Multiple Sclerosis (MS)–test

Multiple-Sclerosis-QR

ACKNOWLEDGEMENTS:

Thanks to Dr. Mark Freedman, MSc, MD, FAAN, FRCPC, Professor of Medicine (Neurology), University of Ottawa, Director, Multiple Sclerosis Research Unit, The Ottawa Hospital-General Campus, Ottawa, ON Canada, and Suzette Mahabeer, RN, MScN, Nursing Faculty – McMaster University, Hamilton, ON Canada for their expertise with the initial review of this topic.

Definition

A Chronic autoimmune inflammatory demyelinating disease that can affect any part of the central nervous system and characterized by periods of clinical worsening (relapses) interspersed with periods of remission.

Etiology

Unknown but appears to be a compilation of several factors including:

  • Autoimmune dysfunction
  • Genetic susceptibility/predisposition
  • Viral etiology
  • Environmental factors (Vit-D deficiency, secondary to reduced sun exposure, smoking)

Classification:

The diagnosis of MS is made on clinical grounds with input from imaging and other laboratory studies. There are four main subtypes and other observed syndromes as follows:

  • Relapsing-remitting MS (RRMS)
    • Most common initial presentation in 85-90% of patients
    • Periods of relapse during which time new symptoms can appear, followed by periods of stability, irrespective of whether the recovery is complete or incomplete
  • Secondary progressive MS (SPMS)
    • Evolves from RRMS
    • SPMS is often typically preceded by a variable period (2–40 years) of RRMS
    • Steady progression of clinical neurologic damage in the absence of intervening relapses
    • Relapses, often with residual deficits may or may not ensue
  • Primary progressive MS (PPMS)
    • Represents 10-15% of those with MS
    • Gradual progression with a changing slope
    • No apparent relapses
  • Progressive relapsing MS (PRMS)
    • Least common form of MS
    • Steady cumulative progression of clinical neurologic damage
    • Superimposed relapses with or without remissions
  • Other:
    • Clinically Isolated Syndrome (CIS): The first clinical presentation of a disease that shows characteristics of inflammatory demyelination that could be MS, but has yet to fulfill criteria of dissemination in time
    • Radiologically Isolated Syndrome (RIS): Incidental imaging suggests inflammatory demyelination in the absence of clinical signs or symptoms. Not considered an MS subtype, as clinical evidence lacking

Epidemiology

The leading cause of nontraumatic neurologic disability in the young.

  • Typical age of onset: 20-40 years; range: 2-80 years
  • Mean age of onset 32 years
  • Female > Male
  • Worldwide incidence ~0.1%
  • Prevalence
    • Canada ~55,000 – 100,000
    • USA ~350,000 – 400,000
    • Worldwide ~2.5 million
  • Increased incidence observed when moving away from the equator in either direction
  • Economic impact: Cost of managing disease plus disability plus loss of manpower productivity for patient and caregivers (the greatest cause of acquired non-traumatic neurological impairment in young people)
  • Death often results from medical complications (e.g. infections)

Pathophysiology

  • Demyelination: An immune-mediated inflammation which denudes axons of their myelin sheath
  • Demyelination is often followed by attempts of remyelination
  • The cycle of demyelination and remyelination, leads to inadequate and often ineffective myelination
  • Axonal injury occurs as either “collateral” damage to the inflammation or as a part of the disease process
  • The initial relapsing-remitting process may evolve into a secondary progression

The mechanism is as follows:

MS-Pathophysiology-Mechanism

Clinical Manifestations:

Variable neurological symptoms separated in space (depending on CNS areas involved) and time by months or years. There may well be a threshold beyond which progressive neurological decline may ensue.

Common eventual signs and symptoms are:

  • Fatigue and generalized weakness
  • Vision disturbances: Impaired or double vision, nystagmus
  • Motor dysfunction: Focal weakness, tremor, incoordination, paroxysmal muscle spasms
  • Sensory disturbances: Paraesthesias, impaired deep sensation, impaired vibratory and position sense
  • Impaired speech: Slurring, scanning (dysarthria)
  • Abnormal reflexes: Absent or exaggerated
  • Urinary dysfunction:
    • Hesitancy, frequency, urgency, retention, incontinence; urinary tract infections (UTI)
    • Urinary dysfunction affects about 90% of patients with MS and UTIs may exacerbate relapse of MS
  • Neurobehavioral syndromes: Depression, cognitive impairment, emotional lability

Symptoms of MS are often unpredictable, varying from person to person and from time to time in the same person.

Workup and Diagnosis

History:

  • History of previous transient neurological episodes, including duration of events and recurrence
  • Information of relapsing remitting phenomenon over time
  • Ocular history – including acuity, loss of color vision
  • History of depression or cognitive impairment

Other symptoms:

Bowel/bladder

  • Urinary urgency and frequency, may progress to incontinence and bladder atony
  • Urinary tract infections are common in MS (F > M), further contributes to bladder dysfunction
  • Constipation, fecal incontinence

Pain

  • Common complain
  • Approximately 43 % of patients report one or more painful symptoms such as trigeminal neuralgia, Lhermitte’s phenomenon, dysesthesia, back pain, visceral pain, and pain due to muscle spasms

Sexual dysfunction

  • Men experience various degrees of erectile dysfunction
  • Women may experience lack of sensitivity and dyspareunia due to decreased vaginal lubrication

Uhthoff’s phenomenon

  • Exposure to hot conditions (sun, sauna, hot-tubs etc.) transiently worsens neurological symptoms
  • Mechanism likely related to conduction block

Fatigue

  • The degree of fatigue is discordant with the level of activity. May precede focal neurological symptoms

Depression

  • More than 50% of patients may have some degree of depression
  • Multifactorial, related to psychological aspect of acquiring a potentially debilitating chronic progressive disorder ±co-morbidities

Cognitive dysfunction

  • Cognitive impairment occurs in 34-65% of patients
  • May be present at time of detection of MS

Epilepsy

  • 2-3% of patients may develop epilepsy

Neurological Examination

Optic nerve assessment for optic neuritis (ON)

Symptoms:

