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 perfor...
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
We read with great interest the recent paper of Sechi et al. that describes 13 patients with anti-GFAP related myelitis and compares them with 41 patients with anti-AQP4 related myelitis.1 To date, very little data is available about anti-GFAP related disorders.2-3 Sechi et al. highlight some differences between the two entities to help clinicians differentiate them.1 One of these clinical differences relates to area postrema syndrome (APS). Indeed, it is well known that APS is a classical feature of neuromyelitis optica spectrum disorders, particularly among anti-AQP4 positive patients.4 Sechi et al. report this syndrome as a prodromal event in 20% of anti-AQP4 related myelitis. Conversely, the authors do not report any case of APS preceding or accompanying myelitis related to anti-GFAP.1 Given these data, APS could be an indicator for ruling out anti-GFAP encephalomyelitis, particularly useful for centers that do not yet have access to biological testing for anti-GFAP Abs.
However, we report the case of a 41-year-old woman who in April 2016 developed intractable nausea and vomiting lasting for five weeks and leading to 35 kilograms in weight loss. An extensive search for a digestive disease was negative, and no neurological explorations were performed. One month following the resolution of digestive symptoms, she developed mental confusion, diplopia, dysarthria, dizziness, bilateral blurred vision (with optic disc edema) and paraparesis. Brain...
We read with great interest the recent paper of Sechi et al. that describes 13 patients with anti-GFAP related myelitis and compares them with 41 patients with anti-AQP4 related myelitis.1 To date, very little data is available about anti-GFAP related disorders.2-3 Sechi et al. highlight some differences between the two entities to help clinicians differentiate them.1 One of these clinical differences relates to area postrema syndrome (APS). Indeed, it is well known that APS is a classical feature of neuromyelitis optica spectrum disorders, particularly among anti-AQP4 positive patients.4 Sechi et al. report this syndrome as a prodromal event in 20% of anti-AQP4 related myelitis. Conversely, the authors do not report any case of APS preceding or accompanying myelitis related to anti-GFAP.1 Given these data, APS could be an indicator for ruling out anti-GFAP encephalomyelitis, particularly useful for centers that do not yet have access to biological testing for anti-GFAP Abs.
However, we report the case of a 41-year-old woman who in April 2016 developed intractable nausea and vomiting lasting for five weeks and leading to 35 kilograms in weight loss. An extensive search for a digestive disease was negative, and no neurological explorations were performed. One month following the resolution of digestive symptoms, she developed mental confusion, diplopia, dysarthria, dizziness, bilateral blurred vision (with optic disc edema) and paraparesis. Brain MRI was highly suggestive of anti-GFAP encephalomyelitis, notably with the presence of diffuse T2 abnormalities in periventricular white matter, with linear perivascular enhancement oriented radially to the ventricles.Spinal cord MRI revealed longitudinally extensive T2 hyperintensity (extended to the brainstem, with an upper limit involving the area postrema), with ill-defined margins, as described by Sechi et al.1. Anti-AQP4 and anti-MOG IgG were negative in the serum. Anti-GFAP IgG were detected in the serum (by cell-based assay and tissue-based assay). Lumbar puncture was performed before the patient was referred to our department, and was not repeated given the dramatic clinical improvement rapidly achieved with intravenous steroids. Among the 13 patients reported by Sechi et al., anti-GFAP IgG were detected only in the serum for two patients for which no CSF was available, like for our patient.
The patient gave written informed consent for information and images to be published
Our case underlines that the clinical spectrum of anti-GFAP encephalomyelitis is not fully described and understood yet and that clinical features of this syndrome may overlap with those of neuromyelitis optica spectrum disorders (related to anti-AQP4 IgG, to anti-MOG IgG or negative for both antibodies). As such, combining clinical data with radiological and biological data remains essential in order to properly classify patients with such rare central nervous system inflammatory disorders.
References
1 Sechi E, Morris PP, McKeon A et al. Glial fibrillary acidic protein IgG related myelitis: characterisation and comparison with aquaporin-4-IgG myelitis. J Neurol Neurosurg Neuropsychiatry 2018 (in press).
2 Fang B, McKeon A, Hinson SR et al. Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis. JAMA Neurol 2016;73(11):1297-1307.
3 Flanagan EP, Hinson SR, Lennon VA et al. Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: analysis of 102 patients. Ann Neurol 2017;81:298-309.
4 Wingerchuk DM, Banwell B, Bennett JL et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85:177-189.
Hou et al. are to be commended for an in-depth systematic review of currently available dementia risk models that quantify the probability of developing dementia, covering both studies on community-dwelling individuals as well as clinic-based MCI studies.1 One of the key conclusions was that “the predictive ability of existing dementia risk models is acceptable, but the lack of validation limited the extensive application of the models for dementia risk prediction in general population or across subgroups in the population.” Based on recent insights, we believe that the discriminative ability of existing dementia prediction models in the general population is currently not acceptable for clinical use.
We recently validated four promising dementia risk models (CAIDE, ANU-ADRI, BDSI, and DRS).2 In addition to external validation of these models in the Dutch general population, we also sought to investigate how these models compared to predicting dementia based on the age component of these models only. We found that full models do not have better discriminative properties than age alone. As such, we would like to make three suggestions to establish a reliable dementia prediction model.
First, prediction models typically only report model performance on the basis of a full model.1-4 For dementia risk, however, age plays a pivotal role. Therefore, any new model should compare its predictive accuracy to age alone.
Hou et al. are to be commended for an in-depth systematic review of currently available dementia risk models that quantify the probability of developing dementia, covering both studies on community-dwelling individuals as well as clinic-based MCI studies.1 One of the key conclusions was that “the predictive ability of existing dementia risk models is acceptable, but the lack of validation limited the extensive application of the models for dementia risk prediction in general population or across subgroups in the population.” Based on recent insights, we believe that the discriminative ability of existing dementia prediction models in the general population is currently not acceptable for clinical use.
We recently validated four promising dementia risk models (CAIDE, ANU-ADRI, BDSI, and DRS).2 In addition to external validation of these models in the Dutch general population, we also sought to investigate how these models compared to predicting dementia based on the age component of these models only. We found that full models do not have better discriminative properties than age alone. As such, we would like to make three suggestions to establish a reliable dementia prediction model.
First, prediction models typically only report model performance on the basis of a full model.1-4 For dementia risk, however, age plays a pivotal role. Therefore, any new model should compare its predictive accuracy to age alone.
