Chapter 173: Chronic Neurologic Disorders

Amyotrophic lateral sclerosis (ALS), often called 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 paralysis, 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 is directed at 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.³

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 degeneration 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 dysfunction, is the first symptom in 65% of patients.⁴ Other associated lower motor neuron dysfunctions include atrophy, cramps, fasciculations, dysarthria, dysphagia, and difficulty in mastication. At the time of initial presentation, asymmetric extremity cramping, fatigue, weakness, muscle fasciculations, and atrophy can be seen, especially in the upper extremities.⁵ Facial weakness, dysarthria, tongue weakness, atrophy, and fasciculations can be seen with bulbar lower motor neuron dysfunction. Despite these profound motor findings, sensory and cognitive function is usually spared. Regardless of the initial symptoms, widespread motor and respiratory dysfunction progresses within weeks to months. Significant extremity atrophy occurs, as well as fasciculations, hyperreflexia, foot drop, and claw deformity of the hand. Patients also may develop monotonous speech caused by tongue atrophy, despite the relative sparing of facial and eye movements. Some patients eventually diagnosed as having ALS present initially with cervical or back pain consistent with an acute compressive radiculopathy. Despite successful operative intervention, significant muscle wasting consistent with motor neuron dysfunction develops shortly after the procedure.⁶ Progressive respiratory muscle weakness initially causes exertional dyspnea and eventual dyspnea at rest. Overt dementia and parkinsonism may occur in up to 15% of patients, especially those with ALS. Other cognitive problems, such as apathy, poor attention and motivation, and altered social skills, may be noted.

DIAGNOSIS

The clinical diagnosis of ALS is suggested when there are signs of both upper and lower motor neuron dysfunction, including weakness, muscle atrophy, fasciculations, and hyporeflexia without other CNS dysfunction.⁷ Given the complexity of diagnosing ALS, the median time to diagnosis is 14 months.¹ ALS-like symptoms can be seen with other systemic illnesses, such as diabetes, dysproteinemia, thyroid and parathyroid dysfunction, vitamin B₁₂ deficiency, heavy metal toxicity, and vasculitis, as well as CNS and spinal cord tumors. The diagnosis requires the exclusion of other inflammatory neuropathies, such as myasthenia gravis. Refer patients with signs suggesting ALS to a neurologist for definitive diagnosis. The Amyotrophic Lateral Sclerosis Functional Rating Scale (revised) is reliable for diagnosis of ALS.⁸ Electromyography, nerve conduction velocity studies, spinal fluid analysis, and neuromuscular biopsies are useful diagnostic studies. MRI excludes other disease processes but does not confirm the diagnosis of ALS.⁹

TREATMENT

Therapy is designed to enhance muscle function, especially those that support breathing, swallowing, and speech, in order to avoid malnutrition, recurrent aspiration, or choking. Riluzole, which modulates the excitotoxin glutamate, may prolong survival.^10,11,12,13 It is most useful in patients with a clear diagnosis of ALS whose symptoms have been present for <5 years, with a forced vital capacity >60% of predicted, who do not have a tracheostomy. Guidelines on care and treatment of ALS patients are available.^12,13

Optimizing pulmonary function, including the eventual use of long-term 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 exercise, which may provide an anti-inflammatory effect, a neuroendocrine effect, or beneficial effects on CNS plasticity and myofiber remodeling.¹⁴

DISPOSITION

Typically, patients with ALS will not present to the ED undiagnosed unless there is extremely rapid disease progression or a long period without medical care. Emergency management usually is required for acute respiratory failure, aspiration pneumonia, choking episodes, or trauma related to extremity weakness. Blood gas determination does not reliably predict impending respiratory failure, because mild hypoxia and hypercarbia may exist throughout the disease course. A forced vital capacity <25 mL/kg, or a 50% decrease from predicted normal, increases the risk of aspiration pneumonia and respiratory failure. Provide treatment to improve pulmonary function (e.g., nebulized medications, steroids, antibiotics, assisted ventilation, and intubation). Because the need for long-term ventilatory assistance rarely reverses, 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 impending respiratory failure, pneumonia, the inability to control secretions, or a worsening overall status that requires social service intervention for long-term placement.

