Peripheral Neuropathy

Neuropathies comprise a group of disorders that affect the neuron of the motor unit. It is important for the veterinary surgeon to understand the pathophysiology of peripheral neuropathy in order to recognize clinical signs and make appropriate decisions for surgical intervention. Clinical presentation of orthopedic, spinal and muscle disorders often will mimic peripheral neuropathy and pose a diagnostic dilemma for the clinician. Conversely, polyneuropathy can cause paraparesis or tetraparesis that must be differentiated from orthopedic or spinal cord disease or other components of the motor unit (neuromuscular junction or muscle). In this chapter we review basic anatomy and physiology of the peripheral nervous system and associated clinical features of peripheral neuropathy. Other excellent resources to consider for more in-depth knowledge relevant to specific neuromuscular diseases and their categorical descriptions are provided by Shelton [1,2] and Braund [3].

Anatomy and Physiology

The peripheral nervous system (PNS) consists of those structures (including cranial nerves and spinal nerves) containing motor, sensory, and autonomic nerve fibers or axons that connect the central nervous system (CNS) with somatic and visceral end organs. Anatomic structures that comprise the peripheral nervous system are derived from the neural crest from which several cranial nerves also receive contributions from ectodermal placodes [4]. Nerve fibers that terminate either in striated muscles or viscera are termed somatic or visceral, respectively. There are 12 pairs of cranial nerves with afferent and efferent fibers that traverse to and from the brainstem [5]. The spinal nerves usually number in 36 pairs for the dog and cat [6]. Of the spinal nerves, 8 are in the cervical (C1-8) region, 13 in the thoracic (T1-13) region, 7 in the lumbar (L1-L7) region, 3 in the sacral (S1-3) region, and 5 or more in the caudal region. Each pair of spinal nerves communicates with the spinal cord segment of the same number. The somatic peripheral nervous system (PNS) consists of ventral and dorsal rootlets, spinal nerve roots, spinal nerves, dorsal and ventral rami, plexuses, and individual peripheral nerves and their branches [6]. The C6-T2 spinal cord segments comprise the cervical intumescence from where the nerve roots of the brachial plexus originate [7,8]. The L4-S3 spinal cord segments comprise the lumbosacral intumescence which contributes to the cauda equina and the lumbosacral plexus [9,10]. Nerve roots are minimally myelinated and traverse within the subarachnoid space containing cerebrospinal fluid (CSF). Thus, nerve roots are more susceptible to traction injury, and exposure to toxic and infectious agents. The nerve roots exit as spinal nerves through intervertebral foramina as myelinated fibers. Similarly, cranial nerves exit from foramina of the skull.

The visceral nervous system includes components of the central and peripheral nervous system that are involved in the homeostatic control of body functions [11]. The autonomic nervous system is subdivided into parasympathetic and sympathetic and includes only the general visceral efferent or motor components [12]. The neural pathway consists of two neurons; the first neuron (preganglionic neuron) is located in the CNS and terminates in ganglia in the PNS. The second neuron (postganglionic neuron) is located outside the CNS in the ganglion and terminates on an effector organ. The parasympathetic division is known as the craniosacral division of the autonomic nervous system because preganglionic neurons are located in the brainstem and the sacral spinal cord. Preganglionic neurons are located in the parasympathetic nuclei of cranial nerves III, VII, IX, X, and XI and in the intermedial lateral gray matter of the sacral spinal cord. The sympathetic division is known as the thoracolumbar division of the autonomic nervous system. The preganglion neurons are located in the intermedial lateral gray matter of the thoracic and first four to five lumbar spinal cord segments. Preganglionic neurotransmission in both systems is cholinergic, by which acetylcholine binds to the nicotinic receptors on the postganglionic neuron. In the parasympathetic system, postganglionic neurotransmission occurs with the binding of acetylcholine to a muscarinic receptor of the effector organ; in the sympathetic system, the postganglionic neurons synapse on noradrenergic receptors via the neurotransmitter norepinephrine [11].

