Dear Editor,

We thank Abat et al. for re-emphasizing an important interpretation of our work, namely that sex-differences in life-expectancy likely influenced the presented lifetime risks [1]. Indeed, in our paper we repeatedly discussed in several sections (for instance in the methods) that differences in life-expectancy between men and women could differentially affect their lifetime risk. It was for this reason that we consequently decided to analyze the data in a sex-specific manner while taking the competing risk of death into account in order to prevent potential overestimation.

Abat et al. unfortunately also allege that we attributed the observed sex-differences in disease risk to sex-specific effects on a biological level. The authors have seemingly missed our discussion at length arguing that observed differences in lifetime risk may be primarily attributed to the effects of differences in life-expectancy between men and women: “Apart from a longer life-expectancy in general, these findings may be explained by smaller differences in life-expectancy between men and women in the Netherlands (1.8 years), compared with the USA (4.8 years). With longer life-expectancy, individuals in this study simply had more time to develop these diseases in a timeframe with high age-specific incidence rates.”

It seems thus that ours and Abat and co-authors’ interpretation of our findings is pretty much congruent, i.e. age, irrespective of sex, should be considered as the main driver for the observed differences in lifetime risks of these diseases. Yet, in order not to rule out other interpretations prematurely, we also indicate that consideration should be given to potential sex-specific risk factors. For example, we observed a lower educational level for women compared to men which may have led to a lower resilience for dementia in women.

Reference
1 Licher S, Darweesh SKL, Wolters FJ, et al. Lifetime risk of common neurological diseases in the elderly population. J Neurol Neurosurg Psychiatry 2018;:jnnp-2018-318650.

Re: A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome

Viraj Bharambe Specialist registrar in neurology
John C Williamson Specialist registrar in neurology
Andrew J Larner Consultant Neurologist

Cognitive Function Clinic
Walton Centre for Neurology and Neurosurgery
Lower Lane
Fazakerley
Liverpool
L9 7LJ
UK
e-mail: a.larner@thewaltoncentre.nhs.uk

Teodoro et al. present evidence for shared cognitive symptoms in fibromyalgia, chronic fatigue syndrome, and functional neurological disorders, and hypothesize that functional cognitive disorders (FCD) may share similar symptoms.1 We present data which speak to this issue.

We have previously reported preliminary data examining performance on the mini-Addenbrooke’s Cognitive Examination (MACE) by patients diagnosed with fibromyalgia2 as part of a larger study of MACE.3 Here, we update these data for fibromyalgia patients (n = 17; F:M = 17:0; age range 33-56 years, median 49) and compare them to MACE performance by patients diagnosed with FCD (n = 43; F:M = 18:25; age range 28-82 years, median 58).4

There was no statistical difference (p > 0.1) in the proportions of patients scoring below the two cut-off scores (≤21/30, ≤25/30) defined in the index MACE report.5 Looking at MACE subscores (Attention, Registration, Verbal fluency, Clock Drawing, Memory recall), the proportions scoring at ceiling were not statistically different (p > 0.1) in the fibromyalgia and FCD groups. Ranking performance in cognitive domains from worst to best showed the same pattern in both patient groups, namely Verbal fluency, Memory recall, Registration, Attention, and Clock drawing.

Although numbers are small and the cognitive testing relatively simple, and the group demographics differ (both gender and age p < 0.05), nevertheless we suggest this evidence supports the hypothesis of Teodoro et al. of shared cognitive symptoms in fibromyalgia and FCD.

