We were interested to read the meta-analysis by Handel and
Ramagopalan,1 summarising the body of evidence which points towards a
reduction of cancer risk in patients with multiple sclerosis.
We performed a study investigating the same question, using our
hospital's clinical coding database to compare the frequency of cancer in
all multiple sclerosis patients admitted over a 10 year period (1090
patients), with...
We were interested to read the meta-analysis by Handel and
Ramagopalan,1 summarising the body of evidence which points towards a
reduction of cancer risk in patients with multiple sclerosis.
We performed a study investigating the same question, using our
hospital's clinical coding database to compare the frequency of cancer in
all multiple sclerosis patients admitted over a 10 year period (1090
patients), with a control group constituting all patients admitted with
epilepsy or migraine over the same time period (5596 patients).
Our results add weight to the meta-analysis' findings with a
significant reduction in risk seen with regards to solid tumours (RR 0.42,
p= 0.05).2
This relationship suggests that the hyperactive immune system
associated with multiple sclerosis might have a protective value; this may
have implications both for understanding tumour genesis and the
pathophysiology of multiple sclerosis, and in the need for vigilance in
our patients treated with an increasingly wide range of immunomodulatory
therapies.
1. Handel AE, Ramagopalan SV, Multiple Sclerosis and Risk of Cancer:
A Meta-Analysis J Neurol Neurosurg Psychiatry 2010;81:1413-1414
2. Needham E, Lee M, The Hyperactive Immune System of Multiple
Sclerosis - An Evolutionary Benefit? Multiple Sclerosis 2009;15:S191
We write in relation to the editorial commentary from Khan et Tselis
(1) who rightly suggest caution to consider chronic cerebrospinal venous
insufficiency (CCSVI) as a pathological entity and cast serious doubt on
its relevance to multiple sclerosis (MS); they forecast properly designed
studies to investigate the relevance of CCSVI to MS, in order to carry out
interventional procedures.
The absence of extracranial venous...
We write in relation to the editorial commentary from Khan et Tselis
(1) who rightly suggest caution to consider chronic cerebrospinal venous
insufficiency (CCSVI) as a pathological entity and cast serious doubt on
its relevance to multiple sclerosis (MS); they forecast properly designed
studies to investigate the relevance of CCSVI to MS, in order to carry out
interventional procedures.
The absence of extracranial venous stenosis at the earliest stage of MS
makes it an unlikely cause of the disease (2). The idea of venous
congestion as a possible contributor to the pathogenesis of MS has been
discussed for the past 40 years, but remained widely unappreciated by the
scientific community.
In contrast with other authors, Zamboni et al (3) defined CCSVI as a
vascular condition associated with MS; it is characterized by multiple
intraluminal stenosing malformations of the principal pathways of
extracranial venous drainage, particularly in the internal jugular veins
(IJVs) and the azygous vein (AZY), that restrict the normal outflow of
blood from the brain.
In the study of Zamboni et al there was significant extracranial venous
stenosis localised at the principal level of the cerebrospinal venous
segments as detected by selective venography and anomalies of venous
outflow at color Doppler high resolution examination. The pathological
consequences of CCSVI have been hypothesised to emanate from chronic
venous reflux and hypertension leading to increased iron deposition in the
brain and subsequent MS pathology, including inflammation and
neurodegeneration. Other recent reports found no differences in
cerebrospinal venous drainage using transcranial and extracranial Doppler
imaging (4-5).
The discrepancies in the results may be explained with the absence of
standardized internationally accepted criteria for normal Doppler venous
flow parameters (2).
We performed complete post-mortem examination of two patients with MS,
died for different causes. One patient, a 74 year-old-woman, was
hospitalized for acute respiratory illness and died because of bacterial
pneumonia; the other one, a 35 year-old-woman, died for otogenic bacterial
meningitis complicated with internal jugular thrombosis as demonstrated on
MR venography.
Postmortem examination demonstrated in both patients a marked stenosis of
left internal jugular vein at the apex of the angle formed by the two
heads of the sternocleidomastoid muscle where the IJV overlie the carotid
artery with ectasia and congestion of the intracranial veins. Venous flow
slowing, caused by the stenosis, had predisposed to IJV thrombosis,
histologically demonstrated in the second case.
Severe inflammatory disease may be a risk factor for deep venous
thrombosis but also chronic cerebrospinal venous insufficiency.
