US can accurately diagnose transected nerves, but is limited by large hematomas, skin lacerations and soft tissue edema. However, the reinnervation is not necessarily perfect, as possible misleading occurs during reinnervation of the proximal axons to target cells. All agents have been tested only in cell-culture or animal models. Forty-three patients with wallerian degeneration seen on MR images after cerebral infarction were studied. %%EOF While Alzheimer's disease (AD) is the most common neurodegenerative disease that causes it, more than 50 [10] Degeneration follows with swelling of the axolemma, and eventually the formation of bead-like axonal spheroids. Question: QUESTION 1 Carpal tunnel and tarsal tunnel syndrome cause nerve degeneration resulting in specific symptoms and changes in the nerves. Schwann cells emit growth factors that attract new axonal sprouts growing from the proximal stump after complete degeneration of the injured distal stump. This testing can further determine Sunderland grade. Within a nerve, each axon is surrounded by a layer of connective tissue . [37] These authors demonstrated by both in vitro and in vivo methods that the protective effect of overexpression of NMNAT1 or the addition of NAD+ did not protect axons from degeneration. Reference article, Radiopaedia.org (Accessed on 04 Mar 2023) https://doi.org/10.53347/rID-18998, {"containerId":"expandableQuestionsContainer","displayRelatedArticles":true,"displayNextQuestion":true,"displaySkipQuestion":true,"articleId":18998,"questionManager":null,"mcqUrl":"https://radiopaedia.org/articles/wallerian-degeneration/questions/1308?lang=us"}, View Maxime St-Amant's current disclosures, see full revision history and disclosures, stage 1: degeneration of the axons and myelin sheaths with mild chemical changes (0-4 weeks), stage 2: rapid destruction of myelin protein fragments that were already degenerated, lipids remain intact (4-14 weeks), stage 4: atrophy of the white matter tracts (months to years), brainstem atrophy with or without hypointensity. In comparison to Schwann cells, oligodendrocytes require axon signals to survive. These require further exploration and clinical trials: The current standards of care for peripheral nerve injury is based on serial examinations and/or electrodiagnostics. Axonotmesis presents as enlarged hyperintensity with loss of fascicular structure, edema, Neurotmesis terminal neuroma, muscle atrophy, fatty replacement. Strategies to promote peripheral nerve regeneration: electrical stimulation and/or exercise. An assessment of fatigability following nerve transfer to reinnervate elbow flexor muscles. The signaling pathways leading to axolemma degeneration are currently poorly understood. Uchino A, Sawada A, Takase Y et-al. Trans. Gordon T, English AW. Many rare diseases have limited information. AJNR Am J Neuroradiol. Injuries to the myelin are usually the least severe, while injuries to the axons and supporting structures are more severe (Fig 2). Disease pathology is the study of the symptoms and signs of diseases and how they change over time. The cell bodies of the motor nerves are located in the brainstem and ventral horn of the spinal cord while those of the sensory nerves are located outside of the spinal cord in the dorsal root ganglia (Fig 1)1. They activate ErbB2 receptors in the Schwann cell microvilli, which results in the activation of the mitogen-activated protein kinase (MAPK). [43] SARM1 activation locally triggers a rapid collapse of NAD+ levels in the distal section of the injured axon, which then undergoes degeneration. Wallerian degeneration in the corpus callosum. Experiments in Wallerian degeneration have shown that upon injury oligodendrocytes either undergo programmed cell death or enter a state of rest. No matter which surgery, postoperative nerve repairs should be immobilized for 10 days to 6 weeks depending on the injury severity. 09/20/2013. Further, microglia might be activated but hypertrophy, and fail to transform into fully phagocytic cells. Axonal degeneration or "axonopathy" The goal when evaluating a patient with a neuropathy is to place them into one of these four categories, based on the history and physical examination, and then to use the Musson R, Romanowski C. Restricted diffusion in Wallerian degeneration of the middle cerebellar peduncles following pontine infarction. In neuropraxia (Sunderland grade 1) there is focal demyelination with impaired sensory and motor function distal to the lesion but preserved axonal continuity. Conclusions. It occurs between 7 to 21 days after the lesion occurs. Delayed macrophage recruitment was observed in B-cell deficient mice lacking serum antibodies. Axonal degeneration is followed by degradation of the myelin sheath and infiltration by macrophages. [45] Activation of SARM1 is sufficient to collapse NAD+ levels and initiate the Wallerian degeneration pathway.