An individual peripheral nerve contains a variable mix of nerve fibers, myelinated and unmyelinated [6]. Most peripheral nerves contain both motor and sensory axons. Motor axons of spinal nerves and cranial nerves originate from neurons that lie within the gray matter of the spinal cord (ventral horn) and brainstem, respectively. Cell bodies for sensory axons are contained within the dorsal root ganglia or ganglia of cranial nerves. One nerve fiber consists of an axon surrounded by a myelin sheath which is composed of neurolemma (sheath of Schwann). Afferent fibers (sensory) can be myelinated or unmyelinated. Efferent fibers (motor) to striated muscle are always myelinated. Unmyelinated efferent fibers are postganglionic sympathetic fibers supplying smooth muscles.

The peripheral nerve in cross-section is composed of many nerve fibers arranged into fascicles (Fig. 43-1). The nerves have three separate connective tissue sheaths: endoneurium, perineurium, and epineurium [13]. The loosely arranged endoneurium immediately surrounds myelinated and unmyelinated fibers. Bundles of fibers are gathered into fascicles surrounded by a perineurium. The epineurial epineurium encases the nerve trunk, containing fascicles that are separated by mesoneurium (epifascicular epineurium). The epineurium contains connective tissue, small lymphatics, and blood vessels that supply the nerve. The number and size of fascicles within a nerve can vary from one nerve to another but also within the same nerve along its course [14].

Figure 43.1. Peripheral nerve in cross section of 7 fascicles surrounded by perineurium that is ensheathed by epineurium and mesonerium. Nerve fibers of varying myelin thicknesses are separated by endoneurium.

Neuron

A neuron consists of three parts: cell body (perikaryon or soma), dendrite, and axon. The cell body contains the nucleus. Dendrites are extensions of the cell body and function to transmit excitatory or inhibitory impulses toward the cell body. Axons are usually single, straight structures that project further away from the cell body than dendrites and branch near their synaptic terminus. Axons often acquire a myelin sheath. Communication of an electrical signal (action potential) between an axon terminal and the dendrite or somatic membrane of another neuron is called electrical transmission. The electrical impulse occupying the axonal terminal (presynapse) leads to release of a transmitter (chemical transmission) which interacts with receptor molecules in the postsynaptic membrane of the receiving cell [15].

Axon

The origin of the axon from the cell body is the axon hillock and initial segment, which are unmyelinated [13]. The axon hillock and initial segment are considered the trigger zone, which contains a high concentration of voltage-gated sodium channels [15]. This area is considered to have a low threshold and be the site for generation of an action potential. Conduction of an action potential is considered polarized relative to the cell body; it propagates in an orthodromic direction toward the terminus. An action potential that is artificially induced on the axon also can conduct toward the cell body (antidromic propagation).

The axoplasm contains neurofilaments, mitochondria, and agranular endoplasmic reticulum [13]. Axoplasmic flow is bidirectional along the axon. Longitudinally oriented neurofilaments and microtubules interconnected by cross-bridges transport substances away from the cell body to the axon terminal (anterograde transport) and from the distal axon to the cell body (retrograde transport). Anterograde and retrograde transport play an important pathophysiologic role in the transmission of neurotoxins (i.e., tetanus toxin) and neurotropic pathogens (i.e., rabies and pseudorabies viruses) [16]. Flow rates differ as slow (1 mm/day) and fast (10 mm to 2 m/day) [13]. Slow flow consists of soluble proteins and of particulate matter for growth and maintenance of the neuron. Fast flow consists of organelles, mitochondria, and materials for enzymatic reactions to facilitate synaptic transmission. Microtubules are organelles that facilitate fast axonal flow.

Myelin

Myelin is formed by Schwann cells in the PNS and oligodendrocytes in the CNS. Processes from these cells wrap around an axon in a unique multilamellar structure analogized as a "Swiss roll" to fuse with the inner axonal membrane. Myelin provides a role in axonal support and maintenance [17]. The correct thickness of the myelin sheath is regulated by a transmembrane protein expressed by the axon [18]. The myelin sheath is not continuous over the length of the axon but is interrupted at regular intervals (1 μm) at the nodes of Ranvier, so that the axon membrane is in direct contact with the extracellular fluid [13]. The cylindrical sheath of myelin between the nodes is called the internode. Internodes can be as long as one mm. The node of Ranvier is considered an electrotonic sink consisting of a high density of sodium channels for depolarization to occur [19]. Myelin acts as an insulator by having high resistance and low capacitance to the internode region. This allows an electrical impulse to propagate rapidly down the axon, jumping from node to node, a process called saltatory conduction (Fig. 43-2).

