HANDBOOK of Neuropsychiatry

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

Neurology and Psychiatry SpRs Teaching Weekend. Handbook. www.bnpa.org.uk

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




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: [email protected] Sheen Lane London SW14 8AE Website: www.bnpa.org.uk Gwen Cutmore Tel/Fax:+ 44 (0)1621 843334 Conference Secretary Email: [email protected] Landbreach Boatyard Chelmer Terrace Maldon, Essex CM9 5HT




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)




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




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




Neurological History Taking Adam Zeman [email protected] 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).




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 [email protected]).




The Neurological Examination (for psychiatrists) Jon Stone Consultant Neurologist and Honorary Senior Lecturer in Neurology Western General Hospital, Edinburgh EH4 2XU [email protected] 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




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)




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 FlexorsLegs – Flexors more than Extensors

Upper Motor Neurone (aka pyramidal)

Stroke, MS, Brain 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, / clumsy arm/leg

Brain stem + cerebellum (same side as clumsy arm/leg)

Stroke, MS

Global collapsing weakness and collapsing / Signs of inconsistency

Brain/Mind Functional Disorder




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.




History taking in neuropsychiatry. Hugh Rickards MD FRCPsych. [email protected] “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.




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”.




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.




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.




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.




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’.




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




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




(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




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




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, [email protected]). Figure 1 The Glasgow Coma Scale




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

ADDENBROOKE'S COGNITIVE EXAMINATION - ACE-R Final Revised Version A (2005)

NameDate of birth Hospital no.

Addressograph

Date of testing:Tester's name:Age at leaving full-time education:Occupation:Handedness:

O R I E N T A T I O N

Ask: What is the

Ask: Which

Day

Building

Date

Floor

Month

Town

Year

County

Season

Country

[Score 0-5]

[Score 0-5]

R E G I S T R A T I O N

Register number of trials

[Score 0-3]

A T T E N T I O N & C O N C E N T R A T I O N

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:

[Score 0-5]

(for the best performed task)

M E M O R Y - Recall

Ask: 'Which 3 words did I ask you to repeat and remember?'

[Score 0-3]

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 doing that 3 times, so you have a chance to learn it. I'll be asking you later'

Score only the third trial

1st Trial 2nd Trial 3rd Trial

Harry Barnes

73 Orchard Close

Kingsbridge

Devon

[Score 0-7]

[Score 0 -4]

M E M O R Y - Retrograde Memory

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

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).

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 check the subsequent answer (i.e. 93, 84, 77, 70, 63 -score 4)

:::

ME

MO

RY

AT

TE

NT

IO

N&

OR

IE

NT

AT

IO

N

copyright 2000, John R. Hodges

V E R B A L F L U E N C Y - Letter 'P' and animals

Letters [Score 0 - 7]

>17 7

14-17 6

11-13 5

8-10 4

6-7 3

4-5 2

2-3 1

<2 0

total correct

Animals [Score 0 - 7]

>21 7

17-21 6

14-16 5

11-13 4

9-10 3

7-8 2

5-6 1

<5 0 total correct

L A N G U A G E - Comprehension

Show written instruction: [Score 0-1]

Close your eyes

3 stage command: 'Take the paper in your right hand. Fold the paper in half. Put the paper on the floor'

[Score 0-3]

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 1 if sentence contains a subject and a verb (see guide for examples)

[Score 0-1]

FL

UE

NC

YL

AN

GU

AG

E

Say: ‘I’m going to give you a letter of the alphabet and I’d like you to generate as many words 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’

Say: ‘Now can you name as many animals as possible, beginning with any letter?

ADDENBROOKE'S COGNITIVE EXAMINATION - ACE-R Final Revised Version (2005)


Ask the subject to repeat: ‘Above, beyond and below’[Score 0-1]

Ask the subject to repeat: ‘No ifs, ands or buts’[Score 0-1]

L A N G U A G E - Naming

Ask the subject to name the following pictures: [Score 0-2] pencil +

watch

[Score 0-10]

L A N G U A G E - Comprehension

Using the pictures above, ask the subject to:

• 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

[Score 0-4]

LA

NG

UA

GE

L A N G U A G E - Repetition Ask the subject to repeat:' hippopotamus'; 'eccentricity; 'unintelligible'; 'statistician' Score 2 if all correct; 1 if 3 correct; 0 if 2 or less.

