Respiratory Failure in Neuromuscular disease

Upper Motor Neuron

Cerebral – Stroke, spinal cord injury

Lower Motor Neuron

Anterior horn cells – poliomyelitis, amyotrophic lateral sclerosis

Peripheral nerves – phrenic nerve injury, Guillain-Barré syndrome, critical illness polyneuropathy

Neuromuscular junction – myasthenia gravis, Lambert-Eaton myasthenic syndrome, botulism, aminoglycosides

Muscle – dystrophy, acid maltase deficiency

Corticosteroids – acute intensive care myopathy

Stroke – Cerebrovascular accident

Spinal cord injury – traumatic spinal cord injury (TSCI), non-traumatic spinal cord injury

Amyotrophic lateral sclerosis (ALS), Lou Gehrig’s disease

Poliomyelitis and postpoliomyelitis syndrome – polio, postpoliomyelitis syndrome (PPS)

Guillain-Barré syndrome (GBS)

Critical Illness polyneuropathy and polyneuromyopathy (CIPNM)

Myasthenia gravis (MG)

Lambert-Eaton myasthenia syndrome (LEMS)

Related Conditions

Stroke: transient ischemic attack

Amyotrophic lateral sclerosis: progressive muscular atrophy, ALS plus syndrome

Guillain-Barré syndrome:

• Acute inflammatory demyelinating polyradiculopathy

• Miller Fisher syndrome

• Acute motor axonal neuropathy

• Acute sensorimotor axonal neuropathy

Myasthenia gravis:

• Myasthenic crisis – exacerbation of MG leading to respiratory failure requiring mechanical ventilation; occurs in 15% to 20% of patients with MG

• Cholinergic crisis – worsening of weakness due to overdose of anticholinesterase medications, leading to depolarizing blockade at myoneuronal junction

• Thymoma – associated with more fulminant course; present in one third of those with myasthenic crisis

• Small-cell lung cancer (SCLC)

• Hodgkin’s lymphoma

• Autoimmune disorders

Lambert-Eaton myasthenia syndrome:

• SCLC (3%) – LEMS may be presenting symptom/sign

• Hodgkin’s lymphoma

• Atypical carcinoid

• Malignant thymoma

• Autoimmune disease (DMI, autoimmune thyroid disorders)

1. Description of the problem

General Clinical Features of Respiratory Failure Due to Neuromuscular Disease

Neuromuscular diseases vary in terms of etiology, pathophysiology, treatment and prognosis. All can lead to respiratory failure due to decreased pump function of respiratory muscles and ineffective cough. May present as acute-on-chronic respiratory failure or failure to wean from mechanical ventilation. In setting of neuromuscular disease, respiratory failure is triggered by progression or exacerbation of the primary disease process or infection.

Hypercapnia typically occurs when inspiratory muscle strength is less than 30% predicted. At baseline, patients have rapid shallow breathing pattern.

• Thrombotic(small or large vessel)

• Embolic

• Hemorrhagic – abrupt focal neurologicdeficits with decreased level of consciousness and evolution overhours. May be accompanied by severe headache.

Spinal cord injury

After spinal cord injury, paresis/paralysis occurs below level of injury.

Amyotrophic lateral sclerosis

Progressive neurodegenerative disorder of upper (UMN) and lower motor neurons (LMN)→loss of skeletal muscle strength, including respiratory muscles.

Most common presenting symptom (80%) are asymmetric limb weakness, followed by bulbar symptoms (20%); 25% may have early bulbar involvement. Link between ALS and frontotemporal dementia: patients may present with cognitive dysfunction. Autonomic symptoms develop later in disease process. Death is typically due to repeated respiratory infections and progressive respiratory failure.

Poliomyelitis and Postpoliomyelitis Syndrome

Acute polio is now rare in the United States.

A quarter of acute poliomyelitis cases may be the paralytic form requiring mechanical ventilation. Typically, respiratory function returns to normal, but progressive muscle weakness may occur years later.

PPS – symptoms/signs due to neurologic and musculoskeletal features. Develops in 20% to 60% of acute poliomyelitis cases at about 29 years after recovering from acute polio. Mean age of onset is 51 years.

Phrenic nerve injury may occur after cardiac surgery (due to cold exposure or nerve stretch), trauma, mediastinal tumors, pleural space infection, forceful neck manipulation. May also be due to motor neuron disease, myelopathy, neuropathy, myopathy. The majority of cases are idiopathic.

Guillain-Barré syndrome

Acute, idiopathic polyneuritis – usually presents as ascending symmetric paralysis (though 10% may begin in arms).

CIPNM

The most prominent symptoms are in the lower extremities. Accompanied by diminished or absent deep tendon reflexes. Often presents with failure to wean from mechanical ventilation. Common in setting of severe sepsis, multisystem organ failure in the surgical or medical intensive care unit.

Presents as flaccid paralysis of upper and lower extremities as early as 5 to 7 days after mechanical ventilation.

Myasthenia Gravis

• Autoimmune disorder directed at postsynaptic acetylcholine receptors, leading to weakness.

• Two clinical forms – ocular and generalized.

• Seropositive disease – detectable antibodies to acetylcholine receptor (AChR-Ab) or muscle-specific receptor tyrosine kinase (MuSK-Ab)

Lambert-Eaton myasthenia syndrome

Rare disorder that results from impaired release of acetylcholine from presynaptic terminals resulting in skeletal muscle weakness.

Botulism

• Rare but possibly life-threatening disorder caused by
  Clostridium botulinum.

• Toxin ingested through improperly cooked or preserved food, wound contamination, absorption through the gastrointestinal tract.

• Five types of botulism – foodborne, infant, wound, adult enteric infectious, and inhaled.

Steroid myopathy

Results from prolonged use of corticosteroids

Clinical Features

Stroke

Strokes in specific locations → predictable effects on respiratory system.

May lead to loss of upper airway function, abnormal breathing pattern, decreased diaphragmatic function, loss of automatic or voluntary breathing control.

• Acute hemispheric stroke → loss of upper airway function and Cheyne-Stokes breathing. Voluntary control of muscles decreased on side of hemiparesis.

• Small stroke in dorsolateral area of medulla → respiratory arrest and sudden death.

• Stroke in midbrain may lead to central neurogenic hyperventilation.

• Stroke in pontomedullary area → apneustic or ataxic breathing pattern.

• Stroke to descending reticulospinal tract in pons or nucleus of vagus ambiguus may lead to loss of breathing control.

• Midpontine stroke may lead to “locked-in syndrome” and loss of voluntary breathing control.

• Oropharyngeal muscle dysfunction → swallowing dysfunction → aspiration → pneumonia.

• Increased intracranial pressure (ICP) from hemorrhage, vertebrobasilar ischemia or bihemispheric ischemia can present with decreased respiratory drive → hypoventilation → hypercapnia → further increase in ICP.

• Muscular upper airway obstruction.

Spinal Cord Injury

• Typically presents with pain at fracture site. Transient paralysis and spinal shock – physiologic loss of all spinal cord function immediately after injury → flaccid paralysis, sensory loss, loss of bowel and bladder control, loss of reflexes, bradycardia and hypotension.

• High C-spine injury (above C1-C3) → paralysis of all major respiratory muscles (accessory and bulbar muscles spared). Requires continuous ventilatory support.

• Injury at C3-C5 → weakness or paralysis of diaphragm → need for continuous ventilatory support.

• Injury below C5 → intercostal and abdominal muscle paralysis but diaphragm spared and chronic ventilatory support often not needed, though may be necessary in acute setting.

• High and low C-spine injury → expiratory muscle weakness or paralysis → ineffective cough → mucus retention, atelectasis, pneumonia.

• Contraction of clavicular portion of pectoralis major possible in some spinal cord injury → increased effectiveness of cough.

Other pulmonary complications – edema, pneumonia, pulmonary embolism.

Cardiovascular complications – spinal shock → bradycardia, hypotension (may be due to neurogenic shock or volume loss from trauma).

Other complications – venous thrombosis/pulmonary embolism occur in 50% to 100% of TSCI cases, stress ulcers, ileus, lack of temperature control.

Amyotrophic Lateral Sclerosis

• UMN signs/symptoms – spasticity, hyperreflexia, bulbar involvement, Babinski sign.

• LMN signs/symptoms – weakness, atrophy, hyporeflexia, fasciculations.

• Acute respiratory failure and nocturnal hypoventilation have been presenting features in 1% to 3% of cases.

Occurs due to early involvement of phrenic nerve neurons within spinal cord. Onset of respiratory failure is often beginning of rapid decline.

Poliomyelitis and Postpoliomyelitis Syndrome

Most common symptoms of PPS are fatigue (80%) and progressive, asymmetric weakness in proximal or distal muscle groups that had been affected by initial illness.

• Associated atrophy present in 50%.

• Pain due to spinal deformities (kyphoscoliosis), degenerative joint disease, joint instability.

• Decreased ability to ambulate.

• Slowly progressive respiratory failure typically due to muscle weakness, and partially due to central hypoventilation; results in recurrent aspiration.

Phrenic Nerve Injury

• Dyspnea most pronounced when supine due to repositioning of abdominal contents.

• Abdominal paradox and active exhalation observed.

• Hypoxemia common in bilateral diaphragm paralysis due to atelectas. Hypoxemia and hypercapnia worsen with sleep.

• Ventilatory failure, pulmonary hypertension and corpulmonale with erythrocytosis may develop.

• Unilateral diaphragm weakness usually tolerated well in absence of underlying lung disease or other neuromuscular dysfunction.

• Absent tendon reflexes.

• Autonomic dysfunction (65%): cardiac arrhythmia, blood pressure lability, pupillary and gastrointestinal dysfunction, urinary retention.

• Variable decree of motor weakness (mild paresis → complete paralysis).

• Facial (60%), oropharyngeal (50%), ocular (15%) involvement may occur.

• Sensory loss variable (40% to 70%), occasionally accompanied by paresthesias.

• Severe back pain may occur.

• 70% preceeded by viral (CMV most common) or bacterial (
  Campylobacter jejuni most common).

• 15% to 30% develop respiratory failure requiring mechanical ventilation for average of 50 to 55 days. Most require tracheostomy.

Critical Illness Polyneuropathy and Polyneuromyopathy

Acute myopathy often occurs with polyneuropathy. Four categories of CIPNM syndrome:

1. Myopathy

• Acute necrotizing myopathy

• Disuse atrophy

2. Neuromuscular junction abnormalities

• Myasthenia-like syndrome

• Prolonged neuromuscular blockade

3. Neuropathy

• Critical illness polyneuropathy

• Acute motor neuropathy

4. Polyneuromyopathy

Risk factors – sepsis, multiorgan failure, prolonged use of corticosteroids and neuromuscular blocking agents, persistent hyperglycemia, hyperosmolality, vasopressor support for more than 3 days, bacteremia, dialysis, immobility, use of aminoglycosides, prolonged mechanical ventilation, APACHE III and SOFA scores

Myasthenia Gravis

• Typical presentation: fluctuating weakness of involved voluntary muscles; improves with rest or acetylcholinesterase agents.

