Magnetic resonance neurography in spinal cord injury: Imaging findings and clinical significance

Abstract

Background and purpose

It is unknown whether changes to the peripheral nervous system following spinal cord injury (SCI) are relevant for functional recovery or the development of neuropathic pain below the level of injury. Magnetic resonance neurography (MRN) at 3 T allows detection and localization of structural and functional nerve damage. This study aimed to combine MRN and clinical assessments in individuals with chronic SCI and nondisabled controls.

Methods

Twenty participants with chronic SCI and 20 controls matched for gender, age, and body mass index underwent MRN of the L5 dorsal root ganglia (DRG) and the sciatic nerve. DRG volume, sciatic nerve mean cross‐sectional area (CSA), fascicular lesion load, and fractional anisotropy (FA), a marker for functional nerve integrity, were calculated. Results were correlated with clinical assessments and nerve conduction studies.

Results

Sciatic nerve CSA and lesion load were higher (21.29 ± 5.82 mm² vs. 14.08 ± 4.62 mm², p < 0.001; and 8.70 ± 7.47% vs. 3.60 ± 2.45%, p < 0.001) in individuals with SCI compared to controls, whereas FA was lower (0.55 ± 0.11 vs. 0.63 ± 0.08, p = 0.022). DRG volumes were larger in individuals with SCI who suffered from neuropathic pain compared to those without neuropathic pain (223.7 ± 53.08 mm³ vs. 159.7 ± 55.66 mm³, p = 0.043). Sciatic MRN parameters correlated with electrophysiological results but did not correlate with the extent of myelopathy or clinical severity of SCI.

Conclusions

Individuals with chronic SCI are subject to a decline of structural peripheral nerve integrity that may occur independently from the clinical severity of SCI. Larger volumes of DRG in SCI with neuropathic pain support existing evidence from animal studies on SCI‐related neuropathic pain.

INTRODUCTION

It has long been assumed that the peripheral nervous system (PNS) is affected as a consequence of spinal cord injury (SCI). Electrophysiological studies have found that axonal lesions of peripheral nerves may be related to the severity of disability and that a relationship between peripheral nerve damage and pressure injury may be relevant, particularly in chronic stages [1, 2, 3, 4]. Potential indirect mechanisms underlying PNS damage in SCI, such as nerve root entrapment and transsynaptic degeneration below the level of injury or changes in autonomic innervation, and direct consequences of SCI, such as lower motoneuron damage, are being discussed as further contributing factors [5]. Yet, it remains to be determined to what extent changes in the structure and function of the PNS after SCI contribute to the impairment of motor or sensory function, with the latter being known to play a crucial role in the development of neuropathic pain [6], a frequent adverse sequel of SCI with limited options for effective treatment, despite intensive research efforts [7]. As of yet, the exact mechanisms underlying the development of neuropathic pain below the level of injury (below‐level pain [BLP]) after SCI remain unclear, with a multifactorial pathogenesis being considered the most plausible cause [8, 9]. Among these factors, which include peripheral, spinal, and not least supraspinal mechanisms, central sensitization is considered one of the crucial consequences and a key process in developing neuropathic pain after SCI [10]. In animal studies, the PNS has recently come into focus in BLP, with hyperexcitability in the pain‐mediating sensory system being discussed as a significant factor [11]. In humans, electrophysiological studies only provide limited information about the location, pattern, and extent of nerve lesions, particularly in proximal regions of the PNS [12]. These particular parts of the PNS, especially in the lower extremities, are poorly accessible for tissue biopsies in the clinical setting. Magnetic resonance neurography (MRN) at 3 T allows for a noninvasive assessment of all parts of the PNS at the fascicular level [13]. Previous MRN studies on various neuropathies came to show that MRN can precisely locate, characterize, and quantify even subtle structural changes of peripheral nerves and the dorsal root ganglia (DRG) earlier and more precisely than electrophysiological examinations alone [14, 15, 16]. Moreover, it could be demonstrated for neuropathies originating from both PNS and central nervous system (CNS) disorders that the maximum load of fascicular nerve lesions predominates at the level of the sciatic nerve [17, 18]. It has further been shown that T2‐weighted (T2w), fat‐suppressed sequences allow for an exact anatomic location and quantification of fascicular nerve lesions, and the fractional anisotropy (FA) of peripheral nerves, a parameter obtained from diffusion‐weighted magnetic resonance imaging (MRI), is a reliable marker for the structural integrity of peripheral nerves that shows strong correlations with electrophysiologic parameters [19, 20]. To investigate SCI‐related changes of the PNS in humans, this study aimed to assess individuals with chronic SCI changes in the proximal mixed sciatic nerve (containing sensory and motor nerve fibers) and of the sensory DRG. For this purpose, T2w (structural) and diffusion‐weighted 3‐T MRN sequences (for the assessment of examined nerves' functional integrity) were used. The results were compared to a matched nondisabled reference cohort. In addition, the SCI cohort was tested for possible associations between MRN outcomes and SCI‐related neurological conditions, myelopathy, and electrophysiological assessments (nerve conduction studies).

