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Assessment of nerve degeneration by gadofluorine MЦenhanced magnetic resonance imaging.

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Assessment of Nerve Degeneration by
Gadofluorine M–Enhanced Magnetic
Resonance Imaging
Martin Bendszus, MD,1 Carsten Wessig, MD,2 Ansgar Schütz, MD,1 Tanja Horn, MS,1
Christoph Kleinschnitz, MD,2 Claudia Sommer, MD,2 Bernd Misselwitz, PhD,3 and Guido Stoll, MD2
Nerve injury represents a major cause of disability. In the peripheral nervous system, nerves have the capacity to regrow
but within weeks after injury, it is impossible to clarify whether proper regeneration is under way or is failing. In this
experimental study, we report on a novel tool to assess nerve outgrowth in vivo. After systemic application, the novel
gadolinium-based magnetic resonance (MR) contrast agent Gadofluorine M (Gf) selectively accumulated and persisted in
nerve fibers undergoing Wallerian degeneration causing bright contrast on T1-weighted MR images. Gf enhancement on
MR imaging was present already at 48 hours within the entire nerve segments undergoing Wallerian degeneration, and
subsequently disappeared from proximal to distal parts in parallel to regrowth of nerve fibers. Most importantly, Gf
enhancement persisted in nonregenerating, permanently transected nerves. Our novel Gf-based MR imaging methodology
holds promise for clinical use to bridge the diagnostic gap between nerve injury and completed nerve regeneration, and
to determine the necessity for neurolysis and engraftment if spontaneous regeneration is not successful.
Ann Neurol 2005;57:388 –395
Axonal injury to peripheral nerves leads to degeneration of nerve fibers distal to the lesion site and to a
highly synchronized set of cellular and molecular responses that facilitate regrowth from the proximal
nerve stump.1–3 Nerve regeneration proceeds at a velocity of 1 to 4mm per day.4 Dislocation of the proximal and distal nerve ends, as is often the case after
sharp nerve injury by transection, or ligation prevents
regeneration.5 Nerve conduction studies are the gold
standard for in vivo assessment of nerve lesions. On
complete axonal injury, the evoked compound muscle
action potentials are lost within 24 to 48 hours and
reappear only after successful nerve regeneration. Reinnervation of target organs (muscle, skin) is delayed for
weeks or months depending on the distance between
the lesion site and the target. During this period, it is
impossible to assess nerve outgrowth noninvasively by
nerve conduction studies unless multiple recording
electrodes are implanted along the nerve.6 For clinical
decision making on surgical interventions it is essential
to know whether nerve regrowth is under way, because
the growth-permissive properties of denervated nerve
stumps and muscles dramatically decrease over time.7
From the Departments of 1Neuroradiology and 2Neurology, University of Würzburg, Würzburg; and 3Research Laboratories of
Schering AG, Berlin, Germany.
Received Sep 29, 2004, and in revised form Dec 20. Accepted for
publication Dec 21, 2004.
In this experimental study, we report on a novel
gadolinium (Gd)-based magnetic resonance (MR) contrast agent, Gadofluorine M (Gf; Schering AG, Berlin,
Germany), which selectively accumulated in nerve fibers undergoing degeneration and disappeared on successful nerve regeneration.
Materials and Methods
Surgical Procedure
A total of 66 male Wistar rats weighting 200 to 250gm were
used in this study. For all experimental procedures, animals
were deeply anesthetized with intraperitoneal injections of
100mg/kg ketamine (Ketanest; Pfizer, New York, NY) and
10mg/kg xylazine (Rompun; Bayer, Leverkusen, Germany).
Nerve crush was performed at the sciatic notch for 60 seconds using a small jeweler’s forceps. Partial nerve damage
was induced by chronic constriction injury (CCI; n ⫽ 3), as
described in detail elsewhere.8 After nerve transection in another experimental group, regeneration was prevented by ligation of the proximal and distal nerve stump. Animal studies were approved by the Bezirksregierung Unterfranken and
performed in accordance with institutional guidelines.
Address correspondence to Dr Bendszus, Department of Neuroradiology, University of Würzburg, Josef-Schneider-Strasse 11,
D-97080 Würzburg, Germany. E-mail: bendszus@neuroradiologie.
uni-wuerzburg.de
Published online Feb 24, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20404
388
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Physical Properties of the Contrast Medium
Gadofluorine M
Gf is an amphiphilic Gd complex with a molecular weight of
about 1,530gm/mol (patent application no. DE 10040381)
and a concentration of 250mmol Gd/L.9 To be used for
autofluorescence in histological studies, we prelabled Gf with
a carbocyanine dye.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) was performed on a clinical 1.5T scanner (Magnetom Vision; Siemens, Erlangen,
Germany). The imaging protocol comprised a scout sequence and a fat-suppressed, T1-weighted sequence (TR,
600 milliseconds; TE, 14 milliseconds) in the axial and coronal plane covering a range from the buttock to the distal
lower leg.