Second, the setting in which a prediction model is to be used will dictate which predictors are available. For instance, a ‘basic’ model would be practical in a primary care setting, by including easily and relatively low-cost obtainable information, such as non-laboratory measurements. In this setting, not only risk factors but also prodromal features of dementia may be useful, such as subjective memory complaints. Therefore, the ability to identify high-risk individuals many years before a clinical dementia diagnosis can be used in future prevention trials to intervene in the earliest phase of the disease process. In settings beyond primary care, an ‘extended’ model could be considered, which adds specialist assessments, such as cognitive testing, brain MRI, and possibly genetics.
Finally, improvements in the use of more advanced modelling techniques and reporting of the underlying model properties are needed. For example, future studies could consider more complex effects of age on dementia risk in their candidate models, by using non-linear effects or interactions with other predictors. We also encourage the exploration of developing age stratified models, but only if sample size permits in order to prevent model overfitting. As the authors briefly pointed out, most of the included models only report discriminative properties (i.e., AUCs or C-statistics), yet information on model calibration is also required to assess model performance.5 Without data on model calibration, proper validation attempts are limited, but most importantly also hamper actual model application to clinical practice.
In conclusion, updated and well-validated dementia risk models are still urgently needed. These models could be used in the near future to design (preventive) trials by reliably selecting high-risk individuals into such trials. Such a tailored approach could eventually benefit progress to delay or even prevent the onset of dementia.
References
1. Hou XH, Feng L, Zhang C, et al. Models for predicting risk of dementia: a systematic review. J Neurol Neurosurg Psychiatry 2018 doi: jnnp-2018-318212 [pii]
10.1136/jnnp-2018-318212 [published Online First: 2018/06/30]
2. Licher S, Yilmaz P, Leening MJG, et al. External validation of four dementia prediction models for use in the general community-dwelling population: a comparative analysis from the Rotterdam Study. Eur J Epidemiol 2018;33(7):645-55. doi: 10.1007/s10654-018-0403-y
10.1007/s10654-018-0403-y [pii] [published Online First: 2018/05/10]
3. Stephan BC, Kurth T, Matthews FE, et al. Dementia risk prediction in the population: are screening models accurate? Nat Rev Neurol 2010;6(6):318-26. doi: nrneurol.2010.54 [pii]
10.1038/nrneurol.2010.54 [published Online First: 2010/05/26]
4. Tang EY, Harrison SL, Errington L, et al. Current Developments in Dementia Risk Prediction Modelling: An Updated Systematic Review. PLoS One 2015;10(9):e0136181. doi: 10.1371/journal.pone.0136181
PONE-D-15-14570 [pii] [published Online First: 2015/09/04]
5. Collins GS, Reitsma JB, Altman DG, et al. Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): the TRIPOD statement. Ann Intern Med 2015;162(1):55-63. doi: 2088549 [pii]
10.7326/M14-0697 [published Online First: 2015/01/07]
Imagine you are an epilepsy health professional seeing a patient with clinical symptoms of depression. What should you do? If you have read Noble et al.’s [1] recent JNNP review, entitled ‘Cognitive-behavioural therapy does not meaningfully reduce depression in most people with epilepsy…’ you may have become sceptical about the potential of CBT, or psychotherapy in general, to alleviate depression in people with epilepsy (PWE). This recent systematic review pooled data from five small randomised controlled trials (RCTs), with some elements of CBT for PWE, and performed an analysis of reliable change. ‘Pooled risk difference indicated likelihood of reliable improvement in depression symptoms was significantly higher for those randomised to CBT’, but the authors focused on the finding that ‘only’ 30% of patients receiving interventions, compared to 10% of controls, could be considered ‘reliably improved’. Emphasising the fact that over 2/3 of patients did not meet this criterion for improvement, the authors suggest CBT is ‘ineffective’, has ‘limited benefit’ and could even lead to lower ‘self–esteem’ and ‘helplessness’. Notably, the latter conclusions were based on hypothetical reactions to treatment, rather than empirically supported outcomes.
Therefore, the purpose of this letter, written by the Psychology Task Force of the International League Against...
Imagine you are an epilepsy health professional seeing a patient with clinical symptoms of depression. What should you do? If you have read Noble et al.’s [1] recent JNNP review, entitled ‘Cognitive-behavioural therapy does not meaningfully reduce depression in most people with epilepsy…’ you may have become sceptical about the potential of CBT, or psychotherapy in general, to alleviate depression in people with epilepsy (PWE). This recent systematic review pooled data from five small randomised controlled trials (RCTs), with some elements of CBT for PWE, and performed an analysis of reliable change. ‘Pooled risk difference indicated likelihood of reliable improvement in depression symptoms was significantly higher for those randomised to CBT’, but the authors focused on the finding that ‘only’ 30% of patients receiving interventions, compared to 10% of controls, could be considered ‘reliably improved’. Emphasising the fact that over 2/3 of patients did not meet this criterion for improvement, the authors suggest CBT is ‘ineffective’, has ‘limited benefit’ and could even lead to lower ‘self–esteem’ and ‘helplessness’. Notably, the latter conclusions were based on hypothetical reactions to treatment, rather than empirically supported outcomes.
Therefore, the purpose of this letter, written by the Psychology Task Force of the International League Against Epilepsy (ILAE), is to argue that caution is needed when considering the authors’ conclusions and potential implications for the psychological care of PWE. Moreover, we offer alternative interpretations of the findings and raise the pertinent issue of how psychotherapy for PWE may continue to improve. Importantly, we hope to encourage health professionals to continue to refer patients for psychotherapy, which is an effective intervention for a substantial subgroup of PWE.
Consistent with Reuber’s [2] editorial commentary, Cognitive-behavioural therapy does meaningfully reduce depression in people with epilepsy, we would like to highlight the heterogeneity of the studies pooled and how this impacts the findings. First, the interventions were very diverse, and most would not be considered standardised CBT protocols for depression. Interestingly, one trial that utilised a standardised CBT protocol, resulted in 50% reliable change reductions in depressive symptoms, equivalent to CBT in the general population [3]. Second, over 10% of patients in the analyses had depressive symptoms within the non-clinical ranges. Further, unlike previous analysis of reliable change in depression [3], this review failed to control for baseline levels of depression severity. Third, Noble et al. collapsed data from four different self-report depression measures, only one designed for PWE. Depression in PWE can have distinct symptomatology, given the presence of seizures (peri-ictal depression) and anti-seizure medication effects, both of which can limit the validity of generic depression measures [4].
Noble et al. [1] describe their conclusion that 30% reliable improvements in depressive symptoms across trials is ‘ineffective’ as a ‘value judgement’, illustrating subjectivity, which Reuber’s [2] editorial commentary argued could be interpreted completely in reverse. That is, one could conclude from the data that the treatments are ‘effective’ for PWE. There is little consensus about what we expect a ‘reliable improvement’ to be in psychological distress for PWE, or for patients with a disabling neurological disorder in general. A stated goal of epilepsy treatment is “no seizures, no side-effects.” However, many PWE continue to have seizures, and all biological treatments have potential side-effects. 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. Arguments regarding quantifying ‘reliable improvement’ aside, we do agree with Noble et al.’s [1] conclusions that there is ‘substantial room for improvement’ in the treatment of depression for PWE.
