Chapter 21 - Neuromuscular system disorders
The nervous system can be considered a reflex arc designed for analyzing the environment through sensation and then modifying the environment through movement. The neuromuscular component of the nervous system is made up of the first and the last components of this reflex. It consists of the first sensory element and the last motor element. Table 21-1 lists the parts of this peripheral apparatus.
The neuromuscular system has a relatively simple design and physiology. Therefore,the clinical expression of symptoms following damage are rather straightforward, consisting of loss of these normal functions. From the type and the distribution of symptoms, it is possible to achieve a diagnosis and to do the following:
- Confirm that such manifestations arise in the peripheral nervous system (either sensory or motor components) rather than in the CNS.
- Determine which part of the system is affected. For example, is the weakness caused by damage to a nerve fiber, neuromuscular junction (NMJ), or muscle fibers.
- In the case of nerve fiber disease, it is possible to determine the level of the lesion along the nerves or roots.
- In disease of the peripheral nerves, the type of injury either to myelin or axons can be determined.
The specific neuromuscular diagnosis is made by history, examination and supported by laboratory studies, neurophysiology and, in selected cases, muscle and nerve biopsies and genetic testing.
What follows is an integrated picture relating normal and abnormal structure, function and clinical manifestations.
There are several components of the peripheral nervous system. These include sensory and motor nerve fibers (axons) which pass through nerve roots, plexi and the peripheral nerves themselves. Sensory nerve fibers (axons) have their origin in receptive elements that may be in the skin, muscles, joints, bones or even the internal organs. They typically have cell bodies located in the dorsal root ganglia located close to the spinal cord. Somatic motor nerve fibers (axons) arise from motor neurons in the ventral horn of the spinal cord. These nerve fibers terminate on muscle fibers at the neuromuscular junction or on muscle spindles (setting the sensitivity to muscle stretch). Autonomic motor nerve fibers terminate on glands, organs or smooth muscle fibers. The autonomic motor nerves are unique since there are typically 2 neurons in a sequence (with the postganglionic neuron located in a ganglion).
The peripheral nerves not only include the nerve fibers but also several layers of connective tissue (endoneurium, perineurium and epineurium) and blood vessels.
Nerve fibers have a high metabolic demand and little reserve of energy stores. Therefore, circulation is critical for moment-to-moment supply of oxygen and metabolic substrates. Peripheral nerves receive collateral arterial branches from adjacent arteries that anastamose with other arteries entering the nerve, above and below. There is usually sufficient collateral circulation to survive damage to one of the feeding arteries.
Individual nerve fibers consist of axons that may be myelinated or unmyelinated. Myelin in the peripheral nervous system derives from Schwann cells, which adhere to nerve cell membranes and create multiple layers or wrappings of the membrane. These are fused layers of Schwann cell membrane, comprising an electrically insulating lipid-rich layer around the nerve fibers. In between these Schwann cells are the nodes of Ranvier, a short segment of the nerve fiber devoid of myelin. At these nodes there is a high density of voltage-gated sodium ion channels that facilitate membrane depolarization. The role of myelin is to increase the velocity of nerve conduction, with speed being proportional to the distances between adjacent nodes of Ranvier. The usual speed of large myelinated fibers is 40-70 meters/ second. The function of nerve fibers can, to some extent, be deduced from the velocity of conduction (see Table 21-2). Most somatic motor axons are large, heavily myelinated fibers. This is also true of the sensory nerve fibers innervating muscle spindle (stretch) and Golgi tendon organ (tension) receptors. Intermediate size fibers convey touch and proprioception and joint position sense. Lightly myelinated fibers convey sharp pain sensation and autonomic preganglionic motor function. Pathologic processes that primarily affect myelin tend to affect functions mediated by the most heavily myelinated nerve fibers and would also profoundly affect the speed of nerve conduction in these nerves.
Unmyelinated nerve fibers conduct very slowly by a continuous mode of propagation of electrical signal (non-saltatory). These fibers convey aching, burning pain and temperature sensation and also include the sympathetic, postganglionic motor nerves. Their speed is approximately 1 meter/second.
Nerves are protected from pressure by connective tissue padding, which also protects them from traction. Nerve roots are less well protected because there is less connective tissue within the nerve root.
In order to accurately diagnose disorders affecting peripheral nerves it is important to recall the anatomical distribution of sensory fibers in the nerve roots (Figure 9-2) and peripheral nerves (Figure 9-3). Nerve roots have nearly complete overlap, so there is limited sensory loss (usually distally, where there is less overlap) with damage to a single nerve root. Peripheral nerve injuries usually produce more sensory loss. It is important to note that there is significant variability in the precise borders of the peripheral nerve distribution, although the general pattern is quite consistent. It is also important to understand the motor innervation of certain major nerve roots and peripheral nerves (Table 10-5). There may be weakness of shoulder abductors and external rotators with C5 nerve root lesions, weakness of elbow flexors with C6 nerve root lesions, possible weakness of wrist and finger extension with C7 nerve root lesions and some weakness of intrinsic hand muscles with C8 and T1 lesions. In the lower extremity, there may be some weakness of knee extension with L3 or L4 lesions, some difficulty with great toe (and, to a lesser extent, ankle) extension with L5 lesions and weakness of great toe plantar flexion with S1 nerve root damage.
It is critical for the survival of nerve fibers that they be able to maintain a stable resting membrane potential by sustaining ion gradients across the axonal membrane. This requires normal integrity of the membrane constituents (lipid layers, membrane proteins and ion channels). It also requires energy, which the neuron uses to create the ion gradients and for transport, moving constituents from the cell body down the axon, and back to the cell body. All of this requires high blood flow to the nerve. Diminished blood flow (ischemia) is poorly tolerated by nerves.
