We read with interest the work by Kim et al that shows relationship
between radiological characteristics and molecular signatures in a group
of 49 patients with anaplastic oligodendroglioma (AO) and 7 patients with
anaplastic oligoastrocytoma (AOAs). Frontal lobe location, indistinct
tumor borders and heterogeneous intratumoral signal intensity were
significantly correlated with the 1p19q codeletion. It has been previous...
We read with interest the work by Kim et al that shows relationship
between radiological characteristics and molecular signatures in a group
of 49 patients with anaplastic oligodendroglioma (AO) and 7 patients with
anaplastic oligoastrocytoma (AOAs). Frontal lobe location, indistinct
tumor borders and heterogeneous intratumoral signal intensity were
significantly correlated with the 1p19q codeletion. It has been previously
published the existence of molecular heterogeneity associated to location
in oligodendroglial tumors showing an increased frequency of 1p19q
codeletion in frontal lobe location whereas temporal lobe location
associated greater number of patients lacking 1p19q codeletion. Previous
works also describe decreased chemosensibility of AO located in temporal
lobe, insula and diencephalus. The authors try to conclude that high-grade
oligodendroglial tumors (AO/AOAs) share a similar relationship between
radiological characteristics and molecular signatures as in
oligodendroglial tumors. We would like to add further comments to these
issues. First, the limited number of patients and doubtful tumoral
anatomical location (eleven tumor cases were located in multiple lobes)
should make see the results cautiously. Previous published experiences
report loss of heterozygosity for 1p and 19q to be significantly
associated with a bilateral pattern of growth [1], but Kim et al do not
refer to bilateral pattern in their paper, nor clearly define multiple
location, and only report 4 patients with parieto-occipital lesion and 11
with temporoinsular location. Second, we would like also to raise the
question of patient selection: management of low grade glioma is very
heterogeneous including total/subtotal removal of the lesion with
functional boundaries, biopsy and even "wait and see" attitude. In our
opinion, only complete or near complete removal of low grade glioma can
give complete information of the histological diagnosis, since it is our
experience that anaplastic transformation loci, and astrocytic component
can be seen after expanded removal in a previously so called low grade
lesion or oligodendroglial lesion without astrocytic component. Third, the
authors report intratumoral heterogeneous to be favorable sign for patient
survival and also that this signal may result from intratumoral
haemorrhage, necrosis or calcification. The 2009 EORTC prospective
randomized study on molecular analysis of anaplastic oligodendroglial
tumors [2], report both necrosis, and 1p(loss)19q(loss) to be independent
prognostic factors. Since necrosis has a profound impact on survival, a
more refined description of intratumoral heterogeneity could help to
establish the association between both radiological and molecular
characteristics. Fourth, we read with surprise that no significant
relationship between 1p19q codeletion and tumor enhancement is found in
the present series. Around 20% of AO have the enhancement pattern, which
is statistically correlated with frequent recurrence, indeed, some series
report not to have found combined 1p/19 loss in any of the cases with
anaplastic oligodendrogliomas with enhancement pattern [3]. Although quite
interesting, the study has several limitations, particularly its
retrospective nature. Further prospective studies including larger numbers
of cases and standardized evaluation of 1p19q codeletion in conjunction
with other relevant prognostic parameters are needed to draw definitive
conclusions on the issue of radiological markers for molecular signatures
in grade III oligodendroglial tumors
1. Zlatescu MC, TehraniYazdi A, Sasaki H, et al. Tumor location and growth
pattern correlate with genetic signature in oligodendroglial neoplasms.
Cancer Res 2001; 61:6713-15.
2. Kouwenhoven MC, Gorlia T, Kros JM, et al. Molecular analysis of
anaplastic oligodendroglial tumors in a prospective randomized study: A
report from EORTC study 26951. Neuro Oncol 2009; 11:737-46.
3. Young Choi, Tae-Young Jung, Shin Jung, et al. Prognosis of
oligodendroglial tumor with ring enhancement showing central necrotic
portion. J Neurooncol 2011; 103:103-110
This is a typical case of diffusion restriction in an early phase of
Wallerian degeneration along the left corticospinal tract secondary to a
large left putaminal hemorrhage.
Diffusion weighted (DW) imaging shows the early phase of wallerian
degeneration as hyperintense associated with decreased ADC, presumably
representing axonal and reactive astrocytic swelling [1, 2]. DW high
signals can be observed after more than 24...
This is a typical case of diffusion restriction in an early phase of
Wallerian degeneration along the left corticospinal tract secondary to a
large left putaminal hemorrhage.
Diffusion weighted (DW) imaging shows the early phase of wallerian
degeneration as hyperintense associated with decreased ADC, presumably
representing axonal and reactive astrocytic swelling [1, 2]. DW high
signals can be observed after more than 24 hours following the associated
territorial infarction or hemorrhage[3].