  • Recent visual disturbances, pain in the eye exacerbated on movement
  • Variable degree of visual loss (scotoma) affecting mainly central vision
  • Seldom involves both eyes

Signs:

  • A moving flashlight produces an unequal pupillary constriction, due to an afferent pupillary defect (Marcus Gunn pupil) on  the affected side
  • Optic disc edema is a rare finding and would suggest something else
  • In retrobulbar lesions; initially, fundus may appear normal, however; pallor may ensue later as a result of axonal loss and gliosis
  • Approximately 90% of patients regain normal vision over 2-6 months

Internuclear opthalmoplegia

  • Abnormal horizontal ocular movements with lost or delayed adduction
  • Horizontal nystagmus of the abducting eye
  • Lesion of the medial longitudinal fasciculus on the side of diminished adduction
  • Convergence preserved

Nystagmus

  • Horizontal, rotational and vertical nystagmus can all be seen with lesions involving various parts of the brain stem and/or cerebellum
  • Pendular nystagmus (rapid, small-amplitude pendular oscillations of the eyes) can be present in <4% of MS patients

Vertigo

Symptoms

  • Sense of movement (often rotational) of a person or to an external environment. May be due to brain stem plaques
  • May also occur in conjunction with other brain stem findings including nystagmus, diplopia, facial weakness or dysesthesia, hyper- or hypoacusis, and long track signs (hemi-sensory or hemi-motor deficits)

Signs:

  • Positive Dix-Hallpike maneuver: Up or down beating, non-rotational nystagmus, without latency (patient lying with neck extended off the examining table and head angled to left or right)

Sensory disturbance:

Symptoms

  • Numbness, tingling, pins-and-needles
  • Band-like tightness around limbs or torso
  • Decreased sensitivity to light touch
  • Paraesthesia, impaired deep, vibratory and positional sensations

Signs

Variable and related to sensory pathway involved

  • Impairment of pin prick and temperature if spinothalamic tract affected
  • Impairment of vibration and light touch, joint position sense if posterior column involved
  • Patchy areas of reduced pain and perception in the limbs and trunk

Lhermitte’s phenomenon

  • Transient sensory disturbance with the sensation of an electric-like shock radiating down the spine into the limbs triggered by neck flexion
  • Occurs with other lesions of the upper cervical cord including tumors, cervical disc herniation, and trauma

Motor symptoms

Symptoms

  • Face, limb or trunk weakness ± associated in-coordination

Signs (typically related to upper motor neuron findings)

  • Limb paresis progressing to plegia
  • Often asymmetric, can lead to hemiparesis/plegia or paraparesis/plegia or tetraparesis/plegia
  • Increased tone/spasticity
  • Hyperreflexia – including clonus, spread of reflexes i.e. activating one reflex recruits another reflex pathway, babinski sign (extensor plantar response)
  • Hyporeflexia – may reflect hypotonia resulting from cerebellar involvement
  • Unilateral facial paresis – both upper motor neuron (Bell’s palsy) and lower motor neuron facial weakness can occur
  • Limb amyotrophy as well as facial myokymia (fine undulating wave-like facial twitching
  • Hemifacial spasm can be associated with MS

Coordination and balance

Symptoms

  • Incoordination of limbs (including finger dexterity), trunk and gait
  • Impact on ADLs such as writing, eating, dressing, walking etc.

Signs (typically related to cerebellar findings)

  • Nystagmus
  • Speech disturbance (staccato or scanning or telegraphic speech)
  • Dysarthria and dysphagia
  • Limb dysmetria/ataxia – uni or bilateral
  • Gait and truncal ataxia with tendency to falls
  • Astasia (inability to stand)
  • Hypotonia (decreased tone)
  • Intention tremor

Cognitive dysfunction

Symptoms

  • Cognitive decline may be discordant with clinical exacerbations
  • Manifests in poor memory and information processing, inattention and difficulty with abstract thought

Signs

  • Poor performance on standardized tests
  • Mini mental status exam (MMSE)
  • Montreal cognitive assessment (MoCA)

Laboratory

Blood

  • Complete blood count (CBC)
  • Electrolytes, calcium
  • B12, folate
  • Erythrocyte sedimentation rate (ESR)
  • ANA/rheumatoid factor
  • Antiphospholipid/anticardiolipin antibodies
  • Thyroid studies (freeT4, TSH)
  • NMO-IgG [if neuromyelitis optica suspected]
  • Anti-MOG antibodies
  • Lyme serology (if in an endemic area)
  • Serology for HTLV I/HTLV II (if tropical spastic paraparesis suspected)
  • HIV (if suspected)

CNS Imaging

MRI

  • 95% sensitive in patients with established disease
  • Detects white matter lesions within the brain and spinal cord
  • T2 weighted images:
    • Hyperintensities lesions typically periventricular and corpus callosum
    • However, Juxtacortical lesions have been reported
    • Provide information about disease burden
  • T1 weighted images:
    • Hypointense black holes suggest areas of permanent axonal/tissue injury/gliosis
  • Gadolinium infusion enhances lesions on T1 images and indicates active inflammation; ring-enhancing mass-like lesions may be suggestive of tumefactive MS
  • Lesions may enhance for up 4-6 weeks post-exacerbation; only 3–5% of MS lesions enhance for >8 weeks, hence persistent enhancement may suggest other pathology, e.g. neurosarcoidosis
  • MRI showing multifocal enhancing lesions with first clinical presentation raises the possibility of MS vs. other disseminated diseases such as acute disseminated encephalomyelitis (ADEM) or neoplasm, sarcoidosis, progressive multifocal leukoencephalopathy (PML)

2010 McDonald criteria for the diagnosis of multiple sclerosis

The revised McDonald criteria replaced the previously used terms such as “clinically definite” and “probable MS” with the following:

  • The diagnosis of “MS” is given if diagnostic criteria are fulfilled
  • The diagnosis of “possible MS” is given if the criteria are not completely met
  • The diagnosis of “not MS” is given if the criteria are fully explored and not met

