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J Pediatr Intensive Care 2023; 12(04): 278-288
DOI: 10.1055/s-0041-1732444
Original Article

Cerebral Metabolic Crisis in Pediatric Cerebral Malaria

Nicole F. O'Brien 
1   Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, United States
,
Karen Chetcuti
2   Department of Radiology, College of Medicine, Chichiri, Blantyre, Malawi
,
Yudy Fonseca
3   Division of Critical Care Medicine, Department of Pediatrics, University of Maryland Medical Center, University of Maryland School of Medicine, Baltimore, Maryland, United States
,
Lorenna Vidal 
4   Division of Neuroradiology, Department of Radiology Children's Hospital of Philadelphia, Clinical Instructor at Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
,
Prashant Raghavan
5   Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States
,
Douglas G. Postels 
6   Department of Neurology, George Washington University/Children's National Medical Center, Washington, District of Columbia, United States
,
Yamikani Chimalizeni
7   Department of Pediatrics and Child Health, University of Malawi, Malawi College of Medicine, Chichiri, Blantyre, Malawi
,
Stephen Ray
8   Department of Paediatric, Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi
,
Karl B. Seydel
9   Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, United States
10   Blantyre Malaria Project, Blantyre, Malawi
,
Terrie E. Taylor
9   Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, United States
› Author Affiliations Funding The work for this project was carried out by MS and P laboratory at the Ohio State University, which is supported by NIH award number (Grant No. P30 CA016058).
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Abstract

Cerebral metabolic energy crisis (CMEC), often defined as a cerebrospinal fluid (CSF) lactate: pyruvate ratio (LPR) >40, occurs in various diseases and is associated with poor neurologic outcomes. Cerebral malaria (CM) causes significant mortality and neurodisability in children worldwide. Multiple factors that could lead to CMEC are plausible in these patients, but its frequency has not been explored. Fifty-three children with CM were enrolled and underwent analysis of CSF lactate and pyruvate levels. All 53 patients met criteria for a CMEC (median CSF LPR of 72.9 [interquartile range [IQR]: 58.5–93.3]). Half of children met criteria for an ischemic CMEC (median LPR of 85 [IQR: 73–184]) and half met criteria for a nonischemic CMEC (median LPR of 60 [IQR: 54–79]. Children also underwent transcranial doppler ultrasound investigation. Cerebral blood flow velocities were more likely to meet diagnostic criteria for low flow (<2 standard deviation from normal) or vasospasm in children with an ischemic CMEC (73%) than in children with a nonischemic CMEC (20%, p = 0.04). Children with an ischemic CMEC had poorer outcomes (pediatric cerebral performance category of 3–6) than those with a nonischemic CMEC (46 vs. 22%, p = 0.03). CMEC was ubiquitous in this patient population and the processes underlying the two subtypes (ischemic and nonischemic) may represent targets for future adjunctive therapies.

