Ischemic Nerve Injury Research Articles

Microscopical anatomy of the peripheral nervous system: An essential notion for understanding the pathophysiology of very early classic Guillain-Barré syndrome.

The aim of this paper is to analyze the pathophysiological mechanisms acting in very early classic Guillain-Barré syndrome (GBS) (≤4 days of symptomatic onset). In this inaugural period, both in GBS and its animal model, experimental autoimmune neuritis, the outstanding pathological feature is inflammatory edema predominating in proximal nerve trunks, particularly spinal nerves, and possibly in preterminal nerve segments. Nerve trunks external to the subarachnoid angle possess epi- perineurium that is relatively inelastic and of low compliance. Here such edema can increase endoneurial fluid pressure that, when sufficiently critical, may stretch the perineurium and constrict transperineurial microcirculation, compromising blood flow and producing the potential for ischemic nerve injury, whose consequence is rapid partial or complete loss of nerve excitability. These histopathological features correlate well with electrophysiological and imaging findings reported in early GBS stages. Spinal nerve edema and ischemia help to understand the pattern of Wallerian-like degeneration observed in the axonal form of GBS, predominating in motor spinal roots at their exit from the dura matter (spinal nerves) with centrifugal distribution in more distant motor nerve trunks, and centripetal extension to the distal portion of intrathecal roots. The similarity of initial pathogenic mechanisms between demyelinating and axonal forms of GBS explains why an early increase of serum biomarkers of axonal damage is detected in both forms. In conclusion, knowledge of the microscopic anatomy of the peripheral nervous system is an essential step for a reliable understanding of pathophysiological mechanisms operating in the early phase of any classic GBS subtype.

Dihydroergotamine protects against ischemic stroke by modulating microglial/macrophage polarization and inhibiting inflammation in mice

ABSTRACT Objectives The search for drugs that can protect the brain tissue and reduce nerve damage in acute ischemic stroke has emerged as a research hotspot. We investigated the potential protective effects and mechanisms of action of dihydroergotamine against ischemic stroke. Methods C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO), and dihydroergotamine at a dose of 10 mg/kg/day was intraperitoneally injected for 14 days. Adhesive removal and beam walking tests were conducted 1, 3, 5, 7, 10, and 14 days after MCAO surgery. Thereafter, the mechanism by which dihydroergotamine regulates microglia/macrophage polarization and inflammation and imparts ischemic stroke protection was studied using enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting. Results From the perspective of a drug repurposing strategy, dihydroergotamine was found to inhibit oxygen-glucose deprivation damage to neurons, significantly improve cell survival rate, and likely exert a protective effect on ischemic brain injury. Dihydroergotamine significantly improved neural function scores and survival rates and reduced brain injury severity in mice. Furthermore, dihydroergotamine manifests its protective effect on ischemic brain injury by reducing the expression of TNF-α and IL-1β in mouse ischemic brain tissue, inhibiting the polarization of microglia/macrophage toward the M1 phenotype and promoting polarization toward the M2 phenotype. Conclusion This study is the first to demonstrate the protective effect of dihydroergotamine, a first-line treatment for migraine, against ischemic nerve injury in vitro and in vivo.

Retinal Ganglion Cell Survival and Axon Regeneration after Optic Nerve Injury: Role of Inflammation and Other Factors.

The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), the neurons that extend axons through the optic nerve, begin to die. Thus, there are few clinical options to improve vision after traumatic or ischemic optic nerve injury or in neurodegenerative diseases such as glaucoma, dominant optic neuropathy, or optic pathway gliomas. Research over the past two decades has identified several strategies to enable RGCs to regenerate axons the entire length of the optic nerve, in some cases leading to modest reinnervation of di- and mesencephalic visual relay centers. This review primarily focuses on the role of the innate immune system in improving RGC survival and axon regeneration, and its synergy with manipulations of signal transduction pathways, transcription factors, and cell-extrinsic suppressors of axon growth. Research in this field provides hope that clinically effective strategies to improve vision in patients with currently untreatable losses could become a reality in 5–10 years.

