What are the 3 parts of the peripheral nervous system

The peripheral nervous system

The PNS functions via a series of reflex arc circuits with afferent and efferent arms controlled by the CNS. An understanding of the many PNS disorders requires an understanding of the complexities of the macro- and microanatomy of peripheral nerves, as well as their molecular biology, immunology, and pathophysiology (Kanda, 2013).

The pathophysiologic mechanisms that result in peripheral neuropathies are almost as diverse as the number of peripheral nerve diagnoses. However, at a microscopic level the patterns of damage are few. Axonal degeneration occurs distal to a site of nerve transection (which may be physical, inflammatory, or vascular; as well as focal, multifocal, or diffuse). Axonal degeneration can also occur as a distal dying-back phenomenon, especially in toxic and metabolic neuropathies (i.e., axonal polyneuropathies). In many inflammatory neuropathies, segmental demyelination occurs, which may result in conduction failure but not necessarily subsequent axonal degeneration (i.e., demyelinative polyneuropathies). Remyelination (with thin myelin, short internodes, and “onion bulbs”) may occur, restoring more or less adequate clinical nerve function. Axonal regeneration occurs less consistently and over distances of centimeters only (Berry et al., 1995).

C α2C-Adrenoceptor Functions

Several peripheral and central nervous system functions were discovered to be mediated by α2C-receptors. In vitro, α2C-receptors cooperated with α2A- and α2B-subtypes to inhibit neuronal norepinephrine exocytosis (Hein, Altman, & Kobilka, 1999; Trendelenburg, Philipp, Meyer, Klebroff, Hein, & Starke, 2003). However, ablation of α2C-expression in vivo did not lead to an increase in circulating norepinephrine levels but rather caused elevated epinephrine plasma concentrations (Brede, Wiesmann, Jahns, Hadamek, Arnolt, & Neubauer, 2002; Brede, Nagy, Philipp, Sorensen, Lohse, & Hein, 2003). Following this observation, α2C-adrenoceptors were identified in chromaffin cells to inhibit adrenal catecholamine release (Brede et al., 2003). Mice with partial or complete loss of α2C-receptor function showed acceleration of heart failure development after chronic pressure overload (Brede et al., 2002; Gilsbach et al., 2007; Lymperopoulos, Rengo, Funakoshi, Eckhart, & Koch, 2007a). Recent studies have shown that high levels of catecholamines may desensitize adrenal α2C-receptor signaling by increasing protein levels of G protein-coupled receptor kinase 2 (Grk2) thus accelerating the progression of cardiac hypertrophy and failure (Lymperopoulos et al., 2007a; Lymperopoulos, Rengo, & Koch, 2007b; Lymperopoulos, Rengo, Zincarelli, Soltys, & Koch, 2008; Lymperopoulos, Rengo, Gao, Ebert, Dorn, & Koch, 2010; Rengo et al., 2010). In addition, internalization of α2-adrenoceptors may contribute to reduced feedback inhibition of catecholamine release from sympathetic nerves in chronic heart failure (Gilsbach et al., 2010).

Taken together, considerable knowledge about subtype-specific functions of α2-adrenoceptor subtypes has been obtained based on studies in gene-targeted mouse models. However despite this progress, the cellular localization of α2-receptors involved in these biological functions was largely unknown until recently.

Central Nervous System

Acidosis and alkalosis impair central and peripheral nervous system function. Alkalemia increases seizure activity. If pH is 7.60 or more, seizures may occur in the absence of an underlying epileptic diathesis. Acidosis depresses the central nervous system (this most frequently occurs in respiratory acidosis). Early signs of impairment include tremors, myoclonic jerks, and clonic movement disorders. At pH of 7.10 or less, there is generalized depression of neuronal excitability. Central effects of severe hypercarbia include lethargy and stupor at pCO2 of 60 mmHg or more, coma occurs at pCO2 of 90 mmHg or more. Metabolic acidosis causes central nervous system depression less commonly. Fewer than 10% of diabetics with ketoacidosis develop coma (hyperosmolarity and the presence of acetoacetate may be more important than acidosis per se).

