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

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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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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

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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

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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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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

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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