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Although MDD is a common symptom in MS, with far-reaching implications on patients’ overall health-related quality of life and other significant domains, the evidence for the effectiveness of antidepressant treatment in MS is actually quite sparse. There have been few published clinical trials of antidepressant treatment in people with MS, and these have not been conclusive because of small study size or methodological problems.

In a recent meta-analysis, Patten1 found only three randomized controlled trials involving antidepressant medications and MS patients with MDD.2-4 Each study used a different antidepressant (desipramine, sertraline, or paroxetine). Patten concluded that “the best available evidence points towards a modest positive effect of certain medications in the treatment of depression in people with MS.”

Studies of antidepressant treatment, in general, provide mixed and modest results at best. For MDD in MS patients, it is best to take a multidisciplinary approach. Some studies have found that a combination of cognitive-behavior therapy, psychotherapy, and medication may improve overall results.3,5 In MS, such a multifaceted approach is most likely optimal, as the cause of depression in MS is typically multidimensional.

References

1. Patten SB. Antidepressant treatment for major depression in multiple sclerosis: the evolving efficacy literature. Int J MS Care. 2009;11:174-179.
2. Ehde DM, Kraft GH, Chwastiak L, et al. Efficacy of paroxetine in treating major depressive disorder in persons with multiple sclerosis. Gen Hosp Psychiatry. 2008;30:40-48.
3. Mohr DC, Boudewyn AC, Goodkin DE, Bostrom A, Epstein L. Comparative outcomes for individual cognitive-behavior therapy, supportive-expressive group psychotherapy, and sertraline for the treatment of depression in multiple sclerosis. J Consult Clin Psychol. 2001;69:942-949.
4. Schiffer RB, Wineman NM. Antidepressant pharmacotherapy of depression associated with multiple sclerosis. Am J Psychiatry. 1990;147:1493-1497.
5. Mohr DC, Goodkin DE. Treatment of depression in multiple sclerosis: review and meta-analysis. Clin Psychol Sci Pract. 1999;6:1-9.

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Healthcare providers, MS societies, and patients alike have been abuzz about the work of Dr. Paulo Zamboni at the University of Ferrara in Italy. Dr. Zamboni’s clinical findings suggest that deposits of iron in the blood vessels in patients with MS leads to abnormal draining of blood from the brain and spinal cord, which may cause damage to the nervous system. He refers to this phenomenon as chronic cerebrospinal venous insufficiency (CCVI). However, to date, there is insufficient evidence that this phenomenon causes MS, or even has a clear role in its existence or development.

Zamboni et al1 looked at the extracranial venous outflow routes in 65 patients with clinically definite MS and 235 controls. Subjects underwent a combined transcranial and extracranial color-Doppler high-resolution examination (TCCS-ECD) aimed at detecting at least two of five parameters of anomalous venous outflow. CDMS and TCCS-ECD venous outflow anomalies were strongly associated (p<0.0001). Venography showed the presence of multiple severe extracranial stenosis, affecting the principal cerebrospinal venous segments in patients with CDMS, but not in controls. Zamboni et al concluded, “CDMS is strongly associated with CCSVI, a scenario that has not previously been described, characterized by abnormal venous haemodynamics determined by extracranial multiple venous strictures of unknown origin. The location of venous obstructions plays a key role in determining the clinical course of the disease.”

Dr. Zamboni believes that CCSVI may be corrected by endovascular surgery, which involves the insertion of a tiny balloon or stent into the blocked veins to free the flow of blood. This treatment has not yet been proven, and serious and even fatal risks are associated with this type of procedure.

Nonetheless, the National Multiple Sclerosis Society is calling on other MS societies around the world to convene an international panel of experts to conduct an accelerated review of proposals and to exchange and coordinate information on this newly discovered phenomenon. In addition, the Buffalo Neuroimaging Analysis Center is looking for participants for a large-scale clinical study. These activities indicate that the MS community is taking this new idea quite seriously, but acting cautiously as well.

Any clear or definite conclusions may be a few years away. At present, any proposed hypothesis as potentially revolutionary as CCVI will have its naysayers as well as supporters who are prematurely or overly hopeful. Time is necessary to determine if this exciting new hypothesis is proven, leading to much needed new developments for the treatment of a disease as potentially devastating as MS.

Reference

1. Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009;80:392-399.

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The Consortium of Multiple Sclerosis Centers (CMSC) has developed guidelines for standardization of MRI imaging in the diagnosis and monitoring of MS.^1,2

Patients With a Clinically Isolated Syndrome (CIS) and Suspected MS
According to the CMSC, a baseline MRI should be obtained for patients with a CIS and suspected MS; recommendations for the baseline evaluation include:

• Brain MRI with gadolinium
• Spinal cord MRI if there is uncertainty about the diagnosis and/or the findings on brain MRI are equivocal, or presenting symptoms are suggestive of spinal involvement

A brain MRI with gadolinium to demonstrate new disease activity is recommended for follow-up evaluation.

Patients With an Established Diagnosis of MS
For patients with an established diagnosis of MS, a brain MRI with gadolinium is recommended for baseline evaluation and for follow-up; a brain MRI also is recommended:

• To evaluate an unexpected clinical worsening of concern for a secondary diagnosis
• To reasses the original diagnosis
• For reassessment before starting or modifying therapy

To assess subclinical disease activity, an MRI should be considered every 1–2 years (frequency may vary depending on clinical course and other clinical features). A spinal cord MRI with gadolinium is recommended for follow-up of MS patients with symptoms indicative of spinal cord involvement and who do not have MRI evidence of disease activity in the brain.

References

1. Consortium of MS Centers MRI protocol for the diagnosis and follow up of MS: proposed 2009 revised guidelines. Available at http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf. Accessed on November 25, 2009.
2. Simon JH, Li D, Traboulsee A, et al. Standardized MR imaging protocol for multiple sclerosis: Consortium of MS Centers consensus guidelines. AJNR Am J Neuroradiol. 2006;27:455-461.

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Infectious agents and lifestyle have been proposed as environmental triggers for MS in genetically susceptible persons, although no causal relationships have been proven. Viruses that are involved in persistent infections (eg, the herpesviruses and retroviruses) appear to be prime candidates. The herpesviruses are neurotropic and ubiquitous and are associated with latent and recurrent infections. Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have been found in most patients with MS.^1,2 HHV-6 has been detected in the oligodendrocytes and astrocytes within MS plaques, and HHV-6 DNA is present in the CSF of patients with MS.³

In addition, IgG and IgM antibodies to HHV-6 are detectable in the serum and CSF of MS patients. Reactivation of latent EBV infections has been shown to correspond with clinical relapses, and the seropositivity of anti-EBV antibodies in patients with MS is 100%, although the rate of seropositivity in the general population is 90%.⁴ Other herpesviruses—HSV-1 and varicella-zoster virus (VZV or HSV-3)—have also been proposed as infectious agents that could trigger MS based on the prevalence of antiviral antibodies in the CSF of patients with MS.^5-7

The role of bacterial triggers in initiating MS attacks in susceptible persons has also been studied. Among these, Chlamydia pneumoniae has been of particular interest, but the results have so far been inconclusive. In one study, C pneumoniae was present in a large proportion of MS patients,⁸ but other studies have failed to observe a similar association.⁹

References

1. Banwell B, Krupp L, Kennedy J, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol. 2007;6:773-781.
2. Wagner HJ, Hennig H, Jabs WJ, et al. Altered prevalence and reactivity of anti-Epstein-Barr virus antibodies in patients with multiple sclerosis. Viral Immunol. 2000;13:497-502.
3. Virtanen JO, Zabriskie JB, Siren V, et al. Co-localization of HHV-66 and tissue plasminogen activator in multiple sclerosis brain tissue. Med Sci Monit. 2005;11:BR84-BR87.
4. Serafini B, Rosicarelli B, Franciotta D, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain [abstract]. J Exp Med. November 5, 2007. doi:10.1084/jem.20071030.
5. Sotelo J, Ordonez G, Pineda B. Varicella-zoster virus at relapses of multiple sclerosis. J Neurol. 2007;254:493-500.
6. Mancuso R, Delbue S, Borghi E, et al. Increased prevalence of varicella zoster virus DNA in cerebrospinal fluid from patients with multiple sclerosis. J Med Virol. 2007;79:192-199.
7. Ferrante P, Mancuso R, Pagani E, et al. Molecular evidences for a role of HSV-1 in multiple sclerosis clinical acute attack. J Neurovirol. 2000;6(suppl 2):S109-S114.
8. Sriram S, Stratton CW, Yao S, et al. Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Ann Neurol. 1999;46:6-14.
9. Pucci E, Taus C, Cartechini E, et al. Lack of Chlamydia infection of the central nervous system in multiple sclerosis. Ann Neurol. 2000;48:399-400.

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This has yet to be determined by agreed-upon consensus guidelines, although there has been some attempt to establish these. MS centers in the United States developed consensus criteria that included more than one relapse per year, no decrease in relapse rate, incomplete recovery from relapses, new or recurrent brainstem or spinal cord lesions visible on MRI, polyregional disease, and worsening of cognitive impairment that disrupts activities of daily living.¹

Using the presence of neutralizing antibodies (NAbs) as a criterion for switching is controversial. In its recommendations, the American Academy of Neurology concluded that there is still insufficient information about the utilization of NAb testing to provide clinical guidance about whether to discontinue IFN β treatment on this basis.²

During the first few years of treatment with a disease-modifying therapy (DMT), at least 30% of MS patients may experience a suboptimal response.^3,4 DMTs appear to be most effective in the earlier stages of MS, when suppression of inflammatory events will most likely help to delay or prevent axonal loss and decline in neurologic function. For this reason, it is important to identify patients who have a suboptimal response as early as possible. Several studies suggest that switching from one first-line DMT to another is a safe and effective strategy in such cases.^5-7

References

1. Cohen BA, Khan O, Jeffrey DR, et al. Identifying and treating patients with suboptimal responses. Neurology. 2004;63(12 suppl 6):S33-S40.
2. Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007;68:977-984.
3. Pozzilli C, Properini L, Sbardella E, De Giglio L, Onesti E, Tomassini V. Post-marketing survey on clinical response to interferon beta in relapsing multiple sclerosis: the Roman experience. Neurol Sci. 2005;26(suppl 4):S174-S178.
4. Rio J, Nos C, Tintoré M, et al. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann Neurol. 2006;59:344-352.
5. Caon C, Din M, Ching W, Tselis A, Lisak R, Khan O. Clinical course after change of immunomodulating therapy in relapsing-remitting multiple sclerosis. Eur J Neurol. 2006;13:471-474.
6. Carrá A, Ohaha P, Luetic G, et al. Therapeutic outcome 3 years after switching of immunomodulatory therapies in patients with relapsing-remitting multiple sclerosis in Argentina. Eur J Neurol. 2008;15:386-393.
7. Zwibel HL. Glatiramer acetate in treatment-naive and prior interferon-beta-1b-treated multiple sclerosis patients. Acta Neurol Scand. 2006;113:378-386.