• Ocular (blurred vision, diplopia, ptosis), facial (expressionless appearance), neck muscle involvement (difficulty holding up head) is common. Pupils spared.

• Bulbar symptoms present in 15%: fatigable chewing, dysarthria, dysphagia, aspiration.

• Limb symptoms: proximal muscle weakness in arms greater than in legs.

• Respiratory symptoms: myasthenic crisis (impending respiratory failure).

One third of patients have respiratory muscle weakness that presents late in disease process. May occur in absence of limb weakness, and may be initial presentation. Precipitating factors include spontaneous infections, tapering immune suppression, medications, surgery. Predictors of postoperative respiratory failure after thymectomy include severe disease with low VC and bulbar symptoms, high levels of AChR-Ab, intraoperative blood loss.

Signs of respiratory failure are discussed in General Clinical Features of Respiratory Failure Due to Neuromuscular Disease.

Lambert-Eaton Myasthenia Syndrome

• Majority present with slow, progressive proximal muscle weakness without significant atrophy. Occasional subacute/acute presentations are more common in LEMS associated with SCLC.

• Weakness is fatigable and always symmetric.

• Limb and girdle muscles predominantly involved.

• Respiratory muscle weakness common. Respiratory failure is uncommon, but may be initial presenting symptom.

• Autonomic dysfunction.

• Cranial nerve symptoms are less common and less severe than in myasthenia gravis.

• Ptosis is most common ocular sign.

• Sensory complaints – low back pain and numbness/parasthesia.

• Absent or diminished deep tendon reflexes.

• May have preceding viral-type illness.

Botulism

• Acute onset of bilateral cranial neuropathies – blurred vision, diplopia, nystagmus, ptosis, dysphagia, dysarthria, facial weakness.

• Followed by descending weakness.

• Urinary retention and constipation are common.

• Respiratory muscle weakness common, especially with type A toxin, characterized by diaphragm paralysis and upper airway compromise.

• Often requires ventilatory support (average of 58 days with type A toxin).

• Absence of fever, sensory deficits, change in mental status.

• Heart rate – normal to bradycardic with normotension

• Foodborne botulism – onset 12 to 36 hours after ingestion.

• Severity ranges from mild symptoms to death.

• Wound botulism occurs in puncture wounds, subcutaneous abscesses, deep space infections as well as abrasions, lacerations, open fractures, surgical incisions, closed hematomas. It May be associated with fever and leukocytosis.

Steroid Myopathy

• Subacute presentation with proximal limb and girdle muscle weakness with muscle wasting.

• Lower extremities usually affected before upper extremities.

• May appear cushingoid.

• Poor correlation between total dose of steroids and severity of myopathy. Course can be as short as 2 weeks.

• Rare with doses less than equivalent of prednisone 10mg/day. Higher doses → higher likelihood of myopathy with more rapid onset.

General Management Principles for Respiratory Failure Due to Neuromuscular Disease

Indications for mechanical ventilation – severe dyspnea, marked accessory muscle use, inability to handle secretions, hemodynamic instability, refractory hypoxemia, acute respiratory acidosis.

Noninvasive ventilation may be tried in the form of positive-pressure ventilation (NIPPV) or negative-pressure ventilation (NPV). These have been shown to attenuate decline in lung function, improve gas exchange and survival.

Patients must be awake, have minimal secretions, stable vital signs, and intact upper airway function.

Ventilatory support is often necessary when forced vital capacity (FVC) is less than 10 to 15 mL/kg or less than 1 L.

Maximum inspiratory pressure (PI_max) less than 20 to 25 cmH₂O.

Stroke

Ischemic stroke – the goal is to minimize extent of ischemic injury

• Maintain airway and oxygenation

• Blood pressure management

• Appropriate imaging

• Head positioning

• Thrombolytic therapy

• Anti-thrombotic therapy

• Carotid endarterectomy

Hemorrhagic stroke:

• Blood pressure control

• Decrease intracranial pressure – intubate and hyperventilate, osmotic diuresis

• Neurosurgical evaluation – possible craniotomy

• Corticosteroids – no benefit

Spinal Cord Injury

Primary assessment – stabilization. Address other life-threatening injuries that may have occurred due to trauma

• Airway management

• Cardiovascular stabilization

• Immobilize neck

• Imaging

Medical care – continuous vital signs, telemetry, pulse oximetry, frequent neurologic evaluation, admission to intensive care unit

• DVT prophylaxis – low-molecular-weight heparin with or without pneumatic compression stockings; IVC filter if anticoagulation contraindicated

• Pain control, avoid pressure ulcers, prophylaxis for stress ulcers, temperature control, occupational and physical therapy

• Glucocorticoids – debated, but only therapy that may improve outcomes

Decompression and stabilization – closed reduction vs surgery

Investigational treatments: spinal cord cooling, electrical stimulation, autologous macrophages, thyrotropin-releasing hormone, neuronal growth factors.

• Abdominal binding with non-elastic straps minimizes dissipation of intrathoracic forces, leading to improved effectiveness of cough.

• Intermittent straight catheterization.

• Physical and occupational therapy.

Amyotrophic Lateral Sclerosis

Comprehensive, multidisciplinary management necessary in acute setting as well as long-term

Respiratory management – see discussion on General Management Principles.

• Consider NIPPV if appropriate as it decreases risk of death by 3.1.

• Use of NIPPV when FVC less than 50% or fall in FVC greater than15% in 3 months: slower decline in lung function and decreased mortality, improves quality and may prolong life.

• Invasive ventilation may be tried if long-term survival is the goal.

• Immunizations – pneumococcal and influenza.

• Anti-glutamate therapy.

Poliomyelitis and Postpoliomyelitis Syndrome

Respiratory dysfunction – see section on General Management Principles for Respiratory Failure Due to Neuromuscular Disease.

• Early NIPPV beneficial – reverses chronic hypoventilation, improves respiratory muscle strength and exercise capacity.

• Muscle weakness – nonfatiguing exercise can lead to improved strength.

• Generalized fatigue – energy conservation and exercise program.

• Modafinil is not beneficial.

• IVIG may be beneficial but further trials are necessary.

Phrenic Nerve Injury

Ventilatory support with NIPPV or NP if needed. Total diaphragm paralysis may lead to need for tracheostomy with intermittent or continuous mechanical ventilation.

Guillain-Barré Syndrome

Supportive care

Respiratory failure: See section on General Management Principles for Respiratory Failure Due to Neuromuscular Disease. FVC averages 33 ± 11% predicted at time of intubation

Other predictors of need for intubation:

• Less than 7 days between symptom onset and hospitalization.

• Inability to lift head.

• Bulbar dysfunction.

• Presence of anti-GQ1b antibodies.

Consider tracheostomy after 2 weeks if no improvement in pulmonary function.

Autonomic dysfunction – close monitoring.

Blood pressure – arterial line placement if severe fluctuations in blood pressure occur:

• Treat hypotension with IV fluids or phenylephrine.

• Treat hypertension with short-acting antihypertensives.

Bowel and bladder care – monitor.

Pain control – minimize opiate use. Treat with gabapentin, carbamazepine or nonsteroidal anti-inflammatory.

DVT prophylaxis – subcutaneous fractionated or unfractionated heparin and support stockings.

Rehabilitation – Disease-modifying therapy – plasma exchange, IVIG.

Critical Illness Polyneuropathy and Polyneuromyopathy

• Supportive care, avoid known risk factors

• Physical therapy

• Aggressive glucose control decreases incidence by 44%, time to resolution, duration of mechanical ventilation

• Physical therapy, early mobilization

• Daily interruption of sedation

Myasthenia Gravis

• Intensive care unit admission for myasthenia crisis.

• Monitoring – pulse oximetry FVC should be measured every 2 to 4 hours.

• Intubation and management of respiratory failure discussed in General Management Principles of Respiratory Failure Due to Neuromuscular Disease.

• Symptomatic treatments – Acetylcholinesterase agents.

• Rapid immune-modulating agents – Plasmapheresis, IVIG.

• Chronic immune-modulating agents – Glucocorticoids.

• Surgical treatment – Thymectomy.

Lambert-Eaton Myasthenia Syndrome

• Evaluate for malignancy.

• Symptomatic therapy – aimed at increasing amount of acetylcholine available. No further therapy needed if symptomatic improvement achieved.

• Immunologic therapy.

Botulism

• Refer to General Management Principles of Respiratory Failure Due to Neuromuscular Disease.

• Antitoxin.

• Full body tick check.

Steroid Myopathy

• Respiratory management – see discussion on General Management Principles.

• Decrease or discontinue corticosteroids.

• Physical therapy.

2. Emergency Management

Stroke

• Airway management if needed.

• Oxygen to prevent hypoxemia.

• Individualize head of bed position – maintain cerebral perfusion by not elevating head too much, avoid cardiopulmonary compromise with flat positioning.

Spinal Cord Injury

Primary assessment – evaluate and stabilize airway, breathing, circulation before assessing for neurologic disability.

• Airway management – one third of patients with cervical injuries require intubation within 24 hours of injury. Chest physiotherapy with aggressive suctioning, reverse hypoxemia. See section on general management for indications for intubation and mechanical ventilation.

• Reverse hypotension with goal MAP 85 to 90 mmHg. Vasopressors and blood products if needed. Attempt to minimize fluids able to decrease risk of further cord edema.

• TSCI assumed if spinal pain, altered mental status, or neurologic deficit and spinal movement should be minimized.

• Complete neurologic exam.

• Imaging is unnecessary if patient denies pain and is awake, alert, not confused or intoxicated, has no spinal tenderness and no other distracting injuries.

Guillain-Barré Syndrome

Airway management as discussed above.

• Delayed intubation in those with bulbar dysfunction → increased risk of pneumonia.

• Aggressive pulmonary toilet.

• Avoid use of succinylcholine during intubation.

• Plasma exchange/IVIG.

Critical Illness Polyneuropathy and Polyneuromyopathy

Typically recognized after the patient has been stabilized and weaning from mechanical ventilation is attempted.

Myasthenia Gravis

• NIPPV may be attempted first, though PaCO₂ >45 mmHg predicts failure.

• Plasmapheresis – directly removes AChR-Ab from circulation. Effects typically last 3-4 weeks.

• IVIG – effects seen in less than a week and typically last about 3 weeks

Glucocorticoids:

• Given in addition to plasmapheresis or IVIG

• Onset of benefit 2-3 weeks

• May be associated with transient worsening of symptoms → mechanical ventilation in 10%

Lambert-Eaton Myasthenic Syndrome

Intubation and management of respiratory failure discussed in General Management Principles of Respiratory Failure Due to Neuromuscular Disease.

Botulism

• Intubation and management of respiratory failure discussed in General Management Principles of Respiratory Failure Due to Neuromuscular Disease.

• Early intubation with mechanical ventilation decreases mortality.