METHODS

Standard protocol approvals, registrations, and patient consents

This prospective explorative cross‐sectional observational study was approved by the ethics committee of the Medical Faculty of Heidelberg University, Heidelberg, Germany as part of a larger observational study focusing on the investigation of neuropathic pain in SCI (S‐655/2019). Recruitment was done by convenient sampling among former participants of the European Multicenter Study About Spinal Cord Injury (EMSCI) at the study site Heidelberg (ClinicalTrials.gov: register no. NCT01571531). All participants with SCI were enrolled at the outpatient clinic of the Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany, and gave written informed consent. Once the examination of the patient cohort had been completed, controls were enrolled at the Department of Neuroradiology.

Recruitment of participants and clinical assessment

A total number of 25 controls (21 male, four female) were examined, of whom 5 (three male, two female) were excluded from the analysis to achieve optimal matching of the two cohorts in terms of sex, age, and body mass index (BMI). A detailed medical history was documented for each participant. Inclusion criteria for participants with chronic SCI were as follows: age between 18 and 70 years, time since SCI ≥ 1 year, and neurological level of SCI above Th11. Exclusion criteria for all participants, including controls, corresponded to those of EMSCI (https://www.emsci.org). Additional exclusion criteria were as follows: pregnancy or any contraindications for MRI, any known risk factors for peripheral neuropathy such as malignant diseases, diabetes, alcoholism, renal function impairment, hypovitaminosis, or any previous or ongoing exposure to neurotoxic agents. Furthermore, chronic conditions of the CNS other than SCI such as Parkinson disease, restless legs syndrome, or multiple sclerosis were also considered as exclusion criteria.

After enrollment, participants with SCI were largely assessed according to the EMSCI protocol including the International Standards for Neurological Classification of Spinal Cord Injuries (ISNCSCI) and, in part, corresponding neurophysiological examinations [21].

Assessments comprised a complete neurologic examination in accordance with ISNCSCI to accurately classify the SCI‐related condition of participants. The most relevant parameters to this study included the American Spinal Injury Association Impairment Scale (AIS) as a measure of the severity of SCI (e.g., complete versus incomplete), the neurological level of injury (NLI), and the lower extremity motor score (LEMS) [22]. All ISNCSCI examinations were done by professionally trained assessors [23]. Evaluation of pain (SCI‐related BLP) was done in accordance with the recommendations of the International Association for the Study of Pain and based on related clinical practice guidelines in the field of SCI medicine [24, 25, 26]. Standardized electrophysiological studies of the tibial, peroneal, and sural nerves were conducted in all participants [27].

MRN procedure and sequence analysis

All participants underwent 3‐T MRN of the lumbosacral plexus, the DRG, and the right sciatic nerve in a 3‐T MRI scanner (Somatom Prisma, Siemens Healthineers, Erlangen, Germany). Total imaging time including the rearrangement of coils and positioning of the participants was kept to <30 min to avoid pressure sores in individuals with SCI.

For imaging of the lumbosacral plexus and DRG, a 32‐channel spine coil (Spine 32 3T TIM Coil, Siemens Healthineers) and an 18‐channel flex coil (Body 18 3T TIM Coil, Siemens Healthineers) were used. Magnetic resonance images were acquired using a T2w, three‐dimensional inversion recovery sequence with sampling perfection with application‐optimized contrasts using different flip angle evolution (SPACE). Sequence parameters were as follows: repetition time (TR) = 3000 ms, echo time (TE) = 202 ms, field of view (FOV) = 305 mm × 305 mm, voxel size = 0.95 × 0.95 × 0.95 mm³, 104 images.

For imaging of the right sciatic nerve, a 15‐channel transmit–receive extremity coil was used. T2w sequences with spectral fat suppression (TR = 5970 ms, TE = 55 ms, FOV = 160 mm² × 160 mm², matrix size = 512 × 512, slice thickness = 4 mm, interslice gap = 0.8 mm, voxel size = 0.3 mm × 0.3 mm × 4.0 mm³, 24 slices) and diffusion‐weighted sequences (TR = 5100 ms, TE = 92.8 ms, b = 0 and 1000 s/mm², directions = 20, FOV = 160 mm² × 160 mm², matrix size 128 × 128, slice thickness = 4 mm, voxel size = 1.3 mm × 1.3 mm × 4 mm³, no interslice gap, 24 slices, 1512 acquired images) were employed. Sequences were centered to midthigh level to ascertain that the mapped part of the sciatic nerve was comparable in all participants.

For an assessment of spinal cord damage, the most recent spinal MRI images (>1 year after injury) of participants with chronic SCI were acquired from the picture archiving and communication system (PACS) of our hospital and retrospectively analyzed. Minimum requirements for image segmentation of spinal cord lesions were defined as axial T2w sequences with a minimum in‐plane resolution of 0.3 × 0.3 mm and a maximum slice thickness of 3 mm covering the entire spinal lesion(s) recorded without metal artifacts or artifacts due to motion.