[Score 0-2]

ADDENBROOKE'S COGNITIVE EXAMINATION - ACE-R


Final Revised Version (2005)

Ask the subject to read the following words: [Score 1 only if all correct]

sewpintsoot

doughheight

[Score 0-1]

V I S U O S P A T I A L A B I L I T I E S

Ov erlapping pentagons: Ask the subject to copy this diagram:

[Score 0-1]

Wire cube : Ask the subject to copy this drawing (for scoring, see instructions guide)

[Score 0-2]

Clock: Ask the subject to draw a clock face with numbers and the hands at ten past five. (for scoring see instruction guide: circle = 1, numbers = 2, hands = 2 if all correct)

[Score 0-5]

L A N G U A G E - Reading

LA

NG

UA

GE

VI

SU

OS

PA

TI

AL




VI

SU

OS

PA

TI

AL

P E R C E P T U A L A B I L I T I E S

Ask the subject to count the dots without pointing them [Score 0-4]




R E C A L L

R E C O G N I T I O N

Ask “Now tell me what you remember of that name and address we were repeating at the beginning’”

Harry Barnes

Close73 Orchard

Kingsbridge

Devon

[Score 0-7]

[Score 0-5]

Jerry Barnes Harry Barnes Harry Bradford recalled

37 73 76 recalled

Orchard Place Oak Close Orchard Close recalled

Oakhampton Kingsbridge Dartington recalled

Devon Dorset Somerset recalled

General Scores MMSE /30ACE-R /100

SubscoresAttention and Orientation /18

Memory /26Fluency /14

/26/16

LanguageVisuospatial

ME

MO

RY

SC

OR

EV

IS

UO

SP

AT

IA

L

P E R C E P T U A L A B I L I T I E S

Ask the subject to identify the letters [Score 0-4]


This test should be done if subject failed to recall one or more items. If all items were recalled, skip the test and score 5. If only part is recalled start by ticking items recalled in the shadowed column on the 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.


Final Revised Version A (2005)

Cut-off <88 gives 94% senstivity and 89% specificity for dementiaCut-off <82 gives 84% sensitivity and 100% specificity for dementia

Normative values based on 63 controls aged 52-75 and 142 dementia patients aged 46-86




Neuroimaging; From Structure to Function Dr David Summers [email protected] 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.




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.




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 [email protected] 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,




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 with them?

What have they been worrying about? Anything specific like MS? What have other doctors said? What does the patient think will help?

5. Asking about depression and anxiety

Leave until the end of the history. Instead of ‘Are you 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




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.




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.




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.




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 getting better

‘I know you didn’t bring this on but there are 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.




Dissociative Seizures John D C Mellers [email protected] 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




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.




Table 2. Comparative semiology of dissociative and epileptic seizures

Dissociative Seizures Epileptic Seizures

Duration over 2 minutes common rare aStereotyped 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 aIncontinence occasional common aInjury 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)




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”,




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

experience as adverse Somatising trait Dissociative trait Avoidant coping style Personality disorder Mood disorder

Adverse (abusive) experiences in childhood Poor Family functioning Traumatic experiences in adulthood Modelling of attacks on others with epilepsy

Precipitating Perception of life-events as negative / unexpected Acute panic attack / syncope

Adverse life events

Maintaining Perception of symptoms as being outwith personal control / due to disease Agoraphobia: Avoidant and safety behaviour Angry / confused / anxious reaction to diagnosis

Angry / confused / anxious reaction of carers Fear of responsibilities of being well / benefits of being ill

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.




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.




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.




Chronic fatigue syndrome: neurological, psychological or both? Peter White, Professor of Psychological Medicine, Barts and the London Medical School [email protected] 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




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.




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.




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.




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.




Neuropsychiatry of Traumatic Brain Injury Dr Simon Fleminger, Consultant Neuropsychiatrist, Maudsley Hospital [email protected] 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.




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.




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.




The Neuropsychiatry of Epilepsy

Dr Manny Bagary, Consultant Neuropsychiatrist, Barberry Centre, Birmingham and Honorary Clinical Research Fellow, Institute Of Neurology, Queen Square, London [email protected]

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.




