I enjoyed reading the paper of Sascha Kopke et al. [1] on the
efficacy of an evidence-based information program for people with recently
diagnosed multiple sclerosis. I noticed, however that the odds ratio (OR)
for the primary endpoint (achieving 'informed choice') is incorrect, both
in the Abstract and in the Results.
Abstract: 'For the primary endpoint, a significant difference was
shown with 50 of 85 (59%) pa...
I enjoyed reading the paper of Sascha Kopke et al. [1] on the
efficacy of an evidence-based information program for people with recently
diagnosed multiple sclerosis. I noticed, however that the odds ratio (OR)
for the primary endpoint (achieving 'informed choice') is incorrect, both
in the Abstract and in the Results.
Abstract: 'For the primary endpoint, a significant difference was
shown with 50 of 85 (59%) participants in the intervention group achieving
informed choice after 6 months compared with 18 of 89 (20%) in the control
group (OR 0.2 (95% CI 0.1 to 0.4), p<0.001).'
Results: 'The intervention led to significantly more participants
with informed choice during 6 months of follow-up (figure 2A), with 50
participants (58.8%) in the IG compared with 18 (20.2%) in the CG
(difference 38.6% (95% CI 24.1% to 53.1%); OR 0.18 (95% CI 0.09 to 0.35),
p<0.001)'.
The OR is should in fact be 5.63 (95% CI 2.87-11.05) meaning that
patients who received the evidence-based information program achieved
informed choice 5.6 times more often than patients who received the
control treatment.
The correct OR (a ratio of ratios) is easily arrived at from
examination of the 2 x 2 table below.
Informed choice- Intervention group: Control group
Yes- 50 : 18
No- 35 : 71
First ratio (informed choice achieved): 50/18 = 2.78.
Second ratio (informed choice not achieved): 35/71 = 0.49.
Ratio of the two ratios (OR): 2.78/0.49 = 5.67.
A simpler but less intuitive formula is: 50 x 71/18 x 35 = 5.67.
Errors are part of science, and sometimes even obvious ones can pass
unnoticed in quality peer-reviewed journals. The OR provides information
that both clinicians and patients can use for decision making. I hope this
letter contributes to making clearer the main findings of this important
paper.
I have some comments concerning the report by S. Jesse, D.R. Thal and
A.C. Ludolph, recently published in JNNP September 15 2015, pag. 1166-1168
"Thiamine deficiency in Amyotrophic Lateral Sclerosis".
In a research dated 1981 Rindi et al. showed that in 12 CSF samples
obtained from different healthy subjects, without any clinical disorder
involving thiamin status, the only thiamin compounds detected after
electrophoretic...
I have some comments concerning the report by S. Jesse, D.R. Thal and
A.C. Ludolph, recently published in JNNP September 15 2015, pag. 1166-1168
"Thiamine deficiency in Amyotrophic Lateral Sclerosis".
In a research dated 1981 Rindi et al. showed that in 12 CSF samples
obtained from different healthy subjects, without any clinical disorder
involving thiamin status, the only thiamin compounds detected after
electrophoretic separation were constantly free thiamine (T) and thiamine-
monophosphate (TMP), their mean percentage being 40.7% and 59.3% of total
thiamin content respectively. EXPERIENTIA 37, 975-976 (1981).
In a successive study Poloni et al. (Arch. Neurol., 1982,39, 507-509)
measured free thiamin and thiamin monophosphate levels in plasma and
cerebral spinal fluid of patients with ALS, alcoholics, and controls. In
plasma of patients with ALS, as well as in plasma and cerebrospinal fluid
(CSF) of alcoholics, both thiamin and thiamin monophosphate concentrations
were decreased. In CSF of patients with ALS, however, thiamin
monophosphate values decreased much more than thiamin levels. This same
finding has been observed, interestingly, only in pigs who showed together
with rabbits, the highest levels of thiamine in the CSF. In our opinion
the selective impairment of thiamin monophosphate production by nerve
cells is likely to result from the reduction of the activity of thiamin
pyrophosphatase, an enzyme synthesized and highly concentrated in the
Golgi complex, a component of the cell where complex molecules such as
proteins are synthesized and packaged for use in the body. Thiamin
pyrophosphatase diminish in ALS, as well as in experimental motor neuronal
degeneration or axotomy. Thus, the thiamin to thiamin monophosphate ratio
could be taken as an index of the impairment of neuronal protein synthesis
in ALS (Poloni et al.., Arch. Neurol., 1982, 39, 507-509).