Blood pH alters hemoglobin oxygen binding and tissue oxygen delivery. Acidemia decreases hemoglobin oxygen affinity, shifts the oxygen dissociation curve “to the right,” and increases tissue delivery of oxygen. On the contrary, alkalemia shifts the curve to the left, increasing the oxygen binding to hemoglobin and tending to decrease tissue delivery.

3.1 The 5-HT system at a glance

The 5-HT system plays a significant role in the modulation of multiple peripheral and central nervous system functions, such as the control of blood pressure, body temperature, mood, emotion, sleep, appetite and motor activity (Bacque-Cazenave et al., 2020; Spoont, 1992). The system is thought to be involved in the etiology of numerous neuropsychiatric disorders, such as depression and anxiety. Conversely, the 5-HT system is also the target of drugs used as antidepressants and anxiolytics. Furthermore, several studies have indicated that 5-HT plays a role in neurodevelopment (Pratelli et al., 2017) and undergoes degeneration in the neurodegenerative process. Although 5-HT is widely distributed through the brain, most 5-HT neurons innervating the forebrain are confined to the raphe nuclei, which are divided into the dorsal and medial raphe nuclei (DRN and MRN) and are localized in the midbrain (Hale and Lowry, 2011; Steinbusch, 1984). These serotonergic neurons synthesize 5-HT from tryptophan by the enzyme tryptophan hydroxylase 2. The neurotransmitter accumulates in secretion granules before being released to the synaptic cleft. In the central nervous system, the action of 5-HT in the synaptic cleft is terminated via neuronal uptake either by membrane-bound 5-HT reuptake transporters (SERTs) located in 5-HT axon terminals or by non-selective organic cation transporters (low affinity, high capacitance) (Daws, 2009). Thereafter, 5-HT is degraded by the enzymatic metabolism transformation to 5-hydroxyindoleacetaldehyde by monoamine oxidase and 5-hydroxyindoleacetic acid (5-HIAA) by aldehyde dehydrogenases (Cooper et al., 2003). Although 5-HT neurons are relatively few, their long-range projections and highly collateralized axons allow them to innervate the entire brain and spinal cord (Gagnon and Parent, 2014; Steinbusch, 1981). 5-HT neurons are heterogeneous; some raphe neurons present a regular firing pattern, while others fire in a burst pattern (Hajós et al., 1995; Miguelez et al., 2011), and intracellular recordings in brain slices found that 5-HT neurons are either silenced or spontaneously active (Burlhis and Aghajanian, 1987). A population of 5-HT raphe neurons express the vesicular glutamate transporter type 3 VGLUT3 (Amilhon et al., 2010) and have the capacity to co-release 5-HT and glutamate (Belmer et al., 2019), and some neurons lack 5-HT but contain VGLUT3, thus comprising a separate population of neurons (“VGLUT3-glutamate cells”) (Soiza-Reilly and Commons, 2011). There are GABAergic cell bodies, also known as GABAergic interneurons, that form a GABAergic intrinsic network in the DRN (Pineyro and Blier, 1999). Two types of 5-HT axons have been described: one type is thin and has sparse small-ovoid varicosities, and the other type is thick and has large-spheroidal varicosities (Gagnon and Parent, 2014; Hornung, 2003).

8.6 Conclusions

The tests discussed in this chapter assess changes in motor behavior that are linked to multiple aspects of central and peripheral nervous system function. Given the differences between humans and rodent models, the rodent motor behavior tests selected for a study should attempt to reflect the damage to specific brain circuitry during disease states, but should not be expected to faithfully reproduce the clinical manifestations of a human disorder. Using a combination of the motor tests listed can provide sensitive endpoint measures to establish motor disability in the rodent model of interest. In addition, other aspects of nonmotor features can be measured, including Straub tail, horizontally extended, rear-limb withdrawal, body weight, tremors, hind-leg abduction, coat appearance, contact righting reflex, or forelimb position. Because the sensitivity to detect motor deficits using certain test may be age and/or disease-stage dependent, these factors should be taken into consideration when designing a study.