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




Cognition and behaviour in dementia Richard J Perry, Imperial College [email protected] 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




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.




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.




Prions and human disease RG Will, University of Edinburgh; [email protected] 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.




Psychological presentations of Movement Disorders Anette Schrag [email protected] 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




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




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.




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?




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.




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

Andrea Eugenio Cavanna

[email protected]

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.




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

TCA

Stimulants

SSRI

SNRI

TCA

SSRI

SNRI

bupropion

SSRI

SNRI

Anxiety SSRI

beta-blockers

SSRI

NaSSA

beta-blockers

SSRI

SNRI

trazodone

SSRI

SNRI

Psychosis atypicals

neuroleptics

atypicals

neuroleptics

atypicals

neuroleptics

atypicals

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)




Hypersomnia and Insomnia Dr Paul Reading, Neurologist, The James Cook University Hospital [email protected] 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




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.




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.




PARASOMNIAS Dr Zenobia Zaiwalla, West Wing, John Radcliffe Hospital, Oxford [email protected] 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

Disorders of arousal from NREM sleep

Other parasomnias

• confusional arousals • sleep walking • sleep terrors

Parasomnia associated with REM sleep

• REM sleep behaviour disorder • recurrent isolated sleep paralysis • nightmare disorder

• sleep related dissociate disorder • sleep enuresis • sleep related groaning • exploding head syndrome • sleep related hallucinations • sleep related eating disorder • parasomnia unspecified • parasomnia due to drugs, substance

abuse or medical condition Table 2

Classification of sleep related movement disorders: ICSD 2

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




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

epilepsy Temporal lobe epilepsy

Parasomnia: NREM arousal disorder

Parasomnia: REM behaviour disorder

Time of night Any time Any time 1st third Mid-third or later Duration <1 min Minutes Several minutes

to 1 hour Minutes

Frequency Very frequent (can be 20 – 30 per night)

Few More than 1 uncommon

Recur during REM sleep periods

Semiology Stereotype complex motor movements and vocalisation

Confused stereotype automatisms

Confused, semi purposeful varying automatisms

Complex dream enactment behaviours

Directed behaviour / violence

No No Can occur Can occur

Resistive aggression

Too brief to cause significant injury

Yes, especially postictal

Yes Yes

Memory of event

Absent Absent Absent Can relate to dream content

Family history

Sometimes Rare Common Rare

Polysom: Relationship to sleep stage

Usually from NREM sleep Seizure starting soon or immediately on arousal

NREM or REM Usually an interval between arousal and seizure

NREM Stages 3 – 4 Behaviour immediately on abrupt arousal

REM sleep Intermittent during REM sleep with loss of REM atonia

EEG Interictal/ictal EEG may be abnormal, but can be normal

Interictal/ictal epileptiform discharge usually present

No epileptiform activity

No epileptiform activity

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.




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

“Nature has placed mankind under the governance of two sovereign masters, pain and pleasure.” — Jeremy Bentham

Most of what is known about pain and pleasure derives from the study of each phenomenon in isolation. Recently, however, neuroscientists investigating opioid and placebo analgesia1–3, drug addiction4 and learning5 have begun to bridge the gap between the pain and pleasure research fields. This development has been strengthened by the increasing focus on the subjective emotional feelings (hedonics) that are elicited by rewards and punishments (BOX 1).

Rewards and punishments are defined as something that an animal will work to achieve or avoid, respectively. Pleasure represents the subjective hedonic value of rewards. The term ‘pain’ encompasses both the hedonic (suffering) and motivational (avoidance) aspects of a painful experience. Clearly, seeking pleasure and avoiding pain is important for survival, and these two motivations probably compete for prefer-ence in the brain. Put simply, which of two coinciding pain and pleasure events should be processed and acted on first? Consistent with the idea that a common currency of emotion6 enables the comparison of pain and pleasure in the brain, the evidence reviewed here points to there being exten-sive overlap in the neural circuitry and chemistry of pain and pleasure processing at the systems level. This article summarizes current research on pain–pleasure interac-tions and the consequences for human behaviour.

