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CHAPTER 173: Chronic Neurologic Disorders 1165 Chronic Neurologic Disorders Tarina L. Kang Tiffany M. Abramson AMYOTROPHIC LATERAL SCLEROSIS Amyotrophic lateral sclerosis (ALS), often referred to as Lou Gehrig’s disease, causes rapidly progressive muscle atrophy and weakness resulting from the degeneration of both upper and lower motor neurons. ALS leads to varying degrees of spasticity, hyperreflexia, and muscle paraly sis, eventually resulting in pulmonary complications and the need for mechanical ventilatory support. Because there is no cure, clinicians attempt to slow disease progression and preserve function as much as possible. Medical management focuses on preventing pulmonary infections and forestalling terminal respiratory failure.  PATHOPHYSIOLOGY Since 2009, 13 genes and loci have been identified that are associated with the disease. 1 Inclusions in the TAR DNA-binding protein-43 have been found in both ALS and frontotemporal dementia. 2 Environmental exposures are suspected to increase the risk of ALS, but no specific ones have been identified to date. Gross CNS pathology includes frontal cortical atrophy, degeneration of both the corticospinal and spinocerebellar tracts, a reduction in large cervical and lumbar motor neurons, and cranial nerve nuclei degeneration. Both motor and sensory peripheral nerves undergo axonal degen eration and segmental demyelination, including motor end plate and axon terminal involvement.  CLINICAL FEATURES Upper motor neuron demyelination and dysfunction cause limb spasticity, hyperreflexia (including Babinski sign and a brisk jaw-jerk reflex), and emotional lability. Limb weakness, a lower motor neuron dysfunc tion, is the presenting symptom in 65% of patients. 4 Other associated lower motor neuron dysfunctions include atrophy, cramps, fascicula tions, dysarthria, dysphagia, and difficulty in mastication. At the time of initial presentation, asymmetric extremity cramping, fatigue, weakness, and atrophy can be seen, most prominently in the upper extremities. Facial weakness, dysarthria, tongue weakness, and atrophy can be seen with bulbar lower motor neuron dysfunction. Despite these profound motor findings, sensory and cognitive function is usually spared. Sig nificant extremity atrophy occurs, as do fasciculations, hyperreflexia, foot drop, and claw deformity of the hand. Patients also may develop monotonal speech caused by tongue atrophy, despite the relative spar ing of facial and eye movements. Parkinsonian dementia may occur in up to 15% of patients. Other cognitive problems, such as apathy, poor attention, decreased motivation, and altered social skills, can be present. Regardless of the initial symptoms, widespread motor and respiratory dysfunction progress within weeks to months.  DIAGNOSIS Patients with ALS typically present to the ED with their diagnosis firmly established. There are multiple diagnostic criteria of ALS, including El Escorial, Airlie House, and the Awaji-Shima criteria, all of which include upper and lower motor neuron dysfunction in the same anatomic dis tribution. Patients present with rapidly progressing weakness, muscle atrophy, fasciculations, and hyperreflexia but without other CNS dysfunction, such as cerebellar ataxia, autonomic dysfunction, or involuntary movements. 6 Given the variation and complexity of symptoms, diagnosis of ALS can be challenging. The median time to diagno sis is 14 months.

apidly progressing weakness, muscle atrophy, fasciculations, and hyperreflexia but without other CNS dysfunction, such as cerebellar ataxia, autonomic dysfunction, or involuntary movements. 6 Given the variation and complexity of symptoms, diagnosis of ALS can be challenging. The median time to diagno sis is 14 months. 1 ALS-like symptoms can be seen with other systemic illnesses, such as diabetes, dysproteinemia, thyroid and parathyroid dysfunction, vitamin B 12 deficiency, heavy metal toxicity, and vasculitis, as well as CNS and spinal cord tumors. Additional differential diagnoses include other neuropathies, such as myasthenia gravis or compressive radiculopathies. ALS is often diagnosed only after significant muscle wasting that is consistent with motor neuron dysfunction develops. The Amyotrophic Lateral Sclerosis Functional Rating Scale (revised) is a sensitive and reliable tool for diagnosis of ALS. 7 Electromyography, nerve conduction velocity studies, spinal fluid analysis, and neuromus cular biopsies are also useful diagnostic studies. MRI excludes other disease processes but does not confirm the diagnosis of ALS. Definitive diagnosis of ALS should be made by a neurologist.  TREATMENT Emergency management is required for acute respiratory failure, aspiration pneumonia, choking episodes, or trauma related to extremity weakness. Blood gas determination does not reliably pre dict impending respiratory failure because mild hypoxia and hyper carbia may already be present from the course of the disease. A forced vital capacity <25 mL/kg or a 50% decrease from predicted normal increases the risk of aspiration pneumonia and respiratory failure . If the patient presents with respiratory complaints, emergency management should focus on improving pulmonary function (e.g., nebulized medications, steroids, antibiotics, assisted ventilation, and intubation). Therapy is designed to enhance muscle function to avoid malnutri tion, recurrent aspiration, and choking. Riluzole, a preferential tetro dotoxin sodium channel blocker, modulates excitotoxin glutamate and has been shown to prolong time to ventilator dependence and possibly increase survival by 2 to 3 months. 9-11 It is most useful in patients with a clear diagnosis of ALS whose symptoms have been present for <5 years, who have a forced vital capacity >60% of predicted, and who do not have a tracheostomy. Optimizing pulmonary function, including the eventual use of longterm assisted ventilation, is an important part of enhancing the quality of life as diaphragm weakness progresses. 12 Many ALS patients will find some benefit from regular progressive resistance exercises, which may provide an anti-inflammatory effect, a neuroendocrine effect, or ben eficial effects on CNS plasticity and myofiber remodeling, just as they would in healthy patients.  DISPOSITION Because the need for long-term ventilatory assistance is rarely revers ible, establish or confirm the patient’s preference regarding intubation through patient and family conversation, a living will, or power of attorney for health care. Hospital admission is indicated with impend ing respiratory failure, pneumonia, the inability to control secretions, or a worsening overall status that requires social service intervention for long-term placement. MYASTHENIA GRAVIS Myasthenia gravis is an autoimmune disease characterized by muscle weakness and fatigue, made worse after repetitive use of voluntary muscles. Acetylcholine receptor antibodies impair receptor function at the neuromuscular junction, causing muscle weakness, most often in proximal muscles. Weakness is generally reversible in the short term by rest and immunotherapy.

