CONTENTS
- Initial approach to acute, diffuse weakness
- Evaluation of respiratory muscle strength:
- Specific neuromuscular disorders
- Related topics
- Podcast
- Questions & discussion
- Pitfalls
history
- Sensory abnormality (e.g., pain, numbness, paresthesias)?
- Muscle cramping or aching?
- Bowel and/or bladder symptoms?
- Ocular involvement (e.g., double vision, droopy eyelids)?
- Bulbar involvement (e.g., voice change)?
- Shortness of breath?
- What activities/movements do you have trouble with?
- Preceding prodromal illness?
- Duration or pattern?
- Acute-onset suggests a vascular etiology.
- Fatigability, waxing/waning suggests myasthenia gravis.
- Exposures? (e.g., mosquitoes, unusual food, travel, intravenous drug use)
- Fever?
examination
- Accurate respiratory rate?
- Cranial nerve abnormalities?
- Weakness distribution:
- Proximal vs. distal?
- Upper vs. lower extremities?
- Symmetric vs. asymmetric?
- Neck flexion weakness? 📖
- Sensory abnormality?
- Reflexes?
- Muscle tone?
- Babinski sign?
#1/6: brain
clinical findings
- Distribution:
- Often distal > proximal weakness.(Torbey, 2019)
- Often asymmetric.
- Cranial nerve/bulbar involvement: Cranial nerve abnormalities may occur (depending on lesion localization).
- Reflexes: Upper motor neuron signs may appear, especially subacutely (e.g., hyperreflexia, spasticity, Babinski sign).
- Sensation: May be affected, depending on the location of the lesion.
- Other findings: Cortical deficits or altered mental status may occur
differential diagnosis is extremely broad:
- Brainstem infection or inflammation (e.g., sarcoidosis, neuromyelitis optica spectrum disorder).
- Structural lesion compressing the brainstem.
- Stroke.
- Acute disseminated encephalomyelitis (ADEM).
#2/6: spinal cord (multiple tracts involved)
clinical findings
- Distribution: Motor and sensory findings may localize to a spinal level.
- Cranial nerve/bulbar involvement: No.
- Reflexes: Upper motor neuron signs may appear, especially subacutely (e.g., hyperreflexia, spasticity, Babinski sign). Acutely, patients may have transient spinal shock, with loss of spinal function below the level of the lesion and areflexia.
- Sensation: Frequently involved.
- Other findings:
- Bowel and bladder dysfunction may occur.
differential diagnosis
- Spinal cord compression (e.g., trauma, epidural abscess, malignancy).
- Inflammation (e.g., idiopathic transverse myelitis 📖, neuromyelitis optica spectrum disorders).
- Infectious processes (e.g., VZV myelitis 📖)
- Spinal cord infarction (e.g., iatrogenic, or complicating meningitis with a local vasculitic process).
#3/6: anterior horn cells in spinal cord (acute flaccid myelitis)
clinical findings
- Distribution is variable:
- Often asymmetric.
- Often proximal > distal.(36333027)
- Cranial nerve/bulbar involvement: No
- Reflexes: Usually reduced.
- Sensation: Unaffected.
differential diagnosis
- Enteroviruses (e.g., poliomyelitis, enterovirus D68, enterovirus D71).
- Arboviruses (e.g., West Nile virus).
- Paraneoplastic motor neuron disease.
- HIV.
#4/6: peripheral neuropathy and/or polyneuropathy
clinical findings
- Distribution: Typically, ascending weakness (distal > proximal).
- Cranial nerve/bulbar involvement: Bulbar involvement may occur, but ocular involvement is rare.
- Reflexes: Reduced (hyporeflexia or areflexia).
- Sensation: Frequently involved.
- Other findings: Lower motor neuron findings may occur (atrophy, fasciculations).
differential diagnosis
- Guillain-Barre syndrome (GBS).
- Lyme disease.
- CMV, HIV, EBV, VZV.
- Hypothyroidism.
- Vitamin deficiency (e.g., thiamine deficiency; B12 deficiency or nitrous oxide poisoning).
- Vasculitic neuropathy (e.g., rheumatoid arthritis, polyarteritis nodosa).
- Acute intermittent porphyria.
- Toxins:
- Heavy metals (e.g., arsenic, mercury).
- Ethylene glycol, methanol.
- n-Hexane.
- Critical illness polyneuropathy.
- Leptomeningeal malignancy.
