Brain Lactic Alkalosis in Aicardi-Goutières Syndrome

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