The utility of pain and pleasureThe large variability between the strength of a sensory stimulus and the resulting hedonic feeling is of great medical and neuroscien-tific interest. For instance, athletes can be oblivious to pain in the heat of competition, in which winning is the reward. A key factor for the interpretation of pain and pleasure is subjective utility7. For example, the reward value of a stimulus increases with the effec-tiveness of that stimulus in restoring bodily equilibrium (homeostasis)6,8. This effect, known as alliesthesia6, is well-documented for food rewards, which are more pleasur-able when they relieve a hunger state9. As the experience of pain represents a deviation from homeostatic balance10, the same principle can be applied to pain and the pleasantness of its relief 11. Similarly, when a perceived threat to an organism becomes greater, pain unpleasantness increases, enhancing defensive and avoidance mechanisms12.

Pain and pleasure encourage the constant optimization of our internal homeostatic balance. Although pleasure-seeking and pain-avoidance generally increase our chances for survival, it is easy to envisage scenarios in which these two motivations are in competition. A simple case would involve a large reward that is only accessible at the ‘price’ of a small pain. Sometimes it seems that overcoming a small amount of pain might even enhance the pleasure, as reflected perhaps by the common expression ‘no pain, no gain’ or the pleasure of eating hot curries. Pain–pleasure dilem-mas abound in social environments13, and culture-specific moral systems, such as

religions, are often used to guide the balance between seeking pleasure and avoiding pain (BOX 2). The subjective utility — or ‘mean-ing’ — of pain or pleasure for the individual is determined by sensory, homeostatic, cultural and other factors that, when com-bined, bias the hedonic experience of pain or pleasure.

The Motivation-Decision Model The processes that underlie the subjective interpretation of a sensory event can be understood as the manifestation of an unconscious decision process4,14. The deci-sion process requires information about the homeostatic state of the individual (such as inflammation or hunger), sensory input and knowledge about impending threats and available rewards. According to the Motivation-Decision Model of pain, as put forward by Fields4,14, the basic premise for the decision process is that anything that is potentially more important for survival than pain should exert anti-nociceptive effects. This allows the animal to ignore the pain and attend to the more important event. The Motivation-Decision Model predicts that pain–pleasure dilem-mas in which a large reward is gained at the price of a small pain are resolved through the antinociceptive effects of the pleasurable reward (FIG. 1). In some instances, threatening and pleasure-related cues are more important for survival than pain, and it is assumed that any antinocic-eptive effects are mediated by the descend-ing pain modulatory system, which is located in the brainstem. This circuit, which consists of excitatory and inhibitory cells, communicates with neurons in the pre-frontal cortex, the hypothalamus and the amygdala to control the nociceptive affer-ent pathway in the spinal and trigeminal dorsal horn4,14,15 (FIG. 2). Opiate drugs and endogenous opioids act on this descending system to produce pharmacological, pla-cebo, stress-induced and pleasure-related analgesia1,2,4,14–20.

Pain–pleasure interactionsEvidence of pleasure-related analgesia has been reported in various human and animal studies: pain is decreased by pleas-ant odours21, images22, pleasurable music23, palatable food16,17 and sexual behaviour18,19. In addition, considerable evidence suggests that expectation of treatment effect, which contributes to placebo analgesia, is a type of reward expectation24,25. Interestingly, when subjects who were not expecting an injec-tion of pain-relieving morphine received

S C I E N C E & S O C I E T Y

A common neurobiology for pain and pleasureSiri Leknes and Irene Tracey

Abstract | Pain and pleasure are powerful motivators of behaviour and have historically been considered opposites. Emerging evidence from the pain and reward research fields points to extensive similarities in the anatomical substrates of painful and pleasant sensations. Recent molecular-imaging and animal studies have demonstrated the important role of the opioid and dopamine systems in modulating both pain and pleasure. Understanding the mutually inhibitory effects that pain and reward processing have on each other, and the neural mechanisms that underpin such modulation, is important for alleviating unnecessary suffering and improving well-being.

P e r s P e c t i v e s

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Nature Reviews | Neuroscience

a hidden injection, its analgesic effects were significantly reduced26. Although the placebo treatment might not be pleasurable in itself, reduced pain represents the better of two alternative outcomes (the other being unchanged pain levels), and therefore has a higher reward value.

