Objective
To visualize and quantify differences of microstructural nerve damage in distal symmetric diabetic neuropathy (DPN) between type 1 diabetes (T1D) and type 2 diabetes (T2D), and to detect ...correlations between neuropathic symptoms and serological risk factors.
Methods
Three‐tesla magnetic resonance neurography of the sciatic nerve was performed in 120 patients (T1D, n = 35; T2D, n = 85) with either DPN (n = 84) or no DPN (n = 36). Results were subsequently correlated with clinical, serological, and electrophysiological patient data.
Results
T2‐weighted (T2w)‐hyperintense lesions correlated negatively with tibial compound motor action potential (r = −0.58, p < 0.0001) and peroneal nerve conduction (r = 0.51, p = 0.0002), and positively with neuropathy disability score (NDS; r = −0.54, p < 0.0001), neuropathy symptom score (NSS; r = 0.52, p < 0.0001), and HbA1c level (r = 0.23, p = 0.014). T2w‐hypointense lesions correlated positively with NDS (r = 0.28, p = 0.002), NSS (r = 0.36, p < 0.0001), and serum triglycerides (r = 0.34, p = 0.0003), and negatively with serum high‐density lipoprotein (HDL; r = −0.48, p < 0.0001). For DPN in T1D, elevated values of T2w‐hyperintense lesions (19.67 ± 4.13% vs 12.49 ± 1.23%, p = 0.027) and HbA1c (8.74 ± 0.29% vs 7.11 ± 0.16%, p < 0.0001) were found when compared to T2D. For DPN in T2D, elevated T2w‐hypointense lesions (23.41 ± 2.69mm3 vs 11.43 ± 1.74mm3, p = 0.046) and triglycerides (220.70 ± 23.70mg/dl vs 106.60 ± 14.51mg/dl, p < 0.0001), and lower serum HDL (51.29 ± 3.02mg/dl vs 70.79 ± 4.65mg/dl, p < 0.0001) were found when compared to T1D.
Interpretation
The predominant type of nerve lesion in DPN differs between T1D and T2D. Correlations found between lesion type and serological parameters indicate that predominant nerve lesions in T1D are associated with poor glycemic control and loss of nerve conduction, whereas predominant lesions in T2D are associated with changes in lipid metabolism. These findings may be helpful for future studies on the underlying pathophysiological pathways and possible treatments for DPN in T1D and T2D. Ann Neurol 2018;83:588–598
•Ultrasound and MRI of the nerves are suitable diagnostic tools in immune-mediated neuropathies.•Multifocal neuropathies exhibit regional, often asymmetric nerve enlargement, mostly affecting single ...fascicles.•In chronic inflammatory demyelinating polyneuropathy nerve enlargement of proximal nerve segments, the roots and the plexus is a hallmark feature.
New imaging modalities like high-resolution-ultrasound (HRUS) and MR-Neurography (MRN) are increasingly used for the evaluation of the peripheral nervous system. The increasing knowledge on morphological changes observed in different neuropathies has led to a better understanding of underlying pathophysiological processes.
The diagnosis of acquired chronic dysimmune neuropathies (CDN) like chronic inflammatory demyelinating polyneuropathy (CIDP), Lewis-Sumner Syndrome (LSS) or multifocal motor neuropathy (MMN) can be challenging. The current diagnostic criteria and outcome parameters are mainly based on clinical and electrophysiological parameters. Especially in CDN cases with atypical presentation or during early disease stages, the diagnostic accuracy is low and standardized protocols for the evaluation of disease activity and treatment response are lacking.
The establishment of combined diagnostic criteria for CDN including imaging modalities could help to improve the diagnostic accuracy, allow a better differentiation of subtypes and facilitate the follow-up of disease course. The appropriate selection of eligible patients and sensitive monitoring of treatment response is mandatory future in treatment trials.
In this article, we briefly summarize the clinical presentations and pathophysiological concepts of different CDN like CIDP, LSS and MMN. Furthermore, this review focuses on the diagnostic value of HRUS/MRN and its potential role for the monitoring of disease activity.
