Multiple Sclerosis [Medicare]
Number: 0264m
Commercial CPB | Medicare CPB
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Medicare Part B Step Therapy Criteria
For Medicare Advantage Plans That Do Not Offer Prescription Drug Coverage (MA)
Lemtrada, for the indication listed below:
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Relapsing forms of multiple sclerosis including:
- Relapsing-remitting disease
- Active secondary progressive disease
Is not covered for new starts, unless the member meets ANY of the following:
- Inadequate response to a trial of Tysabri
- Intolerable adverse event to Tysabri
- Tysabri is contraindicated for the member.
For Medicare Advantage Plans That Offer Prescription Drug Coverage (MAPD)
Lemtrada, for the indication listed below:
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Relapsing forms of multiple sclerosis including:
- Relapsing-remitting disease
- Active secondary progressive disease
Is not covered for new starts, unless the member meets ANY of the following:
- Inadequate response to a trial of Kesimpta
- Intolerable adverse event to Kesimpta
- Kesimpta is contraindicated for the member.
Ocrevus, for the indication listed below:
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Relapsing forms of multiple sclerosis including:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Is not covered for new starts, unless the member meets ANY of the following:
- Inadequate response to a trial of Kesimpta
- Intolerable adverse event to Kesimpta
- Kesimpta is contraindicated for the member.
Policy
Note: Requires Precertification:
Precertification of multiple sclerosis medications are required of all Aetna participating providers and members in applicable plan designs. For precertification of multiple sclerosis medications, call (866) 752-7021, or fax (888) 267-3277. For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.
Note: For commercial plans, Site of Care Utilization Management Policy applies for alemtuzumab (Lemtrada), natalizumab (Tysabri), ocrelizumab (Ocrevus), and immune globulin. For information on site of service, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.
Intravenous Steroid Treatment
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Aetna considers intravenous steroid therapy medically necessary for either of the following indications:
- Treatment of acute exacerbations of multiple sclerosis (MS) when the acute relapse is characterized by functionally disabling symptoms with documented evidence of neurological impairment (persons who have previously responded in a relapse phase are more likely to do so in the future); or
- Use of intermittent pulse dose corticosteroids as a maintenance treatment for MS to delay disease progression. In many cases, members can be treated in the outpatient setting.
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Aetna considers hospital admission for intravenous steroid therapy medically necessary for the treatment of an acute exacerbation of MS that results in any of the following severe neurological deficits:
- Acute cerebral symptoms with severe loss of intellectual capacity; or
- Acute epileptic seizure(s); or
- Acute fulminant MS characterized by headache, vomiting, convulsions and eventually coma, with severe compromise of functioning of the central nervous system; or
- Acute pseudobulbar palsy; or
- Acute quadriplegia; or
- Acute transverse myelitis (or Brown-Sequard syndrome) with loss of function below the level of a suspected lesion in the spinal cord; or
- Acute visual loss.
An inpatient stay may also be considered medically necessary for persons who have had previous complications from high dose intravenous steroids that justify an inpatient admission.
Outpatient Treatment
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Clinically isolated syndrome (CIS)
Aetna considers the following medications medically necessary for the treatment of CIS when criteria are met:
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Ocrelizumab (Ocrevus)
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Criteria for Initial Approval
- For treatment of CIS of MS (ocrelizumab may be considered medically necessary for pediatric members less than 18 years of age when benefits outweigh risks); and
- Ocrelizumab will be prescribed by or in consultation with a neurologist; and
- Members will not use Ocrevus concomitantly with other disease modifying multiple sclerosis agents. Note: Ampyra and Nuedexta are not disease modifying.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
- For members with CIS who are experiencing disease stability or improvement while receiving Ocrevus (continuation of ocrelizumab therapy may be considered medically necessary for pediatric members less than 18 years of age when benefits outweigh risks); and
- Ocrelizumab will be prescribed by or in consultation with a neurologist; and
- Members will not use Ocrevus concomitantly with other disease modifying multiple sclerosis agents. Note: Ampyra and Nuedexta are not disease modifying.
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Interferon beta-1a (Avonex)
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Natalizumab (Tysabri)
See CPB 0751 - Natalizumab (Tysabri) or CPB 0751m - Natalizumab (Tysabri) [Medicare].
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Dimethyl fumarate (Tecfidera), diroximel fumarate (Vumerity), fingolimod (Gilenya), ozanimod (Zeposia), siponimod (Mayzent), teriflunomide (Aubagio), glatiramer acetate (generic formulation, Copaxone, Glatopa), ofatumumab (Kesimpta)
The following oral medications: dimethyl fumarate (Tecfidera), diroximel fumarate (Vumerity), fingolimod (Gilenya), ozanimod (Zeposia), siponimod (Mayzent), teriflunomide (Aubagio), and the following self-administered injectables: glatiramer acetate (generic formulation, Copaxone, Glatopa), ofatumumab (Kesimpta), are included in Aetna's Pharmacy Clinical Policy Bulletins (CPBs).
For CIS, see Aetna's Pharmacy Clinical Policy Bulletins.
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Primary progressive multiple sclerosis (MS)
Aetna considers the following medications medically necessary for treatment of primary progressive MS when criteria are met:
Ocrelizumab (Ocrevus)
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Criteria for Initial Approval
- For treatment of primary progressive MS (ocrelizumab may be considered medically necessary for pediatric members less than 18 years of age when benefits outweigh risks); and
- Ocrelizumab will be prescribed by or in consultation with a neurologist; and
- Members will not use Ocrevus concomitantly with other disease modifying multiple sclerosis agents. Note: Ampyra and Nuedexta are not disease modifying.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
- For members with primary progressive MS who are experiencing disease stability or improvement while receiving Ocrevus (continuation of ocrelizumab therapy may be considered medically necessary for pediatric members less than 18 years of age when benefits outweigh risk); and
- Ocrelizumab will be prescribed by or in consultation with a neurologist; and
- Members will not use Ocrevus concomitantly with other disease modifying multiple sclerosis agents. Note: Ampyra and Nuedexta are not disease modifying.
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Relapsing forms of multiple sclerosis (MS)
Aetna considers the following medications medically necessary for treatment of relapsing forms of MS when criteria are met:
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Alemtuzumab (Lemtrada)
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Criteria for Initial Approval
First course - relapsing forms of MS:
- For members with a diagnosis of a relapsing form of multiple sclerosis (MS) who have had an inadequate response to two or more drugs indicated for MS (alemtuzumab may be considered medically necessary for pediatric members less than 18 years of age when benefits outweigh risks); and
- Alemtuzumab will be prescribed by or in consultation with a neurologist; and
- Members will not use Lemtrada concomitantly with other disease modifying multiple sclerosis agents. Note: Ampyra and Nuedexta are not disease modifying.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections)
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Continuation of Therapy
Subsequent courses - relapsing forms of MS:
- For members with a diagnosis of a relapsing form of MS who have completed at least one previous course of therapy and treatment will start at least 12 months after the last dose of the prior treatment course (continuation of alemtuzumab therapy may be considered medically necessary for pediatric members less than 18 years of age when benefits outweigh risks); and
- Alemtuzumab will be prescribed by or in consultation with a neurologist; and
- Members will not use Lemtrada concomitantly with other disease modifying multiple sclerosis agents. Note: Ampyra and Nuedexta are not disease modifying.
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Mitoxantrone intravenous injection
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Criteria for Initial Approval
For members who have been diagnosed with a relapsing form of multiple sclerosis (including relapsing-remitting, secondary progressive, and progressive relapsing diesease; and mitoxantrone will be prescribed by or in consultation with a neurologist. Note: mitoxantrone is not indicated in the treatment of primary progressive MS.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
For members who meet initial criteria and are experiencing disease stability or improvement, and there is no evidence of unacceptable toxicity while receiving mitoxantrone therapy; and mitoxantrone will be prescribed by or in consultation with a neurologist.
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Ocrelizumab (Ocrevus)
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Criteria for Initial Approval
- For members who have been diagnosed with a relapsing form of multiple sclerosis (including relapsing-remitting and secondary progressive disease for those who continue to experience relapse) (ocrelizumab may be considered medically necessary for pediatric members less than 18 years of age when benefits outweigh risks); and
- Ocrelizumab will be prescribed by or in consultation with a neurologist; and
- Members will not use Ocrevus concomitantly with other disease modifying multiple sclerosis agents. Note: Ampyra and Nuedexta are not disease modifying.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
- For members who are experiencing disease stability or improvement while receiving Ocrevus (continuation of ocrelizumab therapy may be considered medically necessary for pediatric members less than 18 years of age when benefits outweigh risks); and
- Ocrelizumab will be prescribed by or in consultation with a neurologist; and
- Members will not use Ocrevus concomitantly with other disease modifying multiple sclerosis agents. Note: Ampyra and Nuedexta are not disease modifying.
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Interferon beta-1a (Avonex and Rebif), interferon beta-1b (Betaseron and Extavia), and peginterferon beta-1a (Plegridy)
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Natalizumab (Tysabri)
See CPB 0751 - Natalizumab (Tysabri) or CPB 0751m - Natalizumab (Tysabri) [Medicare].
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Rituximab (Rituxan)
See CPB 0314 - Rituximab or CPB 0314m - Rituximab [Medicare].
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Cladribine (Mavenclad), dimethyl fumarate (Tecfidera), diroximel fumarate (Vumerity), fingolimod (Gilenya), ozanimod (Zeposia), siponimod (Mayzent), teriflunomide (Aubagio), glatiramer acetate (generic formulation, Copaxone, Glatopa), ofatumumab (Kesimpta)
The following oral medications: cladribine (Mavenclad), dimethyl fumarate (Tecfidera), diroximel fumarate (Vumerity), fingolimod (Gilenya), ozanimod (Zeposia), siponimod (Mayzent), teriflunomide (Aubagio), and the following self-administered injectables: glatiramer acetate (generic formulation, Copaxone, Glatopa), ofatumumab (Kesimpta), are included in Aetna's Pharmacy Clinical Policy Bulletins (CPBs).
For relapsing forms of MS, see Aetna's Pharmacy Clinical Policy Bulletins.
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Plasma Exchange / Plasmapheresis
Plasma exchange (PLEX) / plasmapheresis is considered medically necessary for members with acute, severe neurological deficits caused by MS who have a poor response to treatment with high-dose glucocorticoids.
Notes
For purpose of this policy, failure of an adequate trial of therapy for multiple sclerosis is defined as follows:
- the member has increasing relapses (defined as two or more relapses in a year, or one severe relapse associated with either poor recovery or MRI lesion progression); or
- the member has lesion progression by MRI (increased number or volume of gadolinium-enhancing lesions, T2 hyperintense lesions or T1 hypointense lesions); or
- the member has worsening disability (sustained worsening of Expanded Disability Status Scale (EDSS) score or neurological examination findings).
Intolerance is defined as intolerable side effects despite optimized management strategies.
For H.P. Acthar Gel, see CPB 0762 - Repository Corticotropin Injection (H.P. Acthar Gel).
For other oral medications used to treat symptoms of MS (e.g., dalfampridine [Ampyra]), see Aetna's Pharmacy Clinical Policy Bulletins.
Dosage and Administration
Alemtuzumab (Lemtrada)
Alemtuzumab is available as Lemtrada in 12 mg/1.2 mL (10 mg/mL) single-dose vials for intravenous infusion.
The recommended dosage of Lemtrada is 12 mg/day administered by intravenous infusion over 4 hours for 2 treatment courses:
- First course: 12 mg/day on 5 consecutive days (60 mg total dose);
- Second course: 12 mg/day on 3 consecutive days (36 mg total dose) administered 12 months after first treatment course.
Following the second treatment course, subsequent treatment courses of 12 mg per day on 3 consecutive days (36 mg total dose) may be administered, as needed, at least 12 months after the last dose of any prior treatment course.
Source: Genzyme, 2022
Mitoxantrone Intravenous Injection
Mitoxantron injection is a sterile aqueous solution contaiing mitoxantrone hydrochloride at a concentration equivalent to 2 mg mitoxantrone free base per mL supplied in vials for multiple-dose use as follows: 20 mg/10 mL (2 mg/mL), 25 mg/12.5 mL (2 mg/mL), and 30 mg/15 mL (2 mg/mL).
The recommended dosage of mitoxantrone for multiple sclerosis is 12 mg/m2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months.
Source: Hospria, 2021
Ocrelizumab (Ocrevus)
Ocrelizumab is available as Ocrevus in 300 mg/10 mL (30 mg/mL) single-dose vials for intravenous infusion.
The recommended starting dosage 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion. Subsequent doses are 600 mg intravenous infusion every 6 months.
Per the label, Hepatitis B virus and quantitative serum immunoglobulin screening are required before the first dose, as well pre-medicating with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion.
Source: Genentech, 2021
For information on interferon beta-1a (Avonex and Rebif), interferon beta-1b (Betaseron and Extavia), and peginterferon beta-1a (Plegridy), see CPB 0404 - Interferons.
For natalizumab (Tysabri), see CPB 0751 - Natalizumab (Tysabri) or CPB 0751m - Natalizumab (Tysabri) [Medicare].
For rituximab (Rituxan), see CPB 0314 - Rituximab or CPB 0314m - Rituximab [Medicare].
Experimental and Investigational
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Aetna considers the following interventions experimental and investigational for MS (not an all-inclusive list):
- Alpha-interferon
- Anti-T-cell monoclonal antibodies other than natalizumab (Tysabri, Antegren)
- Anti-lymphocyte globulin
- APOE genotyping
- Balloon angioplasty / balloon venoplasty / venous angioplasty with or without stent placement (chronic cerebrospinal venous insufficiency (CCSVI) treatment)
- Brainstem auditory evoked response for diagnosing MS
- Cerebrospinal fluid levels of neurofilament as a biomarker of MS
- Clemastine fumarate for the treatment of chronic demyelinating injury in MS
- Cooling garment
- Cosyntropin (Cortrosyn)
- Cyclosporine (Sandimmune)
- Dietary interventions (e.g., gluten-free diets, low fat diets, linoleate supplementation to diet, and dietary regimens with polyunsaturated fatty acids)
- Electronystagmography (in the absence of vertigo or balance disorder)
- Erythropoesis stimulating agents (unless criteria are met in CPB 0195 - Erythropoiesis Stimulating Agents or CPB 0195m - Erythropoiesis Stimulating Agents [Medicare])
- Estrogen receptor beta ligands
- Ferritin/iron status (blood or CSF) for the diagnosis of MS
- Functional electrical stimulation (FES) cycling
- Gamma-interferon
- gMS®DX and gMS®Pro EDSS tests for the diagnosis of MS
- Hyperbaric oxygen
- Intravesical vanilloids (e.g., capsaicin and resiniferatoxin) for the treatment of neurogenic lower urinary tract dysfunction in individuals with MS
- IL-2-toxin
- IL-10
- IL-16
- Interleukin-1 gene polymorphisms testing
- IVIG for Multiple Sclerosis (relapsing MS and progressive MS) (see CPB 0206 - Parenteral Immunoglobulins or CPB 0206m - Parenteral Immunoglobulins [Medicare])
- Mesenchymal stem cell therapy
- Mesenchymal stromal cell-derived neural progenitors
- Methotrexate
- MTHFR testing for MS
- Myelin basic protein peptides
- Myxovirus resistance protein A (MxA) as a biomarker for MS relapse/treatment response
- Naltrexone
- Non-pharmacological interventions (biofeedback, hydrotherapy, hypnosis, reflexology, transcranial direct stimulation, transcranial random noise stimulation, and transcutaneous electrical nerve stimulation) for the treatment of chronic pain in MS
- Optical coherence tomography for screening of member receiving fingolimod (Gilenya) for macular edema (see CPB 0344 - Optic Nerve and Retinal Imaging Methods)
- Oral myelin (Myloral)
- Osteopontin as a biomarker for MS
- Otoacoustic emissions (in the absence of signs of hearing loss)
- Photopheresis (see CPB 0241 - Extracorporeal Photochemotherapy (Photopheresis))
- Plasmapheresis for chronic or secondary progressive MS (maintenance therapy)
- Procarin (transdermal histamine)
- Prolactin
- Pulsed magnetic field therapy
- PUVA (psoralen ultraviolet light)
- Retinal nerve scanning for screening/monitoring persons on fingolimod (Gilenya)
- Ribavirin
- Serum neurofilament as a marker of neuroaxonal injury in early MS and for monitoring disease activity
- Sildenafil
- Statins
- Stem cell transplantation (see CPB 0606 - Stem Cell Transplant for Autoimmune Diseases and Miscellaneous Indications
- T-cell receptor therapy
- T-cell vaccination
- Total lymphoid irradiation
- Transcranial brain sonography for predicting disease progression in MS
- Transforming growth factor (TGF)-beta
- Tumor necrosis factor antagonists
- Tympanometry (in the absence of hearing loss).
Aetna considers assays of neutralizing antibodies (NABs) against interferon beta (Betaseron) to be experimental and investigational because its clinical value has not been established.
Aetna considers measurements of hematopoietic stem and progenitor cells counts as a biomarker of responsiveness to natalizumab experimental and investigational because its clinical value has not been established.
Aetna considers determination of the expression of the splice variants of the tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and its receptors as a biomarker of responsiveness to interferon-beta experimental and investigational because its clinical value has not been established.
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Concomitant Use
Aetna considers alemtuzumab (Lemtrada), cladribine (Mavenclad), dimethyl fumarate (Tecfidera), fingolimod (Gilenya), glatiramer acetate (Copaxone, Glatopa), interferon beta, natalizumab (Tysabri), ocrelizumab (Ocrevus), siponimod (Mayzent) and/or teriflunomide (Aubagio) used concomitantly with other disease modifying multiple sclerosis agents (Note: Ampyra and Nuedexta are not disease modifying) to be experimental and investigational because the clinical value has not been established.
Background
Multiple sclerosis (MS) is an acquired immune-mediated inflammatory disease characterized by the destruction of myelin sheaths with preservation of axons occurring in multiple anatomic sites in the brain and spinal cord. Its clinical course is variable and unpredictable and exact etiology is unknown, although data suggests that it is an autoimmune disease triggered by a viral infection in genetically susceptible individuals.
Multiple Sclerosis (MS) attacks myelinated axons in the central nervous system (CNS), destroying the myelin and the axons. Over 900,000 people in the United States and 2.1 million people worldwide are living with MS (Levin, 2021; National Multiple Sclerosis Society, 2019). Most people with MS are diagnosed between the ages of 20‐50 years old. Though the etiology of MS is unknown, it is hypothesized that MS results when an environmental agent or event (e.g. viral or bacterial infection, exposure to chemical) act in conjunction with a genetic predisposition to immune dysfunction. Risk factors for MS include gender (women 2‐3x increased risk), genetics, age, geography, and ethnic background.
Four disease courses have been identified in multiple sclerosis: clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS).
Clinically Isolated Syndrome (CIS)
CIS is the first episode of neurologic symptoms caused by inflammation and demyelination in the central nervous system. The episode, which by definition must last for at least 24 hours, is characteristic of multiple sclerosis but does not yet meet the criteria for a diagnosis of MS because people who experience a CIS may or may not go on to develop MS. When CIS is accompanied by lesions on a brain MRI (magnetic resonance imaging) that are similar to those seen in MS, the person has a high likelihood of a second episode of neurologic symptoms and diagnosis of relapsing-remitting MS. When CIS is not accompanied by MS-like lesions on a brain MRI, the person has a much lower likelihood of developing MS. Persons with CIS who are considered at high risk for developing MS may be treated with a disease-modifying therapy that has been approved by the U.S. Food and Drug Administration (FDA) for that purpose. Early treatment of CIS has been shown to delay onset of MS (National Multiple Sclerosis Society, 2020).
Primary Progressive MS (PPMS)
Primary progressive MS (PPMS) is characterized by worsening neurologic function (accumulation of disability) from disease onset, without early relapses or remissions. PPMS can be further characterized at different points in time as either active (with an occasional relapse and/or evidence of new MRI activity), or not active, as well as with progression (evidence of worsening disease with or without relapse, or per MRI) or without progression (National Multiple Sclerosis Society, 2020; Olek and Howard, 2021). According to the National Multiple Sclerosis Society, approximately 15% of people with MS are diagnosed with PPMS.
In 2013, medical experts redefined the types of MS. As a result, progressive-relapsing MS (PRMS) is no longer considered one of the distinct types of MS. People who might have received a diagnosis of PRMS in the past are now considered to have primary progressive MS (PPMS) with active disease. Patients experience a steadily worsening disease from the onset but also have clear acute relapses (attacks or exacerbations), with or without recovery. In contrast to relapsing‐remitting MS, the periods between relapses are characterized by continuing disease progression.
Relapsing‐remitting MS (RRMS)
RRMS is the most common disease course and approximately 85% of people with MS are initially diagnosed with RRMS. RRMS is characterized by clearly defined attacks of new or increasing neurologic symptoms. These attackes, also called relapses or exacerbations, are followed by periods of partial or complete recovery (remissions). During remissions, all symptoms may disappear, or some symptoms may continue and become permanent. However, there is no apparent progression of the disease during the periods of remission. At different points in time, RRMS can be further characterized as either active (with relapses and/or evidence of new MRI activity) or not active, as well as worsening (a confirmed increase in disability over a specified period of time following a relapse) or not worsening (National Multiple Sclerosis Society, 2020).