Myasthenia gravis is an autoimmune disease characterized by muscle weakness and fatigue, which is seen especially with repetitive use of voluntary muscles. Acetylcholine receptor antibodies impair receptor function at the neuromuscular junction, causing muscle weakness, most often in proximal muscles. This weakness is generally relieved by rest and requires long-term immunotherapy. The diagnosis of cholinergic and myasthenic crises and the aggressive management of respiratory complications associated with a myasthenic crisis are the most important issues for the ED management of myasthenia gravis patients. Occasionally a first diagnosis of myasthenia gravis can be suspected in the ED if increasing muscle weakness is noted during the ED stay or is reported by the patient to occur over the day.

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 receptors, 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 autoantibodies are seen in approximately 80% of patients.¹⁵ These antibodies react with the acetylcholine receptor. Disease severity can be correlated with acetylcholine receptor autoantibody levels. The autoantibodies cause accelerated acetylcholine receptor degradation, dysfunction, and blockade.

Either dysfunction of the thymus gland or an immune response to exogenous infectious antigens causes the pathologic autoimmune response. The thymus is abnormal in most patients with myasthenia gravis, most often as thymic hyperplasia or a thymoma. Thymectomy resolves or improves the symptoms in most patients, especially those with a thymoma. It is likely that the acetylcholine receptor autoantibodies arise after exposure to similar antigens, such as those caused by herpes simplex virus or bacterial infection, causing a pathologic attack on the acetylcholine receptor proteins.

CLINICAL FEATURES

The symptoms of myasthenia gravis can mimic the symptoms seen in many other chronic neurologic disorders, and some call it "the great imitator." Most myasthenia gravis patients have general weakness, especially of the proximal extremity muscle groups, neck extensors, and facial or bulbar muscles. Although ptosis and diplopia are the most common presenting symptoms, limb weakness and oropharyngeal symptoms, such as dysphagia, dysarthria, dysphonia, 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; internuclear or complete ophthalmoplegia; and end-gaze nystagmus.¹⁶ 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. Myasthenia gravis in elderly patients can be misdiagnosed as ischemic stroke, especially when new-onset facial weakness is seen.¹⁷

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 facial muscles or muscles of mastication and swallowing may suggest myasthenia gravis, as well as the observations that the symptoms fluctuate, often worsening as the day progresses, and are alleviated by rest.¹⁸ The differential diagnosis includes congenital myasthenia gravis, Lambert-Eaton syndrome (seen with small-cell lung tumors), drug-induced myasthenia (e.g., penicillamine, procainamide, quinines, aminoglycosides), botulism, thyroid disorders, and other causes of ocular disorders, such as intracranial mass lesions.

The diagnosis is established through the administration of edrophonium chloride (an acetylcholinesterase inhibitor); electromyography, which demonstrates a postsynaptic neuromuscular junctional dysfunction with repetitive nerve stimulation; and serologic testing for acetylcholine receptor antibodies. In the presence of abnormal neuromuscular transmission, edrophonium or neostigmine is expected to improve muscle strength in objectively weak limb, ocular, and pharyngeal muscles. Because these drugs can actually 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. Electromyographic 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.^19,20,21 A favorable response to thymectomy can occur in patients with a thymoma, a limited response to acetylcholinesterase inhibitor therapy, and a short time interval between diagnosis and operative intervention.^22,23 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 mycophenolate²⁴ can supplement chronic oral steroid therapy and lowers the steroid dose.^24,25 Severe symptoms, such as those that would require hospital admission, might require the use of IV immunoglobulin^26,27 or a combination of high-dose steroids and plasma exchange.

Muscle weakness usually does not return to normal even with the use of immunomodulators. Variability in the amount of muscle weakness occurs in response to asthma exacerbations, infections, menstruation, pregnancy, emotional stress, hot weather, and other disorders that alter the response to medication, such as pulmonary, renal, and GI disease.