We demonstrate, for the first time as far as we are aware, the presence
of anatomical alteration in the veins of the neck with impaired venous
drainage from the central nervous system in two patients with multiple
sclerosis who died from other causes. We do not know the exact
implications in MS pathology and certainly there is no doubt that this
area warrants a great deal more study. Clinical trials for evaluating new
therapeutic agents and other clinical experimental protocols may be
required.
References
1. Khan O, Tselis A.
Chronic cerebrospinal venous insufficiency and multiple sclerosis: science
or science
fiction?
J Neurol Neurosurg Psychiatry 2011;82:355.
2. Yamout B, Herlopian A, Issa Z
Extracranial venous stenosis is an unlikely cause of multiple sclerosis
Mult Scler 2010 16: 1341-9
3. Zamboni P, Galeotti R, Menegatti E, et al
Chronic cerebrospinal venous insuffiency in patients with multiple
sclerosis.
J Neurol Neurosurg Psychiatry 2009;80:392-9.
4. Doepp F, Paul F, Valdueza JM, et al
No cerebrocervical venous congestion in patients with multiple sclerosis.
Ann Neurol 2010, 68:173-183.
5. Sundstrom P, Wahlin A, Ambarki K, et al
Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control
study.
Ann Neurol 2010, 68:255-259.
We read with interest the meta-analysis with the focus on
physiotherapy interventions late after stroke and we would like to thank
the authors for their effort to shed light on this subject. Interventions
late after stroke are an important area of rehabilitation that has been
neglected. There most certainly is a need for rehabilitation and exercise
tailored for stroke survivors late after onset. As the authors point out...
We read with interest the meta-analysis with the focus on
physiotherapy interventions late after stroke and we would like to thank
the authors for their effort to shed light on this subject. Interventions
late after stroke are an important area of rehabilitation that has been
neglected. There most certainly is a need for rehabilitation and exercise
tailored for stroke survivors late after onset. As the authors point out
the disabling process after stroke is complex and resources to maintain
physical functions, after the first months of primary rehabilitation are
scarce. It is not an area prioritized by administrators and health
politicians in any country and we applaud the authors' genuine wish to
forward this need of maintenance and need for exercise late after stroke.
However, the authors do not distinguish between the different underlying
mechanisms in early and late motor function recovery in this meta-
analysis. Most studies are either in the acute scenario OR, as the ones
presented in this meta-analysis late after stroke. Several studies
provided evidence that patients with stroke reach a plateau after 3-6
months and functional improvements seem to stabilize on a "peak
performance" (1-3).
So, the early rehabilitation seems to be very important in regaining
as much function as possible. How successful this is depends on many
factors. But, if treated in a stroke unit with multidisciplinary care and
with proper early rehabilitation all stroke survivors get a functional
profit to some degree. Some of the stroke survivors perform on a higher
level and some on lower levels in accordance with the initial lesion and
the damage that was imposed. Basically, one can speak of a therapeutic
window up till approximately 6 months to regain the function of the lost
bodily motor functions. This does by no means indicate that rehabilitation
after 6 months is futile. For one thing can patients with stroke at any
later stage learn to exploit their obtained motor potential to a larger
extent, and for another thing can patients with stroke like everybody else
gain strength and endurance with the help of training.
There are few studies that have followed stroke patients continuously from
the acute to the chronic stages, with or without interventions. However,
the few that exist indicate an interesting development: If treatment and
exercise is abandoned functions deteriorate, but if treatment and exercise
persist, functions are maintained(4-7).
In the acute early stage of rehabilitation focus is on regaining bodily
functions. After 3-6 months, it seems, you will not see any significant
difference in the RECOVERY of function, as to less paresis, but if
maintained they will be preserved at that level. Some patients may even be
able to improve functional abilities due to practice, but usually on the
basis of the motor function regained early after stroke (8).
However, if this new and improved function is not maintained with exercise
or physical activity the motor functions may and will deteriorate...and
rapidly so. And many stroke survivors are less active and sometimes
overprotected by their kind relatives so performance often DOES
deteriorate (9).
So people with stroke, like the general population, have a need for
maintenance of capacity and function (10).
And this is we would like to argue, that these studies in this meta-
analysis have focused on: maintenance of capacity. So the beauty of it all
is that stroke patients can enhance their capacity like endurance and
strength and thereby their functioning in daily life activities, on line
with healthy people BUT nevertheless seems genuine motor recovery to be
limited to the first 3 - 6 months post stroke.
