|
| A) | near the equator. | ||
| B) | in the extreme north. | ||
| C) | in the extreme south. | ||
| D) | in developed countries. |
Environmental factors are thought to play a significant role in the development of MS. Studies have shown an association between geographic latitude and risk, with the risk increasing from south to north [16,17]. The lowest risk in found among persons living near the equator. As such, the prevalence of MS is higher in geographic locales having less sunlight exposure (and hence diminished production of vitamin D), suggesting that low levels of vitamin D may be a risk factor [17,18,19,20]. In addition, persons who smoke have an increased relative risk compared to those who do not [17,19,21].
| A) | occur only in the brain. | ||
| B) | cluster near the ventricles. | ||
| C) | cluster in the peripheral nerves. | ||
| D) | occur primarily in the gray matter. |
Conceptually, MS is now considered to be an autoimmune inflammatory disorder with complex and variable pathologic features [1,29]. Susceptible individuals are those of genetic predisposition in combination with environmental factors and possibly latent infection. The etiology is unclear, but initiation of disease appears to involve the activation of peripheral T-lymphocytes, programmed to recognize components of the CNS axonal myelin sheath. The disease is triggered by events that permit these autoactivated T-cells to breach the blood-brain barrier and cross-react with myelin components within the white matter of the brain and spinal cord [30]. This precipitates a cascade of immune-mediated inflammatory tissue injury. As seen on radiographic imaging and pathologic examination, the hallmark of the disease is this well-defined, focal zone of injury ("plaque") containing elements of inflammation, demyelination, and axon degeneration [1,6]. Such lesions may be single or multiple, and over time, they may be partially reparative, relapsing, or recurrent in new locations. The location of lesions is variable; early in the disease they appear in white matter, often clustering near the ventricles and sparing peripheral nerves [14].
| A) | impairs nerve transmission. | ||
| B) | bolsters the immune attack on oligodendrocytes. | ||
| C) | causes perpetuation of the proinflammatory condition. | ||
| D) | permits leukocytes to enter the central nervous system (CNS). |
Demyelination impairs nerve impulse transmission and leads to abnormal patterns of nerve conduction, which accounts in large part for the various clinical symptoms and signs of MS. Oligodendrocytes are cells that elaborate the myelin sheath that envelops the axon. During the early, remittent stage of the disease, as inflammation subsides, the number and function of these cells are sufficient to renew the myelin sheath (remyelination) and restore neurologic function. Over time, the repeated inflammatory insults associated with relapsing MS lead to a gradual depletion of functioning oligodendrocytes, and to degenerative changes marked by central scarring within the lesion and focal areas of cerebral atrophy. The clinical correlate is the gradual accumulation of fixed neurologic deficits as the patient with MS transitions to the chronic progressive stage of the disease.
| A) | is never painful. | ||
| B) | does not usually affect ambulation. | ||
| C) | usually affects the muscles of the trunk and face. | ||
| D) | is more prominent in the lower extremities than the upper extremities. |
The majority of patients with MS report some level of spasticity. Painful muscle spasm is experienced by approximately 15% and is often a source of debilitation [39]. Spasticity usually affects the muscles of the extremities (more prominent in the lower extremities than the upper extremities) and can impair an individual's ability to freely move his or her muscles.
| A) | visceral. | ||
| B) | somatic. | ||
| C) | neuropathic. | ||
| D) | musculoskeletal. |
MS pain is mainly neuropathic—the result of nerve damage and faulty conduction—and can include stabbing, burning, and shock-like sensations (e.g., allodynia, dysesthesias, paresthesia). Lhermitte sign is often considered a classic sign of MS and consists of a brief, electric shock-like sensation that runs down the spine and is triggered by bending the neck forward or backward.
| A) | astigmatism. | ||
| B) | optic neuritis. | ||
| C) | upbeat nystagmus. | ||
| D) | intranuclear ophthalmoplegia. |
Impaired vision is frequently present in patients with MS, most commonly unilateral optic neuritis, which is present in approximately in 66% of cases [43]. Optic neuritis usually manifests as acute or subacute unilateral eye pain that increases with eye movements [44]. It can also lead to blurring or graying of vision or blindness in one eye. However, while unilateral optic neuritis is common in MS, simultaneous bilateral optic neuritis (resulting in total blindness) is rare [43]. Approximately 90% of patients with MS regain normal vision over a period of two to six months after an acute episode of optic neuritis [43].