Many drugs used in the ED affect neuromuscular function—especially common antibiotics (Table 173–1). Make sure that myasthenia gravis patients being treated for other conditions receive their usual dose of cholinergic inhibitors, such as pyridostigmine, while waiting 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 medications 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 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, surgery, 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 decision is made primarily on clinical grounds. Because of the increased sensitivity of myasthenia gravis patients to neuromuscular junction inhibitors and an unpredictable reaction to succinylcholine in particular,²⁸ avoid the administration of depolarizing or nondepolarizing paralytic agents in preparation for intubation. 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 etomidate, fentanyl, or propofol in smaller doses.²⁹ Intubation using deep inhalational anesthetics, including halothane, isoflurane, or sevoflurane, is also a possible strategy. If paralytic agents are absolutely necessary, consider using one-half the dose of these agents, although there are no clinical studies supporting this recommendation.

Up to 15% to 20% of myasthenia gravis patients will undergo a myasthenic crisis requiring acute emergency intervention.³⁰ 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 (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, one that suggests that the symptoms are caused by a myasthenia exacerbation, is characterized by the resolution of muscle weakness within a few minutes. To ensure that the patient does not react adversely to the edrophonium test (as a result of excessive baseline cholinergic effects), administer only 1 milligram by slow IV push initially. The development of muscle fasciculations, respiratory depression, or cholinergic symptoms within a few minutes of this test dose of edrophonium suggests that the baseline muscle weakness 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, up to 10 milligrams of edrophonium can then be given in order to demonstrate benefit in the face of a presumed myasthenic crisis. In other words, if the symptoms improve with the 1-milligram edrophonium test dose, then the testing is considered positive for myasthenic crisis, and additional anticholinergic therapy can be provided to reverse the effects of myasthenia gravis itself. 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 with 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 available in children <75 lb (34 kg), the IM edrophonium test dose is 0.5 to 2.0 milligrams.

If giving edrophonium to patients with cardiac disease, place the patient on a cardiac monitor and pulse oximetry, have the crash cart with atropine available, and have intubation equipment prepared. Edrophonium may cause bradycardia, atrioventricular block, atrial fibrillation, and cardiac arrest. 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 cholinergic crisis who worsen with edrophonium test dose administration may require immediate intubation and management of excessive secretions and acute bronchospasm.

DISPOSITION

When determining final disposition, consider other complications of muscle weakness in patients with myasthenia gravis, such as impaired swallowing, aspiration pneumonia, dehydration, and decubitus ulcers.

PRACTICE GUIDELINES

The American Academy of Neurology provides a guideline on medical treatment of the ocular symptoms involved in myasthenia gravis, as well as a summary of thymectomy indications.³¹ Additionally, the European Federation of Neurological Societies has formulated a versatile therapeutic plan for treatment.³² Cyclosporin and cyclophosphamide significantly improve myasthenia gravis, whereas azathioprine, mycophenolate, and tacrolimus have not been found to provide significant benefit.³³ Corticosteroids are stated to be useful short-term.³⁴

Multiple sclerosis (MS) is a neurologic disorder that causes variable motor, sensory, visual, and cerebellar dysfunction as a result of multifocal areas of CNS myelin destruction. Paresthesias, gait difficulty, extremity weakness, poor coordination, and vision disturbances occur most often 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 and a reduction in overall life expectancy of only 5 to 10 years.³⁵

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 cause of MS is unknown. It is best described as an inflammatory disorder resulting in scattered neuron demyelination. The most frequently postulated theory is a genetic predisposition triggered by a virus (such as herpes or human T-cell leukemia virus type I), heavy metals, or other environmental toxins that induce an immune-mediated neuronal inflammation and demyelinization.³⁶ There is no risk of MS from vaccinations.³⁷ 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

MS is suggested when a young person presents multiple times with neurologic symptoms that suggest different areas of pathology, often with resolution of the earlier symptoms. For most patients, lower extremity symptoms are more severe than upper extremity symptoms. For example, a young person might complain of an inability to walk on a street without tripping over a curb or a sense of clumsiness with physical activity. The physical examination may reveal 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 describe these deficits as a heaviness, weakness, stiffness, or extremity numbness. Lhermitte sign is commonly experienced during the course of MS and is described as an electric shock sensation, a vibration, or a pain radiating down the back and often into the arms or legs resulting from the flexion of the neck. Rarely, patients with established MS may present with acute transverse myelitis, with 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 sign of MS in up to 30% of patients. Vision loss, which occurs over several days and is usually unilateral, often is 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"). The optic disc may be pale. Although ocular pain most often resolves over several days, it may take months for the vision disturbances to resolve. Most patients at some time experience blurred vision, compromised color vision, and/or eye pain due to optic neuritis. Nystagmus, diplopia, and internuclear ophthalmoplegia are 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 suggestive of MS.

