Multiple Sclerosis—Pathogenesis, diagnosis, and treatmentweb.brrh.com/msl/Practical Neuroscience...

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.