Letters to the Editor

321

Zolmitriptan Versus Sumatriptan Comparison Trial

The comparative trial of zolmitriptan and suma-triptan for the acute oral treatment of migraine byGallagher et al

1

is a very large clinical trial which addssignificantly to the evidence base available to clini-cians who work with patients with migraine. It is im-portant, however, that clinicians not only be given theresults of clinical drug trials, but also be given suffi-cient information so that they can critically appraisethe evidence presented by the trial. A clinical trial re-port should also, in a very straightforward fashion, in-dicate the clinical significance of the results reported.

Clearly reporting the results of large clinical trialsis no easy task. Despite careful reading of the article byGallagher et al, clarification of several points would behelpful.

The authors indicate in the “Results” section thattheir intent-to-treat population consisted of 1212 pa-tients who treated at least two migraine attacks. Thisintent-to-treat population treated a total of 6187 mi-graine attacks. Following this, in the “Results” sec-tion, they refer several times to headache responserates at 2 hours in terms of “percentage of patients.”However, I suspect they are measuring responserates as a percentage of the headache attacks treated.Could the authors please clarify this? If they were an-alyzing the percentage of headache attacks that re-sponded to either drug, the reader deserves to knowthe “n” in each comparison group. While the numberof patients in each comparison group is given in Ta-ble 1, the number of headache attacks treated in eachcomparison group is not. Headache response at 2hours was the primary efficacy end point of this trial,and the reader deserves the pertinent details includ-ing the mean number of headache attacks treated bypatients in each treatment group.

Similarly, in their analysis of the consistency ofheadache response to both drugs, the reader is leftwith many questions. Consistency of response wasdefined as the percentage of patients who respondedat 2 hours postdose in 80% to 100% of attacks. Pa-tients could have treated from two to six headache at-

tacks. Yet this analysis is difficult, because for pa-tients treating four attacks or less, patients would need100% responsiveness to be classified as responders, aseven a response in three out of four attacks wouldonly provide a 75% response rate. From the article,we know that patient numbers in the intent-to-treatpopulation were roughly similar in the four treatmentgroups. However, we are given no information withregard to whether the four patient groups treatedsimilar numbers of headaches and whether they hadroughly comparable numbers of patients who treatedfive or six attacks. This information would be helpfulfor the reader to assess the findings reported in thetrial. Could the authors provide this information?

My final comment is with regard to clinical signif-icance. Clinical trial reports are read by clinicians,who wish to apply the results to their practice. There-fore, it would be helpful if clinical trial reports madethe clinical significance of their results clear. The twotables which report the results of this trial are not ter-ribly helpful. Table 2 shows odds ratios with 95%confidence intervals, and it is difficult to interpretclinical relevance from such a table despite significant

P

values. Table 3 shows a series of comparisons be-tween the four triptan groups, focusing entirely uponstatistical significance and

P

values. Once again, thisis not very helpful to clinicians. Nowhere in the articleis there mention of the “number needed to treat,” aconcept which is probably the best indicator of clinicalsignificance. Fortunately, in the text of the article,headache response rates are given for the four treat-ment groups. We can see, for example, that the 2-hourheadache response rate for the 2.5-mg zolmitriptandose was 67.1%, and for the 50-mg sumatriptan dose,it was 63.8%. By subtracting the sumatriptan responserate from the zolmitriptan response rate, we can cal-culate that the therapeutic gain of zolmitriptan 2.5 mgover sumatriptan 50 mg was 3.3%. The reciprocal ofthe therapeutic gain (1/0.033) gives us the numberneeded to treat. This number shows that it is neces-sary to treat approximately 30 patients with zolmi-

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triptan 2.5 mg in order to obtain one additional head-ache response at 2 hours over and above theheadache responses that would have been obtainedby using sumatriptan 50 mg.

Well-executed clinical trials have become thecornerstone upon which much of our modern head-ache therapeutics is based. It is important that thesebe reported clearly and completely, and that the clin-ical implications of the findings be stated clearly sothat clinicians can form a clear opinion on the validityof the results, and their clinical significance. This is aformidable challenge, and it is important that all ofus, authors, reviewers, and editors, strive to meet thischallenge.

