Original Article

Acute neurological complications during acute

lymphoblastic leukemia therapy: A single‑center experience
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over 10 years
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Emine A Rahiman , Aruna Rajendran , Naveen Sankhyan 1, Paramjeet Singh 2, Jayashree Muralidharan 3,
Deepak Bansal , Amita Trehan
Pediatric Hematology Oncology Unit, Department of Pediatrics, Advanced Pediatric Center, 1Pediatric Neurology Unit, Department of Pediatrics,
Advanced Pediatric Center, 2Department of Radio-Diagnosis, 3Pediatric Critical Care Unit, Department of Pediatrics, Advanced Pediatric Center,
Postgraduate Institute of Medical Education and Research, Chandigarh, India 

Correspondence to: Amita Trehan, E‑mail: trehanamita@hotmail.com

Abstract
Background: Acute neurological complications occur in 3.6-11% of children treated for acute lymphoblastic leukemia
(ALL). This analysis aimed to evaluate the profile of acute neuro-toxicity and its etiology in children with ALL.
Methods: A retrospective case analysis of central nervous system events in children treated for ALL at our center was
performed. Details of events were retrieved from the case records (January 2006-December 2015) and analyzed.
Results: Ninety (9.5%) neurological events occurred in 923 patients treated for ALL. Phase of therapy were: induction
(38), consolidation (5), interim maintenance (5), intensification (15) and maintenance (27). Seizures and neurological
deficits were the presenting features in 64 and 40 children, respectively. Events included : neuro-infections in 18, posterior
reversible encephalopathy syndrome (PRES) in 7, epilepsy in 6, intracranial bleed in 5, systemic infection with neurological
complication in 4, hydrocephalus and aseptic meningitis in 3 each, methotrexate encephalopathy and metabolic seizures
in 2 children each. Seizures and status epilepticus of unknown etiology and neurological deficits of unknown etiology
was observed in 26 and 13 children, respectively. Seizures occurred mainly in induction (12) and intensification phase
(9). Status epilepticus transpired in maintenance phase in 9/14 patients. Induction phase was complicated by PRES in
7, intracranial bleed in 5 and cerebral sinus venous thrombosis in 1 patient. Neuroimaging was done in 86% of events.
There were 18 (20.6%) deaths: neuro-infections (8), status epilepticus (6), systemic infection (2), bleed (1), and unexplained
encephalopathy (demyelination)(1). At last follow-up, 53 patients were well and 7 children persist to have a neurological
disability.
Conclusion: Ten percent of children on treatment for ALL suffered an acute neuro-toxicity. Morbidity and high-incidence
of neuroinfections are major concerns.
Keywords:
Acute leukemia, encephalopathy, neurotoxicity, seizures, status epilepticus

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How to cite this article: Rahiman EA, Rajendran A, Sankhyan N, Singh P,
Muralidharan J, Bansal D, et al. Acute neurological complications during acute
lymphoblastic leukemia therapy: A single-center experience over 10 years. Indian
DOI: J Cancer 2021;58:545-52.
10.4103/ijc.IJC_422_19 Submitted: 14‑May‑2019 Revised: 16‑May‑2019
Accepted: 25‑May‑2020 Published: 11‑May‑2021

