Neuropsych HANDBOOK

THE BRITISH NEUROPSYCHIATRY ASSOCIATION
www.bnpa.org.uk
Neurology and Psychiatry SpRs Teaching Weekend

12 to 14 December 2008
St Anne’s College – Oxford
Woodstock Road, OX2 6HS
THE ESSENTIALS OF NEUROPSYCHIATRY
The BNPA first Teaching Weekend is kindly supported by the following Companies:
The British Neuropsychiatry Association
Neurology and Psychiatry SpRs Teaching Weekend 12 to 14 December 2008
St Anne’s College, Oxford
Welcome
Introduction
Neurologists and psychiatrists both care for patients with disorders of the brain and its functions,
yet there is remarkably little common training in the two disciplines. There is often both a cultural
and physical divide between the ‘care of the brain’ and the ‘care of the mind’. The aim of this
weekend, the first of its kind, is to bring together roughly equal numbers of neurology and
psychiatry trainees, for a course that will cover the more basic aspects of assessment – history
taking and examination – in the two specialties, review the use of the common approaches to
investigation, and then cover a series of major topics in neuropsychiatry, particularly in areas that
tend to be neglected, such as ‘functional’ or somatoform disorders and disorders of sleep. We
aim to inspire as well as instruct, so we have leavened the mix with some talks that will give
glimpses of exciting current research on mind and brain. We hope that the meeting as a whole
will be informal and highly interactive.
This a new venture for the British Neuropsychiatry Association which exists to foster education in
the middle ground between these disciplines. Our main activity is to hold an annual two-day
meeting, in February, which, uniquely, attracts psychiatrists, psychologists and neurologists. If
you enjoy this weekend, why not join the BNPA, and come to our 2009 meeting (5-6th February at
the Institute of Child health)?
We are very grateful to UCB and Biogen for substantial support from unrestricted educational
grants which have kept down the cost of the meeting.
Adam Zeman
BNPA Chairman
Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

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British Neuropsychiatry Association Committee and administration:
Professor Adam Zeman

Chairman
Professor David Skuse

Treasurer
Dr Hugh Rickards
Secretary
Professor Eileen Joyce

Director
Dr Jon Stone
Director
Professor Rodger Ll Wood

Director
Jackie Ashmenall Tel/Fax: +44 (0)20 8878 0573

Administrator Tel: 0560 114 1307
Unit 3E, (back of) 117-119 E-mail: admin@bnpa.org.uk
Sheen Lane
London SW14 8AE Website: www.bnpa.org.uk
Gwen Cutmore Tel/Fax:+ 44 (0)1621 843334

Conference Secretary Email: gwen@gwen1.orangehome.co.uk
Landbreach Boatyard
Chelmer Terrace
Maldon, Essex
CM9 5HT

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THE ESSENTIALS OF NEUROPSYCHIATRY
Friday 12 December
1 Assessment in neuropsychiatry
13:50 Introduction
14:00 Neurological history taking

Adam Zeman, Professor of Cognitive and Behavioural Neurology, Peninsula Medical
School
14:35 Neurological examination (for psychiatrists)

Jon Stone, Consultant Neurologist, Dept. of Clinical Neurosciences, Western General
Hospital, Edinburgh
15:10 Psychiatric history taking

Hugh Rickards, Consultant Neuropsychiatrist, Queen Elizabeth Psychiatric Hospital
15:45 Tea
16:15 Mental state examination: excluding cognition

Hugh Rickards, Consultant Neuropsychiatrist, Queen Elizabeth Psychiatric Hospital
16:50 Mental state examination: cognition

Adam Zeman, Professor of Cognitive and Behavioural Neurology, Peninsula Medical
School
17:25 Neuroimaging in neuropsychiatry

David Summers, Consultant Neuroradiologist, Western General Hospital, Edinburgh
19:00 Drinks
19:30 Dinner (Ruth Deech Building)

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Saturday 13 December
2 Neurological presentations of psychological disorder
08:30 Weakness, Movement Disorders and Sensory symptoms unexplained by disease

Jon Stone, Consultant Neurologist, Dept. of Clinical Neurosciences, Western General
Hospital, Edinburgh
09:10 Dissociative Seizures

John Mellers, Consultant Neuropsychiatrist, Maudsley Hospital
09:50 Chronic fatigue syndrome: neurological, psychological or both?

Peter White, Professor of Psychological Medicine, Barts and the London Medical School
10:30 Coffee
3 Psychological presentations of neurological disorder
11:00 Traumatic brain injury

Simon Fleminger, Consultant Neuropsychiatrist, Maudsley Hospital
11:40 Epilepsy
Manjinder Bagary, Consultant Neuropsychiatrist, Queen Elizabeth Psychiatric Hospital
12:20 Dementia
Richard Perry, Consultant Neurologist, Charing Cross Hospital
13:00 Lunch
14:00 Prions and human disease

Bob Will, Professor of Neurology, Western General Hospital, Edinburgh
15:00 Movement Disorders

Anette Schrag, Consultant Neurologist, Dept. of Clinical Neurosciences, Royal Free
Hospital, Univ. College London
1540 Tea
4 Management (mainly)
16:15 The EEG and related investigations in neuropsychiatry

Alison Blake, Consultant Neurophysiologist, Queen Elizabeth Psychiatric Hospital
17:00 How to manage depression, anxiety, delirium and psychosis in patients with
neurological disease
Andrea Cavanna, Consultant in Behavioural Neurology, Birmingham and Solihull Mental
Health Trust
17:45 Close

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Sunday 14 December
5 Sleep disorders
09:00 Insomnia and excessive daytime sleepiness

Paul Reading, Consultant Neurologist, The James Cook University Hospital,
Middlesborough
09:40 Parasomnias
Zenobia Zaiwalla, Consultant Neurologist and neurophysiologist, John Radcliffe Hospital,
Oxford
10:20 Coffee
6 Mind and Brain
10:50 Imaging pain in the brain

Irene Tracey, Professor of Anaesthetic Science, University of Oxford
11:30 Cases in neuropsychiatry
12:10 Guest lecture - Anitbodies in neuropsychiatric disorders and more

Angela Vincent, Professor of Neuroimmunology, University of Oxford
CLOSE

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Neurological History Taking
Adam Zeman
adam.zeman@pms.ac.uk
Taking a history serves three main purposes: i) it is an information gathering exercise, providing
data that indicates whether there is neurological (or other) disease, and, if so, which level of the
nervous system is affected, and what pathological process may be involved; ii) it allows informal
but often informative examination, especially of cognitive function, personality and behaviour; iii) it
provides an opportunity to begin a therapeutic relationship with the patient, based on an
interested, sympathetic and receptive attitude. Most neurological diagnoses can be made from
the history, and history-taking is by far the most important part of the consultation. My approach
to history taking has grown from experience of 30-minute new patient consultations (60 minutes
for patients with cognitive disorders).
History of presenting complaint: sometimes there is a single main complaint. If there are several,
it can be helpful to list these initially, to make sure that the patient feels that all aspects of the
problem have been considered. As an aside, the higher the number of symptoms, the lower are
the chances of finding a simple neurological explanation for them. Allow the patient to provide the
narrative with the minimum of interruption. For each main symptom, try to clarify the standard key
information: date of onset, frequency of recurrence, duration of episodes, evolution (ie
progressive, improving or static disorder?), detailed nature of symptoms (eg which part of the
head is involved by a headache, what is the quality of the pain?), associated features (eg visual
aura, nausea, vomiting, photophobia in migraine), triggers, exacerbating/relieving factors
(including response to treatment). Certain specific questions are worth asking on suspicion of
particular disorders (history taking itself is partly hypothesis-driven and therefore partly relies on
specialised knowledge): for example, in suspected Parkinson’s disease ask whether handwriting
has become smaller; in suspected MS ask about exacerbation of symptoms by heat (Uthoff’s
phenomenon), and about shock-like paraesthesiae in the back on neck flexion (L’Hermitte’s
phenomenon); in suspected epilepsy, ask about tongue-biting in convulsive attacks; in suspected
vasovagal syncope check whether all ‘three Ps’ are satisfied (appropriate precipitant, prodrome
and posture).
It can be revealing to ask the patient what he thinks is wrong, as self-diagnosis can both reflect
and contribute to anxiety, and needs to be taken into account in subsequent discussion. It is also
sometimes illuminating, at this stage, to ask what the patient is hoping for from the consultation:
this is not always obvious.
It is often helpful to speak to a witness (it is essential in, for example, suspected epilepsy,
cognitive disorders and parasomnias). This is sometimes best done with the witness on his own.
Functional enquiry: most of us gradually whittle away the functional enquiry, sometimes to
nothing. Certain general questions are, however, always worth asking as they provide an
indication of psychological state which is relevant to management whether the main disorder
turns out to have a psychological basis or not. These are questions about appetite, weight, sleep,
concentration and memory, energy levels, capacity for pleasure, background mood, anxiety and
panic. Depending on the presenting complaint, it may be worth checking out other aspects of
neurological function: headache, pain, sensation, limb function including weakness, impairment of
dexterity, coordination or gait, bladder, bowel and sexual function. In patients with cognitive
disorders, ask about specific domains of memory (eg for recent events, remote events, routes,
faces), language, arithmetic (able to calculate change when shopping?), the abilities to plan, and
to undertake activities of daily living (including shopping and cooking). Where relevant enquire
about symptoms relating to other systems (eg fever, night sweats, lumps and bumps, swollen
glands, cardiovascular, respiratory, gastrointestinal and genitorurinary symptoms).

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Past Medical History: Ask about previous illnesses, operations and chronic disorders
(hypertension, diabetes etc). Developmental history is sometimes relevant. Certain aspects of
past history will be especially relevant to specific disorders eg in epilepsy, ask about birth history,
febrile convulsions, head injuries and CNS infections as these potential causes are sometimes
forgotten. The notes can be an invaluable source of information, and history taking should be
supplemented by a careful review of these (not always easy in a pressed clinic, but always
potentially useful). Ask about current prescribed medication. Recent medication may also be
relevant. Ask about alcohol, tobacco and other recreational drug use, now and in the past.
Personal, social and family history: a brief survey of childhood (parental occupation, sibship,
location of homes, education, whether happy, unhappy, abused), major relationships and career
is often useful, and provides a revealing memory test in those with cognitive complaints. Ask
whether there is any family history of illness, checking specifically for relevant neurological,
cognitive and psychiatric disorders as appropriate.
Summary: it is helpful to get into the habit of summarising the key features of the history in a few
sentences. As already mentioned, most neurological diagnoses can be made from the history,
and history-taking is by far the most important part of the consultation.
A diagnostic hypothesis: The history will indicate the likelihood of neurological disorder. If the
history suggests the presence of neurological disease, use it to frame a hypothesis about the
affected level or levels in the nervous system (muscle, peripheral nerve, neuromuscular junction,
peripheral nerve, spinal cord or brain?), and the pathological process at work (eg MS, infection,
paraneoplastic syndrome etc). The examination can then be used as an opportunity to test the
hypothesis (eg if a brain disorder is suspected, lower motor neuron signs would generally be
unexpected on examination, while upper motor neuron signs would be entirely compatible). Of
course, there will often be the more than one possible level of involvement, and a range of
possibilities in the differential diagnosis of pathologies.
Biopsychosocial approach: the presence of a neurological disorder does not exclude the
possibility of additional psychological disorder, and the presence of psychiatric disorder does not
imply the absence of a biological basis. Rather than trying to sort patients into those with
‘functional’ and ‘organic’ disorders, therefore, it is generally useful to consider the ‘biological’,
‘psychological’ and ‘social’ dimensions of each case. For example, in a patient with multiple
sclerosis, demyelination of the central nervous system provides the biological basis for the
disorder. However, agoraphobia stemming from anxiety about appearing unsteady in public, with
resulting lowering of mood, might accompany this, with resulting consequences for employment
and relationships. Recognising the psychological and social aspects of neurological disorder
sometimes provides the best opportunity for treatment in neurological disease.
Further Reading:
John Hodges. Cognitive Testing for Clinicians. Oxford University Press, 2007.
Adam Zeman. Mind and Brain : building bridges between neurology, psychiatry and psychology.
Oxford Textbook of Medicine, fifth edition, in press (available adam.zeman@pms.ac.uk).

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The Neurological Examination (for psychiatrists)
Jon Stone
Consultant Neurologist and Honorary Senior Lecturer in Neurology
Western General Hospital, Edinburgh EH4 2XU
Jon.Stone@ed.ac.uk
The neurological examination is responsible, in part, for ‘neurophobia’ the mystique and fear
surrounding the business of neurological assessment1. Medical students are interested by
neurology but they find it ‘difficult2’. So, for a psychiatrist, which bits of the neurological
examination are important? Is there any such thing as a routine neurological examination?
MYTH 1 - Neurological diagnosis is all about examination.

Many neurologists rely on the neurological examination much less than you might think. For many
neurological symptom presentations - especially blackouts and headache- the examination adds
little to a diagnosis that is usually made entirely on the basis of the history. But the examination
does become more important when assessing the patient with weakness, movement disorder,
visual symptoms, occasionally dizziness and sometimes numbness.
MYTH 2 - You need to know a lot of neuroanatomy to be able to do a neurological

examination.
Neurological examination is mostly about pattern recognition, not really neuroanatomy. There are
very few ‘essential’ bits of neuroanatomy that you need to know over and above this. It may be
nice to know where the red nucleus is, but this does not help you diagnose and manage
neurological disease!
MYTH 3 - The neurological examination is complicated.

Well…it can be if you want it to be. In Hutchison’s Clinical Examination it runs to 30,000 words.
But in fact, there are only a few basic things to do which will mark you out as a competent doctor.
Leave the rest to neurologists. One of the problems is that books and teachers often don’t tell you
what verbal instructions to give to the patient (hopefully remedied in small part here).
MYTH 3 - I feel a bit of a fraud doing a neurological examination because I’m a psychiatrist.
If you’re on old age, learning disability or liaison psychiatrist a neurological examination will be
especially relevant to your practice. You may feel as if you are doing a better job at examining
people with brain problems, and in return the patient may appreciate some ‘laying on of hands’.
You will only get better at it by doing it repeatedly, especially if you do it on lots of neurologically
normal people as well –few people are just “good at it” without practice

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The Ten Second neurological examination

“Stand up ….wiggle your fingers…stand on one leg….close your eyes”
The One Minute Neurological Examination

There is no such thing as a screening neurological examination, it depends what the complaint is,
but the following are the most ‘cost-effective’ ways to assess a nervous system
1. Stop – look at the patient – is there something obvious

2. “Can you see OK?” – either eye. Look at pupils.
3. Pupillary Response to light then Fundoscopy – buy your own opthalmoscope – claim it
back on tax and never lend it to anyone
4. ‘Look at my nose, point to the finger that’s moving” (Visual fields – both eyes open - four
quadrants - as demonstrated)
5. “Look at my finger” – “any double vision?” left, right, up, down (Eye movements)
6. “Show me your teeth” (grin toothy grin)
7. “Open mouth”, “stick out your tongue”, “waggle it from side to side”, “give me a nice big
cough” (Bulbar)
8. “Wiggle your fingers like this” (make piano playing movements)
9. Waggle arms
10. “Do your arms or legs feel weak or numb?” If patient not complaining of weakness or
numbness probably not worth testing power, reflexes or sensation
11. Ask them to stand then walk normally, then heel to toe
The Two Minute Examination

1. Test power in arms and legs – is it pyramidal? Is it proximal? Is it distal? Is it something
else?. If you find something – try it a few times to make sure.
2. Rapid alternating movements of the hand, Heel shin ataxia
3. Knee reflexes and ankle jerks (and maybe plantar response although this has surprisingly
poor reliability3 )
4. Confirm any history of sensory disturbance using your fingertip – “Can you feel
that?””Does that feel the same or different?” or (for a distal sensory problem) ‘Does this
feel odd? Tell me when it comes back to normal as I go up your leg?”
Special Situations
1. Tremor – “Copy this spiral for me” “Can you pick up this cup and pretend to drink from it”.
“Hold your hands out like this” (shoulders abducted , index fingers nearly touching)
2. Slowness – “Can you do this?” ( open and shut movements with your index and finger
and thumb – left then right), waggle arms, “Can you tap your foot for me like this?” (tap
foot about 2 taps/second – left then right), Stand up – “lets see you walk”, “Turn around
on the spot”, shake at the shoulders and observe arm swing, “I’m going to pull gently
back/forward on your shoulders – but don’t worry you won’t fall, just do what comes
naturally to stop yourself from falling”
3. Cognitive assessment – ACE-revised (pentorch.net/ACEfinal-v05-A1.pdf)
4. Slurred Speech – “Say P,P,P,P,P” (lip), “Say L,L,L,L,L” (tongue), “Say K,K,K,K,K”
(palate), “Say Baby Hippopotamus”(looking for cerebellar speech)
5. Language problems
a. Comprehension – One stage – “Close your eyes / Show me your tongue”; Two
stage – “Touch your nose with you left finger”; More complex – “Show me the
illumination in the room”
b. Expression – “Whats this?” (point at watch, pen, glasses)

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6. Suspected functional disorder – see other chapters in this package

7. Suspected motor neurone disease – Palmomental reflex often positive. Then look for
mixture of upper and lower motor neurone in same ‘bit’
a. Brisk jaw jerk and wasted fasciculating tongue
b. Fasciculations in arm/leg muscles (strip patient, look for 30-60 sec) with brisk
reflexes in same limb as fasciculations
8. Suspected myasthenia gravis – Eye movements look weird. “Look up for 20 seconds”
(looking for fatiguable ptosis), “Stop me from pushing down” (test shoulder abduction) –
“I’m going to do this ten times”
9. Examining Back pain, Neck pain, Headache – mostly pointless to examine but patients
appreciate it. Consider “Does this hurt your back?”(while pressing on head) and “plant
your feet on the ground” (while you rotate trunk). If either of these positive, pain may be
partly behavioural.
10. Coma – think GCS. Shout ‘STICK OUT YOUR TONGUE’. If eyes are open move hand
rapidly in from left then right (menace test), move head up and down(do eyes move
appropriately). Assess limb tone, any response to command, pressure on forehead. For
psychogenic coma insert small tuning fork in nostril.
11. The patient with weak legs – ask about bladder and bowel and look for a sensory level
– you may save someone’s legs one day
12. The patient with proximal weakness – “Fold your ams – can you stand up?”; “Can you
crouch down like this - - (squat), fold your arms and stand up?”. “Can you lie down on the
bed and sit up with your arms folded?”
Things that are fairly useless

1. Visual Fields covering one eye at a time
2. Testing jaw power
3. Rinne / Weber test (but do look in the ear if relevant)
4. A lot of sensory examination – (because if someone is numb they will usually tell you
where it is, inter-rater reliability is awful4 and its easy to find things that are spurious)
5. Romberg test – (because patients so often wobble and its so often reported as positive
when its not)
6. Gag reflex (should be banned)
Some Pattern Recognition
Pattern of weakness / symptoms Localisation As seen in……

Arms - Extensors more than Flexors Upper Motor Neurone (aka Stroke, MS, Brain
Legs – Flexors more than Extensors pyramidal) Tumour
Spinal injury, Cerebral
palsy
Proximal Muscle or Neuromuscular Myopathy, Myasthenia
Distal Neuropathy Peripheral neuropathy
Unilateral Face, Arm Opposite side of brain Stroke, Brain Tumour
Double vision/ dysarthria vertigo, / Brain stem + cerebellum Stroke, MS
clumsy arm/leg (same side as clumsy
arm/leg)
Global collapsing weakness and Brain/Mind Functional Disorder
collapsing / Signs of inconsistency

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Seven sins of neurological examination

1. Just documenting ‘Left side weak’ without having a stab at the distribution of weakness
2. Writing “CNS – NAD”
3. Being too fearful/lazy to attempt it
4. Imagining that the neurological examination (as performed by a neurologist) is so
amazing that it can detect an unusual diagnosis on a patient with psychosis or
depression that you have already taken a good history from and examined
5. Finding an upgoing plantar / positive Romberg’s / nystagmus that is impossible to tie in to
the rest of the story and is almost certainly spurious
6. Not owning a tendon hammer or ophthalmoscope – call yourself a doctor!
7. Doing far too much examination when the history doesn’t require it.
Oh yes………. Neuroanatomy
1. Reflexes…..count from 1 to 8... S1/2 (ankle), L3/4 (knee), C5/6 (biceps), C7/8 (triceps)
2. Median nerve – medial 3.5 fingers, Ulnar – lateral 1.5 (although actually most people with
carpal tunnel syndrome have tingling all over)
3. Dermatomes –
o C7 is middle finger – C5 and C6 are the lateral ones, C8 and T1 medial
o L3 wraps around knee, L5 big toe
4. Vibration sense and proprioception go together
Reference List
1. Ridsdale L, Massey R, Clark L. Preventing neurophobia in medical students, and so future

doctors. Pract.Neurol. 2007;7:116-23.
2. Schon F, Hart P, Fernandez C. Is clinical neurology really so difficult? J

Neurol.Neurosurg.Psychiatry 2002;72:557-9.
3. van Gijn J,.Bonke B. Interpretation of plantar reflexes: biasing effect of other signs and
symptoms. J.Neurol.Neurosurg.Psychiatry 1977;40:787-9.
4. Lindley RI, Warlow CP, Wardlaw JM, Dennis MS, Slattery J, Sandercock PA. Interobserver
reliability of a clinical classification of acute cerebral infarction. Stroke 1993;24:1801-4.

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History taking in neuropsychiatry.
Hugh Rickards MD FRCPsych.

hugh.rickards@bsmht.nhs.uk
“Philosophers have said that the purpose of philosophy is to understand the world. The purpose
is to change it” Karl Marx.
History taking provides the narrative against which the examination (a snapshot) can be
compared. There are many reasons for taking a clinical history from a patient. These include
establishing a therapeutic relationship with the patient, identifying pathogenic and pathoplastic
factors, diagnosis, identifying factors that might influence treatment choice and response,
prognosis and, importantly, for clear documentation purposes.
Neuropsychiatry histories cross the divide between medical and psychiatric histories so tend to
be longer and to focus on specific areas. The history of presenting complaint is particularly
important in the paroxysmal behaviour disorders and the personal/developmental history requires
detailed attention.
The temporal course of symptoms often covers two domains within neuropsychiatry. Firstly,
paroxysmal events have a history of their own and can occur within the overall temporal course of
a disease. Examples of this are the semiology of seizures within the temporal course of epilepsy,
or the semiology of tics within the course of Tourette syndrome. Jargon is commonly used in the
description of paroxysmal events and needs to be clarified (What exactly do you mean when you
say “paranoid”, “depressed”, “fit” etc?). Causative inference is common from patients and needs
to be recognised and given due weight. If consciousness is changed during an episode, histories
are notoriously inaccurate from informants. Use of video/Bluetooth is often helpful. Detailed
history taking is often needed to tease out exacerbating and relieving factors for paroxysmal
events, which can include; the presence or absence of drugs (prescribed and non-prescribed),
emotional environment, sudden movement or noise, change in cognitive set, others’ behaviour,
multi-tasking, temperature, action or rest, suppression of behaviour or very specific situations.
The second domain is the overall course of the disease. Although this is known in general for
many diseases, history taking always takes place during the course of the disease (unless you
are a pathologist) rather than as it has run its course. Some illnesses are defined by their
course/prognosis (relapsing-remitting MS, transient tic disorder) which leads to circular argument
and lessens prognostic value in many cases.
Previous history of both psychiatric and general medical illness can provide information to aid
with diagnosis, treatment response, course of illness and prognosis.
Drug histories need to include non-prescribed drugs (street drugs, drugs for other illnesses,
herbal remedies and miscellaneous non-prescribed medications).
Family history in neuropsychiatry is particularly important. It’s important to ask separately about
neurological, psychiatric and general medical histories within the family. It’s also worth asking if
there is a family history of chronic illness or institutional care. It was (is?) very common for
people with Huntington’s disease to be misdiagnosed as schizophrenia on one hand, or
Parkinson’s disease on the other.

