Multiple Sclerosis—Pathogenesis, diagnosis, and treatment
Joshua Chalkley DO MS
Assistant Professor of Neurology
Marcus Neuroscience Institute
Assistant Professor of Neurology Florida Atlantic University Adjunct faculty
Multiple sclerosis (MS)
an inflammatory, demyelinating, neurodegenerative disease of the central nervous system (CNS).
INFLAMMATION - Is this the cause of or a reaction to the axonal
demyelination and injury?
- Initialing factor of the disease is unknown, but an aberrant immune response plays a critical role.
Multiple sclerosis (MS)
All FDA-approved MS therapies alter immune function and reduce inflammation
Epidemiology
Affects female 2-3X as often as men
Age of onset: rare in pediatric population; risk increases from adolescence to AGE 35, then decreases
Rarely diagnosed after age 65 years
Epidemiology
Uncommon in equatorial climates
-Prevalence increase with northern distance from equator.
-North/south gradient seen within North America, Europe, and Japan, suggesting unidentified environmental risk factor
Strong associations:
-VITAMIN D deficiency, infectious agent (EBV)
Latitude factors - Residence for first 15 years of life determines risk
Genetic component
Twin studies: Concordance rates in monozygotic twins = 25% vs. 5% in dizygotic twins.
Rate of fraternal twins is similar to that of first-degree relatives of patients with MS. Several genes (>12) that make individuals susceptible to MS have been discovered.
Etiology
Unknown
Appears to be a combination of environmental factors (including Vitamin D deficiency, EBV exposure) in genetically predisposed individuals.
Pathology
Plaques – areas of damaged myelin with inflammatory infiltrates
Deep white matter
Near ventricles, corpus callosum, optic nerve
Spinal cord, brainstem, cerebellar peduncles
Some cortical involvement
Pathology
Acute
Demyelination
Axon-sparing
Perivascular infiltrate
Perivascular edema
Activated astrocytes and hyperactive oligo’s at border
Microscopically one sees the pallor on an H&E section in the old plaque because
the myelin which stains pink on this stain is absent in areas of demyelination.
Axons are relatively preserved and astrocytes will be found in the lesion. They
respond to the loss of myelin.
THIS HIGH CERVICAL CORD LESION IS STAINED BLACK FOR MYELIN. THIS LARGE DEMYELINATED PLAQUE AFFECTS THE POSTERIOR COLUMNS, WHICH CARRY PROPRIOCEPTIVE OR POSTIONAL SENSE.
Pathology
Chronic
Oligodendrocytes disappear
Axonal degeneration
Astrocyte hypertrophy and hyperplasia=sclerosis
*Capacity to rebound from acute attacks diminishes with disease duration and age.
Presentation Initial focal neurologic symptoms (weakness, sensory changes, visual loss) develop over hours to days
Optic Neuritis is the most common presentation 30%
May be acute vs. insidious, mild vs. severe (clinic vs. hospital presentation)
MS can present with almost anything, have to keep an open mind
Presentation
Fatigue and general malaise often proceed first focal attack
MS patients visit the doctor more frequently than controls two years proceeding MS diagnosis
General feeling that something is wrong
Presentation - Frequency of Symptoms at Disease Onset:
Sensory changes 34%
Weakness 22%
Vision loss 13%
Ataxia 11%
Diplopia 8%
Frequency of Symptoms During Entire Disease Course:
Weakness 89%
Sensory disturbance 87%
Ataxia 82%
Bladder dysfunction 71%
Fatigue 57%
Cramps 52%
Diplopia 51%, Vision loss 49%
Bowel dysfunction 42% Other: dysarthria, vertigo, facial pain, memory, headache, psychiatric sx, hearing loss, facial weakness, dysphagia
Presentation - History
HISTORY: ask about prior focal neurological deficits with CNS localization
Exclude other diagnoses based on history (time course, symptoms, remissions)
Exacerbations with subsequent resolution of symptoms (i.e. remissions)
Presentation - History
ASSOCIATED SYMPTOMS:
- Fatigue
- Heat sensitivity (Uhthoff’s phenomenon-vision disturbance assoc. with heat)
- Lhermitte’s sign – electrical sensation down spine with neck movement
- Autonomic symptoms (bowel/bladder/sexual dysfunction)
- pain, muscle cramps
- cognitive or psychiatric symptoms
Physical Examination: Mental Status
MS, CNs, Motor, Sensory, Coordination
Affect
Depression screen (PHQ-9, BDI-2)
Memory, cognition (MMSE, MOCA)
Physical Examination: Cranial Nerves
MS, CNs, Motor, Sensory, Coordination
Optic neuritis Red swollen disc followed by pallor vs.
