вход по аккаунту


Deep brain stimulation for Parkinson's disease Potential risk of tissue damage associated with external stimulationЧErratum.

код для вставкиСкачать
Combined Antiretroviral Therapy and the
Incidence of Acquired Immunodeficiency
Syndrome–Related Central Nervous
System Diseases
Maria Dorrucci, MD,1 Benedetta Longo, MD,1
Carla Arpino, MD,2 Stefano Boros, BS,1 and
Giovanni Rezza, MD,1 for the Italian Seroconversion Study
Controversial results of neuropathological studies assessing
the effect of antiretroviral treatment on central nervous system (CNS) diseases1,2 have emphasized the need for longitudinal studies. A recent article published by d’Arminio
Monforte and colleagues3 provides evidence of a decreased
incidence of acquired immunodeficiency syndrome (AIDS)
dementia complex (ADC) and other CNS diseases in a European cohort of human immunodeficiency virus (HIV)–infected individuals between 1994 and 2002. The decrease,
similar to that of non-CNS AIDS-defining illnesses, is almost completely explained by improved immunological conditions and inhibition of viral replication. Although the findings are convincing, this study has potential limits and
biases, specifically, missing information on CNS diseases diagnosed after first AIDS-defining illnesses, short time of observation before the introduction of combined antiretroviral
therapy, and lack of availability of HIV seroconversion dates.
To confirm the results of the above-mentioned study, we
repeated the analysis using data from the Italian Seroconversion Study, a cohort of individuals with known dates of HIV
serconversion.4,5 Kaplan–Meier curves were used to estimate
the risk of developing ADC and other CNS diseases (ie cerebral toxoplasmosis, cryptococcosis, progressive multifocal
leukoencephalopathy, primary brain lymphoma) after HIV
seroconversion (estimated as the midpoint in time between
the last negative and first positive test), before and after the
introduction of highly active antiretroviral therapy. Adjusted
relative hazards (RHs) and their 95% confidence intervals
(CIs) were obtained by multivariate Cox models, with calendar year used as dichotomous time-dependent variable, adjusting for age, sex, and transmission category.
Overall, 2,045 individuals were enrolled. The median age
was 27 years (range, 14 –75); 70% were male subjects. During a median follow-up time of 9 years, 191 participants developed an event (78 ADC, 95 other CNS diseases, and 18
both). The incidence of CNS diseases decreased from 2.3 per
100 person-years in 1996 to 0.3 in 2001– 02. The risk of
developing any CNS disease at 10 years after HIV seroconversion was 0.15 (95% CI, 0.13– 0.19) and 0.05 (95% CI,
0.04 – 0.07) before and after 1997, respectively. At the mul-
tivariate analysis (Table), the risk of developing ADC and/or
any CNS disease decreased significantly since 1997 (tripletherapy era), whereas no effect was observed in 1995–96
(double-therapy era).
In conclusion, we confirm the decline of the incidence of
ADC and other CNS diseases, also when controlling for duration of HIV infection. The decline began after the introduction of triple therapy and has continued over the following years.
The study was funded by “Programma Ricerche AIDS,
Sottoprogetto Epidemiologia,” Istituto Superiore di Sanità.
Centro Operativo AIDS, Department of Infectious Diseases,
Istituto Superiore di Sanità, and 2Department of
Neurosciences, Pediatric Neurology Unit, Tor Vergata
University, Rome, Italy
1. Neuenburg JK, Brodt HR, Herndier BG, et al. HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy. J Acquir
Immun Defic Syndr 2002;31:171–177.
2. Vago L, Bonetto S, Nebuloni M, et al. Pathological findings in
the central nervous system of AIDS patients on assumed antiretroviral therapeutic regimens: retrospective study of 1597 autopsies. AIDS 2002;16:1925–1928.
3. d’Arminio Monforte A, Cinque P, Mocroft A, et al. Changing
incidence of central nervous system diseases in the EuroSIDA
cohort. Ann Neurol 2004;55:320 –328.
