The RNA-binding protein HuR is essential for the B cell antibody response.

Post-transcriptional regulation of mRNA by the RNA-binding protein HuR (encoded by Elavl1) is required in B cells for the germinal center reaction and for the production of class-switched antibodies in response to thymus-independent antigens. Transcriptome-wide examination of RNA isoforms and their abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interactions, revealed that HuR-dependent splicing of mRNA affected hundreds of transcripts, including that encoding dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase (α-KGDH) complex. In the absence of HuR, defective mitochondrial metabolism resulted in large amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for the proliferation and differentiation of B cells.

A large screen for paraneoplastic neurological autoantibodies; diagnosis and predictive values.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are a group of syndromes that affect the central and peripheral neuromuscular system in association with cancer. Specific antibodies may assist in the diagnosis of PNS. The antibodies tested can be classified into those directed against intracellular neuronal proteins ("well characterized" PNS: Hu, Yo, RI, CV2, amphiphysin, Ma1, Ma2) and those directed against neural surface antigens (autoimmune encephalitis syndromes: NMDA, AMPA, LGI1, CASPR2, GABAR). We aimed to characterize patients with unexplained neuropsychiatric symptoms, in whom positive PNS antibodies were detected in the Sheba medical center, a large referral hospital. METHODS: Clinical and demographic data of patients with positive PNS antibodies were collected during the years 2002-2016. Antibodies were tested by either Line immunoassay or by cell-based indirect immunofluorscent assay. RESULTS: During the follow up of 14 years, 4010 PNS tests were performed in patients with unexplained neuropsychiatric symptoms. Seventy-two were found to be positive; among them we had full clinical data access to 44. The most frequent antibodies were anti-Hu (31.8%), anti-Yo (18.2%), anti-CV2 (13.6%), and anti-NMDA (9.1%), and the most common cancers were small-cell lung (SCLC) and ovarian cancers. In the well characterized paraneoplastic group, cancer was diagnosed in 55.9% of the patients, and in the autoimmune encephalitis group, 40.0% were diagnosed with cancer. A positive correlation between antibody titer and the presence of cancer was found. Ninety percent of the tests in patients who were found positive were ordered by a neurologist or neuro-oncologist. CONCLUSIONS: The titers of PNS auto-antibodies can predict cancer in patients whom anti-PNS antibodies are tested. In addition, consultation with a specialist should be considered before this test is ordered.

Case of anti-Hu antibody-mediated encephalopathy associated with ovarian cancer.

The present report describes a case of anti-Hu antibody-mediated encephalopathy associated with ovarian cancer. The patient developed paraneoplastic neurologic syndromes (PNS) during the course of ovarian cancer and showed a symptom of jargon aphasia; diagnosis of PNS was made on the basis of serological and cerebrospinal examination, electroencephalogram (EEG), and magnetic resonance images. EEG initially indicated a condition of non-convulsive status epilepticus; however, levetiracetam administration facilitated complete recovery of this condition. Furthermore, immunotherapy and steroid therapy were very effective and significant improvement was achieved. PNS usually occur before the cancer is identified; however, the possibility of PNS should be considered when neurologic symptoms are noted during the course of oncologic diseases, including ovarian cancer.

Anti-Hu-Associated Autoimmune Limbic Encephalitis in a Patient with PD-1 Inhibitor-Responsive Myxoid Chondrosarcoma.

Autoimmune encephalitis is an uncommon complication of immune checkpoint inhibitor therapy. This article reports a case of fatal anti-Hu-associated autoimmune limbic encephalitis presenting within 8 weeks following anti-PD1 therapy in a patient with myxoid chondrosarcoma and pre-existing anti-Hu antibodies. Although tumor reduction occurred in response to PD-1 inhibitor therapy, the patient had a rapidly progressive decline in neurologic function despite initial stabilization with immunosuppression. Considering the increasing use of immune checkpoint inhibitors for the treatment of various malignancies, an increase in the occurrence of neurologic adverse events is likely, requiring prompt intervention and enhanced pharmacovigilance in malignancies associated with onconeuronal antibodies.