Classical exacerbating-remitting usually begins with the acute or subacute onset of focal neurologic signs and symptoms, typically evolving over 1 to 3 days, stabilizing for a few days, and then improve spontaneously, followed by an onset of new focal symptoms months or years later. On rare occasions, MS has a relatively acute onset with a rapidly progressive course involving multiple areas of the nervous system simultaneously and leading to severe impairment and death within a few weeks or months. In chronic progressive MS, the course is insidious and progressive from the onset, usually occurs in patients greater than 35 years of age, and presents as a chronic myelopathy with slowly or intermittent, progressive symptoms. Neuromyelitis optica (Devic’s syndrome) is a clinical syndrome consisting of both optic neuritis and transverse myelitis, occurring simultaneously or separately by only a brief interval in a patient without prior evidence of MS.
Patients with MS initially present with sensory disturbances in 1 or more limbs, disturbances of balance and gait with ataxia, optic nerve dysfunction with visual loss in 1 eye, diplopia, nystagmus, dysarthria, upper motor neuron spastic weakness, intention tremors, autonomic dysfunction, bladder dysfunction, spastic paraparesis, and retrobulbar neuritis, in various combinations. About 50 % of patients with isolated optic neuritis will develop MS.
The diagnosis of MS remains clinical at present, with demonstration of signs and symptoms spread out in time and space being required. Most patients have initial symptoms which totally resolve only to relapse with progressive residual disability after each exacerbation and significant neurologic dysfunction developing over a period of several years. Less than 1/3 of MS patients have a very benign course with minimal or no disability, and about 10 % have a very malignant course with severe disability within months to a few years.
At onset, about 65 % of patients have a relapsing-remitting form of the disease. These patients have exacerbations with symptoms attributable to central nervous system (CNS) lesions or plaques. The flare-ups usually develop subacutely and resolve over weeks to months. About 15 % of patients have exacerbations similar to the relapsing-remitting disease but less complete recovery that leaves the patients with significant residual disability. This form is referred to as the relapsing-progressive form. Finally, there is the chronic progressive form dominated by spinal cord and cerebellar dysfunction. In about 20 % of patients, the initial symptoms start with this chronic progressive form, whereas, more often, it develops out of the relapsing-remitting disorder over time.
The inflammatory response in the CNS consists predominantly of activated T lymphocytes and macrophages accompanied by a local immune reaction with the secretion of cytokines and the synthesis of oligoclonal immunoglobulin within the CNS. Multiple sclerosis is thought to either be a cell-mediated autoimmune attack against myelin antigens or the presence of a persistent virus or infectious process within the CNS against which the inflammatory response is directed.
Many scattered, discrete areas of demyelination, termed plaques, are the pathologic hallmark of multiple sclerosis. Only limited regeneration of myelin occurs once the myelin sheath is destroyed (shadow plaques). Conduction of nerve impulses along axons denuded of their myelin is slowed or blocked. This loss of conduction is analogous to a segment of electrical wire being stripped of its insulating cover, allowing escape of current and diminishment of its force down the rest of the wire.
The essentials of diagnosis are: episodic symptoms that may include sensory abnormalities, blurred vision, sphincter disturbances, and weakness with or without spasticity; patient is usually under 55 years of age at onset; single pathologic lesion can not explain clinical findings; and multiple foci best demonstrated by magnetic resonance imaging (MRI).
An accurate diagnosis is extremely important because this disorder mimics many diseases of the central nervous system. The clinical history, including a history of at least 2 episodes of neurologic deficit, and physical examination showing objective clinical signs of lesions at more than one site within the CNS, remain of paramount importance in establishing a correct diagnosis. However, the sine qua non of the initial diagnosis is the MRI demonstration that different regions of the white matter of the CNS have been affected by lesions at different times by demonstrating multiple white matter lesions (plaques) which represent a clearly defined patch of demyelination of sheaths of neurons in the CNS signifying areas of slowed or loss conduction leading to symptoms. Diagnosis is confirmed with the aid of a number of procedures. Cerebrospinal fluid (CSF) examination show elevated immunoglobulin G (IgG) and oligoclonal banding (electrophoretic bands which represents fractionations of IgG). Evoked potential testing demonstrates conduction disturbances. The diagnosis of MS rests as much as ever on the considered opinion of the neurologist, based heavily on the clinical features of the patient's illness.
The treatment of MS must be individualized to the patient. Patients with stable disease, mild acute attacks, consisting of minor paresthesias, slight weakness, or incoordination that do not significantly interfere with normal activities require no treatment, as these attacks subside in 1 to 2 weeks without treatment. Symptomatic treatment for spasticity, paresthesias, fatigue, and bowel and bladder difficulties may be required. Patients with progressive MS are treated with immunomodulating therapy, however, unfortunately no therapy has had a significant beneficial effect on the course of progressive MS. Because the clinical examination is a relatively crude indicator to assess the efficacy of treatment, recent studies are using MRI to assess therapeutic benefit.
Early in the disease course, many patient exhibit little neurologic dysfunction and require minimal therapy. Many times their attacks are self-limiting and the main therapy offered is counsel and advise. When intervention is required, therapy is directed toward altering the clinical course with the use of immunosuppressives, or alleviating symptoms (spasticity, fatigue, depression, pain, bladder dysfunction, and cerebellar dysfunction).
Secondary Progressive MS (SPMS)
Secondary progressive MS (SPMS) is characterized by "an initial relapsing-remitting MS disease course followed by gradual worsening with or without occasional relapses, minor remissions, and plateaus" (Olek and Howard, 2021). Some people who are diagnosed with RRMS will eventually transition to a secondary progressive course in which there is a progressive accumulation of disability over time. SPMS can be further characterized as either active (with relapses and/or evidence of new MRI activity during a specified period of time) or not active, as well as with progression (evidence of disability accumulation over time, with or without relapses or new MRI activity) or without progression (National Multiple Sclerosis Society, 2020).
Intravenous Steroid Treatment
Intravenous steroids are safe and effective in treating acute exacerbations of MS. Its use is directed at the early halting or diminishing of the destructive inflammatory process in the central nervous system, so that neurologic disability doesn't accumulate. For an acute relapse, a course of intravenous corticosteroids is typically given (500 mg to 1 gram of methylprednisolone (Solu-Medrol) over 30 to 60 mins for 3 days). This course can be extended up to 5 days (or to even 10 days) if the attack continues to progress or is slow in improving. Intravenous methylprednisolone is also the usual primary treatment for optic neuritis. The somewhat rapid effect of steroid treatment is based partly by reduction of white matter edema, and somewhat by an alteration of immunological factors. It is unusual in practice to give more than 2 or 3 courses of steroids for the treatment of relapses.
Outpatient Treatment
Alemtuzumab
U.S. Food and Drug Administration (FDA)-Approved Indications
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alemtuzumab (Lemtrada) is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, the use of Lemtrada should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.
Limitations of Use: Lemtrada is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile.
Alemtuzumab is available as Lemtrada (Genzyme Corporation). Alemtuzumab is a monoclonal antibody that targets CD52, a protein abundant on T and B cells. Circulating T and B cells are thought to be responsible for the damaging inflammatory process in MS. The precise mechanism by which alemtuzumab exerts its therapetuc efffects in multiple sclerosis is unknown but is presumed to involve binding to CD52, a cell surface antigen present on T and B lymphocytes, and on natural killer cells, monocytes and macrophages. Cell surface binding to T and B lymphocytes results in antibody dependent cellular cytolysis and complement mediated lysis. Alemtuzumab depletes circulating T and B lymphocytes after each treatment course. Lymphocyte counts then increase over time with a reconstitution of the lymphocyte population that varies for the different lymphocyte subtypes (Genzyme, 2022).
FDA approval of Lemtrada was based on two pivotal randomized Phase III open-label rater-blinded studies comparing treatment with alemtuzumab to high-dose subcutaneous interferon beta-1a (Rebif) in patients with relapsing remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II) (Genzyme, 2014).
In CARE-MS I, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rate (0.18 for alemtuzumab and 0.39 for interferon beta-1a (p<0.0001) (Genzyme, 2014; Cohen, et al., 2012). The difference observed in proportion of patients with disability progression at year two did not reach statistical significance (8 percent for alemtuzumab and 11 percent for interferon beta 1-a (p=0.22)). The percent of patients remaining relapse-free at year two for alemtuzumab was 78 percent versus 59 percent for interferon beta-1a (p<0.0001). The percent change in T2 lesion volume from baseline did not reach statistical significance (-9.3 for alemtuzumab and -6.5 for interferon beta 1-a, p=0.31).
In CARE-MS II, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rates (0.26 for alemtuzumab and 0.52 for interferon beta 1-a, p<0.0001) (Genzyme, 2014; Coles, et al., 2012). The proportion of patients with confirmed six-month disability progression was significantly lower for alemtuzumab (13 percent for alemtuzumab versus 21 percent for interferon beta 1-a, p=0.0084). The percent of patients remaining relapse-free at year two for alemtuzumab was 65 percent versus 47 percent for interferon beta-1a (p<0.0001). The percent change in T2 lesion volume from baseline did not reach statistical significance (-1.3 for alemtuzumab and -1.2 for interferon beta 1-a, p=0.14).
The FDA-approved labeling of Lemtrada includes a boxed warning noting a risk of serious, sometimes fatal autoimmune conditions, serious and life-threatening infusion reactions, serious and life-threatening stroke, and also noting alemtuzumab may cause an increased risk of malignancies including thyroid cancer, melanoma and lymphoproliferative disorders. Lemtrada is contraindicated in patients with human immunodeficiency virus (HIV) infection (Genzyme, 2022).
Lemtrada is only available through the Lemtrada REMS (Risk Evaluation and Mitigation Strategy) restricted distribution program (Genzyme, 2021). This program has been developed to ensure that access to Lemtrada is only through certified prescribers, healthcare facilities and specialty pharmacies and to also ensure that patients are enrolled in the REMS program. The program is intended to help educate healthcare providers and patients on the serious risks associated with alemtuzumab and the appropriate periodic monitoring required to support the detection of these risks for 48 months after the last infusion. The REMS is based on a developmental risk management program that was used in the Phase 2 and Phase 3 trials and allowed for early detection and management of some of the serious risks associated with alemtuzumab.
The most common adverse reactions (incidence ≥10% and > interferon beta-1a): rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting.
Mitoxantrone
U.S. Food and Drug Administration (FDA)-Approved Indications
-
Mitoxantrone is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). Mitoxantrone is not indicated in the treatment of patients with primary progressive multiple sclerosis.
The clinical patterns of multiple sclerosis in the studies were characterized as follows: secondary progressive and progressive relapsing disease were characterized by gradual increasing disability with or without superimposed clinical relapses, and worsening relapsing-remitting disease was characterized by clinical relapses resulting in a step-wise worsening of disability.
- Mitoxantrone in combination with corticosteroids is indicated as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer.
- Mitoxantrone in combination with other approved drug(s) is indicated in the initial therapy of acute nonlymphocytic leukemia (ANLL) in adults. This category includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias.
Mitoxantrone is available as generic formulation for intravenous infusion. Mitoxantrone acts in MS by suppressing the activity of T cells, B cells, and macrophages that are thought to lead the attack on the myelin sheath. Mitoxantrone has been approved by the FDA for treatment of both the relapsing-remitting and chronic progressive forms of MS. Because of the potential for functional cardiac changes, the product labeling for mitoxantrone carries a black box warning for cardiotoxicity in which persons receiving mitoxantrone should have cardiac monitoring.
The labeling for mitoxantrone injection includes the following recommendations for patients with MS:
- MS patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone.
- MS patients should be assessed for cardiac signs and symptoms by history, physical examination and ECG prior to each dose.
- MS patients should undergo quantitative reevaluation of LVEF prior to each dose using the same methodology that was used to assess baseline LVEF. Additional doses of mitoxantrone should not be administered to multiple sclerosis patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during mitoxantrone therapy.
- MS patients should not receive a cumulative mitoxantrone dose greater than 140 mg/m2.
- MS patients should undergo yearly quantitative LVEF evaluation after stopping mitoxantrone to monitor for late occurring cardiotoxicity.
Mitoxantrone Injection, USP (concentrate) should be given slowly into a freely flowing intravenous infusion. It must never be given subcutaneously, intramuscularly, or intra-arterially. Severe local tissue damage may occur if there is extravasation during administration. Mitoxantrone should not be administered via intrathecal use. Severe injury with permanent sequelae can result from intrathecal administration (Hospira, 2020).
The use of multiple sclerosis drugs in combination has been an active area of research. The primary rationale for polytherapy in multiple sclerosis is that the involved treatments target different mechanisms of the disease and therefore their use is not necessarily exclusive. Synergies, in which one drug potentiates the effect of another are also possible, but there can also be important drawbacks such as antagonizing mechanisms of action or potentiation of deleterious secondary effects. There have been several clinical trials of combined therapy, yet none has shown positive enough effects to merit the consideration as a viable treatment for multiple sclerosis (Milo & Panitch, 2011).
Natalizumab
See CPB 0751 - Natalizumab (Tysabri) or CPB 0751m - Natalizumab (Tysabri) [Medicare].
Ocrelizumab
U.S. Food and Drug Administration (FDA)-Approved Indications
- ocrelizumab (Ocrevus) is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
- ocrelizumab (Ocrevus) is indicated for the treatment of primary progressive MS, in adults.
Ocrelizumab is available as Ocrevus (Genentech, Inc.). Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells, which are thought to be a key contributors to myelin (nerve cell insulation and support) and axonal (nerve cell) damage. This nerve cell damage can lead to disability in people with multiple sclerosis. Based on preclinical studies, ocrelizumab binds to CD20 cell surface proteins expressed on certain B cells, but not on stem cells or plasma cells, and therefore important functions of the immune system may be preserved.
In 2017, Ocrevus was FDA approved for relapsing or primary progressive forms of multiple sclerosis. The label was subsequently updated to include the treatment of clinically isolated syndrome (CIS) of MS in adults. Per the label, relapsing forms of MS include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
In two identical RMS Phase III studies (OPERA I and OPERA II), ocrelizumab demonstrated superior efficacy on the three major markers of disease activity by reducing relapses per year, slowing the worsening of disability and significantly reducing MRI lesions compared with high-dose interferon beta-1a (Rebif) over the two-year controlled treatment period. Hauser, et al. (2017) examined the effectiveness of ocrelizumab compared to interferon beta-1a in persons with relapsing multiple sclerosis. In two identical phase 3 trials, investigators randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. Key eligibility criteria included an age of 18 to 55 years; a diagnosis of multiple sclerosis (according to the 2010 revised McDonald criteria); an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 at screening (scores range from 0 to 10.0, with higher scores indicating a greater degree of disability); at least two documented clinical relapses within the previous 2 years or one clinical relapse within the year before screening; magneticresonance imaging (MRI) of the brain showing abnormalities consistent with multiple sclerosis; and no neurologic worsening for at least 30 days before both screening and baseline (day 1 trial visit). The key exclusion criteria were a diagnosis of primary progressive multiple sclerosis, previous treatment with any B-cell–targeted therapy or other immunosuppressive medication, and a disease duration of more than 10 years in combination with an EDSS score of 2.0 or less at screening. The primary end point was the annualized relapse rate. The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs.0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. The authors concluded that, among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. The investigators stated that larger and longer studies of the safety of ocrelizumab are required.
Commenting on the studies by Hauser, et al., Naismith (2017) stated: "Early safety appears favorable, but long-term studies and postmarketing surveillance are necessary. Pending FDA approval, this appears to be a promising option for patients needing to switch treatment owing to disease activity and for patients presenting with more concerning prognostic features."
In a separate PPMS Phase III study (ORATORIO), ocrelizumab slowed disability progression and reduced signs of disease activity in the brain (MRI lesions) compared with placebo with a median follow-up of three years. Montalban, et al. (2017) studied ocrelizumab,in the primary progressive form of the multiple sclerosis. In a phase 3 trial, investigators randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. Key eligibility criteria were an age of 18 to 55 years, a diagnosis of primary progressive multiple sclerosis (according to the 2005 revised McDonald criteria), a score on the Expanded Disability Status Scale (EDSS) of 3.0 to 6.5 at screening (range, 0 to 10.0, with higher scores indicating greater disability), a score on the pyramidal functions component of the Functional Systems Scale of at least 2 (range, 0 to 6, with higher scores indicating greater disability), a duration of multiple sclerosis symptoms of less than 15 years in patients with an EDSS score of more than 5.0 at screening or less than 10 years in patients with an EDSS score of 5.0 or less at screening, and a documented history or the presence at screening of an elevated IgG index or at least one IgG oligoclonal band detected in the cerebrospinal fluid. Key exclusion criteria were a history of relapsing–remitting, secondary progressive, or progressive relapsing multiple sclerosis; contraindications to magnetic resonance imaging (MRI); contraindications to or unacceptable side effects from oral or intravenous glucocorticoids; and previous treatment with B-cell–targeted therapies and other immunosuppressive medications, as defined in the protocol. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. The investigators concluded that, among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. The investigators stated that extended observation is required to determine the long-term safety and efficacy of ocrelizumab.
Commenting on the study by Montalban, et al., Naismith (2017) stated: "One third of patients still progressed while taking ocrelizumab, so clinicians should balance optimism with expectations when discussing this treatment with patients. Patients who are older than 55, wheelchair bound, and with disease duration >15 years were not studied; benefits in that population remain unknown. To assess the risk for neoplasms and infectious complications, long-term evaluation of data from clinical trial populations and postmarketing investigations will be needed. For patients with PPMS who fit study criteria, treatment at this time seems recommendable, pending FDA approval."
An accompanying editorial (Calabresi, 2017) noted that "Although ocrelizumab offers promise for patients with primary progressive multiple sclerosis, who are desperately in need of a therapy, side effects must also be considered. Agents that target the immune system often result in some degree of immune suppression, potentially rendering the host susceptible to infections and impaired immune surveillance of new cancer cells, which could increase the risk of neoplasms. Although the dreaded complication of other drugs for multiple sclerosis, infection with JC virus causing progressive multifocal leukoencephalopathy, has not been seen with B-cell depletion in multiple sclerosis to date, there does appear to be a higher-than-normal risk of herpes reactivation and of neoplasms, especially breast cancer. These side effects will need to be studied in future trials and in phase 4 monitoring in the community to understand the extent of the risk. Clinicians are urged to carefully consider which patients might benefit the most from ocrelizumab and to stay vigilant with regard to monitoring for side effects that could be managed effectively if detected early."
Ocrevus carries warnings and precautions for risk of infusion reactions, infections, reduction in immunoglobulins, and malignancies. In MS clinical trials, the incidence of infusion reactions in Ocrevus-treated patients [who received methylprednisolone (or an equivalent steroid) and possibly other pre-medication to reduce the risk of infusion reactions prior to each infusion] was 34 to 40%, with the highest incidence with the first infusion. There were no fatal infusion reactions, but 0.3% of Ocrevus-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization. In RMS trials, 58% of Ocrevus-treated patients experienced one or more infections compared to 52% of Rebif-treated patients. In the PPMS trial, 70% of Ocrevus-treated patients experienced one or more infections compared to 68% of patients on placebo. Ocrevus increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections. Ocrevus was not associated with an increased risk of serious infections in MS patients. Although no cases of PML were identified in Ocrevus clinical trials, JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). The pooled data of Ocrevus clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of immunoglobulin G (IgG<LLN) and increased rates of serious infections. An increased risk of malignancy with Ocrevus may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in Ocrevus-treated patients. Breast cancer occurred in 6 of 781 females treated with Ocrevus and none of 668 females treated with Rebif or placebo. Patients should follow standard breast cancer screening guidelines (Genentech, 2021).
The most common adverse reactions for RMS (incidence 10% or more and greater than Rebof) included upper respiratory tract infections and infusion reactions. For PPMS (incidence 10% or more and greater than placebo): included upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections. Ocrevus is contraindicated in active hepatitis B virus infection (Genentech, 2021).
Rituximab
See CPB 0314 - Rituximab or CPB 0314m - Rituximab [Medicare].
Plasma Exchange / Plasmapheresis
Therapeutic plasmapheresis (also known as platepheresis or plasma exchange) is performed to remove toxic elements from the bloodstream. An intravenous catheter (small tube) is placed into a vein and connected to a machine (cell separator) via plastic tubing. Blood is pumped through the tubing into the machine where it is separated into red blood cells, white blood cells and plasma. The plasma is then discarded while the other components are combined with a plasma substitute and reinfused into the individual.
Plasma exchange has some evidence for the treatment of various stages of MS. Laboratory abnormalities are suggestive that MS is an immune-mediated disease; this is the rational basis of offering plasma exchange. Specifically, it is hypothesized that humoral factors may be involved, as evidenced by the presence of anti-myelin antibodies and non-antibody demyelinating factors in the sera of patients with MS and the presence of circulating autoantibodies. The specific identity of these humoral factors has not yet been identified. Further evidence supporting the use of PE has been its success in other autoimmune diseases. However, available clinical studies, including randomized controlled clinical trials, have not proven that plasma exchange is effective for MS. A systematic review of the literature on plasma exchange for MS (Nicholas and Chataway, 2006) concluded that there is "insufficient evidence to assess plasma exchange in people with acute relapses of multiple sclerosis."
The Multiple Sklerose Therapie Konsensus Gruppe (2006) stated that the monoclonal antibodies provide considerable improvement of treatment for MS, but their use in basic therapy is restricted by their side effect profile. Thus, natalizumab is only approved for monotherapy after basic treatment has failed or for rapidly progressive relapsing-remitting MS. In contrast, long-term data on recombinant beta-interferons and glatiramer acetate (Copaxone) show that even after several years no unexpected side effects occur and that a prolonged therapeutic effect can be assumed which correlates with the dose or frequency of treatment. Recently IFN-beta1b (Betaferon) was approved for prophylactic treatment after the first attack (clinically isolated syndrome, CIS). During treatment with beta-interferons, neutralizing antibodies can emerge with possible loss of effectivity. In contrast, antibodies play no role in treatment with glatiramer acetate. During or after therapy with mitoxantrone, serious side effects (cardiomyopathy, acute myeloid leukemia) appeared in 0.2 to 0.4 % of cases. Plasmapheresis is limited to individual curative attempts in escalating therapy of a severe attack. According to the revised McDonald criteria, the diagnosis of MS can be made as early as the occurrence of the first attack.