4. Rezza G, Dorrucci M, Pezzotti P, et al. The seroconversion study
on the natural history of HIV infection. In: Nicolosi A, ed. HIV
epidemiology: models and methods. New York: Raven Press,
1994:279 –291.
5. Dorrucci M, Balducci M, Pezzotti P, et al. Temporal changes in
the rate of progression to death among Italians with known date
of HIV seroconversion: estimates of the population effect of
treatment. Italian HIV Seroconversion Study (ISS). J Acquir Immun Defic Syndr 1999;22:65–70.
DOI: 10.1002/ana.20171
Amanda Mocroft, PhD,1
Antonella d’Arminio Monforte, MD,2 Paola Cinque, MD,3
and Jens Lundgren, MD4
Dorrucci and colleagues have shown that the incidence of
central nervous system (CNS) diseases has decreased since
the introduction of highly active antiretroviral therapy
(HAART) among a group of Italian seroconverters, confirm-
Table. Adjusted RH of All CNS and ADC in the Italian Seroconversion Study
Calendar Period
Adjusteda RH of Any
CNS Disease
95% CI
Adjusteda RH of ADC
95% CI
Adjusted for age at HIV seroconversion, sex, and HIV-transmission group.
RH ⫽ relative hazard; CNS ⫽ central nervous system; ADC ⫽ AIDS dementia complex; CI ⫽ confidence interval.
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
ing the results of the EuroSIDA study.1 They highlight the
advantage of having information about central nervous system events after the initial AIDS diagnosis, and we agree that
this is an important consideration for observational studies.
Information about all AIDS-defining illnesses, including
those made after an initial AIDS diagnosis are routinely collected in the EuroSIDA study, and these data were included
in our analysis.1 Furthermore, they argue that having the
date of seroconversion may provide important information
not available within EuroSIDA; however, several studies have
shown that the information provided by the date of seroconversion is no longer important after adjustment for the current CD4 count,2 currently one of the strongest markers of
disease progression.
In addition to confirming our incidence findings, we wonder whether the Italian seroconverters study could also find
any evidence of the protective effect of nucleoside reverse
transcriptase inhibitors against AIDS dementia complex. Our
results suggested that these drugs might have a direct additive effect in the central nervous system. Such information, if
confirmed in other observational cohorts, would be relevant
for guiding antiretroviral treatments.
From the 1Department Primary Care and Population Sciences,
Royal Free and University College Medical School, London,
United Kingdom; 2Institute of Infectious and Tropical
Diseases, University of Milan; 3Clinic of Infectious Diseases,
San Raffaele Hospital, Milan, Italy; and 4EuroSIDA
Coordinating Centre, Copenhagen HIV Program, Hvidovre
Hospital, Hvidovre, Denmark
1. d’Arminio Monforte A, Cinque P, Mocroft A, et al. Changing
incidence of CNS HIV-related diseases in the EuroSIDA cohort.
Ann Neurol 2004;55:320 –328.
2. Phillips AN, Lee CA, Elford J, et al. Serial CD4 lymphocyte
counts and development of AIDS. Lancet 1991;337:389 –392.
DOI: 10.1002/ana.20166
Evidence for Pathogenic Heterogeneity in Multiple
Claudia F. Lucchinetti, MD,1 Wolfgang Bruck, MD,2
and Hans Lassmann, MD3
Barnett and Prineas recently described extensive oligodendrocyte apoptosis in the absence of inflammation in a pediatric
multiple sclerosis (MS) case, who died 9 months after disease
onset and 17 hours after presenting with acute pulmonary
edema.1 To what extent perimotem hypoxia may in part
have contributed to the pathological observations in this case
is uncertain. The authors confirm our published reports on
aspects of pattern III MS pathology in a subset of MS patients,2 however, indicate that the coexistence of remyelinating lesions and complement activation in other lesions from
this and six other patients suggest that all MS lesions begin
with this type of pathology.