A related phenomenon predicted by Fields’ Motivation-Decision Model is the effect of pain on the ability to experience pleasure. By decreasing reward pleasant-ness, pain and other threatening events ensure that necessary action is taken to protect the individual, thus attenuating the normal reward-seeking behaviour. Correspondingly, decreased consumption of palatable foods is considered to be a measure of pain suffering and is reversible with morphine treatment27 (FIG. 1). Similarly, sustained pain inhibits morphine reward in rodents; this is likely to be due to sustained activation of the κ-opioid system in the nucleus accumbens (NAc)28. In humans there is extensive co-morbidity between chronic pain and depression, which often involves a reduction in the ability of chronic pain sufferers to enjoy everyday pleasures (anhedonia)29. This reduction in pleasure might form part of a vicious cycle for the patients, in which both negative mood and lack of pleasure result in exacerbated pain, leading to more negative mood and anhedonia.

Opioids and hedonic feelingsPain and reward are complex constructs that encompass motivational, hedonic and learning signals30. As the motivation to seek reward or avoid pain is generally correlated with the pleasantness or aversiveness of an event (respectively), it is difficult to disen-tangle the neuroanatomy of the hedonic and motivational components of pain and reward. In addition, we have only limited

access to our own hedonic and motivational processes, which are thought to be primarily subconscious31. Importantly, however, the motivation and hedonic subsystems seem to be mediated by different neurotransmitters. Carefully controlled studies have found specific effects for two neurotransmitter systems: dopamine increases motivation for, but not the pleasure of, eating palatable foods32,33, whereas the opioid system influ-ences motivation indirectly by modulating subjective emotional feelings of pain and reward34. In summary, opioids are neces-sary for hedonic experience (‘liking’) but dopamine motivates you to get ready for it (‘wanting’)31,35.

µ-opioids have been shown to cause a positive shift in affect across the hedonic spectrum: they enhance the pleasantness of sweet tastes and decrease the aversiveness of pain and bitter foods31. Both painful and pleasant events are associated with the release of endogenous µ-opioids in the brain and, importantly, in the NAc19,36 (FIG. 1). Blocking of µ-opioid signalling with naloxone decreases the pleasantness of food rewards34 and sexual behaviour37 and reverses reward-related analgesia16,18,26. Interestingly, a recent conditional gene-knockout study showed a dissociation of µ-opioid-mediated reward and analgesia: only µ-opioid antinociception depends on an intact central serotonergic system38. The κ-opioid system presents another example of pleasure–analgesia dissociation: κ-opioids reduce pain but also induce feelings of aversion39,40. Furthermore, the κ-opioid activity caused by tonic (sustained) pain has

Box 1 | The increasing focus on pain and reward hedonics

Hedonic feelings — also known as qualia — drive motivation and behaviour. Qualia determine what it is like to be a human being87. No theory of the relationship between the brain and the mind is complete without accounting for hedonic feelings. In recent years, several exciting research directions have emerged in the pain and reward research fields that successfully combine the need for carefully controlled, ‘objective’ research methodologies with a focus on hedonics. One example is a body of work on ‘liking’ and ‘wanting’ — two subconscious reward processes that are thought to underpin conscious pleasure and motivation31. Using taste reactivity as a primary outcome measure (see figure), this research has used pharmacological stimulation and lesion techniques to determine causal relationships between neuronal signalling and hedonic feelings. In the pain field there is growing recognition that the ‘subjective interpretation’ or ‘meaning’ of pain determines the amount of pain-related suffering15,88. The definition of pain, according to the International Association for the Study of Pain, emphasizes the ‘unpleasant’ and ‘emotional’ aspects, and also includes subjective feelings of pain, which are not caused by tissue damage. Other research areas that are turning their attention to hedonic feelings include the fields of obesity research89 and decision making: the shift in focus from ‘cold’ rational consideration to ‘hot’ emotion-based decision making has influenced cognitive neuroscience for more than a decade90,91. Even economists are now looking to hedonic feelings to explain human behaviour such as the ‘warm glow’ that accompanies donations to charity92. Figure modified, with permission, from ReF. 31 (2003) Academic Press.

