Natural Healing for Neuropathy
The peripheral nervous system consists of the sensory receptors such as those that recognize touch or heat in the skin or visual stimuli in the retina of the eye, and the nerves which communicate the stimuli to the brain. The peripheral nervous system is often subdivided into two parts, according to function the somatic portion, which recognizes stimuli in the external environment such as on the skin, and the autonomic portion, which recognizes changes in the internal environment, such as hormone or mineral concentrations in the bloodstream. The somatic portion of the peripheral nervous system in humans consists of twelve pairs of nerves which originate in the brain and which transmit sensory input from the body. For example, nerve endings in the retina of the eye transmit images to the brain sensory fibers in the face transmit impulses affecting the skin or teeth. An additional thirty-one pairs of nerves emerge from the spinal cord, subdivide into branches, and innervate various...
Nowadays, surgical resolution of a disability resulting from a peripheral nerve lesion is no longer an impossible task for the surgeon even if diagnosis and treatment still require a thorough knowledge of the pathophysiology of the nervous system together with the most recent sophisticated microsurgical techniques. Basic knowledge of the pathophysiological processes in a nerve trunk and its neurons after transection injury (degeneration and regeneration) is essential in order to choose the correct surgical treatment, its timing and the rehabilitation program.
Crush injuries of peripheral nerves regenerate relatively well because the proximal and distal segments of the nerve remain aligned so that proximal axon stumps can regenerate into distal endoneurial tubes. Transections, or injuries that necessitate removing segments of nerve, are more difficult to repair. The cut ends of the nerves retract, and it is difficult to suture them back together. Fibroblasts invade the wound space, resulting in the formation of scar tissue that leads sprouting proximal axons to form neuromas. Continuous longitudinal sutures have been used successfully to bridge small gaps in the rat sciatic nerve (Scherman et al., 2004), but this does not suffice for larger gaps. trunks from elsewhere in the body are currently the treatment of choice to bridge gaps in nerves because they contain endoneurial tubes to guide regenerating axons and blood vessels that can quickly connect to the local circulation. The current gold standard is a sensory nerve autograft, such as...
Using immunohistochemical techniques, this group showed that abundant neuronal ingrowth was present in the early phases of healing rat tendon. Interestingly, there was effective, complete regression of these neurons by 12-16 wk after the start of healing. Furthermore, a temporal pattern of specific neuropeptide expression was observed that correlated with the nociceptive responses of experimental animals. They hypothesized that the peripheral nervous system may modulate neuropeptide expression in relation to the phase of tendon healing (10). These findings seem to raise the question of whether coupling of nociceptive and healing responses in animals may provide a protective function by optimizing the physical environment in which tendons undergo healing.
Ries can be avoided as a rule 13, 26, 52, 53 . The basic principles in the pathogenesis of position-induced nerve lesions have been clarified for a long time. Prevention of such lesions entails all doctors and nursing staff responsible for positioning being acquainted with these principles and being capable of recognising which positioning endangers the peripheral nerves. All physiological movements subject the peripheral nerves to a certain stretching load. Their histological structure prepares them well for such load. Sustained, extreme stretching load can cause nerve paralysis. When a critical stretching limit is exceeded, this causes occlusion of the intraneural blood vessels, initially the venules, then also the arterioles and capillaries. Greater stretching causes histologically verifiable changes to the myelin sheaths, axons and connective tissues. The extent of structural injuries depends on the strength and duration of stretching. Abrupt extreme stretching is not well...
Chromogranin A is expressed by other neural tumors in the skin, none of which would be in the histologic differential diagnosis of Merkel cell carcinoma (Table 3). These tumors include primary mucinous eccrine carcinomas, a minority of cellular neurothekeomas, and occasional malignant peripheral nerve sheath tumors (32-34). In all cases, however, there are antibodies that are more useful in arriving at these diagnoses than anti-chromogranin A. While not totally specific for Merkel cell carcinomas, the presence of chromogranin A positivity in a primary cutaneous neoplasm with histologic features of a Merkel cell carcinoma would certainly be strong confirmatory evidence. However, neuroendocrine carcinomas metastatic to the skin would not be excluded based upon this finding (35).
