Population-Based Epidemiology Study of Paraneoplastic Neurologic Syndromes.

OBJECTIVES: Population-based epidemiologic data for paraneoplastic neurologic syndromes (PNSs) in the United States are lacking. Our objective was to evaluate the incidence, prevalence, and associated morbidity of PNS. METHODS: We performed a population-based epidemiology study in Olmsted County, Minnesota, with patients identified between January 1, 1987, and December 31, 2018, using the medical records linkage system of the Rochester Epidemiology Project (REP) who met the definite/probable 2021 PNS criteria and 2004 PNS criteria. Patients with dermatomyositis and myasthenia gravis with underlying tumors were included. Age- and sex-specific population counts were obtained from REP resources for January 1, 2014 (prevalence denominator) and annually for 1987-2018 (incidence denominator). Morbidity was estimated using disability-adjusted life years (DALYs; years lived with disability [YLD] plus years of life lost [YLL]). RESULTS: There were 28 patients with PNS identified (50% female) residing in Olmsted County, Minnesota, with median age at diagnosis of 54.5 (IQR 46.5-69.0) years. All patients had a cancer diagnosis, and 18 (64%) patients were neural autoantibody positive including antineuronal nuclear autoantibody type 1 (ANNA-1/anti-Hu; n = 1), ANNA-2/anti-Ri (n = 1), muscle-type acetylcholine receptor (AChR; n = 6), Purkinje cell cytoplasmic antibody type 1 (PCA-1/anti-Yo; n = 1), kelch-like protein 11 (KLH11; n = 3), collapsin response mediator protein 5 (CRMP-5/anti-CV2; n = 2), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (n = 1), neurofilament light chain (n = 1), leucine zipper 4 (LUZP4; n = 1), and unclassified neural antibodies (n = 1). PNS incidence was 0.6/100,000 person-years and increased over time from 0.4/100,000 person-years (1987-2002) to 0.8/100,000 person-years (2003-2018) (p = 0.06). Prevalence was 5.4/100,000 people. The median follow-up period after PNS diagnosis was 3.1 years (IQR, 1.1-9.9 years). Total disability-adjusted life years (DALYs) for 28 patients with PNS were 472.7 years, based on total years of life lost (YLL) for patients dying between 1987 and 2018 (n = 15) of 445.3 years plus years lived with disability (YLD) 27.4 years. DISCUSSION: PNSs are rare neurologic disorders but are associated with severe morbidity and mortality. The estimated number of prevalent PNS cases in the United States is 17,099, and predicted DALY for all US PNS cases is 292,393 years. Their apparent increasing rate of detection is attributable to increasing physician awareness and availability of serologic testing.

Cellular immune suppression in paraneoplastic neurologic syndromes targeting intracellular antigens.

BACKGROUND Tumor treatment is the mainstay of therapy for paraneoplastic neurologic disorders (PNDs), but it is only effective in some cases and other treatment options are limited. OBJECTIVE To evaluate the short-term use of a combination of prednisone and tacrolimus for acute neurologic worsening in PND in which intracellular antigens are targeted. DESIGN Retrospective single-center case series of patients with PND treated with tacrolimus. SETTING The Rockefeller University Hospital, a research hospital in New York, New York. PATIENTS Twenty-six patients with PND with high titer (≥1:1000) anti-HuD, anti-Yo, or anti-CRMP5 autoantibodies were enrolled. Patients were referred from Memorial Sloan Kettering Cancer Center or self-referred. Two patients discontinued intervention owing to adverse events. INTERVENTIONS Patients were treated with tacrolimus, 0.15-0.30 mg/kg per day, in 2 divided oral doses with 60 mg per day of oral prednisone, tapered off during 1 to 4 weeks. MAIN OUTCOME MEASURES The primary outcome measure was median survival. Neurologic examinations before and after treatment as well as adverse events are described. RESULTS Median survival time was 52 months from time of diagnosis. Some patients experienced neurologic improvement that was functionally meaningful. The incidence of adverse events was similar to that generally reported with tacrolimus. CONCLUSIONS A short course of prednisone and tacrolimus to target central nervous system T cells in patients with PND with acute neurologic decline in which intracellular antigens are targeted was well tolerated and warrants further study. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00378326.

