Nervi Nervorum Research Articles

Chronic pain and local pain in usually painless conditions including neuroma may be due to compressive proximal neural lesion.

It has been unexplained why chronic pain does not invariably accompany chronic pain-prone disorders. This question-driven, hypothesis-based article suggests that the reason may be varying occurrence of concomitant peripheral compressive proximal neural lesion (cPNL), e.g., radiculopathy and entrapment plexopathies. Transition of acute to chronic pain may involve development or aggravation of cPNL. Nociceptive hypersensitivity induced and/or maintained by cPNL may be responsible for all types of general chronic pain as well as for pain in isolated tissue conditions that are usually painless, e.g., neuroma, scar, and Dupuytren's fibromatosis. Compressive PNL induces focal neuroinflammation, which can maintain dorsal root ganglion neuron (DRGn) hyperexcitability (i.e., peripheral sensitization) and thus fuel central sensitization (i.e., hyperexcitability of central nociceptive pathways) and a vicious cycle of chronic pain. DRGn hyperexcitability and cPNL may reciprocally maintain each other, because cPNL can result from reflexive myospasm-induced myofascial tension, muscle weakness, and consequent muscle imbalance- and/or pain-provoked compensatory overuse. Because of pain and motor fiber damage, cPNL can worsen the causative musculoskeletal dysfunction, which further accounts for the reciprocity between the latter two factors. Sensitization increases nerve vulnerability and thus catalyzes this cycle. Because of these mechanisms and relatively greater number of neurons involved, cPNL is more likely to maintain DRGn hyperexcitability in comparison to distal neural and non-neural lesions. Compressive PNL is associated with restricted neural mobility. Intermittent (dynamic) nature of cPNL may be essential in chronic pain, because healed (i.e., fibrotic) lesions are physiologically silent and, consequently, cannot provide nociceptive input. Not all patients may be equally susceptible to develop cPNL, because occurrence of cPNL may vary as vary patients' predisposition to musculoskeletal impairment. Sensitization is accompanied by pressure pain threshold decrease and consequent mechanical allodynia and hyperalgesia, which can cause unusual local pain via natural pressure exerted by space occupying lesions or by their examination. Worsening of local pain is similarly explainable. Neuroma pain may be due to cPNL-induced axonal mechanical sensitivity and hypersensitivity of the nociceptive nervi nervorum of the nerve trunk and its stump. Intermittence and symptomatic complexity of cPNL may be the cause of frequent misdiagnosis of chronic pain.

Ultrasound-Guided Nerve Hydrodissection for Pain Management: Rationale, Methods, Current Literature, and Theoretical Mechanisms.

Nerve hydrodissection (HD), a technique used when treating nerve entrapments, involves the injection of an anesthetic, saline, or 5% dextrose in water to separate the nerve from the surrounding tissue, fascia, or adjacent structures. Animal models suggest the potential for minimal compression to initiate and perpetuate neuropathic pain. Mechanical benefits of HD may relate to release of nervi nervorum or vasa nervorum compression. Pathologic nerves can be identified by examination or ultrasound visualization. The in-plane technique is the predominant and safest method for nerve HD. Five percent dextrose may be favored as the preferred injectate based on preliminary comparative-injectate literature, but additional research is critical. Literature-based hypotheses for a direct ameliorative effect of dextrose HD on neuropathic pain are presented.

Contribution of neurosensory Posturotherapy in the management of specific chronic pain syndrome

