Thomas Nguyen, MD

• Department of Emergency Medicine
• Beth Israel Medical Center, Albert Einstein College of Medicine
• New York, New York

This is caused by the death of large numbers of bacilli during the first or second year after the initiation of treatment and can relapse intermittently erectile dysfunction doctor in chennai discount kamagra chewable uk. Patients are febrile and develop constitutional reactions erectile dysfunction caused by ptsd order kamagra chewable 100 mg without a prescription, including iritis erectile dysfunction and proton pump inhibitors buy generic kamagra chewable 100 mg on line, orchitis erectile dysfunction statistics buy kamagra chewable 100mg free shipping, lymphadenitis and proteinuria erectile dysfunction drugs philippines purchase 100 mg kamagra chewable fast delivery. Typically erectile dysfunction young age treatment buy kamagra chewable 100 mg line, arterioles in the vicinity of perineurium are involved; they can show fibrinoid necrosis and acute inflammation indistinguishable from those of hypersensitivity vasculitis. Reversal reactions (type 1 leprosy reaction) are important in the production of neural damage. Pain and swelling of nerve trunks occur with the appearance of sensory and motor deficits in the territory of affected nerves; loss of nerve function can be dramatic. Endoneurial granulomas, lymphocytic infiltration, vasculitis and perineuritis are observed. The reaction subsides after some months, when many but not all patients are found to have moved towards the tuberculoid form in terms of classification. Patients with pure neuritic leprosy present with asymmetrical involvement of peripheral nerve trunks, display no skin lesions and are skin smear-negative for acid-fast bacilli. Mononeuropathy multiplex is a common clinical pattern of nerve dysfunction in primary neuritic leprosy. In a nerve biopsy study of 39 such patients, a significant proportion showed lepromatous histology and nearly two-thirds had a moderate to heavy bacterial load within the nerves. Whenever possible, a cutaneous sensory nerve such as greater auricular, medial antebrachial, superficial peroneal or sural should be chosen for biopsy. One report documents characteristic histological changes of leprosy in the normal-appearing sensory-altered skin in 31 per cent of patients clinically diagnosed with primary neuritic 1470 Chapter 24 Diseases of Peripheral Nerves leprosy. Eighty per cent of presenting patients are over 50 years of age, and prognosis worsens with increasing age. Systemic features include fever, weight loss, arthralgias and fatigue, which may be related to an associated connective tissue disease. The most commonly affected nerves, in descending order, are the peroneal (60 per cent), popliteal (30 per cent) and ulnar (25 per cent) nerves. Neuropathy often occurs early in the disease and is therefore of important diagnostic value. The vasculitic process usually affects the epineurial vessels, resulting in axonal ischaemia or, less commonly, frank infarction. However, motor nerve conduction velocities are often normal or reduced only slightly. If systemic vasculitis is suspected to be the cause of a peripheral neuropathy and other investigations. Furthermore, because it is the epineurial vessels that are involved, full-thickness rather than fascicular biopsies are required. Fibrinoid necrosis of the vessel wall may also be demonstrated on toluidine blue-stained semi-thin sections. Elastin stains reveal disruption of the internal elastic lamina, evidence of previous injury to the vessel wall. Nerve biopsies with extravasation of neutrophils should be considered suspicious for vasculitis, with the caveat that this can be seen normally if the biopsy procedure takes more than 30 minutes. A definitive diagnosis of necrotizing vasculitis cannot be made in this case, but the degree of suspicion can be raised by finding one or more other pathological features that reflect angiopathic nerve injury. These include ischaemic changes (see later), regional necrosis of the perineurium and new vessel formation. The last represents a more chronic change, with luminal narrowing and vessel recanalization associated with an increased number of epineurial vessels and, in some cases, focal mural 1472 Chapter 24 Diseases of Peripheral Nerves (a) 24. Iron staining reveals the presence of intramural and perivascular iron, suggesting previous vascular injury and haemorrhage. These changes, however, can be seen in other types of small vessel disease such as diabetes, and therefore correlation with clinical history is important. Necrosis of the perineurium is unusual except in vasculitis and in some cases perineurial cell loss with replacement by epineurial collagen is seen. The fascicular centres are predominantly involved, because this is the least vascularized part