Lomitapide ameliorates middle cerebral artery occlusion-induced cerebral ischemia/reperfusion injury by promoting neuronal autophagy and inhibiting microglial migration.

Stroke has a high incidence and is a disabling condition that can lead to severe cognitive, motor, and sensory dysfunction. In this study, we employed a drug repurposing strategy to investigate the neuroprotective effect of lomitapide on focal ischemic brain injury and explore its potential mechanism of action. Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in adult male C57BL/6 mice and simulated by oxygen-glucose deprivation in N2a-BV2 cells in co-cultivation. Lomitapide significantly increased the survival rate, reduced the neuronal tissue loss, and improved the neurological function after MCAO. Furthermore, lomitapide could increase the expression of LC3-II, reduce the expression of P62 and LAMP2, promote autophagic flux, and inhibit apoptosis by increasing and inhibiting the expression of the apoptosis-associated proteins Bcl-2 and Bax, respectively. In addition, lomitapide inhibited the migration of pro-inflammatory microglia. Lomitapide is a lipid-lowering drug, and this is the first study to explore its protective effect on ischemic nerve injury in vitro and in vivo. Our results suggest that lomitapide can be repositioned as a potential therapeutic drug for the treatment of stroke.

Biotransformation, Pharmacokinetics, and Pharmacological Activities of Ginsenoside Rd Against Multiple Diseases.

Panax ginseng C.A. Mey. has a history of more than 4000 years and is widely used in Asian countries. Modern pharmacological studies have proved that ginsenosides and their compounds have a variety of significant biological activities on specific diseases, including neurodegenerative diseases, certain types of cancer, gastrointestinal disease, and metabolic diseases, in which most of the interest has focused on ginsenoside Rd. The evidentiary basis showed that ginsenoside Rd ameliorates ischemic stroke, nerve injury, cancer, and other diseases involved in apoptosis, inflammation, oxidative stress, mitochondrial damage, and autophagy. In this review, we summarized available reports on the molecular biological mechanisms of ginsenoside Rd in neurological diseases, cancer, metabolic diseases, and other diseases. We also discussed the main biotransformation pathways of ginsenoside Rd obtained by fermentation.

Nerve lesions during arthroscopic procedure: a literature overview.

Arthroscopy is more and more popular. Although minimally-invasive, it's not completely free of complications as nerves lesions which can be invalidating for the patient and frustrating for the surgeon with significant economic, psychological and medico-legal implications. The purpose was to review the literature about nerve injuries related to arthroscopy. A scientific literature review was performed in PubMed/Medline, including articles dealing with cases of iatrogen lesions of the peripheral nerves occurred during arthroscopic procedures. These lesions are mainly due to direct damage by nerve section while cutting for making the portals or during surgical maneuvers, or indirect damage due to traction or pressure mechanisms especially for errors in patient positioning. Also the tourniquet can lead to compression and ischemic nerve injury. Arthroscopy can cause both transient and permanent neurological lesions manifested with dysesthesia up to paralysis according to Seddon's classification in neuroapraxia, axonotmesis and neurotmesis. Incidence of complications in general and of nerve injuries during arthroscopy are reported by joint. A rigorous respect for surgical technique and all perioperative precautions, particularly in relation to the positioning of the patient, greatly reduce the risk of nerve injury. The suggested waiting time before surgical nerve revision is 6 months. In the meanwhile the patient should perform physiotherapy constantly and improvements should be evaluated with clinical examination and electromyography 15-20 days after the lesion, and thereafter at 3 and 6 months.

Inhibition of Retinal Ganglion Cell Loss By a Novel ROCK Inhibitor (E212) in Ischemic Optic Nerve Injury Via Antioxidative and Anti-Inflammatory Actions.