In an other study, thiamine and thiamine monophosphate levels were
measured in the CSF of patients with typical sporadic ALS (50 cases), in
other motor neuron diseases (MND) (14 cases), and in patients with upper
and/or lower motor neuron lesions of varying origin (disseminated
sclerosis, polyneuropathy, spondylotic myelopathy). The thiamine to
thiamine monophosphate ratio was greater than or equal to 1 in a high
percentage of patients with typical sporadic ALS (94%), in 35.7% of cases
with other MND, while it was below one in all the other patients. The
decrease of thiamin monophosphate with the inversion of the thiamin to
thiamin monophosphate ratio is a finding highly specific to typical
sporadic ALS (Poloni et al. It.J.Neurol: Sci.,1986).
Other researchers measured the enzymes involved in thiamin synthesis:
thiamin pyrophosphatase (TPPase) and thiamin monophosphatase (TMPase) in
brain tissue obtained at autopsy from ALS and Parkinsonism-dementia
patients from Guam and from Guamanian patients who died from other
diseases (controls). TPPase content, chemically determined at pH 9.0, was
found to be significantly reduced in the frontal cortex of ALS and
Parkinsonism-dementia patients compared to controls. TMPase content, on
the contrary, was unchanged (Laforenza et al., J. Neurol. Sci., 1992).
Thiamin deficiency causes dry beriberi, a neurologic al disease
characterized by "burning" feet, peripheral neuropathy, and Wernicke-
Korsakoff syndrome; on this background, in my opinion the method used in
this paper to determinate the level of thiamine is indirect and easily
subject to drawbacks; Wernicke encephalopathy, istologically observed in
two ALS cases, may be due to undernutrition that may be frequently
associated in a disease where severe dysphagia may be present in the
terminal stage.
The reason of the low TMP CSF levels with inversion of the ratio T/TMP,
peculiar of ALS patients and ineterestingly found only in pigs, remains
unexplained.
We read with great interest the paper by Pagano et al. who conducted
a systematic review of prospective, randomised placebo-controlled trials
(RCT), in order to assess the efficacy and safety of cholinesterase
inhibitors (ChIs) in patients with Parkinson's disease (PD).[1] They
concluded that ChIs are effective in the treatment of cognitive impairment
in patients with PD. We concur with the authors' nuanced conclusion in...
We read with great interest the paper by Pagano et al. who conducted
a systematic review of prospective, randomised placebo-controlled trials
(RCT), in order to assess the efficacy and safety of cholinesterase
inhibitors (ChIs) in patients with Parkinson's disease (PD).[1] They
concluded that ChIs are effective in the treatment of cognitive impairment
in patients with PD. We concur with the authors' nuanced conclusion in the
Discussion that based on this meta-analysis no exclusive position can be
assumed regarding the efficacy of ChIs in the treatment of frequent
falling in PD patients. As the authors point out, the included RCT study
by Chung et al. showed that ChI (donepezil) treatment was most effective
in the subgroup of patients with frequent falls.[2] This observation
suggests that a possible therapeutic indication for cholinergic
augmentation therapy to treat falls in PD may require a more personalised
or precision type of medicine approach. Cholinergic treatment for falling
will most likely have highest efficacy in those PD patients that have the
most profound cholinergic system loss, i.e. frequent falling with comorbid
cognitive impairment. This may be readily identified by a simple clinical
routine, however, this approach would need further validation.[3] It
should be noted that cognitive impairment and frequent falling in PD may
be caused not only by cholinergic system loss. We have recently shown that
cognitive impairment, freezing of gait, and other axial motor impairments
are also associated with the presence of beta-amyloid proteinopathy in
PD.[4-6] Therefore, future studies should not only have a more detailed
fall status assessment but also identify other extra-nigral pathologies in
PD that may preclude optimal cholinergic augmentation therapy in these
patients.
References:
1. Pagano G, Rengo G, Pasqualetti G, et al. Cholinesterase inhibitors
for Parkinson's disease: a systematic review and meta-analysis. J Neurol
Neurosurg Psychiatry 2015;86:767-73.
2. Chung KA, Lobb BM, Nutt JG, et al. Effects of a central
cholinesterase inhibitor on reducing falls in Parkinson disease. Neurology
2010;75:1263-9.
