Silent Intracerebral Microhemorrhages inStroke PatientsStephen Chan, MD,* and David W. Desmond, PhD†

We read with interest the article by Kwa and colleagues,1

which described the association of silent microhemorrhageswith white matter hyperintense lesions on magnetic reso-nance (MR) imaging of patients with ischemic stroke. Theyconcluded that these silent microhemorrhages may representa “manifestation of cerebral small-vessel disease.” We wouldlike to corroborate their findings with our own experiences,both published and unpublished, and discuss the potentialsignificance of this neuroradiological pattern in greater detail.

First, we agree with the authors’ contention that “hyper-tensive small-vessel disease is the underlying pathology [ofsilent microhemorrhages] in most cases.” Our previous workin patients with vascular dementia also indicated that thepattern of multifocal hemosiderin deposits in the deep cere-bral structures, including the basal ganglia, thalami, andcorona radiata, was associated with a history of chronichypertension.2 This also raised the possibility that many“asymptomatic” hypertensive patients may harbor MR signsof cerebrovascular disease. Therefore, we were impressed bythe finding of Kwa and associates that 26% of their ischemicstroke patients had evidence of hemosiderin deposits.

Second, Kwa and co-workers showed that (1) the presenceof cerebral white matter lesions was the only independentfactor associated with hemosiderin deposits (although thatvariable may be serving as a surrogate for other risk factors,including hypertension); and (2) the severity of the whitematter lesions was correlated with the frequency of the he-mosiderin deposits. Their findings suggest that cerebralsmall-vessel disease is the underlying pathology; specific eti-ologies associated with both white matter hyperintense le-sions and hemosiderin deposits include hypertension andamyloid angiopathy.2,3 Based on recent work,4 we suggestadding another pathologic entity to this list: cerebral autoso-mal dominant arteriopathy with subcortical infarcts and leu-koencephalopathy (CADASIL). In our study, a 61-year-oldnonhypertensive patient presented with clinical, pathological,radiological, and genetic evidence of CADASIL, including aNotch3 mutation.4 On gradient-echo MR imaging, we iden-tified focal hemosiderin deposits in both thalami and theright basal ganglia, with an MR appearance similar to thatassociated with hypertension. We believe that this case lendsfurther credence to the concept of cerebral small-vessel dis-ease as the underlying basis for silent intracerebral micro-hemorrhages.

Third, Kwa and colleagues cite the self-limiting nature ofsmall spontaneous hemorrhages in patients with hyperten-sion and then address the relationship between anticoagulanttherapy and intracerebral hemorrhage (presumably symptom-atic). We would like to point out that the presence of mul-tiple silent microhemorrhages in a hypertensive patient alsosuggests the possibility of a future symptomatic, and poten-tially catastrophic, intracerebral hemorrhage. In our first co-hort of 38 patients with multifocal hemosiderin deposits inthe brain, there were 7 patients in whom this pattern wasattributed to hypertension.2 Three-year follow-up of these 7patients found 2 patients with subsequent parenchymal hem-

orrhage (Fig). If future work establishes an increased risk ofsymptomatic parenchymal hemorrhage after the identifica-tion of multiple silent microhemorrhages, it would have thefollowing clinical implications: (1) the identification of silent

Fig. (A) T2*-weighted gradient-echo magnetic resonance imageobtained at the level of the basal ganglia demonstrating focalrounded hypointense lesions within both putamina (arrows),most consistent with silent microhemorrhages, and within theright occipital lobe, most consistent with known symptomatichemorrhage. (B) Follow-up computed tomographic scan 2 yearslater obtained at the level of the frontal lobes indicating anew, acute parenchymal hemorrhage in the right frontal lobe.

LETTERS

412 Copyright © 1999 by the American Neurological Association

intracerebral microhemorrhages in patients with hyperten-sion should lead to the same stringent measures to controlblood pressure as in patients with symptomatic hemorrhag-es;5 and (2) given that transient neurological symptoms maybe the only clinical manifestation in certain patients with “si-lent” microhemorrhages, gradient-echo MR imaging shouldbe considered in hypertensive patients with transient is-chemic attacks in an effort to identify individuals at risk offuture symptomatic intracerebral hemorrhage.