HuR keeps interferon-ß mRNA stable.

The expression of interferon (IFN) ß is highly induced in immune and nonimmune cells in response to virus infection. This upregulation is mediated at both transcriptional and posttranscriptional levels. Whereas the signaling pathways triggered by innate virus receptors leading to transcription factor activation have been extensively studied, the mechanisms by which IFN-ß mRNA stability is posttranscriptionally controlled are not fully understood. In this issue of the European Journal of Immunology, Herdy et al. [Eur. J. Immunol. 2015 45:1500-1511] show that a human RNA-binding protein, embryonic lethal, abnormal vision, drosophila-like 1 (ELAVL1)/Hu antigen R (HuR), strongly associates with IFN-ß mRNA via AU-rich sequences present in its 3' untranslated region in various human cell lines. The authors show that ELAVL1/HuR is required for the stabilization of IFN-ß mRNA, and suppression of ELAVL1/HuR by its inhibitor MS-444 leads to impaired expression of IFN-ß in response to viral dsRNA treatment. Thus, this study uncovers a novel mechanism of posttranscriptional IFN-ß mRNA regulation in response to virus infection, through IFN-ß stabilization by ELAVL1/HuR. Future studies are expected to identify further regulatory mechanisms of IFN-ß stabilization and destabilization in the course of antiviral responses.

The RNA-binding protein HuR/ELAVL1 regulates IFN-ß mRNA abundance and the type I IFN response.

Secretion of type I interferon (IFN) is the first cellular reaction to invading pathogens. Despite the protective function of these cytokines, an excessive response to their action can contribute to serious pathologies, such as autoimmune diseases. Transcripts of most cytokines contain adenylate-uridylate (A/U)-rich elements (AREs) that make them highly unstable. RNA-binding proteins (RBPs) are mediators of the regulatory mechanisms that determine the fate of mRNAs containing AREs. Here, we applied an affinity proteomic approach and identified lethal, abnormal vision, drosophila-like 1 (ELAVL1)/Hu antigen R (HuR) as the predominant RBP of the IFN-ß mRNA ARE. Reduced expression or chemical inhibition of HuR severely hampered the type I IFN response in various cell lines and fibroblast-like synoviocytes isolated from joints of rheumatoid arthritis patients. These results define a role for HuR as a potent modulator of the type I IFN response. Taken together, HuR could be used as therapeutic target for diseases where type I IFN production is exaggerated.

Posttranscriptional gene regulation of IL-17 by the RNA-binding protein HuR is required for initiation of experimental autoimmune encephalomyelitis.

IL-17 is a proinflammatory cytokine produced by activated Th17 cells and other immune cells. IL-17-producing Th17 cells are major contributors to chronic inflammatory and autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Although the transcriptional regulation of Th17 cells is well understood, the posttranscriptional regulation of IL-17 gene expression remains unknown. The RNA-binding protein HuR positively regulates the stability of many target mRNAs via binding the AU-rich elements present in the 3' untranslated region of many inflammatory cytokines including IL-4, IL-13, and TNF-α. However, the regulation of IL-17 expression by HuR has not been established. CD4(+) Th17 cells from HuR knockout mice had decreased IL-17 steady-state mRNA and protein levels compared with wild-type Th17 cells, as well as decreases in frequency of IL-17(+) cells. Moreover, we demonstrated that HuR directly binds to the IL-17 mRNA 3' untranslated region by using RNA immunoprecipitation and biotin pulldown assays. In addition, the knockout of HuR decreased cellular proliferation of CD4(+) T cells. Mice with adoptively transferred HuR KO Th17 cells had delayed initiation and reduced disease severity in the onset of experimental autoimmune encephalomyelitis compared with wild-type Th17 cells. Our results reveal a HuR-induced posttranscriptional regulatory mechanism of Th17 differentiation that influences IL-17 expression. These findings may provide novel therapeutic targets for the treatment of Th17-mediated autoimmune neuroinflammation.