of the nerve and thus is most vulnerable to ischaemia. Haemosiderin deposition, when present, is also suggestive of vasculitic neuropathy. Vasculitic involvement of an endoneurial blood vessel showing both lymphocytes and neutrophils invading the vessel wall (a). The differential diagnosis of granulomatous vasculitis includes leprosy, sarcoidosis and lymphomatoid granulomatosis. Non-vasculitic neural haemorrhage can occur in haemorrhagic diathesis, which can present as mononeuritis multiplex. Acute axonal degeneration or a predominance of epineurial inflammation favours the former, whereas prominent segmental demyelination and an even distribution of epineurial and endoneurial inflammatory cells characterizes the latter. Toluidine blue-stained semi-thin section, showing peripheral nerve affected by vasculitis. A lymphocytic vasculitis of perineurial vessels, thought to be a secondary inflammatory response, also occurs in multifocal diabetic neuropathy. Matrix metalloproteinases, which are able to degrade the subendothelial basement membrane, resulting in vessel destruction, are produced by invading macrophages and T-lymphocytes. Pro-inflammatory cytokines and oxidative stress-derived molecules may also play a role early in the disease. The onset of individual lesions can be abrupt or gradual, and their eventual combination tends to produce symmetrical dysfunction. The lesions are those of a necrotizing arteritis of the vasa nervorum and resemble those that occur in other parts of the body. The predominant lesion is axonal degeneration; this affects myelinated nerve fibres of all sizes and also unmyelinated axons,528 with larger myelinated nerve fibres being especially vulnerable. The two schemes in most common use are those of the American College of Rheumatology and the Chapel Hill Consensus Conference. In contrast, microscopic polyangiitis is a necrotizing non-granulomatous vasculitis. Median nerve compression in the carpal tunnel, secondary to tenosynovitis and arthritis of the carpal bones, is common, and other nerve entrapments related to joint involvement may be observed. Digital mononeuropathies are also well recognized, as is a relatively benign distal sensory neuropathy predominantly affecting the lower limbs. Nerve biopsies show axonal degeneration and perivascular inflammatory infiltrates. Cranial (Giant Cell) Arteritis Peripheral nerve disturbances have been described in patients with giant cell arteritis. Most commonly, these disturbances are mononeuropathies or multifocal neuropathies. Systemic acquired amyloid neuropathy is due primarily to accumulation of immunoglobulin light chains in the setting of lymphoproliferative disorders. A symmetrical Amyloid Neuropathy 1475 syndrome may occur as a complication of amyloid composed of 2 microglobulin deposited in the flexor reticulatum in patients undergoing haemodialysis, but this is not a true amyloid neuropathy. Transthyretin is produced primarily in the liver and functions to transport thyroid hormone and vitamin A through a retinol binding protein. More than 100 other mutations have been described, usually limited to one family or to single cases; 13 of these are non-pathogenic. Usually a positive family history can be elicited, because there is an autosomal dominant inheritance pattern with high penetrance. Several phenotypes, including polyneuropathic, oculoleptomeningeal and cardiac types, have been described. In the leptomeningeal type, cerebral amyloid angiopathy and ocular amyloidosis predominate, leading to cerebral infarction and haemorrhage, with hydrocephalus, ataxia, spastic paralysis, convulsions and dementia. The amyloidosis is a dynamic process, and measures that reduce the supply of the amyloid fibril precursor protein can result in a major regression of the deposits. Patients with features of amyloidosis and multiple myeloma have a survival similar to that of patients with amyloidosis alone. Clinical manifestations are varied and depend on where the amyloid deposition occurs. Note that the lower limbs were involved before the upper limbs and the severe loss of pain and temperature (temp) sensation. The combination of polyneuropathy and autonomic dysfunction is strongly suggestive of amyloid neuropathy in the absence of diabetes mellitus. Autonomic nervous system involvement leads to dyshydrosis, sexual impotence, diarrhoea alternating with constipation, orthostatic hypotension and urinary disturbances. The heart is frequently affected, and other systems that can be involved include the vitreous humour, kidney, lung and bone. The disease is slowly progressive and reaches the terminal stage in approximately 10 years. The onset of neuropathy is usually in the fifth decade, with slow progression marked by facial and minor sensory peripheral nerve signs and occasional carpal tunnel syndrome. A number