Transcript MULTIPLE sclerosis

http://vyuka.lf3.cuni.cz
(lecture 92)
Ales BARTOS
Department of Neurology, Charles Univesity, Third
Faculty of Medicine, Prague, Czech Republic
The questions for the oral state exam
in neurobehavioral sciences :
• 11. Disturbances of motor functions, including druginduced syndromes
• 11. Multiple sclerosis: clinical presentation, diagnosis,
differential diagnosis, complications, treatment
• 15. Polyneuropathy and polyradiculopathy: causes,
classification, clinical presentation, diagnosis, treatment
• 16. Paraneoplastic syndromes affecting the nervous
system. Metastases. Classification, clinical presentation,
diagnosis, treatment
• 23. Neuromuscular junction disorders, namely
myasthenia gravis: clinical presentation, diagnosis,
differential diagnosis, treatment
2
Autoimmune diseases in neurology – outline
• CNS – multiple sclerosis
break
• PNS – inflammatory polyneuropathy
(polyradikuloneuritis)
• neuromuscular junction – myasthenia gravis
• paraneoplastic syndromes if time available
3
Autoimunity
 immune system - protection the organism
against pathogens
 autoimmunity - response of the immune system
to components of the host organism or self
 dysregulated immunity - the normal, protective
immune response is directed toward pathogenderived peptides and determinants that become
apparent to the immune system via inflammatory
processes that lead to upreagulation of MHC,
costimulator ligands, cytokines, and adhesion
molecules in infected cells and tissues
Autoimunity
 lack of autoimmunity in normal situations functional tolerance (deletion or
unresponsiveness) of potential autoimmune
effector cells and lack of access to or recognition
of autoantigens
 molecular mimicry - cross-reactivity between
self and pathogen-derived antigens
Autoimmune diseases in neurology – diagnosis
principle: to prove inflammatory or immune processes
• multiple sclerosis: oligoclonal IgG bands in cerebrospinal
fluid
• inflammatory polyneuropathy (polyradikuloneuritis):
increased protein concentration in cerebrospinal fluid
• myasthenia gravis: positive antibodies against acetylcholine
receptors in serum
• paraneoplastic syndromes: positive paraneoplastic
antibodies in serum, cerebrospinal fluid
6
PRINCIPLES OF IMMUNOTEHRAPY
1. non-antigen-specific immunosupression
 corticosteroids + other immunosupressive
drugs (azathioprine, cyclophosphamide,mitoxantrone)
 relapses X chronic therapy
2. non-antigen-specific immunomodulation
interferons beta 1a,1b
intravenous immunoglobulins (IVIG)
plasmaferesis
3. antigen specific immunotherapy
glatiramer acetat (copolymer)
4. immunoablative treatment
Immunomodulating therapies
for neuroimmune disorders
GENERAL PRINCIPLES
•Drug dosing
•Initial: Use high dose to bring disease into remission
•Follow-up: Taper medications
o Slowly
o To a minimum dose that is effective in
maintaining remission
•Monitor carefully for side effects
8
Immunomodulating therapies
for neuroimmune disorders
SPECIFIC MEDICATIONS
•Corticosteroids (Prednisone or Solumedrol) are used for long-term
immunosuppression and relatively rapid onset of benefit (Months). Side effects are
common.
•Cyclosporine A is an alternative to Prednisone for long-term immunosuppression
and relatively rapid onset of benefit (Months).
•Azathioprine provides long-term immunosuppression with relatively few side
effects. It may be useful to reduce needed doses of corticosteroids. However, there
may be a long latency before benefit begins, and some patients do not improve at
all.
•Methotrexate can have a relatively rapid onset of benefit (Months). It can be
useful when corticosteroids or Cyclosporine A are ineffective or contraindicated.
With routine monitoring, serious side effects are uncommon.
•Cyclophosphamide is useful in immune disorders with life threatening features
and in B-cell mediated disorders that respond to few other treatments. As it has
serious side effects, cyclophosphamide should be considered a treatment of last 9
resort.
Immunomodulating therapies
for neuroimmune disorders
SPECIFIC MEDICATIONS
•Plasma exchange (PE) and human immune globulin (IVIg) are used for rapid
onset, short-term benefit when patients have life-threatening signs such as
respiratory insufficiency, dysphagia, or severe weakness. They are the only
treatments shown to be of benefit in Guillain-Barré syndrome.
PE & IVIg are expensive but are occasionally used for chronic therapy when other
treatments have failed.
10
Epidemiology of multiple sclerosis
11
Multiple sclerosis (MS)
 is a chronic inflammatory disorder of the central
nervous system (CNS)
 age: usually begins between 20 - 40 years
(exceptionally before 12 and over 55)
 sex: female-male ratio 2-3 : 1
 is one of the most common causes of
nontraumatic disability among young and middleaged people
12
Multiple sclerosis
 is the most common disease of the CNS
of young adults
 symptoms of MS are extremely variable and often
subtle
 diagnosis and management have been greatly
enhanced by the development of magnetic resonance
imaging
 therapies that slow the progression of the disease
are now available
 therefore early diagnosis and treatment are
important in limiting the impact of this potentially
13
devastating disease
Multiple sclerosis (MS) - pathogenesis
 unknown, but most likely infectious and/or
autoimmune origin
 genetic predisposition (liability) for MS with
manifestation only in certain envoirmental
circumstances
14
General description – MULTIPLE sclerosis
 multiple: lesions (plaques) on pathology,
clinical attacks, MR foci
 circumscribed lesions confined to CNS, mainly
white matter of the brain and the spinal cord
 disseminated in „space and time“
15
Inflammatory foci
Multiple SCLEROSIS - neuropathology
sclerosis = a final stage of plaque development:
 perivascular inflammation + demyelination +
axonal damage
 reactive gliosis