One important limitation of previous trials is the relatively short duration of psychotherapy offered to PWE, a factor that Noble et al. [1] acknowledge. Across the five RCTs, there was only an average of 7 hours (8 sessions) of psychotherapy, the adherence of which is unclear [5]. Thus, it is very likely that participants did not receive a sufficient dosage of CBT, especially given a minimum of 12 sessions is indicated for depression in the general population [3]. In addition, many PWE experience cognitive difficulties, including memory impairment, which may require more intensive and tailored CBT [5]. These limitations need to be addressed and psychotherapy should be tailored to the unique needs of PWE. 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 (e.g. avoidance of seizure triggers), which Noble et al. did not consider.
Another critical area for improvement is the treatment of comorbid anxiety symptoms within psychotherapy for depression. Anxiety and depression are highly comorbid, and in clinical practice it is difficult to evaluate them separately [4]. As such, transdiagnostic treatments, which treat depression and anxiety in one protocol, are increasingly being adopted and proven to be effective in the general population. We disagree with Noble et al.’s [1] comments regarding the ‘disappointing’ evidence for the treatment of anxiety, as only one small trial is cited assessing the impact of CBT for depression (not anxiety), on a secondary anxiety measure. A conclusion of insufficient evidence would have been more accurate, given the state of the anxiety literature.
Depression in PWE remains underdiagnosed and treated, perhaps partially due to uncertainty about effective treatments [4]. At worse this results in poorer quality of life and higher suicide rates in PWE. Thus, the development of more effective psychotherapies, including alternatives to CBT, is warranted. However, the ILAE Psychology Task Force believes that it is inaccurate to label CBT as ‘ineffective’ based on the findings of Noble et al.’s [1] review. Instead, we encourage health professionals to interpret the Noble et al. [1] conclusions with caution, given the concerns raised with respect to depression outcome measures, dosage and quality of the psychotherapies, and interpretation of results. Further, even with a conservative estimate of 30% responders to the psychotherapies, we posit that CBT shows promise for treating depression in PWE and should remain a strong treatment consideration for the referring clinician.
This document was written by experts selected by the International League Against Epilepsy (ILAE) and was approved for publication by the ILAE. Opinions expressed by the authors, however, do not necessarily represent the policy or position of the ILAE.
References:
1. Noble AJ, Reilly J, Temple J, et al. 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: doi: 10.1136/jnnp-2018-317997
2. Reuber M. Cognitive-behavioural therapy does meaningfully reduce depression in people with epilepsy. Journal of Neurology, Neurosurgery and Psychiatry 2018 doi: 10.1136/jnnp-2018-318743
3. Ogles BM, Lambert MJ, Sawyer JD. Clinical Significance of the National Institute of Mental Health Treatment of Depression Collaborative Research Program Data. Journal of Consulting and Clinical Psychology 1995;63(2):321-26. doi: 10.1037/0022-006X.63.2.321
4. Kwon O-Y, Park S-P. Depression and Anxiety in People with Epilepsy. Journal of Clinical Neurology (Seoul, Korea) 2014;10(3):175-88. doi: 10.3988/jcn.2014.10.3.175
5. Modi AC, Wagner J, Smith AW, et al. Implementation of psychological clinical trials in epilepsy: Review and guide. Epilepsy and Behavior 2017;74:104-13. doi: 10.1016/j.yebeh.2017.06.016
Boentert et al. investigated the prevalence of sleep apnoea and nocturnal hypoventilation (NH) in 250 patients with non-ventilated amyotrophic lateral sclerosis (ALS) by considering gender and severity of bulbar dysfunction (1). Prevalence of NH and apnoea-hypopnoea index (AHI) >5/hour was 40.0% and 45.6%, respectively, and 22.3% of patients had both NH and sleep apnoea. Sleep apnoea was significantly more common in male patients and negatively associated with bulbar function. I have some concerns with this study.
First, the authors did not conduct stratified analysis by gender. As the prevalence of sleep apnoea differs by gender, the association between sleep apnoea, NH and severity of bulbar dysfunction should be analyzed by stratification with gender.
Second, the authors conducted univariate analyses, and adjustment of independent variables cannot be made. Although the number of patients is limited, recommendation for the use of transcutaneous capnography should be based by appropriate adjustments of confounders.
Finally, Park et al. evaluated the relationship between nocturnal hypoxia and cognitive dysfunction in patients with ALS, and patients with nocturnal hypoxia showed poor memory retention and retrieval efficiency. They speculated that patients with ALS might be exposed to repeated episodes of deoxygenation-reoxygenation during sleep, because of the weakness of the respiratory muscles. In order to evaluate the effect of desaturation on ALS...
Boentert et al. investigated the prevalence of sleep apnoea and nocturnal hypoventilation (NH) in 250 patients with non-ventilated amyotrophic lateral sclerosis (ALS) by considering gender and severity of bulbar dysfunction (1). Prevalence of NH and apnoea-hypopnoea index (AHI) >5/hour was 40.0% and 45.6%, respectively, and 22.3% of patients had both NH and sleep apnoea. Sleep apnoea was significantly more common in male patients and negatively associated with bulbar function. I have some concerns with this study.
First, the authors did not conduct stratified analysis by gender. As the prevalence of sleep apnoea differs by gender, the association between sleep apnoea, NH and severity of bulbar dysfunction should be analyzed by stratification with gender.
Second, the authors conducted univariate analyses, and adjustment of independent variables cannot be made. Although the number of patients is limited, recommendation for the use of transcutaneous capnography should be based by appropriate adjustments of confounders.
Finally, Park et al. evaluated the relationship between nocturnal hypoxia and cognitive dysfunction in patients with ALS, and patients with nocturnal hypoxia showed poor memory retention and retrieval efficiency. They speculated that patients with ALS might be exposed to repeated episodes of deoxygenation-reoxygenation during sleep, because of the weakness of the respiratory muscles. In order to evaluate the effect of desaturation on ALS prognosis, cognitive function should also be included for the analysis.
Reference
1. Boentert M, Glatz C, Helmle C, et al. Prevalence of sleep apnoea and capnographic detection of nocturnal hypoventilation in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2018;89(4):418-424.
2. Park SY, Kim SM, Sung JJ, et al. Nocturnal hypoxia in ALS is related to cognitive dysfunction and can occur as clusters of desaturations. PLoS One 2013;8(9):e75324.