Keywords

cerebral malaria - cerebral blood flow - brain blood flow - brain disorders - metabolic - Doppler sonography - transcranial

Supplementary Material



Publication History

Received: 23 March 2021

Accepted: 12 June 2021

Article published online:
10 August 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Report WM. Geneva: World Health Organization; 2020. . Accessed April 15, 2021 at: http://www.who.int/malaria/publications/world_malaria_report/en
  • 2 Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol 2005; 4 (12) 827-840
    CrossrefPubMedGoogle Scholar
  • 3 Langfitt JT, McDermott MP, Brim R. et al. Neurodevelopmental impairments 1 year after cerebral malaria. Pediatrics 2019; 143 (02) e20181026
    CrossrefPubMedGoogle Scholar
  • 4 Seydel KB, Kampondeni SD, Valim C. et al. Brain swelling and death in children with cerebral malaria. N Engl J Med 2015; 372 (12) 1126-1137
    CrossrefPubMedGoogle Scholar
  • 5 Mohanty S, Taylor TE, Kampondeni S. et al. Magnetic resonance imaging during life: the key to unlock cerebral malaria pathogenesis?. Malar J 2014; 13: 276
    CrossrefPubMedGoogle Scholar
  • 6 Mohanty S, Benjamin LA, Majhi M. et al. Magnetic resonance imaging of cerebral malaria patients reveals distinct pathogenetic processes in different parts of the brain. MSphere 2017; 2 (03) e00193-e17
    CrossrefPubMedGoogle Scholar
  • 7 Potchen MJ, Kampondeni SD, Seydel KB. et al. Acute brain MRI findings in 120 Malawian children with cerebral malaria: new insights into an ancient disease. AJNR Am J Neuroradiol 2012; 33 (09) 1740-1746
    CrossrefPubMedGoogle Scholar
  • 8 Kampondeni SD, Potchen MJ, Beare NA. et al. MRI findings in a cohort of brain injured survivors of pediatric cerebral malaria. Am J Trop Med Hyg 2013; 88 (03) 542-546
    CrossrefPubMedGoogle Scholar
  • 9 Ho VB, Fitz CR, Chuang SH, Geyer CA. Bilateral basal ganglia lesions: pediatric differential considerations. Radiographics 1993; 13 (02) 269-292
    CrossrefPubMedGoogle Scholar
  • 10 Bitar R, Leung G, Perng R. et al. MR pulse sequences: what every radiologist wants to know but is afraid to ask. Radiographics 2006; 26 (02) 513-537
    CrossrefPubMedGoogle Scholar
  • 11 Drayer B, Burger P, Hurwitz B, Dawson D, Cain J. Reduced signal intensity on MR images of thalamus and putamen in multiple sclerosis: increased iron content?. AJR Am J Roentgenol 1987; 149 (02) 357-363
    CrossrefPubMedGoogle Scholar
  • 12 Bartek Jr J, Thelin EP, Ghatan PH, Glimaker M, Bellander BM. Neuron-specific enolase is correlated to compromised cerebral metabolism in patients suffering from acute bacterial meningitis; an observational cohort study. PLoS One 2016; 11 (03) e0152268
    CrossrefPubMedGoogle Scholar
  • 13 Tobieson L, Rossitti S, Zsigmond P, Hillman J, Marklund N. Persistent metabolic disturbance in the perihemorrhagic zone despite a normalized cerebral blood flow following surgery for intracerebral hemorrhage. Neurosurgery 2019; 84 (06) 1269-1279
    CrossrefPubMedGoogle Scholar
  • 14 Sala N, Suys T, Zerlauth JB. et al. Cerebral extracellular lactate increase is predominantly nonischemic in patients with severe traumatic brain injury. J Cereb Blood Flow Metab 2013; 33 (11) 1815-1822
    CrossrefPubMedGoogle Scholar