of other families have now been reported with the same or variant mutations, although the majority of kindreds do not present with peripheral neuropathy. Death in these cases is usually due to cardiomyopathy, renal failure or hepatic failure. Amyloid Neuropathy 1477 Pathogenesis Amyloidosis refers to the deposition in organs of collections of -pleated sheet-structured protein, leading to disruption of normal tissue structure and function. With respect to light-chain amyloid, the primary structure of the light chain appears to be the critical feature, with some light chains being highly amyloidogenic and others not. Both intact and cleaved proteins are found in the deposits, but it is not clear whether cleavage is required for deposition. Amyloid misfolding of a monomer subunit of the circulating tetramer generates the amyloidogenic precursor. A similar non-degradable fragment may be responsible for amyloid formation in gelsolin mutations. Another hypothesis is a direct mechanical compression of the nerve fibres by the amyloid, with larger myelinated fibres relatively protected by their myelin sheaths. It may be closely apposed to Schwann cells or collagen fibrils in the endoneurium, but it is found most commonly around blood vessels. Morphometric studies show that, in the early stages, there is a preferential loss of small myelinated and unmyelinated axons. Teased fibre studies demonstrate predominant axonal degeneration, with some segmental demyelination and remyelination, although the presence of the latter is controversial. Ultrastructurally, this consists of thick 9-nm pentagonal discs when examined in extracts from amyloid deposits. The distribution of fibre loss was bimodal in 15 cases, predominantly large fibre in 15 cases and predominantly small fibre in 4 cases. This myelinated fibre loss was associated with ovoids in six cases, regenerative clusters in five cases and both in six cases. Histologically, hyaline thickening of the perineurium and blood vessel walls, increased endoneurial connective tissue and predominant large myelinated fibre loss with degenerating axons were noted in all 14 biopsies and regenerating clusters in most. Onion bulbs were present in 6 patients and teased fibre preparations showed evidence of segmental demyelination. Congophilic amyloid deposition was seen in all cases in the perineurium or in the media of small vessels. Differential Diagnosis/Pitfalls the finding of amyloid deposits in a peripheral nerve biopsy is always abnormal and indicates the diagnosis of amyloid neuropathy. Amyloid deposits are shown in the perineurium (a), in the endoneurium (b) and in a blood vessel wall (c). Oxytalan fibrils in cross-section can be seen in the bottom left of the figure (arrowhead). It should be noted, however, that detection of light chains in the urine is not always sufficient to categorize amyloid deposits, because cases of 1480 Chapter 24 Diseases of Peripheral Nerves Patient with It should also be noted that a negative peripheral nerve biopsy does not rule out the disease. A whole-nerve biopsy with muscle, if possible, is recommended and Congo red and/ or thioflavin stainings should be performed. Ultrastructural examination may also reveal amyloid deposits not recognized at the light-microscopy level. If clinical suspicion is high, then biopsy of another organ, such as rectum or periumbilical fat, should be considered in the event of a negative nerve biopsy. Monoclonal gammopathy of unknown significance Monoclonal gammopathy of unknown significance (recently reviewed)210,347,405 results when a clonal transformation of plasma cells is associated with production of a monoclonal protein consisting of two heavy polypeptide chains of the same subclass and two light polypeptide chains of the same type emerge (IgM is a pentamer of the four-chain basic structure). Although IgG is the most common class of protein in patients with benign paraproteinaemia, IgM is more common in those with neuropathy (60 per cent), followed by IgG (30 per cent) and IgA (10 per cent). Approximately half of patients with peripheral neuropathy and IgM monoclonal gammopathy have antibodies that bind to myelin. The condition initially has predominantly demyelinating features affecting large sensory fibres, which translates to loss of joint and position sense, with gait ataxia and intentional tremor; distal limb weakness, with wasting and foot-drop, develops later. Electromyography and nerve conduction show the classic findings of a demyelinating polyneuropathy, with marked slowing of nerve conduction velocities, prolonged distal latencies and areas of conduction block. The disease in some patients progresses slowly but inexorably over decades, mimicking a genetically determined condition. Fluorescent IgM antibodies give a positive reaction on a large number of myelin sheaths.

