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Cerebrospinal fluid interleukin-6 levels in hypertensive encephalopathy A possible marker of disease activity.

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LETTERS
Treatment of Intracranial Aneurysms: Surgical
Clipping or Endovascular Coiling?
Rafael J. Tamargo, MD,1 Daniele Rigamonti, MD,1
Kieran Murphy, MD,2 Philippe Gailloud, MD,2
James E. Conway, BS,1 and
Richard E. Clatterbuck, MD, PhD1
We read with interest the article by Johnston and colleagues1
and would like to comment on two concerns that we have
about this study. The first is that the design of the study
introduces a selection bias that renders the authors’ conclusions invalid as they may apply to the general population of
patients with aneurysms. The second is that the study fails to
address the most important current concern regarding endovascular coiling of aneurysms, namely, its long-term efficacy
in obliterating these lesions and preventing their rupture.
The failings of this study are underlined by the conclusions
of 2 other recent studies, one a prospective observational
study from Belgium2 and the other a prospective randomized
study from Finland,3 which reach conclusions either diametrically opposed or at odds, respectively, to those of Johnston
and colleagues.
Although the authors describe their study as “a blinded
prospective review,” the fact remains that their study is a
retrospective review of highly selected data. The selection
bias arises from the fact that only 30% of the patients treated
at their institution since 1990 were selected for the study.
No information is provided as to how the study sample differed from the excluded population sample. Not surprisingly,
several epidemiological characteristics of the study sample are
markedly different from those of the major hospital-based
series reported in the literature. Two examples of such epidemiological deviations are the proportion of anterior communicating artery and anterior cerebral artery aneurysms
(39% in prior studies4 but only 10% in Johnston et al) and
the proportion of female patients (61% in prior studies4 but
82% to 85% in Johnston et al). These and other atypical
features of the study group raise concerns as to whether the
authors’ sample is truly representative of the population from
which it is derived.
One of the major emerging concerns regarding endovascular coiling of aneurysms is the increasing proportion of residual or recurrent aneurysms being identified in longitudinal
follow-up. Kuether and colleagues5 have reported a residual
or recurrence rate after endovascular coiling of 58.6% after
an average follow-up of only 1.4 years. In the Johnston et al
study, there is no mention of the efficacy of endovascular
coiling in terms of residual aneurysm at the time of therapy
or of recurrence at angiographic follow-up. It is of particular
concern that three patients in the endovascular group went
on to suffer aneurysmal hemorrhages. This is a critical issue
since, after all, the safety of an alternative treatment is important only if it is proven to be efficacious.
Interestingly, two recently published prospective studies
have addressed the same issue and reached either diametrically opposed or contrary conclusions. Raftopoulos and colleagues2 from Belgium reported a prospective observational
series of 127 aneurysms (unruptured and ruptured) treated
endovascularly or surgically between 1996 and 1999. Although the authors considered endovascular coiling as the
first option in all cases, only 64 of 127 aneurysms could be
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© 2001 Wiley-Liss, Inc.
treated with coils. They found that the proportion of poor
outcomes (Glasgow Outcome scores 1–3) in the endovascular group was about twice that of the surgical group (13.3%
vs 6.1%, respectively). Furthermore, the proportion of residual aneurysms after treatment was 31.2% in the endovascular
group but only 1.6% in the surgical group.
In another study, Koivisto and colleagues3 from Finland
reported a prospective randomized series of 109 consecutive
patients with ruptured aneurysms treated endovascularly or
surgically between 1995 and 1997. They found that the proportion of poor outcomes (Glasgow Outcome scores 1–3) in
the endovascular group was similar to that in the surgical
group (21% vs 25%, respectively) but that the proportion of
residual aneurysms after treatment was 23% in the endovascular group but only 14% in the surgical group.
We believe that the discrepancy between the Johnston et
al study, on the one hand, and the studies of Raftopoulos et
al2 and Kovistos et al,3 on the other, arises at least in part
from an inherent methodological flaw in the former, attributable to its retrospective nature and selection bias.