[44]. Observed time duration for 3. PEG helps fuse cells, develop desired cell lines, remove water at the injured lipid bilayer, and increase the fusion of axolemmal ends. Nerves are honeycomb in appearance and mild hyperintense at baseline. Oligodendrocytes fail to recruit macrophages for debris removal. Promising new developments are under investigation that may help to suppress symptoms and restore function. "Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibres." Physiopedia is not a substitute for professional advice or expert medical services from a qualified healthcare provider. If a sprout reaches the tube, it grows into it and advances about 1mm per day, eventually reaching and reinnervating the target tissue. Neurapraxia is derived from the word apraxia, meaning "loss or impairment of the ability to execute complex coordinated movements without muscular or sensory . The gene was first identified in a Drosophila melanogaster mutagenesis screen, and subsequently knockouts of its homologue in mice showed robust protection of transected axons comparable to that of WldS. The effect of cooling on the rate of Wallerian degeneration. [47] Other pro-degeneration signaling pathways, such as the MAP kinase pathway, have been linked to SARM1 activation. Sunderland grade 2 is only axon damage; Sunderland grade 3 is axon and endoneurium damage; and, Sunderland grade 4 is axon, endoneurium, and perineurium damage. Nervous System Diagram: https://commons.wikimedia.org/w/index.php?title=File:Nervous_system_diagram-en.svg&oldid=292675723. 2023 ICD-10-CM Range G00-G99. When painful symptoms develop, it is important to treat them early (i.e . These include: Select ALL that apply. Sensory symptoms often precede motor weakness. Innovative treatment of peripheral nerve injuries: combined reconstructive concepts. Myelin debris, present in CNS or PNS, contains several inhibitory factors. Possibles implications of the SARM1 pathway in regard to human health may be found in animal models which exhibit traumatic brain injury, as mice which contain Sarm1 deletions in addition to WldS show decreased axonal damage following injury. Open injuries with dirty, blunt lacerations are delayed in surgical repair to better allow demarcation of injury and avoid complications such as infection. Two mechanisms of nerve recovery resulting in re-innervation of end-organs occur simultaneously: Collateral branching/sprouting of intact axons, Primary mechanism when 20-30% of axons injured, Starts within 4 days of injury and proceeds for 3-6 months, Primary method when greater than 90% of axons injured. Whereas conventional magnetic resonance imaging fails to detect signal intensity changes until four weeks after stroke, diffusion tensor imaging (DTI) reveals changes related to WD only after days. If gliosis and Wallerian degeneration are present . Wallerian degeneration is an active process of degeneration that results when a nerve fiber is cut or crushed and the part of the axon distal to the injury (which in most cases is farther from the neuron's cell body) degenerates. [ 1, 2] The term brachial may be a misnomer, as electrodiagnostic and radiologic evidence often . nerve injuries account for approximately 3% of injuries affecting the upper extremity and hand. Endoplasmic reticulum degrades and mitochondria swell up and eventually disintegrate. [13] Although MAPK activity is observed, the injury sensing mechanism of Schwann cells is Managing nerve damage can include the use of:Cryotherapy[6], Exercise, Neurorehabilitation, and Surgery. Wallerian degeneration is named after Augustus Volney Waller. 398 0 obj <>/Filter/FlateDecode/ID[<54E57DDCE89C43429F18A19BD223772B><90A4F5B4A330934DA644DDE1010DB79E>]/Index[385 24]/Info 384 0 R/Length 72/Prev 35308/Root 386 0 R/Size 409/Type/XRef/W[1 2 1]>>stream . 2. Peripheral neurological recovery and regeneration. Axonal degeneration can be caused by at least four different mechanisms. In cases of cerebral infarction, Wallerian . Inoue Y, Matsumura Y, Fukuda T et-al. [11], These findings have suggested that the delay in Wallerian degeneration in CNS in comparison to PNS is caused not due to a delay in axonal degeneration, but rather is due to the difference in clearance rates of myelin in CNS and PNS. Open injuries with complete nerve transection are repaired based on the laceration type. Regeneration is rapid in PNS, allowing for rates of up to 1 millimeter a day of regrowth. Wallerian degeneration is an active process of retrograde degeneration of the distal