© copyright annals of internal medicine, 2014 ann int med. 160 (4): itc4-1. * for best viewing:...
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© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
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© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
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© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
in the clinic
Multiple Sclerosis
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What characteristic symptoms orphysical findings should alertclinicians to the diagnosis of MS?
Optic neuritis: inflammation of the optic nerve
Subacute visual changes + pain with eye movement
Myelitis: focal inflammation within the spinal cord
Sensory or motor symptoms below affected spinal level
Other neurologic symptoms
Eye movement abnormalities from brainstem involvement
Chronic symptoms from widespread cortical demyelination and global brain atrophy
Cognitive dysfunction and mental and physical fatigue
Worsening neurologic symptoms when body temp
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What are the historical characteristics associated with each subtype of MS? Clinically isolated syndrome (CIS)
Full MS diagnostic criteria not met at 1st relapsing event
Relapsing-remitting MS (RRMS): ~85% of pts with MS
Repeated relapse episodes followed by recovery
Secondary progressive MS (SPMS): 50-60% of pts with RRMS
First few years: recovery of previous functioning common
Over time: recovery diminishes, permanent disability occurs
Primary progressive MS (PPMS): ~15% of pts with MS
Progressive disability accumulation from onset of disease
Disability accumulation can occur rapidly
Radiologically-isolated syndrome (controversial)
Incidental MRI findings meet diagnostic criteria for MS w/o any history or symptoms suggestive of MS
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What are the McDonald criteria, and how can they help clinicians diagnose MS?
Official diagnostic criteria for MS Provide guidance on proper integration of clinical and
diagnostic evidence
Criteria help differentiate MS from other conditions
RRMS diagnosis Require clinical evidence of CNS demyelination
disseminated in space and time
For PPMS diagnosis ≥1 yr neurologic disability progression + ≥2 of following:
evidence of dissemination in space on brain MRI
evidence of dissemination in space on spinal cord MRI
cerebrospinal fluid findings consistent with MS
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What is the role of MRI in diagnosis?
Primary diagnostic and prognostic tool in evaluation
McDonald criteria often require confirmation based on MRI
Dissemination in space: ≥2 lesions in ≥2 locations
Dissemination in time:
Asymptomatic contrast-enhancing lesion + asymptomatic nonenhancing T2-bright lesion at baseline or
Development of a new white matter lesion or new contrast enhancement on a follow-up scan
Other MRI changes seen Demyelinating lesions in cortex Cortical and deep gray matter atrophy; white matter structure
atrophy Alterations in quantitative MRI measures in lesions and
normal-appearing white matter
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
Typical MRI manifestations of MS
Lesions in white matter regions appear hyperintense on T2-weighted images; hypointense on T1-weighted images
Lesions represent areas of demyelination and gliosis
Lesions will show enhancement with administration of gadolinium contrast if undergoing active inflammatory process with breakdown of the blood-brain barrier
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What role does lumbar puncture play in diagnosis?
Spinal fluid can reveal signs of MS
Unique oligoclonal bands in spinal fluid by isoelectric focusing (in 90%-95% of patients with MS)
Elevation of IgG index (in 50%-75%)
Mild pleocytosis (in ≈50%)
Negative CSF result alone doesn’t rule out MS
But when clinical and radiologic suspicion is low, a normal CSF result reassures patients they probably don’t have MS
For RRMS diagnosis
Criteria don’t require confirmation by CSF testing
For PPMS diagnosis
Test CSF if MRI features don’t meet criteria for dissemination in space
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
When should clinicians consider obtaining evoked potentials?
When clinical exam and MRI don’t provide evidence of dissemination in space
Helps find evidence of subclinical demyelinating lesions
Evoked potentials: electrophysiologic measurements of the time it takes for nerves to respond to stimulation
Reduced evoked potential conduction velocity on visual-evoked potentials: detects prior demyelination
Brainstem auditory-evoked potentials: provide evidence of a lesion along the acoustic and brainstem pathways
Somatosensory evoked potentials: provide evidence of lesions in spinal sensory pathways
Brainstem and spinal cord potentials less likely to be abnormal than visual-evoked potentials in patients with MS
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
Optical coherence tomography measures the thickness of nerve fiber layers in the retina
Documents dissemination of disease activity in space
In patients presenting with first attack of nonoptic neuritis
Useful but not specific
When should clinicians consider obtaining optical coherence tomography?
