Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

No exaggerated tremor severity perception in functional tremor.

BACKGROUND: Symptoms of functional neurological disorder tend to be variable, yet patients often report them being present constantly and of permanently severe intensity. Furthermore, they typically worsen when they are mentioned or during clinical examination. Such phenomena are sometimes interpreted as indicating symptom exaggeration or even fabrication. METHODS: To test the notion of inaccurate symptom perception or reporting, we directly compared subjective to objective tremulousness of reaching movements in people with a functional action tremor, people with an organic action tremor and healthy controls. Identical subjective and objective measures were used, thus eliminating any potential metacognitive confounders. Furthermore, we assessed both immediate perceptual experience with a real-time perceptual task, offering the most direct comparison; and near-time retrospective reports as the latter contribute to peoples' overall judgement of their condition. RESULTS: There was no significant difference in subjective compared to objective tremor severity between the three groups for either the real-time or retrospective conditions. CONCLUSION: People with functional tremor do not perceive or report their tremor in an exaggerated manner, compared to people with an organic tremor or healthy controls. We propose that symptom exacerbation through attentional mechanisms provides an alternative explanation for findings that are frequently attributed to 'exaggeration'.

Misdirected attentional focus in functional tremor.

A characteristic and intriguing feature of functional neurological disorder is that symptoms typically manifest with attention and improve or disappear with distraction. Attentional phenomena are therefore likely to be important in functional neurological disorder, but exactly how this manifests is unknown. The aim of the study was to establish whether in functional tremor the attentional focus is misdirected, and whether this misdirection is detrimental to the movement, or rather reflects a beneficial compensatory strategy. Patients with a functional action tremor, between the ages of 21-75, were compared to two age and gender matched control groups: healthy control participants and patients with an organic action tremor. The groups included between 17 and 28 participants. First, we compared the natural attentional focus on different aspects of a reaching movement (target, ongoing visual feedback, proprioceptive-motor aspect). This revealed that the attentional focus in the functional tremor group, in contrast to both control groups, was directed to ongoing visual feedback from the movement. Next, we established that all groups were able to shift their attentional focus to different aspects of the reaching movement when instructed. Subsequently, the impact of attentional focus on the ongoing visual feedback on movement performance was evaluated under several conditions: the reaching movement was performed with direct, or indirect visual feedback, without any visual feedback, under three different instruction conditions (as accurately as possible/very slowly/very quickly) and finally as a preparatory movement that was supposedly of no importance. Low trajectory length and low movement duration were taken as measures of good motor performance. For all three groups, motor performance deteriorated with attention to indirect visual feedback, to accuracy and when instructed to move slowly. It improved without visual feedback and when instructed to move fast. Motor performance improved, in participants with functional tremor only, when the movement was performed as a preparatory movement without any apparent importance. In addition to providing experimental evidence for improvement with distraction, we found that the normal allocation of attention during aimed movement is altered in functional tremor. Attention is disproportionately directed towards the ongoing visual feedback from the moving hand. This altered attentional focus may be partly responsible for the tremor, since it also worsens motor performance in healthy control participants and patients with an organic action tremor. It may have its detrimental impact through interference with automatic movement processes, due to a maladaptive shift from lower- to higher-level motor control circuitry.

No increased suggestibility to placebo in functional neurological disorder.

BACKGROUND AND PURPOSE: On the basis of occasional strong placebo responses, increased susceptibility to placebo has been proposed as a characteristic of functional neurological disorder (FND). The aim of this study was to clarify whether people with FND have a stronger placebo analgesic response than healthy controls. METHODS: A study using a classic placebo paradigm, with additional conditioning and open-label components, was performed in 30 patients with FND, and in 30 healthy controls. Ratings of mildly to moderately painful electrotactile stimuli were compared before and after the application of a placebo "anaesthetic" cream versus a control cream, after an additional conditioning exposure, and after full disclosure (open-label component). RESULTS: Pain intensity ratings at the placebo compared to the control site were similarly reduced in both groups. The conditioning exposure had no additional effect. After placebo disclosure a residual analgesic effect remained. CONCLUSION: Patients with FND did not have stronger placebo responses than healthy controls. The notion of generally increased suggestibility or increased suggestibility to placebo in FND seems mistaken. Instead, occasional dramatic placebo responses may occur because functional symptoms are inherently more changeable than those due to organic disease.