These rodent motor tests not only provide tools to assess basic motor behavior that can be altered during disease states, but also provide a foundation to build better, fully automated monitoring systems that go beyond the simplified assessments conducted by the experimenter. Developing more sensitive, high-speed video with sophisticated image processing can enhance behavioral testing, and facilitate our understanding of neural circuitry, motor behavior, and changes to these parameters in motor disorders. Advanced behavioral systems can also provide additional endpoint measures for the study of potential treatments for motor disorders.

Clinical Features

In CS type I, prenatal growth is normal. Growth and developmental failure begins in the first 2 years. Height, weight, and head circumference will be below the 5th percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function lead to severe disability. Death typically occurs in the first or second decade.

The characteristic features of CS type II are growth failure at birth, with little or no postnatal neurological development. Congenital cataracts or other structural anomalies of the eye may be present. Contractures develop in the spine and joints. Patients typically die by age 7 years. CS type III is rare and has late onset. XP-CS includes facial freckling and early skin cancers typical of XP and some features typical of CS, such as mental retardation, spasticity, short stature, and hypogonadism. Approximately 55 % of affected children develop a pigmentary retinopathy and 60 % develop a sensorineural hearing loss.

60.5.7 Workup of Neurotoxicity

The workup of neurotoxicity in individual patients can be divided into the assessment of the peripheral nervous system (PNS) and the central nervous system (CNS). In general, somewhat more objective measurements (neurophysiologic testing) can be made in examination of the PNS compared to the CNS (neuropsychologic testing) with the exception of objective CNS-evoked potential measurements.

For PNS function, it is important to remember that axonal neuropathies often are associated with deficits of both sensory and motor function. Motor function testing includes: (1) inspection for muscle atrophy, unusual movements, and an analysis of coordination; (2) testing muscle tone and resistance to passive stretch of an extremity; (3) the Babinski reflex; and (4) analysis of the strength of individual muscles. Sensory function testing includes evoking the sensations produced by warmth and cold, pinprick, joint movement, tuning fork vibration, and shapes of complex objects. Cranial nerve examination, especially optic nerve (cranial nerve II) and trigeminal nerve (cranial nerve V) function, is important in evaluation of toxic exposures. Similarly, evaluation of the autonomic nervous system for bladder, bowel, and sexual functions, pupil response, lacrimation, salivation, sweating, and supine–upright blood pressure is important (Spencer et al., 1985).

Knowledge of the specific toxin is helpful in planning and analyzing PNS evaluation. For example, in acrylamide (not a pesticide) neuropathy, sensory symptoms and signs are prominent. By contrast, NTE neuropathy from organophosphates may show retention of sensory function in the face of significant distal wasting and weakness. Nerve conduction velocity may not be altered in organophosphate NTE neuropathy, but a large drop in muscle action potential amplitude (EMG testing) may be observed. Acrylamide toxicity can be detected earlier by monitoring vibration sensation in the fingers (e.g., using a portable Optacon device; Spencer et al., 1985). In hexacarbon solvents (e.g., n-hexane or methylbutyl ketone; not pesticides) toxic neuropathy, use of nerve motor conduction velocity measurements is valuable because these solvents may slow conduction. Blue-yellow color vision loss from solvent exposure is well documented. The Lanthony D-15 desaturated panel test for color vision loss has been validated for use at the workplace as an initial screening tool. Perhaps some of the foregoing testing procedures should be studied for their possible validity to monitor workers exposed to various pesticides.

For CNS function, evaluation of mental status includes assessments of the level of consciousness, orientation, concentration, memory, cognitive functions, behavior, mood, and affect. The most frequently reported behavioral adverse effect of chemicals is a disturbance in psychomotor functioning. Usually, this is characterized by a delay or slowness in response time, clumsy or awkward eye–hand coordination or dexterity, or a combination of these. Diminished attention also has been found (Feldman et al., 1980). For a thorough evaluation of suspected neuropsychological deficits, use of a standard battery (group) of psychological tests is the best available procedure. Examples of such tests include the Halstead-Reitan battery, the Luria-Nebraska battery, and the Pittsburgh Occupational Exposure Test (POET) battery (Ryan et al., 1987). Formal testing is time-consuming and usually is done by psychologists trained in the use of such tests. There is a need for standardized neuropsychological tests that have a sufficient degree of simplicity and speed of administration such that they can be administered more readily to blue collar industrial workers as well as individuals with nonoccupational environmental exposures to pesticides. Furthermore, such test results must be adjusted for age and educational level (Feldman et al., 1980).