Axonal transport is critical to the function of the peripheral nerve. All protein constituents of the nerve are synthesized in the neuronal cell body. Microtubules within the axon perform the transport function and may extend over distances that can exceed a meter in the longest nerve fibers. Therefore, all structural proteins as well as enzymes that function in the nerve terminal come from the cell body. Even structural components, such as the mitochondria in the nerve terminal, are transported down the axon. There is a class of protein compounds (trophic factors) that travel orthodromically to the periphery or antidromically to the cell body. These factors are critical to the health of the innerved tissues. Additionally, there are trophic factors released by the peripheral tissues, taken up by nerve terminals and transported in a retrograde manner back to the nerve cell bodies. Loss of these trophic factors can result in either the death of neurons or atrophy of peripheral tissues. This is the reason why a muscle whose innervating axon is sectioned undergoes atrophy much more quickly and severely than one where the axon is intact, as in demyelination with conduction block... In both cases, there is complete weakness of the muscle, yet only in the former case are trophic factors lost.
It is important to note that nerves receive innervation by way of the nervi nervorum. Most of these nerve fibers are either sensory or motor (from the sympathetic nervous system). The density of this innervation is not uniform and varies with the particular nerve in question as well as with the location along the nerve. These fibers may be responsible for some pain associated with nerve injury.
The motor unit is a physiologic unit. Normally, contraction of striated muscle is only possible through firing of motor neurons that are activated either via descending pathways or through reflex connections.
The muscle fibers in a motor unit respond in an all-or-none fashion to excitation by the motor neuron (both to natural excitation and artificial stimulation, such as electric nerve stimulation). The nervous impulse reaches all the muscle fibers in a unit almost at the same time. The result is a brisk twitch. The electric counterpart of this muscle discharge is a motor unit potential. It can be recorded with a needle electrode inserted into the muscle. It is the composite of the summated action potentials of many single muscle fibers. Its amplitude roughly expresses the numbers of muscle fibers activated. Its duration represents the range of terminal conduction times to those activated muscle fibers (temporal dispersion). Repeated activation of the same motor unit produces nearly identical motor unit potentials each time because the times for nerve impulse arrival and neuromuscular transmission are quite constant for any given nerve branch, and because all muscle fibers in the motor unit respond every time.
At rest there is normally no motor unit activity. What is the behavior of motor units in effort? With increasing effort, tension increases by, (1) increasing the firing rates of individual units and by, (2) recruiting more units into the effort. These are recruited such that, with full effort, the electrical activity of individual motor units can no longer be recognized.
Irritation of motor neurons or motor axons can result in spontaneous discharge of individual motor axons and contraction of the motor unit. These can be seen on the skin surface as random, involuntary twitches that are termed fasciculations. While these are often normal (due to temporary irritation of motor nerve fibers) persistent fasciculations, especially in a muscle that is showing weakness or atrophy, indicates damage to the anterior horn cell or its axons.
Muscle fibers that have been denervated for days to weeks become hyperirritable (to the point where they are spontaneously active). The spontaneous contraction of individual muscle fibers is termed a fibrillation but it is not visible from the skin surface. Needle electromyography can detect fibrillations, which are fairly reliable signs of damage to motor nerve fibers, but which may also be seen in muscles diseases (especially those that damage the distal motor axons).
Conditions that damage some motor units (sparing others) usually result in overall weakness of the muscle but high firing rates of individual motor units that are still intact. This is because of the decreased number of motor units which must be activated at maximal frequencies in order to generate any muscle force. Therefore, weakness with a high firing rate indicates a loss of motor neurons or motor axons. Of course, voluntary motor activity is also driven by descending motor tracts of the central nervous system that are collectively referred to as "upper motor neurons." Damage to these "upper motor neurons" makes it impossible to achieve high firing rates of the motor units during voluntary contraction. This is similar to the finding of low frequency of firing of the individual motor units that would be seen with inadequate effort.
Most nerves contain a mixture of myelinated and unmyelinated fibers distributed in three well-defined sizes of populations: large myelinated fibers, small myelinated fibers, and many small unmyelinated fibers. Normally, the largest-diameter fibers conduct the fastest, and fibers of similar diameter conduct at similar velocity. Therefore, following simultaneous stimulation of all fibers in a nerve, the action potentials of individual nerve fibers summate in time, giving rise to compound nerve action potentials (NAP). In the clinic, NAP's are recorded routinely, but we can only record the NAP corresponding to large myelinated fibers.
In the clinic we can also measure nerve conduction velocity (see this discussion of electrodiagnosis for further explanation).
The following discussion will consider the four basic types of neuromuscular disorders, i.e., damage to the anterior horn cells, damage to the peripheral nerves (including myelin), damage to muscle (myopathy) and damage to the neuromuscular junction.
Motor neuron disease is a general terms for conditions that result in degeneration of the anterior horn cells (lower motor neurons) and the upper motor neurons of the cerebral cortex that give rise to descending tracts that control movement. These conditions present with weakness accompanied by lower motor signs (atrophy, fasciculations and decreased reflexes) or upper motor neuron signs (spasticity, increased reflexes and upgoing toes). Sensation and cognition are clinically intact, although we have more recently come to understand that there are subtle signs of damage to other parts of the nervous system. Most patients have clinical signs of both upper and lower motor neuron disease and are diagnosed with amyotrophic lateral sclerosis - ALS. Some show signs that are almost exclusively upper or lower motor neuron in nature and these go by other names.
In addition to these degenerative motor neuron diseases there are two inherited conditions (Werdnig-Hoffmann disease in infants and Kugelberg-Welander disease in children and young adults) that are characterized by anterior horn cell degeneration only, and there are even more rare inherited forms of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis affects mainly adults 40-60 years of age. There is evidence of degeneration not only of the anterior horn cells of the spinal cord, but also some of the cranial nerve motor nuclei, especially those controlling the tongue, face, pharynx and soft palate, while sparing eye movements. Because of additional involvement of corticobulbar and corticospinal tracts, the weakness is of two types and may express quite differently in the arms and in the legs of a single patient. For example, the arms may show more lower motor neuron signs (atrophy and fasciculations) while the legs may show more upper motor neuron signs (spasticity, increased reflexes and Babinski sign). The disease often starts asymmetrically, but usually within months it involves many muscle groups on both sides of the body. The average patient survives three to five years with death resulting from weakness of the bulbar and respiratory musculature and resultant superimposed infection.