3. Muller ML, Bohnen NI, Kotagal V, et al. Clinical markers for
identifying cholinergic deficits in Parkinson's disease. Mov Disord
2015;30:269-73.
4. Petrou M, Bohnen NI, Muller ML, et al. Abeta-amyloid deposition in
patients with Parkinson disease at risk for development of dementia.
Neurology 2012;79:1161-7.
5. Muller ML, Frey KA, Petrou M, et al. Beta-amyloid and postural
instability and gait difficulty in Parkinson's disease at risk for
dementia. Mov Disord 2013;28:296-301.
6. Bohnen NI, Frey KA, Studenski S, et al. Extra-nigral pathological
conditions are common in Parkinson's disease with freezing of gait: an in
vivo positron emission tomography study. Mov Disord 2014;29:1118-24.
The meta-analysis by Xu et al., (2015)[1] reviews over 300 papers and
identified 93 modifiable risk factors for Alzheimer's disease. Among these
risk factors, population attributable risks (PAR) of nine important
factors were estimated to contribute to up to 66% of Alzheimer's disease
cases globally. We acknowledge the great effort of this massive review but
there are some substantial analytical issues which should be highl...
The meta-analysis by Xu et al., (2015)[1] reviews over 300 papers and
identified 93 modifiable risk factors for Alzheimer's disease. Among these
risk factors, population attributable risks (PAR) of nine important
factors were estimated to contribute to up to 66% of Alzheimer's disease
cases globally. We acknowledge the great effort of this massive review but
there are some substantial analytical issues which should be highlighted.
(1) Mixture of odds ratio (OR) and relative risk (RR) in the review
Although the authors clearly knew the difference between odds ratio (OR)
and relative risk (RR) they still combined these results and generated
pooled estimates in the meta-analysis. It is generally considered
problematic to combine these two epidemiological measures.[2] Odds ratios
tend to provide a stronger effect size than relative risks with the two
measures only being very close if the prevalence of a disease/disorder is
very low. Dementia and Alzheimer's disease are not rare therefore this
approach may have led to overestimation of the effect size of risk
factors. Although the authors stratified cohort and case-control studies
in the meta-analyses, they still reported overall pooled estimates. Given
the large number of papers, it would have been possible to focusing only
on studies reporting relative risk.
(2) Grades of evidence
Grades of evidence were based on heterogeneity and pooled population size.
Although heterogeneity indicates consistency of the results across
individual studies, a non-significant I-squared should not be taken as
evidence of no heterogeneity.[3] In particular, observational studies
generally depend on their research settings and use a variety of methods
with diverse study populations. Apparently, similar results can mask
considerable underlying variation.
In the appendix, the authors further excluded some studies according
to concerns about study quality and methods. This is an important
methodological point and exclusion of studies requires a systematic
approach in order for the reader to understand the decisions reviewers
have made. Assessments of study quality should be included in "grades of
evidence". This corresponds to the first point that the authors could have
focused on studies using prospective designs and proper methodologies to
provide robust estimates.
(3) PAR estimation without taking inter-relationship of risk factors
into account
The PAR calculation did not take into account the inter-relationship
between the nine factors leading to spuriously high PAR estimates (66%).
Other studies[4,5] have addressed this recognised limitation and an
updated analysis of the paper cited by Xu et al[6] was published precisely
to correct this important concern. This reduces PAR to around 30%. This is
because risk factors such as obesity/low BMI index, frailty/low BMI index
(and indeed education and depression) are known to be highly related.
Epidemiologists are well aware of the joke that with such naive analyses
we claim to be able to prevent over 100% of disorders.
Finally, some confusing factors such as "current smoking in Asian
population" and "diabetes mellitus-II in Asian population" were included
in the analysis. The authors suggest the PAR estimate was applied to
global Alzheimer's disease cases, but these factors only focus on Asian
populations. It is unclear whether it is appropriate to apply these
globally.
We suggest that the findings of this paper over-estimate the effect
size and contribution of risk factors for dementia and Alzheimer's disease
and that, unfortunately, this contributes to further confusion in wildly
over-interpreted media headlines.
