7T MR neurography-ultrasound fusion for peripheral nerve imaging.

BACKGROUND: We present one patient with an initial diagnosis of Guillain-Barré syndrome (GBS) and one with Charcot-Marie-Tooth disease (CMT) type 1A. METHODS: Both patients underwent ankle tibial nerve fusion-imaging of high-resolution ultrasound (HRUS) with 7T MR neurography (MRN). RESULTS: In GBS, the nerve was enlarged, T2-hyperintense, and showed increased vascularization 21 months after symptom onset. In CMT1A, the enlarged nerve was T2-isointense with normal endoneurial blood flow. CONCLUSIONS: We demonstrate the utility of 7T-MRN-HRUS-fusion-imaging. In GBS, there was evidence of ongoing inflammation resulting in a changed diagnosis to acute-onset chronic demyelinating polyradiculoneuropathy and maintenance of immunotherapy. By MRN-HRUS-fusion, patients with presumed peripheral axonal degeneration could be shown to display imaging markers associated with peripheral nervous system inflammation. Thus, more accurate identification of a treatable inflammatory component may become possible.

Sonographic assessment of nerve blood flow in diabetic neuropathy.

AIMS: To undertake sonographic assessment of nerve blood flow in people with Type 2 diabetes and correlate the findings with neuropathy severity scores and electrophysiological measurements. METHODS: Median and tibial nerve ultrasound scans were undertaken in 75 people with diabetes and 30 aged-matched controls without diabetes, using a high-resolution linear probe at non-entrapment sites. Nerve blood flow was quantified using power Doppler techniques to obtain the vessel score and the maximum perfusion intensity. Neuropathy severity was assessed using a total neuropathy score. RESULTS: Diabetic nerves had higher rates of nerve blood flow detection (28%) compared to the control group (P < 0.0001). Significant correlations were found between nerve blood flow measurements and nerve size (P <0.001), reported sensory symptoms (P < 0.05) and neuropathy severity scores (P < 0.001). The cohort with diabetes had significantly larger median (8.5 ± 0.3 mm2 vs 7.2 ± 0.1 mm2 ; P < 0.05) and tibial nerves (18.0 ± 0.9 mm2 vs 12.8 ± 0.5 mm2 ; P < 0.05) compared with controls. CONCLUSION: Peripheral nerve hypervascularity is detectable by ultrasonography in moderate to severe diabetic neuropathy with prominent sensory dysfunction.

Remodeling of myelinated fibers and internal capillaries in distal peripheral nerves following aerobic exercise in aged rats.

The aim of this study was to determine whether aerobic exercise (AE) in old age contributes to improving the morphologies of myelinated fibers (MFs) in peripheral nerves as well as capillaries. Furthermore, we investigated whether such processes are associated with complementary activity of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in the circulating blood and peripheral nerve tissue. Fourteen male Wistar rats (age: 95 wk) were randomly divided into moderate AE ( n = 8) and sedentary (SED; n = 6) groups. Rats in the AE group performed treadmill running for 1 h per day for 2 wk, following which the bilateral tibial nerves of the two groups were removed to examine MF and capillary structure. Levels of BDNF and VEGF in the serum and peripheral nerves were analyzed via enzyme-linked immunosorbent assay. Myelin thickness, axon diameter, and capillary luminal diameter were significantly larger in the AE group than in the SED group ( P < 0.0001). Levels of serum BDNF and VEGF were significantly lower and higher, respectively, in the AE group than in the SED group ( P < 0.001). Conversely, BDNF and VEGF levels in tibial nerve tissue were significantly higher, respectively, and lower in the AE group than in the SED group ( P < 0.001). In conclusion, our study indicates that regular AE induces enlargement of the capillaries and thickens the myelin in aged peripheral nerves, likely via a complementary process involving BDNF and VEGF. NEW & NOTEWORTHY Accumulating evidence indicates that age-related sarcopenia is accompanied by the degeneration of myelinated fibers (MFs) in peripheral nerves. Our study indicates that regular aerobic exercise contributes to increased thickness of the myelin surrounding MFs and enlargement of the capillaries, likely via a complementary process involving brain-derived neurotrophic factor and vascular endothelial growth factor. Our findings demonstrate that regular, moderate-intensity aerobic exercise may help to prevent and reverse peripheral nerve regression in older adults.

