We read the viewpoint on leg stereotypy1 by Joseph Jankovic with great interest. He has described leg stereotypy as repetitive, 1-4 Hz flexion extension, abduction-adduction movement at hips when the patient is seated and the feet rest on the floor.1 This movement has also been described to manifest as flexion extension at the knee joint or as tapping movement of foot.1 Patients as per this description have also been found to have...
We read the viewpoint on leg stereotypy1 by Joseph Jankovic with great interest. He has described leg stereotypy as repetitive, 1-4 Hz flexion extension, abduction-adduction movement at hips when the patient is seated and the feet rest on the floor.1 This movement has also been described to manifest as flexion extension at the knee joint or as tapping movement of foot.1 Patients as per this description have also been found to have some anxiety when asked to control these movements and also have an inner need to move their legs due to mounting tension. Additionally this movement has been described to reappear on distracting the patient.
Stereotypy has been defined as a non-goal-directed movement pattern that is repeated continuously for a period of time in the same form and on multiple occasions, and which is typically distractible.2,3 The key word discernable from this definition is its distractibility. These movements usually disappear when the patient is distracted with various stimuli especially when observed upon by others. This is in contrast with the above mentioned article where the patient's movements reappeared on distracting the patient. Second, stereotypic movements are not associated with an inner urge to perform the movement or to reduce an inner tension by performing the movement. This feature again contradicts with findings described in the above mentioned article in which patients experience an inner need to make the movement in response to an inner need. Such premonitory urges have however been described in the phenomenology of tics.4 Hence the reappearance of movement on distraction and presence of an inner urge to perform the movement create an uncertainity whether the described leg movement should be termed as stereotypy.
References
1. Leg stereotypy disorder. Jankovic J. J Neurol Neurosurg Psychiatry 2015;0:1-2.
2. Stereotypies: A Critical Appraisal and Suggestion of a Clinically Useful Definition. Mark J. Edwards, Anthony E. Lang,Kailash P. Bhatia. Movement Disorders, Vol. 27, No. 2, 2012.
3. Pandey S, Sarma N. Stereotypy After Acute Thalamic Infarct. JAMA Neurol. 2015;72(9):1068.
4. Christos Ganos, Davide Martino. Tics and Tourette Syndrome. Neurol Clin 33 (2015) 115-136.
The meta-analysis by Xu et al is a valiant effort to map the evidence
for modifiable risk factors of Alzheimer's disease (AD) (1). We
acknowledge this huge effort, however, we have serious concerns regarding
the systematic appraisal and the synthesis of the available data.
On top of the critique by Drs. Wu and Brayne (e-letter), a
comprehensive assessment of the article and its results can reveal
critical error...
The meta-analysis by Xu et al is a valiant effort to map the evidence
for modifiable risk factors of Alzheimer's disease (AD) (1). We
acknowledge this huge effort, however, we have serious concerns regarding
the systematic appraisal and the synthesis of the available data.
On top of the critique by Drs. Wu and Brayne (e-letter), a
comprehensive assessment of the article and its results can reveal
critical errors in data collection and the analysis of the available
evidence. An experienced methodologist could easily spot from the forest
plots in the supplementary material that all risk factors are in the same
direction, an observation that cannot be explained by chance.
Therefore, we tried to re-analyze the meta-analyses using data
reported in the supplementary material of this paper and, indeed, the
summary effect estimates could not be replicated. We figured out that the
authors have inadvertently used the extracted ORs (at least for binary
exposures) derived from the individual studies as is, without transforming
them into the logarithmic scale as it is required, leading to
miscalculations of the summary effect sizes. Thus, most if not all
inferences in the paper are based on these false summary estimates
resulting in misleading conclusions.
