MULTIPLE SCLEROSIS pdf - Prof Akram Al.Mahdawi

Medicine

Dr. Akram

Neurology

“MULTIPLE SCLEROSIS”

Prof. Akram AI-Mahdawi

LECTURE 11

Multiple Sclerosis Prof. Akram Al.Mahdawi

Multiple Sclerosis

Objectives



What is demyelination disease?



How would you diagnose MS?



What are the different treatment options?

History of disease



Multiple Sclerosis, also known as MS, was given its name, multiple

because of the numerous sites of demyelination and ‘sclerosis’ which
means scarring.



“There are accounts of probable MS dating back to the 14th century but
the history of the disease really begins in the 19th century with the first
illustrations and clear clinical description of the disease beginning to
appear in 1838”.



The first actual case was first diagnosed in 1849. It was Jean-Martin

Charcot who is credited with giving us the first signs and symptoms of
Multiple Sclerosis.



Pierre Marie Charcot

The Disease (MS) without his name is

meaningless! His students are: Babinski & Sigmund Feroid

Facts



It is an Immune mediated disease.



It is a life-long disease with no cure.



MS, the body attacks and destroys myelin that insulates an axon/nerve

(demyelination )



If damage is severe it can also destroy the nerve/axon itself.



MS affects the central nervous system and inflames the white matter in

the brain which creates plaques

This box added by students (it is not included in the lecture):

White matter

is composed of bundles of myelinated nerve cell projections (or axons), which

connect various

grey matter

areas (the locations of nerve cell bodies) of the brain to each

other, and carry nerve impulses between neurons.

Myelin acts

as an insulator, increasing

the speed of transmission of all nerve signals

Multiple Sclerosis Prof. Akram Al.Mahdawi

Multiple sclerosis



Most common disabling condition in young adults



Most common demyelinating disorder



Chronic disease of the CNS



Progresses to disability in majority of cases



Unpredictable course / variety of signs and symptoms.



Current theory favors immunologic pathogenesis



Women 2 to 3 times as men



It is rare in the pediatric



MS is rare after age of 60



MS is uncommon in equatorial climates but increase with northern

distance from equator (More in cold northern countries)

Pathophysiology



Both genetic and environment



Low near the equator and increase in temperate



Sunlight, Vitamin D and

Epstein–Barr virus



Familial 15%, monozygotic twins 30%



Polygenic



Immunological-T lymphocyte in CSF and increase immunoglobulin

synthesis in CNS



Entry of activated T lymphocyte



Recognized antigen-presenting cell (microglia).



Inflammatory cascade lead to release cytokines and initiate destruction

of oligodendrocyte-myelin unit by macrophage



Damage myelin associated with inflammatory infiltrate of lymphocyte,

macrophage, antibody, complement deposition, activated microglia and
oligodendroglia cell.



Inflammation + demylination= plaque= gliosis



Mainly select periventricular, optic nerve & subpial region of spinal cord



Absence of myelin will lead to:

1. Conduction abnormalities (delay, blocked, Impairment) lead to negative

symptoms & signs (visual loss, weakness, ataxia and numbness)

2. Emphatic conduction-positive signs and symptoms (pain, paroxysmal

syndrome)

Multiple Sclerosis Prof. Akram Al.Mahdawi

Common initial Symptoms:

(Important!)



Optic neuritis*



Relapsing and remitting (RR) sensory symptoms



Subacute painless spinal cord lesion (transverse mylitis)



Acute brain-stem syndrome



Subacute dorsal column deficit

Case Presentation:

A 20-year – old female. She had three episodes (Relapsing and remitting) of
neurological symptoms including

1- An episode of hemiparesis lasting 3 weeks
2- One episode of optic neuritis in left eye lasting 2 weeks
3- Episode of paresthesias of both legs and lower abdomen with reduce
bladder sensation with residual symptoms

Condition suggestive of MS ?

