Transcript Sildenafil Treatment Of Subacute Ischemic Stroke: A Safety

Guillain Barre, Myasthenia
Gravis and ALS
Mohammed F Rehman, D.O.
NeuroCritical Care
Henry Ford Hospital – Macomb
Campus
Disclosures
• None
Historical Background
•
•
•
•
Georges Guillain
Jean-Alexandre Barre
Andre Strohl
Acute areflexic
paralysis followed by
recovery, with
elevated protein
content and normal
cell count (Year
1916).
Chowdhury D, Arora A. Axonal Guillain±Barre syndrome: a critical review.
Acta Neurol Scand 2001: 103: 267±277. # Munksgaard 2001.
Epidemiology
•
•
•
•
•
0.6-4 per 100.000 (average 1.2-1.9).
Men>women: 1.5/ 1.
1 per 100.000 in <30 years of age.
4 per 100.000 in >75 years of age.
Nonseasonal.
Epidemiology
• Most cases are sporadic.
• Small clusters of outbreaks.
• Variants:
– North America and Europe: >90% AIDP, 5%
axonal.
– China, Japan, Central and South America: 3047% axonal.
Etiology
• Preceding event in 2/3 of
patients/ prior 2-6 weeks.
• Campylobacter jejuni.
• CMV
• EBV, HIV.
• Mycoplasma, Haemophilus
influenza.
• Vaccine(??) Swine flu
vaccine in 1976.
• Rabies vaccine with brain
material: 1:10.000.
• Surgery.
http://www.gifu-u.ac.jp/~kassei/research/guillain.html
Clinical features
• “Acute peripheral
neuropathy”.
• “Acute paralytic ascending
paralysis”.
• Peak in less than 4 weeks.
• Monophasic.
• Initial symptoms: Symmetric.
– Paresthesias.
– Weakness with sensory
symptoms.
– Weakness.
• Areflexia/ hyporeflexia.
Clinical features…
• Cranial nerve involvement: 45-75%.
• Facial paresis, usually bilateral: ½.
• Extraocular movements and lower cranial
nerves: less often.
• Respiratory Failure: 12-30%*****.
– Neck flexion.
– Oropharyngeal involvement.
Clinical features…
• Moderate to severe pain in 85% of cases
(interscapular or low back pain with radiation to
the legs is more common).
• Dysesthetic pain in up to 50% of patients.
• Autonomic dysfunction in 65% of patients:
– Urinary retention, ileus, tachycardia, HTN, cardiac
arrhythmia, postural hypotension (Be careful with
tracheal suction).
– More severe in patients with quadraparesis and
respiratory failure.
Clinical features: Variants
1. Pharyngeal-cervicalbrachial variant:
• Isolated weakness of
the face, oropharynx,
neck and arms.
2. Weakness confined
to the lower limbs.
3. Miller-Fisher
syndrome:***
• Ophthalmoplegia,
ataxia*** and
areflexia.
• It may overlap with
extremity weakness.
Clinical features: Variants…
4. Acute
pandysautonomia*:
• Combined
sympathetic and
parasympathetic
failure without
sensory or motor
component.
5. AMSAN: fulminant,
with peak within 7
days.
• Quadraparesis,
severe muscle
wasting, prolonged
respiratory support.
Clinical features: Variants…
+/- 6. AMAN: Acute
motor axonal
neuropathy.
• Extensive axonal
degeneration.
• Nadir is quicker,
recovery is faster.
missinglink.ucsf.edu/. ../nervepath.html
Laboratory features
• Routine: UA, CBC
with diff., sed rate,
biochemical profile,
coagulation studies,
ECG, CXR.
• PFT’s.
• Vital Capacity:
– DANGER: <20ml/kg
(1400 ml for 70kg).
– Intubation: <15ml/kg.
• Inspiratory pressure:
– <-25 cm H2O (normal:
-60cm H2O).
ORDERS
• Check VC and NIF by respiratory therapy
every 4 hours and call physician if VC
<1500ml or NIF less than -30cm H2O.
• Check VC and NIF by respiratory therapy
every 4 hours and call physician if values
are less than previous values.
Laboratory features…
• CSF: glucose, protein*,
cell count* and bacterial
culture.