Tackenberg et al (2007) stated that the natural course of MS is probably more favorable than previously assumed years ago. Since the introduction of interferons in Germany, the establishment and further development of new diagnostic criteria (McDonald criteria), the causal and symptomatic treatment possibilities and initiation of therapy early in the course of the disease have led to a considerable change in the treatment of MS. Attacks of MS are usually treated with the intravenous administration of high-dosed steroids. When the attack symptoms do not sufficiently subside, plasmapheresis can be considered. For long-term treatment of MS, beta interferon, glatirameracetate and natalizumab are available as basic causal therapy and natalizumab and mitoxantrone are available for escalation therapy. Frequently occurring spasticity, chronic fatigue syndrome, depression, cognitive disturbances, incontinence, pain, ataxia and sexual disorders must be treated symptomatically. Overall, the outpatient treatment of MS is complex and should be carried out with close co-operation between the family doctor, neurological practices and outpatient departments specialized in treating MS.
Oh et al (2008) noted that B-cells and humoral immunity have been implicated in the pathogenesis of MS. The most common pattern of demyelinating pathology in MS is associated with the deposition of antibodies and the activation of complement, as well as T-cells and macrophages. Plasmapheresis has been found to be an efficient therapeutic approach in patients with this type of pathological lesion.
Matsui (2008) noted that Japanese patients with relapsing-remitting MS (RRMS) consists of 2 groups. One is opticospinal form (OSMS), in which major neurological symptoms derive from optic neuritis and myelitis, and the other is conventional form (CMS) that shares similar genetical and clinical features with western type of MS. Patients with OSMS tend to experience disease relapses more frequently with the resultant severer neurological deficit than CMS ones. Both OSMS and CMS patients are treated with intravenous high-dose methylprednisolone in acute exacerbations, and plasmapheresis may be considered for those who do not respond to repeated intravenous steroids. For prevention of disease relapse, interferon-beta is effective; however, patients with long spinal cord lesion extending over 3 vertebral segments should be followed-up with caution, as this finding indicates a risk of treatment failure.
Ohji and Nomura (2008) discussed steroid pulse therapy and apheresis therapy indicated for the treatment of MS. In the basic treatment course for MS, steroid pulse therapy is a first-line treatment for RR-MS in the course of the exacerbation, and apheresis therapy is performed in refractory cases. Treatment strategies for chronic progressive MS are not to be established. Steroid pulse therapy has been established as a treatment for MS in the active phase through randomized controlled trials (RCT). Apheresis therapy includes plasmapheresis and cytapheresis, and plasmapheresis includes plasma exchange (PE) and immunoadsorption plasmapheresis (IAPP). Plasma exchange and IAPP are performed for MS treatment. The former has been established as a useful treatment for active phase MS. The efficacy of IAPP has been frequently reported, but no reports have been based on RCT.
Schroder et al (2009) stated that apheresis is a general term that describes removal of abnormal blood constituents by extracorporeal blood purification methods. To date, therapeutic PE is the most common apheresis procedure. Here, plasma is separated from corpuscular blood constituents and replaced with a substitution fluid. In contrast to immunoadsorption, PE is a non-specific treatment modality with elimination of the entire plasma. The therapeutic effect is based on the removal of circulating, pathogenic immune factors including autoantibodies. Currently, PE is used for treatment of several immune-mediated neurological disorders. While first experiences relate to acute life-threatening conditions, such as treatment of Guillain-Barré syndrome or myasthenic crisis, therapeutic success was also shown in chronic diseases where immunosuppressive therapy is often required for long-term management. Plasma exchange has been applied successfully in chronic inflammatory demyelinating polyneuropathy, paraproteinemic polyneuropathy, stiff person syndrome, and may also be tried in several diseases of paraneoplastic origin. In recent years, PE was also established as an escalation therapy for steroid-unresponsive relapses of MS, and thus has gained more widespread attention.
Olek (2009) stated that PE may be beneficial in patients with acute central nervous system (CNS) inflammatory demyelinating disease who do not respond to glucocorticoid therapy. In the only formally reported clinical trial, 22 patients with CNS demyelinating disease (12 with MS) were randomly assigned to either active PE or sham treatment, with a total of 7 treatments, given every 2 days over 14 days. Moderate or greater improvement in neurologic disability occurred during 8 of 19 (42 %) courses of active treatment compared with 1 of 17 (6 %) courses of sham treatment. Improvement occurred early in the course of treatment and was sustained on follow-up. However, 4 of the patients who responded to the active treatment experienced new attacks of demyelination during 6 months of follow-up. Given these data, the author suggested treatment with PE for patients with acute, severe neurologic deficits caused by MS who have a poor response to treatment with high-dose glucocorticoids.
In January 2011, the American Academy of Neurology (AAN) published a new guideline on PP in neurologic disorders (Cortese et al, 2011). It states that PP/PE can be used as second-line treatment of steroid-resistant exacerbations in relapsing forms of MS. Moreover, PP is established as ineffective and should not be offered for chronic or secondary progressive MS.
ACTH
An acute relapse of MS may require no treatment if it is mild or does not produce functional decline. However, relapses that cause significant disability are usually treated with a course of intravenous corticosteroids. Studies have shown that corticosteroids or ACTH decrease the length of a clinical relapse of MS, and some studies have shown that corticosteroids are superior to and have fewer side effects than ACTH. It is not unusual to see the onset of a major depressive episode coincident with the first relapse episode, in spite of appropriate patient education as to the nature of the illness and in spite of mild severity of symptoms. The response to steroids is often exhilarating (hypomanic, or even psychotic) followed by the return of severe depressive symptoms once the steroids are discontinued. It is not unusual, therefore, that these patients may require a psychological assessment early on if depressive symptoms persist.
Adrenocorticotropic hormone (ACTH) is secreted by the anterior pituitary and stimulates the adrenal cortex to secrete cortisol, aldosterone, and androgenic hormones. The anti-inflammatory, and possibly the inhibition of antibody production, appear to the effects most relevant to MS. The growth of the use of synthetic glucocorticoids arose from efforts to minimize the many undesirable side effects related to aldosterone and androgen stimulation. Therefore, the use of oral glucocorticoids and the intravenous use of high-dose methylprednisolone has largely supplanted ACTH treatment.
Ankle Foot Orthosis (AFOs)
In a cross-sectional study (n = 15), Sheffler and colleagues (2008) examined if an ankle foot orthosis (AFO) would improve gait velocity and tasks of functional ambulation in patients with MS. Subjects experienced dorsiflexion and eversion weakness, and had used a physician-prescribed AFO for more than 3 months. Ambulation was evaluated
- without an AFO and
- with an AFO.
Outcome measures were the Timed 25-Foot (T25-FW) Walk portion of the Multiple Sclerosis Functional Composite and the 5 trials (floor, carpet, up and go, obstacles, and stairs) of the Modified Emory Functional Ambulation Profile (mEFAP). The mean timed differences on the T25-FW and the 5 components of the mEFAP between the AFO versus no device trials were not statistically significant. The authors concluded that in MS subjects with dorsiflexion and eversion weakness, no statistically significant improvement was found performing timed tasks of functional ambulation with an AFO.
Apolipoprotein E Polymorphisms
Shi et al (2008) stated that while the role of apolipoprotein E (APOE) polymorphism has been well recognized in cognitive neurodegenerative disorders, its role in MS is less clear. Studies indicated that 40 % to 60 % of patients with MS have evidence of cognitive impairment. These researchers examined if there is an association between APOE epsilon 4 and cognitive deficits in MS. They performed a standardized battery of neuropsychological tests investigating the 4 cognitive domains commonly impaired in MS and assessed the association of the presence of APOE epsilon 4 with cognition in these patients. A strong association was found between the presence of APOE epsilon 4 and cognitive deficits in patients with MS, especially in the domains of learning and memory. This association was strongest in the youngest cohort (aged 31 to 40 years) of patients with MS. The authors concluded that APOE epsilon 4 is significantly associated with cognitive impairment in patients with MS. However, the modest effects do not justify APOE genotyping of patients with MS in clinical practice.
Guerrero et al (2008) evaluated if there is any correlation between APOE genotype and severity according to Multiple Sclerosis Severity Score (MSSS). This study included 82 patients with disease duration of at least 2 years. These investigators collected data concerning demographic and clinical variables including age of onset, disease duration, Expanded Disability Status Scale (EDSS) score and the total number of relapses. They determined the latency to EDSS scores of 4.0 and 6.0; calculated progression index (PI) and relapse rate (RR); and ascertained MSSS in the global MSSS table. The authors reported that 4 patients heterozygous for the E2 allele and 16 for the E4 allele. No patient was homozygous for E2 or E4. RR (p = 0.017 with 95 % CI] 0.005 to 0.57) and PI (p = 0.016 with 95 % CI: 0.004 to 0.38) were significantly lower in E4 carriers. Multiple Sclerosis Severity Score was not associated with carriership of E2 or E4. The authors concluded that these findings show no effect of the APOE genotype on the severity of MS measured by MSSS, as a recently published meta-analysis has noticed. Thus, the data do not support a role for APOE in MS severity.
Azathioprine (Imuran)
IBM Micromedex, Clinical Pharmacology and Lexicomp compendia do not provide recommendations for use of azathioprine injection for multiple sclerosis.
Biomarker of Responsiveness to Interferon-Beta
Lopez-Gomez et al (2016) evaluated the effects of interferon-beta (IFNβ) treatment on the expression of the splice variants of the Tumor necrosis factor-Related Apoptosis Inducing Ligand (TRAIL) and its receptors in different cell subpopulations (CD14+, CD4+ and CD8+) from patients with MS, and examined if this expression discriminated responders from non-responders to IFNβ therapy. These researchers examined mRNA expression of the TRAIL and TRAIL receptors variants in patients with MS, at baseline and after 1 year of IFNβ therapy, according to responsiveness to this drug. Long-term therapy with IFNβ increased the expression of TRAIL-α in T cell subsets exclusively from responders and decreased the expression of the isoform 2 of TRAILR-2 in monocytes from responders as well as non-responders. Lower expression of TRAIL-alpha, and higher expression of TRAIL-beta in monocytes and T cells, was found before the onset of IFNβ therapy in patients who will subsequently become responders. Baseline expression of TRAILR-1 was also significantly higher in monocytes and CD4+ T cells from responders. The authors concluded that the findings of the present study showed that long-term IFNβ treatment had a direct influence on TRAIL-alpha and TRAILR-2 isoform 2 expression. Besides, receiver operating characteristic analysis revealed that the baseline expression of TRAIL-alpha in monocytes and T cells, and that of TRAILR-1 in monocytes and CD4+ T cells, showed a predictive value of the clinical response to IFNβ therapy, pointing to a role of TRAIL system in the mechanism of action of IFNβ in MS that will need further investigation.
Biomarker of Responsiveness to Natalizumab
Mattoscio and colleagues (2015) determined the mobilization from the bone marrow and the functional relevance of the increased number of circulating hematopoietic stem and progenitor cells (HSPC) induced by the anti-α-4 integrin antibody natalizumab in patients with MS. These researchers evaluated CD45(low)CD34+ HSPC frequency by flow cytometry in blood from 45 natalizumab-treated patients (12 of whom were prospectively followed during the 1st year of treatment as part of a pilot cohort and 16 prospectively followed for validation), 10 untreated patients with MS, and 24 healthy donors. In the natalizumab-treated group, these investigators also assessed sorted HSPC cell cycle status, T- and B-lymphocyte subpopulation frequencies (n = 29), and HSPC differentiation potential (n = 10). Natalizumab-induced circulating HSPC were predominantly quiescent, suggesting recent mobilization from the bone marrow, and were capable of differentiating ex-vivo. Circulating HSPC numbers were significantly increased during natalizumab, but heterogeneously, allowing the stratification of mobilizer and non-mobilizer subgroups. Non-mobilizer status was associated with persistence of disease activity during treatment. The frequency of B cells and CD103+CD8+ regulatory T cells persistently increased, more significantly in mobilizer patients, who also showed a specific naive/memory B-cell profile. The authors concluded that the findings of this study suggested that natalizumab-induced circulating HSPC increase is the result of true mobilization from the bone marrow and has clinical and immunologic relevance. They stated that HSPC mobilization, associated with clinical remission and increased proportion of circulating B and regulatory T cells, may contribute to the treatment's mode of action; thus, HSPC blood counts could represent an early biomarker of responsiveness to natalizumab.
Chronic Cerebrospinal Venous Insufficiency Treatment / Balloon Venoplasty
Chronic cerebrospinal venous insufficiency (CCSVI) has been suggested to be a possible cause of MS. If the presumed mechanism of venous stasis-related parenchymal iron deposition and neurodegeneration were true, then up-regulation of intra-thecal iron transport proteins may be expected. Worthington et al (2010) carried out a cross-sectional (n = 1,408) and longitudinal (n = 29) study on CSF ferritin levels in patients with MS and a range of neurological disorders. Pathologic (greater than 12 ng/ml) CSF ferritin levels were observed in 4 % of the control patients (median 4 ng/ml), 91 % of patients with superficial siderosis (75 ng/ml), 73 % of patients with a subarachnoid hemorrhage (59 ng/ml), 10 % of patients with relapsing-remitting MS (5 ng/ml), 11 % of patients with primary progressive MS (6 ng/ml), 23 % of patients with secondary progressive MS (5 ng/ml), and 23 % of patients with meningoencephalitis (5 ng/ml). In MS, there was no significant change of CSF ferritin levels over the 3-year follow-up period. The authors concluded that these findings do not support an etiologic role for CCSVI-related parenchymal iron deposition in MS.
Doepp et al (2011) stated that CCSVI was proposed as the causal trigger for developing MS. However, current data are contradictory and a gold standard for venous flow assessment is missing. These investigators compared structural magnetic resonance venography (MRV) and dynamic extracranial color-coded duplex sonography (ECCS) in a cohort of patients with MS. They enrolled 40 patients (44 +/- 10 years). All underwent contrast-enhanced MRV for assessment of internal jugular vein (IJV) and azygos vein (AV) narrowing, graded into 3 groups: 0 % to 50 %, 51 % to 80 %, and greater than 80 %. Extracranial color-coded duplex sonography (analysis of blood flow direction, cross-sectional area (CSA), and blood volume flow (BVF) in both IJV and vertebral veins (VV) occurred in the supine and upright body position. Magnetic resonance venography identified 1 AV narrowing. Internal jugular vein analysis yielded 12 patients for group 1 (30 %), 19 patients for group 2 (48 %), and 9 patients for group 3 (22 %). By ECCS criteria, 4 patients (10 %) presented with venous drainage abnormalities. Jugular BVF was different only between groups 1 and 3 (616 +/- 133 versus 381 +/- 213 ml/min, p = 0.02). No other parameters in supine position and none of the parameters in the upright body position, apart from the IJV-BVF decrease in groups 1 and 3 (479 +/- 172 versus 231 +/- 144 ml/min, p = 0.01), were different. The authors concluded that these ECCS data contradict the postulated 100 % prevalence of CCSVI criteria in MS. Magnetic resonance venography seems more sensitive to detect IJV narrowing compared to ECCS. A measurable hemodynamic effect only exists in vessel narrowings greater than 80 %. They stated that these combined data argue against a causal relationship of venous narrowing and MS, favoring the rejection of the CCSVI hypothesis and underline the plea to all clinicians to omit any intervention to remove "stenosis" by dilatation or stent implantation.
Zecca and Gobbi (2011) stated that the so called "CCSVI theory" has recently emerged, supporting the concept of cerebrospinal venous drainage impairment as the cause of MS. Since the first publication on this topic with a claimed 100 % specificity and sensitivity of the condition for MS diagnosis, CCSVI theory has generated a scientific and mass media debate with a great hope for the miracle of a new possible endovascular treatment of MS ("liberation procedure"). These investigators critically summarized the available evidence on CCSVI discussing inconsistent and incomplete replication of the original results by different groups, methodological limits and potential therapeutic implications. The authors concluded that the available data are insufficient to establish conclusively a clear relationship between MS and CCSVI and do not support the role of CCSVI as the primary cause of MS. They stated that until credible scientific evidence replicates the original results, any proposed invasive treatments of CCSVI should be discouraged.
The Canadian Agency for Drugs and Technologies in Health's update on the "Investigation of Chronic Cerebrospinal Venous Insufficiency for the Treatment of Multiple Sclerosis" (CADTH, 2012) states that "[i]t is not yet established whether chronic cerebrospinal venous insufficiency (CCSVI) contributes to MS disease activity, and there have been conflicting data as to the frequency of this condition in people with MS. Recent results from a large clinical trial suggest that CCSVI may be the result of the disease rather than a cause. It is hoped that findings from ongoing studies will provide clarity regarding the need for pan-Canadian therapeutic clinical trials".
Endovascular procedures such as angioplasty with or without stenting has been studied for the treatment of patients with MS. Kostecki et al (2011) prospectively evaluated the mid-term results (6 month follow-up) of the endovascular treatment in patients with CCSVI and MS. A total of 36 patients with confirmed MS and CCSVI underwent endovascular treatment by the means of the uni- or bi-lateral jugular vein angioplasty with optional stent placement. All the patients completed 6 month follow-up. Their MS-related disability status and quality of life were evaluated 1, 3 and 6 months post-operatively by means of the following scales: Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale (MSIS-29), Epworth Sleepiness Scale (ESS), Heat Intolerance scale (HIS) and Fatigue Severity Scale (FSS). For patency and re-stenosis rate assessment, the control ultrasound (US) duplex Doppler examination was used. Six months after the procedure, re-stenosis in post-percutaneous transluminal angioplasty (PTA) jugular veins was found in 33 % of cases. Among 17 patients who underwent stent implantation into the jugular vein, re-stenosis or partial in-stent thrombosis was identified in 55 % of the cases. At the 6 month follow-up appointment, there was no significant improvement in the EDSS or the ESS. The endovascular treatment of the CCSVI improved the quality of life according to the MSIS-29 scale but only up to 3 months after the procedure (with no differences in the 6 month follow-up assessment). Six months after the jugular vein angioplasty (with or without stent placement), a statistically significant improvement was observed only in the FSS and the HIS. The authors concluded that endovascular treatment in patients with MS and concomitant CCSVI did not have an influence on the patient's neurological condition; however, in the mid-term follow-up, an improvement in some quality-of-life parameters was observed.
Kipshidze et al (2011) noted that in recent observational studies performed on patients from distinctive gene pools, the prevalence of CCSVI in MS ranged from 56 % to 100 %. Endovascular treatment (PTA) with or without stenting of CCSVI was reported to be feasible with a minor complication rate. In 4 patients with different forms of MS, venography was performed that revealed stenosis of the proximal region of the jugular vein (right or left). Percutaneous transluminal balloon angioplasty was performed in all patients. There were no complications and mean stenosis was reduced after PTA from 59.75 % to 36.75 %. Follow-up included clinical observations and MRI. In all the cases these researchers observed positive remission of the disease, the first ever documented case of MRI index improvement. PTA seems to be an effective treatment for patients with CCVI and MS. The authors concluded that randomized studies are needed to establish the effectiveness of this new treatment for MS.
A position statement by the Society of Interventional Radiology, endorsed by the Canadian Interventional Radiology Association (Vedantham et al, 2010) considered the published literature to be inconclusive on whether CCSVI is a clinically important factor in the development and/or progression of MS, and on whether balloon angioplasty and/or stent placement are clinically effective in patients with MS.
The Ontario Health Technology Advisory Committee (2010) stated that "OHTAC has undertaken a preliminary evidence review of the safety and effectiveness of endovascular treatments for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis and is unable to make any recommendation at this time due to the paucity of available evidence. OHTAC regards this treatment as experimental at this time".
The National Institute for Health and Clinical Excellence (2012) has concluded: "Current evidence on the efficacy of percutaneous venoplasty for chronic cerebrospinal venous insufficiency (CCSVI) for multiple sclerosis (MS) is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research."
Reekers et al (2011) stated that "many interventional radiologists, who are directly approached by MS patients, contact the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) for advice. Worldwide, several centers are actively promoting and performing balloon dilatation, with or without stenting, for CCSVI. Thus far, no trial data are available, and there is currently no randomized controlled trial (RCT) in progress. Therefore, the basis for this new treatment rests on anecdotal evidence and successful testimonies by patients on the Internet. CIRSE believes that this is not a sound basis on which to offer a new treatment, which could have possible procedure-related complications, to an often desperate patient population".
In a pilot, case-control study, Zamboni et al (2012) examined if PTA of duplex-detected lesions, of the internal jugular and/or azygous veins, was safe, burdened by a significant re-stenosis rate, and whether there was any evidence that treatment reduced MS disease activity. These researchers studied 15 patients with relapsing-remitting MS and duplex-detected CCSVI. Eight patients had PTA in addition to medical therapy (immediate treatment group (ITG)), whereas 7 had treatment with PTA after 6 months of medical therapy alone (delayed treatment group (DTG)). No adverse events occurred. At 1 year, there was a re-stenosis rate of 27 %. Overall, PTA was followed by a significant improvement in functional score compared with baseline (p < 0.02). The annualized relapse rate was 0.12 % in the ITG compared with 0.66 % in the DTG (p = NS). Magnetic resonance imaging blindly demonstrates a trend for fewer T2 lesions in the ITG (p = 0.081), corresponding to a 10 % decrease in the ITG compared with a 23 % increase in the DTG over the first 6 months of the study. The authors concluded that the findings of this study further confirmed the safety of PTA treatment in patients with CCSVI associated with MS. They stated that the results, despite the significant rate of re-stenosis, are encouraging and warrant a larger multi-center double-blinded, randomized study.