Other regions may contain more pleomorphic cells with vague neuronal or glial features or even mesenchymal or epithelial features erectile dysfunction 35 years old kamagra chewable 100 mg generic. Wrapping and moulding of cells similar to that seen in anaplastic medulloblastoma can be present erectile dysfunction cream order kamagra chewable 100 mg overnight delivery. The hallmark of the restricted differentiation is a tubular pseudo-stratified structure; these ependymoblastomatous rosettes are randomly admixed with small to medium primitive cells with variably developed fibrillary processes erectile dysfunction wiki buy discount kamagra chewable 100 mg on line. Ependymoblastomas have mainly been located in the cerebrum female erectile dysfunction treatment discount kamagra chewable uk, particularly deep paraventricular structures impotence emedicine buy kamagra chewable 100 mg with mastercard, but other sites have been described benadryl causes erectile dysfunction cheap kamagra chewable uk, including the leptomeninges. However, because of the neuronal differentiation, ependymoblastoma does not seem appropriate. The ependymal ultrastructural characteristics of the periluminal cells include polarization, junctional complexes of variable length (including zonulae adherentes), blepharoplasts, basal bodies, microvilli and cilia, and the apical granular stippling and epithelial qualities of the periluminal cells at the light microscopic level might be a manifestation of these features. Elsewhere, the tumour is characterized by focally necrotic sheets of densely packed undifferentiated cells with minimal cytoplasm. Occasionally, examples of anaplastic ependymoma achieve a cell density that rivals that of embryonal tumours. However, if sampled sufficiently, they will show typical perivascular rosettes and may show the true rosettes or canals of classic ependymoma, which consist of a monolayer of differentiated ependymal cells. Glomeruloid vascular proliferation, which is usually present in the anaplastic ependymoma, is usually absent from ependymoblastoma. Ependymoblastoma-like elements are found within some examples of medulloepithelioma and immature teratoma, but the ependymoblastoma does not contain tubulopapillary or canalicular structures delimited by an external basement membrane, and it does not exhibit divergent neuronal or glial differentiation. The presence of non-neuroepithelial elements reflecting somatic differentiation readily removes the immature teratoma from further consideration. However, although this suggests that it is derived from an early neuroepithelial stem cell, its histogenesis is obscure. Mitotic figures are readily found, especially in the basal layer of multilayered structures. Aside from areas exhibiting the distinctive architectural phenotype described earlier, medulloepitheliomas usually contain sheets of undifferentiated neuroepithelial cells, like other embryonal tumours. Some examples contain foci of neuronal differentiation, which can amount to ganglion cell formation, or areas of astrocytic, oligodendroglial or ependymal differentiation. Ultrastructural examination has shown that features of the primitive medullary epithelium, few organelles and apical zonulae adherentes, are recapitulated by the undifferentiated cells of the medulloepithelioma. Choroid plexus carcinomas may show a focal papillary architecture and do not contain differentiating glioneuronal elements. Ependymoblastic rosettes are not delimited by a basement membrane, and ependymoblastomas do not show mature neuronal differentiation. Immature teratomas should contain tissues of somatic ectodermal and endodermal origins, and may be part of a mixed germ cell tumour with elements of embryonal carcinoma or yolk sac tumour. Most tumours appear to arise in the nasal vault in association with the cribriform plate, but an intracranial presentation is possible, albeit rare, and initial symptoms are sometimes referable to involvement of the anterior cranial fossa. Therapy involves open or endoscopic surgical excision, radiotherapy and sometimes chemotherapy. This pattern may be interrupted by a vascular network that produces a vague nodular pattern, but a prominent nodularity is characteristic of the variant resembling paraganglioma, which typically contains larger, more epithelioid cells. Neuronal differentiation in the form of ganglion cells and the presence of rhabdomyoblasts are rare events. The immunophenotype of olfactory neuroblastomas typically includes reactivities for neurone specific enolase and synaptophysin, with variable labelling of tumour cells for neurofilament proteins, microtubule-associated protein 2 and chromogranin A. In examples with a nodular phenotype, circumferential cells immunopositive for S-100 mimic the sustentacular cells of paraganglioma. In contrast, immunoreactivity for neurofilament proteins is characteristic of the neuroblastic phenotype. This view accounts best for the neurosensory/neurosecretory ultrastructural features and immunophenotype of the tumour. Andolfo I, Liguori L, De Antonellis P, Cusanelli E, Marinaro F, Pistollato F, et al. Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. 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Mapping of the breakpoints on the short arm of chromosome 17 in neoplasms with an i(17q). Correlation of loss of heterozygosity at chromosome 9q with histological subtype in medulloblastomas. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Rapid, reliable, and reproducible molecular subgrouping of clinical medulloblastoma samples. Primary cerebral neuroblastomas: a clinicopathological study of one adolescent and five adult patients. Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma. Tandem highdose chemotherapy and autologous stem cell transplantation in young children with atypical teratoid/rhabdoid tumor of the central nervous system. Cribriform neuroepithelial tumor in the third ventricle: A case report and literature review. Medulloblastomas with favorable versus unfavorable histology: how many small blue cell tumor types are there in the brain Malignant gliomas with primitive neuroectodermal tumor-like components: a clinicopathologic and genetic study of 53 cases. A melanotic desmoplastic medulloblastoma: report of a rare case and review of the literature. The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children. Neurotrophins and neuronal versus glial differentiation in medulloblastomas and other pediatric brain tumors. Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours. Pleiotropic effects of miR183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma.

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Alpha-internexin is present in the pathological inclusions of neuronal intermediate filament inclusion disease erectile dysfunction at age 20 kamagra chewable 100 mg free shipping. Epidemiology of dementia in Asia: insights on prevalence erectile dysfunction treatment in usa buy cheap kamagra chewable 100 mg on line, trends and novel risk factors doctor for erectile dysfunction in ahmedabad purchase 100mg kamagra chewable free shipping. Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration erectile dysfunction doctor seattle purchase kamagra chewable without a prescription. Pathological correlates of late-onset dementia in a multicentre erectile dysfunction herbal medications discount kamagra chewable 100mg on-line, communitybased population in England and Wales causes of erectile dysfunction in youth discount 100mg kamagra chewable mastercard. Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. 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Additional immunolabelling for other neuropeptides allows assessment of the innervation of sweat glands erectile dysfunction pills thailand buy kamagra chewable master card, arterioles erectile dysfunction drugs cost order generic kamagra chewable on-line, papilla and hair follicles erectile dysfunction treatment in bangladesh cheap kamagra chewable 100 mg on-line. One of the limitations of this technique is the need to have an adequate bank of control specimens from the different parts of the body to correlate with the biopsy sites used erectile dysfunction what causes it kamagra chewable 100 mg otc. In addition best erectile dysfunction doctor in india order kamagra chewable toronto, the normal sample has to be obtained from age-matched controls that have been subjected to rigorous neurological and electrophysiological 24 1416 Chapter 24 Diseases of Peripheral Nerves studies to rule out subclinical disease why alcohol causes erectile dysfunction purchase kamagra chewable with a mastercard. Furthermore, the distribution density of epidermal nerve fibres differs in various parts of the body: studies have shown the density of epidermal fibres to be lower in men and to decrease with age (range 4. Contained within the perineurium is the endoneurium, consisting of a collagenous matrix housing the axons, Schwann cells, fibroblasts, macrophages, mast cells and capillaries. Normal peripheral nerves consist of a bundle of fascicles encased in a fibrovascular stroma termed the epineurium. Individual peripheral and autonomic nerve fascicles are further ensheathed by perineurium, a specialized structure the epineurium the epineurium consists of massed collagen fibrils (types 1 and 3) interspersed with occasional elastin fibres, fibroblasts, mast cells, and the small arterial and venous blood vessels that supply the capillary plexus of the underlying