end of an axon that is a result of a nerve lesion. Wallerian degeneration is a phenomenon that occurs when nerve fiber axons are damaged. Calcium plays a role in the degeneration of the damaged axon during Wallerian degeneration, MRI demonstrating promise in both diagnosing and monitoring injury, especially in the surgical setting. Affiliated tissues include spinal cord, dorsal root ganglion and brain, and related phenotypes are Increased shRNA abundance (Z-score > 2) and nervous system. [21] Grafts may also be needed to allow for appropriate reinnervation. atrophy is the primary ophthalmoscopic manifestation of Wallerian degeneration and correlates with the patient's symptoms of loss of . Another key aspect is the change in permeability of the blood-tissue barrier in the two systems. In experiments conducted on rats,[18] myelin sheaths were found for up to 22 months. Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer. Symptoms: This section is currently in development. . Extensive axonotmesis cannot be differentiated initially from neurotmesis by either clinical or electrodiagnostic examination. 5-7 In either case, the volume loss does not become visible until at least several months poststroke. Fluorescent micrographs (100x) of Wallerian degeneration in cut and crushed peripheral nerves. If the sprouts cannot reach the tube, for instance because the gap is too wide or scar tissue has formed, surgery can help to guide the sprouts into the tubes. In a manner of weeks, fibrillations and positive sharp waves appear in affected muscles. One study found that during a surgical repair of a sharp, complete resection, the application of PEG for 2 minutes after surgical connection of the injured ends, helps to decrease inappropriate calcium-mediated vesicle formation, promote fusion, enhance axonal continuity with nerve healing, and improve sensory recovery, based on static two-point discrimination. De simone T, Regna-gladin C, Carriero MR et-al. 1. With cerebral softening, there are varied symptoms which range from mild to catastrophic. [31], Although the protein created localizes within the nucleus and is barely detectable in axons, studies suggest that its protective effect is due to its presence in axonal and terminal compartments. Waller experimented on frogs in 1850, by severing their glossopharyngeal and hypoglossal nerves. Those microglia that do transform, clear out the debris effectively. Mild to moderate autotomy, guarding, excessive licking, limping of the ipsilateral hind paw, and avoidance of placing weight on the injured side were noticed aer the procedure. The symptoms take effect immediately, but it takes 21 days for acute denervation changes to develop on needle EMG. Following injury, distal axons undergo the process of Wallerian degeneration, and then cell debris is cleared to create a permissive environment for axon regeneration. Also in the CNS, oligodendrocytes inhibit regeneration. Entry was based on first occurrence of an isolated neurologic syndrome . In addition, recovery of injury is highly dependent on the severity of injury. [31] This in turn activates SIRT1-dependent process within the nucleus, causing changes in gene transcription. American Academy of Physical Medicine and Rehabilitation, Neurological recovery and neuromuscular physiology, Physiology, biomechanics, kinesiology, and analysis, Normal development and Models of learning and behavioral modification. Marquez Neto OR, Leite MS, Freitas T, Mendelovitz P, Villela EA, Kessler IM. The only known effect is that the Wallerian degeneration is delayed by up to three weeks on average after injury of a nerve. The macrophages, accompanied by Schwann cells, serve to clear the debris from the degeneration.[5][6]. Another reason for the different rates is the change in permeability of the blood-tissue barrier in the two systems. 4.7-T diffusion tensor imaging of acute traumatic peripheral nerve injury. Recovery by regeneration depends on the cellular and molecular events of Wallerian degeneration that injury induces distal to the lesion site, the domain through which severed axons regenerate back to their target tissues. Wallerian degeneration is a condition that causes the loss of peripheral nerve function (peripheral nerve disease) through degeneration of nerve cells. It occurs between 7 to 21 days after the lesion occurs. hb```aB =_rA Begins within hours of injury and takes months to years to complete. Kuhn MJ, Mikulis DJ, Ayoub DM et-al. Wallerian degeneration of the pontocerebellar fibers. major peripheral nerve injury sustained in 2% of patients with extremity trauma. Wallerian degeneration in response to axonal interruption 4. [6] The process by which the axonal protection