Late Sequelae after Neuroblastoma-Associated Paraneoplastic Anti-Hu Syndrome in a 4-Year-Old Boy

Case Report

Austin J Cancer Clin Res. 2021; 8(1): 1087.

Late Sequelae after Neuroblastoma-Associated Paraneoplastic Anti-Hu Syndrome in a 4-Year-Old Boy

Till A1, Spiegler J1, Callsen F1, Ketzer J1, Langer T1, Tafazzoli K2, Wunsch L2, Winkler B3, Hero B4, Rostasy K5, Wandinger K6 and Lauten M1*

1Department of Pediatrics and Adolescent Medicine, University Hospital Schleswig-Holstein, Germany

2Department of Paediatric Surgery, University Hospital Schleswig-Holstein, Germany

3Department of Pediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Germany

4Department of Pediatric Haematology and Oncology, University Children’s Hospital of Cologne, Germany

5Department of Pediatric Neurology, University of Witten/Herdecke, Germany

6University Hospital of Schleswig-Holstein, Institute of Clinical Chemistry, Germany

*Corresponding author: Melchior Lauten, Department of Pediatrics and Adolescent Medicine, University Hospital Schleswig-Holstein, Ratzeburger Allee 160, 23562 Lubeck, Germany

Received: February 13, 2021; Accepted: March 11, 2021; Published: March 18, 2021


Anti-Hu syndrome is a rare autoantibody associated paraneoplastic disease of the central and peripheral nervous system resulting in a variety of neurological symptoms. In pediatric patients it is described in the context of (ganglio) neuroblastoma associated Opsoclonus-Myoclonus Syndrome (OMS) and other paraneoplastic syndromes. The timely diagnosis of paraneoplastic autoimmunity in childhood is hampered by its rarity as well as by the diversity of clinical symptoms that may occur. We report a 4-year-old boy with gastrointestinal disorder and neurological symptoms due to neuroblastomaassociated anti-Hu syndrome. The patient stabilized under a multimodal oncologic, immunosuppressive and antiepileptic treatment regimen. Treatment of neuroblastoma was individually modified and especially the specific anti- GD2 post-consolidation therapy was substituted by oral cyclophosphamide maintenance therapy in order not to aggravate autoimmune encephalitis. At the age of 8 years, the boy has been in ongoing complete oncologic remission for two years after end of relapse treatment. However, he suffers from neurologic symptoms like focal epilepsy and late sequelae of the oncologic disease.

This case shows that treatment of paraneoplastic anti-Hu syndrome is challenging, encephalitis may persist long after oncologic remission and may lead to developmental delay and a variety of physical sequelae.

Keywords: Paraneoplastic neurological syndromes; ANNA-1; Opsoclonusmyoclonus syndrome; Chronic gastrointestinal pseudo-obstruction; Rituximab; Glucocorticoids; (ganglio) Neuroblastoma; Anti-Hu syndrome; Late sequelae


Anti-Hu syndrome is a rare paraneoplastic disease of the central and peripheral nervous system with detection of antineuronal nuclear autoantibodies against Hu antigens (anti-Hu Ab). Anti-Hu Abs, also termed ANNA-1 (Anti-Neuronal Nuclear Antibody-1), recognize different neuronal nuclear RNA-binding domains (Hu antigens) encoding for proteins regulating messenger RNA and neuronal differentiation of the central and peripheral nervous system [1,2]. Tumor cells outside the nervous system may also express Hu antigens [3] and trigger immune response with cross-reacting anti- Hu Abs and lymphocytes. This results in a variety of paraneoplastic neurological syndromes presenting with encephalomyelitis, sensory neuropathy, chronic gastrointestinal pseudoobstruction, cerebellar degeneration and limbic encephalitis [4]. Anti-Hu syndrome in adults is predominantly associated with small cell lung carcinoma [5] and neurological symptoms often precede tumor diagnosis. In pediatric patients anti-Hu Abs are described in the context of (ganglio) neuroblastoma derived Opsoclonus-Myoclonus Syndrome (OMS) [6] and other paraneoplastic syndromes [7,8].

We report a pediatric patient with paraneoplastic intestinal pseudoobstruction and encephalitis due to anti-Hu syndrome associated with neuroblastoma.

Case Presentation

A four-year-old boy was presented with an 18 months history of failure to thrive, abdominal pain, diarrhea and vomiting after foodintake. In addition, gait ataxia, loss of upright walk and posture, paresthesia of lower extremities, dizziness and adynamia as well as intermittent opsoclonus characterized by conjugated choatic eye movements which had been observed by his parents for the last year, supporting the diagnosis of Opsoclonus-Myoclonus- Syndrome (OMS). Diagnostic work-up revealed a paralytic ileus with distended duodenum due to a right-sided prevertebral mass at the gastric output, measuring 30mm. Metaiodobenzylguanidine (MIBG) scintigraphy was negative, Fluorodeoxyglucose Positron Emission Tomography Computed Tomography (FDG-PET-CT) showed only very low uptake of FDG, serum Neurone Specific Enolase (NSE) was 22.3μg/l and urine catecholamine metabolites were negative. Histologically, a poorly differentiated neuroblastoma (according to the INPC, International Neuroblastoma Pathology Committee) [9], was confirmed (no amplification of MYCN, no deletion of chromosome 1p, no bone marrow involvement). Clinically, feeding via Percutaneous Enteral Gastrostomy (PEG) and jejunostomy (PEJ) was commenced.

Oncologic treatment was initiated according to the GPOHNB2004 protocol, intermediate risk. During the first weeks of treatment, the patient developed epileptic seizures progressing to status epilepticus during episodes of septic fever. Cranial Magnetic Resonance Imaging (MRI) was normal, but laboratory workup pointed at anti-Hu associated encephalitis (serum anti-Hu Ab titer 1:3,200; Cerebrospinal Fluid (CSF): intrathecal immunoglobulin synthesis, no pleocytosis). Four weeks later, anti-Hu Ab were detected in the CSF as well (titre 1:10). Electroencephalography (EEG) showed absence of sleep graphoelements and right-sided frontotemporal focal slowing. Anticonvulsive treatment with levetiracetam and oxcarbazepine was initiated. Immunosuppressive treatment was started with intravenous dexamethasone pulses (20mg/m²/day on days 1-3). After one N6- and two N5-cycles, the tumor was resected and chemotherapy was terminated due to post-hoc down staging to initial stage 2 (International Neuroblastoma Staging System, INSS, [10]). Treatment of the anti-Hu syndrome was continued with intravenous dexamethasone pulse therapies at three- to fourweekly intervals. In addition, Prednisolone (PDN) was administered intrathecally (10mg/dose) and Rituximab was given four times intravenously (375mg/m²) and once intrathecally (2mg/dose). Gait ataxia and paresthesia improved and PEG/PEJ tube could be removed due to sufficient oral food intake. Serum anti-Hu Ab titres decreased to 1:100 and CSF titer dropped from 1:10 to 1:2 within eight months, however, never became negative (Figure 1). Interestingly, intrathecal Rituximab seemed to have a pronounced effect.

Citation: Till A, Spiegler J, Callsen F, Ketzer J, Langer T, Tafazzoli K, et al. Late Sequelae after Neuroblastoma- Associated Paraneoplastic Anti-Hu Syndrome in a 4-Year-Old Boy. Austin J Cancer Clin Res. 2021; 8(1): 1087.