Small-caliber Nerve Fibers Research Articles

Il dolore nella Malattia di Fabry

The pain of the extremities is a very frequent and early symptom,in males, and also in women, with a classic picture of Fabry’s disease, although it is often underestimated or misdiagnosed. It is characterized by attacks of burning pain, of variable intensity and frequency, which affect the extremities of the limbs. Young patients report recurrent episodes of exacerbation of pain attacks. Fever, heat and / or cold intolerance, reduced or absent sweating and gastrointestinal disorders can be associated with the pain of the extremities. These characteristics are indicative of the neuropathic nature of the pain, due to the selective involvement of small-caliber nerve fibers in the peripheral nerves and their ganglia (selective neuropathy of small fibers). The involved small nerve fibers mediate the pain, cold and heat perception, as well as the autonomic nervous system functions. In conclusion, because the selective neuropathy of small fibers is caused by some common disease, such as diabetes mellitus, but also by Fabry disease, it is appropriate that this last is also considered in differential diagnosis of pain of extremities in Youngs. This is because, in the case of M. of Fabry, the correct interpretation of the nature of painful symptomatology can contribute to a timely and reliable diagnosis of the disease itself, as well as to the choice of the most appropriate treatment.

Small-Fiber Neuropathy Nav1.8 Mutation Shifts Activation to Hyperpolarized Potentials and Increases Excitability of Dorsal Root Ganglion Neurons

Idiopathic small-fiber neuropathy (I-SFN), clinically characterized by burning pain in distal extremities and autonomic dysfunction, is a disorder of small-caliber nerve fibers of unknown etiology with limited treatment options. Functional variants of voltage-gated sodium channel Nav1.7, encoded by SCN9A, have been identified in approximately one-third of I-SFN patients. These variants render dorsal root ganglion (DRG) neurons hyperexcitable. Sodium channel Nav1.8, encoded by SCN10A, is preferentially expressed in small-diameter DRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Nav1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutations in SCN9A, and report a novel I-SFN-related Nav1.8 mutation I1706V in a patient with painful I-SFN. Whole-cell voltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistent current, and show that these pro-excitatory gating changes confer hyperexcitability on peripheral sensory neurons, which may contribute to pain in this individual with I-SFN.

Skin matters: identifying pain mechanisms and predicting treatment outcomes.

The skin acts as a complex sensory organ. The emerging new data on peripheral pain mechanisms from within the skin is presented. This data has led to new insights into the potential pain mechanisms for various pain conditions including neuropathic pain (from small fiber neuropathies) and Complex Regional Pain Syndrome. The somatosensory neurons that innervate our skin constantly update our brains on the objects and environmental factors that surround us. Cutaneous sensory neurons expressing nociceptive receptors such as transient receptor potential vanilloid 1 channels and voltage-gated sodium channels are critical for pain transmission. Epidermal cells (such as keratinocytes, Langerhans cells, and Merkel cells) express sensor proteins and neuropeptides; these regulate the neuroimmunocutaneous system and participate in nociception and neurogenic inflammation. In the past two decades, there has been widespread use of modalities such as punch skin biopsies, quantitative sensory testing, and laser-evoked potentials to evaluate small caliber nerve fibers. This paper explores these laboratory techniques as well as the phenomenon of small fiber neuropathy. Treatment using transdermal drug delivery is discussed. There is potential for these findings to predict treatment outcomes in clinical practice and to develop new therapies for different pain conditions. These findings should enhance the physician's ability to evaluate and treat diverse types of pain.

Painful Small Fiber Neuropathies

This article reviews the clinical features, pathophysiology, and treatment of small fiber sensory neuropathy. Neuropathic pain is prevalent among patients with peripheral neuropathies of diverse etiologies. For example, in one recent study using the sensitive Neuropathic Pain Symptom Inventory as a screening tool, neuropathic pain was reported in 94% of patients with different peripheral nervous system diseases. Neuropathic pain is frequently underrecognized or inadequately treated. Furthermore, the paucity of clinical signs with small fiber neuropathy may delay recognition of an organic process. Pain, or uncomfortable symptoms, typically results from damage to small unmyelinated nerve fibers (C fibers) or thinly myelinated nerve fibers (A delta fibers). Recent research has helped discover the location of the "pain generators" within the injured peripheral nerves. Small fiber neuropathies are relatively common in clinical practice, but until recently most of the available neurodiagnostic tests focused on large caliber nerve fibers. In the past two decades, the widespread use of quantitative sensory testing and punch skin biopsies to evaluate small caliber nerve fibers has substantially changed the neurologist's ability to diagnose and manage small fiber sensory neuropathy. Neuropathic pain from small fiber neuropathy is prevalent and is caused by a wide variety of disorders, many of which are treatable, especially if recognized early in the process.