  • 15 Timofeev I, Carpenter KL, Nortje J. et al. Cerebral extracellular chemistry and outcome following traumatic brain injury: a microdialysis study of 223 patients. Brain 2011; 134 (Pt 2): 484-494
    CrossrefPubMedGoogle Scholar
  • 16 Oddo M, Levine JM, Frangos S. et al. Brain lactate metabolism in humans with subarachnoid hemorrhage. Stroke 2012; 43 (05) 1418-1421
    CrossrefPubMedGoogle Scholar
  • 17 Schmidt JM, Ko SB, Helbok R. et al. Cerebral perfusion pressure thresholds for brain tissue hypoxia and metabolic crisis after poor-grade subarachnoid hemorrhage. Stroke 2011; 42 (05) 1351-1356
    CrossrefPubMedGoogle Scholar
  • 18 Carteron L, Patet C, Solari D. et al. Non-ischemic cerebral energy dysfunction at the early brain injury phase following aneurysmal subarachnoid hemorrhage. Front Neurol 2017; 8: 325
    CrossrefPubMedGoogle Scholar
  • 19 Cheng G, Kong RH, Zhang LM, Zhang JN. Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. Br J Pharmacol 2012; 167 (04) 699-719
    CrossrefPubMedGoogle Scholar
  • 20 Jaggi JL, Obrist WD, Gennarelli TA, Langfitt TW. Relationship of early cerebral blood flow and metabolism to outcome in acute head injury. J Neurosurg 1990; 72 (02) 176-182
    CrossrefPubMedGoogle Scholar
  • 21 Muizelaar JP, Marmarou A, DeSalles AA. et al. Cerebral blood flow and metabolism in severely head-injured children. Part 1: relationship with GCS score, outcome, ICP, and PVI. J Neurosurg 1989; 71 (01) 63-71
    CrossrefPubMedGoogle Scholar
  • 22 Glenn TC, Kelly DF, Boscardin WJ. et al. Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism. J Cereb Blood Flow Metab 2003; 23 (10) 1239-1250
    CrossrefPubMedGoogle Scholar
  • 23 Wallin E, Larsson IM, Nordmark-Grass J, Rosenqvist I, Kristofferzon ML, Rubertsson S. Characteristics of jugular bulb oxygen saturation in patients after cardiac arrest: a prospective study. Acta Anaesthesiol Scand 2018; 62 (09) 1237-1245
    CrossrefPubMedGoogle Scholar
  • 24 Cruickshank AM, Telfer AB, Shenkin A. Thiamine deficiency in the critically ill. Intensive Care Med 1988; 14 (04) 384-387
    CrossrefPubMedGoogle Scholar
  • 25 Carre E, Ogier M, Boret H, Montcriol A, Bourdon L, Jean-Jacques R. Metabolic crisis in severely head-injured patients: is ischemia just the tip of the iceberg?. Front Neurol 2013; 4: 146
    CrossrefPubMedGoogle Scholar
  • 26 Vespa P, Bergsneider M, Hattori N. et al. Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab 2005; 25 (06) 763-774
    CrossrefPubMedGoogle Scholar
  • 27 Larach DB, Kofke WA, Le Roux P. Potential non-hypoxic/ischemic causes of increased cerebral interstitial fluid lactate/pyruvate ratio: a review of available literature. Neurocrit Care 2011; 15 (03) 609-622
    CrossrefPubMedGoogle Scholar
  • 28 Johnston AJ, Steiner LA, Coles JP. et al. Effect of cerebral perfusion pressure augmentation on regional oxygenation and metabolism after head injury. Crit Care Med 2005; 33 (01) 189-195 , discussion 255–257
    CrossrefPubMedGoogle Scholar
  • 29 Fahn S. Biochemistry of the basal ganglia. Adv Neurol 1976; 14: 59-89
    PubMedGoogle Scholar
  • 30 Carpenter KLH, Jalloh I, Hutchinson PJ. Glycolysis and the significance of lactate in traumatic brain injury. Front Neurosci 2015; 9: 112
    PubMedGoogle Scholar
  • 31 Fujishima M, Sugi T, Choki J, Yamaguchi T, Omae T. Cerebrospinal fluid and arterial lactate, pyruvate and acid-base balance in patients with intracranial hemorrhages. Stroke 1975; 6 (06) 707-714
