The multiple roles of nerve biopsy in the diagnosis and prognosis of suspected immune neuropathies.

INTRODUCTION: The value of a sural nerve biopsy for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is controversial. Evidence-based recommendations for its implementation are lacking. We investigated factors leading to biopsy and analyzed biopsy outcomes and consequences, assessed the predictability of biopsy outcomes through clinical parameters to avoid unnecessary biopsies, and compared results with electrophysiological and clinical severity to determine their prognostic value. METHODS: 190 sural nerve biopsies were analyzed in two cohorts. One consisted of 163 biopsies and the second of 72 biopsies from the prospective Immune-mediated Neuropathies Biomaterial and Data registry (INHIBIT). Both have an intersection of 45 patients. 75 data sets from patients without biopsy were used. Analysis of nerve conduction studies, treatment, overall disability sum score (ODSS), biopsy outcomes, and diagnosis was performed. RESULTS: 51% of biopsied patients received the diagnosis CIDP (77% fulfilled EFNS/PNS criteria), 21% were not CIDP typical, and 27% were unspecific. Biopsied patients responded less frequently to immunotherapies at time of biopsy than non-biopsied patients (p = 0.003). Immunotherapy was initiated more frequently after biopsy (p < 0.001) and more often with intravenous immunoglobulins (p < 0.0001). 76% of all biopsied patients met the electrophysiological criteria for CIDP. Sensory nerve action potential amplitudes of 0 µV still provide 73% of histological diagnostic value. Histologic signs of degeneration predicted ODSS worsening after 1 year (p = 0.028) but disease severity did not correlate with histological damage severity. DISCUSSION: The main indication for nerve biopsy was the treatment of refractory cases of autoimmune neuropathies with the therapeutic consequence of treatment initiation or escalation. Sural biopsy also provided prognostic information. Even with extinguished sural SNAP, the biopsy can still have diagnostic value.

Pathology explains various mechanisms of auto-immune inflammatory peripheral neuropathies.

Autoimmune neuropathies are a heterogeneous group of rare and disabling diseases in which the immune system is thought to target antigens in the peripheral nervous system: they usually respond to immune therapies. Guillain-Barré syndrome is divided into several subtypes including "acute inflammatory demyelinating polyradiculoneuropathy," "acute motor axonal neuropathy," "acute motor sensory neuropathy," and other variants. Chronic forms such as chronic inflammatory demyelinating polyneuropathy (CIDP) and other subtypes and polyneuropathy associated with IgM monoclonal gammopathy; autoimmune nodopathies also belong to this group of auto-immune neuropathies. It has been shown that immunoglobulin G from the serum of about 30% of CIDP patients immunolabels nodes of Ranvier or paranodes of myelinated axons. Whatever the cause of myelin damage of the peripheral nervous system, the initial attack on myelin by a dysimmune process may begin either at the internodal area or in the paranodal and nodal regions. The term "nodoparanodopathy" was first applied to some "axonal Guillain-Barré syndrome" subtypes, then extended to cases classified as CIDP bearing IgG4 antibodies against paranodal axoglial proteins. In these cases, paranodal dissection develops in the absence of macrophage-induced demyelination. In contrast, the mechanisms of demyelination of other dysimmune neuropathies induced by macrophages are unexplained, as no antibodies have been identified in such cases. The main objective of this presentation is to show that the pathology illustrates, confirms, and may explain such mechanisms.

Quantitative magnetic resonance neurography in chronic inflammatory demyelinating polyradiculoneuropathy: A longitudinal study over 6 years.

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.

Nerve transcriptomes in autoimmune and genetic demyelinating neuropathies: Pathogenic pathway assessment of nerve demyelination.

The pathogenesis of autoimmune demyelinating neuropathies is poorly understood compared to inherited demyelinating forms. We performed whole transcriptome (RNA-Seq) using nerve biopsy tissues of patients with different autoimmune and inherited demyelinating neuropathies (CIDP n = 10, POEMS n = 18, DADS n = 3, CMT1 n = 3) versus healthy controls (n = 6). A limited number of differentially expressed genes compared to healthy controls were identified (POEMS = 125, DADS = 15, CMT = 14, CIDP = 5). Divergent pathogenic pathways including inflammatory, demyelinating and neurite regeneration such as with the triggering receptor expressed on myeloid cells (TREM1) part of the immunoglobulin superfamily and RhoGD1 are found. Shared and discordant pathogenic injury are discovered between autoimmune and inherited forms.