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Complete and differential blood counts and serum chemistries with liver function tests should be obtained at months 1, 3, and 6, then periodically thereafter.¹ Some guidelines advocate more frequent monitoring. If laboratory changes exceed the suggested limits, doses should be temporarily reduced to 25%–50% of the normal dose.²

If extreme deviations from the normal occur, discontinuation is recommended. Discontinuation is also recommended if transferases, alkaline phosphatase, and bilirubin levels increase simultaneously. Once the values have normalized, a gradual increase in dosage of IFN β may be feasible.

The most commonly observed laboratory abnormalities are lymphopenia, neutropenia, leukopenia, and raised liver aminotransferase values.^3-7 These changes were seldom serious and always reversible during clinical trials and postmarketing surveillance. Rare cases of severe hepatic decompensation were reported only as a result of the exacerbation of chronic hepatitis B and C in several patients treated with INF.¹

References

1. Tremlett H, Oger J. Hepatic injury, liver monitoring and the beta-interferons for multiple sclerosis. J Neurol. 2004;251:1297-1303.
2. Bayas A, Rieckmann P. Managing the adverse effects of interferon-beta therapy in multiple sclerosis. Drug Saf. 2000;22:149-159.
3. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39:285-294.
4. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352:1498-1504.
5. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I: clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43:655-661.
6. Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:662-667.
7. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS. Lancet. 1998;352:1491-1497.

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Relatively recently, brain atrophy has emerged as a pathological marker of disease progression in MS. Atrophy can be detected and quantified by MRI; this has led to an increasing amount of research correlating brain tissue loss with clinical manifestations such as motor and cognitive disability.¹

Benedict et al² found that whole-brain and central atrophy are well-correlated with and predictive of cognitive impairment. Gray matter (GM) atrophy is now well-established in MS and has been found to be strongly associated with clinical and cognitive deterioration.² In MS patients with long-term disease, GM atrophy is more prominent than white matter (WM) atrophy and may correlate more strongly with disability than WM atrophy or lesions.³

Tedeschi et al⁴ found that, in addition to their correlation with cognition, GM and WM atrophy may be independent risk factors for fatigue in MS. The researchers studied 222 relapsing-remitting MS patients with low disability (EDSS scores < 2.), who were divided into high-fatigue and low-fatigue groups as measured by the Fatigue Severity Scale. Among MS patients with low disability, those with high fatigue showed higher WM and GM atrophy along with higher lesion load. The results suggest that, in MS, WM and GM atrophy are risk factors for fatigue, independent of disability.

References

1. Grassiot B, Desgranges B, Eustache F, Defer G. Quantification and clinical relevance of brain atrophy in multiple sclerosis: a review. J Neurol. 2009;256:1397-1412.
2. Benedict RH, Carone DA, Bakshi R. Correlating brain atrophy with cognitive dysfunction, mood disturbances, and personality disorder in multiple sclerosis. J Neuroimaging. 2004;14(3 suppl):36S-45S.
3. Fisniku KU, Chard DT, Jackson JS, et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol. 2008;64:247-254.
4. Tedeschi G, Dinacci D, Lavorgna L, et al. Correlation between fatigue and brain atrophy and lesion load in multiple sclerosis patients independent of disability. J Neurol Sci. 2007;15:15-19.

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Skin reactions to DMTs can range from mild irritation to necrosis or abscesses that require medical intervention. The incidence of skin reactions varies based on the method of injection and between IFN β and glatiramer acetate (GA). Autoinjectors reduce the incidence of injection-site pain and injection-site reactions (ISRs).^1,2 The incidence of ISRs associated with subcutaneous (SC) IFN β-1b or IFN β-1a is higher than the incidence associated with low-dose intramuscular (IM) IFN β-1a—37% vs 8% in the EVIDENCE trial, for example.^3,4 Differences in production and formulation also appear to have an effect. These differences were assessed in the BRIGHT study,⁵ which found significantly more pain-free injections and fewer ISRs with IFN β-1b than with IFN β-1a SC; only 9 grade 2 ISRs (ie, induration <25 mm) were reported over 15 consecutive injections in 445 patients. ISRs and injection-site pain can be reduced by premedication with an NSAID.

Subcutaneous therapy can also occasionally cause mild reactions (erythema and swelling) and, rarely, ulcers, granulomas, skin necrosis, or abscesses (<4%).^6,7 While ulcerations may be caused by inoculation of the drug into the dermis, vascular effects combined with local chemokine induction, followed by rapid immune-cell extravasation, are possibly responsible for more severe skin reactions. These events can lead to permanent scarring and can have a significant psychological impact on patients.

Skin reactions seen with GA include injection-site pruritus, swelling, induration, and lipoatrophy. Lipoatrophy, which produces denting or depressions in the skin, is caused by the breakdown of subcutaneous fat tissue and is a possibility in patients treated with GA⁸; it has also been seen with use of the IFN βs. Although lipoatrophy is not painful and does not pose a health risk, it is thought to be permanent and may have a psychological impact on patients. Patients should be instructed to rotate injection sites and avoid repeated injection into sites where lipoatrophy has begun, since repeated injection into these areas can exacerbate the denting.

With any of the DMTs, injection into the same site without rotation can be problematic. Patients should be instructed not to use the same injection site more than once in any 2-week period, and healthcare professionals should frequently reinforce proper injection technique and site rotation.

References

1. Brochet B, Lemaire G, Beddiaf A. Reduction of injection site reactions in multiple sclerosis (MS) patients newly started on interferon beta 1b therapy with two different devices. Rev Neurol (Paris). 2006;162:735-740.
2. Mikol D, Lopez-Bresnahan M, Taraskiewicz S, Chang P, Rangnow J. A randomized, multicentre, open-label, parallel-group trial of the tolerability of interferon beta-1a (Rebif) administered by autoinjection or manual injection in relapsing-remitting multiple sclerosis. Mult Scler. 2005;11:585-591.
3. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359:1453-1460.
4. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE Trial. Neurology. 2002;59:1496-1506.
5. Baum K, O'Leary C, Coret FF, et al. Comparison of injection site pain and injection site reactions in relapsing-remitting multiple sclerosis patients treated with interferon beta-1a or 1b. Mult Scler. 2007;13:1153-1160.
6. Betaseron [package insert]. Montville, NJ; Bayer HealthCare Pharmaceuticals; 2007.
7. Rebif [package insert]. Rockland, MA: EMD Serono, Inc; 2005.
8. Copaxone [package insert]. Kansas City, MO: Teva Neuroscience, Inc; 2007.

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Bladder symptoms are frequent in MS; approximately 68% to 90% of patients with MS experience some type of urinary dysfunction during the course of the disease.^1,2
Bladder dysfunction increases the risk of urinary tract infection and increased bladder pressure. In many patients, bladder disturbances persist and cause significant social concerns including effects on self-esteem, sexual function, and quality of life.³

The diagnostic examination for urinary dysfunction should include patient history, pelvic/prostate examination, and urinalysis. If symptoms persist after diagnosis and appropriate treatment, additional testing is required and referral to a urologist may be necessary. The urologist typically carries out urodynamic and/or imaging tests to determine the appropriate diagnosis and treatment. Such tests include:³

• Postvoid residual volume, which requires catheterization or pelvic ultrasound
• Cystometry, which evaluates detrusor muscle function by measuring the bladder’s pressure and capacity
• The cystometrogram, used to measure intra-abdominal, total bladder, and true detrusor pressures
• Cystoscopy, an endoscopic procedure to view the inside of the bladder and urethra
• X-rays and ultrasound

References

1. Motta R, de Carvelho ML. Management of bladder dysfunction in multiple sclerosis patients: the nurse’s point of view. Neurol Sci. 2008(4 suppl):S356-S359.
2. Nicholas RS, Friede T, Hollis S, Young CA. Anticholinergics for urinary symptoms in multiple sclerosis. Cochrane Database Syst Rev. 2009;1:CD004193.
3. The Urology Chanel website. Diagnosis of urinary incontinence. Available at: http://www.urologychannel.com/incontinence/diagnosis.shtml. Accessed on August 18, 2009.

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EBV is a human DNA herpes virus that infects more than 90% of the world's population.^1,2 The primary symptomatic EBV infection is infectious mononucleosis. A possible role for EBV has been suggested in chronic inflammatory/autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and MS.

MS is currently seen as having a multifactorial etiology, with EBV being one possible factor in its manifestation. Increasing evidence points to EBV as playing a unique role as an infectious risk factor for MS. A nearly 100% seroprevalence of antibodies to EBV in patients with MS, elevated EBV antibody titers years before clinical onset of the disease, and an increased risk for MS after infectious mononucleosis suggest an association of MS with a previous infection with EBV.¹ Laboratory studies have shown that EBV seroprevalence rates are higher in both children and adult subjects with MS compared with controls.¹ In fact, infectious mononucleosis has been shown to increase the risk of developing MS later in life.² In addition to EBV antibody titers, EBV-specific T-cells are increased in MS patients compared with healthy controls. Recently, CNS B-cells of MS patients have been reported to contain EBV.³

However, the exact mechanisms through which EBV may contribute to MS are still not clear. Controversy remains as to whether EBV could be a causative agent as opposed to an "innocent bystander" in the pathogenesis of MS.² Hopefully, increased research in this area will shed more light on the role of EBV in MS and lead to future treatments and perhaps even increased disease prevention.³

References

1. Ruprecht K. Multiple sclerosis and Epstein-Barr virus: new developments and perspectives. Nervenarzt. 2008;79:399-407.
2. Pohl D. Epstein-Barr virus and multiple sclerosis. J Neurol Sci. 2009 Apr 9. [Epub ahead of print]
3. Salvetti M, Giovannoni G, Aloisi F. Epstein-Barr virus and multiple sclerosis. Curr Opin Neurol. 2009;22:201-206.

