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

1 23
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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 dis-
ability 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 neu-
rologists 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 psycho-
logical 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, Introduction
University of Glasgow, Glasgow, Scotland, UK
There is a widespread recognition that some patients who
J. Stone (&)
have a neurological disease such as multiple sclerosis may
Division of Clinical Neurosciences, Western General Hospital,
Edinburgh EH4 2XU, Scotland, UK present with symptoms that are considered to be unex-
e-mail: Jon.Stone@ed.ac.uk plained by that disease. Such patients are often described

123
 Author's personal copy
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 dis-
ability or psychological comorbidity. There is little pub-
lished information on the overlap between neurological
disease and ‘‘symptoms unexplained by disease’’ and par-
ticularly 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 neuro-
logical 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’.
Methods
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 Scot-
land, UK. Ethical approval for the study was granted by a
Multi-centre Research Ethics Committee MREC.
Participating clinics
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, Edin-
burgh, and Glasgow and some of their associated periph-
eral 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 allo-
cated 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.
Patients
All newly referred patients at the participating neurology
outpatient clinics were potentially eligible. The exclusion
criteria were age \16 years, cognitive or physical impair-
ment 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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J Neurol
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 symp-
toms (modified by removing questions about sexual func-
tion 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
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’’, ‘‘lar-
gely’’ or ‘‘completely’’ [5]. Operational criteria were pro-
vided 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.
Analysis
The neurological diagnoses made by the assessing neu-
rologists 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 uninforma-
tive. We calculated 95% confidence intervals for propor-
tions 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).
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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 Neurological disease diagnosis Significance 95% confidence
but rated as having symptoms but rated as having symptoms (t test) interval for
‘‘not at all explained’’ or ‘‘somewhat ‘‘completely explained’’ or difference
explained’’ by disease ‘‘largely explained’’ by disease 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 patients with symptoms unexplained by disease had more

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 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
physical (both neurological and non-neurological) and
more psychological symptoms.
Figure 1 shows the proportion of patients with symp-
toms unexplained by disease in each category of neuro-
logical disease diagnosis. This ranged from 0–29%.
Examination of the relative proportion in each of the
neurological disease categories (excluding the four small-
est 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 propor-
tion in the ‘general medical’ category. There were no
substantial differences between the other categories.
Discussion
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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Fig. 1 Proportion of patients in n 'unexplained by disease' /
each neurological disease n in disease category
category with symptoms
Epilepsy
unexplained by disease (95%
CI) (excluding headache). Mean Peripheral Nerve
% for neurological categories
shown is 12% (shown by "Other" neurological
vertical line)
MS / Inflammatory
Spinal Disorders
Movement Disorders
Syncope
Stroke / TIA
General Medical
Muscle /Neuromuscular
Dementia
Brain Tumour
Motor Neurone Disease
% 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 periph-
eral neurological diseases are equally likely to lead to these
symptoms. We did find a lower rate of symptoms unex-
plained 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 neu-
rology. A previous study reported conversion symptoms in
patients with head injury (32% of 167 behaviourally dis-
turbed patients) [8]. Another recent study found somato-
form 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 Alz-
heimer’s disease (1%, n = 303) [14]. Other reports of
conversion symptoms complicating multiple sclerosis [1,
4] and migraine [23] indicate the broad range of neuro-
logical diseases that have been associated with symptoms
that are considered to be unexplained by the patients
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J Neurol
31/516
48/398
49/395
32/252
36/234
20/2224
25/155
17/130
25/91
3/22
1/22
6/21
0/7
0% 20% 40% 60% 80% 100%
disease diagnosis, a phenomenon sometimes called ‘func-
tional 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 sug-
gested 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 con-
version 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-epi-
leptic 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 rela-
tionship between severity of symptoms and severity of
organic disease in a number of non-neurological medical
conditions [16]. This observation reflects the multi-facto-
rial 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 heteroge-
neity. 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 pro-
cesses which are thought to be linked to emotional symp-
toms (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 patho-
logical 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); psy-
chotic disorder.
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