| A) | benign. | ||
| B) | malignant. | ||
| C) | relapsing-remitting. | ||
| D) | primary progressive. |
Relapsing-remitting multiple sclerosis (RRMS) is characterized by alternating series of clearly defined clinical relapses (or exacerbations) followed by periods of partial or complete recovery (remissions). RRMS affects young adults, is three times more common in women than men, and accounts for about 85% of all cases of MS [51]. Functional and structural impairments suffered during relapses may either resolve or leave sequelae.
| A) | alternating series of clearly defined relapses followed by remissions. | ||
| B) | steady disease progression with occasional remissions and temporary minor improvements. | ||
| C) | a long-term absence of symptoms with no functional impairments 15 years after disease onset. | ||
| D) | progressive neurologic impairment between relapses without any well-defined periods of remission. |
Primary progressive MS (PPMS) is characterized by steady disease progression from the onset of symptoms, perhaps with occasional remissions and temporary minor improvements [47]. Approximately 10% to 15% of patients with MS carry the diagnosis of PPMS [49]. Patients diagnosed with PPMS tend to be older (mean age: 40 years) than those with RRMS, and there is no gender difference in incidence [49].
| A) | occurs most commonly in older adults. | ||
| B) | is also known as Uhthoff phenomenon. | ||
| C) | is associated with smaller lesions involving the cervical spine. | ||
| D) | results in major disability and usually death within one year of onset. |
Malignant MS (also known as Marburg variant) is characterized by a rapidly progressive course resulting in major disability and usually death within one year of the onset. This disease course is most common in children, although older adults may be affected as well.
| A) | accounts for the majority of MS cases. | ||
| B) | is usually characterized by a relapsing-remitting course. | ||
| C) | is only diagnosed in patients younger than 10 years of age. | ||
| D) | most commonly presents with motor, rather than sensory, symptoms. |
Early-onset MS is usually diagnosed in patients younger than 20 years of age. It accounts for approximately 0.4% to 10.5% of all MS cases [56]. Usually, the disease is characterized by a relapsing-remitting course, a high recovery rate from initial attack, and a long remission and slow progression rate. Sensory symptoms are more common than motor symptoms in these patients, and vision loss (optic neuritis) is a common initial presentation. Other functional systems are involved with a variable frequency. Seizures, malaise, irritability, and low-grade fever may also be present.
| A) | optic neuritis. | ||
| B) | loss of proprioception. | ||
| C) | lesions on the cervical spine. | ||
| D) | peripheral vestibular disease. |
NEUROLOGIC SIGNS AND TESTS
| Test | Description | Notes |
|---|---|---|
| Romberg test | Patient stands erect with feet together and eyes closed. Swaying or falling is considered positive. | Used for patients with ataxia. Indicates loss of proprioception. |
| Lhermitte sign | Patient bends the head forward or clinician puts pressure on the posterior cervical spine. An electrical shock sensation is considered positive. | Used to determine the presence of lesions on the cervical spine. Often considered a classic finding in MS but can be caused by a number of conditions. |
| Gait tests | Observe patient walking normally, walking heel-to-toe, and walking on only toes/heels. Any abnormalities should be noted. | This test evaluates ataxia in various parts of the body. |
| Point-to-point movement evaluation | Patients alternate touching their extended index finger to their nose and the examiner's outstretched finger. | These are tests to evaluate ataxia, dysmetria, and cerebellar dysfunction. Positive findings are indicative of loss of motor strength, loss of proprioception, or a cerebellar lesion. |
| Supine patient places right heel on left shin just below the knee and slides it down to the top of the foot as quickly as possible without making mistakes. Repeat on opposite side. Inability to complete quickly is considered positive. | ||
| Visual acuity and color tests | Patient reads letters from a board to assess visual acuity and from the Ishihara Color Vision Test to assess color vision. Inability to distinguish figures is considered positive. | These tests evaluate for the presence of optic neuritis, perhaps the most frequent symptom in MS. |