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Cognitive dysfunction is common MS; however, few studies have evaluated the effects of DMTs on neuropsychological (NP) functioning in patients with clinically isolated syndrome (CIS) or early MS. Fischer et al¹ looked at the effects of intramuscular (IM) interferon β-1a on cognitive functioning. The primary NP outcome measure was 2-year change on the Comprehensive NP Battery, grouped into domains of information processing and learning/memory (set A), visuospatial abilities and problem-solving (set B), and verbal abilities and attention span (set C). The researchers found that IFN β-1a IM had a significant beneficial effect on set information processing and learning/memory, and showed a favorable trend toward visuospatial abilities and problem-solving.

In a 5-year analysis of patients taking IFN β-1b, patients who started earlier with IFN β-1b showed better cognitive function than patients who delayed treatment or were originally on placebo.² Both studies suggest that early initiation of a DMT in early relapsing-remitting MS or after a CIS allows patients the opportunity to obtain maximal long-term benefits, which may include preserving cognitive function.

More recently, a poster presented at the 61st Annual Meeting of the American Academy of Neurology reported that MS patients report improvements in fatigue and overall cognitive function, in some cases after just 3 infusions of natalizumab.³

References

1. Fischer JS, Priore RL, Jacobs LD, et al. Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Ann Neurol. 2000;48:885-892.
2. Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67:1242-1249.
3. Stephenson JJ, Kamat SA, Rajagopalan K et al. Early effects of natalizumab on patient reported fatigue and cognitive function. Paper presented at: American Academy of Neurology 61st Annual Meeting. Seattle, WA; April 25-May 2, 2009. P02.142.

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Because there is no definitive laboratory test for MS, an accurate diagnosis can sometimes be complicated. Adding to this complexity, the symptoms of MS and/or laboratory test results may mimic those of other central nervous system (CNS) disorders. Some examples of differential diagnosis of MS include systemic lupus erythematosus, antiphospholipid antibody syndrome, Sjögren’s syndrome, primary CNS vasculitis, Behçhet’s disease, neurosarcoidosis, Lyme disease, tropical spastic paraparesis, progressive multifocal leukoencephalopathy, acute disseminated encephalomyelitis, vitamin B₁₂ deficiency, and CNS mass lesions.

In 2008, Miller et al published “Differential diagnosis of suspected multiple sclerosis: a consensus approach” in the journal Multiple Sclerosis.¹ Using available literature and consensus, the authors developed guidelines for the differential diagnosis of MS that focus on the exclusion of potential disorders that mimic MS, the diagnosis of CIS, and the differentiation between MS and non-MS idiopathic inflammatory demyelinating diseases. A reprint of this article can be found at http://msj.sagepub.com/cgi/reprint/14/9/1157.

References

1. Miller DH, Weinshenker BG, Filippi M, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler. 2008;14:1157–1174.

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A recently published study¹ in the journal Neurology found that some patients who underwent an MRI scan for reasons unrelated to MS, for example, for migraine or head trauma, showed anomalies highly suggestive of a demyelinating pathology that are similar to those that occur in MS. Approximately one third of those patients developed MS within an average of 5 years.

Researchers performed clinical evaluations of 44 patients at the time of initial imaging; 30 subjects received longitudinal clinical follow-up, and researchers obtained longitudinal MRI data for 41 subjects. In almost all of the cases, the neurologic exam was normal at the time of the initial MRI scan. Radiologic progression was identified in 59% of the patients; however, only 10 patients converted to either clinically isolated syndrome (CIS) or definite MS. The presence of gadolinium-enhancing lesions on the initial MRI scan was predictive of dissemination in time on subsequent MRI scans. The researchers concluded that patients with MRI anomalies highly suggestive of a demyelinating pathology that cannot be accounted for by another disease process are very likely to experience subsequent radiologic or clinical events related to MS.¹

More research is needed to fully comprehend the risk of developing MS for patients with these MRI anomalies, although it may be that in some instances the abnormalities may indicate an increased risk of developing MS.^1,2 According to current diagnostic criteria, patients must experience clinical symptoms to receive a diagnosis of CIS or MS.³ Because no MS symptoms are related to these radiologic anomalies, there is currently no name to describe this particular type of radiologic progression; therefore, Okuda et al refer to this condition as “radiologically isolated syndrome” (RIS).¹

A previously published study by Lebrun et al⁴ reported the results of a retrospective clinical and 5-year MRI follow-up in patients with subclinical demyelinating lesions. In this study, the subjects who were evaluated fulfilled the MRI Barkhof-Tintoré criteria and had normal neurological exam results. Initial brain MRI scans were performed on 30 subjects for a variety of medical reasons, including headache, head trauma, and depression. Twenty-three subjects had temporospatial dissemination, while 11 patients experienced clinical conversion: optic neuritis (n=5), brainstem (n=3), sensitive symptoms (n=2), and cognitive deterioration (n=1). Seventy-two percent (n=8) exhibited criteria of dissemination in space and time before the clinical event. The average time between the first MRI scan and CIS was 2.3 years. Lebrun et al concluded that early treatment should be discussed in light of the predictive value of conversion of the MRI burden of the disease.

Much additional research is needed before any recommendations can be made regarding the diagnosis and potential treatment, if any, of patients with subclinical demyelinating lesions or what is currently referred to as RIS.

References

1. Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009;72:800-805.
2. Bourdette D, Simon J. The radiologically isolated syndrome: is it very early multiple sclerosis? Neurology. 2009;72:780-781.
3. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol. 2005;58:840-846.
4. Lebrun C, Bensa C, Debouverie M, et al. Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile. JNNP. 2008;79:195-198.

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Very few rigorous scientific studies exist in this area. Certain recent studies are beginning to provide some insight into the relationship between MS and cancer risk. However, much more data need to be acquired and analyzed, and, at this point in time, causative factors, if a relationship does indeed exist, are speculative at most.

A recently published study¹ in the journal Neurology suggests that patients with MS may have an overall lower risk of developing cancer; however, the same study also found that MS patients may have an increased risk of developing certain types of cancer, such as brain tumors and urinary organ cancer. The authors examined the medical records of 20,000 patients with MS and 204,000 people without the disease. With an average of 35 years of follow-up, MS patients had a decreased overall risk of developing cancer by 10% compared with those who did not have MS. However, for people with MS, the risk for brain cancer and urinary organ cancer was increased. The researchers also looked at the records of the parents of the patients with MS to see if there was a potential genetic link to the reduced overall cancer risk, but found none.

No definitive explanations exist for these findings. Speculation about the lower risk for cancer among people with MS includes lifestyle changes or treatment following MS diagnosis. While the increase in the risk for brain tumors may be due to inflammation in the brain, this finding may instead reflect the fact that increased neurologic examinations in MS patients make it easier to detect brain tumors earlier than in the general population. Also, chronic irritation to the urinary organs as a result of MS may provide a possible reason for the increase in these types of cancers. In addition, people with MS have on average a lower body mass index (BMI) than the general population. As BMI is a risk factor for cancer, the lower BMI of MS patients may explain some of the reduction in overall cancer risk. It is also possible that some reduction in cancer risk results from the immunologic characteristics of MS activity.

In a study published in 2008,² researchers collected and evaluated the profiles of 7418 MS patients from January 1995 to June 2006 from nine French MS centers. This study also found that MS patients have a significantly reduced risk for several types of cancer. One exception was the relative increase in breast cancer in women treated with immunosuppressive therapy, an area warranting further study.²

References

1. Bahmanyar S, Montgomery SM, Hillert J, Ekbom A, Olsson T. Cancer risk among patients with multiple sclerosis and their parents. Neurology. 2009;72:1170-1177.
2. Lebrun C, Debouverie M, Vermersch P, et al. Cancer risk and impact of disease-modifying treatments in patients with multiple sclerosis. Mult Scler. 2008;14:399-405.

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That is indeed a common question from female patients with MS. Many times it comes up right after diagnosis, ie, before we have even initiated treatment. It is a good idea to discuss DMTs and their respective pregnancy issues with your female patients before they start therapy. However, getting a patient’s active disease under control with the most appropriate DMT should take precedence over future pregnancy concerns, and this should be sympathetically yet firmly explained to the patient.

The interferon betas (IFN βs) are Pregnancy Category C agents (animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans).^1-3 According to a publication by the National Multiple Sclerosis Society, interferons should be discontinued 1 to 2 months before a woman attempts to conceive⁴; however, some clinicians prefer a 3-month period off interferon prior to attempting conception. Information about the pregnancy registries for IFN β is available at www.nationalMSsociety.org/PregReg. Natalizumab is also a Pregnancy Category C agent and should be discontinued before the patient attempts to conceive.⁵ Glatiramer acetate is a Pregnancy Category B agent (animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women).⁶ Most physicians recommend discontinuing glatiramer acetate prior to conceiving.

If you are considering prescribing the immunosuppressant, mitoxantrone, a Pregnancy Category D agent, your patients should be warned that it may cause fetal harm.⁷ You should also advise women of child-bearing age that the drug may cause amenorrhea, which may be permanent in a small percentage of patients. The mitoxantrone label recommends women of child-bearing age be given a pregnancy test prior to each administration of the drug.⁶

Please keep in mind that in your patients with active disease, it is recommended that you advise them to postpone pregnancy attempts until their disease activity is under adequate control.

References

1. Avonex [package insert]. Cambridge, MA: Biogen Idec; 2008.
2. Betaseron [package insert]. Montville, NJ: Berlex Laboratories; 2008.
3. Rebif [package insert]. Rockland, MA: Serono, Inc.; 2008.
4. Geisser B, Benedetto-Anzai MT, Talking with Your MS Patients about Difficult Topics: Talking About Reproductive Issues. National Multiple Sclerosis Society Booklet, 2008. Available at http://www.nationalmssociety.org/for-professionals/healthcare-profession....
5. Tysabri [package insert]. Cambridge, MA: Biogen Idec; 2008.
6. Copaxone [package insert]. Kansas City, MO: Teva Neuroscience, Inc; 2009.
7. Novantrone [package insert]. Rockland, MA: EMD Serono, Inc.; 2007.