Myelin barrier breakdown, mechanical hypersensitivity, and painfulness in polyneuropathy with claudin-12 deficiency.

BACKGROUND: The blood-nerve and myelin barrier shield peripheral neurons and their axons. These barriers are sealed by tight junction proteins, which control the passage of potentially noxious molecules including proinflammatory cytokines via paracellular pathways. Peripheral nerve barrier breakdown occurs in various neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and traumatic neuropathy. Here, we studied the functional role of the tight junction protein claudin-12 in regulating peripheral nerve barrier integrity and CIDP pathogenesis. METHODS: Sections from sural nerve biopsies from 23 patients with CIDP and non-inflammatory idiopathic polyneuropathy (PNP) were analyzed for claudin-12 and -19 immunoreactivity. Cldn12-KO mice were generated and subjected to the chronic constriction injury (CCI) model of neuropathy. These mice were then characterized using a battery of barrier and behavioral tests, histology, immunohistochemistry, and mRNA/protein expression. In phenotype rescue experiments, the proinflammatory cytokine TNFα was neutralized with the anti-TNFα antibody etanercept; the peripheral nerve barrier was stabilized with the sonic hedgehog agonist smoothened (SAG). RESULTS: Compared to those without pain, patients with painful neuropathy exhibited reduced claudin-12 expression independently of fiber loss. Accordingly, global Cldn12-KO in male mice, but not fertile female mice, selectively caused mechanical allodynia associated with a leaky myelin barrier, increased TNFα, decreased sonic hedgehog (SHH), and loss of small axons accompanied by reduced peripheral myelin protein 22 (Pmp22). Other barriers and neurological functions remained intact. The Cldn12-KO phenotype could be rescued either by neutralizing TNFα with etanercept or stabilizing the barrier with SAG, which both also upregulated the Schwann cell barrier proteins Cldn19 and Pmp22. CONCLUSION: These results point to a critical role for claudin-12 in maintaining the myelin barrier presumably via Pmp22 and highlight restoration of the hedgehog pathway as a potential treatment strategy for painful inflammatory neuropathy.

[Diagnostic value of F wave changes in patients with Charcot-Marie-Tooth1A and chronic inflammatory demyelinating polyneuropathy].

OBJECTIVE: To analyze and compare the characteristics and causes of F wave changes in patients with Charcot-Marie-Tooth1A (CMT1A) and chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Thirty patients with CMT1A and 30 patients with CIDP were enrolled in Peking University Third Hospital from January 2012 to December 2018. Their clinical data, electrophysiological data(nerve conduction velocity, F wave and H reflex) and neurological function scores were recorded. Some patients underwent magnetic resonance imaging of brachial plexus and lumbar plexus, and the results were analyzed and compared. RESULTS: The average motor conduction velocity (MCV) of median nerve was (21.10±10.60) m/s in CMT1A and (31.52±12.46) m/s in CIDP. There was a significant difference between the two groups (t=-6.75, P < 0.001). About 43.3% (13/30) of the patients with CMT1A did not elicit F wave in ulnar nerve, which was significantly higher than that of the patients with CIDP (4/30, 13.3%), χ2=6.65, P=0.010. Among the patients who could elicit F wave, the latency of F wave in CMT1A group was (52.40±17.56) ms and that in CIDP group was (42.20±12.73) ms. There was a significant difference between the two groups (t=2.96, P=0.006). The occurrence rate of F wave in CMT1A group was 34.6%±39%, and that in CIDP group was 70.7%±15.2%. There was a significant difference between the two groups (t=-5.13, P < 0.001). The MCV of median nerve in a patient with anti neurofascin 155 (NF155) was 23.22 m/s, the latency of F wave was 62.9-70.7 ms, and the occurrence rate was 85%-95%. The proportion of brachial plexus and lumbar plexus thickening in CMT1A was 83.3% (5/6) and 85.7% (6/7), respectively. The proportion of brachial plexus and lumbar plexus thickening in the CIDP patients was only 25.0% (1/4, 2/8). The nerve roots of brachial plexus and lumbar plexus were significantly thickened in a patient with anti NF155 antibody. CONCLUSION: The prolonged latency of F wave in patients with CMT1A reflects the homogenous changes in both proximal and distal peripheral nerves, which can be used as a method to differentiate the CIDP patients characterized by focal demyelinating pathology. Moreover, attention should be paid to differentiate it from the peripheral neuropathy caused by anti NF155 CIDP. Although F wave is often used as an indicator of proximal nerve injury, motor neuron excitability, anterior horn cells, and motor nerve myelin sheath lesions can affect its latency and occurrence rate. F wave abnormalities need to be comprehensively analyzed in combination with the etiology, other electrophysiological results, and MRI imaging.