Departments of *Radiology and †Neurology, NeurologicalInstitute of New York, New York, NY

References1. Kwa VIH, Franke CL, Verbeeten B Jr, Stam J, for the Amster-

dam Vascular Medicine Group. Silent intracerebral microhemor-rhages in patients with ischemic stroke. Ann Neurol 1998;44:372–377

2. Chan S, Kartha K, Yoon SS, et al. Multifocal hypointense cere-bral lesions on gradient-echo MR are associated with chronic hy-pertension. AJNR 1996;17:1821–1827

3. Greenberg SM, Finklestein SP, Schaefer PW. Petechial hemor-rhages accompanying lobar hemorrhages: detection by gradient-echo MRI. Neurology 1996;46:1751–1754

4. Desmond DW, Moroney JT, Lynch T, et al. CADASIL in aNorth American family. Neurology 1998;51:844–849

5. Arawaka S, Saku Y, Ibayashi S, et al. Blood pressure control andrecurrence of hypertensive brain hemorrhage. Stroke 1998;29:1806–1809

ReplyVincent I. H. Kwa, MD,* Cees L. Franke, MD, PhD,‡Ben Verbeeten, Jr, MD,† and Jan Stam, MD, PhD,* forthe Amsterdam Vascular Medicine Group

We appreciate the supportive comments offered by Chanand Desmond. Our recent work is indeed in accordance withtheir previous work, in which they show an association ofMR signs of hemosiderin deposits with chronic hyperten-sion.1 We agree with their suggestion to add CADASIL asanother disorder that may cause both white matter lesionsand hemosiderin deposits on MR imaging. The case theydescribed supports our hypothesis that silent intracerebralhemorrhages are a consequence of cerebral small-vessel dis-ease.2 We are currently examining the Notch3 mutations inour patients, to study their possible role in the pathogenesisof silent intracerebral microhemorrhages.

The observation by Chan and Desmond that 2 of their 7hypertensive patients with hemosiderin deposits in the braindeveloped a symptomatic intracerebral hemorrhage after 3years is important and suggests that these MR lesions mayidentify patients at risk for an intracerebral hemorrhage. Ofcourse, larger prospective cohort studies of patients with theseMR lesions are needed to establish their clinical significance.

Departments of *Neurology and †Radiology, Academic MedicalCenter, University of Amsterdam, Amsterdam; and‡Department of Neurology, De Wever-Ziekenhuis, Heerlen,The Netherlands

References1. Chan S, Kartha K, Yoon SS, et al. Multifocal hypointense cere-

bral lesions on gradient-echo MR are associated with chronic hy-pertension. AJNR 1996;17:1821–1827

2. Desmond DW, Moroney JT, Lynch T, et al. CADASIL in aNorth American family: clinical, pathologic, and radiologic find-ings. Neurology 1998;51:844–849

Administration of Nitric Oxide Synthase InhibitorsDoes Not Alter Disease Course of AmyotrophicLateral Sclerosis SOD1 Mutant Transgenic MiceM. N. Upton-Rice, BS,* M. E. Cudkowicz, MSc, MD,*†R. K. Mathew, BA,* D. Reif, PhD,‡and R. H. Brown, Jr, MD, DPhil*†

Amyotrophic lateral sclerosis (ALS) is a progressive neurode-generative disease affecting motor neurons in the spinal cordand brain. Ten percent of all ALS cases are familial; 25% ofthese cases have a mutation in the gene that encodes cytoso-lic copper/zinc superoxide dismutase (SOD1). Transgenicmice expressing mutant SOD1 proteins develop a lethal formof motor neuron degeneration similar to human ALS.1