CSF analysis

  • Oligoclonal bands: Distinct electrophoretic patterns reflecting elevation of IgG, present in >95% of patients with established disease but can be non-specific, as can the MRI, and may be seen in other neurodegenerative conditions and CNS infections
  • Elevated IgG index in <90% of patients (values reported as >0.7)
  • Mild pleocytosis (unusual to have WBC >50)
  • Mildly elevated protein is not unusual

Evoked potentials

  • A measure of electrical conductance along the neuroaxis
  • Electrodes placed at different points over peripheral nerves, spinal cord and cortex can be used to detect conduction delays in an induced electrical potential
  • Delays in conduction may help to localize lesions
  • Types of evoked potentials:
    • Somatosensory evoked potential (SSEP)
    • Brain stem auditory evoked potential (BAER)
    • Motor evoked potentials via magnetic stimulation
    • Visual evoked potentials (VEP)-(the most useful of all)
RN/Medical Management:

Goal is to:

  • Shorten the acute exacerbation
  • Decrease the frequency of acute attacks and delay disease progression
  • Relieve the symptoms to maintain the quality of life

Treatment strategies:

  • a) Treatment of acute exacerbation
  • b) Disease-modifying therapy
  • c) Symptomatic treatment
  • d) Non-pharmacological treatment

A) Acute exacerbations:

For patients presenting with functional impairment, in acute phase, the recommended first-line treatment is glucocorticoids.

  • Methylprednisolone: 1 g/day IV usually for 3-5 days (but can be used up to 10 days). Maybe followed by a tapering dose of oral prednisone (e.g. 100 mg x 1 dose then decrease by 10 mg daily until finished)
  • Prednisone: 500-1000 mg PO daily for 3-5 days. Maybe followed by a tapering dose of oral prednisone
  • Plasma exchange:  Considered for steroid-resistant exacerbation

B) Disease-modifying therapy:

Indications:

  • Relapsing-remitting (RRMS) phase
  • Secondary progressive multiple sclerosis (SPMS)
  • Primary progressive (PPMS)

Overview of Disease Modifying Therapy in MS

Comparison of Oral Disease-Modifying Therapies in MS

Other agents which have been tried but without proven benefit include:

Cyclophosphamide:

  • Dose: 700 mg/m2 IV; every month along with 1 g of methylprednisolone
  • Highly myelosuppressive; monitor absolute neutrophils count for dose adjustment

Other experimental modalities include:

  • Hematopoietic stem cell transplantation

Intravenous immunoglobulin (IVIG):

  • In the partum or immediate post-partum period
    • Induction with 0.4 g/kg daily for 5 days followed by monthly 1 g/kg

C) Symptomatic treatment:

  • Inevitable as disease advances
  • Complex due to the widespread compromise of CNS function

Symptoms often requiring attention in MS1) Spasticity:

Pain and constipation may trigger spasticity. Assess and treat before using antispasmodics.

Treatment:

Baclofen:

  • Dose: 5-10 mg PO TID
  • Maximum dose: 80 mg/day

Tizanidine:

  • Dose: 2-4 mg PO TID
  • Maximum dose: 36 mg/day

Gabapentin:

  • Dose: Begin at 100 to 300 mg TID
  • Effective dose range: 900-1800 mg/daily in 3 divided doses
  • Maximum dose: 2400 mg-3600 mg/day

Diazepam:

  • Dose: 5-10 mg PO TID PRN

Cannabinoids (delta-9-tetrahydrocannabinol & cannabidiol)

  • Dose: Buccal 1 spray every 4 hr, 4-5 sprays/day for MS
  • May start initially with 1 spray/day; increase every 1-2 days; Max. ~12 sprays/day

Caution: Abrupt discontinuation of the above agents may cause seizures and withdrawal symptoms.

Botulinum toxin:

  • Dose-dependent on site of administration and severity of the disease

2) Fatigue:

May be characterized as:

  • Neuromuscular fatigue
  • Daytime drowsiness secondary to insomnia
  • Fatigue associated with depression

Treatment:

Amantadine:

  • Dose: 100 mg PO BID; may improve MS associated lassitude

Modafinil:

  • Dose: 100 mg PO BID

Antidepressant:

  • For fatigue associated with depression(e.g. fluoxetine)

Fampridine (4 aminopyridines):

  • Dose: 10 mg PO daily

3) Pain:

  • Acute or chronic pain is a frequent complaint in MS patients affecting the quality of life
  • Chronic pain description include burning, squeezing, lancinating or gritty
  • Neuropathic pain does not respond to NSAIDs

Treatment:

Gabapentin:

  • Dose: Begin at 100 to 300 mg PO TID
  • Effective dose range: 900-1800 mg/daily in 3-4 divided doses
  • Maximum dose: 2400-3600 mg/day

Carbamazepine:

  • Dose: 100-200 mg PO daily
  • Increase up to a total daily dosage of 600-1600 mg (divided) as tolerated
  • Monitor drug levels, CBC, LFTs

Tramadol:

  • Dose: 50-400 mg PO daily as tolerated

Pregabalin:

  • Dose: May begin with 25-75 mg PO daily and increase to 150 mg PO BID
  • Effective dose range: 900-1800 mg/daily in 3-4 divided doses
  • Maximum dose: 600 mg daily in divided doses

Cannabinoids(delta-9-tetrahydrocannabinol & cannabidiol)

  • Dose: Buccal 1 spray every 4 hr, 4-5 sprays/day for MS
  • May start initially with 1 spray/day; increase every 1-2 days; Max. ~12 sprays/day

4) Paroxysmal symptoms:

  • Lhermitte sign or barber chair phenomenon (an electrical sensation that radiates down the vertebra on flexion or extension of neck)
  • Intermittent vertigo

Treatment:

  • Carbamazepine
  • Gabapentin

5) Bladder dysfunction:

Bladder spasticity:

  • Oxybutynin: 5 mg PO TID or QID
  • Tolterodine: 2 mg PO BID
  • Imipramine: Usual dose 75 mg PO daily
  • Solifenacin: 5 mg PO daily
  • Darifenacin: Extended-release 7.5 mg PO daily; may increase to 15 PO daily
  • Trospium: 20 mg PO BID
  • Intravesicular botox: 200 Units

Denervated bladder treated by:

  • Self-catheterization

Nocturia, night-time incontinence/urgency:

  • Desmopressin (DDAVP): 0.1-0.4 mg PO once at bedtime

6) Bowel dysfunction:

Constipation: can be treated with the combination of fiber and stool softeners.