nerve. Superficially, the epineurium merges with the surrounding areolar connective tissue of the deep fascia, and on its deep surface with the outermost layer of the perineurium. It is distinguishable as a separate sheath only in the largest nerves and nerve trunks; its thickness diminishes as the nerves pass distally, and a distinct epineurial layer cannot usually be identified around the smaller peripheral branches in most species. The number of layers is highest proximally, progressively diminishing to a single layer at the finest distal cutaneous and intramuscular nerve branches. In larger nerves, septa composed of two or three layers of perineurial cells arising from the inner aspect of the sheath may subdivide individual funiculi into Peri Endo Epi 24. A, axon; Endo, endoneurium; Epi, epineurium; F, fibroblast; P, perineurium; S, Schwann cell. The connective tissue between the layers shows collagen fibrils (C) and elaunin (e). Blood vessels penetrating the perineurium to supply the endoneurial capillary plexus also carry sleeves of perineurial cells with them into the endoneurium for short distances. In sections, the individual perineurial cells appear as thin sheets of cytoplasm, often no more than 0. Both faces of the perineurial cells are covered by basal lamina, which may become thickened when compared with the basal laminae of other cells, even in quite young subjects, and to which the cell membrane may be anchored by scattered hemi-desmosomes. At their margins, the individual perineurial cells overlap and interdigitate and are linked by tight junctions between their apposed membranes. Note abundant collagen fibrils (C) within the matrix running in parallel with the axons. In addition, each nerve fibre is surrounded immediately outside the Schwann cell basal lamina by a thin sleeve of much finer, more irregularly disposed reticulin fibres. These are angular cells lacking a basal lamina that lie free between the endoneurial collagen fibrils. The endoneurial fibroblast population has been reported to range from 5 per cent to 25 per cent of the nuclear profiles visible in transversely sectioned peripheral nerves, and it is believed to be responsible for the production of the major part of the extracellular endoneurial connective tissue. Other cells that may be found within the endoneurium are mast cells and macrophages. They are situated predominantly near blood vessels or the inner aspect of the perineurium, and they tend to have a dendritic morphology, with their processes oriented along the longitudinal axis of the nerve. Injury to , or disease of, peripheral nerves results in a rapid influx of a further haematogenously derived population of macrophages at the site of the lesion, the trigger for recruitment being the presence of degenerating axons. These cells play the predominant role in myelin phagocytosis, probably aided by the Schwann cells. The massed array of collagen in parallel 1418 Chapter 24 Diseases of Peripheral Nerves with the nerve fibres has considerable mechanical strength and resilience, which may serve to protect the nerve fibres from the stresses imposed by movement of the bodily parts through which they run. The sheaths of peripheral nerves are also resistant to penetration by foreign materials and infective agents. A considerable body of experimental work has demonstrated that the principal barrier to the entry of materials into the peripheral nerve is the perineurial sheath, particularly its innermost layers in which the constituent cells are linked by a continuous series of tight junctional complexes. Such material that does enter the endoneurium appears to be transported actively across the perineurial cells via pinocytotic vesicles. Myelin is a proteophospholipid material produced by Schwann cells enclosing the axon. Nerve fibres have been classified according to their calibre into three groups: A, B and C Table 24. Vasculature of Peripheral nerves Peripheral nerves are supplied by branches from their local regional blood vessels that ramify and branch within the epineurium. Pre-capillary vessels penetrate the perineurium at an oblique angle and are ensheathed for a short distance within the endoneurial compartment by internal prolongations of the innermost layers of the perineurial sheath. They then divide to supply the endoneurial plexus, which appears to consist nearly exclusively of capillaries. The plexus has a predominantly longitudinal orientation and drains directly to collecting blood vessels situated outside the perineurium, with few smooth muscle containing venules being found within the endoneurium. The contacts between the edges of adjacent capillary endothelial cells of the endoneurial circulation are completely sealed by tight junctions, and, in most species, this