3. Diagnosis

General Diagnostic Testing for Respiratory Failure Due to Neuromuscular Disease

Pulmonary function testing (PFT) – restrictive pattern:

• Decreased forced vital capacity (FVC) due to respiratory muscle weakness and decreased lung/chest wall compliance.

• Parallels the decline in respiratory muscle function.

• Preserved FEV₁/FVC.

• Decreased total lung capacity (TLC) and functional residual capacity (FRC).

• Normal/increased residual volume (RV).

Arterial blood gas (ABG) testing – hypoxemia and hypercapnia are late findings:

• Mechanical ventilation may be indicated prior to development of ABG abnormalities.

• Hypoxemia due to: microatelectasis, ineffective cough, retained secretions, mucus plugging → ventilation/perfusion mismatch.

• Hypercapnia does not occur until inspiratory muscle strength <50% predicted.

• Weak respiratory muscles lead to alveolar hypoventilation.

• Hypercapnia also contributes to hypoxemia.

Maximum inspiratory (PI_max) and expiratory (PE_max) pressure – measured at airway opening during voluntary contraction against occluded airway:

• Most sensitive test for respiratory muscle weakness

• Should be part of routine assessment of patients with neuromuscular disease

Stroke

• Non-contrast cat scan (CT) or magnetic resonance imaging (MRI) of the brain: evaluate for hemorrhage, structural pathology that may mimic stroke (subdural hematoma, tumor). It may take 8-24 hours for evidence of stroke to appear on CT. MRI shows evidence of stroke in 30 minutes, superior to CT for brainstem, cerebellar, lacunar strokes.

• Carotid artery imaging (ultrasound or magnetic resonance angiogram (MRA)).

• Laboratory evaluation: CBC, cardiac biomarkers, basic metabolic panel, serum glucose, coagulation profile, lipid profile, hypercoagulable workup, erythrocyte sedimentation rate (ESR).

• Electrocardiogram.

• Echocardiogram if cardiogenic source suspected.

• Lumbar puncture if hemorrhage suspected.

Spinal Cord Injury

• Plain X-rays provide rapid evaluation of alignment, fractures, soft tissue swelling.

• Helical CT – higher sensitivity for spinal fractures. Follow with 2-mm CT of concerning area.

• MRI – indications in TSCI not yet defined. Provides more detailed imaging of spinal cord, ligaments, intervertebral discs, soft tissue. More sensitive than CT for epidural hematoma. Disadvantages: not 100% sensitive for cord damage in early-stage TSCI, contraindicated in those with foreign metal objects, difficulty monitoring vital signs during test. Should be done in those with high suspicion of TSCI and negative CT

• Myelography used only when CT and MRI not available.

Amyotrophic Lateral Sclerosis

El Escorial diagnostic criteria:

• Clinical, electrophysiological (fibrillation potentials), neuropathological evidence of LMN degeneration.

• Clinical evidence of UMN degeneration.

• Progressive signs/symptoms.

• Absence of electrophysiological/pathological/radiographic evidence of alternate disease process.

• Thorough family history (may be familial 5-10%).

• Laboratory evaluation – creatine phosphokinase (CPK) may be elevated to 1,000 U/L, may screen for heavy metal exposure if relevant, genetic testing may be considered in setting of strong family history.

• PFT may be helpful. VC <50% predicted associated with respiratory symptoms, VC <25-30% predicted associated with respiratory failure and death. Progressive decrease in FVC and maximum voluntary ventilation (MVV), progressive increase in RV, decreased maximal inspiratory (MIP) and expiratory pressure (MEP). FVC most specific test to predict survival. TLC and FRC relatively well preserved.

• Electromyography (EMG) and nerve conduction studies (NCS) not diagnostic but may be helpful and are often part of workup.

• EMG – diffuse evidence of acute and chronic denervation.

• NCS – sensory and motor NCS typically normal. Compound motor action potentials (CMAP) may be decreased. Motor unit estimation studies not specific to ALS but demonstrate decreased numbers.

• Muscle biopsy – nonspecific findings of chronic denervation with reinnervation.

Poliomyelitis and Postpoliomyelitis Syndrome

• No definitive way to distinguish PPS from prior polio.

• PPS diagnosed on clinical grounds.

Diagnostic criteria:

• Prior episode of polio with residual motor neuron loss.

• 15 years since acute onset of polio with neurologic/functional stability.

• Gradual onset of new weakness and abnormal muscle fatigability for ≥1 year.

• Exclusion of other medical conditions.

• PFTs – average yearly decrease in FVC about 18.6 ml (1.9%).

• Cerebrospinal fluid (CSF) – may be normal or show mildly increased protein or oligoclonal bands.

• EMG does not clearly distinguish a history of prior polio from PPS. It helps to exclude other diseases (ALS, radiculopathy, neuropathy, myopathy).

• Muscle biopsy – non-specific with evidence of chronic denervation, reinnervation, active degeneration.

Phrenic Nerve Injury

• Chest X-ray – unilateral or bilateral elevated hemidiaphragm with associated atelectasis and low lung volumes.

• Sniff test: fluoroscopic exam of diaphragm during sniff maneuver (90% sensitive for unilateral diaphragm paralysis). Rapid increase in intrapleural pressure during sniff → paradoxical cephalad movement of weak hemidiaphragm

• PFTs in bilateral diaphragm paralysis:

  Normally, VC falls 10% in supine position

  Bilateral diaphragm paralysis → 50% decrease in VC in supine position

  MIP typically less negative than -60 cmH₂O

• Diaphragmatic ultrasound can be used to assess muscle thickness and transdiaphragmatic pressure (Gold standard)

• EMG: shows neuropathic or myopathic pattern depending on cause. Absent signal in cord transsection

Guillain-Barré Syndrome

Diagnostic criteria:

• Required features:

  Progressive weakness of >1 limb.

  Areflexia: may be present only in lower extremities with hyporeflexia elsewhere.

• Supportive features:

  Symptom progression over days-weeks, relative symmetry, sensory findings mild, cranial nerve involvement, recovery starts 2-4 weeks after progression stops, autonomic dysfunction, no fever at presentation, elevated CSF protein, electrodiagnostic studies consistent with GBS.

• Lumbar puncture and neurophysiology studies should be performed if GBS suspected.

• Antibody testing: Anti-GQ1b testing used to diagnose Miller Fisher syndrome (GBS variant).

Critical Illness Polyneuropathy and Polyneuromyopathy

• Standardized muscle exam (Medical Research Council) to evaluate for weakness.

• Incorrect clinical setting, extensive testing not indicated.

• Nerve conduction studies and EMG (ENMG) typically show axonal polyneuropathy +/- myopathy (i.e., decreased amplitude of CMAP, normal velocity with motor nerve stimulation, spontaneous electrical activity with needle recording).

• Myopathic pattern: prolonged CMAP, short duration and low amplitude of motor unit potentials with voluntary activation.

Myasthenia Gravis

Physical exam – fatigability with repetitive muscle activity

Bedside tests:

• Tensilon (edrophonium) test: should be used if significant ptosis present

  Tensilon is a short-acting acetylcholinesterase inhibitor.

  Give 2 mg IV every 60 seconds until result observed (or a total dose of 10 mg) → transient improvement in muscle weakness.

  Positive test suggests MG, but may be positive in Lambert-Eaton myasthenia syndrome.

  Muscarinic side effects may occur: most concerning are bradycardia and bronchospasm.

  ▪ Atropine should be available

• Ice pack test can be used in patients with ptosis (80% sensitive in severe ptosis).

  Neuromuscular transmission increased at lower temperatures.

  Place ice pack on closed lid for 2 minutes, then remove ice and ptosis should be improved.

Serologic testing:

• 80% with generalized MG (60% with ocular) have detectable AChR-Ab.

  Concentration of antibodies does not correlate with disease severity.

  AChR-Ab have also been found in Lambert-Eaton myasthenic syndrome and systemic lupus erythematous.

• MuSK-Ab present in subgroup with higher incidence of bulbar weakness and respiratory failure.

• Electrodiagnostic tests not specific from MG.

  77% will demonstrate 10-15% decreased amplitude of action potential during slow repetitive stimulation.

  92% have single-fiber EMG abnormalities (most sensitive test for MG).

• PFTs: mildly decreased FVC, moderate decrease in MIP, MEP, some improvement after pyridostigmine administration.

Lambert-Eaton Myasthenic Syndrome

Usually a clinical diagnosis, which is then confirmed by presence of antibodies and electrodiagnostic tests.

• Bedside test – post-exercise facilitation.

  Maximal isometric contraction of muscle → temporary restoration of decreased or absent deep tendon reflex.

• Antibodies against voltage gated calcium channel (VGCC): positive testing is confirmatory in presence of symptoms/signs.

  Antibody alone is not diagnostic.

• Electrodiagnostic studies.

  CMAP in resting muscle in LEMS is reduced.

  High-frequency repetitive nerve stimulation or brief maximal isometric stimulation → increased CMAP.

Botulism

• Appropriate clinical setting.

• Serum or wound analysis for toxin by bioassay.

• CSF – usually normal.

• Tensilon test may show false positive.

• EMG not required but may be helpful for diagnosis.

• PFTs typically show restriction.

Steroid Myopathy

• No definitive diagnostic test.

• Diagnosis of exclusion.

• EMG: normal to mild myopathic changes.

• Muscle biopsy: loss of type IIa muscle fibers without inflammation of necrosis.

• Urinary creatine excretion is increased with corticosteroids and inflammatory myopathies.

  Decreases with decreased dose of corticosteroids.

Characteristic Films in Respiratory Failure Due to Neuromuscular Disease

• Helpful for assessment of pneumonia, atelectasis, parenchymal lung disease.

• Small lung volumes seen with inspiratory muscle weakness.

Amyotrophic Lateral Sclerosis

• Neuroimaging only helpful in ruling out other diseases. MRI usually normal in ALS.

Poliomyelitis and Postpoliomyelitis Syndrome

• Routine labs normal in PPS

• Exercise may lead to increased CPK

Critical Illness Polyneuropathy and Polyneuromyopathy

• CPK levels normal or mildly elevated

Steroid Myopathy

• CPK typically normal

How Do I Know This Is What the Patient Has?

Stroke

Based on presenting signs, symptoms, and characteristic imaging.

Spinal Cord Injury

History, physical exam and appropriate imaging.

Botulism

Serum or wound toxin present.

Steroid Myopathy

Correct clinical picture with improvement in symptoms with decreasing or withdrawal of steroids.

What Else Could It Be?

Stroke

TIA, seizure, migraine aura, hypoglycemia, multiple sclerosis, brain tumor, brain abscess, subdural hematoma.

Spinal Cord Injury

Radiation to spinal cord, malignancy, infection/abscess, multiple sclerosis, spinal cord infarction, anterior spinal artery syndrome.