The mechanisms of cytotoxicity of the mutant SOD1molecule are unclear. One possible mechanism involves anaberrant reaction of the mutant molecule with peroxynitrite.This reaction forms nitronium ions that can nitrate tyrosinegroups on critical proteins. Consistent with this hypothesis,nitrotyrosine is present in motor neurons in sporadic andfamilial ALS2 (FALS) and in two different strains of FALSmice.3 Peroxynitrite is formed nonenzymatically from super-oxide anion and nitric oxide (NO). This suggests that mea-sures that inhibit NO formation will reduce formation ofperoxynitrite and nitrotyrosine and thereby ameliorate thecourse of the disease. Indeed, survival of FALS mice was pro-longed by pharmacological but not genetic inhibition of neu-ronal nitric oxide synthase (nNOS).4 Further, NOS inhibi-tion does not prevent apoptotic cell death in PC12 cellsexpressing mutant SOD1 protein.5

We have further tested the nitrotyrosine hypothesis the-ory, using two 100-fold selective nNOS inhibitors (AR-R17338 and AR-R 18512) in transgenic FALS mice.1 Micewere randomized to one of three treatment groups—AR-R17338 (250 mg/ml), AR-R 18512 (150 mg/ml), or placebo.Treatments were administered in drinking water starting at30 days of age. In earlier preliminary dose-finding studies,these doses increased plasma and brain compound levels andinhibited brain nNOS activity by 95% or more without no-ticeable side effects (Reif D, personal communication). Micewere examined for disease onset (hind limb weakness andtremulousness) and survival.1

Neither compound delayed disease onset or prolongedsurvival in these transgenic mice. Our results suggest thatperoxynitrite-mediated nitrotyrosine formation is not neces-sary for cell death in transgenic FALS mice.

Annals of Neurology Vol 45 No 3 March 1999 413

*Day Neuromuscular Laboratory and †Department ofNeurology, Massachusetts General Hospital, Harvard MedicalSchool, Boston, and ‡Astra-Arcus USA, Worcester, MA

This study was supported by Astra-Arcus USA and the MuscularDystrophy Association.

References1. Gurney M, Pu H, Chiu A, et al. Motor neuron degeneration in

mice that express a human Cu,Zn superoxide dismutase muta-tion. Science 1994;264:1772–1775

2. Beal MF, Ferrante R, Browne SE, et al. Increased 3-nitrotyrosinein both sporadic and familial amyotrophic lateral sclerosis. AnnNeurol 1997;42:644–654

3. Bruijn LI, Beal MF, Becher MW, et al. Elevated free nitroty-rosine levels, but not protein-bound nitrotyrosine or hydroxylradicals, throughout amyotrophic lateral sclerosis (ALS)-like dis-ease implicate tyrosine nitration as an aberrant in vivo propertyof one familial ALS-linked superoxide dismutase 1 mutant. ProcNatl Acad Sci USA 1997;94:7606–7611

4. Sakasi M, Facchinetti F, Christov V, et al. Is neuronal nitricoxide synthase involved in the pathogenesis of a transgenicmouse model of familial amyotrophic lateral sclerosis? Soc Neu-rosci 1996;22:2142 (Abstract)

5. Ghadge GD, Lee JP, Bindokas VP, et al. Mutant superoxidedismutase-1-linked familial amyotrophic lateral sclerosis: molec-ular mechanisms of neuronal death and protection. J Neurosci1997;17:8756–8766

ReplyM. Flint Beal, MD

The letter of Upton-Rice and colleagues contains valuableinformation showing that two relatively specific inhibitors ofneuronal nitric oxide synthase (nNOS) failed to show an ef-fect on survival in transgenic familial amyotrophic lateralsclerosis (FALS) mice. The conclusion that peroxynitrite-mediated nitrotyrosine formation is not necessary for celldeath in transgenic FALS mice, however, may not be war-ranted. The authors did not show that nitrotyrosine levelswere reduced by their treatment. There are also several otherNOS isoforms, such as inducible NOS, endothelial NOS,splice variants of nNOS, and possibly mitochondrial NOS,which may contribute to the generation of peroxynitrite.Last, nNOS inhibitors such as the ones used by Upton-Riceand colleagues can show inverted dose–response curves withmore efficacy at lower doses than at higher doses.1 The find-ings of Upton-Rice and colleagues are therefore important,but they cannot be considered definitive in concluding thatperoxynitrite does not play a role in motor neuron death intransgenic FALS mice.

