Which neurological diseases are most likely to be associated with “symptoms unexplained by organic disease”

J. Stone, A. Carson, R. Duncan, R. Roberts, R. Coleman, C. Warlow, G. Murray, A. Pelosi, J. Cavanagh, K. Matthews, R. Goldbeck & M. Sharpe Journal of Neurology Official Journal of the European Neurological Society ISSN 0340-5354 J Neurol DOI 10.1007/ s00415-011-6111-0

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Author's personal copy J Neurol DOI 10.1007/s00415-011-6111-0

ORIGINAL COMMUNICATION

Which neurological diseases are most likely to be associated with ‘‘symptoms unexplained by organic disease’’ J. Stone • A. Carson • R. Duncan • R. Roberts • R. Coleman • C. Warlow • G. Murray • A. Pelosi • J. Cavanagh • K. Matthews • R. Goldbeck • M. Sharpe

Received: 4 January 2011 / Revised: 13 May 2011 / Accepted: 16 May 2011 Ó Springer-Verlag 2011

Abstract Many patients with a diagnosis of neurological disease, such as multiple sclerosis, have symptoms or disability that is considered to be in excess of what would be expected from that disease. We aimed to describe the overall and relative frequency of symptoms ‘unexplained by organic disease’ in patients attending general neurology clinics with a range of neurological disease diagnoses. Newly referred outpatients attending neurology clinics in

J. Stone  A. Carson  C. Warlow  M. Sharpe School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, Scotland, UK G. Murray School of Clinical Sciences and Community Health, University of Edinburgh, Edinburgh, Scotland, UK R. Duncan Institute of Neurology, Southern General Hospital, Glasgow, Scotland, UK R. Coleman  R. Goldbeck Aberdeen Royal Infirmary, Aberdeen, Scotland, UK R. Roberts  K. Matthews Ninewells Hospital, University of Dundee, Dundee, Scotland, UK A. Pelosi Hairmyres Hospital, East Kilbride, Scotland, UK

all the NHS neurological centres in Scotland, UK were recruited over a period of 15 months. The assessing neurologists recorded their initial neurological diagnoses and also the degree to which they considered the patient’s symptoms to be explained by organic disease. Patients completed self report scales for both physical and psychological symptoms. The frequency of symptoms unexplained by organic disease was determined for each category of neurological disease diagnoses. 3,781 patients participated (91% of those eligible). 2,467 patients had a diagnosis of a neurological disease (excluding headache disorders). 293 patients (12%) of these patients were rated as having symptoms only ‘‘somewhat’’ or ‘‘not at all’’ explained by that disease. These patients self-reported more physical and more psychological symptoms than those with more explained symptoms. No category of neurological disease was more likely than the others to be associated with such symptoms although patients with epilepsy had fewer. A substantial proportion of new outpatients with diagnoses of neurological disease also have symptoms regarded by the assessing neurologist as being unexplained by that disease; no single neurological disease category was more likely than others to be associated with this phenomenon. Keywords Psychogenic  Functional overlay  Conversion disorder  Neurology outpatients  Non-organic  Somatoform

J. Cavanagh Division of Community Based Sciences, Faculty of Medicine, Sackler Institute of Psychobiological Research, University of Glasgow, Glasgow, Scotland, UK

Introduction

J. Stone (&) Division of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, Scotland, UK e-mail: [email protected]

There is a widespread recognition that some patients who have a neurological disease such as multiple sclerosis may present with symptoms that are considered to be unexplained by that disease. Such patients are often described

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clinically by neurologists as having ‘functional overlay’ [6], although this term is imprecise and may also be used to refer to ‘‘psychogenic’’ signs on examination, excess disability or psychological comorbidity. There is little published information on the overlap between neurological disease and ‘‘symptoms unexplained by disease’’ and particularly on the question of whether such ‘unexplained symptoms’ are more commonly associated with some neurological diseases than others. We therefore aimed to (a) report the frequency of ‘symptoms unexplained by disease’ in all patients with neurological disease and also within each major neurological disease category, (b) describe the physical and psychological symptoms self-reported by these patients and (c) determine whether any neurological disease category is more likely than others to be associated with ‘symptoms unexplained by disease’.

terminally ill). New patients included patients with existing neurological diagnoses who had been re-referred from primary care. The patients gave their informed consent to be included in the study and completed self-rating scales: the PHQ-15 scale which measures how much the patient has been bothered by each of 15 common physical symptoms (modified by removing questions about sexual function and menstruation and by adding ten common neurological symptoms listed in Table 1) and the Hospital Anxiety and Depression Scale (HADS) which measures psychological symptoms of anxiety and depression. Diagnosis

The data reported here were collected by the Scottish Neurological Symptoms Study [17, 19, 20]. This was a multi-centre study of new neurology outpatients in Scotland, UK. Ethical approval for the study was granted by a Multi-centre Research Ethics Committee MREC.