Amyotrophic Lateral Sclerosis

Myasthenia gravis, Lambert-Eaton myasthenic syndrome, Lyme disease, poliomyelitis or postpoliomyelitis syndrome, heavy metal intoxication, Kennedy syndrome, adult-onset Tay-Sachs disease, hereditary spastic paraplegia, multifocal neuropathy, cervical spondylosis or extramedullary tumor with compressive radiculopathy and myelopathy, inclusion body myositis, progressive bulbar palsy, progressive muscular atrophy, thyrotoxic myopathy.

Poliomyelitis and Postpoliomyelitis Syndrome

ALS, radiculopathy, neuropathy, myopathy.

Phrenic Nerve Injury

On chest x-ray: atelectasis, fibrosis, subpulmonic fluid collections, decreased pulmonary or abdominal compliance, pleural adhesions.

Guillain-Barré Syndrome

Vasculitis with mononeuritis multiplex, Lyme disease, arsenic poisoning, tick paralysis, porphyria, sarcoid, leptomeningeal disease, paraneoplastic disease, critical illness, chronic inflammatory demyelinating polyneuropathy, spinal cord compression, acute transverse myelitis, myasthenia gravis, Lambert-Eaton myasthenic syndrome, botulism, polymyositis.

Critical Illness Polyneuropathy and Polyneuromyopathy

Acute spinal injury with spinal shock, quadriparesis and areflexia, myasthenia gravis, Guillain-Barré, cachectic myopathy, persistent neuromuscular blockade in setting of renal or hepatic failure.

Myasthenia Gravis

Generalized fatigue, ALS, Lambert-Eaton myasthenic syndrome, botulism, penicillamine-induced myasthenia, congenital myasthenic syndromes.

Lambert-Eaton Myasthenic Syndrome

Inflammatory muscle disease, limb-girdle muscular dystrophy, myasth enia gravis, myopathy, neuropathy.

Botulism

Myasthenia gravis, Lambert-Eaton myasthenic syndrome, tick paralysis, Guillain-Barré, poliomyelitis, stroke, heavy metal intoxication, antimicrobial-associated paralysis.

Steroid Myopathy

Inflammatory myopathy (dermatomyositis, polymyositis, HIV myopathy), critical illness polyneuropathy.

Specific Confirmatory Tests

Guillain-Barré Syndrome

• Confirm diagnosis with CSF exam and neurophysiology studies.

• CSF: elevated protein, few cells (albuminocytologic dissociation) found in 90% after 1 week of symptoms.

• Neurophysiologic testing helps predict need for mechanical ventilation.

  Demyelinating pattern: greater need for intubation than axonal or equivocal findings.

Critical Illness Polyneuropathy and Polyneuromyopathy

• Muscles/nerve biopsies not routinely indicated but can confirm diagnosis.

• Muscle biopsy shows type II muscle fiber atrophy, occasional type I atrophy and necrosis.

Botulism

• Demonstration of toxin in blood or wound is diagnostic.

4. Specific Treatment

Stroke

Ischemic stroke:

Blood pressure management:

• Elevated blood pressure should not be treated acutely unless:

  There is extreme hypertension (SBP <220 mmHg or DBP >110)

  Heart failure, coronary artery disease, aortic dissection, or end-organ dysfunction

• Prior to thrombolytic therapy, SBP ≤185 mmHg and DBP ≤110 mmHg for 24 hours

Thrombolytic therapy: give only if patient meets criteria for use.

• Alteplase improves functional outcome when given within 3 hours of symptom onset, increases favorable outcome within 4.5 hours

  No difference in mortality

  Increased incidence of symptomatic intracerebral hemorrhage

Full-dose anticoagulation appropriate for – stroke due to cardiogenic embolization, stroke in evolution, crescendo TIA. Should not be used in large infarctions, uncontrolled hypertension, bleeding.

Aspirin is effective in early treatment of acute ischemic stroke. Comparable efficacy with decreased risk of hemorrhagic complications when compared to warfarin.

Statin therapy.

DVT prophylaxis: subcutaneous heparin and thigh-high stockings.

Spinal Cord Injury

See General Management Principles, Key management points, and emergency management.

Amyotrophic Lateral Sclerosis

• See General Management Principles, Key management points for discussion on airway and ventilation management.

• Anti-glutamate therapy.

• Aminophylline: reported to improve respiratory muscle strength in ALS.

Poliomyelitis and Postpoliomyelitis Syndrome

• Supportive care.

• See General Management Principles, Key management points for discussion on airway and ventilation management.

Phrenic Nerve Injury

• Treatment for unilateral disease typically not necessary

• Surgical plication for significant symptoms or those with pulmonary disease can be helpful

• Bilateral disease – ventilatory support

Guillain-Barré Syndrome

• Plasma exchange: most effective if started within 7 days of symptom onset, though still provides some improvement when started within 30 days.

• IVIG: preferable to plasma exchange (easier to administer). Contraindications: low IgA, uncontrolled hypertension, hyperosmolar state.

• No benefit to plasmapheresis followed by IVIG compared to each therapy alone

• No benefit to corticosteroids alone. May slow recovery, though when used in combination with IVIG, may hasten recovery (no long-term data).

Critical Illness Polyneuropathy and Polyneuromyopathy

No specific treatment. Management discussed above

Lambert-Eaton Myasthenic Syndrome

Symptomatic therapies:

• Guanidine: side effects – bone marrow suppression and renal toxicity limit its use

• Aminopyridines: prolong nerve terminal membrane depolarization → increased calcium entry → increased acetylcholine release

• Acetylcholinesterase inhibitors

Immunologic therapies:

• Plasmapheresis: results not as rapid as in myasthenia gravis. Use in combination with oral immunosuppressive agent

• IVIG → clinical improvement and decrease in VGCC antibodies. Benefits peak at 2-4 weeks

• Oral Immunosuppressive therapy

Botulism

• Intubation

• Supportive care

• Antitoxin: give if clinical suspicion is high and symptoms worsening. Side effects: sensitization, anaphylaxis, serum sickness

• Antibiotics and debridement for wound botulism

• Cathartics for foodborne botulism

• Call State Health Department

Steroid Myopathy

Stop or decrease dose of steroid.

Drugs and Doses

Stroke

Ischemic:

• Aspirin 325 mg within 48 hours followed by 150-325 mg in patients not receiving alteplase, IV heparin, or oral anticoagulants

• IV alteplase for eligible patients:

  Patients ≤100 kg: 0.09 mg/kg IV bolus over 1 minute followed by 0.81 mg/kg continuous infusion over 60 minutes

  Patients >100 kg: 9 mg IV bolus over 1 minute followed by 81 mg continuous infusion over 60 minutes

Spinal Cord Injury

Methylprednisolone 30 mg/kg IV followed by 5.4 mg/kg/hr over next 23 hours.

Amyotrophic Lateral Sclerosis

Riluzole: antiglutamate drug, 50 mg twice daily. This is the only treatment shown to prolong survival.

Guillain-Barré Syndrome

• Plasmapheresis: 250 mL/kg every 2 days for 5 treatments. Early motor recovery and ambulation achieved, decreased number of patients requiring mechanical ventilation, decreased duration of mechanical ventilation.

• IVIG (0.4 g/kg/day for 5 days) started within 2 weeks may be as effective as plasmapheresis.

Myasthenia Gravis

• Plasmapheresis – 5 exchanges over 7-14 days.

• IVIG: 2 g/kg over 2-5 days. No clear difference in response between IVIG and plasmapheresis. Plasmapheresis onset of action may be faster

• Prednisone 60-80 mg/day.

• Other immune-modulating agents. Azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, tacrolimus.

• Acetylcholinesterase agents – Pyridostigmine bromide 30 mg three times a day, titrated up for effect.

• Thymectomy.

Lambert-Eaton Myasthenic Syndrome

Guanidine: maximum 1000 mg/day – use with pyridostigmine

Aminopyridines:

• Dalfampridine: limited use due to side effects (seizures)

• 3,4-Diaminopyridine: best tolerated, though seizures may occur at high doses

• Maximum dose: 20 mg four times a day – note not approved in US

Acetylcholinesterase inhibitors – Pyridostigmine: best tolerated but only mildly effective

Plasmapheresis: 5 exchanges over 7-14 days

IVIG: only randomized trial used 1 g/kg/day for two days

Oral Immunosuppressive therapy:

• Prednisone alone: 1 mg/kg/day until clinical improvement observed (then taper)

• Or in combination with azathioprine: 50 mg twice a day, then titrate up for clinical improvement to maximum dose of 2-3 mg/kg/day

• Or in combination with plasmapheresis

Botulism

Antitoxin

• Equine serum heptavalent botulism antitoxin (for children >1 yr, adults)

• Human-derived botulism immune globulin (for infants <1 yr)

Antibiotics for wound botulism

• Penicillin G 3 million units IV every 4 hours

• Metronidazole 500 mg IV every 8 hours for penicillin allergic

• Avoid aminoglycosides

Refractory Cases

Poliomyelitis and Postpoliomyelitis Syndrome

Tracheostomy with mechanical ventilation.

Phrenic Nerve Injury

Diaphragmatic pacing may be used in high C-spine injuries with intact phrenic nerves.

Guillain-Barré Syndrome

Interferon-beta: may be beneficial in select cases.

Myasthenia Gravis

• Immune suppression – should not be used for myasthenic crisis. Response may not be seen for months.

• Plasmapheresis or IVIG.

• Corticosteroids and anticholinesterase agents should only be started after plasmapheresis or IVIG.

Lambert-Eaton Myasthenic Syndrome

Immune-modulating therapy.

5. Disease monitoring, follow-up and disposition

Expected Response to Treatment

Stroke

• 30-day mortality rate for ischemic strokes 7.6%, for hemorrhagic strokes 37.5%

• Of those who survive 30 days, 20% will need institutionalized care

Spinal Cord Injury

• Methylprednisolone given within 8 hours of trauma → significant improvement in motor, sensation, and touch

• DVT prophylaxis should be continued for 3 months after acute event (risk of thromboembolism approaches that of general population after 3 months)

• Rehospitalization common: 55% in first year, then 37%/year over next 20 years

Amyotrophic Lateral Sclerosis

• Disease is progressive and incurable

• PFTs should be done every 3 months. MIP less negative than -60 cm H
  ₂O 100% sensitive for survival <18 months

• Median time from diagnosis to death: 3-5 years; 10% ALS patients may live >10 years

Poliomyelitis and Postpoliomyelitis Syndrome

PPS – occurs earlier in those with more severe initial disease. It is more likely to occur in those with adolescent/adult polio. A better recovery from the initial illness → increased likelihood of PPS.

Phrenic Nerve Injury

Prognosis depends on inciting event.