Box 2 | The pain–pleasure dilemma

“Pleasure is the greatest incentive to evil” — Plato

The increased neuroscientific interest in pleasure (BOX 1) perhaps reflects a greater general focus on pleasure and positive affect (happiness) in the Western world85. Historically, however, a strong belief in shame and stoicism (in the case of pleasure and pain, respectively) has prevailed. Learning to curb impulses for instant gratification and to tolerate some pain ‘for the greater good’ is an important part of child development. Considering the unnecessary pain of childbirth and the stress of child rearing, it is perhaps not surprising that patience, selflessness and stoicism are highly regarded traits in many cultures13. In neuroscience, prominent addiction researchers 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 Calvinistic focus on moderation, or even abstinence, of pleasure has deep roots in Western culture and is powerfully connected with shame94. Whereas excessive reliance on shame and stoicism might cause unnecessary suffering86, extreme pleasure-seeking and pain avoidance (hedonism) can have undesirable consequences such as drug addiction93,95 and obesity89. However, the inability to take pleasure in everyday rewards is also a form of suffering29. In fact, paradoxical and risky human behaviours such as self-harm and skydiving have been related to a desire to alleviate emotional ‘numbness’, possibly owing to a dysfunction in the opioid and/or dopamine systems78,96,97. The strong historical association between shame, guilt and pleasure might help to explain a number of paradoxical human behaviours, as well as the historical preference for formulating scientific research questions in terms of behaviour rather than pleasure and other hedonic feelings.


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http://www.iasp-pain.org

http://www.iasp-pain.org


OFC

NAc VTAVP

Pain

Pain

Pain+ Pleasure

+ Pleasure+ µ-opioidreceptor antagonists

Pleasure

Pleasure

Pleasure+ Pain

+ Pain+ µ-opioid receptor agonists

a

b

c

Amy

been shown to disrupt the positive interac-tion between µ-opioids and mesolimbic dopamine28.

Dopamine, motivation and analgesiaConsidering the close association that exists between motivation, learning and hedonic feelings, it is not surprising that dopamine signalling has been consistently reported to correlate with stimulus reward value41,42. Striatal dopamine neurons also respond to aversive events43,44 but, in contrast to the firing bursts that signal pleasant events or their cues, aversive stimulation causes a brief inhibition of baseline firing45,46. The many time-courses of the dopamine signal are often measured by different techniques, making the literature on the precise role of dopamine in pain and reward complicated and somewhat inconsistent43,45 (BOX 3). For instance, on the one hand, positron emission tomography (PET) studies of base-line dopamine receptor availability provide a measure of tonic dopamine levels43,47. On the other hand, PET studies comparing receptor availability between two stimulus conditions measure dopamine signalling at the temporal mid-range between brief phasic activation and constant tonic firing24,43,45,48. Despite the complex effects and interactions of the various dopamine time-courses, it is clear that endogenous dopamine is involved in the process-ing of both pain and pleasure3,30,41,43–46,48. Pharmacological manipulation of dopamine levels has also been shown to modulate both pain and reward behaviours20,30,45,49,50.

The precise role of dopamine in pain and reward processing is hotly debated. In the reward literature, one main question has been whether the dopamine signal is necessary for reward learning, salience, motivation or hedonics30,35,45. For pain, dopamine agonists, such as amphetamine, reduce tonic pain but do not change phasic pain behaviours49. Similarly, tonic but not phasic pain events are thought to induce endogenous analgesia through dopamine release in the NAc43. Dopamine receptor availability studies have shown that endog-enous striatal dopamine release correlates positively with sensory and affective com-ponents of tonic pain in healthy subjects43,48. Although these studies in healthy volunteers provide clear demonstrations of dopamine’s involvement in pain processing, they can-not unequivocally answer the question of directionality. The dopamine signal could reflect a sustained increase in dopamine that might exacerbate pain, but it could also reflect brief signals related to pain-avoidance

motivation. Interestingly, in patients it seems that this normal interaction between the dopamine system and pain is disrupted. One study showed that, compared with controls, patients suffering from generalized pain (fibromyalgia) released less dopamine in the striatum yet found the stimulus (hypertonic-saline-induced deep muscle pain) more painful48. This result is consistent with a normal role for dopamine in endogenous antinociception51. Any analgesic effects of dopamine seem to rely on a reactive phasic dopamine system, and this might be disrupted in chronic pain conditions — per-haps through increased tonic dopamine levels that inhibit phasic release48,51 (BOX 3).

