Malignancy masquerading as chronic meningitis in children: A rare differential

Chronic meningitis differs from acute meningitis as the diagnostic possibilities are diverse, ranging from infections, inflammatory disorders, autoimmune disorders, and para-infectious causes to malignancies.[1] The diagnostic process can at times be both challenging and exhausting. In this issue of the journal, Koshy et al.[2] have pointed out a very rare and often missed cause of chronic meningitis in children.

Neoplastic meningitis refers to the infiltration of the meninges by malignant cells. The commonest mode of infiltration is secondary to the spread from a systemic malignancy (either preceding or following the diagnosis of the malignancy) and may be seen in 4–15% of cases.[3] Tumors arising from malignant infiltration of the meninges, without a secondary lesion elsewhere in the neuroaxis are very rare. These are termed as “primary diffuse leptomeningeal tumors.”[4] The earliest description of these tumors was by Connor and Cushing (in 1920s), who used the term “sarcomatosis” of the meninges for these tumors.[5]

Primitive neuroectodermal tumors (PNETs) of the central nervous system are common childhood embryonal tumors arising from the pluripotent neural crest cells. The leptomeningeal PNETs may arise either as infiltration of the meninges along with a mass lesion elsewhere in the neural axis or solely as a malignant propagation of the glial crest cells in the arachnoid.[4,6,7] The latter, as described in the present case report, is an extremely rare tumor. The common symptoms are headache, vomiting, seizures, gait disturbances, meningismus, and altered sensorium. The imaging features can often masquerade the leptomeningeal enhancement, basal exudates, or hydrocephalus (secondary to the exudates) due to other infectious or inflammatory causes.[4,6,8] Tuberculous meningitis is a very common cause of chronic meningitis in our country. The real clinical dilemma occurs when the patient may be deteriorating clinically, and/or a thorough microbiological study is unyielding for a chronic infection such as tuberculosis, slow-growing organisms, fungi, viruses, or parasites. Empirical anti-tubercular therapy with steroids should be discussed with the family and initiated while awaiting a diagnosis in such cases.

The present case report highlights this clinical dilemma and brings out certain peculiar features of this entity. Most cases reported in the literature (either as individual case reports or small series) have been reported in young children, occasionally in older adults. The survival rate is poor (often less than 2 years), with greater chances of relapse, and variable response to chemotherapy.[4,5,6,7,8,9] In the series by Jennings et al.,[9] diagnosis was made antemortem in a few patients, but largely on a postmortem brain biopsy.

The yield of magnetic resonance imaging (MRI) has been reported to be 70%, with certain diagnostic clues such as the appearance of a diffuse or nodular, thick leptomeningeal enhancement involving the brain (often in the posterior fossa) and spinal cord, or involvement of cerebellar folia.[4,7] However, some cases may not show any imaging findings, until a relapse occurs or the disease has progressed further.[7]

The clinico-radiological picture may further be confounded by high cerebrospinal fluid (CSF) proteins or low glucose, which may again be seen in infectious meningitis as well. The CSF yield for malignant cells may also be dismally low (<40%) in such tumors.[4,6] A high index of suspicion with the presence of atypical lymphocytes and small cells, and immunophenotyping for special stains such as GFAP, CD99, GD2, and O13 may help to clinch the diagnosis. Serial sampling may be helpful in some cases.[6]

The present case highlights certain important points in the diagnostic process of chronic meningitis in children. The red flags to be considered for malignancy are as follows: young age at onset; absence of an underlying source of infection or autoimmune etiology; absence of additional imaging features such as vasculitic infarcts, granulomas, or white matter lesions; worsening clinical picture despite aggressive therapy; absence of response to empirical anti-tubercular therapy with steroids with inconclusive microbiology; and a CSF picture suggestive of lymphocytic predominance with negative cultures for tuberculosis, fungi, viruses, or atypical organisms.[3,4,5,6,7,8,9] A dedicated CSF for cytology should be performed in every case of chronic meningitis along with tests for infectious or inflammatory causes. A meningeal biopsy, if performed, should include the arachnoid membrane, and the possibility of initial negative biopsies needs to be kept in mind.[6]