• Example: 80% of phrenic nerve injury after cardiac surgery recovers in 6 months, 90% in one year

• Diaphragm paralysis due to spinal cord injury may never heal

• Unilateral diaphragm paralysis may never heal

Guillain-Barré Syndrome

• Consider weaning trials when:

  VC >8-10 mL/kg

  Adequate oxygenation with FiO₂ ≤40%

  Ability to double minute ventilation

  Negative inspiratory force more negative than -40 cmH₂O

• 10% may relapse after plasma exchange due to antibody rebound

  Treat with additional plasma exchange or IVIG

• Mortality decreased from 15% in 1970s to 3-4% in 1980s

• Common complications: pneumonia, recurrent aspiration, pulmonary embolism

• Prognosis for recovery good, but 85% have residual neurologic sequelae

  50% have maximum weakness within 2 weeks

  80% have maximum weakness within 4 weeks

• Poor prognosis associated with: older age, lower (<20% of normal) mean CMAP during distal nerve stimulation, need for ventilatory support, rapid progression to severe weakness (<1 week)

Critical Illness Polyneuropathy and Polyneuromyopathy

• CIPNM prolongs duration of mechanical ventilation and increases mortality.

  Prolonged weaning time expected.

  Recovery is prolonged and often incomplete.

• Those who survive have prolonged ICU and hospital stay. 68% have complete recovery. 28% have persistent neurologic deficits: absent or reduced deep tendon reflexes, glove and stocking sensory loss, muscle wasting, hyperesthesia, persistent disability with quadriparesis, quadriplegia, or paraplegia.

Myasthenia Gravis

• Weaning trials may be attempted when respiratory status is improved

  MIP more negative than -20 cmH
  ₂O, MEP >40 cmH
  ₂O, FVC >10 mL/kg

• Risk factors for extubation failure: male gender, history of prior myasthenic crisis, atelectasis, duration of mechanical ventilation >10 days

• Risk factors for reintubation: lower pH, lower FVC, presence of atelectasis, need for BiPAP support

• Significant but incomplete improvement expected with anticholinergic medications

• Corticosteroids → remission in up to 80%

  On 6th-10th day of therapy, may observe transient worsening in weakness

• Thymectomy (with or without thymoma) may improve survival and symptoms

• Mortality <5% from myasthenic crisis

• Weakness peaks within a few years of symptom onset

• About 50% of those with only ocular disease will develop generalized disease

Lambert-Eaton Myasthenic Syndrome

• IVIG typically leads to improvement in weakness for only 4-8 weeks

• Plasmapheresis does not lead to rapid relief of symptoms and only provides short-term benefit

• Treatment of SCLC often leads to remission of LEMS

Botulism

• Typically, with early hospitalization and intubation if needed, recovery is expected with normal to near-normal functional status

  Hospitalization typically lasts 1-3 months

  Respiratory muscle strength may take months to recover

  Even when PFTs return to normal, exertional dyspnea and poor exercise tolerance may persist

• Mild disease – complete resolution in 3 months

• Severe disease – may have prolonged course with hospital complications

• Predictors of worse long-term health: need for mechanical ventilation and old age

• Mortality <5-8%

Steroid Myopathy

• Muscle strength improves 3-4 weeks after decreased dose of corticosteroids

• Eventually resolves completely if corticosteroids are discontinued

When Should I Suspect I've Made the Wrong Diagnosis?

Stroke

• Presence of vertigo, dysarthria, dysphagia, or diplopia in the absence of other symptoms

• Tremor, tonic-clonic motor activity, confusion, memory loss, delirium, incontinence

Spinal Cord Injury

Atypical physical exam and imaging findings.

Amyotrophic Lateral Sclerosis

Disease course is relapsing and remitting, presence of involuntary movements, ataxia, EMG findings are not diffuse, motor conduction block is present.

Guillain-Barré Syndrome

CSF cell count >10 mm³(though may be due to coexisting HIV infection), presence of a sensory level, marked persistent asymmetry of weakness, severe persistent bowel or bladder dysfunction.

Critical Illness Polyneuropathy and Polyneuromyopathy

Facial muscle weakness, asymmetric findings, pyramidal signs, significantly elevated CPK

Myasthenia Gravis

Presence of muscarinic symptoms (hypersalivation, sweating, increased secretions, nausea, vomiting, diarrhea) and worsening of symptoms with Tensilon test suggest cholinergic crisis. Presence of UMN signs, symptoms that improve with exercise and pupillary involvement all suggest misdiagnosis.

Lambert-Eaton Myasthenic Syndrome

Presence or predominance of only ocular, extraocular, oropharyngeal or arm symptoms, asymmetric muscle weakness, preserved deep tendon reflexes.

Botulism

Ascending paralysis, significant autonomic symptoms, sensory findings, elevated CSF protein.

Steroid Myopathy

Presence of muscle tenderness and myalgias, patient is only on inhaled corticosteroids.

Follow-up

Stroke

CT brain should be done 24 hours after administration of alteplase to exclude hemorrhage.

Spinal Cord Injury

Continued physical and occupational therapy.

Amyotrophic Lateral Sclerosis

Multidisciplinary care leads to better outcomes.

Poliomyelitis and Postpoliomyelitis Syndrome

Physical therapy, occupational therapy.

Phrenic Nerve Injury

For those with chronic disease, serial physical exam and ABG should be performed to ensure adequate ventilation.

Guillain-Barré Syndrome

Continued physical therapy. Relapses occur in <10% and are treated with plasmapheresis or IVIG.

Steroid Myopathy

Physical therapy.

Pathophysiology

General Pathophysiology for Respiratory Failure Due to Neuromuscular Disease

Different functional components of the respiratory system (central nervous system, peripheral nervous system, neuromuscular junction, respiratory muscle, bony thoracic cage, upper and lower airways, lung parenchyma) may be affected depending on area of neuromuscular dysfunction

Neuromuscular disease can precipitate:

• Pharyngeal collapses, sleep apnea/hypopnea → nocturnal hypoventilation → daytime hypercapnia and hypoxemia

• Decreased tidal volume, poor cough → atelectasis, decreased lung/chest wall compliance → increased work of breathing

• Aspiration and retained secretions → recurrent pneumonia

• Decreased ventilatory response to hypoxemia/hypercapnia due to decreased central drive and abnormal mechanics

Stroke

• When blood flow falls below 10 mL/100 g/minute, basic cellular function cannot be maintained → cell death

  Infarcted brain initially pale. Within hours-days, gray matter congested with dilated blood vessels and small petechial hemorrhage.

  When embolus blocking major vessel lyses, migrates or disperses, may produce edema and hemorrhagic infarction

• Intracerebral hemorrhage → direct brain damage by compressing surrounding tissue

Spinal Cord Injury

• Primary injury: immediate effect of trauma

  Compression, contusion, shear injury

  Transsection and hemorrhage rare in nonpenetrating injury

• Secondary injury: begins after injury and progresses

  Mechanisms: ischemia, hypoxia, inflammation, edema, apoptosis

  Clinically presents with neurologic decompensation 8-12 hours after injury

• Spinal cord edema begins within hours, peaks 3-6 days after injury, decreases after 9th day and is followed by central hemorrhagic necrosis

Amyotrophic Lateral Sclerosis

• Exact etiology unknown.

• 5-10% familial ALS has mutation encoding copper-zinc dismutase (a free oxygen radical scavenger). Neurons may be more susceptible to oxidative stress and glutamate-induced neurotoxicity. Glutamate is principal excitatory neurotransmitter in brain. Decreased uptake of glutamate → overstimulation of glutamate receptors → increased intracellular calcium → activates proteolytic enzymes → cell death.

Poliomyelitis and Postpoliomyelitis Syndrome

PPS – cause unknown, but may be due to:

• Denervation followed by aberrant reinnervation along with possible:

  Susceptibility to aging of reinnervated motor units previously affected

  Overuse of previously damaged muscle

  Immune-mediated attack on abnormal muscle units

Phrenic Nerve Injury

• Diaphragm: most important muscle of respiration. Innervated by C3-C5

• Diaphragmatic paralysis → use of accessory muscles.

Guillain-Barré Syndrome

• Exact etiology unknown

• Risk factors: Viral illness (CMV most common, Epstein-Barr), bacterial illness (
  Campylobacter jejuni most common),
  Mycoplasma pneumoniae infection, influenza vaccination (no solid data), recent surgery, lymphoma

• Is likely a self-limited autoimmune disease due to an aberrant immune response to bacterial lipopolysaccharides with similar epitopes to myelin sheath or Schwann cell basement membrane

• 83% have antibodies against GQ1b (ganglioside component of nerve)

Critical Illness Polyneuropathy and Polyneuromyopathy

• Thought to be due to exaggerated response to severe injury causing muscle and nerve injury

• Systemic and local inflammatory response mediated by: TNF-alpha, IL-1, IL-12, monocytes, macrophages, neutrophils

  Results in endothelial injury, increased vascular permeability endoneurial edema and decreased blood flow to nerve and muscle

• Final result:

  Neuropathic changes 37%

  Myopathy 40%

  Neuropathy and myopathy 23%

  Muscle necrosis 30%

Myasthenia Gravis

• Antibody-mediated, T-cell-dependent autoimmune disease. Antibodies directed at proteins in postsynaptic membrane of neuromuscular junction

• Destruction of acetylcholine receptors causes impaired transmission of neural impulses across neuromuscular junction

Lambert-Eaton Myasthenic Syndrome

Antibodies against VGCC → normal calcium flux necessary for acetylcholine release is interrupted. Postsynaptic sensitivity to acetylcholine is normal. Decreased acetylcholine release despite normal acetylcholine vesicle number, presynaptic concentration and postsynaptic receptors.

Botulism

• Clostridium botulinum: heterogeneous group of gram-positive, rod-shaped, spore-forming obligate anaerobes that are ubiquitous. In appropriate conditions, spores germinate and become toxin-producing bacilli. Anaerobic or semi-anaerobic environment, low-acidity water, temperature between 77-99 degrees Fahrenheit.

• Eight types of toxins exist: human disease only caused by three (A, B, E). Some strains denature protein and cause food to appear or taste sour, but others do not

• Toxin spreads via vascular system and binds to synaptotagmin II (calcium channel) in presynaptic peripheral cholinergic terminals, causing irreversible disruption in stimulation-induced acetylcholine release. Synaptic recovery only occurs with growth of a new synapse (6 months)

• Minimum lethal dose of toxin is 0.0003 mcg/kg

Steroid Myopathy

• Direct catabolic effects

• Corticosteroid receptor likely involved. Effects are prevented with receptor blocker

• Interfere with insulin-like growth factor-1 signaling causing increased myocyte apoptosis

• Akt1 (intracellular signaling molecule with protein kinase activity). Glucocorticoids suppress Akt1, causing increased levels of ubiquitin-ligase atrogin-1, which targets muscles and degrades them.