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Once a treatment plan has been initiated, it is important to monitor disease progression and evaluate the treatment’s efficacy. The key aspects to consider include annual relapse rate, time between relapses, severity of relapses, degree of recovery from relapses, and associated MRI results.¹

If the patient’s disability progresses by 1 or more points on the EDSS, treatment failure is considered to have occurred.¹ If the patient is experiencing a suboptimal response or treatment failure, a low-dose interferon beta (IFN β) can be switched to a different, higher-dose interferon or another therapy altogether. Those taking a high-dose interferon can be switched to glatiramer acetate or vice versa. The BEYOND and FORTE trials found that double doses of IFN β-1b glatiramer acetate were no more effective than their standard respective doses.^2,3

There are no data assessing the benefits of changing DMT in patients who develop neutralizing antibodies (NAbs) during IFN β treatment. However, both the American Academy of Neurology (AAN) and the European Federation of Neurological Societies have issued recommendations for monitoring for NAbs and managing patients who develop NAbs.^4,5 Both committees agree that NAbs probably reduce the clinical and radiographic effectiveness of IFN β; however, neither group concluded that this factor translated to a long-term effect on disability progression. The AAN did consider the effectiveness of low- and high-dose IFN β (the latter is generally associated with a higher incidence of NAbs) when stating that the benefit of high-dose IFN β most likely outweighs the risk of NAbs during the first 2 years of treatment.

References

1. Coyle P, Arnason B, Hurwitz B, Lublin F. Optimizing outcomes in multiple sclerosis: a consensus initiative. Mult Scler. 2009;15:S5-S35.
2. Jeffrey S. BEYOND and PRECISE results suggest equivalence for multiple sclerosis treatments. Medical News. Medscape. http://www.medscape.com/viewarticle/573185. Accessed April 1, 2009.
3. Teva provides update on FORTE trial. Medical News Today. Press release. http://www.medicalnewstoday.com/articles/114183.php. Accessed April 1, 2009.
4. Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007;68:977-984.
5. Sørensen PS, Deisenhammer F, Duda P, et al. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol. 2005;12:817-827.

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Neuropsychiatric symptoms such as apathy are common in patients with MS.¹ One study found that 20.5% of patients with MS reported experiencing apathy.² Widespread lesions of the central nervous system caused by MS may affect frontal and parietal brain regions, which in turn may affect behavioral symptoms, including apathy.³ In addition, gray and white brain-matter atrophy caused by MS may also contribute to neuropsychological deficits such as apathy.⁴

MS patients experiencing apathy should undergo a full neuropsychological assessment, as apathy may be related to depression (a common MS symptom), which may be successfully treated with counseling and/or antidepressants.¹ In addition, researchers have found some “preliminary but methodologically limited evidence of possible efficacy for dopaminergic agents and amphetamines for apathy.”¹ However, much more research needs to be performed in this area, particularly as it affects patients with MS.

References

1. van Reekum, Stuss DT, Ostrander. Apathy: why care? J Neuropsychiatry Clin Neurosci. 2005;17:7-19.
2. Diaz-Olavarrieta C, Cummings JL, Velazquez J, et al: Neuropsychiatric manifestations of multiple sclerosis. J Neuropsychiatry Clin Neurosci. 1999;11:51–57.
3. Chiaravalloti ND, DeLuca J. Assessing the behavioral consequences of multiple sclerosis: an application of the Frontal System of Behavior Scale (FrSBe). Cogn Behav Neurol. 2003;16:54-67.
4. Sanfilipo MP, Benedict RH, Weinstock-Guttman B, Bakshi R. Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis. Neurology. 2006;66:685-692.

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Patients with SPMS experience a slow worsening of their symptoms that is often, but not always, accompanied by occasional flare-ups and minor recoveries. The transition from RRMS to SPMS may be associated with increased axonal loss, increased atrophy on MRI, and impaired recovery mechanisms.¹ A 14-year MRI study in 90 RRMS patients demonstrated that the presence of more than 10 T2 lesions more than doubled the risk of progression to SPMS.² Another trial of 146 patients with SPMS showed that an increase in disease activity (as measured by relapse rate) in the period before therapy was initiated may be suggestive of a greater risk for faster disability progression and consequent conversion to SPMS.³

References

1. Comi G. Why treat early multiple sclerosis patients? Curr Opin Neurol. 2000;13:235-240.
2. Mostert JP, de Groot JC, Ramsaransing GS, et al. Relationship between the extent of T2 lesions and the onset of secondary progression in multiple sclerosis. Eur J Neurol. 2007:1210-1215.
3. Río J, Tintoré M, Nos C, et al. Interferon beta in secondary progressive multiple sclerosis: daily clinical practice. J Neurol. 2007; 254:849-853.

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Erectile dysfunction is a somewhat common problem in men with MS.¹ Erectile function is dependent on both physical (hemodynamic and neurologic) and psychological inputs, and one challenge in treating ED is that the etiology is often unknown. The phosphodiesterase 5 (PDE5) inhibitors, a class of compounds that includes sildenafil, vardenafil, and tadalafil, have been shown to improve erectile function in a range of patients that includes those with psychogenic, hemodynamic, neurological, or mixed etiologies. Inadequate perfusion of the corpora cavernosa is common in many patients enrolled in most PDE5 trials, but sildenafil appears to be effective in patients with spinal cord injuries, suggesting that the requirement for neurological stimulation can be bypassed in some instances.

Sildenafil has been specifically tested in patients with MS in 2 trials, but the outcome of these trials differed.^2;3 Both trials were randomized, double-blind, placebo-controlled studies that enrolled approximately 100 patients into each arm. In the trial conducted by Fowler and colleagues, patients were recruited from 20 sites and were treated for 12 weeks. At the conclusion of the trial, erectile function was improved in 90% of patients receiving sildenafil (compared to 24% taking a placebo), and most of these patients (81 of 100) were able to have satisfactory sexual activity; only 26 of 106 patients in the placebo group responded similarly. Sildenafil treatment was also shown to significantly improve other sexual-health and quality-of-life metrics relative to baseline findings.

A second study by Safarinejad was unable to confirm these findings.³ Data from this trial was based on at least 24 attempts at sexual activity. Erectile function was improved in 33% of patients treated with sildenafil, which was only of borderline significance compared to patients who received placebo (18%, P=0.04). Likewise, the effect of sildenafil on sexual satisfaction was of borderline significance compared to placebo (P=0.04), and the authors conclude that many patients with ED due to MS do not respond to sildenafil. In most of these patients, the author found that pudendal nerve function was abnormal and correlated to ED severity.

How should we apply these findings? Given the effect ED can have on a patient’s quality of life and relationship, we should ask our patients about their sexual health and attempt to treat any problems. The PDE5 inhibitors are a relatively low-risk first line treatment. Even though some patients may not respond, predicting who will and who will not is rarely possible. The adverse effects from this drug class are also relatively mild and this treatment is generally acceptable to patients and their partners, especially when compared to other alternatives such as penile implants or intracavernous injections. Thus, a trial with a PDE5 inhibitor would be reasonable and has a favorable risk-benefit profile. To address the second question, the mechanisms of action for the 3 PDE5 inhibitors are very similar. For a patient who did not respond to one PDE5 inhibitor, the likelihood of responding to another is probably very low. A better course may be to discuss the patient’s expectations for treatment and ensure that he is using it properly. In addition, a urologic or psychological consult may be appropriate, since these specialists will be able to fully investigate the patient’s symptoms.

References

1. Zorzon M, Zivadinov R, Bosco A, Bragadin LM, Moretti R, Bonfigli L, et al. Sexual dysfunction in multiple sclerosis: a case-control study. I. Frequency and comparison of groups. Mult Scler 1999 Dec;5(6):418-27.
2. Fowler CJ, Miller JR, Sharief MK, Hussain IF, Stecher VJ, Sweeney M. A double blind, randomised study of sildenafil citrate for erectile dysfunction in men with multiple sclerosis. J Neurol Neurosurg Psychiatry 2005 May;76(5):700-5.
3. Safarinejad MR. Evaluation of the safety and efficacy of sildenafil citrate for erectile dysfunction in men with multiple sclerosis: a double-blind, placebo controlled, randomized study. J Urol 2009 Jan;181(1):252-8.

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Lymphedema should be treated at its earliest stages to reduce the risk of more serious complications (infection and poor wound healing) that can occur later.^1,2 Stage 1 lymphedema is characterized by pitting; the patient may report progressive swelling and pitting throughout the day.³ Compression stockings are the most common first-line treatment, but may not be sufficient in all patients. Elevation of the legs above the hips should be included in the first step of management.¹ If the patient is ambulatory, exercise is effective at improving circulation and relieving swelling; otherwise, stretching and massage may be helpful. Patients with longstanding lymphedema can be treated with a compression pump system. Maintenance treatment involves commitment to a regimen of elevation, skin care, and compression stockings, with compression pump treatment as needed.

References

1. National Multiple Sclerosis Society. Lymphedema in Mulitple Sclerosis. www nationalmssociety org/download aspx?id=1241 2008 [cited 2008 Dec 21];Available from: URL: www.nationalmssociety.org/download.aspx?id=1241
2. Moffatt CJ, Franks PJ, Doherty DC, Williams AF, Badger C, Jeffs E, et al. Lymphoedema: an underestimated health problem. QJM 2003 Oct;96(10):731-8.
3. Penzer R. Lymphoedema. Nurs Stand 2003 May 14;17(35):45-51.
4. Di PF, Reindl M, Ehling R, Schautzer F, Gneiss C, Lutterotti A, et al. Smoking is a risk factor for early conversion to clinically definite multiple sclerosis. Mult Scler 2008 Sep;14(8):1026-30.

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Smoking is thought to hasten the progression of MS. In 2 recent studies, the effect of smoking was studied in patients who had had a clinically isolated syndrome (CIS) or who had RRMS.^1,2 In the first study, Di Pauli and colleagues found that smokers had a 1.8-fold increased risk for early relapse (ie, clinically-definite MS) compared to non-smokers.¹ The time to conversion to CDMS in smokers was also higher in this study, although the number of relapses and EDSS progression was the same over the 3-year study period. Sundström and Nyström report in the second study² that former smokers are more likely to have progressive disease than nonsmokers, and the age that patients began smoking modified this effect: those who began smoking earlier in life were the most at risk. This effect had been observed in one previous study, in which never-smokers were less likely to convert from RRMS to SPMS, but no effect was demonstrated in a third study.^3,4

Previous studies have shown that the incidence of MS is higher in smokers (eg, ⁵), as is the incidence of other autoimmune conditions. The mechanism by which smoking could increase the risk of autoimmune conditions is not known; in MS, a toxic component of tobacco smoke, such as cyanide, may have a neurotoxic effect that potentiates demyelination. Nicotine is thought to alter the humoral immune system, and other components can have immunosuppressive effects or alter the blood-brain barrier.