is achieved is poorly understood. It may result following neuronal loss due to cerebral infarction, trauma, necrosis, focal demyelination, or hemorrhage . Exercise, stretching, splinting, bracing, adaptive equipment, and ergonomic modification are usual components of the rehabilitation prescription. In neurotmesis (Sunderland grade 5), the axon and all surrounding connective tissue (endoneurium, perineurium, and epineurium) are damaged (i.e., transected nerve). Peripheral neurological recovery and regeneration. Some cases of subclavian steal syndrome involve retrograde blood . If neural regeneration is successful, the conduction velocity of the injury returns to 60% to 90% of pre-injury level (but this does not usually adversely affect clinical recovery). The prognosis, in general, is more favorable for a demyelinating lesion than for a lesion producing axonal loss. In Wallerian degeneration, the SARM1 pathway is likely activated by the consequences of the . Wallerian degeneration is an active process of retrograde degeneration of the distal end of an axon that is a result of a nerve lesion. Common signs and symptoms of peripheral nerve injuries include: Fig 2. A related process of dying back or retrograde degeneration known as 'Wallerian-like degeneration' occurs in many neurodegenerative diseases, especially those where . After the 21st day, acute nerve degeneration will show on the electromyograph. 8@ .QqB[@Up20i_V, i" i. !/$vhwf,cliHx$~gM])BP(Reu[BG4V`URV.//] L7o}%.^xP]-0n'^5w7U?YO}U[QtPog7fj(HY7q G and H: 44 hours post crush. The possible source of error that could result from this is possible mismatching of the target cells as discussed earlier. The somatic nervous system is made up of both motor and sensory nerves. Diffusiontensorimaging(DTI), a type of MR, can quantify axon density and myelin thickness. Some of the agents include erythropoietin, tacrolimus, acetyl-L-carnitine, N-acetylcysteine, testosterone, chondroitinase ABC, dimethylsulfoxide, transthyretin (pre-albumin), ibuprofen, melatonin, and polyethylene glycol. The activity of SARM1 helps to explain the protective nature of the survival factor NMNAT2, as NMNAT enzymes have been shown to prevent SARM1-mediated depletion of NAD+. This page was last edited on 30 January 2023, at 02:58. The axon then undergoes a degeneration process that can be anterograde or orthograde (Wallerian) [1] or retrograde. or clinical procedures, such as a hearing test. Boyer RB, Kelm ND, Riley DC et al. We therefore asked whether genetic deletion of SARM1 also protects from myelinated axon loss in the toes. Innate-immunity is central to Wallerian degeneration since innate-immune cells, functions and . E and F: 42 hours post cut. [36] More recent work, however, raises doubt that either NMNAT1 or NAD+ can substitute for the full length Wlds gene. The authors conclude that MR imaging provides a sensitive method of evaluating wallerian degeneration in the living human brain. Corresponding stages have been described on MRI. It is named after the English neurophysiologist Augustis Volney Waller (1816-1870), who described the process in 1850 6. PNS is much faster and efficient at clearing myelin debris in comparison to CNS, and Schwann cells are the primary cause of this difference. [38], The provided axonal protection delays the onset of Wallerian degeneration. Motor symptoms, which include any changes related to movement, are frequently present with mononeuropathies. In the three decades since the discovery of the Wallerian degeneration slow (WldS) mouse, research has generated . This occurs by the 7th day when macrophages are signaled by the Schwann cells to clean up axonal and myelin debris. PDF | Background Elevated serum creatine kinase (CK) levels have been reported in patients with Guillain-Barr syndrome (GBS), more frequently in. Axonal degeneration occurs either as a primarily axonal process or as a bystander-type axonal degeneration, associated with . , autoimmune disease) or localized damage (e.g., trauma, compression, tumors) and manifest with neurological deficits distal to the level of the lesion. A and B: 37 hours post cut. For axonotmesis and neurotmesis, the EMG findings listed are distal to the lesion in the relevant nerve territory. Axon and myelin are both affected https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-8-110, "An 85-kb tandem triplication in the slow Wallerian degeneration (Wlds) mouse", https://www.youtube.com/watch?v=kbzYML05Vac, https://www.https://www.youtube.com/watch?v=P02ea4jf50g&t=192s, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315870/, https://www.physio-pedia.com/index.php?title=Wallerian_Degeneration&oldid=274325, Reduced or loss of function in associated