Siddiqui et al (2014) reported the results of the investigation of safety and effectiveness of venous angioplasty in patients with MS with findings of extra-cranial venous anomalies, considered hallmarks of CCSVI, in a 2-phase study. Phase 1 was an open-label safety study (10 patients); phase 2 was sham-controlled, randomized, and double-blind (10 sham procedure, 9 treated). All study patients fulfilled venous hemodynamic screening criteria indicative of CCSVI. Assessment was at 1, 3, and 6 months post-procedure with MRI, clinical, and hemodynamic outcomes. Primary end-points were safety at 24 hours and 1 month, venous outflow restoration greater than 75 % at 1 month, and effect of angioplasty on new lesion activity and relapse rate over 6 months. Secondary end-points included changes in disability, brain volume, cognitive tests, and quality of life. No peri-operative complications were noted; however, 1 patient with history of syncope was diagnosed with episodic bradycardia requiring placement of a pacemaker before discharge. Doppler evidence-based venous hemodynamic insufficiency severity score (VHISS) was reduced greater than 75 % compared to baseline in phase 1 (at 1 month) but not phase 2. In phase 2, higher MRI activity (cumulative number of new contrast-enhancing lesions [19 versus 3, p = 0.062] and new T2 lesions [17 versus 3, p = 0.066]) and relapse activity (4 versus 1, p = 0.389) were identified as non-significant trends in the treated versus sham arm over 6 months. Using analysis of co-variance, significant cumulative new T2 lesions were related to larger VHISS decrease (p = 0.028) and angioplasty (p = 0.01) over the follow-up. No differences in other end-points were detected. The authors concluded that venous angioplasty is not an effective treatment for MS over the short-term and may exacerbate underlying disease activity. This is a Class I study demonstrating that clinical and imaging outcomes are no better or worse in patients with MS identified with venous outflow restriction who receive venous angioplasty compared to sham controls who do not receive angioplasty.
In an editorial that accompanied the aforementioned study, Bourdette and Cohen (2014) stated that “Clinical trials of venous angioplasty for MS are placing participants at risk of complications without a reasonable hope of benefit”.
On May 10, 2012, the FDA issued an alert on potential dangers of an experimental procedure sometimes called “liberation therapy” or the “liberation procedure” to treat CCSVI. The alert noted that some researchers believe that CCSVI, which is characterized by a narrowing (stenosis) of veins in the neck and chest, may cause MS or may contribute to the progression of the disease by impairing blood drainage from the brain and upper spinal cord. However, studies exploring a link between MS and CCSVI are inconclusive, and the criteria used to diagnose CCSVI have not been adequately established. The experimental procedure uses balloon angioplasty devices or stents to widen narrowed veins in the chest and neck. However, the FDA has learned of death, stroke, detachment and migration of the stents, damage to the treated vein, blood clots, cranial nerve damage and abdominal bleeding associated with the experimental procedure. Balloon angioplasty devices and stents have not been approved by the FDA for use in treating CCSVI. The FDA also is notifying physicians and clinical investigators who are planning or conducting clinical trials using medical devices to treat CCSVI that they must comply with FDA regulations for investigational devices. Any procedures conducted are considered significant risk clinical studies and require FDA approval, called an investigational device exemption. In February 2012, the FDA sent a warning letter to an investigator who was conducting a clinical study of CCSVI treatment without the necessary approval. The investigator voluntarily closed the study. The FDA stated that it will continue to monitor reports of adverse events associated with “liberation therapy” or the “liberation procedure” and keep the public informed as new safety information becomes available.
In a Cochrane review, van Zuuren et al (2012) evaluated the effects of percutaneous transluminal angioplasty for the treatment of CCSVI in people with MS. These investigators searched the following databases up to June 2012: The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialized Register, CENTRAL in The Cochrane Library 2012, Issue 5, MEDLINE (from 1946), EMBASE (from 1974), and reference lists of articles. They also searched several online trials registries for ongoing trials; RCTs assessing the effects of percutaneous transluminal angioplasty in adults with MS that have been diagnosed to have CCSVI were selected for analysis. The searches retrieved 159 references, 6 of which were to ongoing trials. Based on assessment of the title or abstract, or both, the authors excluded all of the studies, with the exception of 1 that was evaluated following examination of the full text report. However, this study also did not meet the inclusion criteria and was subsequently excluded. No RCTs met the inclusion criteria. The authors concluded that there is currently no high-level evidence to support or refute the safety or effectiveness of percutaneous transluminal angioplasty for treatment of CCSVI in people with MS. They stated that clinical practice should be guided by evidence supported by well-designed RCTs: closure of some of the gaps in the evidence may be feasible at the time of completion of the 6 ongoing clinical trials.
In a randomized, double-blind, sham-controlled, phase-II clinical trial, Traboulsee and colleagues (2018) determined the safety and efficacy of balloon versus sham venoplasty of narrowing of the extra-cranial jugular and azygos veins in MS. Patients with relapsing or progressive MS were screened using clinical and US criteria. After confirmation of greater than 50 % narrowing by venography, participants were randomized 1:1 to receive balloon or sham venoplasty of all stenoses and were followed for 48 weeks. Participants and research staff were blinded to intervention allocation. The primary safety outcome was the number of adverse events (AEs) during 48 weeks. The primary efficacy outcome was the change from baseline to week 48 in the patient-reported outcome MS Quality of Life–54 (MSQOL-54) questionnaire. Standardized clinical and MRI outcomes were also evaluated. A total of 104 subjects were randomized (55 sham; 49 venoplasty) and 103 completed 48 weeks of follow-up; 23 sham and 21 venoplasty participants reported at least 1 AE; 1 sham (2 %) and 5 (10 %) venoplasty participants had a serious AE. The mean improvement in MSQOL-54 physical score was +1.3 (sham) and +1.4 (venoplasty) (p = 0.95); MSQOL-54 mental score was +1.2 (sham) and −0.8 (venoplasty) (p = 0.55). The authors concluded that these findings did not support the continued use of venoplasty of extra-cranial jugular and/or azygous venous narrowing to improve patient-reported outcomes, chronic MS symptoms, or the disease course of MS.
In an editorial that accompanied the afore-mentioned study, Friedemann and Wattjes (2018) stated that “This study is another and hopefully the final milestone of evidence that the CCSVI theory in MS is flat wrong in terms of disease pathophysiology and for therapeutic interventions. Given the high requirements for MS therapeutics to be approved by regulatory authorities and the broad spectrum of available MS drugs with Class I evidence in terms of efficacy, treatment strategies related to the CCSVI concept should be absolutely disregarded. After the aforementioned first Canadian multicenter, case-control study published in 2013, we thought that this was the “final curtain”. Obviously, the Canadian study group has now given us a valuable encore presentation. However, there ought not to be further shouts of “encore”. We do not need more data on this wrong and misleading CCSVI concept. There are other much more relevant and burning research questions that need our attention and allocation of resources and funding”.
Clemastine Fumarate for the Treatment of Chronic Demyelinating Injury in MS
In a randomized, controlled, double-blind, single-center, cross-over study, Green and colleagues (2017) examined the safety and efficacy of clemastine fumarate as a treatment for patients with MS. Patients with relapsing MS with chronic demyelinating optic neuropathy on stable immunomodulatory therapy were eligible for this study. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomization using a random number generator to receive either clemastine fumarate (5.36 mg orally twice-daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5.36 mg orally twice-daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. These researchers analyzed by intention-to-treat. Between January 1, 2014 and April 11, 2015, these researchers randomly assigned 50 patients to group 1 (n = 25) or group 2 (n = 25); all patients completed the study. The primary efficacy end-point was met with clemastine fumarate treatment, which reduced the latency delay by 1.7 ms/eye (95 % CI: 0.5 to 2.9; p = 0.0048) when analyzing the trial as a cross-over. Clemastine fumarate treatment was associated with fatigue, but no serious AEs were reported. The authors concluded that this was the first RCT to document efficacy of a re-myelinating drug for the treatment of chronic demyelinating injury in MS. They stated that these findings suggested that myelin repair can be achieved even following prolonged damage.
Cyclophosphamide
As a result of the current thoughts on the immunological pathogenesis of the disease, immunosuppressive and immunomodulating drugs remain the mainstay of treatment for progressive MS. These drugs are used to prevent relapses and progression, to provide symptomatic treatment of MS, and occasionally for acute flare-ups. There are no large controlled trials of the efficacy of this therapy on acute exacerbations. The immunosuppressive agents currently used are all controversial, with data published supporting and disproving their efficacy. These therapies for acute flare-ups should be reserved for debilitating exacerbations, as patients appear to become resistant to therapy and there is no evidence that the ultimate degree of recovery is altered. A Cochrane review (La Mantia et al, 2007) concluded that the overall effect of cyclophosphamide (administered as intensive schedule) in the treatment of progressive MS does not support its use in clinical practice.
IBM Micromedex, Clinical Pharmacology and Lexicomp compendia do not provide recommendations for use of cyclophosphamide injection for multiple sclerosis.
Dalfampridine
Ampyra (dalfampridine) is a 4‐aminopyridine that selectively blocks fast‐acting axonal potassium channels. When blocked, potassium is kept in the demyelinated axon which prolongs nerve action, not allowing it to dissipate, which in turn increases synaptic conduction and restores minimal neurologic function. Ampyra (dalfampridine) is the first orally administered medication filed for the treatment of underlying neurological deficits in patients with multiple sclerosis (MS). Studies suggest patients taking dalfampridine may experience an increase in ambulation and a decrease in self‐reported disability. Ampyra (dalfampridine) is indicated to improve walking in patients with multiple sclerosis. Ampyra (dalfampridine) is available as 10mg tablets. The recommended dose of Ampyra (dalfampridine) is one tablet taken twice daily.
Dalfampridine is the first agent to shown to improve the resultant motor function disability from MS and is used as an add‐on therapy to other immunomodulators.
The filed indication is to improve walking in patients with Multiple Sclerosis. The most common adverse effects consistent in all three trials were urinary tract infection, insomnia, dizziness, headache, asthenia, and back pain. These adverse events were described as mild‐to‐moderate, and appeared to be more severe as the doses were increased. A more serious adverse event to note occurred in two patients in the MS‐F202 trial and one patient in each of the other two phase III trials was seizures. In MS‐F202, both patients were critically ill and taking higher doses of the medications. Specialists note that seizures are commonly associated with multiple sclerosis and one of the seizures occurred in the placebo arm.
A REMS program is in place for dalfampridine and will consist of a communication strategy to pharmacists and providers regarding the risk of seizures and dalfampridine’ use in renally impaired patients. Acorda will submit REMS assessments to the FDA at 18 months, 3, years, and 7 years from the date of approval.
Ampyra (dalfampridine) will be distributed through a specialty pharmacy network.
Dalfampridine is available as Ampyra in 10 mg extended release tablets. The maximum recommended dose of Ampyra is 10 mg twice a day (approximately 12 hours apart), with or without food.
Ampyra (dalfampridine) is not recommended for patients with the following concomitant conditions: known hypersensitivity to or any of its components; pregnancy; nursing mothers; and pediatric Use.
Ampyra (dalfampridine) should be avoided in persons with a history of seizure disorder, and in moderate to severe renal impairment (CrCl<50ml/min).
Erythropoietin
Ehrenreich et al (2007) performed an investigator-driven, exploratory open label study (phase I/IIa) in patients with chronic progressive MS. Main study objectives were- evaluating safety of long-term high-dose intravenous recombinant human erythropoietin (rhEPO) treatment in MS, and
- collecting first evidence of potential efficacy on clinical outcome parameters.
A total of 8 MS patients: 5 randomly assigned to high-dose (48,000 IU), 3 to low-dose (8,000 IU) rhEPO treatment, and, as disease controls, 2 drug-naïve Parkinson patients (receiving 48,000 IU) were followed over up to 48 weeks: a 6-week lead-in phase, a 12-week treatment phase with weekly EPO, another 12-week treatment phase with bi-weekly EPO, and a 24-week post-treatment phase. Clinical and electrophysiological improvement of motor function, reflected by a reduction in expanded disability status scale, and of cognitive performance was found upon high-dose EPO treatment in MS patients, persisting for 3 to 6 months after cessation of EPO application. In contrast, low-dose EPO MS patients and drug-naïve Parkinson patients did not improve in any of the parameters tested. There were no adverse events, no safety concerns and a surprisingly low need of blood-lettings. The authors concluded that this first pilot study demonstrated the necessity and feasibility of controlled trials using high-dose rhEPO in chronic progressive MS.
Estrogen Receptor Beta Ligands
Itoh and colleagues (2017) stated that protective effects of pregnancy during MS have led to clinical trials of estriol, the pregnancy estrogen, in MS. Since estriol binds to estrogen receptor (ER) beta, ER beta ligand could represent a "next generation estriol" treatment since ER beta ligand treatment was protective in experimental autoimmune encephalomyelitis (EAE) in both sexes and across genetic backgrounds. Neuroprotection was shown in spinal cord, sparing myelin and axons, and in brain, sparing neurons and synapses. Longitudinal in-vivo MRIs showed decreased brain atrophy in cerebral cortex gray matter and cerebellum during EAE. The authors concluded that investigation of ER beta ligand as a neuro-protective treatment for MS is warranted.
Functional Electrical Stimulation (FES) Cycling
In a systematic review, Scally and associates (2019) examined the outcomes of pwMS with mobility impairment following functional electrical stimulation (FES) cycling intervention. These researchers carried out a systematic search of 4 electronic databases (Medline, Web of Science, CINAHL and PEDro) from their inception to January 8, 2019. Inclusion criteria were: human participants with definite diagnosis of MS, age of 18 years, and participants with mobility impairment (determined as an average participant EDSS of greater than or equal to 6.0). Initial searches found 1,163 studies. 9 of which met the full inclusion criteria: 5 pre-post studies with no control group, 2 RCTs, 1 retrospective study, and 1 case study; 2 studies had the same participant group and intervention but reported different outcomes. Outcome data were available for n = 76 unique participants, with n = 82 completing a FES cycling intervention. Of the n = 4 papers with clear drop-out rates, pooled drop-out rate was 25.81 %; 2 papers reported non-significant improvements in aerobic capacity following a FES cycling intervention. A total of 4 papers reported no change in lower limb strength and 2 papers reported significant reductions in spasticity post-training; 4 studies failed to provide information regarding AEs with the other studies reporting n = 10 AEs across 36 participants. The authors concluded that the findings of this study suggested that FES cycle training may reduce cardiovascular disease risk alongside trends for a reduction in spasticity post-training, however the low quality of the literature precluded any definitive conclusions.
Pilutti and Motl (2019) provided a summary of the current evidence for FES cycling as an exercise training modality in pwMS with respect to prescription, safety, tolerability, and acute and chronic effects. These investigators searched the literature for studies involving FES cycling exercise in persons with MS published in English up until July 2019. A total of 8 studies were retrieved: 2 studies examined acute effects, 2 studies examined chronic effects, and 4 studies reported on both acute and chronic effects of FES cycling exercise. The overall quality of the studies was low, with only 1, small, RCT. There is limited but promising evidence for the application of FES cycling exercise among persons with MS who have moderate-to-severe disability. Participants were capable of engaging in regular FES cycling exercise (approximately 30 mins, 2 to 3 times/week), with few, mild AEs experienced. The authors concluded that preliminary evidence from small, mostly uncontrolled trials supported the potential benefits of FES cycling on physiological fitness, walking mobility, and symptoms of fatigue and pain. Moreover, these researchers stated that high-quality RCTs of FES cycling exercise are needed for providing recommendations for integrating exercise training in the management of advanced MS.
In an assessor-blinded, pilot RCT, Pilutti and colleagues (2019) examined the efficacy of supervised FES cycling exercise in pwMS on secondary outcomes, including cognition, fatigue, pain, and health-related QOL. A total of 11 adult participants with MS were randomized to receive FES cycling exercise (n = 6) or passive leg cycling (n = 5) for 24 weeks. Cognitive processing speed was assessed using the Symbol Digit Modalities Test. Symptoms of fatigue and pain were assessed using the Fatigue Severity Scale, the Modified Fatigue Impact Scale, and the short-form McGill Pain Questionnaire. Physical and psychological health-related QOL were assessed using the 29-item MSIS. A total of 8 participants (4, FES; 4, passive leg cycling) completed the intervention and outcome assessments. The FES cycling exercise resulted in moderate-to-large improvements in cognitive processing speed (d = 0.53), fatigue severity (d = -0.92), fatigue impact (d = -0.45 to -0.68), and pain symptoms (d = -0.67). The effect of the intervention on cognitive performance resulted in a clinically meaningful change, based on established criteria. The authors concluded that FES cycling exercise might have beneficial effects on cognition and symptoms of fatigue and pain. Moreover, these researchers stated that larger RCTs are needed to confirm these preliminary findings and establish the potential of this rehabilitation approach for PwMS with higher disability levels. They noted that considering the limited evidence for exercise interventions overall, and FES cycling specifically, in PwMS with higher disability levels, the findings of this pilot study were novel and promising.
The authors stated that the findings of this study were limited by its small sample size (n = 5 for FES cycling) and the EDSS score range of the participants included in this trial, which may limit the generalizability of the findings. The outcomes reported were not the primary outcomes of the trial, and thus, subjects were not selected for inclusion based on criteria related to these measures; however, scores on some of the outcomes reflected an elevated symptomology based on criterion values (e.g., FSS score greater than or equal to 4.0 indicates severe fatigue). These investigators noted that participatory outcomes in this trial were limited to health-related QOL measures. They stated that future studies should examine other participatory measures, such as employment, recreation and leisure, and activities of daily living (ADL). The intervention was delivered in a supervised laboratory environment, and it was unclear whether similar results would be obtained in other clinical, community, or home-based settings. It will be important to examine the feasibility and efficacy of FES cycling for PwMS in other environments to determine the potential of FES cycling exercise as an advanced rehabilitation approach. They further highlighted the importance of examining the timeline of adaptations and the potential for lasting effects of FES cycling exercise, especially in this population.
gMS®Pro EDSS Test
The gMS®Pro EDSS Test is a panel of biomarkers specific to identifying patients who will progress towards higher EDSS scores despite treatment. It was developed to help physicians identify which patients with clinically isolated syndrome (CIS) or newly diagnosed MS will have a higher likelihood of progressing towards meaningful disabilities despite treatment. Physicians may want to consider more aggressive treatment for these patients. In addition, the gMS®Pro EDSS test is targeted for use for diagnosed MS patients and potential MS patients who have had their first neurological event and will be starting therapeutic treatment for MS. However, there is a lack of evidence regtarding the clinical value of this test.
Hyperbaric Oxygen
Hyperbaric oxygen (HBO) therapy has not been shown to be effective in the treatment of MS. Hyperbaric oxygen therapy, the intermittent inhalation of 100 % oxygen under a pressure greater than 1 atmospheres pressure (atm), is one of many unconventional treatments tried as a possible treatment for MS. It can be administered in either a mono-place or multi-place chamber. The latter accommodates 2 to 14 people and can achieve pressures up to 6 atm. Patients breath 100 % oxygen through a face mask, head hood, or endotracheal tube and can be cared for by medical personnel directly within the chamber. Monoplace chambers treat a single patient in an environment maintained at 100 % oxygen, thus, no mask is required. Possible complications of HBO therapy include barotrauma (ear or sinus trauma, tympanic membrane rupture, pneumothorax, air embolism), oxygen toxicity (central nervous system or pulmonary), fire, reversible visual changes and claustrophobia. Although early uncontrolled clinical trials and anecdotal reports suggested that HBO may be beneficial in the management of MS, more recent controlled studies with larger sample sizes indicate that this modality is not effective in the treatment of this central nervous system disease.
Interleukin-1
Huang et al (2013) stated that dysregulated levels of interleukin-1 (IL-1) were observed in patients with MS. Previous studies have provided conflicting evidence implicating the IL-1 gene polymorphisms in MS risk. These investigators performed a meta-analysis of 16 case-control studies involving 3,482 cases and 3,528 controls to evaluate this association. No association was found between the IL-1α -889 (rs1800587), IL-1α +4,845 (rs17561), IL-1β -511 (rs16944), IL-1β +3,953 (rs1143634), IL-1ra variable number tandem repeat (VNTR) polymorphisms and MS risk. However, in subgroup analyses for the IL-1ra VNTR polymorphism, these researchers found that individuals carrying the 2 allele had a 32 % increased risk for bout-onset MS (relapsing remitting and secondary progressive MS) when compared to the LL homozygotes (OR = 1.32, 95 % CI: 1.06 to 1.66, p (z) = 0.014). The authors concluded that common variants in the IL-1 region are not associated with MS risk but these findings suggested that the IL-1ra VNTR polymorphism might be associated with bout-onset MS subtype.
Interleukin-10 / Interleukin-16
Kinzel and Weber (2016) stated that over the past 10 years, evidence condensed that B cells, B cell-derived plasma cells and antibodies play an important role in the pathogenesis and progression of MS. In many patients with MS, peripheral B cells show signs of chronic activation; within the CSF clonally expanded plasma cells produce oligoclonal immunoglobulins, which remain a hallmark diagnostic finding. Confirming the clinical relevance of these immunological alterations, recent trials testing anti-CD20-mediated depletion of peripheral B cells showed an instantaneous halt in development of new CNS lesions and occurrence of relapses. Notwithstanding this enormous success, not all B cells or B cell subsets may contribute in a pathogenic manner, and may, in contrast, exert anti-inflammatory and, thus, therapeutically desirable properties in MS. Naive B cells, in MS patients similar to healthy controls, are a relevant source of regulatory cytokines such as interleukin-10, which dampens the activity of other immune cells and promotes recovery from acute disease flares in experimental MS models. These investigators described in detail pathogenic but also regulatory properties of B and plasma cells in the context of MS and its animal model experimental autoimmune encephalomyelitis. In addition, these researchers reviewed what impact current and future therapies may have on these B cell properties; and focused on the highly encouraging data on anti-CD20 antibodies as future therapy for MS. The author also discussed how B cell-directed therapy in MS could be possibly advanced even further in regard to safety and effectiveness by integrating the emerging information on B cell regulation in MS into future therapeutic strategies.