Image postprocessing and statistical analysis

All recorded MRN sequences were pseudonymized directly after acquisition. To exclude confounding pathologies at the level of the lumbosacral plexus, the acquired T2 SPACE sequences were carefully assessed for structural alterations such as traumatic plexus lesions or lesions that might point to another condition underlying nerve damage such as neuromas, neurofibromas, or swellings in the sense of a chronic demyelinating inflammatory polyneuropathy or critical illness neuropathy. No such changes were found in any of the participants of the two groups.

Segmentation of the DRG and analysis of the sciatic nerve FA, cross‐sectional area (CSA), and T2w‐hyperintense fascicular lesions were performed by two board‐certified neuroradiologists with >7 years of experience in MRN image analysis (J.M.E.J., F.T.K.). All segmentations and subsequent analyzes were performed using ImageJ [28] and custom‐written code in MATLAB [29]. The detailed process of DRG segmentation and volumetry (Figure 1a) has been described previously [15]. CSA, lesion load, and FA were calculated for the sciatic nerve's tibial compartment. After manual segmentation compartment, the mean CSA was calculated in MATLAB. T2w‐hyperintense lesions of the sciatic nerve's tibial compartment that can be considered the anatomical correlate for structural damage and functional impairment of nerve fascicles [30] were detected by comparing the fascicles' signal to that of the adjacent semimembranosus muscle, an approach that has previously been validated and extensively described (Figure 1b–d) [20, 31]. Given potentially denervated thigh muscles in SCI, this can be considered a very conservative approach, as muscle denervation is usually associated with a slight increase in T2 signal [32]. Once the segmentation of lesions was completed, the extent of lesions in percent of the full nerve volume was calculated in an automated approach in MATLAB [31]. The tibial compartment FA, a dimensionless quantity derived from diffusion tensor imaging that ranges from 0 (indicating anisotropic diffusion) to 1 (indicating fully isotropic diffusion), was measured in ImageJ on FA maps automatically provided by the Syngo Software of the MRI scanner.

FIGURE 1.

Illustration of the sciatic nerve and dorsal root ganglia (DRG) imaging and analysis. (a) Isotropic T2‐weighted fat‐suppressed image of both L5 DRG, encircled in yellow, and three‐dimensional reconstruction of the anatomical position of the left (red) and right (green) L5 DRG. (b) Stack of T2‐weighted, fat‐suppressed axial images of the right thigh; the sciatic nerve is encircled in yellow. (c) Segmentation of the sciatic nerve tibial compartment of a healthy control on a T2‐weighted sequence (left) and on a color‐coded map of the nerve's fractional anisotropy. (d) Segmentation of the sciatic nerve tibial compartment in a patient with chronic spinal cord injury and severe neuropathic pain below the level of injury.

In participants with SCI, segmentation of the spinal cord at the level of injury and segmentation of the spinal cord lesion were performed on the axial T2w spinal MRI sequences (Figure 2a,b). The ratio between spinal lesion volume and spinal cord volume at the level of the spinal cord lesion was calculated subsequently.

FIGURE 2.

Illustration of spinal cord lesion segmentation and analysis. (a) Segmentation of the spinal cord (blue), lesions within the spinal cord (magenta), and the surrounding bones and tissue (green) on a T2‐weighted image. (b) The extent of lesions within the spinal cord. (c) The anatomical position of the lesioned spinal cord. Directions are provided for orientation.

For statistical analyzes, MATLAB 7.14.0.0739 (R2012a) and GraphPad Prism 9.4 were used. The D'Agostino–Pearson omnibus normality test was applied to test for Gaussian normal distribution. T‐tests were used for comparisons of two groups, and Pearson correlation coefficients were used for correlation analysis if a Gaussian normal distribution was given. In the case of non‐Gaussian distributed data, the Mann–Whitney test was used for comparisons of two groups, and nonparametric Spearman correlation was used for correlation analyses. The level of significance was defined at p < 0.05 for all tests.

RESULTS

Completion of the study protocol and demographic data

MRN of the sciatic nerve was completed by 20 participants with SCI and 20 controls. In two individuals with SCI, analysis of DRG imaging was not possible due to motion and metal artifacts. Therefore, DRG images of 18 SCI participants and 20 controls were analyzed. In two of the 20 SCI participants, the segmentation of spinal cord lesions was not possible due to metal artifacts at the lesion level. Spinal images of 18 individuals with SCI were analyzed accordingly. A detailed description of the sample sizes used in the analyses is given in Table S1. The general clinical characteristics of individuals with SCI are shown in Table 1. An overview of demographic, clinical, electrophysiologic, and MRN imaging data is provided in Table 2.

TABLE 1.

Characteristics of study participants with SCI.