A Glial Cells in the Peripheral Nervous System

In the peripheral nervous system (PNS), glial cells occur in two categories: (i) the satellite cells that surround the neuronal somata within the ganglionic mass, and (ii) the Schwann cells that surround the axons coursing outside the central nervous system (CNS), whether such axons derive from PNS ganglionic neurons or CNS spinal cord motor ones and whether or not they become myelinated. As shall be pointed out throughout this review, these two subdivisions of peripheral glia are likely to represent the same cell element assuming different morphological, biochemical, and possibly functional properties according to their position relative to the neuron. The term “Schwann cell,” which will be generally used in the review, therefore may well include the satellite subset of peripheral glial cells.

Satellite and Schwann cells spend most of their developmental life in close physical contact with the neuron. This topographical feature has been examined in great detail using histological and ultrastructural techniques and has prompted a firm belief that biochemical and functional interactions must parallel the physical associations. The most conspicuous Schwann-neuron interaction is the generation of myelin around certain axons; formation, maintenance, breakdown, and restoration of myelin have been extensively investigated in vivo. Much less attention, however, has been given to the identification and characterization of other roles that Schwann cells must play. The complex relationship between Schwann cells and the neuronal membrane strongly implies that these other roles are of critical importance to normal PNS function. Glia-neuron interactions in the CNS are equally indicative of similar glial roles (cf. Varon and Somjen, 1979).

Schwann-neuron interactions must be considered to occur in two ways, from neuron to glia and from glia to neuron. Communications in either direction are likely to be mediated by both macrosignals (i.e., macromolecules presented on cell surface membranes or transmitted through the intercellular fluid) and microsignals (ions, neurotransmitter-related molecules, metabolites, etc.). In vivo studies have provided evidence for the occurrence of some such signals. We know that neurites supply Schwann cells with mitogenic and myelinogenic signals, triggering proliferation and myelin-forming processes, respectively (Asbury, 1967; Landan and Hall, 1976; Speidel, 1964; Friede and Samorajski, 1968; Raine, 1977). Certain transmitters, such as γ-amino butyric acid (GABA), have been shown to be avidly taken up by satellite cells (Schon and Kelly, 1974a,b; Bowery et al., 1979a,b), even though the functional meaning of this glial property remains unclear. There is a strong suspicion that Schwann cells provide signals for both growth and guidance of regenerating axons (cf. Varon and Bunge, 1978; Varon and Somjen, 1979). Nevertheless, thus far, in vivo studies have failed to characterize in any detail the signals themselves and/or their immediate responses.

In recent years a new, very powerful tool has been developed, namely the use of neural cell cultures (cf. Varon, 1975b; Fedoroff and Hertz, 1978; Schoffeniels et al., 1978; Giacobini et al., 1980). In vitro studies can strongly complement in vivo ones. Under appropriate culture circumstances, both neurons and glial cells can display the typical features and behaviors for which they are known in vivo, and thus “recapitulate” development or regeneration as they are perceived in situ (Waxman et al., 1977). In addition, they offer opportunities not available to in vivo research, such as (i) purified populations of Schwann cells and neurons, which can be investigated separately from or after controlled recombination with each other, and (ii) living cells that can be examined in an environment that is uniform, controlled, and amenable to experimental modification.

This review will attempt to provide a detailed survey of the in vitro tools that have become available for the investigation of Schwann cells, and of the substantial amount of information already accumulated through their use. As a background to the following sections, the remainder of this first section will summarize main points derived from in vivo studies of normal and pathological situations. For a detailed coverage of in vivo studies, the reader is encouraged to consult some of the several reviews already available on the subject (Bunge, 1970; Webster, 1974; Aguayo et al., 1979; Pannese, 1980; among others).

