Nerve echogenicity in polyneuropathies of various etiologies

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 ($\it p$ < 0.001), the median nerve at the upper arm ($\it p$ < 0.004), and the ulnar nerve at the upper arm ($\it p$ < 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

High-resolution nerve ultrasound to assess nerve echogenicity, fascicular count, and cross-sectional area using semiautomated analysis

BACKGROUND AND PURPOSE Little is known about echogenicity and fascicular structure observed in high-resolution nerve ultrasound (HRUS) in both healthy subjects and patients with peripheral nerve disease. The aim of this study was to evaluate the reliability of echogenicity, fascicle count, and fascicle size analysis, to create standard values and compare these parameters to patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS Median, ulnar, radial, tibial, and fibular nerve of 79 healthy subjects and patients were scanned by one examiner using HRUS. Image analysis regarding echogenicity, fascicle count, and fascicle cross-sectional area (CSA) was performed by two independent raters semiautomatically using ImageJ. Pearson correlation coefficient $\it r$ reflected interrater reliability (IR), and intraclass correlation coefficient (ICC) determined intrarater reliability (IAR). Results of healthy subjects were compared to 20 patients with CIDP by analysis of variance. RESULTS IR was very good for echogenicity ($\it r$ = .9) and good for fascicle count and size of the largest fascicle ($\it r$ = .64/.56). IAR was very good for all three parameters (ICC = .9/.83/.74). Healthy subjects had a wide range of values. CIDP patients were in range of healthy subjects. Clinically progressive CIDP patients (defined as an increase in Overall Disability Sum Score by $\geq$1 point) had a lower fraction of black than healthy controls and stable CIDP patients ($\it P$ < .001). CONCLUSION Semiautomated evaluation of echogenicity, fascicle count, and fascicle CSA is reliable. Cutoff values to differentiate between healthy persons and CIDP do not exist. Echogenicity is useful for detecting clinically progressive CIDP patients and should be used in clinical context or intraindividual course

Pathological spontaneous activity as a prognostic marker in chronic inflammatory demyelinating polyneuropathy

$\textbf {Background and purpose}$ Monitoring of the disease course of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) remains challenging because nerve conduction studies do not adequately correlate with functional disability. The prognostic value of pathological spontaneous activity (PSA) in needle electromyography (EMG) in different CIDP subgroups in a longitudinal context has, to date, not been analysed. We aimed to determine whether PSA was a prognostic marker or a marker of disease activity in a cohort of patients with CIDP. $\bf Methods$ A total of 127 patients with CIDP spectrum disorder were retrospectively analysed over 57 $\pm$ 47 months regarding the occurrence of PSA (fibrillations and positive sharp waves). The presence of PSA at diagnosis, newly occurring PSA, and continuously present PSA were longitudinally correlated with clinical disability using the Inflammatory Neuropathy Cause and Treatment Overall Disability Sum Score (INCAT-ODSS) and CIDP subtype. $\bf Results$ Pathological spontaneous activity occurred in 49.6% of all CIDP patients at first diagnosis. More frequent evidence of PSA was significantly associated with a higher INCAT-ODSS at the last follow-up. Continuous and new occurrence of PSA were associated with higher degree of disability at the last follow-up. The majority of patients with sustained evidence of PSA were characterized by an atypical phenotype, higher degree of disability, and the need for escalation of treatment. $\bf Conclusions$ Pathological spontaneous activity was associated with a higher degree of disability and occurred more frequently in atypical CIDP variants according to the longitudinal data of a large cohort of patients with CIDP. Our results showed that EMG examination was an adequate marker for disease progression and should be evaluated during the disease course

Nerve ultrasound distinguishes non-inflammatory axonal polyneuropathy from inflammatory polyneuropathy with secondary axonal damage