PurposeThis study investigated the neuroprotective effects of administration of ROCK inhibitor E212 on ischemic optic neuropathy.MethodsRats received an intravitreal injection of either E212 or PBS immediately after optic nerve infarct. The oxidative stress in the retina was detected by performing superoxide dismutase activity and CellROX assays. The integrity of retinal pigment epithelium was determined by staining of zona occludens 1. The visual function, retinal ganglion cell (RGC) density, and RGC apoptosis were determined by using flash visual-evoked potential analysis, retrograde FluoroGold labeling, and TdT-dUTP nick end-labeling assay. Macrophage infiltration was detected by staining for ED1. The protein levels of TNF-α, p-CRMP, p-AKT1, p-STAT3, and CD206 were evaluated using Western blotting.ResultsAdministration of E212 resulted in a 1.23-fold increase in the superoxide dismutase activity of the retina and 2.28-fold decrease in RGC-produced reactive oxygen species as compared to the levels observed upon treatment with PBS (P < 0.05). Moreover, E212 prevented the disruption of the blood-retinal barrier (BRB) in contrast to PBS. The P1-N2 amplitude and RGC density in the E212-treated group were 1.75- and 2.05-fold higher, respectively, than those in the PBS-treated group (P < 0.05). The numbers of apoptotic RGCs and macrophages were reduced by 2.93- and 2.54-fold, respectively, in the E212-treated group compared with those in the PBS-treated group (P < 0.05). The levels of p-AKT1, p-STAT3, and CD206 were increased, whereas those of p-PTEN, p-CRMP2, and TNF-α were decreased after treatment with E212 (P < 0.05).ConclusionsTreatment with E212 suppresses oxidative stress, BRB disruption, and neuroinflammation to protect the visual function in ischemic optic neuropathy.

SP1-mediated upregulation of LINGO-1 promotes degeneration of retinal ganglion cells in optic nerve injury.

BackgroundsInsults to the axons in the optic nerve head are the primary cause of loss of retinal ganglion cells (RGCs) in traumatic, ischemic nerve injury or degenerative ocular diseases. The central nervous system–specific leucine‐rich repeat protein, LINGO‐1, negatively regulates axon regeneration and neuronal survival after injury. However, the upstream molecular mechanisms that regulate LINGO‐1 signaling and contribute to LINGO‐1–mediated death of RGCs are unclear.MethodsThe expression of SP1 was profiled in optic nerve crush (ONC)–injured RGCs. LINGO‐1 level was examined after SP1 overexpression by qRT‐PCR. Luciferase assay was used to examine the binding of SP1 to the promoter regions of LINGO‐1. Primary RGCs from rat retina were isolated by immunopanning and RGCs apoptosis were determined by Tunnel. SP1 and LINGO‐1 expression was investigated using immunohistochemistry and Western bolting. Neuroprotection was assessed by RGC counts, RNFL thickness, and VEP tests after inhibition of SP1 shRNA.ResultsWe demonstrate that SP1 was upregulated in ONC‐injured RGCs. SP1 was bound to the LINGO‐1 promoter, which led to increased expression of LINGO‐1. Treatment with recombinant Nogo‐66 or LINGO‐1 promoted apoptosis of RGCs cultured under serum‐deprivation conditions, while silencing of SP1 promoted the survival of RGCs. SP1 and LINGO‐1 colocalized and were upregulated in ONC‐injured retinas. Silencing of SP1 in vivo reduced LINGO‐1 expression and protected the structure of RGCs from ONC‐induced injury, but there was no sign of recovery in VEP.ConclusionsOur findings imply that SP1 regulates LINGO‐1 expression in RGCs in the injured retina and provide insight into mechanisms underlying LINGO‐1–mediated RGC death in optic nerve injury.

Endovascular Treatment of Cavernous Sinus Dural Arteriovenous Fistulae: Review of the Literature and Current Status.

