Ales BARTOS
Department of Neurology, Charles Univesity, Third Department of Neurology, Charles Univesity, Third Faculty of Medicine, Prague, Czech Republic Faculty of Medicine, Prague, Czech Republic
http://vyuka.lf3.cuni.cz(lecture 92)
The questions for the oral state exam in neurobehavioral sciences :
• 11. Disturbances of motor functions, including drug-
induced 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, treatment2
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 pathogen-derived 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
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
Autoimunity
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 fluid6
PRINCIPLES OF IMMUNOTEHRAPY
1. non-antigen-specific immunosupression corticosteroids + other immunosupressive drugs (azathioprine, cyclophosphamide,mitoxantrone)
relapses X chronic therapy
2. non-antigen-specific immunomodulationinterferons beta 1a,1bintravenous immunoglobulins (IVIG)plasmaferesis
3. antigen specific immunotherapyglatiramer 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 resort.
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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.
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11
Epidemiology of multiple sclerosis
Multiple sclerosis (MS)
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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 middle-aged people
Multiple sclerosis
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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 devastating disease
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unknown, but most likely infectious and/or autoimmune origin genetic predisposition (liability) for MS with manifestation only in certain envoirmental circumstances
Multiple sclerosis (MS) - pathogenesis
General description – MULTIPLE sclerosis
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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“
Inflammatory foci
Multiple SCLEROSIS - neuropathology
17
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
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
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Neuropathophysiology in multiple sclerosis
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Two compensatory mechanisms
General clinical features – patterns of MS
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Relapsing - remitting
„multiple“ attacks with complete/incomplete recovery
Stable between attacks
Secondary - progressiveInitially relapsing-remitting
Then progression +/- attacks
Primary progressiveGradual decline
No attacks
1. BenignThis 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/RemittingMajority 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 ProgressivePeople 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 ProgressiveThere is no history of relapses in these patients. Disease begins with a slow progression of neurological deficits. Problems appear and gradually worsen over time.
Description of patterns of MS
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“
Specific clinical features – „multiple“
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„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“
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Examples of common clinical features
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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)
Examples of common clinical features
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bladder:
bowel:
sexual:
Examples of common clinical features
Examples of common clinical features
Examples of common clinical features
Clinical course
dissemination in time??
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multiple lesions ovoid shape perpendicular to the ventricles white matter predominance suggestive localization
periventricular white matter infratentorial: brainstem/cerebellum
corpus callosum juxtacortical
Ancillary investigationsMagnetic resonance of the brain
Evolution of multiple MR lesions
Brain atrophy in MS
= evidence of local intrathecal IgG synthesis
Sérum Mok
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;
Serum CSF
Ancillary investigationsCerebrospinal fluid – oligoclonal IgG bands
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Ancillary investigationsVisual evoked potential test
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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)
Treatment of attacks
39
immunosuppressive drugs among relapses and in progressive forms:
azathioprine cyclophosphamide cyclosporine methotrexate mitoxantron
Long-term treatment
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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
DDDRRRUUUGGG IIIFFFNNN RRROOOUUUTTTEEE FFFRRREEEQQQUUUEEENNNCCCYYY
AAAvvvooonnneeexxx 111aaa iii...mmm... ooonnnccceee aaa wwweeeeeekkk
RRReeebbbiiifff 222222///444444 111aaa sss...ccc... 333 tttiiimmmeeesss aaa wwweeeeeekkk
BBBeeetttaaafffeeerrrooonnn 111bbb sss...ccc... eeevvveeerrryyy ooottthhheeerrr dddaaayyy
Interferons
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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
Glatiramer acetate (Copaxone)
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Natalizumab (Tysabri) monoclonal antibody against adhesive molecule on T cells for active multiple sclerosis, no effect of previous drugs danger: progressive
multifocal leucoencephalopathy
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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
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Fingolimod (Gilenya)
Origins of Fingolimod: A Folk Medicine from Fungi
http://us.quo.novartis.com/gilenya/moa
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Fingolimod (Gilenya)
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Fingolimod (Gilenya)
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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
Summary – MS in one slide
Everything is different and is changing
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New facts about multiple sclerosis
pathologist:
plaques
not normal
surrounding white
matter tissue
radiologist:
lesions
NAWM on
conventional MR
clinician:
relapses
progressive
deterioration 50
Change in understanding of multiple sclerosis
autoimmune and neurodegenerative lesions disseminated in space diffuse (not only inflammatory plaques, but also normal appearing white and gray matter, brain atrophy)
lesions
disseminated in time continuous
demyelinating and axonal white matter and grey matter 51
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Break
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DISORDERS OF NEUROMUSCULAR JUNCTON
presynaptic - Lambert - Eaton syndrome, botulism postsynaptic - myasthenia gravis pre- a postsynaptic - drug induced (penicilamin, steroids, antiarytmics)
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MYASTHENIA GRAVIS - pathogenesis
autoantibodies against the postsynaptic acetylcholine
receptors (AchR) resulting in their reduced
number or altered function
seronegative MG - also antibody-mediated disorder, in which muscle membrane determinants other than the AChR are targeted
is a chronic auto-immune disorder that results in progressive weakness of ocular and skeletal muscles
MYASTHENIA GRAVIS
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57
Myasthenia gravis – clinical features
1. increasing with time : muscle fatigue andweakness
a) during activity (repetitive actions)b) during day (circadial fluctuations)
2. strenght improvement with rest
3. typical distribution - „above breasts“
4. no sensitive impairment
58
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)
???
Associations betweenneuromuscular cranial nerves + muscles +
symptoms and signs
head & neck:- eye muscles - diplopia, ptosis n. III, IV, VI
n. XII - - tongue
n. V- masticatory muscles- difficult chewing, talking
n. VII - facial muscles - dysartrian. IX, X - pharyngeal muscles - dysphagian. XI - m. trapezius - head drooping
- dysartria, chewing weakness 59
Simpson´s sign
eyes are frequently involved
have the patient maintain a sustained upward gaze
one or both eyelids will often begin to droop
MYASTHENIA GRAVIS other muscle groups affected
shoulder girdle pelvic girdle any muscle group incl. respiratory ones
respiratory failure
Myasthenic crisisMyasthenic 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.
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Circadial fluctuations of some myasthenic features
MYASTHENIA GRAVISand
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 atrophyage of manifestation less than 40 30 - 40 over 40M/F ratio 1 : 3 1 : 1 2 : 1---------------------------------------------------------------
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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
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Repetitive stimulation
MYASTHENIA GRAVIS - treatment
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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 )
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 thymus68
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
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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
AIDP - subjective symptoms
1. motor: weakness
2. sensory: paraesthesias, dysesthesias
3. autonomic: palpitations, urinary dysfunction
Clinical features of AIDP – basic principle
nerves + symptoms + signs: motor, sensory, or autonomic involvement
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 :
symmetricaldistally proximallylegs 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