1. neurofilament-positive axons (green)
undergoing DEMYELINATION
(myelin = red)
2. AXONAL TRANSECTION
- one axon ends in a terminal ovoid
17
Neuropathological findings in multiple sclerosis

Demyelination

Axonal damage – histopathology, MR imaging:
widespread (acute and chronic lesions,
NAWM, NAGM)
 early in the disease course
 clinical impact: permanent or increasing disability

18
Neuropathophysiology in multiple sclerosis
19
Two compensatory mechanisms
General clinical features – patterns of MS

Relapsing - remitting
„multiple“ attacks with complete/incomplete recovery
Stable between attacks

Secondary - progressive
Initially relapsing-remitting
Then progression +/- attacks

Primary progressive
Gradual decline
No attacks
21
Description of patterns of MS
1. Benign
This could simply be an initial attack that leads to a diagnosis of MS with no further
activity. However, this does not mean it will always be completely inactive. It can also be
associated with occasional relapses over a period of time, followed by a complete
recovery. In some cases benign MS may worsen in later life.
2. Relapsing/Remitting
Majority of people diagnosed with MS are diagnosed with Relapsing/Remitting. MS is
active during a relapse and nerves are damaged; new symptoms may appear or existing
ones worsen. A relapse can last anything from a few days to several months. The severity
can also vary from mild to more severe. Symptoms will still be there because of damage
done to the nerves. When in remission, the activity quietens down; this can last any length
of time, sometimes even years.
3. Secondary Progressive
People with this type of MS may have started with a diagnosis of Relapsing/Remitting and
then started to experience a worsening of symptoms over many years. Remission periods
lessen and shorten in duration and eventually become non-existent. The course of MS
becomes steadily progressive.
4. Primary Progressive
There is no history of relapses in these patients. Disease begins with a slow progression of
neurological deficits. Problems appear and gradually worsen over time.
Specific clinical features – „multiple“
Physical symptoms may include any of the following:
•Muscle and Motor Disturbances including: loss of control of one or more limbs; Myoclonus; Swallowing difficulties;
Tremor; inability to perform fine movements - e.g. doing up buttons, tying shoe laces etc; Legs or arms may suddenly go
into spasm which is often painful, and walking may become very difficult when sticks or a wheelchair may be necessary.
•Loss of Co-ordination & Spasticity including: dizziness and vertigo; ataxia; staggering; clumsiness (spilling and
dropping things).
•Fatigue including: intense desire for rest affecting motor and/or sensory nerves; dizziness and sometimes, in extreme
cases, breathing difficulties
•Visual including: retro-bulbar (behind the eye ball) & optic neuritis (inflammation of the nerve); nystagmus (rhythmical
oscillation of the eye balls, either horizontal, vertical or rotary); double or blurred vision (a common first symptom);
temporary blindness.
•Sensory including: impairment of sensory perception; loss of feeling, numbness, tingling; different degrees and kinds of
pain, including Neuropathic pain.
•L'hermittes sign is an electric shock-like sensation which radiates down the back and into the legs when someone flexes
their neck. It is a common early symptom of MS. In itself it is not a diagnostic however. It simply indicates a particular
type of nerve damage, for which there are a variety of causes.
•Bladder and Bowel including: frequency; urgency; retention; constipation; incontinence.
•Speech difficulties and swallowing difficulties including: slurring; scanning and choking.
•Psychological - cognitive problems - including: loss of memory and mental concentration; depression.
•Sexual including: loss of sensation and/or lubrication; impotence.
•Pain is one of the lesser known symptoms of MS which, now at long last, is being acknowledged and treated.
•Depression and Anxiety can also be associated with MS.
•Multiple Sclerosis "Hug" or "Girdle" - This is the term for one of the rather strange and weird symptoms of Multiple
Sclerosis which can be classed as one of the many invisible symptoms but also as a spasm-type symptom.
•Heat Intolerance or anhidrosis as it is scientifically known, is a classic symptom of MS where a rise in temperature
whether it’s internally or externally, may temporarily increase symptoms
Specific clinical features – „multiple“
24
„Multiple“ symptoms of MS