Figure 43.2. Saltatory conduction of an action potential along a myelinated axon. Transmembrane action potential currents (inward sodium movement and outward potassium movement) occur only at the nodes of Ranvier that contain a high density of voltage-gated sodium changes. The internodal region of the axon facilitates very rapid movement of currents down the axon. (Modified with permission from Blankenship JE: Neurophysiology. St. Louis, Mosby Inc. – Elsevier Science, 2003) [19].

The conduction velocity in myelinated fibers is much faster than in nonmyelinated axons. Conduction velocity for motor and sensory nerve fibers varies from 50 to 120 m/sec. The larger the diameter of the axon, the thicker is the myelin sheath. The longer the internodal distance, the faster is the conduction of the action potential. Small myelinated fibers (fast, sharp pain) conduct at rates of 12 to 30 m/sec; unmyelinated C fibers (slow, dull pain) conduct at much slower rates of 0.5 to 2 m/sec.

Action Potential

The basis of electrical transmission within the nervous system is the action potential [19]. The action potential, "nerve impulse", is a brief electrical signal within nerve and muscle cells (Fig. 43-2). The change in membrane potential represents a transient change from the resting state, in which the internal potential of the neuron moves from an equilibrium resting state (resting membrane potential -70 mV) to a positive value and then back to the resting state. At the resting potential (-60 mV), the electrical and concentration gradients act on sodium and potassium ions across the membrane. The gradients at rest are nearly equal for potassium, but for sodium both the concentration and electrical gradients are directed inward. The action potential is caused by the membrane's becoming suddenly permeable to sodium ions (depolarization) until the membrane potential reaches the sodium equilibrium potential (+55 mV). As the electrical gradient of sodium and potassium become equal, the electrical gradient for potassium is directed outward. If the neuron is made highly permeable to potassium and impermeable to sodium, the potassium ions readily move out of the cell in response to the outwardly directed concentration and electrical gradients. The efflux of potassium ions causes the neuron to become increasingly negative (repolarization) until the membrane reaches a potassium equilibrium potential (-75 mV; hyperpolarization).

Motor Unit

A motor unit is composed of a neuron cell body, its axon, the neuromuscular junction, and associated muscle fibers. A group of myofibers innervated by one neuron is considered a motor unit. An abnormality in any portion of the motor unit can result in clinical signs of neuromuscular disease - lower motor neuron. The functional component of the motor unit involves the reflex arc. The arc consists of a sense organ, an afferent neuron (cell body in dorsal root ganglion), one or more synapses centrally, an efferent neuron, and an effector organ. An all-or-none action potential is generated in the afferent nerve and modulated centrally to be generated again as an all-or-none potential in the efferent nerve. A reflex with a single central synapse is a monosynaptic reflex (i.e., patellar reflex); a reflex with more than one central synapse (interneurons) is a polysynaptic reflex (i.e., flexor withdrawal reflex).

The LMN system consists of three functional divisions: general somatic efferent, special visceral efferent, and general visceral efferent systems [20]. The general somatic efferent system consists of spinal motor neurons and cranial nerves III, IV, VI, and XII, which innervate voluntary striated muscles. The special visceral efferent system consists of cranial nerves V, VII, IX, X, and XI, which innervate voluntary striated muscle associated with respiratory and gastrointestinal functions. The general visceral efferent system consists of the parasympathetic and sympathetic nervous systems that innervate involuntary smooth muscle.

Pathophysiology of Neuropathy

Peripheral neuropathies consist of disorders that affect the axon -- axonopathies; the Schwann cells or myelin directly -- myelinopathies (demyelinating diseases); or both the axons and Schwann cells -- mixed axonal and demyelinating diseases. Underlying pathologic processes of the peripheral nerve include Wallerian degeneration, axonal degeneration, and segmental and diffuse myelin degeneration (Fig. 43-3) [21]. In most cases, these pathologic reactions are not disease-specific but occur in various combinations with peripheral nerve disease. Axonal degeneration and demyelination specify the underlying pathologic process and location to the peripheral nerve, but rarely occur as separate disease entities. Central neuropathies that affect the neuronal cell bodies are termed motor neuron disease.