1. Castillo M, Mukheriji SK (1999) Early abnormalities related to
postinfarction wallerian degeneration: evaluation with MR diffusion-
weighted imaging. JCAT 23:1004–1007
2. Kang DW, Chu K, Yoon BW, Song IC, Chang KH, Roh JK
(2000) Diffusion-weighted imaging in wallerian degeneration.
J Neurol Sci 178:167–169
3. Pierpaoli C, Barnett A, Pajevic S, Chen R, Penix LR, Virta A, Basser P
(2001) Water diffusion changes in Wallerian degeneration and their
dependence on white matter architecture. Neuroimage 13:1174-1185
Hatano and colleagues recently published a paper of considerable
interest, investigating possible metabolic pathways associated with
Parkinson's disease (PD) by using metabolomic technologies [1]. Their
results on redox homeostasis deserve to be further discussed, since
oxidative stress is possibly involved in PD risk and progression. In
particular, authors found bilirubin, a strong natural antioxidant, to be
significan...
Hatano and colleagues recently published a paper of considerable
interest, investigating possible metabolic pathways associated with
Parkinson's disease (PD) by using metabolomic technologies [1]. Their
results on redox homeostasis deserve to be further discussed, since
oxidative stress is possibly involved in PD risk and progression. In
particular, authors found bilirubin, a strong natural antioxidant, to be
significantly reduced in patients with PD, as compared to controls [1].
However, there are different studies reporting conflicting results on
bilirubin metabolism in PD.
From a pathophysiological perspective, the production of bilirubin and,
subsequently, its plasma levels are mainly related to heme-oxigenase (HO)
activity [2-3]. The up-regulation of the HO-bilirubin pathway is an early
response to oxidative stress within dopaminergic cells and, accordingly,
cytoplasmatic Lewy bodies of PD patients display intense peripheral HO
staining [2]. In line with this, Scigliano and colleagues previously
reported increased total bilirubin levels in PD [4], and, similarly, we
recently confirmed this result in our population of newly-diagnosed, drug-
na?ve PD subjects [5]. These findings are supported by the hypothesis that
HO up-regulation within the substantia nigra is an adaptive response to
increased oxidative stress, occurring since the early phases of PD, and is
subsequently responsible for systemic bilirubin increase [2-3].
On the other hand, Hatano and colleagues reported reduced bilirubin levels
in PD, compared to controls, possibly as a consequence of increased
oxidative stress [1], whereas Qin and colleagues found no difference in
total bilirubin concentrations between PD cases and controls [6].
These discordant results can be explained by the presence of confounding
factors affecting bilirubin levels and/or by bilirubin variations during
the course of the disease. Among possible confounding factors, for
instance, we must report the presence of HO polymorphisms, which probably
modify bilirubin levels in PD cohorts with different genetic background
[7]. There are also several comorbidities affecting bilirubin that are
difficult to exclude completely in clinical practice, in particular for
studies with small sample size [5]. Finally, it is possible to hypothesize
a variability of bilirubin levels during the course of PD. Considering
different studies that have been conducted so far, it can be hypothesized
an increase in bilirubin levels in the early phases of PD, with subsequent
gradual decrease during the course of the disease, due to progressive
reduction of the antioxidant reserve [1,4-5]. However, since bilirubin
increase is generally considered a marker of improved health outcomes in
the general population [2-3], PD patients presenting higher bilirubin
levels in both early and late phases of PD are conceivably those with
better response to the increased oxidative stress and, thus, are expected
to have better motor performances, as described by Hirano and colleagues,
and in our population [1,5]. As a future perspective, considering that all
previous studies presented a cross-sectional design [1,4-6], further
investigations should be conducted with a longitudinal design in order to
specifically investigate the modifications of bilirubin levels during the
course of the disease in relation to dopaminergic treatments, disease
progression and/or PD-related pathological changes [2-3].
In conclusion, the HO-bilirubin pathway seems to be affected by various
factors and, thus, appears a dynamic antioxidant mechanism with a
significant role in PD. In particular, we thank Hatano and colleagues for
their contribution in this field, and strongly encourage further studies
investigating variations in bilirubin levels during the course of PD with
subsequent health outcomes.
References
1. Hatano T, Saiki S, Okusumi A, et al. Identification of novel biomarkers
for Parkinson's disease by metabolomic technologies. J Neurol Neurosurg
Psychiatry 2015.
2. Schipper HM, Song W, Zukor H, et al. Heme oxygenase-1 and
neurodegeneration: expanding frontiers of engagement. J Neurochem
2009;110(2):469-485.
3. McCarty MF. Serum bilirubin may serve as a marker for increased heme
oxygenase activity and inducibility in tissues - A rationale for the
versatile health protection associated with elevated plasma bilirubin. Med
Hypotheses 2013;81(4):607-610.
