A detailed clinical case report published in Breast Cancer Research and Treatment documents a 43-year-old female patient with metastatic breast cancer who developed a severe, treatment-refractory chronic immune-mediated polyradiculoneuropathy with anti-neurofascin antibodies approximately two weeks after initiating the cyclin-dependent kinase 4/6 inhibitor palbociclib. The patient had stage IV infiltrating ductal carcinoma of the right breast that was estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative, classified as cT4b, cN1, cM1, and grade 3, with known metastases to the brain, spine, and lungs. She had previously received six months of therapy with abemaciclib, letrozole, and leuprolide, which was discontinued following an acute kidney injury, prompting a therapeutic switch to palbociclib.
Approximately two weeks after starting palbociclib, the patient experienced initial sensory disturbances characterized by numbness in the fingertips and toes. Her initial outpatient evaluation noted borderline-low vitamin B12 levels of 272 pg/mL and an HbA1c of 6.5% reflecting diabetes mellitus, prompting initial suspicion of metabolic or medication-related side effects. However, subsequent diagnostic testing revealed normal methylmalonic acid and homocysteine levels, and oral vitamin B12 supplementation failed to halt symptom progression. Neurologic deficits advanced as weakness originating in the left upper extremity rapidly spread to involve the right upper extremity and both lower extremities, leading clinicians to discontinue palbociclib four weeks after initiation without any identifiable antecedent infection, vaccination, respiratory illness, or gastrointestinal disturbance.
By six weeks following palbociclib initiation, the patient required acute hospitalization due to progressive weakness and an inability to ambulate independently. Physical examination demonstrated diffuse areflexia, distal sensory loss affecting both the hands and feet, and motor weakness that was markedly more pronounced in the upper extremities, measuring 4/5 proximally and 3/5 distally on muscle grading. Her cranial nerve examination remained normal. Magnetic resonance imaging of the brain and spine excluded intracranial metastases, leptomeningeal disease, or spinal cord compression, revealing only stable thoracolumbar osseous metastases with L5-S1 nerve root compression that could not explain the anatomical distribution or severity of her clinical deficits.
Cerebrospinal fluid analysis revealed normal glucose, a borderline elevated protein concentration of 52.9 mg/dL, mild pleocytosis of 11 nucleated cells/µL, negative infectious evaluations, and no malignant cells on cytologic examination. Electromyography and nerve conduction studies demonstrated a mixed sensory greater than motor large-fiber peripheral neuropathy with prominent axonal and demyelinating features affecting the bilateral upper extremities more than the lower extremities. Diffuse active denervation was present across sampled right arm and proximal leg musculature, fulfilling the 2021 European Academy of Neurology and Peripheral Nerve Society electrodiagnostic criteria for an acquired inflammatory demyelinating polyradiculoneuropathy.
Repetitive nerve stimulation revealed an 11.3% decrement in the left spinal accessory nerve following exercise, which did not reproduce in the ulnar nerve. Diagnostic testing for acetylcholine receptor and muscle-specific kinase antibodies was negative, ruling out a primary disorder of the neuromuscular junction. Serologic investigations further demonstrated antibody positivity for both anti-neurofascin-155 and anti-neurofascin-186 at an immunofluorescence assay titer of 1:32, shifting diagnostic considerations toward an autoimmune nodopathy directed against nodal and paranodal structural proteins involved in saltatory nerve conduction.
Initial immunomodulatory therapy consisting of intravenous immunoglobulin at 0.4 g/kg/day administered over five days produced only limited clinical improvement. As progressive deterioration continued one month later, the patient underwent therapeutic plasmapheresis, but her motor deficits subsequently deteriorated into severe quadriparesis requiring repeat hospitalization. Given her refractory clinical trajectory, she received expanded immunotherapy comprising repeat plasmapheresis, high-dose intravenous methylprednisolone, repeat intravenous immunoglobulin, and two infusions of rituximab.