The variant of motor neuron disease that selectively involves the upper motor neurons is called primary lateral sclerosis. In the great majority of cases there is eventually some evidence of lower motor neuron involvement. For this reason most neurologists no longer feel this to be distinct from ALS despite the fact that the clinical course tends to be longer than in the usual variety of ALS. Some patients survive ten years or longer. There is also a variant that involves only lower motor neurons (progressive muscular atrophy) and one that selectively involves the cranial musculature (termed progressive bulbar palsy). Again, with time these variants often show signs of evolution to a more typical ALS pattern.
Motor neuron disease is a very active field of research. There has been great interest in the possible contribution of environmental toxins to the condition and of chronic very low level activation of inflammatory pathways (despite a lack of overt inflammation in pathological specimens). Most of these lines of investigation have been based on epidemiological identification of specific risk factors. Examples include a toxin-induced motor neuron disease termed the ALS-dementia complex of Guam and also the growing evidence of chronic low-level trauma as a precipitant. The finding of certain families of patients with clearly hereditary ALS has stimulated research identifying neuronal deficit of an antioxidant (superoxide dismutase) as a cause. This has lead to research into free-radical destruction of motor neurons. Despite these preliminary findings, extensive research has yet to lead to any effective therapy, although riluzole does slightly delay the progression of disease. The mechanism of action is unknown, although it does decrease glutamate neurotransmission (decreasing release, increasing reuptake and decreasing activation of glutamate receptors) and also decreases fast sodium channel activation. Needless to say, much research remains to be done on motor neuron disease.
Peripheral neuropathy generally appears in one of three patterns that can be distinguished clinically. These include involvement of one isolated nerve or root (mononeuropathy), several isolated nerves (mononeuropathy multiplex), or peripheral nerves diffusely (polyneuropathy). In each of these patterns, the primary disorder in each case may involve the neuron (or its neurite) or the Schwann cell. The etiologies of the three patterns of presentation are rather distinct and, therefore, recognition of the pattern is clinically important.
The particular nerve or nerves that are affected can be determined by the symptoms. Symptoms may be "positive" (including pain and dysesthesia), may be negative (including loss of sensation, weakness or loss of reflexes), or may be irritative (such as fasciculations or paresthesias).
Mononeuropathy and radiculopathy are most often due to trauma of some type. This may be acute (such as wounds or blows to the nerve) or chronic (by chronic pressure in vulnerable sites). The neuropathy in these cases is recognized by the distribution of symptoms. Both negative (loss of sensation, weakness, atrophy) and positive (paresthesia, pain) may be present in mononeuropathy. Anything that damages peripheral nerves systemically (see the section on polyneuropathy) promotes local nerve injury by lowering the resistance of the nerve to damage. An important clinical feature of local nerve damage is that the nerve becomes very mechanically sensitive at the site of injury. A "Tinel sign" can often be elicited by gentle tapping over the site of injury. This is an "electrical" type of paresthesia percieved in the distal distribution of the irritated nerve. For example in carpal tunnel syndrome the Tinel sign is present at the wrist in the great majority of cases. The distribution of the paresthesias in this case should be in the sensory region supplied by the distal median nerve.
The most common mononeuropathies are due to entrapment of nerves at anatomically vulnerable sites. These sites include places where nerves pass through tight canals in the tissues or where they are surrounded by hard tissues or subject to repeated pressure or motions that stress the nerve. The most common entrapment neuropathy is carpal tunnel syndrome (CTS), which is an entrapment neuropathy that produces chronic damage to the median nerve at the wrist. Anything that compromises the volume of the carpal tunnel (congenitally small carpal tunnel; thickening of the ligaments; disruption or swelling of the joint; inflammation of the synovium) can promote CTS. A controversial subject is how much occupational activities (such as typing) contribute to symptoms. The symptoms of CTS include decreased sensation in the radial digits (sparing the palm) along with potential dysesthesias provoked by wrist position (including at night). There may be weakness in thumb abduction and opposition (often with some clumsiness) and atrophy of the thenar muscles. Pain is common, but is less predictable and the distribution may be well beyond the distribution of the median nerve, especially in the wrist and up the forearm to the elbow or even the shoulder.
Other common nerve entrapments in the upper extremity include the ulnar nerve at the elbow. Damage can be due to bone and joint problems at the elbow, but is also promoted by chronic pressure on the elbow and full elbow flexion. Weakness and atrophy of the intrinsic hand muscles is common. There may be sensory loss over the small digits and the ulnar side of the hand on the palmar and dorsal side. Damage to the ulnar nerve can occur at the wrist, usually due to chronic pressure (such as hand position in bicycle riding). In this case, any sensory symptoms would be minimal.
The radial nerve may be damaged by lesions (such as fractures) of the humerus, since the radial nerve has a course in close proximity to the humeral shaft. It is also somewhat prone to trauma at the lateral elbow. When the main part of the radial nerve is injured, there is weakness of wrist extension (wrist drop) and diminished sensation on the dorsum of the hand (not to the finger tips). The radial nerve divides into a superficial (cutaneous) branch and a deep (muscular) branch at the elbow. The superficial branch can be damaged by trauma or direct pressure over the distal radius (e.g., handcuffs), producing sensory loss and dysesthesia/paresthesia on the dorsum of the hand. The deep branch can be compressed in the tunnel that it makes through and under the supinator muscle. This can weaken many of the extensors (such as for the fingers) while sparing the brachioradialis muscle and the extensors of the radial side of the wrist.