ID	Sex	Age at MRI, years	Time since injury, years	Cause of injury	AIS, A–D	NLI, C2–T10	LEMS, 0–50	Pain (yes = 1, no = 0)	Nociceptive pain (yes = 1, no = 0)	Below‐level neuropathic pain (yes = 1, no = 0)	At‐level neuropathic pain (yes = 1, no = 0)
01	M	60.8	2.7	Traumatic	D	C2	46	1	1	1	0
02	M	37.9	2.7	Traumatic	A	C6	0	0	0	0	0
03	M	19.0	2.1	Traumatic	A	C4	0	0	0	0	0
04	M	58.8	2.2	Traumatic	D	C4	18	0	0	0	0
05	M	34.2	3.5	Traumatic	A	T7	0	1	0	0	1
06	M	21.7	2.4	Traumatic	A	C8	0	1	1	0	0
07	M	23.4	3.2	Traumatic	A	C4	0	1	0	1	0
08	M	42.2	4.1	Traumatic	A	T4	0	1	0	1	0
09	M	53.0	1.1	Ischemic	A	T1	0	1	0	1	0
10	M	57.7	9.4	Traumatic	D	C2	40	1	1	1	0
11	M	57.6	3.3	Traumatic	A	C7	0	1	1	0	0
12	F	23.9	6.4	Traumatic	D	T4	44	1	0	1	0
13	M	25.8	6.2	Traumatic	D	C6	48	0	0	0	0
14	M	29.8	6.2	Traumatic	B	C8	0	0	0	0	0
15	M	31.1	8.6	Traumatic	A	T2	0	0	0	0	0
16	M	53.1	8.7	Ischemic	D	T9	46	0	0	0	0
17	M	34.2	2.8	Traumatic	D	C7	43	1	1	0	1
18	M	33.0	8.8	Traumatic	B	T3	0	1	1	0	0
19	M	29.4	7.5	Traumatic	A	T1	0	1	0	1	0
20	F	66.4	1.1	Ischemic	A	T10	2	1	0	1	0
Mean	n.a.	39.6	4.6	n.a.	n.a.	n.a.	14.35	n.a.	n.a.	n.a.	n.a.
±SD	n.a.	14.8	2.7	n.a.	n.a.	n.a.	20.16	n.a.	n.a.	n.a.	n.a.
Total	2× F	n.a.	n.a.	17× traumatic	11× A	11× C	n.a.	13	6	8	2
	18× M	–	–	3× ischemic	2× B	9× T	–	–	–	–	–
	–	–	–	–	7× D	–	–	–	–	–	–

Abbreviations: AIS, American Spinal Injury Association Impairment Scale; C, cervical; F, female; LEMS, lower extremity motor score; M, male; MRI, magnetic resonance imaging; n.a., not applicable; NLI, neurological level of injury; SCI, spinal cord injury; T, thoracic.

TABLE 2.

Comparison of magnetic resonance neurography and clinical parameters in SCI participants and controls.

Parameter	SCI	Controls	p
Sciatic CSA, mm2	21.29 ± 5.82	14.08 ± 4.62	<0.001 a
Sciatic lesion load, % of full nerve	8.70 ± 7.47	3.60 ± 2.45	0.020 b
Sciatic FA	0.551 ± 0.11	0.63 ± 0.08	0.022 a
DRG volume, mm3	175.70 ± 60.55	184.70 ± 45.53	0.597 a
Age at MRI, years	39.64 ± 15.17	41.90 ± 12.74	0.613 a
BMI, kg/m2	23.44 ± 4.17	26.71 ± 6.85	0.100 a
Tibial NCV, right, m/s	43.91 ± 6.61	45.88 ± 3.84	0.279 a
Peroneal motor NCV, right, m/s	41.84 ± 10.29	46.47 ± 3.02	0.034 b
Sural NCV, right, m/s	44.65 ± 8.58	50.73 ± 5.66	0.027 a
Tibial CMAP, right, mV	12.60 ± 8.28	21.06 ± 10.90	0.004 b
Peroneal CMAP, right, mV	3.71 ± 3.74	8.79 ± 2.79	<0.001 b
Sural SNAP, right, μV	10.80 ± 4.02	14.16 ± 6.82	0.092 a
Tibial DML, right, ms	3.72 ± 0.80	3.49 ± 0.57	0.730 b
Peroneal DML, right, ms	5.39 ± 2.65	3.94 ± 0.44	0.050 b

Note: All values are displayed as mean ± SD.

Abbreviations: BMI, body mass index; CMAP, compound motor action potential; CSA, cross‐sectional area; DML, distal motor latency; DRG, dorsal root ganglia; FA, fractional anisotropy; MRI, magnetic resonance imaging; NCV, nerve conduction velocity; SCI, spinal cord injury; SNAP, sensory nerve action potential.

^a p‐value obtained from t‐test.

^b p‐value obtained from Mann–Whitney test.

MRN parameters that codify structural nerve damage and nerve integrity

Sciatic nerve CSA and lesion load, both indicators of structural nerve damage, were higher in the SCI group compared to controls (21.29 ± 5.82 mm² vs. 14.08 ± 4.62 mm², p < 0.001, Figure 3a and 8.70 ± 7.47% vs. 3.60 ± 2.45%, p < 0.001, Figure 3b, respectively), whereas sciatic nerve FA, a parameter that codifies structural integrity of peripheral nerves, was lower in SCI (0.55 ± 0.11 vs. 0.63 ± 0.08, p = 0.022, Figure 3c). For the two groups of individuals with SCI with and without BLP, no differences could be found for MRN parameters CSA (21.41 ± 4.58 mm² vs. 21.10 ± 7.67 mm², p = 0.908), lesion load (6.23 ± 4.77% vs. 12.41 ± 9.56%, p = 0.068), or FA (0.55 ± 0.10 vs. 0.54 ± 0.14, p = 0.793).