References

1. Di PF, Reindl M, Ehling R, Schautzer F, Gneiss C, Lutterotti A, et al. Smoking is a risk factor for early conversion to clinically definite multiple sclerosis. Mult Scler 2008 Sep;14(8):1026-30.
2. Sundstrom P, Nystrom L. Smoking worsens the prognosis in multiple sclerosis. Mult Scler 2008 Sep;14(8):1031-5.
3. Hernan MA, Alonso A, Logroscino G. Cigarette smoking and dementia: potential selection bias in the elderly. Epidemiology 2008 May;19(3):448-50.
4. Koch M, van HA, Uyttenboogaart M, De KJ. Cigarette smoking and progression in multiple sclerosis. Neurology 2007 Oct 9;69(15):1515-20.
5. Riise T, Nortvedt MW, Ascherio A. Smoking is a risk factor for multiple sclerosis. Neurology 2003 Oct 28;61(8):1122-4.

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Aside from the legal restrictions on marijuana use, the National Multiple Sclerosis Society Clinical Advisory Board has concluded that there is insufficient evidence to support the use of marijuana in MS patients.¹ Cannabinoids have been studied for managing spasticity and pain in humans and animals; in some animal studies, cannabinoids have demonstrated neuroprotective and immunosuppressive activity, and there have been anecdotal accounts of patients having decreased relapses while using marijuana. However, the NMSS concluded that studies of cannabinoids for managing MS symptoms were inconclusive due to methodological problems, variability in patient responses and adsorption, and the route of administration. Nevertheless, a sublingual extract of cannabis sativa (Sativex)—which contains tetrahydrocannabinol and cannabidiol—has been approved in Canada for neuropathic pain in MS patients.² (A study for treating spasticity was inconclusive because of methodological problems, leading to the UK regulatory authority rejecting approval of Sativex.³) This treatment is not available in the US but is undergoing clinical trials for cancer-related pain.

References

1. National Clinical Advisory Board of the National Multiple Sclerosis Society. Recommendations Regarding the Use of Cannabis in Multiple Sclerosis. National Multiple Sclerosis Society, New York. 2008.
2. Barnes MP. Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain. Expert Opin Pharmacother 2006;7:607-615.
3. Zajickek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomized placebo-controlled trial. Lancet 2003;362:1517-1526.

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Some clinical features at presentation can be helpful: for example, if the patient is between 15 and 50, has painful, retrobulbar, unilateral optic neuritis, or has an incomplete sensory transverse myelitis with Lhermitte sign, bowel and/or bladder dysfunction, band-like abdominal or chest pressure, and/or acute dystonias. Multiregional, brainstem, or cerebellar symptoms are also more common in patients who have MS.
MRI features are also predictive of risk. Most patients (56-88%) who have MRI abnormalities will develop MS; in contrast, a patient with a normal MRI is much less likely to later develop MS. In studies of IFN β for CIS, different criteria have been used to enroll patients who are likely to have a second clinical attack. In CHAMPS, patients who had a unifocal CIS with unilateral optic neuritis, incomplete transverse myelitis, or brain-stem/cerebellar syndrome, and at least 2 clinically silent brain lesions had a 50% chance of developing MS within 3 years.¹ In ETOMS, the MRI was considered abnormal if the patient had at least 4 white-matter T2 lesions, or at least 3 white-matter if one was infratentorial or gadolinium enhancing; during the 2-year study, these patients also had a 45% risk of developing MS.² Patients enrolled in BENEFIT had either a monofocal or multifocal attack with at least 2 clinically silent T2 lesions, one of which was ovoid, periventricular, or infratentorial.³ During the first 2 years of the study, 45% of placebo-treated patients developed definite MS and 85% met the McDonald criteria for MS. In the PreCISE study, patients had to have at least 2 T2 lesions ≥6 mm in diameter. Of the patients in the placebo group of PreCISE, 43% developed clinically-definite MS within the 2-year interim study period

References

1. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343:898-904.
2. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357:1576-1582.
3. Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet. 2007;370:389-397.

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Some observational studies have suggested a possible inverse correlation between vitamin D intake and MS risk.¹ In addition, some in vitro and animal studies have shown that vitamin D can affect immune function and the clinical signs of experimental autoimmune encephalitis.¹ Helper T-cell 1 (TH1) activity may be suppressed by vitamin D, while TH2 and TReg cells may benefit from it, although this has only been shown in vitro.¹ Studies in humans are limited, however. In small, uncontrolled, open-labeled studies, patients had a decrease in exacerbation rate and EDSS while taking supplements that included vitamin D.^2,3 A more recent study found a decrease in gadolinium lesions in 12 patients who were taking 1000 µg/day of vitamin D over a 28-week period, and patients with relapsing forms of MS have been shown to have higher 25-hydroxyvitamin D (25[OH]D) serum levels.⁴ Patients with low 25(OH)D levels also had more relapses and greater disability.⁵ Larger trials need to be conducted, not only to resolve the possible benefits, but also to define the safety profile. Vitamin D can cause dose–dependent hypocalcemia, possibly leading to other complications (eg, loss of bone mineral density, renal failure), especially in patients using thiazide diuretics.^6-8

References

1. Smolders J, Damoiseaux J, Menheere P, Hupperts R. Vitamin D as an immune modulator in multiple sclerosis—a review. J Neuroimmunol. 2008;194:7-17.
2. Goldberg P, Fleming MC, Picard EH. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med Hypotheses. 1986;21:193-200.
3. Nordvik I, Myhr KM, Nyland H, Bjerve KS. Effect of dietary advice and n-3 supplementation in newly diagnosed MS patients. Acta Neurol Scand. 2000;102:143-149.
4. Kimball SM, Ursell MR, O'Connor P, Vieth R. Safety of vitamin D3 in adults with multiple sclerosis. Am J Clin Nutr. 2007;86:645-651.
5. Smolders J, Menheere P, Kessels A, Damoiseaux J, Hupperts R. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler. 2008, doi:10.117/1352458508094399.
6. Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci. U S A 1996;93:7861-7864.
7. Lemire JM, Archer DC. 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J Clin Invest. 1991;87:1103-1107.
8. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007;85:6-18.

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Our polls are designed to help us develop educational activities that would benefit MS professionals. The August poll asked physicians about how they interpret and act on positive results from a neutralizing antibody titer test. This is a situation where there is not a clear consensus, and the results from the poll reflect that sentiment. However, there are 2 position papers that address how NAb titers should be interpreted (and what in fact constitutes a positive vs negative titer), and include the results from trials comparing the different forms of IFN β. The American Academy of Neurology issued a consensus statement in 2007, and the European Federation of Neurological Societies issued a position statement in 2005; these 2 statements provide somewhat different recommendations.^1,2 We believe physicians should consider both the advice of the EFNS and the AAN in developing their own approach to monitoring patients for NAbs, and deciding how to treat patients who have several consecutive, “positive” NAb tests.

References

1. Goodin DS, Frohman EM, Hurwitz B, O'Connor PW, Oger JJ, Reder AT, et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007 Mar 27;68(13):977-84.
2. Sorensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J, et al. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 2005 Nov;12(11):817-27.

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What drugs should you consider for a newly diagnosed MS patient who is also positive for hepatitis C and has slightly elevated liver enzymes?
The immediate concern when treating an HCV-positive patient for MS is the risk for liver damage that has been reported with the first-line disease modifying therapies, especially IFN b. Based on reports of increases in liver enzymes during treatment, regular monitoring of liver function is recommended during IFN b treatment.^1-3 However, the incidence of liver enzyme elevations is related to the frequency of IFN b administration and consequently appears to be more common in patients treated with IFN b-1b or IFN b-1a SC.⁴ In comparative trials, the incidence of liver dysfunction was 18% in the IFN β-1a SC group vs 10% in the IFN β-1a IM group (EVIDENCE, P=0.003) and 26% in the IFN β-1a IM group compared to 23% in the IFN β-1b group (P=0.6).^5;6 This effect usually appears within the first 6 months of treatment, and can be more common in patients also receiving IV methylprednisolone.⁴ During post-marketing follow-up, some reports of liver function abnormalities or liver damage have been received for glatiramer acetate and IFN b-1a IM, but these were not necessarily associated with treatment.^1;4 In comparative trials, ALT increases were observed in 3.6% of patients treated with glatiramer acetate, compared to 11.0% in the IFN β-1b 250 µg treatment group (BEYOND, data on file).
Only the IFN b-1a SC prescribing information contains specific warnings about initiating treatment in patients with active liver disease or a history of significant liver disease; in these cases, the package insert recommends dose reduction in patients whose SGPT increases above 5 times the upper limit of normal, with possible re-escalation when SGPT levels normalize.³ Hepatits C infection is not necessarily a contraindication to IFN b treatment, and IFN b has been investigated as a treatment for HPV.^1;7;7-9
Glatiramer acetate in this instance may be more practical, however, since LFT abnormalities are not a common complication with this drug, but they can be with IFN β and natalizumab. No additional monitoring would be necessary with glatiramer treatment, and this treatment would not confound your clinical decision-making if LFT abnormalities did appear.

References

1. Avonex Package Insert. BIOGEN IDEC Inc Cambridge, MA 2006.
2. Betaseron Package Insert. Berlex Montville, NJ 2007.
3. Rebif Package Insert. Serono, Inc Rockland, MA 2005.
4. Tremlett H, Oger J. Hepatic injury, liver monitoring and the beta-interferons for multiple sclerosis. J Neurol 2004 Nov;251(11):1297-303.
5. Panitch H, Goodin D, Francis G, Chang P, Coyle P, O'Connor P, et al. Benefits of high-dose, high-frequency interferon beta-1a in relapsing-remitting multiple sclerosis are sustained to 16 months: final comparative results of the EVIDENCE trial. J Neurol Sci 2005 Dec 15;239(1):67-74.
6. Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002 Apr 27;359(9316):1453-60.
7. Fujimori K, Mochida S, Matsui A, Ohno A, Fujiwara K. Possible mechanisms of elevation of serum transaminase levels during interferon-beta therapy in chronic hepatitis C patients. J Gastroenterol 2002 Jan;37(1):40-6.
8. Mazzoran L, Grassi G, Giacca M, Gerini U, Baracetti S, Fanni-Canelles M, et al. Pilot study on the safety and efficacy of intravenous natural beta-interferon therapy in patients with chronic hepatitis C unresponsive to alpha-interferon. Ital J Gastroenterol Hepatol 1997 Aug;29(4):338-42.
9. Kakizaki S, Takagi H, Yamada T, Ichikawa T, Abe T, Sohara N, et al. Evaluation of twice-daily administration of interferon-beta for chronic hepatitis C. J Viral Hepat 1999 Jul;6(4):315-9.