It is clear that endovascular coiling is one of the most
important developments in the treatment of intracranial aneurysms within the last decade. Although surgical therapy of
aneurysms over the past 32 years has reduced the mortality
associated with aneurysmal subarachnoid hemorrhage from
35% to 17.8%,6 it is also apparent that not all aneurysms
can be optimally treated with surgery. Aneurysms are complex lesions that are best approached by complementary, not
competing, therapies. We believe that the current challenge
is not to prove whether endovascular coiling or surgical clipping is “better” but, instead, to identify which types of aneurysm are best approached surgically, endovascularly, or by
a combination of the two techniques.
1
Division of Cerebrovascular Neurosurgery, Department of
Neurosurgery, Johns Hopkins Hospital; and 2Division of
Neurointerventional Radiology, Department of Neuroradiology,
Johns Hopkins Hospital, Baltimore, MD
References
1. Johnston SC, Wilson CB, Halbach VV, et al. Endovascular and
surgical treatment of unruptured cerebral aneurysms: comparison
of risks. Ann Neurol 2000;48:11–19.
2. Raftopoulos C, Mathurin P, Boscherini D, et al. Prospective
analysis of aneurysm treatment in a series of 103 consecutive
patients when endovascular embolization is considered the first
option. J Neurosurg 2000;93:175–182.
3. Koivisto T, Vanninen R, Hurskainen H, et al. Outcomes of early
endovascular versus surgical treatment of ruptured cerebral aneurysms. A prospective randomized study. Stroke 2000;31:2369 –
2377.
4. Kassell NF, Torner JC, Clark Haley J, et al. The International
Cooperative Study on the Timing of Aneurysm Surgery. Part I:
Overall management results. J Neurosurg 1990;73:18 –36.
5. Kuether TA, Nesbit GM, Barnwell SL. Clinical and angiographic outcomes, with treatment data, for patients with cerebral
aneurysms treated with Guglielmi detachable coils: a single center experience. Neurosurgery 1998;43:1016 –1025.
6. Tamargo RJ, Walter KA, Oshiro EM. Aneurysmal subarachnoid
hemorrhage: prognostic features and outcomes. New Horiz
1997;5:364 –375.
Reply
S. Claiborne Johnston, MD, MPH, and
Daryl R. Gress, MD
We thank Tamargo and colleagues for their comments and
appreciate the opportunity to clarify the methods and limitations of our study.1 They have raised concerns about selection bias and the efficacy of coil embolization.
In terms of selection bias, case selection for inclusion is
part of any study, retrospective or prospective, and has potential implications for validity and generalizability. Selection
bias is a threat to validity and occurs when the method of
selection produces an imbalance in the pretreatment risks.
Avoiding selection bias was precisely the reason we developed
the unusual study design we termed “blinded prospective review.” With this design, the final decision to include a case is
made prospectively without knowledge of the actual treatment or its outcome. This prevents selection of cases in order
to improve apparent outcomes of one group or the other; it
takes advantage of a prospective review of cases to assure that
all patients could have received either therapy and that overall pretreatment risks were similar in both groups. The design measures and avoids selection biases that would have
occurred if all treated cases were included without a prospective review. This form of case selection is designed to enhance validity.
Case selection also affects generalizability. Are the findings
pertinent to the total population of unruptured aneurysms
treated at the University of California, San Francisco, and
more importantly, can they be extended to other centers?
Tamargo and colleagues point out that the study population
is different in several respects from prior case series. They
compare the demographic characteristics to a series of ruptured aneurysm patients,2 who are not entirely representative
of a cohort of unruptured aneurysm patients. A recent large
series of unruptured aneurysms found characteristics more
similar to those in our cohort, with 76% of patients being
female and 14.6% of aneurysms arising from the anterior
communicating or anterior cerebral artery,3 values that are
not significantly different from those in our cohort ( p ⬎
0.05).
