Michael J. Aminoff
Normal motor function involves integrated muscle activity that is modulated by the activity of the cerebral cortex, basal ganglia, cerebellum, and spinal cord. Motor system dysfunction leads to weakness or paralysis, which is discussed in this chapter, or to ataxia (Chap. 31) or abnormal movements (Chap. 30). The mode of onset, distribution, and accompaniments of weakness help suggest its cause.
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 stiffness often is 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, sex, and size. Increased time is required sometimes for full power to be exerted, and this brady-kinesia may be misinterpreted as weakness. Severe proprioceptive sensory loss also may lead to complaints of weakness because adequate feedback information about the direction and power of movements is lacking. Finally, apraxia, a disorder of planning and initiating a skilled or learned movement unrelated to a significant motor or sensory deficit (Chap. 18), sometimes is mistaken for weakness.
Paralysis indicates weakness that is so severe that a muscle cannot be contracted at all, whereas paresis refers to weakness that is mild or moderate. The prefix “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.
The distribution of weakness helps to indicate the site of the underlying lesion. Weakness from involvement of upper motor neurons occurs particularly in the extensors and abductors of the upper limb and the flexors of the lower limb. Lower motor neuron weakness does not have this selectivity but depends on whether involvement is at the level of the anterior horn cells, nerve root, limb plexus, or peripheral nerve—only muscles supplied by the affected structure are weak. Myopathic weakness is generally most marked in proximal muscles, whereas weakness from impaired neuromuscular transmission has no specific pattern of involvement. Weakness often is accompanied by other neurologic abnormalities that help indicate the site of the responsible lesion. These abnormalities include changes in tone, muscle bulk, muscle stretch reflexes, and cutaneous reflexes (Table 12-1).
SIGNS THAT DISTINGUISH THE ORIGIN OF WEAKNESS
Tone is the resistance of a muscle to passive stretch. Central nervous system (CNS) abnormalities that cause weakness generally produce spasticity, an increase in tone associated with disease of upper motor neurons. Spasticity is velocity-dependent, has a sudden release after reaching a maximum (the “clasp-knife” phenomenon), and predominantly affects the antigravity muscles (i.e., upper-limb flexors and lower-limb extensors). Spasticity is distinct from rigidity and paratonia, two other types of hypertonia. Rigidity is increased tone that is present throughout the range of motion (a “lead pipe” or “plastic” stiffness) and affects flexors and extensors equally; it sometimes has a cogwheel quality that is enhanced by voluntary movement of the contralateral limb (reinforcement). Rigidity occurs 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 motion, 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 motor neuron and all the muscle fibers that it innervates.
Muscle bulk generally is not affected in patients with upper motor neuron lesions, although mild disuse atrophy eventually may occur. By contrast, atrophy is often conspicuous when a lower motor neuron lesion is responsible for weakness and also may occur with advanced muscle disease.
Muscle stretch (tendon) reflexes are usually increased with upper motor neuron lesions, although they may be decreased or absent for a variable period immediately after onset of an acute lesion. This is usually—but not invariably—accompanied by abnormalities of cutaneous reflexes (such as superficial abdominals; Chap. 1) and, in particular, by an extensor plantar (Babinski) response. The muscle stretch reflexes are depressed in patients with lower motor neuron lesions when there is direct involvement of specific reflex arcs. The stretch reflexes generally are preserved in patients with myopathic weakness except in advanced stages, when they sometimes are attenuated. In disorders of the neuromuscular junction, the intensity of the reflex responses may be affected by preceding voluntary activity of affected muscles; that activity may lead to enhancement of initially depressed reflexes in Lambert-Eaton myasthenic syndrome and, conversely, to depression of initially normal reflexes in myasthenia gravis (Chap. 47).
The distinction of neuropathic (lower motor neuron) from myopathic weakness is sometimes difficult clinically, although distal weakness is likely to be neuropathic, and symmetric proximal weakness myopathic. Fasciculations(visible or palpable twitch within a muscle due to the spontaneous discharge of a motor unit) and early atrophy indicate that weakness is neuropathic.
Upper motor neuron weakness
This pattern of weakness results from disorders that affect the upper motor neurons or their axons in the cerebral cortex, subcortical white matter, internal capsule, brainstem, or spinal cord (Fig. 12-1). These lesions produce weakness through decreased activation of the lower motor neurons. In general, distal muscle groups are affected more severely than are proximal ones, and axial movements are spared unless the lesion is severe and bilateral. With corticobulbar involvement, weakness usually is observed only in the lower face and tongue; extraocular, upper facial, pharyngeal, and jaw muscles almost always are spared. With bilateral corticobulbar lesions, pseudobulbar palsyoften develops: dysarthria, dysphagia, dysphonia, and emotional lability accompany bilateral facial weakness and a brisk jaw jerk. Spasticity accompanies upper motor neuron weakness but may not be present in the acute phase. Upper motor neuron lesions also affect the ability to perform rapid repetitive movements. Such movements are slow and coarse, but normal rhythmicity is maintained. Finger-nose-finger and heel-knee-shin maneuvers are performed slowly but adequately.