(Important!)



Afferent pupillary defect and optic atrophy (Marcus Gunn pupil)



Lhermitts symptom

(

is an electrical sensation that runs down the back and into the limbs. In

many patients, it is elicited by bending the head forward. It can also be evoked when a practitioner
pounds on the posterior cervical spine while the neck is flexed; this is caused by involvement of the
posterior columns and has many causes not only MS)



Internuclear opthalmoplagia (INO)



Rubral, holmes tremor



Trigeminal neuralgia under the age of 50



Recurrent facial nerve palsy



Urinary sphincter disturbance

Mentioned by Dr. Akram

Optic neuritis: Sudden, painful (especially on eye movement) visual loss with impaired color
vision.

We have to differentiate it from Anterior Ischemic optic neuropathy which is painless
visual loss and has 2 types: Artertic and non artertic (giant cell arteritis.)

Mentioned by Dr. Akram

Marcus Gunn pupil: is a
medical sign observed during the
swinging-flashlight test where
upon the patient's pupils constrict
less (therefore appearing to
dilate) when a bright light is
swung from the unaffected eye to
the affected eye.

Multiple Sclerosis Prof. Akram Al.Mahdawi

Signs and Symptoms:



Weakness 90%



Sensory disturbance



Ataxia



Bladder



Fatigue



Cramps



Diplopia



Visual loss 50%



Dysarthria 30%



Vertigo



Psychatric symptoms



Dysphagia



Loss of consciousness



Loss of taste 6%

Sensory disturbances



Ascending numbness starting in feet



Bilateral hand numbness



Hemiparesthesia / dysesthesia



Generalized heat intolerance



Dorsal column signs:

Loss of vibration/proprioception

ii.

Lhermitte’s sign

Visual disturbances



Unilateral or bilateral partial/complete intranuclear ophthalmoplegia



CN VI paresis



Optic neuritis

- Central scotoma, headache, change in color perception, retroorbital

pain with eye movement)

Mentioned by Dr. Akram

Internuclear ophthalmoplegia: a

disorder caused by injury or dysfunction in the medial

longitudinal fasciculus (MLF) which connects the 6

cranial nerve with 3

cranial nerve. It is a

disorde

r of conjugate lateral gaze in which the affected eye shows impairment of

adduction. When an attempt is made to gaze contralaterally (relative to the affected
eye), the affected eye adducts minimally, if at all. The contralateral eye abducts,
however with nystagmus. Additionally, the divergence of the eyes leads to horizontal
diplopia. If bilateral it is highly suggestive of MS if unilateral may be due to other
causes

Multiple Sclerosis Prof. Akram Al.Mahdawi

Motor disturbances



Weakness



Increased spasticity



Pathologic signs (Babinski, Hoffman)

Crebellar signs



Nystagmus



Dysarthria



Tremor



Dysmetria



Titubation



Stance and gait

Other clinical signs



Urinary incontinence, incomplete emptying



Cognitive and emotional abnormalities (depression, anxiety, emotional

labiality)



Fatigue



Sexual dysfunction

Differential diagnosis



Connective tissue diseases (SLE, Behcet and anti-phosphplipid

syndrome)



Primary CNS vasculitis



Postinfectious encephalomyelitis



Lyme disease



Behcet’s syndrome



Sarcoidosis / Sjogren’s disease



B12 deficiency / tertiary syphylis



Leukodystrophies

Multiple Sclerosis Prof. Akram Al.Mahdawi

Macdonald criteria

(No need to memorize it!)



Two or more relapses, objective clinical evidence of two or more lesions.



Two or more relapses, objective clinical evidence of one lesion (Need

dissemination in space)



One relapse, objective clinical evidence of two or more lesions

(dissemination in time).



Clinically Isolated Syndrome (CIS)



Exclude other structural disease and identify plaques of demylination



Demonstrate other site of involvement (MRI, VER).



