Neurofilament light chain as a marker of peripheral nerve damage in vasculitic neuropathy? A cross-compartmental correlation analysis in patients undergoing nerve biopsy.

Determinants of disease activity and prognosis are limited in anti-NMDA receptor (NMDAR) encephalitis. Neurofilament light chains (NfL) are markers of axonal damage and have been identified as valuable biomarkers for neurodegenerative and other neuroinflammatory disorders. We aimed to investigate serum NfL levels in patients with anti-NMDAR encephalitis as a biomarker for disease severity and outcome. In this retrospective study, NfL values were measured in all available pretreatment serum and paired CSF samples of the nationwide anti-NMDAR encephalitis cohort. The values were analyzed in duplicate using single-molecule array and compared with measurements in healthy references. Follow-up sera were tested to analyze longitudinal responsiveness, if at least available from 2 time points after diagnosis. Serum NfL levels were compared with data on disease activity (seizures, MRI, and CSF findings), severity (modified Rankin Scale [mRS] score, admission days, and intensive care unit admission), and outcome (mRS score and relapses), using regression analysis. We have included 71 patients (75% female; mean age 31.4 years, range 0-85 years) of whom pretreatment serum samples were analyzed. Paired CSF samples were available of 33 patients, follow-up serum samples of 20 patients. Serum NfL levels at diagnosis were higher in patients (mean 19.5 pg/mL, 95% CI 13.7-27.7) than in references (mean 6.4 pg/mL, 95% CI 5.8-7.2, p < 0.0001). We observed a good correlation between serum and CSF NfL values (R = 0.84, p < 0.0001). Serum NfL levels and age correlated in patients (Pearson R = 0.57, p < 0.0001) and references (R = 0.62, p < 0.0001). Increased NfL values were detected in patients post-herpes simplex virus 1 encephalitis (mean 248.8 vs 14.1 pg/mL, p < 0.0001) and in patients with brain MRI lesions (mean 27.3 vs 11.1 pg/mL, p = 0.019). NfL levels did relate to the long-term follow-up (mRS score at 12 months; βNfL = 0.55, p = 0.013), although largely explained by the effect of age on NfL levels and prognosis. In serial samples, NfL values did roughly follow clinical disease activity, albeit with delay. Increased serum NfL levels reflect neuroaxonal damage in anti-NMDAR encephalitis. No relationship was identified with disease severity, whereas the association with outcome was confounded by age. The implied role of sampling timing on NfL levels also limits the applicability of NfL as a prognostic marker.

A study correlating nerve biopsy with clinical diagnosis and its impact on improving management in peripheral neuropathies

Objective:Vasculitic neuropathy can be either restricted to the peripheral nerves or associated with systemic involvement of other organs. The objective of this study was to analyze the nerve biopsies reported as “vasculitic neuropathy” with clinical features.Materials and Methods:All cases diagnosed with vasculitic neuropathy were retrospectively analyzed and categorized as systemic vasculitis and nonsystemic vasculitic neuropathy based on the clinical features. The histological features were further evaluated and classified according to the Peripheral Nerve Society Guidelines.Results:Of the 126 cases, there were 65 nonsystemic vasculitis, 45 secondary systemic vasculitis, and 16 primary systemic vasculitis. Definite vasculitis was more common in the systemic vasculitis group. The epineurial vessels were predominantly involved with chronic axonal changes.Conclusion:The sensitivity of definite vasculitis on nerve biopsy was 54.76%. The sensitivity increases when the diagnostic criteria of definite and probable vasculitis were applied taking into account perivascular inflammation accompanied by vascular changes and axonopathy.

