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Copyright The McGraw-Hill Companies. All rights reserved. Harrison's Internal Medicine > Chapter 23. Weakness and Paralysis > Weakness and Paralysis: Introduction Normal motor function involves integrated muscle activity that is modulated by t he activity of the cerebral cortex, basal ganglia, cerebellum, and spinal cord. Motor system dysfunction leads to weakness or paralysis, which is discussed in t his chapter, or to ataxia (Chap. 368) or abnormal movements (Chap. 367). The mod e of onset, distribution, and accompaniments of weakness help to suggest its cau se. Weakness is a reduction in the power that can be exerted by one or more muscles. Increased fatigability or limitation in function due to pain or articular stiff ness is often confused with weakness by patients. Increased fatigability is the inability to sustain the performance of an activity that should be normal for a person of the same age, gender, and size. Increased time is sometimes required f or full power to be exerted, and this bradykinesia may be misinterpreted as weak ness. Severe proprioceptive sensory loss may also lead to complaints of weakness because adequate feedback information about the direction and power of movement s is lacking. Finally, apraxia, a disorder of planning and initiating a skilled or learned movement unrelated to a significant motor or sensory deficit (Chap. 2 7), is sometimes mistaken for weakness by inexperienced medical staff. Paralysis indicates weakness that is so severe that the muscle cannot be contrac ted at all, whereas paresis refers to weakness that is mild or moderate. The pre fix "hemi-" refers to one half of the body, "para-" to both legs, and "quadri-" to all four limbs. The suffix "-plegia" signifies severe weakness or paralysis. Weakness or paralysis is typically accompanied by other neurologic abnormalities that help to indicate the site of the responsible lesion. These include changes in tone, muscle bulk, muscle stretch reflexes, and cutaneous reflexes (Table 23 -1). Table 23-1 Signs that Distinguish Origin of Weakness

Sign Upper Motor Neuron Lower Motor Neuron Myopathic Atrophy None Severe Mild Fasciculations None Common None Tone Spastic Decreased Normal/decreased Distribution of weakness Pyramidal/regional Distal/segmental Proximal Tendon reflexes Hyperactive Hypoactive/absent Normal/hypoactive Babinski's sign Present Absent Absent

Tone is the resistance of a muscle to passive stretch. Central nervous system (C NS) abnormalities that cause weakness generally produce spasticity, an increase in tone associated with disease of upper motor neurons. Spasticity is velocity-d