Poorly differentiated hepatocellular carcinoma accompanied by anti-Hu antibody-positive paraneoplastic peripheral neuropathy.

The anti-Hu antibody is one of the most famous onco-neural antibodies related to paraneoplastic neurological syndrome, and is associated with small cell lung carcinoma in most cases. Here, we report a case of poorly differentiated hepatocellular carcinoma accompanied by paraneoplastic peripheral neuropathy positive for the anti-Hu antibody. Image inspection before operation revealed that no tumors were found in organs other than the liver, including lung, and that the liver tumor had no metastatic lesion. The liver tumor showed histological appearance of poorly differentiated carcinoma with cartilaginous metaplasia and partial blastoid cell appearance. Most tumor cells presented trabecular-like structure lined by sinusoidal vessels. Immunohistochemically, the tumor cells were positive for low molecular weight cytokeratin and vimentin, partially positive for cytokeratin 19 and CD56, but negative for synaptophysin, chromogranin A and alpha-fetoprotein. Based on the trabecular-like morphology and the results of immunohistochemical staining, we concluded that the tumor was diagnosed as poorly differentiated hepatocellular carcinoma. Anti-Hu antibody-positive paraneoplastic peripheral neuropathy accompanied with liver tumor is extremely rare as far as is known. The presented case indicates that poorly differentiated carcinoma has the potential to be the responsible lesion of anti-Hu antibody-positive paraneoplastic neurological syndrome and systemic work-up is important for the management of this neurological disorder.

Anti-Hu Positive Antibodies and Small Cell Carcinoma: A Single Center Review.

INTRODUCTION: Small cell lung cancer (SCLC), having properties of neuroendocrine cells, accounts for a small (15 percent) but significant percent of all newly diagnosed lung cancers and is distinguished from non-small cell lung cancer by its rapid doubling time, high growth fraction and the early development of widespread metastases. Therefore, investigation into early diagnosis and treatment is crucial. One sequela of SCLC is a paraneoplastic neurological syndrome usually mediated by a high titer of anti-Hu antibodies, a disease which can present in several variations of paraneoplastic encephalomyelitis. The presence of anti-Hu antibodies in patient serum, even at a low titer, may serve as a diagnostic marker for SCLC and as a model for antibody-based early cancer detection. Furthermore, anti-Hu titers may eventually function as a prognostic indicator and trending titers may be a way to monitor treatment of SCLC and associated paraneoplastic syndromes. METHODS: In this retrospective chart review from a single hospital, we review all patients who had positive anti-Hu antibodies and discuss level of titers at diagnosis, outcomes, and length of survival. RESULTS: We describe three cases of positive anti-Hu antibodies and document their diagnosis of SCLC and outcomes. CONCLUSIONS: Anti-Hu antibodies can be used as a diagnostic tool for aiding in the diagnosis of SCLC. Anti-Hu antibodies may be able to be followed as a marker of progression of the disease.

Neuronal uptake of anti-Hu antibody, but not anti-Ri antibody, leads to cell death in brain slice cultures.

