Published online before print August 26, 2004, doi: 10.1161/01.STR.0000142130.43394.38
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(Stroke. 2004;35:2239-a.)
© 2004 American Heart Association, Inc.
Letters to the Editor |
White Matter Hyperintensities: Pearls and Pitfalls in Interpretation of MRI Abnormalities
Dubai Police Medical Services, Dubai, UAE
To the Editor:
Atwood et al acknowledge that the pathophysiology of white matter hyperintensities (WMH) is uncertain and underscore the possibility of ischemic etiology, especially in the elderly.1 These authors regard WMH as an excellent marker of brain aging and emphasize their heritability in patients with negative correlation with cerebrovascular brain injury.
WMH are neither age-specific nor generally heritable, having been found in both sexes in hypertensive encephalopathy, puerperal eclampsia, migraine, and therapy with cyclosporin, interferon-
, and tacrolimus.2,3 Kruit and coworkers found WMH in MRI only in women migraine patients2 which finding likely reflects an investigational artifact. Atwood et al did not exclude hypertensive and migraine patients from their analysis, which prominently confounds their interpretation of WMH as indicative of brain aging.
An important pathophysiologic clue to the nature of WMH is offered by the characteristic difference in the distribution of infarcts and deep WMH in migraine patients. Predominantly posterior circulation territory (PCT) migrainous infarcts in contrast to anterior circulation infarcts in embolic or atherosclerotic thrombotic strokes in general are likely related to rheological factors. Anatomical vulnerability of the posterior cerebral artery renders it particularly susceptible to vasospastic influences in migraine patients.4 The rare occurrence of neuroanatomically nonlateralizing—in relation to headache or aura—PCT infarcts in younger migraineurs might represent an uncommon complication of an adaptive vasospasm that rarely reduces perfusion critically in a particularly labile region.4
Diffuse, nonlateralizing distribution of deep WMH unaffected by triptan use2 indicates that WMH do not reflect the outcome of vasospastic ischemia. Also, local changes during migraine attacks, eg, excessive neuronal activation or excitotoxicity2 should logically manifest lateralizing WMH. Deep WMH, in contrast to infarcts, likely resolve totally along with resolution of symptoms and signs after treatment of hypertension or withdrawal (or reduction of dose) of immunosuppressive agents.3 Vasogenic cerebral edema probably underlies WMH in hypertensive encephalopathy; breakdown of the blood–brain barrier has been shown in man and in rat models.3 Attack-related, inconsistently-lateralized, and prolonged (>48 hours) hyperperfusion prevails in the cerebral cortex, thalamus and basal ganglia in migraine.5 In direct contrast to infarcts, WMH probably result from intense but self-limited cerebral hyperperfusion. I propose that WMH are markers of transient breakdown of the blood–brain barrier rather than aging.
The heritability of WMH volumes is an intriguing feature.1 The decline in heritability estimates after age 601 indicates the nongenetic nature of this observation. Another indicator of the nongenetic nature of WMH is the absence of correlation with aging in women despite higher heritability. Migraine is more prevalent in females than in males, from approximately age 14.6 Breakdown of the aging-marker hypothesis for WMH in women may relate to migraine headaches. Finally, heritability of WMH may relate more to heritability of hypertension or migraine or both. In the absence of any link to cerebrovascular disease, the menopause probably has no independent bearing on WMH. Spontaneous resolution likely underlies significantly smaller WMH volumes at younger age, especially in women,1 in which cohort the highest prevalence of migraine can be expected. These authors also hope to establish a genetic link between WMH and silent brain infarctions.1 Unless the resolution or otherwise of WMH is established prospectively, it is premature to link this MRI finding with cerebrovascular ischemic disease. Cross-sectional studies of WMH cannot establish vascular-related genetic influences, as has been suggested.1 Assumption of the genetic model for WMH1 is probably incorrect.
References
1. Atwood LD, Wolf PA, Heard-Costa NL, Massaro JM, Beiser A, D’Agostino RB, DeCarli C. Genetic variation in white matter hyperintensity volume in the Framingham Study. Stroke. 2004; 35: 1609–1613.