$\bf Introduction:$ Chronic inflammatory demyelinating polyneuropathy (CIDP) may have a similar clinical and electrophysiological presentation to non-inflammatory axonal polyneuropathies (NIAPs) when secondary axonal damage occurs. We aimed to investigate if nerve ultrasound can help to differentiate CIDP with additional secondary axonal damage from NIAP. $\bf Methods:$ In a retrospective analysis, the cross-sectional area (CSA) of the peripheral nerves measured by ultrasound at six suitable nerve sites was compared in 95 patients with CIDP and 82 patients with NIAP. We developed the adjusted Bochum ultrasound score (aBUS) ranging from 0 to 6 resulting from the number of sites with enlarged CSA (median, ulnar, radial, and sural nerve). $\bf Results:$ The mean CSA of patients with CIDP was enlarged at all six nerve sites compared with the mean CSA of patients with NIAP. A total of 21 patients with CIDP did not meet 2010 electrophysiological diagnostic criteria (European Academy of Neurology/Peripheral Nerve Society Guideline, EFNS/PNS criteria) for CIDP at examination timepoint but only in further follow-up, while 25 patients with NIAP fulfilled electrophysiological EFNS/PNS criteria for CIDP as "possible" or "probable" CIDP. To increase diagnostic power, we included aBUS measured by ultrasound in patients classified as "possible" or "probable" resulting in an improved specificity of 94% and a sensitivity of 59%, compared to a specificity of the EFNS/PNS criteria alone of 60% and sensitivity of 78%. $\bf Conclusion:$ Using nerve ultrasound and the aBUS as a complementary method to distinguish CIDP from NIAP in case of secondary axonal damage can facilitate the diagnosis of CIDP

Serum neurofilament light chain as outcome marker for intensive care unit patients

$\bf Objective$ Neurofilament light chain (NfL) in serum indicates neuro-axonal damage in diseases of the central and peripheral nervous system. Reliable markers to enable early estimation of clinical outcome of intensive care unit (ICU) patients are lacking. The aim of this study was to investigate, whether serum NfL levels are a possible biomarker for prediction of outcome of ICU patients. $\bf Methods$ Thirty five patients were prospectively examined from admission to ICU until discharge from the hospital or death. NfL levels were measured longitudinally by a Simoa assay. $\bf Results$ NfL was elevated in all ICU patients and reached its maximum at day 35 of ICU treatment. Outcome determined by modified Rankin Scale at the end of the follow-up period correlated with NfL level at admission, especially in the group of patients with impairment of the central nervous system ($\it n$ = 25, $\it r$ = 0.56, $\it p$ = 0.02). $\bf Conclusion$ NfL could be used as a prognostic marker for outcome of ICU patients, especially in patients with impairment of the central nervous system

Novel variants in a patient with late-onset hyperprolinemia type II

$\bf Background$ 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. $\bf Case presentation$ 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 $\it ALDH4A1$ gene sequencing confirmed two previously unknown compound heterozygous variants ($\it ALDH4A1$ gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and $\it ALDH4A1$ gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B$_6$ therapy no further seizures occurred. $\bf Conclusion$ We describe two novel $\it ALDH4A1$-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

Corneal inflammatory cell infiltration predicts disease activity in chronic inflammatory demyelinating polyneuropathy

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

Induction of regulatory properties in the intestinal immune system by dimethyl fumarate in lewis rat experimental autoimmune neuritis

$\bf Objective:$ Dimethyl fumarate (DMF) exerts immunomodulatory and neuroprotective effects in the animal model of experimental autoimmune neuritis (EAN) in the Lewis rat. DMF has been shown to modulate gut microbiota in veterinary medicine, however the effects of oral DMF on the gut-associated lymphoid tissue (GALT) remain unknown. $\bf Methods:$ Lewis rats were treated orally twice daily with DMF up to day 10 after immunization with immunogenic P2 peptide. Histological, flow cytometric and RT-PCR analyses of the GALT (intraepithelial layer, lamina propria, and Peyer patches) in duodenum, jejunum, and ileum were performed $\textit {ex vivo}$. Moreover, cell transfer experiments were used to examine the protective effects of GALT regulatory T cells of the Peyer patches. $\bf Results:$ In the upper layers of duodenum, DMF induced a reduction of the toll-like receptor 4 (TLR4) mRNA expression. This was combined by a decrease of the pro-inflammatory lamina propria IFN-$\gamma$ mRNA expression. In the ileum, we detected an immunoregulatory phenotype characterized by an increase of FoxP3 mRNA expression and of the nuclear factor (erythroid-derived-2)- like 2 (Nrf2) downstream molecule heme oxygenase-1 (HO-1) mRNA. Finally, CD4$^{+}$ CD25$^{+}$ regulatory T cells were increased in the Peyer patches. (\textit {In vivo}\), the protective effect of these regulatory cells was verified by cell transfer into recipient EAN rats. $\bf Conclusions:$ Our results identified a novel immunomodulatory effect of DMF through the different regions and layers of the small intestine, which led to an increase of regulatory T cells, exerting a protective role in experimental neuritis