References
[1] Xu W, Tan L, Wang H-F, Jiang T, Tan M-S, Tan L, et al. Meta-
analysis of modifiable risk factors for Alzheimer's disease. Journal of
Neurology, Neurosurgery & Psychiatry. 2015. DOI: 10.1136/jnnp-2015-
310548
[2] Bonita R, Beaglehole R & Kjellstrom T. WHO Basic
Epidemiology. 2006. Available:
apps.who.int/iris/bitstream/10665/43541/1/9241547073_eng.pdf
[3] Higgins J & Green S. Cochrane Handbook for Systematic Reviews
of Interventions. 2011. Available:
handbook.cochrane.org/chapter_9/9_5_2_identifying_and_measuring_heterogeneity.htm
[4] Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential
for primary prevention of Alzheimer's disease: an analysis of population-
based data. The Lancet Neurology. 2014;13(8):788-94.
[5] Di Marco LY, Marzo A, Mu?oz-Ruiz M, Ikram MA, Kivipelto M,
Ruefenacht D, et al. Modifiable lifestyle factors in dementia: a
systematic review of longitudinal observational cohort studies. Journal of
Alzheimer's Disease. 2014;42(1):119-35.
[6] Barnes DE, Yaffe K. The projected effect of risk factor reduction
on Alzheimer's disease prevalence. The Lancet Neurology. 2011;10(9):819-
28.
We read with interest the recent systematic review and meta-analysis,
"Pharmacological treat-ment of neuropsychiatric symptoms in Alzheimer's
disease"(1). By examining the evidence for treating heterogeneous range of
neuropsychiatric syndromes in persons with Alzheimer's disease (AD), this
study found favorable results for the use of cholinesterase inhibitors
(ChEIs) and atyp-ical antipsychotics albeit with risk of side ef...
We read with interest the recent systematic review and meta-analysis,
"Pharmacological treat-ment of neuropsychiatric symptoms in Alzheimer's
disease"(1). By examining the evidence for treating heterogeneous range of
neuropsychiatric syndromes in persons with Alzheimer's disease (AD), this
study found favorable results for the use of cholinesterase inhibitors
(ChEIs) and atyp-ical antipsychotics albeit with risk of side effects, but
not for selective serotonin uptake inhibitors (SSRIs), mood stabilizers,
or an N-Methyl-D-Aspartate receptor antagonist. The authors sug-gested
that their result is generalizable across the spectrum of AD severity.
While these findings are important, the results could be expanded. For
example, important points including investiga-tion of the heterogeneity
(in assessment scales, results, and severity of AD), and methodological
limitations need addressing for better understanding of the relative
significance of the findings.
The Neuropsychiatric Inventory (NPI) used in these trials varies and
captures a range of 10 to 12 syndromes. These variations increase the
heterogeneity in the findings. Furthermore, this hetero-geneity is
enhanced when different compounds with differing mechanism of action or
affinity that are designed primarily for individual syndrome use (e.g.,
antipsychotics for psychosis or de-lusion, or antidepressant for
depression, or apathy) are combined. In other words, total NPI score is
not necessarily the best reflection of improvement, rather, looking at
subtest of items is per-haps more relevant not only in light of studying
mechanism of action for each compound, but also for better treatment
planning. Same can be said in light of the NPI that aggregates many dif-
ferent symptoms, although all related to Behavioral and psychological
symptoms of dementia (BPSD), one cannot reasonably expect each medication
to be beneficial to all BPSD - i.e. depres-sion and apathy may require
something slightly stimulating, while anxiety and agitation may re-quire
something slightly sedating. Combining them all under total NPI score and
expecting a medication that can cure all is unreasonable. It would have
been more informative if these stud-ies reported the effect of each drug
on the specific BPSD syndromes and have proper scales to quantify them.
Although well formulated to quantify the benefits and safety profiles of
various compounds on overall neuropsychiatric syndromes, this meta-
analysis could have benefited from taking into account several
methodological points, including 1) whether the goal of the included
studies was primary or secondary to investigate neuropsychiatric
syndromes; and 2) investigated moderating clinical factors.
The first concern of this study is the lack of explicit statement
about the goal of the included studies, which could have shown
experimenter bias. This is important for two reasons, A) if the primary
goal of the studies was other than neuropsychiatric syndrome, the weight
given to indi-vidual compounds would be different. For example, one would
anticipate that the cholinesterase inhibitor trials would not be primarily
set to find differences in behavioral issues versus the atyp-ical
antipsychotic trials, which would be particularly designed to identify
such an effect. B) This could be a power issue in that, if the secondary
data come from post-hoc analysis, the result could have been underpowered.