Single shot brachial plexus and major peripheral nerve blocks can provide 12 to 24 hours analgesia. To avoid the sudden return of severe pain as the block wears off, start suitable sequential analgesia (see section 8.c.i) before the block fully wears off and ensure that it is taken regularly.
The brain is subdivided into four major functional areas. The cerebrum, the largest portion of the brain, regulates sensory and motor functions. The convolutions characteristic of the human brain represent the physical appearance of the cerebrum. The brain stem connects the brain with the spinal cord, carrying out both sensory and motor functions. The diencephalon consists of the thalamus, the relay center for sensory functions entering the cerebrum, and the hypothalamus, which controls much of the peripheral nervous system activity and regulates endocrine processes. The fourth portion of the brain is the cerebellum, the rear of the brain where voluntary muscle activity is controlled.
Enkephalins, discovered in 1975, block pain impulses within the central nervous system in ways similar to the drug morphine. The second class of molecules, subsequently called endorphins, was discovered soon afterward. They appear to act through suppression of pain impulses through suppression of a chemical called substance P. Substance P is released by neurons in the brain, the result of pain impulses from receptors in the peripheral nervous system. By inhibiting the release of substance P, these neuropeptides suppress sensory pain mechanisms. In support of a physiological basis for the placebo effect, patients treated with the endorphin antagonist naloxon produced no discernable response to placebo treatment.
Analysis of a second myelin protein, in this case one from the peripheral nervous system, showed that the use of TICK does not provide a universal answer to myelin-associated proteolytic problems. The 170 kDa protein is detected by immunoblotting using specific antiserum and, in addition to a major 170 kDa band, a series of faster (lower Mr) bands are apparent, a symptom characteristic of stepwise proteolytic degradation (Figure 2b). Proteinase inhibitors, including TLCK, were again screened but no single agent afforded complete protection. The problem was solved by using a cocktail of inhibitors. The 170 kDa protein is probably especially vulnerable to proteolytic attack because of its size and needs far more stringent protection than the CNPase despite the similarity of the source material.
As well as being implicated as a hepatotoxin, the antitubercular drug isoniazid may also cause peripheral neuropathy with chronic use. In practice this can be avoided by the concomitant administration of vitamin B6 (pyridoxine). In experimental animals, however, chronic dosing with isoniazid causes degeneration of the peripheral nerves. The biochemical basis for this involves interference with vitamin B6 metabolism. Isoniazid In man peripheral neuropathy due to isoniazid is influenced by the acetylator phenotype (see page 135), being predominantly found in slow acetylators. This is probably due to the higher plasma level of isoniazid in this phenotype. In this case, therefore, acetylation is a detoxication reaction, removing the isoniazid and rendering it unreactive towards pyridoxal phosphate.
Thalidomide is a glutamic acid derivative thought to have antiangiogenic activity. A randomized, phase II trial of 63 patients utilized low-dose (200 mg daily) and high-dose (up to 1200 mg daily) thalidomide in AIPC patients.47 Prior cytotoxic treatment was allowed. The high-dose arm was terminated early as none of the 13 patients enrolled had a 50 reduction in PSA. The low-dose arm was then expanded to 50 patients. Nine patients (14 ) had a 50 decline in PSA. Four patients (6 ) had a PSA decline of 50 that was sustained for 150 days. No complete or partial responses were seen in patients with measurable disease on CT scan or bone scan. A total of 560 adverse events were reported. The most common complaints were fatigue, constipation and peripheral neuropathy. Median survival for all 63 patients is 15.8 months.
Plasticity in the spinal cord sensory map following peripheral nerve injury in rats. J Neurosci 1981 1 679-684. Koltzenburg M, Torebjork HE, Wahren LK. Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 1994 117 579-591.
Local recurrent RC represents a major problem to the surgical oncologist, occurs in 4-5 of patients after apparently curative resection and is resectable in only 15-20 of cases. This type of pelvic tumour causes significant morbidity and accounts for 90 of disease-related deaths within five years. Surgical resection is the initial choice of treatment. The objective, if feasible, is removal of both the tumour and primary nodal drainage with as wide a margin around them as possible. If recurrence occurs in patients not previously treated with radiation therapy, pre-operative radiochemotherapy is highly recommended and it is possible to complete the radiation treatment in case of suboptimal resection of the tumour with intraoperative radiation therapy boost (IORT). Patients who achieve a gross total resection at the time of IORT have a markedly better prognosis than those with residual gross disease. The major IORT-related post-operative complications are leakage from anastomoses, deep...