Vagal cross-sectional area correlates with parasympathetic dysfunction in Parkinson's disease

The aim of this prospective study was to investigate autonomic function in Parkinson’s disease with a multidimensional approach including clinical evaluation tools, head-up tilt test and morphological studies of the vagus nerve. Head-up tilt test parameters including high frequency power of the heart frequency interval, the ratio of low frequency power of the distance between two consecutive R waves in electrocardiogram (RR interval) to the high frequency and low frequency power of systolic blood pressure were used to evaluate parasympathetic, cardiac sympathetic and vasomotor sympathetic functions, respectively, in 80 patients with Parkinson's disease. We examined the cross-sectional area of the vagus nerves bilaterally using nerve ultrasound and compared mean values with a control group of healthy subjects ($\it n$ = 40) as well as patients with chronic inflammatory demyelinating polyneuropathy ($\it n$ = 76). The cross-sectional area of right/left vagus nerve of Parkinson's patients was significantly lower compared to the right/left vagus nerve of the control group and of chronic demyelinating polyneuropathy patients. Furthermore, the cross-sectional area of the right vagus nerve was significantly larger from the one of the left vagus nerve for all groups. Based on tilt test, 43 patients (disease duration 7 $\pm$ 5, age at evaluation 71 $\pm$ 9, Hoehn and Yahr score 2.8 $\pm$ 8) were diagnosed with autonomic dysfunction (orthostatic hypertension $\it n$ = 11, chronotropic incompetence $\it n$ = 31, postural orthostatic tachycardia syndrome $\it n$ = 1). Patients with orthostatic hypotension showed significantly higher Unified Parkinson’s Disease Rating Scale-III values than those with chronotropic incompetence. The cross-sectional area of the vagus nerve correlated inversely with heart rate in rest and supine position and positively with tilt test parameters representing parasympathetic modulation through vagal activity [high frequency power of the distance between two consecutive R waves in electrocardiogram (RR interval)] at rest. We demonstrate for the first time that morphological characteristics of the vagus nerve correlate with parameters of parasympathetic function from the spectral analysis of cardiovascular parameters in tilt test for Parkinson's patients. This correlation reveals the impact of the atrophy of vagal atrophy for autonomic function in Parkinson's disease. Nerve ultrasound of the vagus nerve could potentially be used as an adjunct to tilt table examination to diagnose autonomic dysfunction

Association of the neonatal Fc receptor promoter variable number of tandem repeat polymorphism with immunoglobulin response in patients with chronic inflammatory demyelinating polyneuropathy

$\textbf {Background and purpose:}$ Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease with humoral and cellular autoimmunity causing demyelination of peripheral nerves, commonly treated with intravenous immunoglobulins (IVIg). The neonatal Fc receptor (FcRn), encoded by the $\it FCGRT$ gene, prevents the degradation of immunoglobulin G (IgG) by recycling circulating IgG. A variable number of tandem repeat (VNTR) polymorphism in the promoter region of the $\it FCGRT$ gene is associated with different expression levels of mRNA and protein. Thus, patients with genotypes associated with relatively low FcRn expression may show a poorer treatment response to IVIg due to increased IVIg degradation. $\bf Methods:$ VNTR genotypes were analyzed in 144 patients with CIDP. Patients' clinical data, including neurological scores and treatment data, were collected as part of the Immune-Mediated Neuropathies Biobank registry. $\bf Results:$ Most patients ($\it n$ = 124, 86%) were VNTR 3/3 homozygotes, and 20 patients (14%) were VNTR 2/3 heterozygotes. Both VNTR 3/3 and VNTR 2/3 genotype groups showed no difference in clinical disability and immunoglobulin dosage. However, patients with a VNTR 2 allele were more likely to receive subcutaneous immunoglobulins (SCIg) than patients homozygous for the VNTR 3 allele (25% vs. 9.7%, $\it p$ = 0.02) and were more likely to receive second-line therapy (75% vs. 54%, $\it p$ = 0.05). $\bf Conclusions:$ The VNTR 2/3 genotype is associated with the administration of SCIg, possibly reflecting a greater benefit from SCIg due to more constant immunoglobulin levels without lower IVIg levels between the treatment circles. Also, the greater need for second-line treatment in VNTR 2/3 patients could be an indirect sign of a lower response to immunoglobulins