The tibial nerve and its vasculature: an anatomical evaluation / El nervio tibial y su vasculatura: una evaluación anatómica

The study has contributed to evaluate the tibial nerve and its vasculature anatomically. Ten preserved cadavers (5 male, 5 female) have been used for this study. Each cadaver was injected with red latex and through incisions the tibial nerve was exposed at the level of bifurcation of sciatic nerve. The tibial nerve in 85 % cadavers was located between middle and lower thirds at upper angle of popliteal fossa; whereas, in 15 % cadavers it was present below the piriformis muscle in gluteal region. The total length of the tibial nerve was at a mean of 65.26±14.42 cm in males and 64.79±67.61 cm in females, without significantly different. Its total diameter was at a mean of 5.51±1.55 mm, with a mean of 4.11±0.88 mm at the popliteal fossa and a mean of 3.24±0.81mm at its termination deep to the flexor retinaculum in male cadavers. In female; the means were 5.11±0.21 mm, 3.97±1.78 mm and 3.14 ± 0.03 mm respectively without significance difference. It was concluded that tibial nerve has sufficient and good blood supply. Moreover, it can be utilized as allogeneic vascularized nerve graft to repair sizable nerves after limb salvage.

El estudio ha contribuido a evaluar anatómicamente el nervio tibial y su vasculatura. Se han utilizado diez cadáveres preservados (5 hombres, 5 mujeres) para este estudio. Cada cadáver fue inyectado con látex rojo y a través de incisiones el nervio tibial fue expuesto al nivel de la bifurcación del nervio ciático. El nervio tibial en el 85 % de los cadáveres se localizó entre los tercios medio e inferior en el ángulo superior de la fosa poplítea; mientras que en el 15 % de los cadáveres estaba presente debajo del músculo piriforme en la región glútea. La longitud total media del nervio tibial fue de 65,26±14,42 cm en hombres y 64,79±67,61 cm en mujeres, sin diferencias significativas. Su diámetro total se situó en una media de 5,51±1,55 mm, con una media de 4,11±0,88 mm en la fosa poplítea y una media de 3,24 ± 0,81 mm en su terminación profunda al retináculo flexor en cadáveres masculinos. En mujeres; Las medias fueron 5,11±0,21 mm, 3,97±1,78 mm y 3,14±0,03 mm, respectivamente, sin diferencia significativas. Se concluyó que el nervio tibial tiene suficiente y buen suministro de sangre. Además, se puede utilizar como injerto de nervio vascularizado alogénico para reparar nervios importantes después de la recuperación de miembros.

Arterial Anatomy of the Posterior Tibial Nerve in the Tarsal Tunnel.

BACKGROUND: Both vascular and compression etiologies have been proposed as the source of neurologic symptoms in tarsal tunnel syndrome. Advancing the understanding of the arterial anatomy supplying the posterior tibial nerve (PTN) and its branches may provide insight into the cause of tarsal tunnel symptoms. The purpose of this study was to describe the arterial anatomy of the PTN and its branches. METHODS: Sixty adult cadaveric lower extremities (thirty previously frozen and thirty fresh specimens) were amputated distal to the knee. The vascular supply to the PTN and its branches was identified, measured, and described macroscopically (the thirty previously frozen specimens, prepared using a formerly described debridement technique) and microscopically (the thirty fresh specimens, processed using the Spälteholz technique). RESULTS: On both macroscopic and microscopic evaluation, the PTN and the medial and lateral plantar nerves were observed to have multiple entering vessels within the tarsal tunnel. On microscopic evaluation, a vessel was observed to enter the nerve at the bifurcation of the PTN into the medial and lateral plantar nerves in twenty-two (73%) of the thirty specimens. There was a significant difference (p < 0.05) in vascular density between the PTN and each of its branches. CONCLUSIONS: The abundant blood supply to the PTN and its branches identified in this study is consistent with observations of other peripheral nerves. This rich vascular network may render the PTN and its branches susceptible to nerve compression related to vascular congestion. The combination of vascular and structural compression may also elicit neurologic symptoms. CLINICAL RELEVANCE: Advancing the understanding of the arterial anatomy supplying the PTN and its branches may provide insight into the cause and treatment of tarsal tunnel syndrome.