The corticospinal tract and related motor pathways synapse in the spinal cord, just before leaving the cord. This anatomic feature is important because motor neurons above the level of this synapse are upper motor neurons (UMN), whereas the peripheral nerve cell bodies in the anterior horn of the cord, and their axonal extensions outside the cord are lower motor neurons (LMN). Upper and lower motor neuron injuries produce different clinical signs. Although lesions at either level result in weakness, the presentations differ.
Second, regenerative responses have been induced or enhanced in a number of tissues of experimental animals. Biodegradable, cell-free artificial regeneration templates have been used to induce dermal regeneration in excisional skin wounds and improve regeneration across gaps in peripheral nerves, though the results have been far from perfect (Yannas, 2001). A variety of neuroprotective agents, as well as agents that neutralize molecules inhibitory to axon regeneration, and enzymes that degrade glial scar, have been used to improve spinal cord regeneration and slow the loss of neurons in Parkinson's disease and amyotrophic lateral sclerosis (ALS). Cell-free ceramic templates can induce bone regeneration across large gaps (Constanz et al., 1995 Yaszemski et al., 1995). Attempts to induce epimorphic limb regeneration from the non- or poorly regenerating limbs of adult frogs have also elicited or enhanced regenerative responses.
This model for dominant inheritance is called haploinsufficiency. In contrast, more than two copies of a gene may also cause disease inherited in an autosomal dominant manner, as is seen with duplication of the PMP22 gene in Charcot-Marie-Tooth IA peripheral neuropathy (Boerkel et al., 2002) or triplication of the a-synuclein gene in familial Parkinson disease (Singleton et al., 2003).
After its reconstruction the peripheral nerve must be kept in a soft and well-vascularized bed. If the lesion is associated to skin problems or necrotic surrounding tissues, the best possible local conditions have to be created with the use of local or distant flaps The more proximal the lesion, the more difficult it will be to obtain a good functional result as fiber mixing increases at the proximal levels. The nerve becomes simpler distally as it leaves its collateral motor or sensory branches. Distally, the terminal branches organize to reach their final targets, so, the best results can be obtained at a distal level. Therefore, from a prognostic point of view, we may divide the possible lesion sites into 4 groups with inferior results from proximal to distal plexus nerve trunks well defined peripheral nerves terminal branches. Scar formation is another factor which has to be technically contrasted as already stated, tension must be avoided while reconstructing peripheral nerve...
Leprosy is a chronic disease that affects not only the skin but particularly the peripheral nerves bilaterally. The hands and feet are the anatomical sites where inflammation, characteristic skin lesions, and nerve damage occur in the course of leprosy. The commonest skin lesions are nodules, erythematous plaques, or hypopigmented patches. Symptoms like hypo- or dysaesthesia, together with motor sensory nerve abnormalities and obvious thickening of peripheral nerve branches, suggest the characteristic demyelinating neuropathy of leprosy. Advanced disease manifests with skin atrophy, pigmentary changes, and in severe cases chronic ulceration leading to mutilation and disability (Figure 9.15). Mutilating lesions of the hands and feet result from bone resorption, mechanical trauma, and secondary bacterial infection.
What is the relationship of this form of C to U RNA editing to that described for apoB We have recently revisited the question of C to U RNA editing of NF1 in tumors from patients with neurofibromatosis. These latest findings suggest that C to U RNA editing occurs in only a subset of peripheral nerve sheath tumors and was undetectable in tissues from unaffected subjects. In exploring the features that distinguish tumors, in which C to U RNA editing was demonstrated, two defining characteristics emerged. First, tumors that demonstrated C to U RNA editing were all found to express apobec-1 mRNA, the catalytic deaminase of the apoB RNA-editing holoenzyme (31). This feature is considered particularly relevant since the underlying mechanism of NF1 RNA editing and its relationship, if any, to apoB RNA editing was previously unresolved. It bears emphasis that only those tumors, in which C to U RNA editing of NF1 was found, demonstrated the presence of apobec-1 mRNA. Secondly, alignment of...