Department of Neurology and Neuroscience, Cornell UniversityMedical College, New York, NY

Reference1. Zhang ZG, Reif D, Macdonald J, et al. ARL 17477, a potent

and selective neuronal NOS inhibitor decreases infarct volumeafter transient middle cerebral artery occlusion in rats. J CerebBlood Flow Metab 1996;16:599–604

Endocrine Function in Lambert-EatonMyasthenic SyndromePaul Maddison, MB BS, MRCP,Ashwin Pinto, MA, MRCP,and John Newsom-Davis, MD, FRS

Lambert-Eaton myasthenic syndrome (LEMS) is anantibody-mediated neuromuscular disease characterized bymuscle weakness and autonomic disturbance. Antibodies toP/Q-type voltage-gated calcium channels (VGCCs) can bedetected in more than 90% of patients and are responsiblefor reduction in nerve-evoked release of neurotransmitter atthe neuromuscular junction and postganglionic parasympa-thetic and sympathetic autonomic synapse.1

VGCCs are important in stimulus–secretion coupling inendocrine tissues. Rat b islet cells express P/Q-type VGCCsthat may play an important role in insulin secretion.2 LEMSIgG has been shown to reduce hormone release in rats fromboth anterior pituitary cells3 and insulinoma cells.4 However,it is unclear whether LEMS patients have evidence of sub-clinical endocrine dysfunction.

We obtained blood samples from 10 LEMS patients (8males and 2 females; age range, 24–77 years), 5 of whomwere taking prednisolone. To control for the effect of ste-roids on glucose metabolism, we also obtained samples from5 patients with myasthenia gravis who were taking equivalentdoses of prednisolone. All LEMS patients had significantlyraised titers of P/Q-type anti-VGCC antibodies; none hadassociated small-cell lung cancer. Measurements of fasting,early morning glucose, insulin, C peptide, human growthhormone, cortisol, thyroid-stimulating hormone, prolactin,and gonadotrophins were made in all patients. The HOMA(homeostasis model assessment) model of glucose homeosta-sis (using fasting glucose and insulin values) was used to es-timate pancreatic b cell function and insulin resistance.5

There was no evidence of impaired b cell function inLEMS patients (Fig). Myasthenia gravis and LEMS patientstaking steroids showed evidence of insulin resistance with acompensatory increase in b cell function, whereas LEMS pa-tients not taking prednisolone had normal values of insulinresistance and b cell function. Prolactin, growth hormone,thyroid-stimulating hormone, cortisol, and gonadotrophinmeasurements were within normal limits in all patients.

We have found no clinical or laboratory evidence of en-docrine dysfunction in LEMS patients. This may be caused,in part, by up-regulation of non–P/Q-type VGCCs in pan-creatic and pituitary cells, or to antigenic differences betweenisoforms of P/Q-type VGCCs expressed in neurons and en-docrine cells. The apparently normal endocrine functiondemonstrated here is reassuring, because LEMS patients of-ten require corticosteroid treatment that can have adverse ef-fects on glucose metabolism. These clinical findings may also

414 Annals of Neurology Vol 45 No 3 March 1999

help to clarify the functional role of different VGCC sub-types in hormone release in vivo.

University Department of Clinical Neurology, RadcliffeInfirmary, Oxford, UK

This research was supported by grants from The Wellcome Trust(A. Pinto) and the Muscular Dystrophy Group of Great Britain (P.Maddison). We gratefully acknowledge the help of Dr David Mat-thews for incorporation and use of the HOMA model of glucosehomeostasis.