© 2021 Indian Journal of Cancer | Published by Wolters Kluwer ‑ Medknow 545

 Indian Journal of Cancer
Introduction
Survival in acute lymphoblastic leukemia (ALL) has
been one of the success stories in medicine, with
survival rates in high‑income countries approaching
90%.[1] With improved survival, the complications and
sequel of therapy are being increasingly recognized.
The problems are possibly amplified in developing
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countries, where ALL therapy is fraught with greater
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morbidity, especially related to infections. Neurotoxicity
has been observed to occur in 3.6–11% across
diverse study groups.[2‑6] Early detection and prompt
treatment of these neurological complications may
avoid permanent sequel. It is a challenging situation
for the physician, as the same manifestation can
be caused by a wide‑ranging etiology. We present
the prevalence, nature, and outcome of neurological
events that occurred in children, on therapy for ALL.
Materials and Methods
Nine hundred and twenty‑three children were
treated for ALL between January 2006 and
December 2015. Children were treated as per
the guidelines of the United Kingdom Acute
lymphoblastic leukemia (UKALL 2003) protocol
from 2005 to 2013 and as per the Indian Childhood
Collaborative Leukemia Group (ICICLE) protocol
since 2014. [7] Till 2013, children were classified
into standard and high‑risk groups as per National
Cancer Institute (NCI) criteria, based on age and
counts at admission. (Standard‑risk: <10 years; total
leucocyte count (TLC) <50 × 10 9/L and High‑risk:
>10  years; TLC  ≥50  ×  10 9/L). Subsequently with
the availability of cytogenetic studies and evaluation
of minimal residual disease (MRD) children were
risk‑stratified into standard, intermediate, and
high‑risk disease. [Standard: Age 1–10 years,
TLC <50 × 10 9/L and MRD <0.01%; Intermediate:
Age >10 years, TLC >50 × 10 9 /L, bulky disease
or testicular involvement and MRD <0.01%; High:
T cell, high‑risk cytogenetics, central nervous
system (CNS) involvement or high MRD (>0.01%)].
Intrathecal (IT) methotrexate (17 to 24 injections
per child) was used for CNS prophylaxis with
cranial radiotherapy reserved for patients with CNS
disease.
Children with any acute neurological event during
therapy were analyzed. Children with neurological
involvement at diagnosis and CNS relapse were
excluded. Vincristine‑related neuropathy (peripheral/
autonomic/sensory) was not analyzed in this study. The
data on clinical features, treatment, and outcome were
taken from the case records and analyzed. The study
was approved by the Institute Ethics committee.
546 Volume 58 | Issue 4 | October-December 2021
Statistical analysis
The recorded parameters were analyzed using
descriptive statistics. Statistical analysis was
performed using IBM Statistical Package for Social
Sciences software for Macintosh, version 21, Armonk,
New York. All the mean values are accompanied with
standard deviations.
Results
Ninety events occurred in 923 patients, with a
prevalence of 9.75%. The mean age at diagnosis of
ALL was: 5.7 ± 3.1 (range: 1 - 11) years and male
to female ratio was 2.4:1. Three children suffered two
different events. Seventy‑five children had B-lineage
ALL and 12 had T-lineage disease. 36 children were
in the standard‑risk, 31 in the intermediate‑risk, and
20 in the high‑risk group. 38, 27, 15, 5, and 5 events
were observed during the induction, maintenance
phase, delayed intensification, consolidation, and
interim maintenance phases of therapy, respectively.
Symptoms and signs
The presenting features were seizures in 64 (71%)
events and neurological deficits in 40 (44%) events.
In 23 events, both seizure and neurological deficits
were observed. Twenty‑four (38%) children had focal
seizures, 33 (52%) had generalized seizures, while
semiology was not clear in 7 children. Status epilepticus
was observed in 14 (22%) children. In four episodes
of status epilepticus, the etiology was neuroinfections
and sepsis in two children each. In nonstatus seizure
episodes, etiology was conclusive in 34 (68%) children
and included isolated neuroinfection (n = 9), posterior
reversible encephalopathy syndrome (PRES) (n = 7),
epilepsy (n = 6), systemic infection (n = 2), intracranial
bleed (n = 4), and hypocalcemia (n = 2). Hyponatremia,
