Correspondence
Bilateral human fetal striatal transplantation in Huntington’s disease
To the Editor: Referring to our report, “Bilateral human fetal striatal transplantation in Huntington’s disease,”1 Greenamyre
and Shoulson2suggest that we concluded that “a lack of
signifi-cant worsening might reflect clinical benefit in a progressive neu-rodegenerative disease” and state that “this conclusion is a stretch.” However, regarding our study, we indicated that “we did not definitively demonstrate a lack of significant worsening owing to the small number of subjects and the open label design of the study. We also cannot exclude the influence of random chance, bias, or placebo effects.” Our study was intended to evaluate fea-sibility and safety, and was not designed to definitively assess efficacy. We concluded that transplantation of human fetal stria-tal cells is feasible and survival of transplanted cells was demon-strated, but patients with moderately advanced Huntington’s disease are at risk for subdural hemorrhage after transplantation surgery. We believe that our published manuscript provides a fair and balanced description of our observations and agree with the editorialists that we need better treatments for this devastating disease.
Robert A. Hauser, MD, Paul R. Sandberg, PhD, DSc, Thomas B. Freeman, MD, FACS,Tampa, FL;A. John Stoessl, MD, FRCPC,
Vancouver, BC, Canada
Reply from the Editorialists:It is unfortunate that we did not have the opportunity to see the final accepted version of the report by Hauser et al.,1who apparently took the reviewers’ comments to
heart and toned down their original conclusion, which we called “a stretch.” We agree with Hauser et al.1 that the final published
version presents a more balanced description of their results.
J. Timothy Greenamyre, MD, PhD,Atlanta, GA;Ira Shoulson, MD,Rochester, NY
Editor’s Note: Inadvertently, theNeurology office did not send the final accepted version of the Hauser et al. paper to Drs. Greenamyre and Shoulson. Thus their editorial criticized state-ments that were no longer part of the published article.1
We apologize to Hauser et al.1 and to Drs. Greenamyre and
Shoulson for the error.
Robert C. Griggs, MD,Editor-in-Chief
Copyright © 2002 by AAN Enterprises, Inc.
References
1. Hauser RA, Furtado S, Cimino CR, et al. Bilateral human fetal striatal transplantation in Huntington’s disease. Neurology 2002;58:687– 695. 2. Greenamyre JT, Shoulson I. We need something better, and we need it
now: fetal striatal transplantation in Huntington’s disease? Neurology 2002;58:675– 676.
Older people with impaired mobility have specific loci of periventricular abnormality on MRI
To the Editor:I read the article by Benson et al.1with interest.
My own data, based on CT imaging, support their conclusions. In a convenience sample of 343 patients, including patients with stroke, gait was examined with a standardized scale2and
leuko-araiosis rated in seven brain regions using a modification of the van Swieten method.2,3 Neurologic abnormalities were quantified
using the NIH Stroke Scale and supplemental scale. The brain region most correlated with gait disturbance was identified by analysis of variance. Ordered logit models were then used for further analysis (because of the ordinal nature of the gait scale).
The patients were predominantly men (96%) with a mean age of 68⫾10 years. Leukoaraiosis was found in 160 patients (47%). A history of stroke was present in 179 patients (52%), and radio-logic evidence of stroke was present in 176 (51%). Leukoaraiosis correlated with the presence of subcortical stroke (64% vs 37%,
p⫽0.001), but not with cortical stroke (47% vs 47%).
Analysis of variance found leukoaraiosis in the left frontal region had the highest correlation coefficient with the gait scale (r⫽0.49,p⬍0.0001; ordered logit coefficient 1.35,p⬍0.001). In the absence of left frontal leukoaraiosis, no other region showed statistical correlation with the gait scale (coefficients ranged from
⫺0.13 to 0.19,p⫽NS). Both a history of stroke (coefficient 1.06,
p⬍0.001) and radiologic evidence of stroke (particularly subcorti-cal stroke: coefficient 0.73,p⬍0.001) correlated with gait distur-bance. Leg weakness or ataxia correlated with gait disturbance but not with left frontal leukoaraiosis. In models including all of the above, only leg weakness and ataxia (coefficient 1.56, p ⬍
0.001) and left frontal leukoaraiosis (coefficient 1.32,p⬍ 0.001) were independent predictors of gait disturbance.