We appreciate Dr. Laura S. Boylan’s interest in our article. However, her viewpoint rather strikingly exemplifies the behaviors that she mistakenly believes we were guilty of in our report, beginning with the “eminence based” statements “in my view” occurring twice in the first paragraph and her conclusion with a personal “old saw I use in teaching”. We strongly disagree with her misinterpretation about our application of “cognitive bias” in the selection of our patients for this case-control study. In fact, most patients with Parkinson’s disease (PD) had functional complications ascertained after several visits –requiring a diagnostic revision once they fulfilled the appropriate positive criteria.1 The diagnostic “delay” in part may have highlighted the absent recognition of functional comorbidities in PD prior to our study, forcing a conservative approach before ascertaining what may be considered a “second” diagnosis in these patients. Furthermore, in contrast to Dr. Boylan’s suggestion, we did not select patients on the basis of comorbid depression, anxiety, cognitive symptoms, pain, nausea, or fatigue. Instead these features segregated more commonly among cases than controls after the patient selection had been completed. She argues that we considered them “supportive” for a diagnosis of functional movement disorder, but we did not. We have instead emphasized the potentially misleading influence of both history and psychiatric features and argued in favor of a diagnos...
We appreciate Dr. Laura S. Boylan’s interest in our article. However, her viewpoint rather strikingly exemplifies the behaviors that she mistakenly believes we were guilty of in our report, beginning with the “eminence based” statements “in my view” occurring twice in the first paragraph and her conclusion with a personal “old saw I use in teaching”. We strongly disagree with her misinterpretation about our application of “cognitive bias” in the selection of our patients for this case-control study. In fact, most patients with Parkinson’s disease (PD) had functional complications ascertained after several visits –requiring a diagnostic revision once they fulfilled the appropriate positive criteria.1 The diagnostic “delay” in part may have highlighted the absent recognition of functional comorbidities in PD prior to our study, forcing a conservative approach before ascertaining what may be considered a “second” diagnosis in these patients. Furthermore, in contrast to Dr. Boylan’s suggestion, we did not select patients on the basis of comorbid depression, anxiety, cognitive symptoms, pain, nausea, or fatigue. Instead these features segregated more commonly among cases than controls after the patient selection had been completed. She argues that we considered them “supportive” for a diagnosis of functional movement disorder, but we did not. We have instead emphasized the potentially misleading influence of both history and psychiatric features and argued in favor of a diagnosis of a functional movement disorder exclusively reliant on neurological examination (i.e., using positive criteria rather than applying a diagnosis of exclusion).2 Importantly, we did not review colleagues' charts; these were our own patients, who had been followed by movement disorders experts over several years. Dr. Boylan exercises far more of her own cognitive bias in highlighting how the diagnosis of functional disorders has been overly considered in females (despite considerable epidemiological evidence that these disorders are more common in women) and in her old teaching saw that “proper diagnosis” of movement disorders (including functional movement disorders) "is the one offered the most senior professor in the vicinity". Her viewpoint ignores modern literature that has shown a very low incidence of misdiagnosis using current evaluations and the application of positive criteria for the diagnosis of functional disorders.3 Thus, in citing old, historical literature and ignoring a growing body of work in the field,4 Dr. Boylan’s letter propagates old thinking and misinformation.
References
1. Gupta A, Lang AE. Psychogenic movement disorders. Curr Opin Neurol. 2009;22(4):430-436.
2. Espay AJ, Lang AE. Phenotype-specific diagnosis of functional (psychogenic) movement disorders. Curr Neurol Neurosci Rep. 2015;15(6):556.
3. Stone J, Carson A, Duncan R, et al. Symptoms 'unexplained by organic disease' in 1144 new neurology out-patients: how often does the diagnosis change at follow-up? Brain. 2009;132(Pt 10):2878-2888.
4. Hallett M, Stone J, Carson A. Functional Neurologic Disorders. Vol 139. Amsterdam, Netherlands. : Handbook of Clinical Neurology, Elsevier. ; 2016.
In my view the data presented in this study (1) which are interpreted as indicating a high prevalence of functional movement disorders (FMD) in PD might also be interpreted as suggesting that diagnostic delay is common in PD, particularly among women patients who present as "high maintenance" patients. The diagnosis of functional movement disorders is a matter of expert opinion and in my view problems with study design and interpretation support rather than minimize cognitive and confirmation bias in this study.
Subjects all met UK brain bank criteria for PD. Subjects diagnosed with FND in this study had high rates of family history of PD. They had depression, anxiety, cognitive symptoms, pain, nausea, fatigue all common complaints among the population in general and most particularly in PD. The presence of these symptoms before or after diagnosis of PD is considered by the authors as supportive for a diagnosis of FMD. However, these same symptoms are known to be associated with PD and might be considered supportive of a PD diagnosis.
Disparities in healthcare for women are well established (2). Neurology has a long history of mistakes distinguishing the "functional" from the "organic" (e.g.3). To choose one example people with blepharospasm, mostly women, were institutionalized long-term as the disease was not recognized as neurologic. Women commonly encounter dismissal in the medical context and this can occasion missed opportuni...
In my view the data presented in this study (1) which are interpreted as indicating a high prevalence of functional movement disorders (FMD) in PD might also be interpreted as suggesting that diagnostic delay is common in PD, particularly among women patients who present as "high maintenance" patients. The diagnosis of functional movement disorders is a matter of expert opinion and in my view problems with study design and interpretation support rather than minimize cognitive and confirmation bias in this study.
Subjects all met UK brain bank criteria for PD. Subjects diagnosed with FND in this study had high rates of family history of PD. They had depression, anxiety, cognitive symptoms, pain, nausea, fatigue all common complaints among the population in general and most particularly in PD. The presence of these symptoms before or after diagnosis of PD is considered by the authors as supportive for a diagnosis of FMD. However, these same symptoms are known to be associated with PD and might be considered supportive of a PD diagnosis.
Disparities in healthcare for women are well established (2). Neurology has a long history of mistakes distinguishing the "functional" from the "organic" (e.g.3). To choose one example people with blepharospasm, mostly women, were institutionalized long-term as the disease was not recognized as neurologic. Women commonly encounter dismissal in the medical context and this can occasion missed opportunities for established clinical interventions (e.g. 4, 5, 6)
Study subjects were selected for assessment for FMD on the basis of their doctors having used language suggesting a suspicion of an FMD in the chart. It sounds as if investigators were reviewing records of colleagues at their own institution. How many, if any, neurologists were considered to have made diagnostic error?
Evidence for the effects of cognitive bias in clinical medicine overshadows evidence for the reliability and validity of expert evaluation of functional movement disorders (4, 7 8).
In the 19th century there was debate over whether Parkinson's disease itself was functional or organic (9). While some cases are clear cut, an old saw I use in teaching is that the proper movement disorder diagnosis is the one offered by the most senior professor in the vicinity.