acterized by muscle weakness and fatigue, made worse after repetitive use of voluntary muscles. Acetylcholine receptor antibodies impair receptor function at the neuromuscular junction, causing muscle weakness, most often in proximal muscles. Weakness is generally reversible in the short term by rest and immunotherapy. The early recognition and aggressive management of cholinergic or myasthenic crises in patients with myasthenia gravis are essential to provide optimal care for these patients in the emergency setting.  PATHOPHYSIOLOGY In the normal neuromuscular junction, acetylcholine release by the nerve fiber causes a localized end-plate potential that leads to muscle fiber contraction. In myasthenia gravis, there is a marked decrease in the number and function of the muscle fiber acetylcholine recep tors, despite normal nerve anatomy and function. Failure to respond to acetylcholine stimulation causes decreased muscle fiber potential amplitudes, leading to decreased muscle strength. Acetylcholine receptor CHAPTER Tintinalli_Sec14_p1101-1186.indd 1165 8/2/19 12:09 PM

function of the muscle fiber acetylcholine recep tors, despite normal nerve anatomy and function. Failure to respond to acetylcholine stimulation causes decreased muscle fiber potential amplitudes, leading to decreased muscle strength. Acetylcholine receptor CHAPTER Tintinalli_Sec14_p1101-1186.indd 1165 8/2/19 12:09 PM 1166 SECTION 14: Neurology autoantibodies are seen in approximately 80% of patients. 14 These antibodies react with the acetylcholine receptor. The autoantibodies cause accelerated acetylcholine receptor degradation, dysfunction, and blockade. Disease severity can be correlated with acetylcholine receptor autoantibody levels. It is believed that either the dysfunction of the thymus gland or an immune response to exogenous infectious antigens causes the pathologic autoimmune response in myasthenia gravis. The thymus is abnormal in most patients with myasthenia gravis, presenting as thymic hyperplasia or a thymoma. Thymectomy resolves or improves the symptoms in most patients, especially those with a thymoma. It is also possible that the acetylcholine receptor autoantibodies arise after exposure to viral or bacterial antigens, such as the herpes simplex virus or Epstein-Barr virus, which causes an autoimmune response to acetylcholine receptor proteins.  CLINICAL FEATURES The symptoms of myasthenia gravis can mimic the symptoms seen in many other chronic neurologic disorders; hence, it has been named “the great imitator. ” Most myasthenia gravis patients have generalized weakness that is most pronounced in the extremity muscle groups, neck extensors, and facial and bulbar muscles. Although ptosis and diplopia are the most common presenting symptoms, limb weakness and oropharyngeal symptoms, such as dysphagia, dysarthria, dyspho nia, and dyspnea, can also be seen initially or occur over time. Ocular signs can include Cogan lid twitch (in which the eyes are lowered for 10 to 20 seconds, then droop or twitch when the patient attempts to raise them); ptosis; cranial nerve III, IV , or VI weakness; gaze palsies; inter nuclear or complete ophthalmoplegia; and end-gaze nystagmus. 15 Symptoms can fluctuate throughout the day, usually worsening as the day progresses or with prolonged muscle group use, such as with prolonged reading or prolonged chewing during a meal. Despite the presence of profound muscle weakness, there usually is no deficit in sensory, reflex, or cerebellar functioning. Elderly patients with myasthenia gravis can be misdiagnosed as a having a cerebral vascular accident if new-onset facial weakness or dysarthria is seen. Although weakness is typically focal and mild to moderate in severity, rarely, undiagnosed patients with myasthenia gravis may present with extreme weakness in the muscles of respiration, resulting in respiratory failure. This life-threatening situation, termed myasthenic crisis , can be seen before diagnosis or as a result of inadequate drug therapy or drug tolerance.  DIAGNOSIS Consider the diagnosis of myasthenia gravis in any patient who complains specifically of ocular disturbances or proximal limb muscle weakness not associated with systemic causes of generalized fatigue. Involvement of the ocular, bulbar, and extremity muscle groups may suggest myasthenia gravis, as well as the observations that the symptoms fluctuate, often worsening as the day progresses, and are alleviated by rest. 17 The differential diagnosis includes congenital myasthenia gravis, Lambert-Eaton syndrome (seen with small-cell lung tumors), druginduced myasthenia (e.g., penicillamine, procainamide, quinines, ami noglycosides), botulism, thyroid disorders, and other causes of ocular disorders, such as intracranial mass lesions.

t. 17 The differential diagnosis includes congenital myasthenia gravis, Lambert-Eaton syndrome (seen with small-cell lung tumors), druginduced myasthenia (e.g., penicillamine, procainamide, quinines, ami noglycosides), botulism, thyroid disorders, and other causes of ocular disorders, such as intracranial mass lesions. The diagnosis is established through the administration of edropho nium chloride (an acetylcholinesterase inhibitor); electromyography, which demonstrates a postsynaptic neuromuscular junctional dys function with repetitive nerve stimulation; and serologic testing for acetylcholine receptor antibodies. In the presence of abnormal neuro muscular transmission, edrophonium or neostigmine is expected to improve muscle strength in objectively weak limb, ocular, and pha ryngeal muscles. Because these drugs can cause profound weakness in the presence of other disorders that impair neuromuscular transmission, be prepared to provide ventilatory support or perform endotracheal intubation as a complication of pharmacologic testing. Electromyo graphic testing with repetitive nerve stimulation demonstrates a rapid reduction in the size of the muscle action potential, a finding that correlates with the clinical observation of enhanced weakness with prolonged or repetitive muscle use.  TREATMENT Treatment includes administration of the acetylcholinesterase inhibitors (pyridostigmine or neostigmine), thymectomy, chronic immune suppression with corticosteroids or azathioprine, and acute immune modulation using plasma exchange or IV immunoglobulin when indicated. 18-20 Patients who undergo thymectomy have lower rates of complications due to immunosuppressive medications and decreased distress related to symptoms. 21 Most patients show improvement with oral corticosteroids in the short term, although high-dose steroids sometimes result first in more weakness before improvement. Azathioprine or mycophenolate can supplement chronic oral steroid therapy and lowers the steroid dose. Prednisone with or without azathioprine is the most effective treatment for controlling symptoms and preventing myasthenic crisis. 23,24 Severe symptoms, such as those that would require hospital admission, might require the use of IV immunoglobulin or a combination of high-dose steroids and plasma exchange. 25,26 The severity of muscle weakness can vary in response to physical insults such as asthma exacerbations, infections, menstruation, preg nancy, emotional stress, hot weather, and other disorders that alter the response to medication, such as pulmonary, renal, and GI disease. Even with immunomodulatory treatment, muscle weakness will unlikely resolve completely. Many drugs used in the ED can affect neuromuscular function. Antibiotics worsen muscle weakness and can cause respiratory failure due to fatigue (Table 173-1). Maintain myasthenia gravis patients with their usual dose of cholinergic inhibitors, such as pyridostigmine, while being treated for other conditions in the ED. The suggested pyridostigmine dose is 60 to 90 milligrams PO every 4 hours. If a dose is missed, the next dose is usually doubled. If the patient cannot take oral medi cations or is intubated, administer one-thirtieth of the PO dose (2 to 3 milligrams) of pyridostigmine by slow IV infusion. The usual IV dose for neostigmine is 0.5 milligram.