FIGURE 3.

Scatterplot diagrams of magnetic resonance neurography parameters in spinal cord injury (SCI) and controls. *Significant difference (p < 0.05) between the SCI group and the control group. (a) Comparison of the sciatic nerve mean cross‐sectional area (CSA) in square millimeters: SCI, 21.29 ± 5.82 mm²; controls, 14.08 ± 4.62 mm²; p < 0.001. (b) Comparison of the sciatic nerve lesion load as a percentage of the full nerve volume: SCI, 8.70 ± 7.47%; controls, 3.60 ± 2.45%; p < 0.001. (c) Sciatic nerve fractional anisotropy (FA; dimensionless), SCI: 0.55 ± 0.11; controls: 0.63 ± 0.08; p = 0.022.

The functionality of distal nerve branches of the sciatic nerve, based on electrophysiological measurements

Peroneal and sural nerve conduction velocities (NCVs) were lower in SCI compared to controls (41.84 ± 10.29 m/s vs. 46.47 ± 3.02 m/s, p = 0.034 and 44.65 ± 8.58 m/s vs. 50.73 ± 5.66 m/s, p = 0.027, respectively). Also, lower tibial and peroneal compound motor action potentials (CMAPs; 12.60 ± 8.28 mV vs. 21.06 ± 10.90 mV, p = 0.004 and 3.71 ± 3.74 mV vs. 8.79 ± 2.79 mV, p < 0.0001, respectively) were found in SCI compared to controls. No such differences were found for sural sensory nerve action potentials or distal motor latencies (DMLs).

DRG as an exclusively sensory compartment of the PNS in consideration of BLP presentation

No difference was found for DRG volume between SCI and controls (181.0 ± 61.61 mm³ vs. 184.7 ± 45.53 mm³, p = 0.597). In SCI with BLP, DRG volume was larger compared to SCI without BLP (223.7 ± 53.08 mm³ vs. 159.7 ± 55.66 mm³, p = 0.043). No such differences were found for sciatic nerve lesion load (12.41 ± 9.46% vs. 6.23 ± 4.77%, p = 0.068), CSA (21.10 ± 7.67 mm² vs. 21.41 ± 4.59 mm², p = 0.91), or FA (0.54 ± 0.14 vs. 0.56 ± 0.10, p = 0.79).

Sciatic nerve CSA as an indicator of structural nerve damage

In SCI, the sciatic nerve CSA correlated negatively with FA, a parameter of both axonal and myelin integrity (r = −0.73, p < 0.001). Further correlations were found for age (r = 0.73, p < 0.001) and tibial CMAPs (r = −0.65, p = 0.005), but none of the other electrophysiologic parameters, which indicates that an increase in nerve diameter is primarily linked to axonal damage. No correlations were found between CSA and the neurological level of injury or other characteristics related to SCI such as the AIS (SCI severity) and LEMS (cumulative motor strength). An overview of correlations between MRN imaging parameters and clinical data in SCI is provided in Table 3.

TABLE 3.

Correlation of spinal cord injury participants' MRI parameters with clinical and electrophysiologic parameters.