  • High fiber diet and stool softeners
  • Docusate Sodium: 100 mg PO TID
  • Stimulants: Senna suppositories 2 tabs at bedtime; digital stimulation sometimes used
  • Adopting a bowel regimen may help to regulate urges and incontinence

7) Sexual dysfunction

Erectile dysfunction:

Oral agents:

  • Sildenafil* 50-100 mg
  • Vardenafil* 5-20 mg
  • Tadalafil* 5-20 mg

*Give medication 30 minutes prior to intercourse; caution advised in the elderly and with cardiac disease.

Injectable agents (intracavernous):

  • Alprostadil:
    • Begin with 2.5 mcg and titrate by 2.5 mcg increments
    • Initial administered under the supervision
    • Doses exceeding 40 mcg not recommended

Vaginismus:

  • Antispasmodics

Vaginal dryness:

  • Water-based lubrication

8) Depression

It can be managed through counseling and/or medication.

Tricyclic antidepressant

  • Amitriptyline: 75-200 mg/day PO at night or in divided doses
  • Imipramine: 75-150 mg/day PO at night or in divided doses
  • Nortriptyline: 25-200 mg/day PO at night or in divided doses

Selective serotonin reuptake inhibitors (SSRIs)

  • Fluoxetine: 20-80 mg PO once daily
  • Paroxetine:
    • 20 mg PO once daily
    • May increase by 10 mg/day to a maximum of 50 mg/day
  • Sertraline:
    • 50 mg PO once daily
  • Citalopram:
    • 20 mg PO once daily; may increase by 20 mg/week to a maximum of 40 mg/day

Serotonin/norepinephrine reuptake inhibitors (SNRIs)

  • Duloxetine:
    • Start 30-60 mg PO once daily; target dose 60 mg/day
    • May titrate dose by 30 mg/day if needed; Max. 120 mg/day
  • Venlafaxine:
    • Start 37.5-75 mg daily; may increase by 75 mg/day as tolerated
    • Maximum 225 mg/day

Prognosis

  • Variable and unpredictable
  • If untreated, more than 50% of patients with multiple sclerosis will develop significant physical disability within 20-25 years from onset
  • 70% of patients lead active, productive lives with prolonged remission
  • 30% relapse in 1 year, 20% in 5-9 years, and 10% in 10-30 years
  • Untreated MS Patients are thought to have an average life expectancy 5-7 years shorter than that of the general population

D) Non-pharmacological treatments

  • Minimize exposure to exacerbating factors such as extreme temperature (hot tubs/saunas)
  • A cooling vest or cold beverages may help lower body temperature
  • Monitor for local sores and ulcers and take preventive measures before they become a source of infection
  • Aerobic exercise may help prevent deconditioning
  • Stretching exercises to help relieve stiffness
  • Assistance with energy conserving techniques e.g. timed rest periods
  • Bowel and bladder regimen to assist voiding; increase fiber and fluid intake
  • Recommend self-catheterization where required
  • Counseling: Psychologist, psychiatrist referral as required
Medications:

ACUTE EXACERBATION-Medications

Corticosteroids

  • Methylprednisolone
  • Prednisone

Use: Acute exacerbations

Mechanism:

  • Decreases inflammation and the normal immune response through multiple mechanisms, also suppresses adrenal function in higher doses

Doses:

Methylprednisolone

  • 1-2 g/day IV usually for 3-5 days (but can be used up to 10 days). Maybe followed by a tapering dose of oral prednisone (e.g. 100 mg x 1 dose then decrease by 10 mg daily until finished)

Prednisone

  • 500-1000 mg PO daily for 3-5 days followed by tapering doses

DISEASE MODIFYING-Medications

Interferon

Types:

  • Interferon Beta-1a (IFNb-1a)
  • Interferon Beta-1b (IFNb-1b)

Use: Immunomodulating therapy

Mechanism:

  • Exact mechanism in the treatment of MS is unknown
  • Immunomodulatory effects include
    • Enhancement of suppressor T cell activity
    • Reduction of pro-inflammatory cytokines
    • Down-regulation of antigen presentation
    • Reduced trafficking of lymphocytes into the central nervous system

Dose:

Interferon Beta-1a (intramuscular)

  • 30 µg once weekly

Note:

  • Should be stored in a refrigerator at 2-8°C. Allow to reach room temperature (about 30 minutes) before giving the injection
  • Prefilled syringe can be stored at room temperature (between 15-30°C) for up to one week

Interferon Beta-1a (subcutaneous)

  • Titrate to 22-44 µg 3 times per week, at least 48 hours apart
  • 44 µg titration: 8.8 µg 3 times per week for 2 wks; then 22 µg 3 times per week for 2 wks; followed by 44 µg 3 times per week
  • 22 µg titration: Start 4.4 µg 3 times/week for 2 wks; then 11 µg 3 times/week for 2 wks; followed by 22 µg 3 times/week

Note: Interferon Beta-1a new HSA-free formulation liquid in a pre-filled syringe or pre-filled cartridge should be stored at 2-8°C. Allow warming to room temperature prior to use; do not use external heat sources such as hot water. It can also be stored for a limited time period at room temperature (up to 25°C), but not more than 1 month.

  • Stored at 2-8°C. Allow to warm to room temperature prior to use, Do not use external heat sources such as hot water
  • May be stored for a limited period at room temperature (up to 25°C), but not more than 1 month

General Care:

  • Protect injection from light and do not freeze
  • Rotate injection site with each injection, to minimize the likelihood of injection site reactions
  • NSAIDs, acetaminophen may be used for flu-like symptoms

Interferon Beta-1b

Multiple sclerosis (relapsing)

  1. Titration: Increase by 0.0625 mg SC every 2 weeks as follows:
    • Week 1-2 = 0.0625 mg every other day
    • Week 3-4 = 0.125 mg every other day
    • Week 5-6 = 0.1875 mg every other day
    • Then 0.250 mg (target dose) every other day

Multiple sclerosis (secondary-progressive)

  • Titration: 0.125 mg SC every other day for 2 weeks as follows; then 0.250 mg every other day

Note: Store between 2-25°C. After reconstitution, if not used immediately, refrigerate solution between 2 and 8°C and use within 3 hours of reconstitution.