In our experience of 201 immunopathologically classified
MS cases to date,2,3 pattern III MS demonstrates inflammatory lesions with a preferential loss of myelin associated glycoprotein (MAG), apoptotic oligodendrocytes, limited remy-
Annals of Neurology
Vol 56
No 2
August 2004
elination, and ill-defined inflammatory lesion borders. When
analyzing multiple active lesions in pattern III autopsy cases,
we have not found evidence of complement activation by
using the monoclonal antibody against C9neo antigen. Although apoptosis is occasionally found in pattern II cases,
this is not associated with MAG loss. In addition, the authors have not stained their cases for MAG. Furthermore, a
subset of pattern III cases in our series also had Balo-type
concentric lesions, with ongoing remyelination, which is
consistent with the presence of remyelination as described by
Barnett and Prineas.
Detailed clinical follow-up of our early MS cohort (n ⫽
99 patients) fails to show any correlation between time of
symptom onset, date of biopsy, and pathological pattern,
thus arguing against all MS lesions beginning with pattern
III pathology.4 In addition, we have observed a striking correlation between therapeutic response to plasma exchange in
MS patients with evidence for antibody and complement activation (pattern II pathology, n ⫽ 10) on biopsy, versus no
response in pattern I (n ⫽ 3) or pattern III (n ⫽ 6) cases.5
The sharp border at the active plaque edge with accumulating macrophages in pattern I and II MS lesions is highly
associated with the presence of ring enhancement on GdMRI, and hypointense T2 rims, whereas these imaging features are not found in pattern III lesions ( p ⬍ 0.001; 54
cases examined). Furthermore, on follow-up MRI, we have
not observed ring enhancing lesions in any pattern III case
(n ⫽ 11).6
Our pathological and clinical observations on a large series
of MS cases continue to support pathogenic heterogeneity in
immune effector mechanisms involved in MS lesion formation, which persist over a period of time, rather than a single
mechanism dominating the formation of all lesions as suggested by the authors.
Department of Neurology, Mayo Clinic, Rochester, MN;
Department of Neuropathology, University of Gottingen,
Gottingen, Germany; and 3Brain Research Institute, University
of Vienna, Austria
1. Barnett MH, Prineas JW. Relapsing and remitting multiple
sclerosis: pathology of the newly forming lesion. Ann Neurol
2004;55:458 – 468.
2. Lucchinetti CF, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707–717.
3. Lucchinetti CF. Merging of minds and matter. Multiple Sclerosis
2003;9(suppl 1):8.
4. Pittock SJ, McClelland FL, Achenbach SJ, et al. The clinical
course of biopsy-proven demyelinating disease and comparison
with a population-based multiple sclerosis prevalence cohort.
Platform presentation at the Eighth Annual ACTRIMS Meeting;
2003; San Francisco, CA.
5. Keegan M, Konig F, Bitsch A, et al. Multiple sclerosis pathological subtype predicts response to therapeutic plasma exchange.
Neurology 2004;62(suppl 5):S29.A259.
6. Lucchinetti CF, Altintas A, Wegner C, et al. Magnetic resonance
imaging correlates of multiple sclerosis pathologic subtypes. Ann
Neurol 2003;54(suppl 7):S37:67.
DOI: 10.1002/ana.20182
Pathological Heterogeneity in Multiple Sclerosis: A
Reflection of Lesion Stage?