Thus, these data support the role of frontal white matter
leu-koaraiosis, particularly on the left side, as a necessary lesion in gait disturbance, but not more posterior leukoaraiosis. This may reflect either different methodology or the larger number of pa-tients examined. Perhaps the specificity that Benson et al.1report
with posterior leukoaraiosis reflects greater disease severity. Al-though leukoaraiosis does appear to be a form of cerebrovascular disease,4my data indicate the effects are independent of those of
overt stroke. I agree that leukoaraiosis may be associated with a “significant portion of mobility impairment” in older individuals and that further natural history studies are necessary as this may portend a poor prognosis.5
Acknowledgment
The author thanks Susan Sergent, PA-C, for data collection; Stuart Thomas, PhD, for data analysis; and his patients at the Huntington Veter-ans Affairs Medical Center, WV.
Dennis Briley,Oxford, UK
Copyright © 2002 by AAN Enterprises, Inc.
References
1. Benson RR, Guttmann CRG, Wei X, et al. Older people with impaired mobility have specific loci of periventricular abnormality on MRI. Neu-rology 2002;58:48 –55.
2. Briley DP, Wasay M, Sergent S, Thomas S. Cerebral white matter changes (leukoaraiosis), stroke and gait disturbance. J Am Geriatr Soc 1997;45:1434 –1438.
3. van Swieten JC, Hijdra A, Koudstaal PJ, van Gijn J. Grading white matter lesions on CT and MRI: a simple scale. J Neurol Neurosurg Psychiatry 1990;53:1080 –1083.
4. Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis. Stroke 1997;28: 652– 659.
5. Briley DP, Haroon S, Sergent SM, Thomas S. Does leukoaraiosis predict morbidity and mortality? Neurology 2000;54:90 –94.
Randomized controlled trial of zonisamide for the treatment of partial-onset seizures
To the Editor:The article by Faught et al.1is exciting news for
epileptologists. However, the authors’ work raises several ques-tions. Their Methods section does not mention prior or concurrent treatment of the patients’ seizures or other concurrent disorders.
Did zonisamide affect blood levels of concurrent anticonvulsant med-ications, such as carbamazepine, or other agents such as digoxin? Did other medications affect zonisamide levels or half-lives? Drug–drug interactions are important treatment considerations.
underlying pathology or EEG finding? Zonisamide should be an important addition to our antiseizure arsenal.
Fred D. Haruda, MD,Albany, OR
Reply from the Authors:We appreciate Dr. Haruda’s comments and agree that knowledge of drug interactions is critical for the proper use of AED. Because of the many permutations of baseline AED regimens among patients, an adjunctive therapy efficacy trial of this type is not well suited to quantification of drug inter-actions or to the identification of which combinations are best. There were more than 20 different concomitant medication regi-mens in use, so insufficient numbers of each were available for meaningful comparison. Although we measured concomitant AED levels throughout this study, the results have not been analyzed. This was done primarily to aid treating physicians in the event of problems such as unexpected seizure increases or toxicity, in which case the data could have been accessed if necessary for emergency patient care. Most patients were taking carbamazepine or phenytoin alone or in combination with other drugs, and there were no identified adverse events related to changes in serum levels of AED.
Data from formal pharmacokinetic studies of zonisamide sug-gest that zonisamide clearance is increased and serum half-life decreased by about 50% in the presence of hepatic enzyme– inducing agents such as phenobarbital, carbamazepine, and pheny-toin.2,3 Although this results in a lower serum zonisamide
concentration for a given steady-state dose, no change in the once-daily zonisamide-dosing interval is necessary because the serum half-life— even in the presence of inducers—remains well above 24 hours.
Zonisamide has little effect upon the serum levels of other AED. There are conflicting reports of effects upon carbamazepine concentrations,4but the effects, if any, are small and unlikely to
be of clinical significance.