At first, nonenhanced MRI was performed 24 hours after
nerve crush (Table: Group 1, n ⫽ 3). In a second series
(n ⫽ 27), MRI was performed at multiple time points at
Days 1, 2, 4, 7 and, in weekly intervals until 6 weeks after
nerve crush. MRI was always applied 1h and 24h thereafter,
systemic application of Gf (0.1mmol/kg body weight; see
Table: Group 2). After MRI, sciatic and tibial nerves were
removed for fluorescence and histological evaluation.
In a third series (n ⫽ 21), Gf was applied at 24 hours
after the nerve injury in all animals, and groups (n ⫽ 3 in
each group) were followed to assess the resolution of the contrast agent from the nerves (see Table: Group 3). Different
groups underwent MRI at 48 hours, 7, 14, 21, 28, 35, or 42
days after the nerve lesion, respectively, and were killed after
MRI for histological evaluation.
In addition, three animals with a double crush lesion (left
sciatic nerve: 3 weeks; right sciatic nerve: 48 hours) underwent MRI 24 hours after application of Gf at Day 2 of the
second crush (see Table: Group 4). In three animals, MRI
was performed 24 hours after Gf application 3 weeks after
nerve transection (see Table: Group 5). After CCI, MRI was
performed at Day 3 and at 24 hours after Gf application (see
Table: Group 6).
Moreover, the sciatic nerve was surgically exposed but not
lesioned in three animals (see Table: Group 7). Twenty-four
hours later, Gf was applied, followed by MRI 24 hours later.
Finally, MRI was performed in three control animals without nerve lesion 1 and 24 hours after application of Gf (see
Table: Group 8).
Histological Assessment of Gadofluorine M Deposition
and Nerve Regeneration
For detection of carbocyanine-prelabeled Gf, nerve segments
were snap-frozen in isopentane. Thereafter, 10␮m-thick sections were analyzed for the presence of Gf by red fluorescence on a Zeiss Axiophot microscope (Zeiss, Thornwood,
NY). Sections were additionally stained by immunocytochemistry with the antibody ED-1 to identify macrophages
using fluorescein isothiocyanate green fluorescence. Moreover, other nerve segments were fixed in 4% paraformaldehyde/0.25% glutaraldehyde and embedded in plastic resin
for histological assessment of the stage of nerve degeneration
and regeneration on semithin 0.5␮m cross sections. Histological results were matched to MR scans.
Results
On nonenhanced T1-weighted MR images, the degenerating distal stump after nerve crush was isointense to
soft tissue, and thus could not be visualized (see Table:
Group 1; Fig 1A, B).
To assess the effect of Gf on nerve signal characteristics, we first performed MR measurements immediately and then 24 hours after Gf application at multiple time points after nerve crush (see Table: Group 2).
After application of Gf and MRI immediately (1 hour)
after nerve injury, a hyperintense signal was present in
the vascular compartment, that is, the femoral and
lower leg vessels (see arrowheads in Fig 1C, D),
whereas the degenerating nerves were unenhanced at
this time. When a second MRI was performed at 24
hours after nerve injury in these animals, the sciatic
nerve demonstrated a marked hyperintense signal down
to the mid-thigh level (see arrow in Fig 1E). When Gf
was applied 24 hours after nerve injury and then MRI
was performed 24 hours later (ie, Day 2 after crush),
the entire sciatic nerve and its branches exhibited con-
Table. Experimental Series
Group No.
Nerve Lesion
1 (n ⫽ 3)
2 (n ⫽ 27)
Unilateral crush
Unilateral crush
3 (n ⫽ 21)
Unilateral crush
4 (n ⫽ 3)
Bilateral crush (3-week interval
between first and second
crush)
Unilateral nerve transection
Chronic constriction injury
Unilateral sham operation
No nerve lesion (control)
5
6
7
8
(n
(n
(n
(n
⫽
⫽
⫽
⫽
3)
3)
3)
3)
Time Point of Gf Application
Time Point of MRI
Nonapplied
Days 1, 2, 4, 7; weeks 2, 3, 4, 5, 6
after nerve crush
Always 24 hours after nerve crush
24 hours after nerve crush
1 and 24 hours after Gf application
48 hours and week 1, 2, 3,
4, 5 after crush
24 hours after Gf application
48 hours after the second nerve
crush
3 weeks after transection
48 hours after ligatures
24 hours after sham operation
Applied
24 hours after Gf application
24 hours after Gf application
24 hours after Gf application
1 and 24 hours after Gf application
Gf ⫽ Gadofluorine m; MRI ⫽ magnetic resonance imaging.