We tested the hypothesis that reduced skin innervation in fibromyalgia syndrome is associated with specific CNS changes. This prospective case-control study included 43 women diagnosed with ...fibromyalgia syndrome and 40 healthy controls. We further compared the fibromyalgia subgroups with reduced (n = 21) and normal (n = 22) skin innervation. Brains were analysed for cortical volume, for white matter integrity, and for functional connectivity. Compared to controls, cortical thickness was decreased in regions of the frontal, temporal and parietal cortex in the fibromyalgia group as a whole, and decreased in the bilateral pericalcarine cortices in the fibromyalgia subgroup with reduced skin innervation. Diffusion tensor imaging revealed a significant increase in fractional anisotropy in the corona radiata, the corpus callosum, cingulum and fornix in patients with fibromyalgia compared to healthy controls and decreased FA in parts of the internal capsule and thalamic radiation in the subgroup with reduced skin innervation. Using resting-state fMRI, the fibromyalgia group as a whole showed functional hypoconnectivity between the right midfrontal gyrus and the posterior cerebellum and the right crus cerebellum, respectively. The subgroup with reduced skin innervation showed hyperconnectivity between the inferior frontal gyrus, the angular gyrus and the posterior parietal gyrus. Our results suggest that the subgroup of fibromyalgia patients with pronounced pathology in the peripheral nervous system shows alterations in morphology, structural and functional connectivity also at the level of the encephalon. We propose considering these subgroups when conducting clinical trials.
To investigate whether the human sciatic nerve might have a consistent somatotopic organization according to proximal fascicle input by spinal nerves.
Twelve patients (55.3 ± 15.5 years) with ...confirmed lesions of either the L5 or S1 spinal nerve root underwent magnetic resonance neurography of sciatic nerve fascicles including thigh and knee levels (T2-weighted sequence with fat saturation, repetition time/echo time 7,552/52 milliseconds, voxel size 0.27 × 0.27 × 3.0 mm(3)). Twenty healthy subjects and 12 additional patients with an established diagnosis of peripheral polyneuropathy served as 2 separate age- and sex-matched control groups. Two blinded readers assessed patients and controls for presence of distinct lesion patterns. Spatial maps of normalized T2 signal were rendered after segmentation and coregistration of sciatic nerve voxels to detect fascicle lesion patterns.
A clear somatotopic distribution of nerve fascicles was observed on cross-sections along the entire course of the sciatic nerve and was distinct between patients with L5 and those with S1 lesions. Fascicles emerging from L5 were ordered in anterolateral positions within sciatic nerve cross-sections, while fascicles emerging from S1 appeared posteromedially. Visual assessment discriminated these somatotopic lesions in all cases from both healthy and polyneuropathy controls.
A distinct pattern of somatotopy was identified within the sciatic nerve according to proximal fascicle input by L5 and S1 spinal nerves. Knowledge of human nerve somatotopy may have clinically useful implications in imaging-aided diagnosis of neuropathies.
Ischemic stroke caused by thromboembolic occlusion of large cerebral arteries, such as the internal carotid (ICA) and/or the middle cerebral artery (MCA), is treated by mechanical thrombectomy (MT). ...MT allows salvage of the vessel-occluding thrombemboli, which most frequently originate from the left atrium or the left ventricle of the heart or from sites of plaque rupture within large arteries above the heart. Clot composition may influence the efficacy of (intravenous) thrombolysis and MT, respectively. We analyzed 37 human thrombemboli obtained from acute ischemic stroke patients during MT with special emphasis on histological staining of neutrophils and neutrophil extracellular traps (NETs). We found neutrophils as the main cellular component of cerebral thrombemboli but encountered considerable morphological heterogeneity. Neutrophils accumulated in the border region of fibrin-rich structures indicating possible interaction of neutrophils with distinct structural thrombembolus components. Web-like NETs were found in 35 of 37 thrombemboli in varying amounts. NETs were almost exclusively found within fibrin-rich areas. Importantly, stroke etiology, age and present oral anticoagulation was associated with morphological patterns and the amount of neutrophils. Correlation of histological data and imaging data revealed that relative Hounsfield units of cerebral thrombemboli positively correlated with the amount of red blood cells. In summary, our results demonstrate that neutrophils and NETs are substantial constituents of cerebral thrombemboli and contribute to their structural complexity.
