Diabetic Neuropathy. Friedrich A. Gries

substance P, neuropeptide Y, vasoactive intestinal peptide, and calcitonin gene-related peptide. By contrast, although nerves containing these neurotransmitters are also found in endoneurium, they are not associated with blood vessels.

      The capacity for autoregulation—to match blood flow to local tissue demand—is well established in the central nervous system. Myogenic mechanisms compensate for changes in perfusion pressure to maintain tissue flow. Levels of metabolites such as O₂, CO₂, and pH influence vessels to supply blood to meet metabolic needs. However, in peripheral nerve, pressure autoregulation of endoneurial blood flow is virtually absent, perhaps a reflection of the lack of smooth muscle in endoneurial microvessels. Furthermore, vasa nervorum responses to systemic hypoxia, hypercapnia, or reduced pH are minimal [36]. These factors would make peripheral nerve more vulnerable than many tissues to hypotension-induced ischemia. Conversely, there is some evidence of local metabolite regulation. Following repetitive electrical nerve stimulation, a functional hyperemia is apparent [37]. Moreover, blood flow can be seen to approximately double during maximal but selective electrical stimulation of large myelinated nerve fibers, which do not innervate vasa nervorum [38].

      Peripheral Ganglia

      Dorsal root (and autonomic) ganglia have blood flow values three to five times greater than the blood flow of peripheral nerve, which reflects the higher metabolic rate of neuronal cell bodies compared to that of nerve fibers [39–41]. The capacity of ganglia to autoregulate their blood supply is considerably better than that of peripheral nerve. Thus, ganglia show excellent flow regulation in the face of changes in systemic blood pressure. However, in common with peripheral nerve and in contrast to brain, there is little response to changes in systemic arterial CO₂ or pH [39].

      Although dorsal root ganglia are surrounded by an impermeable perineurium, a proportion of the vessels have a fenestrated endothelial lining. This renders the ganglion-blood barrier weak, and dorsal root ganglion cells are vulnerable to blood-borne toxic substances such as heavy metals, some anticancer drugs, and infectious agents. The reason for this breakdown of the blood-nervous system barrier is not known, but it has been suggested that a subpopulation of ganglion cells may be chemical sensors providing important information on the body's internal milieu [42].

Concluding Remarks

      The somatic nervous system, with its motor and sensory divisions, forms the basic output and monitoring capability for all movement, both purposive and reflex. The elaborate organization of proprioceptors and skin mechanoreceptors and their central connections are essential for our sense of body position in space, the control of posture, gait, and accuracy of goal-directed movement. The skin is a particularly important sensory organ, the sentry at the interface of body and environment, monitoring not only mechanical but also thermal and potentially damaging events.

The Autonomic Nervous System

      C.J. Mathias

Introduction

      The autonomic nervous system innervates every organ in the body and is closely involved in their function (Fig. 2.13). Additionally, it plays a key role in integrative function and in maintaining the milieu intérieur, for example through the control of blood pressure, body temperature, and metabolic and fluid balance. This enables optimum functioning in a variety of situations, which at times is essential for survival. It is accomplished by numerous pathways and neurotransmitters, providing considerable flexibility and responsiveness. Dysfunction of the autonomic nervous system may be caused at one or more sites centrally or peripherally (Table 23). It can be a particular problem in diabetes mellitus, where neural structures can be affected at various sites and their disturbances compounded by target organ involvement. In this section the principles of structure and function of the autonomic nervous system will be described, along with examples pertaining to derangement of function.

Basic Principles

      The autonomic nervous system is essentially an efferent system encompassing sympathetic, parasympathetic, and enteric components. The sympathetic efferents emerge from the thoracic and lumbar segments of the spinal cord and ultimately supplyall organs and structures. The parasympathetic outflow consists of cranial and sacral efferents. The former accompany cranial nerves III, VII, IX, and X, and supply the eye, lachrymal and salivary glands, heart, lungs, and upper gastrointestinal tract with associated structures down to the level of the colon. The sacral outflow supplies the large bowel, urinary tract, bladder, and reproductive system. The enteric nervous system as originally proposed by Langley in 1898 is effectively the local nervous system of the gut.

      There are specific cerebral nucleii, especially in the hypothalamus, midbrain, and brainstem, that influence autonomic activity; an example is the Edinger-Westphal nucleus through the parasympathetic nerves to the iris musculature which controls pupillary constriction. From the brainstem, sympathetic efferent outflow tracts descend through the cervical spinal cord, where axons synapse in the intermediolateral cell mass (Fig. 2.14). From the thoracic and upper lumbar spinal segments, myelinated axons emerge and synapse in the paravertebral ganglia, which is some distance from sympathetically innervated target organs. Most parasympathetic ganglia are close to target organs. The major neurotransmitter at ganglia (both parasympathetic and sympathetic) is acetylcholine, which acts on the nicotinic receptor (Fig. 2.15). Postganglionic fibers, which are unmyelinated, rejoin the mixed nerves through the gray rami and innervate target organs except for the adrenal medulla, which only has a preganglionic supply. The neurotransmitter at sympathetic postganglionic synapses (as in the heart and blood vessels) is predominantly norepinephrine; sympathetic cholinergic fibers (with acetylcholine as the neurotransmitter that acts on muscarinic receptors) supply sweat glands.

      Fig. 2.13 Parasympathetic and sympathetic innervation of major organs. (From [43], with permission)

      Table 2.3 Classification of disorders resulting in autonomic dysfunction^a

PRIMARY (Etiology unknown) Acute/subacute dysautonomias Pure cholinergic dysautonomia Pure pandysautonomia Pandysautonomia with neurological features Chronic autonomic failure syndromes Pure autonomic failure Multiple system atrophy (Shy-Drager syndrome) Parkinson's disease with autonomic failure SECONDARY Congenital Nerve growth factor deficiency Hereditary Autosomal dominant trait Familial amyloid polyneuropathy Porphyria Autosomal recessive trait Familial dysautonomia (Riley-Day syndrome) Dopamine β-hydroxylase deficiency Aromatic L-amino acid decarboxylase deficiency X-linked recessive Fabry's disease Metabolic diseases Diabetes mellitus Chronic renal failure Chronic liver disease Vitamin B12 deficiency Alcohol-induced Inflammatory Guillain-Barré syndrome Transverse myelitis Infections Bacterial: tetanus Viral: human immunodeficiency virus Infection Parasitic: Trypanosoma cruzi (Chagas' disease) Prion: fatal familial insomnia Neoplasia Brain tumors: especially of third ventricle or posterior fossa Paraneoplastic, to include adenocarcinomas of lung, pancreas, and Lambert-Eaton