Introduction

Myelin sheaths insulate axons of nerves (see Image. Longitudinal Section of a Myelinated Nerve Fiber). Myelin sheaths consist of lipid-rich extensions of the plasma membrane produced by Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS). The myelin sheath is regularly interrupted along the axonal length by specialized regions termed "nodes of Ranvier." These nodes are required for propagation of action potentials along axons and regulate the speed and timing of impulse transmission between neurons.[1] Alterations in node size or function can compromise neuronal function and contribute to the development of neurological disorders.[2]

Structure and Function

Nodes of Ranvier are characterized by short (1 μm), specialized regions of the axonal membrane that are not insulated by myelin. Although bare of myelin at the node, the axon maintains direct contact with Schwann cell microvilli in the PNS or astrocyte processes in the CNS (see Image. Node of Ranvier).[3]

Nodes contain high concentrations of voltage-gated sodium ion channels, which increase membrane voltage during generation of an all-or-none action potential. Loops of myelin form tight, septate-like junctions (SpJs) with the axonal membrane in regions directly adjacent to the nodes, termed "paranodes."[4] These junctions provide structural scaffolding within the axon, compartmentalize axonal molecules, and restrict movement of ion channels within the axonal membrane.[5] The side of this junction opposite the node is termed the "juxtaparanode," which contains high concentrations of voltage-gated potassium ion channels that facilitate return of membrane voltage to baseline following an action potential. Efficient propagation of action potentials requires voltage-gated sodium and potassium channels to remain in distinct regions. The long, myelin-covered segment of axon between nodes is termed the "internode."

The myelin sheath increases transmission speed by acting as an electrical insulator. In nonmyelinated axons, action potentials propagate continuously along the plasma membrane. Within myelinated regions, increased resistance to transmembrane charge movement facilitates rapid propagation of voltage signals within the axonal cytoplasm to the next node. Action potentials require amplification at each node through sodium ion influx as the voltage signal dissipates along the length of the myelinated axon.

Nodes of Ranvier and adjacent regions contain high concentrations of structural proteins, including ankyrins, responsible for anchoring integral membrane proteins to the axonal cytoskeleton. Pathological distribution of essential nodal proteins, including ion channels and cell adhesion molecules, can impair propagation of nerve impulses.

Ganglioside GM1 is instrumental in tethering molecular components of the node within subdomains of the nodal plasma membrane termed "lipid rafts." Damage to GM1 through production of anti-ganglioside antibodies occurs in most autoimmune neuropathies and results in loss of conduction efficacy.

Damage to proteins within the paranode disrupts the paranodal SpJ and leads to subsequent myelin retraction. Appropriate localization of ion channels requires the primary paranodal adhesion molecule, neurofascin 155 (NF155). Dissociation of glial NF155 from axonal adhesion molecules in the context of neonatal hypoxia and autoimmune disorders initiates paranodal degradation and may lead to myelin retraction.[6]

Impaired myelin maintenance due to dysfunctional oligodendrocytes may also result in myelin retraction, with exposure of voltage-gated potassium channels in the juxtaparanode. Exposure of these channels results in impaired function and has been observed in multiple neurological diseases, including stroke, multiple sclerosis, and traumatic or hypoxic brain injury.[7]

Embryology

Nodes form at relatively high density along the axon during development, followed by an increase in internode length as embryonic growth and axonal elongation occur. In humans, peak myelination ensues during the first year of life, beginning in the PNS and extending later to the brain and spinal cord. Axons with the largest diameters are typically myelinated first.[8][9]

Assembly of Ranvier nodes requires expression of specific structural proteins within the axon and interactions with glial-derived signals. Neuronal expression of ankyrin G (ankG) interacts structurally with voltage-gated sodium channels and other nodal proteins. Sodium channels concentrate within the axonal membrane adjacent to new myelin segments, termed "heminodes." Ion channel mobility is restricted by the paranodal SpJ, allowing clustering as adjacent heminodes merge to form a node of Ranvier.