• Electrodiagnostic
studies- NCS/EMG:
(minimum): 3 sensory
nerves, 3 motor nerves,
F waves and bilateral
tibial reflexes.
http://www.neuro.wustl.edu/neuromuscular/
antibody/gbs.htm
Laboratory features…
• Special
circumstances: HIV,
drug-toxic screen,
ANA, urine
porphobilinogen and
delta-aminolaevulinic
acid.
neuro.pathology.pitt.edu/webstuff/Neuro
muscul...
Laboratory features…
• Stool culture and
serology for C. jejuni.
• If pure motor
syndrome, think
polyovirus.
• Serology for
CMV/EBV.
www.pref.aichi.jp/ eiseiken/67f/microbiol.html
Laboratory features…
• Antibodies:
– AMAN:
• GM1: 64%.
• GM1b: 66%.
• GD1a: 45% (ataxia plus facial palsy)
– AIDP: None.
– Fisher’s syndrome: GQ1b- 90%
Differential diagnosis
• Brainstem stroke.
• Brainstem encephalitis.
• Acute anterior
polyomyelitis*.
• Acute myelopathy.
• Myasthenia gravis.
• Hypokalemia,
hypophosphatemia,
myopathy, periodic
paralysis.
• ACUTE PERIPHERAL
NEUROPATHY
• Diphtheria.
• Vasculitis.
• Porphiria.
• Tick paralysis.
• Toxic.
• Critical illness
neuropathy.
General Treatment
• Regular monitoring.
• Ideally in the intensive care setting: 25%
will have respiratory failure, requiring
intubation.
• If severe disease, look for cardiac
arrhythmia.
• Deep venous thrombosis prophylaxis.
• Management of pain, ileus and urinary
retention.
Outcome
• 15% with minor deficits.
• 50-60% with minor
deficits.
• 10-20% with significant
disability.
• 4-15% mortality (8%
average).
•
•
•
•
Poorer outcome:
Older age.
Severe disease.
Mechanical ventilation for
more than 1 month.
• Persistent abnormal EMG
findings.
• Preexisting pulmonary
disease.
Outcome
 Respiratory failure requiring ventilation in
about 25% of patients with GBS
 Death in 4% to 15% of GBS patients
 Persistent disability in about 20% patients with GBS
 Persistent fatigue in 67% of patients with
GBS
Treatment: Immunotherapy
• Plasma exchange: 5 plasma volumes during 1-2
weeks.
– Decreased by half the patients requiring ventilation
after 4 weeks from 27% to 14%.
– Increased the proportion of patients who recover full
strength from 55% to 68%(1)
• IVIg: 0.4 g/kg/day for 5 days **(2).
– Efficacy demonstrated to be similar to plasma
exchange.
– Uncertain if second dose is effective.
1. Raphael, JC, Chevret, S, Hughes, RA, Annane, D.
Plasma exchange for Guillain-Barre syndrome (Cochrane Review).
Cochrane Database Syst Rev 2001; 2:CD001798.
2. Fergusson, D, Hutton, B, Sharma, M, et al. Use of intravenous immunoglobulin
for treatment of neurologic conditions: a systematic review. Transfusion 2005; 45:1640.
Treatment:
• Corticosteroids are ineffective(3).
• Novel approach: To use therapies directed
the antibodies that have an specific affinity
for the individual ganglioside (4).
3. Hughes, RAC. Ineffectiveness of high-dose intravenous me
thylprednisolone in Guillain-Barré syndrome. Lancet 1991; 338:1142.
4. Haupt, WF, Rosenow, F, van der, Ven C, et al. Sequential treatment
of Guillain-Barre syndrome with extracorporeal elimination and
intravenous immunoglobulin. J Neurol Sci 1996; 137:145.
Autoimmune Myasthenia Gravis
Introduction
• Myasthenia Gravis (MG) produces a
symptomatic weakness that predominates in
certain muscle groups and typically fluctuates in
response to effort and rest.
• Diagnosis of MG is based on clinical history and
examination finding demonstrating this
distinctive pattern of weakness.
• Confirmation of the clinical diagnosis may be
obtained using pharmalogic, immunologic,
electrophysiologic and various other tests.