IMMUNOMODULATOR

  • Glatiramer acetate

Use: Immunomodulating therapy

Mechanism:

  • Complete mechanism in the treatment of MS is unknown
  • Supported hypothesis
    • Induces and activate T-lymphocyte suppressor cells specific for a myelin antigen
    • Interferes with the antigen-presenting function of certain immune cells opposing pathogenic T-cell function

Dose:

Glatiramer acetate:

  • 20 mg SC once daily
  • 40 mg SC 3 times per week

Sphingosine 1-phosphate receptor modulator

  • Fingolimod

Use: Immunomodulating therapy

Mechanism:

Complete mechanism in the treatment of MS is unknown

  • Binds to sphingosine 1-phosphate (S1P) receptors 1, 3, 4, and 5
  • It’s binding to S1P receptors on lymphocytes induces S1P receptor down-regulation on lymphocytes, and blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood
  • The amount of lymphocytes available to the central nervous system are decreased which reduces central inflammation

Dose:

Fingolimod:

  • 0.5 mg PO once daily

Pyrimidine synthesis inhibitor

  • Teriflunomide

Use: Relapsing forms of multiple sclerosis (MS)

Mechanism:

Exact mechanism of action in MS is unknown

  • An immunomodulatory agent that inhibits pyrimidine synthesis by inhibiting dihydroorotate dehydrogenase enzyme
  • It also has anti-inflammatory effects

Dose:

Teriflunomide:

    • 7 mg or 14 mg PO once daily (7 mg dose not available in Canada)

Immunomodulator

  • Dimethyl Fumarate

Use: Treatment of adults with relapsing-remitting MS

Mechanism:

  • Complete mechanism in the treatment of MS is unknown
  • It is believed to result from its anti-inflammatory and cytoprotective properties via activation of the Nrf2 pathway

Dose:

Dimethyl Fumarate:

  • Initiate 120 mg PO twice daily for 7 days; then increase to 240 mg PO twice daily

Selective Immunomodulators

  • Alemtuzumab

Use: Adult RRMS

Mechanism:

  • Binds to nucleic acids and inhibits DNA and RNA synthesis
  • Replication is decreased by binding to DNA topoisomerase II
  • Inhibit the incorporation of uridine into RNA and thymidine into DNA
  • Active throughout entire cell cycle (cell-cycle nonspecific)

Dose:

Alemtuzumab:

  • 300 mg IV once in 4 weeks

Selective adhesion molecule inhibitor

  • Natalizumab

Use: Immunomodulation therapy

Mechanism(s):

Complete mechanism in the treatment of MS is unknown.

  • Binds integrins on leukocyte cell walls, preventing migration into inflamed parenchymal tissue (monoclonal antibody)
  • Potentially blocks of T-lymphocyte migration into the CNS

Dose:

Natalizumab:

  • 300 mg IV infusion over 1 hour every 4 weeks

Immune Modifiers/Monoclonal Antibody

  • Ocrelizumab

Use: Relapsing forms of multiple sclerosis (MS), to include

  • Clinically isolated syndrome
  • Relapsing-remitting disease
  • Active secondary progressive
  • Early Primary progressive MS

Mechanism:

  • Selectively depletes CD20-expressing B cells
    • B cells have been implicated in the pathogenesis of MS
    • CD20 is a surface antigen found in pre-B cells and mature and memory B cells

Dose:

Ocrelizumab:

  • Initial dose on day 1: 300 mg (in 250 ml) IV. Follow-up dose on day 15: 300 mg (in 250 ml) IV
  • Maintenance: 600 mg (in 500 ml) IV every 6 months

NB: Premedicate 100 mg IV methylprednisolone (or alternative) and antihistamine (e.g. diphenhydramine), +/-  Acetaminophen ~30 minutes prior to each infusion.

NB: All vaccines should be updated at least 4 weeks before starting treatment; hepatitis B screening required. Hepatitis B virus screening. Monitor for allergic reactions, rash, laryngeal edema, dyspnea, infections; increased risk of respiratory infections.

Immune Modifiers/ Sphingosine-1-phosphate receptor modulator

  • Siponimod

Use: Secondary Progressive MS (SPMS) with active disease evidenced by relapses or imaging features characteristic of multiple sclerosis inflammatory activity.

Mechanism:

  • Retention of lymphocytes (B cells and CD4+ and CD8+ T cells) within lymph nodes and thymus leading to ~ 20% to 30% reduction in circulating lymphocytes and hence reduced lymphocyte transition into the CNS

Dose:

Siponimod:

  • Genotype dependent: Treatment is highly dependent on the CYP2C9 genotype defining those with fast, intermediate, or slow metabolizers. Consequently, CYP2C9 genotype needs to be established prior to initiation of treatment
  • Assess past and present medical history, including diabetes, ophthalmological disease, concomitant use of immunosuppressive therapy, history of varicella-zoster and cardiac history including the use of antihypertensive agents
  • There is a risk of cardiac anomalies including bradyarrhythmias, conduction block, and QTc prolongation that increases as enzyme metabolism decreases, hence the maintenance dose is reduced in intermediate and slow metabolizers and contraindicated in those with the slowest metabolizer genotype (CYP2C9*3*3).  Obtain ECG prior to treatment to assess for pre-existing conduction abnormalities


Immune modifiers/Antineoplastic

  • Mitoxantrone

Use: Immunosuppressant therapy

Mechanism:

The mechanism by which it exerts its therapeutic effects in MS is not fully known.