Neurologists listed their clinical diagnoses (up to three allowed, free text) for each patient immediately following the initial consultation and prior to any investigations being completed. The assessing neurologists were also asked ‘To what extent do you think this patient’s clinical symptoms are explained by organic disease?’ with responses on a four point Likert-type scale: ‘‘not at all’’, ‘‘somewhat’’, ‘‘largely’’ or ‘‘completely’’ [5]. Operational criteria were provided to guide their ratings (Appendix). The ratings of ‘not at all’ or only ‘somewhat’ explained were combined as ‘symptoms unexplained by organic disease’. The age and sex of the patient were also recorded.

Participating clinics

Analysis

Thirty-six of 38 consultant neurologists, working in one of the four Scottish NHS neurology centres participated. Patients were recruited from their general neurology clinics (including their supervised trainee clinics) in the main Scottish neurological centres—Aberdeen, Dundee, Edinburgh, and Glasgow and some of their associated peripheral clinics in Airdrie, East Kilbride, Falkirk, Inverness, Perth, Stirling, Vale of Leven, and Wishaw—in the period December 2002 to February 2004. All the clinics sampled took mainly general practice referrals with patients allocated by medical records staff according to availability of appointment. Tertiary clinics, where patients required a verified diagnosis to attend (such as acute neurovascular and multiple sclerosis clinics) were excluded as were ‘urgent case’ emergency clinics.

The neurological diagnoses made by the assessing neurologists were placed into categories designed by the authors (JS, RD and RR) based on those used in previous studies [2, 9, 12, 15, 18, 22]. We then identified those cases in which the patients was noted to have both a neurological disease diagnosis and symptoms rated as ‘not at all’ or ‘somewhat’ explained by disease to determine (a) how frequently this combination occurred, (b) whether these patients report more physical and psychological symptoms than patients whose symptoms were explained by disease and (c) whether the phenomenon occurred more often with any of the neurological disease categories studied. We excluded the category of ‘headache’ disorders from this analysis because the operational criteria we used to guide neurologist ratings specified tension headache as a symptom ‘‘unexplained by disease’’ and migraine as ‘‘explained by disease’’ making analysis here uninformative. We calculated 95% confidence intervals for proportions of each category using the Clopper Pearson technique. Heterogeneity across categories was assessed using a v2 test. Data on physical and psychological symptoms were compared using unpaired t tests with calculation of 95% confidence intervals of the difference of means (http://www.statsdirect.com).

Methods

Patients All newly referred patients at the participating neurology outpatient clinics were potentially eligible. The exclusion criteria were age \16 years, cognitive or physical impairment of a degree that precluded informed consent, inability to read English, or if the neurologist identified the patient as unsuitable for the study (for example, too distressed,

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Author's personal copy J Neurol Table 1 Frequency of physical and psychological symptoms in patients with a neurological disease diagnosis according to how much their symptoms were rated as ‘‘explained by disease’’ Neurological disease diagnosis but rated as having symptoms ‘‘not at all explained’’ or ‘‘somewhat explained’’ by disease

Neurological disease diagnosis but rated as having symptoms ‘‘completely explained’’ or ‘‘largely explained’’ by disease

Significance (t test)

95% confidence interval for difference between means

Number of patients

293

2174





Age (years, mean)

46.9

48.7

NS (p = 0.08)



Emotional symptoms—HADS (mean) Anxiety (HADS score)

7.9

6.4

p \ 0.0001

0.99–2.12

Depression (HADS score)