Anti-LGI4 Antibody Is a Novel Juxtaparanodal Autoantibody for Chronic Inflammatory Demyelinating Polyneuropathy.

BACKGROUND AND OBJECTIVES: The objective of this study was to discover novel nodal autoantibodies in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We screened for autoantibodies that bind to mouse sciatic nerves and dorsal root ganglia (DRG) using indirect immunofluorescence (IFA) assays with sera from 113 patients with CIDP seronegative for anti-neurofascin 155 and anticontactin-1 antibodies and 127 controls. Western blotting, IFA assays using HEK293T cells transfected with relevant antigen expression plasmids, and cell-based RNA interference assays were used to identify target antigens. Krox20 and Periaxin expression, both of which independently control peripheral nerve myelination, was assessed by quantitative real-time PCR after application of patient and control sera to Schwann cells. RESULTS: Sera from 4 patients with CIDP, but not control sera, selectively bound to the nodal regions of sciatic nerves and DRG satellite glia (p = 0.048). The main immunoglobulin G (IgG) subtype was IgG4. IgG from these 4 patients stained a 60-kDa band on Western blots of mouse DRG and sciatic nerve lysates. These features indicated leucine-rich repeat LGI family member 4 (LGI4) as a candidate antigen. A commercial anti-LGI4 antibody and IgG from all 4 seropositive patients with CIDP showed the same immunostaining patterns of DRG and cultured rat Schwann cells and bound to the 60-kDa protein in Western blots of LGI4 overexpression lysates. IgG from 3 seropositive patients, but none from controls, bound to cells cotransfected with plasmids containing LGI4 and a disintegrin and metalloprotease domain-containing protein 22 (ADAM22), an LGI4 receptor. In cultured rat Schwann and human melanoma cells constitutively expressing LGI4, LGI4 siRNA effectively downregulated LGI4 and reduced patients' IgG binding compared with scrambled siRNA. Application of serum from a positive patient to Schwann cells expressing ADAM22 significantly reduced the expression of Krox20, but not Periaxin. Anti-LGI4 antibody-positive patients had a relatively old age at onset (mean age 58 years), motor weakness, deep and superficial sensory impairment with Romberg sign, and extremely high levels of CSF protein. Three patients showed subacute CIDP onset resembling Guillain-Barré syndrome. DISCUSSION: IgG4 anti-LGI4 antibodies are found in some elderly patients with CIDP who present subacute sensory impairment and motor weakness and are worth measuring, particularly in patients with symptoms resembling Guillain-Barré syndrome.

Diagnostic value of F wave changes in patients with Charcot-Marie-Tooth1A and chronic inflammatory demyelinating polyneuropathy / 北京大学学报(医学版)