4. Scigliano G, Girotti F, Soliveri P, et al. Increased plasma bilirubin
in Parkinson patients on L-dopa: evidence against the free radical
hypothesis? Ital J Neurol Sci 1997;18(2), 69-72.?
5. Moccia M, Picillo M, Erro R, et al. Increased bilirubin levels in de
novo Parkinson's disease. Eur J Neurol 2015.
6. Qin XL, Zhang QS, Sun L, et al. Lower Serum Bilirubin and Uric Acid
Concentrations in Patients with Parkinson's Disease in China. Cell Biochem
Biophys 2014.
7. Ayuso P, Mart?nez C, Pastor P, et al. An association study between Heme
oxygenase-1 genetic variants and Parkinson's disease. Front Cell Neurosci
2014;8:298.
I read with great interest the letter entitled “Resolution of transverse sinus stenoses immediately after CSF withdrawal in idiopathic intracranial hypertension” recently published in JNNP by Scoffings et al(1). This letter presents the case history of a 35 yrs old patient with idiopathic intracranial hypertension (IIH) who had bilateral venous outflow stenosis of the transverse sinuses, which resolved im...
I read with great interest the letter entitled “Resolution of transverse sinus stenoses immediately after CSF withdrawal in idiopathic intracranial hypertension” recently published in JNNP by Scoffings et al(1). This letter presents the case history of a 35 yrs old patient with idiopathic intracranial hypertension (IIH) who had bilateral venous outflow stenosis of the transverse sinuses, which resolved immediately following the removal of CSF. The authors suggest, that the elevated venous pressures noted in this patient were caused by the collapse of the transverse sinuses (1) and go on to assert that stent insertion should not be used as it would not be curative in patients with similar dynamic stenoses. This suggestion is proposed because logically, if the raised CSF
pressure has caused the venous sinus collapse, then the elevated venous pressure cannot also be the cause of the raised CSF pressure. I wish to discuss whether the cause and effect relationship as outlined, is the only one possible, given the data as presented.
The majority of patients with IIH have morphologic stenoses in their venous outflow(2). Many of these stenoses reduce the outflow by greater than 70% in area (as in the current patient) and would be deemed to be
significant if found on the arterial side of the vascular tree. Direct manometry has shown the pressure gradients across these stenoses to average 24 mmHg(3)(19 mmHg in this case) which would also suggest that these stenoses were significant by the usual criteria. Finally, I have
measured the arterial inflow and venous outflow in 21 patients with IIH and stenoses and found on average that there is a 13% reduction in the sagittal sinus outflow as a percentage of the inflow in IIH (4). This suggests 140 ml/min bypasses the dominant out flow stenosis via collateral vessels(4), again suggesting significance.
Can we reconcile the apparent significant nature of the stenoses, with the fact that they occur secondary to the CSF pressure? Intracranial pressure (ICP) is dependant on a balance between CSF production and reabsorption. Davson et al modeled the relationship between ICP and the formation and reabsorption of CSF showing that, ICP= Rout x FRCSF + PSS where Rout is the resistance of CSF outflow, FRCSF is the formation rate of CSF and PSS is the sagittal sinus pressure(5). In Scoffings et als patient, the opening pressure at the time of venous pressure measurement was 26 cm H2O (or 19 mmHg) and the sagittal sinus pressure was 30 mmHg. Indicating that the gradient from CSF to sagittal sinus was –11 mmHg. This
is difficult to reconcile given the need for a pressure gradient of +2-6 mmHg, for CSF to be reabsorbed, suggesting either an error in CSF pressure measurement was made or that the CSF pressure was not at steady state when
the measurement occurred. Irrespective, it appears safe to assume that the gradient was not above the normal range. Similarly, in the 21 IIH patients studied by King et al, a mean CSF pressure of 27 mmHg and sagittal sinus pressure of 22 mmHg, gave a CSF-SSS gradient of 5 mmHg(3), which is in the normal range (2-6 mmHg). Rearranging Davson’s equation we find that the CSF-SSS pressure gradient is equal to the product of the CSF production rate and the resistance to flow across the arachnoid granulations i.e.
ICP- PSS = Rout x FRCSF. Malm et al used a constant flow technique(6) to measure FRcsf and showed it be normal in this condition. If the gradient is normal and the
formation rate is normal, then the Rout must also be normal in IIH. Therefore, the elevated venous pressure is the sole variable bringing about the elevation in CSF pressure despite itself being secondary to the elevated CSF pressure. This indicates that a feed back loop must exist where both the CSF pressure and venous pressure are cause and effect, i.e. both being a mixture of the chicken and the egg, hence an omelette. It follows that this condition could be cured by attacking either side of the
feed back loop i.e. reducing the CSF pressure by shunt or lumbar puncture (secondarily opening the stenosis) or stenting open an overly compliant transverse sinus will break the loop. Thus, I believe that the assertion by Scoffings et al that stenting should not be offered to those with IIH and collapsible stenoses is not necessarily correct. Ultimately, whether the front line treatment of IIH associated with collapsible venous outflow is stenting or shunt insertion will depend on the relative morbidity of these procedures and their long-term success rates.