Corkscrew Collateral Vessels in Buerger Disease: Vasa Vasorum or Vasa Nervorum.

PURPOSE: To investigate the origin of "corkscrew" collateral vessels around the occluded popliteal artery in patients with Buerger disease by Doppler ultrasound (US) and magnetic resonance (MR) imaging in tandem with digital subtraction angiography (DSA). MATERIALS AND METHODS: Between January 2013 and June 2015, 42 patients diagnosed with Buerger disease were identified retrospectively. Patients in whom occlusion of the popliteal artery was found on DSA of the lower extremity were subjected to Doppler US and MR imaging prospectively. Fifteen of 42 patients were identified as having the required characteristics, of whom 10 participated in the present study. RESULTS: Ten patients with occlusion of the popliteal artery were selected for inclusion, and 12 lower limbs of these patients were investigated. The study cohort comprised one woman and nine men with a mean age of 41 years ± 10 (standard deviation; range, 39-58 y). Corkscrew collateral vessels identified on DSA examinations were also identified on secondary imaging (Doppler US and MR imaging) in all patients except one in whom the popliteal artery was reconstituted after short-segment occlusion. The origin of the corkscrew collateral vessels was identified as the vasa nervorum of the tibial nerve in nine patients. CONCLUSIONS: Data from the present study suggest that corkscrew collateral vessels at the knee level in patients with Buerger disease originate from the vasa nervorum of the tibial nerve rather than the vasa vasorum of the popliteal artery if the latter is occluded.

Multifocal enlargement and increased vascularization of peripheral nerves detected by sonography in CIDP: a pilot study.

OBJECTIVE: Detection of nerve enlargement in polyneuropathies by sonography is a new research area. No systematic investigation has been done yet in chronic inflammatory demyelinating polyneuropathy (CIDP). Therefore we investigated this in CIDP. METHODS: Eleven patients with CIDP fulfilling the international criteria on CIDP underwent ultrasonographic examination of the median, ulnar, fibular and posterior tibial nerves and sometimes the brachial plexus bilaterally, using a standardized protocol. We assessed presence of nerve thickening and increased nerve vascularization. RESULTS: In 7 of the 11 patients multiple nerve enlargements were detected: ulnar nerve 7, fibular nerve 5, posterior tibial nerve 4 and median nerve in 4 patients. The number of enlarged nerves was related with the MRC sum-score (p=0.03) and the total protein in the cerebrospinal fluid (CSF) at diagnosis (p=0.02). Increased vascularization was seen in 6 of the 11 patients: 4 in one nerve and in 2 in multiple nerves. The number of nerves with increased vascularization was associated with the number of enlarged nerves (p=0.01) and total protein in the CSF (p=0.006). CONCLUSION: Multiple nerve enlargements occur in CIDP showing a relation with a lower MRC sum-score, increased nerve vascularization and a higher total protein of the CSF. SIGNIFICANCE: Our findings of nerve enlargement and increased nerve vascularization may be tools to monitor disease activity in CIDP, but further studies are needed.

Similarities and dissimilarities of the blood supplies of the human sciatic, tibial, and common peroneal nerves.