Cavernous sinus dural arteriovenous fistulae (CSdAVFs) are characterized by the shunts between dural arteries and dural veins surrounding the cavernous sinus (CS), causing ocular symptoms in addition to intracranial hemorrhage and infarction. As surgical access is difficult, endovascular treatment (EVT) has been considered and performed as the first-line therapy for decades. Although there have been recent advances in techniques and devices, transvenous embolization (TVE) with platinum coils remains the most common procedure. There are multiple access routes to the CS, such as the inferior petrosal sinus, superior ophthalmic vein (SOV), and intercavernous sinus from the contralateral CS. To extirpate the shunt, packing the entire sinus with coils is adopted, occasionally resulting in persistent cranial nerve palsy (CNP) due to compression of the coil mass. To avoid this complication, selective shunt occlusion (SSO), in which the coils are placed in the shunted pouch (SP) defined by the small restricted space where the arterial flow converges, is an effective and safe method. Transarterial embolization (TAE) is another option and use of liquid embolic materials, such as Onyx may be promising; however, the potential risk of ischemic nerve injury due to undesirable ante/retrograde influx of the liquid materials is of concern. In conclusion, EVT, especially TVE, is a safe and effective method for managing CSdAVFs. Understanding the angioanatomy consisting of the feeding artery, shunt point, and the drainage route, including the latent vessels, is essential for a good outcome.

Mallotus oblongifolius extracts ameliorate ischemic nerve damage by increasing endogenous neural stem cell proliferation through the Wnt/β-catenin signaling pathway

Mallotus oblongifolius (MO), an edible medicinal plant from Hainan in China, shows a wide range of bioactivities. The daily consumption of MO or its extracts has been observed to ameliorate ischemic nerve injury. However the mechanisms remain unclear. In this study, the effects of MO both in vitro and in vivo were investigated. The results indicated that MO improved the motor ability, neurosensory ability, balance and grasping ability of mice with ischemic injuries, induced by bilateral common carotid artery ligation (BCCAL). In addition, MO improved the morphology of neurons, resisted the loss of neurons, and enhanced the content of the nestin protein in the cerebral cortex and subgranular zone (SGZ) area. Furthermore, in the oxygen-glucose deprivation and reperfusion (OGD/R) treated cell model, MO could effectively activate the Wnt/β-catenin signaling pathway and promote the proliferation of neural stem cells (NSCs) and increase the protein expression levels of β-catenin and CyclinD1. Our results suggest that Mallotus oblongifolius may be used as nutraceuticals or functional foods to alleviate ischemic nerve damage and promote recovery from ischemic stroke.

Vitamin D as a Potential Agent for Ischemic Axonal Regeneration after Epineurial Devascularization of the Sciatic Nerve.

Although vitamin D has several noncalcemic functions particularly on nervous system, its neuroregenerative roles on ischemic peripheral nerve injury has not been reported. In this study, it was aimed to investigate the effect of vitamin D3 after epineurial devascularization of the sciatic nerve. Forty adult female Wistar rats were randomly divided into four groups: Group 1 (Control), Group 2 (Sham-operated), Group 3 (Epineurial devascularization + vitamin D3 treatment), Group 4 (Epineurial devascularization + vehicle treatment). Recovery of the sciatic nerve was analyzed by functional (sciatic functional index, pinch test and biochemical analyses) and morphological (electron microscopic analysis and wet muscle weight analysis) methods. Comparison of the data revealed that vitamin D3 administration had a beneficial effect on regeneration after epineurial devascularization. We suggest that vitamin D3 is an effective agent in the prevention of ischemic peripheral nerve insults.