Serum neurofilament light chain: a biomarker of neuronal injury in vasculitic neuropathy

Serum Fatty Acid Profiles and Neurofilament Light Chain Levels in the General Population

Sirs, Pure sensory vasculitic neuropathy has been described but is rare [2, 3]. Randomised controlled trial data is lacking, however treatment with various immunosuppressants has been suggested [1]. Postpartum relapses of sensory vasculitic neuropathy have not been described. We report a case of postpartum relapsing vasculitic sensory neuropathy exquisitely responsive to intravenous immunoglobulin (ivIg) with a benign course despite severe endstage features on nerve biopsy. A 27-year-old woman developed a rapidly progressive burning sensation in both feet during the seventh month of her second pregnancy. Two days following delivery of a healthy baby, she was unable to walk and required opiate analgesics for pain control. Examination revealed diminished pinprick and vibration in both feet as well as absent ankle reflexes, however wasting and weakness were not present. Nerve conduction studies (NCS) confirmed a distal sensory neuropathy. Investigations for systemic vasculitis were negative. The patient was given ivIg 0.4 g/kg/day for 5 days on six occasions 6 weeks apart. Her painful sensory symptoms started to improve and she was able to walk by the end of the first week of treatment. By the end of the second cycle of ivIg she was able to discontinue opiates. Subsequently there was gradual improvement in her symptoms, with complete resolution of symptoms by the end of the fourth cycle of ivIg. The patient remained well for 3 years but shortly after the birth of her third child the painful sensory symptoms recurred. Again, the patient’s symptoms responded well to six cycles of ivIg at a dose of 0.4 g/kg/day for 5 days at 6-weekly intervals, with a similar pattern of response as on the first occasion. Examination findings remain unchanged, without evidence of wasting or weakness. Sural nerve biopsy showed perivascular lymphocytic infiltration around in the epineurium with transmural migration of lymphocytes and partial obstruction of vessel walls (Fig. 1a, b). There was almost complete loss of myelinated fibres (Fig. 1c). The appearances were consistent with a severe end-stage vasculitic neuropathy. NCS were repeated 4 years after initial presentation and did not show any significant deterioration compared with the initial studies (Table 1). Distal, symmetric sensory neuropathy secondary to nonsystemic vasculitis [2] is rare but may show a benign course [3]. Randomised controlled trials of therapy in nonsystemic vasculitic neuropathy have not been carried out [3], but anecdotal case series suggest treatment with immunosuppressive therapies such as cyclophosphamide, azathioprine and steroids [1]. Postpartum relapsing vasculitic sensory neuropathy has not been described to our knowledge, although postpartum relapses have been described in systemic vasculitides [4]. This patient demonstrated a dramatic response to ivIg, with prolonged periods of remission after each course of treatment and has not accumulated any functional disability despite the severity of the nerve biopsy findings. She has elected not to have further children due to the perceived risk of relapse. S. M. Murphy (&) M. J. Hennessy Department of Neurology, Galway University Hospital, Newcastle Road, Galway, Ireland e-mail: smurph1@hotmail.com

To elucidate the cause and mechanisms of nerve fiber lesions in a case of mononeuropathy multiplex (MNM). A 65-year-old man had a MNM for 6 months and no previous history of peripheral nerve impairment was known. He underwent a muscle and nerve biopsy by the same skin incision on the right leg. Paraffin-embedded fragments from the superficial peroneal nerve and peroneous brevis muscle disclosed characteristic lesions of necrotizing vasculitis. Complement had low levels, but a search for cryoglobulinemia was negative. Two months later a purpura appeared in the lower limbs and a mixed Type II cryoglobulinemia was disclosed, whereas a search for hepatitis C virus (HCV) remained negative. Five months later the blood contained 8,600 lymphocytes/mm3 and a low grade B cell lymphoma was disclosed in the bone marrow. Although not having HCV infection, our patient had mixed Type II cryoglobulinemia, necrotizing vasculitis and B cell lymphoma. Each of these three abnormalities might be in part responsible for nerve fibers impairment, with acute axonal degeneration. Mixed cryoglobulinemia must be searched carefully in patients with vasculitic neuropathy.