Vision problems
Numbness
Difficulty walking
Fatigue
Depression
Emotional changes
Vertigo & dizziness
Sexual dysfunction






Coordination problems
Balance problems
Pain
Changes in cognitive
function
Bowel/bladder
dysfunction
Spasticity
Specific clinical features – „multiple“
26
Examples of common clinical features
Examples of common clinical features
motor:
 acute-subacute onset (days) / slowly developed
 mono-/hemi-/tri-/para-/quadru
- paresis/plegia
 accompanied with signs of central involvement
sensory:
 acute / subacute onset (days) of numbness (-) or
tingling (+) in one or more limbs
 symptoms migrate, strange distribution
 resolve spontaneously (often missed)
28
Examples of common clinical features
bladder:
bowel:
sexual:
29
Examples of common clinical features
Examples of common clinical features
Clinical course
dissemination in time??
Ancillary investigations
Magnetic resonance of the brain
 multiple lesions
 ovoid shape perpendicular to the ventricles
 white matter predominance
 suggestive localization
periventricular white matter
 infratentorial: brainstem/cerebellum
 corpus callosum
 juxtacortical

33
Evolution of multiple MR lesions
Brain atrophy in MS
Ancillary investigations
Cerebrospinal fluid – oligoclonal IgG bands
= evidence of local intrathecal IgG synthesis
Sérum
Serum
Mok
CSF
;
36
Ancillary investigations
Visual evoked potential test
37
Treatment of attacks
methylprednisolone
 synthetic version of a hormone (cortisone)
produced by the body that reduces
inflammation
 hasten clinical recovery, but do not change
the course of the disease
 transiently restores blood-brain barrier
 a pulse of intravenous drug for 3-5 days,
then the switch to slowly lowering the dosage
of steroids over several weeks (tapering) 38

Long-term treatment
immunosuppressive drugs among relapses
and in progressive forms:





azathioprine
cyclophosphamide
cyclosporine
methotrexate
mitoxantron
39
Long-term treatment
for patients with higher disease activity




interferons 1 a, b – s.c. /i.m. therapy
glatiramer acetate – s.c. therapy
natalizumab – infusion therapy once a month
fingolimod – a mechanistically novel, first
oral therapy for multiple sclerosis
40
Interferons
DR U G
IFN
ROUTE FREQUENCY
Avonex
1a
i . m.
once a week
Rebif 22/44
1a
s .c .
3 times a week
Betaferon
1b
s .c .
every other day
Glatiramer acetate (Copaxone)
 random synthetic mixture of polypeptides
(45 - 100 AK) containing 4 amino acids
(glutamate, lysine, alanine, tyrosine) in
similar ratio as it is in myelin basic protein
(MBP) - autoantigen in MS pathogenesis
 s.c. every day

video
42
Natalizumab (Tysabri)
 monoclonal antibody against adhesive molecule on T cells