Following rituximab administration, the patient exhibited substantial gradual motor recovery and functional improvement over longitudinal follow-up. She regained functional independence, including the capacity to dress herself, tie her shoes, stand from a seated posture, and ambulate short distances without the assistance of a walker. Her residual neurologic deficits were limited to mild distal sensory blunting in the feet and persistent balance instability that required ongoing physical therapy rehabilitation.
The clinical presentation presented substantial diagnostic complexity, sharing overlapping characteristics with acute inflammatory demyelinating polyradiculoneuropathy, acute-onset chronic inflammatory demyelinating polyradiculoneuropathy, multifocal acquired demyelinating sensory and motor neuropathy, and autoimmune nodopathy. A classic post-infectious acute polyradiculoneuropathy was contradicted by asymmetric upper extremity onset, progressive worsening extending past eight weeks, and marked refractoriness to initial intravenous immunoglobulin. While the detection of anti-neurofascin antibodies indicated nodal immune pathology, the patient lacked classical anti-NF155 features such as marked tremor, ataxia, and markedly elevated cerebrospinal fluid protein, and also lacked the cranial neuropathy, dysautonomia, or respiratory failure characteristic of fulminant pan-neurofascin syndromes.
Alternative paraneoplastic etiologies were evaluated in light of the patient’s underlying metastatic malignancy, but high-risk onconeural antibodies including anti-Hu (ANNA-1) and CRMP5 were negative. Under 2021 PNS-Care criteria, neuropathies fulfilling chronic inflammatory demyelinating polyradiculoneuropathy parameters are not classified as paraneoplastic without well-characterized onconeural antibodies. Furthermore, paraneoplastic breast cancer manifestations predominantly produce cerebellar degeneration, myelopathy, or myopathy rather than inflammatory demyelinating polyradiculoneuropathies.
The authors highlight biological plausibility for palbociclib-induced autoimmunity based on established immunomodulatory properties of cyclin-dependent kinase 4/6 inhibitors. Preclinical data show that palbociclib induces G0/G1 cell-cycle arrest in activated T lymphocytes while preserving cytotoxic effector responses, with regulatory T cells displaying preferential susceptibility. Clinical trials, including ORACLE-RIPA and NeoRHEA, have demonstrated that palbociclib-containing regimens reduce circulating regulatory T cells and myeloid-derived suppressor cells, potentially altering immune tolerance and fostering conditions permissive for autoimmune responses.
The authors note that commercial serologic assays did not evaluate IgG4 subclass distribution, limiting detailed molecular characterization of the detected anti-neurofascin antibodies. Additionally, because anti-neurofascin reactivity can occasionally arise secondarily to severe ongoing nerve injury or appear across other neuropathies, and causal links cannot be established from a single patient case report, the authors emphasize the need for continued pharmacovigilance surveillance to evaluate whether cyclin-dependent kinase 4/6 inhibition can trigger or unmask autoimmune neurologic disease in susceptible individuals.
The broader clinical context highlights the significance of monitoring unexpected adverse events during standard breast cancer management. In the United States, breast cancer remains the most frequently diagnosed female malignancy, accounting for roughly 30 percent of new cancer diagnoses in women each year. Hormone receptor-positive and human epidermal growth factor receptor 2-negative disease comprises approximately 65 to 70 percent of all cases. For metastatic presentations, combining endocrine therapy with cyclin-dependent kinase 4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, serves as standard first-line treatment, achieving progression-free survival intervals of 24 to 33 months while improving overall survival and preserving patient quality of life. Consequently, developing well-tolerated therapeutic strategies remains essential to reduce overall disease burden while sustaining long-term functional independence. Although generally well tolerated, these targeted agents produce recognized hematologic and gastrointestinal toxicities, including neutropenia, fatigue, diarrhea, nausea, hepatotoxicity, and QT prolongation. In contrast, neurologic toxicities remain rare, largely limited to headache, dizziness, peripheral neuropathy, and rare instances of posterior reversible encephalopathy syndrome.
