Pearls
Autoimmune nodopathy is a rare, debilitating, demyelinating polyneuropathy triggered by autoantibodies targeting peripheral nerve nodal and paranodal proteins including neurofascin-155 (NF155), contactin-1 (CNTN1), contactin-associated protein-1 (CASPR1), and neurofascin-186/140 (NF186/NF140).
Early testing for nodal and paranodal autoantibodies is crucial in refractory chronic inflammatory demyelinating polyneuropathy (CIDP) because autoimmune nodopathy does not respond robustly to first-line immunomodulatory treatments but improves with B-cell depletion.
Oy-sters
Clinical features of a demyelinating neuropathy that should raise suspicion for an underlying autoimmune nodopathy include tremors, severe sensory ataxia, cranial nerve involvement, and pain.
Severely elevated CSF protein or nephrotic syndrome in CIDP warrants antibody testing for an underlying autoimmune nodopathy.
Case Presentation
A 62-year-old woman presented with distal, symmetric, progressive paresthesias and weakness in her upper and lower extremities after a gastrointestinal illness. Her initial examination, 3–4 weeks after symptom onset, was notable for reduced distal upper and lower extremities strength, absent reflexes, and decreased distal vibration and joint position sensation. Initial electrodiagnostic testing showed several demyelinating findings that met the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) criteria for CIDP.1 These findings include motor conduction velocity slowing, conduction block, prolonged distal motor latencies, and prolonged F-wave latency (Table and Figure 1). MRI of the lumbar spine revealed conus medullaris and cauda equina enhancement (eFigure 1). MRI brain was negative for any demyelinating lesions. A lumbar puncture showed albuminocytological dissociation with a protein level >200 mg/dL, indicating a protein level above the laboratory's detection limit. She was diagnosed with acute inflammatory demyelinating neuropathy (AIDP) and treated with IV immunoglobulin (IVIG). However, her symptoms continued to progress 2 weeks after IVIG. Owing to concern for CIDP, she was treated with IVIG every 3 weeks, but she continued to clinically worsen. She developed upper extremity tremors, bilateral foot drop, and severe sensory ataxia requiring a wheelchair. She was further treated with oral and IV corticosteroids and eventually plasmapheresis. Despite these treatments, she continued to decline and developed dysphonia, dysphagia, and dysarthria. Additional testing, including serum and urine protein electrophoresis, hepatitis B, antinuclear, anti-myelin–associated glycoprotein antibodies, was unremarkable. Owing to suspicion of a paraneoplastic etiology, a paraneoplastic panel and whole-body PET scan were performed, both of which yielded negative results. She received a single cycle of rituximab and started to show clinical improvement. Ultimately, testing for nodal antibodies by Western blot at Washington University Neuromuscular Clinical Laboratories was positive for anti-NF155 IgG4 and anti-NF140 IgG. After an additional course of rituximab, she improved significantly and was given a second dose of rituximab at 6 months. A year into rituximab treatment, she has regained the ability to walk independently and is approaching her previous level of function.
Table 1.
Nerve Conduction Study of the Upper and Lower Extremities
| Motor nerve conduction studies | ||||
| Nerve | Location | Onset latency (milliseconds) | Amplitude (mV) | Conduction velocity (m/s) |
| R Median | Wrist | 6.6 | 9.8 | 32 |
| Elbow | 12.8 | 7.5 | ||
| R Ulnar | Wrist | 5 | 5.7 | 39 |
| B Elbow | 9.2 | 4.7 | 30 | |
| A Elbow | 13.4 | 4.3 | 42 | |
| R Peroneal | Ankle | 11.1 | 1.2 | 15 |
| B fibula | 23.6 | 1.1 | 18 | |
| Popliteal | 26.3 | 0.7 | ||
| L Peroneal | Ankle | 11.3 | 1 | 24 |
| B fibula | 23.6 | 0.6 | 33 | |
| Popliteal | 26.5 | 0.1 | ||
| L Tibial | Ankle | 9.1 | 2.9 | |
| Popliteal | 2.7 | 2.4 | 32 | |
| R Tibial | Ankle | 9.5 | 3.4 | |
| Popliteal | 23.3 | 1.7 | 28 | |
| Sensory nerve conduction studies | ||||
| Nerve | Location | Onset latency (milliseconds) | Amplitude (µV) | Conduction velocity (m/s) |
| L Median | Wrist | NR | NR | NR |
| R Ulnar | Wrist | NR | NR | NR |
| L Sural | Calf | 3.9 | 4.5 | 36 |
| F-wave minimum latencies | |
| Nerves | Value (milliseconds) |
| R Median | NR |
| R Tibial | 73.91 |
This study meets the European Academy of Neurology/Peripheral Nerve Society electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. There is conduction velocity slowing (≥30% below lower limit of normal with preserved amplitudes) in the right median, right ulnar, bilateral peroneal, and right tibial motor responses. There are prolonged distal latencies (≥50% above upper limit of normal) in the right ulnar, bilateral peroneal, and bilateral tibial motor responses. The right median motor response was excluded because prolonged distal latency in this nerve can alternatively be caused by a median neuropathy at the wrist. There is prolonged F-wave latency (≥20% above upper limit of normal) in the right median and right tibial motor response. There is conduction block (≥30% reduction of the proximal relative to distal negative peak compound muscle action potential amplitude) in the bilateral peroneal and right tibial motor responses. There are abnormal sensory responses in the left ulnar, left median, and left sural nerves.