The second concern is the absence of moderating factors such as
inpatient/outpatient, treatment duration, dosage, or severity of AD
investigation. Teasing-apart treatment effect for mild, moderate, or
severe AD would have added more strength to their find-ing. It is possible
that the lack of effect observed in some of the studies is masked because
of se-verity of AD, or that optimal dosage was not applied for the
preferred duration of treatment.
In conclusion, with both favorable and dissenting results, although
the meta-analysis is well de-signed and carried out, it could have been
more informative about the use of psychotropic medi-cation for treating
neuropsychiatric syndromes in AD. It could have informed us about the use
of each compound for specific AD severity, and duration and dosage of
treatment. Also, it could have added notes as to whether these treatment
approaches are optimal when used in combina-tion or alone. Given that this
study compares itself to earlier meta-analysis and reviews, thus fu-ture
studies further benefit by taking into consideration of the above-
mentioned points to opti-mize findings.
References:
1. Wang J, Yu JT, Wang HF, et al. Pharmacological treatment of
neuropsychiatric symptoms in Alzheimer's disease: a systematic review and
meta-analysis. J Neurol Neurosurg Psychiatry. 2015;86(1):101-109.
The article by Roberts and colleagues on formaldehyde and ALS, is
important for its contribution to job related hazards of formaldehyde
exposure. One occupation that would be interesting to examine, is wood
working/carpentry using mainly plywood. At the core of its manufacture, is
formaldehyde. Plywood for indoor use generally uses urea-formaldehyde
glue, which has limited water resistance, while outdoor and marine-grade...
The article by Roberts and colleagues on formaldehyde and ALS, is
important for its contribution to job related hazards of formaldehyde
exposure. One occupation that would be interesting to examine, is wood
working/carpentry using mainly plywood. At the core of its manufacture, is
formaldehyde. Plywood for indoor use generally uses urea-formaldehyde
glue, which has limited water resistance, while outdoor and marine-grade
plywood are designed to withstand moisture, and use a water resistant
phenol-formaldehyde glue.. Working with plywood produces significant
amounts of fine dust containing formaldehyde as well as wood particles. If
adequate protection is not used, and ventilation poor, the results can
range from eye irritation to various forms of respiratory compromise.
Neurological effects are equally likely, especially after years of working
in similar dust/formaldehyde environments.
Anthony David's article on Paralympics and conversion disorder opens
an important and useful debate about the legitimacy of physical disability
when related to a functional (psychogenic) disorder and the extent to
which patients with these disorders should have access to the normal
rights of a disabled person(3). If functional disorders, and to be clear
we are talking here specifically about functional limb weakness, are...
Anthony David's article on Paralympics and conversion disorder opens
an important and useful debate about the legitimacy of physical disability
when related to a functional (psychogenic) disorder and the extent to
which patients with these disorders should have access to the normal
rights of a disabled person(3). If functional disorders, and to be clear
we are talking here specifically about functional limb weakness, are a
genuine cause of disability why would they be excluded from the
paralympics?
The article highlighted the important fact that conversion disorder
does not stand alone in being excluded from Paralympic classification and
that each sport has different rules(5). The classification itself however
is not based on disease categories but on impairments that are
quantifiable and permanent. As a result many disabling conditions do not
'fit'. As well as chronic pain and epilepsy, it is important we think to
highlight that other 'motor' neurological disorders including Parkinson's
disease are usually excluded so this is not an issue about having a
pathological disease to get you "entry to the club".
We recognise the need for fairness and agree there is an inherent
problem in allowing someone with functional limb weakness that, by
definition can transiently improve, in competing against athletes with
fixed deficits. Improvement in motor function in functional disorders
occurs when the patient is not attending to the limb and is often hard for
the person themselves to appreciate(6). Whether this is really an issue in
sports where the limb is not ostensibly being used anyway, such as
wheelchair sports is debatable, although we recognise there may be
advantages in terms of core stability or training for the patient with a
functional disorder and matching deficits could be difficult.
However, we don't agree that issues of 'secondary gain' should come
in to the discussion. "Secondary gain", the interpersonal or social
advantage that occurs secondary to illness which may unconsciously
perpetuate disability, is not specific to patients with functional
disorder but exists across the whole spectrum of disease. What differs is
our social response to it. In many situations we actively encourage it,
helping the patient solicit disability benefits or participation in
'positive' disability activities. But for some disorders we actively
discourage it believing it is not in the patients best interest to benefit
from being unwell- such considerations are almost always made in a
paternalistic fashion with little open discussion with patient about what
is in their interest. In fact decisions on secondary gain can quickly
become moral judgements and are prone to error, prejudice and social bias.