References1. Newsom-Davis J. Neuromyotonia and the Lambert-Eaton myas-

thenic syndrome. In: Latov N, Wokke JHJ, Kelly JJ, eds. Im-munological and infectious diseases of the peripheral nerves.Cambridge, UK: Cambridge University Press, 1998:238–250

2. Ligon B, Boyd AE, Dunlap K. Class A calcium channel variantsin pancreatic islets and their role in insulin secretion. J BiolChem 1998;273:13905–13911

3. Login IS, Kim YI, Judd AM, et al. Immunoglobulins ofLambert-Eaton myasthenic syndrome inhibit rat pituitary hor-mone release. Ann Neurol 1987;22:610–614

4. Sher E, Codignola A, Passafaro M, et al. Nicotinic receptors andcalcium channels in small cell lung carcinoma. Functional role,modulation, and autoimmunity. Ann NY Acad Sci 1998;841:606–624

5. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasismodel assessment: insulin resistance and beta-cell function fromfasting plasma glucose and insulin concentrations in man. Dia-betologia 1985;28:412–419

Cortical Excitability in MigraineW. M. Mulleners, MD,* E. P. Chronicle, PhD,†J. W. Vredeveld, MD, PhD,*and P. J. Koehler, MD, PhD*

We were most interested to read the recent article by Afraand colleagues,1 published in the August issue of this journal.In that article, the authors pursue an hypothesis originallypublished by our group,2 namely, that functional visual cor-tical hyperexcitability may be acquired as a result of repeti-tive physiological insult to area 17 during attacks of migrainewith aura. We are delighted that this hypothesis continues tostimulate research, but we have some reservations about themethodology used by Afra and colleagues1 and the conclu-sions that are drawn from their findings.

First, with regard to Afra and co-workers’ failure to repli-cate the findings of Aurora and colleagues3 using occipitaltranscranial magnetic stimulation (TMS) to elicit phos-phenes, four points related to methodology are of crucial im-portance if phosphenes are to be elicited in any experimentalsubject:

1. The optimal site for stimulation varies widely over theoccipital scalp and is certainly not restricted to themidline.4 Indeed, in our ongoing investigation, 43%of patients experienced phosphenes only when stimu-lated 2 to 3 cm away from the midline.

2. It is our experience that precise positioning of thestimulating coil is necessary; in some subjects, phos-phenes disappeared when the coil was moved by aslittle as 5 to 10 mm. As the probable depth of inducedcurrent is approximately 4 cm below the plane of thecoil,4 it is likely that the angle made between the coiland the scalp surface may also influence findings.

3. The influence of coil design cannot be discounted. Insome of our subjects, phosphenes could be elicitedwith a circular coil but not a figure of eight coil; inothers, thresholds with the figure of eight coil wereconsiderably lower.

4. It is our contention that the definition of a phospheneis difficult for subjects to grasp. There is a risk thatother visual phenomena not related to the magneticstimulus are misinterpreted as phosphenes by the sub-ject. It is therefore important to instruct subjects care-fully and pay close attention to the verbal reportsgiven.

In our ongoing study, it has been possible to elicit phos-phenes in the great majority of migraine patients. Further-more, the phosphene elicitation thresholds were highly reli-able within a testing session; a 1% reduction of TMSintensity was frequently sufficient to abolish the perception ofphosphenes. Patients were not aware of stimulation intensity.

Second, it is by no means a universal finding that TMSmeasures of motor cortex functioning are either normal orindicative of hypoexcitability in migraine as reported by Afraand colleagues.1 Notably, a recent article by Aurora and co-workers5 indicates a significantly shortened cortical stimula-tion silent period in migraine with aura patients as comparedwith controls. This shortening of the cortical stimulation si-lent period is indicative of dysfunctional inhibitory processesat the cortical level.

Fig. HOMA model of pancreatic b cell function (A) and in-sulin resistance (B) in patients with Lambert-Eaton myas-thenic syndrome (LEMS) and control patients with myastheniagravis (MG). (P) 5 patients are taking prednisolone; (NP) 5no prednisolone taken. Each data point is the mean of threeseparate consecutive measurements in each patient.