| Babinski sign | The lateral side of the sole of the foot is lightly stimulated from the heel along a curve to the toes. If the hallux dorsiflexes and the other toes fan out, this is considered a positive Babinski sign. | These tests evaluate for signs of disease process in the motor neurons of the pyramidal tract. They are positive in individuals with neurologic problems of the corticospinal tract, including those with MS. |
| Chaddock sign | Similar to Babinski's sign, this test involves stimulation over the lateral malleolus rather than the bottom of the foot. A positive response elicits an extensor response similar to Babinski sign. | |
| Hoffman reflex | Clinician taps the nail or flicks the terminal phalanx of the middle or ring finger. A positive response is seen with flexion of the terminal phalanx of the thumb. | This test evaluates problems in the corticospinal tract. However, it is also positive in hyper-reflexive patients. Findings that are acute or asymmetrical are more indicative of disease. |
| Halmagyi-Curthoys head impulse test | Clinician randomly moves the patient's head side to side. If the eyes remain stationary while the head is moved, this is considered positive. | Test reveals dissociation between movement of the eyes and of the head. Indicative of peripheral vestibular disease. |
| Perception tests | A monofilament, tuning fork, or pin is applied to patient's body. Ability to perceive the touch or vibration is considered positive. | Evaluates the level of sensory perception in certain parts of the body. |
| Muscle strength tests | Patient attempts to resist pressure applied by the clinician to various muscle groups. Level of resistance can be rated on a scale from none to normal strength. | Patterns of weakness can help localize a lesion to a particular cortical or white matter region, spinal cord level, nerve root, peripheral nerve, or muscle. Differences in strength between left and right sides are easier to evaluate than symmetrical loss unless the weakness is severe. |
| Reflexes | This is done with both ends of the hammer. The reflexes can be normal, brisk (i.e., too easily evoked), or non-existent. | — |
| A) | Ataxia | ||
| B) | Optic neuritis | ||
| C) | Cranial nerve palsies | ||
| D) | Trigeminal neuralgia |
ELOQUENT MS SYNDROMES
| Eloquent Syndrome | Localization | Clinical Manifestations | |||||
|---|---|---|---|---|---|---|---|
| Optic neuritis | Optic nerve |
| |||||
| Internuclear ophthalmoparesis (INO) | Medial longitudinal fasciculus (MLF) |
| |||||
| Skew deviation | Otolith pathways |
| |||||
| Cranial nerve palsies | Brainstem |
| |||||
| Rubral tremor | Superior cerebellar peduncle | Tremor | |||||
| Ataxia | Cerebellum | Instability and reduced postural control | |||||
| Trigeminal neuralgia | Trigeminal system | Paroxysmal facial pain | |||||
| Myelitis | Spinal cord |
|
| A) | tremor. | ||
| B) | visual acuity loss. | ||
| C) | reduced postural control. | ||
| D) | bowel/bladder/sexual dysfunction. |
ELOQUENT MS SYNDROMES
| Eloquent Syndrome | Localization | Clinical Manifestations | |||||
|---|---|---|---|---|---|---|---|
| Optic neuritis | Optic nerve |
| |||||
| Internuclear ophthalmoparesis (INO) | Medial longitudinal fasciculus (MLF) |
| |||||
| Skew deviation | Otolith pathways |
| |||||
| Cranial nerve palsies | Brainstem |
| |||||
| Rubral tremor | Superior cerebellar peduncle | Tremor | |||||
| Ataxia | Cerebellum | Instability and reduced postural control | |||||
| Trigeminal neuralgia | Trigeminal system | Paroxysmal facial pain | |||||
| Myelitis | Spinal cord |
|
| A) | benign MS. | ||
| B) | relapsing-remitting MS. | ||
| C) | primary progressive MS. | ||
| D) | secondary progressive MS. |
The diverse disease processes associated with the subtypes of MS can be detected by MRI as well. In PPMS, MRI will show small lesions that do not enhance with a contrast agent, indicating little or minimal inflammation. This particular characteristic is a clear differentiation from relapsing-remitting disease. The severity and extent of the physical symptoms of MS can be confirmed by visualization of the anatomic location of lesions within the CNS. For example, a lesion present in the spinal cord may result in numbness in the limbs and bladder disturbance. Lesions in the optic nerve are usually responsible for optic neuritis, leading to blurred vision and a loss of color perception.
