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• Reply to “The eye of the beholder and risks of eminence based medicine”
  Anthony E. Lang, Benjamin D. Wissel and Alberto J Espay
  Published on: 24 July 2018
• The eye of the beholder and risks of eminence based medicine
  Laura S. Boylan
  Published on: 6 July 2018
• Degeneration of the locus coeruleus in premotor Parkinson's disease could predispose to functional neurological disorders
  Stoyan Popkirov
  Published on: 24 May 2018

• Published on: 24 July 2018

  Reply to “The eye of the beholder and risks of eminence based medicine”

  • Anthony E. Lang, Movement Disorders Neurologist University of Toronto
  • Other Contributors:
    • Benjamin D. Wissel, Medical Student
    • Alberto J Espay, Movement Disorders Neurologist

  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...

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  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.

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  Conflict of Interest:
  None declared.

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• Published on: 6 July 2018

  The eye of the beholder and risks of eminence based medicine

  • Laura S. Boylan, Neurologist New York University School of Medicine

  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...

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  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.

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  Conflict of Interest:
  None declared.

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• Published on: 24 May 2018

  Degeneration of the locus coeruleus in premotor Parkinson's disease could predispose to functional neurological disorders

  • Stoyan Popkirov, Neurologist University Hospital Knappschaftskrankenhaus Bochum, Germany

  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...

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  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.

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  Conflict of Interest:
  None declared.

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