BACKGROUND: Anti-Hu and anti-Ri antibodies are paraneoplastic immunoglobulin (Ig)G autoantibodies which recognize cytoplasmic and nuclear antigens present in all neurons. Although both antibodies produce similar immunohistological labeling, they recognize different neuronal proteins. Both antibodies are associated with syndromes of central nervous system dysfunction. However, the neurological deficits associated with anti-Hu antibody are associated with neuronal death and are usually irreversible, whereas neurological deficits in patients with anti-Ri antibody may diminish following tumor removal or immunosuppression. METHODS: To study the effect of anti-Hu and anti-Ri antibodies on neurons, we incubated rat hippocampal and cerebellar slice cultures with anti-Hu or anti-Ri sera from multiple patients. Cultures were evaluated in real time for neuronal antibody uptake and during prolonged incubation for neuronal death. To test the specificity of anti-Hu antibody cytotoxic effect, anti-Hu serum IgG was incubated with rat brain slice cultures prior to and after adsorption with its target Hu antigen, HuD. RESULTS: We demonstrated that: 1) both anti-Hu and anti-Ri antibodies were rapidly taken up by neurons throughout both cerebellum and hippocampus; 2) antibody uptake occurred in living neurons and was not an artifact of antibody diffusion into dead cells; 3) intracellular binding of anti-Hu antibody produced neuronal cell death, whereas uptake of anti-Ri antibody did not affect cell viability during the period of study; and 4) adsorption of anti-Hu antisera against HuD greatly reduced intraneuronal IgG accumulation and abolished cytotoxicity, confirming specificity of antibody-mediated neuronal death. CONCLUSIONS: Both anti-Hu and anti-Ri antibodies were readily taken up by viable neurons in slice cultures, but the two antibodies differed markedly in terms of their effects on neuronal viability. The ability of anti-Hu antibodies to cause neuronal death could account for the irreversible nature of paraneoplastic neurological deficits in patients with this antibody response. Our results raise questions as to whether anti-Ri antibody might initially induce reversible neuronal dysfunction, rather than causing cell death. The ability of IgG antibodies to access and react with intracellular neuronal proteins could have implications for other autoimmune diseases involving the central nervous system.

Imbalance in circulating T lymphocyte subsets contributes to Hu antibody-associated paraneoplastic neurological syndromes.

Paraneoplastic neurological syndromes (PNS) are associated with small cell lung cancer (SCLC) and Hu antibodies, which are considered to have an immune-mediated etiology. As a pathogenic role for Hu antibodies (Hu-Ab) in PNS could not be demonstrated, the cellular immune response against the Hu proteins has been further investigated. To delve deeper into the hypothesized cell-mediated immune pathogenesis of these syndromes, imbalances within circulating T lymphocyte subsets were investigated to determine their significance in Hu antibody-associated PNS. The circulating T lymphocyte subsets were analyzed in untreated patients with SCLC, PNS and Hu-Ab (n=10), SCLC without PNS (n=10) and healthy controls (n=12) using flow cytometry. Patients with PNS and SCLC, had a variety of changes within their circulating T lymphocyte subsets, which included; lymphopenia of the CD3(+)and CD4(+) T cells, increased proportions of total activated T cells and activated CD4(+) T cells, and reduced numbers of CD4(+) and CD25(+) regulatory T cells (Treg). These results suggest that the excessive activation of T cells and dysfunction of Treg contribute to Hu antibody-associated PNS.

Paraneoplastic Hu and CRMP5 antibodies are present in smokers without cancer or neurological disease.

BACKGROUND AND OBJECTIVE: We investigated if the paraneoplastic Hu and collapsin response mediator protein 5 (CRMP5) antibodies could be used as early markers for lung cancer in smokers with or without chronic obstructive pulmonary disease (COPD). METHODS: Hu and CRMP5 antibodies were measured by radioimmunoprecipitation assay (RIPA) in sera from 552 smokers; 379 with and 173 without COPD. Three hundred blood donors served as controls. The positive sera were also tested by indirect immunofluorescence and line blot with recombinant proteins. The 552 smokers were matched with data from the Cancer Registry of Norway, and the hospital medical records from the subjects positive for Hu and CRMP5 antibodies were reviewed. The mean follow-up time was 4.4 years (range 2.5-5.7 years). RESULTS: The RIPA showed that 5/379 (1.3%) smokers with COPD had Hu antibodies and 1/379 (0.3%) smokers with COPD had CRMP5 antibodies. Only the smoker with the highest RIPA index had Hu antibodies also detected by immunofluorescence and line blot. One of 173 (0.6%) smokers without COPD had Hu antibodies, but none had CRMP5 antibodies. None of the 300 controls had Hu antibodies, but 2/300 (0.7%) had CRMP5 antibodies. Hu antibodies remained positive for more than 5 years. No cancer or neurological disease was recorded in the Hu or CRMP5 positive patients. The total cancer frequency in the smokers with and without COPD was 70/552 (13%). CONCLUSIONS: Hu and CRMP5 antibodies were not associated with cancer or neurological disease in a large cohort of smokers and are therefore not always paraneoplastic.