Objectives Chronic pain syndromes are frequently associated with balance disorders [1] . For example, studies showed a linear relationship between pain and stability [1] in no-specific low back pain [2] . The reexamination of the links between nerves and pain [3] modifies the traditional perception of these chronic pain syndromes without organic cause and these neural dysfunctions. The aim of this communication is to propose a new, original and innovative clinical approach to the management of chronic pain syndrome by the use of postural investigation and neurosensory stimulation. Methods The neurosensory Posturotherapy [3] uses a simple methodology to understand neural physiology through a palpatory sensory evaluation and then to perform manual neurostimulation. These stimulations include the neural saturation of the dysfunctional nerve associated with a sideration of muscles innervated by the nerve being treated. This approach can be completed by plantar neurostimulations inducing postural remediation. Results Firstly, the dysfunction of a nerve is associated with hypertonia of the muscles which it innervates. Secondly, the nervi nervorum compose the intrinsic innervations of nerve sheath. They are polymodal receptors located at the periphery of the nerve sheath. They encode the mechanical information exerted on the nerve. The response of the mechanoreceptors increases with the intensity of the stimulation up to a plateau and then decreases from a threshold value. Thirdly, pressure and vibration, exerted with intensity higher than the threshold value, induces a saturation of the response of the mechanoreceptor. Lastly, the saturation points used by the treatment are most often found at the points of cutaneous emergence of the nerve. Conclusion The neurosensory Posturotherapy is a simple method of diagnosis and treatment of neural dysfunction involved in neuropathic pain and balance disorders. It represents a new therapeutic contribution in the management of subjects with specific chronic pain syndrome.

Concept of acute neuropathic pain. The role of nervi nervorum in the distinction between acute nociceptive and neuropathic pain

BACKGROUND AND OBJECTIVES: Several pathophysiological mechanisms are involved in the genesis of neuropathic pain. However, available justifications for its onset are unsatisfying and do not explain the participation of nervi nervorum and nervi vasorum abnormalities on functional aberrations which characterize pain generated by injuries to the peripheral nervous system. There are evidences that nervi nervorum contribute to the development and justify many clinical findings and prophylactic, therapeutic and rehabilitation alternatives related to neuropathic pain. This study aimed at presenting a review of anatomic and functional studies and theories about their objectives and at giving examples of conditions in which nervi nervorum have markedly participated in neuropathic pain generation and maintenance. CONTENTS: Nervi nervorum are a set of unmyelinated or poorly myelinated fibers located in peripheral nerves sheaths which, among other functions, seem to participate in the transmission of evoked sensory information and in the environmental regulation of peripheral nervous system structures. CONCLUSION: Nervi nervorum structural and functional abnormalities may contribute to the onset, maintenance and worsening of neuropathic pain and demodulatory painful syndromes. Further studies, especially with the application of more specific and sensitive histological, biochemical and electrophysiological methods are necessary to clarify the realities of their biologies.

A mechanism-based classification of pain in multiple sclerosis

Pharmacological treatment of pain in multiple sclerosis (MS) is challenging due to the many underlying pathophysiological mechanisms. Few controlled trials show adequate pain control in this population. Emerging evidence suggests that pain might be more effectively classified and treated according to symptoms and underlying mechanisms. The new mechanism-based classification we propose here distinguishes nine types of MS-related pain: trigeminal neuralgia and Lhermitte’s phenomenon (paroxysmal neuropathic pain due to ectopic impulse generation along primary afferents), ongoing extremity pain (deafferentation pain secondary to lesion in the spino-thalamo-cortical pathways), painful tonic spasms and spasticity pain (mixed pains secondary to lesions in the central motor pathways but mediated by muscle nociceptors), pain associated with optic neuritis (nerve trunk pain originating from nervi nervorum), musculoskeletal pains (nociceptive pain arising from postural abnormalities secondary to motor disorders), migraine (nociceptive pain favored by predisposing factors or secondary to midbrain lesions), and treatment-induced pains. Identification of various types of MS-related pain will allow appropriate targeted pharmacological treatment and improve clinical practice.

Pathways of Sensory Recovery after Face Transplantation

Severely disfiguring facial injuries have a devastating impact on the patient's quality of life. The advent of facial allotransplantation has allowed optimal anatomical reconstruction to be achieved; however, the need for lifelong immunosuppression and unpredictable functional outcomes preclude it from routine acceptance in clinical practice. Evidence from published reports on the first four face transplant recipients indicates improved and accelerated return of sensation to the facial allograft despite suboptimal repair of the sensory nerves. The authors performed a comparative analysis of the sensory outcomes following face transplantation with the sensory recovery achieved after conventional nerve repair, autologous face and scalp replantation, and vascularized free tissue transfer. Sensory recovery following face transplantation, even when the sensory nerves were not repaired, was comparable to the outcome of microsurgical repair of the peripheral branches of the trigeminal nerve and innervated free flaps. Nearly normal sensory recovery can be expected following facial allotransplantation with or without repair of the sensory nerves. The mechanisms responsible for this surprising outcome include preservation of normal density of the receptors within the facial allograft, regeneration from the recipient bed and allograft margins, transmission of the sensory inputs through afferent fibers contained in the facial nerve, nervi nervorum of the facial nerve, or trigeminofacial communicating rami. Furthermore, immunosuppressive therapy with tacrolimus contributes to the accelerated nerve regeneration. The minimum requirements for quantitative sensory testing and timing of the follow-up assessments are outlined to facilitate comparison of sensory outcomes after face transplantation.