The corticospinal and bulbospinal upper motor neuron pathways. Upper motor neurons 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 somatotopically organized, as illustrated on the right side of the figure.
Axons of the upper motor neurons descend through the subcortical white matter and the posterior limb of the internal capsule. Axons of the pyramidal or corticospinal system descend through the brainstem in the cerebral peduncle of the midbrain, the basis pontis, and the medullary pyramids. At the cervicomedullary junction, most pyramidal axons decussate into the contralateral corticospinal tract of the lateral spinal cord, but 10–30% remain ipsilateral in the anterior spinal cord. Pyramidal neurons make direct monosynaptic connections with lower motor neurons. 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 (vestibulospinal pathway), and the reticular formation (reticulospinal pathway). These pathways influence axial and proximal muscles and are involved in the maintenance of posture and integrated movements of the limbs and trunk. The descending ventrolateral bulbospinal pathways, which originate predominantly in the red nucleus (rubrospinal pathway), facilitate distal limb muscles. The bulbospinal system sometimes is referred to as the extrapyramidal upper motor neuron system. In all figures, nerve cell bodies and axon terminals are shown, respectively, as closed 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 dysfunction of the axons of these neurons as they pass to skeletal muscle (Fig. 12-2). Weakness is due to a decrease in the number of muscle fibers that can be activated through a loss of α motor neurons or disruption of their connections to muscle. Loss of γ 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 spindle afferent fibers.
Lower motor neurons are divided into α and γ types. The larger α motor neurons are more numerous and innervate the extrafusal muscle fibers of the motor unit. Loss of α motor neurons or disruption of their axons produces lower motor neuron weakness. The smaller, less numerous γ motor neurons innervate the intrafusal muscle fibers of the muscle spindle and contribute to normal tone and stretch reflexes. The α motor neuron receives direct excitatory input from corticomotoneurons and primary muscle spindle afferents. The α and γ motor neurons also receive excitatory input from other descending upper motor neuron pathways, segmental sensory inputs, and interneurons. The α motor neurons receive direct inhibition from Renshaw cell interneurons, and other interneurons indirectly inhibit the α and γ motor neurons.
A tendon reflex requires the function of all the illustrated structures. A tap on a tendon stretches muscle spindles (which are tonically activated by γ motor neurons) and activates the primary spindle afferent neurons. These neurons stimulate the α motor 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, it may discharge spontaneously, producing fasciculations that may be seen or felt clinically or recorded by electromyography (EMG). When α motor neurons or their axons degenerate, the denervated muscle fibers also may discharge spontaneously. These single muscle fiber discharges, or fibrillation potentials, cannot be seen or felt but can be recorded with EMG. If lower motor neuron weakness is present, recruitment of motor units is delayed or reduced, with fewer than normal activated at a particular discharge frequency. This contrasts with weakness of the upper motor neuron type, in which a normal number of motor units is activated at a given frequency but with a diminished maximal discharge frequency.
Myopathic weakness is produced by disorders of the muscle fibers. Disorders of the 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 acetylcholine molecules presynaptically and a sufficient number of postsynaptic acetylcholine 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 events that produce an energy-dependent contraction of the muscle fiber (excitation-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, inflammatory myopathies, or myopathies with muscle fiber necrosis, the number of muscle 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 than normal to produce the desired power. Some myopathies produce weakness through loss of contractile force of muscle fibers or through relatively selective involvement of type II (fast) fibers. These myopathies may not affect the size of individual motor unit action potentials and are detected by a discrepancy between the electrical activity and force of a muscle.
Diseases of the neuromuscular junction, such as myasthenia gravis, produce weakness in a similar manner, but the loss of muscle fibers is functional (due to inability 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 rest of the neuromuscular junctions. Thus, fatigable weakness is suggestive of myasthenia gravis or other disorders of the neuromuscular junction.
Hemiparesis results from an upper motor neuron lesion above the midcervical spinal cord; most such lesions are above the foramen magnum. The presence of other neurologic deficits helps localize the lesion. Thus, language disorders, cortical sensory disturbances, cognitive abnormalities, disorders of visual-spatial integration, apraxia, or seizures point to a cortical lesion. Homonymous visual field defects reflect either a cortical or a subcortical hemispheric lesion. A “pure motor” hemiparesis of the face, arm, and leg often is due to a small, discrete lesion in the posterior limb of the internal capsule, cerebral peduncle, or upper pons. Some brainstem lesions produce “crossed paralyses,” consisting of ipsi-lateral cranial nerve signs and contralateral hemiparesis (Chap. 27). The absence of cranial nerve signs or facial weakness suggests that a hemiparesis is due to a lesion in the high cervical spinal cord, especially if it is associated with ipsilateral loss of proprioception and contralateral loss of pain and temperature sense (the Brown-Séquard syndrome).