Annals of Neurology Vol 45 No 3 March 1999 415

Given the heterogeneity of some findings in this area, wesuggest that a number of technical and methodological vari-ables must be considered before firm conclusions can bedrawn about the question of cortical excitability in migraine.On the basis of the single study of the visual cortex by Afraand colleagues,1 we believe that it is premature to discard thehypothesis that visual dysfunction in migraine with aura maybe secondary to loss of inhibitory capability of the visual cor-tex. It is also questionable to make inferences about the stateof the visual cortex in migraine from one, as yet unrepli-cated, study of the motor cortex as Afra and colleagues1 ap-pear to do. There are considerable morphological differencesbetween the two cortical areas, and the relevance of the mo-tor cortex to studies of migraine pathogenesis remains to beconvincingly demonstrated in our view.

*Departments of Neurology and Clinical Neurophysiology,Atrium Medical Center, Heerlen, The Netherlands, and†Mental Health and Neural Systems Research Unit,Department of Psychology, Lancaster University, Lancaster,England, UK

References1. Afra J, Mascia A, Gerard P, et al. Interictal cortical excitability in

migraine: a study using transcranial magnetic stimulation of mo-tor and visual cortices. Ann Neurol 1998;44:209–215

2. Chronicle EP, Mulleners WM. Might migraine damage thebrain? Cephalalgia 1994;14:415–418

3. Aurora SK, Ahmed BK, Welch KMA, et al. Transcranial mag-netic stimulation confirms hyperexcitability of occipital cortex inmigraine. Neurology 1998;50:1111–1114

4. Marg E, Rudiak D. Phosphenes induced by magnetic stimula-tion over the occipital brain: description and probable site ofstimulation. Optom Vis Sci 1994;71:301–311

5. Aurora SK, Al-Sayed F, Norris L, Welch KMA. Cortical stimu-lation silent period is shortened in migraine with aura. Cepha-lalgia 1998;18:397 (Abstract)

Phosphene Generation in MigraineSheena K. Aurora, MD*, and K. M. A. Welch, MD†

We read with interest the article by Afra and colleagues.1 Weare pleased that, after our previous report2 and that of Wrayand associates3 suggesting visual cortex hyperexcitability inmigraine, others have used to study occipital cortex functionin this disorder. In contrast to the study by Afra and col-leagues1 who suggested that the occipital cortex is hypoexcit-able, our migraine patients showed low thresholds for phos-phene generation compared with normal controls. Suchdirectly opposing conclusions requires comment.

First, there are important differences in the methods. Weused the Caldwell MES-10 stimulator and Afra and col-leagues1 used the Magstim-200. Using the Caldwell MES-10, other investigators have experienced difficulty in elicitingphosphenes from normal human subjects.4,5 More recently,however, phosphenes were elicited in 67%,6 68%,7 and82%8 of controls, using new coils provided for the Magstim-200, less than the proportions in the study by Afra and col-leagues.1 Further, unlike this study, most investigators reporteasier elicitation of phosphenes with eyes closed than open.7

Second, the coil size differed for the two studies. We used a

9.2-cm coil placed tangentially over the occiput, with thefocal point 7 cm superior to the inion.

Our results in controls were similar to those of others whoused the same stimulator and coil size.4,5 Afra and col-leagues1 used a larger coil and therefore, at least theoretically,generated stronger electric current resulting in a greater prob-ability of generating phosphenes. Third, coil positioning dif-fered between the studies. Coil position appears critical forreplication of results with the transcranial magnetic stimula-tion technique.9

The absence of phosphene generation in migraine suffer-ers1 is perplexing, however. Again, this might be explainedby technical differences. At higher stimulus intensities, phos-phenes tend to saturate and disappear.8 The stimulus inten-sity for the migraine group, therefore, may have exceededthreshold. Also, we only recruited subjects who had visualaura or suffered headaches triggered by visual stimulation. Inthe study by Afra and colleagues,1 there was no mention ofwhether patients experienced predominantly visual aura. Fur-ther, some patients experienced aura in only 80% of theirattacks. Finally, by using a blinded experimental design, wehave replicated the results of our first study.2 Patients whohave migraine with aura experienced phosphenes at a lowerthreshold than normal controls. In the migraine without auragroup, phosphenes were found in about half the patients.Accordingly, it seems premature to reject the increasingamount of evidence that supports hyperexcitability of the vi-sual cortex on the basis of the study by Afra and colleagues.1

