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Weakness presenting to the ICU is either due to an acute/acquired cause or is a complication of chronic weakness, such as acute on chronic respiratory failure. This chapter will focus on the physical exam of a patient with new-onset weakness and summarize chronic neuromuscular diseases that could lead to ICU presentation.
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LOCALIZATION OF WEAKNESS
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Weakness can arise from pathology at any point along the neuroaxis from brain to muscle. It can be a single discrete lesion causing a focal deficit or a generalized process causing more disseminated signs. Physical exam is one of the key tools for localizing the lesion and narrowing the differential diagnosis. Table 45-1 describes the typical exam findings based on a lesion at each level of the neuroaxis and examples of associated disease states. Table 45-2 lists neurologic signs that are characteristic of specific lesions or disease processes.
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Acute weakness can be caused by ischemia/hypoperfusion, inflammation, toxin, or metabolic derangements affecting the neuroaxis. The following are summaries of pathologic conditions, starting at the spinal cord and moving distally, that could lead to ICU presentations of acute weakness. Other chapters in this handbook address brain pathology, including stroke.
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Transverse myelitis (TM)1,2: TM is classically thought to be an immune-mediated demyelinating disorder of the spinal cord. It can be idiopathic or the initial presentation of an underlying demyelinating disorder such as multiple sclerosis, neuromyelitis optica, or a manifestation of another systemic disease such as systemic lupus erythematosus (SLE).
Clinical features: TM affects children less frequently than adults in a bimodal distribution (<5 yr and >10 yr). Two-thirds have a history of infection in the previous month. It can present initially with back pain, followed by symmetric or patchy sensory changes such as paresthesias or numbness, flaccid motor deficits, and bowel/bladder dysfunction such as urinary retention requiring catheterization.
Diagnosis: Refer to Table 45-3
Evaluation: Magnetic resonance imaging (MRI) with and without contrast of entire spine and brain. Obtain cerebrospinal fluid (CSF) for cell count, protein, glucose, IgG index, oligoclonal bands, bacterial/viral culture, and polymerase chain reaction (PCR).
Treatment: Corticosteroids 30 mg/kg/day for 3 to 5 days (max 1000 mg/day). Consider plasma exchange for five to seven sessions. Consider IVIg 2 gm/kg divided over 2 to 5 days.
Prognosis: 50% have full recovery by 2 years, 25% are nonambulatory or require walking aids, 10% to 20% never regain mobility or normal bladder function. High cervical cord lesions and respiratory failure are associated with increased risk for mortality.
Anterior spinal artery infarction3,4: The anterior spinal artery supplies the anterior two-thirds of the spinal cord, which contains the corticospinal (motor) and spinothalamic (pain and temperature sense) tracts. The dorsal columns (proprioception and vibration) are supplied by the posterior spinal arteries. Anterior spinal artery infarction is a rare neurologic emergency in children and can be difficult to differentiate from transverse myelitis. Risk factors/causes include aortic surgery, trauma, umbilical artery catheter, thrombophilia, fibrocartilaginous embolism, cerebellar herniation, CNS vasculitis secondary to infection, lupus, arteriovenous malformation (AVM), and hypotension/cardiac arrest.
Clinical Features: Patients may have preceding back pain at the site of infarction followed by an abrupt onset of bilateral weakness. Classically there is also a loss of pain and temperature sensation while maintaining vibratory and proprioception sensation; however, case series have shown varying degrees of sensory dysfunction, including complete sensory loss. Bowel and bladder function is often affected. Cord infarction due to fibrocartilaginous embolism may differ in time course, causing a more slowly progressive neurologic deterioration over hours to 1 to 2 days.
Diagnosis: MRI of the spinal cord with diffusion-weighted and T2-weighted imaging in axial and sagittal planes.
Treatment: Treat the underlying mechanism for injury. Optimize oxygen and blood supply to the cord with supportive care. Consider anticoagulation and/or aspirin.
Prognosis: The majority of patients will have some degree of motor and bowel/bladder recovery, including a minority with complete recovery.
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Acute flaccid paralysis5–7: Enteroviruses, of which poliomyelitis is the most notorious, can infect the anterior horn motor neurons leading to cell death and subsequent weakness. In some patients, infection is not restricted to the anterior horn and can involve the brainstem causing cranial neuropathies and bulbar weakness. Nonpolio enteroviruses generally have a milder clinical course; however, an entity called acute flaccid myelitis (AFM), first described in 2012–2014, is a syndrome of acute flaccid paralysis with anterior myelitis, which can cause a prolonged polio-like weakness, and was associated with an outbreak of enterovirus D68 infections, although the etiology is still unclear. Arboviruses such as West Nile virus can also cause an asymmetric flaccid paralysis.