No differences in response related to pathology were observed.
Edward Faught, MD,Birmingham,AL; Ilo Leppik, MD,
Minneapolis, MN; for the Zonisamide 922 Study Group
Copyright © 2002 by AAN Enterprises, Inc.
References
1. Faught E, Ayala R, Montouris GG, Leppik IE, and the Zonisamide 922 Trial Group. Randomized controlled trial of zonisamide for the treat-ment of refractory partial-onset seizures. Neurology 2001;57:1774 – 1779.
2. Sackellares JC, Donofrio PD, Wagner JG, Abou-Khalil B, et al. Pilot study of zonisamide in patients with refractory partial seizures. Epilep-sia 1985;26:206 –211.
3. Ojemann LM, Shastri RA, Wilensky AJ, et al. Comparative pharmaco-kinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy. Ther Drug Monit 1986;8:293–296. 4. Perucca E, Bialer M. The clinical pharmacokinetics of the newer
anti-epileptic drugs. Focus on topiramate, zonisamide, and tiagabine. Clin Pharmaockinet 1996;1:29 – 46.
Chronic ischemic monomelic neuropathy from critical limb ischemia
To the Editor:We read with great interest the recent article by Weinberg et al.1reporting the clinical and electrophysiologic
fea-tures of neuropathy due to chronic and critical arterial leg ische-mia. These authors showed that reduced amplitude of sensory potentials, and especially compound muscle action potentials (CMAP), was far more frequent than previously reported, and they suggested that “regional neuropathy was commonly associ-ated with chronic and critical leg ischemia.” In a comprehensive electrophysiologic study of 40 patients with chronic peripheral arterial disease (PAD), we found only minor nerve conduction changes, mainly sensory.2In agreement with our findings, a low
percentage of nerves with reduced action potential amplitudes was demonstrated in a follow-up study of patients with PAD.3
This discrepancy between the previous reports and the recent one by Weinberg et al.1 could not explain entirely the differences in
the material because all three studies included patients with moderate-to-severe PAD according to the criterion of resting an-kle–brachial blood pressure index (ABI). However, Weinberg et al.,1unlike previous reports, chose patients with resting limb pain
and nonhealing foot ulcers. Therefore, it is possible that, under conditions of critical limb ischemia changes of nonneural tissues (e.g., the skin, connective tissue, interstitial fluid) might pose technical limitations such as insufficient stimulation owing to high attenuation of electrical stimuli by poor volume conduction.4
Furthermore, biological abnormalities of nerve fibers, i.e., reduced nerve fiber excitability also resulting in submaximal stimulation,4
could at least partly account for the frequently observed reduction in amplitude of CMAP in the study by Weinberg et al.1Likewise,
the possibility of conduction block at the distal parts cannot be excluded, in which case measurements of F-wave latencies and persistence is far more useful than conventional maximal motor conduction. In patients with findings in the nerve conduction study, supplementary needle electromyography would be expected to confirm unequivocally axonal loss. Indeed, in our study, as well as that of England et al.,3the major finding was the increase of
duration and amplitude of motor unit potentials, indicative of chronic partial denervation. The aforementioned possible draw-backs of nerve conduction studies performed on a limb “close to amputation” reduce the importance of the reported correlation between ABI and neurophysiologic measurements.1 Such
differ-ence between patients with moderate and severe PAD was not shown in our material.2
We agree with Weinberg et al.1that neuropathy due to PAD is
uncommon in clinical practice unless a stage of critical ischemia is present. However, we believe that even in this situation
abnor-malities of routine nerve conduction studies should be interpreted with caution, as they may not accurately represent the neuro-pathic changes caused by limb ischemia.
Elisabeth Chroni, MD, PhD, Vasiliki Papapetropoulou, MD, Jiannis Tsolakis, MD, Stathis Terzis MD, Christos Paschalis, MD PhD, Theodoros Papapetropoulos, MD,Rion, Greece
Reply from the Authors:We appreciate the opportunity to clar-ify our conclusions regarding the effects of severe leg ischemia on peripheral nerves. We focused on the clinical features of severe (“critical”) limb ischemia but Chroni et al. raise several interesting points about the electrophysiologic data.
