Journal Pre-proof

Pediatric Paraneoplastic Necrotizing Encephalitis Associated with Acute

Lymphoblastic Leukemia

Linda Nguyen, MD, PhD, John Ross Crawford, MD, MS

PII: S0887-8994(19)30927-0
DOI: https://doi.org/10.1016/j.pediatrneurol.2019.11.009
Reference: PNU 9683

To appear in: Pediatric Neurology

Received Date: 29 August 2019

Revised Date: 14 October 2019
Accepted Date: 5 November 2019

Please cite this article as: Nguyen L, Crawford JR, Pediatric Paraneoplastic Necrotizing Encephalitis
Associated with Acute Lymphoblastic Leukemia, Pediatric Neurology (2019), doi: https://doi.org/10.1016/
j.pediatrneurol.2019.11.009.

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© 2019 Published by Elsevier Inc.

Pediatric Paraneoplastic Necrotizing Encephalitis Associated with Acute Lymphoblastic

Leukemia

Linda Nguyen, MD, PhD1 and John Ross Crawford, MD, MS2
1
Department of Neurosciences, University of California, San Diego, California, USA,

lin042@ucsd.edu
2
Department of Neurosciences and Pediatrics, University of California San Diego, San Diego,

California, USA, jrcrawford@ucsd.edu

Corresponding author: Dr. John Ross Crawford, jrcrawford@ucsd.edu

Word count: 1496

shorter running title: paraneoplastic encephalitis and ALL

Abstract

Background: Paraneoplastic encephalitis encompasses a diverse spectrum of neurologic

disorders associated with a variety of pediatric tumor types.

Patient and Methods: We describe a 7-year-old male with paraneoplastic necrotizing encephalitis

associated with precursor B-cell acute lymphoblastic leukemia (pre-B ALL).

Results: The initial presentation involved acute onset upper extremity weakness, seizure-like

activity and agitation. Extensive workup revealed pancytopenia, elevated protein in the cerebral

spinal fluid (CSF) and normal magnetic resonance imaging (MRI) consistent with a clinical

diagnosis of encephalitis of presumed viral etiology. He was treated with antimicrobials and

intravenous immunoglobin (IVIG) and returned to his neurological baseline prior to discharge.

One month later, he was diagnosed with pre-B ALL. Prior to chemotherapy initiation, he again

became encephalopathic. Repeat CSF showed elevated protein, and MRI revealed findings

consistent with diffuse necrotizing encephalitis. He received standard chemotherapy as well as

immunotherapy with IVIG and plasmapheresis, with resolution of MRI abnormalities and

improvement in neurological status. At 6 years post-presentation, he is in remission for ALL,

without significant neurocognitive deficits and mild right spastic hemiparesis.

Conclusion: This is the first reported case of paraneoplastic encephalitis associated with pediatric

leukemia. A hematologic malignancy should be considered in the differential diagnosis of

paraneoplastic encephalitis.

Keywords

Paraneoplastic neurological syndrome, paraneoplastic encephalitis, acute lymphoblastic

leukemia
Introduction

Paraneoplastic neurological syndromes (PNS) are rare, non-metastatic complications that

occur in less than 0.01% of cancer patients 1. They occur with any type of malignancy, though

more commonly associated with small-cell lung, ovarian, breast, neuroendocrine, thymoma and

lymphoma 1. They can damage any part of the nervous system, affecting a single site as in

Lambert-Eaton myasthenic syndrome, single cell type in paraneoplastic cerebellar degeneration,

or multiple areas in paraneoplastic encephalomyelitis 2. A high index of suspicion is necessary as

most PNS develop acutely or subacutely and may resemble a viral process. In addition,

neurological symptoms precede the diagnosis of the underlying tumor in most cases.

Cerebrospinal fluid (CSF) often reveals nonspecific abnormalities such as mild to moderate

lymphocytic pleocytosis, elevated protein, and oligoclonal bands. Neuroimaging is helpful to

exclude other non-paraneoplastic causes but may be normal. Early diagnosis and effective

treatment of the tumor offers the best opportunity to improve or stabilize neurological deficits.

Immunotherapy may be beneficial depending on the PNS type. We report the first case of

paraneoplastic necrotizing encephalitis in a pediatric patient with precursor B-cell acute

lymphoblastic leukemia (pre-B ALL).