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Fatigue is a common symptom of MS that may affect >75% of patients at some point; for many, fatigue will be the most troubling symptom. The Multiple Sclerosis Council for Clinical Practice Guidelines has developed evidence-based guidelines for treating fatigue in patients with MS.¹ After eliminating other causes of fatigue (eg, inappropriate management of other medical comorbidities, depression, and sleep disruption), the Council recommends a nonpharmacological approach that involves lifestyle modifications (eg, smoking cessation, diet modification, energy effectiveness strategies, exercise programs) and methods of reducing symptoms of heat intolerance (cool beverages and showers or baths).

The Council also recommends that physicians consider using amantadine (100 mg bid) either concurrently with nonpharmacological approaches or if the patient’s fatigue is not resolved after trying nonpharmacological approaches. Amantadine has been used as a treatment for fatigue, and several trials support a beneficial effect in some patients with mild to moderate disability. Because of a lack of evidence, the Council does not support the use of selective serotonin reuptake inhibitors (SSRIs) or aminopyridines.

Several other treatments are used off-label for MS-related fatigue, although the Council did not comment on their efficacy. No studies of modafinil were available when the Council convened, but since then, Rammohan et al² conducted a 9-week randomized trial of 200–400 mg/day modafinil and found that the 200 mg/day dose significantly improved self-reported measures of fatigue. In a 5-week trial of 200–400 mg/day modafinil, however, the French Modafinil Study Group did not find a significant improvement in Modified Fatigue Impact Scale scores.^3,4 The National Multiple Sclerosis Society also has an ongoing study of modafinil (NCT00142402). Stimulants such as methylphenidate or Adderall may also be considered.^5-6

References

1. Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and multiple sclerosis: evidence-based management strategies for fatigue in multiple sclerosis. 1998. The Consortium of Multiple Sclerosis Centers website. Available at http://mscare.org/cmsc/images/pdf/fatigue.pdf. Accessed September 10, 2008.
2. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN. J Neurol Neurosurg Psychiatry. 2002;72:179-183.
3. Stankoff B, Waubant E, Confavreux C, et al. Neurology. 2005;64:1139-1143.
4. Lapierre Y, Hum, S. Int MS J. 2007 ;14 :64-71.
5. Mendonca DA, Menezes K, Jog MS. Mov Disor. 2007 ;22 :2070-2076.
6. Lower EE, Harman S, Baughman RP. Chest. 2008 ;133 :1189-1195.

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For patients who continue to have clinical worsening despite treatment with IFN β or glatiramer acetate (GA), several approaches could be considered depending on the severity of the symptoms and the previous treatments received. One consideration would be to switch DMT classes—either from low-dose up to high-dose IFN β, from IFN β to GA, or from GA to IFN β—although there are yet no prospective, randomized studies to support this approach. Checking the patient’s neutralizing antibody titer prior to switching from low-dose IFN β to high-dose IFN β may be helpful but should not be the sole determinant when deciding whether high-dose IFN β is an option (see previous FAQ).^1,2

Natalizumab is indicated in patients who have not responded satisfactorily to a DMT or cannot continue the therapy.³ Natalizumab can only be administered through select infusion centers, and a washout period between DMT and natalizumab is required. For patients who cannot use or fail treatment with natalizumab, mitoxantrone, which is the only treatment specifically approved for progressive disease, may be used.⁴ Other treatment options (eg, methotrexate, pulse steroids, intravenous immunoglobulins, cyclophosphamide, or azathioprine) could also be considered, although none of these compounds has been approved for treatment of patients with MS.

References

1. Sorensen PS, Deisenhammer F, Duda P, et al. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol. 2005;12:817-827.
2. Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007;68:977-984.
3. Tysabri [package insert]. Cambridge, MA: Biogen Idec; 2008.
4. Novantrone [package insert]. Rockland, MA: EMD Serono, Inc; 2007.

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Half of all patients with MS will experience depression during the course of their disease, and in the registration trials for the three approved IFN β compounds, 25%–30% of the patients enrolled reported depressive symptoms.^1-3 In the first placebo-controlled trials of IFN β-1b, more patients in the treatment groups attempted suicide than in the placebo groups (11 vs 5), leading to the concern that IFN β could cause or exacerbate depression. However, the labeling for IFN β cites only a small difference (0%–4%) in the incidence of depression between the patients receiving placebo and IFN β, and other trials have not conclusively found an association between IFN β treatment and increased risk for depression.^1-4 In the most recent trials comparing IFN β to glatiramer acetate (GA) (BEYOND and REGARD), the incidence of depression was also only slightly higher in the IFN β groups than in the GA groups: in BEYOND, 8.8% of patients treated with GA and 11% of patients treated with IFN β developed depression, and the difference was similar in REGARD (5.9% in the GA arm vs 7.9% in the IFN β arm, unpublished data).

The approved labeling for Betaseron, Rebif, and Avonex still contains precautions against the use of IFN β in patients with depression or mood disorders. In addition, patients using IFN β should be advised to report symptoms of depression to their physician, and the package inserts recommend that physicians consider discontinuing treatment in those who develop depression while on treatment.1-3 Although it is not addressed in the labeling, some patients with comorbid depression should certainly be considered for treatment with an antidepressant while on IFN β.

References

1. Betaseron [package insert]. Montville, NJ: Berlex; 2007.
2. Rebif [package insert]. Rockland, MA: Serono, Inc; 2005.
3. Avonex [package insert]. Cambridge, MA: Biogen Idec Inc;0 2006.
4. Feinstein A. Multiple sclerosis, disease modifying treatments and depression: a critical methodological review. Mult Scler. 2000;6:343-348.

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The Consortium of Multiple Sclerosis Centers does not recommend routine repeat MRI scans on a regular basis.¹ Clinicians should consider a follow-up MRI under 3 circumstances:

• For patients who have unexpected worsening of symptoms, or if the clinician has another reason for concern about the patients’ course;
• For reassessment of disease burden when considering treatment initiation; or
• If a secondary diagnosis is suspected.
  These guidelines reflect the uncertain utility of changes that might be observed on a routine MRI scan.

References

1. Simon JH, Li D, Traboulsee A, et al. Standardized MR imaging protocol for multiple sclerosis: Consortium of MS Centers consensus guidelines. AJNR Am J Neuroradiol. 2006;27:455-461.

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OCT is a non-invasive imaging method that was originally developed for retinal imaging in patients with glaucoma.¹ This technique allows measurement of the retinal nerve fiber layer (RNFL) using an infrared interferometer. Thinning of the RNFL occurs in optic neuritis, and is thought to be a function of axonal loss in the optic nerve.^2,3 In some studies, OCT has detected a loss of RNFL tissue before clinical signs of optic neuritis appeared, or in MS patients in the absence of a history of ON.^4,5 ¬The interest in OCT comes from the possibility that this method could allow early and sensitive detection of axonal loss, or could be used to predict clinical course, by identifying subclinical neuronal loss.⁵ In addition, OCT produces higher resolution images and is less expensive than MRI. However, OCT is not a validated method for diagnosing MS or monitoring patients with MS, and this method must be further studied in prospective clinical trials before it can be applied outside of clinical trials.

References

1. Sergott RC, Frohman E, Glanzman R, Al-Sabbagh A. The role of optical coherence tomography in multiple sclerosis: expert panel consensus. J Neurol Sci. 2007;263:3-14.
2. Trip SA, Schlottmann PG, Jones SJ, et al. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol. 2005;58:383-391.
3. Trip SA, Wheeler-Kingshott C, Jones SJ, et al. Optic nerve diffusion tensor imaging in optic neuritis. Neuroimage. 2006;30:498-505.
4. Fisher JB, Jacobs DA, Markowitz CE, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology. 2006;113:324-332.
5. Pulicken M, Gordon-Lipkin E, Balcer LJ, et al. Optical coherence tomography and disease subtype in multiple sclerosis. Neurology. 2007;69:2085-2092.

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The following is a sampling of online articles describing desirable features of MS rehabilitative and psychosocial services:

National Clinical Advisory Board of the National Multiple Sclerosis Society. Rehabilitation: Recommendations for persons with multiple sclerosis. Available at: http://www.nationalmssociety.org/download.aspx?id=132. Accessed June 10, 2008.

http://www.nationalmssociety.org/download.aspx?id=132
Provance PG. Physical therapy in multiple sclerosis rehabilitation. National Multiple Sclerosis Society. Available at: http://www.nationalmssociety.org/download.aspx?id=163. Accessed June 10, 2008.

Finlayson M. Occupational therapy in multiple sclerosis rehabilitation. National Multiple Sclerosis Society. Available at: http://www.nationalmssociety.org/download.aspx?id=162. Accessed June 10, 2008.
Multiple Sclerosis: Your Health Care Team. Available at: http://www.webmd.com/multiple-sclerosis/guide/ms-health-care-team. Accessed June 10, 2008.

Brandis M, Reitman NC, Gruenewald D, Del Bene M. Opening doors: the palliative care continuum in multiple sclerosis. National Multiple Sclerosis Society. Available at: http://www.nationalmssociety.org/download.aspx?id=1027. Accessed June 10, 2008.

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Tests used to measure gait or walking disability in MS patients include the Expanded Disability Status Scale (EDSS),¹ Ambulation Index,² and the MS Functional Composite (MSFC).³ Currently used walking tests include the 6-Minute Walk,⁴ the Timed 25-Foot Walk (the ambulation component of the MSFC),⁵ and the Six Spot Step Test.⁶ These tests measure different components of walking such as speed, coordination, and balance. A promising therapy for gait disability is Fampridine, a potassium channel blocker that enhances nerve signaling. The results from a phase 3 trial of 240 subjects with all types of MS were reported on June 2, 2008; significantly more patients on Fampridine had improved walking speed than the placebo group (42.9% vs 9.3%), as measured by the Timed 25-Foot Walk test.⁷ Improvements in walking speed were also accompanied by significant gains in leg strength.