W.J. Becker, MD12th Floor, Neurology

Foothills Hospital1403 29th Street NW

Calgary, Alberta T2N 2T9Canada

REFERENCE

1. Gallagher RM, Dennish G, Spierings ELH, Chitra R.A comparative trial of zolmitriptan and sumatriptanfor the acute oral treatment of migraine.

Headache.

2000;40:119-128.

Response From Gallagher

Thank you for the opportunity to respond to theinsightful questions raised by Dr. Becker regarding ourcomparative trial of zolmitriptan and sumatriptan.

1

Dr.Becker has made a valid point in terms of the differencebetween “percentage of patients” and “percentage ofheadache attacks treated.” He is correct in that it istechnically more accurate to use “percentage of head-ache attacks treated,” since the analysis was based onmultiple-attack data. However, since the majority ofpatients (

.

63% in all groups) treated all six attacksand the response pattern was relatively stable acrossthe six attacks, it does not seem inappropriate to use“percentage of patients” in the article. This is re-

flected in the response rates for the first attack: 68.3%for zolmitriptan 2.5 mg, 66% for zolmitriptan 5 mg,57.6% for sumatriptan 25 mg, and 64.7% for sumatrip-tan 50 mg. Similarly, the total number of headache at-tacks evaluated was comparable across the four treat-ment groups (zolmitriptan 2.5 mg, n

5

1466; zolmitriptan5 mg, n

5

1493; sumatriptan 25 mg, n

5

1509; sumatriptan50 mg, n

5

1536), as was the mean number of headacheattacks treated per patient (4.97, 4.90, 4.93, and 5.02, re-spectively). We hope that this additional data clarifiesthe clinical relevance of the headache response resultsfor the readers.

With regards to the analysis of consistency of re-sponse, we can confirm that the majority of patientstreated at least five attacks (72% to 76% of patientsacross the four groups). Furthermore, 63% to 67% ofpatients treated all six attacks. Therefore, we feel thatthe use of the high standard of 80% to 100% consistencywas justified, and supports the consistency claims pre-sented in the report.

Dr. Becker’s last question relates to interpreta-tion of clinical versus statistical signficance. We agreethat more emphasis should be put on the clinical in-terpretation of the results, but we also believe thatthese results need to be supported by the

P

values. Weshare Dr. Becker’s opinion that number needed totreat (NNT) is a useful tool for communication, but wehave some reservations in using it. First, NNT doesnot usually have a direct link to the

P

value for thegroups compared, except for a simple percentagecomparison, because NNT obtained from raw (ob-served) percentages does not incorporate covariatesadjustment (eg, center effect, baseline severity). There-fore, if there is a gross imbalance in important covari-ates, NNT will not provide a fair comparison. A morecredible way to calculate NNT may be based on oddsratios which have been adjusted for the covariate im-balance. To do this, we need to assume a credible re-sponse rate for the reference group and calculate aresponse rate for the target group from the odds ra-tio. For example, if we use 64% for sumatriptan 50 mg(63.8% was reported in this trial), then based on anodds ratio of 1.21, zolmitriptan 2.5 mg will have a cal-culated response rate of 68.3%. The difference is4.3% which corresponds to an NNT of 24. If we use60% for sumatriptan 50 mg, then based on an odds

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ratio of 1.21, zolmitriptan 2.5 mg will have a calcu-lated response rate of 64.5%. The difference is 4.5%,corresponding to an NNT of 23. There are also otherstatistical issues associated with NNT. The statisticalproperties of NNT are not well established and it isdifficult to interpret the 95% confidence intervalwhen

P

.

.05. A good alternative to NNT may, there-fore, be a direct interpretation of odds ratios. For ex-ample, an odds ratio of 1.21 for 2-hour headache re-sponse can be described as “the odds of getting aheadache response at 2 hours was 21% higher for zolmi-triptan 2.5 mg than for sumatriptan 50 mg,” which wassupported by a

P

value of .017. This type of descriptiveinterpretation may aid the clinician in translating statis-tical significance into clinical relevance.

Dr. Becker has highlighted the challenge of report-ing trial data in such a way that the clinical significanceand implications of the findings are clear to all. We hopethat the additional information from our study pre-sented above goes some way to meeting this challenge.