Acute or episodic hemiparesis usually results from ischemic or hemorrhagic stroke but also may relate to hemorrhage occurring into brain tumors or may be a result of trauma; other causes include a focal structural lesion or an inflammatory process as in multiple sclerosis, abscess, or sarcoidosis. Evaluation (Fig. 12-3) begins immediately with a CT scan of the brain and laboratory studies. If the CT is normal and an ischemic stroke is unlikely, MRI of the brain or cervical spine is performed.
An algorithm for the initial workup of a patient with weakness. CT, computed tomography; EMG, electromyography; LMN, lower motor neuron; MRI, magnetic resonance imaging; NCS, nerve conduction studies; UMN, upper motor neuron.
Subacute hemiparesis that evolves over days or weeks has an extensive differential diagnosis. A common cause is subdural hematoma, especially in elderly or anticoagulated patients, even when there is no history of trauma. Infectious possibilities include cerebral abscess, fungal granuloma or meningitis, and parasitic infection. Weakness from primary and metastatic neoplasms may evolve over days to weeks. AIDS may present with subacute hemiparesis due to toxoplasmosis or primary CNS lymphoma. Noninfectious inflammatory processes such as multiple sclerosis or, less commonly, sarcoidosis merit consideration. If the brain MRI is normal and there are no cortical and hemispheric signs, MRI of the cervical spine should be undertaken.
Chronic hemiparesis that evolves over months usually is due to a neoplasm or vascular malformation, a chronic subdural hematoma, or a degenerative disease. If an MRI of the brain is normal, the possibility of a foramen magnum or high cervical spinal cord lesion should be considered.
An intraspinal lesion at or below the upper thoracic spinal cord level is most commonly responsible, but a paraparesis also may result from lesions at other locations that disturb upper motor neurons (especially parasagittal intracranial lesions) and lower motor neurons (anterior horn cell disorders, cauda equina syndromes due to involvement of nerve roots derived from the lower spinal cord [Chap. 35], and peripheral neuropathies).
Acute paraparesis may not be recognized as due to spinal cord disease at an early stage if the legs are flaccid and areflexic. Usually, however, there is sensory 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 legs with normal reflexes in the arms. It is important to image the spinal cord (Fig. 12-3). Compressive lesions (particularly epidural tumor, abscess, and hematoma but also a prolapsed intervertebral disk and vertebral involvement by malignancy or infection), spinal cord infarction (proprioception usually is spared), an arteriovenous fistula or other vascular anomaly, and transverse myelitis are among the possible causes (Chap. 35).
Diseases of the cerebral hemispheres that produce acute paraparesis include anterior cerebral artery ischemia (shoulder shrug also is affected), superior sagittal sinus or cortical venous thrombosis, and acute hydro-cephalus. If upper motor neuron signs are associated with drowsiness, confusion, seizures, or other hemispheric signs, MRI of the brain should be undertaken.
Paraparesis may result from a cauda equina syndrome, for example, after trauma to the low back, a mid-line disk herniation, or an intraspinal tumor; although sphincters are affected, hip flexion often is spared, as is sensation over the anterolateral thighs. Rarely, paraparesis is caused by a rapidly evolving anterior horn cell disease (such as poliovirus or West Nile virus infection), peripheral neuropathy (such as Guillain-Barré syndrome; Chap. 46), or myopathy (Chap. 48). In such cases, electrophysiologic studies are diagnostically helpful and refocus 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 involvement, a chronic spinal cord disorder is likely (Chap. 35). If an MRI of the spinal cord is normal, MRI of the brain may be indicated. If hemispheric signs are present, a parasagittal meningioma or chronic hydrocephalus is likely and MRI of the brain is the initial test. In the rare situation in which a long-standing paraparesis has a lower motor neuron or myopathic etiology, the localization usually is 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 the motor unit. Although the terms quadriparesis and generalized weakness often are used interchangeably, quadriparesis is commonly used when an upper motor neuron cause is suspected, and generalized weakness when a disease of the motor unit is likely. Weakness from CNS disorders usually is associated with changes in consciousness or cognition, with spasticity and brisk stretch reflexes, and with alterations of sensation. Most neuromuscular causes of generalized weakness are associated with normal mental function, hypotonia, and hypoactive muscle stretch reflexes. The major causes of intermittent weakness are listed in Table 12-2. A patient with generalized fatigability without objective weakness may have the chronic fatigue syndrome (Chap. 52).