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Social history has a number of functions. It can help you to formulate how an illness has
developed over time (through charting changes in social function). The social history can provide
evidence of current function and disabilities, any cultural issues that might affect diagnosis or
treatment and of the level of social support available, which may influence management choices.
Developmental histories often need informant history (from parents or school reports). Problems
in development can fall into the following domains;
Situational vs. pervasive

Focal vs. generalised
Primary vs. secondary
Normal vs. pathological.
History taking during development offers two complex problems to the history taker. Firstly, it is
retrospective and so prone to bias. Secondly, developmental histories are taken in the context of
a “moving target” (i.e. normal development).
A number of neuropsychiatric conditions have been related to early adverse environmental

experience (particularly somatoform disorders). History taking in this area requires sensitivity.
It’s reasonable to raise the question early on but outright “confrontation” is best reserved for
people with whom a good therapeutic relationship has been established, or as a final gambit
when you have nothing to lose.
The idea of a pre-morbid personality is problematic in neuropsychiatry as, in many cases, the
personality is affected from an early stage. Nevertheless, charting changes in personality over
time, with the aid of an informant, is often useful in the diagnosis of disease and the mapping of
onset and progression.
Neuropsychiatric history should also contain a standard “systems enquiry”.

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Mental State Examination in Neuropsychiatry
Hugh Rickards MD FRCPsych.
The mental status examination is a “snapshot” of current mental function which needs to be
compared with longitudinal information gathered in the history. Mental states are difficult to
ascertain because the brain itself is hard to examine directly and because direct examination
would not, in many cases, yield useful information.
Examination therefore occurs through behavioural observation during the interview, through the
patients’ communication about their mental state and through the performance of tests aimed to
assess specific areas of mental function. Mental status is conventionally divided into the
following areas;
Appearance and behaviour

Speech
Thought content
Mood
Beliefs
Perceptions
Insight
Cognition
Appearance and behaviour
Like many areas of the mental status, appearance and behaviour needs to be viewed in the
context of the history and in terms of cultural or sub-cultural norms. For instance, a very scruffy,
unkempt appearance could be a sign of severe abnormality or completely normal depending on
the context. Symbolic religious or cultural items, self injury or self-mutilation and signs of
substance abuse can also be seen in the same way.
There may be facial or overt bodily signs of disease including asymmetry, dysmorphism or
specific lesions.
State of attention and consciousness needs to be assessed and may change within the space of
the interview. Patients may be distracted during the interview by non-specific stimuli (i.e. the
distractibility of delirium) or by internal mental or physical phenomena (obsessional rumination,
mental rituals, sensory phenomena or hallucinations). There may be episodes of drowsiness or
sleep and, occasionally, a demonstration of a paroxysmal behavioural disorder during
examination. Clear description of semiology is vital. It is important to avoid jargon in this context
as well as the use of pejorative words such as “bizarre” which really only means “I think it’s
psychogenic” and, as such is an opinion, rather than a description.
Any kind of motor disorder should be described carefully bearing in mind that the language of
motor/behaviour disorder has developed over parallel tracks in the last century (see Danny
Rogers: Motor disorder in Psychiatry).
It is important to gauge the emotional approach of the patient and judge the level of rapport
established. This is a tricky area as rapport may also depend on your own reaction to individual
patients.

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Speech.
Speech has many components including rate, volume, prosody (expressive and receptive),
content, articulation, fluency and accent. Specific problems in speech include echolalia (seen in
Tourette, autism, and after brain injury), palilalia (seen in Tourette syndrome) and mutism.
Mood.
Mood state needs to be assessed on its own. Take into account the patients’ own statements
about mood but put this into the context of their mood state over the time course of the illness.
Observations about mood can be made based on verbal and non-verbal communication. In
diseases which affect non-verbal communication (e.g. Parkinson’s disease, autism), changes in
mood state are important as well as the pervasiveness of mood states. Specific questions about
neuro-vegetative symptoms are often asked at this point (sleep, appetite, weight, sexual function)
although these can often be affected by underlying, non-depressive, diseases or treatments.
Suicidal ideation and intent should be enquired upon in a sensitive but direct manner.
Thought content
The content of thought is central to mental status examination and this is usually expressed
through speech. If there is a problem with speech, then thought content can be difficult to
assess. Thought content will provide information about mood (in relation to negative cognitions
for example), arousal (phobic or anxious thoughts), unusual beliefs and perceptions but also of
rarer states such as depersonalisation. As in the history taking, it’s important to let the patient
describe the thoughts in their own terms but also to clarify jargon. Unusual beliefs should be
explored non-judgementally for their cultural salience, shakeability and for the degree of insight
the patient shows into them. Clues for the exploration of thought content are often found in the
history.
Delusions.
These are essentially false beliefs out of cultural context and may be related to incorrect
attribution of salience to external stimuli. Many beliefs may be plausible (“she’s having an affair”,
“they’ve taken my money”, “they’re after me”) so you need to explore the evidence the patient has
for the belief. Delusions may be related to underlying mood state. Very specific organic lesions
can present with false beliefs based on a specific cognitive problem (for instance an agnosia).
Hallucinations/illusions
Hallucinations are perceptions with no object. Illusions are a misperception of an existing object
and are usually divided into affect illusions (seeing a threatening person in a shadow when it’s
dark) and pareidolic illusions (seeing an animate object in a pattern, which is common in
delirium). The modality and temporal presentation of hallucinations is vital in diagnosis.
Insight
Insight into illness may be related to specific neurological lesions (as in anosagnosia), to active
psychotic processes and to psychological denial of illness. Insight is not a binary construct, so
patients may have insight that is situation specific and temporally variable. Currently, insight is
related to capacity and has relevance to the new Mental Capacity Act.
Cognition
This is dealt with in another talk.

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Reading list for neuropsychiatric history taking.
Lishman. Organic Psychiatry.

American Psychiatric Association Textbook of Neuropsychiatry.
JBP Stephenson. Fits and Faints. MacKeith Press.
D Schmidt & S Schachter. 101 puzzling cases of epilepsy. Martin Dunitz Ltd.
D Rogers. Motor Disorder in Psychiatry. Towards a Neurological perspective. John Wiley.

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Cognitive Assessment
Adam Zeman
Cognition is the capacity to acquire, store and use knowledge. Its major components are:
consciousness, attention, perception, memory, language, numeracy, executive function and
praxis. Three introductory points are worth making: i) Although cognitive testing is a distinctive
aspect of assessment, cognitive processes are closely tied to general medical, neurological and
behavioural functioning. The clue to the cause of a cognitive disorder may come from general
medical examination (eg the slow pulse and coarse skin of hypothyroidism), neurological
examination (the choreiform movements of Huntington’s Disease), cognitive assessment itself
(the pure anterograde memory deficit of early Alzheimer’s Disease), or from neuropsychiatric
observations of behaviour (the disinhibition of frontal lobe dementia). ii) Cognitive processes are
not restricted to certain ‘higher’ brain regions. The belief that they are localised in ‘association
cortex’ has given way to the view that they depend on interconnected networks of regions
distributed around the brain, both cortical and subcortical. Damage to the thalamus, for example,
can profoundly disable cognition. iii) Cognitive functions are not entirely separate from one
another, or from related functions such as personality, mood and motivation. Difficulty sustaining
attention, for example, inevitably impacts on memory, and impairments of language have
widespread effects on cognition. Low mood, apathy or a deliberate decision to withhold effort will
also influence the results of cognitive testing. Test results must therefore be interpreted in a broad
cognitive and clinical context.
The elements of cognition

Consciousness
Definition: consciousness normally implies both a particular global behavioural state -
‘wakefulness’ – and the occurrence of experience – ‘awareness’.
Neural basis: the cycle of sleep and waking is controlled by structures in the upper brain stem,
thalamus, hypothalamus and basal forebrain, the ‘ascending reticular activating system’,
incorporating several neurochemically distinct subsystems strategically placed to modulate the
level and mode of function in the cerebral hemispheres. It is possible to be awake but unaware,
as in the vegetative state, in which brain stem function is relatively intact while the functioning of
the cerebral hemispheres is severely impaired. Awareness - the occurrence of experience -
requires adequate amounts of appropriately synchronised and widely distributed activity in the
cerebral hemispheres.
Assessment: the level of consciousness can be quantified using the Glasgow Coma Scale
(Figure 1), which requires examination of the eyes and of verbal and motor responses. The
Epworth Sleepiness Scale (Figure 2) is a useful questionnaire in patients who complain of
excessive daytime sleepiness: scores over 10-11 indicate pathological levels warranting further
assessment.
Pathologies: coma, the vegetative state, the minimally conscious state, the locked in syndrome
and brain death. Excessive daytime sleepiness is an under-recognised cause of cognitive
impairment, due most commonly to insufficient sleep, obstructive sleep apnoea or narcolepsy.
Attention
Definition: the essence of attention is selection. At any moment numerous external and internal
targets are available to consciousness: attention decides on which of these we should focus our
mental energies.
Neural basis: the neural basis of attention is both distributed and localised. It is distributed in the
sense it involves the concerted activity of widespread brain regions. Factors that disrupt the
coherence of distributed brain activity are the most common causes of impaired attention.
However, aspects of the neural basis of attention are localised. For example, the control of
attention is tied to the frontal lobe systems involved in cognitive control - ‘executive function’.

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Assessment: sustained attention is assessed clinically by asking the patient to perform a

moderately demanding repetitive task, for example subtracting 7 from 100 five times, spelling
‘world’ backwards or reciting the months of the year backwards.
Pathologies: sustained attention is most commonly disrupted by factors that globally impair brain
function, such as drugs, drug withdrawal, metabolic upset and infection, giving rise to confusional
states (also known as ‘delirium’). Impairment of attention is also a common accompaniment of a
‘dysexecutive syndrome’. Spatial attention is most commonly impaired by right inferior parietal
damage, causing ‘neglect’, the failure to attend to the contralateral, left, side of space.
Perception
Definition: the ability to gain knowledge of the world through the senses.
Neural basis: much of the brain, especially the posterior parts of the cerebral cortex, is involved in
the processing of sensory information. Two major streams of visual perceptual processing have
been distinguished: a ventral steam, running from the occipital into the temporal lobe, concerned
particularly with object and person identification, and a dorsal stream, running from the occipital
into the parietal lobe, concerned particularly with the visual guidance of action. Although
perception is less strongly lateralised than language, the right hemisphere takes the leading role
in some aspects of perception, for example in face recognition.
Assessment: auditory perception is assessed incidentally by conversation and visual perception
by naming tasks. The standard specific bedside test of visual perception involves copying a
drawing, such as the overlapping pentagons of the MMSE. Pathologies: ‘Agnosias’, literally
‘failures of knowledge’, are disorders in which the early stages of sensation are intact, but the
perception or knowledge, to which they normally gives rise, are impaired. Visual agnosias are
classically divided into ‘apperceptive’ and ‘associative’ types: apperceptive visual agnosias
include specific impairments of colour, movement and form perception; associative visual
agnosias include inabilities to recognise objects or faces, although these can, in many cases, be
copied or matched. These disorders usually result from damage to the ventral stream of visual
processing. Balint’s syndrome follows bilateral damage to the dorsal stream. It involves
‘simultanagnosia’, the inability to make out more than one item in the visual scene at a time, optic
ataxia, difficulty reaching for a seen object, and oculomotor dyspraxia, difficulty in directing eye
movements accurately.
Memory
Definition: the capacity that allows our behaviour and experience to change in response to what
has happened to us in the past. Memories of every kind must be acquired (or ‘encoded’), stored
and later retrieved if they are to be useful. Many memories undergo a complex process of
‘consolidation’ by which they become less vulnerable to loss over time. ‘Anterograde memory’
refers to the ability to acquire memories from a given point in time; ‘retrograde memory’ refers to
the ability to retrieve memories that were formed previously. ‘Declarative’ memories, those we
can articulate are distinguished from ‘procedural’ memories, which underly our know-how; ‘short-
term’ or working memory is memory for the information that we are actively working with. It is
distinguished from ‘long-term’ declarative memory, memory for information that is in store and
can be recollected but that may not be in consciousness currently. ‘Episodic’ memory, memory
for single events is distinguished from ‘semantic’ memory, our data base of knowledge about the
world and language. ‘Autobiographical’ memory, of particular importance in psychiatry, involves
both personal semantic and personal episodic memory (you can probably remember where you
lived when you were eight, a semantic fact – and some of the first-hand details of an important
event from your primary school, an episodic memory).
Neural basis: memory formation depends ultimately on modifications of the strengths of synaptic
connections between neurons. As modifiable synapses are present everywhere in the brain,
memory, in a sense, is everywhere too. However, different kinds of memory involve different brain
regions. Short term, or ‘working’ memory, depends on neural systems that represent the material
we are working with, for example language systems if we are repeating a name and address, and
frontal executive systems that select what we work with at a given moment. Entering material
from working memory into long term declarative memory requires that the ‘circuit of Papez’ is

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intact: this limbic circuit includes structures in the medial temporal lobe (MTL), especially the
hippocampus, the fornix, the large fibre bundle that interconnects the MTL and the thalamus, and
structures in the thalamus, particularly the anterior thalamic nuclei and mamillary bodies. Damage
anywhere along the course of the circuit of Papez can give rise to an amnesic syndrome (see
below). The long-term storage of semantic memories depends on the lateral temporal neocortex.
Rich recollection of past personal experiences activates a widespread network of brain regions in
all four lobes of the brain. The cerebellum, basal ganglia and sensory cortices are required for
conditioning, motor skill learning and sensory priming respectively, forms of procedural memory.
Assessment: short term or working memory is assessed by asking the patient to repeat three
words or a name and address. Long term declarative memory is assessed by asking the patient
to retrieve the three words or name and address after a period of distraction sufficient to ‘wipe’
working memory. Semantic memory is assessed by asking the patient to name objects or to
answer general knowledge questions. These simple standard tests are useful, but fail to tap
important aspects of memory – including longer term retention, autobiographical memory and
procedural memory.
Pathologies: severe damage anywhere along the course of the circuit of Papez causes an
‘amnesic syndrome’. Examples include the early pathology of Alzheimer’s disease which begins
in the MTLs and Korsakoff’s syndrome, due to established thiamine deficiency, in which the
causative lesion lies in the anterior thalamus. A transient amnesic syndrome occurs in disorders
that transiently disable these structures, including concussion, Transient Global Amnesia,
Transient Epileptic Amnesia, and drug induced amnesia. Damage to the temporal neocortex,
most often seen in the temporal lobe variant of Fronto-temporal Dementia, causes semantic
memory impairment. The existence of ‘focal retrograde amnesia’, loss of past memories in the
absence of any impairment of the ability to form new ones, as a result of brain damage, is
controversial. Such cases often turn out to have a psychiatric or forensic explanation. However,
there are now a few well documented cases of this kind suggesting that brain damage can
occasionally give rise to this pattern of deficit.
Language
Definition: the capacity to communicate using words. Language functions include the abilities to
speak, understand, repeat, name, read, write and spell.
Neural basis: language is the most clearly asymmetric cognitive function of the human brain. It is
predominantly represented in the left hemisphere in almost all right handed and the majority of
left-handed people. Broca’s area, in the left inferior frontal lobe, processes fluent speech;
Wernicke’s area in the left superior temporal lobe is required for comprehension of one’s own and
others’ speech. These areas are connected by a fibre bundle, the arcuate fasciculus. Cortical
regions surrounding Broca’s and Wernicke’s area contribute to their function. While language is
predominantly a ‘dominant hemisphere’ function, the right hemisphere contributes to prosody, the
musical and emotional aspects of speech and speech perception.
Assessment: the critical elements of assessment are to listen to the patient’s spontaneous
speech to establish whether it is fluent or dysfluent, and to determine whether the patient’s
comprehension is intact. Comprehension can be tested by using instructions of increasing
complexity (one → several stage), or by using language of increasing sophistication to frame the
request (‘please point to drawing of the marsupial’). A more comprehensive assessment will test
naming, repetition, reading, writing and spelling.
Pathologies: dysphasia – or aphasia – is a disorder of language function, to be distinguished from
‘dysarthria’, a disorder of articulation. Dyslexia is the term specifically applied to disorders of
reading, dysgraphia to disorders of writing. Damage to Broca’s area particularly disrupts fluency
and syntax, the grammatical ordering of language. Patients with Broca’s dysphasia produce
meaningful but dysfluent and effortful speech from which function words (‘the’, ‘to’) are often
omitted. Patients may produce phonetic word approximations known as phonemic paraphasias
(eg ‘mister’ for ‘matter’). Comprehension of syntactically complex sentences may be impaired.
Patients are usually aware of their deficit and frustrated by it. Damage to Wernicke’s area disrupts
the semantic aspect of language, impairing comprehension both of one’s own and of others’
speech: this gives rise to fluent but empty or nonsensical output, containing paraphasic errors

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(both semantic, eg ‘hand’ for ‘foot’ and phonemic). Patients are usually unaware of their deficit.
Wernicke’s dysphasia is sometimes mistaken for thought disorder: thought disordered patients
should, however, be able to follow instructions, indicating that their comprehension is relatively
intact (although it is noteworthy that the region of the brain associated with thought disorder in
schizophrenia overlaps Wernicke’s area). Writing in Broca’s aphasia and comprehension of the
written word in Wernicke’s are usually affected in similar ways to speech production and
comprehension respectively. Damage to the arcuate fasciculus causes conduction aphasia,
impairing repetition out of proportion to other functions. Damage to surrounding cortical regions
that spares Broca’s or Wernicke’s area gives rise to aphasia with similar characteristics to Broca’s
or Wernicke’s but with relative sparing of repetition (‘transcortical motor’ and ‘transcortical
sensory’ aphasias respectively). Dyslexia can occur as a result of damage to the left visual cortex
and adjacent corpus callosum, disconnecting the left hemisphere from information about the
written word (alexia without agraphia); as a result of visual neglect (neglect dysgraphia); or in
‘central’ forms in association with left hemisphere damage, due for example to stroke or
dementia, causing ‘surface dyslexia’ (in which patients become dependent on letter by letter
reading with resulting difficulty in reading irregular words like ‘pint’, which will be read to rhyme
with ‘mint’), or ‘deep dyslexia’, in which the ability to read letter by letter is lost (with resulting
inability to read nonsense words, like ‘proke’, and semantic reading errors, eg ‘brother’ for
‘sister’). Dysgraphia can occur in association with other types of dyspraxia (dyspraxic dysgraphia,
see below), in association with neglect (‘neglect dysgraphia’), or in ‘central’ forms due to left
hemisphere damage analogous to surface and deep dyslexia as above. Dysgraphia is particularly
associated with damage to the angular gyrus, the focus of damage in Gerstmann’s syndrome of
central dysgraphia, acalculia (see below), right-left disorientation and finger agnosia (inability to
name or point to indicated fingers).
Numeracy
Definition: the ability to recognise and manipulate numbers to solve arithmetical problems.
Neural basis: numeracy is principally dependent on the dominant hemisphere, is often but not
always associated with dysphasia, and has a particularly strong association with the posterior left
hemisphere, especially the parietal lobe (including the angular gyrus).
Assessment: oral addition, subtraction, multiplication and division.
Pathologies: dyscalculia is an acquired disturbance of the ability to calculate(1). It can result from
an inability to comprehend, read or write numbers, generally associated with aphasia. Spatial
dyscalculia involves difficulty with written calculations occurring in association with neglect.
Anarithmetria, or ‘primary dyscalculia’, is the specific inability to perform calculations like addition
and subtraction. Spatial dyscalculia is associated with right hemisphere pathology, whereas
impaired use of numerical symbols and anarithmetria occur in association with damage to the
posterior left hemisphere including the angular gyrus.
Executive function and social cognition

Definition: the capacity to organise thought and behaviour. This includes the abilities to plan,
initiate, monitor and adjust a course of action; to ‘shift set’, changing tack from one activity or
approach to another; to reason; to problem solve. These abilities are closely linked to the
capacities for appropriate social interaction, and for empathy, capacities that are, in turn,
important determinants of personality. As self-monitoring is a cardinal executive function, patients
with dysexecutive disorders commonly lack insight into their predicament.
Neural basis: executive functions are associated with the frontal lobes. Whereas the primary
motor cortex and premotor areas are involved in the moment to moment control of action, the
prefrontal cortex – lateral prefrontal, ventromedial prefrontal and anterior cingulate – play a more
strategic role. Lateral prefrontal cortex is linked particularly with working memory functions, of the
kind required, for example, to solve the Wisconsin Card Sort Test in which one must keep track of
the correct criterion – symbol shape, colour or number – by which to sort a pack of cards, and
make appropriate adjustments when the criterion changes. Ventromedial – sometimes called
orbitofrontal – cortex is associated with the control of behaviour, especially social behaviour,
under guidance by emotion, empathy and ‘theory of mind’ (this refers to our ability to impute

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mental states like desires and beliefs to others). Anterior cingulate cortex is thought to play a key
role in the allocation of attention. It mediates between arousal systems, lateral prefrontal cortex
and motor output, thus integrating arousal, cognition and action. The control of executive function
is not limited to prefrontal cortex. The frontal lobes have subcortical connections with basal
ganglia, thalamus and cerebellum: disruption to these structures, or to the links between them,
can also give rise to a dysexecutive syndrome.
Assessment: executive function is notoriously difficult to test in the clinic: patients with
dysexecutive syndromes severe enough to cause major disruption to long-term decision making
can score full marks on standard cognitive tests, like the mini-mental state examination. The
single most useful simple clinical measure of executive function is verbal fluency: this task
requires generation of as many examples as possible in a minute from a particular category, for
example ‘animals’, or ‘words beginning with the letter p’. This task requires an ability to search
semantic memory flexibly. The lower limit of normal is 10 examples. The ability to copy motor
sequences is also dependent on frontal lobe function: Luria’s ‘fist-side-palm’ sequence can be
used to assess this. Confabulation, indifference to failure and perseveration of responses are
common qualitative features of dysexecutive syndromes.
Pathologies: focal damage to the frontal lobes occurs most commonly as a result of trauma,
stroke or neurosurgical excision. The frontal variant of fronto-temporal dementia presents with
changes in personality and behaviour, often involving apathy, disinhibition, and loss of empathy
and interest in others. Similar features can occur as a result of subcortical pathologies, because
of disruption of the looping pathways mentioned above. These include focal pathologies affecting
the basal ganglia or cerebellum and diffuse pathologies affecting white matter, for example
disease of the small blood vessels of the brain and multiple sclerosis. The idea that cerebellar
pathology can give rise to features similar to disorders of the frontal lobe has recently been
enshrined in the concept of the ‘cerebellar cognitive affective syndrome’. Bilateral damage
restricted to the region of the anterior cingulate cortex can give rise to a state of profound ‘will-
less-ness’ or abulia, akinetic mutism.
Praxis
Definition: the ability to learn and to perform skilled actions such as writing, gesturing, using a
toothbrush or playing a musical instrument. ‘Dyspraxia’ involves a deficit in the higher order
control of motor function, not accounted for by sensory loss, more basic motor deficits such as
weakness, tremor, dystonia or ataxia, or by dementia.
Neural basis: praxis is associated with the dominant hemisphere, which controls the more skilled
hand as well as language. Regions of the left frontal and parietal lobes contain the motor
engrams for skilled actions and are required to select and implement these. Performance of
skilled oral movements depends particularly on the inferior frontal lobe and insula.
Assessment: praxis is assessed by asking patients to copy arbitrary hand positions (eg tip of
thumb touching tip of little finger), to perform mimes of transitive and intransitive actions (eg
brushing hair and stopping traffic), and to performed learned skilled movements of the mouth (eg
blowing out a match).
Pathologies: the terminology of dyspraxias is inconsistent. ‘Limb kinetic dyspraxia’ refers to a
type of dyspraxia in which movements are performed adequately but dysfluently. ‘Ideomotor
dyspraxia’ has been used to refer to failure to produce intransitive gestures, impairment in the use
of single objects or, more broadly, to a disorder of the production system for skilled actions.
‘Ideational dyspraxia’ has been used to refer to failure to produce transitive actions, impairment in
the use of a series of objects, as in striking a match or, more broadly, to a disorder of the
conceptual system which contains knowledge of tool functions and actions. Dyspraxia can occur
as part of the behavioural syndrome resulting from focal left hemisphere damage of whatever
cause and early in the course of neurodegenerative diseases including Alzheimer’s disease and
corticobasal degeneration. Oral (or ‘buccofacial’) apraxia may accompany Broca’s aphasia.
These disorders of skilled movement imitation and selection are sometimes associated with
symptoms of motor disinhibition: imitation behaviour (involuntary imitation of the examiner’s
movement), utilisation behaviour (involuntary utililisation of objects that come into view, for
example the donning of several pairs of spectacles), and alien limb behaviour, involving