The Clinical Diagnosis of MG
• Presenting Symptoms of MG
– Ocular (ptosis, diplopia) 45-50%
– Bulbar (dysarthria, dysphagia) 20%
– Extremity weakness (usually proximal) 3035%
– Distal extremity rare
– Respiratory rare
Clinical Signs
• Classic physical signs of MG include
ptosis, ophthalmoparesis, bulbar
weakness and fatigable extremity
weakness.
• Facial Muscles show weakness which may
produce a “sagging” appearance with loss
of facial expression A.K.A facial diplegia.
Clinical Signs
• Majority of patients have initial
involvement of the extraocular muscles
and levator palpebrae (50%)
– Eventually, 90% have involvement.
– 10-15% will have ocular involvement only.
• Lower AChR antibodies
– EOM are single innervated muscles, therefore
are more susceptible to defect.
– EOM also have less prominent postsynaptic
folds, AChR’s, and Na+ channels.
Clinical Signs
• Sustained upgaze for 30 seconds is
usually sufficient to produce medial rectus
muscle weakness which can exaggerate
ptosis.
• Cover/uncover test and red glass testing
are useful to elicit mild weakness of a
specific extraocular muscle.
• May see Cogan’s twitch in the upper
eyelid after eyes moved from downward to
primary position.
Clinical Signs
• Oropharyngeal muscle weakness is characterized by
nasal speech secondary to posterior pharyngeal
weakness and articulation abnormalities and laryngeal
weakness which may cause hyphophonic speech
(breathy, whispered).
• Palatal weakness and weakness of tongue muscles
cause dysphagia secondary to abnormal movement of
food bolus in the oral cavity.
• Difficulty with chewing may be due to masseter and
temporalis muscle weakness causing weakness of jaw
closure. Weakness of jaw closure and strong jaw
opening is typical of MG.
Clinical Signs
• Respiratory muscle weakness due to MG often
present with tachypnea and shallow breathing
along with a weak cough and sniff.
• Formal measurement of pulmonary function
such as FVC are useful. ABG measurement is a
relatively insensitive measurement of impeding
respiratory decompensation as by the time CO2
retention occurs, the respiratory muscle have
already begun to decompensate.
Clinical Signs
• Axial/limb muscle weakness in MG
presents in many different patterns and
may be asymmetric.
• Neck flexion > extension weakness
• Upper > Lower extremity weakness
• Upper extremity - finger/wrist extensor and
shoulder abductor weakness
• Lower extremity – foot dorsiflexors and hip
flexor weakness
Confirmation of Clinical Diagnosis
of MG
• Pharmacologic tests
– Edrophonium
– Neostigmine
– Pyrodostigmine
• Serologic tests
– AChR antibodies
– Muscle antibodies
– MuSK antibodies
• Electrophysiologic
tests
– Repetitive nerve
stimulation
– Single fiber EMG
• Miscellaneous tests
– Ice pack test
– Muscle biopsy
Diagnosis: Electrophysiologic
Testing
Repetitive Nerve Stimulation:
• Peripheral nerve is supramaximally stimulated
and CMAP is recorded.
• Stimulation is at 2-3 Hz and a train of 5-10
responses are recorded.
• Decrement >10% is significant.
– More likely to be abnormal in a facial or proximal
muscle.
– RNS sensitivity for diagnosing MG ranges from 53 to
100% for generalized MG and 10-17% for ocular MG.
Diagnosis: Electrophysiologic
Testing
Single Fiber EMG (SFEMG):
• Most sensitive test for detection of
abnormality at the NMJ.
• Abnormalities are seen even in clinically
unaffected muscles.
• Increased jitter is the most sensitive sign
of NMJ defect.
– Record at least 50 discharges and compare at
least 20 pairs.
Single Fiber EMG: Jitter
Immunological Tests: AntiAcetylcholine Antibodies
Anti-AChR binding antibodies:
• The acetylcholine receptor binding
antibody (AChR-ab) assay has become a
widely utilized diagnostic test for MG.
• The sensitivity of this test ranges from 70
to 95% for generalized MG, and 50-75%
for purely ocular MG.
Blocking Antibodies
Strategy of Diagnostic Testing in
Suspected MG
Amyotrophic Lateral Sclerosis
• Amyotrophic Lateral
Sclerosis
• AKA Lou Gehrig's
Disease in U.S.A
ALS: Epidemiology
• ALS is the most common form of motor
neuron disease.
