Weakness (Case 58)
Case: The patient is a 66-year-old retired man presenting with right upper extremity weakness for several days. His daughter brought him to the hospital after finding that he was unable to hold objects in his right hand during her weekly visit with him. His past medical history includes diabetes mellitus and hypertension. A comprehensive history and neurologic exam performed in the ED revealed that the patient awoke with his symptoms 3 days before his daughter’s visit and that his weakness has been constant, with no change in its severity. On exam, he can barely move his right upper extremity against gravity. In addition, he has increased tone and is hyperreflexic in the same extremity. A right-sided Babinski reflex is also present.
Central nervous system
Peripheral nervous system
Guillain-Barré syndrome (GBS)
Multiple sclerosis (MS)
Spinal cord injury
When a patient presents with weakness, you should immediately assess whether the patient has a peripheral (lower motor neuron) or a central (upper motor neuron) nervous system abnormality. While taking the history and performing the neurologic exam, consider whether the dysfunction is in the brain, spinal cord, spinal nerve roots, peripheral nerves, neuromuscular junction, or muscles. A comprehensive history followed by a good neurologic examination should provide the foundation for determining where the abnormality lies. Imaging, laboratory, and electrophysiologic studies are useful diagnostic adjuncts and confirm the anatomic location and etiology of the abnormality. Since treatments for weakness vary widely based on the etiology of the symptoms, accurate diagnosis is critical to providing effective care. Patients with diseases that cause weakness are often significantly disabled. An interdisciplinary team that includes rehabilitation specialists, neurosurgeons, pain specialists, and mental health professionals can be invaluable to the patient’s recovery.
• Categorizing the physical exam findings in a systematic manner allows for an anatomic localization of the disease process. A differential diagnosis can then be generated once the anatomic basis has been established.
• When a patient reports weakness, it can mean a variety of different things. For example, the patient may be feeling general malaise, or he or she may be referring to weakness of specific muscle groups. It is important to identify the location of the weakness, time of onset, duration and severity of the symptoms, and whether the weakness changes over the course of the day.
• Obtaining a history of any associated symptoms, such as any pain or sensory symptoms, is extremely important in narrowing down the differential diagnosis (numbness suggests neuropathy while pain suggests radiculopathy).
• The physical exam should focus on (1) gross observation for any abnormal or involuntary movements; (2) inspection of muscle bulk and tone; (3) palpation and percussion for tenderness and involuntary contractions; (4) muscle strength testing; (5) reflex testing (deep tendon reflexes and extensor plantar [Babinski] reflex); (6) sensory testing (particularly the pattern of deficits and any correlation with the site of weakness); and (7) cranial nerve involvement.
• Inspection of muscle bulk and tone can give clues as to whether the focus is lower motor neuron (atrophy and fasciculations) or upper motor neuron (increased tone, spasticity). Severe atrophy can also give clues to the time course and chronicity of weakness. Strength testing should be done systematically, comparing each major muscle group to the contralateral side. Subtle weakness can be detected with side-to-side comparison of limbs held against gravity (e.g., pronator drift). If indicated, checking the patient for muscle fatigue with simple repetitive exercise (e.g., maintaining abduction of the shoulder against resistance for 1 minute) can help identify neuromuscular junction disease (e.g., myasthenia gravis).
• Reflex testing is essential in differentiating lower motor neuron from upper motor neuron causes of weakness. Patients with upper motor neuron problems usually have hyperreflexia, whereas patients with lower motor neuron causes often have hyporeflexia. As with strength testing, comparison with the contralateral side is often helpful. Additional upper motor neuron findings include a positive Babinski reflex. Lower motor neuron findings are usually confined to atrophy of the weak limb or muscle, with hyporeflexia and possible fasciculations.
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Pathologic changes include areas of necrosis in the brain due to infarction that correlate with specific neurologic deficits. Patients will usually have risk factors for atherosclerosis or embolic disease, such as hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, peripheral artery disease, and/or atrial fibrillation. Smoking and excess alcohol intake, as well as a sedentary lifestyle and obesity, are also risk factors for strokes.
Typical features include an acute onset of focal neurologic deficits, which are usually unilateral. The location of the weakness correlates to the areas of damage caused by the stroke. Patients may have associated symptoms, including unilateral sensory loss, as well as weakness in facial muscles leading to difficulty with speaking or swallowing.