References

1. Teodoro T, Edwards MJ, Isaacs JD. A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome: systematic review. J Neurol Neurosurg Psychiatry 2018; 89: 1308-19. doi: 10.1136/jnnp-2017-317823.
2. Williamson J, Larner AJ. Cognitive dysfunction in patients with fibromyalgia. Br J Hosp Med 2016; 77: 116. doi: 10.12968/hmed.2016.77.2.116.
3. Williamson J, Larner AJ. MACE for the diagnosis of dementia and MCI: 3-year pragmatic diagnostic test accuracy study. Dement Geriatr Cogn Disord 2018; 45: 300-7. doi: 10.1159/000484438.
4. Bharambe V, Larner AJ. Functional cognitive disorders: demographic and clinical features contribute to a positive diagnosis. Neurodegener Dis Manag 2018; 8: 377-83. doi: 10.2217/nmt-2018-0025.
5. Hsieh S, McGrory S, Leslie F, et al. The Mini-Addenbrooke’s Cognitive Examination: a new assessment tool for dementia. Dement Geriatr Cogn Disord 2015; 39: 1-11. doi: 10.1159/000366040.

Conflicts of interest
The authors declare no conflict of interest

We read with great interest the recent report of Banerjee and colleagues of three cases of minimally symptomatic cerebral amyloid angiopathy-related inflammation (CAA-ri) cases, drawing attention to the possibility of a wider spectrum of clinical manifestations in patients with CAA-ri than previously described1.
Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare form of meningoencephalitis, presenting acutely with cognitive decline, seizures, headache and /or encephalopathy in most patients. The prognosis is poor even in patients under immunosuppressive treatment, with a mortality rate of 30% and only a minority of patients making a full recovery2-3. However, in the three cases reported by Banerjee and colleagues, patients presented with mild symptoms despite the magnitude of the MRI findings and made a full clinical and radiologic recovery in 2 of the cases with immunosuppressant treatment and in the remaining without any treatment.
We have recently evaluated a similar patient, that presented with mild transient symptoms in whom the diagnosis was made following the finding of characteristic CAA-ri changes in brain MRI.
He was a 62 year-old-man with a past history of hypertension, who was referred to the Emergency Department (ER) due to moderate frontal headache followed by left hemisensory numbness with Jacksonian march lasting a few minutes. He was asymptomatic on arrival at the ER and his neurological examination was normal. He performed a cranial CT scan that revealed a right subcortical temporoparietal hypodensity which led to the request of a brain MRI that showed a right pseudotumoral temporoparietal white matter lesion, hyperintense on T2-weighted sequences without gadolinium enhancement, and multiple corticosubcortical microbleeds in T2* co-localized with the T2-lesion. CSF evaluation disclosed a mild elevation of proteins (53mg/dl) with a normal white cell count and no oligoclonal bands. Alzheimer disease (AD) biomarkers in CSF were consistent with a DA-related pathophysiology Aβ1-42: 494 pg/mL (normal range (NR) >542), total-tau: 252 pg/mL (NR <212), phospho-tau: 126 pg/mL (NR < 32). We further evaluated the presence of antibodies against Aβ which were positive (48.17 ng/mL). Neuropsychological evaluation and EEG were normal. At this point, a diagnosis of probable CAA-ri was made, according to the clinicoradiological criteria of CAA-ri4. The Apo-E genotype was ɛ4/ɛ4 further supporting the CAA-ri diagnosis. Given the benign course of the disease, a conservative approach was adopted, and steroid therapy and biopsy were deferred. The patient has been followed for 2 years and remains asymptomatic. A 3-month and 1-year follow up MRI showed complete reversion of the temporoparietal T2-hyperintense lesion and stabilization of the number of microbleeds.
Given the findings reported by Banerjee and colleagues and our own, we agree that CAA-ri might be underdiagnosed, its clinical spectrum might be wider than previously thought, and the entity might be underdiagnosed in patients with mild clinical symptoms. We also believe that the increasing availability of brain MRI will probably keep expanding the clinical spectrum of manifestations associated with CAA-ri.
Dr. Banerjee and colleagues suggested that milder phenotypes of CAA-ri might relate to a genotype of ApoE other than ɛ4/ɛ4, which is known to associate with a higher risk of developing the classic form of CAA-ri. However, in our patient, the genotype of Apo E was ɛ4/ɛ4, and previous reports could not find a relation between the ApoE genotype and the clinical course of CAA-ri5. Still, information regarding the relationship between ApoE genotype and the CAA-ri clinical course is scarce, and further studies will be needed to evaluate this hypothesis.
Finally, in our patient, we identify antibodies against Aβ in the CSF. Although their precise role remains to be established we can speculate a possible implication in the overlap described by Banerjee and colleagues, between the entity of minimal symptomatic amyloid angiopathy and amyloid-related imaging abnormalities (ARIA) found in patients with AD under anti-amyloid immunotherapy
To conclude our case reinforces the existence of a variant of minimal symptomatic CAA-ri described by Dr. Banerjee and colleagues. A high index of suspicion is key to identifying these patients. In the cases described so far, patients’ demographic characteristics and radiologic findings resembled those with a classic form of CAA-ri (the majority were men, with a mean age of 63 years). Further studies are needed to characterize this different phenotype, including CSF findings, ApoE genotype as well as the role of antibodies against Aβ in the CSF.