In the CNS, an additional redundant and independent mechanism of node formation is mediated by glial signaling. Node formation in the CNS also involves interactions with oligodendrocyte-secreted proteins, including chondroitin sulfate proteoglycans.

Surgical Considerations

Disruption of myelin sheath integrity leads to impaired nerve conduction and, if severe enough, complete conduction block. Minor acute injury to peripheral nerves often resolves without intervention. Conduction velocity may remain reduced after recovery because Schwann cell-mediated remyelination produces thinner myelin and more closely spaced nodes along the axon.[10] More severe peripheral nerve injury associated with neurotmesis requires surgical intervention, typically end-to-end nerve repair.[11] Epineurial sutures maintain nerve continuity following removal of necrotic nerve ends and realignment of the nerve and vascular supply. Age is the most critical factor in recovery and accounts for approximately 50% of outcome variance.[12]

Clinical Significance

Disruption of nodes of Ranvier and myelin may result from autoimmune disorders, including multiple sclerosis, Guillain-Barré syndrome (GBS), and lupus. White matter injury, including neonatal hypoxia and traumatic brain injury, may also lead to subsequent demyelination.

Multiple sclerosis characteristically presents with multiple white matter lesions that develop over time. Although reduction of conduction velocity or complete conduction block due to demyelination represents the primary pathology associated with multiple sclerosis, long-term progression of symptoms also correlates with axonal damage caused by direct immune interactions with nodal and paranodal proteins.

Loss of F155, which disrupts paranodal SpJs, impairs conduction by permitting extracellular current flow and inappropriate redistribution of potassium channels into the node.[13] Pharmacological blockade of voltage-gated potassium channels has been demonstrated to attenuate symptoms of multiple sclerosis, including gait and visual disturbances.[14]

Patients presenting with symptoms of multiple sclerosis should undergo blood and cerebrospinal fluid analysis to exclude infections and other conditions with similar clinical features.[15] During the active phase of multiple sclerosis, magnetic resonance imaging of the brain and spinal cord may demonstrate white matter lesions when performed with intravenous gadolinium contrast. Magnetic resonance imaging of the spinal cord also assists in exclusion of spinal stenosis and neoplasm.[16]

Acute treatment with high-dose corticosteroids, including oral prednisone or intravenous methylprednisolone, reduces neural inflammation.[17] Long-term disease modification may be achieved with subcutaneous or intramuscular β-interferon, which decreases expression of inflammatory cytokines and promotes expression of anti-inflammatory and prosurvival factors.[18][19][20]

GBS is an immune-mediated neuropathy driven by antibodies that cross-react with endogenous proteins enriched in peripheral nerves, including ganglioside GM1 and members of the neurofascin adhesion molecule family, such as NF155.[21][22] GBS often manifests following infection, when antibodies generated against infectious agents exhibit cross-reactivity with endogenous gangliosides, such as GM1.[23] Clinical presentation includes symmetrical flaccid weakness, typically accompanied by areflexia or hyporeflexia. Approximately 25% of patients require mechanical ventilation during the disease course. Acute motor axonal neuropathy, a subtype of GBS, demonstrates 2 prognostic patterns: rapid recovery of motor function following resolution of acute conduction block, or persistent long-term deficit associated with Wallerian degeneration and chronic axonal injury.

Clinical evaluation for GBS typically requires lumbar puncture demonstrating albuminocytologic dissociation (elevated cerebrospinal fluid protein levels) and electrophysiologic studies, including nerve conduction studies and electromyography.[24] Blood analysis commonly demonstrates anti-ganglioside antibodies. Standard treatment includes intravenous immunoglobulin and plasma exchange, which are equally effective and remain the primary therapeutic modalities for GBS regardless of electrophysiological subtype. Corticosteroids are not recommended for GBS treatment, as multiple randomized controlled trials have demonstrated they provide no benefit and may even delay recovery. The approach to GBS management differs from multiple sclerosis, where corticosteroid therapy is the standard acute intervention for relapses.[25][26]