#5/6: NMJ (neuromuscular junction)
clinical findings
- Distribution:
- May see proximal limb and neck weakness (similar to myopathy), or descending weakness.
- Symmetric weakness.
- Cranial nerve/bulbar involvement: Frequent ocular and bulbar involvement (e.g., ptosis, diplopia, ophthalmoplegia, dysarthria).
- Reflexes: Normal (unless weakness is severe).
- Sensation: Unchanged.
- Other findings: Fatigability, fluctuation in symptoms and signs.(30743297)
differential diagnosis
- Myasthenia gravis.
- Botulism.
- Tetanus.
- Tick paralysis (toxin interferes with acetylcholine release).
- Organophosphate poisoning, overdose of anticholinesterases.
- Hypermagnesemia.
- Paralytic medications (effects may be prolonged by renal failure, hepatic disease, hypermagnesemia, metabolic acidosis).(35863882)
#6/6: myopathy
clinical findings
- Distribution:
- Proximal limbs and neck especially involved.
- Symmetric.
- Cranial nerve/bulbar involvement: No.
- Reflexes: preserved (unless weakness is severe).
- Sensation: unchanged (although patients may have cramps/myalgias/stiffness).
- Other findings:
- Atrophy may occur (but without fasciculations, as might be seen in lower motor neuron disease).
- Muscle tenderness may occur.(30743297)
causes of myopathy
- Metabolic:
- Hypokalemia (e.g., periodic paralysis).
- Hypomagnesemia.
- Hypophosphatemia.
- Hypo/hyperthyroidism.
- Mitochondrial disease.
- Inflammatory myositis (e.g., polymyositis, dermatomyositis, lupus, scleroderma).
- Infectious myopathies (e.g., Influenza, Coxsackievirus, HIV, Legionella pneumophila, Borrelia burgdorferi).
- Drug-induced myopathy: (36333027)
- Amiodarone.
- Cyclosporine.
- Hydroxychloroquine/chloroquine.
- Labetalol.
- Statins.
- Steroid.
- Zidovudine.
- Hereditary myopathies (late-onset Pompe disease is most likely to present to ICU with undiagnosed respiratory muscle weakness).
- Critical illness myopathy.
- Mitochondrial disease.
- Rhabdomyolysis 📖.
blood tests
- Electrolytes (including Ca/Mg/Phos).
- Creatine kinase elevation may suggest myopathy.
- Consider screening for HIV, if this is a possibility.
- TSH (thyroid-stimulating hormone) may be considered.
lumbar puncture
- CSF is generally normal in:
- Myopathy.
- Neuromuscular junction disorders.
- Peripheral neuropathies (although CSF abnormalities may occur in neuropathies which involve the nerve roots such as Guillain-Barre syndrome, CMV, HIV).
- CSF may be helpful in:
- Guillain-Barre syndrome classically causes albuminocytologic dissociation (elevated protein, despite a normal cell count). However, elevation of protein may take some time to develop. More on CSF findings in Guillain-Barre syndrome here.📖
- Myelitis.
- Pleocytosis is often a sign of various infections (e.g., encephalitis, enterovirus, West Nile virus, HIV, CMV) or inflammatory conditions (e.g., sarcoidosis). However, Guillain-Barre syndrome may have a mild pleocytosis of 5-50 cells.(30743297)
forced vital capacity (FVC)
- Forced vital capacity is the largest volume breath the patient is able to take.
- Forced vital capacity is an integrated reflection of multiple parameters: inspiratory strength, expiratory strength, and lung compliance. The holistic nature of the forced vital capacity may make it a better predictor of respiratory failure than the negative inspiratory force (which measures only diaphragmatic strength).
- Forced vital capacity is more reproducible and less uncomfortable than the negative inspiratory force (discussed below). This makes the forced vital capacity more useful as a serial measurement to track a patient's progress over time.
negative inspiratory force (NIF), a.k.a. maximal inspiratory pressure (MIP)
- This is the largest amount of negative pressure that the patient is able to exert when inhaling (video above).
- This test is uncomfortable and effort-dependent (more so than forced vital capacity). Repeated measurements may fatigue patients.
- There is little role for this test in tracking the progress of a patient with a known neuromuscular disorder (e.g., a patient who has been diagnosed with myasthenia gravis). For the purpose of tracking a patient's trajectory, NIF has not been shown to add any independent information beyond what is provided by the forced vital capacity.(21748507)
- The advantage of NIF is that it may more accurately measure muscle strength in a patient with other pulmonary abnormalities (e.g., in a patient with obstructive lung disease or prior pneumonectomy).
