Performance of 2021 criteria for the diagnosis of PNSs
A new study measures the performance of the 2021 criteria for paraneoplastic neurological syndromes in childhood, a rare condition, often difficult to diagnose.
Paraneoplastic Neurologic Syndromes (PNS)
The term PNSs refers to signs or symptoms that result from damage to organs or tissues that are far from the site of a malignant neoplasm or its metastases. PNSs could cause severe neurological morbidity and mortality and often present to the neurologist in a patient without a known malignancy. PNSs are triggered by an immune response against onconeural antigens expressed by the tumour that are also expressed in the nervous system. Opsoclonus myoclonus syndrome (OMS) is one of the most common paraneoplastic neurologic syndromes in children.
Recently, there is increasing interest in performing research in children with paraneoplastic neurologic syndrome. Still, there is only scarce literature regarding this topic as compared to adults.
The frequency of PNSs is low; they occur in 1% of patients with solid tumours, particularly small-cell lung carcinoma (SCLC), breast, and ovarian cancers in adults and in neuroblastoma most commonly in children.
The 2021 Diagnostic Criteria for Paraneoplastic Neurologic Syndromes
The 2021 criteria for diagnosing PNSs1 represent significant advancements over the 2004 criteria. These updates were driven by the discovery of new antibodies and a better understanding of the clinical presentations of PNS. The revised criteria introduce a tiered diagnostic approach categorising cases into possible, probable, and definite PNS based on a comprehensive scoring system. This system incorporates clinical phenotype, type of antibody, presence or absence of cancer, and duration of follow-up. The criteria also distinguish between high-risk and intermediate-risk antibodies and phenotypes, reflecting their varying associations with cancer.
Do 2021 criteria work well in paediatric PNS?
The study by Zhou et al.2 retrospectively analysed paediatric patients diagnosed with PNSs at Beijing Children's Hospital between June 2015 and June 2023.
A total of 42 patients (20 males) with a median age of 1.75 years were included. The most common neurologic syndrome was opsoclonus-myoclonus syndrome (OMS) (62%), followed by rapidly progressive cerebellar syndrome (26%). Neuroblastoma was the predominant tumor (88%), with ovarian teratomas comprising 10% of cases.
According to the 2021 criteria, 71% of patients were classified as definite, 24% as probable, 2% as possible, and 2% as non-PNS. Tumours were detected in 95% of patients within a month of neurologic symptom onset. Paraneoplastic antibodies were positive in 12% of patients, including anti-NMDAR, Hu, and CV2 antibodies.
Management and outcomes
The management of paediatric PNSs, as outlined in the study, involves a combination of tumour-directed therapies and immunotherapies. The importance of early tumour resection and chemotherapy cannot be overstated, as these interventions address the primary source of the immune response causing the neurologic symptoms. The study's data suggest that timely surgical intervention, coupled with chemotherapy, significantly improves neurologic outcomes in children with neuroblastoma-associated PNSs.
Immunotherapies, including intravenous gamma globulin (IVIG) and glucocorticoids, play a crucial role in modulating the immune response and reducing inflammation. The universal administration of these therapies to all study participants underscores their importance in the management protocol. The significant improvement in modified Rankin Scale (mRS) scores observed over the follow-up period highlights the efficacy of these treatments in restoring neurologic function.
Only 17% of patients showed poor response to treatment, primarily in the low-risk group that did not receive chemotherapy. This finding suggests that a more aggressive treatment approach may be warranted even in cases initially considered low-risk to prevent refractory disease and improve long-term outcomes.
Future Directions
The study highlights that OMS and rapidly progressive cerebellar ataxia are the most prevalent paediatric PNSs, commonly associated with neuroblastoma. Aggressive multimodal immunotherapy can enhance prognosis in these cases. The 2021 diagnostic criteria demonstrated strong performance, though an upgrade in the classification of antibody-negative rapidly progressive cerebellar ataxia with neuroblastoma to a definite diagnosis is recommended to improve diagnostic accuracy.
Future research should focus on further refining the diagnostic criteria to incorporate emerging clinical and immunologic insights. Longitudinal studies tracking the outcomes of patients diagnosed using the 2021 criteria will provide valuable data on their long-term efficacy and potential areas for improvement. Additionally, exploring the role of novel immunotherapies and targeted treatments in paediatric PNSs management could lead to more effective and personalised therapeutic strategies.
The study also highlights the need for increased awareness and education among clinicians regarding paediatric PNSs. Given the rarity and complexity of these syndromes, ongoing training and dissemination of updated guidelines are essential to ensure that healthcare providers can recognize and manage these conditions effectively.
- Graus F, Vogrig A, Muñiz-Castrillo S, Antoine JG, Desestret V, Dubey D, Giometto B, Irani SR, Joubert B, Leypoldt F, McKeon A, Prüss H, Psimaras D, Thomas L, Titulaer MJ, Vedeler CA, Verschuuren JJ, Dalmau J, Honnorat J. Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes. Neurol Neuroimmunol Neuroinflamm. 2021 May 18;8(4):e1014. doi: 10.1212/NXI.0000000000001014. PMID: 34006622; PMCID: PMC8237398.
- Zhou J, Jin M, Su Y, Zhuo X, Fu L, Ren X, Ren C, Zhou A, Li J, Zhang W. Clinical Presentation, Management, and Diagnostic Performance of 2021 Criteria for Paraneoplastic Neurologic Syndromes in Childhood. Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200242. doi: 10.1212/NXI.0000000000200242. Epub 2024 Apr 24. PMID: 38657195; PMCID: PMC11087047.