Transthyretin familial amyloid polyneuropathy is a rare, autosomal-dominant inherited multisystem disorder usually manifesting with a rapidly progressive, axonal, distally-symmetric polyneuropathy. ...The detection of nerve injury by nerve conduction studies is limited, due to preferential involvement of small-fibres in early stages. We investigated whether lower limb nerve-injury can be detected, localized and quantified in vivo by high-resolution magnetic resonance neurography. We prospectively included 20 patients (12 male and eight female patients, mean age 47.9 years, range 26-66) with confirmed mutation in the transthyretin gene: 13 with symptomatic polyneuropathy and seven asymptomatic gene carriers. A large age- and sex-matched cohort of healthy volunteers served as controls (20 male and 20 female, mean age 48.1 years, range 30-73). All patients received detailed neurological and electrophysiological examinations and were scored using the Neuropathy Impairment Score-Lower Limbs, Neuropathy Deficit and Neuropathy Symptom Score. Magnetic resonance neurography (3 T) was performed with large longitudinal coverage from proximal thigh to ankle-level and separately for each leg (140 axial slices/leg) by using axial T2-weighted (repetition time/echo time = 5970/55 ms) and dual echo (repetition time 5210 ms, echo times 12 and 73 ms) turbo spin echo 2D sequences with spectral fat saturation. A 3D T2-weighted inversion-recovery sequence (repetition time/echo time 3000/202 ms) was acquired for imaging of the spinal nerves and lumbar plexus (50 axial slice reformations). Precise manual segmentation of the spinal/sciatic/tibial/common peroneal nerves was performed on each slice. Histogram-based normalization of nerve-voxel signal intensities was performed using the age- and sex-matched control group as normative reference. Nerve-voxels were subsequently classified as lesion-voxels if a threshold of >1.2 (normalized signal-intensity) was exceeded. At distal thigh level, where a predominant nerve-lesion-voxel burden was observed, signal quantification was performed by calculating proton spin density and T2-relaxation time as microstructural markers of nerve tissue integrity. The total number of nerve-lesion voxels (cumulated from proximal-to-distal) was significantly higher in symptomatic patients (20 405 ± 1586) versus asymptomatic gene carriers (12 294 ± 3199; P = 0.036) and versus controls (6536 ± 467; P < 0.0001). It was also higher in asymptomatic carriers compared to controls (P = 0.043). The number of nerve-lesion voxels was significantly higher at thigh level compared to more distal levels (lower leg/ankle) of the lower extremities (f-value = 279.22, P < 0.0001). Further signal-quantification at this proximal site (thigh level) revealed a significant increase of proton-density (P < 0.0001) and T2-relaxation-time (P = 0.0011) in symptomatic patients, whereas asymptomatic gene-carriers presented with a significant increase of proton-density only. Lower limb nerve injury could be detected and quantified in vivo on microstructural level by magnetic resonance neurography in symptomatic familial amyloid polyneuropathy, and also in yet asymptomatic gene carriers, in whom imaging detection precedes clinical and electrophysiological manifestation. Although symptoms start and prevail distally, the focus of predominant nerve injury and injury progression was found proximally at thigh level with strong and unambiguous lesion-contrast. Imaging of proximal nerve lesions, which are difficult to detect by nerve conduction studies, may have future implications also for other distally-symmetric polyneuropathies.
To assess nerve T2 signal and caliber as diagnostic signs at magnetic resonance (MR) neurography in ulnar neuropathy at the elbow (UNE).