Peripheral neuropathies associated with antibodies directed to intracellular neural antigens.

Antibodies directed to intracellular neural antigens have been mainly described in paraneoplastic peripheral neuropathies and mostly includes anti-Hu and anti-CV2/CRMP5 antibodies. These antibodies occur with different patterns of neuropathy. With anti-Hu antibody, the most frequent manifestation is sensory neuronopathy with frequent autonomic involvement. With anti-CV2/CRMP5 the neuropathy is more frequently sensory and motor with an axonal or mixed demyelinating and axonal electrophysiological pattern. The clinical pattern of these neuropathies is in keeping with the cellular distribution of HuD and CRMP5 in the peripheral nervous system. Although present in high titer, these antibodies are probably not directly responsible for the neuropathy. Pathological and experimental studies indicate that cytotoxic T-cells are probably the main effectors of the immune response. These disorders contrast with those in which antibodies recognize a cell surface antigen and are probably responsible for the disease. The neuronal cell death and axonal degeneration which result from T-cell mediated immunity explains why treating these disorders remains challenging.

Anti-Hu antibody associated paraneoplastic neurological syndrome in a child with ganglioneuroblastoma: A rare case report and literature review.

RATIONALE: Paraneoplastic neurological syndrome with anti-Hu antibody (Hu-PNS) is a neurological disorder that occur in patients with malignancy. The syndrome has a wide range of presentations and can present before diagnosis of primary malignancy. Familiarity with these paraneoplastic neurological syndromes can help early recognition and take appropriate regimens. PATIENTS CONCERNS: Diagnosis and treatment of Hu-PNS. DIAGNOSES: This is retrospective study that analyzed the clinical data of this case. Through retrospective analysis and targeted antibody screening, serum anti-Hu antibody was detected. Subsequent spinal imaging revealed a mass in the paraspinal region, which was confirmed as ganglioneuroblastoma by pathologic examination. INTERVENTIONS: The child was treated with a course of intravenous immunoglobulin and radical surgical operation without chemotherapy. OUTCOMES: The neurological symptoms were gradually improved and no signs indicate disease progression or tumor recurrence. LESSONS: Hu-PNS has rarely been reported in children with ganglioneuroblastomas. They can mimic non-neoplastic processes, making detection and diagnosis difficult. Serum and/or cerebrospinal fluid onconeural antibody can strongly indicate occult cancers. Early detection of paraneoplastic neurological syndromes can help take appropriate regimens and improve prognosis.

Dysautonomia in anti-Hu paraneoplastic neurological syndromes.