Yours sincerely
Grant A Bateman, MBBS FRANZCR
Department of Medical Imaging
John Hunter Hospital
References
1. Scoffings DJ, Pickard JD, Higgins JN. Resolution of transverse sinus stenoses immediately after CSF withdrawal in idiopathic intracranial hypertension. J Neurol Neurosurg Psychiatry 2007; 78:911-912.
Sir,
The paper by Rosenow et al1 made interesting reading.
However, there are few concerns with respect to the conclusions of the study.
The study tested for superiority of levetiratecam over lamotrigine with seizure free interval in the first 6 weeks of the trial as the primary endpoint. Assuming a clinically relevant difference of 15% between the groups, the authors estimated a sample size of 183 patients to achieve power o...
Sir,
The paper by Rosenow et al1 made interesting reading.
However, there are few concerns with respect to the conclusions of the study.
The study tested for superiority of levetiratecam over lamotrigine with seizure free interval in the first 6 weeks of the trial as the primary endpoint. Assuming a clinically relevant difference of 15% between the groups, the authors estimated a sample size of 183 patients to achieve power of 80%. With a 10% drop-out estimate, the total sample size calculated was 203 patients.
The study documents 165 protocol violations, 116 in levtiracetam group (56.3%) and 129 in lamotrigine group ( 63%). The authors, however, do not describe the nature of protocol violations.
Given the fact of more than 50% protocol violations, one need to be skeptical about the ability of the trial to demonstrate any valid results on either direction ( either to demonstrate that the null hypothesis is indeed true- that levtiracetam is not significantly different from lamotrigine- or that it is rejected). Here, it would have been interesting if the authors reflected on the power of the study with 50% of the sample lost due to protocol violation.
According to the authors the target daily dose of levetiracetam was achieved by 3 weeks and that of lamotrigine by 7 weeks. In such a situation, one wonders at the prudence of considering seizure free interval at the 6 weeks as the primary end point ( when the comparator agent has not even reached its target dose). This would makes the trial design skewed in favour of levtireacetam. The fact that it still didn't detect a difference between the two drugs could be because of three reasons: 1) Gross underpowering of the study because of protocol violation that it is no longer able to detect any significant change even if there was any
2) Absence of any appreciable difference between the drugs even with a skewed baseline disposition between the two drugs, 3) Absence of sufficient event rates within the 6 weeks period that make such a short term end point inappropriate to compare the efficacy of the drugs studied. The latter scenario is particularly relevant because there are about 20% of patients with 'first seizure' enrolled in the trial. It will be interesting to know about the natural seizure recurrence rate in that subgroup of patients. In the study, however, this cannot be verified because we do not ( and cannot) have a placebo arm.
The authors' statement that the fact of identical ITT and PP analyses results indicate that protocol violations have no influence in the results of the primary analysis does not follow the dictum of a most plausible and direct explanation.
Rather, it is the above-mentioned issues (especially the underpowering of the study and uncertain event rates in untreated patients) that could most plausibly make the ITT and PP analyses give identical results. Again, with such gross underpowering of the study, the lengthy discussion on 'subgroup' analysis appears without much statistical grounds.
In the discussion section, the authors make further claims that is unfounded by the design and the results of the study. For the sake of brevity, I shall list few of them
1) "It is possible that side effects would be less prominent if extended release formulations were used"
2) " More rapid titration does not necessarily translate into a clinically relevant reduction in the rate of early recurrence, especially when considering monotherapy in a population with a relatively low risk of recurrence".
3) The final discussion on the prudence of including patients with single seizure and high risk of recurrence in the discussion section do not bear any relevance with the overall results of the study
In conclusion, the study do not prove or disapprove that levetiracetam is better than lamotrigine for the specified end points.
What appear unclear here are the reasons that makes a short term study of 26-weeks giving protocol violation to the tune of 50%, especially in a condition like epilepsy where patients are generally motivated to be on long term therapy. It will be interesting if authors can clarify on the reasons and nature of 'protocol violations'.
Reference
1. Rosenow F, Schade-Brittinger C, Burchardi N, Bauer S, Klein KM, Weber Y, et al. The LaLiMo Trial: lamotrigine compared with levetiracetam in the initial 26 weeks of monotherapy for focal and generalised epilepsy--an open-label, prospective, randomised controlled multicenter study. J Neurol Neurosurg Psychiatry. 2012 Nov;83(11):1093-8.