Michael H. Barnett, MBBS and John W. Prineas, MBBS
Lucchinetti and colleagues are correct in their assertion that
our findings1 fail to support the concept of a fundamental
dichotomy in multiple sclerosis (MS) pathogenesis. The hypothesis is based on a study that found that most patients
with MS examined at autopsy fall into two quite distinct
groups: one in which remyelinated lesions are absent and
tissue breakdown is accompanied by widespread oligodendrocyte apoptosis (“type 3” lesions) and a second group in
which remyelinated shadow plaques are common and tissue
destruction is associated with the activity of macrophages
located at the edges of plaques devoid of myelin (“type 1
and 2” lesions).2 Although we describe features not previously known to accompany oligodendrocyte apoptosis in
new lesions (ie, complement activation; microglial activation; and the absence of T cells, MRP-14 –positive mononuclear cells and macrophages),1 we agree with Lucchinetti
and colleagues that most active lesions appear at autopsy
either as sharp-edged lesions or as areas of palely staining
myelin sheaths and apoptotic oligodendrocytes. In contrast,
however, we observed, in a study of comparable size, both
types of lesions in individual patients, as well as evidence of
remyelination in all but one of our seven cases with “type
3” lesions.1
Although our findings strongly suggest that apoptotic lesions are prephagocytic and probably represent an early stage
in the formation of most lesions in patients with relapsing
and remitting MS, this is not to say that apoptotic lesions
evolve directly into active sharp-edged plaques, the early history of which is unknown. New oligodendrocytes and remyelinated nerves are often observed within such plaques, suggesting that they may, in fact, be pre-existing lesions
exhibiting fresh activity.2– 4 In support of this notion, apoptotic lesions were found mainly in patients with disease duration of less than 3 months in both our own study and that
of Lucchinetti and colleagues,2 whereas sharp-edged active lesions occurred at all intervals up to 32 years.
Lucchinetti and colleagues are incorrect in asserting that
the only evidence of complement activation we provide is
“based on a figure showing the presence of the serum protein
C3d within macrophages.” In fact, we describe and illustrate
deposition of C3d (Figs 14 and 15) and C9neo (Figs 13 and
12D) on altered myelin and oligodendrocytes.1 The monoclonal C9neo antibody (clone B7) used was the same as that
used in the study by Lucchinetti and colleagues.2
Although the correlation between lesion type, magnetic
resonance imaging findings, and therapeutic response to
plasma exchange reported by Lucchinetti and colleagues is
interesting, we feel that it is premature to conclude that the
apparent pathological heterogeneity of MS lesions reflects the
existence of distinct pathogenic subtypes of the disease.
Institute of Clinical Neurosciences, Department of Medicine,
University of Sydney, Australia
1. Barnett MH, Prineas JW. Relapsing and remitting multiple
sclerosis: pathology of the newly forming lesion. Ann Neurol
2004;55:458 – 468.
2. Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707–717.
3. Prineas JW, Barnard RO, Revesz T, et al. Multiple sclerosis. Pathology of recurrent lesions. Brain 1993;116:681– 693.
4. Raine CS, Scheinberg L, Waltz JM. Multiple sclerosis. Oligodendrocyte survival and proliferation in an active established lesion.
Lab Invest 1981;45:534 –546.
DOI: 10.1002/ana.20188
Deep Brain Stimulation for Parkinson’s Disease:
Potential Risk of Tissue Damage Associated with
External Stimulation—Erratum
Wassilios Meissner, MD,1,2 Christian E. Gross, PhD,1
Daniel Harnack, MD,2 Bernard Bioulac, MD, PhD,1
and Abdelhamid Benazzouz, PhD1
We have been alerted by Medtronic Inc., Minneapolis, MN,
that their external stimulator (Model 3625 Screener) should
deliver a biphasic charge-balanced and not a monophasic
charge-imbalanced current as indicated in our recent letter.1
We have carefully verified this notification, and, indeed, the
external stimulator delivers a biphasic charge-balanced current composed of a pulse width–dependent short-lasting
cathodal pulse with a high-voltage amplitude and a longlasting low-amplitude anodal pulse that persists until the
subsequent cathodal pulse (Fig). Thus, charge-imbalance per
se does not explain the observed tissue damage associated
with the external device. However, although the implantable
stimulator delivers trains of biphasic pulses that are separated
by interpulse intervals with no current flow, such interpulse
intervals do not exist in the external device because of the
long-lasting anodal current. Charge-imbalanced anodal cur-
Fig. Schematic figure of the charge-balanced pulse delivered by
the Model 3625 Screener.