igmine dose is 60 to 90 milligrams PO every 4 hours. If a dose is missed, the next dose is usually doubled. If the patient cannot take oral medi cations or is intubated, administer one-thirtieth of the PO dose (2 to 3 milligrams) of pyridostigmine by slow IV infusion. The usual IV dose for neostigmine is 0.5 milligram. Consult a neurologist to TABLE 173-1 Drugs to Avoid in Myasthenia Gravis Steroids Adrenocorticotropic hormone,* methylprednisolone,* prednisone* Anticonvulsants Phenytoin, ethosuximide, trimethadione, paraldehyde, magnesium sulfate, barbiturates, lithium Antimalarials Chloroquine, * quinine* IV fluids Sodium lactate solution Antibiotics Aminoglycosides, fluoroquinolones,* neomycin,* streptomycin,* kanamycin,* gentamicin, tobramycin, dihydrostreptomycin,* amikacin, polymyxin A, polymyxin B, sulfonamides, viomycin, colisti methate,* lincomycin, clindamycin, tetracycline, oxytetracycline, rolitetracycline, macrolides, metronidazole Psychotropics Chlorpromazine,* lithium carbonate,* amitriptyline, droperidol, haloperidol, imipramine Antirheumatics d-Penicillamine, colchicine, chloroquine Cardiovascular Quinidine,* procainamide,* β-blockers (propranolol, oxprenolol, practolol, pindolol, sotalol), lidocaine, trimethaphan, magnesium, calcium channel blockers (verapamil) Local anesthetics Lidocaine, * procaine* Analgesics Narcotics (morphine, hydromorphone, codeine, meperidine) Endocrine Thyroid replacement* Eyedrops Timolol,* echothiophate Others Amantadine, diphenhydramine, emetine, diuretics, muscle relaxants, central nervous system depressants, respiratory depressants, sedatives, procaine, * phenothiazines Neuromuscular blocking agents Tubocurarine, pancuronium, rocuronium, gallamine, dimethyl tubocurarine, succinylcholine, decamethonium Note: See also discussion on eMedicine from WebMD by William D. Goldenberg, MD, available at: http://emedicine.medscape.com/article/793136-overview#a1. *Case reports implicate drugs in exacerbations of myasthenia gravis. Tintinalli_Sec14_p1101-1186.indd 1166 8/2/19 12:09 PM

tubocurarine, succinylcholine, decamethonium Note: See also discussion on eMedicine from WebMD by William D. Goldenberg, MD, available at: http://emedicine.medscape.com/article/793136-overview#a1. *Case reports implicate drugs in exacerbations of myasthenia gravis. Tintinalli_Sec14_p1101-1186.indd 1166 8/2/19 12:09 PM CHAPTER 173: Chronic Neurologic Disorders 1167 determine the optimal IV dose, rate of infusion, and timing of repeat pyridostigmine or neostigmine dosing. The most significant ED complication of myasthenia gravis is respiratory failure, which is usually precipitated by infection, sur gery, or the rapid tapering of immunosuppressive drugs. Although intubation should be considered in patients with a low forced vital capacity or in the presence of abnormal blood gas analysis, this deci sion is made primarily on clinical grounds. Patients may have increased sensitivity to nondepolarizing agents based on their concurrent use of acetylcholinesterase inhibitors. Additionally, they can have either resistance or prolonged duration from depolarizing agents. Because of the increased sensitivity of myasthenia gravis patients to neuromuscular junction inhibitors and an unpredictable reaction to succinylcholine in particular, avoid the administration of depolarizing or nondepolar izing paralytic agents in preparation for intubation. 27 Patients with myasthenia are extremely sensitive to these agents, and the paralytic effects can be expected to persist at least two to three times longer than in normal patients. Consider using short-acting agents such as fentanyl or propofol in smaller doses, as it is important to avoid further respira tory depression. Sugammadex may be used to reverse rocuronium if necessary. 28 If paralytic agents are absolutely necessary, consider using one with a shorter half-life, such as etomidate, at one half the dose of these agents, although this recommendation is anecdotal. As many as 20% of myasthenia gravis patients will experience a myasthenic crisis requiring acute emergency intervention. Myasthenic crisis, which occurs either because of disease exacerbation or inadequate drug therapy, must be distinguished from cholinergic crisis, which is caused by excessive cholinergic effects of the drugs used to treat the disease. This differentiation can be made in the ED by the use of edrophonium chloride testing, a test that can also be used to diagnose myasthenia (Table 173-2 and Figure 173-1). Edrophonium is used for this purpose because of its rapid onset (30 seconds) and the short duration of effects (5 to 10 minutes). A positive result is characterized by the resolution of muscle weakness within a few minutes, and thus suggests that the symptoms are caused by a myasthenia exacerbation. The development of muscle fasciculations, respiratory depression, or cholinergic symptoms within a few minutes of administering edrophonium suggests that the baseline muscle weak ness is related to a cholinergic crisis, rather than a myasthenic crisis, and further edrophonium administration is contraindicated. If there is no evidence of adverse cholinergic effects after a small dose (such as 1 milligram IV), up to 10 milligrams of edrophonium can then be given in order to demonstrate benefit in the face of a presumed myasthenic crisis. If edrophonium is being used solely for diagnostic purposes, it is administered in similar aliquots looking for improve ment in ocular symptoms. Neostigmine can then be given IM or SC in 0.5- to 2.0-milligram doses, with clinical effectiveness by 30 minutes and lasting for up to 4 hours. Alternatively, 15-milligram neostigmine tablets can be given PO, each having a clinical effect comparable to that of a 0.5-milligram parenteral neostigmine injection.