Besides the aforementioned analytical errors, we are afraid that the
extraction of relevant data points from the primary studies may suffer
from crucial errors as well. We summarise here potential problems for the
association between "ever vs never alcohol use" and AD as it illustrated
in supplementary material (page 184). Unfortunately, in 4 out of the 11
eligible studies the extracted estimates were wrong. Specifically, in 2
studies the authors included an estimate for the comparison of "wine
drinkers vs no drinkers" even though an estimate for "ever vs never
alcohol consumption" was available (2,3). In one study they inadvertently
reported the estimate for a comparison of tuberculosis history (4) instead
of the alcohol use, whereas in another study they extracted an estimate
for an occupational exposure to alcohols and phenols (as organic solvents)
(5). Moreover, it seems that the study "Lindsay, 2002" (3) has overlapping
populations with the study "CHSA, 1994" (6) and therefore it should not be
considered twice. Additionally, in one of the included studies (7) the
authors have captured an estimate that is most probably is a typo. In the
primary study, an OR of 4.10 (95% CI 0.60-80.50) is reported. Our back
calculations (based on the point estimate and the lower confidence
interval) have shown that the upper CI most probable was 28.05 and this
was not corrected by Xu et al, influencing the weight of this study in the
meta-analysis.
Taking all these discrepancies into account we tried to repeat the
meta-analysis for the exposure to alcohol and AD. The summary OR
(estimated by our team using correct analytical methods, correct effect
estimates and after the exclusion of the study with overlapping sample)
was 0.79 (95% CI: 0.63-0.98) for fixed effects and 0.84 (95% CI: 0.57-
1.24) for random effects models with I2=57%. In contrast the authors
presented a summary OR of 0.63 (95% CI, 0.48-0.79) under the fixed-effects
model with I2=11.3%. We have observed similar discrepancies for several
other risk factors. Obviously using these effects to calculate the
population attributable fractions led to the false conclusion that 66% of
the Alzheimer's disease cases could be prevented. Indeed, a more
conservative and thorough estimation of the population attributable risk
for modifiable risk factors of AD indicated that known risk factors are
responsible for only 28.2% (95% CI, 14.2% to 41.5%) of total AD cases
worldwide (8).
Furthermore, inclusion of studies with overlapping samples was also
observed in meta-analyses of key risk factors. For example, in the meta-
analysis of type 2 diabetes mellitus, the authors included three studies
on Cardiovascular Health Cognition Study (Kuller et al 2003, Becker et al
2009 and Irie et al 2008) and another two studies on Baltimore
Longitudinal Study of Aging (Moffat et al 2004, Dal et al 2005). However,
only the study with the longest follow-up period should be included in the
analysis for each of these cohort studies. The same caveat was observed in
the meta-analysis for educational attainment.
Additionally, for other risk factors (e.g socioeconomic status and
educational attainment) the authors have not harmonized the exposure of
interest, presenting separate meta-analyses for "high level versus low
level" and for "low level versus high level" of exposure.
Finally, we should express our concerns regarding the search strategy
applied from the authors. For example in the case of coffee or caffeine
drinking, a previous published meta-analysis in 2015 (9) includes more
studies and yields non-significant effect estimates (5 studies in the
paper by Kim et al and 4 studies in the paper by Xu et al). The authors
report a significant random-effects OR of 0.54 (95% CI: 0.39 to 0.69)
compared to 0.78 [95% CI: 0.78 to 1.22) by Kim et al which is clearly non-
significant. Several similar examples exist throughout the manuscript
(e.g. current vs. never statin use, NSAIDs use, ever vs. never smokers).
Having all these caveats in mind the editorial team of the journal
should thoroughly re-assess all the available evidence presented in this
paper.
References
1. Xu W, Tan LL, Wang H-F, Jiang T, Tan M-S, Tan LL, et al. Meta-
analysis of modifiable risk factors for Alzheimer's disease. J Neurol
Neurosurg Psychiatry. 2015;86(12):1299-306.
2. Tyas SL, Manfreda J, Strain LA, Montgomery PR. Risk factors for
Alzheimer's disease: a population-based, longitudinal study in Manitoba,
Canada. Int J Epidemiol. 2001 Jun;30(3):590-7.