This disorder has some nerve

Guillain-Barre syndrome (GBS) has an easily appreciated clinical pattern of rapidly progressive, generalized weakness, limb paresthesias, and areflexia. Oropharyngeal weakness and ventilatory failure requiring ventilator support occur in 20% to 30% of cases.1 In this clinical context, pain may be underappreciated and therefore untreated. Symptoms include low back and proximal muscle pain, radicular limb pain, acral dysesthesias, and burning and arthralgias. Multiple pain patterns may coexist and overlap, complicating clinical assessment. The pathophysiology of pain in GBS is poorly understood. Hypothesized mechanisms include irritation of the nervi nervorum innervating nerve trunks and the dorsal rami; demyelination of large sensory nerve fibers causing painful dysesthesias; and dysfunction of small nerve fibers, eliciting burning neuropathic pain.2,3 Several elegant animal studies have suggested a role for T-cell–mediated inflammation and the release of proinflammatory cytokines producing thermal hyperalgesia and allodynia in experimental autoimmune neuritis.4 …

Pain around the ear in Bell’s palsy is referred pain of facial nerve origin: The role of nervi nervorum

General somatic afferents of facial nerve innervate skin of the concha, the posterior external ear canal and a small area behind the ear. But pain around the ear that precedes or develops at the same time as Bell's palsy frequently is beyond the territory of sensory innervations of facial nerve. Cranial nerves are richly innervated by their own nerves called nervi nervorum that have nociceptive function. So, stimulation of nervi nervorum dominating facial nerve trunk can be transmitted to trigeminocervical nuclear complex and make referred pain on the craniofacial region segmentally. The reason why referred pain of facial nerve origin develops around the ear is that facial nerve and its ensheathing connective tissue are derivatives of second branchial arch which is homologous to the somites of body.

Post herpetic neuralgia, schwann cell activation and vitamin D

While the underlying pathophysiology of herpes zoster infection has been well characterised, many of the mechanisms relating to the subsequent development of post herpetic neuralgia (PHN) remain uncertain. The dorsal horn atrophy and reduction in skin innervation seen in PHN patients does not adequately explain many clinical features or the efficacy of a number of topical treatments. In the central nervous system the glia, their receptors and their secreted signalling factors are now known to have a major influence on neural function. In the peripheral nervous system, schwann cell activation in response to infection and trauma releases a number of neuroexcitatory substances. Activation of the nervi nervorum in the peripheral nervous system also leads to the release of calcitonin gene related peptide, substance P and nitric oxide. Schwann cell and/or nervi nervorum activation could be an additional mechanism of pain generation in PHN. Such a paradigm shift would mean that drugs useful in the treatment of glial cell activation such as naloxone, naltrexone, minocycline, pentoxifyllline, propentofylline, AV411 (ibudilast) and interleukin 10 could be useful in PHN. These drugs could be used systemically or even topically. High dose topical vitamin D would appear to offer particular promise because vitamin D has the ability to both reduce glial inflammation and reduce nitric oxide production.

Workshop: Clinical implications for clinicians treating patients with non-specific arm pain, whiplash and carpal tunnel syndrome

Nerve sheath inflammation without significant axonal degeneration can result in c fibres (both axons in continuity and the nervi nervorum) becoming spontaneously active and mechanically sensitive. This may help explain the painful responses when examining neural dynamics in patients with non specific arm pain, carpal tunnel syndrome and arm pain following whiplash injury, when longitudinal nerve excursion (measured using ultrasound imaging), appears to be within normal ranges. These findings have implications for the clinical examination and treatment of these patients groups.

Intraneural Injection during Anterior Approach for Sciatic Nerve Block: What Have We Learned and Where to Go from Here?