for active multiple sclerosis, no effect of previous drugs


danger: progressive
multifocal
leucoencephalopathy
43
Natalizumab (Tysabri)
 TYSABRI binds to α4-integrin on white blood cells,
inhibiting interaction with VCAM-1, which, in turn, inhibits
white blood cell migration across the blood-brain barrier.
an innovative mode of action:
 temporary α4-integrin blockade
 does not deplete lymphocytes2: TYSABRI increases the
number of circulating leukocytes due to inhibition of
transmigration out of the vascular space
pharmacokinetic/pharmacodynamic effect
 the mean ± SD half-life and clearance of natalizumab are 11
± 4 days and 16 ± 5 mL/hour, respectively
http://www.tysabrihcp.com/mechanism-of-action-hcp.xml
44
Fingolimod (Gilenya)
Origins of Fingolimod: A Folk Medicine from Fungi
http://us.quo.novartis.com/gilenya/moa
45
Fingolimod (Gilenya)
46
Fingolimod (Gilenya)
47
Summary – MS in one slide
 CNS disease, mostly damage of white matter tracts

Pathology: inflammatory demyelination, axonal damage

Pathophysiology: slowing or failure of neurotransmission

Clinical: optic neuritis, weakness, sensory loss, ataxia,
nystagmus, bladder dysfunction, cognitive impairment

Diagnosis based on clinical and laboratory evidence of
multiple dissemination in time
multiple dissemination in space

Treatment – acute attacks (corticosteroids), long-term
treatment – immunosuppressants, immunomodulators
48
Everything is different and is changing
49
New facts about multiple sclerosis
pathologist:
radiologist:
clinician:

plaques

lesions

relapses

not normal
surrounding white
matter tissue

NAWM on
conventional MR

progressive
deterioration
50
Change in understanding of multiple sclerosis
and neurodegenerative
 lesions
disseminated in space  diffuse
(not

autoimmune
only
inflammatory plaques, but also normal appearing white and gray matter, brain atrophy)
lesions
disseminated in time

demyelinating
 white matter

and
and

continuous
axonal
grey matter
51
52
Break
53
DISORDERS OF NEUROMUSCULAR JUNCTON
presynaptic - Lambert - Eaton syndrome, botulism
 postsynaptic - myasthenia gravis
 pre- a postsynaptic - drug induced (penicilamin,
steroids, antiarytmics)

54
MYASTHENIA GRAVIS - pathogenesis
autoantibodies against the
postsynaptic acetylcholine
receptors (AchR)
resulting in their reduced
number or altered function
seronegative MG - also antibodymediated disorder, in which muscle
membrane determinants other than
the AChR are targeted
MYASTHENIA GRAVIS
is a chronic auto-immune disorder that results in
progressive weakness of ocular and skeletal
muscles

56
Myasthenia gravis – clinical features
1. increasing muscle fatigue and
weakness with time :
a) during activity (repetitive actions)
b) during day (circadial fluctuations)
2. strenght improvement with rest
3. typical distribution - „above breasts“
4. no sensitive impairment
57
Let´s guess
clinical features of myasthenia gravis
above breasts – head and neck
 which nerves innervate head and neck
regions?
„12 cranial nerves“
 which of them may be involved
in myasthenia gravis?
„those
nerves
with
neuromuscular junctions, i.e. ONLY
MOTOR cranial nerves“

12 cranial
nerves
???
motor nerves
(n-m junction)
58
Associations between
neuromuscular cranial nerves + muscles +
symptoms and signs
head & neck:
 n. III, IV, VI - eye muscles - diplopia, ptosis
 n. V - masticatory muscles
- difficult chewing, talking
n. VII - facial muscles - dysartria
n. IX, X - pharyngeal muscles - dysphagia
n. XI - m. trapezius - head drooping
n.
XII - tongue - dysartria, chewing
weakness
59
eyes are frequently
involved
 have the patient
maintain a sustained
upward gaze
 one or both eyelids
will often begin to
droop
Simpson´s sign
MYASTHENIA GRAVIS
other muscle groups affected

shoulder girdle
 pelvic girdle
 any muscle group
incl. respiratory ones
 respiratory failure
Myasthenic crisis
Myasthenic crisis is a life-threatening condition that
occurs when the muscles that control breathing
become too weak to do their jobs. Emergency
treatment is needed to provide mechanical assistance
with breathing.
Circadial fluctuations
of some myasthenic features
62
MYASTHENIA GRAVIS
and
THYMUS
thymic pathology:
 thymic hyperplasia (60 % patients)
 thymoma (10 % patients)
 myoid cells of thymus with presentation
of acetylcholin receptor epitops
 activation of autoreactive cells with
production of autoantibodies
63