ependent, has a sudden release after reaching a maximum (the "clasp-knife" pheno menon), and predominantly affects the antigravity muscles (i.e., upper-limb flex ors and lower-limb extensors). Spasticity is distinct from rigidity and paratoni a, two other types of hypertonia. Rigidity is increased tone that is present thr oughout the range of motion (a "lead pipe" or "plastic" stiffness) and affects f lexors and extensors equally; it sometimes has a cogwheel quality that is enhanc ed by voluntary movement of the contralateral limb (reinforcement). Rigidity occ urs with certain extrapyramidal disorders such as Parkinson's disease. Paratonia (or gegenhalten) is increased tone that varies irregularly in a manner that may seem related to the degree of relaxation, is present throughout the range of mo tion, and affects flexors and extensors equally; it usually results from disease of the frontal lobes. Weakness with decreased tone (flaccidity) or normal tone occurs with disorders of motor units. A motor unit consists of a single lower mo tor neuron and all of the muscle fibers that it innervates. Muscle bulk is generally unaffected in patients with upper motor neuron lesions, although mild disuse atrophy may eventually occur. By contrast, atrophy is ofte n conspicuous when a lower motor neuron lesion is responsible for weakness and m ay also occur with advanced muscle disease. Muscle stretch (tendon) reflexes are usually increased with upper motor neuron l esions, although they may be decreased or absent for a variable period immediate ly after onset of an acute lesion. This is usually but not invariably accompanied by abnormalities of cutaneous reflexes (such as superficial abdominals; Chap. 361) and, in particular, by an extensor plantar (Babinski) response. The muscle stre tch reflexes are depressed in patients with lower motor neuron lesions when ther e is direct involvement of specific reflex arcs. The stretch reflexes are genera lly preserved in patients with myopathic weakness except in advanced stages, whe n they are sometimes attenuated. In disorders of the neuromuscular junction, the intensity of the reflexes may be affected by preceding voluntary activity of af fected muscles such activity may lead to enhancement of initially depressed reflex es in Lambert-Eaton myasthenic syndrome and, conversely, to depression of initia lly normal reflexes in myasthenia gravis (Chap. 381). The distinction of neuropathic (lower motor neuron) from myopathic weakness is s ometimes difficult clinically, although distal weakness is likely to be neuropat hic and symmetric proximal weakness myopathic. Fasciculations (visible or palpab le twitch within a muscle due to the spontaneous discharge of a motor unit) and early atrophy indicate that weakness is neuropathic. Pathogenesis Upper Motor Neuron Weakness This pattern of weakness results from disorders that affect the upper motor neur ons or their axons in the cerebral cortex, subcortical white matter, internal ca psule, brainstem, or spinal cord (Fig. 23-1). Such lesions produce weakness thro ugh decreased activation of the lower motor neurons. In general, distal muscle g roups are affected more severely than proximal ones, and axial movements are spa red unless the lesion is severe and bilateral. With corticobulbar involvement, w eakness is usually observed only in the lower face and tongue; extraocular, uppe r facial, pharyngeal, and jaw muscles are almost always spared. With bilateral c orticobulbar lesions, pseudobulbar palsy often develops: dysarthria, dysphagia, dysphonia, and emotional lability accompany bilateral facial weakness and a bris k jaw jerk. Spasticity accompanies upper motor neuron weakness but may not be pr esent in the acute phase. Upper motor neuron lesions also affect the ability to perform rapid repetitive movements. Such movements are slow and coarse, but norm al rhythmicity is maintained. Finger-nose-finger and heel-knee-shin maneuvers ar e performed slowly but adequately.

Figure 23-1

The corticospinal and bulbospinal upper motor neuron pathways. Upper motor neuro ns have their cell bodies in layer V of the primary motor cortex (the precentral gyrus, or Brodmann's area 4) and in the premotor and supplemental motor cortex (area 6). The upper motor neurons in the primary motor cortex are somatotopicall y organized as illustrated on the right side of the figure. Axons of the upper motor neurons descend through the subcortical white matter an d the posterior limb of the internal capsule. Axons of the pyramidal or corticos pinal system descend through the brainstem in the cerebral peduncle of the midbr ain, the basis pontis, and the medullary pyramids. At the cervicomedullary junct ion, most pyramidal axons decussate into the contralateral corticospinal tract o f the lateral spinal cord, but 10 30% remain ipsilateral in the anterior spinal co rd. Pyramidal neurons make direct monosynaptic connections with lower motor neur ons. They innervate most densely the lower motor neurons of hand muscles and are involved in the execution of learned, fine movements. Corticobulbar neurons are similar to corticospinal neurons but innervate brainstem motor nuclei. Bulbospinal upper motor neurons influence strength and tone but are not part of the pyramidal system. The descending ventromedial bulbospinal pathways originate in the tectum of the midbrain (tectospinal pathway), the vestibular nuclei (ves tibulospinal pathway), and the reticular formation (reticulospinal pathway). The se pathways influence axial and proximal muscles and are involved in the mainten ance of posture and integrated movements of the limbs and trunk. The descending ventrolateral bulbospinal pathways, which originate predominantly in the red nuc leus (rubrospinal pathway), facilitate distal limb muscles. The bulbospinal syst em is sometimes referred to as the extrapyramidal upper motor neuron system. In all figures, nerve cell bodies and axon terminals are shown, respectively, as cl osed circles and forks.