optic atrophy (chronic)
Decreased visual acuity, central scotoma, color desaturation (Ishihara color chart)
Marcus-Gunn pupil (APD)
Disconguate gaze (ex. INO)
Facial dysesthesia, loss of taste, hearing loss, nystagmus, dysphagia, dysarthria
Physical examination: Motor
MS, CNs, Motor, Sensory, Coordination
Strength: Paresis
Tone: Spasticity
Reflexes: Hyperactive reflexes (ex. brisk patellar reflexes, cross-adductors sign)
-clonus in the ankles, Babinski sign
**ALL UPPER MOTOR NEURON SIGNS**
Physical examination: Sensory
MS, CNs, Motor, Sensory, Coordination
Lhermitte’s sign – tested objectively with passive neck flexion
Impaired proprioception and vibration(Posterior columns commonly affected)
**ROMBERG**
Impaired pain, temperature, or light touch
Physical examination: Coordination
MS, CNs, Motor, Sensory, Coordination
Ataxia (appendicular or truncal)
Gait
Tremor
Nystagmus (brainstem vs. cerebellar)
Dysarthria (brainstem vs. cerebellar)
Diagnosis
Hallmark: Waxing and waning neurological deficits that localize to the CNS
No single test can diagnose MS.
Diagnosis relies on recognition of clinical patterns of disease AND exclusion of possible mimics.
Diagnosis is supported by history, exam, MRI brain and spine, analysis of CSF, and evoked-potentials.
Diagnosis
CNS LESIONS SEPERATED BY SPACE AND TIME
OPTIC NERVES, BRAIN, SPINAL CORD
Example: Patient with optic neuritis, who 1) initial MRI shows other MS plaques OR 2) several months later develops cerebellar ataxia.
This represents 2 spaces, 2 times.
Cree, Bruce A. C. CONTINUUM: Lifelong Learning in Neurology Volume 16(5) Multiple Sclerosis October 2010 pp 19-36
Summary of criteria:
If one of five sets of criteria are fulfilled and other etiologies are excluded, the diagnosis is MS.
If suspicious, but the criteria are not completely met, the diagnosis is “possible MS.”
If another diagnosis arises that better explains the entire clinical presentation, then the diagnosis is “not MS.”
Criteria Update
2017 updated criteria
Major change included evaluation of spinal fluid
Can use asymptomatic and symptomatic lesions
Site of lesion can include cortical lesions
Relapsing Remitting: 85% of patients follow this course, at least initially.
Imaging
Abnormalities Periventricular WM lesions
“Dawson’s fingers”
Corpus callosum thinning/scalloping
Infratentorial lesions – pons, cerebellar peduncles, white matter adjacent to the 4th ventricle
Atrophy
Contrast enhancement – evidence of ‘active’ disease (i.e. inflammation)
Physical examination
CSF examination
Perform LP when additional information is needed to confirm the diagnosis.
- MRI is normal
- History, exam, or imaging is concerning for another disease process (infection, inflammatory, vasculitis)
CSF is abnormal in 85-90% of patients with MS
CSF Analysis
Opening pressure – normal
WBC: 5-20 lymphocytes
Protein 40-60
Evidence of intrathecal synthesis of gamma globulins:
- Oligoclonal bands elevated in 90%
- IgG synthesis rate >3 in 80-90%
- IgG index >0.7 in 90%
Myelin basic protein elevated (~2 weeks)
Evoked potentials
Visual Evoked Potentials (VEP)
Somatosensory Evoked Potentials (SSEP)
Brainstem/Auditory Evoked Potentials (BAEP)
Characteristic findings suggest demyelination by showing asymmetric, delayed response or conduction block. May remain abnormal for years after an acute exacerbation
In 75% of patients with MS, VEPs are abnormal.
