Can There Be an Axonal Variant of CIDP?
Yes, chronic inflammatory axonal polyneuropathy (CIAP) exists as a distinct entity that responds to immunotherapy and likely represents an axonal variant of CIDP, though this remains debated.
Evidence for Axonal CIDP
The concept of an axonal variant of CIDP is supported by multiple lines of evidence:
Chronic inflammatory axonal polyneuropathy (CIAP) has been formally defined based on patients with chronic progressive or relapsing polyneuropathy (>2 months duration), electrophysiological evidence of axonal neuropathy without strict demyelinating criteria, and definite responsiveness to immunotherapy 1.
In a cohort of 33 patients with immunotherapy-responding chronic axonal polyneuropathy (IR-CAP), clinical features were remarkably similar to typical CIDP except for the motor neuropathy subtype, with 78% showing elevated CSF protein and 45% demonstrating inflammatory axonal neuropathy on nerve biopsy 1.
Historical case series documented chronic progressive steroid-responsive axonal polyneuropathy in patients with increased CSF protein, normal sural nerve conductions, and complete recovery after steroid treatment, suggesting these cases represent one extreme of the CIDP spectrum characterized by severe axonal loss 2.
Diagnostic Challenges and Pitfalls
The recognition of axonal CIDP variants is complicated by several factors:
Mixed pathology is common: In a series of 67 consecutive CIDP patients, only 31% had pure demyelinating neuropathy on electrodiagnostic studies, while the majority showed some degree of axonal change 3. This highlights that strict adherence to demyelinating criteria may miss genuine CIDP cases.
Proximally located demyelination, secondary axonal loss, or predominant sensory fiber involvement can mask demyelinating parameters on standard nerve conduction studies, leading to misclassification as axonal neuropathy 4.
The French CIDP Study Group has proposed clinical and electrophysiological signs that are atypical for chronic idiopathic axonal polyneuropathy but suggestive of CIDP, specifically to prevent misclassification when demyelinating parameters are not apparent 4.
Clinical Implications and Treatment Response
The therapeutic responsiveness of these axonal variants is critical:
Treatment response rates are comparable: Patients with axonal features respond to immunotherapy (corticosteroids, IVIG, plasma exchange) at rates of 60-75%, similar to typical demyelinating CIDP 5, 6.
For severe or progressing symptoms in suspected axonal CIDP, consider pulse methylprednisolone 1g IV daily for 3-5 days plus IVIG 2g/kg over 5 days 7, 5.
In the original IR-CAP cohort, all patients by definition responded to immunotherapy, supporting the immune-mediated nature of these axonal variants 1.
Diagnostic Approach When Axonal Features Predominate
When evaluating a patient with chronic progressive polyneuropathy showing predominantly axonal features:
Confirm chronicity: Progression must exceed 2 months to distinguish from acute inflammatory neuropathies 7, 5.
Obtain CSF analysis: Elevated protein (cytoalbuminologic dissociation) is present in approximately 78% of axonal CIDP cases and supports an inflammatory etiology 1.
Consider nerve biopsy in atypical cases, as inflammatory changes can be demonstrated in approximately 45% of axonal variants 1.
Look for atypical features that suggest immune-mediated disease rather than chronic idiopathic axonal polyneuropathy, such as elevated CSF protein, treatment-related fluctuations, or asymmetric involvement 4.
Terminology and Classification
The nomenclature remains evolving:
Some experts suggest the term "chronic inflammatory polyneuropathy" should encompass cases from pure demyelinating to pure axonal neuropathies responsive to immunotherapy, similar to how Guillain-Barré syndrome includes both demyelinating (AIDP) and axonal (AMAN/AMSAN) subtypes 2.
The designation CIAP (chronic inflammatory axonal polyneuropathy) is preferred when inflammation is documented by elevated CSF protein or nerve biopsy, in addition to clinical and electrophysiological axonal features 1.
Key Caveat
Do not withhold immunotherapy trials in patients with chronic progressive polyneuropathy showing axonal features if clinical suspicion for immune-mediated disease is high, particularly when CSF protein is elevated or other atypical features are present 4. The distinction between "axonal CIDP" and primary axonal disorders has profound therapeutic implications, and a trial of immunotherapy may be both diagnostic and therapeutic 1, 2.