Parameter	Sciatic CSA, mm2		Sciatic lesion ratio, %		Sciatic FA		DRG volume, mm3		Spinal lesion ratio, %
	r	p	r	p	r	p	r	p	r	p
Sciatic CSA, mm2	n.a.	n.a.	0.37 a	0.112	−0.73 b	<0.001	0.10 b	0.690	−0.09 b	0.718
Sciatic lesion load, %	0.37 a	0.112	n.a.	n.a.	−0.74 a	<0.001	0.02 a	0.940	0.09 a	0.729
Sciatic FA	−0.73 b	<0.001	−0.74 a	<0.001	n.a.	n.a.	−0.16 b	0.510	−0.09 b	0.734
DRG volume, mm3	0.10 b	0.690	0.02 a	0.940	−0.16 b	0.510	n.a.	n.a.	0.17 b	0.491
Age at MRI, years	0.73 b	<0.001	0.48 a	0.034	−0.67 b	0.001	0.12 b	0.628	0.15 b	0.565
Years since spinal cord injury	−0.06 b	0.800	−0.10 a	0.691	0.05 b	0.833	−0.21 b	0.387	−0.62 b	0.006
BMI, kg/m2	0.38 b	0.101	0.41 a	0.070	−0.50 b	0.023	−0.31 b	0.183	−0.23 b	0.363
NLI	−0.32 b	0.176	0.21 a	0.373	−0.08 b	0.746	−0.04 b	0.858	0.186 b	0.459
AIS	0.32 a	0.171	−0.05 a	0.846	−0.17 a	0.463	−0.30 a	0.197	−0.76 a	<0.001
LEMS	0.30 a	0.193	0.06 a	0.801	−0.25 a	0.297	−0.21 a	0.377	−0.57 a	0.013
Tibial NCV, right, m/s	−0.41 b	0.092	−0.72 a	<0.001	0.72 b	<0.001	−0.33 b	0.184	−0.32 b	0.215
Peroneal motor NCV, right, m/s	0.03 b	0.916	−0.26 a	0.338	0.08 b	0.767	−0.24 b	0.363	−0.29 b	0.299
Sural NCV, right, m/s	−0.10 b	0.697	−0.51 a	0.038	0.42 b	0.090	−0.16 b	0.539	−0.13 b	0.622
Peroneal sensory NCV, right, m/s	−0.42 b	0.156	−0.37 a	0.209	0.50 b	0.081	−0.15 b	0.635	−0.28 b	0.400
Tibial CMAP, right, mV	−0.65 a	0.005	−0.50 a	0.041	0.59 a	0.014	−0.54 a	0.027	−0.17 a	0.521
Peroneal CMAP, right, mV	0.12 a	0.649	−0.15 a	0.579	−0.10 a	0.707	−0.15 a	0.580	−0.37 a	0.174
Sural SNAP, right, μV	−0.44 b	0.080	−0.27 a	0.134	0.38 b	0.128	0.36 b	0.158	−0.23 b	0.388
Peroneal SNAP, right, μV	−0.42 a	0.157	−0.31 a	0.297	0.52 a	0.074	0.13 a	0.665	−0.38 a	0.248
Tibial DML, right, ms	0.01 a	0.976	0.49 a	0.046	−0.37 a	0.139	0.16 a	0.529	−0.16 a	0.561
Peroneal DML, right, ms	−0.08 a	0.771	0.24 a	0.379	−0.15 a	0.565	−0.61 a	0.014	−0.27 a	0.327

Abbreviations: AIS, American Spinal Injury Association Impairment Scale; BMI, body mass index; CMAP, compound motor action potential; CSA, cross‐sectional area; DML, distal motor latency; DRG, dorsal root ganglia; FA, fractional anisotropy; LEMS, lower extremity motor score; MRI, magnetic resonance imaging; n.a., not applicable; NCV, nerve conduction velocity; NLI, neurological level of injury; SNAP, sensory nerve action potential.

^a Spearman correlation coefficient.

^b Pearson correlation coefficient.

In controls, the sciatic nerve CSA correlated with age (r = 0.65, p = 0.002), FA (r = −0.56, p = 0.014), and sural NCV (r = −0.54, p = 0.039). An overview of correlations between MRN imaging parameters and clinical data in controls is provided in Table 4.

TABLE 4.

Correlation of controls' magnetic resonance neurography parameters with clinical and electrophysiologic parameters.

Parameter	Sciatic CSA, mm2		Sciatic lesion ratio, %		Sciatic FA		DRG volume, mm3
	r	p	r	p	r	p	r	p
Sciatic CSA, mm2	n.a.	n.a.	0.07 a	0.782	−0.55 a	0.014	0.25 a	0.294
Sciatic lesion load, %	0.07 a	0.782	n.a.	n.a.	−0.16 a	0.518	−0.10 a	0.673
Sciatic FA	−0.55 a	0.014	−0.16 a	0.518	n.a.	n.a.	0.13 a	0.606
Age at MRI, years	0.65 a	0.002	0.23 a	0.322	−0.56 a	0.013	−0.02 a	0.931
BMI, kg/m2	0.27 a	0.249	0.27 a	0.254	−0.26 a	0.278	−0.01 a	0.964
Tibial NCV, right, m/s	−0.11 a	0.661	−0.21 a	0.423	0.66 a	0.006	0.03 a	0.913
Peroneal motor NCV, right, m/s	−0.36 b	0.160	−0.05 b	0.842	0.62 b	0.012	0.19 b	0.453
Sural NCV, right, m/s	−0.54 a	0.039	0.07 a	0.802	0.25 a	0.388	0.24 a	0.390
Tibial CMAP, right, mV	−0.16 b	0.563	−0.39 b	0.135	0.35 b	0.199	0.28 b	0.296
Peroneal CMAP, right, mV	−0.17 a	0.531	−0.24 a	0.366	0.44 a	0.097	−0.01 a	0.975
Sural SNAP, right, μV	−0.30 a	0.254	−0.22 a	0.412	0.23 a	0.405	0.01 a	0.961
Tibial DML, right, ms	0.24 a	0.391	0.49 a	0.064	−0.25 a	0.394	−0.23 a	0.407
Peroneal motor DML, right, ms	0.49 a	0.055	0.33 a	0.217	−0.49 a	0.062	0.06 a	0.819

Abbreviations: BMI, body mass index; CMAP, compound motor action potential; CSA, cross‐sectional area; DML, distal motor latency; DRG, dorsal root ganglia; FA, fractional anisotropy; MRI, magnetic resonance imaging; n.a., not applicable; NCV, nerve conduction velocity; SNAP, sensory nerve action potential.