OBJECTIVE@#To analyze and compare the characteristics and causes of F wave changes in patients with Charcot-Marie-Tooth1A (CMT1A) and chronic inflammatory demyelinating polyneuropathy (CIDP).@*METHODS@#Thirty patients with CMT1A and 30 patients with CIDP were enrolled in Peking University Third Hospital from January 2012 to December 2018. Their clinical data, electrophysiological data(nerve conduction velocity, F wave and H reflex) and neurological function scores were recorded. Some patients underwent magnetic resonance imaging of brachial plexus and lumbar plexus, and the results were analyzed and compared.@*RESULTS@#The average motor conduction velocity (MCV) of median nerve was (21.10±10.60) m/s in CMT1A and (31.52±12.46) m/s in CIDP. There was a significant difference between the two groups (t=-6.75, P < 0.001). About 43.3% (13/30) of the patients with CMT1A did not elicit F wave in ulnar nerve, which was significantly higher than that of the patients with CIDP (4/30, 13.3%), χ2=6.65, P=0.010. Among the patients who could elicit F wave, the latency of F wave in CMT1A group was (52.40±17.56) ms and that in CIDP group was (42.20±12.73) ms. There was a significant difference between the two groups (t=2.96, P=0.006). The occurrence rate of F wave in CMT1A group was 34.6%±39%, and that in CIDP group was 70.7%±15.2%. There was a significant difference between the two groups (t=-5.13, P < 0.001). The MCV of median nerve in a patient with anti neurofascin 155 (NF155) was 23.22 m/s, the latency of F wave was 62.9-70.7 ms, and the occurrence rate was 85%-95%. The proportion of brachial plexus and lumbar plexus thickening in CMT1A was 83.3% (5/6) and 85.7% (6/7), respectively. The proportion of brachial plexus and lumbar plexus thickening in the CIDP patients was only 25.0% (1/4, 2/8). The nerve roots of brachial plexus and lumbar plexus were significantly thickened in a patient with anti NF155 antibody.@*CONCLUSION@#The prolonged latency of F wave in patients with CMT1A reflects the homogenous changes in both proximal and distal peripheral nerves, which can be used as a method to differentiate the CIDP patients characterized by focal demyelinating pathology. Moreover, attention should be paid to differentiate it from the peripheral neuropathy caused by anti NF155 CIDP. Although F wave is often used as an indicator of proximal nerve injury, motor neuron excitability, anterior horn cells, and motor nerve myelin sheath lesions can affect its latency and occurrence rate. F wave abnormalities need to be comprehensively analyzed in combination with the etiology, other electrophysiological results, and MRI imaging.

Combined central and peripheral demyelination: a case report.

Overlapping central nervous system (CNS) and peripheral nervous system (PNS) demyelination is a rare clinical entity, more frequently seen in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multiple sclerosis (MS). This case report showcases a patient with atypical CIDP and CNS demyelination lesions. Demographic data, disease course, treatment responsiveness, neurological examination, laboratory tests, nerve conduction studies (NCS), and brain and spinal cord MRI were registered. The case highlights the difficulty of diagnosis establishment and treatment selection, given the atypical course of the disease and limited answers to the indicated therapies. The data from our report suggest that specific and widely available immunological targets are necessary for diagnosing combined central and peripheral demyelination cases appropriately. The association of different immunotherapeutic agents may be necessary to induce and maintain disease remission.

Processing speed impairment in chronic inflammatory demyelinating polyneuropathy patients: a cross-sectional study.

BACKGROUND: There is a lack of evidence of cognitive involvement in chronic inflammatory demyelinating polyneuropathy (CIDP) and, the reports about the involvement of the brain and central nervous system (CNS) are few and controversial. The Five Digit Test (FDT) evaluates processing speed (PS) and executive functions orally. OBJECTIVE: To evaluate the performance on the FDT of CIDP patients with and without CNS (brain/cerebellum) alterations observed on brain Magnetic Resonance Imaging (MRI) scans. METHODS: The Hospital Anxiety and Depression Scale (HADS, to assess neuropsychiatry symptoms), the Rasch-built Overall Disability Scale (R-ODS; to assess disability), and the FDT (to assess cognition) were applied to 14 CIDP patients and 24 age-matched healthy control subjects. The patients were submitted to routine brain MRI and, according to the results, they were divided into two groups: those with abnormalities on the MRI (CIDPabnl) and those with normal parameters on the MRI (CIDPnl). The FDT data of five CIDPnl patients and nine CIDPabnl subjects were analyzed. Comparisons between the groups were performed for each task of the FDT. RESULTS: We found statistical differences for both groups of CIDP patients in terms of PS, for the patients spent more time performing the PS tasks than the controls. The PS measures were negatively associated with disability scores (reading: r = -0.47; p = 0.003; counting: r = -0.53; p = 0.001). CONCLUSIONS: Our data suggested the presence of PS impairment in CIDP patients. Disability was associated with slow PS.