symptoms. Neostigmine can then be given IM or SC in 0.5- to 2.0-milligram doses, with clinical effectiveness by 30 minutes and lasting for up to 4 hours. Alternatively, 15-milligram neostigmine tablets can be given PO, each having a clinical effect comparable to that of a 0.5-milligram parenteral neostigmine injection. In children, the total edrophonium IV dose is 0.15 milligram/kg, not to exceed 10 milligrams. To test adverse cholinergic effects with a test dose in children, give an initial IV edrophonium dose one tenth that of the total dose. For children weighing <75 lb (34 kg), a test dose of 1 milligram is appropriate, and a total dose of 5 milligrams can be used in 1-milligram increments. In infants, or when IV access is not avail able in children <75 lb (34 kg), the IM edrophonium test dose is 0.5 to 2.0 milligrams. Edrophonium may cause bradycardia, atrioventricular block, atrial fibrillation, and cardiac arrest. Place all patients receiving edrophonium on a cardiac monitor and pulse oximetry, with special caution in those with a cardiac disease. Place a cardiopulmonary resuscitation cart containing atropine and intubation equipment at the bedside. Although atropine will counteract the muscarinic effects (miosis, lacrimation, salivation, bradycardia) of edrophonium, it will not reverse the nicotinic effects (skeletal muscle paralysis) of a cholinergic crisis. Acute respiratory failure can result from either acute myasthenic crisis or acute cholinergic crisis. Patients with a cholinergic crisis who worsen with edrophonium test dose administration may require immediate intubation and management of excessive secretions and acute bronchospasm.  DISPOSITION Admit patients who demonstrate clinical signs of respiratory compro mise to the intensive care unit setting. When admitting the patient, consider other complications of muscle weakness in patients with myasthenia gravis, such as impaired swallowing, aspiration, dehydration, and decubitus ulcer formation. It is generally accepted in the neurol ogy community that cyclosporine and cyclophosphamide significantly improve myasthenia gravis, whereas azathioprine, mycophenolate, and tacrolimus have not been found to provide significant benefit. 1 milligram Edrophonium slow IV Muscle fasciculations, respiratory depression, or cholinergic symptoms (SLUDGE—salivation, lacrimation, urinary incontinence, diarrhea, GI upset, emesis) miosis, bronchial secretions = CHOLINERGIC CRISIS No further edrophonium Resolution of muscle weakness Within a few minutes = MYASTHENIC CRISIS GIVE IM OR SC NEOSTIGMINE 0.5 MILLIGRAM PO NEOSTIGMINE 15 MILLIGRAMS FIGURE 173-1. Edrophonium test for myasthenic versus cholinergic crisis. TABLE 173-2 Edrophonium Testing in Myasthenia Gravis Myasthenic Crisis Cholinergic Crisis Pathology Undermedication, decrease in acetylcholine receptor causes decreased stimulation by ACh Overmedication, excess anticholinesterase drugs, overstimulation by ACh Finding after edrophonium administration Visible improvement in muscle contractibility, fusion of diplopia, or resolution of ptosis Worsening of symptoms, muscle weakness, and possible respiratory paralysis Implication of edrophonium test finding Patient positive for myasthenia gravis, undermedication of anticholinesterase drugs Overmedication has occurred, possibly due to insufficient effect from anticholinesterase drugs Clinical treatment required based on test results Increase in anticholinesterase drugs, such as pyridostigmine and neostigmine Treat with atropine; if respiratory paralysis occurs, assist with ventilation Abbreviation: ACh = acetylcholine. Tintinalli_Sec14_p1101-1186.indd 1167 8/2/19 12:09 PM

m anticholinesterase drugs Clinical treatment required based on test results Increase in anticholinesterase drugs, such as pyridostigmine and neostigmine Treat with atropine; if respiratory paralysis occurs, assist with ventilation Abbreviation: ACh = acetylcholine. Tintinalli_Sec14_p1101-1186.indd 1167 8/2/19 12:09 PM 1168 SECTION 14: Neurology Corticosteroids are known to be useful short term, and these additional modalities should be considered in an effort to lower the dose. 31 MULTIPLE SCLEROSIS Multiple sclerosis (MS) is a neurologic disorder that causes varying degrees of motor, sensory, visual, and cerebellar dysfunction as a result of multifocal areas of CNS myelin destruction. Paresthesias, gait dif ficulty, extremity weakness, poor coordination, and vision disturbances often occur with a relapsing and remitting clinical course. Despite the lack of a definitive cure, immunosuppression and immunomodulation provide adequate symptomatic relief in the majority of patients, such that most have only mild to moderate lifetime morbidity, resulting in a reduction in overall life expectancy of only 5 to 10 years. Three clinical courses are noted in patients with MS. Up to 90% have a relapsing and remitting course, with relapses lasting weeks to months. The remaining patients have either a relapsing and progressive course or a chronically progressive clinical course, the latter of which is more common with advanced age.  PATHOPHYSIOLOGY The disease process of MS is best described as an inflammatory disorder resulting in scattered neuron demyelination, but the cause is unknown. There is no risk of MS from vaccinations. 33 MS causes a dysfunction in oligodendrocytes such that the axonal myelin sheaths are damaged, slowing nerve impulse conduction. Scattered cerebral and spinal plaques cause gliosis primarily in the white matter, with relative axon sparing. Plaques occur in multiple areas, including the cerebrum, brainstem, spinal cord, and cranial nerves. Lesions in the corticospinal tracts, posterior columns, and spinothalamic tracts will cause upper motor neuron, proprioception/vibration, and pain/temperature dysfunction, respectively. Cranial nerve lesions result in optic neuritis, as well as facial motor and sensory deficits.  CLINICAL FEATURES Suspect multiple sclerosis in a young person who presents with mul tiple episodes of transient neurologic symptoms during which each episode suggests pathology from a different area of the brain. For most patients, lower extremity symptoms are more prominent than upper extremity symptoms. The physical examination may reveal general ized decreased strength, increased tone, hyperreflexia, clonus, a positive Babinski reflex, a decrease in both vibration sense and joint proprioception, and a reduction in pain and temperature sensation. Although sensory and motor deficits are present initially in only one third of patients, all patients will experience these findings at some point during the disease course. Patients may describe these deficits as a heaviness, weakness, stiffness, or extremity numbness. Lhermitte sign is commonly experienced during the course of MS and is defined as an electric shock sensation, vibration, or pain radiating down the back and often into the arms or legs resulting from the flexion of the neck. Rarely, patients with established MS will present with acute transverse myelitis that manifests as complete or near-complete loss of motor function. Cerebellar lesions may cause a kinetic tremor, dysmetria, or truncal ataxia. Vertigo may develop as a result of brainstem lesions. Optic neuritis, which usually causes acute or subacute central vision loss, may be the initial diagnosis of MS in up to 30% of patients.