References:
(1) Wissel BD, Dwivedi AK, Merola A, et al. Functional neurological disorders in Parkinson disease. J Neurol Neurosurg Psychiatry. 2018 Jun;89(6):566-571.
(2) Hornbuckle LM, Amutah-Onukagha N, Bryan A, et al. Health Disparities in Women. Clinical Medicine Insights Women’s Health. 2017.
(3) Hamill EB, Yen MT. The History of Blepharospasm in Medicine. Int Ophthalmol
Clin. 2018 Winter;58(1):3-10.
(4) Schulman KA, Berlin JA, Harless W, et al. The effect of race and sex on physicians' recommendations for cardiac catheterization. N Engl J Med. 1999 Feb 25;340(8):618-26.
(5) Faigle R, Urrutia VC, Cooper LA, Gottesman RF. Individual and System
Contributions to Race and Sex Disparities in Thrombolysis Use for Stroke Patients in the United States. Stroke. 2017 Apr;48(4):990-997
(6) Dusenbery M. Doing harm. Harper Collins 2018.
(7) Vickrey BG, Samuels MA, Ropper AH. How neurologists think: A cognitive psychology perspective on missed diagnoses. Ann Neurol. 2010 Apr;67(4):425-33.
(8) Saposnik G, Redelmeier D, Ruff CC, Tobler PN. Cognitive biases associated with medical decisions: a systematic review. BMC Med Inform Decis Mak. 2016 Nov 3;16(1):138.
(9) Bechet E. Contribution a l'etude clinique des formes de la maladie de parkinson. Paris. Ancienne Maison Delahaye. 1892.
Conflict of Interest
Dr. Laura Boylan does medicolegal consulting work.
We read with interest the study presented by Berg et al [1] that showed that prolonged mechanical ventilation (more than 2 months) in Guillain-Barre syndrome (GBS) was associated with poorer outcome and more residual deficits compared to non-ventilated GBS patients.
We recently found very similar results in the same population of patients. Nevertheless, it should be precised that despite this, we could not found any difference in quality of life compared to the general French population [2]. Berg et al. also found that ventilated patients were less likely to have residual fatigue symptoms compared to non-ventilated GBS patients, respectively 20% versus 54% (p=0.007). Among 13 prolonged mechanically ventilated GBS, we could show that 22% of patients displayed DSM IV criteria for long-term post-traumatic stress disorder (PTSD) [2]. Since one of our main hypothesis was that PTSD symptoms were mainly related to the mechanical ventilation, we assessed long-term PTSD in 20 non-ventilated GBS patients (Table). Unexpectedly, 65% of these non-ventilated patients had PTSD as compared to 22% in the ventilated group found in our previous study (Table). As for fatigue, we would have expected a correlation between the severity of the disease (especially mechanical ventilation), and the incidence of PTSD.
One explanation of these unexpected results could be that the acute stress induced by the temporary paralysis, the traumatic aspects of intubation an...
We read with interest the study presented by Berg et al [1] that showed that prolonged mechanical ventilation (more than 2 months) in Guillain-Barre syndrome (GBS) was associated with poorer outcome and more residual deficits compared to non-ventilated GBS patients.
We recently found very similar results in the same population of patients. Nevertheless, it should be precised that despite this, we could not found any difference in quality of life compared to the general French population [2]. Berg et al. also found that ventilated patients were less likely to have residual fatigue symptoms compared to non-ventilated GBS patients, respectively 20% versus 54% (p=0.007). Among 13 prolonged mechanically ventilated GBS, we could show that 22% of patients displayed DSM IV criteria for long-term post-traumatic stress disorder (PTSD) [2]. Since one of our main hypothesis was that PTSD symptoms were mainly related to the mechanical ventilation, we assessed long-term PTSD in 20 non-ventilated GBS patients (Table). Unexpectedly, 65% of these non-ventilated patients had PTSD as compared to 22% in the ventilated group found in our previous study (Table). As for fatigue, we would have expected a correlation between the severity of the disease (especially mechanical ventilation), and the incidence of PTSD.
One explanation of these unexpected results could be that the acute stress induced by the temporary paralysis, the traumatic aspects of intubation and the need for prolonged mechanical ventilation (MV) could promote a stronger resilience process, a mental ability which enables adaption to a stressful event [3], in severe GBS patients compared to milder ones. Nevertheless, to our knowledge, no study has shown that the length of stay or the severity of a traumatic event could be associated to higher resilience. In our studies, median length of stay (LOS) was longer in ventilated versus non-ventilated GBS patient, respectively at 102 days [72-126] and 12 days [11-16) (p<0.0001). In the contrary of most ICU patients, GBS patients with prolonged MV are admitted for a transitory impairment of the peripheral nervous system responsible of respiratory failure, without multiple organ dysfunctions. During their LOS, they are, with full consciousness, hostages to their paralyzed bodies, before the recovering. We can make the hypothesis that this uncommon stressful experience could promote in some patients a resilience process in order to deal transiently with they’re inexorable status, with the hypothesis that higher LOS could promote this resilience process. Such changes in mental status have been described in war prisoners and hostages with prolonged captivity [4, 5].
We totally agree with the authors that based on the actual available studies the prediction of which patients with prolonged mechanical ventilation may reach good outcome is impossible and that prospective studies are mandatory. In such studies, detailed psychological and psychiatric evaluation focusing on PTSD and resilence processes would be valuable.
Figure Legend:
Table : Characteristics of the patients.
References
1. van den Berg, B., et al., Clinical outcome of Guillain-Barre syndrome after prolonged mechanical ventilation. J Neurol Neurosurg Psychiatry, 2018. 7(317968): p. 2018-317968.
2. Le Guennec, L., et al., Post-traumatic stress symptoms in Guillain-Barre syndrome patients after prolonged mechanical ventilation in ICU: a preliminary report. J Peripher Nerv Syst., 2014. 19(3): p. 218-23. doi: 10.1111/jns.12087.
3. Wagnild, G.M. and H.M. Young, Development and psychometric evaluation of the Resilience Scale. J Nurs Meas, 1993. 1(2): p. 165-78.
4. Ranscombe, P., Fear, resilience, and tunnel vision. Lancet Neurol, 2015. 14(12): p. 1158.
5. Park, C.L., et al., Does Wartime Captivity Affect Late-life Mental Health? A Study of Vietnam-era Repatriated Prisoners of War. Res Hum Dev, 2012. 9(3): p. 191-209.
I read the article entitled "Patients with Parkinson disease are prone to functional neurological disorders" by Hallett M published in the Journal of Neurology, Neurosurgery and Psychiatry (Published Online First: 16 March 2018. doi: 10.1136/jnnp-2017-317684). I want to congratulate the author for this successful article, and make some contributions.