Annals of Neurology
Vol 56
No 2
August 2004
rents are known to cause tissue damage.2 Thus, the different
charge-balanced stimulating waveform with a long-lasting
anodal current delivered by the external device may further
explain the observed tissue damage. We are aware that we
were not using exactly the same equipment that is approved
for human deep brain stimulation (DBS), in particular,
platinum-iridium electrodes. Although long-lasting anodal
currents may be critical when using platinum electrodes,2 the
present data do not allow us to judge the effects of using the
Model 3625 Screener with commercially available platinumiridium electrodes for external DBS in humans. However,
the main goal of our letter was (1) to sensitize clinicians
about potential tissue damage with long-term external DBS
in times of increasing application of DBS, and (2) to alert
physicians to potential risks of mixing different pieces of
equipment that are not approved for human DBS, such as
using the Model 3625 Screener to stimulate the subthalamic
nucleus in the operating room through microelectrodes used
for extracellular electrophysiological recordings to guide the
correct placement of the DBS macroelectrode.
Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR
5543, Université Victor Ségalen, Bordeaux Cedex, France,
and 2Department of Neurology, Charité Campus Virchow,
Humboldt-University Berlin, Germany
1. Meissner W, Gross CE, Harnack D et al. Deep brain stimulation
for Parkinson’s disease: potential risk of tissue damage associated
with external stimulation. Ann Neurol 2004;55:449-450.
2. Wetzel MC, Howell LG, Bearie KJ. Experimental performance
of steel and platinum electrodes with chronic monophasic stimulation of the brain. J Neurosurg 1969;31:658-669.
First, the electrodes used for the animal experiments consist of stainless steel electrodes (SNEX 100), which are obsolete in the clinical situation. Instead, platinum-iridium
electrodes are used in DBS of humans, which have been
shown to be essentially inert and cause only little, if any,
histological lesions compared with stainless steel electrodes.2
Any discussion of this essential discrepancy between clinical
and experimental situation (SNEX vs platinum electrodes) is
missing in the publication.
Second, the authors incorrectly state that the external
stimulator generates only monophasic pulses. Using the commercially available external stimulator (Medtronic-Model
3625), we have obtained biphasic, fully charge-balanced
stimulation pulses, which complies with information supplied by the manufacturer (cf Fig; Dr Keith Mullett,
Medtronic-Europe, personal communication).
Third, reanalysis of postmortem investigations in eight patients showed that continuous test stimulation for a mean of
15 hours (3 days, 4 – 6 hours each) while using the 3625
external stimulator (and the approved platinum-iridium electrodes) before chronic stimulation with an implanted device
failed to show any histological evidence for stimulation induced neuronal tissue damage.3
In conclusion, we do not doubt the reported anecdotal
(n ⫽ 1 per group) observation.1 However, the interpretation
of a potential hazard of a commercially available and clinically widely used external stimulator is not supported by the
data presented and furthermore contrasts the experience of
many clinically involved neuroscientists.
DOI: 10.1002/ana.20191
Risk of Tissue Damage and Deep Brain
Stimulation with External Devices: A
Technical Note
Thomas Trottenberg, MD,1 Christine Winter, MD,1
Francois Alesch, MD,2 and Andreas Kupsch, MD1
The letter published by Meissner and colleagues1 addresses the
important question of a potential hazard (defined as detectable
tissue damage by histological methods) of deep brain stimulation (DBS) of the subthalamic nucleus via the commercially
available and clinically widely used external test stimulator
(Model 3625; Medtronic, Minneapolis, MN) in a nonhuman
primate model of Parkinson’s disease. In contrast with the implantable pulse generator (ITREL-II; Medtronic) for longterm stimulation, DBS for 2 hours with the external device
resulted in severe neuronal tissue damage, although duration
and voltage of the external device were lower compared with
the implantable device. The authors conclude that “short-term
stimulation with the external device must be restricted to the
operating room for successful placement of the electrodes in
the target and excludes longer postoperative stimulation, that
is, extensive testing of different parameters or continued therapeutic DBS before implantation of the chronic device.”1
This conclusion though is not corroborated by the experimental data.