Our rigid inclusion criteria accounted for the final cohort
of 130 from 435 cases reviewed. Reasons for initial exclusion
were established a priori and included age ⬍18 years at
follow-up (n ⫽ 6), coexistent arteriovenous malformation or
fistula (n ⫽ 72), no coiling or clipping attempted (n ⫽ 121),
second aneurysm treated within 2 months (n ⫽ 18), and
subarachnoid hemorrhage within 6 months (n ⫽ 2). These
exclusion criteria were established primarily to produce a cohort of cases in whom functional impairment could be attributed to treatment of an unruptured aneurysm. Additional
exclusions in blinded prospective review should produce a
group of patients who could have received either therapy, as
do standard exclusion criteria in a randomized trial. This is
the true population in practice in which treatment decisions
should be made. Selection bias may affect results in any
study that does not establish that included patients could
have received either therapy and that pretreatment prognosis
is comparable, regardless of who is determining how cases are
treated.
We studied treatment of patients with unruptured aneurysms because they are generally nondisabled prior to treatment and therapeutic complications should be apparent. In
patients with ruptured aneurysms, prognosis is largely based
on initial neurological function4 and the impact of therapy is
likely to be more obscure. Therefore, small studies, including
the recent randomized trial,5 are unlikely to have adequate
power to show an effect. This should not be interpreted as
evidence of lack of an effect. The International Subarachnoid
Aneurysm Trial will enroll 2,000 to 3,000 patients in order
to achieve adequate power to compare outcomes in ruptured
aneurysms.6 A study of unruptured aneurysms need not enroll this large of a number.7
In terms of treatment efficacy, we appreciate the opportunity to reinforce that our study did not address this very
important issue, on which current data are sparse. We do not
believe that complete occlusion of aneurysms should be considered an outcome. Since even an apparently completely occluded aneurysm, either coiled or clipped, can rupture, it is
crucial to establish efficacy by measuring rupture rates after
treatment. Rupture rates of untreated, unruptured aneurysms
are generally low,3 so efficacy can be established efficiently
only in a study of treated aneurysms that have previously
ruptured.
We completely agree that outcomes may be better if both
treatment options are considered for individual patients and
have shown that institutions that offer both surgery and coil
embolization have lower rates of adverse events.8 Although a
large study of unruptured aneurysms9 and a report from a
carefully selected cohort that could have received either therapy10 have supported the idea that coil embolization is safer,
further confirmation of safety and efficacy is required to
make evidence-based treatment decisions.
Neurovascular Service, Neurocritical Care and Stroke,
University of California, San Francisco, CA
References
1. Johnston SC, Wilson CB, Halbach VV, et al. Endovascular and
surgical treatment of unruptured cerebral aneurysms: comparison of risks. Ann Neurol 2000;48:11–19.
2. Kassell NF, Torner JC, Haley EC, et al. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1:
Overall management results. J Neurosurg 1990;73:18 –36.
3. The International Study of Unruptured Intracranial Aneurysms
Investigators. Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention. N Engl J Med 1998;339:
1725–1733.
4. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg
1968;28:14 –20.
5. Koivisto T, Vanninen R, Hurskainen H, et al. Outcomes of
early endovascular versus surgical treatment of ruptured cerebral
aneurysms: a prospective randomized study. Stroke 2000;31:
2369 –2377.
6. Molyneux A, Kerr R, Bacon F, Shrimpton J. Health technology
assessment in the management of ruptured intracranial aneurysms. Annu Meet Int Soc Technol Assess Health Care 1999;
15:50.
7. Molyneux A, Kerr R, Bacon F, Shrimpton J. The need for
health technology assessment in the management of unruptured
intracranial aneurysms. Annu Meet Int Soc Technol Assess
Health Care 1999;15:129.
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683
8. Johnston SC. Effect of endovascular services and hospital volume on cerebral aneurysm treatment outcomes. Stroke 2000;
31:111–117.
9. Johnston SC, Dudley RA, Gress DR, et al. Surgical and endovascular treatment of unruptured cerebral aneurysms at university hospitals. Neurology 1999;52:1799 –1805.
10. Gruber DP, Zimmerman GA, Tomsick TA, et al. A comparison between endovascular and surgical management of basilar artery apex aneurysms. J Neurosurg 1999;90:868 – 874.
An Honorable Compromise Regarding Amyloid in
Alzheimer Disease
Robert D. Terry, MD
Amyloid, for almost a century and a half, has been defined as
an extracellular, fibrillar protein; to that definition has been
added only the staining reaction—congophilia.1 On the basis
of that reasonably strict definition ( this is not Alice in Wonderland) and the statistical weakness of correlation between
the number or even total area of neocortical plaques and various measures of cognitive function,2 many investigators have
for a number of years resisted the widely held opinion that
amyloid—qua amyloid—is the cause of Alzheimer dementia.