as complete or near-complete loss of motor function. Cerebellar lesions may cause a kinetic tremor, dysmetria, or truncal ataxia. Vertigo may develop as a result of brainstem lesions. Optic neuritis, which usually causes acute or subacute central vision loss, may be the initial diagnosis of MS in up to 30% of patients. Vision loss, which occurs over several days and is usually unilateral, is often preceded by retrobulbar pain or extraocular muscle pain that may be reproduced with periorbital palpation. Optic neuritis may cause an afferent pupillary defect, or Marcus Gunn pupil. This is found when a light directed into the affected eye causes pupil dilation instead of constriction (see Chapter 241, “Eye Emergencies”). Although ocular pain most often resolves over several days, it may take months for the vision disturbances to resolve. Most patients experience blurred vision, compromised color vision, and/or eye pain due to optic neuritis at some point during the course of the disease. Nystagmus, diplopia, and internuclear ophthalmoplegia are also often seen. Internuclear ophthalmoplegia usually causes abnormal eye adduction bilaterally and horizontal nystagmus. When bilateral internuclear ophthalmoplegia is seen acutely in an otherwise healthy young person, it is highly sugges tive of MS. Dysautonomias can cause vesicourethral dysfunction, resulting in urinary retention, urgency, frequency, detrusor–external sphincter dys synergia, and stress or overflow incontinence. GI dysfunction can cause constipation and fecal incontinence. Sexual dysfunction, especially in males, may be a presenting symptom and correlates with other types of urologic dysfunction. Cognitive and emotional changes, including dementia, decreased motivation, depression, and bipolar mood dis orders, occur in many patients. Cerebral MS, which affects 5% of MS patients, can cause a severe decrease in intellect and seizures. Simple partial seizures are twice as common in patients with MS as in the general population. Of note, the treatment for MS can cause seizures, and antiepileptic drugs used to treat the seizures may further exacerbate MS. MS symptoms can worsen with activities or changes that increase body temperature. Examples include exercise, fever, or hot baths. Visual acuity may worsen with increases in body temperature. Most initial attacks or exacerbations of MS will progress over several days, peak at about 1 week, and resolve over several weeks to months. Complete recovery from an acute exacerbation occurs more commonly early in the course of the disease than it does in later years.  DIAGNOSIS Consider multiple sclerosis when a patient has either two or more episodes of neurologic dysfunction that suggest distinct white matter pathology or spinal cord dysfunction in two or more separate locations. Findings on MRI can aid in the diagnosis to allow for earlier recogni tion and treatment. 35 Optic, cerebrospinal fluid, and neuroimaging findings, as well as typical features such as dysautonomias, all suggest the diagnosis. Symptoms that mimic MS are seen with systemic lupus erythematosus, Lyme disease, neurosyphilis, human immunodeficiency virus disease, and Guillain-Barré syndrome, which are all associated with peripheral nervous system demyelination. MS progression is often monitored with the Expanded Disability Status Scale and the Multiple Sclerosis Functional Composite scores, which are standardized scales used to grade the degree of disability across multiple organ systems to accurately evaluate those affected by the varied clinical expression of multiple sclerosis. 36 These scales are then used to measure progression of disease and guide therapy. Nearly all patients will demonstrate some nervous system pathology on MRI neuroimaging.

the degree of disability across multiple organ systems to accurately evaluate those affected by the varied clinical expression of multiple sclerosis. 36 These scales are then used to measure progression of disease and guide therapy. Nearly all patients will demonstrate some nervous system pathology on MRI neuroimaging. T2-weighted scans demonstrate multiple dis crete lesions in the supratentorial white matter, homogeneous borders surrounding the ventricles, or infratentorial or spinal cord lesions. Although CT is not as sensitive as MRI, it may show cerebral atrophy, ventricular enlargement, and low-density focal lesions in the cerebrum, brainstem, or optic nerves. Lumbar punctures are performed as part of the diagnostic workup. Cerebrospinal fluid protein and gamma-globulin concentrations can be elevated, and a slight increase in the cerebrospinal fluid WBCs (up to 25/mm 3), most of which are T-lymphocytes, can also be seen.  TREATMENT Consult a neurologist for guidance in management options. Treatment modalities include mitoxantrone, glucocorticoids, natalizumab, alemtuzumab, interferon-β, fingolimod, dimethyl fumarate, teriflunomide, and glatiramer. 38 Mitoxantrone has been associated with bone marrow, hepatotoxicity, and cardiac toxicity.39 High-dose methylprednisolone therapy, given either IV or PO, shortens the duration of exacerbations.40,41 There is a 1:1000 incidence of progressive multifocal leukoencephalopathy with natalizumab treatment. 42 IV immunoglobulin is suggested for postpartum exacerbations and for patients with relapsing-remitting disease in whom other therapies such as interferon-β and glatiramer are not tolerated. Tintinalli_Sec14_p1101-1186.indd 1168 8/2/19 12:09 PM

of progressive multifocal leukoencephalopathy with natalizumab treatment. 42 IV immunoglobulin is suggested for postpartum exacerbations and for patients with relapsing-remitting disease in whom other therapies such as interferon-β and glatiramer are not tolerated. Tintinalli_Sec14_p1101-1186.indd 1168 8/2/19 12:09 PM CHAPTER 173: Chronic Neurologic Disorders 1169  DISPOSITION Focus ED management on early diagnosis and treatment of acute exac erbations. Patients with respiratory distress, optic neuritis, pulmonary infections, severe constipation, and worsening muscle weakness should be managed expeditiously due to the propensity of these patients to deteriorate rapidly. Use rapid sequence induction and the Sellick maneuver for endotracheal intubation because of an increased aspiration risk as a consequence of decreased gastric motility. Also, because many patients with MS have labile autonomic nervous system function, be prepared to treat hypotension in the setting of rapid sequence induction, emergency intubation, mechanical ventilation, and surgical anesthesia. Treat seizures with standard anticonvulsant medications and management protocols. Reduce fever to minimize the weakness associated with elevated temperature. Test for urinary tract infections and pyelonephritis, especially in patients with residual urine volumes >100 mL. Obtain a postvoid residual urine volume and a urine culture, and initiate antibiotic therapy whenever there is clinical evidence of a urinary tract infection or significant bacteriuria. When feasible, discharged patients should manage elevated residual urine volumes with intermittent sterile catheterization as opposed to chronic placement of a urinary drainage catheter. Admit for a disease exacerbation or for IV antibiotic or steroid therapy. The American Academy of Neurology has published guidelines describing the use of MRI in MS diagnosis, treatment with natalizumab and mitoxantrone, and the utility of the measurement of interferon-β antibody levels. These guidelines conclude the following: The use of natalizumab reduces clinical features such as relapse rate and dis ease severity but is associated with adverse effects. 44 Mitoxantrone has modest beneficial clinical effects that must be balanced against adverse effects. 45 The presence of MRI-identifiable lesions at the time of symptom onset is associated with later definitive MS diagnosis. 44 The Cochrane Collaboration has published reviews outlining the use of amantadine, azathioprine, corticosteroids, cyclophosphamide, mitoxantrone, and dietary interventions, as well as the treatment of ataxia. These reviews conclude the following: 1. The use of amantadine to reduce fatigue in MS patients is not substantiated. 2. Azathioprine is a useful alternative to interferon-β in patients who frequently relapse and require steroid therapy. 3. There is no clear benefit to the use of PO or IV steroids in the treat ment of optic neuritis in MS patients, although quicker recovery of vision may occur with IV therapy. 4. Cyclophosphamide does not prevent the progression of MS symp toms, and its use is associated with significant adverse effects. 49 5. Mitoxantrone modestly reduces MS patient disease progression and relapse frequency and should be considered for patients with worsening disability caused by MS. 6. Dietary regimens and vitamin supplementation have yet to demon strate clinical benefit for MS patients.51 7. There are insufficient data to support any specific therapies for the treatment of ataxia and/or tremors that occur in MS patients.