Figure 43.3. Basic pathologic processes affecting peripheral nerves. Wallerian degeneration shows degeneration of the axon and myelin distal to the site of axonal damage (arrow). In axonal degeneration, primary neuronal disease causes distal degeneration of the axon and myelin (arrow). Note the eccentric displacement of the nucleus and swelling of the neuron cell body with Wallerian degeneration and axonal degeneration. Both Wallerian and axonal degeneration cause neurogenic muscle atrophy. With segmental demyelination the axon is spared, thus no muscle atrophy occurs.

Wallerian Degeneration

Original classifications of peripheral nerve disorders were based on anatomic and clinical observations following focal nerve damage. Waller demonstrated predictable degeneration of nerve fibers in the distal stump of a transected nerve, describing alterations of the axolemma with subsequent dissolution of axons and myelin [22]. Seddon followed with a clinical classification of nerve injury, using morphologic and electrophysiologic studies [23]. Neurapraxia is a transient interruption of the nerve function and conduction without associated axonal degeneration. Pathology involves myelin injury or an ischemic process. Recovery can occur within hours to weeks. Axonotmesis describes focal destruction of axons and myelin sheaths from the neuronal cell body. The endoneurium and Schwann cell sheath remain intact. Axonal and myelin degeneration (Wallerian degeneration) occurs distal to the lesion site. Wallerian degeneration consists of degeneration of both the axon cylinder and myelin sheath distal to the site of axonal damage. Severance of the axon prevents transport of organelles to the distal axon for replenishing membrane reconstruction and neurotransmitter processes. The motor neuron undergoes chromatolysis with rounding of the cell body, eccentrically displaced nucleus, and dispersion of chromatin. Recovery is prolonged (1 mm per day), occurring first in nerve segments closest to the site of damage. Completeness and length of recovery depend on the degree of nerve disruption and the distance to the end organ. Neurotmesis describes complete transection of the nerve from its cell body. Regenerating axons often take an aberrant course with fibroblastic formation to form a neuroma. Both axonotmesis and neurotmesis are followed by Wallerian degeneration.

Axonal Degeneration

Axonal degeneration results from disease within the neuronal cell body or of the axon itself. Often the degeneration of the axon and its myelin sheath begins distally and extends proximally. The neuron undergoes chromatolysis. This process has been termed as "dying-back" neuropathy, distal axonopathy, or distal sensorimotor neuropathy. These processes preferentially affect long, large-caliber, myelinated nerve fibers. Clinical signs usually are recognized first in the distal limbs as a consequence of the distance of the nerve from the cell body. Both axonal degeneration and Wallerian degeneration cause neurogenic muscle atrophy. The time of onset usually is considered chronic, with a progressive time-course. These disorders often are inherited, idiopathic, or toxic in origin.

Demyelination

Demyelination is caused by disease of the Schwann cell or myelin sheath. Demyelination is loss of the myelin sheath along the length of the internode (segmental demyelination) or near the paranodal area (paranodal demyelination). Disease can occur continuously (diffuse demyelination) or randomly along the nerve path. Diffuse myelinopathies occur with inherited, metabolic, and toxic disorders. In immune-mediated neuropathies, nerves are damaged by cellular or humoral mechanisms on various components of myelin. Repeated processes of demyelination and remyelination also occur with some disease processes, i.e., inflammatory demyelinating polyneuropathies. Remyelination restores function. Disruption of the myelin sheath causes the electrical current to dissipate through the internode as a result of increased capacitance and decreased resistance. This results in a longer time to charge the next internode, thus prolonging the conduction time. Conduction failure occurs with severe demyelination.