- Values between zero and -30 cm water suggest severe respiratory muscle weakness.(30743297)
caveats regarding serial pulmonary function tests ⚠️
- Serial pulmonary function tests are often overutilized. There is no prospective evidence that measuring pulmonary function tests is beneficial. Available data is retrospective and often biased by self-fulfilling prophecy (e.g., patients are intubated based on poor pulmonary mechanics, then subsequently a retrospective study shows that poor mechanics correlate with intubation).
- Serial pulmonary function testing may interfere with sleep or rest.
- Serial pulmonary function testing may cause panic due to random variation in testing (with enough repeat testing, eventually the numbers will decrease solely due to random chance).
- Intubation should never be performed solely on the basis of a low pulmonary function test. Rather, the decision to intubate is a complex clinical decision, integrating numerous sources of information.
appropriate use of pulmonary function tests
- Initial diagnosis of neuromuscular weakness. In a patient with respiratory failure of unclear etiology, pulmonary function tests may be helpful by identifying the presence of neuromuscular weakness.
- Initial evaluation and triage of patients with known neuromuscular weakness.
- If admission FVC is normal and the patient is dyspneic, this suggests that something else is going on (e.g., pulmonary embolism, heart failure). It also suggests that the patient may not require ICU level monitoring for their neuromuscular disorder.
- If the admission FVC is significantly low (e.g., <30 cc/kg), this supports the need for a higher intensity of respiratory monitoring.
- Tracking patient trajectory over time:
- Intermittently measuring the FVC may help determine how the patient is responding to therapy.
- Measuring the FVC about three times per day is probably adequate. There is no evidence-based rationale for frequent FVC measurement (e.g., every four hours). Patients should not be woken from sleep for this.
- To be significant, changes should represent a consistent trend over several measurements (not just one aberrant measurement).
role of a single breath count test
- This may be used as a surrogate for the forced vital capacity (FVC) in resource-limited settings.
how to perform the single breath count test
- The patient should take the deepest possible breath and then count upwards from one as high as they can.
- Patients must count at a rate of about two per second (120 per minute). A metronome is useful to set the appropriate pace (e.g., using the video below).
- Generally, two attempts may be provided. The higher count should be regarded as the most accurate value.
interpretation of the single breath count test
- Single breath count correlates roughly with forced vital capacity, as shown below.(26437790, 33317968)
- A count >25 may suggest a reasonably preserved forced vital capacity (over ~2 liters).
- The single breath test has not been validated in patients with other active respiratory problems (e.g., pneumonia plus neuromuscular weakness), so it's unclear how well it would function in that situation.
blood gas monitoring is worthless in patients without chronic respiratory dysfunction
- Patients without chronic respiratory dysfunction should have a normal respiratory drive. These patients shouldn't become hypercapnic until they are totally exhausted and frankly dying.
- This assumes that they aren't on other medications that would blunt their respiratory drive (e.g., opioids).
- Hypercapnia is an extremely late finding in this context.
- It is generally accepted that blood gas monitoring has little role in most patients with acute neuromuscular weakness.
blood gas measurement may be somewhat useful in patients with chronic hypercapnia
- Patients with chronic hypercapnia (e.g., due to severe COPD) don't have a normal respiratory drive. These patients may develop insidiously worsening hypercapnia without looking distressed.
- Rather than developing respiratory extremis, these patients may quietly accumulate CO2 and become sleepy (due to CO2 narcosis).
- Blood gas analysis may therefore be useful in a patient with altered mental status plus chronic hypercapnia.
- Please note, however, that the decision to intubate is still clinical.
basics
- Clostridium botulinum is an anaerobic, gram-positive, spore-forming rod which produces botulinum toxin.
- Botulinum toxin cleaves proteins required to release acetylcholine (ACh) from the cholinergic terminals within the motor end plate and within the peripheral parasympathetic nervous system (figure below). Regenerating this molecular machinery takes time, so acetylcholine transmission takes time to recover.
- Since botulinum toxin is a protein, it doesn't penetrate the central nervous system.
epidemiology
- Food botulism (preformed toxin in food, primary cause in adults):
- This is associated mostly with home-canned food (boiling without pressure-cooking kills most bacteria, but not C. botulinum spores). Other sources include fermented fish or seal meat, seal oil, and alcohol made from potatoes in prisons.(31794471)
- ⏰ Incubation period: Clinical botulism typically occurs ~12-36 hours after ingestion (although onset may be earlier, or delayed for up to ten days).(31794471)
- Wound botulism
- This may result from subcutaneous injection of black tar heroin, or from severe trauma (e.g., extremity crush injury).