The article particularly mentions certain aspects of the clinical presentation, medical history and examination of patients, which should raise the suspicion of a functional disorder (1). I think it is important to remember patients with functional disorders will not always adhere to these criteria and clinicians should perhaps consider trialling suspected patients on either cognitive behavioural therapy (CBT) or physiotherapy to assess if they experience any improvement with these strategies. There is increasing evidence to show CBT and physiotherapy are beneficial for patients with functional disorders, hence they may be useful in confirming the diagnosis (2)(3).
Furthermore, the author suggests patients with functional symptoms and no sign of Parkinson's Disease should not be pursued further for a diagnosis of Parkinson's Disease. I think a difficulty is often deciding what classifies as a sign of Parkinson's Disease. The cardinal symptoms of bradykinesia, resting tremor, muscular rigidity and postural instability are commonly subtle within patients, making...
I read the article entitled "Patients with Parkinson disease are prone to functional neurological disorders" by Hallett M published in the Journal of Neurology, Neurosurgery and Psychiatry (Published Online First: 16 March 2018. doi: 10.1136/jnnp-2017-317684). I want to congratulate the author for this successful article, and make some contributions.
The article particularly mentions certain aspects of the clinical presentation, medical history and examination of patients, which should raise the suspicion of a functional disorder (1). I think it is important to remember patients with functional disorders will not always adhere to these criteria and clinicians should perhaps consider trialling suspected patients on either cognitive behavioural therapy (CBT) or physiotherapy to assess if they experience any improvement with these strategies. There is increasing evidence to show CBT and physiotherapy are beneficial for patients with functional disorders, hence they may be useful in confirming the diagnosis (2)(3).
Furthermore, the author suggests patients with functional symptoms and no sign of Parkinson's Disease should not be pursued further for a diagnosis of Parkinson's Disease. I think a difficulty is often deciding what classifies as a sign of Parkinson's Disease. The cardinal symptoms of bradykinesia, resting tremor, muscular rigidity and postural instability are commonly subtle within patients, making them a challenge to distinguish from normal limits. This is made even more difficult if a functional disorder is also suspected. Clinicians should therefore consider demonstrating reduced levels of the presynaptic dopamine active transporter (DAT) using a DaTscan, if available, to aid their diagnosis of Parkinson's Disease as the author suggests in another of their articles (4). Guidance surrounding the use of a DaTscan from the National Institute for Health and Care Excellence (NICE) does not currently account for this indication, however it may be worth considering for future recommendations (5).
References:
1. Wissel BD, Dwivedi AK, Merola A, et al Functional neurological disorders in Parkinson disease J Neurol Neurosurg Psychiatry Published Online First: 16 March 2018. doi: 10.1136/jnnp-2017-317378.
2. Nielsen G, Stone J, Matthews A, et al Physiotherapy for functional motor disorders: a consensus recommendation J Neurol Neurosurg Psychiatry 2015;86:1113-1119.
3. Conwill M, Oakley L, Evans K, Cavanna A. CBT-based group therapy intervention for nonepileptic attacks and other functional neurological symptoms: A pilot study. Epilepsy & Behavior. 2014;34:68-72.
4. Hallett M. Psychogenic Parkinsonism. Journal of the neurological sciences. 2011;310(1-2):163-165. doi:10.1016/j.jns.2011.03.019.
5. National Institute for Health and Care Excellence. Parkinson’s disease in adults NICE guideline NG71 [Internet]. Nice.org.uk. 2017 [cited 12 April 2018]. Available from: https://www.nice.org.uk/guidance/ng71/chapter/Recommendations#diagnosing....
Wissel and colleagues recently reported on a large retrospective case series of patients with functional neurological disorder (FND) and Parkinson's disease (PD) [1]. The authors only briefly touched upon the question of shared pathophysiology, noting that in principle certain structural brain diseases may predispose to FND. The study was not designed to tease out any shared or causal pathways between FND and PD, but some speculation based on the presented data could help formulate useful hypotheses concerning this interesting comorbidity. I propose that a disruption of the central noradrenergic system due to degeneration of the locus loeruleus (LC), the sole source of noradrenaline in the brain with far-reaching projections, is a good candidate for a causal link between FND and (prodromal) PD.
In the study by Wissel and colleagues FND antedated the diagnosis of PD in 26% of cases, often by several years [1]. This is significant, because it nearly eliminates the possibility that the comorbidity is entirely a matter of symptom modelling or functional overlay in all cases. Considering the typical neuroanatomical progression of Lewy pathology in PD, this suggests that neurodegenerative effects within the lower brainstem (Braak stage 1 or 2) are likely structural candidates for a causal pathway. Early LC pathology has been associated with other premotor manifestations of Lewy pathology and PD such as REM sleep behaviour disorder and cognitive decline. A study using...
Wissel and colleagues recently reported on a large retrospective case series of patients with functional neurological disorder (FND) and Parkinson's disease (PD) [1]. The authors only briefly touched upon the question of shared pathophysiology, noting that in principle certain structural brain diseases may predispose to FND. The study was not designed to tease out any shared or causal pathways between FND and PD, but some speculation based on the presented data could help formulate useful hypotheses concerning this interesting comorbidity. I propose that a disruption of the central noradrenergic system due to degeneration of the locus loeruleus (LC), the sole source of noradrenaline in the brain with far-reaching projections, is a good candidate for a causal link between FND and (prodromal) PD.
In the study by Wissel and colleagues FND antedated the diagnosis of PD in 26% of cases, often by several years [1]. This is significant, because it nearly eliminates the possibility that the comorbidity is entirely a matter of symptom modelling or functional overlay in all cases. Considering the typical neuroanatomical progression of Lewy pathology in PD, this suggests that neurodegenerative effects within the lower brainstem (Braak stage 1 or 2) are likely structural candidates for a causal pathway. Early LC pathology has been associated with other premotor manifestations of Lewy pathology and PD such as REM sleep behaviour disorder and cognitive decline. A study using neuromelanin-sensitive MRI sequences recently confirmed in vivo that degeneration of the LC is indeed closely associated with (and likely responsible for) the occurrence of REM sleep behaviour disorder, cognitive impairment, EEG slowing and ortostatic hypotension in PD patients [2]. So in terms of premotor progression of pathology, neuroanatomy and functional relevance of neurodegeneration, the LC seems to be a good candidate. But why should central noradrenergic dysfunction predispose to FND?