Lower Motor Neuron Weakness This pattern results from disorders of cell bodies of lower motor neurons in the brainstem motor nuclei and the anterior horn of the spinal cord, or from dysfun ction of the axons of these neurons as they pass to skeletal muscle (Fig. 23-2). Weakness is due to a decrease in the number of muscle fibers that can be activa ted, through a loss of motor neurons or disruption of their connections to musc le. Loss of motor neurons does not cause weakness but decreases tension on the muscle spindles, which decreases muscle tone and attenuates the stretch reflexes elicited on examination. An absent stretch reflex suggests involvement of spind le afferent fibers. Figure 23-2

Lower motor neurons are divided into and types. The larger motor neurons are more numerous and innervate the extrafusal muscle fibers of the motor unit. Loss of motor neurons or disruption of their axons produces lower motor neuron weak ness. The smaller, less numerous motor neurons innervate the intrafusal muscle fibers of the muscle spindle and contribute to normal tone and stretch reflexes. The motor neuron receives direct excitatory input from corticomotoneurons and primary muscle spindle afferents. The and motor neurons also receive excitator

y input from other descending upper motor neuron pathways, segmental sensory inp uts, and interneurons. The motor neurons receive direct inhibition from Renshaw cell interneurons, and other interneurons indirectly inhibit the and motor ne urons. A tendon reflex requires the function of all illustrated structures. A tap on a tendon stretches muscle spindles (which are tonically activated by motor neuron s) and activates the primary spindle afferent neurons. These stimulate the moto r neurons in the spinal cord, producing a brief muscle contraction, which is the familiar tendon reflex.

When a motor unit becomes diseased, especially in anterior horn cell diseases, i t may spontaneously discharge, producing fasciculations that may be seen or felt clinically or recorded by electromyography (EMG). When motor neurons or their axons degenerate, the denervated muscle fibers may also discharge spontaneously. These single muscle fiber discharges, or fibrillation potentials, cannot be see n or felt but can be recorded with EMG. If lower motor neuron weakness is presen t, recruitment of motor units is delayed or reduced, with fewer than normal acti vated at a given discharge frequency. This contrasts with weakness of upper moto r neuron type, in which a normal number of motor units is activated at a given f requency but with a diminished maximal discharge frequency. Myopathic Weakness Myopathic weakness is produced by disorders of the muscle fibers. Disorders of t he neuromuscular junctions also produce weakness, but this is variable in degree and distribution and is influenced by preceding activity of the affected muscle . At a muscle fiber, if the nerve terminal releases a normal number of acetylcho line molecules presynaptically and a sufficient number of postsynaptic acetylcho line receptors are opened, the end plate reaches threshold and thereby generates an action potential that spreads across the muscle fiber membrane and into the transverse tubular system. This electrical excitation activates intracellular ev ents that produce an energy-dependent contraction of the muscle fiber (excitatio n-contraction coupling). Myopathic weakness is produced by a decrease in the number or contractile force of muscle fibers activated within motor units. With muscular dystrophies, inflam matory myopathies, or myopathies with muscle fiber necrosis, the number of muscl e fibers is reduced within many motor units. On EMG, the size of each motor unit action potential is decreased, and motor units must be recruited more rapidly t han normal to produce the desired power. Some myopathies produce weakness throug h loss of contractile force of muscle fibers or through relatively selective inv olvement of the type II (fast) fibers. These may not affect the size of individu al motor unit action potentials and are detected by a discrepancy between the el ectrical activity and force of a muscle. Diseases of the neuromuscular junction, such as myasthenia gravis, produce weakn ess in a similar manner, but the loss of muscle fibers is functional (due to ina bility to activate them) rather than related to muscle fiber loss. The number of muscle fibers that are activated varies over time, depending on the state of re st of the neuromuscular junctions. Thus, fatigable weakness is suggestive of mya sthenia gravis or other disorders of the neuromuscular junction. Hemiparesis Hemiparesis results from an upper motor neuron lesion above the midcervical spin al cord; most such lesions are above the foramen magnum. The presence of other n eurologic deficits helps to localize the lesion. Thus, language disorders, corti