- ⏰ Incubation period: Botulism may not occur for days or weeks after wound infection.(30743297)
- Iatrogenic botulism may result from use of excessive doses of commercial botulinum toxin (e.g., for cosmetic procedures).
clinical findings
- Descending flaccid paralysis:
- Paralysis almost always starts with cranial nerve involvement (e.g., ptosis, opthalmoplegia, dysarthria, dysphagia, facial weakness).
- Subsequently, paralysis descends to involve the limbs.
- Reflexes are generally normal, unless there is severe weakness.(31794471)
- Peripheral anticholinergic autonomic effects:
- Dilated and nonreactive pupils (however, these are present in only half of patients).(31794471)
- Dry mouth.
- Ileus, urinary retention.
- Food botulism: May additionally cause early gastrointestinal symptoms (nausea, vomiting, cramping, diarrhea).
- 💡Clustering of cases due to food poisoning may aid diagnosis.
- Wound botulism: Wound may look benign, or there may be associated features of fever and infection.
core clinical features of botulism
- Afebrile (although fever can occur in wound botulism).
- Normal mental status.
- Normal sensation (except for blurred vision).
- Symmetric, descending motor deficit.
- Cranial neuropathy (including pupillary dilation about half the time).
- 💡Pupillary involvement may be extremely helpful if present, since this is unlikely in many other conditions (e.g., myasthenia gravis).(Torbey, 2019)
- Normal heart rate, or bradycardia.
- Normal blood pressure.
differential diagnostic considerations include:
- Other causes of descending weakness plus cranial nerve palsies: (23983866)
- Organophosphate intoxication (may have exposure history, miosis, diarrhea).
- Guillain-Barre syndrome (especially the Miller Fisher variant, or pharyngeal-cervical-brachial variants 📖).
- Diphtheria infection.
- Myasthenia gravis (diplopia and ptosis are common).
- Other differential diagnostic considerations:
- Tick paralysis. Careful examination of the skin and hair should be undertaken to look for a tick or an infected wound (that may be the source of wound botulism).(31794471)
- Pontine infarction.
laboratory evaluation
- Labs are generally normal (e.g., blood count, lumbar puncture, inflammatory markers).
- Botulinum toxin may be detected in blood, stool, or food – but this must be done at a reference laboratory. These results won't return fast enough to affect management.
electrodiagnostic studies
- Electrodiagnostic studies are not necessary for the diagnosis, which is generally made on clinical grounds. Additionally, characteristic abnormalities are not always present (so treatment should not be delayed pending electrodiagnostic studies).(31794471) Nonetheless, electrodiagnostic studies may support the diagnosis in some cases. Potential findings include the following:
- (1) Decreased amplitude of compound motor action potentials (CMAP) after a single nerve stimulus.
- (2) Facilitation: repetitive stimulation at high frequency (>20 Hz) causes an increased response. Facilitation is also observed after exercise.
- (3) Needle electromyography may show short-duration, low-amplitude motor unit potentials.(31794471)
treatment
- Prompt antitoxin administration can be critical to survival, by reducing the duration of paralysis.
- Wound botulism is an indication for antibiotic therapy (e.g., preferably penicillin G, or alternatively metronidazole). However, this should ideally be initiated after administration of antitoxin and wound debridement (since antibiotic administration may lyse bacteria, thereby releasing botulinum toxin).(30743297)
- Food botulism is due to preformed toxin within the food (rather than invasive infection).
- There is no role for antibiotic therapy. Indeed, it's possible that antibiotics could lyse bacterial cells in the gut, thereby increasing the release and absorption of botulinum toxin.(30743297)
- Whole bowel irrigation may be considered to reduce ongoing absorption of botulinum toxin from the gut, if the contaminated food was recently ingested.
- Supportive management:
- Respiratory muscle weakness may require support, including intubation. Recovery is often slow, over weeks to months.(31794471)
- Autonomic instability may require management.
causes
- Arboviruses (mosquito borne):
- West Nile virus is currently the most common cause in the United States.(35369954)
- Various other enteroviruses, depending on location (e.g., Saint Louis encephalitis; Japanese B encephalitis virus).
- Enteroviruses:
- Especially enterovirus D68 and 71.