Acknowledgments
The authors thank Dr. Fabrizio Piazza for the evaluation of antibodies against Aβ in the CSF.

References
1. Banerjee G, Alvares D, Bowen J, et al. J Neurol Neurosurg Psychiatry. Epub ahead of print: [March 13, 2018]. doi:10.1136/jnnp-2017-317347
2. Corovic A, Kelly S, Markus HS. Int J Stroke. 2018: 13(3): 257-267. doi.org/10.1177/1747493017741569
3. M, Caetano A, Pinto M, et al. Stroke-Like Episodes Heralding a Reversible Encephalopathy: Microbleeds as the Key to the Diagnosis of Cerebral Amyloid Angiopathy–Related Inflammation—A Case Report and Literature Review J Stroke Cerebrovasc Dis. 2015 24(9), e245-e250. 10.1016/j.jstrokecerebrovasdis.2015.04.042
4. Auriel E, Charidimou A, Gurol E, et al. Validation of Clinicoradiological Criteria for the Diagnosis of Cerebral Amyloid Angiopathy-Related Inflammation. JAMA Neurol. 2016; 73 (2):197-292. doi: 10.1001/jamaneurol.2015.4078
5. Kinnecom MS, Lev MH, Wendell L, et al. Neurology. 2007:68 (17): 1411-6. doi: 10.1212/01.wnl.0000260066.98681.2e

