Plexus injury results in lifelong suffering from flaccid paralysis, sensory loss, and intractable pain. For this clinical problem, regenerative medicine concepts set high expectations. However, it is largely unknown how dorsal root ganglia (DRG) are affected by accidental deafferentation. Here, we phenotyped DRG of a clinically and MRI-characterised cohort of 13 patients with plexus injury. Avulsed DRG were collected during reconstructive nerve surgery. For control, we used DRG from forensic autopsy. The cellular composition of the DRG was analysed in histopathological slices with multicolour high-resolution immunohistochemistry, tile microscopy, and deep-learning-based bioimage analysis. We then sequenced the bulk RNA of corresponding DRG slices. In about half of the patients we found loss of the typical DRG units consisting of neurones and satellite glial cells. The DRG cells were replaced by mesodermal/connective tissue. In the remaining patients, the cellular units were well preserved. Preoperative plexus MRI neurography was not able to distinguish the two types. Patients with 'neuronal preservation' had less maximum pain than patients with 'neuronal loss'. Arm function improved after nerve reconstruction, but severe pain persisted. Transcriptome analysis of preserved DRGs revealed expression of subtype-specific sensory neurone marker genes, but downregulation of neuronal attributes. Furthermore, they showed signs of ongoing inflammation and connective tissue remodelling. Patients with plexus injury separate into two groups with either neuronal preservation or neuronal loss. The former could benefit from anti-inflammatory therapy. For the latter, studies should explore mechanisms of neuronal loss especially for regenerative approaches. DRKS00017266.

Fabry disease is a rare monogenetic, X-linked lysosomal storage disorder with neuropathic pain as one characteristic symptom. Impairment of the enzyme alpha-galactosidase A leads to an accumulation of globotriaosylceramide in the dorsal root ganglia. Here, we investigate novel dorsal root ganglia MR imaging biomarkers and their association with Fabry genotype and pain phenotype. In this prospective study, 89 Fabry patients were examined using a standardized 3 T MRI protocol of the dorsal root ganglia. Fabry pain was assessed through a validated Fabry pain questionnaire. The genotype was determined by diagnostic sequencing of the alpha-galactosidase A gene. MR imaging end-points were dorsal root ganglia volume by voxel-wise morphometric analysis and dorsal root ganglia T2 signal. Reference groups included 55 healthy subjects and Fabry patients of different genotype categories without Fabry pain. In patients with Fabry pain, T2 signal of the dorsal root ganglia was increased by +39.2% compared to healthy controls (P = 0.001) and by +29.4% compared to painless Fabry disease (P = 0.017). This effect was pronounced in hemizygous males (+40.7% compared to healthy; P = 0.008 and +29.1% compared to painless; P = 0.032) and was consistently observed across the genotype spectrum of nonsense (+38.1% compared to healthy, P < 0.001) and missense mutations (+39.2% compared to healthy; P = 0.009). T2 signal of dorsal root ganglia and globotriaosylsphingosine levels were the only independent predictors of Fabry pain (P = 0.047; P = 0.002). Volume of dorsal root ganglia was enlarged by +46.0% in Fabry males in the nonsense compared to missense genotype category (P = 0.005) and by +34.5% compared to healthy controls (P = 0.034). In painful Fabry disease, MRI T2 signal of dorsal root ganglia is increased across different genotypes. Dorsal root ganglion MRI T2 signal as a novel in vivo imaging biomarker may help to better understand whether Fabry pain is modulated or even caused by dorsal root ganglion pathology.

Aims: To estimate the long term cost effectiveness of treatment for amblyopia in 3 year old children. Methods: A cost utility analysis was performed using decision analysis including a Markov state transition model. Incremental costs and effects during the children’s remaining lifetime were estimated. The model took into account the costs and success rate of treatment as well as effects of unilateral and bilateral visual impairment caused by amblyopia and other eye diseases coming along later in life on quality of life (utility). Model parameter values were obtained from the literature, and from a survey of experts. For the utility of unilateral visual impairment a base value of 0.96 was assumed. Costs were estimated from a third party payer perspective for the year 2002 in Germany. Costs and effects were discounted at 3%. Uncertainty was assessed by univariate and probabilistic sensitivity analysis (Monte-Carlo simulation). Results: The incremental cost effectiveness ratio (ICER) of treatment was €2369 per quality adjusted life year (QALY). In univariate sensitivity analysis the ICER was most sensitive to uncertainty concerning the utility of unilateral visual impairment—for example, if this utility was 0.99, the ICER would be €9148/QALY. Monte-Carlo simulation yielded a 95% uncertainty interval for the ICER of €710/QALY to €38 696/QALY; the probability of an ICER smaller than €20 000/QALY was 95%. Conclusion: Treatment for amblyopia is likely to be very cost effective. Much of the uncertainty in results comes from the uncertainty regarding the effect of amblyopia on quality of life. In order to reduce this uncertainty the impact of amblyopia on utility should be investigated.