- Coxsackieviruses.
- Echoviruses.
- Poliomyelitis.
- Herpesvirus.
- Tick-borne viruses.
clinical features
- Systemic symptoms are usually seen (e.g., fever, rash, gastroenteritis, lymphadenopathy). These often precede neurologic symptoms.(30743297)
- Variable patterns of weakness, which are often asymmetric. Paralysis often involves the limbs, bulbar muscles, and/or respiratory muscles.
- Reflexes are usually reduced.
- Sensation is unaffected.
- Some infections may be accompanied by encephalitis or meningoencephalitis.
evaluation
- Laboratory evaluation:
- CSF: Usually lymphocytic pleocytosis with elevated protein is seen, but there may be a neutrophilic pleocytosis early on.
- Viral identification depends on the virus.
- MRI shows lesions in the gray matter, including the anterior horns.
- Electrodiagnostic studies may show low-amplitude motor responses with preserved sensory responses.
treatment
- Treatment is supportive.
basics
- Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving upper and lower motor neurons.
- Clinical features include weakness, spasticity, muscle wasting, bulbar dysfunction, and respiratory failure. Some patients may have predominantly bulbar involvement.
- Peak incidence occurs between ages 50-75 years old. Average survival after diagnosis is ~2-5 years, but 5-10% of patients may survive for a decade or longer.(30516604)
- Most patients will be diagnosed with ALS prior to ICU admission, but ~2% may present to ICU with respiratory failure of unknown etiology. Among a series of patients presenting to ICU with neuromuscular weakness of unknown etiology, ALS was the second most common diagnosis after Guillain-Barre syndrome.(35369954)
clinical features of patients with undiagnosed ALS presenting to ICU
- Patients may present with respiratory failure due to diaphragmatic weakness, or bulbar dysfunction with inability to protect their airway.
- Potential clues may include the following:
- (1) Respiratory failure which is otherwise unexplained.
- (2) History of gradually worsening dyspnea over months prior to admission.
- (3) Muscle weakness on examination (e.g., impaired negative inspiratory force).
- (4) Signs of both upper and lower motor neuron involvement:
- Upper motor neuron involvement:
- Hyperreflexia.
- Extensor plantar responses.
- Spasticity.
- Lower motor neuron involvement:
- Muscle atrophy.
- Fasciculations.
- Upper motor neuron involvement:
investigation
- Electromyography:
- Motor nerve conduction over severely atrophic muscles may show low-amplitude responses.
- Needle EMG shows signs of acute denervation (e.g., fibrillations, positive sharp waves, and fasciculation potentials) and chronic denervation/reinnervation (with large, complex motor unit action potentials with reduced recruitment and instability).
- Imaging:
- Imaging is generally normal. The primary role is to exclude alternative etiologies (e.g., multiple sclerosis or cervical cord compression).(Tang 2015)
- There may be hyperintensity within the bilateral corticospinal tracts on T2/FLAIR MRI (which span from the precentral gyri, to the posterior limb of the internal capsule, to the cerebral peduncles, and finally the anterolateral column of the spinal cord).
- Labs: Creatine kinase may be increased up to 1,000 U/L, due to muscle denervation. (Wijdicks, 2019)
- Pulmonary function tests:
- FVC (forced vital capacity) correlates with disease progression and mortality.
management
- ICU management is essentially supportive.
- Salivary secretion management:
- Antisialagogues (e.g., glycopyrrolate or scopolamine patches, amitriptyline).
- Radiation therapy may be considered if refractory.(29990478)
- Cough-assist devices may promote airway clearance.
- Start at +20 cm/-20 cm and titrate up to +40 cm/-40 cm H2O as tolerated.
- Initial settings: 1.8 second inspiratory time, 1.6 second expiratory time, 1.8 second pause.(29990478)
- Nocturnal BiPAP may promote diaphragmatic rest and avoid nocturnal hypercapnia.
- BiPAP has been shown to reduce dyspnea and lengthen survival among appropriately selected patients.
- Potential indications for nocturnal BiPAP in patients with neuromuscular weakness include any of the following:(25503955)
- FVC (forced vital capacity) <50% predicted.
- MIP (maximal inspiratory pressure) ≦60 cm water.
- Awake PaCO2 >45 mm.
- Nocturnal desaturation ≦88% for at least 5 minutes.