ANTECEDENTES: Faltam evidências de envolvimento cognitivo na polineuropatia inflamatória desmielinizante crônica (PIDC), e há poucos e controversos estudos que tratam do envolvimento cerebral e do sistema nervoso central (SNC). O Teste dos Cinco Dígitos (Five Digit Test, FDT, em inglês) avalia a velocidade de processamento (VP) e as funções executivas oralmente. OBJETIVO: Avaliar o desempenho no FDT de pacientes com PIDC com e sem alterações no SNC (cérebro/cerebelo) de acordo com o exame de imagem cerebral por ressonância magnética (RM). MéTODOS: Ao todo, 14 pacientes e 24 controles saudáveis pareados por idade responderam a Escala Hospitalar de Ansiedade e Depressão (que avalia sintomas neuropsiquiátricos), a Escala de Incapacidade Geral elaborada pelo método Rasch (que avalia a incapacidade) e o FDT (que avalia a cognição). Os pacientes foram submetidos a RM cerebral e, de acordo com os resultados, divididos em dois grupos: aqueles com anormalidades (PIDCabnl) e aqueles sem alterações (PIDCnl) na RM. Cinco pacientes PIDCnl e nove PIDCabnl tiveram os dados analisados. Comparações entre os grupos foram realizadas para cada parte do FDT. RESULTADOS: Os dois grupos de pacientes foram estatisticamente mais lentos nas tarefas de VP comparados ao grupo controle. As medidas de VP foram negativamente associadas às pontuações de incapacidade (leitura: r = −0,47; p = 0,003; contagem: r = −0,53; p = 0,001). CONCLUSõES: Os dados indicaram a presença de prejuízo na VP em pacientes com PIDC. A incapacidade foi associada à lentidão na VP.

French recommendations for the management of adult & pediatric chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare autoimmune disorder of the peripheral nervous system, primarily affecting the myelin sheath. The pathophysiology of CIDP is complex, involving both humoral and cellular immunity. The diagnosis of CIDP should be suspected in patients with symmetrical proximal and distal motor weakness and distal sensory symptoms of progressive onset, associated with decreased/abolished tendon reflexes. Treatments include intraveinous immunoglobulins, steroids and plasma exchange, with usually an induction phase followed by a maintenance therapy with progressive weaning. Treatment should be rapidly initiated to prevent axonal degeneration, which may compromise recovery. CIDP outcome is variable, ranging from mild distal paresthesiae to complete loss of ambulation. There have been several breakthroughs in the diagnosis and management of CIDP the past ten years, e.g. discovery of antibodies against the node of Ranvier, contribution of nerve ultrasound and magnetic resonance imaging to diagnosis, and demonstration of subcutaneous immunoglobulins efficiency. This led us to elaborate French recommendations for the management of adult & pediatric CIDP patients. These recommendations include diagnosis assessment, treatment, and follow-up.

CNS Involvement in Chronic Inflammatory Demyelinating Polyneuropathy: Subtle Retinal Changes in Optical Coherence Tomography.

BACKGROUND AND OBJECTIVES: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease primarily affecting the peripheral nervous system. However, several noncontrolled studies have suggested concomitant inflammatory CNS demyelination similar to multiple sclerosis. The aim of this study was to investigate an involvement of the visual pathway in patients with CIDP. METHODS: In this prospective cross-sectional study, we used high-resolution spectral-domain optical coherence tomography to compare the thickness of the peripapillary retinal nerve fiber layer and the deeper macular retinal layers as well as the total macular volume (TMV) in 22 patients with CIDP and 22 age-matched and sex-matched healthy control (HC) individuals. Retinal layers were semiautomatically segmented by the provided software and were correlated with clinical measures and nerve conduction studies. RESULTS: In patients with CIDP compared with healthy age-matched and sex-matched controls, we found slight but significant volume reductions of the ganglion cell/inner plexiform layer complex (CIDP 1.86 vs HC 1.95 mm3, p = 0.015), the retinal pigment epithelium (CIDP 0.38 vs HC 0.40 mm3, p = 0.02), and the TMV (CIDP 8.48 vs HC 8.75 mm3, p = 0.018). The ganglion cell layer volume and motor nerve conduction velocity were positively associated (B = 0.002, p = 0.02). DISCUSSION: Our data reveal subtle retinal neurodegeneration in patients with CIDP, providing evidence for visual pathway involvement, detectable by OCT. The results need corroboration in independent, larger cohorts.