5.8

4.8

p \ 0.0005

0.50–1.56

Physical symptom count from PHQ (mean) Neurological symptoms

4.0

3.4

p \ 0.0005

0.23–0.92

Pain symptoms

2.0

1.5

p \ 0.0001

0.29–0.62

Gastrointestinal symptoms

1.0

0.7

p \ 0.0001

0.12–0.38

Chest symptoms

0.9

0.6

p \ 0.0001

0.16–0.41

Neurological symptoms: paralysis or weakness, double or blurred vision, difficulty swallowing, difficulty speaking, lack of co-ordination, dizziness, fainting spells, memory or concentration, loss of sensation, loss of vision, loss of hearing, seizure or fit; Pain symptoms: stomach pain, back pain, pain in arms, legs joints, headaches, chest pain; Chest symptoms: heart pounding or racing, shortness of breath; Gastrointestinal symptoms: constipation, nausea or gas. Headache, chest pain and stomach pain were counted in two categories

Results Recruitment Between 16 December 2002 and 26 February 2004, 4,299 patients attended the specified clinics as new patients. Of these, 138 were excluded (80 were cognitively impaired, 17 had language difficulties, 15 were considered by the doctor as unsuitable for the study, 12 were too physically disabled or ill, in 10 no reason was recorded, 3 had major behavioural problems, and 1 was too young). Of the remaining 4,161 patients 269 refused to participate, 101 did not complete the assessment and ten neurologist diagnoses were not traceable. The final sample was therefore 3,781 patients (88% of all attendees and 91% of all eligible new outpatients).

patients with symptoms unexplained by disease had more physical (both neurological and non-neurological) and more psychological symptoms. Figure 1 shows the proportion of patients with symptoms unexplained by disease in each category of neurological disease diagnosis. This ranged from 0–29%. Examination of the relative proportion in each of the neurological disease categories (excluding the four smallest categories) found heterogeneity (v2 = 46, df = 8, p \ 0.001) The confidence intervals indicated that this heterogeneity reflected a lower proportion of unexplained symptoms in the ‘epilepsy’ category and a higher proportion in the ‘general medical’ category. There were no substantial differences between the other categories.

Discussion Patients with neurological disease but symptoms unexplained by that disease The neurological diagnoses made in the whole sample of 3,781 patients have been reported elsewhere [20]. 2,467 were given a diagnosis of a neurological disease (excluding 727 with a diagnosis of headache disorders). 293 of these 2,467 patients (11.9%,95% confidence interval 10.6–13.2%) also had symptoms rated by the neurologist as being ‘somewhat’ or ‘not at all’ explained by the organic disease. Table 1 shows the modified PHQ-15 and HADS scores according to whether the patients symptoms were rated as explained by disease or not. The main finding was that the

Many of the patients who attended the neurology clinics we studied who received a diagnosis of a neurological disease also had symptoms regarded by the assessing neurologist as unexplained by that disease. The patients self-reported symptoms indicated that these patients had more physical and more psychological symptoms than patients whose symptoms were considered to be explained by their disease diagnosis. No single neurological disease category was associated with an excess of symptoms unexplained by disease. It has been suggested that some diseases, especially those that disrupt frontal or emotional circuitry in the brain, such as multiple sclerosis [4], may be particularly prone to

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Author's personal copy J Neurol Fig. 1 Proportion of patients in each neurological disease category with symptoms unexplained by disease (95% CI) (excluding headache). Mean % for neurological categories shown is 12% (shown by vertical line)

n 'unexplained by disease' / n in disease category Epilepsy

31/516

Peripheral Nerve

48/398

"Other" neurological

49/395

MS / Inflammatory

32/252

Spinal Disorders

36/234

Movement Disorders

20/2224

Syncope

25/155

Stroke / TIA

17/130

General Medical

25/91

Muscle /Neuromuscular

3/22

Dementia

1/22

Brain Tumour

6/21

Motor Neurone Disease

0/7

0%

20%

40%

60%

80%

100%

% of patients with symptoms rated as 'not at all' or 'somewhat explained' by disease (95% CI)