This prospective study was approved by the institutional ...review board, and written informed consent was obtained from all participants. Twenty patients with UNE were graded by using clinical criteria and nerve conduction studies as mild (n = 12) and severe (n = 8) and were compared with 20 healthy control subjects. All subjects underwent ulnar nerve MR neurography (in-plane resolution of 0.4 × 0.4 mm) covering the elbow region, including T2-weighted imaging with fat suppression (turbo inversion-recovery magnitude sequence: repetition time msec/echo time msec/inversion time msec, 6, 120/66/180) and T1-weighted turbo spin-echo imaging (843/16). Nerve T2 signal increase, measured by using T2-weighted contrast-to-noise ratios across the cubital tunnel, and nerve caliber, determined by using T1-weighted pixelwise measurement of cross-sectional nerve area, were evaluated as diagnostic signs. Qualitative assessment by using visual grading was performed additionally.
Diagnostic performance, as determined with area under the receiver operating characteristic curve (AUC), was excellent for nerve T2 signal to discriminate UNE from a normal finding (AUC = 0.94; 95% confidence interval CI: 0.87, 1.00) and was excellent for nerve caliber to discriminate severe from mild UNE (AUC = 0.95; 95% CI: 0.85, 1.00). Qualitative assessment demonstrated sensitivity of 83% and specificity of 85% for MR neurography of UNE.
Nerve T2 signal increase seems to be an accurate sign to determine the presence of UNE. Nerve caliber enlargement discriminates severe from mild UNE. UNE may be diagnosed with high accuracy by means of quantitative or qualitative evaluation of these signs.
Objective
To detect and quantify peripheral nerve lesions in multiple sclerosis (MS) by magnetic resonance neurography (MRN).
Methods
Thirty‐six patients diagnosed with MS based on the 2010 McDonald ...criteria (34 with the relapsing–remitting form, 2 with clinically isolated syndrome) with and without disease‐modifying treatment were compared to 35 healthy age‐/sex‐matched volunteers. All patients underwent detailed neurological and electrophysiological examinations. Three Tesla MRN with large anatomical coverage of both legs and the lumbosacral plexus was performed by using 2‐dimensional (2D) fat‐saturated, T2‐weighted (T2w) and dual echo turbo spin echo sequences as well as a 3D T2‐weighted, fat‐saturated SPACE sequence. Besides qualitative visual nerve assessment, a T2w signal quantification was performed by calculation of proton spin density and T2 relaxation time. Nerve diameter was measured as a morphometric criterion.
Results
T2w hyperintense nerve lesions were detectable in all MS patients, with a mean lesion number at thigh level of 151.5 ± 5.7 versus 19.1 ± 2.4 in controls (p < 0.0001). Nerve proton spin density was higher in MS (tibial/peroneal: 371.8 ± 7.7/368.9 ± 8.2) versus controls (tibial/peroneal: 266.0 ± 11.0/276.8 ± 9.7, p < 0.0001). In contrast, T2 relaxation time was significantly higher in controls (tibial/peroneal: 82.0 ± 2.1/78.3 ± 1.7) versus MS (tibial/peroneal: 64.3 ± 1.0/61.2 ± 0.9, p < 0.0001). Proximal tibial and peroneal nerve caliber was higher in MS (tibial: 52.4 ± 2.1mm2, peroneal: 25.4 ± 1.3mm2) versus controls (tibial: 45.2 ± 1.4mm2, p < 0.0015; peroneal: 21.3 ± 0.7mm2, p = 0.0049).
Interpretation
Peripheral nerve lesions could be visualized and quantified in MS in vivo by high‐resolution MRN. Lesions are defined by an increase of proton spin density and a decrease of T2 relaxation time, indicating changes in the microstructural organization of the extracellular matrix in peripheral nerve tissue in MS. By showing involvement of the peripheral nervous system in MS, this proof‐of‐concept study may offer new insights into the pathophysiology and treatment of MS. Ann Neurol 2017;82:676–685
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