Nodo‑Paranodopathy
"My AIN, PAIN"
History
1990s Anti-GM1, paradox of electrical demyelination w/ axonal integrity
2012-2013 Uncini & Kuwabara, term nodopathy
2021 EAN guidelines AIN≠CIPD
Pathophysiology
-AIDP/CIDP = macrophage btw myelin lamellae→ T‑cell recruitment→ segmental demyelination
>Schwann cells shift into iDSc (mimicry)
>AKA macrophage‑associated demyelinating (MAD)-neuropathy
>Demyelination = temporal dispersion + conduction block caused by segmental myelin loss
-NP = Ab-mediated
>Start paranodal loops
>AKA pure antibody‑induced neuropathy (AIN-PAIN)
>Reversible conduction failure (RCF)
RCF = nodal dysfunction w/o structural injury
Localization
-Node (Kv7)
>NF‑186 (often severe and fulminant)
-Paranode
>NF‑155 (classically tremulous phenotype)
Triad: Young + ataxic + tremulous
>CASPR1
>Contactin‑1 (CNTN‑1) (classically edematous phenotype)
Triad: Elderly + aggressive + edematous
Assoc w/ membranous glomerulopathy
-Juxtaparanode (Kv1)
>CASPR‑2
>LGI4
PAIN
-2 types = ganglioside & nodal
Ganglioside Ab
-Usually transient
-Typically produce AIDP presentations
-Often reversible
Nodal Ab
-AIDP/CIDP-like
- AIDP-like: RFC; if early, complete recovery
>Severe cases (like IgG3) activate MAC; irreversible
Acute vs. Chronic
-concept of IgG class switch
Acute Phase
-Driven by short‑lived plasmablasts
-IgG3 Ab→ ⊕complement (fulminant damage)
Chronic Phase
-Maintained by long‑lived plasma cells
-switch to IgG4 Ab→ ⊖complement; act as functional blockers
*smoldering neuropathy
Therapy
Seropositivity matters for treatment choice
-RTX→ effective IgG4 disorders
-IVIG→ less effective in IgG4
>IVIG relies on complement inh
Consider Ab-test if:
-tremor, ataxia, speed (aggressive), resistance (IVIG), comorbidies (GN), pain
Summary
-First-line
>RTX for NF155, CNTN1, CASPR1 (IgG4/IgG3)
>IVIG/PLEX for ganglioside-mediated AIN, CASPR2
-Second-line
>Combination RTX + IVIG for overlap or refractory cases