BACKGROUND AND OBJECTIVES: Dysautonomia has been associated with paraneoplastic neurological syndrome (PNS)-related mortality in anti-Hu PNS, but its frequency and spectrum remain ill-defined. We describe anti-Hu patients with dysautonomia, estimate its frequency, and compare them to patients without dysautonomia. METHODS: Patients with anti-Hu antibodies diagnosed in the study centre (1990-2022) were retrospectively reviewed; those with autonomic signs and symptoms were identified. RESULTS: Among 477 anti-Hu patients, 126 (26%) had dysautonomia (the only PNS manifestation in 7/126, 6%); gastrointestinal (82/126, 65%), cardiovascular (64/126, 51%), urogenital (24/126, 19%), pupillomotor/secretomotor (each, 11/126, 9%), and central hypoventilation (10/126, 8%). Patients with isolated CNS involvement less frequently had gastrointestinal dysautonomia than those with peripheral (alone or combined with CNS) involvement (7/23, 30% vs. 31/44, 70% vs. 37/52, 71%; P = 0.002); while more frequently central hypoventilation (7/23, 30% vs. 1/44, 2.3% vs. 2/52, 4%; P < 0.001) and/or cardiovascular alterations (18/23, 78% vs. 20/44, 45% vs. 26/52, 50%; P = 0.055). Median [95% CI] overall survival was not significantly different between patients with (37 [17; 91] months) or without dysautonomia (28 [22; 39] months; P = 0.78). Cardiovascular dysautonomia (HR: 1.57, 95% CI [1.05; 2.36]; P = 0.030) and central hypoventilation (HR: 3.51, 95% CI [1.54; 8.01]; P = 0.003) were associated with a higher risk of death, and secretomotor dysautonomia a lower risk (HR: 0.28, 95% CI [0.09; 0.89]; P = 0.032). Patients with cardiovascular dysautonomia dying ≤ 1 year from clinical onset had severe CNS (21/27, 78%), frequently brainstem (13/27, 48%), involvement. DISCUSSION: Anti-Hu PNS dysautonomia is rarely isolated, frequently gastrointestinal, cardiovascular and urogenital. CNS dysfunction, particularly brainstem, associates with lethal cardiovascular alterations and central hypoventilation, while peripheral involvement preferentially associates with gastrointestinal or secretomotor dysautonomia, being the latest more indolent.

Avidity of onconeural antibodies is of clinical relevance.

Onconeural antibodies are important in the detection of paraneoplastic neurological syndromes (PNS). The avidity of Hu, Yo, and CRMP5 antibodies from 100 patients was determined by immunoprecipitation (IP), and 13 of the Yo positive sera were also tested by surface plasmon resonance (SPR). There was a significant association between the results from IP and SPR. Yo antibodies had higher avidity than Hu and CRMP5 antibodies, and both high- and low-avidity antibodies were associated with tumors and PNS. High-avidity Yo antibodies were mainly associated with ovarian cancer, whereas high-avidity Hu and CRMP5 antibodies were mainly associated with small-cell lung cancer. Low-avidity CRMP5 and Yo antibodies were less often detected by a commercial line blot than high-avidity antibodies. The failure to detect low-avidity onconeural antibodies may result in under diagnosis of PNS.

Ofatumumab for refractory opsoclonus-myoclonus syndrome following treatment of neuroblastoma.

Opsoclonus-myoclonus syndrome (OMS) may be associated with ANNA-1 (anti-Hu) autoantibodies. The standard treatment with IVIG, steroids, and anti-CD20 monoclonal antibody may fail, and optimal therapy is unknown. A patient developed OMS with high-titer ANNA-1 following recovery from neuroblastoma. She failed standard therapy and had only transient response to rituximab. Treatment with the humanized anti-CD20 monoclonal antibody ofatumumab combined with methotrexate resulted in transient neurologic improvement and decrease of ANNA-1. This suggests that ofatumumab combined with methotrexate should further be considered OMS patients, particularly in refractory disease.

Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis.