The PNS

The PNS comprises cranial nerves 3–12, the spinal roots, sensory and autonomic ganglia, and the somatic nerves. At a cellular level, the PNS is that part of the nervous system which is myelinated by Schwann cells, as opposed to the central nervous system (CNS), which is myelinated by oligodendroglial cells. In humans the transition between the CNS and PNS is quite abrupt, occurring a few millimeters distal to the points of exit of the cranial and spinal roots from the brain stem and spinal cord.

The PNS has three basic functions: (1) conveying motor commands to all voluntary striated muscles in the body; (2) carrying sensory information about the external world and the body to the brain and spinal cord (except visual information: the optic nerves, which convey information from the retina to the brain, are in fact outgrowths from the brain); and (3) regulating autonomic functions such as blood pressure or sweating. Most polyneuropathies impair all three types of PNS function, although disorders selectively affecting motor, sensory, or autonomic functions occur.

In most of the PNS, motor, sensory, and autonomic nerve fibers are intermingled to form mixed nerves, and as might be anticipated, most PNS disorders result in a mixture of motor, sensory, and autonomic dysfunction. However, at the proximal and distal extents of the PNS, functions are anatomically segregated: the ventral spinal roots contain efferent motor and autonomic fibers only, and the dorsal roots comprise only afferent sensory fibers. Likewise, neuronal cell bodies in the dorsal root ganglia, which lie in the intervertebral foramina just proximal to the confluence of the dorsal and ventral spinal roots, are exclusively sensory, and autonomic ganglia contain autonomic neurons only. At the distal extent of their distribution, the motor and sensory axons of mixed nerves are sorted into purely motor or sensory terminal branches. An appreciation of these anatomical arrangements is important in diagnosis as localizing the likely site of the disorder helps narrow the possibilities that must be considered. For example, a disorder affecting sensation and sparing motor and autonomic function can be localized to dorsal roots, dorsal root ganglia, or sensory terminal branches and is unlikely to be arising in mixed somatic or cranial nerves, ventral roots, or autonomic ganglia. The process of localization as the first step in diagnosis, which is axiomatic in brain and spinal cord disorders, is equally important in the PNS, yet it is often neglected.

Throughout the PNS, the same basic histological plan is found. Myelinated and unmyelinated axons, Schwann cells, and interspersed capillary-like blood vessels (collectively referred to as endoneurium) are bundled into fascicles by perineurium, composed of five to ten lamellae of cytoplasm of perineurial cells, a type of modified fibroblast. Most nerves consist of several such fascicles, bound together by a loose connective tissue, the epineurium. Within the epineurium, between the fascicles, are found arterioles and venules of various sizes, structurally similar to those found in other tissues. The epineurial vessels are the major blood supply of the nerve, with the capillary-like endoneurial vessels constituting a parallel system. This dual blood supply ensures that peripheral nerve is relatively well protected from ischemic insult. Cells in both the perineurium and the endoneurial microvessels are interconnected by tight junctions, producing a blood–nerve barrier (or blood–nerve interface). This structural specialization ensures that peripheral nerve axons and Schwann cells occupy an environment whose chemical and cellular constituents are carefully regulated, analogous to the situation for neurons and glial cells in the CNS. Certain parts of the PNS lack this regulated blood–nerve interface: the sensory and autonomic ganglia, the portion of spinal roots and cranial nerves traversing the subarachnoid space, and the distal terminations of motor axons at neuromuscular junctions.

The relative simple histology and function of the PNS limits its range of expressions of pathology. In fact, PNS disorders can be conveniently divided into two main types: diseases primarily affecting axons and diseases in which derangement of myelin is the primary problem, a distinction that is useful for diagnosis as well as for a rational approach to therapy. Nerve conduction studies and needle electromyography, which are easily performed in patients and which are widely available, are used to help characterize a process as demyelinating or axonal.