Thank you once again for bringing this topic to attention!
Birgitta Langhammer, Associate Professor, PhD, Oslo University
College, Norway
Iris Brunner, Research Fellow, MSc, University of Bergen, Norway
References
1. Kwakkel G, van Peppen R, Wagenaar RC, Wood Dauphinee S, Richards
C, Ashburn A, Miller K, Lincoln N, Partridge C, Wellwood I, Langhorne P.
Effects of augmented exercise therapy time after stroke: a meta-analysis.
Stroke 2004;35(11):2529-39.
2. Kollen B, van de Port I, Lindeman E, Twisk J, Kwakkel G.Predicting
improvement in gait after stroke: a longitudinal prospective study. Stroke
2005;36(12):2676-80.
3. Verheyden G, Nieuwboer A, De Wit L, Thijs V, Dobbelaere J, Devos
H, Severijns D, Vanbeveren S, De Weerdt W. Time course of trunk, arm, leg,
and functional recovery after ischemic stroke. Neurorehabilitation And
Neural Repair 2008;22(2):173-9.
4. Van de Port IG, Kwakkel G, van Wijk I, Lindeman E. Susceptibility
to deterioration of mobility long-term after stroke: a prospective cohort
study. Stroke 2006 Jan;37(1):167-71.
5. Langhammer B, Stanghelle JK, Lindmark B.An evaluation of two
different exercise regimes during the first year following stroke: a
randomised controlled trial. Physiotherapy Theory And Practice
2009;25(2):55-68.
6. Langhammer B, Stanghelle JK, Lindmark B. Exercise and health-
related quality of life during the first year following acute stroke. A
randomized controlled trial. Brain Injury 2008;22(2):135-45.
7. Langhammer B, Lindmark B, Stanghelle JK. Stroke patients and long-
term training: is it worthwhile? A randomized comparison of two different
training strategies after rehabilitation. Clinical Rehabilitation
2007;21(6):495-510.
8. Langhammer B, Stanghelle JK. Exercise on a treadmill or walking
outdoors? A randomized controlled trial comparing effectiveness of two
walking exercise programmes late after stroke.Clinical Rehabilitation
2010;24(1):46-54.
9. Michael KM, Allen JK, Macko RF. Reduced ambulatory activity after
stroke: the role of balance, gait, and cardiovascular fitness.Archives Of
Physical Medicine And Rehabilitation 2005;86(8):1552-6.
10. Pang MY, Eng JJ, Dawson AS, Gylfad?ttir S. The use of aerobic
exercise training in improving aerobic capacity in individuals with
stroke: a meta-analysis.Clinical Rehabilitation 2006; 20(2):97-111.
We have read with great interest the work of Dhollander et al. [1]
and express our congratulation for their wonderful work, but we would like
to add some considerations.
The authors describe two patients presenting clinically transient
neurological deficit and radiologically with a focal cortical subarachnoid
haemorrhage in the brain CT and multifocal cortical siderosis in brain MR.
They compare their patients with the clas...
We have read with great interest the work of Dhollander et al. [1]
and express our congratulation for their wonderful work, but we would like
to add some considerations.
The authors describe two patients presenting clinically transient
neurological deficit and radiologically with a focal cortical subarachnoid
haemorrhage in the brain CT and multifocal cortical siderosis in brain MR.
They compare their patients with the classical diagnosis of superficial
siderosis but remark the differences with that diagnosis and propose the
term of cortical superficial siderosis.
We think from a radiological point of view it is better to consider these
patients as having suffered a focal cortical convexity subarachnoid
haemorrhage (cSAH), a term previously proposed in the literature [2;3]. In
this way there are some works showing a wide differential diagnosis
between the different aetiologies of cSHA including vasculitic, toxic,
pharmacological, vascular and amyloid angiopathy related causes. In an
interesting manner some reviews have shown how, in the older group of age,
all the cases were associated with amyloid angiopathy [3].
And, secondly, when cSAH appears in the elderly, the clinical
manifestations of transient neurological deficit are repeatedly described
and the hypotheses about its physiopathology have been related to cortical
spreading depression [4;5].
For these reasons we think this clinico-radiological picture of a
cSAH in the brain CT of an elderly patient presenting with neurological
transient deficitary manifestations is emerging as one of the
manifestations of cerebral amiloyd angiopathy, aside from lobar
haemathoma.