^a Pearson correlation coefficient.

^b Spearman correlation coefficient.

Sciatic nerve lesion load in SCI as an indicator of fascicular nerve damage

In SCI, the sciatic nerve lesion load correlated with FA (r = −0.74, p < 0.001), age (r = 0.48, p = 0.034), tibial NCV, CMAP, and DML (r = −0.72, p < 0.001, Figure 4a; r = −0.50, p = 0.041; and r = 0.49, p = 0.046, respectively), and sural NCV (r = −0.51, p = 0.038). In individuals with SCI, no correlations were found between the sciatic nerve lesion load and the neurological level of injury or the AIS (SCI severity) and LEMS (cumulative motor strength). No correlations were found for the sciatic nerve lesion load with any of the acquired parameters in the control group.

FIGURE 4.

Correlation analyses of the sciatic nerve and spinal lesion load in spinal cord injury (SCI). (a) Correlation between sciatic nerve lesion load and tibial nerve conduction velocity (NCV; r = −0.72, p < 0.001). (b) Correlation between sciatic nerve fractional anisotropy (FA) and tibial NCV (r = −0.72, p < 0.001). (c) Correlation between spinal lesion ratio and American Spinal Injury Association Impairment Scale (AIS) score (r = −0.76, p < 0.001). (d) Correlation between spinal lesion ratio and sciatic nerve lesion load (r = 0.09, p = 0.729).

Sciatic nerve structural integrity and its relation to individual and SCI characteristics

In individuals with SCI, the sciatic nerve FA, a parameter for peripheral nerves' structural integrity, correlated with age (r = −0.67, p = 0.001), BMI (r = −0.50, p = 0.023), tibial NCV, and CMAP (r = 0.72, p < 0.001, Figure 4b; and r = 0.59, p = 0.014, respectively). No correlations were found between the sciatic nerve FA and the neurological level of injury or the AIS (SCI severity) and LEMS (cumulative motor strength). In controls, FA correlated with age (r = −0.56, p = 0.013), tibial NCV (r = 0.66, p = 0.006), and peroneal NCV (r = 0.62, p = 0.012).

Myelopathy and its relation to SCI characteristics and MRN findings

In SCI, the mean ratio of the spinal lesion and spinal cord at lesion level (spinal lesion ratio [SLR]) was 13.96 ± 10.33%. Negative correlations were found for the SLR with the AIS (r = −0.76, p < 0.001, Figure 4c) and the LEMS (r = −0.57, p = 0.013). No correlations were found between spinal L/V ratio and the sciatic nerve lesion load (r = 0.09, p = 0.729, Figure 4d), CSA (r = −0.098, p = 0.699), or FA (r = 0.02, p = 0.938) or any of the other acquired parameters.

DISCUSSION

Individuals with SCI were characterized by an accentuated loss of PNS integrity at the fascicular level compared with age‐, gender‐, and BMI‐matched nondisabled controls. This applied to all assessed MRN parameters of the sciatic nerve (nerve diameter, FA, and amount of fascicular nerve lesions). Moreover, in both cohorts, a significant association between structural nerve changes and electrophysiological parameters could be found, albeit electrophysiological parameters were little affected overall. In contrast, no correlations were found between MRN‐derived structural changes and the spinal cord lesion ratio. This suggests that changes in peripheral nerve integrity may not be directly linked to the disruptive impact on the spinal cord. Notably, the volumes of DRGs, representing the sensory system in the PNS, differed between SCI participants with and without BLP. This indicates that the peripheral sensory system is relevant to the occurrence of BLP and also demonstrates PNS involvement in SCI beyond the motor pathways affected by lower motoneuron damage [5].

The changes of sciatic nerve structure and function found in individuals with SCI indicate that not only the CNS but also the PNS is affected by SCI. This is consistent with findings from previous studies on peripheral nerve lesions in PNS and CNS disorders [18, 19].

The electrophysiological measurements in both cohorts yielded results that—in relation to the mean values—lie within a normal range, suggesting a subtle stage of PNS involvement. This, of course, raises the question of whether these MRN parameters are of clinical relevance. In this regard, it should be considered that previous studies on sciatic nerve lesions in peripheral neuropathies have shown that an increase in fascicular lesion load is associated with the occurrence of painful symptoms, independent of electrophysiological parameters [20]. Together with insights from studies using quantitative sensory testing in peripheral neuropathies, this may suggest a certain threshold facilitating the onset of clinical symptoms such as allodynia, which contribute to neuropathic pain [30].

In view of electrophysiology, there was an additional discrepancy between the involvement of motor and sensory pathways. Although the involvement of the motor system may be explained by lower motoneuron damage remote from the injury site [5], reasons for lacking group differences and little affected electrophysiological integrity of the sensory system remain unclear.

Interestingly, no correlations were found between structural changes of the PNS (sciatic nerve or DRG) and the SLR (myelopathy), with the latter representing the extent of structural damage to the spinal cord. This is of particular significance because the SLR was correlated with relevant neurological parameters like severity (AIS) and motor strength (LEMS). This finding renders the assumption that PNS changes are merely the result of direct parenchymal damage to the spinal cord unlikely. Instead, our data suggest that the presence of SCI results in an involvement of the PNS that is not directly related to specific characteristics of SCI.