*Department of Neurology, Henry Ford Hospital, Detroit, MI,and †University of Kansas Medical Center, Kansas City, KS

References1. Afra J, Mascia A, Girard P, et al. Interictal cortical excitability in

migraine: a study using transcranial magnetic stimulation of mo-tor and visual cortices. Ann Neurol 1998;44:209–215

2. Aurora SK, Ahmad BK, Welch KMA, et al. Transcranial mag-netic stimulation confirms hyperexcitability of occipital cortex inmigraine. Neurology 1998;50:1111–1114

3. Wray SH, Mijovic-Prelec D, Kosslyn SM. Visual processing inmigraineurs. Brain 1995;118:25–35

4. Amassian VE, Cracco RQ, Maccabee PJ, et al. Suppression ofvisual perception by magnetic coil stimulation of human occipitalcortex. Electroencephalogr Clin Neurophysiol 1989;74:458–462

5. Beckers G, Homberg V. Impairment of visual perception and vi-sual short term memory scanning by transcranial magnetic stim-ulation of occipital cortex. Exp Brain Res 1991;87:421–432

6. Meyer BU, Diehl R, Steinmetz H, et al. Magnetic stimuli appliedover motor and visual cortex: influence of coil position and fieldpolarity on motor response, phosphenes and eye movements.Electroencephalogr Clin Neurophysiol Suppl 1991;43:121–134

7. Marg E, Rudiak D. Phosphenes induced by magnetic stimulationover the occipital brain: description and probable site of stimula-tion. Optom Vis Sci 1994;71:301–311

8. Kastner S, Demmer I, Ziemann U. Transient visual field defectsinduced by transcranial magnetic stimulation over human occip-ital pole. Exp Brain Res 1998;118:19–26

9. Amassian VE, Eberle L, Maccabee PJ, Cracco RQ. Modelingmagnetic coil excitation of human cerebral cortex with a periph-eral nerve immersed in a brain-shaped volume conductor: the sig-nificance of fiber bending in excitation of human cerebral cortex.Electroencephalogr Clin Neurophysiol 1992;85:291–301

416 Annals of Neurology Vol 45 No 3 March 1999

ReplyJean Schoenen, MD, PhD,Alain Maertens de Noordhout, MD, PhD,and Judit Afra, MD

We are fully aware of the methodological problems related tothe study of phosphenes elicited by transcranial magneticstimulation (TMS) of the occipital cortex and have discussedthem, in part, in our publication. As mentioned in the Pa-tients and Methods section, the coil was moved in our sub-jects until phosphenes were produced. This was chiefly donein the vertical direction but also laterally in several subjects.We did not use the figure-eight coil, because in preliminaryexperiments the circular coil was more effective in producingphosphenes. Intensity was increased stepwise to 100%. Thereappears to be a difference in the width and depth of acti-vated occipital cortex between the Cadwell coil used by Au-rora and co-workers1 and the Magstim coil we have used.The prevalence of phosphenes elicited in normal subjects wasmuch lower with the former (0–27%) than with the latter(.70%).

Concerning patient selection, among our 25 patients withvisual aura, 3 also had rare (620%) attacks of migraine with-out aura. Aurora and co-workers1 used this selection criterionand also included patients in whom “headaches were trig-gered by visual stimuli,” which probably led to a heteroge-neous group of patients including a subgroup of migrainewith aura, but also patients who have migraine without aura.Another possible confounding factor in the study of corticalactivities in migraineurs is the time interval before the nextattack. Dramatic changes of evoked cortical responses, andthus of cortical excitability, occur 24 hours before and dur-ing the attack.2 Although the date of the last attack beforethe recording can be checked by history, the occurrence ofan attack within days after the procedure must be checked bytelephone calls, which was done in our study but was notdone in the study by Aurora and co-workers.1

