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of different diseases. For example, demyelinatinglesions may have improved conspicuity at lower bvalues, whereas cortical lesions may be depictedbetter at higher b values. Although the article byMeyer et al focuses primarily on acute infarction,

it also notes that the hypointense appearance of le-sions with facilitated diffusion is accentuated withincreasing b values. Most striking is an example ofan oligoastrocytoma, which appears isointense at b 1000 s/mm2, but markedly hypointense at b 2000 s/mm2 and b 3000 s/mm2. Clearly, muchof the advantage of increased b values may lie notwith the diagnosis of lesions with restricted diffu-sion, especially acute infarcts, but with allowing amore complete understanding of other types of dis-ease. For example, in demyelinating and dysmye-linating diseases, the true nature of enhancing le-sions may become more obvious. The differences

in the diffusion characteristics of the advancing, en-hancing rim versus the central portion of the lesionmay be accentuated, confirming even more stronglythe behavior of these types of diseases as involvingnot only the destruction of myelin, but also of ax-ons in the central core of the lesion.

Ultimately, all three articles in this issue pointout how simplistic much of our current approachto clinical diffusion-weighted imaging is at the mo-ment, and how much room for future exploration

remains. Diffusion imaging has become an essen-tial part of clinical MR imaging, and it is difficultto imagine routine imaging without it. Nonetheless,we are on the threshold of an even higher level ofcomplexity and understanding of diffusion-weight-

ed imaging.

GORDON SZE, M.D.Member, Editorial Board

ADAM ANDERSON, PH.D.Yale University School of Medicine

New Haven, CT

References

1. Niendorf T, Mijkhuizen RM, Norris DG, van Lookeren CampagneM, Nicolay K. Biexponential diffusion attenuation in variousstates of brain tissue: implications for diffusion-weighted im-aging. Magn Reson Med 1996;36:847857

2. Mulkern RV, Gudbjartsson H, Westin CF, et al.Multi-componentapparent diffusion coefficients in human brain. NMR Biomed1999;12:5162

3. Bito Y, Hirata S, Yamamoto E. Optimal gradient factors forADCmeasurements. In: Proceedings of the 3rd Annual Meetingof the ISMRM, Nice, France; 1995;913

4. Jones DK, Horsfield MA, Simmons A. Optimal strategies formeasuring diffusion in anisotropic systems by magnetic reso-nance imaging. Magn Reson Med 1999;42:515525

The Status of Status: Seizures Are Bad for Your Brains Health

What is the relationship between seizures andbrain dysfunction? Because seizures and epilepsyrepresent symptoms of an underlying disorder, rath-er than the disorder itself, their relationship to cog-nitive function is variable. Although 0.5% to 1%of the population suffers from recurrent seizures,most lead productive lives. In some cases, abnor-mal cognitive function coincides with seizure ac-tivity because both represent different phenotypicdisplays of the underlying etiology, such as in dif-fuse developmental conditions like the agyria-pach-ygyria disorders. Cognitive impairment also occurs

during and after the ictus, and may accompanytreatment with antiepileptic drugs. Two importantquestions are raised: do seizures directly causebrain damage, and do they augment epileptogen-icity? If seizures do cause progressive brain or ep-ileptogenic dysfunction, then early intervention forseizure control is indicated in order to prevent fur-ther brain injury.

A number of experimental animal and clinicalimaging studies support the idea that seizures bythemselves cause brain damage (1). Experimentalanimal models have shown that intense limbic sei-zures result in a pattern of hippocampal damage

similar to hippocampal sclerosis. Similar imagingchanges have been reported in the human hippo-campus after prolonged nonfebrile or febrile sei-zures; the hippocampus initially becomes enlarged

and hyperintense, and then later atrophies. SeveralMR imaging studies have correlated hippocampalatrophy with duration of epilepsy. Gray matter vol-ume has been negatively correlated with seizureduration, suggesting that neocortical changes maybe a consequence of seizures. One study found thatgeneralized seizures appear to cause progressivebrain dysfunction in patients with temporal lobe ep-ilepsy. Frequent generalized seizures were correlat-ed with bilateral temporal lobe metabolic dysfunc-tion by use of MR spectroscopy, and ipsilateralatrophy by use of MR volumetry.

When seizure activity is markedly prolonged, asin status epilepticus, brain damage can occur quick-ly and be profound. Histologic studies from bothhumans and animal models have shown that braindamage primarily affects the hippocampus, amyg-dala, and piriform cortex; the cerebral cortex, cer-ebellar cortex, and thalamus are affected to a lesserextent. MR imaging with long TRs have shown re-gional hyperintense changes that occur during orimmediately after onset of seizure activity in hu-mans with status epilepticus (2). These changesusually resolve with time, followed by regionalatrophic changes.