be associated with symptoms that are not explained by the disease. This study suggests that both central and peripheral neurological diseases are equally likely to lead to these symptoms. We did find a lower rate of symptoms unexplained by disease in patients with epilepsy. This could have been a chance finding or might plausibly reflect the fact that epilepsy is an intermittent condition and one that is either present or not present, unlike for example a patient with peripheral neuropathy where disability is typically continuous and where clinicians may be more confident in dividing that disability into ‘explained’ and ‘unexplained’ components. We suspect that the higher rate in the ‘general medical’ category reflects a tendency for some doctors to record a general diagnosis such as ‘osteoarthritis’ for patients with symptoms are unexplained by neurological disease. There are few comparable studies of this topic in neurology. A previous study reported conversion symptoms in patients with head injury (32% of 167 behaviourally disturbed patients) [8]. Another recent study found somatoform disorder to be more common in patients with Parkinson’s disease (7%, n = 412) and dementia with Lewy bodies (12%, n = 124) than in patients with Alzheimer’s disease (1%, n = 303) [14]. Other reports of conversion symptoms complicating multiple sclerosis [1, 4] and migraine [23] indicate the broad range of neurological diseases that have been associated with symptoms that are considered to be unexplained by the patients

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disease diagnosis, a phenomenon sometimes called ‘functional overlay’. The question addressed by this paper has been more often examined the other way round, i.e., how common is neurological disease in patients identified as having ‘functional’ or ‘conversion’ symptoms? Studies of patients with conversion symptoms have been reported organic diseases in 20–60% [7, 10, 11, 13]. Analyses of the type organic diseases reported in these studies have not suggested that any one neurological disease is more common than others. For example, in the study by Crimlisk et al of the 31 patients with organic disease who also had conversion disorder, there was a spread of conditions ranging from migraine (n = 6), disc surgery (n = 9) and peripheral nerve palsy (n = 3). In studies of patients with non-epileptic attacks, the frequency of epilepsy is probably between 10 and 20% with higher proportions in more specialised settings [3]. The relationship of a patient’s subjective symptoms to objectively measured organic disease is less simple than is often supposed. Indeed, there is evidence of a poor relationship between severity of symptoms and severity of organic disease in a number of non-neurological medical conditions [16]. This observation reflects the multi-factorial aetiology of symptoms, including not only the effect of organic disease, but also the patient’s fears and beliefs, focusing of attention on bodily sensations and the presence of anxiety and depression [21].

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Limitations This study had several limitations. First it was of outpatient neurological practice (excluding specialty clinics) in Scotland UK and may not necessarily represent practice elsewhere. In addition we only reported on those patients who consented to take part, although this did represent 88% of all new patients. Second, the categorisation of disease diagnoses we used in this analysis was broad and may have masked differences between narrower disease categories (such as Parkinson’s disease vs. Alzheimer’s disease), or differences between patients at different stages of their disease (for example, early vs. late multiple sclerosis). Third, despite the guidance provided, the interpretation and rating of symptoms unexplained by organic disease may have varied between the participating neurologists. Fourth, there were four disease categories, neuromuscular disease, motor neurone disease, brain tumours and dementia, which were too small to be included in the analysis of heterogeneity. Finally we obtained details of the patients’ symptoms by self-report questionnaires which may not necessarily be the same as those which they presented to the assessing neurologist. Implications Patients with a diagnosis of neurological diseases often have symptoms regarded by neurologists as unexplained by that disease. This phenomenon is common, occurring in approximately 12% of patients and has a broadly similar frequency in all neurological disease categories. The diagnosis and management of this problem deserves more attention in service provision, teaching and research. Acknowledgments We would like to thank Carina Hibberd and all the neurologists and general practitioners who took part in this study; S Tennant, L Alder, J Sim, M Selkirk, D McConachie—the researchers who administered the questionnaires. This study was funded by the Clinical Research Audit Group (CRAG) NHS Scotland and the Chief Scientist Office, Health Department of the Scottish Government. Conflict of interest

None.

Appendix: Guidance given to doctors on ‘What we mean by organic disease’ The following is meant as a guide for this study and we are aware that any divisions like this are imperfect. Many patients have a mixture of symptoms, syndromes or disease and the final coding is your decision based on these guidelines.

‘‘Not organic disease’’ for the purpose of this study: tension headache; aetiologically controversial symptom ‘syndromes’ (e.g., chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome); physiologically explained processes which are thought to be linked to emotional symptoms (e.g., hyperventilation); emotional disorders (e.g., depression, anxiety, panic disorder). ‘Organic disease’ for the purpose of this study: migraine; any neurological disorder with a known pathological basis; Neurological disorders with defined and characteristic features but without a clear pathological basis (e.g., Gilles de la Tourette syndrome, idiopathic focal dystonia); Physiological explained processes NOT linked to emotional symptoms (e.g., micturition syncope); psychotic disorder.

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