Demonstrate inflammatory nature of lesions (CSF, cellcount, oligoclonal

bands)



Exclude other conditions (B12, CTS, CXR, ACE)

MRI findings:



Patchy areas of white matter in paraventricular cerebral areas



Lesions in cerebellum/brainstem/ cervical and thoracic spinal cord



Gadolinium enhancement identifies active lesions



**Caveat: **



Abnormal MRI without clinical evidence is not sufficient to confirm

the diagnosis of MRI.



Absence of abnormal MRI in clinically definite MS doesn’t disprove
diagnosis

Multiple Sclerosis Prof. Akram Al.Mahdawi

Fig (1): Abnormal MRI of the cerebellum

Fig (2):

Abnormal MRI of the optic nerve

Fig (3): Abnormal MRI of the
cerebral hemishperes

Multiple Sclerosis Prof. Akram Al.Mahdawi

Cerebro Spinal Fluid (CSF) findings

(Important!)



Increased immunoglobulin concentration in >90% of patients



IgG index (CSF/serum) elevated



Oligoclonal bands—85%



Elevated protein—50%



Modest increase in mononuclear cells

Evoked potentials



VER (visual evoked response)—75% abnormal regardless of optic

neuritis history



BAER (brainstem auditory evoked response)—30% abnormal



SSER (somatosensory evoked response) – 80% abnormal

- Helps distinguish peripheral from central lesions

Types of MS:



Relapse-remitting MS

(RRMS): Here you have an
attack, go into complete or
partial remission, and then
have the symptoms return.



Primary-progressive MS

(PPMS): Here you
continually decline and have
no remissions.

 A few patients have malignant

MS which is where they have
a quick decline which leaves
them severely disabled or
even lead to death.



Secondary-progressive MS

(SPMS): This stage of MS
starts with RRMS symptoms
and continues on to show
signs of PPMS.



Progressive-relapsing MS

(PRMS): This is a rare form
but here it takes a progressive
route made worse by acute
attacks.

 20% of the people with MS

have a benign form. Here
they show little progression
after the first attack.

Most

common

85%

Multiple Sclerosis Prof. Akram Al.Mahdawi

Favorable prognostic factors

(Important!)



Female gender



Low rate of relapses per year



Complete recovery from 1st attack



Long interval between 1st and 2nd attack



Younger age of onset



Later cerebellar involvement



Low disability 2-5 years from onset

Treatment of relapse attack



Methylprednisolone -500 to 1000 mg (1gm) /daily for 5 days.



PE, IV immune globulin for fulminate disease.



Interferon-beta -- Immune modulation -- widespread use for reducing

relapse rate (RCT evidence).



Glatiramer acetate --Immune modulation --Similar efficacy to interferon-

beta (RCT evidence).



Fingolimod --Immune modulation -- Superior efficacy to interferon-beta

in RCTs.



Monoclonal antibody to alpha4-integrin (natalizumab) --Immune

modulation. Possibly more effective than other drugs.



Teriflunomide (AUBAGO).



Dimethyl fumarate (Tecfidera ).

When Interferon beta therapy is initiated



Liver function tests and CBC at baseline.



Lab tests should then be repeated in 1, 3, 6 months during initiation of

therapy.



Monitoring can then be performed every 3 to 6 months thereafter.



Thyroid function tests are recommended in patients with history of

thyroid dysfunction every 6 months

Multiple Sclerosis Prof. Akram Al.Mahdawi

Adverse events



Inflammation at site of injection.



Headache, flu like symptoms (myalgia,fever, rigor, rhinitis and fatigue).