"Thoracic outlet syndrome" (TOS) is actually a heterogeneous group of disorders that all involve some mechanical compression of structures in the region of the upper thorax. While most patients who are diagnosed with TOS have compression of the subclavian or axillary artery when their limb is in certain positions, some patients have compression of the lower brachial plexus in the region around the first rib and the scalene muscles that attach to it. In this case, the condition can be called a "neurogenic thoracic outlet syndrome." This compression may be associated with a cervical rib or band of connective tissue connecting from the cervical spine to the first rib. Neurogenic TOS produces symptoms in the distribution of the ulnar nerve (which arises from the lower brachial plexus) and also in the ulnar aspect of the forearm. A full discussion of "vascular TOS" is beyond the scope of this book (see this site for further information). However, vascular TOS is defined by compression of the great vessels in the region around the clavicle and/or upper ribs. Symptoms of ischemia of the limb may be brought on by sustained depression of the shoulders, abduction and external rotation of the arm or sustained rotation and extension of the neck. If these maneuvers reproduce the patient's complaints and, at the same time, abolish the radial pulse, consideration should be given to possible TOS.
In the lower extremity, the most common entrapment neuropathies include damage to the lateral femoral nerve, the fibular (peroneal) nerve, the posterior tibial nerve and the interdigital nerves. The lateral femoral cutaneous nerve can be entrapped where it goes under the lateral part of the inguinal ligament. This can result from weight gain, tight belts or pregnancy, and produces decreased sensation and dysesthesia in the lateral thigh. Fibular (peroneal) nerve damage usually occurs at the fibular head due to direct trauma or pressure. This may produce "numbness" on the dorsum of the foot and weakness of foot and toe dorsiflexion and eversion. Inversion should be unaffected. Tibial nerve entrapment at the medial aspect of the ankle has been termed "tarsal tunnel syndrome." This is rare, occurring after severe ankle trauma or with connective tissue disorders such as rheumatoid arthritis. Interdigital neuromas are common and result from a pinching of the common digital nerves between metatarsal heads. This results in paresthesia and dysesthesia on the sides of adjacent toes (particularly after walking).
Radiculopathy indicates damage to nerve root(s), and typically occurs as a component of several spinal diseases. In younger individuals this is usually due to intervertebral disc herniation. In older individuals, this is more often due to degenerative changes in the disc, bones and joints, which result in thickening of the tissues. Thinning of the discs can result in narrowing of intervertebral foramina, which can also result in nerve compression. These problems tend to occur in the lower lumbar region and the mid- to lower cervical area (which are the levels of the most commonly damage nerve roots).
Nerve root entrapment most often occurs in the cervical and lumbar areas, but should be considered when symptoms follow a well-defined nerve root distribution and whenever distal symptoms are coupled with pain in the back or neck. The symptoms often include pain projected along the distribution of the nerve root along with provocation when the nerve root is stretched (such as by straight leg raising or lateral flexion of the neck) or pinched (such as by arching the back or compression of the neck). Coughing, sneezing and straining also often worsen symptoms. There may also be a more constant, deeper, aching pain ("like a toothache") although this is less specific and can result from many painful processes.
There is usually not much sensory loss because of overlap of nerve roots, although there are a few areas of the distal limbs (called "autonomous zones") where there is little overlap between roots (see Table 21-3). Other signs of radiculopathy include weakness (of a "lower motor neuron" type) and reflex loss. The most common symptoms of radiculopathy are noted in Table 21-3.
Polyneuropathy is a common condition. It is not always easy to determine its cause. In this condition the longest peripheral nerve fibers are usually first. Peripheral neuropathy can affect either the axon, or myelin sheaths (demyelinating), or both. This syndrome is usually symmetrical. Patients with polyneuropathy are also more susceptible to compression neuropathy.
Since the nerves to the lower limbs are the longest, they are the most dependent on a good supply of metabolic substrates, and also have the greatest exposure to toxins or conditions damaging myelin. Therefore, symptoms and signs are most prominent in the feet. Loss of sensation ("numbness") is the most common finding but paresthesias or dysesthesias (prickling, tingling, burning, etc) are also common. When large-diameter nerve fibers are affected, vibration and joint position sense are impaired. Many patients with large-fiber damage in the feet complain about balance trouble (and have Romberg sign). Such patients may have difficulty walking in the dark or on irregular surfaces because of proprioceptive problems with the feet. Polyneuropathy may also result in distal weakness and atrophy if there is actual loss of motor axons. Ankle jerk reflexes are most often lost.
There are a few conditions that damage small nerve fibers early in their course. Such conditions would be expected to result in decreased sensitivity to pain and temperature. When patients lose pain sensitivity, they may injure themselves without awareness (which can result in tissue loss, including amputation).
In around 2/3 of cases, polyneuropathy has an identifiable cause (table 21-4). The most common single cause is diabetes mellitus, which can damage axons as well as myelin. High alcohol intake can also result in peripheral nerve damage but this is most likely due to nutritional deficiencies, especially the B vitamins. In the United States, the most common single deficiency is in vitamin B12 (secondary to poor absorption of Vitamin B12). Usually B-12 deficiency causes more of a myelopathic picture than a polyneuropathy. Paradoxically, excesses of pyridoxine can also result in a polyneuropathy. Toxins such as heavy metals, certain organic solvents and industrial exposures (such as carbon disulfide) may result in peripheral neuropathy. Usually, there is some history of significant exposure, although testing may be necessary. A variety of medications, especially some chemotherapeutic agents and some drugs used to treat seizures or HIV infection (HAART therapy), can be neurotoxic. Certain systemic inflammatory conditions such as systemic lupus erythematosus, Sjogren Syndrome, Wegner granulomatosis, and polyarteritis nodosa are associated with neuropathy but most of the time it is in the pattern of mononeuropathy multiplex (see below). Certain chronic infectious conditions such as tertiary syphilis, Lyme disease and HIV, may result in polyneuropathy and should be evaluated in the appropriate clinical setting; although, again, the pattern may be a pattern of mononeuropathy multiplex. Leprosy causes a patchy sensory neuropathy, which can result in mutilation of the patient's digits. There are some other metabolic conditions that can cause neuropathy, including severe sprue and porphyria. Abnormal proteins in the blood may result in a polyneuropathy associated with monoclonal gammopathy or amyloid.