Epidemiology

Stroke

• Third leading cause of death

• 85% ischemic – 25% due to small vessel disease, 2% due to embolism, 50% due to large vessel disease

• 15% hemorrhagic

• Risk factors: age, African American race, male sex, atrial fibrillation, carotid bruit, history of prior stroke, diabetes, coronary artery disease, hypertension, cigarette smoking, hyperlipidemia

• Incidence 750,000 cases/year

• Prevalence in Americans over 65 years of age: 40/1,000

• Death rate from stroke doubles every 10 years between ages of 55-85

Spinal Cord Injury

• Incidence of TSCI: 40/1,000,000/year

• 250,000 survivors in US in 2005

• Leading cause of death is venous and pulmonary thromboembolism

• About 50% are cervical cord injuries → quadriplegia/quadriparesis

• Causes of TSCI in US: motor vehicle accidents (47%), violence (14%), sports accidents (9%), other (7%)

• Risk factors for TSCI: 80% male, underlying spinal disease

• Non-traumatic SCI through to be 3-4 times the number of TSCI

Amyotrophic Lateral Sclerosis

• Incidence: 1-3/100,000 people

• No ethnic or racial predisposition

• Affects males > females prior to age of 65, after which incidence in genders equalizes

• Peak age of diagnosis: 7th-8th decade, though can be diagnosed as early as 3rd decade

• Majority of cases sporadic, though 5-10% are familial (autosomal dominant inheritance)

• 5-year mortality 80%, generally due to respiratory failure

Poliomyelitis and Postpoliomyelitis Syndrome

• Prior to widespread use of oral polio vaccine in 1954, poliomyelitis was most common cause of respiratory failure

• Acute polio now rare in US

• Sequelae of polio still affect a significant number of people, causing decreased muscle strength and function. PPS: occurs decades after initial illness in 20-30%

Phrenic Nerve Injury

• Neurologic causes: spinal cord transsection, MS, ALS, cervical spondylosis, polio, Guillain-Barré, phrenic nerve dysfunction (compression by tumor, cardiac surgery, trauma, idiopathic, post-viral, radiation therapy)

• Myopathic causes: Limb-girdle dystrophy, hypo/hyperthyroidism, malnutrition, acid maltase deficiency, connective tissue disease, amyloidosis, idiopathic

Guillain-Barré Syndrome

Incidence of GBS worldwide: 1.1 cases/100,000/year – 1.8 cases/100,000/year. Increases after age of 50 to 1.7 cases/100,000/year – 3.3 cases/100,000/year

Critical Illness Polyneuropathy and Polyneuromyopathy

• Incidence depends on severity of illness, diagnostic criteria used, timing of diagnosis

• 25-63% in those requiring mechanical ventilation for >7 days

• Highest incidence (70-100%) occurs in sepsis population

Myasthenia Gravis

• Most common disorder of neuromuscular transmission

• Incidence 10-20 cases/million

• Prevalence 100-200 cases/million

• Women of child-bearing age affected two times more than men

• Thymic tumors present in 10% (usually in older men)

• Bimodal age distribution (though disease can occur at any age). Early peak 2nd-3rd decade (female predominance). Late peak 6th-8th decade (male predominance)

Lambert-Eaton Myasthenic Syndrome

• Incidence unknown

• Less frequent than myasthenia gravis

• 50% of LEMS cases are associated with malignancy (SCLC and Hodgkin’s lymphoma)

• Increased incidence of autoimmune disease in both paraneoplastic and non-paraneoplastic LEMS

Botulism

110 cases/year reported in US:

• 72% infant

• 25% foodborne (usually involving home-canned food, with highest rates in Alaska)

• 3% wound: incidence increasing due to “black tar heroin” used subcutaneously or intramuscularly

Has been reported in cocaine inhalation.

Respiratory failure is most common cause of death.

Steroid Myopathy

Increased risk – elderly, presence of malignancy, negative nitrogen balance prior to starting corticosteroids, inactivity.

Prognosis

Spinal Cord Injury

• Early death after admission for TSCI: 4-20%

• Factors affecting survival – age, level of injury, neurologic grade

• Compared to thoracic or lower injuries – C1-C3: 6.6 increased risk of death, C4-C5: 2.5 increased risk of death, C6-C8: 1.5 increased risk of death

• Increased risk of mortality -severe systemic injury, traumatic brain injury, medical comorbidities

• Mortality rates highest in first year

• Life expectancy 90% of normal

• Risk of suicide increased

Special considerations for nursing and allied health professionals.

NA

What's the evidence?

Demedts, M, Bechers, J, Rochette, F, Bulcke, J. “Pulmonary function in moderate neuromuscular disease without respiratory complaints”. Eur J Respir Dis. vol. 63. 1982. pp. 62-7. (Pulmonary function studies were done in 29 patients with moderate neuromuscular disease with minimal to no respiratory complaints. Decreased transpulmonary pressures and decreased static lung compliance were found to be the earliest abnormalities.)

Braun, NM, Arora, NS, Rochester, DF. “Respiratory muscle and pulmonary function in polymyositis and other proximal myopathies”. Thorax. vol. 38. 1983. pp. 616-23. (Fifty-three patients with proximal myopathy were studied. Maximal static inspiratory and expiratory pressures were less than 50% of normal in half of the patients. Decreased muscle strength was associated with decreased vital capacity, total lung capacity and maximum voluntary ventilation. Hypercapnia was more likely when respiratory muscle strength was less than 30% and vital capacity was less than 55% of normal.)

“The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke”. Lancet. vol. 349. 1997. pp. 1569-1581. (The aim of this large trial was to study the effect of aspirin and subcutaneous heparin for the treatment of acute ischemic stroke. There was a significant reduction in death or non-fatal recurrent stroke in the group treated with aspirin.)

“Tissue plasminogen activator for acute ischemic stroke”. N Engl J Med. vol. 333. pp. 1581-1587. (This was a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) given within three hours of acute ischemic stroke symptom onset. While there was a significant increase in symptomatic intracerebral hemorrhage in the group given t-PA, at three months, this group was more likely to have minimal or no disability. There was no difference in mortality between the groups.)

Capes, SE, Hunt, D, Malmberg, K, Pathak, P, Gerstein, HC. “Stress hyperglycemia and prognosis of stroke in nondiabetic patients: a systematic overview”. Stroke. vol. 32. 2001. pp. 2426-32. (This is a meta-analysis that shows that the relative risk of 30 day or in-hospital mortality is increased nondiabetic patients after acute ischemic stroke but not hemorrhagic stroke.)

Castillo, J, Leira, R, Gargia, MM, Serena, J, Blanco, M, Divalos, A. “Blood pressure decrease during the acute phase of ischemic stroke is associated with brain injury and poor stroke outcome”. Stroke. vol. 35. 2003. pp. 520(304 patients with acute ischemic stroke were studied. A U-shaped relationship was observed between blood pressure and poor outcomes, risk of early neurological deterioration, and mortality.)

“Thigh-length versus below-knee stockings for deep venous thrombosis prophylaxis after stroke: a randomized trial”. Ann Intern Med. vol. 153. 2010. pp. 553-62. (This was a large randomized study comparing the effectiveness of thigh-length stockings with that of below-knee stockings for preventing proximal DVT in immobile, hospitalized patients with stroke. Proximal DVT was found to occur more in those who wore knee-length stockings than in those who wore thigh-length stockings.)

Scanlon, PD, Loring, SH, Pichurko, BM, McCool, FD, Slutsky, AS, Sarkarati, M. “Respiratory mechanics in acute quadriplegia”. Am Rev Respir Dis. vol. 139. 1989. pp. 615-620. (Lung and chest wall compliance were measured in five acute C4-C7 quadriplegics and were found to be lower than measurements done in chronic quadriplegics and normal controls.)

Fishburn, MJ, Marino, RJ, Ditunno, JF. “Atelectasis and pneumonia in acute spinal cord injury”. Arch Phys Med Rehabil. vol. 71. 1990. pp. 197-200. (Forty-six complete spinal cord injury patients (C3-T11) were studied and found to have a 50% incidence of atelectasis or pneumonia in the first 30 days after the injury. The incidence was higher in higher-level quadriplegics than lower-level quadriplegics. The pneumonia and atelectasis were more common in the left side.)

DeVivo, MJ, Kartus, PL, Stover, SL, Rutt, RD, Fine, PR. “Cause of death for patients with spinal cord injuries”. vol. 149. 1989. pp. 1761-66. (This epidemiologic study of 5131 patients with spinal cord injuries demonstrated that the leading cause of death was pneumonia in those 55 years of age and older. Younger patients died from subsequent unintentional injuries and suicide.)

Estenne, M, Koop, C, Vanvaerenberg, J, Heilporn, A, De Troyer, A. “The effect of pectoralis muscle training in tetraplegic subjects”. Am Rev Respir Dis. vol. 139. 1989. pp. 1218-1222. (Six patients with traumatic tetraplegia underwent training of the pectoralis major muscle with repetitive, strenuous, isometric contractions for six weeks and were compared to a control group. There were increases in muscle strength and expiratory reserve volume, potentially increasing the effectiveness of cough in this population.)

Bourke, SC, Tomlinson, M, Williams, TL, Bullock, RE, Shaw, PJ, Gibson, GJ. “Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomized controlled trial”. Lancet Neurol. vol. 5. 2006. pp. 140-147. (Patients with amyotrophic lateral sclerosis were randomized to either non-invasive ventilation or standard care when orthopnea with a decreased maximum inspiratory pressure (<-60cmH2O) or symptomatic hypercapnia developed. Patients without severe bulbar dysfunction had improved survival and quality of life with the use of non-invasive ventilation.)

Kleopa, KA, Sherman, M, Neal, B, Romano, GJ, Heiman-Patterson, T. “Bipap improves survival and rate of pulmonary function decline in patients with ALS”. J Neurol Sci. vol. 164. 1999. pp. 82-88. (ALS patients with FVC<50% predicted were retrospectively evaluated. Those who tolerated BiPAP and used it >4 hours/day had improved survival and a slower decline in lung function.)

Fitting, JW, Paillex, R, Hirt, L, Aebischer, P, Schluep, M. “Sniff nasal pressure: a sensitive respiratory test to assess progression of amyotrophic lateral sclerosis”. Ann Neurol. vol. 46. 1999. pp. 887(16 patients with ALS were included in this study. At enrolment, forced vital capacity and maximum voluntary ventilation measures were normal, but nasal sniff pressure, maximum inspiratory pressure and maximum expiratory pressures were low. Late in the course of disease, sniff pressure testing was able to be performed, while maximal muscle pressure testing was not.)

Dalakas, MC, Elder, G, Hallett, M, Ravits, J, Baker, M, Papadopoulos, N. “A long-term follow-up study of patients with post-poliomyelitis neuromuscular symptoms”. N Engl Med. vol. 314. 1986. pp. 959-963. (Twenty-seven patients who developed new muscle weakness after recovering from acute polio were studied with quantitative muscle testing, muscle biopsy, electromyography, and virologic and immunologic examination of the CSF. All subjects were found to have decreased muscle strength with evidence of chronic and new denervation.)

Dean, E, Ross, J, Road, JD, Courtenay, L, Madill, KJ. “Pulmonary function in individuals with a history of poliomyelitis”. Chest. vol. 100. 1991. pp. 118-123. (Subjects with a history of acute poliomyelitis were studied. FEV1, FVC and maximum inspiratory and expiratory pressures were found to be significantly lower than predicted values. Risk factors for worse lung function were the need for mechanical ventilation and age older than 10 years at the time of acute polio and were older than 10 years of age at the time of acute polio.)