Diagnostic Approach

Establishing an accurate diagnosis is based on following a logical sequence of diagnostic tests. History provides the signalment, presenting clinical signs, background, and time of onset and temporal progression of clinical signs. Specifically, disorders of the motor unit with acute onset include polyradiculoneuritis, tick paralysis, botulism, and fulminant myasthenia gravis. Myopathic and neuromuscular junction (i.e., myasthenia gravis) diseases often are episodic in onset. Signalment is especially important in young animals with a predilection for breed-specific neuropathies. A physical examination is performed to localize the clinical signs and detect other systemic abnormalities. The neurologic examination will establish the existence of peripheral nervous system disease and further assist with determining disease symmetry and distribution (focal, multifocal, or diffuse). The neurologic examination should include sensory testing. Proper neuroanatomic localization is crucial to the direction of the diagnostic approach. A complete blood count, serum chemistry (including creatine kinase concentration and electrolytes), and a urinalysis serve to establish a baseline health profile and further identify other systemic abnormalities. Thoracic radiography may show evidence of concurrent megaesophagus and aspiration pneumonia, which can be a sequela of peripheral neuropathy. Additionally, thoracic radiography and abdominal ultrasonography are used to screen for underlying metastatic disease and evidence of paraneoplastic neuropathy. CSF analysis will show abnormalities in cellularity and protein concentration with some peripheral neuropathies. Serology is useful to evaluate for infectious and immune-mediated diseases. Endocrine function testing, especially thyroid hormone, will further delineate any underlying cause of the neuropathy.

Diagnostic Electrophysiology

Electrophysiology is useful for determining disease localization within the motor unit and the extent of the disease process [24]. Temporal development of neuropathies has important implications for diagnostic yield of the electrophysiologic examination. Neuropathic disease must be present for 3 to 7 days before evidence can be detected by electrodiagnostic examination [25]. Diagnostic electrophysiology is thoroughly reviewed in Chapter: Electrodiagnosis

Briefly, electromyography (EMG) will assess electrical activity within a discrete region of an accessible muscle. The activity is recorded by inserting a needle electrode into the muscle. The pattern of electrical activity in muscle has been characterized and abnormalities have been correlated with some disorders at different levels of the motor unit. Relaxed muscle normally shows no spontaneous electrical activity except in the end-plate region, but various types of abnormal activity occur spontaneously in diseased muscle. Typically, abnormalities caused by denervation occur on EMG with axonal disease but not with pure demyelinating disorders.

Nerve conduction studies provide a technique of confirming the presence and extent of peripheral nerve damage. Studies of several types of acquired and hereditary axonal and demyelinating neuropathies have shown different patterns of distribution, which further assist with differential diagnosis. Motor nerve conduction studies are performed by recording the electrical response of a muscle to stimulation of its motor nerve at two or more points along its course. This permits the conduction velocity, amplitude, and duration of action potentials to be determined in the fastest-conducting motor fibers between the points of stimulation. Results may give an indication of altered function of axons and myelin. Sensory nerve conduction studies are performed by determining the conduction velocity and amplitude of action potentials in sensory fibers when these fibers are stimulated and responses recorded at another point along the course of the nerve. Conduction studies do not provide information regarding smaller fiber function; thus autonomic nerve abnormalities go undetected. F wave- response studies evaluate the latter motor response; F waves may be abnormal when lesions of the proximal portions (nerve roots) of the peripheral nervous system are present.

Muscle and Nerve Biopsy

Histopathologic examination of a muscle biopsy specimen is a critical part of the evaluation of a motor unit disease and can indicate whether the underlying weakness is neurogenic or myopathic in origin [26]. With neuropathic disease, myofibers can show angular atrophy, small and large grouped atrophy, fiber-type grouping if denervation has been followed by reinnervation, replacement of muscle fibers by fatty tissue, and pyknotic nuclear clumps in end-stage disease (Fig. 43-4). In myopathic disease, pathologic changes can include variability in fiber size, necrosis and phagocytosis, cellular infiltrations, connective tissue expansion, cytoarchitectural abnormalities, and inclusions and vacuoles (Fig. 43-5).

Figure 43.4. Specific patterns of muscle fiber atrophy are present in denervation. Angular atrophied fibers may be scattered among fibers of normal size or be present in small and large groups (A: H&E stain). With end-stage denervation, pynotic nuclear clumps are obvious (B: H&E stain), and muscle fibers are replaced with fatty or connective tissue. Fiber type grouping is an indicator of chronicity and reinnervation (C: ATPase reaction at pH 9.8; type 1 fibers are light and type 2 fibers are dark; D: acid reversal of ATPase reaction at pH 4.3 with type 1 fibers dark and type 2 fibers light). Note loss of the normal mosaic pattern of muscle fiber types. Magnification X 100 for all images.

