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    -  Rahiman EA
    -  Rajendran A
    -  Sankhyan N
    -  Singh P
    -  Muralidharan J
    -  Bansal D
    -  Trehan A

 
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ORIGINAL ARTICLE
Ahead of print publication
 

Acute neurological complications during acute lymphoblastic leukemia therapy: A single-center experience over 10 years


1 Pediatric Hematology Oncology unit, Department of Pediatrics, Advanced Pediatric Center, Chandigarh, India
2 Pediatric Neurology unit, Department of Pediatrics, Advanced Pediatric Center, Chandigarh, India
3 Department of Radio-diagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4 Pediatric Critical Care unit, Department of Pediatrics, Advanced Pediatric Center, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission14-May-2019
Date of Decision16-May-2019
Date of Acceptance25-May-2020
Date of Web Publication11-May-2021

Correspondence Address:
Amita Trehan,
Pediatric Hematology Oncology unit, Department of Pediatrics, Advanced Pediatric Center, Chandigarh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_422_19

PMID: 34380827

  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
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.



How to cite this URL:
Rahiman EA, Rajendran A, Sankhyan N, Singh P, Muralidharan J, Bansal D, Trehan A. Acute neurological complications during acute lymphoblastic leukemia therapy: A single-center experience over 10 years. Indian J Cancer [Epub ahead of print] [cited 2021 Sep 25]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=315807





  Introduction Top


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 countries, where ALL therapy is fraught with greater morbidity, especially related to infections. Neurotoxicity has been observed to occur in 3.6–11% across diverse study groups.[2],[3],[4],[5],[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 Top


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. (St\andard-risk: <10 years; total leucocyte count (TLC) <50 × 109/L and High-risk: >10 years; TLC ≥50 × 109/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 × 109/L and MRD <0.01%; Intermediate: Age >10 years, TLC >50 × 109/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.

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 Top


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 encephalopathy, (vi) CSVT (vii) aseptic meningitis, (viii) hydrocephalus, (ix) epilepsy, (x) metabolic seizures, (xi) systemic infection related neurological complications and (xii) neurological deficits of unknown etiology [Figure 1].
Figure 1: Distribution of events. PRES: Posterior reversible encephalopathy syndrome, CSVT=Cerebral sinus venous thrombosis

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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 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, 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 induction phase of therapy. Transient neurological deficits of visual defect, facial nerve palsy, and ataxia 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 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 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 child relapsed and one child is well on AED.

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].
Figure 2: Distribution of events across phases of therapy

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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 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.
Table 1: Distribution of deaths due to neurological and non-neurological complication according to risk

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  Discussion Top


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],[9],[10],[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],[3],[4],[5],[6] In our analysis, the prevalence is 10%. The major complications reported include seizures, meningitis, neuropathy, leucoencephalopathy, thrombosis, and long-term neurocognitive dysfunction.[2],[3],[4],[5],[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].
Table 2: Compilation of studies on neurotoxicity in children treated for ALL

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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 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 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 assessed. The MRI brain changes of T2/fluid-attenuated inversion recovery hyperintensities in these children could 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 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 Top


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.



 
  References Top

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Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): A randomised controlled trial. Lancet Oncol 2013;14:199-209.  Back to cited text no. 7
    
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Mahoney DH, Shuster JJ, Nitschke R, Lauer SJ, Steuber CP, Winick K, et al. Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy- a Pediatric Oncology Group study. J Clin Oncol. 1998;16:1712-22.  Back to cited text no. 18
    
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Lackner H, Sovinz P, Benesch M, Smolle-Jüttner F, Mokry M, Schwinger W, et al. Management of brain abscesses in children treated for acute lymphoblastic leukemia. Pediatr Blood Cancer 2009;52:408-11.  Back to cited text no. 20
    
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Banerjee JS, Heyman M, Palomäki M, Lähteenmäki P, Arola M, Riikonen PV, et al. Posterior reversible encephalopathy syndrome: Risk factors and impact on the outcome in children with acute lymphoblastic leukemia treated with nordic protocols. J Pediatr Hematol Oncol 2018;40:e13-8.  Back to cited text no. 22
    
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Tang J-H, Tian J-M, Sheng M, Hu S-Y, Li Y, Zhang L-Y, et al. Study of posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia after induction chemotherapy. J Child Neurol 2016;31:279-84.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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