Dysautonomias can cause vesicourethral dysfunction, resulting in urinary retention, urgency, frequency, detrusor–external sphincter dyssynergia, 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 disorders, occur in many patients. Cerebral MS, which affects only 5% of MS patients, can cause a severe, disabling decrease in intellect as well as seizures. Overall, the incidence of generalized seizures is the same in patients with MS as in the general population. Simple partial seizures are twice as common in patients with MS than in the general population. Treatment can cause seizures, and the treatment of seizures can worsen symptoms of MS.³⁸

MS symptoms often worsen with increases in body temperature, as occurs with exercise, fever, or even 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

The diagnosis of MS is suggested when a patient has either two or more prolonged or worsening episodes of neurologic dysfunction that suggest distinct white matter pathology or spinal cord dysfunction in two or more distinct locations.³⁹ 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 is associated with peripheral nervous system demyelination. MS progression is often monitored with the Expanded Disability Status Scale and the Multiple Sclerosis Functional Composite scores.⁴⁰

Nearly all patients will demonstrate some nervous system pathology on MRI neuroimaging. T2-weighted scans demonstrate multiple discrete lesions in the supratentorial white matter, homogeneous borders surrounding the ventricles, or infratentorial or spinal cord lesions.⁴¹ 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. Cerebrospinal fluid protein and gamma-globulin concentrations can be elevated. A slight increase in cerebrospinal fluid WBCs (up to 25/mm³) can also be seen, most of which are T lymphocytes.

TREATMENT

Consult a neurologist for diagnosis or treatment. Treatment modalities include mitoxantrone, glucocorticoids, natalizumab, interferon-β, and glatiramer.⁴² Mitoxantrone has been associated with bone marrow and cardiac toxicity.⁴³ High-dose methylprednisolone therapy shortens the duration of exacerbations.^44,45 There is a 1:1000 incidence of progressive multifocal leukoencephalopathy with natalizumab treatment.⁴⁶ 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.⁴⁷

DISPOSITION

Prioritize management at identifying the complications of acute exacerbations, such as respiratory distress, optic neuritis, pulmonary infections, severe constipation, and worsening muscle weakness. 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. Hospitalize for a disease exacerbation or for IV antibiotic or steroid therapy. Admission is also indicated when depression or suicidal ideation require inpatient management.

PRACTICE GUIDELINES

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 disease severity but is associated with adverse effects.⁴⁸ Mitoxantrone has modest beneficial clinical effects that must be balanced against adverse effects.⁴⁹ The presence of MRI-identifiable lesions at the time of symptom onset is associated with later definitive MS diagnosis.⁵⁰ The European Federation of Neurological Societies also provides similar guidelines that address neuroimaging, MS treatment options, and the use of interferon-β antibody levels.^51,52,53,54 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.⁵⁵

2. Azathioprine is a useful alternative to interferon-β in patients who frequently relapse and require steroid therapy.⁵⁶

3. There is no clear benefit to the use of oral or IV steroids in the treatment of optic neuritis in MS patients, although quicker recovery of vision may occur with IV therapy.⁵⁷

4. Cyclophosphamide does not prevent the progression of MS symptoms, and its use is associated with significant adverse effects.⁵⁸

5. Mitoxantrone modestly reduces MS patient disease progression and relapse frequency and should be considered for patients with worsening disability caused by MS.⁵⁹

6. Dietary regimens and vitamin supplementation have yet to demonstrate clinical benefit for MS patients.⁶⁰

7. There are insufficient data to support any specific therapies for the treatment of ataxia and/or tremors that occur in MS patients.⁶¹