The specific area of ischemia can be identified using CNS imaging modalities, including CT and MRI.
Treatment can be divided into management of acute events and prevention of further events. The thrombolytic agent, t-PA, should be administered to eligible patients who present within 3 hours of symptom onset. Stroke prevention should include antiplatelet agents such as acetylsalicylic acid (aspirin) or clopidogrel (Plavix). Anticoagulants such as warfarin (Coumadin) should be given to patients with risk factors for cardioembolic stroke such as atrial fibrillation. Cholesterol and blood pressure should be optimized with statin medications and antihypertensive agents, respectively. Optimal glucose management is important for diabetics. Patients should be encouraged to lead a healthy lifestyle, including a low-fat, low-cholesterol diet, regular exercise, and smoking cessation. See Cecil Essentials 124.
Transient Ischemic Attack
Because TIAs are reversible events, they cause no permanent pathologic changes. Patients will usually have a past medical history that includes risk factors for atherosclerosis and/or embolic disease.
TIAs are characterized by an acute onset of transient focal neurologic deficits caused by reversible ischemia. By definition, symptoms should last no longer than 24 hours, but typically they last for only a few minutes. TIAs are warning signs of future strokes.
TIA is a clinical diagnosis that includes a history and physical exam consistent with a reversible focal neurologic deficit. CNS imaging studies should not show an acute stroke, as this would indicate infarction rather than a transient event.
Treatment should focus on stroke prevention. This includes encouraging regular exercise and a low-fat, low-cholesterol diet. Medications include antiplatelet agents, as well as agents to optimize blood pressure and to manage cholesterol and glucose levels. See Cecil Essentials 124.
Pathologically, patients with MS have multiple areas of demyelination and inflammation in the CNS that eventually form gliotic scars.
MS is the most common autoimmune inflammatory demyelinating disorder that affects the CNS. The typical age at onset of MS is 20–40 years, but the disease can also present in patients outside these age limits. There is an approximately 2 : 1 female predominance. Weakness can occur in any extremity or part of an extremity, depending on the site of the demyelinating lesion. Symptoms of an acute attack should last >24 hours. Patients often have associated symptoms based on the area of the CNS that is damaged. Since nerve conduction in demyelinated nerves slows down in warmth, patients may complain of worsening neurologic symptoms with increased temperatures, a condition called Uhthoff syndrome.
The diagnosis of MS requires the dissemination of clinical events (and CNS lesions on MRI) that are separated by both time and space. CSF findings include elevated oligoclonal bands, IgG synthesis, and IgG index. In addition, some patients may have mildly elevated CSF protein and WBC counts.
Treatment for MS includes the use of immunomodulatory medications. These disease-modifying medications are chronic treatments that prevent future exacerbations and delay the progression of the disease. They include interferon-β and glatiramer acetate, although immunosuppressive therapies such as mitoxantrone and natalizumab may be used for some refractory or progressive cases. IV methylprednisolone is used to treat acute exacerbations. An interdisciplinary team, including psychiatrists, social workers, physical therapists, and a dedicated nursing staff, is important in the treatment process. See Cecil Essentials 129.
Spinal Cord Injury
Pathologic changes will show the specific etiology of the spinal cord injury, which can include malignancy, osteoarthritis, trauma, infection, hemorrhage, or inflammation.
The site of weakness depends on the location of the spinal cord injury, with cervical spine disease affecting the upper and lower extremities, and thoracic and upper lumbar spine disease affecting the lower extremities. Since the spinal cord ends at L1–L2, lesions lower than this level affect the nerve roots and not the cord itself. Symptoms can have an acute or gradual onset, depending on the etiology of the injury. Patients will often have other associated symptoms, including pain, sensory loss, urinary/fecal incontinence or retention, and insidious gait abnormalities.
Certain aspects of the history can be helpful in determining the etiology of the injury, including a history of cancer, bleeding diathesis, trauma, or osteoarthritis. Diagnostic studies such as CT scans and MRI scans will typically reveal the cause of the injury and should be done urgently when this diagnosis is suspected.
Spinal cord injuries usually require urgent management to avoid irreversible neurologic deficits. Treatment may include surgery to prevent spinal cord compression from tumors, intervertebral disk herniations, abscesses, or hemorrhages. Radiation and/or corticosteroids should be offered to eligible patients with tumors compressing the spinal cord. Pain management is often critical in the care of these patients. Physical therapy should be offered after the acute management of a spinal cord injury to minimize permanent disability. See Cecil Essentials 125.