It is remarkable the elegant demonstration of Dhollander et al. [1]
of beta-amyloid deposition, in their patients, in the regions of the brain
usually involved in Alzheimer disease and, especially, in the areas
previously affected of a focal cortical subarachnoid bleeding. In our
knowledge this has not previously been reported as a demonstration of
amyloid pathology in cSAH.
1. Dhollander I, Nelissen N, Van Laere K, Peeters D, Demaerel P, Van
Paesschen W, Thijs V, Vandenberghe R. In vivo amyloid imaging in cortical
superficial siderosis. J Neurol Neurosurg Psychiatry 2011;82:469-71.
2. Spitzer C, Mull M, Rohde V, Kosinski CM. Non-traumatic cortical
subarachnoid haemorrhage: diagnostic work-up and aetiological background.
Neuroradiology 2005;47:525-31.
3. Kumar S, Goddeau RP, Jr., Selim MH, Thomas A, Schlaug G,
Alhazzani A, Searls DE, Caplan LR. Atraumatic convexal subarachnoid
hemorrhage: clinical presentation, imaging patterns, and etiologies.
Neurology 2010;74:893-9.
4. Izenberg A, Aviv RI, Demaerschalk BM, Dodick DW, Hopyan J, Black
SE, Gladstone DJ. Crescendo transient Aura attacks: a transient ischemic
attack mimic caused by focal subarachnoid hemorrhage. Stroke 2009;40:3725-
9.
5. Brunot S, Osseby GV, Rouaud O, Kazemi A, Ricolfi F, Couvreur G,
Catteau A, Hervieu M, Moreau T, Giroud M, Bejot Y. Transient Ischaemic
Attack Mimics Revealing Focal Subarachnoid Haemorrhage. Cerebrovasc Dis
2010;30:597-601.
Most authorities, from Samuel Johnson's to the current Oxford
University Dictionary, define "progression" as a change for the better
stemming from the Latin "prograde" to improve continuously and
"deterioration" as a change for the worse (Latin "deteriore"). Yet most
neurological journals appear to accept "disease progression" (as in
secondary progressive multiple sclerosis and progressive supranuclear
palsy) to indicat...
Most authorities, from Samuel Johnson's to the current Oxford
University Dictionary, define "progression" as a change for the better
stemming from the Latin "prograde" to improve continuously and
"deterioration" as a change for the worse (Latin "deteriore"). Yet most
neurological journals appear to accept "disease progression" (as in
secondary progressive multiple sclerosis and progressive supranuclear
palsy) to indicate that the natural history of an illness is deteriorating
in character; most patients and their families would not agree. The most
insensitive of neurologists would hardly tell an anxious family that their
dear one's terminal illness was progressing. While lexicographers
emphasise the dynamic flexibility of language, I doubt whether they would
favour contrary ambiguity. Nor would they agree with a definition
expressed in "Alice through the looking glass". "When I use a word "Humpty
Dumpty said in a rather scornful tone, "it means just what I choose it to
mean - neither more nor less". It seems legitimate to propose that
"progression" should be applied to the disease process and hopefully to
its elucidation, and that "deterioration" should apply to the history of a
patient's illness.
Perhaps the author's conventional confessions at the end of a submitted
article, such as competing interests, provenance and particularly
patient's consent should also indicate whose side they are on: the disease
or the patient?
Gerald Stern
University College Hospitals, Queen Square, London WC1
In their recently published article, Kim et al (1) describe the
imaging characteristics of anaplastic oligodendroglioma and anaplastic
oligoastrocytoma (AO/AOAs) in an effort to correlate them with molecular
alterations. They try to conclude that high-grade oligodendroglial tumors
(AO/AOAs) share a similar relationship between radiological
characteristics and molecular signatures...
In their recently published article, Kim et al (1) describe the
imaging characteristics of anaplastic oligodendroglioma and anaplastic
oligoastrocytoma (AO/AOAs) in an effort to correlate them with molecular
alterations. They try to conclude that high-grade oligodendroglial tumors
(AO/AOAs) share a similar relationship between radiological
characteristics and molecular signatures as in oligodendroglial tumors.
More specifically, they found that 1p19q codeleted AO/AOAs involved the
frontal areas more frequently, were more frequently bilateral with a
tendency towards widespread growth across the midline, and had poorly
delineated limits in T1 with irregular aspect in T2. However, they failed
to find any association of molecular alterations with contrast
enhancement, cortical involvement and other radiological features such as
calcification, hemorrhage, cystic formation.