  • The drug may involve immunomodulation through the depletion and repopulation of lymphocytes

Dose:

Mitoxantrone:

  • 5-12 mg/m2 IV every 3 months for 2 years, with maximum lifetime cumulative dose of 140 mg/m2

Antineoplastic/Immunosuppressant

  • Cyclophosphamide

Use: Immunosuppressant therapy

Mechanism:

  • An alkylating agent that prevents cell division by cross-linking DNA strands and inhibiting DNA synthesis
  • Interferes with DNA replication and RNA transcription
  • It is a cell cycle phase, nonspecific agent and potent immunosuppressive agent

Dose:

Cyclophosphamide

Various treatment protocols exist for cyclophosphamide and methylprednisolone one of them stated below:

  • 800 mg/m2 IV infusion given once every 4 weeks plus 1 g of methylprednisone. Dose adjustments based on preinfusion and 10 day post-infusion WBC

SYMPTOMATIC TREATMENT-Medications

Antispasmodic

  • Baclofen
  • Tizanidine
  • Cannabinoids

Use: Spasticity

Mechanism:

Complete mechanism of action unknown.

Baclofen

  • It inhibits both monosynaptic and polysynaptic spinal reflexes, possibly by hyperpolarization of afferent terminals (resultant relief of muscle spasticity)

Tizanidine

  • It is chemically-related to clonidine and other α2-adrenergic agonists, which acts as a centrally acting muscle relaxant with anti-hypertensive properties
  • Presumably, it reduces spasticity by increasing presynaptic inhibition of motor neurons

Dose:

Baclofen

  • 5-10 mg PO TID, may increase 5 mg/dose every 3 days; Max. 80 mg/day

Tizanidine

  • 2-4 mg PO TID; may increase by 2-4 mg PO as needed to a maximum of 3 doses in 24 hrs, with at least 6-8 hrs interval between doses; Max. 36 mg/day

Dose in renal impairment:

  • CrCl <25: Decrease dose (e.g. 2-4 mg PO)

Cannabinoids

  • Buccal 1 spray every 4 hr, 4-5 sprays/day for MS, may start initially with 1 spray/day; increase every 1-2 d, Max ~12 sprays/day

Anticonvulsant:

  • Gabapentin
  • Carbamazepine

Gabapentin

Use: Neuropathic pain, Lhermitte’s, Seizures

Mechanism:

Exact mechanism of action unknown.

  • It is structurally related to GABA (gamma-aminobutyric acid)
  • It does not affect the synthesis or uptake of GABA
  • High-affinity gabapentin binding sites have been located throughout the brain

Dose:

Gabapentin

  • Begin at 100 to 300 mg TID; increase as tolerated every 3-7 days. Effective dose range: 900-1800 mg daily in 3 divided doses. Max dose: 2400-3600 mg/day

Dose in renal impairment:

  • CrCl 30-60: 200-700 mg twice daily
  • CrCl 16-29: 200-700 mg once daily
  • CrCl 15: 100-300 mg once daily
  • CrCl <15: Decrease dose proportionately to creatinine clearance
  • Hemodialysis: Single dose of 125-350 mg as a supplement every 4 hrs of dialysis

Carbamazepine

Use: Neuropathic pain, Lhermitte’s, Seizures

Mechanism:

  • Decreases synaptic transmission
  • Within CNS by affecting sodium channels in neurons
  • It had anticonvulsant, anticholinergic, antineuralgic, antidiuretic, muscle relaxant, antimanic, antidepressive, and antiarrhythmic properties

Dose:

Carbamazepine

  • 100-200 mg/day PO; may increase up to a maximum of 600-1600 mg
  • Monitor: CBC and risk of bone marrow suppression within the first 2 months of initiating therapy

Analgesic; Neuropathic pain

  • Pregabalin
  • Cannabinoids

Pregabalin

Primary use: Neuropathic pain may assist with Lhermitte’s; used for partial-onset seizures in some countries

Mechanism:

Exact mechanism of action is unknown.

  • Binds to alpha2-delta subunit of voltage-gated calcium channels within the CNS, inhibiting excitatory neurotransmitter release
  • Produces antinociceptive and antiseizure effects

Dose:

Pregabalin

  • 75-150 mg PO BID; Max. dose 600 mg daily in 2-3 divided doses

Dose in renal impairment:

Cannabinoids

  • Buccal 1 spray every 4 hr, 4-5 sprays/day for MS, may start initially with 1 spray/day; increase every 1-2 d, Max. ~12 sprays/day

Benzodiazepine

  • Diazepam

Use: Spasticity, anxiety, sedation

Mechanism:

  • Binds to benzodiazepine receptors and enhances GABA effects
  • Depresses the CNS, produces skeletal muscle relaxation, has anticonvulsant properties due to enhanced presynaptic inhibition

Dose:

Diazepam

  • 5-10 mg PO TID PRN; can be given as monotherapy or in combination

Dopamine agonist

  • Amantadine

Use: Fatigue

Mechanism: Unclear

Dose:

Amantadine

  • 100 mg PO BID; Max. 300 mg PO daily in divided doses

Central nervous system stimulant

  • Modafinil

Use: Fatigue in MS

Mechanism:

Exact mechanism of action is unknown.

  • It may exert its stimulant effects by decreasing GABA-mediated neurotransmission

Dose:

Modafinil:

  • 100 mg PO BID

Selective serotonin reuptake inhibitors (SSRIs)

  • Fluoxetine

Use: MS induced fatigue, depression

Mechanism:

  • Inhibits the presynaptic reuptake of neurotransmitters and increases synaptic serotonin concentration and potentiates its effect
  • Little effect on the reuptake of norepinephrine or dopamine
  • Does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors

Dose:

Fluoxetine

  • Start 20 mg/PO daily every morning; may increase dose gradually after several weeks if inadequate response; Max. 80 mg/day

Potassium channel blocker

  • Fampridine – Approved by Health Canada
  • Dalfampridine – Approved by FDA

Use: Help to improve walking in patients with MS

Mechanism:

Exact mechanism of action is unknown.