Myasthenia gravis and thymus
weakness varies in distribution and
severity
 in young women and old men

I
II
III
------------------------------------------------------thymus pathology hyperplasia thymoma atrophy
age of manifestation less than 40 30 - 40
over 40
M/F ratio
1:3
1:1
2:1
---------------------------------------------------------------
64
MYASTHENIA GRAVIS
diagnosis
characteristic clinical picture
 EMG - repetitive motor nerve stimulation

results in a typical pattern (increased decrement)
serum anti-AChR antibodies (80 - 90 %
of patients), no correlation with clinical status
 clear clinical response to AChE
inhibitors treatment
 CT of the chest to exclude thymoma or
thymic abnormalities
65

Repetitive stimulation
MYASTHENIA GRAVIS - treatment
1) anticholinesterase drugs:
ambenonium,
pyridostigmine, (neostigmine)
2) thymectomy
(remission in 25 % and
improvement in 50 %)
in the young < 40 years at disease onset
(usually hyperplastic gland )
67
MYASTHENIA GRAVIS - treatment
3) immunomodulation
1. short-term (myasthenic crisis, rapid destabilization)
intravenous immunoglobulins
 plasma exchange (removing circulating antibodies)
 steroid puls

2. long-term (to maintain clinical remission)
steroids
 immunosupression (azathioprine, cyclophosphamide)

- often in older patients, mainly atrophic or involuted thymus
68
MYASTHENIA GRAVIS
– summary in videos
videos:
http://www.youtube.com/watch?v=YtypsBCjuyQ
historical one: http://www.youtube.com/watch?v=uRoRsmvkhTI
http://mgakc.org/videos
69
Acute inflammatory demyelinating
polyneuropathy
AIDP = Guillain - Barré syndrom
• prodrome – 50 % of patients in 2 weeks before
the disease onset
(upper respiratory infection, gastrointestinal disorder campylobacter jejuni, other infections (EBV, hepatitis A,
mycoplasma), vaccinations, post-partum, operations
• progression - average: 5 to 10 days (2-28 days)
• course - usually monophasic, rare relapses
• prognosis - recovery in most
Clinical features of AIDP – basic principle
nerves + symptoms + signs:
motor, sensory, or autonomic involvement
AIDP - subjective symptoms
1. motor: weakness
2. sensory: paraesthesias, dysesthesias
3. autonomic: palpitations, urinary dysfunction
AIDP - objective signs
1. motor : peripheral paresis of various degree and
distribution in limbs (a/hypo-reflexia/tonia/trofia),
in 50-70 % facial palsy, rare oculomotor or pharyngeal
weakness
2. sensory : disturbances or loss of various extend
and type, mainly :
a) tactile - sock-like or glove-like distribution with
ascending progression
b) deep - loss of vibration sense
3. dysautonomic - blood pressure, cardiac
arrhythmias, urinary retention, ileus
! AIDP - core clinical features !
sensory and motor
signs :
symmetrical
distally  proximally
legs  arms
rapidly progressive weakness or paresthesias often spreading
from the legs upwards
AIDP - diagnostics
EMG: demyelination (= prolonged distal
motor latencies, conduction block) ± axonal
loss
AIDP - Cerebrospinal fluid
Albumino-cytological dissociation
(high protein (> 0.55 g/L) + few or no cells)
 Protein
 early (1st 2 days): usually (85%) normal
 later
 high; 66% in 1st week; 82% in 2nd week
 highest with most slowing of NCV
 Cells normal cell count or < 50 cells/ul (~90%),
unless associated disorder present
Course of autoimmune polyradiculoneuritis
AIDP - treatment - immunomodulation
• Plasma Exchange or IV IgG definitely indicated
 Patients with inability to walk
 1st 2 weeks of disease
 Probably indicated: Milder weakness; early in disease
course
 Plasma Exchange and IV IgG
 Often provide similar degrees of benefit
 Not Corticosteroids (no significant benefit)
respiratory failure  ventilatory support