nd should be considered for patients with worsening disability caused by MS. 6. Dietary regimens and vitamin supplementation have yet to demon strate clinical benefit for MS patients.51 7. There are insufficient data to support any specific therapies for the treatment of ataxia and/or tremors that occur in MS patients. LAMBERT-EATON MYASTHENIC SYNDROME Lambert-Eaton myasthenic syndrome is an autoimmune disorder that causes fluctuating weakness and fatigue, most notably in the proximal limb muscles, that improves with sustained or repeated exercise (in contrast to myasthenia gravis where repeated exercise causes worsening fatigue). Lambert-Eaton myasthenic syndrome is predominantly a disease associated with older men with a history of cigarette smoking and lung cancer. The syndrome can precede detection of malignancy by several years. Approximately 40% to 62% of patients with Lambert- Eaton myasthenic syndrome are found to have concurrent small-cell lung cancer. 53 Diagnosis is confirmed by electromyography. Small-cell lung cancer correlates strongly with more rapid disease progression. Electromyography is abnormal as a result of diseased calcium channels at the cholinergic nerve terminals. Reduced compound muscle action potentials that increase by >100% following maximal voluntary action on electrophysiologic testing help to confirm the diagnosis. The etiology of Lambert-Eaton myasthenic syndrome is likely from an autoimmune response of P/Q-type voltage-gated calcium channels on axon nerve terminals. 55,56 These channels are integral to the release of acetylcholine during the action potential. If there is any impairment in the calcium ion flow, it results in muscle weakness. In seronegative Lambert-Eaton myasthenic syndrome, there is an absence of the anti- P/Q–type voltage-gated calcium channel antibodies. It is hypothesized that seronegative Lambert-Eaton myasthenic syndrome is also incited by autoantibodies. 57 Patients often complain of myalgias, muscle stiff ness (especially in the hip and shoulders), paresthesias, metallic taste in their mouth, and autonomic symptoms (e.g., dry mouth and impo tence) caused by muscarinic cholinergic insufficiency. Although eye movements are unaffected, pupillary reflexes can be abnormal. Motor reflexes may be diminished. The sensory examination can be normal, but because the disease is associated with malignancy, paraneoplastic or chemotherapy-induced neuropathy can lead to a superimposed sensory deficit.  TREATMENT Treatment is supportive. Progression to respiratory or bulbar failure is rare. Neuromuscular transmission can also be enhanced by a neuromuscular transmission enhancer, 3,4-diaminopyridine, which is considered first-line treatment. 58,59 Immunosuppression with corticosteroids, IV immunoglobulin, guanidine, aminopyridines, and azathioprine also can be used to reduce symptom severity. 60,61 Hospital admission is indicated when infectious complications occur or when severe disability requires inpatient immunotherapy. PARKINSON’S DISEASE Parkinson’s disease is an extrapyramidal movement disorder characterized by a resting tremor, cogwheel rigidity, bradykinesias or akinesias, and impaired postural reflexes. The disease is associated with a reduced number of functional dopaminergic receptors in the substantia nigra. Drug therapy is designed to enhance central dopaminergic activity, thus decreasing the relative excess in central cholinergic activity. Even though multiple drug and surgical therapies can be used to minimize symptoms, the disease still progresses without symptom remission in most patients.  PATHOPHYSIOLOGY Parkinson’s disease is characterized by the presence of cellular cytoplasmic inclusions, termed Lewy bodies .

ess in central cholinergic activity. Even though multiple drug and surgical therapies can be used to minimize symptoms, the disease still progresses without symptom remission in most patients.  PATHOPHYSIOLOGY Parkinson’s disease is characterized by the presence of cellular cytoplasmic inclusions, termed Lewy bodies . In the pigmented areas of the midbrain, especially the substantia nigra, there is depigmentation, dopaminergic neuron loss, and gliosis. These cellular changes result in the loss of functional dopaminergic receptors, causing a decrease in the overall level of striatal dopamine.  CLINICAL FEATURES The clinical diagnosis of Parkinson’s disease is based on the presence of one or more of four hallmark neurologic signs identified in the mne monic TRAP: resting tremor , cogwheel rigidity, bradykinesia or akinesia, and impairment in posture and equilibrium. Patients may also present with facial and postural changes, voice and speech abnormali ties, depression, and muscle fatigue. Initial symptoms can be insidious with vague symptoms such as a feeling of slow, stiff, or decreased manual dexterity progressing over months to years. Due to this slow disease progression with nonspecific symptoms, diagnosis is often delayed. The first stage of the disease is the premotor phase that includes reduced olfaction and constipation. This is followed by the motor phase, which responds to l-dopa in the honeymoon phase of the disease. In late-stage disease, patients experience motor disabilities, freezing of their gait, falls, incontinence, orthostatic hypotension, and dementia. Tintinalli_Sec14_p1101-1186.indd 1169 8/2/19 12:09 PM

and constipation. This is followed by the motor phase, which responds to l-dopa in the honeymoon phase of the disease. In late-stage disease, patients experience motor disabilities, freezing of their gait, falls, incontinence, orthostatic hypotension, and dementia. Tintinalli_Sec14_p1101-1186.indd 1169 8/2/19 12:09 PM 1170 SECTION 14: Neurology Early in the disease, patients can present with a unilateral resting tremor of the upper extremity. The tremor is a repetitive, low-amplitude movement that involves the fingers and thumb, but can also affect the legs or face, that occurs five or more times per minute. This repetitive movement is described as “pill rolling. ” Tremors can dissipate when intentional movement is performed, which differentiates it from the kinetic tremor of other neurologic disorders. For example, on physical examination, the resting tremor of Parkinson’s disease will become less prominent as the patient performs the finger-to-nose test, and tremor resumes once this purposeful movement is ended and the limb is at rest and supported. Cogwheel rigidity, a common feature in Parkinson’s disease, is rigidity and tremor that causes jerky resistance to passive movements. Bradykinesia, the general sense of slowness of voluntary movement, is often felt to be the most debilitating symptom. In severe cases of Parkinson’s disease, patients may develop marked akinesia that limits their ability to perform activities of daily living, such as turning in bed, rising from a seated position, or ambulating. When the disorder impairs postural reflexes, patients may have an impaired ability to turn or change direction while walking or may lose their balance and fall. Patients are also commonly affected by impulse control disorders.  DIAGNOSIS The clinical diagnosis of Parkinson’s disease follows an algorithm based on the TRAP symptoms. There is no definitive laboratory or neuroimaging study that is pathognomonic for diagnosis. CT and MRI most often only show CNS atrophy. While the diagnosis of Parkinson’s disease is based on recognition of the TRAP symptoms and response to dopami nergic therapy, there is a broader group of neurologic disorders that fall under parkinsonism. Parkinsonism is characterized by tremors, rigidity, and bradykinesia and is often associated with other disorders such as postencephalitis, neurosyphilis, subacute spongiform encephalopathy, and acquired immunodeficiency syndrome. Parkinsonism can also occur as a result of street drugs, toxins, neuroleptic drugs, hydrocepha lus, head trauma, and more rare and complex neurologic disorders. In drug-induced Parkinson’s disease, akinesia is the most common sign, with resting tremor less commonly observed. Other character istics of drug-induced parkinsonism include a history of drug inges tion known to interfere with central dopamine activity, short interval between symptom onset and maximal disability, bilateral presentation of motor dysfunction, and the presence of other drug-related motor abnormalities. In cases of parkinsonism, there is no specific treatment. By treating the underlying disorder and removing any offending agents, the process can sometimes be halted or occasionally reversed.  TREATMENT The goal of all currently available therapies is symptom reduction. Therapies include anticholinergic agonists, such as trihexyphenidyl and benztropine; drugs that increase central dopamine levels, such as amantadine, levodopa, and carbidopa; and dopamine receptor agonists, such as bromocriptine and pergolide. Ergot agonists are no longer recom mended, as newer agents have replaced them. 64 When symptoms cause severe motor dysfunction, the monoamine oxidase inhibitor selegiline and the catechol methyltransferase inhibitors entacapone and tolcapone may be effective.