The LC noradrenergic system is critically involved in three interconnected cognitive domains that are highly relevant for FND: arousal, attention and affective learning [3]. The LC projects directly to the prefrontal cortex, where it is involved in selective attention and attentional shifts, as well as to various limbic structures including the hippocampus and amygdala, where it mediates arousal and affective learning. A persistent dysregulation of attention, arousal and affective learning can lead to abnormal stress responsivity and maladaptive behavioural changes. General hyperarousal is common in many forms of FND, and is assumed to be pivotal in the emergence and maintainance of functional and dissociative symptoms [4]. Dysregulated attentional control can lead to increased self-directed attention (attentional biases) and dissociative experiences, both common in FND [4]. Furthermore, current mechanistic frameworks of FND predict that disproportionate attentional weighting of sensory expectations and illness beliefs can distort or even override contradictory sensory inputs to produce functional symptoms beyond volitional control [5]. To summarize, if Lewy pathology critically disrupts LC function (possibly years before the dopaminergic system is affected) the resulting dysregulation of attentional control, arousal and affective learning can directly predispose to the development of functional sensory or motor symptoms. The additional findings by Wissel and colleagues that PD-FND patients had worse depression and anxiety than PD without FND, and that FND presented nearly always on the PD-affected side are also in line with the potential role of LC pathology.
Future studies could test this proposition by investigating the effect of noradrenergic medication on FND, and by prospectively evaluating patients with isolated/idiopathic REM sleep behaviour disorder (and no dopaminergic dysfunction) for FND.
References
1. Wissel BD, Dwivedi AK, Merola A, et al. Functional neurological disorders in Parkinson disease. J Neurol Neurosurg Psychiatry. Published Online First: 16 March 2018. doi: 10.1136/jnnp-2017-317378
2. Sommerauer M, Fedorova TD, Hansen AK, Knudsen K, Otto M, Jeppesen J, Frederiksen Y, Blicher JU, Geday J, Nahimi A, Damholdt MF, Brooks DJ, Borghammer P. Evaluation of the noradrenergic system in Parkinson's disease: an 11C-MeNER PET and neuromelanin MRI study. Brain. 2018 Feb 1;141(2):496-504. doi: 10.1093/brain/awx348.
3. Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci. 2009 Mar;10(3):211-23. doi: 10.1038/nrn2573. Epub 2009 Feb 4.
4. Roelofs K, Pasman J. Stress, childhood trauma, and cognitive functions in functional neurologic disorders. Handb Clin Neurol. 2016;139:139-155. doi: 10.1016/B978-0-12-801772-2.00013-8.
5. Edwards MJ, Adams RA, Brown H, Pareés I, Friston KJ. A Bayesian account of 'hysteria'. Brain. 2012 Nov;135(Pt 11):3495-512. doi: 10.1093/brain/aws129. Epub 2012 May 28.
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.
Show MoreCerebral 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 perfor...
Dear Editor,
We read with great interest the recent paper of Sechi et al. that describes 13 patients with anti-GFAP related myelitis and compares them with 41 patients with anti-AQP4 related myelitis.1 To date, very little data is available about anti-GFAP related disorders.2-3 Sechi et al. highlight some differences between the two entities to help clinicians differentiate them.1 One of these clinical differences relates to area postrema syndrome (APS). Indeed, it is well known that APS is a classical feature of neuromyelitis optica spectrum disorders, particularly among anti-AQP4 positive patients.4 Sechi et al. report this syndrome as a prodromal event in 20% of anti-AQP4 related myelitis. Conversely, the authors do not report any case of APS preceding or accompanying myelitis related to anti-GFAP.1 Given these data, APS could be an indicator for ruling out anti-GFAP encephalomyelitis, particularly useful for centers that do not yet have access to biological testing for anti-GFAP Abs.
Show MoreHowever, we report the case of a 41-year-old woman who in April 2016 developed intractable nausea and vomiting lasting for five weeks and leading to 35 kilograms in weight loss. An extensive search for a digestive disease was negative, and no neurological explorations were performed. One month following the resolution of digestive symptoms, she developed mental confusion, diplopia, dysarthria, dizziness, bilateral blurred vision (with optic disc edema) and paraparesis. Brain...
Hou et al. are to be commended for an in-depth systematic review of currently available dementia risk models that quantify the probability of developing dementia, covering both studies on community-dwelling individuals as well as clinic-based MCI studies.1 One of the key conclusions was that “the predictive ability of existing dementia risk models is acceptable, but the lack of validation limited the extensive application of the models for dementia risk prediction in general population or across subgroups in the population.” Based on recent insights, we believe that the discriminative ability of existing dementia prediction models in the general population is currently not acceptable for clinical use.
We recently validated four promising dementia risk models (CAIDE, ANU-ADRI, BDSI, and DRS).2 In addition to external validation of these models in the Dutch general population, we also sought to investigate how these models compared to predicting dementia based on the age component of these models only. We found that full models do not have better discriminative properties than age alone. As such, we would like to make three suggestions to establish a reliable dementia prediction model.
First, prediction models typically only report model performance on the basis of a full model.1-4 For dementia risk, however, age plays a pivotal role. Therefore, any new model should compare its predictive accuracy to age alone.
Second, the setting in which a prediction...
Show MoreImagine you are an epilepsy health professional seeing a patient with clinical symptoms of depression. What should you do? If you have read Noble et al.’s [1] recent JNNP review, entitled ‘Cognitive-behavioural therapy does not meaningfully reduce depression in most people with epilepsy…’ you may have become sceptical about the potential of CBT, or psychotherapy in general, to alleviate depression in people with epilepsy (PWE). This recent systematic review pooled data from five small randomised controlled trials (RCTs), with some elements of CBT for PWE, and performed an analysis of reliable change. ‘Pooled risk difference indicated likelihood of reliable improvement in depression symptoms was significantly higher for those randomised to CBT’, but the authors focused on the finding that ‘only’ 30% of patients receiving interventions, compared to 10% of controls, could be considered ‘reliably improved’. Emphasising the fact that over 2/3 of patients did not meet this criterion for improvement, the authors suggest CBT is ‘ineffective’, has ‘limited benefit’ and could even lead to lower ‘self–esteem’ and ‘helplessness’. Notably, the latter conclusions were based on hypothetical reactions to treatment, rather than empirically supported outcomes.
Therefore, the purpose of this letter, written by the Psychology Task Force of the International League Against...
Show MoreBoentert et al. investigated the prevalence of sleep apnoea and nocturnal hypoventilation (NH) in 250 patients with non-ventilated amyotrophic lateral sclerosis (ALS) by considering gender and severity of bulbar dysfunction (1). Prevalence of NH and apnoea-hypopnoea index (AHI) >5/hour was 40.0% and 45.6%, respectively, and 22.3% of patients had both NH and sleep apnoea. Sleep apnoea was significantly more common in male patients and negatively associated with bulbar function. I have some concerns with this study.