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apparently purposeful limb movements disavowed by the patient. Grasp, pout and palmo-mental
reflexes can occur in association with dyspraxia and with dysexecutive syndromes as they reflect
a loss of the motor inhibition normally exercised by the frontal lobes (grasp: the patient’s hand
grasps the examiner’s despite a request not to do so; pout: a puckering of the lips when a spatula
is placed against them; palmo-mental: a puckering of the chin on stroking the ipsilateral thenar
eminence).
Dementia and delirium: cognitive assessment should make it possible to identify focal cognitive
deficits, and the, usually insidious, impairment of two or more domains of cognition, with impact
on social functioning, that characterises dementia. The neuropsychological hallmark of delirium,
or ‘confusion’, is the prominent disorder of attention, with impairment of working memory. It is
important to distinguish delirium from dementia as their causes and management are very
different. It can be helpful to distinguish ‘cortical’ from ‘subcortical’ dementias – the former, such
as Alzheimer’s disease, give rise to the classical neuropsychological deficits of amnesia, aphasia,
apraxia etc, while the most prominent feature of subcortical dementia, as seen for example in
multiple sclerosis, is slowing of cognition, often with dysexecutive features.
The Minimental State Examination (MMSE) and the Adenbrooke’s Cognitive Examination
(ACE): standard proformas are a great help in assessing cognition. The MMSE is brief and easy
to administer but fails to assess executive function and praxis. The ACE (at end) is a slightly
lengthier test, incorporating the MMSE, providing individual scores for each of the major domain
of cognition. A score below 24 on the MMSE or 82 on the ACE is suggestive of dementia, though
of course false positives and false negative occur.
Further reading:
John Hodges. Cognitive Testing for Clinicians. Oxford University Press, 2007.
Adam Zeman. Cognitive Assessment, In: Psychiatry - An Evidence-based Text, ed Basant

Puriand and Ian Treasaden. Hodder Arnold, in press (pre-print available via email,
adam.zeman@pms.ac.uk).
Figure 1 The Glasgow Coma Scale

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Figure 2 Epworth Sleepiness Scale
Daytime sleepiness:
• Sitting and reading

• Watching T.V.
• Sitting inactive in a public place,
eg. theatre, meeting
• Passenger in a car for an hour
• Lying down to rest in the afternoon
• Sitting and talking to someone
• Sitting quietly after lunch
• In a car whilst stopped in traffic
0 = would never dose

1 = slight chance of dosing
2 = moderate chance
3 = high chance

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ADDENBROOKE'S COGNITIVE EXAMINATION - ACE-R
Final Revised Version A (2005)
Name : Date of testing:

Date of birth : Tester's name:
Hospital no. : Age at leaving full-time education:
Occupation:
Handedness:
Addressograph
ORIENTATION
[Score 0-5]
A T T E N T I O N & O R I E N T A T I O N
Ask: What is the Day Date Month Year Season
Ask: Which Building Floor Town County Country [Score 0-5]
REGISTRATION
[Score 0-3]
Tell: 'I'm going to give you three words and i'd like you to repeat after me: lemon, key and ball'.
After subject repeats, say 'Try to remember them because i'm going to ask you later'. Score only
the first trial (repeat 3 times if necessary).
Register number of trials
ATTENTION & CONCENTRATION

[Score 0-5]
Ask the subject: ' could you take 7 away from a 100? After the subject responds, ask him or her
to take away another 7 to a total of 5 subtractions. If subject make a mistake, carry on and (for the best
check the subsequent answer (i.e. 93, 84, 77, 70, 63 -score 4) performed task)
Stop after five subtractions (93, 86, 79, 72, 65).
Ask: 'could you please spell WORLD for me? Then ask him/her to spell it backwards:
M E M O R Y - Recall
[Score 0-3]
Y
Ask: 'Which 3 words did I ask you to repeat and remember?'
M E M O R Y - Anterograde Memory
Tell: ' I'm going to give you a name and address and I'd like you to repeat after me. We'll be
[Score 0-7] R
doing that 3 times, so you have a chance to learn it. I'll be asking you later'
Score only the third trial

O
1st Trial 2nd Trial 3rd Trial
Harry Barnes
73 Orchard Close
M
Kingsbridge
Devon
M E M O R Y - Retrograde Memory
E
[Score 0 -4]
Name of current Prime Minister
Name of the woman who was Prime Minister
Name of the USA president
Name of the USA president who was assassinated in the 1960's
M
copyright 2000, John R. Hodges

ADDENBROOKE'S COGNITIVE EXAMINATION - ACE-R Final Revised Version (2005)
V E R B A L F L U E N C Y - Letter 'P' and animals

Letters
[Score 0 - 7]
Say: ‘I’m going to give you a letter of the alphabet and I’d like you to generate as many words
Y
as you can beginning with that letter, but not names of people or places. Are you ready? You’ve
got a minute and the letter is P’
>17 7
C
14-17 6
11-13 5
8-10 4
6-7 3
N
4-5 2
2-3 1
<2 0
total correct
E
Animals
Say: ‘Now can you name as many animals as possible, beginning with any letter? [Score 0 - 7]
U
>21 7
17-21 6
14-16 5
L
11-13 4
9-10 3
7-8 2
5-6 1
F
<5 0
total correct
L A N G U A G E - Comprehension
Show written instruction: [Score 0-1]
E
Close your eyes
G
A
U
3 stage command: [Score 0-3]

'Take the paper in your right hand. Fold the paper in half. Put the paper on the floor'
G
L A N G U A G E - Writing
Ask the subject to make up a sentence and write it in the space below: [Score 0-1]
Score 1 if sentence contains a subject and a verb (see guide for examples)
N
A
L

L A N G U A G E - Repetition
[Score 0-2]
Ask the subject to repeat:' hippopotamus'; 'eccentricity; 'unintelligible'; 'statistician'
Score 2 if all correct; 1 if 3 correct; 0 if 2 or less.
[Score 0-1]
Ask the subject to repeat: ‘Above, beyond and below’
[Score 0-1]
Ask the subject to repeat: ‘No ifs, ands or buts’
L A N G U A G E - Naming
Ask the subject to name the following pictures: [Score 0-2]
pencil +
watch
E
G
[Score 0-10]
A
U
G
N
A
L
L A N G U A G E - Comprehension
Using the pictures above, ask the subject to:

[Score 0-4]
• Point to the one which is associated with the monarchy
• Point to the one which is a marsupial
• Point to the one which is found in the Antarctic
• Point to the one which has a nautical connection
L A N G U A G E - Reading
E
Ask the subject to read the following words: [Score 1 only if all correct] [Score 0-1]
G
sew
A
pint
U
soot
G
dough
N
height
A
L
VISUOSPATIAL ABILITIES
[Score 0-1]
Ov erlapping pentagons: Ask the subject to copy this diagram:
L
A
I
T
A
[Score 0-2]
P
Wire cube : Ask the subject to copy this drawing (for scoring, see instructions guide)
S
O
U
S
I
[Score 0-5]
Clock: Ask the subject to draw a clock face with numbers and the hands at ten past five. V
(for scoring see instruction guide: circle = 1, numbers = 2, hands = 2 if all correct)

PERCEPTUAL ABILITIES
Ask the subject to count the dots without pointing them [Score 0-4]
L
A
I
T
A
P
S
O
U
S
I
V

ADDENBROOKE'S COGNITIVE EXAMINATION - ACE-R Final Revised Version A (2005)
PERCEPTUAL ABILITIES
Ask the subject to identify the letters [Score 0-4]
L
A
I
T
A
P
S
O
U
S
I
V
RECALL
Ask “Now tell me what you remember of that name and address we were repeating at the beginning’”
Y
Harry Barnes [Score 0-7]
73 Orchard Close
R
Kingsbridge
Devon
O
RECOGNITION
This test should be done if subject failed to recall one or more items. If all items were recalled, skip the [Score 0-5]
test and score 5. If only part is recalled start by ticking items recalled in the shadowed column on the
M
right hand side. Then test not recalled items by telling “ok, I’ll give you some hints: was the name X, Y or
Z?” and so on. Each recognised item scores one point which is added to the point gained by recalling.
Jerry Barnes Harry Barnes Harry Bradford recalled
E
37 73 76 recalled
Orchard Place Oak Close Orchard Close recalled
M
Oakhampton Kingsbridge Dartington recalled

Devon Dorset Somerset recalled
General Scores
MMSE /30
E
ACE-R /100
R
Subscores
Attention and Orientation /18
O
Memory /26
Fluency /14
C
Language /26
S
Visuospatial /16
Normative values based on 63 controls aged 52-75 and 142 dementia patients aged 46-86
Cut-off <88 gives 94% senstivity and 89% specificity for dementia
Cut-off <82 gives 84% sensitivity and 100% specificity for dementia
Neuroimaging; From Structure to Function
Dr David Summers
david.summers@ed.ac.uk
Imaging in medicine was founded when Wilhelm Roentgen first identified X-rays in 1895,
producing an image of his wife’s hand. Within a year, over 1000 papers had been published on
the potential uses of the new rays, and Roentgen received a Nobel Prize in 1901 for his
discovery.
Prior to this, it had been impossible to see within the living brain or spine; In the introduction of his
two-volume textbook, 'Diseases of the Nervous System', published in 1886 and 1888, Sir William
Gowers wrote:
'The nervous system is almost entirely inaccessible to direct examination. The exceptions to this
are trifling. The termination of one nerve, the optic, can be seen within the eye. Some of the
nerve-trunks in the limbs can be felt; a few, as the ulnar. in the normal state; others only when
enlarged by disease.'
And in the same era Sir William Macewen, a Glasgow neurosurgeon, described the brain as 'the
dark continent'. The opportunity to see within the protective skull and vertebral bodies, and to try
and identify the pathological processes within was a huge new field of medical endeavour.
Whilst radiography of the skull was taken up enthusiastically, it provided very limited information.
The erosion of the pituitary sella by adenoma, or the displacement of normal calcified structures
such as the pineal gland by a mass were the extent of plain radiography’s utility. Some
physicians in the newly developing specialty of radiology then realised that the introduction of
‘contrast agents’ within the skull and spine would delineate those soft tissue structures more
effectively – and so myelography, encephalography (using air and iodine) and cerebral
angiography were developed. The latter technique was invented in 1927 by Egas Moniz, a
Portuguese neurosurgeon and polymath who was later Minister for Foreign Affairs, and who also
won a Nobel Prize, but for his work on prefrontal leucotomy rather than angiography.
In the early 1970s Godfrey Hounsfield, an electrical engineer at EMI’s central laboratories in
England developed the Computed Tomography (CT) scanner. This was a means of projecting x-
rays through an object from multiple angles and reconstructing the resultant image. The first
clinical scanner was installed at Atkinson Morley’s Hospital in 1971, and Hounsfield went on to
receive the Nobel Prize for medicine in 1979 for his work. CT development has continued with
multidetector CT, which permits very fact image acquisition and is now replacing cerebral
catheter angiography in some instances; and other promising techniques such as CT perfusion
that may help in the assessment of acute stroke and acute stroke therapy.
All of these techniques relied on x-rays, a form of ionising radiation. Whilst the medical benefits
are undoubted, there remains a risk to biological tissues of x-ray exposure. The next great
advance was in the early 1980s, when a number of researchers applied the well-known principles
of nuclear magnetic resonance of hydrogen atoms to medical imaging. Several important
developments allowed these resonant nuclei to be localised in space, and hence an image
created. Magnetic resonance imaging relies on interactions between very strong magnetic fields,
and radio frequencies; the images created are very different from the x-ray based techniques that
went before, and there are now dozens of different ways in which the signals from hydrogen ions
within the body can be manipulated, providing a wide spectrum of appearances of tissue in health
and disease. The technical advances in MRI have allowed higher detail images to be produced in
reasonable timeframes – the most modern 3 tesla MR units can now produce structural images of
temporal lobes with sub-millimetre spatial resolution. As far as we are aware there are few
biological hazards from the use of MRI, although the precautionary principle of applying these
technologies with clinical discretion should be maintained.

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All of the techniques describes thus far have been focussed on achieving better quality imaging of
the macroscopic structure of the nervous system. MRI has also allowed the development of
imaging techniques based more upon tissue function;
Spectroscopic MRI, returning to the roots of nuclear magnetic resonance, allows
analysis of the levels of certain organic molecules within localised regions of the brain, and has
been applied particularly to tumour imaging in attempts to define more accurately the lesion type
before surgery.
Functional MRI, which relies upon the brains use of oxygen to identify areas of increased
metabolic activity, has opened whole new fields of research into the areas of brain function during
life, and the interconnections between them.
MR Diffusion imaging measures the ability of water to move around in the extracellular
environment. It was initially applied to the early identification of ischaemia in the brain; a number
of subsequent developments of this technique have allowed mapping of the major white-matter
tracts, and identification of early damage to these tracts. Disruption to these tracts may occur due
to tumour infiltration, but also in other neurodegenerative diseases, for example Multiple Sclerosis
where the degree of abnormality seen in diffusion imaging may be significantly more advanced
than that appreciated on standard structural imaging.
MR Perfusion imaging can show in-vivo cerebral blood flow and volume, which may be
disrupted by tumour or vascular events.
There is now increasing interest in molecular imaging, in which biomarkers are used to identify
processes at a cellular level in vivo. This work is still in its infancy but it is likely that this will be a
major area of growth in both MRI and nuclear medicine over the next decades. A number of
advances in nuclear medicine scanning, particularly positron emission tomography, have allowed
identification of amyloid plaque in Alzheimer type dementia, and many other radiotracers are
being developed targeted at specific receptors within the brain. Both structural and functional
variations are seen in the brains of patients with schizophrenia; and functional imaging has shown
significant changes in brain metabolic activity and functional activation in major depression, and
resolution of these changes with treatment.
The application of many of these techniques to neurosciences has been rapid, but we still lack
good evidence for outcomes for many of the imaging strategies employed. The cost-benefit ratio
is also unknown, and with the exponentially rising cost of healthcare across the developed world,
much attention has fallen recently on whether concrete and tangible benefits in outcome can be
identified for these technologies. The research evidence is mixed; in the absence of effective
treatments for some diseases, it is difficult to justify expensive interventions to identify the illness
at an earlier stage; but there may be benefits in terms of planning patient care and
prognostication that are difficult to quantify. It seems intuitive that better quality preoperative
imaging of meningiomas will help the surgeon perform a safer procedure to remove them, but this
is unlikely to be subjected to randomised trial at any time in the near future. Perhaps the ever-
rising demand for these investigations is some indication of their utility in clinical practice,
although patient expectation is also a contributing factor. MR activity has doubled in the UK over
the past 7 years, although still lags behind many other developed countries, and demand shows
no sign of abating.
Neuroimaging continues to develop on several fronts – the continuing quest for more accurate
structural imaging of the neuraxis, as fast and as safely as possible; the role and application of
techniques which bridge the gap between structure and function; and the pursuit of more
accurate imaging markers of disease activity to allow earlier and more accurate diagnosis, to
permit treatment effects to be measured, and to avoid the need for more invasive and potentially
more harmful diagnostic tests.

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Weakness, Movement Disorders and Sensory symptoms unexplained by disease
Jon Stone
Consultant Neurologist and Honorary Senior Lecturer in Neurology
Western General Hospital, Edinburgh EH4 2XU
Jon.Stone@ed.ac.uk
This chapter is adapted from a short article from ACNR (www.acnr.co.uk)
Terminology
There is a baffling array of terms: ‘non-organic’, ‘psychogenic’, ‘dissociative’ ‘hysterical’,
‘somatisation’, ‘conversion disorder’, ‘functional’, ‘medically unexplained’ and ‘symptoms
unexplained by disease’. None is perfect and you should give some thought to which one you
prefer on the basis of: how you see the problem; how you are going to communicate it to the
patient (preferably including copying your clinic letter); whether you are a mind body dualist /
psychoanalyst. Ultimately the label is not as important as the way that you describe the label. The
terms that work best to describe motor and sensory symptoms with patients in my experience are
“functional” and “dissociative” since they a) describe a mechanism not an aetiology; b) sidestep
unhelpful and illogical dualistic debates about whether symptoms are in the mind or the brain; c)
map on to newer findings in functional imaging studies; d) allow for the possibility of improvement.
The risk is that psychological factors may be ignored in these kinds of descriptions but
paradoxically, giving the problem an acceptable name may allow these factors to emerge more
easily
How common?
• Around one third of all new neurology outpatients report symptoms such as dizziness,
weakness, tingling and blackouts that have little or no disease to explain them. Recent
data suggest that around 5% of all new outpatient consultations to neurology are about
symptoms that could be classed as conversion symptoms (that is blackouts, weakness,
movement disorders and numbness unexplained by recognised disease).
• Functional weakness has an incidence of at least 5/100,000 making it as common as
multiple sclerosis
• Functional movement disorders are increasingly recognised in specialist movement
disorder services
The Clinical Approach

Table 1 outlines an approach to history taking in the patient with functional symptoms. We find
that starting with an exhaustive list of the patient’s physical symptoms (‘draining the symptoms
dry’) gets the consultation off to a good start and can actually save time later on. Eliciting the
patient’s fears and beliefs about their symptoms and their previous experience of doctors can be
helpful in helping you to individualize the explanation you give them for their illness. Depression
and anxiety are best asked about at the end of the history framing the question around the
physical symptoms (e.g. ‘has this weakness got you down?’ rather than ‘do you feel depressed’)
to avoid the patient assuming that you are jumping to unwanted (psychological) conclusions. Do
not be put off by a lack of obvious life events, there may not be any especially in patients with
somatisation disorder (defined as lifelong symptoms from <30 years 1 neuro, 4 pain, 2 GI, 1
sexual). Look as hard as you would in someone who has had their first panic attack. If time is
limited it is often of little benefit to uncover history of childhood abuse on the first assessment.
These questions are better asked at a later date once trust has been established. Whilst all of this
information is helpful in planning management but it does not really assist greatly in making the
neurological diagnosis. For that we are particularly reliant on the physical examination,

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The following table lists key points in the history from someone with functional symptoms
Points in the history in a

suggested order
1. List the symptoms Start by writing a list of all current symptoms. Say that
you’ll come back to them individually later. Ask everyone
about fatigue, pain, sleep and concentration. Avoid
descriptions of past events at this stage
2. Onset and time course If vague use a ‘graph’ of symptoms over time. If sudden,
look carefully for somatic symptoms of panic especially
derealisation / depersonalisation
3. Previous functional symptoms For example: Irritable bowel syndrome, chronic fatigue,
early hysterectomy in women, testicular complaints in
men. Try to corroborate with medical notes.
4. What do they think is wrong What have they been worrying about? Anything specific
with them? like MS? What have other doctors said? What does the
patient think will help?
5. Asking about depression and Leave until the end of the history. Instead of ‘Are you
anxiety depressed?’ try ‘Do your symptoms get you down?’ or
‘Do you worry about your symptoms?’
Examination
In patients with weakness and movement disorder, the judgement about lack of disease depends
crucially on finding evidence of inconsistency, either internally in the examination (or in the case
of visual symptoms, with the laws of optics). The initial diagnosis should be done by someone
very used to seeing motor and sensory symptoms in a wide variety of situations – this is usually a
neurologist. But if you are interested in liaison psychiatry / neuropsychiatry it will pay dividends to
be familiar with eliciting these signs. Showing them to patients and their relatives can be a
powerful form of persuasion. You will note that there are no reliable sensory signs

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Table 2. Physical Signs of functional weakness, movement disorders and sensory

symptoms
Helpful signs Unhelpful signs

Weakness and Sensory disturbance General
Hoover’s sign (Figure 1)* ‘La belle indifference’*
The monoplegic ‘dragging’ gait Looking psychiatrically unwell
Collapsing weakness
Sensory Disturbance
Movement disorders Midline splitting*
Entrainment of tremor* Split vibration across the forehead*
‘Fixed’ clenched hand or inverted foot
Movement Disorders
Visual Symptoms Worsening with anxiety
Tubular field defect
Spiralling visual fields
See references for more information(1;2)*some evidence from controlled studies
Figure 1. Hoover's sign - (a) Hip extension is weak when tested directly (b) Hip extension is
normal when the patient is asked to flex the opposite hip.

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Old Chestnuts
They are making it all up – Distinguishing malingering (where symptoms are under voluntary
control) from hysteria (where they are not) is extremely difficult since both diagnoses rely on
inconsistency. The only reliable way of telling the two apart is to obtain a confession or uncover
an example of gross inconsistency between the consultation room and other situations (for
example a wheelchair bound patient who is filmed playing tennis). In favour of the idea that most
patients are not making their symptoms up are long term follow up studies find that most patients
remain symptomatic and disabled in the long term5-7, the similarities in the way patients describe
their complaints and the keenness of most patients to pursue investigations. There is no doubt
that some patients who simulate symptoms do find their way in to NHS neurology clinics,
although many more of these will be seen in medico-legal assessments.. However we take the
approach that (a) outside medical legal practice it is our job simply to help the patient and not to
detect those malingering for financial gain and (b) simulating symptoms solely in order to obtain
medical care (factitious disorder) is itself a sign of a significant problem. Finally if a patient is
apparently exaggerating their symptoms it is worth asking yourself whether they might be doing
this to try to convince you, as a sceptical doctor, that there is something wrong
There might be a hidden organic cause for their symptoms. Neurologists generally don’t
worry about this too much; but psychiatrists do, largely because of an influential paper by Slater10
published in 1965. Slater was wrong, and the misdiagnosis rate since 1970 has on average been
around 5%(3). This is the same rate as for other neurological and psychiatric conditions such as
MS and schizophrenia. When neurologists do get it wrong, gait and movement disorders and
patients with a psychiatric history (probably because this biased the diagnosis) figure
disproportionately.
They don’t get better whatever you do. Studies of neurological symptoms have lagged behind
other functional symptoms but there is systematic review level evidence for the effectiveness of
cognitive behavioural therapy(4) and antidepressant drugs(5) in the treatment of a wide range of
other functional somatic symptoms such as fatigue, fibromyalgia and irritable bowel syndrome. Of
course many patients don’t get better but that’s no different to many other neurological conditions.
They are the worried well - patients with ‘real’ disease or psychosis are much more
deserving. This traditional attitude leads to irritable doctors and angry patients. Disease is just
one of many causes of symptoms and illness. Normal physiology, psychology and the society we
live in all play their part. We know that patients with functional symptoms are just as disabled and
even more distressed than their diseased counterparts11. There is a personal choice to make
here about your role as a doctor.
It’s all psychodynamic isn’t? Conversion disorder is the last bastion of psychoanalysis in DSM-
IV diagnoses. Although the theory may be relevant to some patients it doesn’t appear relevant to
most – the more symptoms, or the more severe they are, the worse the emotional distress.
Findings on functional imaging challenge a purely psychogenic view of these symptoms and
encourage a view that takes in to accounts multiple factors to explain the vulnerability and the
mechanism of these symptoms.
Managing the patient with functional motor sensory symptoms
A good assessment is the basis for effective treatment. I try wherever possible to show the
patient how we are making the diagnosis. This may include a demonstration of Hoover’s sign or
perhaps a videotape of an examination under sedation. There is a misconception that all the
patient wants at this stage is reassurance that they don’t have disease. Of course patients benefit
from being told that they do not have epilepsy or MS but usually what they want more is to be told
what they do have. This turns out to be of key importance in treatment.