Evaluation of the EFNS/PNS diagnostic criteria in a cohort of CIDP patients.

OBJECTIVE: To evaluate the European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) in a cohort of patients diagnosed and treated for CIDP in a tertiary university hospital. METHODS: In a monocentric retrospective study of 203 CIDP patients, diagnosed according to expert opinion, we evaluated the EFNS/PNS diagnostic criteria. Clinical course and nerve conduction studies (NCS) over 1 year from first referral were studied. Secondarily, we compared the clinical and paraclinical characteristics, including nerve ultrasound, of patients who failed with those who fulfilled the criteria in order to identify clinically relevant differences. RESULTS: At 1 year, 182 (89.7%) patients fulfilled the criteria (156/76.9% definite, 22/10.8% probable, and 4/2% possible). Twenty-one (10.3%) patients did not because the electrodiagnostic criteria remained negative. These still showed signs of demyelination but did not reach the cut-off values. They also presented typical, albeit less pronounced, multifocal nerve enlargement in ultrasonography. Mean disability at presentation and 1 year after was significantly lower. Most importantly, a relevant proportion of these patients also responded to therapy (6/21 = 28.6% vs. 82/182 = 45.3% of those fulfilling the criteria). INTERPRETATION: CIDP diagnosis could be established for 89.7% of patients over the course of 1 year using EFNS/PNS criteria. The remaining patients (10.3%) presented with milder disability, less accentuated demyelination, but otherwise similar characteristics and still considerable probability of treatment response. Failure to fulfill diagnostic criteria should not automatically preclude treatment. Nerve ultrasound should be considered as a complementary diagnostic tool to detect signs of inflammation in CIDP.

Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy: CISP-Plus.

OBJECTIVE: Sensory loss with normal nerve conduction studies (NCS) from focal sensory root inflammatory demyelination is characteristic of chronic immune sensory polyradiculopathy (CISP). However, nonpure cases involving motor and distal sensory nerves exist (CISP-plus). We hypothesize that CISP-plus and CISP are fundamentally part of the same syndrome through comparison of clinical, neurophysiologic, and pathologic features. METHODS: CISP-plus (primary dorsal root with lesser motor and sensory nerve involvement) and CISP cases were retrospectively analyzed (1986-2019). RESULTS: We identified 44 CISP-plus and 28 CISP cases (n = 72) with 86% (38/44) of patients with CISP-plus and 79% (22/28) of patients with CISP experiencing imbalance. On examination, large fiber sensory loss was present in 98% (43/44) of patients with CISP-plus and 96% (27/28) of patients with CISP. Gait ataxia was evident in 93% (41/44) of patients with CISP-plus and 79% (22/28) of patients with CISP. Mild distal weakness was common in CISP-plus (75%, 33/44). NCS showed mild abnormalities in all patients with CISP-plus and were normal (by definition) in all patients with CISP. Elevated CSF protein, slowing of somatosensory evoked potentials, and MRI root enhancement occurred in most CISP-plus and CISP cases. Eleven CISP-plus nerve biopsies showed loss of large myelinated fibers and onion-bulb formations, most prominent in rootlet biopsies. Immunotherapy resulted in marked improvement of gait ataxia in 84% (27/32) of patients with CISP-plus and 93% (13/14) of patients with CISP with return to normal neurologic examination in half (25/46). CONCLUSION: The recognition of CISP-plus expands the spectrum of CIDP by combining CISP-plus (predominant sensory polyradiculopathy with mild motor and sensory nerve involvement) with pure CISP (focal sensory polyradiculopathy) together as proximal sensory CIDP.