mine receptor agonists, such as bromocriptine and pergolide. Ergot agonists are no longer recom mended, as newer agents have replaced them. 64 When symptoms cause severe motor dysfunction, the monoamine oxidase inhibitor selegiline and the catechol methyltransferase inhibitors entacapone and tolcapone may be effective. Levodopa, an amino acid precursor to neurotransmitters including dopamine, can cause symptoms such as anorexia, nausea, and vomit ing due to increases in peripheral dopamine levels. When levodopa is combined with carbidopa, a peripheral decarboxylase inhibitor, smaller doses of levodopa are required for effectiveness, reducing side effects. Over time, the effectiveness of levodopa will diminish, requiring the additional use of dopamine receptor agonist therapy. Individuals who are fully mobile, in the “on” state, can suddenly convert to the “off ” state and become akinetic, especially in the morning shortly after rising and before taking the initial daily dose. This “on-off ” phenomenon is treated by the use of controlled-release preparations of the combined carbidopalevodopa therapy. Human aromatic l-amino acid decarboxylase allows for more effective levodopa conversion to dopamine without the adverse effects of high doses of levodopa. 65 Other dopamine agonists that have been found to be effective as monotherapy included piribedil, pramipexole, ropinirole, rotigotine, and cabergoline.66 When drug effectiveness diminishes over time or when significant motor or psychiatric complications occur, a “drug holiday” lasting approximately 1 week can be attempted. Despite the fact that with drawal of dopaminergic therapy can worsen symptoms, functioning may improve once therapy is resumed, with improvement lasting weeks to months. Deep brain stimulation can treat advanced disease with motor disabilities and can improve quality of life. The treatment for drug-induced parkinsonism is termination of the causative agents. Patients who are refractory to optimal drug therapy for all types of Parkinson’s disease may benefit from pallidotomy, a stereotactic neurosurgical procedure that enhances medical therapy effectiveness and reduces dyskinesia severity. 68,69 Thalamic stimulation or thalamotomy is useful for patients with severe tremor.  SPECIAL CONSIDERATIONS Although most patients with Parkinson’s disease present to the ED with an established diagnosis, some might present undiagnosed with motor or sensory symptoms that may not be attributed immediately to the disorder. Patients may experience motor symptoms such as freez ing episodes, dysphagia, or abnormalities of whole-body movement. Sensory complaints may include akathisias, paresthesias, muscles aches, or extremity pain. Although severe pain is usually related to the loss of medication efficacy, it can be a prominent symptom of undiagnosed Parkinson’s disease. Complications related to motor, gait, and truncal disabilities include deep venous thrombosis, pulmonary embolism, aspiration pneumonia, compressive neuropathies, and trauma from frequent falls. Autonomic disturbances, such as orthostatic hypotension, intestinal motility disorders, and bladder dysfunction, can occur, as well as facial seborrhea. Behavior abnormalities caused by frontal lobe dysfunction and dementia also are seen. Dyspnea, respiratory distress, and pneumonia are more likely dur ing the “off ” periods, when drug efficacy is reduced. Adjust chronic therapies in consultation with the patient’s primary care physician or neurologist, who can often help to determine which symptoms reflect dopaminergic excess and whether prior drug holidays have improved the patient’s symptoms. The most common cause of death in severe Parkinson’s disease is respiratory failure.

hronic therapies in consultation with the patient’s primary care physician or neurologist, who can often help to determine which symptoms reflect dopaminergic excess and whether prior drug holidays have improved the patient’s symptoms. The most common cause of death in severe Parkinson’s disease is respiratory failure. Dopaminergic therapy toxicities can include cardiac dysrhythmias, orthostatic hypotension, dyskinesias, and dystonias. Psychiatric and sleep disturbances, including nightmares, auditory and visual hal lucinations, paranoia, and psychosis, are related to the treatment dose and duration and can be improved by a reduction in dosage or a drug holiday. Depression and panic attacks are common and can occur in patients independent of dopaminergic therapy. Psychotropics (such as haloperidol) that can cause tardive dyskinesia must be used carefully, if at all, in patients with Parkinson’s disease. In the ED setting, continue a patient’s Parkinson’s medication and consult with a pharmacist if they are unable to take medications by mouth. There have been cases of patients developing life-threatening parkinsonism-hyperpyrexia syndrome in the setting of abrupt with drawal of dopamine and amantadine. 70 This syndrome is similar to neuroleptic malignant syndrome (NMS) with hyperthermia, rigidity, dysautonomia, and altered mental status. POLIOMYELITIS AND POST-POLIO SYNDROME Poliomyelitis is a neurotropic enterovirus that causes paralysis through motor neuron destruction, muscle denervation, and atrophy. Indig enously acquired wild poliovirus was eradicated from the United States in 1979 and from the Western Hemisphere in 1991. While 80% of the world’s population lives in polio-free areas, the disease is still endemic in Pakistan, Afghanistan, and Nigeria. Mass immunization with the inactivated poliovirus vaccine or attenuated oral poliovirus vaccine has dramatically reduced the incidence of polio, but polio outbreaks still occur in populations that are not consis tently or adequately immunized. Immunocompromised patients are at greater risk for contracting polio, most often after exposure to children Tintinalli_Sec14_p1101-1186.indd 1170 8/2/19 12:09 PM