Dear Editor,
Re: A response from Noble et al. to e-letter by Psychology Task Force of the International League Against Epilepsy
Cognitive behavioural therapy (CBT) has been recommended for treating depression in people with epilepsy (PWE).[1, 2] The clinical significance of the effects of CBT for PWE has though, not been considered. We therefore systematically searched the literature for randomised controlled trials of CBT for PWE [3] and used Jacobson’s criteria [4] to empirically determine whether PWE made clinically reliable improvement. We compared this to that seen in the control arms of these trials.
Our main findings were that the likelihood of statistically reliable improvement in symptoms of depression was significantly higher for those PWE randomised to CBT compared to control conditions. The overall proportion of PWE achieving reliable improvement was low – 30% compared to 10% in the control arms. For most PWE, symptoms were unchanged.
The proportion of PWE who improve following CBT is limited. It should serve as a clarion call for the development of more effective treatments. Indeed, our review may have inflated CBT’s benefit since some trials included PWE without clinical distress at baseline and so it was not possible to apply Jacobson’s second, more stringent criterion and calculate for what proportion CBT also resulted in recovery.
The Psychology Task Force of the International League Against Epilepsy submitted a response to our article. [5] We are pleased that our article has drawn attention to the issue of what currently available treatments are able to offer PWE and that is has stimulated a needed discussion on the topic. Our paper agreed with many of the points raised by the Task Force:
1. More well conducted trials of psychological interventions are needed. Methodologically weak trials are known to overestimate treatment effects;
2. CBT can alleviate depression for some PWE in clinical practice, but substantial room for improvement exists;
3. Participant samples need to be better described and standardised criteria should be used to do this. Evaluations of sample representativeness can then be made, and potential treatment moderators identified;
4. Trials need to test the benefit of treatments for the full range of clinical depression. Trials have so far tended to exclude those with severe levels of depression, and some have included PWE without depression at baseline;
5. Trials should use measures of depression that are valid and reliable for the epilepsy population and for the context in which they are used.
However, there were several comments in the Task Force’s response which misrepresented our position. The Task Force also presented some reasons that they felt might explain the low rate of improvement in depression detected by our review. Below we clarify our position and address the explanations forwarded by the Task Force.
MISREPRESENTATIONS
Comment 1 by Task Force: “...we hope to encourage health professionals to continue to refer patients for psychotherapy... We argue that if just under 1 in 3 PWE reliably improve with CBT, which has no known side-effects, this is better than a possible alternative of unmanaged depression... the ILAE Psychology Task Force believes that it is inaccurate to label CBT as ‘ineffective’.”
Nowhere in our article did we recommend not referring PWE who are distressed for CBT or psychotherapy. Our review explicitly states that CBT does lead to statistically reliable improvement for some PWE and is preferable to offering no treatment. Depression has many deleterious effects and should not be left unmanaged.
Our review indicates that substantial room for treatment improvement exists. Consequently, we said “that it seems reasonable to conclude that when only 30% of treated patients make an improvement that highly effective CBT treatments for distress in epilepsy do not exist.” We did not, as asserted, label CBT as ineffective. Rather, we said the approach was “largely ineffective”.
Comment 2 by Task Force: “the authors suggest CBT... could even lead to lower ‘self–esteem’ and ‘helplessness’... the latter conclusions were based on hypothetical reactions to treatment, rather than empirically supported outcomes.”
Here a discussion point is mistaken for a conclusion. In our discussion we appropriately considered what implications our results have for what therapists should tell PWE considering CBT and related this to ethical and professional guidelines. We questioned how patients might feel if they were not informed about likely treatment response and went on to experience no benefit. Based on clinical experience amongst our team, and evidence from the literature,[6] we suggested possible reactions might include increased feelings of helplessness and hopelessness and lower expectations of therapy being successful in the future.
REASONS PRESENTED BY TASK FORCE TO ACCOUNT FOR LOW RATE OF IMPROVEMENT:
Comment 3 by Task Force: “we offer alternative interpretations of the findings...we would like to highlight the heterogeneity of the studies pooled and how this impacts the findings... First, the interventions were very diverse... Interestingly, one trial that utilised a standardised CBT protocol, resulted in 50% reliable change reductions in depressive symptoms... Second, over 10% of patients in the analyses had depressive symptoms within the non-clinical ranges.”
The pooled risk difference (RD) across the trials in our review was 0.20 – meaning 20% more PWE randomised to the CBT treatment arms reliably improved compared to the control arms. The trials in our review used different modes of treatment delivery and had samples with different levels of pre-treatment distress. We acknowledged this in our article and to explore whether this heterogeneity obscured higher rates of improvement in some trials, we presented RDs for the individual trials and also pooled RDs for trials using similar treatments and/or samples.
Unfortunately, regardless of how one approached the dataset (i.e., just looking at change in individuals who received face to face treatments or focusing on change in just participants who were distressed at baseline) only around 20% more patients in the CBT groups reliably improved compared to the control arms (see supplementary Figures 1-2 of our review [3]).
The Task Force highlighted the rate of reliable change reported by one trial in our review and implied that it’s results better reflect the potential of CBT for PWE. The trial in question was by Ciechanowski et al.[7]. Unfortunately, the benefit of CBT in that trial was actually not much better than indicated by the pooled RD. The Task Force correctly point out that the proportion of reliable change in the treatment arm of Ciechanowski et al.’s trial was 50%. They neglected to consider though that the proportion who reliably improved in that trial’s (treatment as usual) control arm was 24%. Thus, the RD for Ciechanowski et al.’s trial is 0.26 – not that much different to the pooled RD of 0.20.
Comment 4 by Task Force: “One important limitation of previous trials is the relatively short duration of psychotherapy offered to PWE, a factor that Noble et al. [1] acknowledge... it is very likely that participants did not receive a sufficient dosage of CBT... many PWE experience cognitive difficulties, including memory impairment, which may require more intensive and tailored CBT [5].”
Our review could only comment on the extent of change elicited by CBT treatments so far evaluated for PWE by trials. On average, the treatments offered by the trials in our review lasted 8.8 sessions. The Task Force suggest more treatment sessions may be required for PWE due to the presence of cognitive impairment. Whilst some PWE do experience such difficulties, this explanation does not appear to be able to account for the low rate of improvement seen in the trials in our review since most of them excluded patients with such difficulties.
Comment 5 by Task Force: “One advantage of CBT is that many of the behavioural skills; such as problem solving, sleep hygiene and controlled relaxation can also be tailored to assist with the self-management of epilepsy... which Noble et al. did not consider.”
We focused on trials for which the primary outcome measure was depression and examined the degree of change achieved