First, the authors did not conduct stratified analysis by gender. As the prevalence of sleep apnoea differs by gender, the association between sleep apnoea, NH and severity of bulbar dysfunction should be analyzed by stratification with gender.
Second, the authors conducted univariate analyses, and adjustment of independent variables cannot be made. Although the number of patients is limited, recommendation for the use of transcutaneous capnography should be based by appropriate adjustments of confounders.
Finally, Park et al. evaluated the relationship between nocturnal hypoxia and cognitive dysfunction in patients with ALS, and patients with nocturnal hypoxia showed poor memory retention and retrieval efficiency. They speculated that patients with ALS might be exposed to repeated episodes of deoxygenation-reoxygenation during sleep, because of the weakness of the respiratory muscles. In order to evaluate the effect of desaturation on ALS...
Show MoreWe appreciate Dr. Laura S. Boylan’s interest in our article. However, her viewpoint rather strikingly exemplifies the behaviors that she mistakenly believes we were guilty of in our report, beginning with the “eminence based” statements “in my view” occurring twice in the first paragraph and her conclusion with a personal “old saw I use in teaching”. We strongly disagree with her misinterpretation about our application of “cognitive bias” in the selection of our patients for this case-control study. In fact, most patients with Parkinson’s disease (PD) had functional complications ascertained after several visits –requiring a diagnostic revision once they fulfilled the appropriate positive criteria.1 The diagnostic “delay” in part may have highlighted the absent recognition of functional comorbidities in PD prior to our study, forcing a conservative approach before ascertaining what may be considered a “second” diagnosis in these patients. Furthermore, in contrast to Dr. Boylan’s suggestion, we did not select patients on the basis of comorbid depression, anxiety, cognitive symptoms, pain, nausea, or fatigue. Instead these features segregated more commonly among cases than controls after the patient selection had been completed. She argues that we considered them “supportive” for a diagnosis of functional movement disorder, but we did not. We have instead emphasized the potentially misleading influence of both history and psychiatric features and argued in favor of a diagnos...
Show MoreIn my view the data presented in this study (1) which are interpreted as indicating a high prevalence of functional movement disorders (FMD) in PD might also be interpreted as suggesting that diagnostic delay is common in PD, particularly among women patients who present as "high maintenance" patients. The diagnosis of functional movement disorders is a matter of expert opinion and in my view problems with study design and interpretation support rather than minimize cognitive and confirmation bias in this study.
Show MoreSubjects all met UK brain bank criteria for PD. Subjects diagnosed with FND in this study had high rates of family history of PD. They had depression, anxiety, cognitive symptoms, pain, nausea, fatigue all common complaints among the population in general and most particularly in PD. The presence of these symptoms before or after diagnosis of PD is considered by the authors as supportive for a diagnosis of FMD. However, these same symptoms are known to be associated with PD and might be considered supportive of a PD diagnosis.
Disparities in healthcare for women are well established (2). Neurology has a long history of mistakes distinguishing the "functional" from the "organic" (e.g.3). To choose one example people with blepharospasm, mostly women, were institutionalized long-term as the disease was not recognized as neurologic. Women commonly encounter dismissal in the medical context and this can occasion missed opportuni...
Dear Editor,
We read with interest the study presented by Berg et al [1] that showed that prolonged mechanical ventilation (more than 2 months) in Guillain-Barre syndrome (GBS) was associated with poorer outcome and more residual deficits compared to non-ventilated GBS patients.
We recently found very similar results in the same population of patients. Nevertheless, it should be precised that despite this, we could not found any difference in quality of life compared to the general French population [2]. Berg et al. also found that ventilated patients were less likely to have residual fatigue symptoms compared to non-ventilated GBS patients, respectively 20% versus 54% (p=0.007). Among 13 prolonged mechanically ventilated GBS, we could show that 22% of patients displayed DSM IV criteria for long-term post-traumatic stress disorder (PTSD) [2]. Since one of our main hypothesis was that PTSD symptoms were mainly related to the mechanical ventilation, we assessed long-term PTSD in 20 non-ventilated GBS patients (Table). Unexpectedly, 65% of these non-ventilated patients had PTSD as compared to 22% in the ventilated group found in our previous study (Table). As for fatigue, we would have expected a correlation between the severity of the disease (especially mechanical ventilation), and the incidence of PTSD.
One explanation of these unexpected results could be that the acute stress induced by the temporary paralysis, the traumatic aspects of intubation an...
Show MoreDear Editor,
I read the article entitled "Patients with Parkinson disease are prone to functional neurological disorders" by Hallett M published in the Journal of Neurology, Neurosurgery and Psychiatry (Published Online First: 16 March 2018. doi: 10.1136/jnnp-2017-317684). I want to congratulate the author for this successful article, and make some contributions.
The article particularly mentions certain aspects of the clinical presentation, medical history and examination of patients, which should raise the suspicion of a functional disorder (1). I think it is important to remember patients with functional disorders will not always adhere to these criteria and clinicians should perhaps consider trialling suspected patients on either cognitive behavioural therapy (CBT) or physiotherapy to assess if they experience any improvement with these strategies. There is increasing evidence to show CBT and physiotherapy are beneficial for patients with functional disorders, hence they may be useful in confirming the diagnosis (2)(3).
Furthermore, the author suggests patients with functional symptoms and no sign of Parkinson's Disease should not be pursued further for a diagnosis of Parkinson's Disease. I think a difficulty is often deciding what classifies as a sign of Parkinson's Disease. The cardinal symptoms of bradykinesia, resting tremor, muscular rigidity and postural instability are commonly subtle within patients, making...
Show MoreWissel and colleagues recently reported on a large retrospective case series of patients with functional neurological disorder (FND) and Parkinson's disease (PD) [1]. The authors only briefly touched upon the question of shared pathophysiology, noting that in principle certain structural brain diseases may predispose to FND. The study was not designed to tease out any shared or causal pathways between FND and PD, but some speculation based on the presented data could help formulate useful hypotheses concerning this interesting comorbidity. I propose that a disruption of the central noradrenergic system due to degeneration of the locus loeruleus (LC), the sole source of noradrenaline in the brain with far-reaching projections, is a good candidate for a causal link between FND and (prodromal) PD.
Show MoreIn the study by Wissel and colleagues FND antedated the diagnosis of PD in 26% of cases, often by several years [1]. This is significant, because it nearly eliminates the possibility that the comorbidity is entirely a matter of symptom modelling or functional overlay in all cases. Considering the typical neuroanatomical progression of Lewy pathology in PD, this suggests that neurodegenerative effects within the lower brainstem (Braak stage 1 or 2) are likely structural candidates for a causal pathway. Early LC pathology has been associated with other premotor manifestations of Lewy pathology and PD such as REM sleep behaviour disorder and cognitive decline. A study using...
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