cal sensory disturbances, cognitive abnormalities, disorders of visual-spatial i ntegration, apraxia, or seizures point to a cortical lesion. Homonymous visual f ield defects reflect either a cortical or a subcortical hemispheric lesion. A "p ure motor" hemiparesis of the face, arm, or leg is often due to a small, discret e lesion in the posterior limb of the internal capsule, cerebral peduncle, or up per pons. Some brainstem lesions produce "crossed paralyses," consisting of ipsi lateral cranial nerve signs and contralateral hemiparesis (Chap. 364). The absen ce of cranial nerve signs or facial weakness suggests that a hemiparesis is due to a lesion in the high cervical spinal cord, especially if associated with ipsi lateral loss of proprioception and contralateral loss of pain and temperature se nse (the Brown-Squard syndrome). Acute or episodic hemiparesis usually results from ischemic or hemorrhagic strok e, but may also relate to hemorrhage occurring into brain tumors or as a result of trauma; other causes include a focal structural lesion or inflammatory proces s as in multiple sclerosis, abscess, or sarcoidosis. Evaluation begins immediate ly with a CT scan of the brain (Fig. 23-3) and laboratory studies. If the CT is normal and an ischemic stroke is unlikely, MRI of the brain or cervical spine is performed. Figure 23-3

An algorithm for the initial workup of a patient with weakness. EMG, electromyog raphy; LMN, lower motor neuron; NCS, nerve conduction studies; UMN, upper motor neuron.

Subacute hemiparesis that evolves over days or weeks has an extensive differenti al diagnosis. A common cause is subdural hematoma, especially in elderly or anti coagulated patients, even when there is no history of trauma. Infectious possibi lities include cerebral abscess, fungal granuloma or meningitis, and parasitic i nfection. Weakness from primary and metastatic neoplasms may evolve over days to weeks. AIDS may present with subacute hemiparesis due to toxoplasmosis or prima ry CNS lymphoma. Noninfectious inflammatory processes, such as multiple sclerosi s or, less commonly, sarcoidosis, merit consideration. If the brain MRI is norma l and there are no cortical and hemispheric signs, MRI of the cervical spine sho uld be undertaken. Chronic hemiparesis that evolves over months is usually due to a neoplasm or vas cular malformation, a chronic subdural hematoma, or a degenerative disease. If a n MRI of the brain is normal, the possibility of a foramen magnum or high cervic al spinal cord lesion should be considered. Paraparesis An intraspinal lesion at or below the upper thoracic spinal cord level is most c ommonly responsible, but a paraparesis may also result from lesions at other loc ations that disturb upper motor neurons (especially parasagittal intracranial le sions) and lower motor neurons [anterior horn cell disorders, cauda equina syndr omes due to involvement of nerve roots derived from the lower spinal cord (Chap. 372), and peripheral neuropathies]. Acute paraparesis may not be recognized as due to spinal cord disease at an earl y stage if the legs are flaccid and areflexic. Usually, however, there is sensor y loss in the legs with an upper level on the trunk; a dissociated sensory loss suggestive of a central cord syndrome; or exaggerated stretch reflexes in the le