Lambert-Eaton myasthenic syndrome is an autoimmune disorder that causes fluctuating weakness and fatigue, especially of the proximal limb muscles. Patients with Lambert-Eaton myasthenic syndrome may show some improvement in strength with sustained or repeated exercise. For example, when the patient is asked to grasp the examiner's hand, the squeeze becomes more forceful over several seconds—this is termed the Lambert sign. Lambert-Eaton myasthenic syndrome is sometimes associated with an antibody attack of P/Q-type voltage-gated calcium channels of axon nerve terminals.^62,63 These channels are integral to the release of acetylcholine during the action potential, and thus any calcium ion flow impairment results in muscle weakness. Lambert-Eaton myasthenic syndrome diagnosed in the absence of these anti-P/Q–type voltage-gated calcium channel antibodies is termed seronegative. It is hypothesized that seronegative Lambert-Eaton myasthenic syndrome is also incited by autoantibodies.⁶⁴ Patients often complain of myalgias, muscle stiffness (especially in the hip and shoulders), paresthesias, metallic tastes, and autonomic symptoms (e.g., dry mouth and impotence) 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.

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 half of patients have concurrent small-cell lung cancer. Diagnosis is confirmed by electromyography. Small-cell lung cancer in Lambert-Eaton myasthenic syndrome patients correlates strongly with more rapid disease progression.⁶⁵ 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 helps to confirm the diagnosis.⁶⁶

TREATMENT

Treatment is mostly supportive. Progression to respiratory or bulbar failure is rare. Neuromuscular transmission can also be enhanced with 3,4-diaminopyridine, which is considered first-line treatment.^67,68 Immunosuppression with corticosteroids, IV immunoglobulin, guanidine, aminopyridines, and azathioprine also can be used to reduce symptom severity.^69,70 Hospital admission is indicated when infectious complications occur or when severe disability requires inpatient immunotherapy.

PRACTICE GUIDELINES

Guidelines suggest that treatment with either 3,4-diaminopyridine or IV immunoglobulin could provide some benefit by improving muscle strength and compound muscle action potential amplitudes.^71,72,73

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, and extracellular pigment granules that stimulate macrophage activity. 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 mnemonic TRAP: resting tremor, cogwheel rigidity, bradykinesia or akinesia, and impairment in posture and equilibrium. Besides these signs, there also may be facial and postural changes, voice and speech abnormalities, depression, and muscle fatigue. Before diagnosis, most patients will have symptoms for months to years, including a general feeling of slowness or stiffness and/or difficulties with handwriting and other skills that require manual dexterity. 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. When patients start to see motor complications, they experience fluctuations and dyskinesia. In late-stage disease, patients experience motor disabilities, freezing of their gait, falls, incontinence, orthostatic hypotension, and dementia.⁷⁴

Patients typically will complain initially of a unilateral resting tremor of the upper extremity. The tremor is a repetitive low-amplitude movement usually involving the fingers and thumb, but also of the legs or face, that occurs five or more times per minute, 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 supported and at rest. Cogwheel rigidity is elicited by causing passive movement of the limb through a full range of motion. As the limb is moved, its muscles develop an increased tone, and a ratchet-like movement is noted. Bradykinesia, the general sense of slowness of voluntary movement, is often felt to be the most debilitating symptom. The most severely affected patients can develop akinesia, the inability to perform the movements necessary for daily living, such as turning over in bed, rising from a seated position, or walking. 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.⁷⁵

DIAGNOSIS

The clinical diagnosis of Parkinson's disease is straightforward, if all of the TRAP symptoms are present. The symptoms of Parkinson's disease also can be seen in postencephalitis patients and those with other infections such as neurosyphilis, subacute spongiform encephalopathy, and acquired immunodeficiency syndrome. Parkinsonism can occur as a result of street drugs, toxins, neuroleptic drugs, hydrocephalus, 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 characteristics of drug-induced parkinsonism include a history of drug ingestion 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.

There is no definitive laboratory or neuroimaging study that is pathognomonic for diagnosis. CT and MRI most often only show CNS atrophy.

TREATMENT

Currently available therapies do not change the underlying pathology but can reduce symptoms. Therapies include anticholinergics, 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 recommended, as newer agents have replaced them.⁷⁶ When symptoms cause severe motor dysfunction, the monoamine oxidase inhibitor selegiline and the catechol methyltransferase inhibitors entacapone and tolcapone may be effective.