Age-dependent changes in the molecular distribution of nodal and paranodal proteins may contribute to cognitive decline. Inappropriate redistribution of voltage-gated potassium channels into nodal and paranodal regions is increased in aged rodent and primate nerves. This redistribution of channels maintains the node at a more hyperpolarized membrane potential, thereby impairing action potential conduction. Older patients demonstrate higher thresholds for electrical stimuli required to induce action potentials compared with younger patients. Older humans also demonstrate longer latencies, smaller amplitudes, and slower conduction velocities compared with younger individuals.[27]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Arancibia-Carcamo IL, Attwell D. The node of Ranvier in CNS pathology. Acta Neuropathol. 2014 Aug;128(2):161-75. [PMC free article: PMC4102831] [PubMed: 24913350]

2.

Eshed-Eisenbach Y, Brophy PJ, Peles E. Nodes of Ranvier in health and disease. J Peripher Nerv Syst. 2023 Jul;28 Suppl 3:S3-S11. [PubMed: 37272548]

3.

Davis JQ, Lambert S, Bennett V. Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+/third FNIII domain-) and NrCAM at nodal axon segments. J Cell Biol. 1996 Dec;135(5):1355-67. [PMC free article: PMC2121080] [PubMed: 8947556]

4.

Poliak S, Peles E. The local differentiation of myelinated axons at nodes of Ranvier. Nat Rev Neurosci. 2003 Dec;4(12):968-80. [PubMed: 14682359]

5.

Rasband MN, Peles E. The Nodes of Ranvier: Molecular Assembly and Maintenance. Cold Spring Harb Perspect Biol. 2015 Sep 09;8(3):a020495. [PMC free article: PMC4772103] [PubMed: 26354894]

6.

Zhang YP, Huang QL, Zhao CM, Tang JL, Wang YL. GM1 improves neurofascin155 association with lipid rafts and prevents rat brain myelin injury after hypoxia-ischemia. Braz J Med Biol Res. 2011 Jun;44(6):553-61. [PubMed: 21670940]

7.

Mahoney SO, Chowdhury NF, Ngo V, Imms P, Irimia A. Mild Traumatic Brain Injury Results in Significant and Lasting Cortical Demyelination. Front Neurol. 2022;13:854396. [PMC free article: PMC9262516] [PubMed: 35812106]

8.

Snaidero N, Simons M. Myelination at a glance. J Cell Sci. 2014 Jul 15;127(Pt 14):2999-3004. [PubMed: 25024457]

9.

Yu Q, Guan T, Guo Y, Kong J. The Initial Myelination in the Central Nervous System. ASN Neuro. 2023 Jan-Dec;15:17590914231163039. [PMC free article: PMC10052612] [PubMed: 36974372]

10.

Fex Svennigsen A, Dahlin LB. Repair of the Peripheral Nerve-Remyelination that Works. Brain Sci. 2013 Aug 02;3(3):1182-97. [PMC free article: PMC4061866] [PubMed: 24961524]

11.

Howarth HM, Alaziz T, Nicolds B, O'Connor S, Shah SB. Redistribution of nerve strain enables end-to-end repair under tension without inhibiting nerve regeneration. Neural Regen Res. 2019 Jul;14(7):1280-1288. [PMC free article: PMC6425842] [PubMed: 30804260]

12.

M F G, M M, S H, Khan WS. Peripheral nerve injury: principles for repair and regeneration. Open Orthop J. 2014;8:199-203. [PMC free article: PMC4110386] [PubMed: 25067975]

13.

Howell OW, Palser A, Polito A, Melrose S, Zonta B, Scheiermann C, Vora AJ, Brophy PJ, Reynolds R. Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain. 2006 Dec;129(Pt 12):3173-85. [PubMed: 17041241]

14.

Griggs RB, Yermakov LM, Susuki K. Formation and disruption of functional domains in myelinated CNS axons. Neurosci Res. 2017 Mar;116:77-87. [PubMed: 27717670]

15.

Ford H. Clinical presentation and diagnosis of multiple sclerosis. Clin Med (Lond). 2020 Jul;20(4):380-383. [PMC free article: PMC7385797] [PubMed: 32675142]

16.