We appreciate the interest of Dr. Blumenthal et al. in our case report on intraneural administration of local anesthetic during an anterior approach of the sciatic nerve.1We agree completely with these authors but would like to clarify a few details.Our patients had been included in a study intended to evaluate the accessibility of the sciatic nerve using the anterior approach. We aimed at determining the reliability and stability of the catheter for postoperative analgesia in this approach. Despite this explanation of why we conducted these blocks in the computerized tomographic radiologic room, we believe that the near future will see an increasing participation of neuroimaging techniques in helping with anesthetic block procedures.2Moreover, the sciatic nerve is hidden behind the minor trochanter in a nonnegligible proportion of patients (> 10%) when we effect an anterior approach, independently of the rotation of the hip, and the risk of puncture of the femoral vessels exists.3,4The computerized tomography–guided approach should help to avoid risks.We agree with Blumenthal et al. in that, with the current state of our knowledge, the best praxis would have been to withdraw the catheter. This was what we did in the second patient reported. In the first patient, however, we were not aware of the intraneural puncture and anesthetic administration because the images were analyzed off-line.The structure of the nerve trunk is complex (fig. 1). Basically, the nerves run along different body compartments surrounded by tissues with their own fascia. These fascias, which are not part of the nerve, are the “recommended points” for injection to avoid nerve damage—or, that is what we thought. Inside the nerve trunk, the axons, enwrapped by the endoneurium, are grouped in fascicles surrounded by the perineurium, a relatively resistant membrane that is difficult to puncture because of its elasticity, mobility, and adaptability to external forces. The fascicles are embedded within the epineurium, which is surrounded by a thicker membrane, the epineurium sheath. The epineurium is a slack collagen and fatty tissue, which contains the vasa and nervi nervorum.5–8Most of the nerve section (between 30–75%) is occupied by nonneural structures.5,9The sciatic nerve produces abundant epineurium, which covers between 72 and 78% of the nervous section.10Intraepineural injection of anesthetic would not necessarily lead to nerve damage.11On the contrary, intrafascicular injection is more likely to induce nerve lesions.12However, because of their elastic properties, the fascicles probably separate from each other and get out of the way if a needle penetrates the nerve trunk. Although direct neural tissue lesion is unlikely, it should be taken into account that intraepineural injection of a substance can cause an increase in neural pressure and secondary damage because of compression or a vascular lesion.Clinical experience supports neurostimulation as a safe and effective technique with minimal incidence of nerve lesions. However, a large number of unresolved questions stemming out from our observations remain: How often does intraepineural injection occur in routine practice? Does it occur preferentially in certain nerves? What are the clinical and radiologic signs suggesting intraneural puncture? What is the safe threshold for electrical near-nerve stimulation?* Hospital Clínic, Barcelona, Spain. xsala@clinic.ub.es

Sir Victor Horsley, Mr John Marshall, the Nervi Nervorum, and Pain

Sir Victor Horsley (1857-1916) is best known for the many pioneering neurosurgical procedures that he developed during the late 19th century. These advances enabled surgery to be performed on the brain with an acceptable mortality level.' Horsley's research was not limited to neurosurgery; it also extended into basic neurology (eg, motor cortex function) 2 and even general medicine, including many studies on the function of the thyroid gland.

Rat peripheral nerve components release calcitonin gene-related peptide and prostaglandin E 2 in response to noxious stimuli: evidence that nervi nervorum are nociceptors

The presence of an intrinsic afferent innervation of nerves and their connective tissues (nervi nervorum) suggests that these neural elements participate in sensation and pathological processes affecting nerves. Primary afferent nociceptors contain and release neuropeptides including calcitonin gene-related peptide, implicated in inflammatory vasodilatation. We sought to evaluate the ability of different peripheral nerve components, in vitro, to release calcitonin gene-related peptide and prostaglandin E 2 in response to electrical and noxious chemical stimuli, using sensitive enzyme immunoassays. We observed significant increases in both calcitonin gene-related peptide and prostaglandin E 2 in response to a mixture of inflammatory mediators (bradykinin, histamine, and serotonin; 10 −5 M) applied to the intact nerves (+37% and +700%, respectively) and isolated sheaths (35% and 430%, respectively), but not when this mixture was applied to isolated axons. Proximal (antidromic) but not distal (orthodromic) electrical stimulation also evoked a comparable release of calcitonin gene-related peptide (+30%) from intact nerves. These results suggest that nervi nervorum nociceptors participate in neural inflammation. Capsaicin (10 −6 M) elicited a very large release of calcitonin gene-related peptide when applied to either the intact nerve (+400%), isolated sheaths (+500%), or isolated axons (1400%). The latter effect was substantially but not completely blocked by Ruthenium Red and capsazepine, and was completely blocked using a calcium-free bathing solution. The results support the presence of capsaicin receptors in peripheral nerves that can effect calcitonin gene-related peptide release from axons as well as from terminals.