A major question since the beginning of regeneration research has been which tissues contribute cells to the blastema and by what mechanism. Experiments tracing the origin of the blastema through transplantation of marked tissues showed that the blastema derives from multiple tissues, including dermis, peripheral nerve, bone and muscle.26-31 In these classical experiments, however, the grafted tissue constituted a complex mix of differentiated cells including connective tissue and blood vessels. Therefore the transplantation of tissue did not completely resolve the cellular origin and the mechanism by which the blastema was formed.
Similarly to the olfactory system, the optic nerve is not a peripheral nerve, as it is mostly an evagination of the telencephalon. Retinic photoreceptors, cones and rods, relay the signal for further processing to other retinic neurons bipolar cells, horizontal cells, amacrine cells, retinal ganglion cells, and interplexiform cells. Axons from the ganglion cells form the optic nerve. The potentials generated are transmitted via the optic nerve to the lateral geniculate nucleus (visual information), superior colliculus (somatic reflexes), and pretectal areas (autonomic reflexes). In mammals, visual information is relayed to the thalamic lateral geniculate body, from which optic information is directed to the primary visual cortex through the geniculo-striate projection, or optic radiation. In humans, the cortical area surrounds both walls
Knowledge of the anatomy of the brachial plexus and of the pathological changes of peripheral nerve lesions allows better understanding of the clinical symptoms and the findings of paraclinical diagnostic examination. Classification of nerve injuries on the other hand, is essential for the therapeutic approach and for the evaluation of the results. In the majority of cases, the injury is the result of motorcycle accidents involving young adults and the lesions are usually more severe. Although a small number of patients spontaneously recover in the early months following trauma, the majority of cases with total palsies diagnosed in the emergency department, do not recover spontaneously.
Toxic metal to which there is wide exposure. Exposure is via inhalation (main source leaded petrol) and ingestion (water, old paint). Multi-organ toxicity occurs with kidneys, central and peripheral nervous system, testes, red cells, bones and gastrointestinal tract all damaged. After initial distribution into red blood cells it is eventually deposited in bone. The main biochemical effect is interference with haem synthesis at several points. Kidney toxicity may be due to lead-protein complexes and inhibition of mitochondrial function. Damage to nerves leads to peripheral neuropathy. Treatment involves use of chelating agents (EDTA).
Transthyretin (TTR), a homotetramer with 127 amino acid residue in each chain, is synthesized in the liver and is found in blood plasma and cerebrospi-nal fluid (57). TTR is able to form amyloid which accumulate in different peripheral nerves of patients affected by familial amyloid polyneuropathy or in the heart of people affected by familial amyloid cardiomyopathy (58). It has been published that TTR is a major AP-binding protein in cerebrospinal fluid (59), and further studies demonstrated that TTR is able to prevent formation of AP fibrils in vitro, sequestering AP from cerebrospinal fluid by a stable complex formation (49).
To decrease the area that needs to be covered by epidermis and filled in by scar tissue. Contraction is characterized by the sliding and stretching of perilesional skin over the defect and should not be confused with contracture, which is the shortening of scar tissue, leading to deformity and loss of function. Dermal contraction accounts for a much greater percentage of wound closure in rodents than in pigs or humans (figure 2.5). In vivo, contraction accounts for up to 90 of wound closure in mice (Yannas, 2001). In humans, less than 50 of excisional wound closure is due to contraction the majority is due to scar tissue formation. In addition to dermis, contraction has been shown to help close wounds in peripheral nerve, ligaments, ureter, esophagus, and duodenum (Yannas, 2001).
Arsanto J-P, Komorowski TE, Dupin F, Caubit X, Diano M, Geraudie J, Carlson BM, Thouveny Y (1992) Formation of the peripheral nervous system during tail regeneration in urodele amphibians Ultrastructure and immunohistochemical studies of the origin of the cells. J Exp Zool 264 273-292. Bisby MA (1995) Regeneration of peripheral nervous system axons. In Waxman SG, Kocsis J, Stys PK (eds.). The Axon Structure, Function and Pathophysiology. New York, Oxford University Press, pp 553-578. Bunge R (1987) Tissue culture observations relevant to the study of axon-Schwann cell interactions during peripheral nerve development and repair. J Exp Biol 132 21-34. Fu SY, Gordon T (1997) The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 14 67-116. Goodrum JF, Bouldin TW (1996) The cell biology of myelin degeneration and regeneration in the peripheral nervous system. J Neuropath Exp Neurol 55 943-953. Lefcourt F, Venstrom K, McDonald JA, Reichardt LK (1992) Regulation of...