- Eventually, patients will face a decision regarding tracheostomy versus comfort-directed care.
basics
- Partial deficiency of porphobilinogen deaminase leads to accumulation of porphobilinogen and delta-aminolevulinic acid, with toxic effects on various tissues. Delta-aminolevulinic acid may inhibit GABA receptors, leading to excess neurological excitability.(31908464)
- This section focuses on acute intermittent porphyria, since it is the most common form that will be encountered in a critical care unit. Other, less common forms of acute porphyria may manifest in a similar manner, albeit occasionally combined with photodermatitis (e.g., hereditary coproporphyria and variegate porphyria). The diagnostic and therapeutic strategy for these varying forms of acute porphyria are similar.
epidemiology
- Inherited as an autosomal dominant pattern with low penetrance (~10%).(31402774)
- Most patients develop symptoms following puberty, especially during the 30s-40s.(31908464)
precipitants
- Fasting, alcohol.
- Physiologic stress (e.g., infection, surgery).
- Medications, especially including the following:
- Antimicrobials:
- Azoles (fluconazole, itraconazole, ketoconazole, voriconazole).
- Dapsone.
- Erythromycin.
- HIV medications.
- Isoniazid.
- Nafcillin.
- Nitrofurantoin.
- Rifampin.
- Trimethoprim-sulfamethoxazole.
- Antiseizure medications:
- Barbiturates.
- Carbamazepine.
- Oxcarbazepine.
- Phenytoin.
- Topiramate.
- Cardiovascular:
- Clonidine.
- Diltiazem.
- Hydralazine.
- Nifedipine.
- Nicardipine.
- Nimodipine.
- Nitroprusside.
- Verapamil.
- Endocrine:
- Danazol.
- Estrogens.
- Megestrol.
- Progestins.
- Testosterone.
- Sedatives/analgesics/anesthetics:
- Barbiturates.
- Benzodiazepines.
- Etomidate.
- Inhalational anesthetic agents.
- Lidocaine, ropivacaine, mepivacaine.
- Ketamine.
- NSAIDs (some, including ketorolac, diclofenac).
- Paralytics (rocuronium, vecuronium).
- Others
- Chemotherapeutics.
- Hydroxyzine.
- Metoclopramide.
- Modafinil.
- Ondansetron.
- Oxybutynin.
clinical manifestations
- Acute attacks can last days to months. These may be triggered by factors listed above.
- Clinical manifestations are variable. In many patients, abdominal pain may be a dominant feature. However, in other cases, acute intermittent porphyria may mimic Guillain-Barre syndrome, or autoimmune encephalitis.
- Gastrointestinal manifestations
- Abdominal pain is present in >80% of patients.(31908464)
- Pain is often poorly localized and out of proportion to physical examination findings.
- Other features may include nausea, emesis, ileus, distension, constipation, or diarrhea.
- Central nervous system
- Porphyria may cause symptoms due to direct neurotoxicity of porphyrins, hyponatremia, or by causing PRES (posterior reversible encephalopathy syndrome). If PRES occurs, this may cause a variety of symptoms (e.g., headaches, seizures, and visual abnormalities). 📖
- Seizures can occur (which may be due to PRES, hyponatremia, or hypomagnesemia).
- Depression, anxiety, psychosis, or delirium may occur.(31908464)
- Peripheral nervous system (“GBS mimic”)
- Peripheral nervous system involvement often occurs relatively late (after the development of abdominal pain and central nervous system involvement).(34661997)
- Progressive, ascending quadriparesis with suppressed reflexes may occur – mimicking Gillian-Barre Syndrome.(31402774) However, weakness may also be asymmetric, or it can begin proximally in the legs.(34661997)
- Cranial nerve involvement with bulbar paralysis is often severe (e.g., including dysarthria and dysphagia).(31908464)
- Respiratory failure may occur, requiring intubation.
- Sensory involvement may commonly cause pain (potentially involving the extremities, chest, and back).(31908464) Hyperesthesia is common.
- Dysautonomia
- Increased sympathetic tone may cause arrhythmias, hypertension, diaphoresis, and occasionally hyperthermia.
- Tachycardia occurs in >80% of patients.(31908464)
- Urinary retention can occur.
- Urine may have a deep red “port wine” color, due to porphobilinogen. However, this may be absent – so normal urine cannot exclude acute porphyria.(34661997)
radiology
- Neuroimaging is generally unrevealing. The primary role may be to exclude alternative diagnostic possibilities (e.g., for patients with abdominal pain, CT scans may help exclude alternative abdominal pathology).