Magnetic resonance neurography in diagnosing childhood chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Peripheral nerve imaging is increasingly recognized as a powerful tool to evaluate nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth diseases (CMT), whereas data in pediatric patients are limited. CASE DESCRIPTION: We describe the case of a 15-year-old Japanese girl with asymmetric demyelinating polyneuropathy, who, at the age of 10 years, was initially diagnosed with a demyelinating form of CMT. Fluorescence in situ hybridization for peripheral myelin 22 was negative, and already-known pathogenic variants were not detected by whole-genome sequencing, and nerve conduction studies revealed multifocal conduction blocks. Over the next 5 years, the patient showed gradual improvement in muscle weakness and sensory disturbance without immunological treatment and was referred to our hospital. RESULTS: At the age of 15 years, magnetic resonance (MR) neurography showed asymmetric multifocal fusiform enlargement of nerve roots, brachial and lumbosacral plexuses, and intermediated nerve trunks, as well as cranial nerves. Based on the MR neurography findings and multifocal nerve conduction blocks, she was diagnosed as having multifocal CIDP (multifocal demyelinating sensory and motor neuropathy [MADSAM]) according to the European Federation of Neurological Societies/Peripheral Nerve Society diagnostic criteria. DISCUSSION: Clinical diagnosis of childhood CIDP is challenging because its neurological manifestations and nerve conduction study findings occasionally resemble those of inherited demyelinating neuropathies. MR neurography is helpful for the assessment of patterns of nerve hypertrophy; MADSAM-CIDP is characterized by multiple fusiform nerve enlargement, whereas CMT shows symmetric and diffuse nerve hypertrophy. CONCLUSION: The MR neurography patterns would help in diagnosing pediatric demyelinating neuropathies.

Over-Expression of Immune-Related lncRNAs in Inflammatory Demyelinating Polyradiculoneuropathies.

Long non-coding RNAs (lncRNAs) have crucial roles in the pathogenesis of immune-related disorders. However, their role in the pathobiology of inflammatory demyelinating polyradiculoneuropathies remains unclear. In the current study, we measured peripheral expression of four lncRNAs, namely TUG1, FAS-AS1, NEAT1, and GAS5, in patients with acute/chronic inflammatory demyelinating polyradiculoneuropathies (AIDP/CIDP) compared with healthy subjects. Notably, all lncRNAs were over-expressed in patients compared with controls (P < 0.0001 for all lncRNAs). When assessing their expressions in AIDP and CIDP groups separately, TUG1 and NEAT1 were up-regulated in both patient groups compared with controls, yet FAS-AS1 and GAS5 were only up-regulated in CIDP cases. There were remarkable pairwise correlations between expression levels of these lncRNAs in all study groups. Based on the above-mentioned data, we suggest participation of these for lncRNAs in the pathogenesis of inflammatory demyelinating polyradiculoneuropathies. Moreover, FAS-AS1 and GAS5 lncRNAs have type-specific roles in this regard. Future functional studies are needed to elaborate the molecular mechanisms of the contribution of these transcripts in AIDP/CIDP.

Chronic inflammatory demyelinating polyradiculoneuropathy-Diagnostic pitfalls and treatment approach.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by progressive weakness and sensory loss, often affecting patients' ability to walk and perform activities of daily living independently. With the lack of a diagnostic biomarker, the diagnosis relies on clinical suspicion, clinical findings, and the demonstration of demyelinating changes on electrodiagnostic (EDx) testing and nerve pathology. As a result, patients can often be misdiagnosed with CIDP and unnecessarily treated with immunotherapy. Interpreting the EDx testing and cerebrospinal fluid findings in light of the clinical phenotype, recognizing atypical forms of CIDP, and screening for CIDP mimickers are the mainstays of the approach to patients suspected of having CIDP, and are detailed in this review. We also review the currently available treatment options, including intravenous immunoglobulin (IVIg), corticosteroids (CCS), and plasma exchange (PE), and discuss how to approach treatment-refractory cases. Finally, we emphasize the need to adopt objective outcome measures to monitor treatment response.

The Wide Spectrum of Pathophysiologic Mechanisms of Paraproteinemic Neuropathy.

Monoclonal gammopathy is encountered quite frequently in the general population. This type of hematologic abnormality may be mild, referred to as monoclonal gammopathy of undetermined significance or related to different types of hematologic malignancies. The association of a peripheral neuropathy with monoclonal gammopathy is also fairly common, and hemopathy may be discovered in an investigation of peripheral neuropathy. In such a situation, it is essential to determine the exact nature of the hematologic process in order not to miss a malignant disease and thus initiate the appropriate treatment (in conjunction with hematologists and oncologists). In this respect, nerve biopsy (discussed on a case-by-case basis) is of great value in the management of such patients. We therefore propose to present the objectives and main interests of nerve biopsy in this situation.