CAUSES OF EPISODIC GENERALIZED WEAKNESS
Acute quadriparesis with onset over minutes may result from disorders of upper motor neurons (e.g., anoxia, hypotension, brainstem or cervical cord ischemia, trauma, and systemic metabolic abnormalities) or muscle (electrolyte disturbances, certain inborn errors of muscle energy metabolism, toxins, and periodic paralyses). Onset over hours to weeks may, in addition to these disorders, be due to lower motor neuron disorders. Guillain-Barré syndrome (Chap. 46) is the most common lower motor neuron weakness that progresses over days to 4 weeks; the finding of an elevated protein level in the cerebrospinal fluid is helpful but may be absent early in the course.
In obtunded patients, evaluation begins with a CT scan of the brain. If upper motor neuron signs are present but the patient is alert, the initial test is usually 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 determine 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, brainstem, and cervical spinal cord is usually possible clinically. An MRI is obtained of the clinically suspected site of pathology. EMG and nerve conduction studies help distinguish lower motor neuron disease (which usually presents with weakness that is most profound distally) from myopathic weakness, which is typically proximal.
Monoparesis usually is due to lower motor neuron disease, with or without associated sensory involvement. Upper motor neuron weakness occasionally presents as a monoparesis of distal and nonantigravity muscles. Myopathic weakness rarely is limited to one limb.
If the weakness is predominantly in distal and nonantigravity muscles and is not associated with sensory impairment or pain, focal cortical ischemia is likely (Chap. 27); diagnostic possibilities are similar to those for acute hemiparesis. Sensory loss and pain usually accompany acute lower motor neuron weakness; the weakness commonly is localized to a single nerve root or peripheral nerve within the limb but occasionally reflects plexus involvement. If lower motor neuron weakness is suspected or the pattern of weakness is uncertain, the clinical approach begins with an EMG and a nerve conduction study.
Subacute or chronic monoparesis
Weakness and atrophy that develop over weeks or months are usually of lower motor neuron origin. If they are associated with sensory symptoms, a peripheral cause (nerve, root, or plexus) is likely; in the absence of such symptoms, anterior horn cell disease should be considered. In either case, an electrodiagnostic study is indicated. If weakness is of the upper motor neuron type, a discrete cortical (precentral gyrus) or cord lesion may be responsible, and an imaging study of the appropriate site is performed.
Involvement of two or more limbs distally suggests lower motor neuron or peripheral nerve disease. Acute distal lower limb weakness results occasionally from an acute toxic polyneuropathy or cauda equina syndrome. Distal symmetric weakness usually develops over weeks, months, or years and, when associated with numbness, is due to diseases of peripheral nerves (Chap. 45). Anterior horn cell disease may begin distally but is typically asymmetric and without accompanying numbness (Chap. 32). Rarely, myopathies present with distal weakness (Chap. 48). Electrodiagnostic studies help localize the disorder (Fig. 12-3).
Myopathy often produces symmetric weakness of the pelvic or shoulder girdle muscles (Chap. 48). Diseases of the neuromuscular junction (such as myasthenia gravis [Chap. 47]), may present with symmetric proximal weakness often associated with ptosis, diplopia, or bulbar weakness and fluctuating in severity during the day. The extreme fatigability present in some cases of myasthenia gravis may even suggest episodic weakness, but strength rarely returns fully to normal. In anterior horn cell disease, proximal weakness is usually asymmetric, but it may be symmetric if familial. Numbness does not occur with any of these diseases. The evaluation usually begins with determination of the serum creatine kinase level and electrophysiologic studies.
Weakness in a restricted distribution
Weakness may not fit any of these patterns, being limited, for example, to the extraocular, hemifacial, bulbar, or respiratory muscles. If it is unilateral, restricted weakness usually is due to lower motor neuron or peripheral nerve disease, such as in a facial palsy or an isolated superior oblique muscle paresis. Weakness of part of a limb usually is due to a peripheral nerve lesion such as carpal tunnel syndrome or another entrapment neuropathy. Relatively symmetric weakness of extraocular or bulbar muscles usually is due to a myopathy (Chap. 48) or neuromuscular junction disorder (Chap. 47). Bilateral facial palsy with areflexia suggests Guillain-Barré syndrome (Chap. 46). Worsening of relatively symmetric weakness with fatigue is characteristic of neuromuscular junction disorders. Asymmetric bulbar weakness usually is due to motor neuron disease. Weakness limited to respiratory muscles is uncommon and usually is due to motor neuron disease, myasthenia gravis, or polymyositis/dermatomyositis (Chap. 49).