We are currently told, however, that it is the oligomeric form
of 1– 42 ABeta peptide that is mostly responsible for the
damage, rather than the fibrillar form.3 As a morphologist, I
have frequently been reluctant to accept anything that is not
visible in my microscope, but one must admit that the
weight of chemical and biological evidence in favor of ABeta
oligomer toxicity is very nearly convincing, if not absolute.
Presumably, the oligomer is soluble and is partially intracellular. There, in excess, it might well interfere with any
number of cell functions, including axoplasmic flow, leading
to loss of axonal terminals prior to the death of the neuronal
perikaryon.4 Lying invisible in the extracellular space, it
might also have significant toxic effects on local structures,
such as the synapse. Some of these effects have been demonstrated in vitro, and many are apparent in transgenic animals,5 but all are very difficult to prove in the human. One
can assume that amyloid immunization6 is removing the oligomer in regard to clinical effect, as well as the fibrillar
plaque amyloid for histologic effect.
But the mechanism of the disease remains obscure. Foremost is still the question of the connection between plaque
and tangle. There are many disorders, such as dementia pugilistica, with prominent tangles but no amyloid-laden
plaques. So tangles clearly do not cause plaques. On the
other hand, the two classical lesions usually do coexist in
Alzheimer disease. Alzheimer’s second case as recently republished7 and our collection of eighteen others8 remain as exceptions, because they did not have neocortical tangles nor
did they have Lewy bodies, but otherwise presented in all
respects as typical advanced Alzheimer disease. Quite possibly, though this is still undemonstrated, those cases had considerable intraneuronal phosphorylated tau protein which for
unknown reasons had not polymerized into paired helical filaments. Nevertheless, these cases show that plaques do not
necessarily cause tangles.
It is curious that those Alzheimer cases without neocortical tangles occur exclusively in patients older than 70 years.
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Annals of Neurology
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Do these elderly people lose the ability to phosphorylate tau
protein, or have they lost the ability to polymerize the phosphorylated protein into paired helical filaments? These questions might be readily answered with current immunohistochemical techniques and available antibodies.
Could it be that Beta peptide stimulates the neuronal production of tau protein, an excess of which inhibits kinesin,
thus reducing anterograde axoplasmic flow9 causing synapses
to die off in the neuropil apart from plaques? In the plaque
the swollen, dystrophic axon terminals filled with degenerating mitochondria and lysosomes10 might well be the result of
a local inhibition of retrograde flow. Is the retrograde motor
protein dynein inhibited by Beta peptide oligomer or by
plaque amyloid?
It is really time to recognize that neither the senile plaque
nor fibrillar amyloid is the major operative lesion in Alzheimer disease. It would be reassuring if investigators in the
field stopped referring to Beta amyloid as the causal agent ,
and instead spoke more accurately of ABeta peptide or oligomer as the probable major player. Amyloid, after all, is not
the same as the peptide of which it is made, anymore than
steam is the same as water, or animal glue is the same as
hooves.
References
1. Bennhold H. Eine spesifische Amyloid-farbung mit Kongrot.
Munchen Med Wochenschr 1922;69:1537–1538.
2. Terry RD, Masliah E, Salmon DP LA, et al. Physical basis of
cognitive alterations in Alzheimer disease: synapse loss is the
major correlate of cognitive impairment. Ann Neurol 1991;30:
572–580.
3. Selkoe DJ. Biology of beta amyloid precursor protein and the
mechanism of Alzheimer disease. In: Terry RD, Katzman R,
Bick KL, Sisodia SS, eds. Alzheimer disease. Philadelphia: Lippincott Williams and Wilkins, 1999:293–310.
4. Terry RD, Masliah E, Hansen LA. The neuropathology of Alzheimer disease and the structural basis of its cognitive alterations. In: Terry RD, Katzman R, Bick KL, Sisodia SS, eds.