1. We agree that under most circumstances of mild or moderate leg ischemia, there are few significant changes in conventional nerve conduction studies. The essential difference between our patients and those of the referenced studies is in the severity of the ischemia. Our patients had either rest pain or distal skin ulcers, underscoring the severity of the distal ischemia. We would also point out that even with the lesser degree of ische-mia in the patients studied by Papapetropoulou et al.,2there
were numerous electrophysiologic abnormalities when com-pared with the control patients. Our interpretation is that their data supported the presence of a neuropathy.
2. A single, quite experienced electromyographer performed all of our studies. There is no reason to suspect technical error. How-ever, we were concerned that muscle necrosis may have con-tributed to the reductions in CMAP amplitude. Our rationale for concluding that a neuropathy was the major or sole cause was discussed extensively in the article and based largely on the clinical syndrome and a large body of histopathologic data from human subjects that demonstrate neuropathic, not myo-pathic, changes in patients such as these.5-7
3. The possibility of distal conduction block was also addressed in our discussion. Rare cases of low distal CMAP amplitude from conduction block have been reported,8but usually other
demy-elinating features are present. None of the CMAP in our pa-tients showed prolonged distal latencies, temporal dispersion, or proximal conduction block.
Therefore, we feel there is strong neurophysiologic evidence that a monomelic neuropathy results from chronic and specifically criti-cal lower extremity ischemia.
David H. Weinberg, MD, Drasko Simovic, MD, Allan Ropper, MD,Boston, MA
Copyright © 2002 by AAN Enterprises, Inc.
References
1. Weinberg DH, Simovic D, Isner J, Ropper AH. Chronic ischemic monomelic neuropathy from critical limb ischemia. Neurology 2001;57: 1008 –1012.
2. Papapetropoulou V, Tsolakis J, Terzis S, Paschalis C, Papapetropoulos Th. Neurophysiologic studies in peripheral arterial disease. J Clin Neu-rophysiol 1998;15:447– 450.
3. England JD, Ferguson MA, Hiatt WR, Regensteiner JG. Progression of neuropathy in peripheral arterial disease. Muscle Nerve 1995;18:380 – 387.
4. Krarup C. Pitfalls in electrodiagnosis. J Neurol 1999;246:1115–1126. 5. Farinon AM, Marbini A, Gemignani F, et al. Skeletal muscle and
peripheral nerve changes caused by chronic arterial insufficiency: sig-nificance and clinical correlations: histological, biochemical and ultra-structural study. Clin Neuropathol 1984;3:240 –252.
6. Clyne CA, Weller RO, Bradley WG, Silber DI, O’Donnell TFJ, Callow AD. Ultrastructural and capillary adaptation of gastrocnemius muscle to occlusive peripheral vascular disease. Surgery 1982;92:434 – 440. 7. Regensteiner JG, Wolfel EE, Brass EP, et al. Chronic changes in
skele-tal muscle histology and function in peripheral arterial disease. Circu-lation 1993;87:413– 421.
8. Cros D, Triggs WJ. There are no neurophysiologic features charac-teristic of “axonal” Guillain-Barre´ syndrome. Muscle Nerve 1994; 17:675– 677.
Cognitive deficits in patients with essential tremor
To the Editor:Lombardi et al.1report on a series of 18 patients
with essential tremor (ET) preoperatively assessed for cognition and mood and contrasted their results with similar studies in 18 patients with PD.
