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Background: Vagal atrophy is a hallmark of Parkinson’s disease (PD) and has been found to be associated with autonomic dysfunction, while analyses of the vagus nerve (VN) in atypical Parkinsonian syndromes (APS) have not yet been performed. We here investigate the characteristics of the VN in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and, in a second step, its potential as a possible biomarker for orthostatic dysregulation. Objectives: The aim was to compare the VN pathology in MSA and PSP with healthy individuals and patients with PD as a differentiating factor and to further analyse the correlation of the VN with clinical parameters and cardiovascular response. Design: We conducted a monocentric, cross-sectional cohort study in 41 APS patients and compared nerve ultrasound (NUS) parameters with 90 PD patients and 39 healthy controls. Methods: In addition to a detailed neurological history and examination, several clinical severity and motor scores were obtained. Autonomic symptoms were reported in the Scales for Outcomes in Parkinson’s Disease – Autonomic questionnaire. Further scores were used to detect other non-motor symptoms, quality of life and cognition. Additionally, we performed a head up tilt test (HUTT) and NUS of the VN. We conducted correlation analyses of the VN cross-sectional area (CSA) with clinical scores and the heart rate and blood pressure variability parameters of the HUTT. Results: The examination demonstrated a high prevalence of abnormal autonomic response in both MSA (90%) and PSP (80%). The VN CSA correlated with spectral parameters of the HUTT, which are associated with sympatho-vagal imbalance. In addition, the CSA of the VN in patients with PD and PSP were significantly smaller than in healthy controls. In MSA, however, there was no marked vagal atrophy in comparison. Conclusion: The occurrence of autonomic dysfunction was high in MSA and PSP, which underlines its impact on these syndromes. Our findings indicate a connection between vagal pathology and autonomic dysfunction and might contribute to a better comprehension of APS. To further evaluate the clinical relevance and the VN as a possible marker of autonomic dysfunction in APS, prospective longitudinal observations are necessary.

ObjectiveHRUS is increasingly being used in the diagnosis and evaluation of autoimmune neuropathies such as CIDP. Recently, studies focused not only on changes of nerves size, but also the fascicular structure and the echogenicity changes in CIDP. However, little is known about the alterations of echogenicity in the long-term course in CIDP. The aim of this study was to evaluate echogenicity in CIDP patients in a long-term follow-up period and to analyze the benefit of the evaluation of echogenicity compared to nerve size.Methods20 patients fulfilling the definite diagnostic criteria of CIDP received clinical examination, nerve conduction studies and HRUS every 6 months over a median follow-up time of 34 months. Patients were divided into clinically stable/regressive disease course or progressive disease course according to the development of the inflammatory neuropathy cause and treatment overall disability sum score. Echogenicity of peripheral nerves was measured semi-automated and quantitative. Echogenicity was divided into three classes by fraction of black: hypoechogenic, mixed hypo-/hyperechogenic, hyperechogenic.ResultsPatients with hyperechogenic arm nerves more frequently show clinical worsening, whereas patients with hypoechogenic arm nerves remain stable or even improved over time. In the long-term course of the disease, echogenicity mostly did not change, and if changes occured echogenicity did not correspond to ODSS changes.ConclusionEchogenicity of the arm nerves in CIDP may be used as a prognostic marker, but not as a follow-up tool for evaluating clinical changes. Further studies in a larger cohort are needed to confirm these results.