The aim was to investigate the arterial supply of the sciatic, tibial, and common peroneal nerves. Thirty-six lower limbs of 18 human fetuses were studied. The fetuses had been fixed in buffered formalin and the blood vessels injected with barium sulfate. Fetal age ranged from 12 to 28 weeks of gestation. Microdissection of the fetal lower extremities was done under ×5 magnifying lenses. The sciatic nerves of 10 lower extremities were dissected and excised and radiographs taken. The extraneural arterial chain of the sciatic nerve was composed of 2-6 arterial branches of the inferior gluteal artery, the medial circumflex femoral artery, the perforating arteries, and the popliteal artery. The extraneural arterial chain of tibial nerve was composed of 2-5 arteries, which were branches of the popliteal, the peroneal, and the posterior tibial arteries. Radiographs showed the presence of complete intraneural arterial chains in the sciatic and tibial nerves, formed from anastomosing vessels. Dissection showed that, in 97.2% of the specimens, the common peroneal nerve was supplied only by one popliteal artery branch, the presence of which was confirmed radiologically. The sciatic and tibial nerves are supplied by numerous arterial branches of different origins, which provide for collateral circulation. In contrast, the common peroneal nerve is most frequently supplied only by one elongated longitudinal blood vessel, a branch of the popliteal artery. Such a vascular arrangement may make the common peroneal nerve less resistant to stretching and compression.

Common peroneal and posterior tibial ischemic nerve damage, a rare cause.

A 56-year old gentleman presented to our orthopaedic foot and ankle clinic, with unusual symptoms in his left foot. He described a tight sensation over his toes, "like sandpaper under his skin". The pain had started post operatively following a bilateral aorto-femoral bypass. He was subsequently investigated and found to have an ischemic lesion Identified in his common peroneal and posterior tibial nerve with associated muscle atrophy on EMG. This represents a previously unreported complication of aorto-femoral bypass surgery.

Orchestration of the inflammatory response in ischemia-reperfusion injury.

Ischemia to nerve can cause fiber degeneration and reperfusion following ischemia [ischemia-reperfusion (IR)] adds the additional insult of an inflammatory response and oxidative injury. Limited information is available on the molecular mediators and their endoneurial targets. In this study, using a highly reproducible animal model of IR injury to nerve and selective immunolabeling methods [for nuclear factor kappa B (NF-kappaB), intercellular adhesion molecule-1 (ICAM-1), cytokines, and inflammatory cells] over an expanded time frame, we evaluated the temporal pattern and localization of mediators of the inflammatory response. Sixty rats were used. Nine groups (N=6 each) underwent complete hind limb ischemia for 4 h, followed by reperfusion durations of 0, 3, 12, 24, and 48 h, and 7, 14, 28, and 42 days. One group underwent sham operation (N=6). The earliest change was ICAM-1 expression in the microvessel (endothelial cell) followed almost immediately by NF-kappaB activation with axonal expression (24 and 48 h), followed by endoneurial edema and ischemic fiber degeneration (7 and 14 days). Granulocytic infiltration was followed by endoneurial infiltration of mononuclear phagocytes (14 days), expression of interleukin 6 (IL-6) (microvessels), and subsequent Schwann cell NF-kappaB expression. Granulocytes, tumor necrosis factor alpha, and IL-6-positive cells were observed primarily within the epineurium. IR results in changes in a number of interacting networks of targets and inflammatory mediators. NF-kappaB activation has a central orchestrating role involving both the axon and the Schwann cell in effecting the inflammatory response.

Acupuncture treatment improves nerve conduction in peripheral neuropathy.

The etiology of peripheral neuropathy (PN) often remains elusive resulting in a lack of objective therapeutic strategies. We conducted a pilot study to evaluate the therapeutic effect of acupuncture on PN as measured by changes in nerve conduction and assessment of subjective symptoms. One hundred and ninety-two consecutive patients with PN as diagnosed by nerve conduction studies (NCS) were evaluated over a period of 1 year. Of 47 patients who met the criteria for PN of undefined etiology, 21 patients received acupuncture therapy according to classical Chinese Medicine as defined by the Heidelberg Model, while 26 patients received the best medical care but no specific treatment for PN. Sixteen patients (76%) in the acupuncture group improved symptomatically and objectively as measured by NCS, while only four patients in the control group (15%) did so. Three patients in the acupuncture group (14%) showed no change and two patients an aggravation (10%), whereas in the control group seven showed no change (27%) and 15 an aggravation (58%). Importantly, subjective improvement was fully correlated with improvement in NCS in both groups. The data suggest that there is a positive effect of acupuncture on PN of undefined etiology as measured by objective parameters.

Effects of irradiation on nerve graft vasculature.