With interest we read the article by You et al. describing the
identification of risk factors for aneurysm rupture and providing
estimations for the likelihood of rupture in unruptured intracranial
aneurysms [1]. However, we have concerns about the study design, the
presented analysis and the conclusions regarding the predictors for
aneurysm rupture.
With interest we read the article by You et al. describing the
identification of risk factors for aneurysm rupture and providing
estimations for the likelihood of rupture in unruptured intracranial
aneurysms [1]. However, we have concerns about the study design, the
presented analysis and the conclusions regarding the predictors for
aneurysm rupture.
First, the authors used a study population which included patients
with a newly diagnosed intracranial aneurysm who were treated by surgical
or endovascular techniques. Thus, for the unruptured aneurysms the authors
considered the risk of rupture too high to leave the aneurysm untreated.
Assessing predictors for rupture of aneurysms that are considered having a
risk of rupture high enough to warrant treatment is not very relevant.
From a clinical point of view predicting the risk of rupture of aneurysms
that are not treated (and thus may rupture in the near or distant future)
is much more relevant.
Second, the authors used a nested case control design and matched for
several clinical variables. This is an efficient design for etiologic
research (identification of risk factors), but is not suitable for
prognostic research (determine the risk of rupture based on multiple
predictors). Data from a case control study nested in a cohort of known
size can be used, but only when no matching is performed. The design most
suitable to address prognostic questions is a cohort study in which all
patients with a certain condition are followed for some time to monitor
the development of the outcome [2].
Finally, and not least important, the underlying frequencies of
potential predictors according to outcome in Table 1 do not correspond
with the univariable odds ratios mentioned in Table 2. For example, we do
not understand how the crude odds ratio for female sex can be different
from 1 (odds ratio 1.4, 95% CI 0.9-2.4) whereas the authors matched on
sex. Also, we do not understand how the crude odds ratio for the
association between hypertension and aneurysm rupture could be 1.9 (95% CI
1.2-3.2) whereas hypertension was less frequent in patients with a
ruptured aneurysm (35%) compared with patients with an unruptured aneurysm
(51%).
These concerns make interpretation of the presented results extremely
difficult. The study as presented can neither provide reliable information
on predictive risk factors for rupture nor can it form a proper basis for
decisions regarding the optimal therapeutic strategy for unruptured
intracranial aneurysms.
JP Greving1, Gabriel JE Rinkel2, Ale Algra1,2.
1 Julius Center for Health Sciences and Primary Care, University
Medical Center Utrecht, The Netherlands and 2 Department of Neurology and
Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical
Center Utrecht, Utrecht, The Netherlands.
Correspondence to: Dr JP Greving, Julius Center for Health Sciences
and Primary Care, University Medical Center Utrecht, Stratenum 6.131, PO
Box 85500, 3508 GA Utrecht, The Netherlands. j.p.greving@umcutrecht.nl
Competing interests: None.
References
[1] You SH, Kong DS, Kim JS, et al. Characteristic features of unruptured
intracranial aneurysms: Predictive risk factors for aneurysm rupture. J
Neurol Neurosurg Psychiatry 2009; 0: jnnp.2008.169573v1.
[2] Moons KGM, Royston P, Verhouwe Y et al. Prognosis and prognostic
research: what, why, and how? BMJ 2009;338:b375.
Dear Sirs,
Gold and colleagues recently found a significantly decreased risk of
developing multiple sclerosis (MS) after the onset of HIV infection in a
large cohort of national linked data set of English Hospital Episode
Statistics.(1) The possible causes of this negative association have been
hypothesized to be immunodeficiency and antiretroviral treatment (ART) as
MS is usually treated with immunosuppressive drugs and...
Dear Sirs,
Gold and colleagues recently found a significantly decreased risk of
developing multiple sclerosis (MS) after the onset of HIV infection in a
large cohort of national linked data set of English Hospital Episode
Statistics.(1) The possible causes of this negative association have been
hypothesized to be immunodeficiency and antiretroviral treatment (ART) as
MS is usually treated with immunosuppressive drugs and its pathogenesis
has been linked to human endogenous retroviruses. Since the ART might
improve HIV-related immunodeficiency being these two variables inversely
correlated, and reliable data on the ART could not be deduced with
certainty from the database of the study, this supposition leaves some
doubts. With this letter we want to discuss the supposed protective
mechanism of HIV against MS.
