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: 30-

47% 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-cervical-brachial 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/

Neuromuscul...

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 inabout 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 methylprednisolone 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) 30-

35%– 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: Anti-Acetylcholine 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 StoneFounder of the show Sesame Street

Died of ALSMarch 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 asvillain Roger Thorpe on CBS's Guiding Light

Died of ALS December 6, 1998

Acknowledgements

Questions???