- Some patients may develop PRES (posterior reversible encephalopathy syndrome) as a consequence of hypertension. Neuroradiology may reveal features of PRES.
laboratory investigations
- General labs:
- Hyponatremia is common (due to factors including SIADH, hypothalamic involvement, and hypovolemia from emesis).
- Aminotransferase levels are elevated in ~13% of cases, but this is quite nonspecific among critically ill patients.(31908464)
- CSF is generally normal or demonstrates isolated elevation of protein levels (albuminocytological dissociation 📖).(34661997)
- Spot urinary porphobilinogen (PGB):
- First-line testing for suspected acute intermittent porphyria (with a sensitivity of 95% and specificity of 100%).(31908464)
- Normal levels are <2 mg/L (or <8.8 uM). During an acute attack of porphyria, levels are usually ~20-200 mg/L (or ~80-800 uM).(31908464)
- The test code to order this from Mayo Clinic is: PQNRU / Porphyrins, Quantitative, Random, Urine.
management of an acute attack
- Identify and remove triggers:
- (1) Medications listed above should be discontinued.
- (2) Fasting may exacerbate porphyria. Alternatively, carbohydrate administration may be used as a therapy. For patients unable to take enteral nutrition, IV dextrose is a reasonable consideration (e.g., D10W at ~150 ml/hour, with a goal of providing ~300-500 grams/day of dextrose. (31908464) For intubated patients, high-carbohydrate enteral nutrition should be utilized.
- Intravenous hemin is the key therapy: 💊
- The usual dose is 1-4 mg/kg/day IV, for 3-14 days (a typical dose may be 3 mg/kg/day up to a maximum of 250 mg).(34661997)
- The dose should not exceed 6 mg/kg over a 24 hour period.
- The main risk is phlebitis, which may be avoided via slow administration or infusion through a central line.
- It usually takes ~2-5 days for symptoms to resolve. (31908464)
- Supportive care:
- Muscle weakness may require respiratory support (e.g., noninvasive or invasive mechanical ventilation).
- Sympathetic hyperactivity may require sympatholytic medications.
- Hyponatremia may be managed using usual protocols.
- Seizures may require management. Antiseizure medications must be chosen carefully, as many agents will exacerbate porphyria. Safe antiseizure medications in porphyria include lorazepam, midazolam, propofol, levetiracetam, and lacosamide.(34661997)
basics
- Critical illness polyneuropathy is a length-dependent, symmetric, axonal sensorimotor polyneuropathy.
- Among critically ill patients, this may develop as rapidly as within three days(Torbey, 2019)
clinical findings (Torbey, 2019)
- Generalized weakness, ranging from moderate paresis with hyporeflexia to complete quadriparesis and areflexia.
- Symmetric, distal-to-proximal distribution of weakness.
- Respiratory function is often affected. The initial presentation is often failure to wean from mechanical ventilation.(Wijdicks, 2019)
- Cranial nerves are usually spared.
- Sensory involvement is often subclinical. However, half of patients may have some sensory impairment.
- Deep tendon reflexes may be initially preserved, but ultimately may become reduced or absent.(Wijdicks, 2019)
- Reduced reflexes may suggest a diagnosis of critical illness polyneuropathy rather than critical illness myopathy.
diagnostics
- Nerve conduction studies:
- Axonal polyneuropathy: compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) have reduced amplitudes or are absent.(34618763)
- Normal latencies and conduction velocities should be seen (this isn't a demyelinating process).
- CSF should be normal.
management
- Supportive.
epidemiology
- Critical illness myopathy may occur alone or in combination with critical illness polyneuropathy.
- This is associated with prolonged use of therapeutic paralysis, high-dose steroid, severe pulmonary disease, and sepsis.
clinical findings
- Proximal diffuse muscle weakness, occasionally with facial involvement (but not involving the extraocular muscles).(34618763)
- Sensation is intact.
- Reflexes are relatively preserved.
- There may be muscle wasting and failure to wean from mechanical ventilation.
labs
- Creatinine kinase is usually normal or mildly elevated. Markedly elevated creatinine kinase should raise concern for another process (e.g., rhabdomyolysis, inflammatory myopathy).
electromyography
- Compound motor action potentials (CMAPs) have reduced amplitude and prolonged duration.
- Needle examination reveals fibrillation potentials and small, myopathic motor units.
treatment
- Management is supportive (including avoidance of causative risk factors).