Alzheimer disease. Philadelphia: Lippincott Williams and
Wilkins, 1999:187–206.
5. Masliah E. Transgenic animal models of Alzheimer disease. In:
Terry RD, Katzman R, Bick KL, Sisodia SS, eds. Alzheimer
disease. Philadelphia: Lippincott Williams and Wilkins, 1999:
245–261
6. Schenk D, Barbour R, Dunn W, et al. Immunization with
amyloid beta attenuates Alzheimer disease-like pathology in the
PDAPP mouse. Nature 1999;400:173–177.
7. Graeber MB, Kosel S, Egensperger RP, et al. Rediscovery of the
case described by Alois Alzheimer in 1911: historical, histologic
and molecular genetic analysis. Neurogenetics 1997;1:73– 80.
8. Terry RD, Hansen LA, DeTeresa R, et al. Senile dementia of
the Alzheimer type without neocortical tangles. J Neuropathol
Exp Neurol 1987;46:262–268.
9. Stamer K, Trinczek B, Mandelkow EM. Over expression of tau
protein inhibits the outward flow of vesicles and organelles
along microtubules. Neurobiol Aging 2000;21:S15.
10. Suzuki K, Terry RD. Fine structural localization of acid phosphatase in senile plaques in Alzheimer’s presenile dementia.
Acta Neuropathol 1967;8:276 –284.
Department of Neurosciences, University of California at San
Diego, La Jolla, CA
Cerebrospinal Fluid Interleukin-6 Levels in
Hypertensive Encephalopathy: A Possible Marker
of Disease Activity
Tomoyuki Takano, MD, Akiko Koyanagi, MD,
Yu Osawa, MD, Takashi Taga, MD, and
Hidetoshi Fujino, MD
In hypertensive encephalopathy, the exact cellular mechanisms leading to loss of endothelial function are poorly understood.1 Proinflammatory responses, such as secretion of
cytokines and monocyte chemotactic protein, are putative
mechanisms that promote local inflammation and resultant
endothelial dysfunction.2 To investigate the role of cytokines
in hypertensive encephalopathy, cerebrospinal fluid (CSF),
interleukin-1␤ (IL-1␤), IL-6, and tumor necrosis factor-␣
(TNF-␣) levels were analyzed in 2 pediatric patients with
hypertensive encephalopathy.
Patient 1 was an 8-year-old girl with acute lymphocytic
leukemia. Seventeen days after induction therapy, she complained of abdominal pain and visual disturbance. Later in
the afternoon, she became disoriented and somnolent and
progressed to a generalized tonic seizure. Blood pressure was
170/110 mm Hg. T2-weighted brain magnetic resonance
imaging (MRI) demonstrated multiple subcortical highsignal lesions in the parietal and occipital lobes. By treatment
with oral nifedipine, her blood pressure was maintained at
around 130/70 mm Hg and neurological symptoms were
completely recovered until 2 days after onset. On the fourth
day after onset, the CSF immunoglobulin G (IgG) index was
0.76. Cytokine analysis showed detection limits of IL-1␤
(⬍10 pg/ml) and TNF-␣ (⬍5 pg/ml), but IL-6 was elevated
to 328 pg/ml (normal ⬍4 pg/ml). On day 35 after onset, the
IgG index was unremarkable (0.73) but the level of IL-6 was
decreased to below 1.0 pg/ml (Table).