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Table 3 gives an indication of the kind of explanations that help in our experience. This is all part
of persuading the patient that (a) you believe them; (b) they have something recognisable and
potentially reversible and (c) that its not their fault but they can help themselves to get better. For
some patients this may be all that is required. More advanced treatment involves some form of
rehabilitation. This may mean referral to an experienced physiotherapist, a liaison psychiatrist,
specialist rehabilitation service or perhaps in the future a nurse practitioner with specific expertise
in a cognitive behavioural approach to somatic complaints. In some patients there is a role for
treatment with antidepressants. However, public belief about these agents is such that very
careful explanation may be required, for example: ‘These are drugs that have widespread effects
on the nervous system and are helpful even in people who are not depressed’. For some patients
there may be also a role for more unusual treatments such as hypnosis or examination under
sedation. I have made a new self-help website for patients geared to these problems
(www.neurosymptoms.org.uk)
Conclusion
Patients with functional symptoms make up a large proportion of an average neurologist’s
workload. These patients are, on the criteria of distress, disability and persistence of symptoms,
as deserving as patients with pathologically defined disease. If you are prepared to accept the
reality of their symptoms and to use a less overtly ‘psychological’ approach than has traditionally
been advocated you may find that they can be much more rewarding to treat than you thought.

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Table 3. The elements of a constructive explanation of functional neurological symptoms
Element Example
1. Indicate you believe the patient “I do not think you are making up or imagining
your symptoms”
2. Explain what they don’t have “You do not have MS, epilepsy etc”
3. Explain what they do have “You have ‘functional weakness’ – this is a

common problem. Your nervous system is not
damaged but it is not working properly. That is
why you cannot move your arm. There are lots
of reasons why this happens”
4. Emphasise that it is common ‘I see lots of patients with similar symptoms’
5. Emphasise reversibility ‘Because there is no damage you have the

potential to get better’
6. Emphasise that self-help is a key part of ‘I know you didn’t bring this on but there are
getting better things you can do to help it get better’
7. Metaphors may be useful ‘The hardware is alright but there’s a software
problem’; ‘Its like a car / piano that’s out of
tune’; ‘Its like a short circuit of the nervous
system’ (non-epileptic attacks)
8. Introducing the role of depression/anxiety ‘If you have been feeling low/worried that will
tend to make the symptoms even worse’
8. Use written information Send the patient their clinic letter. Give them a
leaflet
9. Suggesting antidepressants ‘We find that ‘so-called’ antidepressants often
help these symptoms even in patients who are
not feeling depressed. They are not addictive.’
9. Making the psychiatric referral ‘I don’t think you’re mad but Dr X has a lot of
experience and interest in helping people you
to manage and overcome their symptoms’
(1) Stone J, Carson A, Sharpe M. Functional symptoms and signs in neurology: assessment
and diagnosis. J Neurol Neurosurg Psychiatry 2005; 76 Suppl 1:i2-i12.
(2) Hallett M, Cloninger CR, Fahn S, Jankovic J, Lang AE, Yudofsky SC. Psychogenic
Movement Disorders. Lippincott Williams & Wilkins and the American Academy of
Neurology, 2005.
(3) Stone J, Smyth R, Carson A, Lewis S, Prescott R, Warlow C et al. Systematic review of
misdiagnosis of conversion symptoms and "hysteria". BMJ 2005; 331(7523):989.
(4) Kroenke K, Swindle R. Cognitive-behavioral therapy for somatization and symptom
syndromes: a critical review of controlled clinical trials. Psychother Psychosom 2000;
69(4):205-215.
(5) O'Malley PG, Jackson JL, Santoro J, Tomkins G, Balden E, Kroenke K. Antidepressant
therapy for unexplained symptoms and symptom syndromes. J Fam Pract 1999;
48(12):980-990.

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Dissociative Seizures
John D C Mellers
mellers@winstreet.u-net.com
Dissociative seizures (DS) are psychologically mediated episodes of altered awareness and
behaviour that may mimic any type of epilepsy.
Table 1.
The differential Diagnosis of Epilepsy
A. Medical Causes of paroxysmal neurological dysfunction
1. Syncope
- vasovagal
- cardiogenic
2. Neurological
- cerebrovascular
- migraine
- vertigo
- cataplexy
- parasomnias
- movement disorders
- startle induced phenomena
3. Endocrine and metabolic
- hypoglycaemia
- hypocalcaemia
- hereditary fructose intolerance
- pheochromocytoma
- drugs and alcohol
B. Psychiatric disorders
1. Dissociative Seizures
2. Psychiatric disorders that may be mistaken for epilepsy
- panic disorder
- psychosis
- Attention Deficit Hyperactivity Disorder
- Depersonalisation disorder
3. Factitious Disorder

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The differential diagnosis of epilepsy
A list of the medical and psychiatric disorders that may be mistaken for epilepsy is given in table
1. Syncope is probably the most frequent source of diagnostic confusion in general medical
settings but by the time patients are referred to specialist clinics DS is by far the most important
differential diagnosis. Indeed, among patients referred to epilepsy clinics with apparently
intractable epilepsy, about one in five have DS.
Apart from DS a number of psychiatric disorders may occasionally be mistaken for epilepsy.
These include panic disorder, paroxysmal symptoms in psychosis, and depersonalisation
disorder. In children, attentional problems in a child may raise the differential diagnosis of
attention deficit hyperactivity disorder and petit mal seizures. Overall, the abrupt onset, brief
duration and highly stereotyped nature of epileptic symptoms help distinguish them from
functional psychiatric disorder.
Factitious disorder (Munchausen’s syndrome) refers to the situation in which a patient is

discovered to be (or admits) deliberately feigning symptoms. In factitious disorder the patient’s
motivation is held to be psychological (understandable in terms of the patients psychological
background, personality, dependency needs etc). By contrast malingering (not a medical
diagnosis) involves fraudulently imitating illness to achieve some obvious practical advantage (eg:
compensation, to avoid a criminal conviction)
DS are regarded, by definition, as being involuntary or unconscious and experienced clinicians

generally agree that this is probably true for most patients. This concept is, however, impossible
to prove. Three characteristics of these patients are worth considering. 1) the majority of patients
are compliant with their anti-epileptic drugs, often for many years and to the point of toxicity; 4 14
2) when they are admitted for telemetry the majority have a seizure in a setting which they must
surely recognize involves intensive monitoring; 3) the seizure is usually a poor imitation of
epilepsy. None of these points is by any means conclusive but if deception is involved, it is of a
kind that is difficult to understand.
While psychiatric classification systems assume a dichotomy between conscious and

unconscious symptom generation (implying factitious or dissociative seizures respectively) the
two are best regarded as opposite ends of a continuum. The concept of self deception lies
somewhere in the middle and provides a useful paradigm for understanding how subjective
experience and behaviour are prone to influences that are not always fully conscious – even in
“normal” individuals.
Clinical Features of Dissociative Seizures
The prevalence of DS has been estimated as between 2 and 33 per 100,000.

Around three quarters of patients are female. Seizures typically begin in the late teens or early
twenties, but there is a wide range. Seizures have typically been present for 3 or 4 years before
the correct diagnosis is made. Probably no more than 15 or 20 % of patients with DS also have
epileptic seizures.

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Table 2.
Comparative semiology of dissociative and epileptic seizures
Dissociative Seizures Epileptic Seizures
Duration over 2 minutes common rare

a
Stereotyped attacks common common
Motor Features
Gradual onset common rare
Fluctuating course common very rare
Thrashing, violent movements common rare
Side to side head movement common rare
Asynchronous movements common very rare
Eyes closed common rare
Pelvic thrusting occasional rare
Opisthotonus, “arc de cercle” occasional very rare
Automatisms rare common
Weeping occasional very rare

a
Incontinence occasional common
a
Injury
Biting inside of mouth occasional common
Severe tongue biting very rare common
Recall for period of unresponsiveness common very rare
Note:
a
Three features that are commonly misinterpreted as evidence for epilepsy have been included.
Otherwise the table lists clinical features that are useful in distinguishing DS from ES. Figures for
frequency of these features are approximate: common > 30%; occasional = 10-30%; rare < 10%;
very rare < 5%.
(Adapted from Mellers 20)

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Clinical Assessment
No single semiological feature can be relied upon to distinguish DS from epileptic seizures with
anything approaching 100% accuracy. The most helpful features, as well as some important
pitfalls - symptoms that are commonly mistaken as strong evidence for epilepsy - are listed in
table 2. Epileptic seizures are brief, highly stereotyped, paroxysmal alterations in neurological
function that conform to a number of now well-described syndromes. Broadly speaking, it is any
variation from these clinical pictures – an atypical sequence of events – that will raise the
suspicion of DS.
Psychiatric Comorbidity
High rates of depression, anxiety, personality disorder and post-traumatic disorder have been
reported in patients with DS, but findings have varied considerably. A history of previous
medically unexplained symptoms is very common.
Ictal observation / examination

An opportunity to observe a seizure may provide invaluable information. Whether the patient is
responsive should be established. Movements should be described carefully. If the patient’s eyes
are shut (an important observation in itself, suggesting DS) the examiner should attempt to open
them noting any resistance. A simple test to look for avoidance of a noxious stimulus is to hold
the patients hand over their face and drop it: in DS the patient may be seen to control their arm
movement so their hand falls to one side. If the eyes can be held open easily, evidence of visual
fixation may be sought by holding a small mirror in front of the patient and look for evidence of
convergent gaze and fixation on the reflection. This procedure will also often stop the seizure.
Investigations
EEG
Non-specific EEG abnormalities are found in up to 15% of healthy individuals and all too often
interpreted as supporting a diagnosis of epilepsy. Narrowly defined epileptiform abnormalities are
much less common, occurring in less than 1% of the healthy population.
VideoEEG telemetry
A video of a seizure, perhaps obtained on a mobile phone, will often allow a confident diagnosis.
VideoEEG (vEEG) telemetry is obviously the gold-standard investigation but there are some
limitations and traps. vEEG is of limited use in a patient who has infrequent seizures.
Movement artefact may obscure or even be mistaken for epileptiform discharges. Care must be
taken in patients who have multiple seizure-types to ensure that an example of each seizure is
seen, and it is very important to establish that if a seizure is captured it is representative of the
patients habitual attacks. Special mention should also be made of simple partial seizures and
frontal lobe seizures that are often not accompanied by any electrographic changes on the ictal
scalp EEG. Recently, techniques have been described in which suggestion, combined with
routine activation techniques, can be used to provoke DS during a brief vEEG recording.
Serum Prolactin
Serum prolactin rises after tonic-clonic epileptic seizures, peaking after 20 or 30 minutes. A
prolactin rise is less reliable following partial seizures. It has now been established that rises may
be seen following syncope and even DS and the test is therefore falling out of favour. However, a
negative finding after an apparent tonic-clonic seizure may still be helpful.
Psychiatric Formulation
Dissociation may be defined as a psychologically mediated alteration of awareness and/or control

of neurological function. Dissociation thus encompasses a spectrum of mental processes
including normal phenomena, such as focussed or divided attention (eg: “domestic deafness”,

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mental absorption), and pathological states involving perceptual, cognitive and motor function.
The advantage of such a definition is that, by explicitly assuming that dissociative disorders lie on
a continuum with normal experience, it facilitates an empathic understanding of what might
otherwise seem unintelligible, if not frankly unbelievable, behaviour. This is equally important for
professionals, patients and carers.
The psychophysiological basis for dissociative states is not understood. Many patients with DS
describe becoming gradually cut-off or distant from their environment and experience symptoms
of autonomic arousal during their seizures. This suggests that for some patients, DS may
represent a dissociative response to paroxysmal physiological arousal triggered by intense
emotion. Most patients, however, deny emotional symptoms in their attack (DS may be likened to
“panic attacks without panic”)66, the hypothesis being that the triggering emotion is concealed by
the dissociative state (for Freud this was the primary gain of hysterical symptoms).
Many predisposing, triggering and maintaining factors for DS have now been reported
(summarised in table 3).
Table 3: Predisposing, precipitating and maintaining factors in DS
Psychological Social
Predisposing Perception of childhood Adverse (abusive) experiences
experience as adverse in childhood
Somatising trait Poor Family functioning
Dissociative trait Traumatic experiences in

adulthood
Avoidant coping style
Modelling of attacks on others
Personality disorder with epilepsy
Mood disorder
Precipitating Perception of life-events as Adverse life events

negative / unexpected
Acute panic attack / syncope
Maintaining Perception of symptoms as Angry / confused / anxious reaction

being outwith personal control / of carers
due to disease
Fear of responsibilities of being well
Agoraphobia: Avoidant and / benefits of being ill
safety behaviour
Angry / confused / anxious

reaction to diagnosis
There is no evidence at present for biological factors which are therefore not listed in the
table. However, there may be genetic influences on relevant personality attributes, coping
styles and traits.

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Management
An early diagnosis (within a year of onset) and the way in which the diagnosis is conveyed to the
patient are possibly the two most important factors determining outcome. Points that might be
covered in discussing the diagnosis with a patient are outlined in Table 4.
Table 4: Presenting the Diagnosis of Dissociative Seizures
The discussion should cover:-
1. Explanation of the diagnosis

• Reasons for concluding they don’t have epilepsy
• What they do have (describe dissociation)
2. Reassurance
• they are not suspected of “putting on” the attacks
• the disorder is very common
3. Causes of the disorder

• Triggering “stresses” may not be immediately apparent.
• Relevance of aetiological factors in their case.
• Maintaining factors
4. Treatment
• DS may improve simply following correct diagnosis
• Caution that AED withdrawal should be gradual
• Describe psychological treatment
There have been no controlled treatment trials in DS. Pharmacotherapy is appropriate for the
relatively small proportion of patients with significant psychiatric comorbidity. For the majority of
patients, however, some form of psychological treatment is recommended. Involvement of carers
is clearly sensible in view of the role the patient’s social environment may play in perpetuating the
disorder. There is no evidence on which to base the choice of psychotherapy, although it is
widely supposed that the nature of any associated psychiatric comorbidity (if any) is an important
consideration.
The paroxysmal nature of DS, prominent somatic symptoms of arousal in many patients and an
association with agoraphobic avoidant behaviour suggest that techniques developed in Cognitive
Behavioural Therapy (CBT) for the treatment of panic disorder might readily be adapted for DS.
CBT techniques developed for post-traumatic stress disorder and dysfunctional personality traits
may be helpful, but these and other techniques require evaluation.
Long-term follow-up studies suggest a relatively poor outcome, with approximately two thirds of
patients suffering ongoing DS after 3 or more years and more than half remaining dependent on
social security. Psychiatric treatment has been associated with a positive outcome in some
studies, but not others. A poor prognosis is predicted by a long delay in diagnosis and the
presence of psychiatric comorbidity, including personality disorder.

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Further Reading
Mellers JDC. The diagnosis and management of dissociative seizures (2007) www.e-
epilepsy.org.uk/pages/articles/pdfs/Chapter20Mellers.pdf.
Reuber M. Psychogenic nonepileptic seizures: answers and questions. Epilepsy & Behavior.
2008; 12:622-35.
Goldstein LH. Mellers JD. Ictal symptoms of anxiety, avoidance behaviour, and dissociation in
patients with dissociative seizures. Journal of Neurology, Neurosurgery & Psychiatry. 77:616-21,
2006.
Reuber M, Howlett S, Kemp S. Psychologic treatment of patients with psychogenic nonepileptic

seizures. Expert Rev Neurother 2005; 5:737–752.
Cook M. Differential diagnosis of epilepsy. In Shorvorn S. Perucca E. Fish D. Dodson E. (eds).

The Treatment of Epilepsy(2nd Edition). Oxford, Blackwell, 2004; 64-73.
Goldstein LH, Deale AC, Mitchell-O'Malley S, Toone BK, Mellers JDC. An evaluation of cognitive
behavioral therapy as a treatment for dissociative seizures. A pilot study. Cognitive and
Behavioral Neurology 2004;17:41-9.

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Chronic fatigue syndrome: neurological, psychological or both?
Peter White, Professor of Psychological Medicine, Barts and the London Medical School
p.d.white@qmul.ac.uk
Epidemiology of fatigue and CFS
Fatigue is a common symptom in both the community and primary care. When asked, between
10 and 20 per cent of people in the community will report feeling abnormally tired at any one time.
At the same time, fatigue is continuously distributed within the community, with no point of rarity.
Therefore any cut-off is arbitrary and the prevalence will vary by how the question is asked, the
symptom volunteered, and its context. Between 1.5 % and 6.5 % of European patients will
consult their general practitioner with a primary complaint of fatigue every year, the incidence
varying by age and population. Fatigue is more commonly reported and presented to general
practitioners by women and the middle-aged, and is most closely associated with mood disorders
and reported stress. It does not seem to vary by ethnicity in the UK, but there is an intriguing
paradox in that it is reported more commonly by those in high income countries, yet is presented
to medical care more often in low income countries.
Prolonged or chronic fatigue is significantly less common than the symptom of fatigue and it is
only in the last 10 years that consensus has emerged about the existence of a chronic fatigue
syndrome (CFS), also called myalgic encephalomyelitis (ME). CFS is now accepted as a valid
diagnosis by medical authorities in the UK, in the United States of America, as well as
internationally. About one third of patients presenting to their doctor with six months of fatigue will
meet criteria for a chronic fatigue syndrome. The other two thirds have fatigue secondary to
another condition, most commonly mood and primary sleep disorders. Its primary symptom is
fatigue, both physical and mental, which particularly follows exertion. Other symptoms agreed in
consensual guidelines include poor concentration and memory, sleep disturbance, headache,
sore throat, tender lymph glands, muscle and joint pain. There are several criterion based
definitions of CFS. These definitions were derived by consensus and have not been supported by
empirical studies, and continue to be refined. Their utility stems from providing reliable criteria for
research studies, rather than clinical use. The prevalence of CFS is between 2.5 % and 0.4 %
depending on the definition used and whether comorbid mood disorders are excluded (that is
mood disorders that are not thought to be the primary diagnoses). It is most common in women,
the middle-aged, and ethnic minorities (unlike fatigue) – at least in English speaking countries.
The diagnosis and classification of CFS
The clinical taxonomy for CFS is a mess. The ICD-10 classification defines CFS within both the
neurology chapter and mental health chapters. Myalgic encephalomyelitis, the alternative name
for CFS, is classified as a neurological disease (G93.3)(a.k.a. post-viral CFS), whereas
neurasthenia (a.k.a. CFS not otherwise specified) is classified within mental health (F48).
(Incidentally, this mess is not specific to CFS, since there are several conditions within the
neurology chapter of ICD-10 that are also classified in the mental and behavioural disorders
chapter. For instance, Alzheimer’s disease is classified within neurology, whereas dementia due
to Alzheimer’s disease is classified under mental health. My personal view is that it is high time
that all mental health disorders and neurological diseases affecting the brain were classified
within the same chapter, simply called diseases/disorders of the brain and nervous system.)
There is also a current debate between “lumpers” and “splitters” about the nosology of
“functional” somatic syndromes (symptom defined conditions), such as CFS, IBS and
“fibromyalgia”. Some argue that the close associations between the syndromes (those with CFS
are also more likely to have fibromyalgia and/or IBS) argues in favour of their being different
manifestations of one over-arching functional somatic syndrome (the “lumpers”). Others argue

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that these syndromes are best understood by exploring their heterogeneity (the “splitters”). There
is evidence to support both arguments, but two large and recent epidemiological studies suggest
that chronic unexplained fatigue, for one, is both associated with and separate from other
“functional” somatic syndromes. In particular, predisposing risk factors are shared whereas
triggering factors are different.
CFS is not an easy diagnosis to make, since misdiagnosis is common in patients diagnosed as
having CFS. A recent audit of my CFS clinic revealed that 4 out of 10 new patients (n = 250)
assessed did not have CFS, and that was after a third of referrals had already been rejected as
not being CFS. The most common misdiagnoses were mood disorders, especially depressive
disorders, and primary sleep disorders, particularly sleep apnoea. Other misdiagnoses included
coeliac disease and autoimmune conditions. Alternative neurological diagnoses were made in 2
%.
Aetiology and pathophysiology
The aetiology of CFS is unknown, but there is evidence that different risk markers are associated
with predisposition, triggering, and maintenance of the illness. Predisposing risk markers include
female sex, middle age, mood disorders (especially depressive disorders), other symptom
defined syndromes, such as irritable bowel syndrome, and possibly either sedentary behaviour or
excessive activity. As might be expected CFS patients are more likely to have attended their GP,
than healthy matched controls, even up to 15 years before onset, but recent work shows that
those with IBS (and no CFS) have the same tendency.
Triggering risk markers are less well established, but there is sufficient evidence to support
certain infections as aetiological factors not only for fatigue but also CFS, with the best replicated
evidence supporting a role for Epstein-Barr virus infection, which triggers CFS in 10% of those
infected.
Maintaining or perpetuating risk markers are most important in determining treatment

programmes, since reversing maintaining factors should lead to improvement. Reasonably well
established factors include mood disorders, such as dysthymia, illness beliefs such as believing
the whole condition is physical, pervasive inactivity, avoidant coping, membership of a patient
support group, and being in receipt of or dispute about financial benefits.
Few pathophysiological findings in CFS have been replicated in independent studies. Those that
have been include down-regulated hypothalamic-pituitary-adrenal axis, physical deconditioning,
and discrepant reports between perception of symptoms and disability and their objective tests.
The latter finding is now supported by functional brain scanning studies suggesting altered brain
activity with specific tasks. The discrepancy between subjective states and objective tests has
been found before in other symptom defined syndromes, such as “fibromyalgia”, and may be
related to enhanced interoception (the perception of visceral phenomena), a concept first
described by Charles Sherrington in 1904. One hypothesis currently being tested is that the
common predisposition to “functional” somatic syndromes is caused by enhanced interoception.
Recent work suggests that these factors may be reversed by rehabilitation.
Prognosis
Without treatment the prognosis of CFS is poor with a systematic review of outcomes finding the
median full recovery rate was 5 % (range 0–31%) and the median proportion of patients who
improved of 39.5% (range 8–63%). Being younger, having less fatigue baseline, a sense of
control over symptoms and not attributing illness to a physical cause were all associated with a
better outcome. The prognosis is considerably better after treatment.