HIV is an immunodeficiency syndrome with progressive CD4+ T lymphocyte
loss leading to the development of opportunistic infections, cancers and
death especially in untreated patients. However, also autoimmune diseases
with rheumatological, haematological, endocrinological and neurological
manifestations have been already described in the early pre-ART era.(2)
Similarly to what was observed for MS,(1) clinical and serological
improvement of systemic lupus erythematosus during the onset of HIV has
been reported in some cases, therefore, a therapeutic effect of HIV on
autoimmune diseases was already hypothesized.(2) In the ART age, while
several autoimmune diseases have been shown to occur at a lower rate than
before in HIV patients, other ones (e.g. sarcoidosis) have contrariwise a
higher incidence.(2) Furthermore, some autoimmune manifestations may occur
contemporarily with the immune reconstitution inflammatory syndrome (IRIS)
associated with ART, making particularly difficult their diagnosis.(2)
Therefore, the hypothetical protective effect of HIV against MS could be
explained in part by a possibility of misdiagnosis of the latter, as
acknowledged by the authors themselves.(1) In effect, the authors excluded
from the analysis of the HIV cohort five people with prior MS and three
people with a simultaneous record of HIV and MS, whereas they included 7
new observed cases during the median follow-up period of 2454 days after
the diagnosis of HIV. Indeed, HIV infection might manifest with MS-like
clinical and radiological features and with presence of oligoclonal bands
in cerebrospinal fluid (CSF), as well as severe inflammatory demyelinating
lesions have been observed during IRIS after the onset of ART. Since the
diagnostic criteria of MS recommend the exclusion of other pathologies, it
is logical to assume that after being diagnosed with HIV the new
neurological manifestations are more readily attributed to the latter
omitting the diagnosis of MS.
In our opinion, the effect of HIV on MS is more correct to be defined as
subjugating rather than protective. However, we agree with the authors
that by studying the relationships between these two diseases we can
better understand the pathogenesis of MS due to its immunological
similarities with HIV.
Even if for a long time the role of CD4+ and CD8+ T lymphocytes has been
emphasized in both MS and HIV, more recently a dysregulation of the innate
immunity has been extensively demonstrated in HIV, MS and other autoimmune
disorders.(3,4) In particular the natural killer (NK) cells have been
demonstrated to be implicated in these pathologies influencing the
activity of other components of the innate and adaptive immune systems.(5)
NK cells foster anti-viral and anti-tumour immunity recognizing and
killing virally-infected or neoplastic cells.
A small RNA HIV-1 virus has developed specific strategies to evade control
of the NK cells.(3) A functional impairment of NK cell response and in
particular their decreased cytotoxic activity has been shown since the
early phases of HIV infection persisting during disease progression.(3)
HIV-infected individuals have shown progressive expansion of functionally
anergic NK cell subset, thus it has been hypothesized that these subjects
have an incomplete activation of NK cells due to chronic stimulation
leading to NK cell exhaustion and anergy.(3) These anergic NK cells,
accumulated during progressive HIV-1 infection, have not produced IFNgamma
and TNFalpha by a stimulation with MHC-devoid target cells, reducing a
consequent activation of antigen-presenting dendritic cells and components
of adaptive immunity.(3)
Interestingly, NK cells show similar alterations in both HIV infection and
autoimmune diseases, even if the latter are not generally considered as
infectious disorders.(4) Several studies have reported both a decreased
number of peripheral blood NK cells and an impairment of their
cytotoxicity in patients with different autoimmune diseases.(4) However,
more recent works have demonstrated accumulation of NK cells in target
tissues of several autoimmune diseases such as in pancreatic islets in
type I diabetes mellitus, hair follicles in alopecia areata, muscles in
juvenile dermatomyositis and synovia in rheumatoid arthritis, supporting
the possibility that a decrease of circulating NK cells in autoimmune
disorders is consequent to their trafficking to the affected tissues.(4)
The functional impairment of NK cells was found prevalently in the early
phase of autoimmune diseases and, even at the time of their diagnosis it
appears more likely that the NK defect is primary and not secondary to the
disease progression or to the treatments.(4) Moreover, the NK dysfunction
is present in active but not in quiescent phase, suggesting that NK cells
may be involved particularly in the initiation of the disease process.(4)
Finally, the same killer immunoglobulin-like receptor/HLA associations
fostering NK activation protect against the infections and predispose to
autoimmune diseases including MS.(4)
In MS, the NK cells might lyse directly oligodendrocytes, astrocytes,
microglia and activated T cells, thus having a probable immunoregulatory
role.(4) Moreover, transitory reductions of NK cytolytic activity, called
"valleys", have been demonstrated to precede radiological and clinical
relapses whereas the CD56bright NK cells, more efficient cytokine and
chemokine producers compared to the potent cytolytic CD56dim effectors,
have been shown a substantial enrichment in the CSF.(4)
Finally, NK cells show close modifications also during viral infections,
being their number and their cytotoxicity reduced in the peripheral blood
with a shift from CD56dim to CD56bright cells.(5)
Taken together, these features support the hypothesis that MS as well as
other autoimmune diseases may be an expression of latent, chronic
infections due to an inadequate immune response to pathogens. Such immune
reaction weakens further in HIV infection up to be completely subjugated
in the most severe HIV stages.