| A) | central cord. | ||
| B) | dorsal columns. | ||
| C) | lateral corticospinal tract. | ||
| D) | lateral spinothalamic tract. |
MS lesions found in the spinal cord usually give rise to identifiable symptoms and are highly eloquent of the disease process; new spinal MS lesions are strongly correlated to new clinical manifestations. Approximately 75% of patients with MS have lesions within the spinal cord, principally the cervical cord, and most spinal cord lesions are located in the dorsal columns [68]. These lesions are usually oval or cigar-shaped and can span one or two vertebral segments (referred to as skip lesions).
| A) | lesion load on MRI. | ||
| B) | demyelination detected by myelin water fraction imaging. | ||
| C) | detection of oligoclonal bands in cerebrospinal fluid by isoelectric focusing. | ||
| D) | assessment of glutamate levels by proton magnetic resonance spectroscopy. |
Detection of oligoclonal bands in CSF by isoelectric focusing is the most sensitive laboratory test for MS and the most sensitive predictor of conversion from clinically isolated syndrome to MS. It is also the best test to show local intrathecal IgG synthesis. Patients with suspected MS who lack oligoclonal IgG bands in CSF should be investigated for other diagnoses, although it is important to remember that not all patients with MS display oligoclonal bands. Studies have demonstrated that the frequency of oligoclonal bands in the CSF of patients with MS varies in different regions of the world, with higher rates in Northern Europe and North America and lower rates in Asia [93].
| A) | Visual evoked potentials | ||
| B) | Somatosensory evoked potentials | ||
| C) | Brainstem auditory evoked potentials | ||
| D) | All of the above |
Only results of visual evoked potentials are considered part of the diagnostic criteria for MS. Visual evoked potentials can detect sluggish neurotransmission along the optic nerve pathways, a finding common in individuals with asymptomatic MS. However, a positive finding on evoked potential testing is not specific to MS, and the abnormalities detected may also be present in other conditions.
| A) | Progressive from onset | ||
| B) | Lack of peripheral symptoms | ||
| C) | Abnormal neurologic examination | ||
| D) | MRI abnormalities in multiple locations |
Atypical clinical features that suggest an alternate diagnosis include [96]:
Normal neurologic examination
Abnormality in a single location (i.e., no dissemination in space)
Progressive from onset (i.e., no dissemination in time)
Onset in childhood or at an age older than 50 years
Psychiatric disease present
Systemic disease present
Prominent family history (may suggest genetic disease)
Gray matter symptoms (e.g., dementia, seizures, aphasia)
Peripheral symptoms (e.g., peripheral neuropathy, fasciculations)
Acute hemiparesis
Lack of typical symptoms (e.g., no optic neuritis, bladder problems, Lhermitte sign)
Prolonged benign course (i.e., diagnosis made several years ago with few current findings)
| A) | interferons. | ||
| B) | corticosteroids. | ||
| C) | adrenocorticotropic hormone (ACTH). | ||
| D) | Both B and C |
Treatment of the acute exacerbations seen with relapsing types of MS relies primarily on corticosteroids and adrenocorticotropic hormone (ACTH). These agents have been found to promote speedier resolution of the neurologic deficits, lessen the severity of an attack, and effectively reduce the risk of permanent residual deficits. Both corticosteroids and ACTH are capable of restoring the breakdown of the blood-brain barrier, reducing inflammation, and immunomodulating mononuclear trafficking mechanisms. Corticosteroids also promote quick recovery from disability [98,99].
| A) | 80–120 units ACTH for one to three weeks. | ||
| B) | IV methylprednisolone (1 g) for five to seven days. | ||
| C) | 44 mcg ß-interferon subcutaneously three times per week. | ||
| D) | 500–1,250 mg oral prednisone daily divided for three to seven days. |
The first-line treatment of MS-related exacerbations involves administration of high doses of IV corticosteroids, usually methylprednisolone (1 g daily), for five to seven days [100,101]. Alternative approaches for patients who do not tolerate large intravenous dosage or have poor venous access include:
Repository ACTH (corticotropin injection gel): 80–120 units daily for one to three weeks
Oral prednisone: 500–1,250 mg daily divided for three to seven days
"Smoothie Medrol:" 1 g methylprednisolone mixed in smoothie or juice taken orally with breakfast for three to seven days
Dexamethasone: 160–200 mg orally/IV daily divided for three to seven days
| A) | a malignant course. | ||
| B) | few current signs of disease. | ||
| C) | progressive (primary or secondary) course. | ||
| D) | severe relapses who have failed to respond to IV corticosteroids. |
It is now known that B-cell immunity also plays a key role in the pathogenesis of MS. Plasma exchange may be beneficial for relapsing forms of MS in which severe neurologic exacerbations prove refractory to parenteral corticosteroid therapy. It may also be beneficial for some patients with severe, rapidly progressive MS and similar disorders; however, it does not show any efficacy for SPMS or PPMS.