R. Michael Gallagher, DOUniversity of Medicine and

Dentistry of New JerseyHeadache Center

513 South Lenola RoadMoorestown, NJ 08057

REFERENCE

1. Gallagher RM, Dennish G, Spierings ELH, Chitra R.A comparative trial of zolmitriptan and sumatriptanfor the acute oral treatment of migraine.

Headache.

2000;40:119-128.

“Herbal” Remedies and Patient Protection

The prophylactic antimigraine properties of anextract of

Petasites hybridus

(the butterbur or bogrhubarb) have recently been reported.

1,2

In this clini-cal trial, the active treatment group received 50 mg ofthe extract twice a day under double-blind condi-tions. The efficacy data appear to be sound.

This plant has been used medicinally for manycenturies: poultices made from it are described in Di-soscorides’

Herbal Book

, and it is recommended forurinary incontinence.

3

The manufacturer of this for-mulation discloses that the foliage of

Petasites hybri-dus

contains pyrrolizidine derivatives (PD) and thatthese alkaloids are potentially carcinogenic. How-ever, the extract is solely from the roots of the plant,which are apparently free of PD, and the manufactur-ing method is also believed to exclude such toxinsfrom the tablets.

In assessing the therapeutic value of any therapy,there is a need to balance benefit with risk, ie, effi-cacy with tolerability. Assessment of tolerability be-gins with nonhuman toxicology. After multiple appli-cations to the manufacturer, no substantial responsehas been received on this matter.

The promotional materials for this herbal productaddress the issue of toxicology with the following: (1)no

chemically

detectable toxins are present in the ex-tract, (2) long-term clinical experience with the extractfor other indications has been satisfactory,

3

and (3) thisproduct was approved by Commission E of the regula-tory authorities in Germany. We also recognize themanufacturer’s long and good reputation in Europe.

Conversely, adverse events to herbal therapiesneed not be reported to regulatory authorities andtend not to be assiduously sought.

4

In the subject clin-ical trial, it is reported that there were no adverseevents among the 33 active-treated and 27 placebo-treated patients, during 3 months of oral therapy.

1

This is unique among clinical trials involving patientswith migraine!

Patients can easily locate Internet advertisementsfor this herbal product by using the search word “mi-graine.”

5

The Web pages specifically state: “Nowavailable in the United States.” No prescription isneeded, and the product is dispensed by mail. Theseadvertisements contain the following statements

6

:

• “The special advantage of this remedy is itshigh tolerability. In all the years that it has beenused, no side effects have been reported.”

• “No side effects of butterbur root are reportedin the literature.”

• “A product with no potential risks.”

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March 2001

• “Migraine prophylaxis without side effects.”

• “In this respect [adverse events], . . . is superiorto all other migraine prophylactics.”

The manufacturer’s general contention is that herbaltherapies are natural and thus automatically harmless.

In our view, it is illogical to assume that any phar-macologically active material, especially mixtures ofcomplex biological molecules, will not have diverseproperties. In fact, we cannot tell whether these tab-lets are well tolerated or not.

In the United States, the Food and Drug Adminis-tration (FDA) is restricted from regulating herbal thera-pies in the same way as allopathic drugs.

7

The FDA canonly take action against an herbal product when there isunequivocal evidence that the public is at “significantand unreasonable risk,” ie, when harm has actually beendone. There is no requirement that herbal therapies musthave demonstrated efficacy or safety before marketing.There is also no control over advertising claims. The situ-ation is essentially the same in the United Kingdom.

8,9

In this clinical trial, an herbal medicine of un-known tolerability has been administered as a chronicoral therapy. Patients deserve access to complete infor-mation about the materials that they take, not only inordinary practice but also in clinical trials. This infor-mation should be accurate and in an understandablecontext. We wonder how well informed the patients inthis clinical trial were about the preclinical testing ofthis product. We believe that an appropriate contextfor that information would be the standards that areusually applied to investigational drugs for migraine.

“First, do no harm.” The assertion that herbalremedies are obviously harmless, merely becausethey are herbal, is a meaningless circularity: Romeo’sand Juliet’s poison was herbal.