References
1. Gold J, Goldacre R, Maruszak H, Giovannoni G, Yeates D, Goldacre M. HIV
and lower risk of multiple sclerosis: beginning to unravel a mystery using
a record-linked database study. J Neurol Neurosurg Psychiatry. 2015
Jan;86(1):9-12. doi:10.1136/jnnp-2014-307932.
2. Stratton R, Slapak G, Mahungu T, Kinloch-de Loes S. Autoimmunity and
HIV. Curr Opin Infect Dis. 2009 Feb;22(1):49-56. doi:
10.1097/QCO.0b013e3283210006.
3. Altfeld M, Fadda L, Frleta D, Bhardwaj N. DCs and NK cells: critical
effectors in the immune response to HIV-1. Nat Rev Immunol. 2011
Mar;11(3):176-86. doi: 10.1038/nri2935.
4. Fogel LA, Yokoyama WM, French AR. Natural killer cells in human
autoimmune disorders. Arthritis Res Ther. 2013 Jul 11;15(4):216. doi:
10.1186/ar4232.
5. Mandal A, Viswanathan C. Natural killer cells: In health and disease.
Hematol Oncol Stem Cell Ther. 2014 Dec 27. pii: S1658-3876(14)00108-3.
doi:10.1016/j.hemonc.2014.11.006.
In the light of the recent review, which highlighted the inability of most tests of cognitive function to specify what "proportion of people who are classified by the screen as impaired who really are impaired"(ie the
positive predictive value of the test)(1) it will be difficult, if not impossible, to apply the golden rule from the case of Kenward v Adams(2) to patients who are being evaluated for...
In the light of the recent review, which highlighted the inability of most tests of cognitive function to specify what "proportion of people who are classified by the screen as impaired who really are impaired"(ie the
positive predictive value of the test)(1) it will be difficult, if not impossible, to apply the golden rule from the case of Kenward v Adams(2) to patients who are being evaluated for their capacity to make a will(3),
using the tests listed in Table 2, except for the one test which specified a positive predictive value of 91% and a negative predictive value of 96% for Alzheimer's disease. Even that test failed specify positive predictive
values for the other subtypes of dementia, namely, vascular dementia, frontotemporal dementia, and Lewy body dementia, respectively.
Accordingly, the specification in the golden rule, that the making of a will by an aged testator or a testator who has suffered a serious illness "ought to be witnessed or approved by a medical practitioner who satisfies himself of the capacity and understanding of the testator"(2) is one whose fulfilment will have to await more rigourous studies evaluating the positive predictive value in each of the subtypes of dementia
Oscar M Jolobe
References
(1) Cullen B., O'Neill B., Evans JJ., Coen RF., Lawlor BA
A review of screening tests for cognitive impairment
Journal of Neurology, Neurosurgery, and Psychiatry 2007:78:790-99
(2) Kenward v Adams(1975) Times 29 November
(3)Jacoby R., Steer P
How to assess capacity to make a will
British Medical Journal 2007:335:155-7
Dear Editor:
The paper by Joanna Kitley et al1 was consoling at the outset.The
understanding about pathogenesis of neuromyelitis optica has greatly
increased the use of immunosuppressants for relapse prevention. But in
resource limited settings, especially in developing countries most of the
patients cannot afford these drugs. Here comes the utility of methotrexate
which has been widely used by many neurologists in develo...
Dear Editor:
The paper by Joanna Kitley et al1 was consoling at the outset.The
understanding about pathogenesis of neuromyelitis optica has greatly
increased the use of immunosuppressants for relapse prevention. But in
resource limited settings, especially in developing countries most of the
patients cannot afford these drugs. Here comes the utility of methotrexate
which has been widely used by many neurologists in developing countries
for multiple sclerosis and neuromyelitis optica. Since majority of
patients are relapse free if treated with long term immunosuppressants2,
methotrexate should be used in those patients who cannot afford other
drugs. Joanna Kitley et al have given inspiration to physicians working in
resource limited settings by showing the utility of methotrexate in NMO
spectrum disorders.
References
1. Kitley J, Elsone L, George J et al. Methotrexate is an alternative to
azathioprine in neuromyelitis optica spectrum disorders with aquaporin-4
antibodies. J Neurol Neurosurg Psychiatry. 2013 Mar 6. [Epub ahead of
print]
2. Palace J, Leite MI, Jacob A. A practical guide to the treatment of
neuromyelitis optica. Pract Neurol. 2012 Aug;12(4):209-14.
I read with interest the article by Geraldes et al.[1] on the use of
transcranial magnetic stimulation (TMS) in psychogenic paralysis. The
Authors showed in a young lady with a reversible left body limbs paresis
due to conversion disorders (CD), a significant increase of corticomotor
threshold and reduction in amplitude of motor evoked potentials (MEP) in
the affected side. These changes were resto...