Immunohistochemical localisation of neuropeptides and nitric oxide synthase in sural nerves from Egyptian mummies

Paleopathology is a well established science with numerous papers and books on the subject but, in contrast, paleoneurobiology is almost non-existent. We examined sections of sural nerves obtained from seven embalmed Egyptian mummies and one naturally dessicated Peruvian mummy, immunohistochemically stained for several neurochemicals. Immunoreactivity for type I nitric oxide synthase (NOS), protein gene-product 9.5, galanin, and calcitonin gene-related peptide immunoreactivity was observed in the nervi nervorum. No immunoreactivity was seen using antibodies directed against substance P, vasoactive intestinal polypeptide or neuropeptide Y. NOS-immunoreactivity was also observed in biopsied samples of contemporaneous human sural nerves. Thus, using a standard immunohistochemical technique it was possible to detect neurochemicals in ancient sural nerves that had been preserved by mummification. Furthermore, the finding of NOS in the ancient nerves led to its detection in contemporaneous sural nerves.

An alternative mechanism for neuropathic pain: Nervi nervorum

The Focus article by Doctors Sove and Light calls attention to the generally neglected inner­ vation of nerve sheaths, the nervi nervorum. It is asserted that the hypotheses that were pro­ posed during the last century concerning the diagnosis and treatment of neuropathic and musculoskeletal pain have failed to withstand scientific scrutiny and that the nervi nervorum may be at least one of the offending agents that cause neuropathic pain. The Focus article gives a historical review of what is known about the nervi nervorum (including in this cate­ gory the nervi vasorum nervorum , the nerve fibers that supply the blood vessels within the nerve sheath). They are chiefly unmyelinated axons havinq free endings (although some have encapsulated endings) in the lay­ ers of connective tissue about peripheral nerves [13], and many of these axons contain neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP) [2,6]. The authors have recently shown that at least some nervi nervorum in the deep paraspinal tis­ sues are nociceptors [7]. The nervi nervorum afferents have multiple, punctate receptive fields and respond to noxious mechanical, chemical , and thermal stimuli. Interestingly, they can also have receptive fields in adja­ cent muscles or tendons. The authors agree with Asbury and Fields [3] that the nervi nervorum contribute to nerve trunk pain. Damage to a peripheral nerve or application of cap­ saicin results in hyperemia as a result of the release of SP and CGRP from the nervi nervorum [26,27]. The hyperemia can be prevented by local administration of a

The nervi nervorum: Missing link for neuropathic pain?

The nervi nervorum constitute the intrinsic innervation of nerve sheaths. Recent studies have revealed nociceptors with multiple receptive fields that branch within the nerve sheaths and to other deep tissues. Their sensitivities and anatomic location combined with scientific and clinical evidence implicate nervi nervorum in neuropathic and other chronic pain. It is proposed that, besides signaling pain from direct stimulation, nervi nervorum play a role in initiating events leading to these syndromes. Stimulation of nervi nervorum may also maintain central nervous system changes thought to occur in chronic pain states.

The nerve of these nerves!