Optic, trigeminal, and facial neuropathy related to anti-neurofascin 155 antibody.

OBJECTIVE: To characterize the frequency and patterns of optic, trigeminal, and facial nerve involvement by neuroimaging and electrophysiology in IgG4 anti-neurofascin 155 antibody-positive (NF155+ ) chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Thirteen IgG4 NF155+ CIDP patients with mean onset age of 34 years (11 men) were subjected to neurological examination, blink reflex, and visual-evoked potential (VEP) testing, and axial and/or coronal T2-weighted head magnetic resonance imaging (MRI). RESULTS: Among 13 patients, facial sensory impairment, facial weakness, and apparent visual impairment were observed in three (23.1%), two (15.4%), and two (15.4%) patients, respectively. All 12 patients tested had blink reflex abnormalities: absent and/or delayed R1 in 11 (91.7%), and absent and/or delayed R2 in 10 (83.3%). R1 latencies had strong positive correlations with serum anti-NF155 antibody levels (r = 0.9, P ≤ 0.0001 on both sides) and distal and F wave latencies of the median and ulnar nerves. Absent and/or prolonged VEPs were observed in 10/13 (76.9%) patients and 17/26 (65.4%) eyes. On MRI, hypertrophy, and high signal intensity of trigeminal nerves were detected in 9/13 (69.2%) and 10/13 (76.9%) patients, respectively, whereas optic nerves were normal in all patients. The intra-orbital trigeminal nerve width on coronal sections showed a significant positive correlation with disease duration. INTERPRETATION: Subclinical demyelination frequently occurs in the optic, trigeminal, and facial nerves in IgG4 NF155+ CIDP, suggesting that both central and peripheral myelin structures of the cranial nerves are involved in this condition, whereas nerve hypertrophy only develops in myelinated peripheral nerve fibers.

The Noninvasive Diagnostic Value of MRN for CIDP: A Research from Qualitative to Quantitative.

STUDY DESIGN: We examined the chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients and non-CIDP patients who have similar symptoms and difficult to differential diagnosis with CIDP by magnetic resonance neurography to find the difference among them. OBJECTIVE: To investigate the differential diagnostic value of magnetic resonance neurography (MRN) for CIDP and other peripheral neuropathies. SUMMARY OF BACKGROUND DATA: Thirty-two consecutive patients with CIDP and 22 non-CIDP patients with symptoms similar to CIDP and difficult to be discriminate were recruited and imaged as a control group between May 2017 and May 2019. METHODS: In this prospective study, the brachial plexus and lumbosacral plexus of 32 CIDP patients and 22 non-CIDP patients were examined by MRN. The clinical features and the nerve roots cross-sectional area (CSA) of the brachial plexus and lumbosacral plexus were measured. RESULTS: The CSA of nerve roots of CIDP, Charcot-Marie-Tooth disease type-1 and polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes syndrome patients were all shown extensive by MRN. The sensitivity of MRN in diagnosing CIDP was 81.25% (26/32), the specificity was 68.18% (15/22), the positive predictive value was 78.79% (26/33), the negative predictive value was 71.43% (15/21), the accuracy was 75.93% (40/54), the misdiagnosis rate was 24.07% (13/54), and the kappa value was 0.498. Receiver operating characteristic analysis showed higher diagnostic accuracy for CIDP with the CSA of the lumbosacral plexus (area under the curve [AUC] = 0.762) and that of the brachial plexus (AUC = 0.762), and the combined of both examinations did not improve the diagnostic efficacy compared with either (AUC = 0.769). CONCLUSIONS: The nerve roots of CIDP, Charcot-Marie-Tooth disease type-1, and polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes syndrome were difficult to distinguish by MRN. Atypical CIDP patients had less nerve root injury compared with typical CIDP patients. MRN of either the brachial plexus or the lumbosacral plexus had a high diagnostic accuracy for CIDP, and it is not necessary to perform both parts of the examination. LEVEL OF EVIDENCE: 2.