In line with this evidence, and based on interactions between the descending pain system and the mesostriatal dopamine circuit for drug and food reward, the Motivation-Decision Model proposes that phasic dopamine has a key role in endogenous analgesia in situations in which reward is expected4. Evidence from human studies perhaps supports this concept, as low tonic dopamine levels, present in individu-als with the catechol-O-methyltransferase (COMT) val/val polymorphism, produce high phasic dopamine52 and concomitantly high endogenous-opioid release during tonic pain53. val/val subjects also reported significantly lower pain compared with Met/Met subjects with higher tonic dopamine levels. A recent molecular-imaging study investigated the link between reward expectancy, dopamine and analgesia more directly, and showed that inter-individual variation in NAc dopamine release during a placebo manipulation correlated with subsequent variability in placebo analgesia3. Furthermore, NAc activation during antici-pation of a monetary reward accounted for 28% of the variance in the formation of placebo analgesia in the same individuals. This study therefore supports a direct link between dopamine and endogenous-opioid release with regards to reward and analgesia in humans.

Common regions for pain and pleasureAlthough the opioid and dopamine systems are closely related neuroanatomically54, they interact in complex ways. Phasic dopamine has been shown to increase opioid levels55, whereas tonic dopamine decreases opioid levels53,56. Conversely, opioids upregulate phasic dopamine in the striatum (by inhibit-ing local GABAergic interneurons in the ventral tegmental area)57,58 and downregu-late slower striatal dopamine signalling, as measured by PET59.

Just as the colocalization of opioid and dopamine pathways highlights the impor-tance of interactions between these two systems, the striking overlap in regions that are involved in pain and pleasure processing (FIG. 2) might explain the modulatory effects

Figure 1 | schematic illustration of pain– pleasure inhibition. The Motivation-Decision Model of pain4,14 posits that anything of poten-tially greater importance than pain should have antinociceptive effects (be it a greater threat or the possibility of a reward). By the same evolution-ary-psychology rationale, it is clear that anything that is potentially more important than a reward (such as an even greater reward or a threat for which action is needed) should similarly decrease its pleasantness, thus allowing for the appropriate avoidance or approach behaviours. The µ-opioid and mesolimbic dopamine systems are the prime candidates for systems that transmit signals relat-ing to motivational and hedonic aspects of both pain and pleasure and, in particular, their interac-tions, as illustrated here. a | Both pain and pleasure have been shown to elicit opioid release in the orbitofrontal cortex (OFC), the amygdala (Amy), the nucleus accumbens (NAc) and the ventral pal-lidum (VP)2,65,68. Pleasure and reward expectation are also associated with increased phasic dopa-mine signalling from the ventral tegmental area (VTA) to the NAc and VP42, which in turn causes increased µ-opioid release in the NAc55. Pain has been associated with both increases and decreases in mesolimbic dopamine signalling, depending on the type of measurement and pain model that have been used42,43,46,48,49. b | µ-opioid receptor antagonists, such as naloxone, reverse pleasure-related analgesia16,18,19. c | µ-opioid recep-tor agonists, such as morphine, have been shown to re-enable pleasure that has been previously reduced by concomitant pain27.




http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1312&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


PFCINS

OFC

Region Pleasure/reward Pain

Lateral prefrontalcortex

•Humans, fMRI, taste reward101 •Humans, H2O PET, hyperalgesic pain 102

•Humans, fMRI, pain103

Anterior insula •Humans, fMRI, food cravings104

•Humans, H2O PET, chocolate reward75•Humans, fMRI, pain105

•Humans, fMRI, placebo analgesia106

Posterior insula •Humans, fMRI, hypothetical reward107 •Humans, direct brain stimulation108