We challenge their findings. Gliomatosis have taught us that tumors
with 1p19q loss involve the white matter more frequently than other
tumors, suggesting that this radiological characteristic can be related to
intrinsic differences in tumor cells and, perhaps, to the different
microenvironnement between gray matter and white matter. (2)
In the report of Kim et al, eleven tumor cases were located in
multiple lobes making the diagnosis of gliomatosis most probable.
Consequently, in our opinion, it would be very useful to further
investigate if AO/AOAs share also the same clinical and radiological
correlation of gliomatosis. Moreover, the figure 1 in their article is a
good example of radio-genetic relationship found in gliomatosis.
How can these studies be reconciled in our daily practice? Surely,
the most likely impact is that radiological characteristics may be
considered as phenotype of intrinsic characteristics of tumors. Thus, they
may have prognostic value as a surrogate marker for molecular alterations.
References:
1. Kim JW, Park CK, Park SH, et al. Relationship between
radiological characteristics and combined 1p and 19q deletion in World
Health Organization grade III oligodendroglial tumours. J Neurol Neurosurg
Psychiatry 2011; 82: 224-227
2. Kaloshi G, Guillevin R, Martin-Duverneuil N, et al. Gray matter
involvement predicts chemosensitivity and prognosis in gliomatosis
cerebri. Neurology 2009;11;73(6):445-9.
we read with great interest the paper by Cruz de Souza et al (1) ,
since we conducted a similar clinical experience, with slightly different
findings
In order to achieve data regarding the usability and reliability in the
"real world" of CSF biomarkers in the early differentiation of Alzheimer
Disease (AD) from frontal variant of Fronto-Temporal Dementia (fvFTD) , we
designed a prospective study in w...
we read with great interest the paper by Cruz de Souza et al (1) ,
since we conducted a similar clinical experience, with slightly different
findings
In order to achieve data regarding the usability and reliability in the
"real world" of CSF biomarkers in the early differentiation of Alzheimer
Disease (AD) from frontal variant of Fronto-Temporal Dementia (fvFTD) , we
designed a prospective study in which patients with initial doubtful
diagnoses underwent lumbar puncture besides usual clinical,
neuropsychological and neuroimaging tools. These patients were then
followed up for at least 3 years, in order to confirm their diagnoses:
the accuracy of the initial CSF diagnosis was assessed by comparison with
the final clinical diagnosis
The CSF samples have been collected by lumbar puncture in the morning,
immediately centrifuged and stored at -80? until analysis. Beta-amyloid
peptide 1-42 (bA) , tau and Ptau (phosphorilated at 181 Thr) were measured
with ELISA kits (Innogenetics, Ghent, Belgium) in a laboratory where the
operators were blinded to clinical information. The typical CSF AD
profile was defined as a score below 1 calculated with the formula: bA/
240+1.18 tau, which is known to distinguish AD from controls and from
other dementias with optimal sensitivity and specificity (2)
This prospective study started on January 2006. All consecutive
patients admitted to our tertiary Memory Clinic with a doubtful diagnosis
of AD or fvFTD according to current research criteria underwent lumbar
puncture as a diagnostic tool. On the basis of full clinical,
neuropsychological and bioimaging evaluations, they were initially
classified as AD or fvFTD independently from CSF metabolites levels..
Afterwards, they were evaluated at six months intervals by two expert
neurologists (MF and MZ), blind to the CSF results, who had to confirm
or discard the previous diagnosis.
Thirty nine patients with AD and 37 patients with fvFTD showed
significantly different CSF levels of tau and Ptau (increased in AD, p=
0.0004 and p= 0.009, respectively), bA (reduced in AD, p = 0.018), and
ratios of tau and Ptau to bA (p = 0.0009 and p = 0.014, respectively).
Seventy-seven per cent of AD and 30% of fvFTD patients showed the typical
AD CSF pattern, with a K-index of concordance of CSF and clinical
diagnoses of 47% .
The not negligible prevalence of CSF AD pattern in fvFTD was unexpected
but coherent with the findings of Visser et al (3) who found a typical AD
CSF pattern in 31% of their 89 healthy controls.