In a hypothetical future in which spinal cord injury could be cured
with regenerative medicine, would we ban all patients with potentially
curable conditions from taking part to make sure that they were all
correctly motivated to treatment? Patients with epilepsy sometimes refuse
surgery even when its offered(2) and experience the 'burden of normality'
that seizure freedom may bring(7). But we do not ban patients with
epilepsy from state related financial benefits if they refuse treatment.
The reality for many patients with functional motor disorders is that
their condition may not be reversible even if it retains the potential for
improvement. Patients may not even be a candidate for treatment, either
because of lack of success of previous treatment or poor availability of
adequate treatment. Furthermore, many well motivated patients do not
achieve improvement even with access to treatment(4). Is paralympic sport
a bad outcome in such circumstances?
Finally we dont agree that the DSM-5 definition of conversion
disorder (CD) which includes the criterion that "The symptom or deficit
causes significant distress, psychosocial impairment or warrants medical
evaluation" implies that 'the person with CD is barred from overcoming or
compensating for their predicament, or coping with it positively, e.g.
taking up competitive sports), without distress'(1)(3). The criterion is
worded with an 'or' to ensure that patients can receive this diagnosis who
are coping it with positively but still require medical evaluation to
determine why they have a motor symptom.
We can see the difficulties of classifying patients with functional
limb weakness for Paralympic sport but do not think issues of secondary
gain should be a factor in deciding eligibility.
1. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5TM). Arlington, Virginia:
American Psychiatric Press, Inc.; 2013.
2. Anderson CT, Noble E, Mani R, Lawler K, Pollard JR. Epilepsy
Surgery: Factors That Affect Patient Decision-Making in Choosing or
Deferring a Procedure. Epilepsy Res Treat 2013; 2013:10.1155/2013/309284.
3. David AS. Paralympics and conversion disorder. J Neurol Neurosurg
Psychiatry 2015; :10.1136/jnnp - 2014-309957.
4. Gelauff J, Stone J, Edwards M, Carson A. The prognosis of
functional (psychogenic) motor symptoms: a systematic review. J Neurol
Neurosurg Psychiatry 2014; 85:220-6.
5. International Paralympic Committee. Athletics Classification
Rules and Regulations. www.paralympic.org 2014;
6. Pare?s I, Saifee T, Kassavetis P. Believing is perceiving: mismatch
between self-report and actigraphy in psychogenic tremor. Brain 2012;
135:117-23.
7. Wrench J, Wilson SJ, Bladin PF. Mood Disturbance before and after
Seizure Surgery: A Comparison of Temporal and Extratemporal Resections.
Epilepsia 2004; 45:534-43.
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.
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.
As a research intern aspiring to be a neurologist, I found Dr. Mathew
et al. article highly interesting and thought provoking [1]. Multiple
sclerosis is a complex neurological condition to manage, given its
numerous phenotypes.
It was very interesting to note that the authors found similar
imaging features on conventional MR brain scan in patients with multiple
sclerosis (MS)-like disease in association with LH...
As a research intern aspiring to be a neurologist, I found Dr. Mathew
et al. article highly interesting and thought provoking [1]. Multiple
sclerosis is a complex neurological condition to manage, given its
numerous phenotypes.
It was very interesting to note that the authors found similar
imaging features on conventional MR brain scan in patients with multiple
sclerosis (MS)-like disease in association with LHON (LMS) as well as
multiple sclerosis (MS) and hypothesized that mitochondrial dysfunction
could be a common pathophysiological pathway in the formation of white
matter lesions in these disorders [1].
Diffusion tensor MR imaging (DT MRI) has shown to be useful in
detecting micro-structural alterations in white matter and grey matter in
MS, in seemingly "normal -appearing white matter and gray matter" on
conventional MR images [2,3]. Recent studies also indicate that DT MRI may
demonstrate characteristic features in LHON such as decreased fractional
anisotropy (FA) and an increased mean diffusivity and radial diffusivity,
affecting exclusively the optic tracts and optic radiations, and in some
patients the acoustic radiations [4,5]. In that regard, it would be
useful to know if DT MRI could further identify any specific micro-
structural alteration that are common in these two conditions, which may
indeed act as a biomarker, and perhaps fuel future research in genotype-
phenotype correlation utilizing advanced MRI techniques including DT MRI
and functional MRI techniques.