One may argue that the changes found in the PNS could be based primarily on confounding factors such as age, obesity, and secondary diseases that are known to have a structural impact on the PNS [33]. Besides relevant diseases such as known history of diabetes and renal insufficiency being part of the exclusion criteria in both cohorts, it is important to consider that both cohorts were matched for gender, age, and BMI. Therefore, it appears unlikely that the differences in structural changes found between SCI participants and controls were essentially related to physiological processes such as aging [34, 35] or other confounders.

The question remains to what extent pressure injuries could have played a role in the structural PNS damage, given a cohort with chronic SCI [1]. Although this cannot be excluded with certainty, pressure palsies as a sole cause for the findings in individuals with SCI are unlikely, because MRN of the sciatic nerve was focused on the nerve's bifurcation, a region where the nerve is covered by abundant soft tissue including adjacent muscles. Moreover, if structural changes in the sciatic nerve were caused by pressure injury, one would expect that the structural nerve damage would increase with the time since SCI. However, this could not be demonstrated in view of the lack of correlations between duration of SCI and MRN parameters. Also, the time since SCI was comparatively short (4.64 ± 2.71 years) when considering cohorts of previous electrophysiological studies of PNS involvement in chronic SCI that included participants up to 19 years postinjury [4].

The enlargement of DRG in individuals with SCI and BLP suggests that changes at the level of the junction between PNS and CNS are of relevance for the development of neuropathic pain below the level of injury. This assumption of direct PNS involvement in BLP is supported by recent studies that revealed neuronal nociceptive hyperexcitability after SCI in animal models [11, 36]. An association between pain and structural changes of the sciatic nerve could not be found for MRN parameters of the sciatic nerve in our cohort, which may be due to the fact that it is not yet possible to discriminate between sensory and motor fiber lesions in mixed peripheral nerves using MRN. In addition, it is possible that the transmission of sensory input from the PNS to cortical regions may be completely interrupted in some of the SCI participants, particularly considering that most of the participants in the present cohort were characterized by a clinically complete SCI (AIS A) [37]. Hence, individuals characterized by such a lesion pattern may not perceive painful symptoms, albeit displaying structural changes in the PNS and being susceptible to neuropathic pain. The finding of larger DRGs in SCI with BLP may suggest that although there may be an overall DRG atrophy in SCI with impaired signal transduction, those individuals with BLP exhibit relative hypertrophy in the SCI cohort.

This study is limited in terms of generalizability by its explorative nature, the sample size, which does not allow exclusion of all potential confounders, and the cross‐sectional nature of the data. Furthermore, that the cohort with SCI was not equally balanced for women and men may also play a role. It should be considered, however, that the primary aim of this study was to detect structural nerve changes in chronic SCI by imaging techniques and not to assess the development of changes to peripheral nerves or gender‐specific differences.

In summary, this study found structural and functional alterations of peripheral nerves in individuals with chronic SCI that were not related to the extent of spinal cord damage or the overall severity of disability. The finding of larger DRG in participants with SCI and BLP supports the relevance of the PNS to the development of BLP in SCI. Further studies on the development and clinical impact of PNS involvement in SCI are warranted.

AUTHOR CONTRIBUTIONS

Johann Jende: Conceptualization; investigation; funding acquisition; writing – original draft; methodology; visualization; writing – review and editing; formal analysis; resources. Laura Heutehaus: Investigation; writing – review and editing; conceptualization; project administration; methodology. Fabian Preisner: Investigation; writing – review and editing. Christina M. Verez Sola: Investigation; writing – review and editing; project administration. Christoph Mooshage: Investigation; writing – review and editing. Sabine Heiland: Investigation; methodology; writing – review and editing. Rüdiger Rupp: Conceptualization; writing – review and editing. Martin Bendszus: Conceptualization; writing – review and editing. Norbert Weidner: Conceptualization; investigation; validation; writing – review and editing; supervision. Felix T. Kurz: Conceptualization; investigation; writing – original draft; writing – review and editing; software; formal analysis; data curation; supervision. Steffen Franz: Supervision; data curation; resources; conceptualization; investigation; writing – original draft; methodology; writing – review and editing; formal analysis.

FUNDING INFORMATION

This study was supported by the International Foundation for Research in Paraplegia and the Else Kröner‐Fresenius‐Stiftung to J.M.E.J and F.T.K and by the German Research Foundation (Deutsche Forschungsgemeinschaft, SFB1158) to N.W., L.H., R.R., and S.F.

CONFLICT OF INTEREST STATEMENT

All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Supporting information

TABLE S1

Jende JME, Heutehaus L, Preisner F, et al. Magnetic resonance neurography in spinal cord injury: Imaging findings and clinical significance. Eur J Neurol. 2024;31:e16198. doi: 10.1111/ene.16198

DATA AVAILABILITY STATEMENT

Anonymized data will be made available upon reasonable request from any qualified investigator.