We retrospectively studied 55 patients with ET (34 women) for cognitive and affective state. The mean age was 57 (vs 66 years in the study by Lombardi et al.1) but an equal level of education to
the Lombardi study at 14 ⫾3 years.2 Our patients had milder
tremor, rating scale score 12 ⫾4 vs 18⫾ 9. Our patients were assessed while taking no medications, whereas eight of the 18 patients in the Lombardi study were taking either propranolol or primidone; the latter is known to have potential negative cognitive effects. Results in our ET patient population were contrasted with 79 patients with cervical dystonia and tremor (CD/T). Tremor was objectively defined similarly to those with ET, utilizing an acceler-ometer, motus tremacceler-ometer, and voice oscilloscopic assessments on two or more occasions with a fixed tremor rate for durations of 2 minutes or longer in each recording. In the ET population, there was a family history of tremor (49%), dystonia (2%), and scoliosis (5.5%). The last two are less frequent than in relatives of those with CD/T or CD/no T. Depression in first-degree relatives in our ET patient pool was 31% and anxiety 7%. Using Minnesota Mul-tiphasic Personality Inventory criteria, depression occurred in 49% and anxiety in 55% of our patients with ET. Neuropsycholog-ical test performance more than 1.5 SD below age norm data was considered abnormal. Like Lombardi et al., we observed infre-quent impairment of visual construction (5%) or visual memory abilities (27%) on the Rey–Osterrieth Complex Figure Test.3Like
Troster et al.4and unlike Lombardi et al.,1we found infrequent
impairment of digital memory on Digit Span (19%). In contrast to Lombardi et al.,1performance on the Rey version of the Auditory
Verbal Learning Test3was less impressively impaired—20% on
verbal memory and 24% on verbal learning using normative data from the Aging Epidemiological Project (Mayo Clinic, Rochester, MN).5Executive dysfunction as measured by the Wisconsin Card
Sorting Test3 was observed in only 28%. The most impressive
deficits in our study were on measures not included in the battery by Lombardi et al.,1which documented impaired visual attention
(56% on the Letter Cancellation Task3and 71% on the Test of
Variables of Attention or the Conners’ Continuous Performance Test, not explained on the basis of any motor skill deficit judged to be normal on quantitative neurologic examination). At the time of this report, our battery did not include the FAS or the Boston Naming Test.
Rather than employing a cerebellar-cortical dysfunction hy-pothesis, we interpreted our findings to represent possible basal ganglion to cortical dysfunction. However, the difference in age, tremor duration and severity, and the use of medications in al-most half of their patients makes direct comparison of these two studies difficult. In partial support of the findings of Lombardi et al.,1however, our patients with ET were more apt to have
prob-lems in auditory verbal learning or memory than a comparison population of 79 patients with CD/T. Depression was even more prevalent in those with CD/T (72%). Furthermore, in our ET group, older patients were more prone to have cognitive perfor-mances below age expectancy than younger subjects. The differen-tial findings between these two studies may represent stage or evolution effects in the cognitive/affective correlates of ET. We
intend to expand our assessment protocol and to continue to mon-itor our patients over time to further assess this possibility.
Drake D. Duane, MD, Kendall J. Vermilion, BS,Scottsdale, AZ
Reply from the Authors:We thank Dr. Duane and Mr. Vermil-ion for their comments on our article.1We are encouraged by the
results reported by Vermilion et al.,2which demonstrate cognitive
and affective impairment in a large group of patients with ET. Their results demonstrate depression, executive dysfunction, and impairment in attention, verbal learning, and verbal memory. Unfortunately, their test battery did not include a test of verbal fluency, the measure on which we obtained the largest deficits in our ET group. On those cognitive processes assessed in both stud-ies, the data are impressively consistent.
Duane and Vermilion note that on several measures, including the Digit Span8test of auditory attention, tests of verbal learning
and memory, and the Wisconsin Card Sorting Test,9our group of
patients with ET displayed greater impairment than did their patient group. Although many of our patients were taking medica-tion for tremor control, this factor appeared unlikely to be a con-tributing factor in the cognitive impairment of our ET group, inasmuch as the medicated ET group outperformed the unmedi-cated group on many of the tests in our battery. A more likely explanation for the greater severity of cognitive impairment in our patients is the greater severity of ET itself in our patients, as evidenced by the higher tremor ratings in our patient group (19.1 ⫾8.2 in our study [incorrect clinical rating in Duane and Vermilion letter] vs 12⫾4 reported by Vermilion et al.2).