Neuroprotective effect of glycosides in Buyang Huanwu Decoction on pyroptosis following cerebral ischemia-reperfusion injury in rats

Ethnopharmacological relevanceBuyang Huanwu Decoction (BYHWD) is used in classical traditional Chinese medicine to prevent and treat cerebral ischemia. Glycosides, which are effective components extracted from BYHWD, mainly include astragaloside IV, paeoniflorin, and amygdalin. These glycosides are the primary pharmacologically effective constituents of BYHWD that act against cerebral ischemic nerve injury; however, the mechanism of action of BYHWD is still unclear. Aim of the studyThe present study aimed to determine the effect of BYHWD glycosides on pyroptosis after cerebral ischemia reperfusion injury and explore whether its mechanism involves the classical pyroptosis pathway mediated by NLRP3. Material and methodsAdult male Sprague-Dawley rats (n = 140) were randomly divided into seven groups: sham, cerebral ischemia and reperfusion (I/R), glycosides (0.064 g/kg, 0.128 g/kg, and 0.256 g/kg), BYHWD, and AC-YVAD-CMK (caspase-1 inhibitor). A rat model of cerebral I/R was established via classic middle cerebral artery occlusion (MCAO) for 2 h, followed by 24-h reperfusion. Neurological function was estimated using neurological defect scores. Brain infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and nerve cell damage was evaluated by Nissl staining. Pyroptosis was detected using TUNEL and caspase-1 immunofluorescence double staining. Protein expression of NLRP3, ASC, caspase-1, pro-caspase-1, and IL-1β was analyzed using Western blot analysis. ResultsGlycosides improved neurological dysfunction, alleviated neuronal damage, and inhibited neuronal pyroptosis. The 0.128 g/kg glycosides group showed the most significant effects. Furthermore, we observed that this group showed significant inhibition of the expression of NLRP3, ASC, pro-caspase-1, caspase-1, and IL-1β proteins of the NLRP3-mediated classical pathway of pyroptosis. ConclusionsGlycosides exert neuroprotective effects by inhibiting pyroptosis of neurons after cerebral I/R injury. The underlying mechanism of action is closely related to the regulation of the classical pyroptosis pathway by NLRP3.

Inflammatory Ischemic Nerve Injury Can Cause CIDP-like Neuropathy (P2.4-014)

Inflammatory Ischemic Nerve Injury Can Cause CIDP-like Neuropathy (P2.4-014)

The results of closed reduction and percutaneous pinning in supracondylar fractures of humerus in children

Introduction: Supracondylar fracture of the humerus is the most common type of elbow injury in children, accounting for 60% of fractures in this area and represent about 3% of all the fractures in children. Treatment of supracondylar fractures is fraught with many complications including Volkmann’s ischemic contracture, nerve injury, arterial injury, myositis ossificans and cubitus varus deformity. Closed reduction and percutaneous was initially described by Swenson and later popularized by Flynn et al. Materials and Methods: The present study consisted of thirty displaced supracondylar fractures of the humerus in children. All the patients were under thirteen years of age treated in Orthopaedics Department of Government Medical College, Jammu during the period of May 2015 to Oct. 2017.Fractures were classified according to Gartlands classification and all the displaced fractures were treated by closed reduction and percutaneous pinning under c-arm. Results: The minimum age was 4.5 years and maximum age was 11 yrs. Males outnumbered females in all the age groups. According to Flynn's criteria, excellent results were reported in 23 cases (76.7%), good in 4 cases (13.3%), fair in 2 cases (6.7%) and poor in one case (3.3%). The time of Radiological evidence of union was around 3-5 weeks. The average time of regaining normal range of motion was 9 weeks. Conclusion: This study shows that close reduction and percutaneous pinning under image intensifier is the treatment of choice in severely displaced supracondylar fractures of the humerus in children.