Case presentation

A 7-year-old previously healthy, developmentally normal male presented with less than a

1-day history of upper extremity weakness, seizure-like activity, and agitation. Prior to this, he

had 2 weeks of intermittent headache, malaise, decreased appetite, and tactile fevers that had
improved before the onset of the encephalopathy that required intubation. Basic metabolic panel

and head computed tomography were normal. CSF analysis demonstrated highly elevated protein

(Table 1). Magnetic resonance imaging (MRI) with and without contrast and MR venography

(MRV) brain were normal. He was pancytopenic on admission: normocytic anemia (9.9 g/dL),

thrombocytopenia (60,000/µL), and leukopenia (2470/µL) with an absolute neutrophil count

(ANC) of 1600. He required one packed red blood cell transfusion for hemoglobin nadir of 6.8

g/dL. His platelets spontaneously recovered to above 100,000. He developed mild neutropenia

(ANC 1100) that remained stable prior to discharge. He also had mild transaminitis (AST/ALT

126/86 U/L) and low albumin (2.9 g/dL), with normal coagulation panel. The transaminitis

resolved, and albumin improved after infusion. An extensive infectious evaluation revealed

normal C-reactive protein; negative serum herpes simplex virus (HSV), syphilis, Lyme,

parvovirus, West Nile virus, cytomegalovirus (CMV), enterovirus, Epstein-Barr virus (EBV),

mycoplasma and coccidiomycosis; and negative CSF HSV and enterovirus. Blood, CSF, urine

and throat cultures were negative. Serum immunoglobulins, paraneoplastic panel and N-methyl-

D-aspartate receptor (NMDA-R) antibody testing were normal. The working diagnosis at the

time was viral encephalitis associated with pancytopenia and transaminitis. He received empiric

antibiotics, acyclovir, and intravenous immunoglobulin (IVIG). He was started phenytoin on

admission due to concern for subclinical seizures. However, routine electroencephalogram (EEG)

done 1 day after admission and prolonged EEG a few days later did not show any electrographic

seizures, and phenytoin was discontinued. His mental status returned to baseline, and he was

discharged ten days after admission.

Two weeks after discharge, he began to have decreased energy and appetite, weight loss,

abdominal pain and diarrhea. CBC revealed a hemoglobin of 9.4 g/dL, platelets of 105,000/µL,
ANC of 498/µL. He was readmitted 1-month post-discharge for pancytopenia and underwent a

bone marrow aspiration and biopsy. Flow cytometry was significant for 44% blasts, positive for

CD45, CD19, CD10, CD34 and Tdt consistent with pre-B ALL.

Three days after the bone marrow procedure, he became profoundly encephalopathic. and

MRI brain showed diffuse T2 signal abnormality involving bilateral basal ganglia, mesial

temporal lobes, dorsal midbrain, and pons (Figure 1A-B) with areas of reduced diffusivity in the

lentiform nuclei (Figure 1C). Post-contrast imaging revealed enhancement in bilateral basal

ganglia, gyrus recti and pons (Figure 1D). Some central regions of cavitation were seen

consistent with necrosis. EEG was negative for electrographic seizures. CSF was significant for

elevated protein, with no leukocytosis or malignant cells (Table 1). Extensive infectious work up

was again unremarkable. Repeat paraneoplastic evaluation of serum was negative. CSF lactate,

pyruvate, myelin basic protein, oligoclonal bands, and aquaporin-4 were normal. He was treated

with standard chemotherapy, IVIG, and plasmapheresis with slow but eventual improvement in

his neurological status. He received induction chemotherapy per pre-B ALL standard protocol,

with the following exceptions: (1) initial intrathecal (IT) chemotherapy was held until day 8

induction due to worsening encephalopathy; (2) he received hydrocortisone and cytarabine but

not IT methotrexate due to potential for superimposed methotrexate leukoencephalopathy; and (3)

his fourth dose of VCR was held on day 22 due to concern for neuropathy. His day 29 bone

marrow evaluation showed no evidence of leukemia; and he was started on consolidation therapy

with VCR omitted. For immunotherapy, he had 4 courses of IVIG (first course given on day 5

induction) and 2 courses of plasmapheresis (first course given on day 25 induction). Repeat MRI

brain on day 16 induction showed slow resolution of the T2-weighted abnormalities (Figure 1E-

F). MRI 3 years post-diagnosis showed evidence of stable encephalomalacia in the basal ganglia
(Figure 1G-H). He was discharged home after 10 weeks of hospitalization. The patient is

currently in remission for ALL 6 years post diagnosis without significant neurocognitive deficits

and a mild residual right spastic hemiparesis.

Discussion

The clinical presentation of this patient along with the MRI findings, CSF inflammatory

features, eventual diagnosis of pre-B ALL, and subsequent resolution of MRI abnormalities

following IVIG and plasmapheresis are very consistent with a diagnosis of PNS. While PNS can

occur with any type of malignancy, hematologic disease is much less prevalent than solid tumors.

In the largest reported database of PNS involving 979 patients, there were only 58 cases

associated with hematologic disease, all of which were lymphomas 3. This is to our knowledge

the first case report of PNS in pediatric leukemia.