Status epilepticus can also be evaluated by dif-fusion-weighted MR imaging and apparent diffu-sion coefficient (ADC) measurements (2, 3). Al-though a number of studies describe these rela-

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tionships in detail, the reports by Men et al (a clin-ical case report, page 1837) and Wall et al (an an-imal study, page 1841) in the current issue of theAJNR enhance our knowledge by their wonderfulcorrelation with histopathologic findings. While

diffusion changes have been reported in humanswith status epilepticus, there is a paucity of histo-pathologic correlation (2). With regard to animalmodels of status epilepticus, diffusion changes arewell documented. Sequential, correlative diffusion-pathologic changes, however, have not been de-scribed for the first 24 hours after the onset of sta-tus epilepticus as provided by Wall et al.Correlative studies are imperative for us to under-stand what seizure-induced imaging findings trulyrepresent, and in turn, the pathophysiology of thistype of brain damage.

What is the current understanding of diffusionchanges induced by status epilepticus? Transientdecreases in ADC (and increased signal changes ondiffusion-weighted images) are observed in regionsof seizure activity, usually accompanied by hyper-intense signal changes on long-TR images. The re-gions with decreased ADC correspond to regionsof transient, increased perfusion and EEG abnor-malities. The most affected regions are the amyg-dala, piriform cortex, and hippocampus. The cere-bral cortex, cerebellar cortex, and thalamus areinvolved to a lesser extent. In animal models, de-creases in ADC occur as early as 1 hour after statusepilepticus, become most pronounced at about 24hours, and then normalize over the next week (3).

In humans, the time course is less well defined, butalso appears to be transient. The diffusion changes,accompanied by signal changes on T2-weightedimages, usually resolve when imaged weeks laterand atrophy ensues. Hyperintense signal changeson long-TR images may persist, especially in thehippocampus and amygdala. These acute changescan be differentiated from those caused by strokeby using perfusion-weighted MR imaging tech-niques. Unlike in cases of stroke, there is a focalincrease in regional cerebral blood volume and anincreased mean transit time.

The diffusion changes appear to be due to sei-

zure-induced changes in cellular membrane per-meability and ion homeostasis, with a resulting el-evation of extracellular potassium and an influx ofsodium and calcium. Swelling of neurons and glialcells occurs as free water rapidly follows the os-motic gradient into the cells. ADC values are

thought to increase because of the rapid shift ofwater from extracellular compartments to the morerestrictive intracellular environment. T2 measure-ments are prolonged because of the increase in wa-ter content. Swelling of cells may lead to irrevers-

ible cellular edema, resulting in selective neuronalnecrosis as described by Wall et al and Suleymanet al. As the cells lyse, ADC values normalize overtime and MR imaging reveals atrophic changes

While there is now abundant evidence that statusepilepticus is detrimental to brain tissue, and thatdiffusion-weighted imaging (and ADC maps) candocument this damage, several questions remain.Does abnormal diffusion (and ADC values) alwaysmean subsequent neuronal death? The answer ap-pears to be no for the retrospenial cortex, accordingto Wall et al. Case reports of seizure-induced, tran-sient diffusion changes without associated T2changes may also represent cases of reversible cel-lular changes. What is the explanation for the ADCchanges in the hippocampus in the study by Wallet al? The answer is not clear. ADC increases inthe amygdala and piriform cortex in the pilocarpinemodel of status epilepticus as reported by Wall etal and the kainic acid model reported by others (3).However, Wall et al report a decrease in hippocam-pal ADC values, whereas those using the kainicacid model report an increase. The explanation pro-vided by the authors does not appear to besufficient.

Our understanding of the pathogenesis of sei-zures is still incomplete, but studies that correlate

imaging findings with cellular microenvironment(like the reports in this journal) will help fill in thegaps.

RICHARD A. BRONEN, M.D.Yale University School of Medicine

New Haven, CT

References

1. Sutula TP, Hermann B. Progression in mesial temporal lobe ep-ilepsy. Ann Neurol 1999;45:553556

2. Lansberg MG, OBrien MW, Norbash AM, Moseley ME, MorrellM, Albers GW. MRI abnormalities associated with partial sta-tus epilepticus. Neurology 1999;52:10211027

3. Nakasu Y, Nakasu S, Morikawa S, Uemura S, Inubushi T, HandaJ. Diffusion-weighted MR in experimental sustained seizureselicited with kainic acid. AJNR Am J Neuroradiol 1995;16:11851192