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Treatment
The NICE guidelines, published in 2007, were based on an updated systematic review. The
essence of specialist care is rehabilitation, provided on an individual basis with an appropriately
qualified and trained therapist. The two approaches with the greatest evidence of efficacy are
cognitive behaviour therapy (CBT) and graded exercise therapy (GET). Approximately 60% of
patients report significant improvement with these approaches and about 25% report full
recovery, which lasts. No pharmacological treatments are recommended (antidepressants are
ineffective), but symptomatic pharmacotherapy for specific symptoms (such as pain) or comorbid
conditions (such as depressive illness) can be helpful complementary treatments.
These rehabilitation approaches have not received universal approval from patient charities, with
concerns that patients may be harmed by exercise therapies or that CBT implying that the
condition is psychological.
Is CFS neurological or psychological?
This is a nonsensical question when one considers the neuroscience of consciousness and
recent advances in functional brain physiology. The philosopher, John Searle, stated the answer
to this Cartesian dualism that still bedevils western medicine. “Conscious states are caused by
neurophysiological mechanisms, and are realised in neurophysiological systems.” Therefore it is
not possible to have a psychological process or event without a neurological mediating process. It
is neither of the mind or body; it is both.
Fatigue secondary to neurological diseases
Fatigue is commonly associated with chronic medical disorders, but it should be

differentiated from fatiguability. Fatiguability is the onset of a physical sensation of
fatigue and weakness after exertion and is commonly reported with neurological
diseases such as multiple sclerosis and myopathies.
Apart from measures of disease activity, other associations of secondary fatigue in general that
have been repeatedly found include sleep disturbance, mood disorders, inactivity and physical
deconditioning. Studies of fatigue associated with multiple sclerosis are instructive and
exemplary. As in all studies of secondary fatigue, measures of the severity or pathophysiology of
the disease itself are associated with fatigue. Some cytokines are associated, but others are not.
Associations vary depending on the fatigue measure, confirming the multidimensional nature of
fatigue, but all measures are associated with depression. Objectively confirmed sleep disturbance
is also associated with fatigue. Fatigue associated with MS therefore requires biopsychosocial
management.
There have been a number of studies of various treatments aimed at reversing

the associations of secondary fatigue in general, in the hope they would help fatigue
directly, with variable results. As with CFS, the most consistent evidence of efficacy has been
with graded exercise programmes and CBT.

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Bibliography
Attarian HP, Brown KM, Duntley SP, et al. The relationship of sleep disturbances and fatigue in
multiple sclerosis. Arch. Neurol. 61 (2004), 525–8.
Baker R, Shaw EJ. Diagnosis and management of chronic fatigue syndrome or myalgic
encephalomyelitis (or encephalopathy): summary of NICE guidance. BMJ 2007
doi: 10.1136/bmj.39302.509005.AE
Chambers D, Bagnall A-M, Hempel S, Forbes C. Interventions for the treatment, management
and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an
updated systematic review. J R Soc Med 2006;99:506-20.
Cleare AJ. The neuroendocrinology of chronic fatigue syndrome. Endocr. Rev. 24 (2003), 236–
52.
Flachenecker P, Bihler I, Weber F, et al., Cytokine mRNA expression in patients with

multiple sclerosis and fatigue. Mult. Scler. 10 (2004), 165–9.
Fulcher KY, White PD. Strength and physiological response to exercise in patients with the
chronic fatigue syndrome. J. Neurol. Neurosurg. Psychiatry 69 (2000), 302–7.
Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue and chronic fatigue
syndrome: a systematic review. Q. J. Med. 90 (1997), 223–33.
Kroencke DC, Lynch SG, Denney DR. Fatigue in multiple sclerosis: relationship to
depression, disability, and disease pattern. Mult. Scler. 6 (2000), 131–6.
Lyall M, Peakman M, Wessely S. A systematic review and critical evaluation of the

immunology of chronic fatigue syndrome. J. Psychosom. Res. 55 (2003), 79–90.
National Institute for Health and Clinical Excellence. Clinical guideline CG53. Chronic fatigue
syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management. London,
NICE, 2007. http://guidance.nice.org.uk/CG53.
ReevesvWC et al. Identification of ambiguities in the 1994 chronic fatigue syndrome research
case definition and recommendations for resolution.BMC Health Serv Res 3 (2003), 25.
Romani A, Bergamaschi R, Candeloro E, et al., Fatigue inmultiple sclerosis: multidimensional

assessment and response to symptomatic treatment. Mult. Scler. 10 (2004), 462–8.
M. C. Tartaglia, S. Narayanan, S. J. Francis, et al., The relationship between diffuse axonal

damage and fatigue in multiple sclerosis. Arch. Neurol. 61 (2004), 201–7.
Wessely SC, Hotopf M, Sharpe M. Chronic Fatigue and its Syndromes (Oxford: Oxford University
Press, 1998).
Wessely S, Nimnuan C, Sharpe M. Functional somatic syndromes: one or many? Lancet

354 (1999), 936–9.
Wessely S, White PD. In debate: there is only one functional somatic syndrome. Br. J.
Psychiatry 185 (2004), 95–6.
White PD, Thomas JM, Kangro HO, et al., Predictions and associations of fatigue syndromes and
mood disorders that occur after infectious mononucleosis. Lancet 358 (2001), 1946–54.

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White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; on behalf of the PACE trial group.
Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour
therapy, and graded exercise, as supplements to standardised specialist medical care versus
standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic
encephalomyelitis or encephalopathy. BMC Neurol 2007;7:6.

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Neuropsychiatry of Traumatic Brain Injury
Dr Simon Fleminger, Consultant Neuropsychiatrist, Maudsley Hospital

s.fleminger@iop.kcl.ac.uk
Approximately 200 per 100,000 population per year suffer a traumatic brain injury (TBI), a head
injury, and of these about 80% are classified as mild (see below). Because the sequelae,
particularly of those with severe injury, are often lifelong, head injury results in a major cause of
disability in the population. The commonest cause of TBI are acceleration / deceleration injuries
to the head, eg from RTAs, falls and assaults. These result in closed head injuries. When there
is penetration of the dura, as in a gunshot or stab wound to the head, the injury is defined as an
open head injury. These differ from closed head injuries in as much as there may be relatively
little loss of consciousness.
The psychological sequelae of TBI can be divided into three overlapping areas; cognitive
impairment, personality / behavioural change, and psychiatric disorder. These neuropsychiatric
sequelae outstrip the neurophysical sequelae (eg. ataxia, hemiplegia or dysphasia) of TBI as
causes of disability.
To understand the psychological sequelae of TBI it is necessary to understand

1. the person who has been injured
2. the brain damage sustained
3. the psychological consequences of the injury and the impairments.
The starting point is an assessment of the severity of the brain injury and the likely degree of
brain injury / damage. Three measures of injury severity are the Glasgow Coma Scale (GCS)
shortly after injury, the duration of loss of consciousness (LoC), and the duration of post traumatic
amnesia (PTA). PTA is defined as the duration of loss of memory from the time of injury till
continuous day to day memories are restored.
Duration of PTA and LoC are the best predictors of outcome. Of those with PTA duration of less
than one week the majority will return to work in due course, but of those with PTA of 1 to 2
months and more, the majority will be left with significant disability.
Mild TBI (mTBI) is defined as a GCS of 13, 14 or 15 (15 = normal conscious level), LoC of less
than 30 minutes, and PTA of less than 24 hours. Of those with mTBI about half still have
significant symptoms at 3 months, a quarter at six months and about one eighth at one year.
Neuroimaging may also be helpful and demonstrate areas of contusion or diffuse axonal injury.
The former are particularly likely to occur in medial orbital frontal regions and anterior temporal
regions (both areas that are involved in social function). Diffuse axonal injury involves white
matter tracts throughout the brain, often involving corpus callosum and superior cerebellar
peduncle. Gradient echo T2 MRI sequences are the most sensitive for identifying the small
haemorrhages in the white matter associated with diffuse axonal injury. In those with severe
injury ischaemic injury is likely to contribute to the overall degree of brain damage; either due to
global ischaemia, eg because of raised intracranial pressure from generalised brain oedema, or
due to more focal arterial damage or compression.
Some psychological sequelae show a clear dose response in terms of injury severity. So for
example cognitive impairment increases as severity of brain injury increases. Whereas other
symptoms, in particular anxiety and depression, show a flat or even inverse dose response curve,
for example with greater symptoms being seen in those with less severe injury.

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In those with severe injury after recovery of consciousness, for example after hours or days of
coma, there is a period of confusion. This can be described as a post traumatic delirium. It
overlaps with the period of post traumatic amnesia. The symptoms of the delirium are similar to
those of delirium from other causes, with agitated or obtunded behaviour, hallucinations, often
visual, and delusional misidentification, and fear or persecutory delusions, being common.
Troublesome problems during this period are usually due to wandering / attempts to abscond,
agitated / violent behaviour, and sexually disinhibited behaviour.
The majority of the recovery is over the first few weeks or months so that by one or two years
post injury the patient has reached a plateau of recovery and is now left with permanent deficits.
But longer term improvements over the first 5 to 10 years may be seen. On the other hand some
actually get worse over time since injury, often due to alcohol misuse or depression. It is possible
that in the longer term patients may be at greater risk of dementia.
Slowing of speed of information processing and impairment of executive function, attention,

concentration and memory are the most common cognitive impairments. Intellectual function, as
measured using tests of IQ, may be relatively spared. It is useful to compare post-injury
performance against premorbid estimates of function, eg. measured with the National Adult
Reading Test (NART), in order to determine any decline due to the TBI.
Impairments of executive function, resulting in the dysexecutive syndrome, are common and
often very disabling. The dysexecutive syndrome overlaps with changes in personality and
behaviour, so for example the patient is described as chaotic and poorly organised or impulsive
and showing bad judgement. Lack of insight is a very common associated problem. Other
common personality / behavioural problems include apathy, self-centredness, lack of emotional
warmth, childishness, disinhibited behaviour, moodiness, irritability and ready fatigue.
Anxiety and depression are the commonest psychiatric sequelae. The anxiety is often associated
with travel anxiety, eg. if the injury was sustained in an RTA, or symptoms of PTSD. Depression
is fairly common with a proportion of patients after the injury becoming depressed for the first time
during the course of the first year post injury, whereas others who are initially depressed are
recovered by one year post injury. Depression may present with atypical symptoms, and in
particular failure to improve or regression of progress in rehabilitation. Alcohol and substance
misuse are common, though the majority who have these problems post injury will have had
problems before the injury. Some patients will develop OCD or psychosis. There is probably an
elevated risk of psychosis post injury, though it tends to lack the typical feature of schizophrenia
or an affective psychosis. There is probably a 2 – 3 fold increased risk of suicide post injury
compared with age / sex matched controls.
When considering the causes of the psychological sequelae of TBI it is necessary to remember
that many of the problems that are seen post injury are in fact the same as make the person at
risk of having the injury in the first place. This “reversed causality” may therefore explain the
association, rather than that the symptom is caused by the injury. So for example those with a
family history of schizophrenia are at increased risk of injury; people who sustain head injuries
have higher rates of manic depressive illness than controls. Often the personality problems that
emerge post injury seem to be based on pre-injury personality traits. Occasionally a TBI causes
an improvement in psychological functioning, eg. by reducing symptoms of OCD; some families
will describe how the person is much easier to live with after the injury, for example because they
are no longer as tense and demanding. However for most cases family burden is a major
problem after TBI; social networks tend to become smaller and the care often falls to close family.
Parents sometimes adjust better to this than spouses, who find the change in roles very
distressing.

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About 10 – 20% of patients after an mTBI do unexpectedly badly and develop chronic symptoms.
Typical symptoms in these patients include headaches, tinnitus, sensitivity to noise or light,
dizziness, fatigue, poor concentration and memory, mood lability and irritability, and anxiety and
depression. Travel anxiety and PTSD may also be present. These patients are diagnosed as
suffering post concussion syndrome; the role of brain injury in these patients is uncertain.
Particularly in those with long persistent symptoms after a very mild injury psychological factors
are probably primary. The problem is akin to a somatisation disorder. Compensation issues
often seem to aggravate the problem.
Secondary complications need to be considered in the assessment of post traumatic

neuropsychiatric problems; in particular subdural, hydrocephalus and post traumatic epilepsy. In
terms of drug treatment the principles of treatment rest largely on those for the same psychiatric
problems in the absence of brain injury, taking account of the brain injured person’s vulnerability
to side effects. Cognitive behaviour therapy is often required alongside rehabilitation for cognitive
impairments. Work with family and carers is frequently required.
References
Fleminger S. The Neuropsychiatry of Head injury. In The New Oxford Textbook of Psychiatry 2nd
edition. Eds Gelder M et al. In press
Silver, J.M., McAllister, T.W., and Yudofsky, S.C. (2005). Textbook of traumatic brain injury.
American Psychiatric Publishing Inc., Washington, DC.
Neurobehavioral Guidelines Working Group. Warden, D.L., Gordon, B., McAllister, T.W., et al.
(2006). Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic
brain injury. Journal of Neurotrauma, 23, 1468–501.

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The Neuropsychiatry of Epilepsy
Dr Manny Bagary, Consultant Neuropsychiatrist, Barberry Centre, Birmingham and Honorary

Clinical Research Fellow, Institute Of Neurology, Queen Square, London
manny.bagary@bsmht.nhs.uk
Biological, psychosocial and iatrogenic factors contribute to the comorbidity between epilepsy and
psychiatric disorders.
The incidence and prevalence of neuropsychiatric comorbidity in epilepsy is not firmly

established. A particular difficulty is that neuropsychiatric disorders in epilepsy can be atypical
and/or episodic and may not conform easily to existing standardised classification systems (ICD-
10 and DSM-IV). This, amongst other factors, contributes to variability in study methodology and
has lead some authors to suggest apparent overrepresentation is due to sampling errors or
inadequate control groups. Others argue to the contrary, that neuropsychiatric conditions are
common in patients with epilepsy despite being under-diagnosed, under-treated and contributing
adversely to quality of life.
Neuropsychiatric disorders that are co-morbid with epilepsy may be directly related to seizures
such as ictal and post-ictal disorders. Ictal neuropsychiatric syndromes remit as the seizure
resolves. Post-ictal neuropsychiatric syndromes are usually characterised by a lucid interval after
a seizure with self-limiting behavioural, psychological or cognitive symptoms (such as mood
disturbance, anxiety, psychosis) lasting several days. Management is aimed at improving seizure
frequency but may necessitate the use of dopamine blockers or benzodiazepines. Interictal
neuropsychiatric disorders are not directly associated with seizures and often require specific
treatment including psychological therapies such as cognitive behavioural therapy and/or
pharmacotherapies.
The risk of suicide is increased in epilepsy by a factor of 4-10. The risk is particularly pronounced
in those patients with comorbid psychiatric disease (RR 13.7) and within the first 6 months of
diagnosis. The relative risk has been shown to remain high (1.9) after excluding those with a
history of psychiatric disease and adjusting for socioeconomic factors1.
Depression is observed in 10–20% of individuals with controlled epilepsy and in up to

60% of patients with treatment-resistant epilepsy. Population-based case control studies support
a bidirectional relationship between epilepsy and depression2,3,4.
It is apparent most neurologists do not routinely screen for depression in epilepsy. Depression
has been found to be strongly correlated with lower quality of life regardless of seizure type or
severity5. After controlling for depression, similar findings concerning anxiety and epilepsy have
been observed6. The NDDI-E is a self-rating scale which is sensitive and specific for depressive
symptoms in epilepsy7.
Comorbid interictal psychosis is up to six times more common in people with epilepsy than in
other individuals. Compared to schizophrenia the phenomenology is characterised by paranoid
delusions and delusions of reference. It has a more benign and variable course with better
preservation of premorbid personality and affect. Negative symptoms are uncommon.
Management of psychiatric symptoms in epilepsy require good communication between

clinicians. Appropriate psychological therapies should be considered. SSRI’s and atypical
antipsychotics are relatively safe in epilepsy.

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References
1. Christensen et al, Epilepsy and risk of suicide: a population-based case-control study.
Lancet Neurol. 2007 Aug;6(8):693-698
2. Forsgren L, Nystrom L. An incident case referent study of epileptic seizures in adults.
Epilepsy Res 1990; 6: 66–81.
3. Hesdorffer DC, Hauser WA, Annegers JF, Cascino G. Major depression is a risk factor
for seizures in older adults. Ann Neurol 2000; 47: 246–249.
4. Hesdorffer DC, Ludvigsson P, Hauser WA, Olafsson E. Depression is a risk factor for
epilepsy in children. Epilepsia 1998;39: 222A
5. Cramer JA, Blum D, Reed M, Fanning K, for the Epilepsy Impact Project Group. The
influence of comorbid depression on quality of life for people with epilepsy. Epilepsy &
Behavior 2003; 4: 515-521.
6. Tara W. Strine, Rosemarie Kobau, Daniel P. Chapman, David J. Thurman, Patricia Price
and Lina S. Balluz. Psychological Distress, Comorbidities, and Health Behaviors among
U.S. Adults with Seizures: Results from the 2002 National Health Interview Survey.
Epilepsia, 46(7):1133–1139, 2005
7. Frank G Gilliam MD, John J Barry MD, Bruce P Hermann PhD, Kimford J Meador MD,
Victoria Vahle MPH, Andres M Kanner MD. Rapid detection of major depression in
epilepsy: a multicentre study The Lancet Neurology, Volume 5, Issue 5, Pages 399 - 405,
May 2006
Recommended Reading
1. The Neuropsychiatry of Epilepsy. Michael Trimble and Bettina Schmitz. Cambridge

University Press. 2002

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Cognition and behaviour in dementia
Richard J Perry, Imperial College

Richard.Perry@imperial.nhs.uk
Introduction
This presentation compares cognition and behaviour in Alzheimer’s Disease (AD) and
Frontotemporal dementia (FTD). In doing so, it emerges that Alzheimer’s disease is
predominantly a cognitive disorder, while frontotemporal dementia is predominantly a disorder of
behaviour.
In order to explain these differences and to provide a framework for the description of abnormal
behaviours in dementia, it is useful to return to the anatomy of the limbic system. The
phylogenetic development of this system creates two divisions: the paleocortical division involving
the orbitofrontal, insula, anterior temporal and anterior cingulate cortices is the focus of atrophy in
Frontotemporal dementia and results in specific behavioural abnormalities whereas the
archicortical division, centred on the hippocampus and spreading to the posterior cingulate cortex
is involved in memory and attention – the initial core deficits in Alzheimer’s disease.
The middle section of the presentation focuses on the clinical features of abnormal behaviour in
frontotemporal dementia and the research that demonstrates the progressive breakdown in
complex social behaviour that is observed in this condition.
Finally, more recent theories of how a specific and unique set of neurons seen only in social
complex mammals may be selectively vulnerable in the frontotemporal dementias, is described.
The limbic system and its divisions

The limbic system was named as the cerebri limus in 1664 by Thomas Willis before Paul Broca
used the term grand lobe limbique in 1878. Later ablation studies showed that aggressive and
dominant monkeys could be turned into tame and docile animals after bilateral temporal
lobectomy. In 1937 Papez described emotional deficits as a result of limbic system lesions and
conceived of three divisions of brain function; a stream of movement, a stream of emotion, and a
stream of emotion, a theme continued by MacLean’s model of a triune brain reflecting the
phylogenetic stages of CNS development from invertebrates through reptiles and early mammals
and on to neocortical development in man.
Two waves of phylogenetic development originating from primordial regions of the limbic system
have been described.
In one, the paleocortical division spreads developmentally from the orbitofrontal and infracallosal
cingulated region of the olfactory paleocortex, through the insula, temporal pole and
parahippocampal area. The functions of this division are dominated by appetite drives with
aversion or attraction to stimuli, implicit processing and visceral integration.
The second, or archicortical division, has the hippocampus as its centre and spreads posteriorly
through the entorhinal region to the posterior cingulate. This division is concerned with explicit
processing, memory encoding, attentional systems, and integration of sensory information and is
a move away from the thalamic control seen in reptiles towards the neocortical control seen in
mammals.
The two paralimbic divisions in dementia

The phylogenetic development of the archicortical or hippocampal paralimbic division mirrors the
spread of pathology in Alzheimer’s disease. Neurofibrillary tangles and synaptic loss, hallmarks of
the pathology of Alzheimer’s disease, first appear in the transenthorhinal region of the medial
hippocampal complex. The spread of pathology involves the temporal lobes, posterior cingulate
cortex and then parietal cortices. Paralleling this spread of pathology is an evolution of cognitive
deficits where the cognitive functions of the respective brain regions are lost. Thus the early
pathology in the hippocampus is reflected in the first symptoms of Alzheimer’s disease with poor
memory for day-to-day events and repetitiveness, measured on neuropsychological tasks as

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impaired episodic memory. As pathology spreads from the hippocampal complex to the temporal
neocortex and posterior cingulate, attentional function and semantic memory become affected.
In contrast, the phylogenetic development of the paleocortical or orbitofrontal division mirrors the
areas of earliest involvement in frontotemporal dementia. Pathological as well as imaging studies
have demonstrated greatest atrophy in the orbitofrontal cortices, anterior insula, and anterior,
particularly infracallosal, cingulate gyrus. The behaviours that characterise frontotemporal
dementia are linked to these brain regions and will be described in the following section.
Behavioural abnormalities in frontotemporal dementia

In frontotemporal dementia, behavioural features, rather than cognitive features, are the
presenting symptoms and dominate the clinical course of the condition. The core diagnostic
features from the consensus guidelines reached by the Manchester and Lund groups for the
diagnosis of FTD include and early decline in social conduct and regulation of social conduct, loss
of empathy, and loss of insight. Supportive features include mental rigidity, hyperorality and
dietary changes, disinhibition, perseverative and stereotyped behaviour.
Patients generally lack basic emotional responses such as sadness and may have a long history
of loss of empathy that extends back 10 years or more prior to presentation. The above features
can differentiate FTD from AD whereas behaviours such as apathy, depression, delusions, and
hallucinations are equally common in both patient groups
Behaviours that are almost pathognomonic of FTD include the specific changes in dietary habits
and stereotypies, particularly vocal stereotypies. Disturbances of eating behaviour are common in
FTD and include hyperphagia, a change in preference for sweet foods and hyperorality with non-
food items being put into the mouth. Imaging studies have suggested that these behaviours are
linked to atrophy in the orbitofrontal cortex, anterior insula, temporal poles and caudate nucleus,
more frequently on the right side. Stereotypies are repetitive, co-ordinated movements that
resemble normal actions but have no discernable purpose. In FTD they are common and one
particular type, the verbal stereotypy in frequently seen in the temporal variant of FTD in the form
of ‘catch-phrases’ that are repeated over and over again.
The temporal variant of FTD, which shares many of the behavioural abnormalities of the frontal
variant, may present in an asymmetrical fashion with either predominant right or left sided
atrophy. Investigation has shown far greater impairments on tasks of emotion processing,
empathy, and social cognition in the right temporal cases lending support to the notion that the
right hemisphere is ‘dominant’ for these functions.
The recognition of FTD as a model of impaired social behaviour has highlighted similarities to
other developmental conditions such as autism and some of the core deficits seen in autism are
also seen in FTD. During development one of the skills that enables children to engage in
complex social behaviour is the emergence of Theory of Mind. This facility relates to the ability to
infer other peoples states of mind, belief and feelings and develops in complexity from the age of
around three upwards. When applied to dementia groups, performance on theory of mind tasks is
significantly impaired in FTD subjects relative to AD and again, these deficits may be more
severe in predominantly right sided cases.
Neurons specific for complex social behaviour affected in frontotemporal dementia

Von Economo neurones (VENs), previously known as spindle neurones, are large bipolar cells
situated in layer 5b of the anterior cingulate and anterior insula cortices. They were initially
described only in humans and great apes but not in the orang-utan, placing their evolutionary
emergence. They have subsequently been described in whale where they developed
independently from primates which may be an example of convergent evolution in large brained
socially complex animals.