Annals of Neurology
Vol 56
No 2
August 2004
Fig. The stimulating outputs of the Medtronic internal device
Model 7428 (A) and the external device Model 3625 (B), both
with a load resistance of 1 k⍀, are shown using parameter settings of approximately 1V, 450 microseconds, 130Hz. The area
under the curve is equivalent for the positive and negative
charge in both stimulators. For registration a Power 1401,
CED, Cambridge, was used sampling at 100kHz. Note the
slowly decaying anodal overshot with the 3625 (B) and hence
the different methods of balancing the charges between the two
stimulators, which could account for differential electrochemical
consequences especially in steel electrodes.4
Charité, Campus Virchow, University Medicine Berlin,
Department of Neurology, Berlin, Germany; and 2General
Hospital Vienna, Department of Neurosurgery, Vienna, Austria
This work was supported by a grant from Medtronic (89741038,
1. Meissner W, Gross CE, Harnack D, et al. Deep brain stimulation for Parkinson’s disease: potential risk of tissue damage associated with external stimulation. Ann Neurol 2004;55:449 – 450.
2. Wetzel MC, Howell LG, Bearie KJ. Experimental performance
of steel and platinum electrodes with chronic monophasic stimulation of the brain. J Neurosurg 1969;31:658 – 669.
3. Haberler C, Alesch F, Mazal PR, et al. No tissue damage by
chronic deep brain stimulation in Parkinson’s disease. Ann Neurol 2000;48:372–376.
4. Weinman J. Biphasic stimulation and electrical properties of
metal electrodes. J Appl Physiol 1965;20:787–790.
Takuya Hayashi, Takashi Ohnishi, Shingo Okabe,
Noboru Teramoto, Yukio Nonaka, Hiroshi Watabe,
Etsuko Imabayashi, Yoichiro Ohta, Hiroshi Jino,
Norimasa Ejima, Tohru Sawada, Hidehiro Iida,
Hiroshi Matsuda, Yoshikazu Ugawa. Long-term
Effect of Motor Cortical Repetitive Transcranial
Magnetic Stimulation Induces. Ann Neurol 2004;
56:77– 85.
Due to an editing error, the title of the published
article above was reproduced incorrectly. The correct
title is “Long-Term Effect of Motor Cortical Repetitive
Transcranial Magnetic Stimulation.”
The publishers regret this error.
DOI: 10.1002/ana.20245
DOI: 10.1002/ana.20181
Daniel G. Healy, Patrick M. Abou-Sleiman, Tetsutaro Ozawa, Andrew J. Lees, Kailash Bhatia,
Kourosh R. Ahmai, Ullrich Wullner, Jose Berciano,
J. Carsten Moller, Christoph Kamm, Katrin Burk,
Paolo Barrone, Eduardo Tolosa, Niall Quinn,
David B. Goldstein, and Nicholas W. Wood. A
Functional Polymorphism Regulating Dopamine
␤-Hydroxylase Influences against Parkinson’s Disease. Ann Neurol 2004;55:443– 446 (March 2004).
Due to an author oversight, Paolo Barrone’s name
was incorrectly reproduced in the published article.
The correct spelling is Paolo Barone.
The authors reget this oversight.
DOI: 10.1002/ana.20235
Annals of Neurology
Vol 56
No 2
August 2004
Без категории
Размер файла
91 Кб
potential, associates, deep, damage, disease, parkinson, brain, external, tissue, risk, stimulating, stimulationчerratum
Пожаловаться на содержимое документа