10-14

Anthony W. Fox, MD, FFPM, FIBiolEBD Group

6120 Paseo del Norte, Suites J2-L2Carlsbad, CA 92009

Emile A.J. de Sousa, MBBSurg, FRCPWeybridge Health Center

Weybridge, KT13 8DOUK

REFERENCES

1. Mauskop A, Grossmann WM, Schmidramsl H. Peta-sites hybridus (Butterbur root) extract is effective inthe prophylaxis of migraines. Results of a randomized,double-blind trial [abstract].

Headache.

2000;40:420.2. Max-Planck-Institut für Züchtungsforschung, Co-

logne, Germany Web site. Plant illustration avail-able at: http://www.mpiz-koeln. mpg.de/

z

stueber/lindman/24.jpg. Texas A&M University Web site.Photograph available at: http://www.csdl.tamu.edu/FLORA/bleeker/holland/petshyb.jpg. Accessed Jan-uary 11, 2001.

3. Elkins R. Natural Treatments for Urinary Inconti-nence. Pleasant Grove, Utah: Woodland Publishing;2000:19-20.

4. Barnes J, Mills SY, Abbot NC, Willoughby M, ErnstE. Different standards for reporting ADRs to herbalremedies and conventional OTC medicines: face-to-face interviews with 515 users of herbal remedies.

BrJ Clin Pharmacol.

1998;45:496-500.5. Peroutka SJ. Analysis of Internet sites for migraine

[abstract].

Headache.

2000;40:424.6. Weber & Weber GmbH, Germany Web site. Avail-

able at: http://www.webernweber.com/migraine.htm.Accessed January 11, 2001.

7. Dietary Supplement Health and Education Act, PubL No. 103-417, 108 USC 4325 (1994).

8. Ernst E. Herbal medicines: where is the evidence?

BMJ.

2000;321:395-396.9. Jowell T. Herbal medicines.

Hansard House of Com-mons.

1999;March 26:426-427.10. Huxtable RJ. The myth of beneficent nature: the

risks of herbal preparations.

Ann Intern Med.

1992;117:165-166.

11. Ernst E. Harmless herbs? A review of the recent lit-erature.

Am J Med.

1998;104:170-178.12. Cupp MJ. Herbal remedies: adverse effects and drug

interactions.

Am Fam Physician.

1999;59:1239-1245.13. Tomlinson B, Chan TY, Chan JC, Critchley JA, But

PP. Toxicity of complementary therapies: an easternperspective.

J Clin Pharmacol.

2000;40:451-456.14. Nortier JL, Martinez MC, Schmeiser HH, et al.

Urothelial carcinoma associated with the use of aChinese herb (

Aristolochia fangchi

).

N Engl J Med.

2000;342:1686-1692.

Headache

325

Response from Mauskop

Thank you for allowing me to respond to the let-ter by Fox and de Sousa.

I agree with the authors of the letter that com-plete lack of side effects raises methodological ques-tions about this study performed by my German col-leagues. However, I think that the manufacturer ofPetadolex, which the authors of the letter admit has“a long and good reputation,” should be commendedfor attempting to bring scientific research to the fieldof herbal remedies.

Alexander Mauskop, MDNew York Headache Center

30 East 76th StreetNew York, NY 10021

This is a response by the representatives of themanufacturer, Weber & Weber:

The letter by Fox and de Sousa makes certainstatements regarding our company and product Peta-dolex (extract of

Petasites hybridus

). We would like tocomment on the letter and provide the following infor-mation in the order of appearance in the letter.

1. The letter states that

Petasites

is recom-mended for urinary incontinence.

Petasiteshybridus

is extensively reviewed in a clini-cal monograph by the German Commis-sion E at the German Regulatory Author-ity BfArM; the original indication wasurinary tract spasm and not incontinence.Petadolex, which contains an extract of

Petasites hybridus

, is sold in Germany andregistered for the indications of migraineand asthma.

2. Regarding the statement about pyrrolizi-dine derivatives, all parts of the plant, in-cluding the roots contain pyrrolizidine de-rivatives. It is not correct, as stated in theletter, that the roots are free of the alka-loids. However, our company has suc-ceeded in removing all alkaloids from the

root extracts by a patented extractionmethod to undetectable levels.