Figure 43.5. Pathologic changes typical of muscle disease include degeneration and regeneration as in muscular dystrophy (A: H&E), multifocal areas of mononuclear cell infiltration in inflammatory myopathy (B: H&E), excessive accumulation of storage products such as neutral triglycerides in lipid-storage myopathy (C: oil red O stain), and cytoarchitectural changes such as the central accumulations of mitochondria in inherited myopathy of Great Danes, previously called central core myopathy (D: succinic dehydrogenase reaction). Magnification X 100 for all images.

A properly processed peripheral nerve biopsy often provides insight into the pathologic process of peripheral nerve disease. Techniques for collection of nerve biopsies have been described in detail, but often consist of a fascicular biopsy [26,27]. Evaluation of resin-embedded semi-thin sections provides the most information regarding axonal degeneration and regeneration, demyelination and remyelination, and abnormalities of supporting structures (Fig. 43-6). In selected cases, electron microscopy, teased nerve fibers, and nerve fiber morphometry can provide additional information. Processing of peripheral nerve biopsies for only paraffin or frozen sectioning provides only limited information.

Figure 43.6. Pathologic changes in resin-embedded nerve-biopsy sections typical of peripheral nerve disease. Nerve fiber loss and endoneurial fibrosis (A) are common findings in dogs with chronic peripheral neuropathy and may also be found in cats. Nerve fiber loss is usually a sequela of chronic axonal degeneration (B). Myelin ovoids (black arrows) and foamy macrophages (white arrows) may be seen. Active axonal degeneration (C; black arrows) and regenerating clusters (white arrows) are commonly found. In chronic demyelinating disorders (D), onion bulbs (arrows) and inappropriately thinly myelinated fibers are typical of recurrent episodes of demyelination and remyelination. Toluidine blue-basic fuchsin, magnification X 40 for A and X 100 for B-D.

Clinical Features and Differentials

Pattern recognition of clinical signs assists with ascertaining an underlying cause and formulating a diagnostic plan and possibilities of treatment. Specifically, establishing a time course of the disease process is informative. Most acute polyneuropathies develop over 2 to 3 days and include inflammatory, immunologic, toxic, or vascular causes. Some toxic, nutritional, and systemic diseases of the nerve will develop over weeks. Chronic neuropathies that develop over weeks to months include inherited and/or degenerative, metabolic, paraneoplastic, and idiopathic diseases. Chronic neuropathy also may have a time course with intermittent periods of improvement.

Patterns of peripheral neuropathy are described based on distribution: neuronopathy, polyneuropathy, polyradiculopathy, mononeuropathy, and plexopathies. Neuronopathies are selective for loss of sensory or motor neurons. Polyneuropathies are diffuse lesions of the peripheral nerves that produce weakness, sensory disturbance, and/or reflex abnormalities. In general, polyneuropathies involve several nerves and are bilateral and symmetrical. Differential diagnoses for symmetric neuropathies include degenerative, metabolic, idiopathic, and toxic diseases. Idiopathic polyneuropathy is the most common diagnosis. Polyradiculopathies imply nerve root involvement and present with asymmetric signs, weakness, and multifocal sensory disturbance. Asymmetric and multifocal neuropathies often are associated with inflammatory, immune-mediated, or ischemic disease.

Mononeuropathy is a disorder of a single peripheral or cranial nerve, often owing to trauma or entrapment and, less commonly, from tumor infiltration, inflammation, and ischemic infarction. Mononeuropathies of cranial nerves also occur as idiopathic disease. Plexopathies involve multiple nerves within the brachial or lumbar plexus and usually affect one limb. Disorders of the brachial plexus and other mononeuropathies (Table 43-1) are covered in more detail in Chapter 44: Traumatic and Neoplastic Diseases of the Brachial Plexus.