Traboulsee AL, Li DK. The role of MRI in the diagnosis of multiple sclerosis. Adv Neurol. 2006;98:125-46. [PubMed: 16400831]

17.

Hauser SL, Cree BAC. Treatment of Multiple Sclerosis: A Review. Am J Med. 2020 Dec;133(12):1380-1390.e2. [PMC free article: PMC7704606] [PubMed: 32682869]

18.

Kieseier BC. The mechanism of action of interferon-β in relapsing multiple sclerosis. CNS Drugs. 2011 Jun 01;25(6):491-502. [PubMed: 21649449]

19.

Zettl UK, Rommer PS, Aktas O, Wagner T, Richter J, Oschmann P, Cepek L, Elias-Hamp B, Gehring K, Chan A, Hecker M. Interferon beta-1a sc at 25 years: a mainstay in the treatment of multiple sclerosis over the period of one generation. Expert Rev Clin Immunol. 2023 Jul-Dec;19(11):1343-1359. [PubMed: 37694381]

20.

Filipi M, Jack S. Interferons in the Treatment of Multiple Sclerosis: A Clinical Efficacy, Safety, and Tolerability Update. Int J MS Care. 2020 Jul-Aug;22(4):165-172. [PMC free article: PMC7446632] [PubMed: 32863784]

21.

Kira JI, Yamasaki R, Ogata H. Anti-neurofascin autoantibody and demyelination. Neurochem Int. 2019 Nov;130:104360. [PubMed: 30582947]

22.

Gorson KC. Evolving understanding of Guillain-Barré syndrome pathophysiology and the central role of the classical complement pathway in axonal injury. Front Neurol. 2025;16:1572949. [PMC free article: PMC12117664] [PubMed: 40438570]

23.

van den Berg B, Walgaard C, Drenthen J, Fokke C, Jacobs BC, van Doorn PA. Guillain-Barré syndrome: pathogenesis, diagnosis, treatment and prognosis. Nat Rev Neurol. 2014 Aug;10(8):469-82. [PubMed: 25023340]

24.

van Doorn PA, Van den Bergh PYK, Hadden RDM, Avau B, Vankrunkelsven P, Attarian S, Blomkwist-Markens PH, Cornblath DR, Goedee HS, Harbo T, Jacobs BC, Kusunoki S, Lehmann HC, Lewis RA, Lunn MP, Nobile-Orazio E, Querol L, Rajabally YA, Umapathi T, Topaloglu HA, Willison HJ. European Academy of Neurology/Peripheral Nerve Society Guideline on diagnosis and treatment of Guillain-Barré syndrome. Eur J Neurol. 2023 Dec;30(12):3646-3674. [PubMed: 37814552]

25.

Zaki HA, Iftikhar H, Najam M, Masood M, Al-Marri NDR, Elgassim MAM, Fayed M, Shaban EE. Plasma exchange (PE) versus intravenous immunoglobulin (IVIG) for the treatment of Guillain-Barré syndrome (GBS) in patients with severe symptoms: A systematic review and meta-analysis. eNeurologicalSci. 2023 Jun;31:100468. [PMC free article: PMC10242495] [PubMed: 37288440]

26.

Bellanti R, Rinaldi S. Guillain-Barré syndrome: a comprehensive review. Eur J Neurol. 2024 Aug;31(8):e16365. [PMC free article: PMC11235944] [PubMed: 38813755]

27.

Palve SS, Palve SB. Impact of Aging on Nerve Conduction Velocities and Late Responses in Healthy Individuals. J Neurosci Rural Pract. 2018 Jan-Mar;9(1):112-116. [PMC free article: PMC5812134] [PubMed: 29456354]

Disclosure: Michael Grider declares no relevant financial relationships with ineligible companies.

Disclosure: Benjamin Covington declares no relevant financial relationships with ineligible companies.

Disclosure: Vamsi Reddy declares no relevant financial relationships with ineligible companies.

Disclosure: Felix Jozsa declares no relevant financial relationships with ineligible companies.