We thank you for the opportunity to respond to the Task Force’s letter. We trust that we have clarified our position on a range of points, including the need at present to continue to refer PWE who are distressed for CBT. We stand by our position though that there remains an urgent need for more effective treatments to be developed.

Yours sincerely,
Adam J. Noble
James Temple
James Reilly
Peter L. Fisher.

REFERENCES
[1] Kerr MP, Mensah S, Besag F, de Toffol B, Ettinger A, Kanemoto K, Kanner A, Kemp S, Krishnamoorthy E, LaFrance WJ, Mula M, Schmitz B, van Elst LT, Trollor J, Wilson SJ. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy. Epilepsia 2011;52: 2133-2138.
[2] Barry JJ, Ettinger AB, Friel P, Gilliam FG, Harden CL, Hermann B, Kanner AM, Caplan R, Plioplys S, Salpekar J, Dunn D, Austin J, Jones J, Advisory Group of the Epilepsy Foundation as part of its Mood Disorder. Consensus statement: the evaluation and treatment of people with epilepsy and affective disorders. Epilepsy & Behavior 2008 13: S1-29.
[3] Noble AJ, Reilly J, Temple J, Fisher PL. Cognitive-behavioural therapy does not meaningfully reduce depression in most people with epilepsy: a systematic review of clinically reliable improvement. Journal of Neurology, Neurosurgery & Psychiatry 2018; doi: 10.1136/jnnp-2018-317997.
[4] Jacobson NS, Truax P. Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. Journal of Consulting and Clinical Psychology 1991;59: 12-19.
[5] Gandy M, Reuber M, LaFrance Jr WC, Modi A, Wagner JL, Goldstein LH, Tang V, Donald KA, Valente KD, Michaelis R. Why it’s still important to consider referring patients with epilepsy (PWE) with depression for psychotherapy – including Cognitive Behaviour Therapy. Response from the Psychology Task Force of the International League Against Epilepsy. Journal of Neurology, Neurosurgery & Psychiatry 2018; Published on: 11 July 2018.
[6] Crawford MJ, Thana L, Farquharson L, Palmer L, Hancock E, Bassett P, Clarke J, Parry GD. Patient experience of negative effects of psychological treatment: results of a national survey. The British Journal of Psychiatry 2016;208: 260-265.
[7] Ciechanowski P, Chaytor N, Miller J, Fraser R, Russo J, Unutzer J, Gilliam F. PEARLS depression treatment for individuals with epilepsy: a randomized controlled trial. Epilepsy & Behavior 2010;19: 225-231.