Peripheral Nerve Disease

Peripheral neuropathies are broadly classified as motor neuron disease, motor neuropathy/radiculopathy, sensory neuropathy, autonomic neuropathy, and mixed neuropathy. Most peripheral neuropathies or polyneuropathies involving spinal nerves are considered mixed neuropathies that affect motor, sensory, and autonomic nerves in varying degrees. Pathologic studies of peripheral neuropathies show a combination of demyelination and axonal degeneration. The distal axon of the nerve is more sensitive to disease as a result of its distance from the cell body and interruption of axonal transport. Some peripheral nerve diseases affecting the axons and myelin involve both the CNS and PNS, but clinical signs manifest as disease of the PNS. Differential diagnoses for polyneuropathy consist of a wide spectrum of diseases (Table 43-2).

Motor Neuron Disease

Motor neuronopathies are disorders of the ventral horn cells that cause generalized weakness. Loss of motor neurons results in progressive weakness with muscle atrophy. A characteristic feature of motor neuron disease that differs from peripheral neuropathy is muscular weakness and fasciculations with muscle atrophy, but preservation of reflexes until the disease is advanced [28]. Motor neuron diseases are rare, usually occur in young growing animals, and have an insidious and progressive clinical disease course. Inherited forms have been described in the Brittany spaniel [29], English pointer [30], Swedish Lapland dogs [31], and the Maine coon cat [32], and are suspected for other breeds [28]. An adult form has been reported in cats [33].

Motor Neuropathy/Radiculopathy (Polyneuropathies and Mononeuropathies)

Peripheral neuropathies that involve the motor nerve and nerves roots often manifest as hallmark signs of lower motor neuron disease with impairment of motor function. Motor neuropathies are characterized by a flaccid paresis or paralysis, postural reaction deficits, neurogenic muscle atrophy, and reduced to absent spinal reflexes [22]. Muscle fasciculations, spasms, and cramps also can occur. Tremors can be a clinical feature with some pure demyelinating diseases [34,35]. Neurogenic muscle atrophy is rapid and severe, occurring within 1 to 2 weeks from onset of clinical signs and progressing to joint contracture in chronic cases [3]. Muscle atrophy is a clinical feature for Wallerian degeneration and axonal degeneration, but not for pure myelinopathies (axons still remain intact).

Gait evaluation commonly reveals moderate to severe sensory ataxia with loss of proprioceptive fibers. Animals with lower motor neuron dysfunction often have a shortened stride and an inability to support weight associated with the appendicular and axial musculature. Limb tone is reduced, and flaccidity often becomes more apparent in the distal limbs [36]. Limb posture will be crouched with tendency for joints to be flexed. Ventroflexion of the neck also signifies generalized weakness. Dogs with only distal polyneuropathy often show a high-steppage or pseudohypermetric pelvic limb gait [37]. This represents a compensatory response to allow the carpi or tarsi to flip forward for limb placement. It is not uncommon for polyneuropathy to manifest as paraparesis before tetraparesis because the longer (sciatic nerve) and more myelinated proprioceptive fibers usually are affected first.

Loss of tendon and flexor withdrawal reflexes is a sign of peripheral nerve disease. Early in acute polyneuropathy, the reflexes may be diminished although not absent, but they become more reduced from day to day. In disease of small fibers, tendon reflexes still may be retained [38]. Conversely, reflexes can be diminished out of proportion to weakness because of involvement of the large afferent fibers of muscle spindles.

Disease of spinal nerves (mixed nerves) often causes sensory loss along with motor deficits distal to the lesion [39]. Hypesthesia or anesthesia may be evident with involvement of the sensory component of the nerve. Hypesthesia denotes decreased sensation or partial lesion; anesthesia refers to a complete lesion. Sensory function may be normal or decreased with polyneuropathy. A hallmark feature of mononeuropathy associated with complete nerve transection is anesthesia of a specific dermatome. A dermatome refers to a cutaneous region innervated by afferent nerve fibers from a single spinal nerve [6]. Cutaneous sensory testing uses the two-step pinch technique to assess nociception (superficial and deep pain) with the autonomous zone of the dermatome being tested [40]. A conscious response or withdrawal reflex indicates function of the peripheral nerve being tested. Loss of deep nociception indicates a poor prognosis.