Peripheral nerve damage can be classified into two broad categories: lesions affecting the axons of the nerve (axonal) and lesions affecting the myelin sheath surrounding the axons (demyelinating). Neuropathies often have features of both types of damage depending on the etiology, but one type of damage typically predominates. The most common cause of diffuse, symmetrical sensory and motor neuropathy is diabetes mellitus. Less common causes include other metabolic, inherited, infective, inflammatory, toxic, and paraneoplastic diseases.
Age at presentation varies depending on etiology. Most patients with diabetic neuropathy present after several years of poor glycemic control. Weakness is typically preceded by several years of sensory abnormalities, including numbness, pain, and paresthesias. The onset is insidious and slowly progressive over years. Symptoms are invariably symmetrical and distal, with a “stocking–glove” distribution affecting the distal limbs and slowly ascending proximally over time. Characteristic weakness may include bilateral foot drop with a “slapping gait” due to limited dorsiflexion of the feet. Absent deep tendon reflexes, particularly distally and in the distribution of symptoms, are also characteristic.
The diagnosis of peripheral neuropathy is often made on clinical grounds as a result of the pathognomonic presentation of slowly progressive, distal, symmetrical ascending sensory and motor abnormalities. Additional testing includes NCSs, which can characterize the distribution of sensory or motor abnormalities, as well as determine whether the pathologic process is axonal or demyelinating. EMG of weak limbs may show evidence of denervation in affected muscles. Additional tests for metabolic or infective diseases may be necessary to determine the underlying etiology for neuropathy. Diabetes should be excluded in all patients presenting with any form of peripheral neuropathy before any other investigations are considered.
Strict glycemic control can help halt or slow the progression of diabetic neuropathy. Treatment is typically focused on the underlying cause of the neuropathy. Additional interventions include symptomatic treatment to alleviate pain and paresthesias with medications or topical ointments. For patients with weakness, braces and orthotics may help prevent development of contractures and provide stability for movement. Patients with diabetic neuropathy should also have routine foot care with regular inspection of the feet for early abrasions or ulcers. See Cecil Essentials 130.
GBS, also known as acute inflammatory demyelinating polyneuropathy (AIDP), is an acute inflammatory process affecting the myelin sheath of peripheral nerves. These inflammatory changes are characterized by degradation of myelin with disruption of Schwann cell basal lamina by macrophages and lymphocytic infiltration of the nerves.
The age at presentation is variable. Symptoms can be preceded by nonspecific upper respiratory infections or gastrointestinal infection with Campylobacter jejuni. Patients typically present with acute onset of ascending paresthesias and weakness that can be initially distal or proximal. Progression varies widely, with most patients reaching a clinical nadir at 2–4 weeks after onset of symptoms. The hallmark of GBS is areflexia or hyporeflexia out of proportion to the degree of weakness. GBS is associated with a 10% mortality rate, and approximately one third of patients require ventilatory support at some point during the illness, making this a neurologic emergency.
LP typically reveals elevated protein with a normal to modestly elevated leukocyte count in the CSF (cytoalbuminologic dissociation). Serum studies may include assays for myelin antibodies known to have an association with GBS, such as antibodies specific to ganglioside subtypes GM1 and GQ1b. NCSs confirm the presence of a demyelinating process affecting sensory and motor nerves.
Management involves close monitoring and supportive care. Serial forced vital capacities (FVCs) should be performed to detect impending respiratory failure. Autonomic instability can also occur, requiring blood pressure and cardiac monitoring. Immunomodulating therapy with IV immunoglobulin and plasmapheresis are equally effective in mitigating progression and should be instituted early in the course of more severe presentations. See Cecil Essentials 130.
Myasthenia gravis is the prototypical neuromuscular junction disease. Autoantibody binding to the acetylcholine receptors (AChRs) lining the muscle postsynaptic membrane causes internalization and degradation of the receptors. Decreased numbers of functional receptors result in decreased capacity for repeated muscle contraction, resulting in muscle fatigue and weakness with exercise.