Increasing doses of therapeutic irradiation are known to impair nerve regeneration after grafting. One possible factor is the effect of irradiation on the endoneurial vasculature. This study investigates the effects of postoperative irradiation on the size, number, and cross-sectional area of endoneurial vessels in the rat posterior tibial nerve graft model. Sixty-five Sprague-Dawley rats underwent 1.5-cm interposition grafts to the tibial nerve. Postoperatively, they were assigned to one of five groups. The animals in Group 1 were unirradiated controls. Groups 2 to 5 received postoperative irradiation in the amounts of 46, 66, 86, and 106 Gy, respectively. One hundred and twenty days after grafting, sections of the proximal, grafted, and distal nerve were harvested and analyzed with digital morphometry. Statistical analysis of the average vessel area, number of vessels, and total vascular area was performed. The grafted segments of Groups 4 and 5 and the distal segments of all irradiated groups showed a statistically significant decrease in the number of vessels, compared to controls. The average size of the vessel was smaller in the proximal segment of the irradiated groups, compared to controls. There was no difference in size in either the grafted or distal segments of the irradiated groups, compared to controls. The observed changes in the endoneurial vasculature resulted from both the action of regeneration and the effects of irradiation. The irradiation effects appear to be dose-dependent.

The therapeutic window of hypothermic neuroprotection in experimental ischemic neuropathy: protection in ischemic phase and potential deterioration in later reperfusion phase.

Hypothermia will neuroprotect peripheral nerve from ischemia-reperfusion (IR) injury, but the therapeutic window of hypothermic neuroprotection has not been defined. Unilateral IR injury was produced by the ligation and release of nooses tied around supplying arteries to the right sciatic-tibial nerve of the rat. Using this model, 114 rats were divided into 12 groups according to the delay (0, 1, 3, and 4 h) and the depth of hypothermia (28, 32, and 35 degrees C). All rats were subjected to 3 h ischemia and 7 days reperfusion followed by behavioral, electrophysiological, and pathological evaluations. We demonstrated significant hypothermic neuroprotection with both deep (28 degrees C) and mild (32 degrees C) hypothermia initiated during ischemia (0 and 1 h delay), but not hypothermia initiated during reperfusion (3 and 4 h delay) in both behavioral and electrophysiological evaluations. In addition, the pathologically significant differences were observed between deep hypothermia (28 degrees C) and normothermia (35 degrees C) initiated during ischemia. We conclude that the therapeutic window of hypothermic neuroprotection is optimal during the intraischemic period and that mild and deep hypothermia provide neuroprotection. Prolonged delay of hypothermic treatment results in worsening of IR injury.

Acute hyperglycemia attenuates nerve conduction velocity and nerve blood flow in male Sprague-Dawley rats: reversal by adenosine.

Hyperglycemia is implicated to play a major role in development of diabetic neuropathy. Since most of the diabetics are hyperglycemic much before they develop full-blown diabetes, we felt, it would be very important to know the effects of acute hyperglycemia on nerve function so that early pathophysiological events could be understood and appropriate therapeutic intervention can be made. Moreover, effect of acute hyperglycemia on motor nerve conduction velocity (MNCV) and nerve blood flow (NBF) is not known. Hence, we studied the effects of acute hyperglycemia on sciatic MNCV and sciatic NBF in healthy male Sprague-Dawley (SD) rats. Three different animal models of acute hyperglycemia (50% glucose (3 g kg(-1), i.v. (intra-venous) or i.p. (intra-peritoneally)) or 24 h post-streptozotocin (STZ) injected rats were used. Acute hyperglycemia but not mannitol or sucrose significantly attenuated MNCV and NBF. Adenosine (10 mg kg(-1), i.p.) prevented the acute hyperglycemia-induced attenuation of MNCV and NBF in all the three rat models of acute hyperglycemia. Adenosine effects were blocked by theophylline (50 mg kg(-1), i.p.) suggesting the role of adenosinergic receptor mediated mechanisms in acute hyperglycemia-induced neuropathy. Acute glucose administration in 8 weeks, STZ diabetic rats did not further affect MNCV or NBF. Adenosine (10 mg kg(-1), i.p.) did not produce any adverse effects on the blood pressure and heart rate. From the results, we conclude that acute hyperglycemia attenuates MNCV and NBF via an adenosinergic receptor-dependent mechanism.