Retinal nerve fiber layer reductions seen
Can be seen in patients with MS who have had optic neuritis as well as those who have not had optic neuritis
In patients with isolated optic neuritis
In patients with neuromyelitis optica
Can occur with compressive lesions of optic nerve
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What are the differential diagnoses? Other demyelinating diseases
Acute disseminated encephalomyelitis
Neuromyelitis optica (Devic disease)
Idiopathic transverse myelitis
Systemic inflammatory disease Systemic lupus erythematosus
The Sjögren syndrome
Sarcoidosis
The Behçet syndrome
Metabolic disorders Adult-onset leukodystrophy
Vitamin B12 deficiency
Copper deficiency
Zinc toxicity
Vitamin E deficiency
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
Infections
HIV, Lyme disease, syphilis
Human T-lymphotropic virus
Vascular disorders
Sporadic and genetic stroke syndromes
CNS vasculitis
The Susac syndrome
Dural arteriovenous fistula
Migraine
Neoplasia (i.e., primary CNS neoplasm (glioma or lymphoma) or metastatic disease)
Paraneoplastic syndromes
Somatoform disorders
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
When should clinicians considerconsulting with a neurologist orother specialist for diagnosis?
Consult neurologist to confirm the diagnosis or facilitate further testing
If MRI findings suggest possible MS
Obtain second opinions from MS specialty clinics
If the diagnosis is unclear
If treatment has failed
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
CLINICAL BOTTOM LINE: Diagnosis…
Use the revised 2010 McDonald criteria Clinical Hx + physical exam findings + radiologic findings Show dissemination in disease activity over space & time
Patients with RRMS have relapsing symptoms
Patients with PPMS and SPMS experience progressive disability accumulation
Additional testing not required for Dx but can be helpful Lumbar puncture Evoked potentials Optical coherence tomography
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What is the overall approach to treatment of patients with MS?
Multidisciplinary and comprehensive approach can significantly improve quality of life of patients with MS
Prevent and manage relapses
Use medication and nonmedical approaches for fatigue
Treat spasticity and bladder dysfunction
Assess cognitive functioning
Consider ways to help patients maximize daily function
Delay disease progression and reduce relapse rate with medications
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What role does clinical subtype play in guiding treatment decisions?
Subtyping: critical 1st step before initiating drug therapy
Many medications approved for CIS and RRMS
Limited treatment options for SPMS and PPMS
With progressive MS, clinical guidelines recommend against using immunomodulatory drugs
For most patients with RRMS, immunotherapy is indicated
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What medications are typically used? Interferon-β1a and β1b
1st line Rx; reduce relapse rates by one third vs. placebo
Glatiramer acetate
1st line Rx; reduces relapse rates by one third vs. placebo
Natalizumab
Reduces relapse rates by about two thirds vs. placebo and slows disability progression by approximately 40%
Risk for potentially fatal infection (PML)
Teriflunomide
Reduces relapse rates by one third vs. placebo
Reduces risk for disability & accumulation of lesions on MRI
Class X (teratogenicity): contraception counseling essential
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
Fingolimod
Reduces relapse rates by about 50% vs. placebo and reduces risk for disability & accumulation of lesions
1st-dose bradycardia often occurs; don’t use with β-blockers or if patient has known heart block
Risk of retinal macular edema; eye exam required
Varicella vaccination needed before treatment, if not immune
Dimethyl Fumarate
Reduces disability progression by about one-third vs placebo and reduces new lesions on MRI scans
FDA-approved for use in patients with RRMS
Mitoxantrone
Reduces relapse rates and is only drug ever shown to reduce rate of disability accumulation in SPMS
Use limited by risks for cardiac toxicity, secondary leukemia
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
Initiate at the time of diagnosis
In the past: clinicians waited until a clinically definite diagnosis established
Now: Guidelines recommend initiating at the time of first clinical symptoms for RRMS and CIS with risk factors for later conversion
Early treatment can reduce relapse rates and new lesion formation and prevent disability accumulation
When should clinicians consider immunomodulatory therapy?