Acquired myasthenia has a bimodal age at onset, with a predominantly female presentation in the second to third decades and male presentation in the sixth to eighth decades. Symptoms include fluctuating, intermittent weakness with spontaneous improvement, usually worse with repetitive activity and toward the end of the day. Fluctuating diplopia and ptosis are the most common symptoms and can improve after application of an ice pack to the affected eye (ice pack test). Clinical course is variable but is usually progressive without any intervention. Sensory symptoms are absent, and reflexes are typically preserved.
AChR antibodies are found in ~85% of cases. Myasthenic patients lacking AChR antibodies may have circulating antibodies specific to muscle-specific receptor tyrosine kinase (MuSK). RNS studies demonstrate a decremental muscle response to repeated stimulation, correlating with clinical findings of fatigue with exercise. The edrophonium test involves administration of acetylcholinesterase inhibitor (edrophonium chloride) in incremental doses followed by observation of the patient for an abrupt improvement in symptoms. All patients presenting with acquired myasthenia require CT of the chest to exclude the presence of a thymoma (present in 10% to 20% of myasthenic patients).
Pharmacologic treatment includes symptomatic and immunosuppressant medications. Pyridostigmine bromide (Mestinon) is the first-line cholinesterase inhibitor for alleviation of weakness and fatigue. Prednisone is the first choice for immunosuppressant therapy and is indicated when symptoms are not adequately controlled by cholinesterase inhibitors. See Cecil Essentials 132.
Myopathies are a broad group of disorders causing impairment in the function and/or structure of skeletal muscle. Pathophysiology is determined by whether the cause is hereditary (i.e., muscular dystrophy) or acquired (i.e., inflammatory myopathies). Myopathic features on muscle biopsy include possible inflammatory infiltration and/or atrophy in clinically weak muscles.
Age at presentation is variable. Symmetrical proximal weakness without sensory symptoms always warrants investigation for myopathy. The most common myopathic condition encountered in adults is inclusion body myositis (IBM), which is characterized by slowly progressive proximal and distal weakness generally after the age of 50 years. The hallmark of IBM is early weakness and atrophy of the quadriceps, forearms, and ankle dorsiflexors. Polymyositis and dermatomyositis also manifest as symmetrical proximal muscle weakness; cutaneous manifestations of dermatomyositis (i.e., Gottron papules or periorbital heliotrope rash) may precede the onset of muscle disease. Different myopathies preferentially affect different muscle groups, making categorization of the pattern of weakness imperative in diagnosing these conditions.
Serum CK is elevated in most patients with muscle disease. Electrophysiologic studies confirm the clinical diagnosis by revealing myopathic features on needle EMG. Muscle biopsy of a clinically weak muscle can also help confirm the diagnosis. In addition, it can also help pinpoint the etiology of muscle disease by revealing characteristic histologic features. Molecular genetic testing can also be performed if a hereditary condition is suspected (e.g., dystrophin in Duchenne muscular dystrophy).
Management is determined by the cause of the disease. Acquired inflammatory myopathies may respond to immunomodulating therapy such as corticosteroids (prednisone). Immunosuppressive therapy (e.g., methotrexate, azathioprine, or IV immunoglobulin) can be employed as a second-line intervention if the disease is refractory to steroids. IBM responds poorly to immunosuppressive therapy. All patients with muscle disease require physical and occupational therapy to help maintain and build strength. See Cecil Essentials 131.
a. Amyotrophic lateral sclerosis (ALS, Lou Gehrig disease, motor neuron disease): Progressive degeneration of the anterior horn cells causes asymmetric weakness with atrophy and fasciculations in skeletal muscles of the face, pharynx, thorax, and limbs. Lower motor neuron weakness is always coupled with upper motor neuron signs, such as hyperreflexia with Babinski signs. This degenerative disease is associated with very high mortality, and most patients succumb to respiratory compromise due to progressive weakness of the pharynx and loss of airway protection.
b. Neurosarcoidosis: Sarcoidosis is an inflammatory granulomatous disorder that can affect the central and/or peripheral nervous systems. Five percent of patients with sarcoidosis will have a neurologic manifestation of the disease. The most common age at onset is during the fourth or fifth decade of life. Diagnostic aids include MRI, electrophysiology studies, and laboratory studies (including CSF analysis and serum angiotensin-converting enzyme [ACE] levels). Symptomatic muscle, nerve, or brain biopsy can help confirm the diagnosis. Treatment is primarily with steroids and immunosuppression.