gs with normal reflexes in the arms. It is important to image the spinal cord (F ig. 23-3). Compressive lesions (particularly epidural tumor, abscess, or hematom a, but also a prolapsed intervertebral disk and vertebral involvement by maligna ncy or infection), spinal cord infarction (proprioception is usually spared), an arteriovenous fistula or other vascular anomaly, and transverse myelitis, are a mong the possible causes (Chap. 372). Diseases of the cerebral hemispheres that produce acute paraparesis include ante rior cerebral artery ischemia (shoulder shrug is also affected), superior sagitt al sinus or cortical venous thrombosis, and acute hydrocephalus. If upper motor neuron signs are associated with drowsiness, confusion, seizures, or other hemis pheric signs, MRI of the brain should be undertaken. Paraparesis may result from a cauda equina syndrome, for example, following trau ma to the low back, a midline disk herniation, or an intraspinal tumor; although sphincters are affected, hip flexion is often spared, as is sensation over the anterolateral thighs. Rarely, paraparesis is caused by a rapidly evolving anteri or horn cell disease (such as poliovirus or West Nile virus infection), peripher al neuropathy (such as Guillain-Barr syndrome; Chap. 380) or myopathy (Chap. 382) . In such cases, electrophysiologic studies are diagnostically helpful and refoc us the subsequent evaluation. Subacute or chronic paraparesis with spasticity is caused by upper motor neuron disease. When there is associated lower-limb sensory loss and sphincter involvem ent, a chronic spinal cord disorder is likely (Chap. 372). If an MRI of the spin al cord is normal, MRI of the brain may be indicated. If hemispheric signs are p resent, a parasagittal meningioma or chronic hydrocephalus is likely and MRI of the brain is the initial test. In the rare situation in which a longstanding par aparesis has a lower motor neuron or myopathic etiology, the localization is usu ally suspected on clinical grounds by the absence of spasticity and confirmed by EMG and nerve conduction tests. Quadriparesis or Generalized Weakness Generalized weakness may be due to disorders of the CNS or of the motor unit. Al though the terms quadriparesis and generalized weakness are often used interchan geably, quadriparesis is commonly used when an upper motor neuron cause is suspe cted, and generalized weakness when a disease of the motor unit is likely. Weakn ess from CNS disorders is usually associated with changes in consciousness or co gnition, with spasticity and brisk stretch reflexes, and with alterations of sen sation. Most neuromuscular causes of generalized weakness are associated with no rmal mental function, hypotonia, and hypoactive muscle stretch reflexes. The maj or causes of intermittent weakness are listed in Table 23-2. A patient with gene ralized fatigability without objective weakness may have the chronic fatigue syn drome (Chap. 384). Table 23-2 Causes of Episodic Generalized Weakness

1. Electrolyte disturbances, e.g., hypokalemia, hyperkalemia, hypercalcemia, hyp ernatremia, hyponatremia, hypophosphatemia, hypermagnesemia 2. Muscle disorders a. Channelopathies (periodic paralyses) b. Metabolic defects of muscle (impaired carbohydrate or fatty acid utilizatio n; abnormal mitochondrial function) 3. Neuromuscular junction disorders a. Myasthenia gravis b. Lambert-Eaton myasthenic syndrome 4. Central nervous system disorders

a. Transient ischemic attacks of the brainstem b. Transient global cerebral ischemia c. Multiple sclerosis

Acute Quadriparesis Acute quadriparesis with onset over minutes may result from disorders of upper m otor neurons (e.g., anoxia, hypotension, brainstem or cervical cord ischemia, tr auma, and systemic metabolic abnormalities) or muscle (electrolyte disturbances, certain inborn errors of muscle energy metabolism, toxins, or periodic paralyse s). Onset over hours to weeks may, in addition to the above, be due to lower mot or neuron disorders. Guillain-Barr syndrome (Chap. 380) is the most common lower motor neuron weakness that progresses over days to 4 weeks; the finding of an el evated protein level in the cerebrospinal fluid is helpful but may be absent ear ly in the course. In obtunded patients, evaluation begins with a CT scan of the brain. If upper mo tor neuron signs are present but the patient is alert, the initial test is usual ly an MRI of the cervical cord. If weakness is lower motor neuron, myopathic, or uncertain in origin, the clinical approach begins with blood studies to determi ne the level of muscle enzymes and electrolytes and an EMG and nerve conduction study. Subacute or Chronic Quadriparesis When quadriparesis due to upper motor neuron disease develops over weeks, months , or years, the distinction between disorders of the cerebral hemispheres, brain stem, and cervical spinal cord is usually possible clinically. An MRI is obtaine d of the clinically suspected site of pathology. EMG and nerve conduction studie s help to distinguish lower motor neuron disease (which usually presents with we akness that is most profound distally) from myopathic weakness, which is typical ly proximal. Monoparesis This is usually due to lower motor neuron disease, with or without associated se nsory involvement. Upper motor neuron weakness occasionally presents as a monopa resis of distal and nonantigravity muscles. Myopathic weakness is rarely limited to one limb. Acute Monoparesis If the weakness is predominantly in distal and nonantigravity muscles and not as sociated with sensory impairment or pain, focal cortical ischemia is likely (Cha p. 364); diagnostic possibilities are similar to those for acute hemiparesis. Se nsory loss and pain usually accompany acute lower motor neuron weakness; the wea kness is commonly localized to a single nerve root or peripheral nerve within th e limb but occasionally reflects plexus involvement. If lower motor neuron weakn ess is suspected, or the pattern of weakness is uncertain, the clinical approach begins with an EMG and nerve conduction study. Subacute or Chronic Monoparesis Weakness and atrophy that develop over weeks or months are usually of lower moto r neuron origin. If they are associated with sensory symptoms, a peripheral caus e (nerve, root, or plexus) is likely; in the absence of such symptoms, anterior horn cell disease should be considered. In either case, an electrodiagnostic stu

