Subscribe to RSS
DOI: 10.1055/s-2004-815787
Georg Thieme Verlag Stuttgart · New York
Brain Lactic Alkalosis in Aicardi-Goutières Syndrome
Publication History
Received: 12. Juni 2003
Accepted after Revision: 1. Dezember 2003
Publication Date:
04 March 2004 (online)
Abstract
Aicardi-Goutières syndrome is a rare progressive encephalopathy characterized by acquired microcephaly, basal ganglia calcification, and chronic CSF lymphocytosis, raised levels of interferon alpha in CSF and plasma and chill-blain type lesions. A possible mechanism of injury is cytokine related microangiopathy. We report brain imaging and proton (1H) and phosphorus-31 (31P) magnetic resonance spectroscopy (MRS) findings during the first year after birth in two patients. In patient 1 the evolution of brain metabolite ratios and intracellular pH obtained from serial 1H (long TE) and 31P MRS studies are described; in patient 2 a single 1H (short TE) MRS study is described. Imaging findings included basal ganglia calcifications, cerebral atrophy, and leukodystrophy. The MRS results demonstrated that Aicardi-Goutières syndrome is associated with reduced NAA/Cr, reflecting decreased neuronal/axonal density or viability, increased myo-inositol/Cr, reflecting gliosis or osmotic stress and a persisting brain lactic alkalosis. A brain lactic alkalosis has also been observed in those infants surviving perinatal hypoxia-ischaemia but with a poor neurodevelopmental outcome. A possible mechanism leading to brain alkalosis is up-regulation of the Na+/H+ transporter by focal areas of ischaemia related to the microangiopathy or by pro-inflammatory cytokines. Such brain alkalosis may be detrimental to cell survival and may increase glycolytic rate in astrocytes leading to an increased production of lactate.
Key words
Aicardi-Goutières syndrome - magnetic resonance spectroscopy - magnetic resonance imaging - brain lactate - brain intracellular pH - alkalosis
References
- 1 Aicardi J, Goutières F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol. 1984; 15 49-54
- 2 Azzopardi D, Wyatt J S, Cady E B, Deply D T, Baudin J, Stewart A L. et al . Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1989; 25 445-451
- 3 Barth P G. The neuropathology of Aicardi-Goutières syndrome. Eur J Pediatr Neurol. 2002; 6 27-31
- 4 Benos D J, McPherson S, Hahn B H, Chaikin M A, Benveniste E N. Cytokines and HIV envelope glycoprotein GP 120 stimulate Na+/H+ exchange in astrocytes. J Biol Chem. 1994; 269 3811-3816
- 5 Bond J M, Chacon E, Herman B, Lemasters J J. Intracellular pH and Ca2+ homeostasis in the pH paradox of reperfusion injury to neonatal rat cardiac myocytes. Am J Physiol. 1993; 265 129-137
- 6 Brand A, Richter-Landsberg C, Leibfritz D. Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci. 1993; 15 289-298
- 7 Campbell I L, Krucker T, Steffensen S. Structural and functional neuropathology in transgenic mice with CNS expression of IFN-α. Brain Res. 1999; 835 46-61
- 8 Chang L, Ernst T, Leonido-Yee M, Walot I, Singer E. Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex. Neurology. 1999; 52 100-108
- 9 Crow Y J, Jackson A P, Roberts E, van Beusekom E, Barth P, Corry P. et al . Aicardi-Goutières syndrome displays genetic heterogeneity with one locus (AGS1) on chromosome 3 p21. Am J Hum Genet. 2000; 67 213-221
- 10 Fidelman M L, Seehilzer S H, Walsh K B, Moore R D. Intracellular pH mediates action on glycolysis in frog skeletal muscle. Am J Physiol. 1982; 242 87-93
- 11 Ferimer H N, Kutina K L, LaManna J C. Methylisobutylamiloride delays normalization of brain intracellular pH after cardiac arrest in rats. Crit Care Med. 1995; 23 1106-1111
- 12 Goutières F, Aicardi J, Barth P G, Lebon P. Aicardi-Goutières syndrome: an update and results of interferon-α studies. Ann Neurol. 1998; 44 900-907
- 13 Grinstein S, Rothstein A. Mechanisms of regulation of the Na+/H+ exchanger. J Membrane Biol. 1986; 90 1-12
-
14 LaManna J C.
Hypoxia-ischaemia and the pH paradox. Ince C, Kesecioglu J, Telci L, Akpir K Oxygen Transport to Tissue XVII. New York; Plenum Press 1996: 283-292 - 15 Lemasters J J, Nieminen A L, Qian T, Trost L C, Herman B. The mitochondrial permeability transition in toxic, hypoxic and reperfusion injury. Mol Cell Biochem. 1997; 174 159-165
- 16 Mabe H, Blomqvist P, Siesjo B K. Intracellular pH in the brain following transient ischaemia. J Cereb Blood Flow Metab. 1983; 3 109-114
- 17 Parades A, Macmanus M, Kwon H M, Strange K. Osmoregulation of Na+/myo-insoitol co-transporter activity and mRNA levels in brain glial tissue. Am J Physiol. 1992; 263 1282-1288
- 18 Patton H K, Zhou Z H, Bubien J K, Benveniste E N, Benos D J. gp120-induced alterations of human astrocyte function: Na+/H+ exchange, K+ conductance, and glutamate flux. Am J Physiol Cell Physiol. 2000; 279 700-708
- 19 Pellerin L, Pellegri G, Bittar P G, Charnay Y, Bouras C, Martin J L, Stella N, Magistretti P J. Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev Neurosci. 1998; 20 291-299
- 20 Robertson N J, Cox I J, Cowan F M, Counsell S J, Azzopardi D, Edwards A D. Cerebral intracellular lactic alkalosis persisting months after NE measured by magnetic resonance spectroscopy. Pediatr Res. 1999; 46 287-296
- 21 Robertson N J, Cowan F M, Cox I J, Edwards A D. Brain alkaline intracellular pH and adverse neurodevelopmental outcome after neonatal encephalopathy. Ann Neurol. 2002; 52 732-742
- 22 Roos A, Boron W F. Intracellular pH. Physiol Rev. 1981; 61 296-434
- 23 Siesjo B K, Katsura K, Mellergard P, Ekholm A, Lundgren J, Smith M L. Acidosis-related brain damage. Prog Brain Res. 1993; 96 23-48
- 24 Traynelis S, Cull-Candy S. Proton inhibition of NMDA receptors in cerebellar neurons. Nature. 1990; 356 347-349
- 25 Vornov J J, Thomas A G, Jo D. Protective effects of extracellular acidosis and blockade of sodium/hydrogen ion exchange during recovery from metabolic inhibition in neuronal tissue culture. J Neurochem. 1996; 67 2379-2389
N. J. Robertson
Perinatal Brain Repair Group · Department of Obstetrics and Gynaecology · University College London
86 - 96 Chenies Mews
London WC1E 6HX
UK
Email: n.robertson@ucl.ac.uk