structures to damaged nerves, Gradual onset of numbness, prickling or tingling in feet or hands, which can spread upward into legs and arms, Sharp, jabbing, throbbing, freezing, or burning pain. With time, partial axonal loss may result in reduced amplitude and slowed conduction, while complete axonal injury results in loss of action potentials. This proliferation could further enhance the myelin cleaning rates and plays an essential role in regeneration of axons observed in PNS. Muscle and tendon transfers can lead to adhesive scarring in the antagonist muscle and prevent proper tendon function. Read more, Physiopedia 2023 | Physiopedia is a registered charity in the UK, no. In the cord, Wallerian degeneration can occur both rostrally (involving the dorsal columns above the injury) and caudally (involving the lateral corticospinal tracts below the injury) 8. This leads to possible reinnervation of the target cell or organ. Surgical repair is further classified based on the size of the nerve gap and include primary repair, conduits, allografts, and autografts. Fig 1. Various possibilities have been studied to improve/accelerate nerve repair/regeneration via neuronal-death reduction and axonal-growth enhancement. Symptoma empowers users to uncover even ultra-rare diseases. These cookies will be stored in your browser only with your consent. Panagopoulos GN, Megaloikonomos PD, Mavrogenis AF. neuropraxia) recover in shorter amount of time and to a better degree. Peripheral nerve injuries result from systemic diseases (e.g., diabetes. In PNS, the permeability increases throughout the distal stump, but the barrier disruption in CNS is limited to just the site of injury. endstream endobj 386 0 obj <>/Metadata 13 0 R/PageLayout/OneColumn/Pages 383 0 R/StructTreeRoot 17 0 R/Type/Catalog>> endobj 387 0 obj <>/Font<>>>/Rotate 0/StructParents 0/Type/Page>> endobj 388 0 obj <>stream Nerve Regeneration. 2001;13 (6 Pt 1): 1174-85. You also have the option to opt-out of these cookies. According to the FA AH/UH, patients were also classified into groups with minimal or extensive Wallerian degeneration (WD). Nerve entrapment syndromes (meaning a common group of signs and symptoms), occurs in individuals as a result of swelling of the surrounding tissues, or anatomical abnormalities. Medical & Exercise Physiology School.Wallerian degeneration/ regeneration process of nerve fiber/axon cut and progressive response. Neuroradiology. We report a 54 year old male patient, referred to our hospital for sudden-onset left hemiparesis. Reinnervated fibers develop an increase in type II motor fibers (fast twitch, anaerobic fibers). In their developmental stages, oligodendrocytes that fail to make contact to axon and receive axon signals undergo apoptosis.[17]. Patients with more extensive WD had poorer grip strength, dexterity, and range of movement. [24] Macrophages also stimulate Schwann cells and fibroblasts to produce NGF via macrophage-derived interleukin-1. The fact that the enhanced survival of WldS axons is due to the slower turnover of WldS compared to NMNAT2 also helps explain why SARM1 knockout confers longer protection, as SARM1 will be completely inactive regardless of inhibitor activity whereas WldS will eventually be degraded. . Pierpaoli C, Barnett A, Pajevic S et-al. For example, retrograde and anterograde degeneration [such as Wallerian degeneration (Pierpaoli et al. Physiopedia articles are best used to find the original sources of information (see the references list at the bottom of the article). Macrophage entry in general into CNS site of injury is very slow. Reinnervated fibers have been shown to fatigue earlier compared to non-injured fibers, especially during isometric repetitive actions. The authors' results suggest that structural and functional integrity of the CFT is essential to maintain function of . A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. The mutation occurred first in mice in Harlan-Olac, a laboratory producing animals the United Kingdom. Willand MP, Nguyen MA, Borschel GH, Gordon T. Electrical Stimulation to Promote Peripheral Nerve Regeneration. 3-18-2018.Ref Type: Online Source. Sullivan R, Dailey T, Duncan K, Abel N, Borlongan CV. [41][42], SARM1 catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) from NAD+ to ADP-ribose. hmk6^`=K Iz 5. 8. Severity is classified by pathologic findings: neurapraxia, axonotmesis, and neurotmesis, also known as Seddon Classification. . [31] NAD+ by itself may provide added axonal protection by increasing the axon's energy resources. DTI was used to monitor the time course of Wallerian degeneration of the . Acute crush nerve injuries and traction injuries can be detected. Wallerian degeneration after cerebral infarction: evaluation with sequential MR imaging. 