Klingman, J, Chui, H, Corgiat, M, Perry, J. “Functional recovery”. A major risk factor for the development of postpoliomyelitis muscular atrophy. Arch Neurol. vol. 45. 1988. pp. 645-7. (This was a retrospective study done to evaluate risk factors associated with the development of postpoliomyelitis syndrome. Those who developed postpoliomyelitis syndrome had more widespread disease initially with relatively greater functional recovery. This subgroup was less disabled and reported higher activity levels. Therefore, enlarged motor units may carry increased susceptibility for dysfunction or degeneration.)

Gillis-Haegerstrand, C, Marktrom, A, Barle, H. “Bi-level positive airway pressure ventilation maintains adequate ventilation in post-polio patients with acute respiratory failure”. Acta Anaesthesiol Scand. vol. 50. 2006. pp. 580-5. (Eight post-polio patients on nocturnal volume control ventilation were studied. Bi-level pressure support ventilation reduced the oxygen cost of breathing and decreased PaCO2 in these patients.)

Trojan, DA, Gendron, D, Cashman, NR. “Electrophysiology and electrodiagnosis of the post-polio motor unit”. Orthopedics. vol. 14. 1991. pp. 1353-61. (This paper discusses the electrodiagnostic findings present in postpoliomyelitis syndrome. Though electrodiagnostic studies may provide pertinent data, there are no specific findings diagnostic of pospoliomyelitis syndrome.)

Large, SR, Heywood, LJ, Flower, CD, Cory-Pearce, R, Wallwork, J, English, TA. “Incidence and aetiology of a raised hemidiaphragm after cardiopulmonary bypass”. Thorax. vol. 40. 1985. pp. 444-447. (A prospective study of 36 patients that underwent cardiopulmonary bypass was performed. 44% were found to have left diaphragm paralysis or weakness, 5.5% had right-sided weakness, and 5.5% had bilateral weakness. 80% had resolution at 6 months, and 90% had resolution at 1 year.)

Laroche, CM, Carroll, N, Moxham, J, Green, M. “Clinical significance of severe isolated diaphragm weakness”. Am Rev Respir Dis. vol. 138. 1988. pp. 862-6. (Six patients with isolated bilateral paralysis or severe weakness of the diaphragm were studied. Resting arterial blood gas was found to be normal and no oxygen desaturation occurred with exercise, though maximum voluntary ventilation was found to be low. None of the patients developed symptoms of nocturnal hypoventilation or chronic respiratory failure during five-year follow-up.)

Ciccolella, DE, Daly, BD, Celli, BR. “Improved diaphragmatic function after surgical plication for unilateral diaphragmatic paralysis”. Am Rev Respir Dis. vol. 146. 1992. pp. 797-9. (A 37-year-old man with left unilateral diaphragm dysfunction was studied before and after surgical plication. FVC, FEV1, TLC, FRC, PaO2, and diaphragm strength all increased after surgery.)

Katz, MG, Katz, R, Schachner, A, Cohen, AJ. “Phrenic nerve injury after coronary artery bypass grafting: will it go away?”. Ann Thoracic Surg. vol. 65. 1998. pp. 32-5. (64 patients with chronic obstructive pulmonary disease who underwent coronary artery bypass grafting and had phrenic nerve dysfunction post-operatively were evaluated. At follow-up, 13 patients had persistent diaphragm dysfunction, which was associated with increased morbidity and decreased quality of life.)

Laub, GW, Muralidharan, S, Chen, C, Perritt, A, Adkins, M, Pollock, S. “Phrenic nerve injury. A prospective study”. Chest. vol. 100. 1991. pp. 376-9. (This prospective study demonstrated that phrenic nerve insulation during cardiac surgery can significantly decrease the incidence of phrenic nerve injury.)

Orlikowski, D, Sharshar, T, Porcher, R, Annane, D, Raphael, JC, Claire, B. “Prognosis and risk factors of early onset pneumonia in ventilated patients with Guillain-Barré syndrome”. Intensive Care Med. vol. 32. 2006. pp. 1962-69. (81 patients that required intubation for GBS were evaluated. Mean vital capacity was 33+11%predicted at the time of intubation. A significant portion of the patients developed early onset pneumonia, which may have been associated with aspiration. Delayed intubation may increase the risk of early-onset pneumonia.)

Chevrolet, JC, Deleamont, P. “Repeated vital capacity measurements as predictive parameters for mechanical ventilation need and weaning success in the Guillain-Barré syndrome”. Am Rev Respir Dis. vol. 144. 1991. pp. 814-8. (In five patients with GBS who required intubation, vital capacity decreased in the 48 hours preceding intubation. Average VC at the time of intubation was 15.2+3.7 ml/kg. Vital capacity was stable and greater than 40 ml/kg in those who did not require intubation.)

“Plasmapheresis and acute Guillain-Barré syndrome”. Neurology. vol. 35. 1985. pp. 1096-1104. (The use of plasmapheresis was studied in 245 patients with acute GBS. Plasmapheresis was shown to have improved outcomes at four weeks, decreased time to independent walking and outcome at 6 months. Treatment was particularly effective when given within seven days of symptom onset and in those who required mechanical ventilation.)

Van der Meche, FGA, Schmitz, PI. “A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome”. N Engl J Med. vol. 326. 1993. pp. 1123-1129. (Patients with acute GBS with associated inability to walk were assigned to receive either five plasma exchanges or five doses of IVIG. IVIG led to a significant improvement in strength and a trend towards decreased time to improvement compared to plasmapheresis. There were fewer side effects in the IVIG group, suggesting that IVIG is at least as effective or better than plasma exchange.)

Ropper, AH, Kehne, SM. “Guillain-Barré syndrome: management of respiratory failure”. Neurology. vol. 35. 1985. pp. 1662(This paper reported on 19 of 38 patients with GBS who were treated with mechanical ventilation. Mechanical ventilation was used for vital capacity below 12-15 ml/kg, hypoxemia or fatigue. When VC was greater than 8-10 ml/kg, mechanical ventilation was discontinued. 12 patients required tracheostomy and mechanical ventilation was required for an average of 49 days.)

Lawn, ND, Fletcher, DD, Henderson, RD, Wolter, TD, Wijdicks, EF. “Anticipating mechanical ventilation in Guillain-Barré syndrome”. Arch Neurol. vol. 58. 2001. pp. 893-8. (This was a retrospective study examining 114 patients with GBS admitted to the intensive care unit. Progression to mechanical ventilation was likely to occur in patients with rapid disease progression, bulbar dysfunction, bilateral facial weakness, or dysautonomia. Vital capacity <20 ml/kg and maximal inspiratory pressures <30 cm H2O were associated with respiratory failure. There were no clinical predictors to anticipate the progression to respiratory failure.)

Leijten, F, De Weerd, AW, Poortvliet, DC, De Ridder, VA, Ulrich, C, Harink-De Weerd, JE. “Critical illness polyneuropathy in multiple organ dysfunction syndrome and weaning from the ventilator”. (This study found that critical illness polyneuropathy was present in 47% of patients with increased organ dysfunction scores. These patients had longer courses of mechanical ventilation that was not necessarily due to failure to wean. The presence of critical illness polyneuropathy did not necessarily mean that difficulty weaning from mechanical ventilation would be present.)

De Letter, MA, van Door, PA, Savelkoul, HF, Laman, JD, Schmitz, PL, Op de Coul, AA. “Critical illness polyneuropathy and myopathy (CIPNM): evidence for local immune activation by cytokine expression in the muscle tissue”. (This was a longitudinal prospective study that evaluated muscle biopsy tissue in subjects that developed (CIPNM). Neuropathic, myopathic, and a combination of patterns were found. Additionally, activated leukocytes with both proinflammatory and anti-inflammatory cytokines were present.)

Bednarik, J, Vondracek, P, Dusek, L, Moravcova, E, Cundrie, I. “Risk factors for critical illness polyneuromyopathy”. J Neurol. vol. 252. 2005. pp. 343-51. (This study evaluated the clinical (27.9%) and electrophysiological incidence (57.4%) of CIPNM. CIPMN was associated with the duration of SIRS and the severity of muscle, respiratory, nervous system and cardiovascular dysfunction. The development of CIPNM was associated with longer duration of mechanical ventilation.)

Van den Berghe, G, Schoonheydt, K, Becx, P, Bruyninckx, F, Wouters, PJ. “Insulin therapy protects the central and peripheral nervous system of intensive care patients”. Neurology. vol. 64. 2005. pp. 1348-53. (This study found that intensive insulin therapy reduced ventilatory dependency and the risk of CIPNM. In those with isolated brain injury, intensive insulin therapy decreased mean and maximal intracranial pressure. Seizures and diabetes insipidus occurred less, and at 12 months these subjects were better able to care for their own needs.)

Witt, NJ, Zochodne, DW, Bolton, CF, Grand’Maison, F, Wells, G, Young, GV. “Peripheral nerve function in sepsis and multiple organ failure”. Chest. vol. 99. 1991. pp. 176-184. (In patients with sepsis and multiple organ failure, axonal degeneration of motor and sensory fibers was present in 70%. 30% had difficulty weaning from mechanical ventilation, weakness of limb muscles, and decreased or absent deep tendon reflexes.)

Garnacho-Montero, J, Amaya-Villar, R, Garcia-Garmendia, JL, Madrazo-Osuna, J, Ortiz-Leyba, C. “Effect of critical illness polyneuropathy on the withdrawal from mechanical ventilation and the length of stay in septic patients”. Crit Care Med. vol. 33. 2005. pp. 349-54. (This was a prospective cohort study of patients with severe sepsis or septic shock who required mechanical ventilation for ≥ 7 days. Patients who had critical illness polyneuropathy had significantly longer duration of mechanical ventilation, longer hospital and ICU length of stay.)

Gajdos, P, Chevret, S, Clair, B, Tranchant, C, Chastang, C. “Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis: Myasthenia Study Group”. Ann Neurol. vol. 41. 1997. pp. 789-796. (This study evaluated 87 patients with MG to determine the efficacy and tolerance of treatment with either IVIG or plasmapheresis. There was no difference in the myasthenic muscle score between the two treatments, though IVIG was better tolerated.)

Seneviratne, J, Mandrekar, J, Wijdicks, EFM, Rabinstein, AA. “Noninvasive ventilation in myasthenia crisis”. Arch Neurol. vol. 65. 2008. pp. 54-58. (This was a retrospective cohort study evaluating the use of BiPAP in myasthenia crisis. BiPAP was found to be effective in preventing intubation and decreasing the length of mechanical ventilation. A PaCO2 of >45 mmHg was associated with BiPAP failure.)

Varelas, PN, Chua, HC, Natterman, J, Barmadia, L, Zimmerman, P, Yahia, A. “Ventilatory care in myasthenia gravis crisis: assessing the baseline adverse event rate”. Crit Care Med. vol. 30. 2002. pp. 2663(This was a retrospective study evaluating the effect of aggressive respiratory treatment on the clinical outcomes in patients with myasthenic crisis. Patients were found to have less atelectasis and pneumonia, shorter duration of mechanical ventilation and shorter intensive care unit stays compared to previously published papers.)