A special note should be made of immune demyelinating conditions that can present either acutely or chronically. The acute form is termed Guillain-Barre syndrome or AIDP (acute inflammatory demyelinating polyradiculoneuropathy). It is markedly different from the other causes of neuropathy in its rapid course and severe weakness, produced by immune attack on myelin (demyelination). It is critical to recognize this condition since it can progress rapidly to respiratory paralysis and life-threatening autonomic instability. This is usually recognized by subacute weakness (sometimes ascending from the legs and sometimes descending, starting with eye, face or oropharyngeal muscles). There may or may not be sensory loss, but reflexes are usually lost early (including often in clinically unaffected muscles). Protein is usually elevated in the CSF, while there is little, if any, elevation in white cells in CSF. It may follow a viral or diarrheal illness (particularly Campylobacter jejuni) by a week or two. AIDP patients usually recover quite well with time. However, the clinical course may be shortened by certain immune modulating treatments (especially intravenous immunoglobulin).
A chronic immune mediated neuropathy (chronic inflammatory demyelinating polyradiculoneuropathy - CIDP), may result in relapsing or progressive polyneuropathy. This usually results in an asymmetric weakness and sensory loss. This condition is associated with very high cerebrospinal fluid protein levels. As with AIDP, reflexes are lost early in CIDP because the most heavily myelinated nerve fibers are the muscle stretch sensory nerve fibers and these are affected first. CIDP requires chronic immune modulating therapies.
Finally, there are a large number of peripheral neuropathies that may be familial. Some of these have very clear pattern of inheritance, such as Charcot-Marie-Tooth Disease or hereditary motor sensory neuropathy (HMSN). Sometimes, the hereditary peripheral neuropathies may not have a clear pattern of inheritance. It is always necessary to examine many of the patient's relatives in order to make a diagnosis. EMG/NCS are performed to characterize the peripheral neuropathy in the patient and it may also be performed on relatives to gain more information. Most familial neuropathies do not have a rapidly progressive course. Weakness is usually prominent and there may be marked sensory loss. In HMSN, pain was thought to be rare but this may not be the case. Finally genetic testing may be done to help with confirmation of the diagnosis. In HMSN type I, which is the demyelinative form, nerve conduction testing is most useful. It is less helpful in the axonal forms, known as HMSN II.
Many patients (at least 25%, and maybe as high as 40%) with polyneuropathy have no identifiable cause of their condition. Therefore, it is often somewhat difficult to determine how much investigation is required. Most patients with idiopathic neuropathy have relatively mild sensory symptoms and are older. Additionally, their symptoms are generally quite slowly progressive. Therefore, when a patient is identified with polyneuropathy, initial consideration must be given to the identifiable causes listed above, recognizing that the findings may be negative. These patients do require a good history of the timing of symptoms and of possible risk factors and exposures to medications and toxins. NCS/EMG are routinely done to confirm diagnosis and to characterize the peripheral neuropathy. If symptoms are acute, then urgent consideration must be given to inflammatory conditions (such as Guillain-Barre), severe metabolic abnormalities or to toxic exposures. Most patients with polyneuropathy should have certain basic metabolic tests performed, including a CBC, glucose level, HgbA1C, TSH, serum protein electrophoresis, and sedimentation rate. In selected cases, an RPR, HIV, Lyme titer, ANA, rheumatoid factor, antineutrophil cytoplasmic antibody titer, and screen for heavy metals and porphyrins may be indicated. If these tests are negative, a follow-up examination after a number of months (or sooner if symptoms suggest rapid progression) is imperative. In younger patients and those with acute or subacute progression, specialty referral for more sophisticated testing such as sural nerve biopsy or skin biopsy looking for unmyelinated fiber loss is necessary. Some investigators feel that abnormal glucose tolerance in the absence of diabetes can cause a painful small fiber neuropathy.
There are several important clinical concerns when managing the patient with polyneuropathy. First of all, any hope of arresting the polyneuropathy requires an identification of the cause. In some cases, removing the causative agent can actually improve the polyneuropathy. Patients who have lost sensitivity to pain are at high risk of damaging their feet (resulting in ulcers or Charcot joints). Therefore, particular attention must be given to proper footwear and foot mechanics. Significant proprioceptive loss produces instability, especially when walking on irregular surfaces or when vision is obscured. These individuals will typically have a Romberg sign that improves dramatically when touching a stationary object with one finger. These patients improve with use of a cane.
"Mononeuritis multiplex" is a relatively rare presentation of certain disorders that damage nerves primarily by interfering with blood flow to nerves or plexi or by an autoimmune process damaging either the myelin or axon. This results in unpredictable and patchy nerve damage. If this is produced by interruption of circulation, the symptoms can occur abruptly.
The most common cause of mononeuritis multiplex is diabetes mellitus. This may occur along with or independent of diabetic polyneuropathy. Other potential causes of mononeuritis multiplex include any conditions that result in systemic vasculitis (such as the autoimmune conditions like systemic lupus erythematosus or polyarteritis nodosa) or infectious vasculitis (such as with Lyme disease). If the etiology of the condition is not clear, specialty evaluation is necessary since treatment is critically dependent on identifying the cause.
In diabetes, an inflammatory disorder of the lumbar plexus or, rarely, the brachial plexus can occur. This usually affects the femoral nerve, with prominent weakness of the quadriceps muscle and loss of patellar reflex (termed diabetic amyotrophy). The condition is heralded by severe pain in the hip or shoulder with prominent weakness of the ilipsosas, thigh adductors, and quadriceps muscles; when the lumbosacral plexus is affected. Usually the patient has poor control of their diabetes and systemic symptoms such as weight loss and fatigue. The diagnosis is aided by NCS/EMG. Treatment is focused on control of diabetes and the judicious use of IVIG or IV pulse steroids (with very careful monitoring of blood glucose levels). The condition typically shows slow and variable recovery over months.