Clinical Features: Patients may have a few days of prodromal symptoms such as fever, sore throat, headache, nausea, constipation, and malaise. After resolution of these symptoms, patients can develop a rapidly progressive, flaccid, asymmetric weakness involving the limbs. It is classically proximal, with the legs usually involved in polio and arms with AFM. Cranial nerves and muscles of respiration can also be involved, leading to respiratory failure. Sensation is usually preserved, and patients may experience myalgias and/or arthralgias. Autonomic dysfunction, especially bowel and bladder dysfunction, may be present.
Diagnosis: CSF may show pleocytosis with lymphocytic predominance (PMNs may predominate early on), normal to slightly elevated protein, and normal glucose. Polio can be confirmed by stool or throat culture. Suspected cases of polio should be reported to the state health department. For AFM, MRI of brain and spinal cord shows T2, nonenhancing, confluent, and longitudinally involved lesions of the gray matter of the cord +/− brainstem.
Treatment: Provide supportive care. For AFM, IVIg, plasmapheresis, and corticosteroids have been used. There are no current guidelines for immunomodulatory therapies.
Prognosis: For polio, 50% of patients with paralysis will have some residual deficits. For AFM, most patients will show improvement in strength; but only a minority will have full recovery. Some have ventilator dependence at time of hospital discharge.
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Guillain-Barre syndrome (GBS)8,9: GBS is an acute inflammatory demyelinating polyneuropathy or an acute axonal motor (+/− sensory) neuropathy. Preceding infection, classically Campylobacter jejuni, or immune stimulation, such as vaccines, leads to an autoimmune response by molecular mimicry in a susceptible host.
Clinical Features: Patients may have a respiratory or gastrointestinal illness in the month prior to symptom onset. Ascending, progressive, and generally symmetric flaccid weakness with areflexia then follows. Mild sensory symptoms and pain may be present. Autonomic dysfunction such as cardiac arrhythmias, blood pressure lability, ileus, and urinary retention should be monitored. Weakness can progress to respiratory failure. The Miller-Fisher variant has the triad of ophthalmoplegia, ataxia, and areflexia.
Diagnosis: GBS is a clinical diagnosis. Physical exam should show a progressive, relatively symmetric weakness in upper and lower extremities with areflexia. Nerve conduction studies can be helpful in supporting the diagnosis early in the course as evidenced by prolongation or loss of F-wave responses. It can also help in differentiating between demyelinating and axonal subtypes. MRI of spine may show enhancement of nerve roots. CSF analysis often reveals an albuminocytologic dissociation.
Treatment: IVIg 2 g/kg over 2 to 5 days or plasmapheresis for five cycles over 2 weeks. Provide supportive care, with close monitoring of respiratory function, including negative inspiratory force (NIF) and vital capacity (VC). Consider intubation if NIF > −30 or VC <20 cc/kg. Should also monitor for autonomic dysfunction leading to cardiac rhythm disturbances.
Prognosis: Recovery can take months to years.
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NEUROMUSCULAR JUNCTION (NMJ)
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Myasthenia gravis (MG)10–12: MG is an autoantibody-mediated disorder against acetylcholine receptor (AChR-Ab) and/or muscle-specific tyrosine kinase (anti-MuSK Ab) in most patients. These antibodies lead to direct blocking of acetylcholine at the receptor, receptor degradation, and NMJ membrane damage.
Clinical Features: The characteristic findings are fatigability, ptosis, ophthalmoplegia, and bulbar dysfunction. Weakness of the limbs is proximal and usually does not occur without ocular findings. Some patients may have isolated ocular findings. Myasthenic crisis is a rapid and life-threatening worsening of MG leading to airway compromise from ventilatory or bulbar dysfunction. Exacerbations can be triggered by heat, illness, stress, or medications (e.g. aminoglycosides, fluoroquinolones, neuromuscular blockade, magnesium sulfate, etc.)
Diagnosis: Diagnosis is made by a combination of history, physical exam, decrement on repetitive nerve stimulation, abnormal jitter on single-fiber electromyography, and positive AChR-Ab or anti-MuSK Ab. Absence of autoantibodies does not exclude the diagnosis.
