Cranial nerve involvement is a well-recognized feature in Guillain-Barré syndrome (GBS) but remains less well understood in chronic forms of autoimmune neuropathies. Earlier studies of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were conducted before updated diagnostic criteria and the recognition of autoimmune nodopathy (AN), which may limit the interpretation of their findings. We retrospectively analyzed 582 patients with chronic autoimmune neuropathies-CIDP (n = 431), multifocal motor neuropathy (MMN) (n = 64), anti-myelin-associated glycoprotein (MAG) neuropathy (n = 54), and AN (n = 33)-from 4 Korean and 1 UK centers. Patients with cranial nerve involvement were identified and described. CIDP patients with cranial nerve involvement (cranial+ CIDP) were compared with those without (cranial- CIDP). Cranial nerve involvement was observed in 8.8% (38/431) of CIDP and 24.2% (8/33) of AN patients but was absent in MMN (0/64) and anti-MAG neuropathy (0/54). Facial palsy was overall the most common manifestation (CIDP: 45%, AN: 50%). Patients with AN more frequently exhibited bilateral optic neuropathy (50%) and facial diplegia (38%), while CIDP patients more often showed trigeminal neuropathy and oculomotor nerve palsy (both 32%). Compared with cranial- CIDP, cranial+ CIDP patients were more often younger, of variant subtypes (especially multifocal), presented (sub)acutely with preceding infection/vaccination, followed by relapsing-remitting rather than progressive courses, and achieved greater improvement despite greater pre-treatment disability. Cranial nerve involvement serves as a diagnostic clue in chronic autoimmune neuropathies, particularly in identifying AN and CIDP. Cranial+ CIDP appears to represent a distinct subset with partial overlap to GBS, suggesting unique underlying mechanisms.

The aim of this study was to elucidate the clinical spectrum and mechanisms of autoimmune nodopathy (AN) with autoantibodies against leucine-rich repeat leucin-rich glioma inactivated 1 (LGI) family member 4 (LGI4) localized at juxtaparanodes and satellite glia in the dorsal root ganglion. We developed a live cell-based assay for LGI4-immunoglobulin (Ig) G and surveyed 131 patients with chronic inflammatory demyelinating polyneuropathy. LGI4-IgG, anti-LGI4 antibody-negative CIDP-IgG, or healthy control (HC)-IgG were applied to Schwann cells, and cell proliferation was assayed using 5-bromo-2'-deoxyuridine labeling. Quantitative real-time PCR was used to assess the expression of Krox20 and Prx, both of which independently control peripheral nerve myelination. LGI4-IgG or HC-IgG was intraneurally injected into mouse sciatic nerves, and the effects were immunohistochemically and morphometrically assessed. Eight anti-LGI4 antibody-positive (LGI4+) patients were identified; dominant tissue-binding IgG subclasses were IgG4 in 4 patients and IgG2 and IgG3 in 2 patients each. Patients had a relatively old onset age (median 72 years, range 41-90 years). Four patients had acute/subacute monophasic courses, and 4 had chronic progressive/relapsing courses. Predominant symptoms/signs were motor weakness (8 cases), muscle atrophy (4), deep and superficial sensory impairment (8 and 7, respectively), Romberg sign (4), and hand/finger tremor (5). CSF showed extremely high protein levels (median 253 mg/dL). Three chronic cases had nerve hypertrophy. IVIg and efgartigimod were partially (7/7 patients) and markedly (1/1 patient) effective, respectively. Notably, 1 chronic patient with predominant tissue-binding LGI4-IgG2 but without LGI4-IgG4 showed a moderate reduction in myelinated fibers with endoneurial edema, numerous onion bulbs, and few inflammatory cell infiltrates in the biopsied sural nerve. Electron microscopy demonstrated onion bulb formations around the axons and subtle detachment of myelin terminal loops from axonal membranes in the paranodes. In Schwann cell culture, proliferation was significantly higher, and Krox20 but not Prx mRNA levels were lower after incubation with LGI4-IgG from chronic (but not acute-onset) cases compared with HC-IgG incubation. With intraneural injection, both LGI4-IgG4 and LGI4-IgG2 deposited mainly at the nodes extending toward the paranodes and caused nodal/paranodal alterations. LGI4+ AN manifests as acute/subacute monophasic and chronic progressive/relapsing diseases, sometimes exhibiting nerve hypertrophy with onion bulbs through nonmyelinating Schwann cell proliferation.