Vasculitic peripheral neuropathy (VPN) is caused by vessel inflammation leading to peripheral nerve injury of acute-to-subacute onset. When VPN occurs in the context of systemic disease it is classified as Systemic Vasculitic Neuropathy (SVN) and as Non-Systemic Vasculitic Neuropathy (NSVN) when restricted to the nerves. This study aimed to compare the clinical characteristics, biopsy findings and disease outcome in patients with VPN. Clinical records of adult patients with VPN diagnosed at our institution between June-2002 and June-2019 were retrospectively reviewed. Demographic characteristics, clinical manifestations, nerve conduction studies, nerve biopsies, treatment and clinical evolution were analyzed in all patients with at least 6 months follow-up. Twenty-five patients with VPN were included (SVN, n = 10; NSVN, n = 15). No significant differences in demographic or clinical features were found between groups. The median delay between symptom onset and nerve biopsy was significantly longer in NSVN patients (10 vs 5.5 months, p = 0.009). Erythrocyte sedimentation rate (ESR) values over 20 mm/h were significantly more common in SVN patients (100% vs. 60%, p = 0.024). Nerve biopsies showed active lesions more frequently in treatment-naive patients compared to those who had received at least 2 weeks of corticosteroids (92% vs 38%; p = 0.03), with a higher proportion of definite VPN cases (92 vs 46%; p = 0.04). Although the clinical manifestations are similar, ESR is an important tool to help distinguish between both conditions. Early nerve biopsy in untreated patients increases diagnostic accuracy, avoiding misdiagnosis.

12. Clinical and neurophysiological predictors of vasculitic neuropathy diagnosed on nerve biopsy

Neurofilament light chain (NFL) levels reflect axonal damage in different inflammatory and neurodegenerative central nervous system conditions, in correlation with disease severity. Our aim was to determine the possible diagnostic and prognostic value of serum and cerebrospinal fluid (CSF) NFL levels in subjects with different forms of acquired peripheral neuropathies (PN). Paired serum and CSF samples of 25 patients with acquired PN were analysed for NFL using an ultrasensitive technique (Quanterix, Simoa, Lexington, MA, USA) and compared with a group of 25 age-matched healthy subjects. Demographic, clinical, CSF and neurophysiological data were reviewed. Cases with Guillain-Barré syndrome (N = 5), multifocal motor neuropathy (N = 3), chronic inflammatory demyelinating polyneuropathy (CIDP) and variants (N = 12), anti-myelin-associated glycoprotein (MAG) neuropathy (N = 3), both CIDP and anti-MAG neuropathy (N = 1), and non-systemic vasculitic neuropathy (N = 1) were studied. NFL levels were significantly (P < 0.001) increased in patients with PN and were higher in the CSF (median: 1407 pg/mL, range: 140.2-12 661) than in serum (median: 31.52 pg/mL, range: 4.33-1178). A statistically significant correlation was observed between serum and CSF levels in cases with blood-nerve-barrier damage (r = 0.71, P < 0.01), and between serum NFL levels and disease activity at sampling (r = 0.52, P < 0.01) and at last follow-up (r = 0.53, P < 0.01) in all subjects. The increase of NFL values in both serum and CSF of patients with acquired PN and the significant correlation between serum NFL levels, disease severity and final outcome support the possible role of NFL as disease activity and prognostic biomarker also in peripheral nervous system disorders.

A study on structural imaging changes and serum neurofilament light chain (NfL) levels in individuals with white matter hyperintensities, combining imaging techniques with biomarker analysis.

vasculitic neuropathy can be confirmed by demonstrating vasculitis in a nerve biopsy, but it is uncertain to what extent combined (i.e. nerve/muscle) biopsy improves the yield. a random-effects meta-analysis was performed to assess the additional yield of combined biopsy in vasculitic neuropathy. Medline, Embase, LILACS and ISI were searched from January 1980 until January 2009 for relevant articles on the yield of nerve, muscle or combined biopsy to diagnose vasculitic neuropathy. Fourteen (15%) studies were included. Methodological quality was scored using a modified Quality Assessment for Diagnostic Accuracy Studies tool. in patients clinically suspected of vasculitic neuropathy, the additional yield of definite vasculitis in combined biopsy was 5.1% (95% CI 1.1-9.2%; P = 0.013). In patients diagnosed with vasculitic neuropathy, the additional yield of definite vasculitis in combined biopsy was 15% (95% CI 2.1-28%; P = 0.023). there is a modest additional yield of definite vasculitis in combined biopsy compared to nerve biopsy alone. Because of methodological flaws in analysed studies, the findings should be validated in a prospective study.