However, one striking difference between knockout and wild-type mice has been characterized mice lacking protein kinase Cy display reduced responses to nonnoxious pain stimuli following painful stimulation such as resulting from nerve injury, reduction in a phenomenon referred to as neuropathic pain. Studies with knockout mice in protein kinase Ce have also implicated this isozyme as a potential target for pain and, also, anxiety, for example, mice lacking this isozyme display less anxiety in response to threatening situations. Targeted disruption of the gene encoding protein kinase CP results in mice with an impaired immune response, with analysis of B cells from these mice revealing that the P isozymes are involved in B-cell activation. However, the molecular basis for many of the physiological differences observed in knockout mice is largely unresolved.
The surgical treatment of these lesions must take into consideration the various factors which condition nerve regeneration. Therefore, the different techniques of nerve repair are described through the analysis of these factors together with the indications for the treatment of peripheral nerve injuries.
The nervous system, both peripheral and central, is a common target for toxic compounds, and the cells which make up the system are particularly susceptible to changes in their environment. Thus, anoxia, lack of glucose and other essential metabolites, restriction of blood flow, and inhibition of intermediary metabolism, may all underlie damage to cells of the nervous system as well as direct, cytotoxic damage. The nervous system is a highly complex network of specialized cells, and damage to parts of this system may have permanent and serious effects on the organism as there is little capacity to regenerate and little reserve functional capacity. Peripheral neuropathy is a toxic response to a variety of foreign compounds such as organophosphorus compounds, methyl mercury and isoniazid for example. The 'designer drug' contaminant, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) causes specific damage to the dopamine containing cells in the substantia nigra area of the brain....
In diabetic rats, TRPV1 is enhanced on myelinated fibres and is hyperphos-phorylated by PKC 127 . In accordance with these findings, anti-TRPV1 antiserum was shown to ameliorate pain in a murine model of diabetic neuropathy 128 . In humans, the density of TRPV1-positive nerve fibres is increased in women with chronic breast pain 129 and with vulvodynia 19 . Disruption of TRPV1 gene causes attenuation of bone cancer pain in mice 130 . Pharmacological blockade of TRPV1 by agonists relieved pain in AIDS patients 131 .
The nervous system consists of millions of nerve cells known as neurons, which are responsible for receiving and processing sensory information and then controlling muscles to respond to external stimuli. It is divided into two primary components the central nervous system and the peripheral nervous system. Neurons (Figure 10.5) consist of the cell body or soma, where the nucleus resides an axonal portion, which extends outward from the soma and dendrites, which are short-branched structures extending from the soma. The junction between the axon terminus of one neuron and the dendrites of an adjacent neuron is termed the synapse or synaptic junction. Neurons are able to regulate the electrical potential across their cellular membrane as a part of normal cell function. In the nervous system, such membranes are responsible for the transmission of electrical impulses along the cell. Electrical signals are transmitted along the axon by an ionic pump. In its resting state, the neuron has...
Lead is toxic to a number of organs and organ systems, including the nervous system, the blood, and the kidneys. The neurotoxicity of lead has been recognized for millennia (ATSDR 2005b). Human exposure to lead has historically been high, due to the many industrial uses of lead, such as fabrication of corrosion-resistant water pipes, as a paint additive, and as an additive in gasoline. The chemical similarity of lead and calcium allows lead to mimic calcium, thereby disrupting a variety of calcium-mediated effects. Lead neurotoxicity seems to be associated with interference with the normal neurotransmitter functions of the nervous system, due to its ability to mimic calcium chemically as well as its ability to interfere with synaptic receptor-ligand interactions. The peripheral nervous system effects of lead involve the degradation of motor nerve function due to damage to the myelin lamellae surrounding the axons.
The rotarod is an established test for evaluating pharmacological actions of psychotropic agents such as skeletal muscle relaxants, anticonvulsants, and antidepressants in the central or peripheral nervous system (Dunhan and Miya, 1957). Morimoto and Kito (1994) have shown that this test is useful to evaluate the antidepressive effects of serotonergic and adrenergic antidepressants. As shown in Figure 5, chronic stress impaired the rotarod performance, concomitant with unchanged traction performance and locomotor activity, suggesting that the impaired rotarod performance is not due to muscle relaxation or motor dysfunction. As antidepressants increase the riding time on the rotating rod in normal rats (Morimoto and Kito, 1994), the impaired rotarod performance suggests a depressive behavioral state.