3. The authors state that no reply was receivedfrom the manufacturer following an inquiryregarding tolerability and toxicology. Acomprehensive reply was immediately sentto the author via e-mail. We regret that ourstatement was apparently not received. Weapologize and include the reply.

4. Regarding the long-term experience withthis product, it is important to note thatPetadolex is very well tolerated and effica-cious. This is underlined by the fact thatPetadolex has been on the market for 25years with no report of any toxicity andsince 1992, 900 000 packages of Petadolexhave been sold.

5. The authors state that adverse events ofherbal therapies need not be reported tothe regulatory authorities. This is not cor-rect since, eg, in Germany where the prod-uct is registered and manufactured, herbaltherapies have to fulfill the same regula-tory requirements as chemical drugs, ie,registration of all adverse events to the reg-ulatory authorities.

6. The authors find it unique that no adverseevents were found in a clinical trial with 60patients. In fact, this observation is un-usual. Conversely, all patients were veryyoung and otherwise healthy; therefore, itis not too surprising that no adverse eventswere noted.

7. The letter states that the manufacturercontends that all herbal therapies areharmless since they are natural. This is notcorrect and has never been stated by ourcompany. Of course, we realize that drugs,irrespective of their origin (chemical syn-thesis or plant), have risks, although herbaltherapies have been shown to have a muchbetter safety profile in general than allo-pathic drugs.

8. The authors state that herbal therapies donot need to demonstrate efficacy or safetybefore marketing. In Germany, herbal ther-

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March 2001

apies are treated as allopathic drugs. It istherefore mandatory that efficacy, quality,and safety data are provided for marketing.This applies to Petadolex.

9. The letter claims that the clinical trial wasperformed with a herbal medicine (Petado-lex) of unknown tolerability and that thepatients need to be informed about thepreclinical testing. The fact is that the trialwas performed according to the GCPguidelines and extensive preclinical experi-ence regarding the risks with the productwere adequately reflected in the informedconsent.

10. The comment that herbal remedies are ob-viously harmless has been responded to inthis letter (see number 7) and does not re-flect our opinion.

Toxicological Data

Mutagenicity

The Ames method with and without metabolicactivation was used to investigate the carbon dioxideextract. In the agar plates, 50, 100, 250, 500, 1000,1500, and 2500

m

g of the extract are incorporated.The following strains of

Salmonella typhimurium

were used:

TA 98 and TA 100 without metabolic activation

TA 98, TA 100, and TA 102 with and withoutmetabolic activation

TA 1535 and TA 1537 with and without meta-bolic activation

The results show that Extr. Petasitidis e rad 30:1does not reveal any mutagenic effect at doses up to2500

m

g per plate.

Carcinogenicity

In the European Union, studies for carcinogeni-city are not required as long as the substance does notshow mutagenic effects in vitro. This is confirmed forExtr. Petasitidis e rad. 30:1 by the above-mentionedresults.

LD50 2.5 g/kg p.o. (rat)>

The content of toxic pyrrolizidine alkaloids (PAs)is limited to less than 0.1

m

g per daily dose. This limitis given by the German Central Health authority.However, toxic PAs are not detectable in PetadolexGelcaps.

Dr. V. Koch and Dr. U. DaneschWeber & Weber GmbH & Co. KG

Migraine-Associated Seizure: A Case of Reversible MRI Abnormalities and Persistent NondominantHemisphere Syndrome

Friedenberg and Dodick described a 51-year-oldpatient with the occurrence of an epileptic seizureduring a migraine attack which persisted in associa-tion with both focal neurologic signs of up to 5 weeks’duration and magnetic resonance imaging (MRI) ab-normalities.

1

The authors hypothesize the pathogene-sis of migraine-induced seizures and explain the MRIabnormalities based on an underlying migraine mech-anism. However, I do not agree with some basic inter-pretations.

Firstly, the authors define the 5 weeks’ durationof persistent neurologic features as “a prolonged mi-graine attack without aura.” This phenomenon hasnot been defined by the International Headache So-ciety (IHS). Also, the reported “migraine with pro-longed aura” is not in agreement with the IHS crite-ria, ie, not more than 7 days’ duration.