| A) | 0.5 mg capsule daily. | ||
| B) | 20 mg subcutaneous injection daily. | ||
| C) | 30 mcg intramuscular injection weekly. | ||
| D) | 250 mcg subcutaneous injection every other day. |
APPROVED LONG-TERM TREATMENTS FOR MS
| Drug | Type | Side Effects | Administration | Notes |
| Self-injected medications | ||||
| ß-interferon 1aa (Avonex) | Immunomodulator with antiviral properties | Flu-like symptoms, headache | 30 mcg IM injection weekly | Side effects may be prevented and/or managed effectively through various treatment strategies; side effect problems are usually temporary. Blood tests may be given periodically to monitor liver enzymes, blood-cell counts, and neutralizing antibodies. |
| ß-interferon 1ba (Betaseron, Extavia) | Immunomodulator with antiviral properties | Flu-like symptoms, injection-site skin reaction, blood count and liver test abnormalities | 250 mcg SC injection every other day | Side effects may be prevented and/or managed effectively through various treatment strategies; side effect problems are usually temporary. Blood tests may be given periodically to monitor liver enzymes, blood-cell counts, and neutralizing antibodies. |
| Glatiramer acetate (Copaxone, Glatopa, generic) | Immunomodulator that inhibits attacks on myelin | Injection-site skin reaction as well as an occasional systemic reaction—occurring at least once in approximately 10% of those tested | 20 mg SC injection daily or 40 mg SC injection three times per week | Systemic reactions such as flushing, dizziness, anxiety, and chest tightness arise 5 to 15 minutes following injection. The symptoms persist for a few minutes and lack long-term adverse effects; specific treatment is unnecessary. |
| ß-interferon 1aa (Plegridy) | Immunomodulator with antiviral properties | Flu-like symptoms, injection-site reaction, blood count and liver test abnormalities | 125 mcg SC injection once every two weeks | Side effects may be prevented and/or managed effectively through various treatment strategies; side effect problems are usually temporary. Blood tests may be given periodically to monitor liver enzymes, blood-cell counts, and neutralizing antibodies. |
| ß-interferon 1aa (Rebif) | Immunomodulator with antiviral properties | Flu-like symptoms, injection-site skin reaction, blood count and liver test abnormalities | 44 mcg SC injection three times per week | Side effects may be prevented and/or managed effectively through various treatment strategies; side effect problems are usually temporary. Blood tests may be given periodically to monitor liver enzymes, blood-cell counts, and neutralizing antibodies. |
| Ofatumumab (Kesimpta) | Monoclonal antibody that binds to and depletes B cells associated with MS disease activity | Upper respiratory tract infection, headache | 20-mg dose monthly self-administered SC | Serious side effects include infections, HBV reactivation, PML, weakened immune system, injection-related reactions. |
| Infused medications | ||||
| Alemtuzumab (Lemtrada) | Humanized monoclonal antibody that rapidly depletes or suppresses immune system cells (T and B cells), which can damage the myelin and nerves of the CNS | Rash, itching, headache, pyrexia, nasopharyngitis, nausea, diarrhea and vomiting, insomnia, numbness/tingling, dizziness, pain, flushing, infection | Five-day course of IV infusion followed one year later by a second three-day course | Adverse events can include infusion reactions, an increased risk of infection, emergent autoimmune diseases, immune thrombocytopenic purpura (ITP), and an increased risk of malignancies including thyroid cancer, melanoma and lymphoproliferative disorders. For early detection and management of these risks, the drug is only available through a restricted distribution program. |
| Mitoxantrone (Novantrone) | Antineoplastic immunomodulator/immunosuppressor | Usually well tolerated; side effects include nausea, thinning hair, amenorrhea, bladder infection, and mouth sores. Additionally, urine and whites of the eyes may turn a bluish color temporarily. | IV infusion once every three months (for two to three years maximum) | Carries the risk of cardiotoxicity and leukemia; it may not be given beyond two or three years. People undergoing treatment must have regular testing for cardiotoxicity, white blood cell counts, and liver function. Because of the potential risks, it is seldom prescribed for MS. Anyone who is taking or has taken mitoxantrone should have annual evaluations of his or her heart function, even if no longer receiving this medication. |