The minor discrepancies in the results of the two studies should not obscure the important fact that Vermilion et al.2have
provided a replication of our results demonstrating cognitive im-pairment in patients with ET. Their results should provide fur-ther impetus for the study of cognitive functioning in these patients.
W.J. Lombardi, PhD, D.J. Woolston, BA, J.W. Roberts, MD, R.E. Gross, MD, PhD,Salt Lake City, UT
Copyright © 2002 by AAN Enterprises, Inc.
References
1. Lombardi WJ, Woolston DJ, Roberts JW, Gross RE. Cognitive deficits in patients with essential tremor. Neurology 2001;57:785–790. 2. Vermilion K, Stone A, Duane D. Cognition and affect in
idiopathic-essential tremor. Mov Disord 2001;16(suppl 1):S30.
3. Lezak MD. Neuropsychological assessment. 3rd ed. New York, Oxford University Press, 1995.
4. Troster AI, Fields JA, Pahwa R, et al. Neuropsychological and quality of life outcome after thalamic stimulation for essential tremor. Neurology 1999;53:1774 –1780.
5. Ivnik RJ, Malec JF, Smith GE, et al. Mayo’s older Americans Norma-tive Studies: WAIS-R, WMS-R, and AVLT norms for ages 56 –97. Clin Neuropsychol 1992;6(suppl):1–104.
6. Greenberg LM, Kindschi CL. Test of Variables of Attention Clinical Guide. St. Paul, MN: T.O.V.A. Research Foundation, 1996.
7. Conners CK. Conners’ Continuous Performance Test Computer Pro-gram User’s Manual. Toronto: Multi-Health Systems, 1995.
8. Wechsler Adult Intelligence Scale, 3rd edition. San Antonio: The Psy-chological Corporation, 1997.
Relationship between severity of MR perfusion deficit and DWI lesion evolution
To the Editor:We were interested to read the article by Thijs et al.1examining the relationship between severity of MR perfusion
deficit and diffusion-weighted imaging (DWI) lesion evolution. We have recently published a similar analysis of sub– 6-hour ischemic stroke patients with acute perfusion-weighted imaging (PWI) DWI mismatch.2 We also found that mean transit time (MTT) and
cerebral blood volume (CBV) lesions closely predicted final infarct size. However, the strong correlation between acute cerebral blood flow (CBF) lesions and final infarct size in our 23 patients was not reproduced in the 12 patients studied by Thijs et al.1
Perhaps the differing methodology explains the lack of agree-ment. It would not be unreasonable to expect the CBF ratio to be similar to CBV ratio/MTT ratio (as MTT ⫽CBV/CBF at a pixel level). However, there are three of the 12 patients (Patients 7, 11, and 12 in the original table1) in whom the CBF ratio presented
exceeds the predicted CBF value by more than 25%. We wonder if reflecting the larger MTT lesion onto the CBF map led to inclusion of tissue with normal or increased CBF within the “lesion,” thus leading to a higher-than-anticipated CBF ratio.
Furthermore, as Thijs et al.1and others have shown, the
visu-ally apparent acute MTT lesion almost always overestimates final infarct size.1-3Therefore, patient 2 in the original table,1who has a
final infarct 65% greater than the acute MTT lesion, may have an artifactual result. This could be caused by the significant suscep-tibility artifact on the PWI maps, which the authors acknowledge. We agree that MTT maps are the most practical of the PWI maps to use in stroke and concur that thresholded MTT maps are reasonably accurate at predicting tissue at risk of infarction. How-ever, we believe that some caution should be applied when inter-preting the CBF results of the current study, particularly in view of the small number of patients presented.
Mark W. Parsons, FRACP, P. Alan Barber, PhD, FRACP, Stephen M. Davis, MD, FRACP,Melbourne, Australia
Reply from the Authors:We appreciate the comments of Par-sons et al. The focus of our study was not to predict final infarct volume using the lesion volumes identified on baseline MTT, CBF, or CBV maps, as was performed elegantly by Parsons et al.2Our
goal was to evaluate the predictive value of the relative signal intensities identified on these hemodynamic maps, rather than differentiate between the value of individual maps. Our results
show that the more hyperintense the MTT lesion, the more likely the diffusion lesion was to grow to equal the size of the baseline MTT lesion. As acknowledged in the article,1the lack of predictive
value of our CBF ratios may have been caused by the small sam-ple size, the inclusion of regions of normal or increased CBF within the “CBF lesion,” or susceptibility artifacts.
