Letters to the Editor

Catamenial Epilepsy and Menopause

To the Editor:We read with interest the analysis of the impact of

menopause on epilepsy recently reported by Harden et al.(1). I would like to comment on their findings in patientswho reported having had a catamenial seizure patternbefore menopause. The study was done retrospectively,and patients were asked to report the course of theirepilepsy over time.

The definition of catamenial epilepsy was adaptedfrom Herzog et al. (2). As a result, a history of catame-nial seizure pattern was significantly associated with adecrease in seizures at menopause. The authors con-cluded that a catamenial seizure pattern may be an en-dogenous factor influencing the course of epilepsy. How-ever, the method applied is not appropriate to draw sucha conclusion: women with epilepsy often believe thattheir seizures are related to their menstrual cycle.

Not surprisingly, the number of patients with catame-nial seizures varies in different studies and may be as lowas 12.5% (3) and as high as 72% (4). In my ownpro-spectivestudy of 21 women who reported having in-creased seizures related to their menstrual cycle, catame-nial seizures could be documented in only 24% (5).Therefore, aretrospectivestudy not based on the analysisof seizure diaries will overestimate the number of pa-tients with catamenial seizures. Therefore, I advise notdrawing final conclusions from the reported data withrespect to the correlation between catamenial seizuresand menopause (1).

J. BauerDepartment of Epileptology

University of BonnBonn, Germany

REFERENCES1. Harden CL, Pulver MC, Ravdin L, Jacobs AR. The effect of meno-

pause and perimenopause on the course of epilepsy.Epilepsia1999;40:1402–7.

2. Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epi-lepsy.Epilepsia1997;38:1082–8.

3. Duncan S, Read CL, Brodie MJ. How common is catamenial epi-lepsy?Epilepsia1993;34:827–31.

4. Laidlaw J. Catamenial epilepsy.Lancet1956;271:1235–7.5. Bauer J, Hocke A, Elger CE. Catamenial seizures: an analysis [in

German].Nervenarzt1995;66:760–9.

REPLY

To the Editor:J. Bauer, M.D., believes that our questionnaire over-

estimated the number of patients with a catamenial sei-zure pattern in our retrospective study on “The Effect of

Menopause and Perimenopause on the Course of Epi-lepsy” (1). He then recommends that we not draw finalconclusions from the reported data with respect to thecorrelation between catamenial seizures and menopause.

First, given the inherent limitations of our retrospec-tive methods, we were careful to say that our data showthat the course of epilepsy “may be significantly influ-enced” by a catamenial seizure pattern. We also recom-mended a prospective analysis of these issues. Second,our questionnaire asked women not only if their seizurefrequency showed any relationship to their menstrualcycle, but also required them to describe the relationship.Only those questionnaires that reported a catamenial pat-tern and that actually described that pattern as premen-strual, periovulatory, or luteal, that is, as Type 1, Type 2,or Type 3 according to Herzog et al. (2), were acceptedfor inclusion in the catamenial seizure patter group.

Because estrogens generally have a proseizure influ-ence, and progesterone has an antiseizure influence in thebrain, it would be predicted that the hormonal milieuduring perimenopause would be seizure promoting. Fur-ther, the hormonal milieu after menopause, a time whenhormonal influences abate altogether, would be seizuremitigating, especially in women whose epilepsy had pre-viously shown an inherent sensitivity to the modulatingeffects of reproductive hormones, i.e., women with ahistory of catamenial epilepsy. Our data are well ex-plained by and are consistent with these neuroactive hor-monal effects.

Finally, the fraction of patients in our study reportingcatamenial seizure patterns (38%) is within the expectedrange put forth by Herzog et al. (2). If, in fact, we didoverestimate the number of women with catamenial epi-lepsy, we would expect those women wrongly labeledcatamenial to skew our results toward randomness, not tohave their seizure patterns change in a manner that waspredicted by our hypothesis.

Cynthia L. HardenMelissa C. Pulver

Lisa RavdinAlan R. Jacobs

Comprehensive Epilepsy CenterNew York Presbyterian Hospital–Weill Medical

College of Cornell UniversityNew York, New York, U.S.A.

REFERENCES1. Harden CL, Pulver MC, Ravdin L, Jacobs AR. The effect of meno-

pause and perimenopause on the course of epilepsy.Epilepsia1999;40:1402–7.

2. Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epi-lepsy.Epilepsia1997;38:1082–8.

Epilepsia,42(4):572-574, 2001Blackwell Science, Inc.© International League Against Epilepsy

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Minor Head Trauma UnmaskingAsymptomatic Lesions

To the Editor:Clear and Chadwick (1) reported a patient who twice

had generalized tonic–clonic seizures shortly after head-ing a ball during a soccer game and turned out to have alarge frontoparietal lesion, probably an arachnoid cyst.They remarked that they are unaware of any other reportsof this phenomenon, and it is indeed some time sincesuch cases were last published.

However, there was a time when neurologists in train-ing were taught that if a patient responded to a trivialhead trauma with disproportionate symptoms, such asepileptic seizures or a twilight state, one had to watch outfor a brain tumor because such “pathological reactions”often indicated preexisting cerebral pathology, of whichthey could be the first sign.

Hallen (2) reported six cases of “pathological reac-tions.” In three patients, the reaction consisted of focalepileptic seizures, including a case of status epilepticus.The seizures occurred within 30 min to a few hours aftera minor head trauma that was not accompanied by loss ofconsciousness (a blow received in a fight, a concussioncaused by a fall with the bicycle, and a headed ball in asoccer game). In all cases, these “reactions” were the firstsign of a brain tumor (oligodendroglioma, meningioma,sarcoma of the dura mater). The author believed that thesymptoms were due to edema developing rapidly aroundthe lesions.

Krayenbuhl et al. (3) published a report that stands outfor its unreserved self-critique: about 25 patients withepilepsy caused by brain tumors who had at first beenincorrectly diagnosed as having posttraumatic epilepsy.Of their four exemplary case histories, one is very similarto the case of Clear and Chadwick. During a handballgame, one player struck the chin of the patient with hisknee. One minute later, the injured player lost conscious-ness and had a tonic–clonic convulsion. The same hap-pened again 4 months later when a ball hit his head. Thispatient was later found to have a right frontal oligoden-droglioma. Three other patients in their series seem tohave been similar, whereas the time intervals betweenthe trauma and the first seizure were longer in the others.The authors proposed that “the mechanical impact acti-vated a latent symptomatic epilepsy, which was caused pri-marily by the otherwise silent oligodendroglioma.” In theircritical analysis, they strongly made the point that “oneshould never be satisfied with the diagnosis of posttrau-matic epilepsy when the injury was of minor impor-tance.”

Paal (4) reported on 27 (6.5%) of 415 patients withbrain tumors whose symptoms had been misinterpretedas being caused by an accident. In six of these, the symp-toms had followed the trauma “immediately.” However,

the article does not state how many patients had seizuresas part of their symptoms, and the article contains noindividual case histories.

I vividly remember a student in his early twenties, whomI saw not long after these reports had appeared. He hadheaded a ball during a soccer game, felt dizzy, left the fieldimmediately, and had a generalized tonic–clonic seizure.Two more seizures occurred in the next 24 h. He had acerebral glioma from which he died a few months later.

The reports on these cases seem to have stopped after1970, and that may have to do with the introduction ofnew brain-imaging techniques. Awareness of the “patho-logical reactions of the damaged brain” lost some impor-tance when it became standard to investigate all patientswith seizures of focal onset with computer tomographyor magnetic resonance imaging scans. However, mostpatients live in parts of the world where they are not soprivileged to have easy access to such investigations.Therefore, Clear and Chadwick deserve credit for havingdrawn attention again to a piece of half-forgotten butmost valuable neurologic knowledge.

Peter WolfEpilepsy Centre Bethel

Klinik Mara IBielefeld, Germany

REFERENCES

1. Clear D, Chadwick DW. Seizures provoked by blows to the head.Epilepsia2000;41:243–4.

2. Hallen O. Uber “die organische pathologische Rektion des bereits(wenn auch nur im Verborgenen) kranken” Gehirns.Nervenarzt1969;40:460–2.

3. Krayenbu¨hl H, Hess R, Weber G, Siegfried J. Pseudo-traumaticepilepsy.Epilepsia1970;11:59–71.

4. Paal G. Unfall und Hirntumor aus klinisch diagnostischer Sicht.Med Welt1968;1:295–9.

Sleep and Epilepsy: A Role for Nitric Oxide

To the Editor:We read with great interest the paper of Faradji et al.

