Paraneoplastic encephalitis as a first evidence of recurrent neuroblastoma: A rare case entity.

Prevalence of paraneoplastic encephalitis in association with recurrent neuroblastoma (NB) is rare. Here, we report a case of recurrent NB presented as paraneoplastic encephalitis, treated successfully with high dose steroids leading to complete neurological recovery. This case highlights the importance of early recognition, diagnosis, and treatment of paraneoplastic encephalitis in a pediatric patient with the new development of neurological symptoms in the background of NB. Paraneoplastic encephalitis also served as an early sign of disease relapse.

Introduction

Paraneoplastic syndromes (PNSs) are rare in cancer patients. It should be considered in a cancer patient with neurological symptoms without any alternative diagnosis after the exclusion of known etiologies.[1] Paraneoplastic neurological disorders (PND) are caused by an autoimmune response against the antigens that are common to tumor and nerve cells. We hereby report a case of paraneoplastic encephalitis as a presenting sign of recurrent pediatric neuroblastoma (NB).

Case Report

A 4 year old, ill looking male child presented one and half years back with one month history of left sided abdominal mass and intermittent fever. Developmental milestones were normal. Physical examination revealed large, irregular, firm, and nontender lump in the left iliac region. Complete blood counts (CBCs) showed hemoglobin 11.2 g/dl, total leukocyte count 7700/mm3, and platelet count 303,000/mm3. Liver and renal function tests were within normal limits including alkaline phosphatase. Lactate dehydrogenase was elevated. Chest X-ray was normal. Initial abnormal abdominal/pelvic ultrasonography supplanted by contrast enhanced computed tomography (CT) of abdomen and pelvis showed 12 cm × 10 cm × 12 cm heterogeneously enhancing soft tissue density lesion with internal necrotic areas and few specks of calcification in the region of the left suprarenal gland displacing left kidney, spleen and reaching up to the midline suggesting the possibility of left suprarenal mass. Biopsy and histopathology of the left suprarenal mass showed small uniform cells with dense hyperchromatic nuclei and scanty cytoplasm suggesting malignant round cell tumor possibly NB [Figure 1]. Immunohistochemistry was positive for chromogranin and synaptophysin [Figure 2]. Bone scan was normal. Bone marrow aspiration and biopsy showed involvement by metastatic tumor cells. Based on these findings, a definitive diagnosis of International Neuroblastoma Staging System stage IV NB was made. Patient was treated with Pediatric Oncology Group 8742 protocol consisting of five cycles of course A (cisplatin 40 mg/m2/day from day 1 to 5, etoposide 100 mg/m2/day from day 2 to 4) alternating every 21 days with course B (cyclophosphamide 150 mg/m2/day PO from day 1 to 7, doxorubicin 35 mg/m2 on day 8). The patient tolerated chemotherapy well without any toxicity. Evaluation by CT abdomen/pelvis showed partial remission in primary suprarenal mass and bone marrow was uninvolved. He underwent left adrenalectomy (R0 resection). Postoperative imaging did not reveal any abnormality at primary or at any other site (complete remission) [Figure 3]. He had very good clinical recovery but, unfortunately, was lost to follow-up.

Figure 1

(a) Histopathology of the left suprarenal mass (×10) showing small uniform cells with dense hyperchromatic nuclei and scanty cytoplasm suggesting malignant round cell tumor possibly neuroblastoma. (b) Histopathology of left suprarenal mass (×40) showing small uniform cells with dense hyperchromatic nuclei and scanty cytoplasm suggesting malignant round cell tumor possibly neuroblastoma

Figure 2

(a) Immunohistochemistry showing positivity for chromogranin. (b) Immunohistochemistry showing positivity for synaptophysin

Figure 3

Postoperative computed tomography (abdomen and pelvis) showing no abnormally enhancing lesion at the operated site

After about 6 months, the patient again presented to local emergency department with acute onset altered sensorium and seizures. Routine blood tests such as CBC, renal function tests, liver function tests, serum electrolytes, viral studies for HIV/hepatitis C virus, and chest X-ray were normal. Magnetic resonance imaging (MRI) brain showed multiple patchy areas of cortical hyperintensities on T2/fluid-attenuated inversion recovery (FLAIR) images involving bilateral cerebral hemispheres and subcortical U-fibers without any postcontrast enhancement [Figure 4]. Cerebrospinal fluid (CSF) examination had mild pleocytosis, elevated protein level but was negative for malignant cells. Considering the possibility of acute encephalitis, he was treated successfully with intravenous methylprednisolone 30 mg/kg/day for 3 days followed by oral prednisolone (1 mg/kg/day) and gradual taper with dramatic complete recovery over a period of 2 weeks after which he was referred to our institute. There was a period of around 4 weeks between the onset of this acute episode and admission to our centre. On repeated enquiry history of occasional, intermittent, mild abdominal pain were elicited. The patient was conscious, oriented, and cooperative without any focal deficit. Physical examination revealed left supraclavicular lymphadenopathy, palpable mass in the left iliac region. CT abdomen/pelvis/thorax showed extensive recurrent lesion involving the left suprarenal region causing displacement of adjacent structures with extension to the thoracic cavity [Figures 5 and 6]. Serum paraneoplastic titer had high levels of anti-Hu antibody. Biopsy of left supraclavicular lymphadenopathy favored recurrent NB. Hence, a final diagnosis of paraneoplastic encephalitis preceding recurrent NB was done. Due to disseminated nature of the disease, he was planned for palliative chemotherapy. An extensive review of literature revealed only single case report of paraneoplastic encephalitis that too in the setting of recurrent NB prior to this one.