methotrexate encephalopathy, cerebral sinus venous
thrombosis (CSVT), and aseptic meningitis were
recorded in one child each. The neurological deficits
observed were encephalopathy (n = 14), facial nerve
palsy (n = 11), hemiparesis (n = 11), aphasia (n = 4),
chorea (n = 2) ataxia (n  =  2), and visual deficit in two
children. Dystonia and monoparesis were observed in
one child each, with  >1 deficit noted in seven patients.
The etiology of deficits was neuroinfections  (n = 11),
PRES (n = 3), methotrexate encephalopathy (n = 2),
Bell’s palsy (n = 2), and systemic infection in two
children. Hyperleukocytosis, hypocalcemia, hyponatremia,
cytomegalovirus infection, intracranial bleed, infarct, and
hydrocephalus were observed in one child each. In 13
children, the etiology of deficit was not conclusive.
Nature of events
The events were categorized into (i) seizures
of unknown etiology (ii) neuroinfection, (iii)
intracranial bleed, (iv) PRES, (v) methotrexate
 Acute neuro-toxicity profile in ALL
Key Message
Acute neurological complications occur in about 10% cases of acute lymphoblastic leukemia being seen
mainly in the induction phase. Neuro-infections are high in ‘our’ set up. Prognosis depends on the
nature of the insult.
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encephalopathy, (vi) CSVT (vii) aseptic meningitis, (viii)
hydrocephalus, (ix) epilepsy, (x) metabolic
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seizures, (xi) systemic infection related neurological
complications and  (xii) neurological deficits of unknown
etiology [Figure 1].
Seizures
Status epilepticus
Status epilepticus (SE) contributed to 14
(15.5%) events. SE occurred during induction
phase (n = 3), consolidation phase (n = 1),
interim maintenance (n = 1), and the maintenance
phase (n = 9) of therapy. Seizure semiology
was generalized in eight and focal in four. The
median IT to event duration was 45 [interquartile
range (IQR); 14,60] days and the median number of
IT prior to the event was 9 (IQR; 2,16). Cerebrospinal
fluid  (CSF) analysis done in eight children was normal.
Neuroimaging performed in 12 children revealed an
abnormality in seven. Eight children required paralysis
and ventilation and all succumbed to refractory
status. Six children recovered. Three children
had a recurrence of seizures on the anti‑epileptic
drug (AED). At a median follow‑up of 24 (IQR; 10,
39.7) months, two children are well and off drugs,
one child is on AED, one has a disability, one had
a relapse of ALL, and one died of respiratory illness.
Seizures of unknown etiology
Seizures of unknown etiology contributed to 16/50
(32%) of seizure episodes. Semiology was available
Figure  1: Distribution of events. PRES: Posterior reversible
encephalopathy syndrome, CSVT=Cerebral sinus venous thrombosis
Volume 58 | Issue 4 | October-December 2021
in 15; generalized seizures observed in 10, and
focal seizures in five children. Six, seven, and
three events occurred in high‑risk, intermediate‑risk,
and standard‑risk disease, respectively. Seizures
occurred during induction (n = 7), delayed
intensification (n = 6), maintenance (n = 2), and
consolidation (n = 1). The mean number of IT
administered prior to seizure was 6 ± 5 (range:
0 - 17). The median IT‑to‑event duration was
10 (IQR; 6.5, 14) days. Neuroimaging performed
in 16 children was normal in eight (50%) children.
The observed neuroimaging abnormalities
on magnetic resonance imaging (MRI) were
nonspecific hyperintensities  (n = 4), while computed
tomography  (CT) revealed calcified foci, white matter
hypodensity, hyperdense lesion, and suspected
infarct (n = 1 each). Electroencephalogram (EEG) and
CSF studies, performed in eight and four children,
respectively were normal.
Seizure recurrence on AED while on chemotherapy
was observed in 14 (87.5%) children, mandating
long‑term AED. At a mean follow‑up of 23 (range:
0.25-87) months, 11 (69%) are well without AED. One
child continues to be on AED, two children defaulted
therapy, and two suffered a relapse.
Neuroinfections
Neuroinfections were observed in 18 (20%)
patients, 10 (55%) occurring during induction
therapy. Clinical presentation included seizures,
raised intracranial pressure, status epilepticus, and
febrile encephalopathy. Nine patients had a brain
abscess. Aspergillus was identified in 4 cases and
no organism was identified in 5 cases. Invasive