A wide spectrum of neurological symptoms (NS) has been described in patients with COVID-19. We examined the plasma levels of neuron-specific enolase (NSE) and neurofilament light chain (NFL) together, as neuronal damage markers, and their relationships with clinical severity in patients with NS at acute COVID-19.A total of 20 healthy controls and 59 patients with confirmed COVID-19 were enrolled in this pilot prospective study. Serum NSE and NFL levels were measured by using the enzyme-linked immunoassay method from serum samples.Serum NSE levels were found to be significantly higher in the severe group than in the nonsevere group (p = 0.034). However, serum NFL levels were similar between the control and disease groups (p > 0.05). For the mild group, serum NFL levels were significantly higher in patients with the sampling time ≥5 days than in those with the sampling time <5 days (p = 0.019). However, no significant results for NSE and NFL were obtained in patients with either single or multiple NS across the groups (p > 0.05).Increased serum NSE levels were associated with disease severity regardless of accompanied NS in patients with acute COVID-19 infection. However, serum NFL levels may have a role at the subacute phase of COVID-19.

To evaluate the diagnostic value of nerve and muscle biopsy in suspected cases of vasculitis and their correlation with the clinical and electrophysiological data. We conducted a retrospective review of I 15 nerve and muscle biopsy specimens from cases in the past 20 years at the University of Alabama at Birmingham (UAB) Muscle and Nerve Histopathology Laboratory. Clinical and electromyography data in available cases were analyzed to evaluate the histopathologic correlation,: : The diagnostic sensitivity of nerve biopsy was 39%, Nerve biopsy showed a statistically higher diagnostic yield (P = 0-0001) than muscle biopsy (17%), although muscle biopsies resulted in a more definite diagnosis m 3%. of cases. The highest diagnostic yield (73%) of vasculitis on nerve biopsy was observed in patients with known rheumatologic disease and accompanying neuropathy or myopathy. Nerve conduction study was able to identify diffuse neuropathy in the majority of patients with vasculitis, including asymptomatic neuropathy. Abnormal sural nerve conduction was highly correlated (P = 0.03) with positive nerve biopsy. There was a wide spectrum of neurologic manifestations in vasculitic neuropathy, with the most common clinical manifestation of vasculitic neuropathy being polyneuropathy. Nerve biopsy is superior to muscle biopsy for the diagnosis of vasculitis among suspected cases of vasculitis. The highest diagnostic yield of nerve biopsy is observed when patients with known rheumatologic diseases have neuropathy or myopathy. Abnormal sural nerve conduction can be used as a guide for nerve biopsy.

Nerve biopsy represents the conclusive step in the diagnostic work-up of peripheral neuropathies, and its diagnostic yield is still debated. The aim of this study is to consider the impact of nerve biopsy on reaching a useful diagnosis in different peripheral neuropathies and its changing over time. We retrospectively analyzed 1,179 sural nerve biopsies performed in the period 1981–2017 at Neurological Clinic of Policlinico San Martino (Genoa). We relied on medical records and collected both clinical and pathological data in a database. Biopsy provided univocal diagnoses in 53% of cases (with an increase over time), multiple diagnostic options in 14%, while diagnosis was undetermined in 33% (undetermined reports decreased during the years). In 57% of patients, the pre-biopsy suspicion was confirmed, while in 43% sural biopsy modified the clinical diagnosis. The highest yield was in axonal neuropathies (29% undetermined reports vs. 40% in demyelinating and 48% in mixed neuropathies). In 68% of patients with vasculitic neuropathy, this etiology was already suspected, whereas in 32% nerve biopsy modified the clinical diagnosis. During the years, the number of annually performed biopsies decreased significantly (p = 0.007), with an increase in the mean age of patients (p < 0.0001). The percentage of hereditary neuropathies had a significant decrease (p = 0.016), while the rate of vasculitic and chronic inflammatory neuropathies increased (p < 0.0001). This is the largest Italian study addressing the yield of sural nerve biopsy. During the years, we observed a progressive refinement of the indication of this procedure, which confirms its utility for interstitial neuropathies, particularly if non-systemic vasculitic neuropathy is suspected.