The sensitivity and the specificity of typical CSF AD pattern were 77%;
the positive predictive value (PPV) was 73% and negative predictive value
(NPV) was 80%
When we tried to correlate CSF metabolites with main clinical and
demographic features, only the ratio tau/bA negatively correlated with
MMSE scores, both in AD (r = - 0.33; p = 0.022) and fvFTD (r = - 0.34; p
= 0.030)
These results are similar to those of Pijnenburg et al (4) who studied CSF
tau and bA of 35 FTD and 51 AD patients, clinically defined but not
followed up. They found significant differences in the comparison of the
two groups, but concluded that the "measurement of tau and bA is not
useful for the diagnosis of FTD"
Notwithstanding similarities in sizes of AD and fvFTD groups, methological
design, diagnostic criteria and biochemical measurements, our findings are
less optimistic than those of Cruz de Sousa et al. A major limitation
of both studies is the lack of pathological confirmation of the
diagnoses. Until now there is only one paper (5) in which the diagnoses
were definite neuropathologically or genetically. The CSF biomarkers of
19 AD were compared with those of 30 FTD patients and, using ROC analysis,
the ratio tau/bA at a cut-off value of 1.06 had a sensitivity of 79% and a
specificity of 97% at distinguishing AD from FTD. We suggest that until
there will be a convincingly ample study comparing CSF markers from
autopsy-verified AD and FTD patients, the CSF analysis must be
considered useful but not definite diagnostic criteria
REFERENCES
1) Cruz de Sousa L, Lamari F, Belliard S, Jardel C, Houillier C, de
Paz R, Dubois B, Sarazin M.
Cerebrospinal fluid biomarkers in the differential diagnosis of
Alzheimer's disease from other cortical dementias. JNNP 2011;82:240-246
2) Riemenschneider M, Lautenschlager N, Wagenspfeil S, Diehl J, Drzezga A,
Kurz A Cerebrospinal fluid tau and bA proteins identify Alzheimer's
disease in subjects with mild cognitive impairment. Arch Neurol 2002;
59: 1729-1734.
3) Visser PJ, Verhej F, Knol DL, et al. Prevalence and prognostic value of
CSF markers of Alzheimer's disease pathology in patients with subjective
cognitive impairment or mild cognitive impairment in the DESCRIPA study :
a prospective cohort study. Lancet Neurol 2009; 8: 619-627.
4) Pijnenburg YAL, Schoonenboom NSM, Rosso SM, et al. CSF tau and bA are
not useful in the diagnosis of frontotemporal lobe degeneration. Neurol
2004; 62:1649
5) Bian H, van Swieten JC, Leight S, et al. CSF biomarkers in
frontotemporal lobar degeneration with known pathology Neurol 2008; 70:
1827-1835.
We read with great interest a recent article by D'hooghe et al. (1)
on long-term effects of childbirth on MS. Unfortunately, the study appears
to have been subject to important biases (in addition to those discussed
by the authors themselves, including, notably, confounding).
The first bias - namely, the left-truncation bias (2) - has to do
with the fact that to be included in the analyses, patients had to be
"...
We read with great interest a recent article by D'hooghe et al. (1)
on long-term effects of childbirth on MS. Unfortunately, the study appears
to have been subject to important biases (in addition to those discussed
by the authors themselves, including, notably, confounding).
The first bias - namely, the left-truncation bias (2) - has to do
with the fact that to be included in the analyses, patients had to be
"under regular care" at the referral centre in 2005-2007. Thus, patients
who had the onset of MS in 1975, for example, would only be included in
the study sample if they survived at least until 2005. Because MS survival
is correlated with the rate of disease progression, those who were
included represent a subpopulation with a slower rate of progression than
among all MS patients (if they were followed from the onset of MS). As a
result of the left truncation, the estimated Kaplan-Meier "survival"
curves are upwardly biased.
The second bias - namely, the immortal-time bias (3,4) - has to do
with the fact that the person-time contributed by patients who had no
children and those who had children after the onset of MS was handled
incorrectly. Specifically, to be included in the "children only after
onset of MS" group, a woman with no children before the onset of MS had to
reach the time of the post-MS-onset childbirth without reaching EDSS of 6.
During that time period, there were no events of reaching EDSS of 6 by
definition - otherwise, the woman would have been included in the "no
children" group. Thus, instead of being considered to have been
contributed by women who had children after the onset of MS, this
"immortal" time should have been considered to be contributed by women who
had had no children up to that point. As a result of the immortal-time
bias, the median time to EDSS of 6 was underestimated in the reference
group (no children) but overestimated in the group with children only
after the onset of MS. Through a similar mechanism, the median time to
EDSS of 6 was underestimated in the group with children only before onset
of MS but overestimated in the group with children before and after onset
of MS.