    CrossrefPubMedGoogle Scholar
  • 32 Zhang WM, Natowicz MR. Cerebrospinal fluid lactate and pyruvate concentrations and their ratio. Clin Biochem 2013; 46 (7-8): 694-697
    CrossrefPubMedGoogle Scholar
  • 33 Ståhl N, Mellergård P, Hallström A, Ungerstedt U, Nordström CH. Intracerebral microdialysis and bedside biochemical analysis in patients with fatal traumatic brain lesions. Acta Anaesthesiol Scand 2001; 45 (08) 977-985
    CrossrefPubMedGoogle Scholar
  • 34 Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP. Impaired cerebral mitochondrial function after traumatic brain injury in humans. J Neurosurg 2000; 93 (05) 815-820
    CrossrefPubMedGoogle Scholar
  • 35 Engquist H, Lewén A, Hillered L. et al. CBF changes and cerebral energy metabolism during hypervolemia, hemodilution, and hypertension therapy in patients with poor-grade subarachnoid hemorrhage. J Neurosurg 2020; 1-10
    PubMedGoogle Scholar
  • 36 Planche T, Onanga M, Schwenk A. et al. Assessment of volume depletion in children with malaria. PLoS Med 2004; 1 (01) e18
    CrossrefPubMedGoogle Scholar
  • 37 Planche T. Malaria and fluids--balancing acts. Trends Parasitol 2005; 21 (12) 562-567
    CrossrefPubMedGoogle Scholar
  • 38 Maitland K, Levin M, English M. et al. Severe P. falciparum malaria in Kenyan children: evidence for hypovolaemia. QJM 2003; 96 (06) 427-434
    CrossrefPubMedGoogle Scholar
  • 39 Kotlyar S, Olupot-Olupot P, Nteziyaremye J. et al. Assessment of myocardial function and injury by echocardiography and cardiac biomarkers in african children with severe plasmodium falciparum malaria. Pediatr Crit Care Med 2018; 19 (03) 179-185
    CrossrefPubMedGoogle Scholar
  • 40 Newton CR, Crawley J, Sowumni A. et al. Intracranial hypertension in Africans with cerebral malaria. Arch Dis Child 1997; 76 (03) 219-226
    CrossrefPubMedGoogle Scholar
  • 41 Taylor TE, Fu WJ, Carr RA. et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med 2004; 10 (02) 143-145
    CrossrefPubMedGoogle Scholar
  • 42 Omanga U, Ntihinyurwa M, Shako D, Mashako M. [Hemiplegia in pernicious attacks of Plasmodium falciparum in children]. Ann Pediatr (Paris) 1983; 30 (04) 294-296
    PubMedGoogle Scholar
  • 43 Cabrales P, Zanini GM, Meays D, Frangos JA, Carvalho LJM. Murine cerebral malaria is associated with a vasospasm-like microcirculatory dysfunction, and survival upon rescue treatment is markedly increased by nimodipine. Am J Pathol 2010; 176 (03) 1306-1315
    CrossrefPubMedGoogle Scholar
  • 44 Day NP, Phu NH, Mai NT. et al. The pathophysiologic and prognostic significance of acidosis in severe adult malaria. Crit Care Med 2000; 28 (06) 1833-1840
    CrossrefPubMedGoogle Scholar
  • 45 Clavier N, Rahimy C, Falanga P, Ayivi B, Payen D. No evidence for cerebral hypoperfusion during cerebral malaria. Crit Care Med 1999; 27 (03) 628-632
    CrossrefPubMedGoogle Scholar
  • 46 Hiffler L, Rakotoambinina B, Lafferty N, Martinez Garcia D. Thiamine deficiency in tropical pediatrics: new insights into a neglected but vital metabolic challenge. Front Nutr 2016; 3: 16
    CrossrefPubMedGoogle Scholar
  • 47 Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg 2000; 94 (Suppl. 01) S1-S90
    PubMedGoogle Scholar