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The presence of these cells in brain regions known to be primarily affected in FTD led
researchers to look for loss of these cells. Examination of the cingulate cortex found a 60%
reduction in VEN numbers in FTD but not AD. Subsequent studies are needed to see if similar
degrees of VEN loss or dysfunction are seen across all the pathologies seen in FTD.
Conclusions
The initial locus and spread of pathology in two distinct dementia syndromes follows the
evolutionary development of two paralimbic divisions in the brain. In Alzheimer’s disease, the
initial locus of pathology is in the hippocampal complex before spreading to the posterior
cingulate region and these regional pathological changes lead to a predominant deficit in
cognitive functions of memory and attention. In the other dementia syndrome, frontotemporal
dementia, the pathology of the disease follows the paleocortical paralimbic division and affects
orbitofrontal cortex, anterior cingulate cortex, insula, and anterior temporal lobe. There is now a
wealth of evidence from studies of frontotemporal dementia and functional imaging in normal
controls that these regions, particularly on the right side are important for emotional processing,
empathy, and complex social cognition.
These regions are the locus of von Economo neurons, a set of neurons unique to socially
complex mammals, which may be selectively vulnerable in frontotemporal dementia and be a
neural substrate for complex social behaviour.

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Prions and human disease
RG Will, University of Edinburgh;

r.g.will@ed.ac.uk
Human prion diseases include a range of conditions with differing aetiology and contrasting
phenotypes. The commonest form is sporadic CJD, which occurs worldwide with an incidence of
1-1.5 cases per million per year. Genetic forms, including genetic CJD, Gerstmann-Straussler
syndrome and Fatal Familial Insomnia, occur with a dominant pattern of inheritance and are
associated with mutations of the prion protein gene. Acquired forms of human prion disease
include kuru, iatrogenic CJD and variant CJD are rare, but have had an important impact on
public health because of concern regarding transmission of the infectious agent from human to
human or from animal to human.
All human prion diseases present primarily with neurological dysfunction in keeping with the
predominant central nervous system involvement in these conditions. However, neuropsychiatric
features are important components of the clinical presentation and, although varying in frequency
and characteristics, often important to accurate diagnosis. About 5% of cases of sporadic CJD
present initially to psychiatrists because of changes in behaviour; which can be associated with
psychotic features including visual hallucinations. A similar proportion of cases present atypically
with gradually evolving dementia which can be difficult to distinguish from more common
conditions such as Alzheimer’s disease. Genetic forms of CJD vary in their phenotype depending
upon the precise underlying mutation, with a significant proportion mimicking sporadic CJD and a
minority presenting with slowly evolving symptoms, which can include personality change and
behavioural symptoms.
In acquired forms of human prion disease the clinical phenotype is influenced by route of
exposure and strain of infectious agent. In iatrogenic CJD related to human growth hormone
treatment and in kuru the clinical presentation is nearly always dominated by a progressive
cerebellar syndrome, whereas in CJD linked to human dura mater grafts the presentation is often
similar to sporadic CJD.
Variant CJD is a zoonotic condition linked to human exposure to the BSE agent. The early clinical
features are mainly psychiatric, with patients usually presenting with depression, apathy and
anxiety. After a mean of about 6 months frank and progressive neurological impairments develop.
Diagnosis is difficult in the early stages and the clinical features result in psychiatric referral in the
majority of cases. Neuropsychological assessment in human prion disease is compromised by
their rapid and progressive nature, but in variant CJD there is some evidence of particular
neuropsychological deficits that may be helpful in diagnosis.
References:
Zeidler,M, E C Johnstone, R W K Bamber, C M Dickens, C J Fisher, A F Francis, R
Goldbeck, Higgo, E C Johnson-Sabine, G L Lodge, P McGarry, S Mitchell, L Tarlo, M
Turner, P Ryley, R G Will, 1997, New variant Creutzfeldt-Jakob disease: psychiatric
features: Lancet, v. 350, p. 908-910.
Spencer,MD, R S G Knight, R G Will, 2002, First hundred cases of variant Creutzfeldt-

Jakob disease: retrospective case note review of early psychiatric and neurological
features: British Medical Journal, v. 324, p. 1479-1482.
Kapur,N, P Abbott, A Lowman, R G Will, 2003, The neuropsychological profile associated

with variant Creutzfeldt-Jakob disease: Brain, v.126, p. 2693-2702.

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Psychological presentations of Movement Disorders
Anette Schrag
a.schrag@medsch.ucl.ac.uk
The basal ganglia were long believed to have exclusively motor function. However, it is now well-
recognised that they are involved in cognitive, emotional and behavioural processing, and
movement disorders commonly are have psychiatric features as well as motor features. The
underlying basis for this are close connections between the basal ganglia and the limbic system
and cortical structures, particularly the prefrontal cortical structures, with at least five major
connective circuits between them. The basal ganglia are also thought to be involved in classical
psychiatric disorders, such as schizophrenia, depression and obsessive-compulsive disorder. In
this talk I will discuss the major movement disorders and their psychiatric presentations.
We know from correlations of pathological basal ganglia lesions and clinical presentations that
these are commonly neuropsychiatric: caudate lesions led to abulia in 28% and disinhibition in
11%, but to chorea and dystonia in only 6% and 9%; lesions in the lentiform nucleus to abulia in
10% and dystonia (esp. putamen) in 49%; and lesions in the bilateral lentiform nucleus lesions to
parkinsonism in 19% or dystonia-parkinsonism in 6% (Bhatia and Marsden, 1994). There is also
evidence for the behavioural influence of the substantia nigra and the cognitive influence of the
cerebellum (learning, attention, language), but this is currently a controversial topic (Glickstein,
2007). There is however a report of pronounced influence of mood state by alternation in the
setting of deep brain stimulation for Parkinson’s disease (PD), which give clear evidence for the
importance of the basal ganglia in emotional functioning (Bejjani et al, 1999).
Parkinson’s disease (PD)

There are a number of different psychiatric presentations seen in PD:
Cognitive impairment, which is predominantly fronto-subcortical and subtle at the beginning, but
develops into clinical dementia in up to 80% after a disease duration of 10 years (Aarsland et al,
2003). When dementia predates parkinsonian features or occurs in the first year of onset, the
diagnosis may be dementia with Lewy bodies where patients typically have fluctuating cognition
and visual hallucinations (McKeith et al; see section on dementia).
Depression is present at any one time in approximately 50% of patients, and anxiety in 40%. The
vast majority suffer from mild depression, but 10-20% (fewer in population-based studies) fulfils
DSM IV criteria for major depression. Depression is known to be one of the most important
predictors of patients’ quality of life, and may also be a risk factor for the development of
dementia and more rapid depression. Whilst depression is more common in advanced disease,
there is no strong relationship to disease severity, and depression and anxiety may predate the
onset of motor symptoms by many years. This, together with the finding from imaging studies and
a greater family history of depression in patients with PD, supports a neurobiological basis of
depression in PD, although psychosocial factors are also likely to play a role. Depression is
generally underdiagnosed in PD, partly due to the difficulty in distinguishing some of the features
of PD and depression. Treatment options for depression in PD include dopaminergic medication
(dopamine agonists), SSRIs, anticholinergics (cave side effects) and non-pharmacological
options (particularly for milder cases). In cases were there is simultaneous poor mobility,
depression is likely to be an off-period phenomenon and responds dramatically to
antiparkinsonian medication. The same is true for anxiety, in particular panic attacks.
Psychosis complicates PD in approximately 40% of cases. Initially, many patients describe vivid
dreams or visual illusions (misinterpretations), with the typical hallucinations being of people or
animals. More rarely acoustic, olfactory or tactile hallucinations are described. Delusions, which
are commonly of a paranoid or jealous nature, can also occur. Risk factors for psychosis
(hallucinations and delusions) include cognitive impairment, polypharmacy, age, disease severity
(Fenelon et al, 2000). Its occurrence is a poor prognostic factor. Mania may occur rarely, but

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isolated hypersexuality on antiparkinsonian medication is relatively common. Psychosis, mania

and hypersexuality frequently respond to reduction in antiparkinsonain medication, with standard
levodopa at the lowest possible dose sometimes being the only tolerated antiparkinsonian
treatment. The addition of a typical neuroleptic is relatively contraindicated due to the high risk of
deterioration of parkinsonism, and most atypical neuroleptics also cause worsening of
parkinsonism. Clozapine at low doses has been shown to be an effective drug for psychosis in
PD, but its prescription requires regular monitoring. The mild atypical neuroleptic quetiapine is
typically used first, but double-blind trials have not found it to be more effective than placebo. In
patient with cognitive impairment cholinesterase inhibitors can be effective. In recent years, it has
also been recognised that dopaminergic treatment, particularly dopamine agonists, can lead to
impulse control disorders (e.g. pathological gambling or shopping) and dopamine dysregulation
syndrome, with excessive and increasing intake of levodopa containing drugs despite side effects
and high rate of associated psychiatric comorbidity, including punding (stereotyped motor
behaviour with repetitive manipulation of objects), drug hoarding, hypomania.
Atypical parkinsonism
Progressive supranuclear palsy (PSP), which is characterised by a typically symmetrical
parkinsonian syndrome with early falls and a supranuclear gaze palsy, has prominent cognitive
features of fronto-subcortical impairment, often from the onset of the disease. Apathy, emotional
lability and disinhibition are more common than in PD, whereas psychosis is typically rare
(Aarsland et al, 2001). Depression and anxiety are also common in both PSP and multiple system
atrophy (MSA), which otherwise is rarely associated with neuropsychiatric features.
Hallucinations may be a useful clinical sign differentiating PD from MSA patients, who rarely have
psychosis.
Huntington’s disease
The classical triad of Huntington’s disease, which is an autosomal dominant disorder with 100%
penetrance, includes chorea and other movement disorders such as myoclonus, parkinsonism,
dystonia and tics, dementia, which is initially predominantly of a dysexecutive type (covered in
more detail in the section on dementia: organising, planning, checking, adapting), and
neuropsychiatric features. These include personality change, which may be predating motor
features for years, irritability and aggression, depression (in 40-100%) and suicide (in ~10%),
disinhibition, obsessive-compulsive behaviours, mania, apathy and, occasionally, psychosis.
Treatment options for depression include counseling, SSRIs, tricyclics, mirtazapine and (typical
and) atypical neuroleptics, and for irritability and aggression (after environmental adaptation and
avoidance of triggers) sodium valproate (also useful for myoclonus), carbamazepine, SSRIs, and
(typical and) atypical neuroleptics. Neuroleptics (for chorea or neupsychiatric features) should
always be used cautiously due to the risk of aggravating underlying parkinsonism. Tetrabenazine
is often used for chorea but can cause depression (and parkinsonism), and should therefore be
monitored.
Gilles de la Tourette Syndrome

This childhood onset disorder is defined by the presence of motor and vocal tics for more than a
year, but frequently is associated with psychiatric comorbidity. Cognitive function is normal, and
some patients have no associated psychiatric features. However, approximately 50% have
associated obsessive-compulsive disorder, which may be genetically related, and 30-85% ADHD,
with common co-occurrence of depression and occasionally conduct disorder or oppositional
defiant disorder. These comorbidities, if present, often have much greater impact on emotional
and social functioning than the tic disorder itself. Therefore, recognition and treatment of these
conditions is often most important. The disorder of PANDAS (paediatric autoimmune
neuropsychiatric disorder associated with streptococcal infection)is a relatively recently
recognized tic disorder, analogous to Sydenhams chorea. Like Sydenhams, there is a sudden
onset movement disorder (tics) associated with neuropsychiatric manifestations (especially OCD)
occurring after a streptococcal infection and associated with raised ASO titres and antibasal

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ganglia antibodies. The relationship of this disorder to Tourette syndrome is currently

controversial.
Wilson’s disease (WD)

WD presents with neurological or psychiatric features in probably 40-50% of cases rather than
the more classical hepatic impairment (although this is usually present asymptomatically). Subtle
neurological and psychiatric features can predate the overt motor and psychiatric features by a
number of years. There is frequently a delay in diagnosis with subtle motor impairment
(clumsiness, gait disturbance, handwriting disturbance) and personality changes or failing school
performance in a teenager not being noticed or suspected to be due to underlying disease. Liver
enzyme abnormalities may be present at this stage or be absent. The diagnosis is made by
testing copper levels in 24-hour urine (elevated) and caeruloplasmin in serum (low). Kayser
Fleischer Rings (KF rings) are present in virtually all patients with neurological or psychiatric
presentations of WD and should always be checked in those with equivocal
copper/caeruloplasmin results. The motor features may include tremor, dystonia, gait
disturbance, cerebellar features, parkinsonism, spasticity, dysarthria, dysphagia and oculomotor
signs and, more rarely, chorea. Neuropsychiatric presentations include personality change
(irritability, aggression, reckless bizarre behaviour, apathy), depression, suicidality, psychosis or
mania. Cognitive impairment is often present, even when MRI changes are restricted to the basal
ganglia. Treatment is with copper chelating drugs but psychiatric features may required
symptomatic treatment.
References
The behavioural and motor consequences of focal lesions of the basal ganglia in man. Bhatia KP,
Marsden CD. Brain. 1994 Aug;117 ( Pt 4):859-76.
Hallucinations in Parkinson's disease: prevalence, phenomenology and risk factors. Fénelon G,

Mahieux F, Huon R, Ziégler M. Brain. 2000 Apr;123 ( Pt 4):733-45.
What does the cerebellum really do? Glickstein M. Curr Biol. 2007 Oct 9;17(19):R824-7
Transient acute depression induced by high-frequency deep-brain stimulation. Bejjani BP, Damier
P, Arnulf I, Thivard L, Bonnet AM, Dormont D, Cornu P, Pidoux B, Samson Y, Agid Y. N Engl J
Med. 1999 May 13;340(19):1476-80.
Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study.

Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sørensen P. Arch Neurol. 2003
Mar;60(3):387-92.
Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
McKeith IG, et al; Consortium on DLB. Neurology. 2005 Dec 27;65(12):1863-72.
Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson's

disease. Aarsland D, Litvan I, Larsen JP. J Neuropsychiatry Clin Neurosci. 2001 Winter;13(1):42-
9.

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The EEG in Neuropsychiatry: Uses and abuses
Dr Alison Blake
M.B. Ch.B.(Hons.) F.R.C.P.
Consultant Clinical Neurophysiologist: Worcestershire Royal Hospital. Hereford County Hospital

Birmingham Children’s Hospital. South Birmingham Mental Health Trust: Barberry
Perpatetic EEG service for adults and children with Learning Difficulties Worcestershire Mental
Health Trust
Title “The Trouble with EEGs”

This talk will features visual tour of EEGs in relevant Organic conditions.
Aims: to answer the following questions:
When is the EEG useful?
When is it not likely to help?
When is it useless?
When is it misleading?

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To underline:
The use of routine and sleep EEGs.
The role of activation procedures.
Ambulatory monitoring
Video- EEG monitoring
Problems:
The technique
The patient
The referring doctor.
Medication.
A Result!
You will know a little more about EEG recordings. When to ask for them and when not to.

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How to manage depression, anxiety, delirium and psychosis in patients with neurological
disease
Andrea Eugenio Cavanna

a.cavanna@ion.ucl.ac.uk
The growth of the twin disciplines of neuropsychiatry and behavioural neurology is fuelled by the
remarkable advances in both diagnostic tools (i.e. structural and functional brain imaging
techniques) and treatment options (i.e. safe and effective behavioural, pharmacological, and
neurosurgical strategies). Over the last few years these advances have significantly improved the
care of patients with disturbed brain-behaviour relations.
The purpose of this talk is to build upon the recent advances in basic and clinical neuroscience in
order to provide a clear and concise rationale to the integrated treatment of the neuropsychiatric
disorders most commonly encountered in the clinical practice of neurologist, psychiatrists, and
neuropsychiatrists. These include affective, anxiety, and psychotic symptoms in the context of
traumatic brain injury, dementia, Parkinson disease, and epilepsy.
Mood disturbances are reported in a vast proportion of neuropsychiatric patients. The prevalence
figures of depression in patients with neurological disease range from 30-40% (traumatic brain
injury, Alzheimer disease, Parkinson disease) to 50-60% (epilepsy). Recommended
management strategies for depression in patients with neurological disease include: (1)
optimisation of neurological pharmacotherapy; (2) brief, structured psychotherapeutic
interventions, esp. cognitive behavioural therapy; (3) antidepressant pharmacotherapy for severe
and resistant cases - first line: SSRI (sertraline, citalopram), SNRI (venlafaxine); second line:
TCA, bupropione (except in epilepsy); (4) ECT sessions/add-on atypical antipsychotics for
patients with suicidal/psychotic features not responding to antidepressants.
Anxiety symptoms have an increased prevalence in patients with neurological disease. One
fourth to one third of patients with neurological disease fulfil diagnostic criteria for generalised
anxiety disorder. Management is based on environmental interventions and targeted
pharmacotherapy (SSRI: sertraline, citalopram, escitalopram; SNRI: venlafaxine; beta-blockers:
propranolol; trazodone, TCA, and atypical antipsychotics represent second-line options).
Psychotic symptoms are known to complicate the clinical picture of a number of neurological
disorders, especially neurodegenerative conditions; for instance it is estimated that up to 50% of
patients with Alzheimer’s dementia develop behavioural and psychotic problems. Atypical
antipsychotics (risperidone, aripiprazole, olanzapine) are preferred to neuroleptics (haloperidol),
since they carry less risk of extrapyramidal symptoms and tardive dyskinesia. However caution is
needed, especially in the elderly predisposed to stroke, because of the increased risk of death
from cerebrovascular accidents. Clozapine is the atypical antipsychotic drug of choice in patients
with Parkinson disease because of its anticholinergic activity.
The acute management of organic delirium is based on i.v. haloperidol, although there is growing
experience with the use of the atypical antipsychotics risperidone, olanzapine and quetiapine.

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Of note, in most cases management recommendations are based on clinical observations and
open-label studies; controlled studies are needed for the development of evidence-based
guidelines.
Recommended psychopharmacological treatments in patients with neurological disease (from

Coffey et al 2007)
TBI AD PD Epilepsy
Depression SSRI SSRI SSRI SSRI
TCA SNRI SNRI SNRI
Stimulants TCA bupropion
Anxiety SSRI SSRI SSRI SSRI
beta-blockers NaSSA SNRI SNRI
beta-blockers trazodone
Psychosis atypicals atypicals atypicals atypicals
neuroleptics neuroleptics neuroleptics neuroleptics
Abbreviations: TBI, traumatic brain injury; AD, Alzheimer disease; PD, Parkinson disease;
SSRI, selective serotonin reuptake inhibitors; SNRI, serotonin and noradrenaline reuptake
inhibitors; TCA, tricyclic antidepressants; NaSSA, noradrenergic and specific serotonergic
antidepressant.
Essential references
Coffey CE, McAllister TW, Silver JM (Eds). Guide to Neuropsychiatric Therapeutics.

Philadelphia, PA: Lippincott 2007
Cummings JL, Trimble MR. Concise guide to Neuropsychiatry and Behavioral Neurology.
Washington, DC: American Psychiatric Press 2002
Yudofsky SC, Hales RE (Eds). Textbook of Neuropsychiatry and Behavioral Neurosciences.

Washington, DC: American Psychiatric Press 2007 (5th Ed)

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Hypersomnia and Insomnia
Dr Paul Reading, Neurologist, The James Cook University Hospital

Paul.Reading@stees.nhs.uk
Introduction
Although not yet formally recognised as a separate discipline in the UK, sleep medicine is
increasingly recognised as an area worthy of interest for a variety of specialities, particularly
neurology and psychiatry. When the sleep-wake cycle “goes wrong”, apart from deleterious
effects on quality of life, there can be major implications for cognitive, mental and even physical
health. Although the armamentarium, pharmacological and non-pharmacological, for treating
sleep disorders is relatively limited, increasing options and evidence for efficacy are available.
This presentation will deal with the assessment of those subjects who sleep excessively through
the day and those who cannot achieve or maintain nocturnal sleep adequately, two populations
by no means mutually exclusive. Although hypersomnolence strictly describes those who sleep
more than average during a 24-hour period, here it will refer simply to those who have excessive
sleepiness during conventional waking hours.
It will be emphasised that, contrary to common perception, investigations in most sleep-
disordered patients are not always needed for confident diagnosis. As in so many areas of
neurology and psychiatry, a clear history corroborated, if possible, by close friends or relatives
remains essential.
Hypersomnia
Causes
With occasionally (in)famous exceptions, most people require between 7 and 7.5 hours of good
quality sleep on a regular basis. The commonest causes of acute and chronic sleepiness,
respectively, reflect insufficient sleep and poor quality sleep. The former population, assuming
they come to medical attention, are fairly easy to identify from history and sleep diaries, if
necessary. The latter includes numerous conditions such as sleep apnoea, arousing periodic leg
movements during sleep, and Parkinson’s disease. The key historical pointer is a report of
awakening feeling unrefreshed despite seemingly adequate or even excessive amounts of
nocturnal sleep.
It is recognised that around 5% of the population are excessively sleepy. Prevalence data
indicate that 1% of this population may have narcolepsy, the prototypical primary sleep disorder
causing striking daytime somnolence. Narcolepsy presents as a spectrum both in terms of
severity and nature, perhaps not surprisingly given the recent revelation that it is usually due to a
specific neuro-chemical deficiency of the hypothalamic peptide hypcretin (orexin). Around two-
thirds will have recognisable cataplexy, an extremely specific phenomenon. The third that don’t,
will usually have REM sleep-related symptoms such as vivid dreams either at night or during
naps, frank hallucinatory intrusions into wakefulness, or sleep paralysis. Nocturnal sleep is
characteristically fragmented in narcolepsy and may be disturbed by a the whole gamut of
parasomnias. Furthermore, the narcoleptic syndrome is being increasingly defined and also
appears to include appetite dysregulation with associated metabolic changes and altered cerebral
reactions to risk and reward.
The condition idiopathic hypersomnolence may mimic narcolepsy in some respects but is
relatively rare. Its neurobiology is much less understood although treatment options are similar.
Narcoleptic levels of sleepiness are also seen in a variety of neurological conditions such as
Parkinson’s disease, myotonic dystrophy and hypothalamic pathology, including tumours. The
notion of “secondary” narcolepsy is now well established although cataplexy outside idiopathic
narcolepsy remains exceptionally rare. Some patients with multiple sclerosis appear truly
narcoleptic although general fatigue without actual sleepiness is far commoner.
Medication can clearly contribute to daytime somnolence in many ways. Occasionally, this may
not be obvious, however, if a drug is adversely affecting overnight sleep quality rather than
quantity. For example, tricyclics given primarily to improve sleep may actually worsen nocturnal
leg movements and disturb sleep quality. Although dopamine levels do not vary greatly across