Given myelin’s physiological role in greatly enhancing the speed of action potential propagation along axons, demyelinating polyneuropathies can be identified by marked slowing of nerve conduction. In genetic disorders of PNS myelination, the nerve conduction slowing affects all peripheral nerves uniformly, whereas acquired causes of PNS demyelination typically affect myelin in a patchy, nonuniform way. A consequence of the latter point is that there may be marked variability in conduction slowing between adjacent nerves, dispersion of compound nerve action potentials, or focal conduction block. In axonal neuropathies, by contrast, nerve conduction velocities are preserved or only minimally slowed, and the loss of functioning motor or sensory axons is reflected in decreased amplitudes of motor or sensory compound nerve action potentials. This dichotomous view of polyneuropathies as either demyelinating or axonal is useful, but it is an oversimplification. Myelin and axon integrity are interdependent, so all types of polyneuropathies ultimately have an impact on both axon and myelin.

The clinical manifestations of a polyneuropathy are determined by the classes of nerve fibers involved. Motor findings are those of the lower motor neuron type, that is, weakness accompanied by decreased muscle tone and decreased or absent reflexes. Axonal loss is also marked by muscle atrophy and, sometimes, fasciculation. The main symptoms of sensory fiber involvement are sensory loss and paraesthesia (abnormal sensations such as prickling or ‘pins and needles’), and the latter are often painful. Examination may show relatively selective loss of only some sensory modalities in diseases that affect only certain classes of sensory fibers (e.g., in most acquired demyelinating neuropathies, the main sensory finding is of vibration and joint position sensation, reflecting a disease process mainly involving large-diameter myelinated axons). Most often the motor and sensory impairments are first manifest and remain most pronounced in the distal parts of the legs and arms, a pattern referred to as a glove-and-stocking distribution. Autonomic dysfunction is prominent in some types of polyneuropathy, and usually vasomotor symptoms such as orthostatic hypotension are the most troublesome. However, a host of other symptoms reflecting autonomic failure may be seen, including absent or excessive sweating, impaired lacrimation and salivation, bladder dysfunction, abnormal intestinal motility, and erectile impotence and other impairments of sexual function.

Determining that a patient has a polyneuropathy usually presents little difficulty, but discovering the cause of the neuropathy can be challenging. The list of potential causes is long (at least 100 are known), and the clinical manifestations of many of these are indistinguishable. The usual clinical approach is to sift through the symptoms, neurological examination findings, and nerve conduction data to see whether the patient may have a syndrome with a short list of possible causes. For example, sensory symptoms and impairment of all sensory modalities without motor or autonomic impairment might lead one to diagnose a dorsal root polyganglionopathy, of which there are only a few causes. In a patient with motor and sensory abnormalities in the distal legs and arms, finding slowed nerve conduction velocities greatly limits the potential diagnoses.

Often, however, a distinctive syndrome is not present, and a broad range of possibilities must be considered. One approach to classifying the possibilities is to separate inherited from acquired diseases and to subdivide the acquired causes into four large categories: metabolic (e.g., diabetes mellitus), infectious (e.g., leprosy), toxic/deficiency states (e.g., vinca alkaloids and other antineoplastic drugs), and immune-inflammatory (e.g., vasculitic neuropathy). Worldwide, the three most common types of polyneuropathy are probably leprotic, diabetic, and inherited. The population from which patients are drawn influences the likelihood of certain diagnoses. For example, leprosy is common in developing countries but rare in North America and Europe. In a hospital-based practice, chemotherapeutic drugs are a common cause of neuropathy.

Establishing a clear etiology for a patient’s polyneuropathy may lead to specific therapy, but equally important, establishing the cause allows the physician to advise the patient about the long-term prognosis (some types of polyneuropathy can lead to major loss of function, but more often the disability is mild or less and does not worsen substantially over the years). Some therapies can be useful in almost all types of polyneuropathy, regardless of cause. Pain is common in many types of polyneuropathy, and drugs for neuropathic pain are a mainstay of therapy in many patients. Medications used include amitriptyline (a tricyclic antidepressant) and gabapentin (an anticonvulsant that reduces synaptic release of neurotransmitters by inhibiting voltage-gated calcium channels). In patients with distal leg weakness, the ankle–foot orthosis (an L-shaped plastic brace that fits into a shoe and is strapped to the leg) holds the foot in neutral position and stabilizes the ankle, improving walking and stability, irrespective of the cause.