Skundric (2018) re-evaluated fundamental approaches of current MS therapies with focus being placed on their targeted underlying immune, molecular and cellular mechanisms. Currently used therapies were discussed in regard to their mechanisms of action, clinical accomplishments and unwanted AEs and complications. Special emphasis was given to current disease modifying therapies (DMT) and their actions at immune mechanisms of disease. Effects on DMT on CD4+Th1 cells and related cytokine and signaling pathways were discussed in more detail. Attention was paid to emerging role of a cytokine IL-16 in regulation of relapsing MS and its model, EAE. Immune mechanisms mediated by IL-16 were critically evaluated in the context of mechanisms of DMT and its potential as prospective MS therapy.
Intravesical Vanilloids for the Treatment of Neurogenic Lower Urinary Tract Dysfunction in Multiple Sclerosis
On behalf of the Neuro-Urology Promotion Committee of the ICS, Phe and associates (2018) evaluated available evidence on the safety and efficacy of vanilloids for the treatment of neurogenic lower urinary tract dysfunction (NLUTD) in patients with MS. This systematic review and meta-analysis was performed according to the PRISMA statement. Studies were identified by electronic search of Cochrane register, Embase, Medline, Scopus, (last search January 8, 2016). After screening a total of 7,848 abstracts, 4 RCTs and 3 prospective cohort studies were included. Pooled data from 3 RCTs evaluating intravesical capsaicin showed the standardized mean difference (SMD) to be -2.16 (95 % CI: -2.87 to -1.45) in incontinence episodes/24 hours and -0.54 (95 % CI: -1.03 to -0.05) in voids/24 hours. There was no statistically significant effect on maximum cystometric capacity and maximum storage detrusor pressure. Overall, AEs were reported by greater than 50 % of the patients, most commonly were pelvic pain, facial flush, worsening of incontinence, autonomic dysreflexia, urinary tract infection and hematuria. Risk of bias and confounding was relevant in both RCTs and non-RCTs. The authors concluded that preliminary data suggested that intravesical vanilloids might be effective for treating NLUTD in patients with MS. However, the safety profile appeared unfavorable, the overall quality of evidence was low and no licensed substance is currently available. These researchers stated that well-designed, adequately sampled and properly powered RCTs are needed to further investigate the safety and effectiveness of intravesical vanilloids for the treatment of NLUTD in patients with MS.
IVIG
See CPB 0206 - Parenteral Immunoglobulins or CPB 0206m - Parenteral Immunoglobulins [Medicare].
Medicinal Cannabinoids for the Treatment of Pain, Spasticity and Bladder Dysfunction in Multiple Sclerosis
Torres-Moreno and colleagues (2018) noted that cannabinoids have anti-spastic and analgesic effects; however, their role in the treatment of MS symptoms is not well-defined. These investigators carried out a systematic review and meta-analysis to examine the efficacy and tolerability of medicinal cannabinoids compared with placebo in the symptomatic treatment of patients with MS. Data sources included Medline and the Cochrane Library Plus up to July 26, 2016; no restrictions were applied. The search was completed with information from ClinicalTrials.gov. Randomized, double-blind, and placebo-controlled trials evaluating the effect of medicinal cannabinoids by oral or oro-mucosal route of administration on the symptoms of pain, spasticity, or bladder dysfunction in adult patients with MS were selected for analysis. The PRISMA reporting guidelines were followed. Effect sizes were calculated as SMD for efficacy, and rate ratio for tolerability. Within each study, those SMDs evaluating the same outcome were combined before the meta-analysis to obtain a single value per outcome and study. Pooling of the studies was performed on an intention-to-treat (ITT) basis by means of random-effect meta-analysis. Main outcome measures were pain, spasticity (on the Ashworth and Modified Ashworth scales and subjective), bladder dysfunction, AEs and withdrawals due to AEs. A total of 17 selected trials including 3,161 patients were analyzed. Significant findings for the efficacy of cannabinoids versus placebo were SMD = -0.17 SD (95 % CI: -0.31 to -0.03 SD) for pain, -0.25 SD (95 % CI: -0.38 to -0.13 SD) for spasticity (subjective patient assessment data), and -0.11 SD (95 % CI: -0.22 to -0.0008 SD) for bladder dysfunction. Results favored cannabinoids. Findings for tolerability were rate ratio = 1.72 patient-years (95 % CI: 1.46 to 2.02 patient-years) in the total AEs analysis and 2.95 patient-years (95 % CI: 2.14 to 4.07 patient-years) in withdrawals due to AEs. Results described a higher risk for cannabinoids. The serious AEs meta-analysis showed no statistical significance. The authors concluded that the findings of this study suggested that cannabinoids produced a limited and mild reduction of pain, subjective spasticity, and bladder dysfunction in patients with MS, but no changes in objectively measured spasticity. They can be considered safe drugs, as the analysis of serious AEs did not show statistical significance, although the total number of AEs was higher than in placebo for the treatment of symptoms in patients with MS. Moreover, these researchers stated that shortcomings exist with respect to research into the efficacy of cannabinoids in the treatment of MS; the quantity of available studies is limited. There is no evidence of studies that examine the efficacy of cannabinoids versus other treatments in MS. They noted that research into the possible combinations of cannabinoids and other therapies might result in greater synergy benefits than in an individual form.
The authors stated that the drawbacks of this study entailed the small number of studies included; differences in the length of treatment, particularly in tolerability calculations; inclusion of cross-over studies as parallel design; calculations made on the basis of an ITT principle by data extrapolation, which may have provoked bias in the findings, although ITT analysis is the standard for medication evaluation; and publication bias. Another potential drawback was that blinding procedures could be affected in studies with drugs with such large difficulties in masking and blinding. Consequently, a large allocation-dependent placebo effect could be expected. This was particularly evident in the study with 2 phases in which the responders in the 1st phase were selected for the 2nd phase. In addition, most of the studies included were funded by the pharmaceutical industry, especially for nabiximols. As explained in the “Results” section, the exclusion of these studies had an impact on the results on subjective spasticity. In the interpretation of trends favoring experimental or control treatments, difficult decisions arose in some cases owing to the different forms of exposure across the studies.
Mesenchymal Stem Cell Therapy
In a systematic review, Oliveira and colleagues (2019) examined the safety, tolerability, and efficacy of mesenchymal stem cells (MSCs) therapies in the treatment of patients with MS; 3 electronic databases (Web of Science, PubMed, and Cochrane) were searched from April until June 2019. Clinical trials or case reports with information related to the effects of MSC therapies in MS patients were considered for this review. A total of 10 manuscripts were selected, namely 7 uncontrolled clinical trials, 2 RCTs, and 1 case report. The overall quality of the studies was considered good. Besides minor AEs, there were 1 case of encephalopathy with seizures and 2 cases of iatrogenic meningitis, which were not related to the treatment, but with the administration route. The analyses of the EDSS in the uncontrolled clinical trials showed that 48 patients improved, 39 maintained and 16 worsened their clinical condition. Regarding the randomized studies, 1 did not show statistically significant variations in the mean EDSS score and in the other the mean EDSS score was statistically significantly lower for the experimental group. The case report also showed an improvement in the EDSS score. The authors concluded that MSCs transplantation proved to be a safe and tolerable therapy. Their potential therapeutic benefits were also validated. Moreover, these researchers stated that larger placebo-controlled, blinded clinical trials are needed to determine the long-term safety and efficacy profile of these therapies for MS.
Mesenchymal Stromal Cell-Derived Neural Progenitors
Harris et al (2016) previously characterized the immuno-regulatory and trophic properties of neural progenitors derived from bone marrow mesenchymal stromal cells (MSC-NPs) and established that cells derived from MS and non-MS patients alike were therapeutically viable. In an experimental model of MS, intrathecal MSC-NP injection resulted in disease amelioration with decreased T-cell infiltration, and less severe lesion pathology associated with recruitment of resident progenitors to inflammatory sites. In a pilot feasibility study, these researchers examined safety and dosing of intrathecal MSC-NP therapy in 6 patients with MS. Patients with progressive MS and advanced disability who were refractory to all other conventional MS treatments were enrolled in the study. For each dose, MSC-NP cells were cultured from autologous MSCs and tested for quality control before intrathecal administration. Patients were evaluated for AEs and neurological status to assess safety of the treatment. Six patients with progressive MS were treated with between 2 and 5 intrathecal injections of escalating doses of autologous MSC-NPs and were followed-up for an average of 7.4 years after initial injection. There were no safety concerns noted, no serious AEs, and the multiple dosing regimen was well-tolerated; 4 of the 6 patients showed a measurable clinical improvement following MSC-NP treatment. The authors concluded that the findings of this pilot study supported preliminary first-in-human safety and tolerability of autologous MSC-NP treatment for MS. These preliminary findings need to be validated by well-designed studies.
MTHFR
There are inconsistent reports of an association between methylenetetrahydrofolate reductase (MTHFR) mutations and MS, but no established clinical utility of such testing. Currently, there are no studies demonstrating that manipulation of diet and vitamins in persons with this mutation can either prevent or delay progression of MS.
Alatab et al (2011) stated that both genetic and inflammatory factors are suspected in the etiology of MS. Of genetic factors, the MTHFR C677T polymorphism has been associated with increased levels of plasma homocysteine, a neuronal excitotoxic amino acid. Sclerotic patients also have elevated levels of plasma and CSF homocysteine. In this study, the association between C677T polymorphism and MS was tested by recruiting 230 healthy and 194 multiple sclerotic age- and gender-matched patients. The MTHFR C677T polymorphism and the serum levels of inflammatory mediators IL-1β, tumor necrosis factor- alpha (TNF-α), and C-reactive protein (CRP) were measured. The levels of TNFα, CRP, and IL-1β were significantly higher in sclerotic patients. T allele was 1.7 times more present in this group. In patient's group, the levels of all inflammatory mediators were higher in T/T compared to 2 other genotypes. Evaluation of the age of onset of disease revealed that subjects with T allele developed the MS disease, almost 4 years sooner than other genotype. The authors concluded that having T allele of C677T in MS might be accompanied with higher levels of serum inflammatory mediators and a vulnerability to earlier age of onset of disease. Moreover, they stated that further studies are needed to elucidate the underlying mechanisms.
Fekih Mrissa et al (2013) stated that MS is a chronic neurological disease characterized by CNS inflammation and demyelination of nerve axons. These researchers investigated a possible association between the methylenetetrahydrofolate reductase (MTHFR) gene and MS in Tunisian patients. The genotyping of 2 missense variants of the MTHFR gene, C677T and A1298C was performed in 80 MS patients and 200 healthy controls. No significant differences were found in the frequency of the MTHFR C677T polymorphism between MS patients and healthy controls. However, the genotype prevalence of the missense variant MTHFR A1298C was significantly different between patients and controls (A/C: 55 % versus 7 %, p<10(-3); C/C: 13.75 % versus 0 %, p < 10(-3), respectively). The authors concluded that although these preliminary findings suggested no association between the MTHFR C677T variants and MS, there is evidence to suggest a significant association between the MTHFR A1298C polymorphisms and MS.
Ineichen et al (2014) noted that MTHFR is necessary for the synthesis of methionine and S-adenosylmethionine, which is necessary for CNS (re-)myelination. The MTHFR variant c.1298A>C was associated with the development of RRMS in a German population. These researchers examined if further genetic variants of methionine metabolism are associated with the development or the clinical course of RRMS. Therefore, genomic DNA of 147 serial German RRMS patients and 147 matched healthy controls was genotyped for 5 polymorphic variants of methionine metabolism. Statistical analyses were performed using multi-variate binary and linear regression analyses. They showed that the insertion allele of cystathionine beta-synthase (CBS) c.844_855ins68bp and the G-allele of reduced folate carrier 1 (RFC1) c.80G>A were associated with an earlier age of onset of MS, suggesting gene-dose effects (median age of onset in years: 25-26-32; standardized regression coefficient beta: 0.216; p = 0.030, and 29-31-35 years; beta: 0.282; p = 0.005, respectively). The authors concluded that mutant variants of CBS and RFC1 may be associated with the age of RRMS onset. They stated that since methionine metabolism can be manipulated by supplementation of vitamins and amino acids, these data provided a rationale for novel ideas of preventive and therapeutic strategies in RRMS.
Furthermore, UpToDate reviews on “Diagnosis of multiple sclerosis in adults” (Olek, 2014a), “Clinical features of multiple sclerosis in adults” (Olek, 2014b), and “Treatment of relapsing-remitting multiple sclerosis in adults” (Olek, 2014 c), and “Pathogenesis and epidemiology of multiple sclerosis” (Olek, 2014 d) do not mention the use of MTHFR testing.
Myelin Basic Protein Peptides
Lomakin et al (2016) previously showed that immunodominant myelin basic protein (MBP) peptides encapsulated in mannosylated liposomes (Xemys) effectively suppressed EAE. Within the frames of the successfully completed phase I clinical trial, these researchers investigated changes in the serum cytokine profile after Xemys administration in MS patients. These investigators observed a statistically significant decrease of MCP-1/CCL2, MIP-1β/CCL4, IL-7, and IL-2 at the time of study completion. In contrast, the serum levels of TNF-α were remarkably elevated. The authors concluded that these data suggested that the administration of Xemys led to a normalization of cytokine status in MS patients to values commonly reported for healthy subjects; these data are an important contribution for the upcoming Xemys clinical trials.
Belogurov et al (2016) previously showed that CD206-targeted liposomal delivery of co-encapsulated immunodominant MBP sequences MBP46-62, MBP124-139 and MBP147-170 (Xemys) suppressed EAE in dark Agouti rats. These researcher evaluated the safety of Xemys in the treatment of patients with RRMS and SPMS, who failed to achieve a sustained response to first-line disease-modifying therapies. In a phase I, open-label, dose-escalating, proof-of-concept study, a total 20 patients with RRMS or SPMS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2.675 mg. Clinical examinations, including EDSS score, MRI results, and serum cytokine concentrations, were assessed before the first injection and for up to 17 weeks after the final injection; Xemys was safe and well-tolerated when administered for 6 weeks to a maximum single dose of 900 μg; EDSS scores and numbers of T2-weighted and new gadolinium-enhancing lesions on MRI were statistically unchanged at study exit compared with baseline; nonetheless, the increase of number of active gadolinium-enhancing lesions on weeks 7 and 10 in comparison with baseline was statistically significant. During treatment, the serum concentrations of the cytokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and IL-7 decreased, whereas the level of TNF-α increased. The authors concluded that these results provided evidence for the further development of Xemys as an antigen-specific, disease-modifying therapy for patients with MS.
Myxovirus Resistance Protein A
van der Voort and colleagues (2010) determined if myxovirus resistance protein A (MxA) mRNA is related to clinical disease activity in MS. Baseline MxA mRNA levels were measured in a prospective cohort of 116 untreated patients with early MS and were related to clinical relapses and MRI at baseline and at follow-up. Low levels of MxA mRNA were associated with the occurrence of relapses (p = 0.002) and contrast-enhancing lesions (CELs) on baseline MRI (p = 0.045). In addition, high baseline MxA mRNA levels were related to a longer time to a first new relapse (hazard ratio [HR]: 0.59; 95 % CI: 0.35 to 1.00; p = 0.044). Adding the absence of CELs to high MxA mRNA, the predictive value increased (HR: 0.35; 95 % CI: 0.17 to 0.74; p = 0.006), clearly showing a cumulative value for combining both factors. The authors concluded that MxA mRNA is related to clinical exacerbations, the number of CELs on MRI, and is indicative for the time to a subsequent relapse. They stated that if confirmed (by larger studies), MxA mRNA has potential as a biomarker for clinical disease activity in MS.
Neurofilament Heavy Chain Protein
Kuhle et al (2011) examined if CSF levels of neurofilament heavy chain protein (NfH(SMI35)) correlate with disability, disease activity, or specific stages of MS. An electrochemiluminescence immunoassay was used to retrospectively measure NfH(SMI35) in CSF of patients with clinically isolated syndrome (CIS) (n = 63), RRMS (n = 39), secondary progressive multiple sclerosis (SPMS) (n = 25), primary progressive multiple sclerosis (PPMS) (n = 23), or controls (n = 73). Cell count and CSF levels of immunoglobulin and albumin were also measured. CSF levels of NfH(SMI35) increased with age in controls (r(s) = 0.50, p < 0.0001) and CIS (r(s) = 0.50, p < 0.0001); this effect was less pronounced in RRMS (r(s) = 0.35, p = 0.027) and absent in SPMS/PPMS. After age correction, NfH(SMI35) levels were found to be higher in all disease stages compared to control. Relapses were associated with higher CSF NfH(SMI35) values compared with stable disease. NfH(SMI35) levels correlated with EDSS scores in patients with CIS and RRMS (r(s) = 0.33, p = 0.001), and during relapse (r(s) = 0.35, p = 0.01); the correlation was most prominent in RRMS during relapse (r(s) = 0.54, p = 0.01). This was not the case for any of the other CSF markers examined. The authors concluded that neuronal loss is a feature of aging, and the age-dependent increase of CSF NfH(SMI35) suggests that this loss accelerates over time. For MS, increased NfH(SMI35) levels reflect the super-imposed presence of further neurodegenerative processes. Evaluation of NfH(SMI35) levels is likely to provide a useful surrogate for measuring the rate of neurodegeneration in MS. Furthermore, the dissociation of NfH(SMI35) levels with biomarkers of inflammation suggests that the mechanisms responsible for their production are at least partly independent. One major drawback of this study was the use of EDSS to measure disability; it is imprecise and not a good overall measure of MS. More work is needed for CSF levels of neurofilament to become a useful biomarker for MS.
In an editorial that accompanied the afore-mentioned study, Giovannoni and Nath (2011) stated that "[e]levated CSF Nf is a simple indicator of axonal damage, and is predictive of severity and poor recovery from acute attacks and the development of long-term disability in patients with MS. We would encourage the MS community to take these observations on board and to insist on the inclusion of this valuable biomarker in all future clinical trials".
Neutralizing Antibodies Against Interferon Beta
Assays of neutralizing antibodies (NABs) against interferon beta (Betaseron) have not been proven to be useful in MS. About 1/3 of individuals develop NABs against interferon beta. A number of laboratories have developed assays for these NABs (e.g., MxA Assay (Berlex Laboratories), NabFeron (Athena Diagnostics)). However, according to the peer-reviewed medical literature, the clinical utility of these assays has not been established. Evidence-based guidelines on MS from the American Academy of Neurology (Goodin et al, 2002) state: "The rate of neutralizing antibody (NAb) production is probably less with IFN-1a treatment than with IFN-1b treatment, and the presence of NAb may be associated with a reduction in clinical effectiveness of IFN treatment. The existing data are, however, ambiguous in this regard, and the clinical utility of measuring NAb in an individual on IFN therapy is uncertain."
While the European Federation of Neurological Societies Task Force on anti-IFN-beta antibodies in multiple sclerosis (Sorensen et al, 2005) recommended that tests for the presence of NABs should be performed in all patients at 12 and 24 months of interferon beta therapy, the consensus statement from an international conference on the significance of NABs to interferon beta during treatment of MS (Hartung et al, 2005) stated that “an international standardized assay for NAb is needed; and all patients with MS who receive IFN-beta therapy should be evaluated for the presence of Nab. Moreover, guidelines on how to manage NAb-positive patients should be developed to optimize IFN-beta therapy; these treatment guidelines should be based on the results of well-controlled clinical studies …. An international standardized assay will facilitate direct comparison of NAb titers amongst studies and will provide further information regarding the immunogenicity of the various types of IFN-beta products and how NAb impact clinical efficacy".
Antonelli and colleagues (2005) stated that “[t]here is a lack of substantial information on the biological/immunological phenomenon of neutralising antibodies in vivo development. Nevertheless, sufficient experimental data are available to provide a rationale for monitoring the presence of anti-IFN antibodies in patients treated with IFN beta. A standardised quantitative assay to detect antibody to IFNs must be agreed. Only when results can be compared, both in terms of the qualitative presence and quantitative measurement of antibodies, will it be possible to monitor fully the ability of antibodies to cause a relapse during treatment. Although there is increasing evidence to indicate that the development of antibodies to IFN beta may be associated with a failure of the beneficial effects of the therapy, the use of the seropositivity for neutralising antibodies to IFN beta as the only surrogate marker for clinical and therapeutic decision-making is questionable”. Also, guidelines on MS from the Association of British Neurologists (2001) stated that monitoring neutralizing antibodies for beta interferon is not necessary.
Noronha (2007) noted that an effect on relapse rates and imaging parameters was noted in patients who tested positive for NAbs, but disability measures were unaffected or showed a trend toward improvement. Patients who developed NAbs during IFN-beta1a therapy tended to remain NAb+, whereas those who developed NAbs during IFN-beta1b therapy tended to revert to NAb- over time. The author stated that the prevalence of NAbs in suboptimal responders does not support a causal relationship of suboptimal responses to the development of NAbs. Thus, decisions to alter treatment should be rendered by clinicians based on the clinical state of the patient.