Treatment for myasthenic crisis: Provide respiratory support if needed: noninvasive positive pressure ventilation (NIPPV) vs. endotracheal intubation. Administer IVIg 1 g/kg/day × 2 days OR plasma exchange × five cycles. Consider prednisone/methylprednisolone (1 mg/kg/day, max 100 mg/day), although its use can cause a transient exacerbation of weakness.
Chronic treatment: Titrate pyridostigmine (mestinon) to effect while monitoring for cholinergic side effects. Chronic immunomodulation should be managed by an expert (corticosteroids, azathioprine, cyclosporine, mycophenolate, tacrolimus, rituximab, chronic IVIg, or PLEX)
Prognosis: Variable.
Botulism13: Botulism is caused by a neurotoxin released by Clostridium botulinum that disrupts presynaptic acetylcholine release. In infants, ingested spores from raw honey or environmental dust/soil develop into toxin-secreting bacteria, which leads to disease. Adults require ingestion of preformed toxin from improperly canned foods to cause disease.
Clinical Features: In infants, constipation is followed by symmetric descending weakness with cranial neuropathies such as dilated unreactive pupils and facial weakness. About half will require respiratory support during hospitalization. Adults present similarly with cranial neuropathies and descending symmetric weakness. Either age group may have bradycardia.
Diagnosis: Positive stool botulinum toxin. Repetitive nerve conduction studies can be helpful while waiting for stool studies to result.
Treatment: For infant botulism: BabyBIG (intravenous botulism immunoglobulin). For botulism in patients >1yo: equine serum botulism antitoxin. Provide supportive care, including possible need for mechanical ventilation.
Prognosis: Excellent prognosis for full recovery although it may take weeks to months. The mortality rate for infant botulism is <1% in the United States.
Organophosphate and carbamate intoxication14: Organophosphates and carbamates are acetylcholinesterase inhibitors and are generally used as pesticides. Exposure to these compounds leads to excessive cholinergic stimulation at muscarinic and nicotinic receptors.
Clinical Features: Muscarinic stimulation leads to diarrhea, urination, miosis, bronchorrhea/bronchospasm/bradycardia, emesis, lacrimation, salivation (“DUMBELS”). Nicotinic stimulation leads to fasciculations, muscle weakness, and paralysis, which can cause respiratory arrest. Nicotinic stimulation of sympathetic ganglia can lead to tachycardia and hypertension, making the diagnosis of cholinergic poisoning challenging. CNS effects can lead to anxiety, ataxia, seizures, and coma.
Diagnosis: Diagnosis is made by clinical signs and symptoms.
Treatment: Decontaminate the patient by removing clothing and washing with soap and water. For muscarinic toxicity, atropine 2 to 5 mg IV for adults, 0.05 mg/kg IV for children. The dose should be doubled every 5 minutes until respiratory secretions and bronchoconstriction are alleviated and hemodynamics are acceptable. An atropine continuous infusion then should be initiated at 10% to 20% of the total given dose. For nicotinic toxicity, pralidoxime 1 to 2 G IV for adults, 20 to 50 mg/kg IV for children (max 2 G). Repeat dose at 1 hour, then every 10 to 12 hours until weakness resolves. For seizures, use benzodiazepines.
Prognosis: Variable depending on severity of poisoning.
Tick paralysis15: Female gravid ticks secrete a salivary neurotoxin that can induce paralysis of the host during blood feeding. In North America, Dermacentor andersoni (most common), Dermacentor variabilis, Amblyomma americanum, Amblyomma maculatum, and Ixodes scapularis are the causal ticks.
Clinical Features: After the initial tick bite, which may go unnoticed by the patient, the patient can develop ataxia followed by rapid ascending symmetric weakness with areflexia, progressing to cranial nerve involvement and ultimately respiratory muscle failure.
Diagnosis: Careful inspection to locate the tick on the patient.
Treatment: Remove tick. Provide supportive care.
Prognosis: Improvement in weakness can be observed within hours and full recovery within 1 to 2 days.
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Rhabdomyolysis/myositis16: Muscle injury, ischemia, and/or inflammation leads to necrosis, which results in release of intracellular contents of myocytes into the systemic circulation. It can be triggered by a preceding viral infection, trauma, strenuous exercise, heat stroke, metabolic myopathy, and medications such as statins.
Clinical Features: Myalgias, weakness, and dark urine are classic findings. Complications of rhabdomyolysis are acute kidney injury, electrolyte disturbances, and rarely compartment syndrome.