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What is the role of vitamin D?
Vitamin D deficiency linked to pathophysiology of MS
Immunoregulatory vitamin D receptors present on T cells
Vitamin D interacts with the immunomodulatory effects of estrogen and testosterone
Reduced serum vitamin D levels are shown to predict accumulation of new lesions
High vitamin D levels linked with decreased relapse risk
? Ideal dosing and 25-hydroxyvitamin D serum levels
Studies show benefit for serum levels of ≥50 nmol/L
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
How should clinicians choose therapy for patients who are having an acute relapse?
Relapse: new or worsening neurologic symptoms lasting ≥24h without clear underlying triggers of pseudo-relapse
Standard treatment: high-dose corticosteroids
IV infusion methylprednisolone, 1g/d for 3-5 days
Alternate regimens: oral methylprednisolone, 1g/d for 5 days; oral prednisone, 1250 mg/d for 5 days
Rescue treatment if relapse doesn’t respond to steroids
Plasma exchange
5 days of IM or SC adrenocorticotrophic hormone gel
Pulse-dose IV cyclophosphamide
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
When should a patient with MS be hospitalized?
Severe relapse causes complete loss of mobility
Severe relapse causes impaired bladder / bowel control
Marked worsening during relapse warrants care that’s beyond the capacity of the family
Special monitoring needed during relapse treatment
Such as blood glucose monitoring for steroid administration in a patient with diabetes
Administering rescue treatment
Plasma exchange, pulse-dose cyclophosphamide therapy
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What treatments are used to alleviate chronic symptoms? Use DMT to alleviate symptoms that remain chronic
Other symptomatic management:
Spasticity Physical therapy, stretching, massage
Baclofen, tizanidine, cyclobenzaprine, gabapentin, benzodiazepines, carisoprodol, botulinum toxin
Neuropathic pain Gabapentin, pregabalin, duloxetine, tricyclic antidepressants,
tramadol, carbamazepine, topiramate, capsaicin patch
Fatigue Proper sleep hygiene, regular exercise
Modafinil, armodafinil, amantadine, amphetamine stimulants
Depression Individual or group counseling; Antidepressants
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
Cognitive dysfunction Cognitive rehabilitation and accommodation strategies
Mobility PT and OT, use of braces, canes, rolling walkers,
electrostimulatory walk-assist devices; Dalfampridine
Urinary urgency / frequency Timed voids, avoidance of caffeine; Oxybutynin, tolterodine
Urine retention Manual pelvic pressure, intermittent catheterization
Heat Intolerance Avoidance of hot weather, hot tubs, etc., cooling equipment
Pseudobulbar affect Dextromethorphan/quinidine
Limb tremor Occupational therapy; Botulinum toxin
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
How should clinicians monitor patients being treated for MS?
Regularly assess safety and efficacy of DMT
Focus safety assessments toward known AEs of treatment
Catalog relapses
Order regular MRI scanning
Perform neurologic exam
Consider changing treatment in patients with recurrent relapses, new lesion formation, or disability accumulation
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
What should clinicians do about immunizations in patients with MS?
Clinical practice guidelines recommend regular immunizations for patients with MS
Risk for MS relapses is significantly increased in the weeks surrounding infectious episodes
No evidence that MS worsens due to immunization with any vaccines
Fingolimod: special considerations
Decreases the ability to combat viral infections
Avoid using live viral vaccines while receiving the drug
© Copyright Annals of Internal Medicine, 2014Ann Int Med. 160 (4): ITC4-1.
CLINICAL BOTTOM LINE: Treatment…
Prevent relapses: use DMTs and vitamin D supplementation DMTs only approved for CIS and RRMS Poor evidence for any benefit for SPMS or PPMS
Use acute treatments at the time of relapses High-dose corticosteroids Plasma exchange Adrenocorticotrophic hormone gel Cyclophosphamide
Manage symptoms on an individual basis Use pharmacologic and nonpharmacologic interventions