The speculation in the letter by Welch and Aurora, thatphosphenes might disappear at high-stimulation intensitiesbecause of saturation, is interesting but not confirmed byexperimental data. Kastner and associates3 report that phos-phenes were elicited in 14 of 17 (82%) subjects, by using theMagstim coil at an output of up to 1 T. As mentioned be-fore, we increased stepwise the stimulation intensity startingat field strengths as low as 0.1 to 0.2. T, thus covering arange of intensities well below the 1.1- to 1.4-T level atwhich Kastner and associates3 found visual field defects.Moreover, Welch and Aurora neglect our results on motorcortex stimulation, which also favor decreased or normalexcitability.

Mulleners and colleagues mention their ability to elicitphosphenes in most of their migraine patients. This is notdifferent from our results as far as migraine without aura isconcerned. A review of the available literature would haveconvinced Mulleners and colleagues that, indeed, most pub-lished data on TMS of the motor cortex in migraineurs in-dicate hypoexcitability rather than hyperexcitability. The

study on cortical silent periods, which is published in ab-stract form,4 can be interpreted in different ways. First, handmuscle silent periods induced by TMS of the motor cortexare highly variable between individuals and thus are not veryreliable in a small group of subjects such as the one studiedby Aurora and co-workers.3 Second, the underlying mecha-nisms are multiple, both cortical and spinal. Third, if thecortical silent period is reduced in migraine (which was notthe case in our study), one possible explanation could be thatcortical inhibitory interneurons are hypoexcitable, as are theirexcitatory companions. The hypothesis by Chronicle andMulleners,5 of interneuronal damage in area 17 because ofrepeated insults during migraine attacks, has not receivedexperimental verification up to now. On the contrary, thewell-known amelioration of migraine with age and severalelectrophysiological studies, including the one by Khalil6

showing an amplitude decrease of the visual evoked potentialwith disease duration, do not favor such a hypothesis.

Finally, the results of the psychophysical studies of the vi-sual system,7 cited by Welch and Aurora as supporting cor-tical hyperexcitability, were not confirmed in a more recentstudy.8 It appears, therefore, that most available data in mi-graine, as long they were obtained at a distance from an at-tack, are compatible with cortical hypoexcitability. The lat-ter, possibly due to dysfunctioning ion channels and/orsubcorticocortical pathways, may be responsible for the lackof habituation and incrementing responses on stimulus rep-etition, which could increase metabolic strain2 in the cortex.Some of the conflicting results reported in the literature maybe explained by fluctuations of cortical excitability, especiallyby an increase of excitability occurring just before and duringthe attack.

Department of Neurology, CHR Citadelle, University of Liege,Liege, Belgium

References1. Aurora SK, Ahmad BK, Welch KMA, et al. Transcranial mag-

netic stimulation confirms hyperexcitability of occipital cortex inmigraine. Neurology 1998;50:1111–1114

2. Schoenen J. Cortical electrophysiology in migraine and possiblepathogenetic implications. Clin Neurosci 1998;5:10–17

3. Kastner S, Demmer I, Ziemann U. Transient visual field defectsinduced by transcranial magnetic stimulation over human occip-ital pole. Exp Brain Res 1998;118:19–26

4. Aurora SK, Al-Sayed F, Norris L, Welch KMA. Cortical stimu-lation silent period is shortened in migraine with aura. Cepha-lalgia 1998;18:397 (Abstract)

5. Chronicle EP, Mulleners WM. Might migraine damage thebrain? Cephalalgia 1994;14:415–418

6. Khalil NM. Investigations of visual function in migraine usingvisual evoked potentials and visual psychophysical tests. PhDthesis. London: University of London, 1991

7. Wray SH, Mijovic-Prelec D, Kosslyn SM. Visual processing inmigraineurs. Brain 1995;118:25–35

8. Palmer J, Chronicle E. Cognitive processing in migraine: a fail-ure to find facilitation in patients with aura. Cephalalgia 1997;17:338 (Abstract)

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