Diagnosis: Elevated creatine kinase, typically at least five times the upper limit of normal. Urinalysis with positive blood and absence of red blood cells (RBCs), consistent with myoglobinuria.
Treatment: Treat the underlying cause of muscle injury. Supportive care with aggressive intravenous hydration and close monitoring of electrolytes and kidney function. Consider urine alkalinization with a goal urine pH >6.5 for the theoretical benefit of preventing acute kidney injury (AKI) from myoglobin toxicity. Renal replacement therapy may be necessary to treat hyperkalemia, acidosis, fluid overload, and anuria.
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Electrolyte derangements such as hypokalemia/hyperkalemia, hypercalcemia, hypoglycemia, hypermagnesemia, and hypophosphatemia can precipitate weakness. Generally, correction of the derangement will lead to a rapid resolution of weakness.
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Chronic weakness in pediatrics can be caused by congenital/genetic changes leading to disruption of neuromuscular function. Presentation to the ICU is generally a consequence of acute or chronic respiratory failure, cardiomyopathy, or postsurgical management.
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ANTERIOR HORN CELL DISORDER
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Spinal muscular atrophy (SMA)17: SMA is caused by a mutation/deletion of the SMN1 gene (survival motor neuron) and is traditionally inherited in an autosomal-recessive pattern. Loss of SMN1 gene function results in degeneration of alpha motor neurons in the spinal cord and motor nuclei in the brainstem causing a lower motor neuron pattern of weakness. SMA, in order of decreasing weakness/morbidity, is most commonly categorized into type 1 (cannot sit), 2 (sit but cannot walk), and 3 (walk but is weak). SMA0 kids are weak at birth and do not survive into infancy. Pulmonary complications cause significant morbidity and mortality for these patients.
Clinical Features: SMA is characterized by a progressive, symmetric flaccid weakness that is proximal > distal and involves the lower extremities > upper extremities, paradoxical breathing due to weak intercostal muscles with initially preserved diaphragmatic strength, and absence of deep tendon reflexes. Bulbar dysfunction increases the risk for aspiration. Respiratory insufficiency is most pronounced for type 0 to 2 SMA and causes impaired cough and secretion clearance, nocturnal hypoventilation that progresses to continuous hypoventilation, chest wall and lung underdevelopment, and recurrent infections that exacerbate muscle weakness.
Treatment: For respiratory insufficiency: cough assistance, chronic noninvasive positive pressure ventilation, and consideration for tracheostomy, depending on family's goals for care. Involving primary care and palliative care teams early on in the process of respiratory failure helps support the family. For malnutrition/aspiration, consider early gastrostomy placement (no consensus guideline). When placing a G-tube, Nissen fundoplication should be strongly considered. Orthopedic care includes management of scoliosis, hip subluxation, and joint contractures. Nusinersen, an antisense oligonucleotide delivered by intrathecal injection that increases production of full-length SMN protein by the SMN2 gene, was approved by the Food and Drug Administration (FDA) in December 2016 and is available at some institutions.
ICU Considerations: For acute-on-chronic respiratory failure, management should include cough assistance and airway clearance therapies, escalation of NIPPV, and possible intubation, if family goals for care align. Factors to consider for extubation readiness include low secretion burden, lack of atelectasis on chest x-ray, minimal ventilator support, and ability to extubate to NIPPV.
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Duchenne muscular dystrophy (DMD)18,19: DMD is the most common and most severe muscular dystrophy. It is caused by an X-linked recessive mutation in the dystrophin gene. The resultant lack of functional dystrophin protein causes degeneration of striated muscle, elevated creatine kinase levels, progressive weakness, and cardiomyopathy. It overwhelmingly affects males; however, female carriers may also develop weakness and cardiomyopathy.
Clinical Features: Weakness onset is in early childhood with eventual progression to being nonambulatory. It initially involves proximal > distal and lower extremities > upper extremities. Neuromuscular scoliosis often results. Other classic findings are Gower's sign and calf pseudohypertrophy. Respiratory insufficiency is progressive and may begin with sleep-disordered breathing. Symptoms of dilated cardiomyopathy and cardiac conduction defects usually begin in early adolescence. Varying degrees of intellectual disability are present.
Treatment: Chronic corticosteroids have been shown to improve strength and pulmonary function and delay cardiomyopathy.20 Chronic NIPPV can ameliorate sleep-disordered breathing and hypoventilation. Heart failure can be managed with angiotensin-converting enzyme (ACE) medications and/or beta blockers. Arrhythmia management may require antiarrhythmics and possible implantable cardioverter defibrillator (ICD) placement.21 Orthopedics can address scoliosis, contractures, and fractures.