• Sporadic forms (unknown cause) account
for about 90-95 percent of ALS cases.
• Familial forms (AD inherited disease)
make up approximately 5-10 percent.
• Slight male predominance for sporadic
ALS.
ALS: Epidemiology
• The incidence of ALS increases with
each decade, especially after age 40
years.
• Peak age of onset is 50-70’s.
• The only established risk factors for
ALS are age and family history.
ALS: Clinical Features
• The clinical hallmark of ALS is the
combination of upper motor neuron (Brain
and Brain-Stem) and lower motor neuron
signs (Spinal Cord).
• UMN signs include hyperreflexia,
spasticity, extensor plantar response (up
going toes), and positive jaw jerk.
• LMN signs include weakness, muscle
atrophy, cramps and fasciculation's.
Upper Motor Neuron Degeneration
•
•
•
•
•
•
•
•
muscle stiffness or rigidity
emotional lability (decreased ability to control emotions)
excessive fatigue
dysphagia (difficulty swallowing)
dyspnea (shortness of breath)
dysarthria (a speech disorder caused by impairment of the
muscles used for speaking. Speech is slurred, slow, and
difficult to produce)
hyperreflexia (increased or 'brisk' reflexes)
gait spasticity (stiffened legs with toes that drag and catch
when walking)
Lower Motor Neuron Degeneration
•
•
•
•
•
•
•
•
muscle weakness and atrophy
involuntary contraction of muscle fibers
muscle cramps
weakened reflexes
flaccidity (decreased muscle tone)
difficulty swallowing
disordered articulation
shortness of breath at rest
ALS: Clinical Features
• The loss of motor neurons results in the primary
clinical symptoms and signs ALS. These may
produce impairment affecting limb, bulbar, axial
and respiratory function.
• Differences in site of onset, pattern and speed of
spread, and the degree of upper motor neuron
(UMN) and/or lower motor neuron (LMN)
dysfunction produce a disorder that is
remarkably variable between individuals.
ALS: Initial Clinical Features
• Asymmetric limb weakness is the most common
presentation of ALS (80 percent).
• Bulbar symptoms, usually manifested as
dysarthria or dysphagia, is the next most
common presentation (20 percent).
• Less common patterns of ALS onset include:
– respiratory muscle weakness (1 to 3 percent)
– generalized weakness in the limbs and bulbar
muscles (1 to 9 percent)
– axial muscle weakness
– weight loss with muscle atrophy.
ALS: Clinical Features of Limb
Weakness
• Upper extremity onset is most often
heralded by hand weakness but may
begin in the shoulder girdle muscles.
• Patients with hand weakness may
complain that they drop things and have
difficulty with tasks such as pinching,
writing, typing, managing buttons or
zippers, and picking up small objects.
ALS: Clinical Features of Limb
Weakness
• Patients with shoulder girdle weakness
may report difficulty using their arms in
activities such as washing, drying, or
combing their hair as well as lifting things
above their head.
ALS: Clinical Features of Limb
Weakness
• Lower extremity onset of ALS most often
begins with foot drop.
• Patients with proximal leg weakness often
complain of difficulty climbing stairs and
difficulty arising from chairs.
• Either proximal or distal leg weakness can
cause falls.
ALS: Clinical Features of Bulbar
Weakness
• Patients with dysarthria complain of slurring of
speech that is often worse at the end of the day
or with more vigorous use of their voice.
• Patients with dysphagia initially complain of
difficulty swallowing thin liquids, and may report
the need to swallow multiple times in order to
manage a single liquid bolus.
ALS: Clinical Features of
Respiratory Muscle Weakness
• Initially complain of fatigue/shortness of
breath triggered by decreasing levels of
activity or by lying flat.
• Often develop disturbed nocturnal sleep
with frequent awakenings and excessive
daytime sleepiness.
ALS: Clinical Features of Axial
Muscle Weakness
• Patients with axial neck weakness complain of
posterior neck pain or strain with a gradually
worsening tendency for head drop.