| Ocrelizumab (Ocrevus) | Humanized monoclonal antibody designed to selectively target CD20-positive B cells | Infusion reactions, increase in infections, most commonly upper respiratory tract in patients with RMS and PPMS or skin and lower respiratory tract infection in patients with PPMS | 600 mg IV every six months. For the initial dose, two 300-mg doses are given, separated by two weeks. | Should not be used in patients with hepatitis B infection or a history of life-threatening infusion-related reactions to the drug. Other rare adverse events, including cancer and progressive multifocal leukoencephalopathy (PML), could potentially occur, but these risks are still being studied. |
| Natalizumab (Tysabri) | Humanized monoclonal antibody | Headache, fatigue, depression, joint pain, abdominal discomfort, infection | IV infusion every four weeks | Risk of infection (including pneumonia) was the most common serious adverse event (occurring in a small percentage of patients). The TOUCH Prescribing Program monitors patients for signs of PML, an often-fatal viral infection of the brain. Risk factors for PML include the presence of JC virus antibodies, previous treatment with immunosuppressive drugs, and taking natalizumab for more than two years. |
| Oral medications | ||||
| Teriflunomide (Aubagio) | Immunomodulator affecting the production of T and B cells | Headache, elevations in liver enzymes, hair thinning, diarrhea, nausea, neutropenia, paresthesia | 7 mg or 14 mg tablet once daily | More severe adverse events include the risk of severe liver injury and the risk of birth defects if used during pregnancy. A TB test and blood tests for liver function must be performed within six months prior to initiation of therapy, and liver function must be checked regularly. If liver damage is detected, or if a patient becomes pregnant while taking this drug, accelerated elimination is prescribed. |
|
Fingolimod (Gilenya) |
S1P-receptor modulator |
Headache, flu, diarrhea, back pain,abnormal liver tests, cough |
0.5 mg capsule once daily |
Other adverse events include a reduction in heart rate (dose-related and transient); infrequent transient AV conduction block of the heart; a mild increase in blood pressure; macular edema; reversible elevation of liver enzymes; and a slight increase in lung infections (primarily bronchitis). Infections, including herpes infection, are also of concern. A six-hour observation period is required immediately after the first dose to monitor for cardiovascular changes. |
| >para>Cladribine (Mavenclad) |
Selectively targets and depletes the immune system’s B cells and T cells, followed by a “reconstitution,” as new B cells and T cells are produced |
Upper respiratory tract infections, headache, and decreased lymphocyte counts |
Two annual courses of up to 20 days over two years. No treatment is needed for years 3 and 4. |
Potential adverse events include lymphopenia and herpes zoster infection. Increased risk of malignancy and fetal harm. Should not be used in patients with an increased risk of cancer or who are pregnant; men and women of reproductive potential must use effective contraception. |
|
Siponimod (Mayzent) |
Primary actions at the S1P1 and S1P5 receptors, blocking movement of lymph cells from lymph nodes |
Headache, hypertension, changes in liver function tests |
After starting at a low dose, the recommended maintenance dosage is 2 mg taken orally once daily starting on day 6 |
Serious adverse events include a decrease in white blood cells, heart rate, and rhythm abnormalities, as well as hypertension, swelling of the macula of the eye, varicella zoster reactivation, and convulsions. Patients should be monitored for changes in vision caused by macular edema, transient decreases in heart rate, decline in lung function, and changes in liver enzymes. Women who could become pregnant should use contraception to avoid potential risk of fetal harm. |
|
Dimethyl fumarate (Tecfidera) |
Immunomodulator with anti-inflammatory properties |
Flushing and gastrointestinal events, reduced lymphocyte counts, elevated liver enzymes (rare) |
240 mg tablet twice daily |