References

1. Bowen J, Gibbons L, Gianas A, Kraft GH. Self-administered Expanded Disability Status Scale with functional system scores correlates well with a physician-administered test. Mult Scler. 2001;7:201-206.
2. Schwid SR, Goodman AD, Mattson DH, et al. The measurement of ambulatory impairment in multiple sclerosis. Neurology. 1997;49:1419-1424.
3. Rudick RA, Cutter G, Baier M, et al. Use of the Multiple Sclerosis Functional Composite to predict disability in relapsing MS. Neurology. 2001;56:1324-1330.
4. Goldman MD, Marrie RA, Cohen JA. Evaluation of the six-minute walk in multiple sclerosis subjects and healthy controls. Mult Scler. 2008;14:383-390.
5. Cohen JA, Cutter GR, Fischer JS, et al. Use of the multiple sclerosis functional composite as an outcome measure in a phase 3 clinical trial. Arch Neurol. 2001; 58:961-967.
6. Nieuwenhuis MM, Van Tongeren H, Sorensen PS, Ravnborg M. The six spot step test: a new measurement for walking ability in multiple sclerosis. Mult Scler. 2006;12:495-500.
7. Fampridine-SR improves walking speed in all types of MS in second phase 3 study. Available at: http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=237. Accessed June 10, 2008.

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Natalizumab is currently the only monoclonal antibody approved for the treatment of multiple sclerosis.¹ It works by inhibiting lymphocyte migration into the central nervous system (CNS) by binding integrins needed for lymphocyte adherence.¹ In the AFFIRM trial, a 2-year clinical trial of natalizumab in relapsing-remitting multiple sclerosis (RRMS) patients, natalizumab reduced existing and new or enlarging lesions by 92% and 83%, respectively, as compared to placebo.^2,3 Natalizumab, which is administered every 4 weeks, also decreased the relapse rate and the risk of sustained disability progression.^2,3 Another mAb, alemtuzumab, is currently in phase 3 trials. Alemtuzumab binds to cells that express CD52, including lymphocytes, monocytes, and macrophages. The antibody-bound cells are then destroyed, presumably by an antibody-dependent lysis mechanism.⁴ In a large phase 2 trial of RRMS patients, alemtuzumab decreased the number of relapses over two years by 75% and reduced the risk of sustained accumulated disability by 65% when compared with interferon beta-1a.⁵ Rituximab and ocrelizumab are mAbs that recognize and bind to CD20 on pre-B and B cells, targeting these cells for destruction. Rituximab is a chimeric mouse and human antibody that is currently in large phase 2 RRMS trials, while ocrelizumab is a fully humanized antibody. In a phase 2 trial, rituximab, which is administered once every 6 months, decreased the total number of brain lesions by 91% and halved the relapse rate over one year.⁶ Ocrelizumab has not been studied in MS at present, but a phase 1/2 trial in rheumatoid arthritis showed effective B-cell depletion at 6 months with various doses.⁷ Natalizumab and alemtuzumab have been associated with serious adverse effects in MS patients such as progressive multifocal leukoencephalopathy (PML) and idiopathic thrombocytopenic purpura, respectively.^4,8 Rituximab has been associated with several cases of PML in patients with lymphoproliferative cancers,^9,10 where it has been more extensively studied than in MS. No PML cases in patients treated with the newer ocrelizumab have been reported in the literature to date. Long-term clinical studies of all the mAbs are needed to determine the safety and efficacy of these therapies over longer periods of time.

References

1. Tysabri (natalizumab) prescribing information. 2008. Elan Pharmaceuticals, Inc.
2. Polman CH, O’Connor PW, Havrdova E, et al; for the AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899-910.
3. Rudick RA, Miller D, Hass S, et al; and the AFFIRM and SENTINEL Investigators. Health-related quality of life in multiple sclerosis: effects of natalizumab. Ann Neurol. 2007;62:335-346.
4. Cree B. Emerging monoclonal antibody therapies for multiple sclerosis. Neurologist. 2006;12:171-178.
5. Coles AJ, The CAMMS223 Study Group. Efficacy of alemtuzumab in treatment-naïve relapsing-remitting multiple sclerosis: analysis after two years of study CAMMS223. Presented at: 59th Annual Meeting of the American Academy of Neurology; May 1, 2007; Boston, MA.
6. Hauser SL, Waubant E, Arnold DL, et al; for the HERMES Trial Group. B cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358:676-688.
7. Genovese MC, Kaine JL, Kohen MD, et al. Safety and clinical activity of ocrelizumab (a humanized antibody targeting CD20+ B cells) in combination with methotrexate in moderate-severe rheumatoid arthritis patients (Ph I/II ACTION study). 2006 American College of Rheumatology National Scientific Meeting Highlights. Available at: http://www.hopkins-arthritis.org/physician-corner/education/acr2006/RA/B.... Accessed June 10, 2008.
8. Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive leukoencephalopathy. N Engl J Med. 2006;354:924-933.
9. Bonavita S, Conforti R, Russo A, et al. Infratentorial progressive multifocal leukoencephalopathy in a patient treated with fludarabine and rituximab. Neurol Sci. 2008;29:37-39.
10. Pelosini M, Focosi D, Rita F, et al. Progressive multifocal leukoencephalopathy: report of three cases in HIV-negative hematological patients and review of literature. Ann Hematol. 2008;87:405-412.

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There are a variety of online resources available, providing information about topics that range from assistive equipment and technology to work accommodations. These include the following:

Promoting Function, Independence, and Mobility. National Multiple Sclerosis Society.
This page has links to many other resources on assistive devices and technology, as well as strategies for adapting home and work environments.
http://www.nationalmssociety.org/living-with-multiple-sclerosis/mobility...

Abledata. National institute on Disability and Rehabilitation Research of the US Department of Education.
This site contains information and articles about assistive technology products and rehabilitation equipment. It also offers links to many other resources, including physical, occupational, and speech and language therapy services, support groups, and assistive technology consulting services.
http://www.abledata.com/abledata.cfm?pageid=19337

Staying in the Game: MS and Employment. National Multiple Sclerosis Society.
This page offers answers to some common employment questions and concerns of MS patients. Information about the Career Crossroads: Employment and MS program, designed by employment and MS experts, is also included.
http://www.nationalmssociety.org/living-with-multiple-sclerosis/employme...

Bruyère SM, ed. Workplace Accommodations for People Living with Multiple Sclerosis. Ithaca, NY: Cornell University; 2001. (Original work written by Johnson KL.)
This brochure summarizes the different workplace needs MS patients with disabilities, and provides solutions to help fulfill these needs.
http://digitalcommons.ilr.cornell.edu/edicollect/17

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Fatigue is the most common symptom of MS, being present in 75%–90% of patients.¹ In addition, 50%–60% of patients describe it as the worst symptom of the disease.¹ Fatigue is defined as a subjective lack of physical and/or mental energy that is perceived by the patient or caregiver as interfering with usual and desired activities.² According to the MS Council for Clinical Practice Guidelines, chronic fatigue is defined as fatigue presenting on 50% of days for more than 6 weeks, limiting functional activities or quality of life (QoL).² Acute fatigue is defined as new or significant increase in feelings of fatigue in the previous 6 weeks, limiting functional activities or QoL.² After symptoms of fatigue are identified, the cause of fatigue needs to be investigated, which involves distinguishing between secondary fatigue and MS-related fatigue.^3,4 Secondary fatigue results from causes other than MS (eg, comorbid diseases, depression not related to MS, sleep abnormalities, and use of sedative medications).⁴ If secondary fatigue has been ruled out, then fatigue is MS-related, and may be either secondary or primary. Secondary MS-related fatigue occurs as a result of MS symptoms (eg, weakness, spasticity, and ataxia) that sap energy and increase the amount of exertion needed to perform daily activities.⁴ Primary fatigue occurs because of MS itself, and remains after other factors have been examined and addressed.⁴

References

1. Zifko UA. Management of fatigue in patients with multiple sclerosis. Drugs. 2004;64:1295-1304.
2. Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and Multiple Sclerosis: Evidence-Based Management Strategies for Fatigue in Multiple Sclerosis. Washington, DC: Paralyzed Veterans of America; 1998.
3. Rosenberg JH, Shafor R. Fatigue in multiple sclerosis: a rational approach to evaluation and treatment. Curr Neurol Neurosci Rep. 2005;5:140-146.
4. National Clinical Advisory Board of the National Multiple Sclerosis Society. Management of MS-Related Fatigue. New York, NY: National Multiple Sclerosis Society; 2008.

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Several oral therapies are currently being developed. Furthest along in the pipeline are FTY720/fingolimod and cladribine, both of which are presently in phase III clinical trials. In the 6-month FREEDOMS study of 281 patients with relapsing-remitting MS (RRMS), fingolimod reduced the annualized relapse rate by more than 50%, compared with placebo.¹ After the 6-month study period, a proportion of the patients participated in an extension study in which all subjects received fingolimod. Recent findings show that, after 3 years of the extension study, patients maintained low relapse rates, with more than 67% remaining free of relapses, 89% free of disease activity, and 75% free of new or newly enlarged lesions.² The most frequently reported adverse events with fingolimod were headache, fatigue, and flu and cold symptoms.² A phase III trial is ongoing to test the efficacy and adverse effects of fingolimod in RRMS patients over a 2-year period,³ and a separate phase III study is underway to compare the efficacy of fingolimod with IFN β-1a in RRMS patients.⁴ Cladribine is another oral therapy, and is being tested in 1290 RRMS patients in the phase III CLARITY trial. This study has just completed patient recruitment; data collection for primary outcome measures is projected to complete in December 2008.⁴ Other oral MS therapies under development include teriflunomide, laquinimod, and fumaric acid.⁵ Based on the findings thus far, the use of oral therapies appears to be a promising future option for treating patients with MS, especially those who cannot tolerate the injection-related adverse events of current therapies. Emerging results from larger studies involving greater numbers of patients as well as different patient types will increase understanding of the efficacy and tolerability of oral therapies.