3. Lindsay J, Laurin D, Verreault R, H?bert R, Helliwell B, Hill GB,
et al. Risk factors for Alzheimer's disease: a prospective analysis from
the Canadian Study of Health and Aging. Am J Epidemiol. 2002;156(5):445-
53.
4. Harmanci H, Emre M, Gurvit H, Bilgic B, Hanagasi H, Gurol E, et
al. Risk factors for Alzheimer disease: a population-based case-control
study in Istanbul, Turkey. Alzheimer Dis Assoc Disord. 2003;17(3):139-45.
5. Kukull WA, Larson EB, Bowen JD, McCormick WC, Teri L, Pfanschmidt
ML, et al. Solvent exposure as a risk factor for Alzheimer's disease: a
case-control study. Am J Epidemiol. 1995;141(11):1059-71.
6. The Canadian Study of Health and Aging: risk factors for
Alzheimer's disease in Canada. Neurology. 1994;44(11):2073-80.
7. Harwood DG, Barker WW, Loewenstein DA, Ownby RL, St George-Hyslop
P, Mullan M, et al. A cross-ethnic analysis of risk factors for AD in
white Hispanics and white non-Hispanics. Neurology. 1999;52(3):551-6.
8. Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential
for primary prevention of Alzheimer's disease: An analysis of population-
based data. Lancet Neurol. 2014;13(8):788-94.
9. Kim Y-S, Kwak SM, Myung S-K. Caffeine intake from coffee or tea
and cognitive disorders: a meta-analysis of observational studies.
Neuroepidemiology. 2015;44(1):51-63.
We thank Dr. Solari for pointing out an aspect of possible
misunderstanding, but surely not incorrectness. We agree that the reverse
odds ratio of 5.63 (95% CI 2.87 to 11.05, p<0.001) would more clearly
refer to the odds of achieving informed choice. Still the reported odds
ratio of 0.18 (95% CI 0.09 to 0.35, p<0.001) gives exactly the same
information and is probably more intuitively underst...
We thank Dr. Solari for pointing out an aspect of possible
misunderstanding, but surely not incorrectness. We agree that the reverse
odds ratio of 5.63 (95% CI 2.87 to 11.05, p<0.001) would more clearly
refer to the odds of achieving informed choice. Still the reported odds
ratio of 0.18 (95% CI 0.09 to 0.35, p<0.001) gives exactly the same
information and is probably more intuitively understood as an odds ratio
below 1 usually represents a positive intervention effect by avoiding an
unwanted outcome, i.e. in this study avoiding the "absence of informed
choice". Therefore, it needs to be stressed that this is not an instance
of "errors as part of science" as implied by Dr. Solari, but simply a
matter of reporting.
Furthermore, the proposed way of calculating the odds ratio is rather
unusual, as odds are normally calculated within exposure groups and not
within outcome groups. The latter would describe the odds to be in the
control or in the intervention group, which clearly does not make sense as
we want to describe the odds of achieving the outcome. Of course, the odds
ratio will be the same for both approaches.
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.
The meta-analysis by Xu et al is a valiant effort to map the evidence for modifiable risk factors of Alzheimer's disease (AD) (1). We acknowledge this huge effort, however, we have serious concerns regarding the systematic appraisal and the synthesis of the available data.
On top of the critique by Drs. Wu and Brayne (e-letter), a comprehensive assessment of the article and its results can reveal critical error...
Dear Editor,
We thank Dr. Solari for pointing out an aspect of possible misunderstanding, but surely not incorrectness. We agree that the reverse odds ratio of 5.63 (95% CI 2.87 to 11.05, p<0.001) would more clearly refer to the odds of achieving informed choice. Still the reported odds ratio of 0.18 (95% CI 0.09 to 0.35, p<0.001) gives exactly the same information and is probably more intuitively underst...
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...
Pages