Other possible adverse events include mild or moderate upper respiratory infection, pruritus, and erythema. In studies, the only serious adverse events to occur in two or more patients were gastroenteritis and gastritis. Reduced lymphocyte counts were seen during the first year of treatment. Liver enzymes were elevated in 6%, compared to 3% on placebo. |
|
Monomethyl fumarate (Bafiertam) |
Immunomodulator with anti-inflammatory properties |
Flushing, gastrointestinal events, redness, itching, rash, diarrhea |
Starting dose one 95-mg tablet twice daily for 7 days. Maintenance two 95-mg tablets (total 190 mg) twice daily. |
Side effects similar to those listed for dimethyl fumarate, including allergic reactions, PML, serious infections, and liver injury. |
|
Ponesimod (Ponvory) |
S1P-receptor modulator |
Upper respiratory tract infections, elevated liver enzymes, hypertension |
Using a 14-day starter pack, the dose starts low and gradually increases to 20 mg taken orally, once per day. |
Adverse effects can include more serious infections and a slowed heartrate (bradycardia or bradyarrhythmia). Contraindicated in those with certain heart conditions, or women who are planning to be or are currentlypregnant. |
|
Diroximel fumarate (Vumerity) |
Immunomodulator with anti-inflammatory properties |
Flushing, stomach problems |
231 mg twice daily |
The exact mechanism of action by which this medication exerts therapeutic effect in MS is not completely understood. However, upon entering the body, the medication is rapidly converted into the molecule monomethyl fumarate, which is the same active component found in dimethyl fumarate. |
|
Ozanimod (Zeposia) |
S1P-receptor modulator |
Upper respiratory infection, elevated liver enzymes, orthostatic hypotension |
0.92 mg once daily |
This medication is started at a lower dose and gradually increased until the full dose is reached, reducing the risk of a transient decrease in heartrate and atrioventricular conduction delays, which may occur if introduced too quickly. Warnings include an increased risk of infections, heart rhythm issues, liver injury, fetal risk, a decline in pulmonary (respiratory) function, and macular edema (swelling behind the eye). |
|
aAdditional information about interferons: Some individuals develop neutralizing antibodies to the interferons, but their impact on the effectiveness of these medications has not been established. Many continue to do well on these drugs despite the presence of neutralizing antibodies. Others may have sub-optimal results even without neutralizing antibodies present. The MS Council and the American Academy of Neurology have concluded that the higher-dosed interferons are likely to be more effective than lower-dosed interferons. Several factors, however, must be considered when selecting one of these drugs, and this decision must be made on an individual basis. AV = atrioventricular, IM = intramuscular, IV = intravenous, JC = John Cunningham virus, PML = progressive multifocal leukoencephalopathy, SC = subcutaneous, TB = tuberculosis. | ||||
| A) | Nausea | ||
| B) | Flu-like symptoms | ||
| C) | Injection-site reaction | ||
| D) | Gastrointestinal events |
Glatiramer acetate reduces the risk and severity of MS attacks and reduces MRI lesions over time. Studies comparing treatment with ß-interferon 1b or glatiramer have demonstrated similar efficacy. Glatiramer acetate has fewer adverse effects compared to the ß-interferons. Good injection technique and site rotation can help to reduce post-injection site reactions, but in some cases, repetitive injection of glatiramer acetate can cause lipoatrophy [118].
| A) | leukemia and cardiotoxicity. | ||
| B) | liver and thyroid dysfunction. | ||
| C) | injection site reactions and lipoatrophy. | ||
| D) | infusion-related hypersensitivity and anaphylaxis. |
Mitoxantrone, a cytostatic drug and a powerful anti-inflammatory, is used in the treatment of both RRMS and progressive forms of MS [119,120]. It is considered one of the most effective drugs in resolving relapses; however, due to the risks for leukemia and cardiotoxicity, it should only be prescribed to patients with rapidly advancing disease who are refractory to other therapies [121]. Some patients, especially with a subtype of RRMS called rapidly worsening MS, do not respond to immunomodulators and are managed with immunosuppressants, particularly mitoxantrone [122,123].