rhinocerebral mucormycosis was identified in three
children, with two having co‑existing cerebral
sinovenous thrombosis (CSVT). Six children had
meningoencephalitis. Herpes encephalitis and
Aspergillus encephalitis was identified in one child
each, while the etiology remained undetermined
in four patients. All four children with Aspergillus
meningoencephalitis had multisystem involvement.
Ventilation support was required in eight (44%)
children. Omaya reservoir and ventriculoperitoneal
shunt were required in six (33%). The median duration
of hospitalization was 21 days (range: 3–120).
Mortality was high with 8/18 (44%) of 18 children
succumbing to neuroinfection. Ten children survived,
547
 Indian Journal of Cancer
with three having a neurological disability at follow‑up.
Four children are well without a disability. Three
children succumbed to non-neurological complications.
Other complications
PRES was diagnosed in seven children. All patients
presented with seizures, focal in five, and generalized
in two, at mean 3.1 ± 1.1 (range 2-5) weeks of the
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induction phase of therapy. Transient neurological
deficits of visual defect, facial nerve palsy, and ataxia
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were observed. Neuroimaging was corroboratory, with
T2/fluid attenuation inversion recovery hyperintensities
in bilateral parieto‑occipital regions recorded in all.
At a mean follow‑up of 21 ± 8.1 (range: 11-35)
months, five children are well. One child succumbed to
non‑neurological complication and one had a relapse.
Intracranial bleed was diagnosed in five children.
Seizure was the presenting feature in four children at
median 1 week (range: 1-2 weeks) of the induction
phase of therapy. Neuroimaging was diagnostic.
One child succumbed. Four children recovered and
received antiepileptics for a median duration of
3 weeks. At a median follow‑up of 30 (range: 6-72)
months, three children succumbed, the death being
unrelated to the neurological event, and one suffered
a relapse. One child got well.
Methotrexate encephalopathy was diagnosed in two
children during the maintenance phase of therapy.
Focal seizures, ipsilateral hemiparesis, facial nerve
palsy, and ataxia were the presenting features.
Neuroimaging was consistent with the diagnosis
Figure 2: Distribution of events across phases of therapy
548 Volume 58 | Issue 4 | October-December 2021
of methotrexate encephalopathy. The median
number of IT methotrexate received was 14 and the
mean duration of IT to the event was 55 (range:
2-55) days. Both children were subsequently given
cytarabine and hydrocortisone as IT therapy and are
well at a mean follow‑up of 13 ± 9.8 (range: 6-20)
months.
Aseptic meningitis was diagnosed in three children,
one each during consolidation, delayed intensification,
and maintenance. They presented with fever and neck
pain. CSF examination was performed in two and was
suggestive of viral meningitis in one child who had
co‑existing mumps. All recovered from the event and
are well at a median follow‑up of 68 (range: 2-93)
months.
Hydrocephalus was diagnosed in three children, one
in induction, and two in maintenance. They presented
with hemiparesis, fever, and seizure. Neuroimaging
was diagnostic. CSF examination was performed
in one child and was cellular. She was treated for
presumed neurotuberculosis. All recovered from
the event and are well at a follow‑up of 51.5 ± 6.3
(range: 56-59) months.
Epilepsy was diagnosed in six children. Two children
each in the delayed intensification and maintenance
phase and one child each in induction and interim
maintenance. All had generalized seizures, with
one child being a known case of cerebral palsy
and another having Costello syndrome. The median
duration of AED was 25 months (IQR: 13,33). One
 Acute neuro-toxicity profile in ALL
child died later due to sepsis. Five are currently
seizure‑free, three being on AED.
Systemic infections manifesting with seizures were
observed in four children. Two events occurred in
consolidation, one each in the induction and interim
maintenance. One child had culture‑positive enterobacter
sepsis. Two children succumbed to the infection. One
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child relapsed and one child is well on AED.
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Isolated neurological deficits of unknown etiology