Values in bold are abnormal. Normal values: median and ulnar motor onset latency <4.2 milliseconds, amplitude >5 mV, conduction velocity >50 m/s. Peroneal and tibial motor onset latency <6 milliseconds, amplitude >2.5 mV, and conduction velocity >40 m/s. Median sensory onset latency <3.6 milliseconds, amplitude 10 μV, conduction velocity >45 m/s. Ulnar sensory onset latency <3.6 milliseconds, amplitude 15 μV, conduction velocity >45 m/s. Median nerve F-wave minimum latency <33 milliseconds. Tibial nerve F-wave minimum latency <61 milliseconds.
Figure 1. Motor Nerve Conduction Study of the Left Peroneal Nerve.
Image shows conduction block characterized by a decrease in compound muscle action potential (CMAP) amplitude by more than 30% with proximal compared with distal stimulation, and temporal dispersion, manifested by widening of CMAP duration with proximal compared with distal stimulation.
Discussion
Autoimmune nodopathy (AN) results from antibodies targeting the cell adhesion molecules that link glial cells to axons in the nodal and paranodal regions of peripheral nerves. These antibodies target NF155, CNTN1, CASPR1, and pan-neurofascin (NF186/NF140 and NF155), leading to pathogenic effects by disrupting myelin loops from the axolemma and slowing conduction.1-4 These antibodies generally belong to the IgG4 subclass, which lacks the capability to activate the complement system and demonstrates minimal affinity to Fc receptors, resulting in a poor response to IVIG.2
AN presents similarly to CIDP with acute-to-subacute onset and a progressive or relapsing course. However, owing to underlying pathology, unique clinical features, and response to treatment, AN was classified as a distinct entity by the EAN/PNS in 2021.1 Each AN antibody has distinct clinical features. Anti-NF155 is the most common autoantibody causing AN. Patients with anti-NF155–associated AN are typically younger with predominantly distal sensorimotor weakness; sensory ataxia; and high-amplitude low-frequency postural/intentional tremors in the tongue, voice, and extremities.5,6 NF155 is also present in CNS and, therefore, can cause CNS demyelinating lesions in addition to peripheral nerve demyelination.6,7 Patients with anti-contactin-1–associated AN have acute-to-subacute onset with prominent sensory ataxia, neuropathic pain, cranial nerve involvement (facial nerve predominant), postural tremors, and respiratory failure. Nephrotic syndrome is also present in anti-contactin-1–positive patients.1,2 The clinical picture of anti-CASPR–associated AN is similar to that of anti-contactin–associated AN.2 However, it can present initially as a monophasic GBS-like course and is not associated with nephrotic syndrome.2 AN cases presenting with either anti-contactin-1 or anti-CASPR antibodies can also exhibit an initial response to IVIG during the acute phase, given that IgG3 antibodies mediate the pathogenesis early in the disease course. However, the transition to a chronic phase involves class switching to IgG4, rendering IVIG less effective.3 Last, anti-pan-neurofascin–associated AN with anti-NF155 and anti-NF186/140 presents with an aggressive acute-subacute polyneuropathy involving all 4 extremities with cranial nerves and respiratory and autonomic involvement.8 Some cases of isolated anti-NF186 have also been reported and mimic distal acquired demyelinating neuropathy with sensory ataxia.9
In addition to clinical presentation, a diagnosis of AN is often supported by extremely high CSF protein levels and the observation of nerve root enhancement or thickening on neuroimaging, representing blood-nerve barrier disruption.10 It is difficult to differentiate AN from CIDP based on electrodiagnostic testing because both will show evidence of acquired demyelination. Nerve biopsy, if pursued, will show detachment of terminal myelin loops, widening of the periaxonal space, and endoneurial edema without inflammatory infiltrates, which can differentiate AN from CIDP.5
In conclusion, AN is a relatively new entity that can easily be missed. Thus, a high clinical suspicion is essential for early detection of nodal antibodies, especially in refractory CIDP cases with atypical features such as tremors, severe sensory ataxia, and very high CSF protein. Early testing of these antibodies is important when there is a lack of response to IVIG treatment because AN may be reversible with B-cell–depleting agents.