• Patients with axial truncal weakness complain of
difficulty maintaining an erect posture when
standing and of stooping when walking. Some
will support their trunk by placing their hands in
their front pants pockets or on their upper thighs.
ALS: Other Clinical Features
• Front temporal executive dysfunction may
precede or follow the onset of UMN and
LMN dysfunction.
• Symptoms include changes in personality,
impairment of judgment, and development
of obsessional behaviors.
ALS: Diagnosis
• The clinical standard for diagnosis is the
Revised El Escorial World Federation of
Neurology criteria which requires:
– Evidence of LMN degeneration by clinical,
electrophysiological, or neuropathological
examination
– Evidence of UMN degeneration by clinical
examination
– Progressive spread of symptoms or signs within a
region or to other regions (The body is divided into
four regions: cranial, cervical, thoracic and
lumbosacral)
– Absence of electrophysiological, pathological or
neuroimaging evidence of other disease processes.
ALS: Diagnosis
• ALS is primarily a clinical diagnosis, sensory and
motor nerve conduction studies and
electromyography (EMG) are a standard part of
the evaluation of motor neuron disease.
• EMG findings in ALS combine features of acute
and chronic denervation.
• Sensory and motor NCS are most often normal
in ALS.
ALS: Differential Diagnosis
• Other Motor Neuron Diseases
– Primary lateral sclerosis (UMN
only)
– Progressive muscular atrophy
(LMN only)
– Progressive bulbar palsy
• Neuropathies
– GB, CIDP
• Myopathies
– PM, inclusion body myositis
• NM Junction
– Myasthenia gravis
• Neurodegenerative Diseases
– Parkinson’s, Progressive
Supranuclear Palsy, MS
• Malignancy
– Primary/mets CNS
– Motor neuron syndromes with
MM, Lymphoma, lung, breast
• Toxic Exposure
– EtOH, heavy metals
• Endocrine
– TSH, adrenal, pituitary
• Infectious
– HIV, CMV
ALS: Progression and
Prognosis
• ALS is a relentlessly progressive disorder with a
clinical course that is nearly always linear, with a
relatively constant slope. (i.e. no remissions or
exacerbations)
• Rate of progression varies between individuals.
• Symptoms initially spread within the segment of
onset and then to other regions in a relatively
predictable pattern.
ALS: Progression and
Prognosis
• Patients with unilateral limb onset the
pattern of spread is to the contralateral
limb, then to the ipsilateral U/LE, then to
the contralateral remaining U/LE, and then
to the bulbar muscles.
• In patients with bulbar onset the most
common pattern of spread is to one arm
and then to the contralateral arm.
ALS: Progression and
Prognosis
• The life-threatening aspects of ALS are
neuromuscular respiratory failure and
dysphagia.
• The median survival from the time of
diagnosis is three to five years.
• 10% of ALS patients can live 10 years or
more.
ALS: Supportive Treatment
• Progressive neuromuscular respiratory failure is
the most common cause of death in ALS.
• Initiation of noninvasive positive pressure
ventilation (in patients with FVC < 50%) can
prolong survival up to 20 months.
• 5 to 10 percent of patients choose tracheotomy
and permanent ventilation when respiratory
compromise becomes severe.
ALS: Supportive Treatment
• Dysphagia poses a risk for aspiration of
food, liquids, or secretions with resultant
pneumonia and may also lead to
malnutrition and dehydration.
• Symptoms can be minimized in patients
who choose gastrostomy tube insertion
with aggressive management of
secretions.
ALS: Pharmacologic Treatment
• Riluzole (Rilutek®) is the only currently
available medications for the treatment of
ALS.
• Glutamate Inhibitor although precise
mechanism of action in ALS is unclear.
• Clinical trials have shown prolonged
survival of approximately 2-3 months.
Jim Catfish Hunter- 8-time AL All-Star
Inducted into the National Baseball Hall
of Fame in 1987
Died of ALS in 1999
Jon Stone
Founder of
the show
Sesame
Street
Died of ALS
March 13,
1997
Was the thirty-third
Vice President of the
United States (1941–45)
1948 Presidential
Progressive Party candidate
Died of ALS
November 18, 1965
Best known for
his role as
villain Roger Thorpe
on CBS's Guiding Light
Died of ALS
December 6, 1998
Acknowledgements
Questions???