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the sleep-wake cycle and dopamine, itself, has been though to contribute little to its control, both
neuroleptics and dopamine agonists, in particular, can produce significant excessive somnolence
by a variety of mechanisms.
A third broad cause of daytime somnolence relates to so-called circadian “dysrhythmias” in which
there is a mismatch between an individual’s internal clock mechanism or sleep propensity and the
need to sleep based on external factors. Shift work and jet lag are obvious examples. A number
of subjects, however, may have constitutionally altered clocks such that they are either extreme
“night owls” or “morning larks”. The genetic basis of these “phase syndromes” is starting to
become apparent.
Assessment
A significant proportion of sleepy patients require no specific diagnostic investigations. However,
if obstructive sleep apnoea is thought at least partially responsible, home oximetry or more
detailed respiratory tests are indicated.
Measuring objective levels of sleepiness is clearly difficult. Indeed, for the most part, a subjective
scale, the Epworth score, is used instead. This is rarely helpful diagnostically, however. Of the
questions asked on the Epworth, the one most likely to discriminate subjects with and without
excessive sleepiness concerns the ability to routinely stay awake if a passenger in a car for an
hour without a break.
If objective evidence for excessive sleepiness and its nature is required, the multiple sleep
latency test is considered a gold standard. However, there are numerous reasons why this
investigation may give misleading results, especially in units not specialising in sleep medicine.
Overnight polysomnography can give useful information in certain situations and illustrative cases
are described.
In classical cases of narcolepsy and cataplexy, CSF levels of hypocretin are almost always
undetectable. Unfortunately, in cases of diagnostic uncertainty, the levels are unpredictable and
therefore not usually helpful.
Insomnia
Causes
In sleep medicine, (chronic) insomnia is rather loosely defined as an inability to achieve or
maintain adequate sleep for at least four weeks despite an adequate opportunity to do so.
Prevalence figures suggest that 10% of the population have significant insomnia with a clear
relation to increasing age, particularly with respect to impaired sleep continuity or consolidation.
Insomnia can be divided into primary and secondary forms although the distinction is often
blurred.
The commonest form of primary insomnia is so-called “psycho-physiological” insomnia. The best
explanation of this phenomenon proposes that subjects are somehow predisposed to developing
insomnia prior to it being triggered by a specific event such as childbirth. The sleep problems are
then perpetuated by maladaptive habits and continuing cognitive over-arousal such that the
concerns over poor sleep and its consequences fuel the problem itself. Put simply, when sleep
onset requires effort or active thought rather than occurring spontaneously or automatically,
insomnia persists. The putative predisposing factors behind “restless mind syndrome” are poorly
defined although may reflect a relative deficiency of inhibitory neurotransmitters such as GABA.
Alternatively, a constitutional, possibly genetic, “wiring problem” in the sleep-onset centre in the
anterior hypothalamus has been proposed. Anxiety traits and personality variants undoubtedly
contribute. Despite very limited nocturnal sleep, such patients invariably are unable to nap during
the day.
In the neurology sleep clinic, there is usually an emphasis on identifying secondary factors that
may cause or contribute to insomnia. Common overlooked examples include restless legs
syndrome, delayed sleep phase syndrome, undiagnosed sleep-related breathing disorders,
nocturnal gastric reflux and bruxism. Certain neurodegenerative conditions such as parkinsonism
are particularly associated with poor quality sleep, most likely as a direct consequence of the
disease process within the brainstem and possibly the hypothalamus.

www.bnpa.org.uk
Assessment
Tests are rarely helpful in chronic cases of primary insomnia, often than simply demonstrating or
confirming poor quality sleep. Occasionally, overnight recordings or prolonged measurements
with actigraphy can confirm “paradoxical insomnia” in which subjects grossly overestimate their
levels of insomnia.
The role of psychiatric illness, particularly mood disorder, undoubtedly affects sleep adversely.
Psychiatric drug treatments may or may not improve sleep quality overall.
If secondary factors fuelling insomnia are picked up from history, tests may be useful in
confirming suspicions.
Conclusions
Hypersomnia and insomnia, in particular, are common symptoms in neurological and psychiatric
disease. In the former, both poor nocturnal sleep and daytime somnolence often occur together,
sometimes resembling secondary narcolepsy. In psychiatry, insomnia usually dominates although
sleep disorders are usually much less well characterised. Schizophrenia and its treatment, for
example, have major implications for the sleep-wake cycle although this aspect is often
overlooked.
It has been proposed, not entirely frivolously, that a sleep centre has far more need for a
psychiatrist than an EEG machine. Certainly, a good history is far more useful than detailed
investigations in the vast majority of sleep-disordered subjects.
Useful references
Silber MH, Krahn LE, Morgenthaler TI. Sleep Medicine in Clinical Practice. 2004. Taylor and
Francis, London.
An up to date, wide ranging and very informative textbook of ideal size, written predominantly by
a neurologist highly regarded for his teaching along with help from a psychiatrist and a
pulmonologist.
Parkes D. Sleep and its Disorders. 1985. Saunders, Philadelphia.

This monograph, if you can get hold of it, is a classic. Despite its relative advanced age, the
clinical and historical perspectives on all aspects of sleep and its disorders are superb.
Espie C. Overcoming Insomnia and Sleep Problems. 2006. Robinson.

This small book is written by a UK psychologist with an international reputation in sleep medicine.
Primarily directed at an educated public readership, it is nonetheless an insightful read with
helpful tips on managing insomniacs.

www.bnpa.org.uk
PARASOMNIAS
Dr Zenobia Zaiwalla, West Wing, John Radcliffe Hospital, Oxford

Zenobia.Zaiwalla@orh.nhs.uk
Parasomnias are undesirable physical events or experiences that occur during entry into sleep,
within sleep or during arousals from sleep. “Basic drive state” can emerge with parasomnias,
such as sleep related aggression or sexual behaviours.
Many of the parasomnias are self limiting, frequent in childhood, spontaneously resolving by
adolescence. However, when the sleep related behaviours persist into adolescence and adult
life, they can become socially disruptive, affect sleep quality, have potential to cause injury to the
patient and bed partner and other innocent bystanders, and can have a significant negative effect
on psychosocial health. Persistence of parasomnias, or the appearance for the first time in adult
life, may be secondary to other primary sleep disorders, such as obstructive sleep apnoea or
periodic leg movements in sleep, or induced by certain drugs, including alcohol. Parasomnias
starting later in life include REM sleep behaviour disorder, when the sleep disturbance may pre
date the clinical onset of certain neurodegenerative diseases. Occasionally there may be difficulty
in differentiating between nocturnal epilepsies and parasomnias.
Classification of Parasomnias
Table 1
Classification of parasomnias:
ICSD 2
¾ Disorders of arousal from NREM ¾ Other parasomnias

sleep
• confusional arousals • sleep related dissociate
• sleep walking disorder
• sleep terrors • sleep enuresis
• sleep related groaning
¾ Parasomnia associated with REM • exploding head syndrome
sleep • sleep related hallucinations
• REM sleep behaviour disorder • sleep related eating disorder
• recurrent isolated sleep paralysis • parasomnia unspecified
• nightmare disorder • parasomnia due to drugs, substance
abuse or medical condition
Table 2
Classification of sleep related movement disorders: ICSD 2
¾ Restless leg syndrome

¾ Periodic limb movement disorder
¾ Sleep related leg cramps
¾ Sleep related bruxism
¾ Sleep related rhythmic movement disorder
¾ Sleep related movement disorder unspecified
¾ Sleep related movement disorder due to drug / substance use or medical condition

www.bnpa.org.uk
Diagnosis and Management
Parasomnias, especially non REM arousal parasomnias, rarely occur in sleep laboratories.
Polysomnography recording is essential for the diagnosis of REM sleep behaviour disorder. For
other parasomnias, sleep studies are only indicated to exclude intrinsic triggers, such as
obstructive sleep apnoea and when nocturnal epileptic seizures is a possibility.
Table 3 Lists possible differentiating features between frontal and temporal lobe epileptic seizures
& NREM arousal parasomnias and REM sleep behaviour disorder, conditions with potential for
misdiagnosis.
Table 3
Frontal lobe Temporal lobe Parasomnia: Parasomnia:

epilepsy epilepsy NREM arousal REM behaviour
disorder disorder
Time of night Any time Any time 1st third Mid-third or later
Duration <1 min Minutes Several minutes Minutes
to 1 hour
Frequency Very frequent Few More than 1 Recur during REM sleep
(can be 20 – 30 uncommon periods
per night)
Semiology Stereotype Confused Confused, semi Complex dream
complex motor stereotype purposeful enactment behaviours
movements and automatisms varying
vocalisation automatisms
Directed No No Can occur Can occur
behaviour /
violence
Resistive Too brief to cause Yes, especially Yes Yes

aggression significant injury postictal
Memory of Absent Absent Absent Can relate to dream
event content
Family Sometimes Rare Common Rare
history
Polysom: Usually from NREM or REM NREM Stages 3 – REM sleep
Relationship NREM sleep 4
to sleep Usually an
stage Seizure starting interval between Behaviour Intermittent during REM
soon or arousal and immediately on sleep with loss of REM
immediately on seizure abrupt arousal atonia
arousal
EEG Interictal/ictal Interictal/ictal No epileptiform No epileptiform activity

EEG may be epileptiform activity
abnormal, but can discharge
be normal usually present
Video Usually diagnostic Usually helpful Helpful May be helpful
*There is no polysomnography signature, diagnostic of NREM arousal parasomnias in the

absence of clinical events occurring during the sleep study.

www.bnpa.org.uk
The management of the parasomnias will depend on the type of parasomnia, intrinsic and
extrinsic triggers identified, and in many cases, addressing the underlying psychological /
emotional issues. Advice on precautions to avoid injury during the sleep related behaviours is
important. Medication is indicated in high risk behaviours and for REM sleep behaviour disorder.
Reading:
The international Classification of Sleep disorders : diagnostic and coding manual, produced by
the American Sleep Disorder Association
SchenkCH, Mahwold MW. REM sleep behaviour disorder : Clinical, developmental and
Neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 2002; 25:120-
38
Zucconi M, Ferrini-Strambi I. NREM parasomnias : arousal disorders and differentiation from

nocturnal frontal lobe epilepsy. Review. Clin. Neurophysiology 2000; 111 (Suppl. 2): S 129-35

www.bnpa.org.uk
Perspectives
religions, are often used to guide the balance

SCIENCE & SOCIETY
between seeking pleasure and avoiding pain
(BOX 2). The subjective utility — or ‘mean-
A common neurobiology for pain ing’ — of pain or pleasure for the individual
is determined by sensory, homeostatic,
and pleasure cultural and other factors that, when com-
bined, bias the hedonic experience of pain
or pleasure.
Siri Leknes and Irene Tracey
The Motivation-Decision Model
Abstract | Pain and pleasure are powerful motivators of behaviour and have The processes that underlie the subjective
historically been considered opposites. Emerging evidence from the pain and interpretation of a sensory event can be
reward research fields points to extensive similarities in the anatomical substrates understood as the manifestation of an
of painful and pleasant sensations. Recent molecular-imaging and animal studies unconscious decision process4,14. The deci-
have demonstrated the important role of the opioid and dopamine systems sion process requires information about
the homeostatic state of the individual
in modulating both pain and pleasure. Understanding the mutually inhibitory (such as inflammation or hunger), sensory
effects that pain and reward processing have on each other, and the neural input and knowledge about impending
mechanisms that underpin such modulation, is important for alleviating threats and available rewards. According
unnecessary suffering and improving well-being. to the Motivation-Decision Model of
pain, as put forward by Fields4,14, the basic
premise for the decision process is that
“Nature has placed mankind under the The utility of pain and pleasure anything that is potentially more important
governance of two sovereign masters, pain The large variability between the strength of for survival than pain should exert anti
and pleasure.” — Jeremy Bentham a sensory stimulus and the resulting hedonic nociceptive effects. This allows the animal
feeling is of great medical and neuroscien- to ignore the pain and attend to the more
Most of what is known about pain and tific interest. For instance, athletes can be important event. The Motivation-Decision
pleasure derives from the study of each oblivious to pain in the heat of competition, Model predicts that pain–pleasure dilem-
phenomenon in isolation. Recently, however, in which winning is the reward. A key factor mas in which a large reward is gained
neuroscientists investigating opioid and for the interpretation of pain and pleasure is at the price of a small pain are resolved
placebo analgesia1–3, drug addiction4 and subjective utility7. For example, the reward through the antinociceptive effects of
learning5 have begun to bridge the gap value of a stimulus increases with the effec- the pleasurable reward (FIG. 1). In some
between the pain and pleasure research tiveness of that stimulus in restoring bodily instances, threatening and pleasure-related
fields. This development has been equilibrium (homeostasis)6,8. This effect, cues are more important for survival than
strengthened by the increasing focus on known as alliesthesia6, is well-documented pain, and it is assumed that any antinocic-
the subjective emotional feelings for food rewards, which are more pleasur- eptive effects are mediated by the descend-
(hedonics) that are elicited by rewards able when they relieve a hunger state9. ing pain modulatory system, which is
and punishments (BOX 1). As the experience of pain represents a located in the brainstem. This circuit, which
Rewards and punishments are defined deviation from homeostatic balance10, the consists of excitatory and inhibitory cells,
as something that an animal will work to same principle can be applied to pain and communicates with neurons in the pre-
achieve or avoid, respectively. Pleasure the pleasantness of its relief 11. Similarly, frontal cortex, the hypothalamus and the
represents the subjective hedonic value of when a perceived threat to an organism amygdala to control the nociceptive affer-
rewards. The term ‘pain’ encompasses both becomes greater, pain unpleasantness ent pathway in the spinal and trigeminal
the hedonic (suffering) and motivational increases, enhancing defensive and dorsal horn4,14,15 (FIG. 2). Opiate drugs and
(avoidance) aspects of a painful experience. avoidance mechanisms12. endogenous opioids act on this descending
Clearly, seeking pleasure and avoiding pain Pain and pleasure encourage the constant system to produce pharmacological, pla-
is important for survival, and these two optimization of our internal homeostatic cebo, stress-induced and pleasure-related
motivations probably compete for prefer- balance. Although pleasure-seeking and analgesia1,2,4,14–20.
ence in the brain. Put simply, which of two pain-avoidance generally increase our
coinciding pain and pleasure events should chances for survival, it is easy to envisage Pain–pleasure interactions
be processed and acted on first? Consistent scenarios in which these two motivations Evidence of pleasure-related analgesia
with the idea that a common currency of are in competition. A simple case would has been reported in various human and
emotion6 enables the comparison of pain involve a large reward that is only accessible animal studies: pain is decreased by pleas-
and pleasure in the brain, the evidence at the ‘price’ of a small pain. Sometimes it ant odours21, images22, pleasurable music23,
reviewed here points to there being exten- seems that overcoming a small amount palatable food16,17 and sexual behaviour18,19.
sive overlap in the neural circuitry and of pain might even enhance the pleasure, In addition, considerable evidence suggests
chemistry of pain and pleasure processing as reflected perhaps by the common that expectation of treatment effect, which
at the systems level. This article summarizes expression ‘no pain, no gain’ or the pleasure contributes to placebo analgesia, is a type of
current research on pain–pleasure interac- of eating hot curries. Pain–pleasure dilem- reward expectation24,25. Interestingly, when
tions and the consequences for human mas abound in social environments13, and subjects who were not expecting an injec-
behaviour. culture-specific moral systems, such as tion of pain-relieving morphine received
314 | april 2008 | volume 9 www.nature.com/reviews/neuro

© 2008 Nature Publishing Group
Perspectives
Box 1 | The increasing focus on pain and reward hedonics access to our own hedonic and motivational
processes, which are thought to be primarily
Hedonic feelings — also known as qualia — subconscious31. Importantly, however, the
drive motivation and behaviour. Qualia motivation and hedonic subsystems seem to
determine what it is like to be a human being87.
be mediated by different neurotransmitters.
No theory of the relationship between the
brain and the mind is complete without Carefully controlled studies have found
accounting for hedonic feelings. In recent specific effects for two neurotransmitter
years, several exciting research directions have systems: dopamine increases motivation
emerged in the pain and reward research fields for, but not the pleasure of, eating palatable
that successfully combine the need for foods32,33, whereas the opioid system influ-
carefully controlled, ‘objective’ research ences motivation indirectly by modulating
methodologies with a focus on hedonics. One subjective emotional feelings of pain and
example is a body of work on ‘liking’ and reward34. In summary, opioids are neces-
‘wanting’ — two subconscious reward sary for hedonic experience (‘liking’) but
processes that are thought to underpin
dopamine motivates you to get ready for it
conscious pleasure and motivation31. Using taste reactivity as a primaryNature
outcome measure
Reviews (see
| Neuroscience
figure), this research has used pharmacological stimulation and lesion techniques to determine (‘wanting’)31,35.
causal relationships between neuronal signalling and hedonic feelings. In the pain field there is µ-opioids have been shown to cause a
growing recognition that the ‘subjective interpretation’ or ‘meaning’ of pain determines the positive shift in affect across the hedonic
amount of pain-related suffering15,88. The definition of pain, according to the International spectrum: they enhance the pleasantness of
Association for the Study of Pain, emphasizes the ‘unpleasant’ and ‘emotional’ aspects, and also sweet tastes and decrease the aversiveness
includes subjective feelings of pain, which are not caused by tissue damage. Other research of pain and bitter foods31. Both painful and
areas that are turning their attention to hedonic feelings include the fields of obesity research89 pleasant events are associated with the
and decision making: the shift in focus from ‘cold’ rational consideration to ‘hot’ emotion-based release of endogenous µ-opioids in
decision making has influenced cognitive neuroscience for more than a decade90,91. Even the brain and, importantly, in the NAc19,36
economists are now looking to hedonic feelings to explain human behaviour such as the ‘warm
(FIG. 1). Blocking of µ-opioid signalling
glow’ that accompanies donations to charity92. Figure modified, with permission, from Ref. 31 
(2003) Academic Press. with naloxone decreases the pleasantness
of food rewards34 and sexual behaviour37
and reverses reward-related analgesia16,18,26.
a hidden injection, its analgesic effects Opioids and hedonic feelings Interestingly, a recent conditional gene-
were significantly reduced26. Although the Pain and reward are complex constructs knockout study showed a dissociation of
placebo treatment might not be pleasurable that encompass motivational, hedonic and µ-opioid-mediated reward and analgesia:
in itself, reduced pain represents the better learning signals30. As the motivation to seek only µ-opioid antinociception depends on
of two alternative outcomes (the other being reward or avoid pain is generally correlated an intact central serotonergic system38. The
unchanged pain levels), and therefore has a with the pleasantness or aversiveness of an κ-opioid system presents another example
higher reward value. event (respectively), it is difficult to disen- of pleasure–analgesia dissociation: κ-opioids
A related phenomenon predicted by tangle the neuroanatomy of the hedonic reduce pain but also induce feelings of
Fields’ Motivation-Decision Model is the and motivational components of pain and aversion39,40. Furthermore, the κ-opioid
effect of pain on the ability to experience reward. In addition, we have only limited activity caused by tonic (sustained) pain has
pleasure. By decreasing reward pleasant-
ness, pain and other threatening events
Box 2 | The pain–pleasure dilemma
ensure that necessary action is taken to
protect the individual, thus attenuating “Pleasure is the greatest incentive to evil” — Plato
the normal reward-seeking behaviour. The increased neuroscientific interest in pleasure (BOX 1) perhaps reflects a greater general focus
Correspondingly, decreased consumption on pleasure and positive affect (happiness) in the Western world85. Historically, however, a strong
of palatable foods is considered to be a belief in shame and stoicism (in the case of pleasure and pain, respectively) has prevailed. Learning
measure of pain suffering and is reversible to curb impulses for instant gratification and to tolerate some pain ‘for the greater good’ is an
with morphine treatment27 (FIG. 1). Similarly, important part of child development. Considering the unnecessary pain of childbirth and the
sustained pain inhibits morphine reward in stress of child rearing, it is perhaps not surprising that patience, selflessness and stoicism are
rodents; this is likely to be due to sustained highly regarded traits in many cultures13. In neuroscience, prominent addiction researchers
activation of the κ-opioid system in the advocate a ‘hedonic Calvinistic’ approach to pleasure, in which the use of the reward system is
restricted, as they believe that unregulated pleasure-seeking might lead to addiction93. The
nucleus accumbens (NAc)28. In humans
Calvinistic focus on moderation, or even abstinence, of pleasure has deep roots in Western culture
there is extensive co-morbidity between and is powerfully connected with shame94. Whereas excessive reliance on shame and stoicism
chronic pain and depression, which often might cause unnecessary suffering86, extreme pleasure-seeking and pain avoidance (hedonism)
involves a reduction in the ability of chronic can have undesirable consequences such as drug addiction93,95 and obesity89. However, the
pain sufferers to enjoy everyday pleasures inability to take pleasure in everyday rewards is also a form of suffering29. In fact, paradoxical and
(anhedonia)29. This reduction in pleasure risky human behaviours such as self-harm and skydiving have been related to a desire to alleviate
might form part of a vicious cycle for the emotional ‘numbness’, possibly owing to a dysfunction in the opioid and/or dopamine
patients, in which both negative mood systems78,96,97. The strong historical association between shame, guilt and pleasure might help to
and lack of pleasure result in exacerbated explain a number of paradoxical human behaviours, as well as the historical preference for
pain, leading to more negative mood and formulating scientific research questions in terms of behaviour rather than pleasure and other
hedonic feelings.
anhedonia.
nature reviews | neuroscience volume 9 | april 2008 | 315

Perspectives
been shown to disrupt the positive interac- motivation. Interestingly, in patients it seems Just as the colocalization of opioid and
tion between µ-opioids and mesolimbic that this normal interaction between the dopamine pathways highlights the impor-
dopamine28. dopamine system and pain is disrupted. One tance of interactions between these two
study showed that, compared with controls, systems, the striking overlap in regions that
Dopamine, motivation and analgesia patients suffering from generalized pain are involved in pain and pleasure processing
Considering the close association that exists (fibromyalgia) released less dopamine in the (FIG. 2) might explain the modulatory effects
between motivation, learning and hedonic striatum yet found the stimulus (hypertonic-
feelings, it is not surprising that dopamine saline-induced deep muscle pain) more
signalling has been consistently reported painful48. This result is consistent with a a
to correlate with stimulus reward value41,42. normal role for dopamine in endogenous
Striatal dopamine neurons also respond to antinociception51. Any analgesic effects OFC
aversive events43,44 but, in contrast to the of dopamine seem to rely on a reactive
firing bursts that signal pleasant events or phasic dopamine system, and this might be
NAc VTA
their cues, aversive stimulation causes a disrupted in chronic pain conditions — per-
VP
brief inhibition of baseline firing45,46. The haps through increased tonic dopamine Amy
many time-courses of the dopamine signal levels that inhibit phasic release48,51 (BOX 3).
are often measured by different techniques, In line with this evidence, and based on b
making the literature on the precise role of interactions between the descending pain Pain
+ Pleasure
dopamine in pain and reward complicated system and the mesostriatal dopamine
and somewhat inconsistent43,45 (BOX 3). circuit for drug and food reward, the Pain
For instance, on the one hand, positron Motivation-Decision Model proposes + Pleasure
emission tomography (PET) studies of base- that phasic dopamine has a key role in + µ-opioid Pain
line dopamine receptor availability provide endogenous analgesia in situations in which receptor antagonists
a measure of tonic dopamine levels43,47. On reward is expected4. Evidence from human
the other hand, PET studies comparing studies perhaps supports this concept, as low c
+ Pain Pleasure
receptor availability between two stimulus tonic dopamine levels, present in individu-
conditions measure dopamine signalling als with the catechol‑O-methyltransferase Pleasure
at the temporal mid-range between brief (COMT) Val/Val polymorphism, produce + Pain
phasic activation and constant tonic high phasic dopamine52 and concomitantly + µ-opioid Pleasure
firing24,43,45,48. Despite the complex effects high endogenous-opioid release during receptor agonists
and interactions of the various dopamine tonic pain53. Val/Val subjects also reported Figure 1 | Schematic illustration of pain–
time-courses, it is clear that endogenous significantly lower pain compared with Met/ pleasure inhibition. TheReviews
Nature Motivation-Decision
| Neuroscience
dopamine is involved in the process- Met subjects with higher tonic dopamine Model of pain4,14 posits that anything of poten-
ing of both pain and pleasure3,30,41,43–46,48. levels. A recent molecular-imaging study tially greater importance than pain should have
Pharmacological manipulation of dopamine investigated the link between reward antinociceptive effects (be it a greater threat or
the possibility of a reward). By the same evolution-
levels has also been shown to modulate both expectancy, dopamine and analgesia more
ary-psychology rationale, it is clear that anything
pain and reward behaviours20,30,45,49,50. directly, and showed that inter-individual that is potentially more important than a reward
The precise role of dopamine in pain variation in NAc dopamine release during (such as an even greater reward or a threat for
and reward processing is hotly debated. In a placebo manipulation correlated with which action is needed) should similarly decrease
the reward literature, one main question subsequent variability in placebo analgesia3. its pleasantness, thus allowing for the appropriate
has been whether the dopamine signal is Furthermore, NAc activation during antici- avoidance or approach behaviours. The µ-opioid
necessary for reward learning, salience, pation of a monetary reward accounted and mesolimbic dopamine systems are the prime
motivation or hedonics30,35,45. For pain, for 28% of the variance in the formation of candidates for systems that transmit signals relat-
dopamine agonists, such as amphetamine, placebo analgesia in the same individuals. ing to motivational and hedonic aspects of both
reduce tonic pain but do not change phasic This study therefore supports a direct link pain and pleasure and, in particular, their interac-
tions, as illustrated here. a | Both pain and pleasure
pain behaviours49. Similarly, tonic but not between dopamine and endogenous-opioid
have been shown to elicit opioid release in the
phasic pain events are thought to induce release with regards to reward and analgesia orbitofrontal cortex (OFC), the amygdala (Amy),
endogenous analgesia through dopamine in humans. the nucleus accumbens (NAc) and the ventral pal-
release in the NAc43. Dopamine receptor lidum (VP)2,65,68. Pleasure and reward expectation
availability studies have shown that endog- Common regions for pain and pleasure are also associated with increased phasic dopa
enous striatal dopamine release correlates Although the opioid and dopamine systems mine signalling from the ventral tegmental area
positively with sensory and affective com- are closely related neuroanatomically54, they (VTA) to the NAc and VP42, which in turn causes
ponents of tonic pain in healthy subjects43,48. interact in complex ways. Phasic dopamine increased µ-opioid release in the NAc55. Pain has
Although these studies in healthy volunteers has been shown to increase opioid levels55, been associated with both increases and
provide clear demonstrations of dopamine’s whereas tonic dopamine decreases opioid decreases in mesolimbic dopamine signalling,
depending on the type of measurement and pain
involvement in pain processing, they can- levels53,56. Conversely, opioids upregulate
model that have been used42,43,46,48,49. b | µ-opioid
not unequivocally answer the question of phasic dopamine in the striatum (by inhibit- receptor antagonists, such as naloxone, reverse
directionality. The dopamine signal could ing local GABAergic interneurons in the pleasure-related analgesia16,18,19. c | µ-opioid recep-
reflect a sustained increase in dopamine ventral tegmental area)57,58 and downregu- tor agonists, such as morphine, have been shown
that might exacerbate pain, but it could also late slower striatal dopamine signalling, as to re-enable pleasure that has been previously
reflect brief signals related to pain-avoidance measured by PET59. reduced by concomitant pain27.