Effect of perineurial window size on nerve regeneration, blood-nerve barrier integrity, and functional recovery.

End-to-side neurorrhaphy is used clinically to reconstruct nerve injuries when the lack of a suitable proximal nerve stump precludes conventional approaches to microsurgical repair. In end-to-side neurorrhaphy, the distal stump of a transected nerve is sutured to the side of an intact nerve that serves as an axon donor. Prior studies suggest that this perineurial window is a prerequisite for effective nerve regeneration into the recipient nerve. However, the optimal size for this perineurial window remains uncertain. This study evaluated the effect of perineurial window size on collateral axonal sprouting, blood-nerve barrier architecture, and functional impairment of the donor nerve. One hundred twenty Lewis rats were randomized to 1 and 5 mm perineurial window groups and examined at serial time points. The 5 mm perineurial window group exhibited significantly greater fiber counts at the repair zone than the 1mm group within 4 weeks (p < 0.005). Marked breakdown of the blood-nerve barrier was present 2 week postoperatively and resolved by 4 weeks regardless of 1 versus 5 mm perineurial window size. Tibial function indices in both groups normalized between 4 and 6 weeks postoperatively. A large (5 mm) perineurial window induced greater collateral sprouting or regenerative response than a small (1 mm) perineurial window without increasing cross sectional nerve injury or delaying functional recovery.

Peripheral nerve ischemia: reperfusion injury and fiber regeneration.

We continued our studies of ischemia-reperfusion (IR) injury, extending the reperfusion duration to 42 days to capture the fiber regeneration process. We used a rat model for IR injury produced by ligation and release of nooses around supplying vessels to the sciatic nerve. Fifty-six rats were used. One group (control N = 8) underwent sham ischemia; the other six groups (N = 8 each) underwent complete hind limb ischemia for 4 h followed by reperfusion durations of 0 h (ischemia alone), 3 h, 7 days, 14 days, 28 days, and 42 days. Behavioral and electrophysiological data were obtained immediately before euthanasia. Pathologically, three phases were identifiable: Phase 1 (0-3 h)-minimal pathological changes, minimal edema; phase 2 (7 days, 14 days)-prominent fiber degeneration, endoneurial edema; phase 3 (28 days, 42 days)-abundant small regenerating fiber clusters, minimal edema. Compound muscle action potential (CMAP) was the most sensitive index of neural deficits and recovery, showing progressive recovery beyond 14 days. Severe functional deficits developed immediately and persisted with a trend to recovery at the 42-day time-point. It was concluded that reperfusion, by oxidative injury, worsened nerve function and aggravated fiber degeneration, but in the longer time frame, permitted fiber regeneration to occur.

Hypoglycaemic neuropathy: microvascular changes due to recurrent hypoglycaemic episodes in rat sciatic nerve.

Intensive diabetes treatment causes a considerable increase in the number of severe hypoglycaemic episodes which could aggravate the progression of diabetic neuropathy. However, the effect of repeated hypoglycaemic episodes on nerve morphology has never been previously investigated. The aims of the present study were: (i) to establish a rat model of recurrent episodes of severe hypoglycaemia, and (ii) to assess morphological changes after repeated hypoglycaemic episodes in rat sciatic nerves. We induced hypoglycaemic episodes, blood glucose level <3.0 mmol/l for 3 h, by injecting regular insulin intravenously on 4 consecutive days. We found endothelial swelling of endoneurial microvessels at the thigh level of sciatic and tibial nerves 24 h after four daily episodes of hypoglycaemia. Endothelial swelling was confirmed by vascular morphometry which showed significantly increased endothelial and pericyte areas. No obvious abnormalities were seen on nerve fibres. In conclusion, recurrent hypoglycaemic episodes cause early vascular anomalies in endoneurial microvessels in rat sciatic nerves without any observable changes in nerve fibres.