  • 48 Taylor TE. Caring for children with cerebral malaria: insights gleaned from 20 years on a research ward in Malawi. Trans R Soc Trop Med Hyg 2009; 103 (Suppl. 01) S6-S10
    CrossrefPubMedGoogle Scholar
  • 49 Barrow GI, Feltham RKA. Cowan and Steel's Manual for the Identification of Medical Bacteria. 3rd ed.. Cambridge (United Kingdom): Cambridge University Press; 1993
    CrossrefGoogle Scholar
  • 50 Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 1982; 57 (06) 769-774
    CrossrefPubMedGoogle Scholar
  • 51 Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebral autoregulation dynamics in humans. Stroke 1989; 20 (01) 45-52
    CrossrefPubMedGoogle Scholar
  • 52 Lindegaard KF, Nornes H, Bakke SJ, Sorteberg W, Nakstad P. Cerebral vasospasm diagnosis by means of angiography and blood velocity measurements. Acta Neurochir (Wien) 1989; 100 (1-2): 12-24
    CrossrefPubMedGoogle Scholar
  • 53 Bode H, Wais U. Age dependence of flow velocities in basal cerebral arteries. Arch Dis Child 1988; 63 (06) 606-611
    CrossrefPubMedGoogle Scholar
  • 54 Applegarth DA, Edelstein AD, Wong LTK, Morrison BJ. Observed range of assay values for plasma and cerebrospinal fluid amino acid levels in infants and children aged 3 months to 10 years. Clin Biochem 1979; 12 (05) 173-178
    CrossrefPubMedGoogle Scholar
  • 55 Benoist JF, Alberti C, Leclercq S. et al. Cerebrospinal fluid lactate and pyruvate concentrations and their ratio in children: age-related reference intervals. Clin Chem 2003; 49 (03) 487-494
    CrossrefPubMedGoogle Scholar
  • 56 Wyatt DT, Nelson D, Hillman RE. Age-dependent changes in thiamin concentrations in whole blood and cerebrospinal fluid in infants and children. Am J Clin Nutr 1991; 53 (02) 530-536
    CrossrefPubMedGoogle Scholar
  • 57 Fiser DH. Assessing the outcome of pediatric intensive care. J Pediatr 1992; 121 (01) 68-74
    CrossrefPubMedGoogle Scholar
  • 58 Fiser DH, Tilford JM, Roberson PK. Relationship of illness severity and length of stay to functional outcomes in the pediatric intensive care unit: a multi-institutional study. Crit Care Med 2000; 28 (04) 1173-1179
    CrossrefPubMedGoogle Scholar
  • 59 O'Brien NF, Mutatshi Taty T, Moore-Clingenpeel M. et al. Transcranial Doppler ultrasonography provides insights into neurovascular changes in children with cerebral malaria. J Pediatr 2018; 203: 116-124.e3
    CrossrefPubMedGoogle Scholar
  • 60 Nordström CH. Cerebral energy metabolism and microdialysis in neurocritical care. Childs Nerv Syst 2010; 26 (04) 465-472
    CrossrefPubMedGoogle Scholar
  • 61 Sanni LA, Rae C, Maitland A, Stocker R, Hunt NH. Is ischemia involved in the pathogenesis of murine cerebral malaria?. Am J Pathol 2001; 159 (03) 1105-1112
    CrossrefPubMedGoogle Scholar
  • 62 Warrell DA, White NJ, Veall N. et al. Cerebral anaerobic glycolysis and reduced cerebral oxygen transport in human cerebral malaria. Lancet 1988; 2 (8610): 534-538
    CrossrefPubMedGoogle Scholar
  • 63 Quinn CT, Dowling MM. Anemia and ischemia: how low can you go?. Blood 2015; 125 (10) 1516-1517
    CrossrefPubMedGoogle Scholar
  • 64 A quick guide to pediatric cardiopulmonary care. Brian Boville and Caulette Young. Edwards Lifesciences. Irvine, California. Accessed 2015 at: https://www.researchgate.net/publication/260060738_Quick_Guide_to_Pediatric_Cardiopulmonary_Care
    PubMedGoogle Scholar