Neurological course of long-term surviving patients with SCLC and anti-Hu syndrome.

Patients with small-cell lung cancer (SCLC) have a poor prognosis with a three year survival rate of 4%. Our report concerns three patients with histologically proven SCLC and anti-Hu associated paraneoplastic neurological syndrome who have survived for 11 in two cases and 16 years respectively. The patients showed progressive deterioration which was only partly beneficially modulated by steroid therapy or tumor treatment, even in the cases with complete tumor remission.

Neoplastic meningitis-related encephalopathy.

BACKGROUND: A retrospective comparison evaluating survival in two well-matched cohorts of patients with cytologically positive neoplastic meningitis (NM) presenting with or without encephalopathy. METHODS: Two cohorts were studied: 20 with and 20 without of NM-related encephalopathy defined as a confusional syndrome. Cohorts were matched with respect to age, primary tumor, performance status, absence of CSF compartmentalization and absence of neuroradiographic bulky CNS disease. Primary tumor histology included the following: breast(10 patients); non-small cell lung cancer (8); non-Hodgkin's lymphoma (8); colorectal cancer (6); melanoma (4); small cell lung cancer (2); prostate cancer (2). NM at presentation revealed: encephalopathy (20 patients); spinal cord dysfunction (18); and cranial neuropathy (15). Radiotherapy was administered to 31 patients (whole brain only in 17 patients; restricted spine only in 8 patients; whole brain and restricted spine in 6 patients). All patients received intraventricular chemotherapy and 16 patients received concurrent tumor-specific systemic chemotherapy. RESULTS: Median survival was 2.5 months (range 1.5-5 months) in the cohort with NM-related encephalopathy compared to 6 months (range: 2-10 months) in the cohort without NM-related encephalopathy (p < 0.001). No treatment-related deaths were observed. All patients demonstrated progressive disease and died of either NM or systemic cancer. CONCLUSIONS: NM-related encephalopathy is a clinical variable that predicts for poor survival in patients with NM. As a consequence, patients with NM-related encephalopathy may be best served by offering supportive care.

Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies-a report from the Children's Cancer Group Study.

BACKGROUND: Opsoclonus-myoclonus-ataxia (OMA) is a paraneoplastic neurologic syndrome affecting 2-3% of children with neuroblastoma. Although children with OMA and neuroblastoma may have higher survival, many experience a significant amount of late neurologic impairment, which may be immunologically mediated. The aim of this study was to compare the outcome of neuroblastoma patients with and without OMA, relating to prognostic factors, treatment, and the presence or absence of anti-neuronal antibodies. PROCEDURE: Questionnaires were mailed out requesting information on the current neurologic status of patients who submitted sera at diagnosis to the Children's Cancer Group serum bank from 1980 to 1994. Information was requested on clinical and biological patient characteristics as well as clinical aspects of the patients identified as having OMA syndrome, including presentation and treatment for OMA, late sequelae of OMA, the presence or absence of antineuronal antibodies, and survival. Sera from 16 of the OMA patients and 48 case-controls with neuroblastoma were assayed for anti-neuronal antibodies. RESULTS: Of the 675 responses received, 21 patients had OMA. Ninety percent of OMA patients presented with non-metastatic disease, vs. 35% of non-OMA patients. Estimated 3-year survival for the OMA patients with nonmetastatic disease (stage I, II, III) greater than 1 year of age was 100% vs. 77% for similar non-OMA patients (P = 0.0222). At follow-up, 14/19 evaluable OMA patients displayed some form of developmental or neurologic abnormality. There was no significant correlation of late sequelae with antineuronal antibodies, age, time between OMA symptoms and diagnosis, or treatment given for tumor or OMA. There was a significant correlation of late sequelae with lower stage disease (I and II) compared to more advanced disease (III and IV). CONCLUSIONS: Patients with OMA and neuroblastoma have excellent survival but a high risk of neurologic sequelae. Favorable disease stage correlates with a higher risk for development of neurologic sequelae. The role of anti-neuronal antibodies in late sequelae of OMA needs further clarification.