2. Kruit MC, van Buchem MA, Hofman PA, Bakkers JTN, Terwindt GM, Ferrari MD, Launer LJ. Migraine as a risk factor for subclinical brain lesions. JAMA. 2004; 291: 427–434.
3. Donnan GA. Posterior leucoencephalopathy syndrome. Lancet. 1996; 347: 988.[Medline] [Order article via Infotrieve]
4. Gupta VK. Regional cerebral blood flow patterns in migraine: what is the contribution to insight into disease mechanisms? Eur J Neurol. 1995; 2: 586–587.
5. Kobari M, Meyer JS, Ichijo M, Imai A, Oravez WT. Hyperperfusion of cerebral cortex, thalamus and basal ganglia during spontaneously occurring migraine headaches. Headache. 1989; 29: 282–289.[CrossRef][Medline] [Order article via Infotrieve]
6. Ziegler DK. Headache. Public health problem. Neurol Clin. 1990; 8: 781–791.[Medline] [Order article via Infotrieve]
Response
Department of Neurology,, UCLA Stroke Center, University of California, Los Angeles, Los Angeles, Calif
We thank Dr. Gupta for his interest in our study, but we strongly disagree with his assessment of the pertinent literature. In fact, the basic neuropharmacology of magnesium sulfate provides substantial support for clinical stroke trials in humans.
Several studies show that magnesium does cross the blood–brain barrier, in both animals and in humans.1 Brain magnesium concentrations are regulated by active blood–brain barrier transport.2,3 Cerebrospinal fluid magnesium concentration increases by 20% to 25% in response to doubling of the serum concentration, and peaks around 4 hours after parenteral administration.3–5 While this overall increase in cerebrospinal fluid magnesium concentration is modest, magnesium concentration is selectively substantially increased in regions of pathology, including focal ischemia and seizures.6,7
It is also well known that the mild negative inotropic effect of magnesium sulfate is offset by its lowering of peripheral vascular resistance, resulting in no clinically substantial impairment in cardiac pump function.8,9 Several physiological studies suggest that magnesium increases cardiac output.10,11 Even in patients experiencing active myocardial ischemia, magnesium sulfate showed only a very small increase in the incidence of cardiogenic shock or congestive heart failure in the large ISIS-4 trial,12 and no adverse effect on cardiac pump function was reported in the more recent MAGIC clinical trial.13 Most saliently, among stroke patients in the phase 3 IMAGES trial, there was no excess of cardiac events related to administration of magnesium sulfate.14
In addition, magnesium sulfate is a potent cerebral vasodilator, in part due to calcium channel antagonism at vascular smooth muscle cells and possibly effects on myosin-binding proteins that regulate contraction.15,16 Consequently, magnesium sulfate typically increases, rather than decreases, cerebral perfusion.17–19
Magnesium sulfate has been demonstrated to reduce infarct volume in multiple animal models of stroke, has numerous identified beneficial neuroprotective and vascular effects, is already known to be efficacious in treating in humans a condition characterized by altered cerebral blood flow (eclampsia), and has shown a potential signal of efficacy when administered early after stroke onset (within 3 hour subgroup) in a randomized clinical trial.14 Further trials of magnesium sulfate in early time epochs in acute stroke are well-supported by preclinical and clinical neuropharmacology.20
References
1. Muir KW. Magnesium for neuroprotection in ischaemic stroke: rationale for use and evidence of effectiveness. CNS Drugs. 2001; 15: 921–930.[CrossRef][Medline] [Order article via Infotrieve]
2. Oppelt WW, MacIntyre I, Rall DP. Magnesium exchange between blood and cerebrospinal fluid. Am J Physiol. 1963; 205: 959–962.
3. Fuchs-Buder T, Tramer MR, Tassonyi E. Cerebrospinal fluid passage of intravenous magnesium sulfate in neurosurgical patients. J Neurosurg Anesthesiol. 1997; 9: 324–328.[Medline] [Order article via Infotrieve]
4. Thurnau GR, Kemp DB, Jarvis A. Cerebrospinal fluid levels of magnesium in patients with preeclampsia after treatment with intravenous magnesium sulfate. Am J Obstet Gynecol. 1987: 1435–1438.