  • 65 Avery RA. Interpretation of lumbar puncture opening pressure measurements in children. J Neuroophthalmol 2014; 34 (03) 284-287
    CrossrefPubMedGoogle Scholar
  • 66 Avery RA, Shah SS, Licht DJ. et al. Reference range for cerebrospinal fluid opening pressure in children. N Engl J Med 2010; 363 (09) 891-893
    CrossrefPubMedGoogle Scholar
  • 67 Kerscher SR, Schöni D, Neunhoeffer F. et al. The relation of optic nerve sheath diameter (ONSD) and intracranial pressure (ICP) in pediatric neurosurgery practice - Part II: influence of wakefulness, method of ICP measurement, intra-individual ONSD-ICP correlation and changes after therapy. Childs Nerv Syst 2020; 36 (01) 107-115
    CrossrefPubMedGoogle Scholar
  • 68 Alexandrov AV. The Spencer's Curve: clinical implications of a classic hemodynamic model. J Neuroimaging 2007; 17 (01) 6-10
    CrossrefPubMedGoogle Scholar
  • 69 Kim S, Han SC, Gallan AJ, Hayes JP. Neurometabolic indicators of mitochondrial dysfunction in repetitive mild traumatic brain injury. Concussion 2017; 2 (03) CNC48
    PubMedGoogle Scholar
  • 70 Wu Q, Xia SX, Li QQ. et al. Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury. Brain Res 2016; 1630: 134-143
    CrossrefPubMedGoogle Scholar
  • 71 Krishna S, Taylor AM, Supanaranond W. et al. Thiamine deficiency and malaria in adults from Southeast Asia. Lancet 1999; 353 (9152): 546-549
    CrossrefPubMedGoogle Scholar
  • 72 Friedman SD, Shaw DW, Ishak G, Gropman AL, Saneto RP. The use of neuroimaging in the diagnosis of mitochondrial disease. Dev Disabil Res Rev 2010; 16 (02) 129-135
    CrossrefPubMedGoogle Scholar
  • 73 Xu Y, McArthur DL, Alger JR. et al. Early nonischemic oxidative metabolic dysfunction leads to chronic brain atrophy in traumatic brain injury. J Cereb Blood Flow Metab 2010; 30 (04) 883-894
    CrossrefPubMedGoogle Scholar
  • 74 Vander Jagt DL, Hunsaker LA, Campos NM, Baack BR. D-lactate production in erythrocytes infected with Plasmodium falciparum. Mol Biochem Parasitol 1990; 42 (02) 277-284
    CrossrefPubMedGoogle Scholar
  • 75 Pfaller MA, Krogstad DJ, Parquette AR, Nguyen-Dinh P. Plasmodium falciparum: stage-specific lactate production in synchronized cultures. Exp Parasitol 1982; 54 (03) 391-396
    CrossrefPubMedGoogle Scholar
  • 76 Idro R, Marsh K, John CC, Newton CRJ. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res 2010; 68 (04) 267-274
    CrossrefPubMedGoogle Scholar
  • 77 Sánchez-Guerrero A, Mur-Bonet G, Vidal-Jorge M. et al. Reappraisal of the reference levels for energy metabolites in the extracellular fluid of the human brain. J Cereb Blood Flow Metab 2017; 37 (08) 2742-2755
    CrossrefPubMedGoogle Scholar
  • 78 Reinstrup P, Ståhl N, Mellergård P, Uski T, Ungerstedt U, Nordström CH. Intracerebral microdialysis in clinical practice: baseline values for chemical markers during wakefulness, anesthesia, and neurosurgery. Neurosurgery 2000; 47 (03) 701-709 , discussion 709–710
    PubMedGoogle Scholar
  • 79 Mori K, Nakajima K, Maeda M. Long-term monitoring of CSF lactate levels and lactate/pyruvate ratios following subarachnoid haemorrhage. Acta Neurochir (Wien) 1993; 125 (1-4): 20-26
    CrossrefPubMedGoogle Scholar
  • 80 Renfrow JJ, Frey CD, Arnel M, Wolfe SQ, McLouth C, Datar S. Utility of cerebrospinal fluid lactate in aneurysmal subarachnoid hemorrhage. Surg Neurol Int 2018; 9: 155
    CrossrefPubMedGoogle Scholar