There are rare, idiopathic cases of mononeurities multiplex that most often affect the brachial plexus distribution. This is most common in middle-aged men and has been termed neuralgic amyotrophy (also known as idiopathic brachial neuralgia or Parsonage-Turner syndrome) due to the fact that it is usually painful at the outset, with subsequent appearance of atrophy and weakness. The typical course is very slow improvement. In this condition early judicious use of IVIG and pulse IV steroids may be helpful. There are more minor and quite focal varieties of this syndrome, which can complicate diagnosis.
With few exceptions each muscle fiber has one (and only one) end-plate; this is the plug for a nerve terminal branch. Acetylcholine is the neurotransmitter at this synapse that couples motor nerve activity with response in the muscles.
Much of the early electrophysiological understanding of chemical synapses was gained from study of the neuromuscular junction. At rest there are normally intermittent discharges at the end-plate region of fairly constant amplitude and duration (miniature end-plate potentials). These are not capable of triggering muscle action potentials. Subsequently, electron microscopists discovered the synaptic vesicles that contain acetylcholine (ACh). It had been known that ACh is capable of depolarizing the postsynaptic membrane and, in view of the regular size of such synaptic vesicles and the morphologic evidence that vesicles may open to the synaptic cleft, it became obvious that each miniature end-plate potential is the result of spontaneous emptying of a fairly constant number (quantum) of molecules of ACh from a vesicle. Arrival of a nervous impulse at the presynaptic terminal causes release of many quanta, and this is normally sufficient to fire an end-plate potential, which spreads at 4 m/second along the whole muscle fiber membrane as the muscle fiber action potential. From the membrane, the potential propagates into the depth of the muscle fiber to trigger calcium entry into the fibers. This calcium, which is normally sequestered in the sarcoplasmic reticulum, couples excitation to the interaction between myofilaments that shorten the fiber.
Once ACh is released into the synaptic cleft, its action is terminated by acetylcholinesterase in the end-plate, which destroys the ACh molecule with recycling of the fragments. Drugs with anticholinesterase activity facilitate the depolarizing effect of ACh. It is noteworthy that excess ACh eventually may block neuromuscular transmission (i.e., cholinergic block) by preventing normal repolarization of the muscle. This is the action of many insecticides and biological warfare agents. Also, the neuromuscular junction may be blocked by many agents, including those that prevent release of ACh (such as botulinum toxin) or that block the nicotinic ACh receptor (such as curare).
Myasthenia gravis is the most common disorder affecting neuromuscular transmission. This condition is autoimmune, with antibodies directed against nicotinic acetylcholine receptors of the neuromuscular junction. It is not extremely common (about 1:10,000) and incidence is highest in young adult women. There is another small spike in late middle age men, who may have thymic tumors. Thymic epithelial cells have surface proteins with epitopes that cross react with acetylcholine receptors at the neuromuscular junction. Thymic tumor or hyperplasia may be found in myasthenic patients.
The earliest symptoms of myasthenia gravis are usually seen in the eyes, with ptosis and/or diplopia ("ocular myasthenia"). The second most commonly affected muscles are in the pharynx and soft palate ("bulbar myasthenia") with problems speaking and swallowing. "Generalized myasthenia" involves many muscles of the body, including the diaphragm. Additionally, it can result in autonomic instability and may be life-threatening. Myasthenia may present in any one of these patterns and may remain as only ocular involvement or progress to generalized weakness (it will usually do so within the first two years if it is going to generalize).
In this condition, there is a reduction in the size of the miniature end-plate potentials caused by a decrease in the number of ACh receptors on the postsynaptic side. The consequence is a reduced safety factor for neuromuscular transmission. The "safety factor" is defined as the excess in excitatory transmitter (in this case, acetylcholine) release above that which is necessary to activate the muscle fiber. When the safety factor is reduced, conduction of a nerve impulse may not be followed by contraction of the muscle fiber.
There are degrees of neuromuscular block (as there are of nerve conduction block). The mildest form consists of only increased N-M delay in some junctions of motor units. In severe forms, many end-plates are blocked, but the functional state of a given end-plate varies with time and use. During high-frequency activations (as in exercise) more end-plates fail to activate the muscle due to insufficient release of acetylcholine. So, in myasthenia gravis motor units contract without their full number of muscle fibers; sometimes all contract, sometimes a few, and sometimes none.
The cardinal clinical feature of myasthenia gravis is that repetitive or sustained use of a muscle contributes to depletion of acetylcholine in the motor nerve terminal, with ultimate failure of conduction. This explains why weakness fluctuates in connection with exercise and rest, that is, fatigability. The effects of this can be seen by repetitive electrical nerve stimulation with a recording of the amplitude of the compound muscle action potential (summation of all muscle fiber potentials from all excitable motor units in the muscle). Normally, there is little variation in successive firings. In myasthenia gravis, there may be an abnormal decrement due to N-M block (or fatigue). This may be followed by post-tetanic facilitation (Figure 21-2).
Acetylcholine or cholinergic substances or anticholinesterases improve this N-M transmission defect (before leading to cholinergic block). However, myasthenia gravis is more than just a functional end-plate disorder. It may lead to muscle fiber atrophy and fixed weakness. Indeed, often there is evidence of neurogenic atrophy of muscle and also selective type II fiber atrophy.
The thymus gland and immune mechanisms (autoimmunity against ACh receptor) have a great deal to do with myasthenia gravis, although their exact roles are not totally clear. In practice, thymectomy, corticosteroids, immunosuppressive drugs, human immunoglobulin and removal of antibodies by plasma exchange may be useful in treatment.
There is another interesting and uncommon disorder of neuromuscular transmission -- the myasthenic syndrome or Lambert Eaton Syndrome (LEMS). It may be associated with carcinoma. LEMS may improve after removal of the tumor (usually bronchogenic small-cell carcinoma). The defect in neuromuscular transmission is caused by reduced numbers of quanta released from nerve terminals in response to a nerve impulse. This is due to defective calcium channel function in the presynaptic membrane. It causes weakness that tends to improve with exercise; repetitive stimulation causes facilitation rather than the fatigue seen with myasthenia gravis (see Figure 21-2). The defect can be demonstrated also in vitro in nerve/muscle biopsies from other patients. Acetylcholine-releasing agents such as 4-aminopyridine may help correct the transmission defect.