were observed in 13 (14.4%). They include
hemiparesis (n = 4), facial nerve palsy (n = 4),
encephalopathy (n = 3), aphasia (n = 1),
monoparesis (n = 1), with more than one deficit
observed in three children. Two children had
co‑existing seizures. This complication transpired
during induction (n = 2), consolidation (n = 1), interim
maintenance (n  =  1), delayed intensification  (n = 4),
and the maintenance phase (n = 5). Neuroimaging
performed in 13 was normal in 6. Abnormalities in six
patients included nonspecific white matter changes
in two, nonspecific hyperintensity of the putamen in
two, and basal ganglia demyelination in one. CSF
analysis performed in four children was normal. The
median duration from IT to the event was 28.5 (IQR;
11.5, 45) days. At a median follow‑up of 34 (IQR; 16,
56) months, five children are well, two children died
of non‑neurological complications, two children are
on AED, two children have disability, and one child
suffered a relapse.
Distribution of complications according to the phase of
therapy
Seizures, neuroinfections, PRES, and bleed
predominated in the induction phase, while SE was
seen mainly during the maintenance phase. The
distribution of complications is depicted in Figure 2.
Mortality and morbidity
Eighteen (20.6%) children expired. Neuroinfections
and SE accounted for eight and six deaths. Two
children died due to systemic infection while one
child each had intracranial bleed and encephalopathy
with demyelination (focal deficit). Of the children
who succumbed to neurological complications,
standard‑risk, intermediate‑risk, and high‑risk
disease were present in seven, ten, and one child,
respectively [Table 1]. The median duration of
Table 1: Distribution of deaths due to neurological and non‑neurological complication according to risk
Total number Number of children died due to
of patients non‑neurological complication
Standard‑risk 36
Intermediate‑risk 31
High‑risk 20
Volume 58 | Issue 4 | October-December 2021
hospitalization was 8 (IQR; 4, 18) days. A recurrence
of seizure episodes while on AED was observed
in 20 (31%) of 64 children, predominantly in those
who had seizures of unknown etiology (n = 14). At a
follow‑up of 24 (IQR; 11, 47) months, 53 patients are
well, with seven children persisting with a neurological
disability. The disabilities include blindness,
developmental delay, hemiparetic gait, facial nerve
palsy, learning disability, and encephalopathy.
Discussion
The survival rates of ALL in low- and middle‑income
countries (LMIC) are inferior to those reported in
high‑income countries. The survival rates reported
from India range from 45 to 60%. [8‑11] Higher
treatment‑related toxicity and infections are in part
responsible for lower survival in LMIC.[10] Neurological
complications in ALL are serious events owing to their
life‑threatening nature and the sequel of disability.
These complications represent a prime example of
treatment‑related morbidity. The reported prevalence
of neurotoxicity is 3.6–11%. [2‑6] In our analysis,
the prevalence is 10%. The major complications
reported include seizures, meningitis, neuropathy,
leucoencephalopathy, thrombosis, and long‑term
neurocognitive dysfunction. [2‑6,12,13] Seizures have
been reported to be the most common complication,
amounting to 20–70%. [2,4,5,12] As the complications
are diverse and reports in literature are from
heterogeneous groups, the comparison is challenging.
The published experience on neurotoxicity in children
treated for ALL is given in Table 2.
In our analysis, seizure of unknown etiology was the
most common event and typically observed during
the intensive phase of chemotherapy. The prevalence
of seizures has been observed in up to 13% in older
studies when cranial radiotherapy was in use.[14,15] The
incidence has reduced to 4.7% with the omission of
prophylactic cranial radiotherapy. [16] Our cohort had
a comparable prevalence of 3.0%. These events
have been considered secondary to drug toxicity.
Intrathecal methotrexate results in folate deficiency
elevated homocysteine, and glutamate excess, which
are postulated to be the mechanisms of epilepsy in
children being treated for ALL.[17] The short duration
of intrathecal methotrexate administration to the
Number of children died due
to neurological complication
3 7
4 10
3 1
549
 Indian Journal of Cancer