The best functional MR method to predict final infarct volume in hyperacute stroke patients is currently unknown. ADC, MTT, CBF and CBV, separately or in combination, have been proposed as having a high, although imperfect, predictive ability for detect-ing ischemic lesion growth.2, 4-6We suspect that discrepancies
be-tween the results of these studies are related to differences in MR acquisition technique, mathematical analysis, and definition of PWI/DWI mismatch, variable clinical inclusion criteria, and inher-ent biological variability. To resolve this issue, multicinher-enter studies are needed that include large numbers of patients and uniform criteria for data acquisition and analysis. Different postprocessing methods should be directly compared to identify the method with the best predictive value. Until these important studies are per-formed, the superiority of one approach over another will remain unestablished.
Vincent Thijs, MD,Leuven, Belgium;Gregory W. Albers, MD,
Palo Alto, CA
Copyright © 2002 by AAN Enterprises, Inc.
References
1. Thijs VN, Adami A, Neumann-Haefelin T, Moseley ME, Marks MP, Albers GW. Relationship between severity of MR perfusion deficit and DWI lesion evolution. Neurology 2001;57:1205–1211.
2. Parsons MW, Yang Q, Barber PA, et al. Perfusion magnetic resonance imaging maps in hyperacute stroke: relative cerebral blood flow most accurately identifies tissue destined to infarct. Stroke 2001;32:1581– 1587.
3. Barber PA, Darby DG, Desmond PM, et al. Prediction of stroke outcome with echoplanar perfusion- and diffusion-weighted MRI. Neurology 1998;51:418 – 426.
4. Oppenheim C, Grandin C, Samson Y, et al. Is there an apparent diffu-sion coefficient threshold in predicting tissue viability in hyperacute stroke? Stroke 2001;32:2486 –2491.
5. Wu O, Koroshetz WJ, Ostergaard L, et al. Predicting tissue outcome in acute human cerebral ischemia using combined diffusion- and perfusion-weighted MR imaging. Stroke 2001;32:933–942.
6. Sorensen AG, Copen WA, Ostergaard L, et al. Hyperacute stroke: si-multaneous measurement of relative cerebral blood volume, relative cerebral blood flow, and mean tissue transit time. Radiology 1999;210:519 –527.
Localization of Claude’s syndrome
To the Editor:Seo et al.1revisit Claude’s syndrome, reviewing a
small number of reported cases and adding six cases of their own. A recurring theme is the notion that the red nucleus is not a major site of neuropathology in the genesis of this relatively rare brainstem syndrome. This is based predominantly on MRI of their six cases and inclusion of eight previously reported cases.
I refer the authors and readers to our case study of a patient presenting with bilateral Claude’s syndrome.2 This patient
pre-sented with acute complete bilateral third nerve palsies, bilateral cerebellar ataxia, and absence of pyramidal tract signs. CT scan-ning was the chief diagnostic tool at the time this stroke occurred and demonstrated a hypodense midline lesion in the midbrain. On pathologic examination multiple coronal sections showed infarc-tions in the midline involving the inferior thalamus and the area of the subthalamic nucleus. The lesion, confirmed by microscopic examination, extended directly into the midbrain and involved the midportion of the raphe and extended into the red nucleus area on both sides.
Thus, our study does not support the minimization of the red nucleus as an important site of pathology in this syndrome. Addi-tionally, of the eight cases not excluded from their article review of 18, two pathologically examined cases (it is unclear whether these are the only direct tissue studies, but such seems implied) also showed red nucleus involvement.
As a neurologist whose practice predates the advent of routine MRI I wish to state the obvious. The ultimate determination in correlating sites of pathology with clinical syndromes must be
based on tissue examination and not solely on black and white two-dimensional images.