arrangement provides a second and effective barrier to the penetration of higher-molecular-weight materials into the endoneurial compartment. The principal partitioned ion is sodium, and this is pumped outwards into the extracellular space. The advance of current through the axoplasm causes depolarization of adjacent segments of the axolemma, resulting in a continuously propagated wave of depolarization, which spreads along the axon. In unmyelinated fibres, the large capacitance of the axon membrane attenuates forward axial flow of current within the axoplasm and limits conduction to a speed of around 1 m/s. In myelinated fibres, on the other hand, electrical activity is restricted to the narrow spaces between the myelin segments, the nodes of Ranvier (The Internode and Node of Ranvier, see p. The principal functional implication of this saltatory activity is a considerable enhancement of conduction velocity in myelinated fibres over that achieved by nonmyelinated fibres, i. Loss of one or more myelin segments from a myelinated axon, as a consequence of either naturally occurring pathology or localized experimental injury, results acutely in conduction block, but the axon subsequently develops the capacity to sustain continuous conduction, in a manner comparable to that seen in normal unmyelinated fibres. Because of its great length (which may exceed 1 m in nerves to and from the human lower limb), when compared with the dimensions of the cell soma, the axonal cytoplasm, in most instances, contributes by far the largest component to the total mass of the neuron. Neurofilaments, microtubules, mitochondria and smooth endoplasmic reticulum are present, but there is no rough endoplasmic reticulum or Golgi apparatus. They appear to be homologous with the thin filaments of muscle cells and contribute approximately 10 per cent to the total complement of 24. They are most conspicuous in the growth cones of actively elongating neurites and are less evident in unmyelinated axons and in the internodal portions of myelinated axons, where they appear to be confined to the cortical zone of axoplasm immediately subjacent to the axolemma. They may have contractile function and play a part in the mechanisms responsible for intra-axonal transport, growth cone motility and axon guidance. The three principal constituent proteins have been identified and have molecular masses of 70 kDa (L), 160 kDa (M) and 200 kD (H). The L, M and H proteins are the products of separate genes and are immunocytochemically distinct. All contain -helical, coiled-coil core domains with highly homologous amino acid sequences, and all are phosphorylated in vivo on both amino-terminal head and carboxy-terminal tail regions, with numerous isoforms. The degree of phosphorylation is an important determinant of their functional and immunological properties. Phosphorylation of the carboxy-terminal domain may play a part in stabilizing the axonal cytoskeleton by promoting cross-linking between the individual filaments. The degree of phosphorylation of the amino-terminal head regions of the subunits may be of importance in controlling their assembly into filaments and the stability of such filaments once formed. They play a major role in axonal transport (see Axoplasmic Flow and Intra-axonal Transport, below). In crosssection, the microtubular walls can be seen to be composed of 13 globular, 4-nm subunits of the protein tubulin, arranged in a simple 4 nm by 5 nm lattice. The greater part of this material exists in two distinct monomeric forms, and, having molecular weights of 57 kDa and 54 kD, respectively. Each microtubule is composed of helically arranged chains of alternating and monomers. The axoplasm also contains a variety of types of membranous organelle, including mitochondria, smooth endoplasmic reticulum, lysosomes and empty and dense-cored vesicles of a range of sizes. Most of the proteins that are needed in the axon and synaptic terminals are synthesized in the cell body and transported along the axon in membranous organelles or protein complexes. In the axon and dendrites, microtubules run in a longitudinal orientation and serve as rails along which membranous organelles and macromolecular complexes can be transported. Microtubules in axons and distal dendrites are unipolar, with the plus end pointing away from the cell body. Molecular motors of the kinesin and dynein super-families move along microtubules. By contrast, retrograde transport, from the axonal or dendritic terminals to the cell body, is carried out mostly by cytoplasmic dyneins, which are minus enddirected motors. The anterograde transport mechanisms have been found to operate at a minimum of two and probably in excess of five different rates. For the purposes of