  • Inhibits potassium channels
  • Delay repolarization and prolongs the duration of action potentials, improves conduction of action potentials in demyelinated axons

Dose:

Fampridine/Dalfampridine

  • 10 mg PO every 12 hr

Opioid analgesic

  • Tramadol

Use: Pain management

Mechanism:

The precise mechanism is unclear but may be related to:

  • The binding of its active metabolites to mu-opioid receptors in the CNS which inhibits the reuptake of serotonin and norepinephrine
  • The binding causes inhibition of ascending pain pathway which in turns alter the perception of and response to pain

Dose:

Tramadol

  • 50-400 mg PO daily as tolerated

Anticholinergic

  • Oxybutynin
  • Tolterodine
  • Solifenacin
  • Darifenacin
  • Trospium

Use: Urinary incontinence

Mechanism:

  • Antagonizes the action of acetylcholine at postganglionic receptors
  • Relaxes bladder smooth muscle, inhibits involuntary detrusor muscle contractions

Dose:

Oxybutynin

  • 5 mg PO BID or TID; Max. of 5 mg PO 4 times a day

Tolterodine

  • 2 mg PO BID

Solifenacin

  • 5 mg PO daily, if tolerated may increase to 10 mg once daily
  • Note: Maximum 5 mg/day if on potent CYP3A4 inhibitor

Darifenacin

  • 7.5 mg PO daily; may increase if required at least after 2 weeks to 15 mg PO daily

Trospium

  • Immediate-release: 20 mg PO BID
  • Extended-release: 60 mg PO daily

Neuromuscular blocking agent, (Botulinum toxin)

  • Botox

Use: Muscle spasticity, Urinary incontinence

Mechanism:

  • Blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, inhibits the release of acetylcholine and produces a state of denervation that could last for weeks-months

Dose:

Botox (intramuscular)

  • Exact dosage and number of injection sites are based on patient size, extent and location of muscles involved, severity of spasticity, presence of local muscle weakness, and response to prior treatment

Botox (intravesical)

  • Recommended dose is 200 Units
  • Treatment benefits usually last a minimum of three months.

Antidiuretic

  • Desmopressin

Use: Nocturia

Mechanism:

  • Increases cyclic adenosine monophosphate (cAMP) in renal tubular cells with an increase in water permeability in distal tubules and collecting ducts leading to decreased urine volume and increased urine osmolality
  • Increases plasma levels of von Willebrand factor, factor VIII, and t-PA

Dose:

Desmopressin

  • 0.1-0.4 mg PO daily at bedtime

Antidepressants

  • Tricyclic antidepressant (TCAs)
  • Selective serotonin reuptake inhibitors (SSRIs)
  • Serotonin/norepinephrine reuptake inhibitor (SNRIs)

Tricyclic antidepressants (TCAs)

  • Amitriptyline
  • Imipramine
  • Nortriptyline

Use: Depression

Mechanism:

  • Inhibits the presynaptic reuptake of neurotransmitters, increases synaptic serotonin and/or norepinephrine
  • Also has significant anticholinergic properties

Dose:

Amitriptyline

  • Start 25-50 mg/day; may increase dose gradually; usual effective dose 75 to 200 mg PO daily or in divided doses; Max. 300 mg/day

Imipramine

  • Start 75 mg/day and increase dose gradually to 150 mg PO daily or in divided doses; Max. 200 mg/day

Nortriptyline

  • 25-50 mg/day PO; may increase gradually to 200 mg/day, if needed

Selective serotonin reuptake inhibitors (SSRIs)

  • Fluoxetine
  • Paroxetine
  • Sertraline
  • Citalopram

Use: Depression

Mechanism:

  • Inhibits the presynaptic reuptake of neurotransmitters, increases synaptic serotonin concentration
  • Little effect on the reuptake of norepinephrine or dopamine
  • Does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors

Dose:

Fluoxetine

  • Start 20 mg PO daily in the morning; may increase dose gradually after several weeks if inadequate response; Max. 80 mg/day

Paroxetine

  • Immediate-release: Start 20 mg PO daily in the morning; may increase dose gradually by 10 mg/day after at least 1 week of interval; Max. 50 mg/day
  • Controlled-release (CR): Start 25 mg PO daily in the morning; may increase dose gradually by 12.5 mg/day after at least 1 week of interval; Max. 62.5 mg/day

Sertraline

  • Start 50 mg PO in the morning or at bedtime once daily; may increase dose gradually after at least 1 week of interval; usual dose 50-100 mg/day; Max. 200 mg/day

Citalopram

  • Start 20 mg PO in the morning or at bedtime once daily; may increase dose gradually after at least 1 week of interval; usual dose 20-40 mg/day; Max. 60 mg/day

Serotonin/Norepinephrine reuptake inhibitors (SNRIs)

  • Duloxetine
  • Venlafaxine

Use: Depression, pain

Mechanism:

Exact mechanism of action is unknown.

  • A potent serotonin and norepinephrine reuptake inhibitor
  • Weakly inhibits dopamine reuptake

Dose:

Duloxetine

  • 30-60 mg PO once daily; target dose 60 mg/day; may titrate dose by 30 mg/day if needed; Max. 120 mg/day

Venlafaxine

  • 37.5-75 mg PO daily; may increase in ≤75 mg/day increments at intervals of ≥4 days as tolerated (maximum daily dose: 225-375 mg)

Stool softener

  • Docusate sodium

Use: Stool softener

Mechanism:

  • Facilitates mixture of stool fat and water
  • May also promote electrolyte and water secretion into the colon

Dose:

Docusate sodium

  • 100 mg PO TID

Phosphodiesterase type 5 inhibitors (PDE5 inhibitors)

  • Sildenafil
  • Tadalafil
  • Vardenafil

Use: Erectile dysfunction

Mechanism:

  • Does not directly cause penile erections
  • Inhibits the enzyme phosphodiesterase type 5 (PDE5), which inactivates cGMP
  • Enhances the effects of nitric oxide released during sexual stimulation
  • Nitric oxide activates guanylatecyclase enzyme and increases cGMP level which leads to smooth muscle relaxation of corpus cavernosumhence promotes increased blood flow and subsequent erection

Dose:

Sildenafil

  • 50-100 mg PO, prior to intercourse (~1 hour before)