Overall, the evidence produced in the study by D'hooghe et al. (1)
is, thus, seriously flawed and does not allow for any meaningful inference
about the effect of childbirth on MS progression.
References:
1. D'hooghe MB, Nagels J, Uitdehaag BM. Long-term effects of
childbirth in MS. J Neurol Neurosurg Psychiatry 2010; 81:38-41.
2. Gail MH, Benichou J. Encyclopedia of epidemiologic methods. West
Sussex, UK. Wiley 2000.
3. Levesque LE, Hanley JA, Kezouh A, Suissa S. Problem of immortal
time bias in cohort studies: example using statins for preventing
progression of diabetes. BMJ 2010; 340:907-911.
4. Renoux C, Suissa S. Immortal time bias in the study of
effectiveness of interferon-bias in multiple sclerosis. Ann Neurol 2008
64:109-10.
In 2002, we reported in this journal a patient with corticosteroid-
responsive oculopharyngeal myopathy and an absence of chondroitin sulfate
in muscle biopsies [1]. In recent years, the patient was found to have
antibodies against muscle-specific kinase (MuSK). This female patient
presented in 1993 at the age of 42 years with proximal muscle weakness in
the neck and difficulty in swallowing, followed by blepharoptosis an...
In 2002, we reported in this journal a patient with corticosteroid-
responsive oculopharyngeal myopathy and an absence of chondroitin sulfate
in muscle biopsies [1]. In recent years, the patient was found to have
antibodies against muscle-specific kinase (MuSK). This female patient
presented in 1993 at the age of 42 years with proximal muscle weakness in
the neck and difficulty in swallowing, followed by blepharoptosis and
double vision. The symptoms showed no obvious diurnal variation with
normal repetitive stimulation tests and a negative Tensilon test, and
there was no thymoma. The patient developed respiratory failure associated
with hypercapnia and had to receive artificial respiration, but eventually
showed a dramatic recovery with oral corticosteroid therapy. The initial
diagnosis remained undetermined. Reports in the medical literature
describing corticosteroid-responsive myopathic cases with similar clinical
symptoms and signs associated with deficient chondroitin sulfate prompted
us to examine chondroitin sulfate in stored muscle specimens from the
patient and the results provided evidence for deficient chondroitin
sulfate [1,2]
In 2004, the patient had a worsening of her respiratory function
while given predonisolone orally at a dose of 12 mg/day. An increase of
predonisolone to 60 mg/day resulted in a marked resolution of the serious
symptoms, and this was followed by a gradual tapering of corticosteroids.
In 2008, a similar serious episode also induced a respiratory problem when
the patient was given predonisolone at a dose of 20 mg/day, in which an
increase of the dose to 60 mg/day again improved the symptoms. Thereafter,
predonisolone was gradually tapered to 30 mg/day as a maintenance dose.
Given the presence of similar symptoms in cases that were positive
for antibodies against MuSK [3], we examined the levels of these
antibodies in the patient's serum in 2008. We observed anti-MuSK
antibodies at a concentration of 10.0 nM (less than 0.01 nM in controls).
This high antibody titer led to a diagnosis of anti-MuSK antibody-positive
oculopharyngeal myopathy, although the patient did not have the clinical
features of myasthenia gravis. To the best of our knowledge, there are
only 2 cases, our current case and a previously reported case,
characterized by chondroitin sulfate-deficient myopathy [1,2].
The pathogenic relationship between deficient chondroitin sulfate and
anti-MuSK antibodies remains to be defined. It is possible that the
absence of chondroitin sulfate may involve an event that is secondary to
the myopathy associated with the presence of anti-MuSK antibodies. MuSK
forms a complex with several factors such as Dok7 [4]. Further studies are
necessary to examine whether chondroitin sulfate interacts with one of
these factors.
References
1. Yabe I, Kikuchi S, Higashi T, et al. A Japanese case of steroid
responsive myopathy with deficient chondroitin sulphate. J Neurol
Neurosurg Psychiatry 2002; 73: 89-90.
2. al-Lozi MT, Hemelt VB, Pestronk A. Steroid-responsive myopathy with
deficient chondroitin sulfate C in skeletal muscle connective tissue.