Additionally, neurotherapeutic intervention must first involve rational, justified, and above all, safe means. Without a stated cardiac rationale I question the initial use of IV heparin in five of the six patients.
Robert J. Coppola, DO, MS,Tampa, Florida
Reply from the Authors: We appreciate Dr. Coppola’s com-ments. Our findings1clearly showed that lesions of the superior
cerebellar peduncle just below and medial to the red nucleus is responsible for Claude’s syndrome. To our knowledge, no cases with isolated lesions confined to the red nucleus have been re-ported to present as Claude’s syndrome. In the case described by Coppola,2lesions were not confined to the red nucleus or midbrain
but were extended to the subthalamic nucleus, and the inferior thalamus. Cerebellar ataxia can occur because of lesions of the dentatothalamic fibers at any level from the midbrain to the thala-mus. In the midbrain at the red nucleus level, a lesion may produce both ataxia and oculomotor nerve palsy. However, the lesion should be large enough to damage both oculomotor nerve fascicles and dentatothalamic fibers that run outside the red nucleus.3
was demonstrating clinical features. In the case cited by Coppola,2
for example, clinical features of Claude’s syndrome were corre-lated with pathologic findings obtained 2 years later. It is uncer-tain whether the patient still had typical clinical features of the syndrome at the time of pathologic examination. Dynamic bio-chemical, functional, and morphologic changes occur in ischemic tissues during the acute stage of cerebral infarctions, which are the most common cause of Claude’s syndrome. Timely examined imaging studies while a patient is demonstrating typical clinical features of Claude’s syndrome may provide real-time morphologic reflections on the functional deficits. Current MRI technology is good enough to delineate the brainstem structures. The red nucleus and its relation to infarctions were nicely shown in our article.1
Regarding the issue of heparin used in our patients, no studies are available to conclude the efficacy or safety of heparinization in patients with small cerebral infarctions.4However, IV tissue
plas-minogen activator, which may carry a higher risk of hemorrhages than heparin, has been reported to be safe and effective in lacunar
infarctions. In our institute, IV heparin has long been used safely in selected patients with atherothrombotic and lacunar infarctions and in those with cardioembolic infarctions under the strict titra-tion of doses.
S.W. Seo, MD, J.H. Heo, MD, K.Y. Lee, MD, W.C. Shin, MD, D.I. Chang, MD, S.M. Kim, MD, K. Heo, MD,Seoul, Korea
Copyright © 2002 by AAN Enterprises, Inc.
References
1. Seo SW, Heo JH, Lee KY, Shin WC, Chang DI, Kim SM, Heo K. Localization of Claude’s syndrome. Neurology 2001;57:2304 –2307. 2. Coppola RJ, Freedman H. Bilateral Claude syndrome: clinical and
neu-ropathological study. Buckeye Osteopathic Physician 1991;60:4 – 6. 3. Haines DE. Neuroanatomy: an atlas of structures, sections, and
sys-tems. 4th ed. Baltimore: Urban and Schwarzenberg, 1995.
4. Fischer CM. A Career in cerebrovascular disease: a personal account. Stroke 2001;32:2719 –2724.
Correction
Fatigue is not associated with raised inflammatory markers in multiple sclerosis
In the letter to the editor from Dr. Jorge Iriarte (re: “Fatigue is not associated with raised inflammatory markers in multiple sclerosis,”Neurology2002;58:1134 –35), one of the authors was accidentally omitted. Purificacio´n de Castro, MD, should be listed as the second author. The publisher apologizes for this error.
Ictal heart rate differentiates epileptic from non-epileptic seizures
In the article “Ictal heart rate differentiates epileptic from non-epileptic seizures” by Opherk and Hirsch (Neurology2002;58: 636 – 638), there were some errors in the table. The authors apologize for these errors. The corrected table is printed below.
TableContingency table
Temporal lobe CPS
Non-epileptic staring spells
Ictal HRⱖ130% of baseline 30 1 31
Ictal HR⬍130% of baseline 6 28 34
36 29 65