Abnormal Function of C-Fibers in Patients with Diabetic Neuropathy

The mechanisms underlying the development of painful and nonpainful neuropathy associated with diabetes mellitus are unclear. We have obtained microneurographic recordings from unmyelinated fibers in eight patients with diabetes mellitus, five with painful neuropathy, and three with neuropathy without pain. All eight patients had large-fiber neuropathy, and seven patients had pathological thermal thresholds in their feet, indicating the involvement of small-caliber nerve fibers. A total of 163 C-fibers were recorded at knee level from the common peroneal nerve in the patients (36-67 years old), and these were compared with 77 C-fibers from healthy controls (41-64 years old). The ratio of mechano-responsive to mechano-insensitive nociceptors was approximately 2:1 in the healthy controls, whereas in the patients, it was 1:2. In patients, a fairly large percentage of characterized fibers (12.5% in nonpainful and 18.9% in painful neuropathy) resembled mechano-responsive nociceptors that had lost their mechanical and heat responsiveness. Such fibers were rarely encountered in age-matched controls (3.2%). Afferent fibers with spontaneous activity or mechanical sensitization were found in both patient groups. We conclude that small-fiber neuropathy in diabetes affects receptive properties of nociceptors that leads to an impairment of mechano-responsive nociceptors.

Later-Onset Fabry Disease

Classic Fabry disease, an X-linked recessive lysosomal storage disease due to the deficient activity of alpha-galactosidase A, typically presents in early childhood with acroparesthesias, angiokeratomas, hypohidrosis, and corneal dystrophy. The neuropathic pain presumably results from glycosphingolipid accumulation in the vascular endothelium and in small-caliber nerve fibers, and is treatable by enzyme replacement therapy. Later-onset variants with residual alpha-galactosidase A activity lack vascular endothelial involvement and classic symptoms, which lead to the development of cardiac and/or renal disease after the fourth decade of life. To expand the later-onset Fabry phenotype to include cramp-fasciculation syndrome without small-fiber neuropathy. A 34-year-old man who presented with chronic exercise-induced pain, fasciculations, and cramps of the feet and legs, and his similarly affected mother, were evaluated. Clinical, biochemical, and molecular studies were performed. Clinical evaluation suggested the diagnosis of Fabry disease, which was confirmed by reduced plasma and leukocyte alpha-galactosidase A activities (8.8% and 13.4% of normal, respectively) due to a missense A143T mutation. His mother was heterozygous for the A143T mutation. The presentation of cramps and fasciculations without apparent small-fiber neuropathy expands the phenotype of later-onset Fabry disease.

Vascular changes in animal models of diabetic neuropathy

Blood flow to neural tissues is reduced by diabetes. For peripheral nerve and ganglia, this occurs within a week of diabetes induction in experimental rat models. Some of the metabolic changes in diabetes target blood vessels, including vasa nervorum, resulting in attenuation of endothelial vasodilatory mechanisms based on nitric oxide, endothelium‐derived hyperpolarizing factor, and prostanoids. Moreover, there is increased production of and reactivity to some vasoconstrictors, particularly angiotensin II and endothelin‐1. Impaired vasa nervorum blood flow leads to endoneurial hypoxia, which causes or contributes of function defects affecting both large and small caliber nerve fibers. Intervention with vasodilator treatments corrects many diabetic neural deficits without affecting the hyperglycemic state, including reduced motor and sensory conduction velocity, elevated resistance to hypoxic conduction failure, impaired regeneration following nerve damage, aspects of hyperalgesia and allodynia, and autonomic dysfunction.

Interactions between hyperglycemia‐induced metabolic abnormalities and vascular factors in experimental diabetic neuropathy

Metabolic and vascular changes in diabetes conspire to cause nervous system dysfunction, which is particularly apparent for peripheral nerves. Hyperglycemia and hyperlipidemia give rise to numerous metabolic changes including, elevated polyol pathway flux, oxidative stress, formation of advanced glycation and lipoxidation end products, increased protein kinase C activity, and impaired essential fatty acid utilization. These disturbances interact to target neurons and their vascular supply. Experiments employing joint therapeutic approaches have revealed synergistic interactions between some of these mechanisms for both large and small caliber nerve fibers. Successful drug combinations conferring 5–10‐fold increases in efficacy include protein kinase C inhibitors and antioxidants, statins and angiotensin receptor antagonists, and antioxidants and essential fatty acids. This could provide a potentially important advantage for the treatment of diabetic neuropathy.

Axonal swellings and degeneration in mice lacking the major proteolipid of myelin.

Glial cells produce myelin and contribute to axonal morphology in the nervous system. Two myelin membrane proteolipids, PLP and DM20, were shown to be essential for the integrity of myelinated axons. In the absence of PLP-DM20, mice assembled compact myelin sheaths but subsequently developed widespread axonal swellings and degeneration, associated predominantly with small-caliber nerve fibers. Similar swellings were absent in dysmyelinated shiverer mice, which lack myelin basic protein (MBP), but recurred in MBP*PLP double mutants. Thus, fiber degeneration, which was probably secondary to impaired axonal transport, could indicate that myelinated axons require local oligodendroglial support.