The initial asymmetric presentation directed diagnostic attention toward atypical chronic inflammatory demyelinating polyradiculoneuropathy variants, specifically multifocal disease, historically termed Lewis-Sumner syndrome. Classic disease typically exhibits symmetric motor weakness affecting both proximal and distal musculature, characterized by progressive or relapsing sensorimotor impairment extending beyond eight weeks due to peripheral nerve demyelination. In contrast, multifocal presentations involve asymmetric deficits across multiple individual nerves, often demonstrating distinct electrophysiologic profiles and variable responses to standard immunotherapy. Mechanistically, multifocal disease is believed to result from localized immune-mediated peripheral nerve damage, potentially involving breakdown of the blood-nerve barrier at sites of nerve conduction block. Unlike acute inflammatory demyelinating polyradiculoneuropathy, which typically follows an antecedent infection or vaccination and reaches its nadir within two to four weeks, multifocal chronic neuropathy demonstrates no consistent link to preceding infections and follows an indolent, prolonged course.
Differentiating autoimmune nodopathies from chronic inflammatory demyelinating polyradiculoneuropathy remains essential under the 2021 European Academy of Neurology and Peripheral Nerve Society guidelines, which classify nodopathies as distinct conditions. Autoimmune nodopathies target specialized structural proteins within nodal and paranodal regions responsible for saltatory conduction. Clinically, patients with autoimmune nodopathies experience greater motor disability, more pronounced weakness, and reduced responsiveness to intravenous immunoglobulin compared to those with classic demyelinating disease, while showing substantial improvement following B-cell therapies like rituximab. Electrophysiologically, typical nodopathies display demyelinating features without prominent axonal loss, alongside elevated cerebrospinal fluid protein without pleocytosis. In this patient, the detection of diffuse denervation denoting axonal injury alongside mild pleocytosis represented atypical features, demonstrating diagnostic overlap between classic inflammatory neuropathies and emerging nodopathies.
Beyond regulatory T-cell suppression, experimental investigations in glioma models indicate that cyclin-dependent kinase 4/6 inhibitors alter innate immune signaling pathways, providing further evidence of broad immunologic modulation beyond tumor cell-cycle regulation. While pharmacovigilance surveillance has documented generic peripheral neuropathy, chronic immune-mediated polyradiculoneuropathy presenting with neurofascin antibodies represents an unprecedented adverse event temporally linked to palbociclib. Because autoimmune nodopathies and atypical demyelinating variants require distinct therapeutic strategies, frequently proving refractory to conventional intravenous immunoglobulin while responding to targeted B-cell depletion, oncology teams should maintain vigilance for immune-mediated neuropathies when evaluating unexplained weakness, sensory loss, and areflexia during treatment. Continued reporting and investigation remain crucial to establish whether kinase inhibition unmasks or accelerates latent neuroautoimmune disease.
Subject of Research: Palbociclib-associated chronic immune-mediated polyradiculoneuropathy mimicking CIDP
Article Title: A rare neurological adverse event of palbociclib: a chronic inflammatory demyelinating polyneuropathy (CIDP) mimic
Article References: Zeynoun, J., Evans, M., Boldig, K., & Ali, H. (2026). A rare neurological adverse event of palbociclib: a chronic inflammatory demyelinating polyneuropathy (CIDP) mimic. Breast Cancer Research and Treatment, 220(1), Article 27. https://doi.org/10.1007/s10549-026-08081-6
Image Credits: AI Generated
DOI: 10.1007/s10549-026-08081-6
Keywords: palbociclib, CDK4/6 inhibitors, breast cancer, chronic inflammatory demyelinating polyneuropathy, autoimmune nodopathy, neurofascin antibodies, rituximab, adverse drug event, rare, neurological, adverse, event
News Source: Nathaniel Bowman. (November 6, 2026). Breast Cancer Drug Palbociclib Linked to Rare Autoimmune Neuropathy Mimicking CIDP. Scienmag.