Sensory disturbance also may reflect increased sensitivity to stimuli. Pain associated with disease of the peripheral nerve is termed neuropathic pain [38]. In humans, types of neuropathic pain manifest as symptoms (i.e., tingling, burning, prickling, etc.) that we are unable to recognize in animals. Sensory disturbances in animals may manifest as clinical signs of dysesthesia (paresthesia) and hyperesthesia [39]. Hyperesthesia is a general term for increased cutaneous sensitivity from a non-noxious stimulus. Dysesthesia denotes an abnormal sensation without application of an external stimulus. Animals with peripheral nerve regeneration are predisposed to mutilation of the anatomic area undergoing reinnervation as a result of axonal sprouting and excessive excitation causing dysesthesia [39]. Dysesthesia also may result from irritation of the nerve sheath itself. Tactile stimuli may cause a perversion of sensation or allodynia, which refers to a type of stimulus that evokes another type of sensation (i.e., touch as pain). This may be related to the type of pain observed with polyradiculopathies and diabetes mellitus.

Sensory Neuropathy

An animal with a pure sensory neuropathy may show gait and postural reaction deficits (sensory ataxia), decreased nociception, paresthesia, evidence of self-mutilation, and reduced to absent spinal reflexes without muscle atrophy [36]. Pure sensory neuropathies are rare and often have an inherited cause [41]. Some acquired diseases also may show sensory disturbances [42]. Unlike in humans, clinical signs of sensory loss (numbness, pain, temperature alterations) associated with polyneuropathy in animals often are impossible to recognize or go undetected.

Autonomic Neuropathy

Autonomic nerve dysfunctions arise coincident with a variety of diseases. Autonomic neuropathy can occur as a single disease entity (dysautonomia) or in conjunction with other polyneuropathies. In veterinary medicine, the term dysautonomia refers to acute or subacute idiopathic panautonomic failure in animals [43]. Common clinical signs of autonomic nerve dysfunction include pupillary impairment, altered tear production and salivation, micturition dysfunction, gastrointestinal stasis, and decreased heart rate variability. These signs can be isolated to a single nerve (i.e., Horner's syndrome) or be multiple as with panautonomic nerve dysfunction. Horner's syndrome (miosis, enophthalmos, ptosis, and third-eyelid protrusion) can occur with disease of the first, second, or third order neuron system. Differential diagnoses include trauma, inflammation, neoplasia, or idiopathic causes [44]. Lower motor neuron injuries (trauma, iatrogenic) are the most common cause of Horner's syndrome in animals [45].

Cranial Nerve Disease

Peripheral neuropathy of cranial nerves can occur with focal, multifocal, or diffuse (polyneuropathy) disease. Mentation, gait, postural reactions, and spinal reflexes are normal with focal neuropathy of a cranial nerve. Typically, only one cranial nerve is affected. If disease is in the brainstem, mentation, postural reactions, gait, and multiple cranial nerves will show abnormalities. Neurologic deficits are more severe on the ipsilateral side. Myopathic and neuromuscular junction diseases also can mimic neuropathy of cranial nerves, i.e,. myasthenia gravis will manifest clinical signs of megaesophagus (regurgitation). Some neuropathies are specific for a particular cranial nerve (Table 43-3) [46-48]. These disorders usually are congenital or idiopathic in origin. Idiopathic neuropathies more commonly affect cranial nerves V and VII [47]. Multifocal disease processes include some hematogenous neoplasms and inflammatory diseases that may cause asymmetric multiple cranial nerve deficits [49]. Neoplastic disease can affect multiple cranial nerves by mass effect or direct extension. Many cranial nerves are located within the superficial structures of the head and are more susceptible to trauma [47].

Multiple cranial nerve deficits with generalized LMN signs should suggest polyneuropathy. Cranial nerves V, VII, VIII, IX, X, and XI usually are involved. Animals with polyneuropathy may also have clinical signs of dysphagia, dysphonia, and dyspnea [47]. Dyspnea associated with upper respiratory tract signs suggests laryngeal paralysis [50]. The laryngeal abductor muscles are innervated by the recurrent laryngeal nerve, which is one of the longest peripheral nerves and thus susceptible to distal neuropathy. Polyneuropathy must be considered as an underlying cause of laryngeal paralysis.51 Diffuse motor neuropathies also cause respiratory compromise if the intercostal and phrenic nerves are involved.