2

The migrainouspathogenesis of this episode is also doubtful because ofthe fact that described episode was the first time the pa-tient suffered from headache in association with focalneurologic features which did not disappear using herusual treatment with sumatriptan.

Secondly, the authors discuss the possible patho-genesis of the association between the prolonged mi-graine attack and the MRI abnormalities. Thequestion may be raised—was this a genuine migraineattack or a manifestation of some other underlying

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327

disease? The authors do not consider that the de-scribed features could be a part of the clinical spec-trum of isolated angiitis of the central nervous system(CNS), a primary cerebral vasculitis. From my pointof view, the following arguments are in favor of iso-lated angiitis of the CNS. Severe and throbbing head-ache with simultaneous focal neurologic and diffusefeatures

3,4

can be present with localized or diffuseextension

3

; the neurologic signs depend on the local-ization of the vasculitic lesions. The frequency of oc-currence of epilepsy and mental disturbances has beenreported to be 25% and 95%, respectively.

4

All thesefeatures are presented in this case report. The T1-weighted and gadolinium-enhanced MRI shows a re-markable enhancement of both the subcortical andcortical region on only one side corresponding to the pa-tient’s clinical features. These MRI features are a fre-quent sign of isolated angiitis of the CNS caused by thevasculitis of the (mainly) small peripheral (sub)corticalarteries and veins.

5

The resolution of the patient’s com-plaints after 5 weeks is also in accordance with the re-lapsing course of the isolated angiitis of the CNS, whichwas confirmed by the normal MRI after 6 months.

In addition, the authors performed an extensivelaboratory analysis but did not mention parametersof causative mitochondrial diseases which they men-tion in their discussion. In conclusion, there exists theobvious possibility of the existence of isolated angiitisof the CNS as another pathogenetic explanation. I amaware that this disease is a complex diagnosis becauseof the nonspecific symptoms and signs. If the patientpresents with recurring clinical manifestations, a brainbiopsy—the primary diagnostic tool—could contrib-ute to the diagnosis and treatment of this patient.

6

Hans W.M. ter Berg MD, PhDDepartment of Neurology

Maasland HospitalPO Box 5500, 6130 MB Sittard

The Netherlands

REFERENCES

1. Friedenberg S, Dodick DW. Migraine-associated sei-zure: a case of reversible MRI abnormalities and per-sistent nondominant hemisphere syndrome.

Head-ache.

2000;40:487-490.

2. ICD-10 Guide for headaches.

Cephalalgia.

1997;17(suppl 19):1-82.

3. Moore PM. Diagnosis and management of isolatedangiitis of the central nervous system.

Neurology.

1989;39(pt 1):167-173.4. Vollmer TL, Guarnaccia J, Harrington W, Pacia SV,

Petroff DA. Idiopathic granulomatous angiitis of thecentral nervous system. Diagnostic challenges.

ArchNeurol.

1993;50:925-930.5. Ehsan T, Hasan S, Powers JM, Heiserman JE. Serial

magnetic resonance imaging in isolated angiitis of thecentral nervous system.

Neurology.

1995;45:1462-1465.6. Alrawi A, Trobe JD, Blaivas M, Musch DC. Brain bi-

opsy in primary angiitis of the central nervous sys-tem.

Neurology.

1999;53:858-860.

Response From Friedenbergand Dodick

We sincerely appreciate Dr. ter Berg’s interestand thoughtful insights after carefully reviewing ourarticle. We wish to take this opportunity to try to con-structively respond to his comments.

First, Dr. ter Berg disagreed with our use of thephrase “a prolonged migraine attack without aura,”in light of the fact that this phenomena has not beendefined by the International Headache Society(IHS). The use of this phrase was meant only to sig-nify that this migraine attack, which lasted 4 days,was a prolonged attack for this individual, in whomattacks were usually terminated within hours after us-ing medication. When attacks did not respond ade-quately to medication, their natural resolution oc-curred within 24 hours. The attack was also prolongedin that the upper limit for an untreated attack of mi-graine without aura is 72 hours according to the IHScriteria.