Bendszus et al: Nerve Regrowth Assessed by MRI
389
Fig 1. Visualization of nerve degeneration by Gadofluorine M (Gf)–enhanced magnetic resonance imaging (MRI). Axial T1weighted images at mid-sciatic (A, C, E) and mid-thigh level (B, D, F). (A, B) Unenhanced T1-weighted images of degenerating
sciatic and tibial nerves that show no nerve signal alterations. (C–E) The left sciatic nerve was always crushed at the level of the
sciatic notch, whereas the contralateral intact nerve served as the control. MR scans were obtained 1 (C, D), 24 (E), and 48 hours
(F) after crush and after simultaneous (C–E) or 24-hour delayed (F) systemic Gf application. At 1 hour after crush, Gf-induced
enhancement was restricted to blood vessels (arrowheads denote femoral artery [C] and anterior tibial artery [D]). At 24 hours after crush and concomitant Gf application, the proximal part of the degenerating sciatic nerve became hyperintense (arrow in E).
Gf-induced hyperintensity extended to the peroneal and tibial nerves at the thigh at 48 hours after crush when Gf was administered
24 hours earlier (arrows in F).
trast enhancement down to the lower leg (see arrows in
Fig 1F). This pattern of contrast enhancement persisted for 2 weeks. Three weeks after nerve crush and
24 hours after Gf application, the proximal portion of
the sciatic nerve showed no more contrast enhancement (Fig 2A), whereas the distal parts and the tibial
and peroneal nerve still showed an increased signal (see
Fig 2B). Four or more weeks after nerve injury and 24
hours after injection of Gf there was almost no Gf en-
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March 2005
hancement in the sciatic nerve and its branches (see Fig
2C, D).
In a third series of experiments, we examined the
resolution of Gf enhancement in lesioned nerves over
time. In these animals, Gf was applied at 24 hours after nerve crush, followed by MR measurements at multiple time points involving different stages of nerve degeneration and regeneration (see Table: Group 3).
From Day 2 up to 2 weeks after nerve crush, the sciatic
Fig 2. Reversal of Gadofluorine M (Gf)–induced hyperintensity of injured nerves on magnetic resonance imaging (MRI) indicates
successful nerve regeneration. Nerve regeneration occurs at a velocity of about 1 to 2 mm per day; thus, regenerating nerves have
passed the knee level at 3 weeks after crush injury. Proximal sciatic (A, C, E) or mid-thigh tibial nerves (B, D, F) at 3 (A, B, E,
F) and 4 weeks (C, D) after injury. After 3 weeks, the regenerated sciatic nerve no longer showed Gf enhancement regardless of
whether the contrast agent had been applied 24 hours before MRI (A, note contrast enhancement in vessels marked by arrowheads
indicating recent Gf application) or 24 hours after nerve injury (E). At that time point, Gf enhancement (B, F), however, was still
present in more distal parts (tibial nerve) regardless of whether the contrast agent was applied shortly before MRI (arrows in B) or
at the time of nerve injury (arrows in F). On completed regeneration at 4 weeks after crush, both sciatic (C) and tibial nerves (D)
no longer showed Gf enhancement despite Gf presence in vessels 24 hours after systemic application (arrowheads in C).
nerve and its branches showed a marked hyperintense
signal. Three weeks after the nerve lesion, nerve Gf
contrast enhancement had disappeared at the upper leg
level (see Fig 2E) but was still present in the more distal parts (see Fig 2F). Nerve contrast accumulation
subsequently also vanished in the distal parts of the legs
during the following 2 weeks.