Patient 2 was a 10-year-old girl with juvenile rheumatoid
arthritis. Prompt remission was obtained by oral prednisone,
but she experienced sudden onset of generalized tonic-clonic
seizure and was admitted to our hospital. Blood pressure was
Table. Results of Immunoglobulin G (IgG) Index and
Cytokine Analysis in Cerebrospinal Fluid
Patient 1
Days after Onset
Serum
Albumin (g/dl)
IgG (mg/dl)
Cerebrospinal fluid
Albumin (mg/dl)
IgG (mg/dl)
IgG index
Cerebrospinal fluid
Interleukin-1␤
(pg/ml)
Interleukin-6
(pg/ml)
Tumor necrosis
factor-␣
(pg/ml)
Patient 2
4th
Day
35th
Day
3rd
Day
19th
Day
4.1
910
4.3
562
3.6
535
4.1
635
27.7
4.7
0.76
⬍ 10
328
⬍5
17.7
1.7
0.73
⬍ 10
⬍1.0
⬍5
11.1
4.1
2.48
⬍ 10
109
⬍5
12.6
1.7
0.87
⬍ 10
2.9
⬍5
185/125 mm Hg, and T2-weighted and fluid attenuation inversion recovery (FLAIR) brain MRIs showed multiple foci
of increased signal intensity in the parietal and occipital
lobes. On the third hospital day, blood pressure was maintained at around 140/90 mm Hg and physical and neurological findings were unremarkable. CSF IgG index was
2.48, suggesting local IgG overproduction in the central nervous system (CNS). Cytokine analysis showed detection limits of IL-1␤ and TNF-␣ but IL-6 was elevated to 109 pg/ml.
The second CSF analysis on day 19 after onset was unremarkable, with a normal IgG index, detection limits of
IL-1␤ and TNF-␣, and a reduction in IL-6 activity (2.9 pg/
ml) (see Table).
The CSF IL-6 activity in the present cases was increased
when hypertensive encephalopathy showed active CNS disease and decreased when patients recovered from CNS manifestations. We suggest that CSF IL-6 activity is closely related to CNS disease activity in hypertensive encephalopathy.
Department of Pediatrics, Shiga University Medical Science,
Shiga, Japan
References
1. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet
2000;356:411– 417.
2. Okada M, Matsumori A, Ono K, et al. Cyclic stretch upregulates
production of interleukin-8 and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in human endothelial cells. Arterioscler Thromb Vasc Biol 1997;18:894 –901.
Hypoglycorrhachia: A Simple Clue, Simply Missed
Michèl A.A.P. Willemsen, MD,1 Aad Verrips, MD,1
Marcel M. Verbeek, PhD,2 Thomas Voit, MD,3 and
Jörg Klepper, MD3
The central nervous system (CNS) depends on glucose as the
fuel for its energy requirements. Persistent hypoglycorrhachia, ie, low glucose concentrations in cerebrospinal fluid
(CSF), in normoglycemic patients is expected to lead to neurological abnormalities.
At the blood–brain barrier, transport of glucose is facilitated by the type 1 glucose transporter (GLUT1), which is
also present in the erythrocyte membrane. In 1991, 2 patients
with developmental delay, seizures, and persistent hypoglycorrhachia were shown to suffer from GLUT1 deficiency.1
The molecular basis for the disorder was unraveled in 1998.2
So far, approximately 20 cases have been reported in the literature.
We postulated that GLUT1 deficiency might be more
common than is currently recognized because unexplained
hypoglycorrhachia might be overlooked. Therefore, we performed a retrospective study for the years 1994 to 1999, using our computerized laboratory database. Patients included
satisfied the following criteria: (1) age 0 to 16 years, (2) CSF
glucose concentrations ⬍2.0 mmol/l or ratio of CSF glucose
to blood glucose ⬍0.5, and (3) CSF leukocytes ⬍10/␮l. The
medical files of all selected patients (n ⫽ 65) were studied.
We rejected patients with reasonable explanations for the hypoglycorrhachia, such as hypoglycemia (8%), ventriculoperitoneal shunt dysfunction (20%), (posthemorrhagic) hydrocephalus without shunt (40%), CNS infection (14%), and
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Table. Laboratory Findings in 3 Patients with Type 1 Glucose Transporter Deficiency, with Reference to the Literature
Patient Sex, Age
(years)
Age at Lumbar Puncture
(years)
CSF Glucose
(mmol/l)
CSF/Blood Glucose
Uptake
(%)1
F, 8
F, 10
F, 14
Other patients2
Control values2
6
5
8
1.8
1.9
1.8
1.7 (⫾0.02)
3.5 (⫾0.05)
0.39
0.29
0.41
0.32 (⫾0.04)
0.65 (⫾0.01)
49
42
26
44 (⫾8)
100 (⫾22)
1
Erythrocyte uptake of 3-O-methyl-D-glucose.
2
See references 4 and 5.