description, these are usually divided into a slow transport component, moving at 0. Each smalldiameter axon lies recessed within a separate cleft in the surface of the Schwann cell, itself one of a chain of similar cells arranged end-to-end with some overlap and Axoplasmic Flow and Intra-axonal Transport the problems of maintenance and communication presented to a cell such as the neuron, in which most of the cytoplasm is at a considerable distance from the cell soma and its nuclear-controlled metabolic systems have been much investigated (see review187). There are wellorganized transport mechanisms within axons capable of moving material both towards and away from the cell 24. Normal Structure of Peripheral Nerve 1421 interdigitation of the terminal processes at their points of junction. A not uncommon feature of unmyelinated fibres is the enclosure of bundles of endoneurial collagen fibrils within a longitudinal furrow in the surface of the Schwann cell. Such collagen pockets appear to be formed only by the Schwann cells of unmyelinated fibres, and it has been suggested that they may serve to anchor the unmyelinated fibre to the adjacent endoneurial connective tissue. The axoplasm of unmyelinated fibres shows no evidence of regional specialization and contains representatives of all of the subcellular components listed in the aforementioned general description of axoplasm. The only general features that distinguish them from the axons of myelinated fibres are the much higher proportion of axonal microtubules compared with neurofilaments, the frequent presence of dense-cored vesicles in autonomic efferent fibres, and a higher density of sodium channels; unmyelinated fibres possesses sodium channels at a density of around 110/m2 compared with 25/m2 in the internodal axolemma of myelinated fibres. Myelinated fibres the features of myelinated axons that distinguish them from their unmyelinated neighbours are their large diameter (which may occasionally exceed 20 m), the enclosure of each within its own individual chain of Schwann cells, and the presence of a myelin sheath, which is a proteophospholipid multilayered spiral derived from the apposed and compacted membranes of a greatly elaborated Schwann cell mesaxon. Ultrastructurally, a radially repeating structure of alternately dense and less dense lines is seen. The dense lines are derived from the cytoplasmic aspect of each pair of membranes, and the less dense lines from the apposed outer surfaces of each pair of membranes. The thickness of the myelin sheath varies in fibres of differing axonal diameters, large fibres having thicker sheaths than smaller diameter fibres. Differential extraction of myelin glycolipid content during processing accounts for variation in staining. They accompany, or possibly precede, the outgrowing neurites of the primitive peripheral nerves. The factors that lead to the selection of some axons but not others for myelination are still largely unknown, but experimental studies have shown that all Schwann cells, including those of normally wholly unmyelinated autonomic nerve trunks, are competent to produce myelin. The axon provides the stimulus (probably neuregulin-1)377 necessary for the initiation of myelin formation, the signalling being related to axon calibre. The gap between the innermost Schwann cell membrane and the axolemma is known as the periaxonal space. Apart from this specialized myelin attachment zone, specific contacts have not been described between the axolemma and the adaxonal Schwann plasma membrane. The external compartment of the Schwann cell is more substantial and more complex in its arrangement. Major accumulations of material occur adjacent to both poles of the longitudinally oriented ellipsoidal nucleus, which generally lies slightly distal to the midpoint of the internodal segment. Both occur most frequently in the perinuclear zone of the Schwann cell, and both are probably forms of secondary lysosomes. Lamellar continuity is maintained, but the major dense line, the fused cytoplasmic surfaces of the paired membranes that constitute each lamella, is replaced by a continuous spiral of Schwann cytoplasm, which thus Normal Structure of Peripheral Nerve 1423 24 24. The intraperiod line of the myelin to either side of the cytoplasmic spiral also separates at the incisure, creating potential paired spiral extracellular connections between the endoneurium and the periaxonal space beneath the myelin sheath. The adjacent extracellular spirals at the intraperiod line to either side of the cytoplasmic component may also permit interchange of ions between the periaxonal space and the exterior of the fibre, although it is claimed that both the outer and the inner ends of this cleft are sealed by tight junctions.