Protective effects of bellidifolin in hypoxia-induced in pheochromocytoma cells (PC12) and underlying mechanisms

ABSTRACTBellidifolin, a xanthone compound derived from plants of Gentiana species, is known to exert a variety of pharmacological activities including anti-oxidation, anti-inflammatory and antitumor actions as well as a protective effect on cerebral ischemic nerve injury. The aim of this study was to examine the protective effects of bellidifolin on nerve injury produced by hypoxia and possible underlying mechanisms using pheochromocytoma cells (PC12). Data showed that the viability of PC12 cells subjected to hypoxia resulted in a significant decrease; however; pretreatment with certain concentrations of bellidifolin (20 or 40 μmol/L) prior to hypoxia significantly increased the survival rate. The results of immunohistochemical staining analysis revealed that there were no marked alterations in the expression of pERK protein between all bellidifolin groups while the expression of p-p38MAPK protein was significantly enhanced by hypoxia. Pretreatment with different concentrations of bellidifolin followed by hypoxia significantly decreased the expression of p-p38MAPK protein. The results of western blot analysis showed that hypoxia induced the expression of the MAPK signaling pathway downstream of the key apoptosis factor caspase-3. Compared to hypoxia, the expression of caspase-3 in the presence of belliidifolin was significantly lower. Data suggest that bellidifolin may contribute to the protective effects associated with nerve injury initiated by hypoxia by mechanisms related to inhibition of cell apoptosis independent of the ERK pathway, but may involve blockade of p38MAPK signaling pathway activation and downstream caspase-3 expression.

Myocardial denervation coincides with scar heterogeneity in ischemic cardiomyopathy: A PET and CMR study

BackgroundMismatch between myocardial innervation and perfusion assessed with positron emission tomography (PET) is a potential risk marker for ventricular arrhythmias in patients with ischemic cardiomyopathy. This mismatch zone originates from residual viable myocardium that has sustained ischemic nerve injury. Heterogenic scar size assessed with late gadolinium-enhanced (LGE) cardiac magnetic resonance imaging (CMR) is also a risk marker of ventricular arrhythmias. These two imaging parameters may represent identical morphological tissue features. The current study explored the relation between innervation-perfusion mismatch and heterogenic scar size. MethodsTwenty-eight patients (26 males, age 67 ± 8 years) with ischemic cardiomyopathy and a left ventricular ejection fraction below 35%, eligible for ICD implantation were included. All patients underwent both [11C]-hydroxyephedrine and [15O]-water PET studies to assess myocardial sympathetic innervation and perfusion. LGE CMR was conducted to assess total myocardial scar size, scar core size, and heterogenic scar size. ResultsPerfusion defect size was 16.6 ± 9.9% and innervation defect size was 33.7 ± 10.8%, which resulted in an innervation-perfusion mismatch of 17.6 ± 8.9%. Total scar size, scar core size, and heterogenic scar size were 21.2 ± 8.6%, 14.7 ± 6.6%, and 6.5 ± 2.9%, respectively. No relation between scar core size and perfusion deficit size was observed (r = 0.18, P = .36). Total scar size was correlated with the innervation defect size (r = 0.52, P = .004) and the heterogenic scar zone displayed a significant correlation with the innervation-perfusion mismatch area (r = 0.67, P < .001). ConclusionsDenerved residual viable myocardium in ischemic cardiomyopathy as observed with innervation-perfusion PET is related to the heterogenic scar zone as assessed with LGE CMR.

Ciliary neurotrophic factor (CNTF)-mediated ganglion cell survival in a rodent model of non-arteritic anterior ischaemic optic neuropathy (NAION)

BackgroundCiliary neurotrophic factor (CNTF) has been shown to protect retinal ganglion cells (RGCs) in traumatic optic nerve injury. We sought to evaluate this neuroprotective effect of CNTF after an ischaemic...