CSF, cerebrospinal fluid.
malignancy with CNS involvement (9%). Six patients (9%)
remained and were studied for GLUT1 function by analyzing the erythrocyte uptake of 3-O-methyl-D-glucose using
the methods reported previously.3 Three patients (from 3
different families) were diagnosed as GLUT1-deficient (Table). They all suffered from developmental delay, behavioral
disturbance, and intractable epilepsy. Neurological examination revealed ataxia and pyramidal signs. This neurological
picture had led to extensive diagnostic procedures in the
past, including a lumbar puncture showing hypoglycorrhachia that did not alert the clinician at that time.
In conclusion, our findings show that in day-to-day practice, a low glucose level in CSF might not be given the
weight it deserves or might simply be overlooked rather than
recognized as the laboratory sign that points to GLUT1 deficiency. Diagnosing GLUT1 deficiency protects the patient
against ongoing diagnostic procedures and opens the way to
a rational treatment strategy. Moreover, early diagnosis
should be sought in view of the benefit of the ketogenic dietary treatment for this disorder. Finally, our findings suggest
that the true prevalence of GLUT1 deficiency might be
much higher than expected.
1
Department of Pediatric Neurology, University Medical
Center St Radboud, Nijmegen, The Netherlands; 2Department
of Neurology, University Medical Center St Radboud,
Nijmegen, The Netherlands; and 3Departments of Pediatrics
and Pediatric Neurology, Children’s Hospital, University of
Essen, Essen, Germany
References
1. De Vivo DC, Trifiletti RR, Jacobson RI, et al. Defective glucose
transport across the blood-brain barrier as a cause of persistent
hypoglycorrhachia, seizures, and developmental delay. N Engl
J Med 1991;325:703–709.
2. Seidner G, Garcia-Alvarez M, Yeh J-I, et al. GLUT-1 deficiency
syndrome caused by haploinsufficiency of the blood–brain barrier hexose carrier. Nat Genet 1998;18:188 –191.
3. Klepper J, Garcia-Alvarez M, O’Driscoll KR, et al. Erythrocyte
3-O-methyl-D-glucose uptake assay for diagnosis of glucosetransporter-protein syndrome. J Clin Lab Anal 1999;13:116 –121.
4. De Vivo DC, Garcia-Alvarez M, Ronen GM, Trifiletti RR. Glucose transport protein deficiency: an emerging syndrome with
therapeutic implications. Int Pediatr 1995;10:51–56.
5. De Vivo DC, Burke C, Trifiletti R, et al. Glucose transporter
protein deficiency: an emerging syndrome with therapeutic implications. Ann Neurol 1994;36:491.
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Are Transfectant Cells Essential for Measuring
Cytotoxic T Cells in Paraneoplastic Cerebellar
Degeneration?
Masami Tanaka, MD,1 and Keiko Tanaka, MD2
The recent letter from Drs. Darnell and Albert stressed that
our experimental method has serious technical flaws.1 Because they did not cite the relevant papers, their letter has
caused misunderstanding that dendritic cells (DCs) were
used as the target and that recombinant cdr2 (Yo) fusion
protein was the target antigen in all of our studies of cytotoxic T cells (CTLs) in paraneoplastic cerebellar degeneration
(PCD). We have been studying CTLs by various methods.
They stated that we used CTLs induced from monocytes
stimulated with recombinant cdr2 protein,1 an impossibility.
CTLs were induced from mononuclear cells taken from patients’ peripheral venous blood, not from monocytes.2,3 We
previously reported two experiments on mononuclear cells of
different patients with PCD with anti-Yo antibodies, in
which DCs were the target of CTLs. In the first, five days
after stimulation with recombinant Yo protein we found no
CTL activity when DCs were the target.2 In the second, we
examined the CTL activity of a CD4-positive T-cell line two
months after stimulation with recombinant Yo protein.3 The
CD4-positive T-cell line was used as an effector in the CTL
assay only in that paper.3 We could not exclude possible involvement of CD4-positive CTLs in the neuronal loss of
PCD with anti-Yo antibodies, but HLA class I-restricted
CD4-positive CTLs were uncommon, as reported.3 DCs
pulsed with soluble proteins provide peptide epitopes derived
from exogenous antigens on HLA class I molecules and induce an antigen-specific CTL response.4 The most serious
drawback when DCs are used as antigen-presenting cells
(APCs) or target cells is that several kinds of peptide can
bind even to an HLA class I molecule such as A 24. Moreover, DCs produce weak induction of CTLs when used as
APCs and low CTL activity sensitivity when used as the target. Therefore, we examined HLA class I-restricted CD8positive CTL activity using autologous fibroblasts as the targets several days after peptide stimulation.