Extensive proliferation of peripheral type myelin in necrotic spinal cord lesions of multiple sclerosis

Peripheral type “remyelination” in the spinal cord was investigated in a 34-year-old woman with relapsing multiple sclerosis (MS) over 7 years following her initial presentation with myelopathy. Confined to the large necrotizing cord lesions involving the gray matter, there was prominent proliferation of peripheral type myelin, measuring up to one-third of the cross-sectional field of the cord. These nerve bundles with peripheral type myelin, which was devoid of glial fibrillary acidic protein immunoreactivity, consisted of relatively monotonous, small-caliber nerve fibers arranged in parallel along the long axis of the cord. The ratio of the myelin thickness to axonal diameter was not as small as that of the ordinary remyelination. Co-existing abundant neuroma formation indicated exuberant regenerative activity of the peripheral nerves. These findings suggest that the peripheral nerve fibers with their axons originating from nerve roots may enter the necrotic MS cord lesions in such a way as to manifest in spinal cord trauma. Relatively frequent occurrence of this extensive proliferation of peripheral type myelin in Japanese MS subjects appears to be related to the severity of tissue destruction experienced in Japanese as compared with that of occidental MS.

Distribution of a novel 57 kDa intermediate filament (IF) protein in the nervous system

A 57 kDa protein, that is not vimentin, is the major component of intermediate filaments (IF) obtained after 2 cycles of in vitro assembly from PC12 cells (Parysek and Goldman, 1987). By use of an antiserum to the 57 kDa protein, a cross-reacting antigen (of identical molecular weight) was detected on immunoblots of IF preparations and by immunofluorescence of various rat tissues. Immunolocalization studies on 3-4 micron frozen sections of tongue, small intestine, and adrenal gland showed bright labeling of nerve bundles and fine-caliber nerve fibers. The chromaffin cells and ganglion cells of the adrenal medulla also were labeled. In the nervous system, intense labeling was seen in small-caliber nerve fibers in sciatic nerve and spinal cord dorsal roots, as well as in the dorsal white columns and dorsal root ganglia. Of the ganglion cells, preferential labeling was seen in small-sized ganglion cells, whereas a monoclonal antibody to the 150 and 200 kDa neurofilament triplet (NFT) components labeled the large-sized ganglion cells. In the areas of the brain thus far examined with 57 kDa antiserum, there was labeling of components of cranial nerves and labeling of thin fibers in several areas, including the granular layer of the cerebellum and the corticospinal tract in the brain stem. For each tissue, adjacent sections treated with vimentin or glial fibrillary acidic protein antibody revealed labeling patterns distinct from that seen with either the 57 kDa or NFT antibodies. These results indicate that the 57 kDa IF protein is a neural IF component. Furthermore, this protein is distributed in only certain neuronal elements; these elements may be unified by an as yet unrecognized pattern of function in the nervous system.

Fetal spinal cord homografts ameliorate the severity of lesion-induced hind limb behavioral deficits

Fetal spinal cord grafts survive for long periods in host spinal cord. We explored the ability of such grafts into a lesion in C3 fasciculus gracilis to influence the expected deterioration of hind limb performance following this lesion. Ten adult Sprague-Dawley rats were placed on a schedule of 23 h off and 1 h on water. These subjects were then trained to traverse a narrow platform for a water reward. Criterion was established as 10 trials/day completed in 15 s a trial for 2 consecutive days. Animals were ranked for hind limb and forelimb performance utilizing slips, recovery, and manner of traversing the platform. In a triple-blind experimental design, the animals' identification was coded and laminectomy performed at C3. The fasciculus gracilis was bilaterally transected at the rostral and caudal borders of the segment and aspirated. Five subjects were chosen at random immediately after the lesion was made for the implantation of two 1-mm segments of E14 spinal cord from fetuses of timed pregnant Sprague-Dawley dams at the time of the lesion. Coded lesion and lesion-transplant animals were then tested after 21, 30, 45, 60, and 90 days until criterion or for 4 days. Hind limb performance of the lesion-only (ANOVA χ 2 = 13.04, df 5; P < 0.05) and lesion-transplant groups (ANOVA χ 2 = 11.82, df 5; P < 0.05) showed that the C3 fetal transplants significantly decreased ( P < 0.05) the severity of hind limb deficit at 21 days postlesion and significantly ( P < 0.05) decreased the expected foot slips and limb recovery to the platform that was expected and did develop in lesion-only animals at 90 days. There were no significant differences in forelimb performance (ANOVAs P > 0.05). There were few small-caliber nerve fibers in the fasciculus gracilis at the level of C1 indicating that reinnervation was not a major factor in the reduction of the deficit.