Muscle Trauma from Tourniquet (Mis)Use

A 16-YR-OLD obese male (body mass index: 35 kg/m2) underwent a 5-h left knee multiligamentous reconstruction under tourniquet application for a football-related injury. Postoperative analgesia was provided with 0.2% ropivacaine infused through femoral and sciatic nerve catheters. After surgery the patient complained of excessive pressure in his thigh. On postoperative day 1, he developed loss of ankle dorsiflexion, cola-colored urine (myoglobinuria), and increased blood creatine phosphokinase (more than 32,000 units/l). His thigh compartment pressures were found to be high but did not warrant fasciotomy. He was treated with forced alkaline diuresis to prevent acute renal failure. His foot weakness recovered after 9 months of physical therapy.An axial fat saturated contrast enhanced T1-weighted magnetic resonance image of his left thigh (fig.) was obtained on postoperative day 3. There is heterogeneous muscle enhancement involving anterior, medial, and posterior compartments (predominantly adductor magnus and vastus lateralis). Central areas of lack of enhancement indicate muscle necrosis (arrows), an imaging appearance consistent with rhabdomyolysis.1Extreme tourniquet-induced ischemia causes metabolic (anaerobic), cellular, and microvascular changes (endothelial injury), leading to muscle breakdown (rhabdomyolysis) and compartment syndrome.2Alhough there are no tourniquet guidelines specifically pertaining to muscle injury, inflation pressure ⩽100 mmHg above systolic blood pressure, inflation time ⩽120 min, deflation time ≥30 min, and reinflation time ⩽90 min are recommended to prevent ischemic nerve injury.3Tourniquet pressure (300 mmHg) and duration (150 min inflation, 30 min deflation, and 100 min reinflation) in our patient exceeded guidelines. It is likely that ischemia was exaggerated by tourniquet size-mismatch due to obesity. Our case calls for strict adherence to tourniquet guidelines, prompt diagnosis, and timely intervention to prevent tourniquet related morbidity.

Pupil-sparing complete third nerve palsy from cryptogenic midbrain stroke in an otherwise-healthy young adult with patent foramen ovale

Although pupil-sparing in acute unilateral complete third nerve palsy is often a sign of ischemic nerve injury, it is not specific for injury outside of the midbrain. This report documents acute pupil-sparing complete third nerve palsy in an otherwise healthy young adult with patent foramen ovale and associated atrial dilatation who suffered cryptogenic focal midbrain stroke, presumably from a paradoxical embolism. The patent foramen ovale was surgically closed. Over the next several months neurological recovery was complete except for diplopia and relatively comitant hypotropia, which responded well to conventional strabismus surgery.

A sleeping phantom leg awakened following hemicolectomy, thrombosis, and chemotherapy: a case report

IntroductionWe describe the case of a patient who experienced phantom pain that began 42 years after right above-the-knee amputation. Immediately prior to phantom pain onset, this long-term amputee had experienced, in rapid succession, cancer, hemicolectomy, chemotherapy, and thrombotic occlusion. Very little has been published to date on the association between chemotherapy and exacerbation of neuropathic pain in amputees, let alone the phenomenon of bringing about pain in amputees who have been pain-free for many decades. While this patient presented with a unique profile following a rare sequence of medical events, his case should be recognized considering the frequent co-occurrence of osteomyelitis, chemotherapy, and amputation.Case presentationA 68-year-old Australian Caucasian man presented 42 years after right above-the-knee amputation with phantom pain immediately following hemicolectomy, thrombotic occlusion in the amputated leg, and chemotherapy treatment with leucovorin and 5-fluorouracil. He exhibited probable hyperalgesia with a reduced pinprick threshold and increased stump sensitivity, indicating likely peripheral and central sensitization.ConclusionOur patient, who had long-term nerve injury due to amputation, together with recent ischemic nerve and tissue injury due to thrombosis, exhibited likely chemotherapy-induced neuropathy. While he presented with unique treatment needs, cases such as this one may actually be quite common considering that osteosarcoma can frequently lead to amputation and be followed by chemotherapy. The increased susceptibility of amputees to developing potentially intractable chemotherapy-induced neuropathic pain should be taken into consideration throughout the course of chemotherapy treatment. Patients in whom chronic phantom pain then develops, perhaps together with mobility issues, inevitably place greater demands on healthcare service providers that require treatment by various clinical specialists, including oncologists, neurologists, prosthetists, and, most frequently, general practitioners.