Human immunoglobulin, delivered either intravenously (IVIg) or subcutaneously, is used to treat a range of immune-mediated neurological disorders. It has a role in acute or subacute inflammatory disease control and as a maintenance therapy in chronic disease management. This review considers mechanisms of IVIg action and the evidence for IVIg in neurological conditions. We use Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as frameworks to demonstrate an approach to IVIg use in acute and chronic dysimmune neurological conditions across two different healthcare systems: the UK and Australia. We highlight the benefits and limitations of IVIg and focus on practical considerations such as informed consent, managing risks and adverse effects, optimal dosing and monitoring response. We use these basic clinical practice principles to discuss the judicious use of an expensive and scarce blood product with international relevance.

Acute motor and sensory axonal neuropathy (AMSAN) is a rare, severe subtype of Guillain-Barré syndrome (GBS) associated with a poorer prognosis and greater resistance to standard immunotherapies. While immunomodulatory therapies are the traditional mainstay therapies for GBS and its variants, as autoimmune-mediated processes, refractory cases can present unique challenges. In addition, chronic inflammatory demyelinating polyneuropathy (CIDP) is a known persistent variant of GBS with its own wide array of variations, including neurofascin IgG4-positive axonal nodopathy, associated with an antibody that provides an additional layer of immunoprotection. This condition has been found in previously documented case series to require non-traditional immunoregimens. We present a unique case of a highly refractory AMSAN with concomitant chronic axonal motor and sensory axonal nodopathy with high multimodal immunotherapy resistance. This case illustrates the importance of considering neurofascin IgG4 in refractory subacute axonal nodopathies and, consequently, the potential role of empiric rituximab, while also highlighting the need for further research into B-cell-depleting therapeutic alternatives in resistant cases.

Walking impairment represents a relevant symptom in patients with neurological diseases often compromising social participation. Currently, mixed methods studies on robot-assisted gait training (RAGT) in patients with rare neurological diseases are lacking. This study aimed to explore the feasibility, acceptability, goal attainment and preliminary effects of RAGT in patients with common and rare neurological diseases and understand the intervention context and process. A mixed-methods feasibility study was conducted at an Austrian rehabilitation centre. Twenty-eight inpatients after stroke in the subacute and chronic phases, with multiple sclerosis, Parkinson's disease, spinal cord injury, spinocerebellar ataxia, acute/chronic inflammatory demyelinating polyneuropathy and motor neuron disease were included. Patients received RAGT for 45 minutes, 4x/week, for 4 weeks. Baseline and post-intervention assessments included gait parameters, walking and balance, and questionnaires. Semi-structured observations were conducted twice during the intervention period and analysed using thematic analysis. Descriptive statistics within the respective disease groups and calculation of effect sizes for the total sample were performed. Triangulation was employed to develop a deeper understanding of the research topic. Data from 26 patients (mean age 61.6 years [standard deviation 13.2]) were analysed. RAGT was highly accepted by patients and feasible, indicated by recruitment, retention, and adherence rates of 84.8% (95% confidence interval, CI 0.7-0.9), 92.2% (95% CI 0.7-1.0) and 94.0% (95% CI 91.4-96.2), respectively. Goal attainment was high, and only mild adverse events occurred. Improvements in walking speed (10-Metre Walk Test, effect size r = 0.876), walking distance (6-Minute Walk Test, r = 0.877), functional mobility (Timed Up and Go, r = 0.875), gait distance (r = 0.829) and number of steps (r = 0.834) were observed. Four themes were identified: familiarising with RAGT; enjoyment and acceptance through a trusting therapeutic relationship; actively interacting; and minimising dissatisfaction. Sufficiently powered randomised controlled trials are needed to validate our results. German Clinical Trials Register, DRKS00027887.