Another well-known and fortunately rare disorder of transmitter-release blockade is botulism.
There are many things that can go wrong in muscles: failure to propagate a muscle action potential to invade the T-system; failure of electromechanical coupling; failure in the physical mechanism of sliding filaments; and failure of the normal energy production mechanisms. In recent years, there have been an overwhelming number of "new" muscle diseases based on very specific failures in the system. However, most of these conditions present in a rather stereotyped manner, and clarification of the precise etiology may require very elaborate procedures. We will discuss a practical approach to the recognition of muscle disease, while electron microscopic, metabolic and genetic testing may be required for precise diagnosis. A list of conditions damaging muscle can be found in Table 21-5.
Recognition of a myopathy usually begins with recognition of a symmetrical, proximal muscle weakness, although cramping of muscles (particularly with exercise) or, in rare cases, symmetrical, aching discomfort in muscles may be the initial findings (especially in inflammatory myopathies). Muscle enzymes (particularly CK levels), may be helpful in clarifying that there is actual muscle disease and electromyography can establish that the disorder lies in muscle as opposed to the neuron or nerve fiber. On EMG, examination of the motor unit action potentials reveal small, brief and polyphasic (myopathic) motor potentials (see Figure 21-1). Muscle biopsy may help confirm and classify the myopathy but special staining of the muscle biopsy and genetic testing may be necessary. Unfortunately, few muscle diseases are effectively treated.
The following is a very oversimplified but practical review. Two major groups of muscle disease can be distinguished. The first group includes disorders of muscle that cause destruction of muscle fibers, leading to (usually progressive) muscle weakness and wasting. The second main group includes diseases that cause more of a functional defect than structural fiber degeneration (little wasting). Most of these are "channelopathies" that cause altered muscle function without a lot of fiber death. Within each of these groups of conditions, there are subtypes that we will briefly discuss.
Diseases that actually progressively destroy muscle fibers fall into three main types: the dystrophies, the metabolic myopathies and the inflammatory myopathies.
- Muscular dystrophies: These conditions are non-inflammatory degenerative conditions of muscle that are genetically determined, not effectively curable, and progressive. The types of muscular dystrophy are usually classified according to inheritance and distribution of weakness. The earliest (and most devastating) is Duchenne dystrophy. This is an X-linked disorder due to mutation of the gene for a normal protein (inappropriately named "dystrophin") that attaches the contractile elements to the muscle membrane. Early in life, another protein performs this function, so symptoms usually don't start until after the child is standing and beginning to walk. The child experiences a progressive decline in muscle strength (wheelchair in late childhood and usually death from cardiac involvement in the early 20s). A less severe mutation in the same gene causes a somewhat later onset condition (Becker dystrophy). There are other dystrophies (most with onset in late childhood or early adolescence) including: facioscapulohumoral dystrophy, limb girdle dystrophy and oculopharyngeal dystrophy. Each of these has its own hereditary pattern. The names describe the predominant muscle groups involved. Myotonic dystrophy is unique in that it tends to affect distal muscles and causes noticeable myotonia. It is more severe in children of affected mothers and the severity of symptoms is based on the number of repeats found in a specific part of the genome. Clinical characteristics of some of the more common dystrophies are discussed below.
- Metabolic myopathies: Within this category are both acquired and genetic disorders. The prototypical acquired disorder is thyroid disease. Both hyper- and hypothyroidism can result in myopathy due to interference with the normal metabolic activity of muscles. Certain medications and toxins can affect the metabolic machinery of muscles, causing myopathy. Examples of this include myopathy secondary to statins (lipid-lowering drugs), colchicine, hydroxychloroquine or large amounts of alcohol. There are genetic disorders that interfere with metabolism of carbohydrates or fats, resulting in myopathy and, often, accumulation of intracellular inclusions (usually due to buildup of metabolic products). Some of these conditions result in exercise intolerance, occasionally with myoglobinuria and some result in exercise-induced cramping (due to insufficient energy production needed for muscle relaxation). Some, more poorly defined conditions result in intracellular inclusions seen on electron microscopy (nemaline myopathy, myotubular myopathy). The mitochondrial myopathies are a heterogeneous group of muscle diseases associated with excessive replication of somewhat defective mitochondria that accumulate in cells. Not surprisingly, muscles are commonly affected (since they are major consumers of energy), but many other areas (including the brain) are also affected. Extraocular muscles are often affected in mitochondrial disease due to the tonic activity of these muscles. Mitochonidrial myopathies may be associated with exercise intolerance and elevated serum lactate due to problems with aerobic metabolism. Not surprisingly, these conditions also may target heart muscles (and some affect the brain).
- Inflammatory myopathy: Inflammatory myopathies may be acquired or autoimmune. The acquired inflammations include sarcoidosis and certain infectious conditions (such as HIV/AIDS and trichinosis). The autoimmune myopathies include polymyositis and dermatomyositis, as well as inclusion body myositis.
Polymyositis usually appears in people 30-60 years old and presents as insidious onset of symmetrical, proximal muscle weakness, occasionally accompanied by muscle soreness. The proximal weakness makes it difficult to climb stairs and to lift things overhead. Occasionally this is associated with another autoimmune condition or cancer (especially lymphoma, lung or bladder).
Dermatomyositis also includes insidious weakness of proximal muscles, but there is also a red/purple rash. This is most characteristic over the eyelids (heliotrope) and extensor parts of joints, such as the knuckles, elbows, knees, and toes. The rash may also include the face, chest and elsewhere (particularly over affected muscles). Muscle soreness is more common than with polymyositis. Dermaotomyositis tends to be seen in children (5-15 years old) and in later adulthood (50s and 6os) and has a higher association with underlying autoimmune or neoplastic disease than polymyositis. In addition to lymphoma and lung cancer, breast and ovarian cancers should be considered.