I read with interest the article by Geraldes et al.[1] on the use of
transcranial magnetic stimulation (TMS) in psychogenic paralysis. The
Authors showed in a young lady with a reversible left body limbs paresis
due to conversion disorders (CD), a significant increase of corticomotor
threshold and reduction in amplitude of motor evoked potentials (MEP) in
the affected side. These changes were restored with the normalization of
clinical pictures. Geraldes et al. concluded that neurophysiological
changes were due to brain modulation proper of CD moreover they affirm
that in no previous study corticomotor threshold was investigated.
In a previous TMS-psychogenic palsy larger (21 patients) study [2]
corticomotor threshold and MEP amplitude were explored without any
significant differences respect to the unaffected side nor to the controls
group. CD frequently represents a great challenge for neurologist and TMS
contribute to speed up this diagnosis in psychogenic paralysis [2].
Although the hypothesis of Geraldes et al. may be intriguing, their TMS
findings could confuse the already complex diagnostic pathway in patients
with psychogenic paralysis.
Geraldes R, Coelho M, Rosa MM, Severino L, Castro J, de Carvalho M.
Abnormal transcranial magnetic stimulation in a patient with presumed
psychogenic paralysis.J Neurol Neurosurg Psychiatry. 2008 ;79(12):1412-
1413.
Cantello R, Boccagni C, Comi C, Civardi C, Monaco F. Diagnosis of
psychogenic paralysis: the role of motor evoked potentials. J Neurol. 2001
;248: 889-897.
We read with interest the work by Kim et al that shows relationship between radiological characteristics and molecular signatures in a group of 49 patients with anaplastic oligodendroglioma (AO) and 7 patients with anaplastic oligoastrocytoma (AOAs). Frontal lobe location, indistinct tumor borders and heterogeneous intratumoral signal intensity were significantly correlated with the 1p19q codeletion. It has been previous...
This is a typical case of diffusion restriction in an early phase of Wallerian degeneration along the left corticospinal tract secondary to a large left putaminal hemorrhage. Diffusion weighted (DW) imaging shows the early phase of wallerian degeneration as hyperintense associated with decreased ADC, presumably representing axonal and reactive astrocytic swelling [1, 2]. DW high signals can be observed after more than 24...
Hatano and colleagues recently published a paper of considerable interest, investigating possible metabolic pathways associated with Parkinson's disease (PD) by using metabolomic technologies [1]. Their results on redox homeostasis deserve to be further discussed, since oxidative stress is possibly involved in PD risk and progression. In particular, authors found bilirubin, a strong natural antioxidant, to be significan...
Dear Sir,
I read with great interest the letter entitled “Resolution of transverse sinus stenoses immediately after CSF withdrawal in idiopathic intracranial hypertension” recently published in JNNP by Scoffings et al(1). This letter presents the case history of a 35 yrs old patient with idiopathic intracranial hypertension (IIH) who had bilateral venous outflow stenosis of the transverse sinuses, which resolved im...
Dear Editor,
With interest we read the article by You et al. describing the identification of risk factors for aneurysm rupture and providing estimations for the likelihood of rupture in unruptured intracranial aneurysms [1]. However, we have concerns about the study design, the presented analysis and the conclusions regarding the predictors for aneurysm rupture.
First, the authors used a study popul...
Dear Sirs, Gold and colleagues recently found a significantly decreased risk of developing multiple sclerosis (MS) after the onset of HIV infection in a large cohort of national linked data set of English Hospital Episode Statistics.(1) The possible causes of this negative association have been hypothesized to be immunodeficiency and antiretroviral treatment (ART) as MS is usually treated with immunosuppressive drugs and...
Dear Editor,
In the light of the recent review, which highlighted the inability of most tests of cognitive function to specify what "proportion of people who are classified by the screen as impaired who really are impaired"(ie the positive predictive value of the test)(1) it will be difficult, if not impossible, to apply the golden rule from the case of Kenward v Adams(2) to patients who are being evaluated for...
Dear Editor: The paper by Joanna Kitley et al1 was consoling at the outset.The understanding about pathogenesis of neuromyelitis optica has greatly increased the use of immunosuppressants for relapse prevention. But in resource limited settings, especially in developing countries most of the patients cannot afford these drugs. Here comes the utility of methotrexate which has been widely used by many neurologists in develo...
Dear Editor,
I read with interest the article by Geraldes et al.[1] on the use of transcranial magnetic stimulation (TMS) in psychogenic paralysis. The Authors showed in a young lady with a reversible left body limbs paresis due to conversion disorders (CD), a significant increase of corticomotor threshold and reduction in amplitude of motor evoked potentials (MEP) in the affected side. These changes were resto...
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