Perspectives
Region Pleasure/reward Pain

Lateral prefrontal • Humans, fMRI, taste reward101 • Humans, H2O PET, hyperalgesic pain 102
cortex • Humans, fMRI, pain103
Anterior insula • Humans, fMRI, food cravings104 • Humans, fMRI, pain105
PFC • Humans, H2O PET, chocolate reward75 • Humans, fMRI, placebo analgesia106
INS
Posterior insula • Humans, fMRI, hypothetical reward107 • Humans, direct brain stimulation108
• Humans, fMRI, pain105
OFC Orbitofrontal • Humans, fMRI, pleasant touch74 • Humans, fMRI, pain 74
cortex • Humans, fMRI, chocolate reward75 • Humans, fMRI, placebo analgesia106
Medial prefrontal • Humans, H2O PET, pleasurable music64 • Humans, fMRI, pain110,111
cortex • Humans, fMRI, monetary reward109
Anterior cingulate • Monkeys, electrophysiology112 • Humans, fMRI, pain113
gyrus • Humans, H2O PET, chocolate reward75 • Humans, opioid PET83
Dorsal striatum • Humans, fMRI, fruit juice114 • Humans, dopamine ligand PET, pain43
• Humans, fMRI, monetary reward115 • Humans, fMRI, pain116
Nucleus accumbens/ • Humans, fMRI and dopamine ligand PET3, • Humans, dopamine ligand PET43
ventral striatum monetary reward 65 • Humans, fMRI, expectation of pain44
• Rodents, hedonic hotspot, taste reactivity • Rodents, pain-induced analgesia20
• Humans, dopamine ligand PET41, drug
reward
Ventral pallidum • Rodents, taste reactivity 62,65 • Rodents, tracing, pain affect72
• Humans, µ-opioid PET, sustained pain 2
Thalamus • Humans, H2O PET, chocolate reward 75

• Humans, fMRI, placebo analgesia 106
Hypothalamus • Humans, H2O PET, pleasurable music117 • Rodents, tracing of nociceptive pathway 72
• Humans, direct brain stimulation118
Midbrain • Humans, H2O PET, chocolate reward 75 • Humans, fMRI, anticipation of pain119
• Humans, H2O PET, pleasurable music64 • Humans, fMRI, pain120
Amygdala • Humans, H2O PET, pleasurable music 64 • Humans, fMRI, pain70,120
• Primates, reward anticipation/learning63
Hippocampus • Humans, fMRI, unexpected reward121 • Humans, fMRI, pain122
• Humans, H2O PET, pleasurable music 64 • Humans, fMRI, anticipation of pain119
Cerebellum • Humans, fMRI, unexpected reward121 • Humans, fMRI, pain123
Brainstem • Rodents, taste reactivity 124
• Humans, fMRI, pain123
• Rodents, conditioned place preference40 • Rodents, pain40
Figure 2 | Brains regions implicated in pain and pleasure processing. in animals, show striking overlap. The studies included as examples in this
At the systems level, the major regions that have been implicated in pain figure unequivocally demonstrate the involvement of each |region
Nature Reviews in both
Neuroscience
and reward processing by functional imaging studies and direct brain pain and pleasure processing. fMRI, functional MRI; PET, positron emission
stimulation in humans, as well as by electrophysiology and tracing studies tomography.
of one over the other. Whether one or cues63. Evidence from human patient studies proportion of the signals that are generated
two neural systems (at any spatial scale) also highlights the importance of the NAc by the unmyelinated primary afferent
underpin aversive and appetitive process- and the pallidum for reward processing, as nociceptor pathway72. These pallidal ‘pain
ing in the brain60 is still subject to debate5. dysregulation or lesion of these regions is affect’ neurons seem to be located laterally
Regions that are particularly well situated associated with anhedonia66,67. to the pallidal pleasure hotspot65,72. Thus,
to mediate interactions between pain and In addition to their participation in it seems that two distinct subregions of the
pleasure include the NAc, the pallidum pleasure processing, the amygdala, the pallidum are involved in appetitive and
and the amygdala. These regions receive NAc and the pallidum have distinct but aversive processing. A similar finding has
direct or indirect reward-related signals from important roles for pain. All three regions been reported for the NAc. Whereas neurons
dopamine neurons in the midbrain and are have been shown to release endogenous located in the rostral part of the NAc shell
thought to signal either reward-prediction µ-opioids during painful stimulation in mediate pleasure, stimulation of more caudal
error (discrepancy between the expected humans2,68. The amygdala modulates pain regions of the NAc causes a negative shift
and the received reward; NAc42,61 and amyg perception through direct connections with in affect73. A similar rostrocaudal ‘hedonic
dala61) or hedonic reward value (pallidum62 the descending pain inhibitory system69,70. gradient’ in the ventral striatum was recently
and amygdala63,64). The NAc and pallidum The amygdala and the NAc mediate both reported for economic gains and losses in
each contain a ‘hedonic hotspot’ in which reward- and stress-induced analgesia4,69, and humans5. In the amygdala, adjacent neuronal
µ-opioid stimulation increases the liking of these two regions show alterered endog- populations represent positive and negative
rewards65. In fact, these two ~1mm³ regions enous-opioid analgesic activity in fibromy- hedonic value63.
are necessary for the opioid-mediated algia patients71. Stress-induced analgesia can The close adjacency of such pain and
enhancement of food palatability65. Different be blocked by intra-accumbens injection pleasure hotspots suggests that functional
neuron populations in the amygdala have of dopamine and opioid antagonists20. The interactions between them are involved in the
been found to encode the negative and posi- pallidum contains a population of encepha- mechanism by which pain decreases pleasure
tive hedonic value of reward and punishment lin-containing neurons that receive a large and rewards induce analgesia. Evidence

Perspectives
Box 3 | Aristotle’s ‘Golden Mean’ and phasic dopamine signalling between competing pleasant and aversive
events. As the Motivation-Decision Model
To maintain homeostasis, animals must aim for suggests, being able to ‘switch off ’ pain in
Normal tonic dopamine level
the ‘Golden Mean’ — that is, the right balance order to gain a reward could increase sur-
between pleasure-seeking and pain-avoidance.
vival, if the pain–pleasure (or cost–benefit)
The responsiveness of the phasic dopamine
system (a system which is caused by brief bursts ratio is right. Similarly, aversive cues
of neuronal firing and relates to reward Normal phasic dopamine signal must be able to disrupt pleasure-seeking
motivation and prediction error) is important if the potential danger outweighs the
for the regulation of appetitive and aversive potential gain.
behaviours. Impulsive behaviour and An important and as yet unanswered
schizophrenia have been linked to an question concerns the effects of chronic
excessively responsive phasic dopamine Increased tonic dopamine level pain on the ability to enjoy rewards29.
system98, whereas depression, chronic pain and Anhedonia is a major symptom of depres-
anhedonia have been associated with low sion, and several recent papers have sug-
Pain and stress syndromes
responsiveness to reward cues78,79.
gested that it might be related to reductions
Tonic dopamine activity refers to the level of Reduced phasic dopamine signal
extrasynaptic dopamine that is present at a in dopaminergic neurotransmission that
steady-state concentration in the extracellular are similar to those that are seen during
space45,99. The baseline dopamine concentration abstinence of addictive drugs78,79. By
is thought to enable a number of behavioural contrast, positive mood and cognitive flex-
Decreased tonic dopamine level
processes, many of which are affected in ibility are thought to arise from a highly
Parkinson’s disease . Importantly, tonic
42
responsive phasic dopamine system80. The
dopamine levels regulate the responsiveness of significant co-morbidity between chronic
the phasic dopamine system to salient Impulsive behaviour
pain and depression suggests that these
environmental cues: high tonic dopamine patients might also lose-out on the poten-
attenuates phasic dopamine release45,99 whereas
tial analgesic effects of the rewarding every
low tonic dopamine facilitates phasic dopamine Increased phasic dopamine signal
firing98. The level of tonic dopamine in the limbic day events that they are no longer able to
striatum is in turn modulated by corticostriatal savour. A lack of reward-induced analgesia
and hippocampal afferents and homeostasis98,99. Nature Reviews | Neuroscience
has been reported in ‘anhedonic’ stressed
Increased tonic dopamine is known to result from prolonged stress or pain51 (see figure), a rats81. Indeed, endogenous-opioid activity
mechanism that might have evolved to ensure rest and low activity levels during injury. is disrupted both during sad mood82 and in
Unfortunately, the same mechanism is thought to cause increased pain sensitivity in certain pain chronic pain patients83.
syndromes through its inhibition of endogenous phasic dopamine antinociception48,51. Abstinence For Jeremy Bentham, a ‘good life’ consisted
from addictive drugs has also been associated with hyperalgesia and increased tonic signalling. The of the presence of pleasures combined with
resulting inhibition of phasic signalling is thought to underpin reduced responsiveness to pleasure the absence of pains7. As we have seen, the
(anhedonia) during abstinence, and can be reversed by re-administering the addictive drug79. At
inability to feel pleasure is associated with
the other extreme, decreased tonic dopamine, causing hyper-responsiveness of phasic dopamine,
has been related to positive symptoms in schizophrenia98. Impulsivity in schizophrenia is associated negative mood and depression. By contrast,
with excessive pleasure-seeking and substance abuse100. positive affect is considered the hallmark
of well-being80 and might actually improve
health84. Bentham’s view might nevertheless
that separate neuronal populations encode µ-opioid signalling truly reflects pleasurable be too simplistic. As stated in the beginning,
aversive and appetitive processing in the and analgesic effects in the brain. Similarly, closely related to the subjective interpretation
amygdala, the NAc and the pallidum supports although dopamine firing patterns differ in of a sensory stimulus is the concept of mean-
the existence of two neural systems for pain response to reward prediction, uncertainty ing. Meaning allows for many alternative
and pleasure at the within-region spatial scale. and aversive events, the mutual reinforce- paths to well-being85. Consideration of this
A similar finding has also been reported for ment of phasic dopamine and opioid release factor might help to explain the abundance
higher cortical regions: different subregions in is consistent with the idea that dopaminer- of paradoxical aversive or life-threatening
the orbitofrontal cortex represent the hedonic gic motivation signalling takes place during human behaviours found across society that
value of reward and punishment74–77. preparation for, or consummation of, a are considered ‘pleasurable’. Even suffering
pleasurable reward. The finding that high can be rewarding if it has meaning to the suf-
A common currency for hedonic experience tonic dopamine activity is associated with ferer86. Continued study of the commonalities
The robust evidence for opioid and both increased pain and decreased pleasure, and differences between pain and pleasure
dopamine involvement in the processing of and that tonic over-activity of the dopa is therefore necessary if we are to advance
pain and pleasure makes these two neuro- mine system is known to reduce phasic our understanding of human suffering and
transmitter systems the prime candidates dopamine and µ-opioid release, further well-being.
for mediating the mutually inhibitory corroborates the idea that interactions Siri Leknes and Irene Tracey are at the Oxford Centre
effects of pain and reward. Although both between µ-opioids and phasic dopamine for Functional MRI of the Brain, Department of Clinical
pleasurable and painful events are often signalling mediate pleasure and analgesic Neurology, Nuffield Department of Anaesthetics,
Oxford University, John Radcliffe Hospital, Oxford,
accompanied by endogenous-opioid effects in the brain. These two neurotrans- OX3 9DU, UK.
neurotransmission, the pleasure-enhancing mitter systems are thus likely to mediate Correspondence to I.T.
and antinociceptive effects of µ-opioid the brain’s common currency, allowing for e-mail: irene@fmrib.ox.ac.uk
agonist treatment suggest that endogenous action selection based on the comparison doi:10.1038/nrn2333

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Case Presentations
Case 1: AW, male, 60 years

This gentleman was referred to the General Adult Psychiatry clinic for assessment of memory
problems. I met him in clinic with his wife on 15 November 2007. Presenting complaint was
offered by the wife and she described him as "slowed" with altered judgment and a "shaky"
signature. History revealed a 4-month history of slower reaction times, forgetfulness, getting lost
in familiar places and becoming overall very slowed. While he scored 30/30 on mini-mental state
examination, he scored 87/100 on Addenbrooke's Cognitive Assessment losing one point on
anterograde memory, one point on retrograde memory and 11 points on verbal fluency. On
mental state examination, he had odd affect and did not seem concerned by these difficulties. On
physical observation and examination he had a broad-based gait with reduced arm-swing, normal
power with increased tone in upper limbs and some tremor in both hands which was not
continuous.
Amal Al Sayegh
amal.alsayegh@nhs.net
Case 2
A 72 year old gentleman presented with 2 episodes of transient amnesia lasting for less than an
hour. There was a background history of an isolated fit 4 years ago and long standing classical
migraines. Investigations were unhelpful. Diagnoses of transient global amnesia and transient
epileptic amnesia were suggested.
Dr Seema Kalra MRCP MBBS

Speciality Registrar In Neurology (ST4)
New Cross Hospital
kalraseema@yahoo.com

www.bnpa.org.uk
Antibodies in neuropsychiatric disorders and more
Angela Vincent
angela.vincent@imm.ox.ac.uk
It is well recognized that diseases of the peripheral nervous system can be caused by
autoantibodies and respond well to immunotherapies associated with a fall in antibody levels.
The best examples are, of course, myasthenia gravis and the Lambert Eaton myasthenic
syndrome with antibodies to the acetylcholine receptor and voltage gated calcium channels
respectively. In addition, Guillain Barre syndrome and Miller Fisher syndrome are associated with
antibodies to gangliosides such as GM1 or GQ1b, although these conditions are not necessarily
exclusively antibody-mediated.
Over the last decade it has become clear that there are some CNS diseases strongly associated
with specific antibodies to ion channels or receptors. Antibodies to GluR3 were first reported in
Rasmussen’s encephalitis, a rare but devastating form of childhood epilepsy for which the
treatment is often hemispherectomy. In fact, there are now some doubts about how frequently
these antibodies are found in Rasmussen’s (Watson et al Neurology 2005) and they are
measured routinely in very few centres. The general conception is that Rasmussen’s is a T cell
mediated inflammatory disorder and that the antibodies, if present, may not be the primary
pathological entity.
Antibodies to voltage-gated potassium channels, of the shaker-type that binds the snake toxin
dendrotoxin, were first identified in patients with an acquired peripheral nerve hyperexcitability
syndrome called Isaac’s syndrome or neuromyotonia. This condition causes muscle twitching,
fasciculations and cramps and is very uncomfortable but not life-threatening. It responds well to
anti-epileptic drugs such as phenytoin, and immunotherapies are seldom required. Sometimes,
however, neuromytonia is associated with autonomic dysfunction, sleep disorders, and cognitive
impairment. This triad is usually referred to as Morvan’s syndrome (Liguori et al Brain 2001).
Although rare, it is highly interesting since the patients can present with such a range of
symptoms, and some of their abnormalities reflect psychiatric disorders. A recent case reported
by Spinazzi et al (Neurology 2008 ePub) illustrates this point. A 64 year old patient exhibited
prominent compulsive behaviour with increased catecholamine and serotonin secretion as well as
epileptic seizures and circadian rhythm suppression. Brain F-FDG-PET demonstrated markedly
increased activity in the basal ganglia. Although the presence of multiple neurological signs
suggested an organic disease, the history was complex and the diagnosis not clear for some
time. Subsequently it was found that VGKC antibodies were clearly raised at 2000 pM, and
indeed most of the symptoms and signs reversed following immunosuppressive treatment with a
marked fall in VGKC antibodies. Basal ganglia hypermetabolism had not preveiously been
reported with VGKC antibodies but is found in compulsive and psychotic disorders. Thus some of
the features of Morvan’s syndrome can mimic psychiatric disease.
Much more common is VGKC-antibody associated limbic encephalitis (VGKC-LE) which is now a
well-recognised, most often non-paraneoplastic, form of LE. The VGKC antibodies are usually
>400 pM often >3000 pM and fall dramatically following successful immunotherapies. These may
include iv steroids, plasma exchange or intravenous immunoglobulins, and long-term high dose
oral steroids that can be tapered to nil following clinical improvement. Most patients present
with amnesia and seizures with personality change, but psychiatric presentations are not
uncommon (Vincent et al 2004; Harrower et al 2006). High signal on MRI in the mesial temporal
lobes, often restricted to the hippocampus, is found in the majority of patients. The cerebrospinal
fluid is often unremarkable without oligoclonal bands or increased lymphocytes although protein
may be slightly raised. Although the majority of patients do well following treatment, some
relapse and anecdotal reports suggest that this may be due to lack of compliance or intolerance
to steroids. On the other hand in some patients steroids clearly increases psychotic features. No
clear guidelines to alternative therapies exist at this time.

www.bnpa.org.uk
Antibodies to glutamic acid decarboxylase are typically found at very high titre in stiff person
syndrome. The antibodies themselves may not be pathogenic as GAD is an intracellular enzyme
rather than a membrane protein. There may be other antibodies to neuronal cell surface
membranes in these patients that are the pathogenic entity. Nevertheless, GAD antibodies are
proving to be an important marker of immune-mediated neurological disease and found in an
increasing number of patients with cerebellar ataxia, epilepsy and other neurological syndromes.
Although not yet reported specifically in psychotic syndromes, it is well known that stiff person
syndrome may be complicated by psychiatric features and it would not be surprising if some
patients with psychosis turned out to have this antibody.
A newly described antibody to glycine receptors (GlyR) has been reported in one patient with an
exaggerated startle response progressing to encephalomyelitis with rigidity and mycolonus
(Hutchinson et Neurology 2008). Although only reported in a single case so far, this antibody
has recently been found in other patients, mainly with a form of stiff person syndrome but some of
whom exhibit psychiatric features (Leite, Vincent unpublished). One patient was diagnosed as
psychogenic until the antibody was detected and has since been treated successfully with
immunosuppression (unpublished results).
Finally, there is a form of autoimmune encephalitis that seems to present frequently with
psychiatric features, although it then usually progresses to a full-blown encephalitis with marked
movement disorders, mutism, catatonia, seizures and hypothalamic disturbance. NMDAR
antibodies are associated with both paraneoplastic (ovarian tumours in young women) and non-
paraneoplastic (both sexes but mainly younger patients so far) conditions. Both do well after
treatments (removal of the tumour if relevant) although the long-term progrnosis may not be so
good in the non-paraneoplastic form (Dalmau et al Ann Neurol 2007; Lancet Neurology 2008).
VGKC, GlyR, GAD and NMDAR antibodies are now being searched in patients with various form
of neuropsychiatric disorders. The methods in use, recent results and future prospects will be
discussed.

www.bnpa.org.uk

Neuropsych HANDBOOK

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THE BRITISH NEUROPSYCHIATRY ASSOCIATION

Neurology and Psychiatry SpRs Teaching Weekend

THE ESSENTIALS OF NEUROPSYCHIATRY

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

British Neuropsychiatry Association Committee and administration:

Professor Adam Zeman

Professor David Skuse

Professor Eileen Joyce

Professor Rodger Ll Wood

Jackie Ashmenall Tel/Fax: +44 (0)20 8878 0573

Gwen Cutmore Tel/Fax:+ 44 (0)1621 843334

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

THE ESSENTIALS OF NEUROPSYCHIATRY

14:00 Neurological history taking

14:35 Neurological examination (for psychiatrists)

15:10 Psychiatric history taking

16:15 Mental state examination: excluding cognition

16:50 Mental state examination: cognition

17:25 Neuroimaging in neuropsychiatry

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

2 Neurological presentations of psychological disorder

08:30 Weakness, Movement Disorders and Sensory symptoms unexplained by disease

09:10 Dissociative Seizures

09:50 Chronic fatigue syndrome: neurological, psychological or both?

3 Psychological presentations of neurological disorder

11:00 Traumatic brain injury

14:00 Prions and human disease

15:00 Movement Disorders

16:15 The EEG and related investigations in neuropsychiatry

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

09:00 Insomnia and excessive daytime sleepiness

6 Mind and Brain

10:50 Imaging pain in the brain

11:30 Cases in neuropsychiatry

12:10 Guest lecture - Anitbodies in neuropsychiatric disorders and more

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

Neurological History Taking

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

The Neurological Examination (for psychiatrists)

MYTH 1 - Neurological diagnosis is all about examination.

MYTH 2 - You need to know a lot of neuroanatomy to be able to do a neurological

MYTH 3 - The neurological examination is complicated.

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

The Ten Second neurological examination

The One Minute Neurological Examination

1. Stop – look at the patient – is there something obvious

The Two Minute Examination

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

6. Suspected functional disorder – see other chapters in this package

Things that are fairly useless

Some Pattern Recognition

Pattern of weakness / symptoms Localisation As seen in……

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

Seven sins of neurological examination

1. Ridsdale L, Massey R, Clark L. Preventing neurophobia in medical students, and so future

2. Schon F, Hart P, Fernandez C. Is clinical neurology really so difficult? J

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

History taking in neuropsychiatry.

Hugh Rickards MD FRCPsych.

Neurology and Psychiatry SpRs Teaching Weekend. Handbook.

 Situational vs. pervasive

A number of neuropsychiatric conditions have been related to early adverse environmental

Situational vs. pervasive

Appearance and behaviour