Acknowledgment
The authors extend their gratitude to the patient for generously sharing her information for educational purposes.
Appendix. Authors
| Name | Location | Contribution |
| Roopa Sharma, MD | Rutgers New Jersey Medical School, Newark | Drafting/revision of the manuscript for content, including medical writing for content |
| Nicholas J. Bellacicco, DO | Rutgers New Jersey Medical School, Newark | Drafting/revision of the manuscript for content, including medical writing for content |
| Walter G. Husar, MD | Rutgers New Jersey Medical School, Newark; East Orange Veterans Hospital, NJ | Drafting/revision of the manuscript for content, including medical writing for content |
| James H. Park, MD, PhD | Rutgers New Jersey Medical School, Newark; East Orange Veterans Hospital, NJ | Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data |
| Eric Lancaster, MD, PhD | University of Pennsylvania, Philadelphia; Philadelphia VA Medical Center, PA | Drafting/revision of the manuscript for content, including medical writing for content |
| Madeline Singer, MD | University of Pennsylvania, Philadelphia | Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data |
Study Funding
No targeted funding reported.
Disclosure
The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.
References
- 1.Van den Bergh PY, Van Doorn PA, Hadden R, et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force—second revision. Eur J Neurol. 2021;28(11):3556-3583. doi: 10.1111/ene.14959 [DOI] [PubMed] [Google Scholar]
- 2.Martín-Aguilar L, Lleixà C, Pascual-Goñi E. Autoimmune nodopathies, an emerging diagnostic category. Curr Opin Neurol. 2022;35(5):579-585. doi: 10.1097/WCO.0000000000001107 [DOI] [PubMed] [Google Scholar]
- 3.Uncini A. Autoimmune nodo-paranodopathies 10 years later: clinical features, pathophysiology and treatment. J Peripher Nerv Syst. 2023;28(suppl 3):S23-S35. doi: 10.1111/jns.12569 [DOI] [PubMed] [Google Scholar]
- 4.Burnor E, Yang L, Zhou H, et al. Neurofascin antibodies in autoimmune, genetic, and idiopathic neuropathies. Neurology. 2018;90(1):e31-e38. doi: 10.1212/WNL.0000000000004773 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Martín-Aguilar L, Lleixà C, Pascual-Goñi E, et al. Clinical and laboratory features in anti-NF155 autoimmune nodopathy. Neurol Neuroimmunol Neuroinflamm. 2022;9(1):e1098. doi: 10.1212/NXI.0000000000001098 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Devaux JJ, Miura Y, Fukami Y, et al. Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy. Neurology. 2016;86(9):800-807. doi: 10.1212/WNL.0000000000002418 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Cortese A, Devaux JJ, Zardini E, et al. Neurofascin-155 as a putative antigen in combined central and peripheral demyelination. Neurol Neuroimmunol Neuroinflamm. 2016;3(4):e238. doi: 10.1212/NXI.0000000000000238 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Appeltshauser L, Junghof H, Messinger J, et al. Anti-pan-neurofascin antibodies induce subclass-related complement activation and nodo-paranodal damage. Brain. 2023;146(5):1932-1949. doi: 10.1093/brain/awac418 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Liu B, Zhou L, Sun C, et al. Clinical profile of autoimmune nodopathy with anti-neurofascin 186 antibody. Ann Clin Transl Neurol. 2023;10(6):944-952. doi: 10.1002/acn3.51775 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Kanda T. Biology of the blood-nerve barrier and its alteration in immune mediated neuropathies. J Neurol Neurosurg Psychiatry. 2013;84(2):208-212. doi: 10.1136/jnnp-2012-302312 [DOI] [PubMed] [Google Scholar]