- Critical illness myopathy has a much more favorable prognosis than critical illness polyneuropathy, with patients often completely recovering.(Wijdicks 2019)
basics
- Plasma exchange usually involves the placement of a large-bore hemodialysis catheter. This is followed by exchanging the patient's plasma with either albumin or fresh frozen plasma (usually albumin; fresh frozen plasma may be preferred for patients with coagulopathy).
- Plasma exchange removes a broad range of proteins from the patient's blood. For example, this may be used to rapidly remove auto-antibodies. However, plasma exchange may also remove endogenous anti-inflammatory cytokines as well.
contraindications
- Inability to obtain large-bore vascular access.
- Severe hemodynamic instability (including marked dysautonomia).
- Severe coagulopathy (especially hypofibrinogenemia).
- Refractory hypocalcemia.
- ACE inhibitors may increase the risk of angioedema.
- Pregnancy (relative contraindication) – plasmapheresis causes hormonal shifts that could cause premature labor.(26600443)
potential complications
- Catheter-related complications (e.g., pneumothorax, line infection, hematoma). The catheter often must remain in place for ~10 days, so the risk of line infection can be significant.
- Removal of certain medications that are either highly protein-bound or proteins themselves. This includes: (Albin 2022)
- Apixaban, dalteparin, enoxaparin, heparin, and rivaroxaban.
- IVIG, rituximab, and natalizumab.
- Some antiseizure medications that are protein-bound (probably not removed to a significant degree, but when possible schedule dose administration after a session of plasma exchange).
- Hypocalcemia due to citrate anticoagulant in the extracorporeal circuit.
- Transfusion reaction (if fresh frozen plasma is used for plasma exchange).
- Coagulopathy (exchange removes coagulation factors).
- Immunocompromise (removal of immunoglobulins is a fundamental goal of the therapy, but this may hamper the immune response to some infections).
- Angioedema (exchange can activate the kallikrein-kinin system, resulting in elevated levels of bradykinin that cause angioedema).
basics
- IVIG is composed of pooled immunoglobulin from blood donors. As such it contains a polyspecific mixture of antibodies that react to various common antigenic targets (e.g., common infections).
- The mechanism whereby IVIG exerts acts to suppress autoimmune disorders is unclear. IVIG may alter immunoglobulin metabolism, or compete with other immunoglobulins for binding to Fc-receptors on immune cells.
contraindications
- Refractory volume overload (IVIG involves administration of a large volume of fluid).
- Renal failure.
- History of allergic reaction to IgA.
- Known IgA deficiency:
- There is an increased risk of anaphylaxis among patients with congenital IgA deficiency.
- When possible, it may be desirable to measure IgA levels prior to the administration of IVIG. However, realistically, this rarely occurs within the context of critical care medicine. In emergencies, it is the norm to provide IVIG without checking an IgA level (a test which often takes several days to result).
potential complications
- DIAM (drug induced aseptic meningitis). 📖
- Acute kidney injury.
- Volume overload.
- Infusion-related side effects including fatigue, fever, nausea, headache, flushing (up to 24 hours).
- Allergic reactions (especially among patients with IgA deficiency).
- Thrombotic complications (especially venous thromboembolism).
- Antibody-mediated cytopenias.
dose
- The usual dose is 0.4 grams/kg/day for five days (dosed based on ideal body weight or, in morbid obesity, on adjusted body weight).
The selection of plasma exchange vs. IVIG is a source of perpetual controversy that often varies between centers. Below are some considerations, but this decision is often based on local norms and logistic considerations. 🌊
cost and availability
- IVIG is widely available, whereas plasma exchange is restricted to larger referral centers. Even at large centers, plasma exchange may be unavailable during nights or weekends.
- IVIG is very expensive. Depending on how interventions are priced, plasma exchange may be more cost effective.
disease-specific considerations
- The relative utility may vary between different disease states.
- For Guillain-Barre syndrome, both interventions have the same efficacy.
- For patients in myasthenic crisis:
- Plasma exchange may work a bit faster – so this is often preferred.
- Plasma exchange may be more effective in MuSK+ patients.
individual patient considerations
- Contraindications and complications for both interventions are listed above. Depending on any individual patient's comorbidities, one therapy might be safer than another.
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- Excessive use of frequent pulmonary function tests in patients with neuromuscular weakness.
- Failure to consider neuromuscular weakness as an etiology of dyspnea or failure to wean from mechanical ventilation.
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- 📄 = Link to open-access journal article.
- = Link to supplemental media.
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