References

1. Kappos L, Antel J, Comi G, et al; and the FTY720 D2201 Study Group. N Engl J Med. 2006;355:24-40.
2. Comi G, O’Connor P, Montalban X, et al. Oral FTY720 (fingolimod) in patients with relapsing multiple sclerosis. 3-year extension shows sustained low relapse rate and MRI activity. 60th American Academy of Neurology Annual Meeting. April 15, 2008; Chicago, IL.
3. Long term efficacy and safety of FTY720 in patients with relapsing-remitting multiple sclerosis. Available at: http://clinicaltrials.gov/ct2/show/NCT00662649?term=FTY720&rank=4. Accessed May 7, 2008.
4. Efficacy and safety of fingolimod in patients with relapsing-remitting multiple sclerosis with optional extension phase (TRANSFORMS). Available at: http://clinicaltrials.gov/ct2/show/NCT00340834?term=FTY720&rank=8. Accessed May 7, 2008.
5. CLARITY – Safety and efficacy of oral cladribine in subjects with relapsing-remitting MS. Available at: http://clinicaltrials.gov/show/NCT00213135. Accessed May 7, 2008.
6. Kieseier BC, Wiendl H. Oral disease-modifying treatment for multiple sclerosis: the story so far. CNS Drugs. 2007;21:483-502.

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Studies have been conducted to determine the efficacy of IFN β-1b, IFN β-1a IM, IFN β-1a SC, and glatiramer acetate in patients with CIS, defined as a first clinical demyelinating episode, with inflammatory and demyelinating MRI lesions, lasting at least 24 hours.¹ IFN β-1b and IFN β-1a IM have been shown to delay CDMS (defined as a second attack or the fulfillment of the Revised McDonald criteria),^1-4 and are approved for CIS.^5-6 In The Early Treatment of Multiple Sclerosis (ETOMS) trial, IFN β-1a SC reduced progression of CIS to CDMS when compared with placebo (fewer patients converted to CDMS, and those who did took a longer time to convert).⁷ Recently, Giancarlo Comi reported findings from the PreCISe study of glatiramer acetate in CIS patients at the 2008 annual meeting of the American Academy of Neurology (AAN).⁸ The unpublished PreCISe results indicated that glatiramer acetate significantly delayed the progression of CIS to CDMS, when compared with placebo. Some MS patients demonstrate a better response to one medication versus others. The results of the studies mentioned above suggest that if a patient is not responding well to one medication, clinicians can substitute another medication from among these three therapies.

References

1. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol. 2001;50:121-127.
2. Kappos L, Freedman S, Polman CH et al; for the BENEFIT Study Group. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet. 2007;370:389-397.
3. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343:898-904.
4. Kinkel RP, Kollman C, O'Connor P, et al. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology. 2006;66:678-684.
5. Avonex [package insert]. Cambridge, MA: Biogen Idec; 2006.
6. Betaseron [package insert]. Montville, NJ: Bayer Healthcare Pharmaceuticals; 2007.
7. Comi G, Filippi M, Barkhof F, et al; and the Early Treatment of Multiple Sclerosis Study Group. Effect of early interferon treatment on version to definite multiple sclerosis: a randomised study. Lancet. 2001;357:1576-1582.
8. Comi G. Treatment with glatiramer acetate delays conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndromes. 60th American Academy of Neurology Annual Meeting. April 16, 2008; Chicago, IL.

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Treatment should be initiated as soon as the diagnosis of MS can be confirmed, either by clinical signs and symptoms or MRI.1 Treatment should also be considered for patients who have had a clinically isolated syndrome (CIS) and are considered to be at high risk for MS.¹ Axonal damage is known to coincide with demyelination, suggesting that permanent neurological damage and possible future disability occurs when the active inflammatory events associated with MS are not prevented, even if clinical signs are not present.^2-4 Of the approved treatments, IFN β-1b and IFN β-1a IM are approved for use in patients who have had a CIS and have MRI findings that are consistent with MS.^5,6

References

1. Medical Advisory Board of the National Multiple Sclerosis Society. The National Multiple Sclerosis Society Disease Management Consensus Statement Summary. 2005.
2. Richert ND, Zierak MC, Bash CN, et al. MRI and clinical activity in MS patients after terminating treatment with interferon beta-1b. Mult Scler. 2000;6:86-90.
3. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338:278-285.
4. Freedman M, Polman C, Kappos L, et al. Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT): effects of immediate vs early onset of interferon beta-1b treatment. 59th American Academy of Neurology Annual Meeting. April 28, 2007; Boston, MA.
5. Avonex [package insert]. Cambridge, MA: Biogen Idec, 2006.
6. Betaseron [package insert]. Montville, NJ: Bayer Healthcare Pharmaceuticals, 2007.

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Only IFN β-1b and IFN β-1a IM are approved for treating an initial demyelinating event consistent with MS.^2-4 No clinical trials have compared the relative efficacy or safety of these therapies in this patient population, but both have been shown to delay clinically definite MS (ie, a second attack or fulfillment of the Revised McDonald criteria).^1,5-7 In the BENEFIT trial, disability progression was also reduced in patients who received immediate treatment with IFN β-1b compared with those patients who received treatment only after presenting with clinically definite MS or at the conclusion of the 2-year placebo-controlled period.^1,5 IFN β-1a SC did not improve time to clinically definite MS or disability progression in patients with a CIS, but the total weekly IFN β-1a SC dose used was lower than the currently approved dose for patients with RRMS.⁸ An ongoing trial (REFLEX) is testing the standard IFN β-1a SC dose in this patient population. No trials have assessed glatiramer acetate in patients with a CIS.

References

1. Freedman M, Polman C, Kappos L, et al. Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT): effects of immediate vs early onset of interferon beta-1b treatment. 59th American Academy of Neurology Annual Meeting. April 28, 2007; Boston, MA.
2. Avonex [package insert]. Cambridge, MA: Biogen Idec, 2006.
3. Betaseron [package insert]. Montville, NJ: Bayer Healthcare Pharmaceuticals, 2007.
4. Rebif [package insert]. Rockland, MA: EMD Serono, Inc., 2005.
5. Kappos L, Polman C, Freedman M, et al, . Betaferon® in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): clinical results. ECTRIMS/ACTRIMS 2005 Congress. September 28, 2005; Thessaloniki, Greece.
6. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343:898-904.
7. Kinkel RP, Kollman C, O'Connor P, et al. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology. 2006;66:678-684.
8. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357:1576-1582.

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Both IFN β-1b and IFN β-1a SC have recommended protocols for initiating treatment. IFN β 1b is titrated to the full dose over a 6-week period. Patients receive 25% of the full dose during the first 2 weeks of treatment, 50% during the third and fourth weeks, 75% during the fifth and sixth weeks, and the full dose thereafter.¹ For IFN β-1a SC, patients initially receive 20% of the full dose three times per week; after 2 weeks of treatment, the dose is increased to 50% of the full dose, and after the fifth week, patients are given the full dose.² No dose titration is indicated for IFN β-1a IM or glatiramer acetate.

References

1. Betaseron [package insert]. Montville, NJ: Bayer Healthcare Pharmaceuticals, 2007.
2. Rebif [package insert]. Rockland, MA: EMD Serono, Inc., 2005.

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Low- and high-dose IFN β refers to the frequency of administration. IFN β-1a IM is administered once weekly and is considered a low-dose IFN β regimen. IFN β-1b and IFN β-1a SC are administered at least three times per week and are considered high-dose IFN β regimens. In two trials, low- and high-dose IFN β regimens have been compared, and in both trials, relapse rates were significantly lower in the high-dose groups.^1-3

References

1. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359:1453-1460.
2. Panitch H, Goodin D, Francis G, et al. Benefits of high-dose, high-frequency interferon beta-1a in relapsing-remitting multiple sclerosis are sustained to 16 months: final comparative results of the EVIDENCE trial. J Neurol Sci. 2005;239:67-74.
3. Schwid SR, Thorpe J, Sharief M, et al. Enhanced benefit of increasing interferon beta-1a dose and frequency in relapsing multiple sclerosis: the EVIDENCE Study. Arch Neurol. 2005;62:785-792.

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High-dose IFN β has been compared with glatiramer acetate in the BEYOND and REGARD studies, and some of these data have been made public. IFN β-1b was compared with glatiramer acetate in the BEYOND study, and IFN β-1a SC was compared with glatiramer acetate in the REGARD study. In both cases, clinical and MRI measures of disease activity were similar for patients in the IFN β and glatiramer acetate treatment groups. However, the adverse effect profile for IFN β and glatiramer acetate is not the same—patients treated with IFN β in BEYOND and REGARD generally had more flu-like symptoms, while patients who received glatiramer acetate had more injection-site reactions. These data suggest that, while the efficacy of high-dose IFN β is equivalent to that of glatiramer acetate, other clinical considerations differentiate these treatments. However, the complete efficacy and safety data from these studies have not yet been released or published.

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There are no data assessing the benefits of changing DMT in patients who develop NAbs during IFN β treatment. However, both the American Academy of Neurology (AAN) and the European Federation of Neurological Societies (EFNS) have issued recommendations for monitoring for NAbs and managing patients who develop NAbs.^1,2 Both committees agree that NAbs probably reduce the clinical and radiographic effectiveness of IFN β; however, neither group concluded that this effect translated to a long-term effect on disability progression. The AAN did consider the effectiveness of low- and high-dose IFN β (the latter are generally associated with a higher incidence of NAbs) when stating that the benefit of high-dose IFN β most likely outweighs the risk of NAbs during the first 2 years of treatment.

References

1. Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007;68:977-984.
2. Sorensen PS, Deisenhammer F, Duda P, et al. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol. 2005;12:817-827.

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The pharmaceutical companies that make the four approved DMTs have patient support programs, staffed by certified nurses, who can answer patient questions or, in some cases, assist with treatment.

Bayer HealthCare Pharmaceuticals (Betaseron) https://www.mspathways.com/welcome_to_ms_pathways/your_beta_nurses/ask_a...

Biogen Idec (Avonex)
http://www.avonex.com/msavProject/avonex.portal/_baseurl/twoColLayout/SC...

EMD Serono (Rebif)
http://www.mslifelines.com/rebif/treatment-routine/index.jsp

Teva Pharmaceuticals Industries, Ltd (Copaxone)
http://www.copaxone.com/supportServices/therapRes.aspx

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