All nine of the Japanese patients examined had HLA A24.5
The peptide-binding groove of HLA class I molecules fits the
peptides of nine amino acids. Allele specificity has been shown
in the interaction between peptide and HLA molecules.6 We
showed the presence of HLA class I-restricted CTL activity in
fibroblasts using a peptide of the Yo protein with the HLA
A24-specific allele defined by the HLA-based approach called
reverse immunogenetics.7 Albert et al.8 showed CTL activity
in all of five patients with HLA A2.11; however, they did not
report HLA analysis of other American patients, so it is not
known whether HLA A2.1 is common among American patients. They examined CTL activity using transfectant cells
with the introduced HLA A*0201 gene.8 We also have reported CTL activity in Japanese patients with HLA A24,
based on findings for a stable transfectant cell line that expresses HLA A*2402 on the cell surface.9 Are transfectant cells
essential to the measurement of CTL activity? If transfectant
cells are considered as targets, the involvement of HLA molecules may differ among ethnic groups. Different types of transfectant cell therefore may have to be obtained, depending on
the ethnic group.
There is another possible role for activated Th1 cells in
the cerebrospinal fluid of patients with PCD and anti-Yo
antibodies. Interferon-␥ from activated Th1 cells is the most
potent inducer of the HLA class I molecules required for
recognition of target cells by CTLs because HLA class I and
II molecules are not expressed on the surfaces of cells in the
central nervous system. The roles of activated Th1 cells,
therefore, are (1) CTL induction, (2) antibody production,
and (3) HLA class I molecule induction.
1
Department of Neurology, National West Niigata Central
Hospital, Niigata, Japan; 2Department of Neurology, Brain
Research Institute, Niigata University, Niigata, Japan
References
1. Darnell RB, Albert ML. cdr2-specific CTLs are detected in the
blood of all patients with paraneoplastic cerebellar degeneration
analyzed. Ann Neurol 2000;48:270.
2. Tanaka M, Tanaka K, Idezuka J, Tsuji S. Failure to detect cytotoxic T cell activity against recombinant Yo protein using autologous dendritic cells as the target in a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody. Exp Neurol
1998;150:337–338.
3. Tanaka M, Tanaka K, Shinozawa K, et al. Cytotoxic T cells react
with recombinant Yo protein from a patient with paraneoplastic
cerebellar degeneration and anti-Yo antibody. J Neurol Sci 1998;
161:88 –90.
4. Brossart P, Bevan MJ. Presentation of exogenous protein antigens on major histocompatibility complex class I molecules by
dendritic cells: pathway of presentation and regulation by cytokines. Blood 1997;90:1594 –1599.
5. Tanaka M, Tanaka K. HLA A24 in paraneoplastic cerebellar degeneration with anti-Yo antibody. Neurology 1996;47:606 – 607.
6. Sette A, Sidney J. Nine major HLA class I supertypes account for
the vast preponderance of HLA-A and -B polymorphism. Immunogenetics 1999;50:201–212.
7. Davenport MP, Hill AVS. Reverse immunogenetics: from HLAdisease associations to vaccine candidates. Mol Med Today 1996;
2:38 – 45.
8. Albert M, Darnell JC, Bender A, et al. Tumor-specific killer cells
in paraneoplastic cerebellar degeneration. Nat Med 1998;11:
1321–1324.
9. Tanaka M, Tanaka K, Kira J, et al. Cytotoxic T cell activity
against the peptide “AYRARALEL” from the Yo protein in patients with either HLA A24 or A2 and paraneoplastic cerebellar
degeneration. Neurology 2000;54(Suppl 3):A38.
Annals of Neurology
Vol 49
No 5
May 2001
687
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