Non-Pharmacological Interventions for the Treatment of Chronic Pain in Multiple Sclerosis
Amatya and colleagues (2018) stated that chronic pain is common and significantly impacts on the lives of persons with MS (pwMS). Various types of non-pharmacological interventions are widely used, both in hospital and ambulatory/mobility settings to improve pain control in pwMS, but the safety and effectiveness of many non-pharmacological modalities is still unknown. In a Cochrane review, these investigators examined the safety and effectiveness of non-pharmacological therapies for the management of chronic pain in pwMS. Specific questions to be addressed by this review include the following: Are non-pharmacological interventions (uni-disciplinary and/or multi-disciplinary rehabilitation) effective in reducing chronic pain in pwMS? What type of non-pharmacological interventions (uni-disciplinary and/or multi-disciplinary rehabilitation) are effective (least and most effective) and in what setting, in reducing chronic pain in pwMS? A literature search was performed using the specialized register of the Cochrane MS and Rare Diseases of the Central Nervous System Review Group, using the Cochrane MS Group Trials Register which contains CENTRAL, Medline, Embase, CINAHL, LILACUS, Clinical trials.gov and the WHO International Clinical Trials Registry Platform on December 10, 2017. Hand-searching of relevant journals and screening of reference lists of relevant studies was carried out. All published RCTs and cross-over studies that compared non-pharmacological therapies with a control intervention for managing chronic pain in pwMS were included. Clinical controlled trials (CCTs) were eligible for inclusion. All 3 review authors independently selected studies, extracted data and assessed the methodological quality of the studies using the GRADE tool for best-evidence synthesis. Pooling data for meta-analysis was not possible due to methodological, clinical and statistically heterogeneity of the included studies. A total of 10 RCTs with 565 subjects that examined different non-pharmacological interventions for the management of chronic pain in MS fulfilled the review inclusion criteria. The non-pharmacological interventions evaluated included: transcutaneous electrical nerve stimulation (TENS), psychotherapy (telephone self-management, hypnosis and electroencephalogram (EEG) biofeedback), transcranial random noise stimulation (tRNS), transcranial direct stimulation (tDCS), hydrotherapy (Ai Chi) and reflexology. There was very low-level evidence for the use of non-pharmacological interventions for chronic pain such as TENS, Ai Chi, tDCS, tRNS, telephone-delivered self-management program, EEG biofeedback and reflexology in pain intensity in pwMS. Although there were improved changes in pain scores and secondary outcomes (such as fatigue, psychological symptoms, spasm in some interventions), these were limited by methodological biases within the studies. The authors concluded that despite the use of a wide range of non-pharmacological interventions for the treatment of chronic pain in pwMS, the evidence for these interventions is still limited or insufficient, or both. These researchers stated that more studies with robust methodology and greater numbers of participants are needed to justify the use of these interventions for the management of chronic pain in pwMS.
Osteopontin as a Biomarker for MS
Agah and colleagues (2018) conducted a systematic review and meta-analysis of studies that measured peripheral blood and CSF levels of osteopontin (OPN) in MS patients and controls to evaluate the diagnostic potential of this biomarker. These investigators searched PubMed, Web of Science and Scopus databases to find articles that measured OPN concentration in peripheral blood and CSF samples from MS patients up to October 19, 2016. Q statistic tests and the I2 index were applied for heterogeneity assessment. If the I2 index was less than 40 %, the fixed-effects model was used for meta-analysis. Random-effects meta-analysis was chosen if the I2 value was greater than 40 %. After removal of duplicates, a total of 918 articles were identified, and 27 of them fulfilled the inclusion criteria. These researchers included 22 eligible studies in the final meta-analysis; MS patients, in general, had considerably higher levels of OPN in their CSF and blood when compared to all types of controls (p < 0.05). When the comparisons were made between different subtypes of MS patients and controls, the results pointed to significantly higher levels of OPN in CSF of MS subgroups (p < 0.05). All subtypes of MS patients, except clinically isolated syndrome (CIS); patients, had increased blood levels of OPN compared to controls (p < 0.05). In the second set of meta-analyses, these researchers compared the peripheral blood and CSF concentrations of OPN between MS patient subtypes; CIS patients had significantly lower levels of OPN both in their peripheral blood and CSF compared to patients with progressive subtypes of MS (p < 0.05); CSF concentration of OPN was significantly higher among RRMS patients compared to the CIS patients and SPMS patients (p < 0.05). Finally, patients with active MS had significantly higher OPN levels in their CSF compared to patients with stable disease (p = 0.007). The authors stated that although the existing data strongly suggested that higher levels of OPN were present in peripheral blood and CSF of MS patients compared to the controls, very limited studies were included in most of the subgroup analyses; so to achieve more reliable results, more studies needed to be included in these subgroups. They also stated that considerable heterogeneity among the included studies was another drawback of this study. Furthermore, publication bias was a challenging issue in biomarker studies which may affect results of meta-analyses and their reliability. The authors concluded that the result of this study confirmed that increased levels of OPN exist in CSF and peripheral blood of MS patients and strengthened the evidence regarding the clinical utility of OPN as a promising and validated biomarker for MS. An elevated level of OPN in a patient at risk of MS may be suggestive of active inflammation. They stated that given the fact that OPN levels were higher during relapses, monitoring this biomarker might be able to predict the disease course.
Prolactin
Zhornitsky et al (2013) noted that MS is more common among women than men; and MS often goes into remission during pregnancy, when prolactin (PRL) levels are known to be high. In an animal model of demyelination, PRL promoted myelin repair, suggesting it has potential as a re-myelinating therapy in MS. I n this systematic review, these investigators examined the known associations between PRL and MS, in order to elucidate its potential role in the pathophysiology and treatment of MS. A systematic search was performed in the electronic databases PubMed and EMBASE, using the keywords "prolactin" AND "multiple sclerosis". The inclusion criteria were met by 23 studies. These studies suggested that elevated PRL may be more common in MS patients than in controls. Hyper-prolactinemia may also be associated with clinical relapse in MS, especially among patients with hypothalamic lesions or optic neuritis; however, it is unknown if this is a cause or consequence of a relapse. The authors concluded that overall most people with MS have normal PRL levels; and the impact of PRL on MS outcomes remains unclear.
Respiratory Rehabilitation / Respiratory Muscle Training in MS
An American Academy of Neurology systematic evidence review of rehabilitation in multiple sclerosis (Haselkorn et al, 2015) concluded that a 10-week inspiratory muscle training program possibly is effective for improving maximal inspiratory pressure as measured by pulmonary function testing in relapsing-remitting MS (RRMS), secondary progressive multiple sclerosis (SPMS), and primary progressive multiple sclerosis (PPMS), Expanded Disability Status Scale (EDSS) 2–6.5 (1 study, Class II objective measures). The evidence review found that data are inadequate to support/refute the use of inspiratory muscle training for fatigue and expiratory muscle training.
Rietberg and colleagues (2017) examined the effects of respiratory muscle training versus any other type of training or no training for respiratory muscle function, pulmonary function and clinical outcomes in people with MS. These investigators searched the Trials Register of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group (February 3, 2017), which contained trials from the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL, LILACS and the trial registry databases ClinicalTrials.gov and World Health Organization (WHO) International Clinical Trials Registry Platform. Two authors independently screened records yielded by the search, hand-searched reference lists of review articles and primary studies, checked trial registers for protocols, and contacted experts in the field to identify further published or unpublished trials. These researchers included RCTs that investigated the efficacy of respiratory muscle training versus any control in people with MS. One reviewer extracted study characteristics and study data from included RCTs, and 2 other reviewers independently cross-checked all extracted data. Two review authors independently assessed risk of bias with the Cochrane “risk of bias” assessment tool. When at least 2 RCTs provided data for the same type of outcome, these researchers performed meta-analyses. They assessed the certainty of the evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. A total of 6 RCTs, comprising 195 participants with MS were included in this analysis. Two RCTs investigated inspiratory muscle training with a threshold device; 3 RCTs, expiratory muscle training with a threshold device; and 1 RCT, regular breathing exercises; 18 participants (˜approximately 10 %) dropped out; trials reported no serious AEs. These investigators pooled and analyzed data of 5 trials (n = 137) for both inspiratory and expiratory muscle training, using a fixed-effect model for all but one outcome. Compared to no active control, meta-analysis showed that inspiratory muscle training resulted in no significant difference in maximal inspiratory pressure (mean difference (MD) 6.50 cm H2O, 95 % CI: -7.39 to 20.38, p = 0.36, I2 = 0 %) or maximal expiratory pressure (MD -8.22 cmH2O, 95 % CI: -26.20 to 9.77, p = 0.37, I2 = 0 %), but there was a significant benefit on the predicted maximal inspiratory pressure (MD 20.92 cm H2O, 95 % CI: 6.03 to 35.81, p = 0.006, I2 = 18 %). Meta-analysis with a random-effects model failed to show a significant difference in predicted maximal expiratory pressure (MD 5.86 cm H2O, 95 % CI: -10.63 to 22.35, p = 0.49, I2 = 55 %). These studies did not report outcomes for health-related quality of life (QOL); 3 RCTS compared expiratory muscle training versus no active control or sham training. Under a fixed-effect model, meta-analysis failed to show a significant difference between groups with regard to maximal expiratory pressure (MD 8.33 cm H2O, 95 % CI: -0.93 to 17.59, p = 0.18, I2 = 42 %) or maximal inspiratory pressure (MD 3.54 cm H2O, 95 % CI: -5.04 to 12.12, p = 0.42, I2 = 41 %). One trial assessed QOL, finding no differences between groups. For all pre-determined secondary outcomes, such as forced expiratory volume, forced vital capacity and peak flow pooling was not possible. However, 2 trials on inspiratory muscle training assessed fatigue using the Fatigue Severity Scale (range of scores 0 to 56 ), finding no difference between groups (MD, -0.28 points, 95 % CI:-0.95 to 0.39, p = 0.42, I2 = 0 %). Due to the low number of studies included, these researchers could not perform cumulative meta-analysis or subgroup analyses. It was not possible to perform a meta-analysis for AEs, no serious AEs were mentioned in any of the included trials. The quality of evidence was low for all outcomes because of limitations in design and implementation as well as imprecision of results. The authors concluded that this review provided low-quality evidence that resistive inspiratory muscle training with a resistive threshold device was moderately effective post-intervention for improving predicted maximal inspiratory pressure in people with mild-to-moderate MS, whereas expiratory muscle training showed no significant effects. The sustainability of the favorable effect of inspiratory muscle training is unclear, as is the impact of the observed effects on QOL.
Levy and associates (2018) performed a systematic review of the published literature related to respiratory rehabilitation in MS. These investigators searched the databases Medline via PubMed, PEDro and Cochrane Library for English or French reports of clinical trials and well-designed cohorts published up to December 2016 with no restriction on start date by using the search terms "multiple sclerosis", "respiratory rehabilitation", "respiratory muscle training", "lung volume recruitment", "cough assistance", and "mechanical in-exsufflation". Literature reviews, case reports and physiological studies were excluded. The Maastricht criteria were used to assess the quality of clinical trials. These researchers followed the Oxford Centre for Evidence-Based Medicine guidelines to determine level of evidence and grade of recommendations. Among the 21 reports of studies initially selected, 11 were retained for review; 7 studies were RCTs, 2 were non-RCTs, and 2 were observational studies. Respiratory muscle training (inspiratory and/or expiratory) by use of a portable resistive mouthpiece was the most frequently evaluated technique, with 2 level-1 RCTs. Another level-1 RCT evaluated deep-breathing exercises. All reviewed studies evaluated home-based rehabilitation programs and focused on spirometric outcomes. The disparities in outcome measures among published studies did not allow for a meta-analysis and cough assistance devices were not evaluated in this population. The authors concluded that although respiratory muscle training can improve maximal respiratory pressure in MS and lung volume recruitment can slow the decline in vital capacity, evidence is lacking to recommend specific respiratory rehabilitation programs adapted to the level of disability induced by the disease.
Serum Neurofilament as a Marker of Neuroaxonal Injury in Early MS and for Monitoring Disease Activity
Kuhle and colleagues (2017) examined a potential effect of riluzole on serum neurofilaments (Nf) compared to placebo and the relationship between longitudinal clinical and MRI outcomes and serum Nf levels. Serum samples were obtained from participants enrolled in a randomized double-blind trial of neuroprotection with riluzole versus placebo as an add-on to weekly interferon-β (IFN-β)-1a IM initiated 3 months after randomization; Nf measurements were performed by ELISA and electrochemiluminescence immunoassay. Longitudinal serum samples were available from 22 riluzole and 20 placebo participants over 24 months. There was no observed treatment effect with riluzole; Nf light chain (NfL) levels decreased over time (p = 0.007 at 24 months), whereas the Nf heavy chain was unchanged (p = 0.997). Changes in NfL were correlated with EDSS change (p = 0.009) and neuropsychological outcomes. Brain volume decreased more rapidly in patients with high baseline NfL (p = 0.05 at 12 months and p = 0.008 at 24 months) and this relationship became stronger at 24 months (p = 0.024 for interaction). Higher and increasing NfL predicted higher number of gadolinium-enhancing lesions (p < 0.001 for both). The authors concluded that these findings supported the potential value of serum NfL as a marker of neuroaxonal injury in early MS. Its reduction over time could represent regression to the mean, or a possible treatment effect of IFN-β-1a. The association with whole brain atrophy and the formation of acute white matter lesions has relevant implications to use serum NfL as a non-invasive biomarker of the overall consequences of brain damage and ongoing disease activity. Moreover, they stated that these findings should be interpreted with caution and need to be replicated independently including a broader range of patients with cognitive changes. The unexpected lack of association of NfH with clinical and most imaging outcomes needs to be investigated further to determine whether the difference relates to disease stage. The drawbacks of this study included the relatively small sample size limiting the ability to detect a treatment effect of riluzole on various markers. Due to the design of the original trial, longitudinal samples from untreated patients or healthy controls were not available. Finally, analyses of Nf were not a priori defined in the original trial, hence not corrected for multiple comparisons and therefore exploratory in nature.
In an editorial that accompanied the afore-mentioned study, Bodini and Calabresi (2017) stated that prospective longitudinal studies including patients with all phenotypes of the disease and healthy controls, directly comparing Nf with MR-derived metrics over time, will be able to establish whether Nf, alone or combined with other imaging biomarkers, can have a place in MS clinical practice and therapeutic trials. Such studies could also inform on the evolution of Nf levels over a long time course, determining the rate and the timeframe in which Nf levels rise and fall in each individual. They also noted that another major issue that needs to be addressed is reproducibility, which remains suboptimal. This was particularly true for Nf quantified on serum samples, which even more than CSF samples are affected by the lack of reproducibility validation. These editorialists concluded that presently the measure of CNS and serum Nf levels is an interesting candidate to quantify neuroaxonal degeneration in MS, but remains for now a research tool. They stated that further validation steps are needed before considering Nf biomarkers of neuroaxonal degeneration a reliable outcome measure for clinical trials of neuroprotective treatments.
Novakova and colleagues (2017) examined the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in MS. NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay (ELISA). The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay. In MS, the correlation between serum and CSF NFL was r = 0.62 (p < 0.001). Serum concentrations were significantly higher in patients with RRMS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, p < 0.001 and p < 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6 to 32.7) ng/L to 15.7 (IQR 9.6 to 22.7) ng/L (p < 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (p < 0.001) or those without new lesions on MRI (p < 0.001). These investigators noted that the high correlation between serum and CSF NFL suggested that the temporal course of serum NFL was similar to that described for CSF NFL. However, this has to be further investigated in prospective studies. In monitoring of the effect of DMT on axonal damage, a 3-month interval between blood tests for monitoring serum NFL would reveal the occurrence of new disease activity. However, these researchers could not determine from their data whether this would detect a step-wise accumulation of T2 lesions, accumulation of disability, or conversion to a progressive disease course. There is a need for long-term follow-up studies to collect data on the correlation between NFL concentrations over time and such outcomes. The authors concluded that these findings suggested that measuring serum NFL may be useful in trials and in clinical practice for evaluating the effect of DMTs in MS.
Spasticity Treatments
Alleviation of the symptoms of MS becomes necessary, since effective curative therapy is not yet available. Symptomatic treatment provides the means of improving the quality of life of individuals with MS. Oral baclofen commonly is used to treat spasticity, however, a major side effect is increased weakness of the limb with possible negative effects on ambulation. Oral tizanidine can also be used to treat spasticity, where loss of strength appears to be less of a problem. Intrathecal baclofen via an implantable pump has been shown to be very effective in treating severe, intractable spasticity; however, careful selection of patients is mandatory as this is an invasive procedure with a number of potentially dangerous complications (hypotension, respiratory insufficiency, and meningitis). When all forms of medical treatment are insufficient to prevent spasticity-related complications, injection of phenol can be used to perform neurolysis. Tenotomies of fixed contractures can also be useful in extremely disabled patients to allow adequate nursing. Oral clonazepam, hydroxyzine and beta-blockers can be used to treat tremors. Irritative or obstructive bladder symptoms, as a result of spinal lesions causing detrusor hyperreflexia and incomplete bladder emptying, can be treated with oral anticholinergic medication (e.g., oxybutynin) and intermittent self-catheterization. Carbamazepine can be used to treat trigeminal neuralgia, the most common neurologic symptom in multiple sclerosis patients, and bouts of itching, burning sensations, twitching of the face, and a current of electricity flowing the length of their spine.
Statins
It is not known whether statins are effective therapy for MS. Birnbaum et al (2008) explored whether high-dose atorvastatin can be administered safely to persons with relapsing-remitting MS taking thrice-weekly, 44 microg dose subcutaneous interferon (IFN) beta-1a. Subjects were randomized in a double-blind fashion to receive either placebo or atorvastatin at dosages of 40 or 80 mg/day for 6 months. Blinded neurological examinations and brain MRI readings were obtained at months 0, 3, 6, and 9. Laboratory blood testing was performed monthly. Main outcome measures were the determination of drug toxicity using blood tests and ECG and determination of MS-related disease activity, either clinical relapses or new or contrast-enhancing lesions on MRI. A total of 26 subjects received at least one dose of study drug. Ten of 17 subjects on either 80 mg or 40 mg of atorvastatin per day had either new or enhancing T2 lesions on MRI or clinical relapses. One of the 9 subjects on placebo had a relapse with active lesions on MRI. Subjects receiving atorvastatin were at greater risk for either clinical or MRI disease activity compared to placebo (p = 0.019). Significant changes in blood tests were noted only for lower cholesterol levels in subjects receiving atorvastatin. The authors concluded that the combination of 40 or 80 mg atorvastatin with thrice-weekly, 44 microg IFN beta-1a in persons with MS resulted in increased MRI and clinical disease activity; caution is suggested in administering this combination.
In an editorial that accompanied the afore-mentioned article, Goldman and Cohen (2008) stated that "there are several ongoing larger studies of statins in MS, both as monotherapy and combined with other medications. Hopefully these studies will clarify whether statins are useful as MS therapy".
Transcranial Ultrasound
An early neurodegenerative affection of subcortical gray matter has been suggested in patients with MS. Transcranial sonography (TCS) shows hyper-echogenic lesions of substantia nigra (SN) and basal ganglia, thought to reflect iron accumulation, in a number of primary neurodegenerative diseases. Walter and colleagues (2009) examined if TCS can also display deep gray matter lesions in patients with MS and whether sonographic findings relate to severity and progression of MS. These researchers prospectively studied 75 patients with different courses of MS and 55 age-matched healthy subjects clinically and with TCS. Additionally, 23 patients had 1.5-T MRI at the time of TCS. Disease progression was assessed clinically 2 years after TCS. Abnormal hyper-echogenicity of SN, lenticular nucleus (LN), caudate nucleus, and thalamus was found in 41 %, 54 %, 40 %, and 8 % of the patients with MS, with similar frequency in patients with relapsing-remitting and primary or secondary progressive MS if corrected for disease duration, but only in 13 %, 13 %, 5 % (each, p < 0.001), and none (p = 0.028) of the control subjects. Hyperechogenicity of SN and LN correlated with more pronounced MRI T2 hypointensity, thought to reflect iron deposition. Larger bilateral SN echogenic area was related to higher rate of disease progression, whereas small SN echogenic area (SN hypo-echogenicity) predicted a disease course without further progression within 2 years. The authors concluded that neurodegenerative disease-like deep gray matter lesions can be frequently detected by TCS in patients with MS. They stated that these findings suggest that TCS shows changes of brain iron metabolism which correlate with future progress of MS. These investigators also noted that future studies are needed to determine if patients with MS with or without LN hyper-echogenecity represent different pathological sub-types that may benefit from different treatment strategies.
In an editorial that accompanied the afore-mentioned article, Pirko and Zivadinov (2009) stated that there are a number of issues that raise questions regarding the universal applicability of this technique:- increased echo-genecity of gray matter nuclei was reported only in 40 to 50 % of MS cases at baseline;
- the echo-genecity was evaluated by means of a 3-grade visual scale as opposed to an objective calculated numerical intensity measure; and
- investigator agreement -- a human factor that may introduce bias -- was needed to ascertain if the TCS findings are really abnormal; and
- blinding in this study was practically impossible.
The editorialists stated that to validate these TCS findings, large case-control studies are needed.
Appendix
2017 McDonald Criteria for Diagnosis of Multiple Sclerosis in Patients with a Disease Course Characterised by Progression from Onset (Primary Progressive Multiple Sclerosis)
-
Primary progressive multiple sclerosis can be diagnosed in patients with:
- 1 year of disability progression (retrospectively or prospectively determined) independent of clinical relapse
-
Plus two of the following criteria:
- One or more T2-hyperintense lesionsFootnote3*** characteristic of multiple sclerosis in one or more of the following brain regions: periventricular, cortical or juxtacortical, or infratentorial;
- Two or more T2-hyperintense lesionsFootnote3*** in the spinal cord;
- Presence of CSF-specific oligoclonal bands.