Secondly, Dr. ter Berg questions the diagnosis ofmigraine, and raises the possibility of primary centralnervous system (CNS) vasculitis. We feel that this di-agnosis is very unlikely from a clinical standpoint.First, the only new signal abnormality on the mag-netic resonance imaging (MRI) scan was cortical/gyriform enhancement with no evidence for white

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March 2001

matter abnormalities other than long-standing andunchanged radiation-induced changes. Secondly, theimaging abnormalities resolved within 9 days, makingan inflammatory CNS vasculitis unlikely.

Finally, the headache, other than lasting longerthan usual, was very similar to many previous attacks.Subsequent to her recovery, she has had no furtherneurologic symptoms or signs over the ensuing 2.5years, and a 6-month follow-up MRI was unremark-able. Therefore, we feel that in addition to the clinicaland laboratory findings during her presentation, thenormal follow-up MRI and benign clinical coursemake a diagnosis of CNS vasculitis highly unlikely.

Scott Friedenberg, MDDavid W. Dodick, MD

Department of NeurologyMayo Clinic Scottsdale

13400 East Shea BoulevardScottsdale, AZ 85259

Re: “Acute Intracranial Hemorrhage Caused by Acupuncture” (Choo DC, Yue G.

Headache

. 2000;40:397-398.)

A patient is described who had subarachnoidhemorrhage following acupuncture to the back of hisneck at the “feng fu” trigger point, 3 cm below the ex-ternal occipital protuberance.

The hemorrhage was coincident with the treat-ment. I think that they overstated the cause by attrib-uting the hemorrhage to the acupuncture treatment. Iam also surprised that they did not perform contrastangiography. Magnetic resonance angiography canmiss aneurysms if the flow within the aneurysms iscircular or if the aneurysm has a clot in it.

Richard S. Sohn, MDDepartment of Neurology

Campus Box 8111Washington University School of Medicine

660 South Euclid AvenueSt. Louis, MO 63110-1093

Response From Choo

I am writing in response to the letter by Dr. Rich-ard Sohn regarding our case report “Acute Intracra-nial Hemorrhage Caused by Acupuncture” publishedin the May 2000 issue of

Headache

(40:397-398).In our case the strongest argument for intracra-

nial hemorrhage caused by acupuncture is the clinicalpresentation. The headache started during the acu-puncture treatment while the needle was still inplace. Our patient experienced a sudden onset of se-vere occipital headache minutes after the insertion ofthe needle.

The head computed tomography (CT) that wesubmitted for publication showed hemorrhage pre-dominantly in the fourth ventricle with small amountsin the third and frontal horns of the lateral ventricles.There was no obvious subarachnoid hemorrhage onthe head CT. The positive blood seen on lumbarpuncture was likely due to intraventricular hemor-rhage. Injury to branches of the vertebral arteries 3cm below the occipital protuberance could causethis pattern of hemorrhage. In addition, it is veryuncommon for spontaneous rupture of an aneu-rysm to present as predominant intraventricular hem-orrhage. Our patient was offered contrast angiogra-phy, but he flatly refused the invasive procedurefor fear of having another complication. The 0.5-Tmagnetic resonance angiography (MRA) has a sen-sitivity of 93% and a specificity of 100% in detect-ing cerebral aneurysm in one study done by Grandinet al.

1

We acknowledge the small possibility that themagnetic resonance imaging (MRI)/MRA can stillmiss a small aneurysm; however, a ruptured aneu-rysm is highly unlikely given the above clinical sce-nario. The brain MRI done 20 days after the initialbleeding should have detected a thrombosed aneu-rysm if present.

Previous reports, as cited in our article, docu-ment subarachnoid hemorrhage as a potential com-plication of spinal acupuncture. With the addition ofour case report, we believe that clinicians should beaware of the possibility of intracranial hemorrhage asa potential complication of acupuncture in the highposterior neck.

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329

Daniel Choo, MDDepartment of Medicine

Loma Linda University Medical Center11234 Anderson StreetLoma Linda, CA 92354

REFERENCE

1. Grandin CB, Mathurin P, Duprez T, et al. Diagnosisof intracranial aneurysms: accuracy of MR angiog-raphy at 0.5 T.

AJNR Am J Neuroradiol.

1998;19:245-252.