Both Polymyositis and dermatomyositis often elevate inflammatory markers (such as erythrocyte sedimentation rate and C-reactive protein) and markers of muscle damage (such as muscle CPK). However, a finding of normal ESR and CPK do not rule out these conditions, especially in milder cases. Muscle biopsy of affected muscles is diagnostic. They myopathy usually responds to immunosuppresion but both of these conditions may be triggered by underlying neoplasm.
Inclusion body myositis is a slowly progressive symmetrical myopathy that, in addition to affecting proximal muscles (often affecting the ability to climb stairs) also affects flexors of the fingers and wrists. This also generally has elevated CK levels but the sedimentation rate is variably elevated. This condition is characterized by cytoplasmic inclusions on muscle biopsy, and there is no effective treatment. Distinct from dermatomyositis and polymyositis, this generally occurs in late middle aged and older individuals and is more insidious. Unfortunately, this does not usually respond to immunosuppression.
The second main group of disorders affecting muscles includes diseases that cause more of a functional defect than a structural fiber degeneration (little wasting). These conditions are ion channelopathies.
- Myotonic disorders: Myotonic disorders: Here we have congenital myotonia and paramyotonia congenita. In the former condition (due to chloride transport abnormality) the symptoms improve with exercise, while the latter condition (due to sodium channelopathy) worsens with exercise and with cold. Needle insertion into muscles usually easily identifies myotonic potentials.
- Periodic paralysis: These are thyrotoxic periodic paralysis and familial periodic paralysis (hypo-, hyper-, or normokalemic and Andersen syndrome). These often produce generalized and temporary weakness after large meals or exercise. Diagnosis can be made by provoking the weakness with a glucose load and exercise.
Myotonias and periodic paralyses are rare and are recognized clinically. Electromyography may show typical myotonic discharges. Treatment of symptoms and avoidance of precipitating factors may be helpful in both groups.
Collectively, these conditions result in non-inflammatory degeneration of muscles
This is the most common type and is a sex-linked recessive trait. It affects young boys, in whom pseudohypertrophy of the calves and weakness of the hip and shoulder girdles progress from early childhood. Levels of serum muscle enzymes (CPK and aldolase) are extremely high. The children are usually confined to a wheelchair by the age of 10, and they usually die in the second to third decade. It is due to a mutation in the gene for an inappropriately-named normal protein named dystrophin. A less severe mutation in this same gene is responsible for a somewhat later onset dystrophy, Becker dystrophy. No effective therapy is known, although steroids may slightly prolong the course.
This is a heterogeneous group of conditions that usually appear in adolescence or adult life with proximal limb weakness. The weakness usually progresses slowly, but it may arrest spontaneously. There are at least 15 different mutations that contribute to this presentation and some are passed on recessively while others have dominant inheritance.
This condition also can be recessive or dominant and appears to have at least several different genetic abnormalities producing this phenotypically distinct pattern of weakness and wasting. Symptoms usually appear in adolescence or very early adult life with weakness of face muscles and of muscles attached to the scapula and proximal upper limb. The weakness usually progresses slowly and life expectancy is normal. Mental retardation is common and there may be abnormalities of cardiac rhythm.
In this disease myotonia (delayed relaxation of muscles) is combined with dystrophy (muscle atrophy not secondary to peripheral nerve or anterior horn cell involvement). The disease, which is transmitted as an autosomal dominant condition, usually begins in childhood or young adult life (possibly infancy with maternal transmission). There are cases where it has been unrecognized until advanced ages, however. It is due to repeats in the sequence of the myotonic protein kinase gene. These repeats often get longer in sequential generations, with earlier onset of symptoms.
Myotonic dystrophy, as opposed to most forms of myopathy, is distal, affecting the muscles of the hands before more proximal musculature. In addition, facial and neck musculature are involved early. Evidence points to an abnormality of membranes that is not restricted to muscle. Numerous non-neurologic problems are found: frontal balding, testicular atrophy, diabetes, cardiac arrhythmias, and others. It progresses slowly. Many victims succumb to respiratory failure and superimposed infection by the fifth decade.
- Brooke, M.H.: A Clinician's View of Neuromuscular Diseases. Baltimore, Williams & Wilkins Co., 1977.
- Dyck, P.J., Thomas, P.K., Lambert, E.H.: Peripheral Neuropathy, Philadelphia, W.B. Saunders Co., 1975.
- Engle, E.J., Banker, B.Q.: Myology. New York, McGraw-Hill, 1986.
- Walton J.N.: Disorders of Voluntary Muscle, ed. 4, New York, Churchill Livingston, 1981.
Define the following terms:neuropathy, myopathy, neuromuscular junction/myoneural disease, "dying back", demyelinative, Wallerian degeneration, epineurium, perineurium, endoneurium, Schwann cells, myelin, entrapment neuropathy, carpal tunnel, lateral femoral cutaneous neuropathy/meralgia paresthetica, polyneuropathy, Charcot-Marie Tooth, Lambert-Eaton myasthenic syndrome, paraneoplastic syndrome, myasthenia gravis, nerve conduction study, electromyography.
21-1. What modalities are conveyed by large, myelinated nerve fibers?
21-2. What do small-diameter sensory nerve fibers convey?
21-3. What is entrapment neuropathy?
21-4. What are symptoms of polyneuropathy?
21-5. What are the causes of polyneuropathy?
21-6. What are the potential causes of myopathy?
21-7. What are the common symptoms of myopathy?
21-8. What effect do myopathies have on reflexes?
21-9. What additional test would point to myopathy as a cause of weakness?
21-10. What is the most common neuromuscular/myoneural junction disease?
21-11. Who is most often affected by myasthenia gravis?
21-12. What are the symptoms of myasthenia gravis?
21-13. What blood test may be helpful in diagnosis of myasthenia gravis?
21-14. What regions of the body are most commonly affected by myasthenia gravis?
21-15. What is the treatment for myasthenia gravis?
21-16. What is Lambert-Eaton myasthenic syndrome?
21-17. What is the function of nerve conduction studies?
21-18. What does electromyography evaluate?