (volume of interest) over two years, and the NAWM (normal appearing white matterO it increased by 10.7 and 7.1 in the treated group, and DECREASED by 8.9 and 8.2 % in the respective control groups.

Fred Lublin comments that while the number of patients is small, the study is ongoing (four more years) but warns that the attempts to correlate surrogate MRI markers for clinical disability have been "continually disappointing." Lublin wants to see proof that the marker NAA in MRS correlates with clinical measures, and also with other MRI measures such as balck holes and atrophy.

extension trials in MS-- Noseworthy

Extension trials-- limited benefit Noseworthy JH How much can we learn from long-term extension trials in multiple sclerosis? Neurology 2006; 67: 930-931 editorialcomments on Kappos et al. Long term interferon beta 1a therapy in patients with relapsing MSNeurology 67: 944-953 200632 % patients randomized in PRISMS did not participate in the extension. Blinding was eliminated. Visits were in some cases conducted every two years or retrospecive evaluations were substituted. About 25 % patients entering extension did not remain on treatment. Brain atrophy was not reduced. The NTT (number to treat) early v 24 months later to prevent one point progression on EDSS was 27. Conclusion of safety is warranted, not that of efficacy.Kappos et al-- 382 patients followed 8 years. 19 % progressed to spms. NABS generally disappeared with treatment. The authors claim 44 dose worked better than 22. 396/560 patients had EDSS < 3 at baseline; of those, 27 % went to EDSS of 4, 20 % went to an EDSS of six, 12 % to 6.5, and 6 % to edss of 7. Relapse rate was about .61 per patient per year in treated patients.

Antimeylin Antibodies and progression to MS

462 patients with CIS and at least 2 clinically silent lesions had anti MOG and anti MBP IgG and IgM antibodies measured with Western blot, and were followed for 24 months. There was no association found between the antibodies being present and the development of CDMS