Tadalafil

  • 5-20 mg PO, prior to intercourse (at least 30 minutes)

Vardenafil

  • 5-20 mg PO, prior to intercourse (~1 hour before)

Prostaglandin

  • Alprostadil

Use: Erectile dysfunction

Mechanism:

  • Vasodilator – relaxes arterial smooth muscle and dilates cavernosal arteries

Dose:

Alprostadil

  • 2.5-40 mg intracavernosal injection
Diagnosis and Goals:

Diagnosis:

  • Deficiency in taking care of one’s self-related to neuromuscular deficits, such as spasticity, pain, etc.
  • Impaired physical mobility due to muscle weakness or paralysis and muscle spasticity
  • Sensory or perceptual alteration related to visual disturbances
  • Sensory loss or paraesthesias
  • Difficulty in swallowing
  • Altered urination and constipation related to immobility, inadequate fluid intake, improper diet, and neuromuscular impairment
  • Cognitive impairment
  • Dementia, loss of memory and emotional liability-Self-concept disturbance relate to prolonged debilitating condition
  • Ineffective coping issues, due to uncertainty of the disease course
  • Physical, psychological, and social limitations, affecting the home environment
  • Sexual dysfunction and associated psychological impact related to neuromuscular deficits

Goals:

  • To promote physical mobility
  • Avoidance of injury
  • Achieve bladder or bowel continence
  • Improve speech and swallowing
  • Improve cognitive functions
  • Develop strategies to strengthen coping abilities
  • Improve home management to assist with coping with activities of daily living (ADLs)
  • Strategies to improve or cope with sexual dysfunction
Nursing Intervention:

Promoting physical mobility:

  • Improve muscle function through coordination and relaxation exercises
  • Strengthen muscles through resistive exercises
  • Walking may help to improve gait and sense of position
  • Muscle stretching to avoid contractures and frozen joints
  • A beneficial type of physical therapy is water exercise
  • A stretch-hold-relax routine may help relieve spasticity
  • Frequent short rest in between exercises is advised
  • In end-stage disease to avoid pressure ulcers for immobile patients though appropriate padding and repositioning. Clear bronchial secretions as required, watch for infections, etc.

Preventing injury:

  • Incoordination and clumsiness leads to the risk of fall – advise to walk with wide stance when necessary to improve balance
  • Encourage the use of walking aids, cane, walker, crutches where indicated
  • Upper extremities wrist cuffs may be used when there are pronounced tremors

Bladder and bowel control:

  • Advise for a bladder training program to reduce incontinence
  • Assess for urine retention, and catheterize for residual urine if needed
  • Patient should report urinary tract infection immediately
  • Ensure adequate fluid intake to prevent infections and renal stone
  • Constipation, fecal impaction, and incontinence are taken care by adequate fluid, dietary fiber, suppositories, and bowel training program

Speech and swallowing difficulties:

  • Speech therapist to assist with speech difficulties
  • Impaired swallowing carries a risk of aspiration; suction may be required

Improving sensory and cognitive functions:

  • Persistent diplopia may require the use of an eye patch and/or prism glasses
  • Emotional support to assist patients with cognitive and emotional impairments
  • Referrals for counseling to alleviate stress and assist with coping

Improving self-care abilities:

  • Assistive eating devices, raised toilet seats, bathing aids, long-handled combs, and modified clothing are all advised to achieve self-care

Promoting sexual functioning:

  • An experienced sexual counselor can help patients advise the different type of resources and therapies

Community and home care considerations:

  • To control symptoms teach patients to use his/her own judgment
  • Teach how to conduct daily self-assessment to improve by modifying the treatment plan

Expected outcomes:

  • Reduce exacerbations
  • Perform exercises correctly
  • Improve strength and stability
  • Moves around without reduced risk of injury
  • Voids every 2 hours with no incontinent episodes
  • Can verbalize and discuss fears and concerns
  • Satisfied with sexual performance
Nursing Alerts:
  • Elderly patients and those with a cognitive and chronic physical disability may require close monitoring of their medications and adverse events
  • Side effects of steroids, including hyperglycemia, hypertension, delirium, electrolyte imbalance and presence of osteoporosis should always be kept in mind particularly patients who have other co-morbidities (e.g. diabetes) and who require frequent use of steroids for exacerbations phase
  • The client with multiple sclerosis should be informed of triggers that may provoke an exacerbation of the disease. Exacerbations of MS are triggered by infection (particularly upper respiratory, urinary tract infections), trauma, and immunization, delivery after pregnancy, and stress. The nurse should help the client identify particular triggers and develop avoidance strategies to minimize their effects

References

Core Resources:

  • Brust J, ed. Current Diagnosis and Treatment (Neurology). 2nd edition. New York: McGraw-Hill; 2011
  • Compendium of Pharmaceuticals and Specialties (CPS). Canadian Pharmacist Association. Toronto: Webcom Inc. 2012
  • Day RA, Paul P, Williams B, et al (eds). Brunner & Suddarth’s Textbook of Canadian Medical-Surgical Nursing. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2010
  • Foster C, Mistry NF, Peddi PF, Sharma S, eds. The Washington Manual of Medical Therapeutics. 33rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010
  • Freedman MS, Selchen D, Arnold DL, et al. Treatment Optimization in MS: Canadian MS Working Group Updated Recommendations. Can J Neurol Sci. 2013; 40(3):307-23
  • Gray J, ed. Therapeutic Choices. Canadian Pharmacists Association. 6th ed. Toronto: Webcom Inc. 2011
  • Katzung BG, Masters SB, Trevor AJ, eds. Basic and Clinical Pharmacology. 11th ed. New York: McGraw-Hill; 2009
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  • McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 49th ed. New York: McGraw-Hill; 2010
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  • Skidmore-Roth L, ed. Mosby’s nursing drug reference. 24th ed. St. Louis: Elsevier-Mosby; 2011

Online Pharmacological Resources:

  • e-Therapeutics
  • Lexicomp
  • RxList
  • Epocrates

Journals/Clinical Trials:

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  • Ebers GC; PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomized double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet.1998;352:1498-1504
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