Table 2: Compilation of studies on neurotoxicity in children treated for ALL

Serial Author Center Population and protocol used Prevalence/ Observation
Number Year of incidence
study
1 Lo Nigro Italy 122 patients of ALL Prevalence: 8.2%
Seizures: 7/10 (70%)
et al.[2] 1987– AIEOP‑ALL87, 91 and 95 protocols AIEOP 91: 5.8%Flaccid paralysis: 2 (20%)
1997 Intrathecal and cranial irradiation in AIEOP 95: 18.4%
Intensified regimen leads to increased
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87, triple IT in 91 and 95 protocol neuro‑toxicity and better survival

2 Aytec Turkey 265 patients of ALL Incidence: 9.5%
Neuropathy: 27.5%
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et al.[4] 1991– St Jude Total XI original protocol Convulsion: 20%

1997 (n=139) and Total XIII protocol (n=126) Meningitis: 10%
3 Kuskonmaz Turkey 203 patients of ALL Prevalence: 9.9%
Seizures: 42%
et al.[5] 1991– Modified St. Jude Total XI and St. Meningitis: 6/24 (25%)
2003 Jude Total XIII protocols Infarct and thrombosis: 5/24 (21%)
Induction: 33% and maintenance: 58%
Mortality rate: 30%
4 Parasole 2000– 253 patients of ALL Incidence: 11% Seizures: 48.2%
et al.[6] 2009 AIEOP‑BFM‑ALL‑2000 protocol Induction phase: 10 (37%)
Consolidation: 5 (18.5%)
Re‑induction: 2 (7.5%)
Maintenance: 9 (33.3%)
PRES: 10 (37%)
Stroke: 5 (18.5%)
Temporal lobe epilepsy and MTX
toxicity: 2 (7.5%) each
5 Schmidt Germany 950 children receiving chemotherapy/ Prevalence: 8.4% Seizures: 50%
et al.[12] 1992– HSCT Infections: 27%, toxicity: 21%, vascular
2004 events: 11%, metabolic: 8.5%, unknown
14.6%
CNS infections (22): Aspergillus (6);
mortality 8/22 (36%)
Diagnosis ascertained in 60%
Mortality: 23.7%
6 Millan 1995– 1379 patients of ALL Incidence: 3.6% MLE: 35.4%
et al.[13] 2015 ALL90‑GATLA, 1‑ALL96‑BFM/HPG, CSVT: 26.5%
ALL IC‑BFM 02 and ALLIC‑ BFM 2009 VVCP: 14%
protocols Stroke associated vasospasm: 14%
Severe polyneuropathy: 6%
Methotrexate myelopathy: 2%
MRC=Medical research council; UK ALL=United Kingdom acute lymphoblastic leukemia; HDMTX=high-dose methotrexate; HSCT=hematopoietic stem cell
transplantation; CNS=central nervous system; ALL=acute lymphoblastic leukemia; AIEOP‑ALL=Associazone Italiana di Ematologia ed Oncologia Pediatrica;
IT=Intrathecal; BFM=Berlin‑Frankfurt‑Münster; MTX=methotrexate; PRES=posterior reversible encephalopathy syndrome; MLE=methotrexate leuco encephalopathy;
CSVT=cerebral sinous venous thrombosis; VVCP=vincristine-induced vocal cord paralysis, GATLA=Grupo Argentino de Tratamiento de la leucemia, HPG=Hospital
de Pediatria Garrahan, IC-BFM=Intercontinental Berlin Frankfurt Munster

occurrence of seizure indicates a plausible role of drug
toxicity in the pathogenesis.
In the Children’s Oncology Group (COG) trial
POG 9005, acute neurotoxicity was observed in
95 (7.4%) of 1218 patients. Seizures (focal and
generalized) were the most common event, observed
in 82%, with children in the arm receiving high-
dose methotrexate having a greater prevalence
of neurotoxicity corroborated by neuroimaging. [18]
In our study, neuroimaging was not contributory
in children with seizures. Seizures have been
reported to occur predominantly during the acute
phase and usually do not recur in the absence of
cerebral structural lesions or neurological deficits.
The reported long‑term outcome is good.[11,15] Khan
et al. reported a seizure recurrence rate of 25%,
similar to that in children without cancer. [19] The
recurrence of seizures on therapy in our cohort was
31%. The high recurrence observed in children with
seizures of unknown etiology indicates a pathogenic
epileptic effect of chemotherapeutic drugs. However,
a long‑term neurological disability was observed
only in one child. Hence, despite the recurrence of
seizures and long‑term AED use, the neurological
outcome appears to be good, although a formal
neurodevelopmental assessment is required to
confirm the same.
The occurrence of epilepsia partialis continua in
children while on maintenance chemotherapy in our
cohort has been an ominous event, predominantly