A large body of evidence suggests that whether or not axons regenerate depends in large part on their associated glial cells (Yannas, 2001). Differences in the ability of peripheral and central glial cell populations to support regeneration have been well documented by experiments in which the regeneration of central axons was promoted by peripheral nerve sheaths grafted into the central nervous system, whereas central nerve sheaths inhibit the regeneration of peripheral axons (Aguayo, 1985). These differences appear to reside largely in the adhesion molecules and soluble signals synthesized by glial cells. Glial cells that support regeneration provide most or all of the molecules that are
The COUP-TFs are highly expressed in the developing nervous system indicating a possible involvement in neuronal development and differentiation. In the mouse, the COUP-TF genes (I and II) exhibit expression patterns that overlap extensively. Gene knockout studies demonstrate that mCOUP-TFI null animals die perinatally and mutant embryos show abnormal development of a subset of neurons in the peripheral nervous system. Interestingly, although COUP-TFI expression is widespread, the knockout phenotype is very specific, suggesting that in certain tissues COUP-TFI activity is compensated by COUP-TFII.
Peripheral neuropathy None reported None reported 1) Studies did not consistently report common side effects. However, suc guidelines for dosing should be followed as risk of side effects and or complications may increase with dosage increases. 2) Do not exceed 100 mg daily secondary to the risk of peripheral neuropathy and other adverse effects. 3) Patients may elect to use over-the-counter agents, e.g., TUMS. It may be administered by chewing 4 tablets daily (two tablets twice daily). 4) A carbohydrate rich drink that was available for research purposes. There may be limited general availability.
Lesion-induced changes in cortical topography are furthermore accompanied by a rapid increase in the expression of neurotrophins, including BDNF and NT-3, and relevant receptors (Obata et al., 1999). Neurotrophins are important regulators of synaptic development and plasticity in both the central and peripheral nervous system. Neurotrophins can modulate synaptic transmission at the pre- and postsynaptic level in a target-specific fashion. In the visual cortex, BDNF can influence GABAergic intracortical inhibitory neurons and serotonergic afferents from the Raphe nucleus (Berardi et al., 2003). The observation that the elevation of the neurotrophin levels is sustained for up to two years after induction of retinal lesions may reflect the fact that even though visually driven activity restores in the cortical scotoma, the level of activity never fully returns to that of the surrounding cortex and some imbalance of activity persists (Das and Gilbert, 1995b).
The concomitant use of antiretroviral agents with chemotherapy is generally accepted practice with the possible exceptions of zidovudine, which significantly adds to the myelosuppression of combination chemotherapy, and didanosine, which may worsen the peripheral neuropathy caused by vincristine. Little is known about the pharmokinetic interaction of protease inhib
Chronic nerve compression is one of the most common clinical phenomena in the peripheral nervous system. Surgical decompression of entrapped peripheral nerves is generally efficacious. However, a significant number of patients do not experience good long-term results with this treatment, and the socioeconomic impact is enormous. Multiple attempts of surgical releases can create more scar tissue which develops and further compresses the nerve. The epineural surface of the nerve is surrounded by scar tissue and stressed by strenuous work or a new injury. The result is a chronic neuropathy, called a traction neuropathy and the optimal treatment may be a combination of procedures. Mobilization of the nerve followed by internal neuroly-sis cannot alleviate these problems, due to recurrent scar. Most authors agree that soft tissue coverage is necessary to prevent this phenomenon, and several options have been suggested for this purpose. For recurrent carpal tunnel syndrome the hypothenar...