(1). Those authors concluded that endogenous nitric ox-ide (NO) might play a key role as an antiepileptic sub-stance capable of reducing the amount of spike-wavedischarges (SWD) in absence epilepsy.

Their conclusion is based on three datasets generatedin Genetic Absence Epilepsy Rats from Strasbourg(GAERS). First, an inverse relationship was found be-tween paradoxical sleep (PS) and SWD in the sleep-wake cycle. Second, NO donor or inhibitor drugs re-duced or increased the amount of SWD, respectively.Third, valproate and ethosuximide caused release of NO.It is, however, generally accepted that occurrence ofSWD depends greatly on levels of vigilance in both hu-mans and rat models, including GAERS rats (2–4). Intheir paper, Faradji et al. (1) do not offer evidence for a

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Epilepsia, Vol. 42, No. 4, 2001

direct (that is, not via influencing vigilance and sleeppatterns) effect of NO. Patterns of wake (W) and slowwave sleep (SWS) are shown in the first dataset only. Wand SWS must also be further divided when they arecorrelated with SWD. For example, in active W there arebasically no SWD, while in passive W there is; this con-trast is even greater when the occurrence of SWD is ana-lyzed during different stages of SWS. This is evident inhumans and also genetic rat models (Fig. 1). Thus, if NO isplaying a key role in absence epilepsy, one would expectopposite changes in NO release in light and deep SWS.

Without these data, a primary role for NO remainsonly a hypothesis. Concerning the effects of NO donor,inhibitor, and antiepileptic drugs, vigilance states areprovided only in a cumulative manner. Thus, relation-ships of SWD to sleep-wake states over time are notshown. In addition, there is evidence that vigilance isalso affected by antiepileptic drugs.

Could an effect of antiepileptic drugs be mediated byNO? The NO donor had only minimal effect on theSWD. In contrast, valproate and, according to the textethosuximide also caused dramatic, immediate decreasesin SWD that paralleled similar NO peaks caused by theNO donor. With regard to ethosuximide, there is con-vincing evidence that the anti-SWD effect is based on theaction of T-type Ca2+ channels in the thalamocorticalsystem, and this is in agreement with the known patho-physiological data.

These points raise the question as to any primary rolefor NO.

Peter HalaszJanos Filakovszky

Gyorgy BagdyEpilepsy Center and Laboratory of Neurochemistry

and Experimental MedicineNational Institute of Psychiatry and Neurology

Budapest, Hungary

REFERENCES

1. Faradji H, Rousset C, Debilly G, Vergnes M, Cespuglio R. Sleepand epilepsy: a key role for nitric oxide.Epilepsia2000;41:794–801.

2. Lannes B, Micheletti G, Vergnes M, Marescaux Ch, Depaulis A,Wartex JM. Relationship between spike-wave discharges and vigi-lance levels in rats with spontaneous petit mal-like epilepsy.Neu-rosci Lett1985;94:187–91.

3. Halasz P. Sleep, arousal and electroclinical manifestations of gen-eralized epilepsy with spike-wave pattern. In: Degen R, Nieder-meyer E, eds.Epilepsy, sleep and sleep deprivation.Elsevier Sci-ence Publisher B.V., 1984:97–107.

4. Drinkenburg WHIM, Coenen AML, Vossen JMH, Van LuijtelaarELJM. Spike-wave discharges and sleep-wake states in rats withabsence epilepsy.Epilepsy Res1991;9:218–24.

REPLY

To the Editor:In response to the letter of Prof. Halasz and his col-

leagues, I am happy to see the great interest those re-searchers have taken in my work related to nitric oxide(NO) as a potential contributor to absence epilepsy. Theircomments and suggestions are, of course, sound and ju-dicious.

I deliberately tried to present a general view of theproblem and limited space precluded including all thedetails I would have liked. We will be publishing addi-tional data soon.

We invite the Hungarian researchers to contact us di-rectly for specific details. They are also welcome to visitour laboratory.

Helene Faradji-PrevautelINSERM U480

Claude Bernard UniversityLyon, France

FIG. 1. A: Percentage of spike-wave discharge in different vigilance levels in WAG/Rij rats (n = 18). B: Percentage of spike-wavedischarge density in different vigilance levels in 4 × 12 h consecutive EEG registration of 10 idiopathic generalized epileptic patients.

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