us vaccine has dramatically reduced the incidence of polio, but polio outbreaks still occur in populations that are not consis tently or adequately immunized. Immunocompromised patients are at greater risk for contracting polio, most often after exposure to children Tintinalli_Sec14_p1101-1186.indd 1170 8/2/19 12:09 PM CHAPTER 173: Chronic Neurologic Disorders 1171 who were vaccinated with the attenuated oral poliovirus vaccine. With the use of attenuated oral poliovirus vaccine, there is a one in 1.4 to 2.8 million risk of developing polio, with a higher rate in immunocom promised recipients. Additionally, one in 6.7 million people who are exposed to children who have been vaccinated with the attenuated oral poliovirus vaccine may develop polio as well. In developing countries, recent intramuscular injections, tonsillectomy, and strenuous exercise are associated with increased polio infection severity. Post-polio syndrome is expected to affect up to 100,000 of the 250,000 U.S. adults with a history of polio. Post-polio syndrome, also called post-poliomyelitis progressive muscular atrophy, is an important sequela of acute poliomyelitis. This disorder is characterized by the recurrence of motor symptoms, following a latent period of several decades, after the resolution of the motor symptoms caused by the initial infection. Because most cases of polio occurred before mass immunization, patients diagnosed now with post-polio syndrome most likely will be >50 years old. Disease onset is 20 to 35 years after the initial infection. Although post-polio syndrome most often occurs after a stable, diseasefree period of at least 15 years by definition, 71 there are risk factors that predict an earlier onset of post-polio syndrome. These include advanced age at the time of initial polio infection, greater residual motor disabil ity, residual bulbar or respiratory signs, and the occurrence of recent injuries that require limb immobilization. Post-polio syndrome is a diagnosis of exclusion.  PATHOPHYSIOLOGY In developed countries, the viral transmission of polio is oral to oral, whereas in developing countries, where the sanitation is poor, the transmission is fecal to oral. Acutely, the polio enterovirus enters the body through the GI tract and reproduces in the GI lymphoid tissue, termed gut-associated lymphoid tissue. Oral secretion of the virus takes place for several days, whereas stool excretion can last for several weeks. At a critical concentration, the virus spreads to the large motor nuclei of the spinal cord, the brainstem, and the reticular formation. The vestibular and brainstem motor nuclei, hypothalamus, thalamus, cerebellum, and precentral motor cerebral cortex also can be infected by the poliovirus. There is loss of infected neurons. Neuron loss then causes a cycle of muscle denervation and reinnervation, resulting in loss of muscle function. The cause of the post-polio syndrome is unknown. The motor neuron degeneration is thought to be a result of dysfunction in the individual nerve axons in surviving motor neurons.  CLINICAL FEATURES Acute Poliomyelitis Polio infection is asymptomatic in >90% of cases. The majority of symptomatic polio infections involve only a minor viral illness that causes no paralysis, termed abortive polio. After an incubation period of a few days, symptoms may include fever, malaise, headache, sore throat, and GI symptoms. Some of the patients who experience the minor viral illness, especially young children, may develop aseptic meningitis as the infection resolves. Only 1% to 2% of all poliovirus infections result in the major illness associated with neu rologic involvement.

nclude fever, malaise, headache, sore throat, and GI symptoms. Some of the patients who experience the minor viral illness, especially young children, may develop aseptic meningitis as the infection resolves. Only 1% to 2% of all poliovirus infections result in the major illness associated with neu rologic involvement. Often there is resolution of the minor viral illness symptoms before development of neurologic symptoms, making it dif ficult to identify the preceding minor viral illness. Muscle pain, stiffness, and weakness during the early viral syndrome may be predictive of later paralysis. When the major illness occurs, most commonly the spinal cord anterior horn cells are affected, causing asymmetric proximal limb weakness, especially in the lower extremities. Flaccid and weak muscles, absent tendon reflexes, and fasciculations characterize spinal polio. Although polio patients note pain, paresthesias, and transient sensory abnormalities, sensory deficits are usually not found on clinical exami nation. Maximal paralysis usually occurs within 5 days, and muscle wasting then occurs over several weeks. Autonomic dysfunction, including sweating disturbances, urine retention, delayed gastric emptying, and constipation, is commonly found. Most spinal polio patients will demonstrate improved motor function, with resolution of the paralysis occurring within the first year after the acute infection. Up to 20% of polio patients with paralysis will develop bulbar polio, which can cause speech, swallowing, facial muscle, and extraocular muscle dysfunction. Acute polio infection also can cause encephalitis and can disturb the reticular formation, resulting in cardiac dysrhyth mias, blood pressure alterations, hypoxia, and hypercarbia. Patients who survive the acute episode of encephalitis normally recover without residual effects. Consider acute paralytic poliomyelitis whenever an at-risk patient develops an acute febrile illness, aseptic meningitis, and asymmetric flaccid paralysis associated with the loss of deep tendon reflexes and normal sensation. As with other causes of aseptic meningitis, the cere brospinal fluid reveals pleocytosis during the first week after paralysis onset. The cerebrospinal fluid WBC count can elevate into the hun dreds, with a predominance of neutrophils early in the disease course. Although the poliovirus can be cultured from the cerebrospinal fluid early in the disease course, throat and rectal swabs provide a greater yield. When a particular viral serotype is identified, serial serum anti body titers can be used to verify the cultures. The most important cause of paralysis on the differential diagnosis that must be considered and excluded is Guillain-Barré syndrome, which, unlike the acute polio infection, causes more symmetric mus cle weakness. Acute paralysis can result from peripheral neuropathies caused by infectious mononucleosis, Lyme disease, or porphyria. Paralysis also can result from inflammatory myopathies, electrolyte abnor malities, toxins, or other viruses, such as coxsackie viruses, mumps, echoviruses, and nonpolio enteroviruses. Paralysis also can result from acute spinal cord compression, vascular lesions, and transverse myelitis, all of which should produce a sensory level and sphincter disturbances. In children, it is necessary to exclude spinal muscular atrophy, which can be undiagnosed until it is manifested by dramatic limb weakness caused by an acute febrile illness. Post-Polio Syndrome Patients with post-polio syndrome complain of muscle fatigue, joint pain, worsening of skeletal deformities, or weakness in muscles that were spared during the initial viral infection.

ophy, which can be undiagnosed until it is manifested by dramatic limb weakness caused by an acute febrile illness. Post-Polio Syndrome Patients with post-polio syndrome complain of muscle fatigue, joint pain, worsening of skeletal deformities, or weakness in muscles that were spared during the initial viral infection. When muscle weakness is observed, atrophy, pain, paresthesias, and fasciculations may be noted both in previously unaffected muscle groups and in those previously involved. 73 Patients may also develop new bulbar, respiratory, or sleep difficulties. For example, laryngeal muscle weak ness can cause progressive dyspnea, dysphagia, and/or hoarseness. Some patients complain of abnormal movements in sleep that disturb normal sleep, requiring therapy with benzodiazepines or dopaminergic drugs. These symptoms occur independently of any concurrent neurologic, orthopedic, psychiatric, or systemic medical illness. To diagnose post-polio syndrome, the patient should have a history of acute paralytic poliomyelitis with stable recovery of motor function associated with residual muscle atrophy, weakness, and areflexia with normal sensation in at least one limb. Additionally, there should be new muscle symptoms or weakness not attributable to an acute injury, neuropathy, radiculopathy, or systemic, neurologic, or psychiatric illness. Treatment of the new muscle weakness seen with post-polio patients is primarily symptomatic, with the use of analgesic and anti-inflammatory medications. Most patients with post-polio syndrome benefit from muscle training 75 and daily exercise. 76 An additional therapeutic option is lamotrigine (Lamictal  ). When used in conjunction with an exer cise routine, lamotrigine may improve the quality of life in post-polio patients by reducing pain and fatigue. Acknowledgments: The authors would like to thank Daniel A. Handel and Sarah Andrus Gaines for their work on previous editions of this chapter. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec14_p1101-1186.indd 1171 8/2/19 12:09 PM