The Flip Side of Distractibility-Executive Dysfunction in Functional Movement Disorders.

Attention plays a crucial role in functional neurological disorders. Attention to the symptoms leads to their exacerbation and distraction to their improvement or even transitory disappearance. Objective: The aim was to test if the alerting, orienting and particularly the executive aspect of attention are affected in functional movement disorders. Methods: Thirty patients with a functional movement disorder, 30 patients with an organic movement disorder and 30 healthy controls performed the attention network test. Results: The alerting and orienting effects were normal, but executive control of attention under conflict was abnormal in patients with functional movement disorders, compared to patients with an organic movement disorder and healthy controls. Conclusion: Executive dysfunction seems to be an important secondary feature of functional movement disorders, due to the overutilization of attentional resources for explicit movement control. Furthermore, it provides an explanation for seemingly unrelated symptoms commonly associated with functional movement disorders, such as concentration difficulties and fatigue.

Modulation of Reaction Times and Sense of Agency via Subliminal Priming in Functional Movement Disorders.

Background: In functional movement disorders, explicit movements are impaired, while implicit movements are preserved. Furthermore, there is evidence that the sense of agency is abnormal. Aim: We aimed to investigate how motor responses and sense of agency were affected by subliminal or supraliminal cues in people with functional movement disorders. Methods: Twenty-three people with a functional movement disorder and 26 healthy controls took part in a subliminal and supraliminal priming experiment which investigated reaction times, choice and sense of agency. Participants pressed a left or right arrow key in response to an imperative left or right pointing arrow. Either key could be pressed in response to bidirectional arrows. The imperative arrow was preceded by a small left or right pointing prime arrow, that was non-predictive (50% correct) and was presented in either subliminal or supraliminal conditions. The participant's response caused the appearance of a colored circle and they rated the degree of control they felt over its appearance (sense of agency). The circle's color depended on whether their response was congruent or incongruent with the prime arrow direction. After exclusion, 19 participants remained in each group. Results: Prime-compatible responses led to faster reaction times in both the subliminal and supraliminal condition. Subliminal prime-compatible responses were chosen more frequently in the free choice condition. The sense of agency did not depend on prime-response congruency. There were no significant differences in any of these measures between the two groups. Conclusion: With non-predictive cues, reaction times, choices, and the sense of agency remain normal in people with functional movement disorders, for both subliminal and supraliminal primes. The findings suggest that it is not so much conscious awareness of the movement, but rather conscious motor preparation that is detrimental to motor function in functional movement disorders.

Rheumatoid meningitis occurring during adalimumab and methotrexate treatment.

Rheumatoid arthritis is well known for multiple extra-articular manifestations. Here, we present a case of chronic rheumatoid meningitis occurring during treatment with methotrexate and the tumour necrosis factor (TNF) alpha antibody adalimumab. Nine and seven months, respectively, into the course of these two treatments, a 59-year-old Caucasian lady with mild, early, seropositive rheumatoid arthritis developed headaches and psychomotor retardation followed by seizures. The diagnosis was confirmed by a brain biopsy showing a necrotizing granulomatous meningitis. Withdrawal of both drugs and high dose corticosteroids led to marked improvement. The addition of the anti-CD20 antibody rituximab allowed discontinuation of the corticosteroids. This is the fifth published case describing the occurrence of rheumatoid meningitis during treatment with TNF blockers. TNF blockers and methotrexate thus do not appear to prevent this complication, and may even contribute to its development.