Footnote3*** Unlike the 2010 McDonald criteria, no distinction between symptomatic and asymptomatic MRI lesions is required.
Source: Thompson et al., 2018
Expanded Disability Status Scale (EDSS)
The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist.
| EDSS Scale Scoring | Disability Status |
|---|---|
| 1.0 | No disability, minimal signs in one FS |
| 1.5 | No disability, minimal signs in more than one FS |
| 2.0 | Minimal disability in one FS |
| 2.5 | Mild disability in one FS or minimal disability in two FS |
| 3.0 | Moderate disability in one FS, or mild disability in three or four FS. No impairment to walking |
| 3.5 | Moderate disability in one FS and more than minimal disability in several others. No impairment to walking |
| 4.0 | Significant disability but self-sufficient and up and about some 12 hours a day. Able to walk without aid or rest for 500m |
| 4.5 | Significant disability but up and about much of the day, able to work a full day, may otherwise have some limitation of full activity or require minimal assistance. Able to walk without aid or rest for 300m |
| 5.0 | Disability severe enough to impair full daily activities and ability to work a full day without special provisions. Able to walk without aid or rest for 200m |
| 5.5 | Disability severe enough to preclude full daily activities. Able to walk without aid or rest for 100m |
| 6.0 | Requires a walking aid - cane, crutch, etc - to walk about 100m with or without resting |
| 6.5 | Requires two walking aids - pair of canes, crutches, etc - to walk about 20m without resting |
| 7.0 | Unable to walk beyond approximately 5m even with aid. Essentially restricted to wheelchair; though wheels self in standard wheelchair and transfers alone. Up and about in wheelchair some 12 hours a day |
| 7.5 | Unable to take more than a few steps. Restricted to wheelchair and may need aid in transfering. Can wheel self but can not carry on in standard wheelchair for a full day and may require a motorised wheelchair |
| 8.0 | Essentially restricted to bed or chair or pushed in wheelchair. May be out of bed itself much of the day. Retains many self-care functions. Generally has effective use of arms |
| 8.5 | Essentially restricted to bed much of day. Has some effective use of arms retains some self care functions |
| 9.0 | Confined to bed. Can still communicate and eat |
| 9.5 | Confined to bed and totally dependent. Unable to communicate effectively or eat/swallow |
| 10.0 | Death due to MS |
Source: Kurtzke, 1983; Olek and Mowry, 2020
References
The above policy is based on the following references:
- Acorda Therapeutics, Inc. Ampyra (dalfampridine). Prescribing Information. Ardsley, NY: Acorda Therapeutics; revised February 2021.
- Adams E. Bibliography: Bone Marrow Transplant for Multiple Sclerosis. Boston, MA: U.S. Department of Veterans Affairs, Office of Patient Care Services, Technology Assessment Program (VATAP); September 2006.
- Agah E, Zardoui A, Saghazadeh A, et al. Osteopontin (OPN) as a CSF and blood biomarker for multiple sclerosis: A systematic review and meta-analysis. PLoS One. 2018;13(1):e0190252.
- Agrawal YP. Low dose naltrexone therapy in multiple sclerosis. Med Hypotheses. 2005;64(4):721-724.
- AHFS DI (Adult and Pediatric) [database online]. Hudson, OH: Lexi-Comp, Inc.; updated periodically. Available at: http://online.lexi.com/lco/action/index/dataset/complete_ashp [available with subscription]. Accessed March 30, 2022.
- Alatab S, Hossein-nezhad A, Mirzaei K, et al. Inflammatory profile, age of onset, and the MTHFR polymorphism in patients with multiple sclerosis. J Mol Neurosci. 2011;44(1):6-11.
- Amatya B, Young J, Khan F. Non-pharmacological interventions for chronic pain in multiple sclerosis. Cochrane Database Syst Rev. 2018;12:CD012622.
- American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: APA; 2013.
- Antonelli G, Bagnato F, Dianzani F. Considerations on the development of serum antibodies to interferon-beta. New Microbiol. 2005;28(3):183-192.
- Arnason BG. Immunologic therapy of multiple sclerosis. Annu Rev Med. 1999;50:291-302.
- Atkins H. Hematopoietic SCT for the treatment of multiple sclerosis. Bone Marrow Transplant. 2010;45(12):1671-1681.
- Bakhuraysah MM, Siatskas C, Petratos S. Hematopoietic stem cell transplantation for multiple sclerosis: Is it a clinical reality? Stem Cell Res Ther. 2016;7:12.
- Ball CM. Hyperbaric oxygen therapy for multiple sclerosis. STEER: Succint and Timely Evaluated Evidence Reviews. Bazian, Ltd., eds. London, UK: Wessex Institute for Health Research and Development, University of Southampton; 2002;2(6).
- Bansil S, Troiano R, Rohowsky-Kochan C, et al. Multiple sclerosis: Pathogenesis and treatment. Semin Neurol. 1994;14(2):146-153.
- Barnes D, Hughes RA, Morris RW, et al. Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet. 1997;349(9056):902-906.
- Barrett SD. Be wary of multiple sclerosis 'cures.' Allentown, PA: Quackwatch; updated October 4, 2000. Available at:http://www.quackwatch.com/01QuackeryRelatedTopics/ms.html. Accessed May 17, 2001.
- Beard S, Hunn A, Wight J. Treatments for spasticity and pain in multiple sclerosis: A systematic review. Health Technol Assess. 2003;7(40):1-124.
- Beck RW, Cleary PA, Trobe JD, et al. A randomized controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritits Study Group. N Engl J Med. 1993;329(24):1764-1769.
- Beenakker EA, Oparina TI, Hartgring A, et al. Cooling garment treatment in MS: Clinical improvement and decrease in leukocyte NO production. Neurology. 2001 11;57(5):892-894.
- Belogurov A Jr, Zakharov K, Lomakin Y, et al. CD206-targeted liposomal myelin basic protein peptides in patients with multiple sclerosis resistant to first-line disease-modifying therapies: A first-in-human, proof-of-concept dose-escalation study. Neurotherapeutics. 2016;13(4):895-904.
- Bennett M, Heard R. Hyperbaric oxygen therapy for multiple sclerosis. Cochrane Database Syst Rev. 2004;(1):CD003057.
- Bennett M, Heard R. Treatment of multiple sclerosis with hyperbaric oxygen therapy. Undersea Hyperbaric Med. 2001 28:117-122.
- Bindoff L, Lyons PR, Newman PK. Methylprednisolone in multiple sclerosis: A comparative study, J Neurol Neurosurg Psychiatry. 1988;51:1108-1109.
- Blue Cross Blue Shield Association (BCBSA), Technology Evaluation Center (TEC). Extracorporeal photopheresis for the treatment of autoimmune disease. TEC Assessment Program. Chicago IL: BCBSA; 2001:16(10).
- Bodini B, Calabresi PA. From neurofilament research to multiple sclerosis clinical practice: Where do we stand? Neurology. 2017;88(9):816-817.
- Bourdette DN, Cohen JA. Venous angioplasty for "CCSVI" in multiple sclerosis: Ending a therapeutic misadventure. Neurology. 2014;83(5):388-389.
- Bowling A; National Multiple Sclerosis Society Research and Clinical Programs Department. Low dose naltrexone update. Clinical Updates: Treatments. New York, NY: National Multiple Sclerosis Society; October 2006. Available at:http://www.nationalmssociety.org/site/PageServer?pagename=HOM_LIVE_clinup_naltrexone. Accessed April 17, 2007.
- Branas P, Jordan R, Fry-Smith A, et al. Treatments for fatigue in multiple sclerosis: A rapid and systematic review. Health Technol Assess. 2000;4(27):1-61.
- Brusaferri F, Candelise L. Steroids for multiple sclerosis and optic neuritis: A meta-analysis of randomized controlled clinical trials. J Neurol. 2000;247(6):435-442.
- Burton JM, O'Connor PW, Hohol M, Beyene J. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev. 2009;(3):CD006921.
- Burton JM, O'Connor PW, Hohol M, Beyene J. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev. 2012;12:CD006921.
- Calabresi PA. B-cell depletion - a frontier in monoclonal antibodies for multiple sclerosis. N Engl J Med. 2017;376(3):280-282.
- Canadian Agency for Drugs and Technologies in Health (CADTH). An update on the investigation of chronic cerebrospinal venous insufficiency for the treatment of multiple sclerosis. Ottawa, Ontario: CADTH; 2012;20.
- Capello E, Gardella M, Leandri M, et al. Lowering body temperature with a cooling suit as symptomatic treatment for thermosensitive multiple sclerosis patients. Ital J Neurol Sci. 1995;16(8):533-539.
- Casetta I, Iuliano G, Filippini G. Azathioprine treatment for multiple sclerosis. Cochrane Database Syst Rev. 2007;(3):CD003982.
- Ciccone A, Beretta S, Brusaferri F, et al. Corticosteroids for the long-term treatment in multiple sclerosis. Cochrane Database Syst Rev. 2008:(1):CD006264.
- Ciucci G, Floriani I. Plasma exchange for multiple sclerosis (Protocol for a Cochrane Review). Cochrane Database Syst Rev. 2001;(3):CD003609.
- Clegg A, Bryant J, Milne R. Disease-modifying drugs for multiple sclerosis: A rapid and systematic review. Health Technol Assess. 2000;4(9):1-101.
- Clinical Pharmacology powered by ClinicalKey. Tampa, FL: Elsevier; updated periodically. Available at: https://www.clinicalkey.com. Accessed May 21, 2021.
- Cohen JA, Coles AJ, Arnold DL, et al.; CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet. 2012;380(9856):1819-1828.
- Coles A. Low-dose naltrexone as a treatment for multiple sclerosis. Research Explained. Multiple Sclerosis Society [website]. London, UK: Multiple Sclerosis Society; June 11, 2004. Available at: http://www.mssociety.org.uk/research/research_explained/ldn.html. Accessed April 17, 2007.
- Coles AJ, Twyman CL, Arnold DL, et al.; CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet. 2012;380(9856):1829-1839.
- Cortese I, Chaudhry V, So YT, et al. Evidence-based guideline update: Plasmapheresis in neurologic disorders: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011;76(3):294-300.
- Costa V, McGregor M, Brophy J. The use of mitoxantrone in the treatment of patients with multiple sclerosis: Report update. Report No. 24. Montreal, QC: Technology Assessment Unit of the McGill University Health Centre (MUHC); 2006.
- Doepp F, Würfel JT, Pfueller CF, et al. Venous drainage in multiple sclerosis: A combined MRI and ultrasound study. Neurology. 2011;77(19):1745-1751.
- Drugs.com [online]. Leustatin (intravenous). Reviewed December 28, 2020. Available at: https://www.drugs.com/cons/leustatin.html. Accessed May 21, 2021.
- Durelli L, Cocito D, Riccio A, et al. High-dose intravenous methylprednisolone in the treatment of multiple sclerosis: Clinical-immunologic correlations. Neurology. 1986;36:238-243.
- Edan G, Miller D, Clanet M, et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: A randomized multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry. 1997;62(2):112-118.
- EDMS, LLC. Letter from EDMS describing unpublished of Procarin in multiple sclerosis. Stanwood, WA: EDMS; 2001. Available at: http://welcome.to/procarin. Accessed May 17, 2001.
- Ehrenreich H, Fischer B, Norra C, et al. Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain. 2007;130(Pt 10):2577-2588.
- Farinotti M, Simi S, Di Pietrantonj C, et al. Dietary interventions for multiple sclerosis. Cochrane Database Syst Rev. 2007;(1):CD004192.
- Farinotti M, Vacchi L, Simi S, et al. Dietary interventions for multiple sclerosis. Cochrane Database Syst Rev. 2012;12:CD004192.
- Fekih Mrissa N, Mrad M, Klai S, et al. Association of methylenetetrahydrofolate reductase A1298C polymorphism but not of C677T with multiple sclerosis in Tunisian patients. Clin Neurol Neurosurg. 2013;115(9):1657-1660.
- Filippini G, Brusaferri F, Sibley WA, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev. 2000;(4):CD001331.
- Flensner G, Lindencrona C. The cooling-suit: A study of ten multiple sclerosis patients' experiences in daily life. J Adv Nurs. 1999 Jun;29(6):1444-1453.
- Flensner G, Lindencrona C. The cooling-suit: Case studies of its influence on fatigue among eight individuals with multiple sclerosis. J Adv Nurs. 2002;37(6):541-550.
- Friedemann P, Wattjes MP. Venoplasty in MS: Therapeutic intervention without any evidence. Neurology. 2018;91(18):815-816.
- Galetta S L, Markowitz C, Lee AG. Immunomodulatory agents for the treatment of relapsing multiple sclerosis: A systematic review. Archiv Internl Med. 2002;162(19):2161-2169.
- Gasperi C, Stuve O, Hemmer B. B cell-directed therapies in multiple sclerosis. Neurodegener Dis Manag. 2016;6(1):37-47.
- Genentech, Inc. Ocrevus (ocrelizumab) injection, for intravenous use. Prescribing Information. South San Francisco, CA: Genentech; revised March 2021.
- Genentech. FDA approves Genentech’s Ocrevus (ocrelizumab) for relapsing and primary progressive forms of multiple sclerosis. Press Release. South San Francisco, CA: Genentech; March 28, 2017.
- Gensicke H, Leppert D, Yaldizli O, et al. Monoclonal antibodies and recombinant immunoglobulins for the treatment of multiple sclerosis. CNS Drugs. 2012;26(1):11-37.
- Genzyme Corporation. Genzymes Lemtrada approved by FDA. Press Release. Cambridge, MA: Genzyme; November 14, 2014.
- Genzyme Corporation. Lemtrada (alemtuzumab) injection, for intravenous use. Prescribing Information. Cambridge, MA: Genzyme; revised January 2022.
- Gillson G, Wright JV, DeLack E, Ballasiotes G. Transdermal histamine in multiple sclerosis: Part one -- clinical experience. Altern Med Rev. 1999;4(6):424-428.
- Gillson G, Wright JV, DeLack E, Ballasiotes G. Transdermal histamine in multiple sclerosis: Part two: A proposed theoretical basis for its use. Altern Med Rev. 2000;5(3):224-248.
- Giovannoni G, Cohen JA, Coles AJ, et al; CARE-MS II Investigators. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016 87(19):1985-1992.
- Giovannoni G, Nath A. After the storm: Neurofilament levels as a surrogate endpoint for neuroaxonal damage. Neurology. 2011;76(14):1200-1201.
- Goldman MD, Cohen JA. Statins to treat multiple sclerosis: Friend or foe? Neurology. 2008;71(18):1386-1387.
- Goodin DS, Arnason BG, Coyle PK, et al. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;61(10):1332-1338.
- Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58(2):169-178.
- Goodkin DE, Kinkel RP, Weinstock-Guttman B, et al. A phase II study of IV methylprednisolone in secondary-progressive multiple sclerosis. Neurology. 1998;51(1):239-245.
- Gray O, McDonnell GV, Forbes RB. Methotrexate for multiple sclerosis. Cochrane Database Syst Rev. 2004;(2):CD003208.
- Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): A randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489.
- Griffiths TD, Newman PK. Steroids in multiple sclerosis. J Clin Pharm Therapeutics. 1994;19:219-222.
- Gronseth GS, Ashman EG. Practice parameter: The usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;54(9):1720-1725.
- Guerrero AL, Laherrán E, Gutiérrez F, et al. Apolipoprotein E genotype does not associate with disease severity measured by Multiple Sclerosis Severity Score. Acta Neurol Scand. 2008;117(1):21-25.
- Hailey D. Hyperbaric oxygen therapy - recent findings on evidence for its effectiveness. Update. IP-13 Information Paper. Edmonton, AB: Alberta Heritage Foundation for Medical Research (AHFMR); 2003.
- Harris VK, Vyshkina T, Sadiq SA. Clinical safety of intrathecal administration of mesenchymal stromal cell-derived neural progenitors in multiple sclerosis. Cytotherapy. 2016;18(12):1476-1482.
- Hartung HP, Munschauer F 3rd, Schellekens H. Significance of neutralizing antibodies to interferon beta during treatment of multiple sclerosis: Expert opinions based on the Proceedings of an International Consensus Conference. Eur J Neurol. 2005;12(8):588-601.
- Haselkorn JK, Hughes C, Rae-Grant A, et al. Summary of comprehensive systematic review: Rehabilitation in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2015;85(21):1896-1903.
- Hauser SL, Bar-Or A, Comi G, et al.; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221-234.
- 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(7):676-688.
- He D, Guo R, Zhang F, et al. Rituximab for relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev. 2013;12:CD009130.
- Hospira Inc. Mitoxantrone injection, USP. Prescribing Information. Lake Forest, IL; revised April 2021.
- Huang J, Xie ZK, Lu RB, Xie ZF. Association of interleukin-1 gene polymorphisms with multiple sclerosis: A meta-analysis. Inflamm Res. 2013;62(1):97-106.
- Huntley A, Ernst E. Complementary and alternative therapies for treating multiple sclerosis symptoms: A systematic review. Complement Therap Med. 2000;8(2):97-105.
- IBM Watson Health. IBM Micromedex [electronic versin]. Armonk, NY: IBM Micormedex; updated periodically.
- Ineichen BV, Keskitalo S, Farkas M, et al. Genetic variants of homocysteine metabolism and multiple sclerosis: A case-control study. Neurosci Lett. 2014;562:75-78.
- Institute for Clinical Systems Improvement (ICSI). Interferon beta-1a, interferon beta-1b, glatiramer acetate, and mitoxantrone. Technology Assessment Report. Bloomington, MN: ICSI; 2001.
- Itoh N, Kim R, Peng M, et al. Bedside to bench to bedside research: Estrogen receptor beta ligand as a candidate neuroprotective treatment for multiple sclerosis. J Neuroimmunol. 2017;304:63-71.
- Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing- remitting multiple sclerosis: Results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45(7):1268-1276.
- Johnson KP, Brooks BR, Cohen JA, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1998;50(3):701-708.
- Johnson KP. A review of the clinical efficacy profile of copolymer 1: New U.S. phase III trial data. J Neurol. 1996;243(4 Suppl 1):S3-S7.
- Johnson KP. Management of relapsing/remitting multiple sclerosis with copolymer 1 (Copaxone). Mult Scler. 1996;1(6):325-326.
- Kaufman DI, Trobe JD, Eggenberger ER, Whitaker JN. Practice parameter: The role of corticosteroids in the management of acute monosymptomatic optic neuritis. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;54(11):2039-2044.
- Kes P. Therapeutic plasma exchange in neurologic disorders. Acta Med Croatica. 1997;51(4-5):225-228.
- Khalil M, Langkammer C, Ropele S, et al. Determinants of brain iron in multiple sclerosis: A quantitative 3T MRI study. Neurology. 2011;77(18):1691-1697.
- Khan F, Turner-Stokes L, Ng L, Kilpatrick T. Multidisciplinary rehabilitation for adults with multiple sclerosis. Cochrane Database Syst Rev. 2007;(2):CD006036.
- Khatri BO, McQuillen MP, Hoffmann RG, et al. Plasma exchange in chronic progressive multiple sclerosis: A long-term study. Neurology. 1991;41(3):409-414.
- Killestein J, Polman CH, Uitdehaag BMJ. Cannabinoids for multiple sclerosis (Protocol for Cochrane Review). Cochrane Database Syst Rev. 2002;(4):CD003981.
- Kinnman J, Andersson T, Andersson G. Effect of cooling suit treatment in patients with multiple sclerosis evaluated by evoked potentials. Scand J Rehabil Med. 2000;32(1):16-19.
- Kinzel S, Weber MS. B cell-directed therapeutics in multiple sclerosis: Rationale and clinical evidence. CNS Drugs. 2016;30(12):1137-1148.
- Kipshidze N, Rukhadze I, Archvadze A, et al. Endovascular treatment of patients with chronic cerebrospinal venous insufficiency and multiple sclerosis. Georgian Med News. 2011;(199):29-34.
- Korczyn AD, Nisipeanu P. Safety profile of copolymer 1: Analysis of cumulative experience in the United States and Israel. J Neurol. 1996;243(4 Suppl 1):S23-S26.
- Kostecki J, Zaniewski M, Ziaja K, et al. An endovascular treatment of Chronic Cerebro-Spinal Venous Insufficiency in multiple sclerosis patients - 6 month follow-up results. Neuro Endocrinol Lett. 2011;32(4):557-562.
- Ku YT, Montgomery LD, Lee HC, et al. Physiologic and functional responses of MS patients to body cooling. Am J Phys Med Rehabil. 2000;79(5):427-434.
- Kuhle J, Leppert D, Petzold A, et al. Neurofilament heavy chain in CSF correlates with relapses and disability in multiple sclerosis. Neurology. 2011;76(14):1206-1213.
- Kuhle J, Nourbakhsh B, Grant D, et al. Serum neurofilament is associated with progression of brain atrophy and disability in early MS. Neurology. 2017;88(9):826-831.
- Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology. 1983 Nov;33(11):1444-52.
- La Mantia L, Milanese C, D"Amico R. Meta-analysis of clinical trials with copolymer 1 in multiple sclerosis. Europ Neurol. 2000;43(4):189-193.
- La Mantia L, Milanese C, Mascoli N, et al. Cyclophosphamide for multiple sclerosis. Cochrane Database Syst Rev. 2007;(1):CD002819.
- Le Page E, Leray E, Taurin G, et al. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: Treatment response factors in a 5 year follow-up observational study of 100 consecutive patients. J Neurol Neurosurg Psychiatry. 2008;79(1):52-56.