The PNS

The PNS comprises cranial nerves 3–12, the spinal roots, sensory and autonomic ganglia, and the somatic nerves. At a cellular level, the PNS is that part of the nervous system which is myelinated by Schwann cells, as opposed to the central nervous system (CNS), which is myelinated by oligodendroglial cells. In humans the transition between the CNS and PNS is quite abrupt, occurring a few millimeters distal to the points of exit of the cranial and spinal roots from the brain stem and spinal cord.

The PNS has three basic functions: (1) conveying motor commands to all voluntary striated muscles in the body; (2) carrying sensory information about the external world and the body to the brain and spinal cord (except visual information: the optic nerves, which convey information from the retina to the brain, are in fact outgrowths from the brain); and (3) regulating autonomic functions such as blood pressure or sweating. Most polyneuropathies impair all three types of PNS function, although disorders selectively affecting motor, sensory, or autonomic functions occur.

In most of the PNS, motor, sensory, and autonomic nerve fibers are intermingled to form mixed nerves, and as might be anticipated, most PNS disorders result in a mixture of motor, sensory, and autonomic dysfunction. However, at the proximal and distal extents of the PNS, functions are anatomically segregated: the ventral spinal roots contain efferent motor and autonomic fibers only, and the dorsal roots comprise only afferent sensory fibers. Likewise, neuronal cell bodies in the dorsal root ganglia, which lie in the intervertebral foramina just proximal to the confluence of the dorsal and ventral spinal roots, are exclusively sensory, and autonomic ganglia contain autonomic neurons only. At the distal extent of their distribution, the motor and sensory axons of mixed nerves are sorted into purely motor or sensory terminal branches. An appreciation of these anatomical arrangements is important in diagnosis, as localizing the likely site of the disorder helps narrow the possibilities that must be considered. For example, a disorder affecting sensation and sparing motor and autonomic function can be localized to dorsal roots, dorsal root ganglia, or sensory terminal branches and is unlikely to be arising in mixed somatic or cranial nerves, ventral roots, or autonomic ganglia. The process of localization as the first step in diagnosis, which is axiomatic in brain and spinal cord disorders, is equally important in the PNS, yet it is often neglected.

Throughout the PNS, the same basic histological plan is found. Myelinated and unmyelinated axons, Schwann cells, and interspersed capillary-like blood vessels (collectively referred to as endoneurium) are bundled into fascicles by perineurium, composed of five to 10 lamellae of cytoplasm of perineurial cells, a type of modified fibroblast. Most nerves consist of several such fascicles, bound together by a loose connective tissue, the epineurium. Within the epineurium, between the fascicles, are found arterioles and venules of various sizes, structurally similar to those found in other tissues. The epineurial vessels are the major blood supply of the nerve, with the capillary-like endoneurial vessels constituting a parallel system. This dual blood supply ensures that peripheral nerve is relatively well-protected from ischemic insult. Cells in both the perineurium and the endoneurial microvessels are interconnected by tight junctions, producing a blood–nerve barrier (or blood–nerve interface). This structural specialization ensures that peripheral nerve axons and Schwann cells occupy an environment whose chemical and cellular constituents are carefully regulated, analogous to the situation for neurons and glial cells in the CNS. Certain parts of the PNS lack this regulated blood–nerve interface: the sensory and autonomic ganglia, the portion of spinal roots and cranial nerves traversing the subarachnoid space, and the distal terminations of motor axons at neuromuscular junctions.

The relative simple histology and function of the PNS limits its range of expressions of pathology. In fact, PNS disorders can be conveniently divided into two main types: diseases primarily affecting axons and diseases in which derangement of myelin is the primary problem, a distinction that is useful for diagnosis as well as for a rational approach to therapy. Nerve conduction studies and needle electromyography, which are easily performed in patients and which are widely available, are used to help characterize a process as demyelinating or axonal.