Neurology 1998; 50: 526-9.
3. Ohta K, Shigemoto K, Fujinami A, et al. Clinical and experimental
features of MuSK antibody positive MG in Japan. Eur J Neurol 2007; 14:
1029-34.
4. Bergamin E, Hallock PT, Burden SJ, et al. The cytoplasmic adaptor
protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization.
Mol Cell 2010; 39: 100-9.
We read with interest the recent study by Zheng et al.[1] The authors
assessed the predictive value of hyponatremia for poor outcome or cerebral
infarction in high-grade patients after aneurysmal subarachnoid
haemorrhage (aSAH), and concluded that hyponatremia did not predict poor
outcome in all-grade aSAH patients, whereas late-onset (3 days after aSAH)
hyponatremia in high-grade aSAH patients was associated with cerebral...
We read with interest the recent study by Zheng et al.[1] The authors
assessed the predictive value of hyponatremia for poor outcome or cerebral
infarction in high-grade patients after aneurysmal subarachnoid
haemorrhage (aSAH), and concluded that hyponatremia did not predict poor
outcome in all-grade aSAH patients, whereas late-onset (3 days after aSAH)
hyponatremia in high-grade aSAH patients was associated with cerebral
infarction. We would like to add further comment to this issue.
Hyponatremia and hypovolemia caused by cerebral salt wasting syndrome
(CSWS) are common in patients with aSAH, and these conditions are known as
one of the major risk factors for developing SCV, which is followed by
cerebral infarction.[2] To prevent SCV, we routinely manage aSAH patients
by early start (from day 1) of administering physiological saline and
sodium chloride so as to maintain a positive water balance and serum
sodium level of >140mEq/l. We previously reported the records of 115
aSAH patients managed with this protocol and found that SCV occurred in 7
patients (6.1 %); low-grade in three patients, high-grade in four
patients, and that SCV occurred within the first 6 days in 6 of 7 patients
(85.7%).[3] The occurrence rate of SCV after aSAH in our series was
substantially lower compared than those previously reported.[4],[5]
Statistical analysis revealed that accumulated water balance on day 2 had
an impact on the occurrence of SCV. In addition, from day 2 to day 6,
sodium intake of SCV group was required much more than that of non-SCV
group to maintain the serum sodium level. In spite of larger sodium
intake, serum sodium level in SCV group showed precipitous fall compared
with that in non-SCV group during the period. These findings suggest that
more severe salt wasting occurred in SCV group than in non-SCV group.
Based on these results, we suppose that early start of decent correction
of hyponatremia and hypovolemia might result in decrease of the incidence
of SCV after SAH. Special attention for management of CSWS should be paid
within the first 6 days.
References
1. Zheng B, Qiu Y, Jin H, Wang L, et al. A predictive value of
hyponatremia for poor outcome and cerebral infarction in high-grade
aneurysmal subarachnoid haemorrhage patients. J Neurol Neurosurg
Psychiatry 2011;82:213-7.
2. Chandy D, Sy R, Aronow WS, Lee WN, Maguire G, Murali R. Hyponatremia
and cerebrovascular spasm in aneurysmal subarachnoid hemorrhage. Neurol
India 2006;54:273-5.
3. Uozumi Y, Tsuzuki N, Katoh H, et al. Outcome in patients with ruptured
cerebral aneurysms following surgical clipping: management of cerebral
salt wasting syndrome and prevention of symptomatic cerebral vasospasm.
Surgery for Cerebral Stroke 2009;37:258-63.
4. Kassell NF, Sasaki T, Colohan AR, Nazar G: Cerebral vasospasm following
aneurysmal subarachnoid hemorrhage. Stroke 1985; 16: 562-72.
5. Kassell NF, Torner JC, Haley EC Jr, Jane JA, Adams HP, Kongable GL: The
International Cooperative Study on the Timing of Aneurysm Surgery, part 1:
overall management results. J Neurosurg 1990; 73: 18-36.
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We read with interest the recent study by Zheng et al.[1] The authors assessed the predictive value of hyponatremia for poor outcome or cerebral infarction in high-grade patients after aneurysmal subarachnoid haemorrhage (aSAH), and concluded that hyponatremia did not predict poor outcome in all-grade aSAH patients, whereas late-onset (3 days after aSAH) hyponatremia in high-grade aSAH patients was associated with cerebral...
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