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.

Conflict of Interest:

None declared

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.

Conflict of Interest:

None declared

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.

Conflict of Interest:

None declared

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.

Conflict of Interest:

None declared