Seneviratne, J, Mandrekar, J, Wijdicks, FM, Rabinstein, AA. “Predictors of extubation in myasthenic crisis”. Arch Neurol. vol. 65. 2005. pp. 929-933. (This paper sought to clarify risk factors for and to assess the risk of extubation failure. The risk factors associated with extubation failure (44%) were male sex, history of previous crisis, atelectasis, and intubation for more than 10 days. Predictors for the need for reintubation (26%) were a lower pH and forced vital capacity at the time of extubation, atelectasis, and the need for BiPAP support.)

Qureshi, Al, Choudhry, MA, Akbar, MS, Mohammad, Y, Chua, HC, Yahia, AM. “Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis”. Neurology. vol. 52. 1999. pp. 629-32. (This was a multicenter chart review that compared the efficacy and tolerance of plasma exchange and intravenous immunoglobulin in the treatment of myasthenic crisis. Plasma exchange was associated with better ventilatory status at 2 weeks and functional outcome at 1 month. However, the complication rate was higher with plasma exchange.)

Qureshi, Al, Choundry, MA, Mohammad, Y, Chua, HC, Yahia, AM, Ulatowski. “Respiratory failure as a first presentation of myasthenia gravis”. Med Sci Monit. vol. 10. 2004. pp. CR684-9. (In a study of 51 patients with MG, 14% presented with respiratory failure and had no prior diagnosis of MG, though 5 of them had prior episodes of unexplained respiratory failure.)

Nicolle, MW, Stewart, DJ, Remtulla, H, Chen, R, Bolton, CF. “Lambert-Eaton myasthenic syndrome presenting with severe respiratory failure”. Muscle Nerve. vol. 19. 1996. pp. 1328-33. (This paper presents two cases of LEMS that presented with primary respiratory failure. The diagnosis was made through clinical suspicion and electrophysiologic testing. With treatment, the severe respiratory failure was reversed.)

Oh, SJ. “Diverse electrophysiological spectrum of the Lambert-Eaton myasthenic syndrome”. Muscle Nerve. vol. 12. 1989. pp. 464-9. (Thirteen patients with LEMS were studied and were found to have three different patterns on the repetitive nerve stimulation test that likely represented different degrees of blocking in LEMS, two of which could be misinterpreted as myasthenia gravis patterns.)

Elrington, GM, Murray, NM, Spiro, SG, Newsom-Davis, J. “Neurological paraneoplastic syndromes in patients with small cell lung cancer. A prospective survey of 150 patients”. J Neurol Neurosurg Psychiatry. vol. 54. 1991. pp. 764-7. (One hundred and fifty patients with small cell lung cancer were studied. 44% were found to have neuromuscular or autonomic deficits. The overall prevalence of LEMS in small cell lung cancer was 3% in this study.)

Maddison, P, Lang, B, Mills, K, Newsom-Davis, J. “Long term outcome in Lambert-Eaton myasthenic syndrome without lung cancer”. J Neurol Neurosurg Psychiatry. vol. 70. 2001. pp. 212-7. (Forty-seven patients with LEMS without small cell lung cancer were retrospectively evaluated. The prognosis was found to be favorable, but substantial immunotherapy was required to maintain clinical stability. Initial clinical muscle strength but not anti-VGCC antibody titres or electrophysiological scores were predictive of outcomes.)

Kamenskaya, MA, Elmqvist, D, Thesleff, S. vol. 32. 1975. pp. 505-9. (This is an animal study that demonstrated the ability of guanidine to increase the amount of acetylcholine released by a motor neuron.)

Oh, SJ, Kim, DS, Head, TC, Claussen, GC. “Low-dose guanidine and pyridostigmine: a relatively safe and effective long-term symptomatic therapy in Lambert-Eaton myasthenic syndrome”. Muscle Nerve. vol. 20. 1997. pp. 1146-52. (Low-dose guanidine and pyridostigmine was used in nine patients with LEMS and was shown to improve clinical status in all patients without any serious side effects from the guanidine.)

Dau, PC, Denys, EH. “Plasmapheresis and immunosuppressive drug therapy in the Eaton-Lambert syndrome”. Ann Neurol. vol. 11. 1982. pp. 570-5. (Five patients with LEMS were first treated by plasmapheresis alone followed plasmapheresis along with prednisone and azathioprine. The greatest improvement was seen with treatment with plasmapheresis with prednisone and azathioprine.)

Bain, PG, Motomura, M, Newsom-Davis, J, Misbah, SA, Chapel, HM, Lee, ML. “Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome”. Neurology. vol. 47. 1996. pp. 678-83. (This was a randomized, double-blind, placebo controlled crossover trial that evaluated the effect of IVIG on nine patients with LEMS. Improvement in muscle function peaked at 2-4 weeks and declined by 8 weeks.)

Streib, EW, Rothner, AD. “Eaton-Lambert myasthenic syndrome: long-term treatment of three patients with prednisone”. Ann Neurol. vol. 10. 1981. pp. 448-53. (Three patients with LEMS were treated with prednisone for 6 months, 12 months, and three years resulting in increased muscle strength and electromyographic improvement. Decreased doses of prednisone led to deterioration in all patients.)

Hughes, JM, Blumenthal, JR, Merson, NH, Lombard, GL, Dowell, VR, Gangarosa, EJ. “Clinical features of types A and B food-borne botulism”. Ann Intern Med. vol. 95. 1981. pp. 442-5. (This paper reviewed 55 patients with type A and B food-borne botulism.)

Sobel, J, Tucker, N, Sulka, A, McLaughlin, J, Maslanka, S. “Foodborne botulism in the United States, 1990-2000”. Emerg Infect Dis. vol. 10. 2004. pp. 1606-11. (Surveillance data and reports of foodborne botulism were reviewed. The median age was 48 years, 59% were female, and the case-fatality rate was 4%. 51% were caused by type A and type E caused 90% of cases in Alaska.)

Werner, SB, Passaro, D, McGee, J, Schechter, R, Vugia, DJ. “Wound botulism in California, 1951-1998: a recent epidemic in heroin injectors”. Clin Infect Dis. vol. 31. 2000. pp. 1018-24. (The increase in the number of cases in the final years of the study was due to black tar heroin, mostly in those who injected the drug subcutaneously.)

Passaro, DJ, Werner, SB, McGee, J, Mac Kenzie, WR, Vugia, DJ. “Wound botulism associated with black tar heroin among injection drug users”. JAMA. vol. 279. 1998. pp. 859-63. (Subjects who injected black tar heroin subcutaneously or intramuscularly and who did so more frequently and with greater cumulative doses were more likely to develop botulism. The development of wound botulism was not effected by cleaning the skin or by cleaning the injection paraphernalia.)

Roblot, F, Popoff, M, Carlier, JP, Godet, C, Abbadie, P, Matthis, S. “Botulism in patients who inhale cocaine: the first cases in France”. Clin Infect Dis. vol. 43. 2006. pp. e51-2. (This article described two cases of mild botulism in patients who inhaled cocaine.)

Varma, JK, Katsitadze, G, Moiscrafishvili, M, Zardiashvili, T, Chokheli, M, Tarkhashvili, N. “Signs and symptoms predictive of death in patients with foodborne botulism—Republic of Georgia, 1980-2002”. Clin Infect Dis. vol. 39. 2004. pp. 357-62. (The Republic of Georgia has the highest rate of foodborne botulism in the world. 8% of the 706 cases identified died. Those with shortness of breath, impaired gag reflexes, and the absence of diarrhea were 23 times more likely to die.)

Tacket, CO, Shandera, WX, Mann, JM, Hargrett, NT, Blake, PA. “Equine Antitoxin use and other factors that predict outcome in type A foodborne botulism”. Am J Med. vol. 76. 1984. pp. 794-8. (The effect of antitoxin therapy on 132 cases of foodborne botulism was evaluated. Those who received antitoxin had a lower fatality rate and a shorter course than those who did not receive it. The timing of administration of the antitoxin did not affect the fatality rate.)

Konagaya, M, Bernard, PA, Max, SR. “Blockade of glucocorticoid receptor binding and inhibition of dexamethasone-induced muscle atrophy in the rat by RU38486, a potent glucocorticoid antagonist”. Endocrinology. vol. 119. 1986. pp. 375-80. (This study evaluated the use of a glucocorticoid antagonist to determine the role of intracellular glucocorticoid receptors in steroid myopathy. In mice, the glucocorticoid receptor antagonist blocked the loss of body and muscle weight caused by dexamethasone.)

Ferrando, AA, Stuart, CA, Sheffeild-Moore, M, Wolfe, RR. “Inactivity amplifies the catabolic response of skeletal muscle to cortisol”. J Clin Endocrinol Metab. vol. 84. 1999. pp. 3515-21. (Six male subjects were studied before and after 14 days of bed rest during 12-hour infusions of hydrocortisone. Inactivity was found to increase the catabolic effects of hypercortisolemia.)

Bowyer, SL, LaMothe, MP, Hollister, JR. “Steroid myopathy: incidence and detection in a population with asthma”. J Allergy Clin Immunol. vol. 76. 1985. pp. 232-43. (Asthma subjects treated with corticosteroids underwent muscle strength testing. Those taking prednisone 40mg/day or greater were found to have significant muscle weakness. Only one taking less than 30 mg/day had muscle weakness.)

Singleton, JR, Baker, BL, Thorburn, A. “Dexamethasone inhibits insulin-like growth factor signaling and potentiates myoblast apoptosis”. Endocrinology. vol. 141. 2000. pp. 2945-50. (Using a rat model, this study demonstrated that insulin-like growth factor acts to inhibit apoptosis and that dexamethasone inhibits this antiapoptotic effect of IGF-1.)

Dropcho, EJ, Soong, SJ. “Steroid-induced weakness in patients with primary brain tumors”. Neurology. vol. 41. 1991. pp. 1235-9. (Steroid myopathy was found to occur in 10.6% of 216 adult patients with primary brain tumors who received ≥ 2 weeks of daily dexamethasone. There was a wide range of peak and cumulative doses of dexamethasone that caused steroid myopathy. Two-thirds developed steroid myopathy in the 9th-12th weeks of treatment.)

Khaleeli, AA, Edwards, RH, Gohil, K, McPhail, G, Rennie, MJ, Round, J. “Corticosteroid myopathy; a clinical and pathological study”. Clin Endocrinol (Oxf). vol. 18. 1983. pp. 155-66. (Six patients with Cushing’s syndrome and three with steroid myopathy were studied. Proximal muscle weakness occurred in all patients and preferentially affected the lower limbs. Type II fiber atrophy was the most common pathologic abnormality. Plasma creatine kinase was at the lower limit of normal, the EMG showed a myopathic pattern, and 24-hour urinary 3-methylhistidine/creatinine ratio was elevated.)

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