- Levin MC. Multiple sclerosis. Merck Manual Consumer Version [online]. Kenilworth, NJ: Merck Sharp & Dohme Corp; revised March 2021.
- Levy J, Prigent H, Bensmail D. Respiratory rehabilitation in multiple sclerosis: A narrative review of rehabilitation techniques. Ann Phys Rehabil Med. 2018;61(1):38-45.
- Lexicomp Online. AHFS DI (Adult and Pediatric) Online. Hudson, OH: UpToDate, Inc; updated periodically.
- Lomakin Y, Belogurov A Jr, Glagoleva I, et al. Administration of myelin basic protein peptides encapsulated in mannosylated liposomes normalizes level of serum TNF-α and IL-2 and chemoattractants CCL2 and CCL4 in multiple sclerosis patients. Mediators Inflamm. 2016;2016:2847232.
- Lopez-Gomez C, Oliver-Martos B, Pinto-Medel MJ, et al. TRAIL and TRAIL receptors splice variants during long-term interferon β treatment of patients with multiple sclerosis: Evaluation as biomarkers for therapeutic response. J Neurol Neurosurg Psychiatry. 2016;87(2):130-137.
- MacFarland HF. The B cell — old player, new position on the team. N Engl J Med. 2008;358(7):664-665.
- Mancardi GL, Sormani MP, Gualandi F, et al; ASTIMS Haemato-Neurological Collaborative Group, On behalf of the Autoimmune Disease Working Party (ADWP) of the European Group for Blood and Marrow Transplantation (EBMT); ASTIMS Haemato-Neurological Collaborative Group On behalf of the Autoimmune Disease Working Party ADWP of the European Group for Blood and Marrow Transplantation EBMT. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A phase II trial. Neurology. 2015;84(10):981-988.
- Mangas A, Coveñas R, Geffard M. New drug therapies for multiple sclerosis. Curr Opin Neurol. 2010;23(3):287-292.
- Martinelli Boneschi F, Rovaris M, Capra R, Comi G. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2005;(4):CD002127.
- Matsui M. Classification of MS and treatment strategy. Nippon Rinsho. 2008 Jun;66(6):1112-1116.
- Mattoscio M, Nicholas R, Sormani MP, et al. Hematopoietic mobilization: Potential biomarker of response to natalizumab in multiple sclerosis. Neurology. 2015;84(14):1473-1482.
- McNamee P, Parkin D. Cost-effectiveness of interferon beta for multiple sclerosis: The implications of new information on clinical effectiveness. Health Technol Assess. 1999;2(4):1-7.
- Millefiorini E, Gasperini C, Pozzilli C, et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol. 1997;244(3):153-159.
- Miller DM, Weinstock-Guttman B, Bethoux F, et al. A meta-analysis of methylprednisolone in recovery from multiple sclerosis exacerbations. Multip Scleros. 2000;6(4):267-273.
- Milligan NM, Newcombe R, Comptson DAS. A double-blind controlled trial of high-dose methylprednisolone in patients with multiple sclerosis: Clinical effects. J Neurol Neurosurg Psychiatry. 1987;50:511-516.
- Mills RJ, Yap L, Young CA. Treatment of ataxia in multiple sclerosis. Cochrane Database Syst Rev. 2007;(1):CD005029.
- Milo R, Panitch H. Combination therapy in multiple sclerosis. J. Neuroimmunol. 2011;231(1-2): 23–31.
- Mitchell G. Update on multiple sclerosis therapy. Med Clin North Am. 1993;77(1):231-249.
- Montalban X, Hauser SL, Kappos L, et al.; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209-220.
- Monthly Prescribing Reference (MPR). Roche discontinues Zenapax injection. News. New York, NY: Haymarket Media Inc.;December 22, 2009. Available at: https://www.empr.com/home/news/roche-discontinues-zenapax-injection/. Accessed April 30, 2019.
- Mostert S, Kesselring J. Effect of pulsed magnetic field therapy on the level of fatigue in patients with multiple sclerosis--a randomized controlled trial. Mult Scler. 2005;11(3):302-305.
- Multiple Sclerosis Association of America (MSAA). Zinbryta withdrawn from marketplace. Latest News. Cherry Hill, NJ: MSAA; March 5, 2018. Available at: https://mymsaa.org/news/zinbryta-withdrawn. Accessed April 30, 2019.
- Multiple Sclerosis Society of Canada (MSSC). MS Research. Claim of Procarin benefit still unproven. Medical Update Memo. Toronto, ON: MSSC; April 3, 2000. Available at: http://www.mssociety.ca/entxt/research/CAT000403.htm. Accessed May 17, 2001.
- Multiple Sklerose Therapie Konsensus Gruppe (MSTKG), Rieckmann P. Escalating immunomodulatory therapy of multiple sclerosis. Update (September 2006). Nervenarzt. 2006;77(12):1506-1518.
- Muraro PA. Andiamo! Moving forward with autologous hematopoietic transplantation for highly active MS. Neurology. 2015;84(10):968-969.
- Murray TJ. Oral and intravenous methylprednisolone were equally efficacious for relapses in multiple sclerosis: commentary. ACP Journal Club. 1997;127(2):38.
- Naismith RT. Ocrelizumab demonstrates superiority to interferon in relapsing multiple sclerosis. JWatch Neurol. 2017 Jan 27.
- Naismith RT. Positive clinical trial results for ocrelizumab in primary progressive multiple sclerosis. JWatch Neurol. 2017 Jan 27.
- National Collaborating Centre for Chronic Conditions. Multiple sclerosis. National clinical guideline for diagnosis and management in primary and secondary care. Clinical Guideline 8. London, UK: National Institute for Clinical Excellence (NICE); 2004.
- National Horizon Scanning Centre (NHSC). Mitoxantrone for multiple sclerosis - horizon scanning review. Birmingham, UK: NHSC: 2002.
- National Institute for Clinical Excellence (NICE). Multiple sclerosis. Management of multiple sclerosis in primary and secondary care. Clinical Guideline 8. London, UK: NICE; November 2003.
- National Institute for Health and Clinical Excellence (NICE). Percutaneous venoplasty for chronic cerebrospinal venous insufficiency for multiple sclerosis. Interventional Procedure Guidance 420. London, UK: NICE; March 2012.
- National Multiple Sclerosis Society (NMSS). Clinical Updates. Procarin® Update. New York, NY: NMSS; March 2001. Available at: http://www.nationalmssociety.org/clinup-procarin.asp. Accessed May 17, 2001.
- National Multiple Sclerosis Society. Chemotherapy. Information Sourcebook. New York, NY: National Multiple Sclerosis Society; March, 2006. Available at:http://main.nationalmssociety.org/docs/HOM/chemotherapy.pdf. Accessed March 5, 2008.
- National Multiple Sclerosis Society. Landmark study estimates nearly 1 million in the U.S. have multiple sclerosis. News. New York, NY; National Multiple Sclerosis Society; February 15, 2019. Available at: https://www.nationalmssociety.org/About-the-Society/News/Landmark-Study-Estimates-Nearly%C2%A01-Million-in-the-U. Accessed May 24, 2021.
- National Multiple Sclerosis Society. Types of MS. What is MS? New York, NY: National Multiple Sclerosis Society; 2020. Available at: https://www.nationalmssociety.org/What-is-MS/Types-of-MS, Accessed May 24, 2021.
- Nicholas R, Chataway J. Multiple sclerosis. In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; June 2008.
- Nicholas RS, Friede T, Hollis S, Young CA. Anticholinergics for urinary symptoms in multiple sclerosis (Protocol for Cochrane Review). Cochrane Database Syst Rev. 2003;(2):CD004193.
- Nicholson T, Milne R. Copolymer 1 in relapsing-remitting multiple sclerosis. DEC Report No. 63. Southampton, UK: Wessex Institute for Health Research and Development; 1996.
- No author listed. Hyperbaric oxygen for MS: Update. Bandolier Library. London, UK: Bandolier; May 26, 2003. Available at: http://www.jr2.ox.ac.uk/bandolier/band104/b104-4.html. Accessed June 30, 2003.
- Noronha A. Neutralizing antibodies to interferon. Neurology. 2007;68(24 Suppl 4):S16-S22.
- Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343(13):938-952.
- Novakova L, Zetterberg H, Sundström P, et al. Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology. 2017;89(22):2230-2237.
- Oh S, Cudrici C, Ito T, Rus H. B-cells and humoral immunity in multiple sclerosis. Implications for therapy. Immunol Res. 2008;40(3):224-234.
- Ohji S, Nomura K. The indication of steroid pulse therapy and apheresis therapy for multiple sclerosis. Nippon Rinsho. 2008;66(6):1127-1132.
- Olek MJ, Howard J. Clinical presentation, course, and prognosis of multiple sclerosis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed March 2021.
- Olek MJ and Mowry E. Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2021.
- Olek MJ and Mowry E. Treatment of primary progressive multiple sclerosis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2020.
- Olek MJ. Clinical course and classification of multiple sclerosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed November 2016.
- Olek MJ. Clinical features of multiple sclerosis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2014b.
- Olek MJ. Diagnosis of multiple sclerosis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2014a.
- Olek MJ. Pathogenesis and epidemiology of multiple sclerosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2014d.
- Olek MJ. Treatment of acute exacerbations of multiple sclerosis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed September 2009.
- Olek MJ. Treatment of progressive multiple sclerosis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2014e.
- Olek MJ. Treatment of progressive multiple sclerosis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2018.
- Olek MJ. Treatment of relapsing-remitting multiple sclerosis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2012.
- Olek MJ. Treatment of relapsing-remitting multiple sclerosis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2014c.
- Oliveira AG, Gonçalves M, Ferreira H, M Neves N. Growing evidence supporting the use of mesenchymal stem cell therapies in multiple sclerosis: A systematic review. Mult Scler Relat Disord. 2019 Nov 18 [Epub ahead of print].
- Olyaeemanesh A, Rahmani M, Goudarzi R, Rahimdel A. Safety and effectiveness assessment of intravenous immunoglobulin in the treatment of relapsing-remitting multiple sclerosis: A meta-analysis. Med J Islam Repub Iran. 2016;30:336.
- Ontario Health Technology Advisory Committee. Multiple sclerosis and chronic cerebrospinal venous insufficiency. OHTAC Recommendation. Toronto, ON: OHTAC; May 2010.
- Optic Neuritis Study Group. The 5-year risk of MS after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Neurology. 1997;49(5):1404-1413.
- OSI Pharmaceuticals Inc. Novantrone (mitoxantrone for injection concentrate). Prescribing Information. Melville, NY: OSI Pharmaceuticals; August 2008.
- Otten N. Comparison of drug treatments for multiple sclerosis - systematic review. Technology Report Issue 3. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 1998.
- Paisley S, Beard S, Hunn A, Wight J. Clinical effectiveness of oral treatments for spasticity in multiple sclerosis: a systematic review. Multip Scleros. 2002;8(4):319-329.
- Parkin D, Miller P, McNamee P, et al. A cost-utility analysis of interferon beta for multiple sclerosis. Health Technol Assess. 1998;2(4):1-58.
- Phe V, Schneider MP, Peyronnet B, et al. Intravesical vanilloids for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: A systematic review and meta-analysis. A report from the Neuro-Urology Promotion Committee of the International Continence Society (ICS). Neurourol Urodyn. 2018;37(1):67-82.
- Pichon Riviere A, Augustovski F, Alcaraz A, et al. Hyperbaric oxygen therapy: Diagnostic usefulness and indications [summary]. Report ITB No. 94. Buenos Aires, Argentina: Institute for Clinical Effectiveness and Health Policy (IECS); 2006.
- Pihl-Jensen G, Tsakiri A, Frederiksen JL. Statin treatment in multiple sclerosis: A systematic review and meta-analysis. CNS Drugs. 2015;29(4):277-291.
- Pilutti LA, Motl RW. Functional electrical stimulation cycling exercise for people with multiple sclerosis. Curr Treat Options Neurol. 2019;21(11):54.
- Pilutti LA, Edwards T, Motl RW, Sebastiao E. Functional electrical stimulation cycling exercise in people with multiple sclerosis: Secondary effects on cognition, symptoms, and quality of life. Int J MS Care. 2019;21(6):258-264.
- Pirko I, Zivadinov R. Transcranial sonography of deep gray nuclei: A new outcome measure in multiple sclerosis? Neurology. 2009;73(13):1006-1007.
- Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005;58(6):840-846.
- Pucci E, Branãs P, D'Amico R, et al. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 2007;(1):CD002818.
- Rajanikant GK, Zemke D, Kassab M, Majid A. The therapeutic potential of statins in neurological disorders. Curr Med Chem. 2007;14(1):103-112.
- Reekers JA, Lee MJ, Belli AM, Barkhof F. Cardiovascular and Interventional Radiological Society of Europe commentary on the treatment of chronic cerebrospinal venous insufficiency. Cardiovasc Intervent Radiol. 2011;34(1):1-2.
- Rice CM, Kemp K, Wilkins A, Scolding NJ. Cell therapy for multiple sclerosis: An evolving concept with implications for other neurodegenerative diseases. Lancet. 2013;382(9899):1204-1213.
- Richards RG, Sampson FC, Beard SM, Tappenden P. A review of the natural history and epidemiology of multiple sclerosis: Implications for resource allocation and health economic models. Health Technol Assess. 2002;6(10):1-73.
- Rietberg MB, Brooks D, Uitdehaag BMJ, Kwakkel G. Exercise therapy for multiple sclerosis. Cochrane Database Syst Rev. 2004;(3):CD003980.
- Rietberg MB, Veerbeek JM, Gosselink R, et al. Respiratory muscle training for multiple sclerosis. Cochrane Database Syst Rev. 2017;12:CD009424.
- Rock GA, Tricklebank GW, Kasaboski CA. Plasma exchange in Canada. The Canadian Apheresis Study Group. CMAJ. 1990;142(6):557-562.
- Rog DJ, Young C, Hollis S, Friede T. Treatment of neuropathic pain for multiple sclerosis (Protocol for Cochrane Review). Cochrane Database Syst Rev. 2001;(4):CD003736.
- Ropper AH. Selective treatment of multiple sclerosis. N Engl J Med. 2006;354:965-967.
- Rovira A, Montalban X. MR brain iron mapping in MS: A potential neurodegenerative marker or just another technique? Neurology. 2011;77(18):1660-1661.
- Scally JB, Baker JS, Rankin J, et al. Evaluating functional electrical stimulation (FES) cycling on cardiovascular, musculoskeletal and functional outcomes in adults with multiple sclerosis and mobility impairment: A systematic review. Mult Scler Relat Disord. 2020;37:101485.
- Schroder A, Linker RA, Gold R. Plasmapheresis for neurological disorders. Expert Rev Neurother. 2009;9(9):1331-1339.
- Schwid SR, Petrie MD, Murray R, et al.; NASA/MS Cooling Study Group. A randomized controlled study of the acute and chronic effects of cooling therapy for MS. Neurology. 2003;60(12):1955-1960.
- Shakespeare DT, Boggild M, Young C. Anti-spasticity agents for multiple sclerosis. Cochrane Database Syst Rev. 2003;(4):CD001332.
- Sheffler LR, Hennessey MT, Knutson JS, et al. Functional effect of an ankle foot orthosis on gait in multiple sclerosis: A pilot study. Am J Phys Med Rehabil. 2008;87(1):26-32.
- Shehata N, Kouroukis C, Kelton JG. A review of randomized controlled trials using therapeutic apheresis. Transfus Med Rev. 2002;16(3):200-229.
- Shi J, Zhao CB, Vollmer TL, et al. APOE epsilon 4 allele is associated with cognitive impairment in patients with multiple sclerosis. Neurology. 2008;70(3):185-190.
- Shirani A, Okuda DT, Stuve O. Therapeutic advances and future prospects in progressive forms of multiple sclerosis. Neurotherapeutics. 2016;13(1):58-69.
- Siddiqui AH, Zivadinov R, Benedict RH, et al. Prospective randomized trial of venous angioplasty in MS (PREMiSe). Neurology. 2014;83(5):441-449.
- Silberberg DH. Specific treatment of multiple sclerosis. Clin Neuroscience. 1994;2:271-274.
- Skundric D. Basic approaches in therapy of multiple sclerosis (MS) and related diseases: Current achievements and prospective. Cent Nerv Syst Agents Med Chem. 2018;18(1):21-31.
- Solari A, Uitdehaag B, Giuliani G, et al. Aminopyridines for symptomatic treatment in multiple sclerosis. Cochrane Database Syst Rev. 2002;(4):CD001330.
- 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(11):817-827.
- Sorensen PS, Lisby S, Grove R, et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: A phase 2 study. Neurology. 2014;82(7):573-581.
- Sorensen PS, Wanscher B, Szpirt W, et al. Plasma exchange combined with azathioprine in multiple sclerosis using serial gadolinium-enhanced MRI to monitor disease activity: A randomized single-masked cross-over pilot study. Neurology. 1996;46(6):1620-1625.
- Straus Farber R, Harel A, Lublin F. Novel agents for relapsing forms of multiple sclerosis. Annu Rev Med. 2016;67:309-321.
- Tackenberg B, Himmerich H, Wellek A, et al. Advances in the treatment of multiple sclerosis? MMW Fortschr Med. 2007;149 Suppl 2:51-55.
- The Canadian cooperative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet. 1991;337(8739):441-446.
- The Multiple Sclerosis Coalition. The use of disease-modifying therapies in multiple sclerosis: Principles and current evidence. New York, NY: National Multiple Sclerosis Society; updated September 2019. Available at: https://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/DMT_Consensus_MS_Coalition.pdf. Accessed June 24, 2021.
- Thomas PW, Thomas S, Hillier C, et al. Psychological interventions for multiple sclerosis. Cochrane Database Syst Rev. 2006:(1):CD004431.
- Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Position Paper. Lancet Neurology. 2018;17(2):162-173.
- Torres-Moreno MC, Papaseit E, Torrens M, Farre M. Assessment of efficacy and tolerability of medicinal cannabinoids in patients with multiple sclerosis: A systematic review and meta-analysis. JAMA Netw Open. 2018;1(6):e183485.
- Traboulsee AL, Machan L, Girard JM, et al. Safety and efficacy of venoplasty in MS. A randomized, double-blind, sham-controlled phase II trial. Neurology. 2018;91(18) e1660-e1668.
- Tramacere I, Del Giovane C, Filippini G. Association of immunotherapies with outcomes in relapsing-remitting multiple sclerosis. JAMA. 2016;315(4):409-410.
- Tramacere I, Del Giovane C, Salanti G, et al. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: A network meta-analysis. Cochrane Database Syst Rev. 2015;9:CD011381.
- U.S. Food and Drug Administration (FDA). FDA issues alert on potential dangers of unproven treatment for multiple sclerosis. FDA News. Silver Spring, MD: FDA; May 10, 2012.
- U.S. Food and Drug Administration (FDA). Ocrevus (ocrelizumab) injection, for intravenous use. Prescribing Information. Reference ID: 4462419. Rockville, MD: FDA; revised July 2019.
- Vamvakas EC, Pineda AA, Weinshenker BG. Meta-analysis of clinical studies of the efficacy of plasma exchange in the treatment of chronic progressive multiple sclerosis. J Clin Apheresis. 1995;10(4):163-170.
- van der Voort LF, Vennegoor A, Visser A, et al. Spontaneous MxA mRNA level predicts relapses in patients with recently diagnosed MS. Neurology. 2010;75(14):1228-1233.
- van Oosten BW, Truyen L, Barkhof F, et al. Multiple sclerosis therapy: A practical guide. Drugs. 1995;49(2):200-212.
- van Zuuren EJ, Fedorowicz Z, Pucci E, et al. Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients. Cochrane Database Syst Rev. 2012;12:CD009903.
- Vedantham S, Benenati JF, Kundu S, et al; Society of Interventional Radiology; Canadian Interventional Radiology Association. Interventional endovascular management of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: A position statement by the Society of Interventional Radiology, endorsed by the Canadian Interventional Radiology Association. J Vasc Interv Radiol. 2010;21(9): 1335-1337.
- Vedula SS, Brodney-Folse S, Gal RL, Beck R. Corticosteroids for treating optic neuritis. Cochrane Database Syst Rev. 2007;(1):CD001430.
- Walter U, Wagner S, Horowski S, et al. Transcranial brain sonography findings predict disease progression in multiple sclerosis. Neurology. 2009;73(13):1010-1017.
- Weber MS, Zamvil SS. Statins and demyelination. Curr Top Microbiol Immunol. 2008;318:313-324.
- Weiner HL, Hohol MJ, Khoury SJ, et al. Therapy for multiple sclerosis. Neurol Clinics. 1995;13(1):173-195.
- Weinshenker BG, Issa M, Baskerville J. Meta-analysis of the placebo-treated groups in clinical trials of progressive MS. Neurology. 1996;46(6):1613-1619.
- Weinshenker BG, O'Brien PC, Petterson TM, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol. 1999;46:878-886.
- Worthington V, Killestein J, Eikelenboom MJ, et al. Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. Neurology. 2010;75(18):1617-1622.
- Zamboni P, Galeotti R, Weinstock-Guttman B, et al. Venous angioplasty in patients with multiple sclerosis: Results of a pilot study. Eur J Vasc Endovasc Surg. 2012;43(1):116-122.
- Zecca C, Gobbi C. Chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS): A critical review. CNS Neurol Disord Drug Targets. 2011;10(6):757-761.
- Zhornitsky S, Yong VW, Weiss S, Metz LM. Prolactin in multiple sclerosis. Mult Scler. 2013;19(1):15-23.
- Zivadinov R, Rudick RA, De Masi R, et al. Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology. 2001;57:1239-1247.