The proximodistal reversal of Gf contrast enhancement and its time course suggested a causal relation to
nerve regeneration. To support this notion, we performed sequential nerve crush experiments and correlated MRI to histological stages of nerve degeneration
and regeneration (see Table: Group 4). Initially, the
left sciatic nerve and, after 3 weeks, also the contralateral right sciatic nerve were crushed; Gf was applied 2
days after the second crush. MRI performed 24 hours
later showed strong contrast enhancement of the recently crushed right sciatic nerve (arrows in Fig 3D),
whereas the 3-week-old crush lesion on the left side
showed mild contrast enhancement in the distal tibial
nerve only (see in Fig 3D), but not the proximal part
(see arrowheads in Fig 3D). Corresponding semithin
nerve sections indicated early stages of axonal and myelin disintegration of the recent right nerve crush (see
Fig 3A), whereas nerve fibers had fully regenerated in
the noncontrast-enhancing proximal part of the left sci-
Bendszus et al: Nerve Regrowth Assessed by MRI
391
atic nerve (see Fig 3B). In contrast, the persistent,
contrast-enhancing tibial nerve showed morphological
signs of incomplete regeneration (see Fig 3C). Thus,
reversal of Gf enhancement indicated successful nerve
regeneration.
To further corroborate our findings, we transected
Fig 3. Gadofluorine M (Gf) enhancement declines during nerve regeneration but persists after permanent nerve transection. Histopathological assessment of different stages of sciatic nerve degeneration and regeneration in toluidine-stained 0.5␮m plastic sections
(A–C, F) in relation to Gf enhancement on magnetic resonance imaging (MRI) (D, E). (D) The sciatic nerve on the left side and
the contralateral right nerve were crushed 3 weeks and 3 days, respectively, before MRI. Gf was given 24 hours before MRI. Note
that the recently injured right sciatic nerve shows proximally pronounced intense Gf enhancement (dotted arrows in D) and disintegrated axons on histological sections as an early sign of nerve degeneration (A). In contrast, hardly any hyperintensity is seen in the
proximal part of the regenerated left sciatic nerve of the older crush (arrowheads in D). The corresponding histological section shows
nerve fibers with normal axonal diameter and myelin thickness (B). In the tibial nerve, some Gf enhancement still persists (D) and,
correspondingly, regeneration is incomplete on histological examination, which shows clusters of nerve growth cones and a reduction
of fiber numbers, size, and myelin thickness (C). After transection of the left sciatic nerve and prevention of regeneration, Gf enhancement persists at 3 weeks as shown in E. The corresponding histological nerve section confirms the lack of regenerating nerve
fibers (F).
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the sciatic nerves (see Table: Group 5). These nonregenerating sciatic nerves showed persistent contrast enhancement along the entire nerve at 3 weeks after transection (see Fig 3E). Semithin sections confirmed the
lack of reinnervation (see Fig 3F). To test the sensitivity of Gf-enhanced MR neurography, we induced partial nerve injury by chronic constriction (see Table:
Group 6). An intense nerve enhancement similar to after crush was seen 3 days after CCI (not shown).
We also assessed the effect of Gf application in
sham-operated animals (see Table: Group 7) and control animals without lesions (see Table: Group 8). In
both groups, no nerve contrast enhancement was seen.
We finally addressed the question to which histological structures Gf might bind in degenerating nerves.
Deposition of carbocyanine-prelabeled Gf was restricted to the perineurium in normal nerves (Fig 4A).
In contrast, the entire endoneurial space exhibited
strong Gf fluorescence after nerve crush (see Fig 4B,
C). Phase contrast microscopy indicated that Gf was
associated with fibrillary components of the extracellular matrix (see arrowheads in Fig 4C, D) and additional vesicular structures most likely representing degenerating myelin (see arrows in Fig 4C, D). Gf could
also be localized intracellularly in macrophages, as indicated by combined fluorescence and immunohistochemistry using the macrophage marker ED-1 (see arrows in Fig 4E, F). Macrophages that rapidly clear
myelin debris after nerve injury10 most likely have locally phagocytosed Gf, which was bound to myelin
components. At 3 weeks after crush, Gf could still be
detected in tibial but not proximal sciatic nerves (see
Fig 4G, H), thus corresponding to the disappearance
of contrast enhancement on MRI of regenerated
nerves, as shown in Figure 2C and D. Moreover, no
more Gf deposition was seen in both proximal and distal parts at 4 weeks after completed nerve regeneration
(not shown).
Discussion
As the principal finding we show that degenerating
nerve fibers in the peripheral nervous system persistently accumulate the novel MR contrast agent Gf, and
thereby can be specifically visualized in vivo by MRI.
Most importantly, Gf enhancement is reversible on
successful regeneration, and thus can identify moving
zones of nerve growth from proximal to distal parts of
injured peripheral nerves. Our notion is based on the
following observations. First, degenerating nerves
showed reproducible Gf enhancement regardless of
whether the contrast agent was applied early (24 hours
after crush) or at later time points. These MRI findings
could be confirmed by the accumulation of
carbocyanine-prelabeled Gf on histological sections.
Second, Gf deposition was no longer detectable in previously crushed and Gf-prelabeled nerves after success-
ful regeneration (“growing out” of the contrast agent).