Classical paraneoplastic encephalitis syndromes with 'onconeural' antibodies directed to intracellular antigens, and the recently described paraneoplastic or non-paraneoplastic encephalitides and antibodies against both neural surface antigens (voltage-gated potassium channel-complexes, N-methyl-d-aspartate receptors) and intracellular antigens (glutamic acid decarboxylase-65), constitute an increasingly recognized group of immune-mediated brain diseases. Evidence for specific immune mechanisms, however, is scarce. Here, we report qualitative and quantitative immunopathology in brain tissue (biopsy or autopsy material) of 17 cases with encephalitis and antibodies to either intracellular (Hu, Ma2, glutamic acid decarboxylase) or surface antigenic targets (voltage-gated potassium channel-complex or N-methyl-d-aspartate receptors). We hypothesized that the encephalitides with antibodies against intracellular antigens (intracellular antigen-onconeural and intracellular antigen-glutamic acid decarboxylase groups) would show neurodegeneration mediated by T cell cytotoxicity and the encephalitides with antibodies against surface antigens would be antibody-mediated and would show less T cell involvement. We found a higher CD8/CD3 ratio and more frequent appositions of granzyme-B(+) cytotoxic T cells to neurons, with associated neuronal loss, in the intracellular antigen-onconeural group (anti-Hu and anti-Ma2 cases) compared to the patients with surface antigens (anti-N-methyl-d-aspartate receptors and anti-voltage-gated potassium channel complex cases). One of the glutamic acid decarboxylase antibody encephalitis cases (intracellular antigen-glutamic acid decarboxylase group) showed multiple appositions of GrB-positive T cells to neurons. Generally, however, the glutamic acid decarboxylase antibody cases showed less intense inflammation and also had relatively low CD8/CD3 ratios compared with the intracellular antigen-onconeural cases. Conversely, we found complement C9neo deposition on neurons associated with acute neuronal cell death in the surface antigen group only, specifically in the voltage-gated potassium channel-complex antibody patients. N-methyl-d-aspartate receptors-antibody cases showed no evidence of antibody and complement-mediated tissue injury and were distinguished from all other encephalitides by the absence of clear neuronal pathology and a low density of inflammatory cells. Although tissue samples varied in location and in the stage of disease, our findings strongly support a central role for T cell-mediated neuronal cytotoxicity in encephalitides with antibodies against intracellular antigens. In voltage-gated potassium channel-complex encephalitis, a subset of the surface antigen antibody encephalitides, an antibody- and complement-mediated immune response appears to be responsible for neuronal loss and cerebral atrophy; the apparent absence of these mechanisms in N-methyl-d-aspartate receptors antibody encephalitis is intriguing and requires further study.

Blepharospasm and apraxia of eyelid opening associated with anti-Hu paraneoplastic antibodies: a case report.

PURPOSE: To report a case of blepharospasm associated with anti-Hu paraneoplastic antibodies that was treated successfully with botulinum toxin A. DESIGN: Case report. PARTICIPANTS: A 57-year-old man had altered mental status and a 20-pound weight loss at presentation. Evaluation revealed an occult small-cell lung cancer. Despite initiating appropriate chemotherapy, his mental status worsened and over the course of several weeks, he was unable to open his eyes because of forceful orbicularis contractions. Neuroimaging and cerebrospinal fluid studies found no evidence of intracranial metastases. However, his paraneoplastic panel was positive for anti-Hu antibodies. He was diagnosed with paraneoplastic encephalitis and blepharospasm. INTERVENTION: Intravenous Solu-Medrol (Pharmacia & Upjohn Co, Bridgewater, NJ) and periocular injections of botulinum toxin A. MAIN OUTCOME MEASURES: Ocular disease control. RESULTS: Intravenous Solu-Medrol improved his mental status, but did not change his ocular symptoms. Subsequent botulinum toxin A injections allowed spontaneous eyelid opening. CONCLUSIONS: Although paraneoplastic blepharospasm is rare, it is an important diagnosis to be aware of because paraneoplastic disorders often herald an occult tumor. This is the only case of paraneoplastic blepharospasm that the authors know of that was the result of anti-Hu antibodies as well as the only case that was treated with botulinum toxin A.

An unusual presentation of anti-Hu-associated paraneoplastic limbic encephalitis.

Paraneoplastic limbic encephalitis is a rare disorder characterized by personality changes, seizures, memory loss, and psychiatric symptoms often associated with antineuronal antibodies. It is well described in the adult literature but is still underreported in the pediatric literature. Symptoms are usually multifocal and subacute in presentation, occurring over days to weeks; however, in rare cases, symptom onset can be more gradual. We report the case of a 9-year-old male with anti-Hu-associated paraneoplastic limbic encephalitis that presented as episodic ataxia and behavioral changes evolving to intractable epilepsy and worsening behavioral changes over the course of a year. This case highlights the importance of considering a paraneoplastic disorder in the differential diagnosis for unexplained multifocal neurological symptoms of subacute or chronic onset as earlier detection and treatment may result in an improved outcome.