Rare side effects: Depression, suicide, epileptic events, Thyroid
abnormalities, lymphopenia, thrombocytopenia, asymptomatic elevated
liver transaminase levels and rarely symptomatic hepatitis

Symptomatic therapy



Spasticity: physiotherapy, baclofen, tizanidine, benzodiazepine, dantrolen

Botulinm toxin type A



Fatigue: amantadine,Modafinil,SSRIs



Depression: SSRIs, TAD (tricyclic anti-depressent)



Anxaiety: alprazolam



Ataxia: isoniazid,clonazepam



Dysthesia: carbamazepine,gabapentin



Paroxysmal disordersl: evetiracetam, carbamazepine



Trigeminal neuralgia: carbamazepine, levetiracetam



Tonic spasms: anticonvulsant,baclofen



Cerebellar dysfunction: levetiracetam, INH, carbamazepine

Breakthrough Relapsing



An increase in NO of relapses coupled with increase No of T2 hypertense

and or T1 enhancing lesion on MRI



Approach –Switch to another agent

Restoring conduction in area of demyelination

Dalfampridine (ampyria) is a broad- spectrum K channel blocker that increases
conduction of action potential in area of demyelination.



Counseling: provision of pre-conception counseling is best practice.



Relapse risk: endocrine effects on the immune system ensure that relapse

risk drops during pregnancy.

Multiple Sclerosis Prof. Akram Al.Mahdawi



Disease-modifying drugs: risk of teratogenicity means that all disease-

modifying drugs should ideally be stopped 6–8 wks before conception
and recommenced after.



Breastfeeding has stopped.



Post-partum relapse rate: rebound of immune system activity means that

the highest risk of relapse is in the first year after delivery.

Clinically isolated Syndrome (CIS)



An episode of symptoms of demylinating affecting the optic nerve, spinal

cord, brain stem in isolation.



85% of MS patients, onset is heralded by single episode.



Early treatment with interferon can delay progression to CDMS after CIS

presentation



Guidelines give beta interferon a level A recommendation for use in CIS.



Early initiation of treatment can delay progression to CDMS

MS & neuromyelitis optica (NMO)

The two conditions were long thought to represent variations of same disease.



Neuropathologic differences as well as the recent identification of an

autoantibody to the aquaporin-4 water channel (NMO-IgG) in patients
with NMO suggest is pathologically distinct from MS.



Acute bilateral optic neuritis should suggest the diagnosis of NMO.



The vision loss in NMO also tends to be more severe and recovery is less

complete than in MS.



Spinal cord lesion extending over at least three segment.



Absence of oligoclonal band in the CSF.



Strong association with other autoimmune disease.



Paucity or absence of brain lesions on MRI



Presence of NMO-IgG antibody

Multiple Sclerosis Prof. Akram Al.Mahdawi

Treatment of NMO



IV MP was associated at 6 months with a significantly faster recovery.



Short-term improvements with corticosteroid use have been demonstrated

in several studies.



IV MP is often given at a dose of 500mg to 1000 mg for 3 to 5 days,

sometimes followed by an oral prednisone taper for 10 to 14 days.



Other therapy includes plasma exchange and IVIG, Rituximab, anti-CD-

20 monoclonal antibody, azathioprin.

Acute disseminated encephalomyelopathy (ADEM):



Occurs in children and young adult



Typically follows febrile illness or vaccination



Low grade fever, headache and meningism followed by encephalopathy



Muti-focal deficit and seizure



Diagnosis depend on history, clinical findings, CSF, MRI (extensive,

large , multifocal lesion)



Usually monophasic illness, recovery occurs in 50-70%



Recurrent or multiphase occur in 20%



Neurological squeal in 1/3



Treatment, supportive, antiviral medication (because it looks like herpes

encephalitis), high dose IV MP followed by tapering oral steroid.

End

Multiple Sclerosis Prof. Akram Al.Mahdawi

Appendix (added by student not included in the lecture)

Case (1)

A 26-year-old white female presents with worsening weakness of her right upper
extremity, Left lower extremity and ataxia. She also complains of unilateral eye pain and
visual loss. The eye pain is worsened by ocular movements. On eye examination there is a
central visual field defect in her right eye. Fundoscopy is normal. Neurological
examination shows spastic paraparesis in the right upper extremity and the left lower
extremity. What is the most appropriate next step in this patient's management?

