In vivo detection of nerve injury in familial amyloid polyneuropathy by magnetic resonance neurography

Abstract

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.

Keywords: MR imaging; MR neurography; amyloid polyneuropathy; hereditary amyloidosis; transthyretin familial amyloid polyneuropathy.

Figure 1

Cumulated nerve lesion count. Cumulated nerve–lesion voxel number from proximal-to-distal for the tibial fascicles within the sciatic nerve and their distal continuation as tibial nerve (left, slice positions 0 to 139), and for the peroneal fascicles within the sciatic nerve and their distal continuation as common peroneal nerve (right, slice positions 0 to 69). Mean frequencies of nerve–lesion voxels numbers were calculated and referenced to the control group which was set as baseline. Note the marked increase in the cumulated lesion voxel numbers in manifest TTR-FAP (TTR⁺-FAP⁺, squares). Lesion voxel number in asymptomatic gene carriers (TTR⁺-FAP⁻, circles) revealed also strong statistical differences compared to symptomatic TTR-FAP patients, as well as compared to the healthy volunteers.

Figure 2

Lesion localization. Proximal to distal mapping of lesion-voxels-numbers within the tibial nerve [slice positions 0 (= proximal thigh) to 139 (= tibiotalar joint)]. Mean frequencies of lesion voxel number within the tibial nerve were calculated and referenced to the control group which was set as baseline. Note the predominant and statistically significant proximal focus of nerve lesions at thigh level in both, the manifest TTR-FAP patients (TTR⁺-FAP⁺, squares) and the asymptomatic gene carriers (TTR⁺-FAP⁻, circles). Differences in the proximal lesion voxel number between manifest TTR-FAP and gene carriers were also highly significant.

Figure 3

Signal quantification. Quantification of mean proton spin density (ρ) and T₂ relaxation time (T_2app) at thigh level, the site of predominant lesion focus plotted for each group. Differences in ρ (left) were highly significant between all three groups: manifest TTR-FAP versus asymptomatic gene carriers (P = 0.002); manifest TTR-FAP versus controls (P < 0.0001); asymptomatic gene carriers versus controls (P = 0.004). Significant differences were also found in T_2app between manifest TTR-FAP and asymptomatic gene carriers (P = 0.003) and between manifest TTR-FAP and controls (P = 0.0011) but not between asymptomatic gene carriers and controls (P = 0.783), indicating that ρ has higher sensitivity in detecting early nerve injury, whereas T_2app may better differentiate between increasing severity of clinical nerve impairment. TTR⁺-FAP⁺ = manifest/symptomatic TTR-FAP; TTR⁺-FAP⁻ = asymptomatic gene carriers.

Figure 4

Magnetic resonance neurography source images. Representative source images (right leg; high-resolution T₂-weighted turbo spin echo fat-saturated sequences, 3 T) with overlaid coloured regions of interest indicating segmented tibial and peroneal fascicles within the sciatic nerve (at proximal thigh and distal thigh levels) and the distal continuation of tibial fascicles as tibial nerve (at proximal lower leg and distal lower leg levels). One healthy control, an asymptomatic gene carrier (TTR⁺-FAP⁻) and a manifest TTR-FAP patient (TTR⁺-FAP⁺) at equal slice positions are shown. Nerve lesions and nerve calibre increase are apparent already in the asymptomatic group but not in controls. Further increase in lesion contrast and calibre is observed in manifest TTR-FAP. Nerve-lesion contrast and nerve calibre show a clear proximal focus at thigh level in both TTR-FAP groups, indicating that nerve injury in distally-symmetric TTR-FAP starts and progresses at this proximal site of the peripheral nervous system. Tibial fascicles within the sciatic nerve and tibial nerve, respectively (encircled in red); peroneal fascicles within the sciatic nerve (encircled in blue).

Figure 5

Histopathology. Sural nerve biopsy of a male patient showing peri- and endoneural amyloid deposits with a homogeneous eosinophilic appearance in haematoxylin and eosin-stained sections (A). Congo red staining yields a pale red staining in bright light (B, left), apple green birefringence in polarized light (B, middle) and an orange fluorescence in fluorescence microscopy (B, right). Immunostaining with an antibody directed against transthyretin shows a strong and even immunoreaction of the amyloid deposits (C).