Given myelin's physiological role in greatly enhancing the speed of action potential propagation along axons, demyelinating polyneuropathies can be identified by marked slowing of nerve conduction. In genetic disorders of PNS myelination, the nerve conduction slowing affects all peripheral nerves uniformly, whereas acquired causes of PNS demyelination typically affect myelin in a patchy, non-uniform way. A consequence of the latter point is that there may be marked variability in conduction slowing between adjacent nerves, dispersion of compound nerve action potentials, or focal conduction block. In axonal neuropathies, by contrast, nerve conduction velocities are preserved or only minimally slowed, and the loss of functioning motor or sensory axons is reflected in decreased amplitudes of motor or sensory compound nerve action potentials. This dichotomous view of polyneuropathies as either demyelinating or axonal is useful, but it is an oversimplification. Myelin and axon integrity are interdependent, so all types of polyneuropathies ultimately have an impact on both axon and myelin.

The clinical manifestations of a polyneuropathy are determined by the classes of nerve fibers involved. Motor findings are those of the lower motor neuron type, that is, weakness accompanied by decreased muscle tone and decreased or absent reflexes. Axonal loss is also marked by muscle atrophy and, sometimes, fasciculation. The main symptoms of sensory fiber involvement are sensory loss and paresthesia (abnormal sensations such as prickling or “pins and needles”), and the latter are often painful. Examination may show relatively selective loss of only some sensory modalities in diseases that affect only certain classes of sensory fibers (e.g., in most acquired demyelinating neuropathies, the main sensory finding is loss of vibration and joint position sensation, reflecting a disease process mainly involving large-diameter myelinated axons). Most often the motor and sensory impairments are first manifest and remain most pronounced in the distal parts of the legs and arms, a pattern referred to as a glove-and-stocking distribution. Autonomic dysfunction is prominent in some types of polyneuropathy, and usually vasomotor symptoms such as orthostatic hypotension are the most troublesome. However, a host of other symptoms reflecting autonomic failure may be seen, including absent or excessive sweating, impaired lacrimation and salivation, bladder dysfunction, abnormal intestinal motility, and erectile impotence and other impairments of sexual function.

Determining that a patient has a polyneuropathy usually presents little difficulty, but discovering the cause of the neuropathy can be challenging. The list of potential causes is long (at least 100 are known), and the clinical manifestations of many of these are indistinguishable. The usual clinical approach is to sift through the symptoms, neurological examination findings, and nerve conduction data to see whether the patient may have a syndrome with a short list of possible causes. For example, sensory symptoms and impairment of all sensory modalities without motor or autonomic impairment might lead one to diagnose a dorsal root polyganglionopathy, of which there are only a few causes. In a patient with motor and sensory abnormalities in the distal legs and arms, finding slowed nerve conduction velocities greatly limits the potential diagnoses.

Often, however, a distinctive syndrome is not present, and a broad range of possibilities must be considered. One approach to classifying the possibilities is to separate inherited from acquired diseases and to subdivide the acquired causes into four large categories: metabolic (e.g., diabetes mellitus), infectious (e.g., leprosy), toxic/deficiency states (e.g., due to vinca alkaloids and other antineoplastic drugs), and immune-inflammatory (e.g., vasculitic neuropathy). Worldwide, the three most common types of polyneuropathy are probably leprotic, diabetic, and inherited. The population from which patients are drawn influences the likelihood of certain diagnoses. For example, leprosy is common in developing countries but rare in North America and Europe. In a hospital-based practice, chemotherapeutic drugs are a common cause of neuropathy.

Establishing a clear etiology for a patient's polyneuropathy may lead to specific therapy, but equally important, establishing the cause allows the physician to advise the patient about the long-term prognosis (some types of polyneuropathy can lead to major loss of function, but more often the disability is mild or less and does not worsen substantially over the years). Some therapies can be useful in almost all types of polyneuropathy, regardless of cause. Pain is common in many types of polyneuropathy, and drugs for neuropathic pain are a mainstay of therapy in many patients. Medications used include amitriptyline (a tricyclic antidepressant), gabapentin, and pregabalin (the latter two, originally developed as anticonvulsants, reduce synaptic release of neurotransmitters by binding to the alpha2-delta subunit of presynaptic voltage-gated calcium channels). In patients with distal leg weakness, the ankle–foot orthosis (an L-shaped plastic brace that fits into a shoe and is strapped to the leg) holds the foot in neutral position and stabilizes the ankle, improving walking and stability, irrespective of the cause.