Levodopa, which is converted into dopamine by decarboxylases that are present peripherally, can cause symptoms such as anorexia, nausea, and vomiting 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 carbidopa-levodopa therapy. Human aromatic L-amino acid decarboxylase allows for more effective levodopa conversion to dopamine without the adverse effects of high doses of levodopa.⁷⁷ Other dopamine agonists that have been found to be effective as monotherapy included piribedil, pramipexole, ropinirole, rotigotine, and cabergoline.⁷⁸

When drug effectiveness diminishes over time or when significant motor or psychiatric complications occur, a "drug holiday" lasting approximately 1 week is often attempted. Despite the fact that withdrawal of dopaminergic therapy can worsen symptoms, functioning actually can 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.⁷⁹

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.^80,81 Thalamic stimulation or thalamotomy is useful for patients with severe tremor.

SPECIAL CONSIDERATIONS

Although most patients with Parkinson's disease present to the ED already diagnosed, 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 freezing 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 during the "off" periods, when drug efficacy is reduced. 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 hallucinations, 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.

Adjustment of chronic therapies should be done 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.

Poliomyelitis is a neurotropic enterovirus that causes paralysis through motor neuron destruction, muscle denervation, and atrophy. Indigenously acquired wild poliovirus was eradicated from the United States in 1979 and from the Western Hemisphere in 1991. However, the disease is still endemic in India, Pakistan, Afghanistan, and Nigeria.⁸² Postpolio syndrome, also called postpoliomyelitis 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.

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 consistently or adequately immunized. Immunocompromised patients are at greater risk for contracting polio after exposure to children who were vaccinated with the attenuated oral poliovirus vaccine. With the use of attenuated oral poliovirus vaccine, some immunized children will develop polio, as will some young adults who are exposed to children who have been vaccinated with the attenuated oral poliovirus vaccine; immunocompromised patients are at greater risk for this. In developing countries, recent intramuscular injections, tonsillectomy, and strenuous exercise all are associated with increased polio infection severity.

Postpolio syndrome is expected to affect up to 100,000 of the 250,000 U.S. adults with a history of polio. Because most cases of polio occurred before mass immunization, patients diagnosed now with postpolio syndrome most likely will be >50 years old. Disease onset is 20 to 35 years after the initial infection. Although postpolio syndrome most often occurs after a stable, disease-free period of 20 to 30 years, current retrospective reviews claim 35 years.⁸³ There are risk factors that predict an earlier onset of postpolio syndrome. These include advanced age at the time of initial polio infection, greater residual motor disability, residual bulbar or respiratory signs, and the occurrence of recent injuries that require limb immobilization. Postpolio syndrome is a diagnosis of exclusion.⁸⁴

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 postpolio 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 neurologic involvement. Often there is resolution of the minor viral illness symptoms before development of neurologic symptoms, so that it is difficult to identify the preceding minor viral illness. Muscle pain, stiffness, and weakness during the early viral syndrome may be premonitory 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 examination. 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 dysrhythmias, 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 cerebrospinal fluid reveals pleocytosis during the first week after paralysis onset. The cerebrospinal fluid white cell count can elevate into the hundreds, 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 antibody 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 muscle weakness. Acute paralysis can result from peripheral neuropathies caused by infectious mononucleosis, Lyme disease, or porphyria. Paralysis also can result from inflammatory myopathies, electrolyte abnormalities, toxins, or other viruses, such as coxsackieviruses, 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.

Postpolio Syndrome

Patients with postpolio syndrome complain of muscle fatigue, joint pain, worsening of skeletal deformities, or weakness in muscles that were spared during the initial viral infection.⁸⁵ When muscle weakness is observed, atrophy, pain, and fasciculations may be noted both in previously unaffected muscle groups and in those previously involved. Patients may also develop new bulbar, respiratory, or sleep difficulties. For example, laryngeal muscle weakness 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.⁸⁶ These symptoms occur independently of any concurrent neurologic, orthopedic, psychiatric, or systemic medical illness.

To diagnose postpolio 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 postpolio patients is primarily symptomatic, with the use of analgesic and anti-inflammatory medications. Most patients with postpolio syndrome benefit from muscle training⁸⁷ and daily exercise.⁸⁸ An additional therapeutic option is lamotrigine (Lamictal). When used in conjunction with an exercise routine, lamotrigine may improve the quality of life in postpolio patients.⁸⁹

Acknowledgments: The authors would like to thank Edward P. Sloan for his work on previous editions of this chapter.