Visual Evoked Potentials
Differential Diagnosis
Idiopathic CNS Demyelnating Diseases: Acute disseminated encephalomyelitis(ADEM), Neuromyelitis optica (Devic’s)
Systemic Autoimmune diseases: Lupus (SLE), Sjogren syndrome, Sarcoidosis)
Chronic infections {most common:HTLV 1 and 2, HIV, syphilis, JC virus (PML)}
Differential Diagnosis (cont.)
Vascular diseases (stroke, leukoariosis, primary CNS vasculitis, Susac disease)
Malignancies (primary CNS lymphoma, paraneoplastic syndromes)
Nutritional (Vitamin B12 deficiency – dorsal columns)
Somatization, conversion disorders
Treatment
Require ongoing treatment
Immunomodulation to decrease frequency and severity of recurrence
Treatment of acute exacerbation
Symptomatic treatment of associated MS symptoms (fatigue, spasticity, etc.)
Long-term Treatment: Disease Modifying
Therapies
Disease Modifying therapy
Wide variety of medication
No perfect treatment
Reduce inflammation and prevent attacks
Some of the newer drugs may also aid in preventing progression
Disease Modifying Therapies (DMTs) – FDA Approved Agents
Inteferon Beta
injections
Reduce antigen presentation and T cell response
Improve relapse rates and disability
Safe and effective
Have significant side effects
Psychiatric symptoms flu like illness can affect the liver and white blood cells
Glatiramer Acetate
Injections given daily or three times weekly
4 amino Acids found in myelin basic protein
Disease Modifying Therapies (DMTs)
Pros
Safe
Effective
No serious side effects
Cons
Daily injection
Painful
Injection site reactions
Natalizumab
Blocks T cell Migration into the CNS
Approved for inflammatory bowel disease and MS
Very effective in the treatment of MS
Monthly infusion
Pros
Very effective
Tolerated well
Overall good safety profile
Cons
PML
JCV virus testing before initiation of treatment and routine monitoring throughout treatment
Risk stratification for treatment
Disease Modifying Therapies (DMTs)
Fingolimod .
- once daily medication
- reduces exacerbation frequency and delay accumulation of physical disability
Sphingosine-1-phosphate receptor modulator
Traps lymphocytes in lymph tissue
Pros
Very effective
Likely most effective of the oral medications
Minimal reported side effects
Overall safe
Cons
Difficult to initiate
Lymphopenia
Can affect the liver
Slows heart rate
PML and other rare infections and cancer
Karposi Sarcome, skin cancer, Varicella
Dimethyl Fumerate
Twice day oral medication
Likely works by transitioning T cells into more inert state, exact mechanism is not known
Effective
Pros
Effective
Oral medication
Easy to initiate therapy
Cons
GI upset
flushing
Can cause lymphopenia
Can affect the liver
PML- handful of cases likely related to overall lymphocyte count
Other medications
There are more medications including but you will not be tested on these so we will hold them for now
Terflunimide- approved
Alemtuzumab-approved
Rituxumab- trials showing efficacy
Ocrelizumab-
Daclizumab- recently pulled from the market
Acute Exacerbation: To treat or
not to treat an exacerbation?
Methylprednisolone 1000 mg x 3-5 days
- No evidence of change in disease course, but may
shorten acute exacerbation.
If not responsive and exacerbation is severe, plasma exchange can be beneficial.
Symptomatic Treatment
MS symptoms can cause disability from workforce and social isolation.
Focusing on symptom management can significantly improve quality of life.
Effective symptomatic treatments for:
Gait impairment – Ampyra (dalfampridine-SR) - improvement in walking speed
Disabling spasticity
Pain, severe facial pain
Disabling fatigue
Heat-induced fatigue and vision loss (Uhtoff phenomenon)
Symptom Management
Symptom Management (cont.)
Depression, anxiety
Pseudobulbar affect
Bladder spasticity (urgency, frequency, incontinence)
Bladder hyptonicity
Erectile dysfunction
Symptomatic treatment
Also encourage non-medication treatment with:
- Physical, occupational, and speech therapy
- Exercise, including stretching, swimming, yoga, tai-chi
- Psychotherapy, meditation for depression and anxiety
Better Prognosis
Females
Predominantly sensory
Complete or near-complete resolution of symptoms after relapse
Worse Prognosis
Males, older age of onset
Multifocal
Progression
Ability to recover from exacerbations lessens as the disease progresses.