Conversely, regenerated nerves no longer exhibited Gf
contrast enhancement when Gf was applied shortly (24
hours) before MRI. Third, permanently transected
nerves showed persistent Gf uptake and enhancement.
Interestingly, partial nerve injury by CCI was already
sufficient for Gf uptake in degenerating nerves. Histologically, Gf bound to fibrillary structures of the extracellular space and to vesicular formations, most likely
representing myelin debris, which could also be localized intracellularly in macrophages. In summary, this
novel contrast-enhanced MR technique offers a tool for
in vivo differentiation between intact and degenerated
nerve fibers.
Previous studies have assessed nerve injury by MRI.
Degenerating nerves show a prolongation of the T2 relaxation time on MR images at the lesion site and distally.11–14 These MR signal changes, however, are
caused by a variety and a combination of nonspecific
nerve tissue alterations such as edema, demyelination,
and axonal loss.13,14 In contrast, the application of
contrast media allows assessment of pathophysiological
processes, especially when contrast media with specific
binding properties to cells or molecules are used. We
recently have used superparamagnetic iron particles as
an MR contrast agent in peripheral nerve lesions.15
Systemic application of superparamagnetic iron particles led to signal loss on T2-weighted images within
degenerating nerves, which could be attributed to acute
migration of iron-labeled macrophages from the circulation into nerves. Active macrophage invasion, however, was restricted to a tight time frame up to day 8
after crush injury. Gf enhancement adds another MR
tool to assess pathophysiological processes during degeneration and regeneration of the peripheral nervous
system. In contrast to iron-based contrast agents, Gf
enhancement was present until complete regeneration
was accomplished. Moreover, Gf caused a bright signal
on T1-weighted images, whereas signal loss caused by
local iron accumulation may not be differentiated from
hemorrhage on MRI.16 Gf has unique properties as an
MR contrast agent because it persists in nerve lesions
for a long time, similar to how it persists in atherosclerotic plaques17,18 and in functional lymph node tissue.9,19 Interestingly, Gd-diethylenetriamine pentaacetic acid, an established clinical MR contrast agent for
assessment of disturbances of the blood–brain barrier,
showed no accumulation in degenerating nerves at a
similar dose of 0.1mmol/kg body weight.13 Because
leakage of the blood–nerve barrier has been described
in nerves undergoing Wallerian degeneration,20 Gf
most likely obtains access to the lesioned nerves by passive diffusion and subsequently binds to degenerating
nerve tissue. The main mechanism for accumulation/
trapping of Gf in target tissues appears to be hydrophobic interactions.
Bendszus et al: Nerve Regrowth Assessed by MRI
393
Fig 4. Localization of carbocyanine-prelabeled Gadofluorine M (Gf) on histological nerve sections. (A) In normal nerves, Gf accumulates only at the perineurium, whereas the entire endoneurial space is spared. (B, C) In contrast, endoneurial accumulation of
Gf in the distal stump of a degenerating sciatic nerve at day 5 after crush is shown. Note that the contrast medium is associated
with globular formations (arrows in B, C) and additional fibrillary structures most likely resembling extracellular matrix (arrowheads in B, C). Labeled globular formations correspond to vesicles on phase contrast images of the same section (C, D) and are
partly located intracellularly within macrophages (F). (E) Immunostained, ED1-positive macrophages (green) that on superimposition of Gf autofluorescence in F contain intracellular Gf deposits (red; arrows denote examples). Arrowhead shows an area with Gf
deposition in the absence of macrophages. Gf deposition or uptake is reversible on successful regeneration (G, H). (G, H) Images of
sciatic (G) and tibial (H) nerves at 3 weeks after nerve crush. Note that the proximal sciatic nerve shows no more significant Gf
autofluorescence, which still persists in the not yet fully regenerated tibial nerve (H). (See also Figures 2 and 3 for comparison with
MR findings.)
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In summary, we describe a novel, contrast-based,
MR technique allowing tracing of peripheral nerve fiber degeneration and regeneration. In the future, the
novel MR tracer, Gf, may close the diagnostic gap between acute nerve lesions and the delayed electrodiagnostic proof of nerve regeneration or its failure in clinical practice.
The study was supported by the State of Bavaria (IZKF Wü project
F-20, M.B., G.S.) and by a professorship (donated by Schering AG,
Berlin to the University of Würzburg, M.B.).
We thank H. Klüpfel and G. Köllner for expert technical assistance
and Profs K. Reiners, L. Solymosi, and K. Toyka for helpful comments.
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