5. Fong J, Gurewitsch ED, Volpe L, Wagner WE, Gomillion MC, August P. Baseline serum and cerebrospinal fluid magnesium levels in normal pregnancy and preeclampsia. Obstet Gynecol. 1995; 85: 444–448.[Medline] [Order article via Infotrieve]
6. Hallak M, Berman RF, Irtenkauf SM, Evans MI, Cotton DB. Peripheral magnesium sulfate enters the brain and increases the threshold for hippocampal seizures in rats. Am J Obstet Gyneco. 1992; 167: 1605–1610.
7. Sjostrom LG, Wester P. Accumulation of magnesium in rat brain after intravenously induced hypermagnesemia (abstract). Cerebrovasc Dis. 1995; 4: 241.
8. Nakaigawa Y, Akazawa S, Shimizu R, Ishii R, Ikeno S, Inoue S, Yamato R. Effects of magnesium sulphate on the cardiovascular system, coronary circulation and myocardial metabolism in anaesthetized dogs. Br J Anaesth. 1997; 79: 363–368.
9. Shechter M. Does magnesium have a role in the treatment of patients with coronary artery disease? Am J Cardiovasc Drugs. 2003; 3: 231–239.[CrossRef][Medline] [Order article via Infotrieve]
10. Reinhart RA. Clinical correlates of the molecular and cellular actions of magnesium on the cardiovascular system. Am Heart J. 1991; 121: 1513–1521.[CrossRef][Medline] [Order article via Infotrieve]
11. Rasmussen HS, Larsen OG, Meier K, Larsen J. Hemodynamic effects of intravenously administered magnesium on patients with ischemic heart disease. Clin Cardiol. 1988; 11: 824–828.[Medline] [Order article via Infotrieve]
12. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet. 1995; 345: 669–685.[CrossRef][Medline] [Order article via Infotrieve]
13. Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium In Coronaries (MAGIC) trial: a randomised controlled trial. Lancet. 2002; 360: 1189–1196.[CrossRef][Medline] [Order article via Infotrieve]
14. Muir KW, Lees KR, Ford I, Davis S. Magnesium for acute stroke (intravenous magnesium efficacy in stroke trial): randomised controlled trial. Lancet. 2004; 363: 439–445.[CrossRef][Medline] [Order article via Infotrieve]
15. Kemp PA, Gardiner SM, Bennett T, Rubin PC. Magnesium sulphate reverses the carotid vasoconstriction caused by endothelin-I, angiotensin II and neuropeptide-Y, but not that caused by NG-nitro-L-arginine methyl ester, in conscious rats. Clin Sci (Lond). 1993; 85: 175–181.[Medline] [Order article via Infotrieve]
16. Alborch E, Salom JB, Perales AJ, Torregrosa G, Miranda FJ, Alabadi JA, Jover T. Comparison of the anticonstrictor action of dihydropyridines (nimodipine and nicardipine) and MG2+ in isolated human cerebral arteries. Eur J Pharmacol. 1992; 229: 83–89.[CrossRef][Medline] [Order article via Infotrieve]
17. Belfort MA, Moise KJ, Jr. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: a randomized, placebo-controlled study. Am J Obstet Gynecol. 1992; 167: 661–666.[Medline] [Order article via Infotrieve]
18. Lysakowski C, Von Elm E, Dumont L, Junod J, Tassonyi E, Kayser B, Tramer MR. Effect of magnesium, high altitude and acute mountain sickness on blood flow velocity in the middle cerebral artery. Clin Sci. 2004; 106: 279–285.[Medline] [Order article via Infotrieve]
19. Scardo JA, Hogg BB, Newman RB. Favorable hemodynamic effects of magnesium sulfate in preeclampsia. Am J Obstet Gynecol. 1995; 173: 1249–1253.[Medline] [Order article via Infotrieve]
20. Muir KW. Magnesium in stroke treatment. Postgrad Med J. 2002; 78: 641–645.
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