O ur Focus article dealt with a possible locus of spontaneous and movement-induced pain following nerve injury, not the enhanced and spontaneous cutaneous pain remote from an injury site. Most of the evidence Sorkin et al. present is from behavioral studies that measure distal symptoms such as these. Thus, the data collected in this fashion do not detract from the notion that local nerve damage leads to local nociception , possibly amplified by known nerve regrowth mechanisms. Nonetheless, we agree that much work remains to be performed on nervi nervorum (NN), including their density, distribution, and response to specific injury. Observations of patients with radicular pain suggest that tumor necrosis factor alpha (TNF) is not always involved in neuropathic pain. Leg pain associated with back pain can be made worse by the straight-leg-raising test or other movements that stretch involved nerves. These movements are not painful in normal humans, innocuous to a normal nerve, and not sufficient to elicit discharge from normal NN [2]. The pain begins and ends at a specific angle of the test. This response pattern is not consistent with ectopic activity induced by TNF as described in the work of Sorkin et al. [13]. The response is consistent with local, abnormal nociceptor activity, and the NN are certainly likely candidates. Tests like these produce excursions of 0-5 mm of spinal nerves at 90° [4], not enough to cause the straightening

Valid versus redundant links in the theory for “Neuropathic Pains”

T his intelligent essay emanates from discovery on the fact that among the nerve fibers contained in nervi nervorum there exist nociceptors with conduction velocities in the C-fiber range and with characteristics of polymodal receptors. Details of that important study are given by the authors in previous publication. The authors then join in the irresistible want of offering their finding as possible explanation for the mystery of chronic neuropathic pains, curse for humankind. They lament that despite much research, a hypothesis regarding their etiologies has not been accepted. The authors' broad fund of knowledge on neuroanatomy, neuropathology, and neurophysiology, as capitalized with controlled imagination, yields logically appealing hypothesis. Bone and Light propose that fine chronic posttraumatic pathology of nociceptors in nervi nervorum would generate afferent input that would be perpetuated through circumstantial use-induced friction against hypothetical intraor paraneural scars. Such input would hypothetically maintain state of hyperexcitability in central neurons that would have been sensitized through past injurious afferent barrage and that would signal impulses decoded by the brain as pain. That would be the authors' basic hypothesis for the enigmatic condition of chronic neuropathic pains. Is this almost intuitive syllogism valid as clinical reality? Clinical facts must now be factored into this clinically targeted theory.

Role of the nervi nervorum in neuropathic pain: Innocent until proven guilty

D octors Sove and Light present an important and interesting hypothesis on the function of unmyelinated sensory fibers with free endings in the perineurium. They suggest that these nociceptive fibers of the nervi nervorum serve an integral and unique role in the pathogenesis of neuropathic pain by signaling pain from direct stimulation and by initiating and reinforcing the electrophysiologic events that characterize the neuropathic pain state. Their hypothesis is based on several of their own observations and a substantial literature on the anatomy, function, and chemical sensitivity of nerve fibers. As the authors point out, the hypothesis has been expressed in slightly different forms in the past, but has not been formally tested. It extends a more fundamental hypothesis suggesting that the primary role of the nervi nerverum is to guard the fascicular axons from physical injury by nociceptive signaling and to help regulate the endoneurial environment through the release of neuropeptides that alter the blood-nerve barrier. That the nervi nervorum may contribute directly to the pathogenesis of neuropathic pain is an appealing hypothesis, but one that is difficult to test given the technical problems of isolating perineurial fibers and stimulating them without affecting the very large number of adjacent somatic fibers in the fascicular endoneurial space. To think that compression of the perineurium or chemical alterations in its environment could cause aberrant firing in the terminal receptors of the nervi ner-

96/03780 Effect of curing conditions on high-volume fly ash concrete made with ASTM Type I and III cements and silica fume

Paleopathology is a well established science with numerous papers and books on the subject but, in contrast, paleoneurobiology is almost non-existent. We examined sections of sural nerves obtained from seven embalmed Egyptian mummies and one naturally dessicated Peruvian mummy, immunohistochemically stained for several neurochemicals. Immunoreactivity for type I nitric oxide synthase (NOS), protein gene-product 9.5, galanin, and calcitonin gene-related peptide immunoreactivity was observed in the nervi nervorum. No immunoreactivity was seen using antibodies directed against substance P, vasoactive intestinal polypeptide or neuropeptide Y. NOS-immunoreactivity was also observed in biopsied samples of contemporaneous human sural nerves. Thus, using a standard immunohistochemical technique it was possible to detect neurochemicals in ancient sural nerves that had been preserved by mummification. Furthermore, the finding of NOS in the ancient nerves led to its detection in contemporaneous sural nerves.