dy is indicated. If weakness is of upper motor neuron type, a discrete cortical (precentral gyrus) or cord lesion may be responsible, and an imaging study is pe rformed of the appropriate site. Distal Weakness Involvement of two or more limbs distally suggests lower motor neuron or periphe ral nerve disease. Acute distal lower limb weakness occurs occasionally from an acute toxic polyneuropathy or cauda equina syndrome. Distal symmetric weakness u sually develops over weeks, months, or years and, when associated with numbness, is due to metabolic, toxic, hereditary, degenerative, or inflammatory diseases of peripheral nerves (Chap. 379). Anterior horn cell disease may begin distally but is typically asymmetric and without accompanying numbness (Chap. 369). Rarel y, myopathies present with distal weakness (Chap. 382). Electrodiagnostic studie s help to localize the disorder (Fig. 23-3). Proximal Weakness Myopathy often produces symmetric weakness of the pelvic or shoulder girdle musc les (Chap. 382). Diseases of the neuromuscular junction [such as myasthenia grav is (Chap. 381)], may present with symmetric proximal weakness often associated w ith ptosis, diplopia, or bulbar weakness and fluctuating in severity during the day. Extreme fatigability present in some cases of myasthenia gravis may even su ggest episodic weakness, but strength rarely returns fully to normal. In anterio r horn cell disease proximal weakness is usually asymmetric, but may be symmetri c if familial. Numbness does not occur with any of these diseases. The evaluatio n usually begins with determination of the serum creatine kinase level and elect rophysiologic studies. Weakness in a Restricted Distribution Weakness may not fit any of the above patterns, being limited, for example, to t he extraocular, hemifacial, bulbar, or respiratory muscles. If unilateral, restr icted weakness is usually due to lower motor neuron or peripheral nerve disease, such as in a facial palsy (Chap. 379) or an isolated superior oblique muscle pa resis (Chap. 382). Weakness of part of a limb is usually due to a peripheral ner ve lesion such as carpal tunnel syndrome or another entrapment neuropathy. Relat ively symmetric weakness of extraocular or bulbar muscles is usually due to a my opathy (Chap. 382) or neuromuscular junction disorder (Chap. 381). Bilateral fac ial palsy with areflexia suggests Guillain-Barr syndrome (Chap. 380). Worsening o f relatively symmetric weakness with fatigue is characteristic of neuromuscular junction disorders. Asymmetric bulbar weakness is usually due to motor neuron di sease. Weakness limited to respiratory muscles is uncommon and is usually due to motor neuron disease, myasthenia gravis, or polymyositis/dermatomyositis (Chap. 383). Acknowledgment Richard K. Olney, MD, was the author of this chapter in previous editions, and h is contributions in the last three editions of Harrison's are appreciated.

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