References
1. Matthews L, Enzinger C, Fazekas F et al. MRI in Leber's hereditary
optic neuropathy: the relationship to multiple sclerosis. J Neurol
Neurosurg Psychiatry. 2015 May; 86(5):537-42
2. Fox RJ. Picturing multiple sclerosis: conventional and diffusion
tensor imaging. Semin Neurol. 2008 Sep; 28(4):453-66
3. Goldberg-Zimring D, Mewes AU, Maddah M, Warfield SK. Diffusion
tensor magnetic resonance imaging in multiple sclerosis. J Neuroimaging.
2005;15(4 Suppl):68S-81S.
4. Milesi J, Rocca MA, Bianchi-Marzoli S et al. Patterns of white
matter diffusivity abnormalities in Leber's hereditary optic neuropathy: a
tract-based spatial statistics study. J Neurol. 2012 Sep; 259(9):1801-7
5. Manners DN, Rizzo G, La Morgia C et al. Diffusion Tensor Imaging
Mapping of Brain White Matter Pathology in Mitochondrial Optic
Neuropathies. AJNR Am J Neuroradiol. 2015 Mar 19.
I enjoyed reading the paper of Sascha Kopke et al. [1] on the efficacy of an evidence-based information program for people with recently diagnosed multiple sclerosis. I noticed, however that the odds ratio (OR) for the primary endpoint (achieving 'informed choice') is incorrect, both in the Abstract and in the Results.
Abstract: 'For the primary endpoint, a significant difference was shown with 50 of 85 (59%) pa...
I have some comments concerning the report by S. Jesse, D.R. Thal and A.C. Ludolph, recently published in JNNP September 15 2015, pag. 1166-1168 "Thiamine deficiency in Amyotrophic Lateral Sclerosis". In a research dated 1981 Rindi et al. showed that in 12 CSF samples obtained from different healthy subjects, without any clinical disorder involving thiamin status, the only thiamin compounds detected after electrophoretic...
We read with great interest the paper by Pagano et al. who conducted a systematic review of prospective, randomised placebo-controlled trials (RCT), in order to assess the efficacy and safety of cholinesterase inhibitors (ChIs) in patients with Parkinson's disease (PD).[1] They concluded that ChIs are effective in the treatment of cognitive impairment in patients with PD. We concur with the authors' nuanced conclusion in...
The meta-analysis by Xu et al., (2015)[1] reviews over 300 papers and identified 93 modifiable risk factors for Alzheimer's disease. Among these risk factors, population attributable risks (PAR) of nine important factors were estimated to contribute to up to 66% of Alzheimer's disease cases globally. We acknowledge the great effort of this massive review but there are some substantial analytical issues which should be highl...
We read with interest the recent systematic review and meta-analysis, "Pharmacological treat-ment of neuropsychiatric symptoms in Alzheimer's disease"(1). By examining the evidence for treating heterogeneous range of neuropsychiatric syndromes in persons with Alzheimer's disease (AD), this study found favorable results for the use of cholinesterase inhibitors (ChEIs) and atyp-ical antipsychotics albeit with risk of side ef...
The article by Roberts and colleagues on formaldehyde and ALS, is important for its contribution to job related hazards of formaldehyde exposure. One occupation that would be interesting to examine, is wood working/carpentry using mainly plywood. At the core of its manufacture, is formaldehyde. Plywood for indoor use generally uses urea-formaldehyde glue, which has limited water resistance, while outdoor and marine-grade...
Anthony David's article on Paralympics and conversion disorder opens an important and useful debate about the legitimacy of physical disability when related to a functional (psychogenic) disorder and the extent to which patients with these disorders should have access to the normal rights of a disabled person(3). If functional disorders, and to be clear we are talking here specifically about functional limb weakness, are...
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...
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...
As a research intern aspiring to be a neurologist, I found Dr. Mathew et al. article highly interesting and thought provoking [1]. Multiple sclerosis is a complex neurological condition to manage, given its numerous phenotypes.
It was very interesting to note that the authors found similar imaging features on conventional MR brain scan in patients with multiple sclerosis (MS)-like disease in association with LH...
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