10-21-2006. In contrast to PNS, Microglia play a vital role in CNS wallerian degeneration. Time: provider may be able to have study done sooner if a timely EMG isdifficultto obtain. [29][30] The gene mutation is an 85-kb tandem triplication, occurring naturally. In most cases Physiopedia articles are a secondary source and so should not be used as references. The pathological process of Wallerian degeneration is in 3 stages; Within approximately 30 minutes of injury, there is a separation of the proximal and distal ends of the nerve. [3][4], Wallerian degeneration occurs after axonal injury in both the peripheral nervous system (PNS) and central nervous system (CNS). Wallerian degeneration is well underway within a week of injury. However, if the injury is at the end of the axon, at a growth of 1mm per day, the distal segment undergoes granular disintegration over several days to weeks and cytoplasmic elements begin to accumulate.[3]. The recruitment of macrophages helps improve the clearing rate of myelin debris. Neuregulins are believed to be responsible for the rapid activation. axon enter cell cycle thus leading to proliferation. The type of surgery can be guided by the size of the gap of injury: Autologous graft to provide a conduit for axonal regrowth. After this, full passive and active range of motion may be introduced for rehabilitation. Finally, the entire nerve is wrapped in a layer of connective tissue called theepineurium.[1]. These symptoms include muscle weakness or atrophy, the loss of muscle mass of the affected area. If soma/ cell body is damaged, a neuron cannot regenerate. which results in wallerian degeneration. Needle electromyography (EMG): normal spontaneous activity but may show decreased motor unit action potential (MUAP) recruitment due to conduction block. The following code (s) above G31.9 contain annotation back-references that may be applicable to G31.9 : G00-G99. Granular disintegration of the axonal cytoskeleton and inner organelles occurs after axolemma degradation. Increased distance between hyperechoic lines, Multiple branches involved with loss of fascicular pattern, Proximal end terminal neuroma, homogenous hypoechoic echotexture, Time: very quick to do, faster than EMG or MRI, Dynamic: real time assessment, visualize anatomy with movement and manipulation, Cost: Relatively low cost compared to other modalities, Cannot assess physiological functioning of the nerve, Prognosis: cannot distinguish between neurotmetic and neuropraxic lesions. Read More . After the 21st day, acute nerve degeneration will show on the electromyograph. Nerve conduction studies (NCS): Delayed conduction (prolonged distal latency, conduction block, and/or slow conduction velocity) across the lesion but normal conduction distal to the lesion. Wilcox M, Brown H, Johnson K, Sinisi M, Quick TJ. %PDF-1.5 % [46] This relationship is further supported by the fact that mice lacking NMNAT2, which are normally not viable, are completely rescued by SARM1 deletion, placing NMNAT2 activity upstream of SARM1. [48][49] One explanation for the protective effect of the WldS mutation is that the NMNAT1 region, which is normally localized to the soma, substitutes for the labile survival factor NMNAT2 to prevent SARM1 activation when the N-terminal Ube4 region of the WldS protein localizes it to the axon. Axonal regeneration is faster in the beginning and becomes slower as it reaches the nerve end. Presentations of nerve damage may include: Depends on various criteria including pain and psychosocial skills but could include: Wallerian Degeneration can instigate a nerve repair mechanism. An example of a peripheral nerve structure, Table 1 Classification of Peripheral Nerve Injury, A. Wallerian degeneration is the simplest and most thoroughly studied model of axonal degeneration. sciatic nerve constriction was linked to intraneural edoema, localised ischemia, and wallerian degeneration. [32][33] The protection provided by the WldS protein is intrinsic to the neurons and not surrounding support cells, and is only locally protective of the axon, indicating an intracellular pathway is responsible for mediating Wallerian degeneration. In experiments on Wlds mutated mice, macrophage infiltration was considerably delayed by up to six to eight days. In neurapraxia, diminished muscle strength and/or sensation develop acutely, but because of axon continuity, nerve conduction of the distal segment remains intact regardless of the length of time following injury. This is thought to be due to increased production of neurotrophic factors by Schwann cells, as well as increased production of cytoskeletal proteins.