Sleep related breathing disorders (SRBD) are common in patients with ischemic stroke and are associated with poor outcome. SRBD after stroke were assumed to be a direct consequence of injury of specific central nervous system structures. However, whether specific locations of ischemic infarcts cause SRBD is yet unknown. We therefore investigated the association of ischemic lesion location with SRBD. Patients with acute ischemic stroke treated on our stroke unit were included in a prospective observational study. All patients underwent magnetic resonance imaging (MRI) and polygraphy in the acute phase after stroke. SRBD was defined by an apnea-hypopnea index (AHI) ≥10. MRI were evaluated using standardized maps to depict voxel-wise probability distribution of infarction for patients with and without SRBD. Groups were compared using logistic regression analysis. Of 142 patients included, 86 (59%) had a SRBD. Age, body mass index and prevalence of arterial hypertension were significantly higher in patients with SRBD. There was no statistically significant association between any lesion location and SRBD. We found no association of lesion location and SRBD in stroke patients, whereas established risk factors for SRBD, known from general population, were significantly associated with SRBD. Given the high prevalence of SRBD in stroke patients, these findings suggest that cerebral ischemia facilitates the occurrence of SRBD in patients with pre-existing risk factors rather than causing it by damaging specific central nervous system structures. Our findings can be used to identify stroke patients who might benefit from polygraphy screening.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common chronic inflammatory neuropathy. CIDP is diagnosed according to the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria, which combine clinical features with the electrophysiological evidence of demyelination. However, firstly, diagnosis is challenging, as some patients e.g. with severe early axonal damage do not fulfil the criteria. Secondly, objective and reliable tools to monitor the disease course are lacking. Thirdly, about 25% of CIDP patients do not respond to evidence-based first-line therapy. Recognition of these patients is difficult and treatment beyond first-line therapy is based on observational studies and case series only. Individualized immunomodulatory treatment does not exist due to the lack of understanding of essential aspects of the underlying pathophysiology. Novel diagnostic imaging techniques and molecular approaches can help to solve these problems but do not find enough implementation. This review gives a comprehensive overview of novel diagnostic techniques and monitoring approaches for CIDP and how these can lead to individualized treatment and better understanding of pathophysiology.

The assessment of disease activity is fundamental in the management of chronic inflammatory demyelinating polyneuropathy (CIDP). Previous studies with small patient numbers found an increase of corneal immune cell infiltrates as a potential marker of inflammation in patients with CIDP. However, its clinical relevance remained unclear. The present study aimed to determine whether the amount of corneal inflammatory cells (CIC) measured by corneal confocal microscopy (CCM) detects disease activity in CIDP. CIC were measured in 142 CCM-investigations of 97 CIDP-patients. Data on clinical disease activity, disability (INCAT-ODSS) and need for therapy escalation at the timepoint of CCM, 3 and 6 months later were analyzed depending CIC-count. Pathological spontaneous activity during electromyography was examined as another possible biomarker for disease activity in comparison to CIC-count. An increased CIC-count at baseline was found in patients with clinical disease activity and disability progression in the following 3–6 months. An increase to more than 25 CIC/mm 2 had a sensitivity of 0.73 and a specificity of 0.71 to detect clinical disease activity and a sensitivity of 0.77 and a specificity of 0.64 to detect disability progression (increasing INCAT-ODSS) in the following 6 months. An increase to more than 50 CIC/mm 2 had a sensitivity of about 0.51 and a specificity of 0.91 to detect clinical disease activity and a sensitivity of 0.53 and a specificity of 0.80 to detect disability progression. CIC count is a non-invasive biomarker for the detection of disease activity in the following 6 months in CIDP.

Short-chain fatty acids (SCFAs), including propionic acid (PA), are key in immunological research. Supplementing PA has shown benefits for autoimmune diseases. A comprehensive understanding of the PA pharmacokinetics is essential for the optimal design and execution of studies utilizing orally administered PA. We propose two methods of measuring PA in serum, carried out by different laboratories. Blood samples from 20 volunteers were collected hourly following PA supplementation. Serum propionate quantification was performed with two independent mass spectrometry-based (MS) analyses, including liquid-chromatography (LC)-MS and direct-infusion (DI)-MS. PA levels increased within 1 h of ingestion of 500 mg PA. Serum concentrations ranged from 1.3 to 4.5 µmol/L, rising significantly after 1 h (  < 0.05). Serum levels returned to baseline within 2 h. No significant differences were found regarding sex or diet. The shown pharmacokinetics can be used in future PA research.