The most common PNS in children include opsoclonus myoclonus syndrome, limbic

encephalitis, and anti-NMDA-R encephalitis 4. This patient presented with limbic encephalitis

initially thought due to a viral etiology. It was unclear at that point if he had improved due to

antimicrobials or IVIG. One month after being discharged, however, he was readmitted with the

diagnosis of pre-B ALL. Before the start of induction chemotherapy, he became encephalopathic

again, with worsened MRI brain findings. Most reported cases of PNS have a subacute,

aggressive clinical course and then stabilize. There are case reports of patients developing a

second PNS clinically different from the first, though the median delay was 15 months 5. Our

patient likely had the same PNS with symptoms manifesting about 7 weeks apart due to his

initial response to IVIG. Notably, he was pancytopenic during his first admission; however, no

bone marrow biopsy was performed due to rapid count revovery.

 Other differential diagnoses to consider include a secondary post-viral illness related to

his immunocompromised state in the setting of pre-B ALL. More commonly associated

pathogens with this type of necrotizing encephalopathy include influenza, parainfluenza, HHV-6,

EBV, and Japanese encephalitis virus 6. Similar post-viral syndromes are associated with an

acute disseminated encephalomyelitis syndrome or clinically isolated syndrome, which this case

would qualify for the former since he was encephalopathic. Atypical posterior reversible

encephalopathy syndrome can involve the basal ganglia and/or brain stem 7, though less likely

than PNS as the patient was normotensive and did not have acute or chronic renal disease,

systemic lupus erythematosus, or immunosuppressive therapy. Bilateral relatively symmetric T2

hyperintensities can also be seen in mitochondrial and metabolic cytopathies, infection,

nutritional deficiency, and drug toxicity. The preceding neurologic syndrome prior to diagnosis

of ALL in an otherwise healthy boy however is most suggestive of a paraneoplastic etiology.

It is generally accepted that many PNS are caused by autoimmune processes triggered by

the cancer and directed against antigens common to both the cancer and nervous system.

However, about one-third of patients do not have detectable antibodies, and 5 to 10% have an

atypical antibody that is not well-characterized 8. Thus, the absence of paraneoplastic antibodies

does not rule out the diagnosis of PNS. Tumor therapy remains the mainstay treatment and

should be instituted as quickly as possible. The efficacy of immunosuppression in PNS is less

well supported in the literature, with many PNS being poorly responsive to immunotherapy.

Syndromes with intracellular antibodies tend to less responsive compared to those with synaptic

or neuronal cell-surface antibodies 2. In this case, no paraneoplastic antibodies were identified.

The patient, however, had a dramatic response to IVIG during his first admission. During the

second admission, he had a noticeable improvement after the first course of IVIG. His progress
then plateaued after the initial good response, but he eventually improved clinically and

radiographically with the combination of immunotherapy and chemotherapy.

This case report emphasizes that recognition of PNS is important for early detection of an

underlying malignancy and prompt imitation of therapies, which offers the best opportunity to

stabilize or improve neurological deficits. A hematologic malignancy should be on the

differential for a pediatric patient presenting with pancytopenia and encephalitis, particularly in

the absence of an identifiable infectious source.

Declarations of interest: none

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Figure 1. MRI Brain Findings of Patient with Paraneoplastic Necrotizing Encephalitis.

T2-weighted MRI findings following formal diagnosis of pre-B ALL and 7 weeks following

initial encephalitis presentation reveal signal abnormality within the bilateral basal ganglia

predominantly involving the lentiform nuclei and caudate with marked edema of the surrounding

white matter and pons (A-B) associated with areas of reduced diffusivity on apparent diffusion

coefficient sequences (C, arrow) and mild enhancement of the bilateral lentiform nuclei (D,

arrow). MRI 2 weeks (E-F) and 3 years (G-H) following treatment with chemotherapy and

immunotherapy reveals stable encephalomalacia in the region of basal ganglia with resolution of

pontine abnormalities.
Table 1. Cerebrospinal spinal fluid studies. Serial cerebrospinal fluid studies performed in the

first and second hospital admission.

Hospital admission 1 2

Days from initial presentation 2 50 51 52 74 81 88 95 102

Protein (15-45 mg/L) 2151 ⃰ 247 ⃰ 297 ⃰ 195 ⃰ 49 ⃰ 93 ⃰ 24 30 24

Glucose (40-70 mg/dL) 87 ⃰ 66 64 73 ⃰ 68 62 60 59 52

Nucleated cell (0-10 #/µL) 2 2 2 2 1 2 2 2 0

RBC (#/µL) <1 2 26 145 330 85 20 14 0

Culture Neg Neg Neg Neg Neg

Cytology Neg Neg Neg Neg Neg Neg

Pyruvate (0.06-0.19 mmol/L) 0.20 ⃰ 0.14

Lactic acid (<2.80 mmol/L) 2.3 3.0 ⃰ 2.1 1.5

Oligoclonal bands, IgG Neg Neg

Myelin basic protein Neg

Aquaporin-4 test Neg

⃰ Represents values higher than reported laboratory reference range.