ICU Considerations: Heart failure and respiratory failure are the leading causes of death. DMD-associated dilated cardiomyopathy is a cardiomyopathy out of proportion to weakness and respiratory dysfunction. It increases the risk for ventricular arrhythmias causing sudden death. For treatment of acute on chronic respiratory failure, consider escalation of airway clearance therapies, NIPPV, and possible endotracheal intubation if in line with the patient's goals of care. The following precautions should be observed with anesthesia22: depolarizing muscle relaxants are contraindicated due to risk for rhabdomyolysis, hyperkalemia, and cardiac arrest; and inhalational anesthetics are associated with a risk for malignant hyperthermia.
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CONGENITAL MYOPATHIES
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Congenital myopathies are a clinically heterogeneous group of disorders that cause generalized weakness that result from mutations in multiple genes that code for and support the contractile apparatus of the muscle. These can include actin, tropomyosin, and ryanodine receptors, to name a few. A characteristic phenotype can help with focused genetic testing, or sometimes a muscle biopsy may be done prior to genetic testing to help narrow the differential. Genetic testing can elucidate the specific gene mutation; however, mutations in the same gene can lead to different types of congenital myopathies, and different myopathies can be caused by mutations in overlapping genes. Weakness generally does not progress after the neonatal/infantile period, and some patients may even gain strength and mobility. Patients with severe respiratory failure in the neonatal/infantile period are also at the highest risk for mortality. Multidisciplinary subspecialty care is recommended to manage the pulmonary, nutritional, orthopedic, and neurologic complications of these diseases. Following is a summary of clinical complications of interest to an intensivist that may arise in congenital myopathies.23
Respiratory failure: All patients with congenital myopathy are at risk for respiratory insufficiency. Respiratory failure presenting in the neonatal period is common in X-linked tubular myopathy and severe cases of nemaline myopathy with ACTA1 mutations. Respiratory weakness out of proportion to overall muscle weakness can be seen in multiminicore disease with SEPN1 mutations, nemaline myopathy with NEB or ACTA1 mutations, and selected patients with TPM3 mutation. Patients who did not have respiratory failure during infancy who then develop progressive respiratory failure during adolescence and adulthood generally carry the following mutations: SEPN1, TPM3, ACTA1, NEB, DNM2, MTM1.
The most common phenotype of respiratory insufficiency is sleep disordered breathing. Respiratory failure can also develop from progressive hypoventilation and progressive atelectasis that is not initially clinically apparent, or restrictive lung disease from scoliosis. Decompensations during intercurrent illness may require escalation of cough assistance, airway clearance, and noninvasive positive pressure ventilation, and if unsuccessful, endotracheal intubation if within the patient's goals of care.
Cardiomyopathy: Primary cardiomyopathies are unusual in congenital myopathies. There have been observed cases with actin α1 (ACTA1), dynamin 2 (DNM2), and tropomyosin 2 (TPM2) mutations. Secondary right ventricular dysfunction may be present in patients with significant pulmonary disease.
Orthopedic: Scoliosis can develop in all congenital myopathies, especially when axial weakness is a prominent feature. Scoliosis correction with risk for postoperative respiratory failure may necessitate ICU admission and monitoring.
Anesthesia Risk: As a general rule, inhalational anesthetics and depolarizing muscle relaxants should be avoided in patients with congenital myopathies and are contradindicated in patients with RYR1 mutation due to the risk for malignant hyperthermia.
Bulbar Dysfunction: Bulbar dysfunction is commonly present in nemaline myopathy and can also be seen with recessive mutations in RYR1 causing multiminicore disease and subgroups of centronuclear myopathy. Gastric or jejunal feeding may be required due to poor handling of oral contents and the risk for aspiration. Anticholinergic agents may be trialed to treat sialorrhea while monitoring for the side effects of constipation and creation of thick tenacious secretions.
Cognitive Impairment: Cognitive impairment is unusual in congenital myopathies, unless respiratory failure led to hypoxic-ischemic brain injury. Alternative or additional diagnoses should be explored if this is a prominent feature.
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Weakness is a relatively common clinical entity requiring admission to the intensive care unit. Acute weakness should start with localization of the lesion in order to focus the differential diagnosis and diagnostic evaluation. Patients with chronic weakness are often cared for by intensivists in the setting of respiratory complications of their disease, but may have multiorgan involvement, including cardiac, gastrointestinal, and orthopedic.
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