The novel criteria for the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) have established imaging with nerve ultrasound (NUS) and magnetic resonance neurography (MRN) as complementary methods for CIDP diagnosis. Our goal was to investigate the role of MRN and NUS for CIDP monitoring. We longitudinally examined 12 CIDP patients from 2016 to 2022 using NUS, MRN, nerve conduction studies (NCS), and clinical parameters (inflammatory neuropathy cause and treatment (INCAT)/overall disability sum score (ODSS)). NUS evaluated the cross-sectional area (CSA) of the median, ulnar, radial, tibial, fibular, and sural nerve as well as the intranerve CSA variability (INV ) of the tibial, fibular, ulnar, and median nerve, whereas MRN evaluated T2-weighted sequences of the fibular and tibial nerve at the popliteal fossa. Five patients showed clinical improvement/stability with corresponding improved or stable NCS/NUS parameters (number of nerves with increased CSA and INV ). Seven deteriorating patients showed deteriorating NCS and either increasing or decreasing NUS markers possibly indicating inflammatory activity or degenerative CSA reduction. The difference ΔINCAT/ODSS correlated positively with NUS ΔINV (  = 0.007,  = 0.731,  = 12) and with NUS ΔCSA of the tibial nerve (  = 0.0005,  = 0.865,  = 12). Further, NUS-CSA of the tibial nerve in the popliteal fossa in 2016 correlated inversely with the difference of the INCAT/ODSS score (ΔINCAT/ODSS ;  = -0.653;  = 0.033;  = 11). Finally, the Bland-Altman analyses for the tibial and fibular nerve showed a bias of -1.903 and 2.195 mm (bias = NUS-CSA - MRN-CSA) accordingly revealing a difference between MRN and NUS measurements for deeper nerves. CSA and INV of the tibial and fibular nerve can be used for monitoring in CIDP, and increased CSA of the tibial nerve is a good prognostic marker. MRN is more reliable for evaluating inflammation in proximal leg nerve segments.

Echogenicity of peripheral nerves in high-resolution ultrasound (HRUS) provides insight into the structural damage of peripheral nerves in various polyneuropathies. The aim of this study was to compare nerve echogenicity in different primarily axonal or demyelinating polyneuropathies to examine the significance of this parameter. Performing semi-automated echogenicity analysis and applying Image J, we retrospectively used HRUS images of 19 patients with critical illness polyneuropathy (CIP), and 27 patients with chemotherapy-induced polyneuropathy (CIN) and compared them to 20 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The fraction of black representing echogenicity was measured after converting the images into black and white. The nerves of patients with progressive CIDP significantly differed from the hyperechogenic nerves of patients with other polyneuropathies at the following sites: the median nerve at the forearm (p < 0.001), the median nerve at the upper arm (p < 0.004), and the ulnar nerve at the upper arm (p < 0.001). The other polyneuropathies showed no notable differences. Altogether, the comparison of echogenicity between different polyneuropathies supports the assumption that there are differences depending on the genesis of the structural nerve damage. However, these differences are slight, and cannot be used to show clear differences between each polyneuropathy form.

Background Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood. Case presentation The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55–2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12–2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B 6 serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The ALDH4A1 gene sequencing confirmed two previously unknown compound heterozygous variants ( ALDH4A1 gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and ALDH4A1 gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B 6 therapy no further seizures occurred. Conclusion We describe two novel ALDH4A1 -variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation.

Objective To evaluate magnetic resonance neurography (MRN) for the longitudinal assessment of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods Prospective examination of twelve CIDP patients by neurological assessment, MRN, and nerve conduction studies in 2016 and 6 years later in 2022. Imaging parameters were compared with matched healthy controls and correlated with clinical and electrophysiological markers. The MRN protocol included T2‐weighted imaging, diffusion tensor imaging (DTI), T2 relaxometry, and magnetization transfer imaging (MTI). Results Nerve cross‐sectional area (CSA) was increased in CIDP patients compared to controls (plexus: p = 0.003; sciatic nerve: p < 0.001). Over 6 years, nerve CSA decreased in CIDP patients, most pronounced at the lumbosacral plexus (p = 0.015). Longitudinally, changes in CSA correlated with changes in the inflammatory neuropathy cause and treatment validated overall disability sum score (INCAT/ODSS) (p = 0.006). High initial nerve CSA was inversely correlated with changes in the INCAT/ODSS over 6 years (p < 0.05). The DTI parameter fractional anisotropy (FA) showed robust correlations with electrodiagnostic testing both cross‐sectionally and longitudinally (p < 0.05). MTI as a newly added imaging technique revealed a significantly reduced magnetization transfer ratio (MTR) in CIDP patients (p < 0.01), suggesting underlying changes in macromolecular tissue composition, and correlated significantly with electrophysiological parameters of demyelination (p < 0.05). Interpretation This study provides evidence that changes in nerve CSA and FA reflect the clinical and electrophysiological course of CIDP patients. Initial nerve hypertrophy might predict a rather benign course or better therapy response.