Figure 4

(a and b) Magnetic resonance imaging brain showing multiple patchy areas of cortical hyperintensities on T2/fluid-attenuated inversion recovery images involving bilateral cerebral hemispheres and subcortical U-fibers without any post contrast enhancement.

Figure 5

Coronal section showing recurrent extensive lesion extending from abdominal to thoracic cavity

Figure 6

Computed tomography (abdomen and pelvis) showing large, recurrent lesion at the operated site causing displacement of adjacent structures like kidney

Discussion

PNS is defined as symptom complexes in cancer patients that cannot be readily explained, either by the local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue from which tumor arose.[2] A classical PND include encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, opsoclonus-myoclonus, subacute sensory neuronopathy, chronic gastrointestinal pseudo-obstruction, and Lambert–Eaton myasthenic syndrome (LEMS), dermatomyositis.

Definite paraneoplastic syndrome

Classical PNS and cancer that develop within 5 years of the diagnosis of the neurological disorder

Nonclassical syndrome that resolves or significantly improve after cancer treatment without concomitant immunotherapy provided that the syndrome is not susceptible to spontaneous remission

Nonclassical syndrome with onconeural antibodies (well-characterized or not) and cancer that develops within 5 years of the diagnosis of the neurological disorder

Neurological syndrome (classical or not) with well-characterized onconeural antibodies (anti-Hu, Yo, CV2, Ri, Ma2, or amphiphysin) and no cancer.

Possible paraneoplastic syndrome

Classical syndrome, no onconeural antibodies, no cancer is diagnosed, but at high risk for having an underlying tumor

Neurological syndrome (classical or not) with partially characterized onconeural antibodies and no cancer

Nonclassical syndrome, no onconeural antibodies and cancer present within 2 years of diagnosis.

According to the diagnostic criteria for PNS mentioned below, our patient had definite PNS with recurrent NB diagnosed within 1 month of classical paraneoplastic encephalitis. Although neurological manifestations usually precede the diagnosis of malignancy, variable presentations may occur.

Diagnostic criteria for definite and possible paraneoplastic syndrome[3]

Various malignancies have been described in association with the anti-Hu antibody. Most commonly small cell lung carcinoma was seen in 77–90% of cases, others being less common such as Hodgkin's lymphoma, thymic carcinoma, nonseminomatous germ cell tumor, rarely NB, and small cell carcinoma of the gall bladder.[45] Among the pediatric malignancies, anti-Hu antibodies are most commonly seen in association with NB [Table 1].[6]

Table 1

Classical PND, their associated antibodies and malignancies

NB is the most common extracranial solid tumor in children, accounting for 7% of all childhood malignancies and 15% of childhood cancer mortality. Peak age incidence is 2 years. Common PNS described in association with NB are opsoclonus-myoclonus ataxia syndrome and Kerner–Morrison syndrome due to vasoactive intestinal peptide secretion.

Contrast MRI is to be done to rule out any infectious, structural, vascular causes. It is usually normal but may show abnormal findings in some patients with paraneoplastic encephalitis. Characteristic findings include signal hyperintensities on FLAIR or T2-weighted images in affected brain regions with variable contrast enhancement. CT scan is not sensitive enough to detect these changes. CSF analysis may be normal or may show lymphocytic pleocytosis and elevated protein levels. Only 60–70% of the patients have a demonstrable serum or CSF onconeural antibodies. Detection of paraneoplastic antibodies is useful for syndrome diagnosis, although it is not compulsory according to diagnostic criteria.[3] Once the reversible or underlying structural causes are excluded by routine blood tests, MRI scan, CSF analysis; diagnosis of PND depends upon demonstration of underlying malignancy and/or onconeural antibodies. Diagnosis is not ruled out even if both are negative and requires repeat investigations until an alternative diagnosis is established.

Management of PNS includes immunosuppression with high dose steroids, immunoglobulin's, plasmapheresis and treatment of the underlying tumor. Response to treatment is highly variable from rapid, complete recovery to minimal to no response. Severely disabled patient with chronic PNS often do not benefit from immunosuppression. Few PNS like LEM's, dermatomyositis, neuromyotonia may show a good response to treatment while unsatisfactory results with others. In a study by Dalmau et al., 2 out of 71 patients showed neurological improvement with steroids, both had limbic encephalitis.[4]

There is some evidence to suggest that rapid initiation of immunosuppression may be beneficial when there is mild and reversible neuronal damage so as to arrest PNS at an early stage.[7] After the exclusion of treatable causes; patient should be treated with immunosuppression/immunomodulation even before the tumor search is concluded. Our patient had a good neurological recovery with high dose steroids started at the first suspicion of PNS that was followed by work up for recurrence.

Conclusion

This case illustrates the importance of early recognition of paraneoplastic encephalitis in a pediatric patient with new development of neurological symptoms in the background of NB. It may also help to predict a disease relapse. Rapid initiation of appropriate treatment may improve the neurological recovery and outcome.

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Conflicts of interest

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