The dorsal root ganglion (DRG) contains all primary sensory neurons, but its functional role in somatosensory and pain processing remains unclear. Recently, MR imaging techniques have been developed for objective in vivo observation of the DRG. In particular, DRG MR imaging endpoints such as DRG volume and DRG T2w signal are emerging as biomarkers with initial evidence of meaningful correlations with biochemical and genetic parameters as well as neuropathic pain as clinically relevant applications. However, the future validation and use of these novel imaging biomarkers critically depends on the development of fully automated methods for DRG image analysis. To date, DRG detection and evaluation on MR images has been limited to expert annotation through manual segmentation. Fast and operator-independent, yet accurate and robust, segmentation methods are required to enable observation of larger patient cohorts and across multiple sites. Thus, fully automated DRG segmentation is a prerequisite for the analysis of more complex microstructural and functional image datasets, such as from DRG diffusion tensor or perfusion metabolic imaging. Here, we developed a fully automated DRG segmentation workflow based on deep learning. A convolutional neural network (CNN) was trained using the nnU-Net framework on a large dataset of high-resolution 3D T2-weighted MR images of healthy controls (220 DRGs). Automated DRG segmentations generated with this network were on par with expert annotations (dice similarity coefficient of 0.87 for human expert vs. 0.89 for trained CNN) while being faster by a factor of 10. Finally, we validated the method in Fabry disease as a genetic model disorder for DRG pathomorphological injury. The trained CNN was able to reproduce the manually segmented changes known in FD patients as a function of FD genotype and FD pain phenotype. We developed a fully automated method for DRG MRI segmentation and validated its application as a novel imaging biomarker using the DRG injury example of Fabry disease.

Background/Objectives: Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterised by progressive glycolipid accumulation affecting multiple organs, including the peripheral nervous system. The dorsal root ganglia (DRG) play a key role in Fabry-related neuropathy, but non-invasive biomarkers of DRG involvement and their association with overall disease severity remain limited. This study evaluated lumbosacral DRG T2 relaxation time (DRG-T2) in FD patients as a potential imaging biomarker of FD severity. Methods: In a prospective, single-centre study, 80 genetically confirmed FD patients underwent 3T MRI with quantitative T2 mapping of the lumbosacral DRG. DRG-T2 was analysed in relation to sex, genetic subtype and Fabry-specific biomarkers. Results: Results showed that DRG-T2 was higher in patients with classical FD mutations than in those with nonclassical mutations (p = 0.03). Furthermore, DRG-T2 showed a negative correlation with body weight (ρ = −0.31, p = 0.005) and BMI (ρ = −0.32, p = 0.004), while no associations were found with lyso-Gb3 levels or alpha-galactosidase A activity. The inter-rater and test–retest reliability of DRG-T2 were good to excellent (ICC = 0.76 and 0.89, respectively). Conclusions: These results demonstrate DRG-T2 as a marker of neuronal involvement, making it a strong and reliable imaging biomarker of disease severity in FD. However, future studies need to correlate its changes with clinical and histological studies.

Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterised by skin and nervous system anomalies, primarily involving glial cells and nerve tumours. Pain, particularly chronic pain, is a significant but often overlooked symptom in NF1 patients, affecting their health-related quality of life. The dorsal root ganglion (DRG) is essential for pain signal transmission, yet in vivo studies of DRG in NF1 patients are lacking. Methods: This prospective study included 20 NF1 patients (8 with neuropathic pain) and 28 healthy controls. Magnetic resonance imaging (MRI) scans of lumbosacral DRG (L5 + S1) were performed using a 3-T scanner. Quantitative MRI techniques were applied to assess DRG volume, T2 relaxation time, and proton density (PD). Statistical analyses compared NF1 patients and controls, and NF1 patients with and without pain. Results: NF1 patients had a significantly larger DRG volume and higher quantitative T2 and PD values compared to controls. Furthermore, DRG PD was significantly higher in NF1 patients with neuropathic pain than in those without pain. Receiver operator characteristic curve analysis identified DRG PD as the best discriminator of pain in NF1 patients, with an area under the curve of 0.84, indicating relevant and useful discriminatory power. Conclusion: NF1 patients showed objective macrostructural and microstructural DRG injury changes using dedicated DRG MRI, discriminating neuropathic pain status from non-pain status at the disease-symptom group level. These findings highlight the potential of DRG MRI to quantify DRG pathology in vivo and to determine the risk of functional pain status by imaging. Relevance statement: The identification of structural and microstructural changes of the DRG by quantitative MRI provides a novel in vivo biomarker for understanding neuropathic pain mechanisms, pain risk assessment and treatment monitoring in NF1. Key Points: Dorsal root ganglia (DRG) in NF1 are enlarged by 176.3% in MRI. In quantitative MRI of DRG NF1, T2 relaxation time is increased by 22.9% and PD by 8.4%. DRG PD can distinguish a painful from a non-painful NF1 phenotype. Graphical