550 Volume 58 | Issue 4 | October-December 2021

 Acute neuro-toxicity profile in ALL
culminating in death (64%) with the major neurological
deficit being seen in 42%. The etiology behind this
event is conjectural with available investigations. The
nonavailability of genetic tests precluded us from
identifying any genetic predisposition to such toxicity in
these children. The possibility of nutritional causes that
can be a risk factor to this complication was also not
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assessed. The MRI brain changes of T2/fluid-attenuated
inversion recovery hyperintensities in these children could
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be consistent with drug‑induced leukoencephalopathy or
secondary to the prolonged seizure activity.
Neuroinfections have been observed to account for
15–27% of neurotoxic events in previous studies.[4,5,12]
In our cohort, infections accounted for 15% of
events. Infections included meningoencephalitis
and brain abscess. Brain abscess has been
reported sporadically in children with ALL. The
main causative agent observed has been
Aspergillus. [12,20] In our analysis, invasive fungal
infections predominated (53%). Neuroinfections are
observed to have a high mortality rate, of up to
74%.[2, 20] The German experience reported Aspergillus
in six (27%) of 22 of neuroinfections with a mortality
rate of 36%. [12] In our cohort, 44% succumbed to
the infection. Lackner et al. reported successful
management of four children with brain abscess
in their cohort, which included toxoplasma gondii
and acanthamoeba.[20] An aggressive multi‑modality
diagnostic and therapeutic approach is required for
the successful management of neuroinfections.
The incidence of PRES in pediatric leukemia
patients ranges from 1.7%–4.5%. [4,21,22] The Nordic
group recorded PRES to be a major etiology
for neurotoxicity in their cohort and identified
hypertension, constipation, and >15 days of
alkalization to be contributory risk factors.[22] We have
a low incidence of PRES of 0.7%. This observation
suggests probable underestimation in the previous
decade due to sparing use/availability of MRI. PRES
is commonly observed in the induction phase of
chemotherapy, as was observed in our analysis, with
the drugs employed during induction chemotherapy
considered to predispose to PRES. [23] Long‑term
neurotoxicity is reported in <10%.[21, 23] Similarly, in our
cohort, no child with PRES had long‑term neurological
morbidity.
Acute neurotoxicity across various studies has been
reported predominantly in the induction phase of
chemotherapy. The incidence of complications range
from 8.2% to 55% during the induction phase. [5,6,13]
Similarly in our study, 42.8% of events occurred
during the induction phase. The intense therapy, drug
interactions, and higher neurotoxicity profile of drugs
Volume 58 | Issue 4 | October-December 2021
used in induction therapy are the possible reasons for
the higher rate of complications in this phase. A higher
threshold of suspicion in this phase and management
is required to ameliorate the associated morbidity.
Conclusions
The study highlights the 10% prevalence of acute
neurotoxicity profile of children with ALL. Drug toxicity
and neuroinfections were the major adverse events
encountered in our cohort. Neuroinfections with high
morbidity and mortality are a challenge and possibly
higher in LMICs. This study is a retrospective analysis
restricted to acute neurotoxicity in children treated for
ALL and the long‑term neurodevelopmental outcome
has not been assessed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
ORCID iDs:
Emine A Rahiman: https://orcid.org/0000-0002-2441-6188
Aruna Rajendran: https://orcid.org/0000-0002-7502-7887
Naveen Sankhyan: https://orcid.org/0000-0003-4929-1163
Paramjeet Singh: https://orcid.org/0000-0002-3340-0751
Jayashree Muralidharan: https://orcid.org/0000-0002-6149-1355
Deepak Bansal: https://orcid.org/0000-0002-1009-7649
Amita Trehan: https://orcid.org/0000-0001-9071-7651
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