For example, the aromatic hydroxylation of guanoxon, S-oxidation of penicillamine, oxidation of sparteine (figure 5.24) and the hydroxylation of bufuralol (figure 5.1) have all been shown to be polymorphic. There are now a number of adverse drug reactions which are associated with the poor metabolizer status. For example perhexiline may cause hepatic damage and peripheral neuropathy in poor metabolizers in
This group of compounds is used as pesticides and nerve gases. The structure and therefore metabolism and potency varies. However, they all act in a similar manner. There are two toxic effects, cholinesterase inhibition and delayed neuropathy, but all OPs do not necessarily cause both. The cholinesterase inhibition results from the similarity between the organophosphorus compound and acetylcholine. The organophosphorus compound therefore acts as a pseudosubstrate but blocks the enzyme, in some cases permanently. This is because the organophosphate intermediate binds to the active site irreversibly or very strongly and the phosphorylated enzyme, unlike the natural acetylated enzyme, is only hydrolysed slowly. This enzyme blockade allows acetylcholine to build up and so the toxicity and symptoms are a result of excessive stimulation of receptors muscarinic receptors, leading to salivation, lacrimation, urination, defecation, bronchoconstriction, bradycardia,...
Certain organophosphorus compounds, such as tri-orthocresyl phosphate, cause this toxic effect. The symptoms, which may result from a single dose, may not be apparent for 10-14 days afterwards. The result is degeneration of peripheral nerves in the distal parts of the lower limbs which may spread to the upper limbs. Pathologically it is observed that the nerves undergo 'dying back' with axonal degeneration followed by myelin degeneration. The effect does not seem to be dependent on cholinesterase inhibition as tri-orthocresyl phosphate is not a potent cholinesterase inhibitor but causes delayed neuropathy. It seems that there is a covalent interaction with a membrane-bound protein, known as neuropathy target esterase, and the organophosphorus compound which may disturb metabolism in the neurone. This is followed by an ageing process which involves loss of a group from the phosphorylated protein. This protein seems to have a function critical to the neurone. The reaction with the...
Although rabies virus receptors appear to coincide with the distribution of acetylcholine receptors, the virus can enter the cell independently of these receptors. The virus may access the peripheral nerves directly or it may replicate in the muscle tissue, remaining at or near the site of introduction into the host for most of the incubation period, essentially at motor endplates, replicating in monocytes and later involving the peripheral nerves via the neuromuscular junctions. The virus then moves cen-tripetally to the central nervous system for replication. Subsequently it moves centrifugally to many tissues, including the salivary glands. Pathological changes in the brain are not profound, apart from the pathognomonic Negri bodies. Few neurons are involved, there is limited tissue necrosis and some perivascular cuffing.
The spectrum of pathological effects includes peripheral neuropathy, brain damage, myocardial ischaemia and infarction, muscle necrosis and pulmonary oedema. However, the main target organs are the brain and heart. This is because these organs have a relative inability to sustain an oxygen debt and they utilize aerobic metabolic pathways extensively. The brain damage may be due to several mechanisms including metabolic acidosis, hypotension, metabolic inhibition and decreased blood flow and oxygen availability. The progressive hypotension which is observed may be an important contributor to the ischaemia which occurs. Neural damage may follow both acute and chronic exposure. Death is due to brain tissue hypoxia, and respiratory failure may also occur.
FIGURE 5.6 Diagram showing adhesive relationships between Schwann cells (SC), axons (A) and basement membrane (BM). N-cadherin, L1 and N-CAM mediate adhesion between axons and between axons and Schwann cells. Integrins on the surface of axons mediate adhesion to laminin and tenascin in the basement membrane. Reproduced with permission from Fu and Gordon, The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 14 67-116. Copyright 1997, Humana Press, Inc.
The option of spreading to contiguous cells (direct cell-to-cell spread) or to noncontiguous cells, which are surrounded by interstitial space. In the case of direct cell-to-cell spread, rabies virus spreads despite a continuous presence of serum virus-neutralizing antibody (VNA). Alternatively, virus that buds from an infected cell into the surrounding interstitial space must find another cell to infect. In this case, the spread of virus is limited by the presence, in vitro and in vivo, of VNA that blocks virus attachment to cellular receptors and subsequent virus entry into a susceptible cell (Dietzschold et al., 1985 Flamand et al., 1993). In vivo, rabies virus also can spread in the cell, particularly cells of peripheral nerves and neuronal cells of the CNS, through intraaxonal transport in a microtubule network-dependent process. Virus that moves intraaxonally can cover great distances, particularly in bipolar neurons, before reaching and crossing the synapse of one dendritic...
|Living with Peripheral Neuropathy|
Peripheral Neuropathy Natural Treatment Options
This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.