A.  CT scan with contrast
B.  MRI of the brain
C.  Lumbar puncture
D.  Brain biopsy
E.  PET scan

Explanation:

The above patient is most likely suffering from multiple sclerosis (MS). Her history is
consistent with patchy neurological problems (e.g. right upper extremity, left lower extremity
and optic neuritis). Which is characteristic for MS. Optic neuritis presents as a painful loss of
vision and is an important presentation. Patients usually have a central visual field defect and
fundoscopy is normal. Sensory abnormalities may also occur.

MRI is the test of choice to support the clinical diagnosis of MS. It is also a better
predictor of evolution to clinically definite MS than other studies such as CT scan CSF
examination or evoked potentials. The characteristic MRI lesions are cerebral or cerebellar
plaques. The typical locations of the plaques are the periventricular regions, corpus callosum,
deep white matter and basal ganglia.

So the answer is B

Multiple Sclerosis Prof. Akram Al.Mahdawi

Case (2)

A 25-year-old woman comes to the office and complains of intermittent dizziness and an
unsteady gait for the last few days. Her symptoms worsen with exercise. Her past medical
history is significant for tingling and numbness of her right foot that lasted 3-4 days (1
year ago), and visual loss in her right eye which spontaneously resolved (3 years ago).
She is currently nursing her 2-month-old baby. Her obstetrical history was
uncomplicated. Her neurological examination shows right hyperactive deep tendon
reflexes.

On attempted left gaze, her left eye abducts and exhibits horizontal jerk

nystagmus, but her right eye remains stationary. When she attempts to look to the right,
her right eye abducts and exhibits horizontal jerk nystagmus, but her left eye remains
stationary

. The patient is able to converge both eyes together, without any associated

nystagmus. The facial muscles show no signs of weakness. Where is the most likely site of
this patient's lesion?

A.  Optic nerve
B.  Oculomotor nerve
C.  Trochlear nerve
D.  Abducent nerve
E.  Medial longitudinal fasciculus
F.  Medial lemniscus

Explanation:

Suspect multiple sclerosis in a patient with neurological deficits that cannot be explained by a
single lesion. Exacerbation of these neurological deficits by hot weather or exercise is a
useful clue. Complete internuclear ophthalmoplegia (excellently described in this patient's
current eye movement dysfunctions) is a characteristic finding, and is caused by
demyelination of the medial longitudinal fasciculus in the dorsal pontine tegument.

So the answer is E

Case (7)

A 36-year-old white female is brought to the emergency department due to paraplegia and
bladder incontinence. She immediately tells you that she has, "multiple sclerosis in
remission." She has a history of optic neuritis and internuclear ophthalmoplegia and both
resolved with treatment at that time MRI showed plaques in the periventricular region. She is
currently not taking any medications. Which of the following is the most appropriate next
step in the management of this patient?

A.  Corticosteroids
B.  Plasmapheresis
C.  Interferon
D.  Cyclophosphamide
E.  Intravenous Immunoglobulins
F.  Glatiramer acetate

Multiple Sclerosis Prof. Akram Al.Mahdawi

Explanation:

Acute exacerbations of multiple sclerosis are generally treated with IV steroids. Steroids are
the most widely used drugs in the treatment of acute exacerbations because these can hasten
the recovery of such patients. A high-dose intravenous steroid (i.e. methylprednisone) is used
when patients present with disabling symptoms. Mild sensory symptoms generally do not
require steroids. Long-term steroid therapy provides no benefit, and does not prevent future
relapses. To reduce the frequency of acute exacerbations interferon, plasmapheresis,
cyclophosphamide, intravenous immunoglobulins and glatiramer acetate may be used.

So the answer is A

For those who are interested to read more clinical cases please see the
uploaded file on