| A) | limiting cytokine secretion. | ||
| B) | inhibiting repair of myelin sheath lesions. | ||
| C) | modulating of oxidative pathways to decrease autoimmunity. | ||
| D) | preventing migration of auto-reactive lymphocytes into the brain. |
Natalizumab, a monoclonal antibody, may be used in the treatment of RRMS, and it is considered one of the most effective drugs in reducing the relapse rate (although long-term studies are lacking) [125,126,127]. Natalizumab prevents migration of autoreactive lymphocytes into the brain, which results in a profound decrease in CNS mononuclear cell trafficking that reduces MS exacerbations by 70% and disease progression by about 50% [128]. It also accelerates repair of myelin sheath lesions. Some studies have demonstrated that natalizumab can reduce new gadolinium-enhancing lesions by more than 90% [128,129].
| A) | Fingolimod | ||
| B) | Natalizumab | ||
| C) | Teriflunomide | ||
| D) | Mitoxantrone |
Treatment with fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, results in reduction of the relapse rate in patients with RRMS; however, it is associated with an increased risk of opportunistic infections, which can be fatal [135,136,137,138]. Fingolimod was the first oral agent with a labeled indication for relapsing forms of MS [136]. It promotes the redistribution of lymphocytes from the circulation to the lymphoid organs and prevents the entry of lymphocytes back into circulation. Several studies have demonstrated that it significantly reduces both clinical and radiographic MS disease activity. Its side effects include first-dose bradycardia, arrhythmia, reactive airway events, macular edema, skin cancers, and increased susceptibility to infections [118]. Fingolimod is the only drug approved for the treatment of highly active (or rapidly worsening) RRMS.
| A) | baclofen. | ||
| B) | tizanidine. | ||
| C) | dantrolene. | ||
| D) | gabapentin. |
Baclofen and tizanidine are commonly used to treat and reduce spasticity, and the benzodiazepines (e.g., diazepam) also have a beneficial effect. Other possible agents include gabapentin and dantrolene [102]. In general, baclofen is considered the drug of choice for spasticity in patients with MS [152]. An intrathecal baclofen pump may be indicated for patients with unilateral or bilateral phasic lower limb spasticity. Dantrolene should be used with caution because of the potential for hepatotoxicity [102].
| A) | Avoiding alcoholic beverages | ||
| B) | Avoiding spicy and acidic foods | ||
| C) | Increasing caffeine consumption | ||
| D) | Decreasing fluid intake two to three hours prior to bedtime |
Patients who experience nocturia or nocturnal enuresis should be advised to empty their bladder before going to bed and decrease or avoid fluid intake two to three hours prior bedtime. Caffeinated products, alcoholic beverages, and spicy and acidic foods can cause bladder irritation and urinary frequency and should be avoided. If these behavioral strategies are ineffective, treatment with oral desmopressin is indicated [157].
| A) | reduced libido. | ||
| B) | erectile dysfunction. | ||
| C) | orgasmic dysfunction. | ||
| D) | premature ejaculation. |
Type of sexual dysfunction varies. Reduced libido is the most frequent manifestation of primary sexual dysfunction for women with MS. Among ambulatory men with MS, approximately 60% experience erectile dysfunction, 50% report orgasmic dysfunction, and 40% experience reduced libido [160].
| A) | continue their treatment without pause. | ||
| B) | stop treatment for no more than one month prior to conception. | ||
| C) | be warned that pregnancy can dramatically worsen MS symptoms. | ||
| D) | stop treatment for at least three months prior to conception, if safe. |
If safe, women intending to conceive should stop their MS treatment for at least three months prior to conception. A study conducted in Sweden concluded that pregnancies that were not exposed to the ß-interferon in utero for at least a two-week period prior to conception resulted in healthier infants than pregnancies with such exposure [263]. A small Canadian study found that pregnancies exposed to ß-interferon resulted in a higher number of miscarriages, low birth weight, and prematurity [264]. However, a larger study did not find a significantly higher rate of complications in pregnancies accidentally exposed to immunomodulators [265]. In general, even the higher incidence of complications observed in some studies was only slightly greater than that of the general population. If continued treatment is necessary, modifications to the prescribed regimen (with preference for lower risk options) may be necessary. Many drugs used to treat MS and its related symptoms are contraindicated during pregnancy.