Orbitofrontalcortex

•Humans, fMRI, pleasant touch74

•Humans, fMRI, chocolate reward75•Humans, fMRI, pain74

•Humans, fMRI, placebo analgesia106

Medial prefrontalcortex

•Humans, H2O PET, pleasurable music64

•Humans, fMRI, monetary reward109•Humans, fMRI, pain110,111

Anterior cingulategyrus

•Monkeys, electrophysiology112

•Humans, H2O PET, chocolate reward75•Humans, fMRI, pain113

•Humans, opioid PET83

Dorsal striatum •Humans, fMRI, fruit juice114

•Humans, fMRI, monetary reward115•Humans, dopamine ligand PET, pain43


Nucleus accumbens/ ventral striatum

•Humans, fMRI and dopamine ligand PET ,monetary reward

3

•Rodents, hedonic hotspot, taste reactivity

65

•Humans, dopamine ligand PET , drug reward

41

••

Humans, dopamine ligand PET43

•Humans, fMRI, expectation of pain44

Rodents, pain-induced analgesia20

Ventral pallidum •Rodents, taste reactivity 62,65 •Rodents, tracing, pain a�ect72

•Humans, µ-opioid PET, sustained pain 2

Hypothalamus •Humans, H2O PET, pleasurable music117 •Rodents, tracing of nociceptive pathway 72

•Humans, direct brain stimulation118

Midbrain •Humans, H2O PET, chocolate reward75

•Humans, H2O PET, pleasurable music64•Humans, fMRI, anticipation of pain119


Amygdala •Humans, H2O PET, pleasurable music64

• Primates, reward anticipation/learning63•Humans, fMRI, pain70,120

Hippocampus •Humans, fMRI, unexpected reward121

•Humans, H2O PET, pleasurable music64•Humans, fMRI, pain122

•Humans, fMRI, anticipation of pain119

Cerebellum •Humans, fMRI, unexpected reward121 •Humans, fMRI, pain123

Brainstem •Rodents, taste reactivity124

•Rodents, conditioned place preference40•Humans, fMRI, pain123

•Rodents, pain40

Thalamus •Humans, H2O PET, chocolate reward75 •Humans, fMRI, placebo analgesia106

of one over the other. whether one or two neural systems (at any spatial scale) underpin aversive and appetitive process-ing in the brain60 is still subject to debate5. Regions that are particularly well situated to mediate interactions between pain and pleasure include the NAc, the pallidum and the amygdala. These regions receive direct or indirect reward-related signals from dopamine neurons in the midbrain and are thought to signal either reward-prediction error (discrepancy between the expected and the received reward; NAc42,61 and amyg-dala61) or hedonic reward value (pallidum62 and amygdala63,64). The NAc and pallidum each contain a ‘hedonic hotspot’ in which µ-opioid stimulation increases the liking of rewards65. In fact, these two ~1mm³ regions are necessary for the opioid-mediated enhancement of food palatability65. Different neuron populations in the amygdala have been found to encode the negative and posi-tive hedonic value of reward and punishment

cues63. Evidence from human patient studies also highlights the importance of the NAc and the pallidum for reward processing, as dysregulation or lesion of these regions is associated with anhedonia66,67.

In addition to their participation in pleasure processing, the amygdala, the NAc and the pallidum have distinct but important roles for pain. All three regions have been shown to release endogenous µ-opioids during painful stimulation in humans2,68. The amygdala modulates pain perception through direct connections with the descending pain inhibitory system69,70. The amygdala and the NAc mediate both reward- and stress-induced analgesia4,69, and these two regions show alterered endog-enous-opioid analgesic activity in fibromy-algia patients71. Stress-induced analgesia can be blocked by intra-accumbens injection of dopamine and opioid antagonists20. The pallidum contains a population of encepha-lin-containing neurons that receive a large

proportion of the signals that are generated by the unmyelinated primary afferent nociceptor pathway72. These pallidal ‘pain affect’ neurons seem to be located laterally to the pallidal pleasure hotspot65,72. Thus, it seems that two distinct subregions of the pallidum are involved in appetitive and aversive processing. A similar finding has been reported for the NAc. whereas neurons located in the rostral part of the NAc shell mediate pleasure, stimulation of more caudal regions of the NAc causes a negative shift in affect73. A similar rostrocaudal ‘hedonic gradient’ in the ventral striatum was recently reported for economic gains and losses in humans5. In the amygdala, adjacent neuronal populations represent positive and negative hedonic value63.

The close adjacency of such pain and pleasure hotspots suggests that functional interactions between them are involved in the mechanism by which pain decreases pleasure and rewards induce analgesia. Evidence

Figure 2 | Brains regions implicated in pain and pleasure processing. At the systems level, the major regions that have been implicated in pain and reward processing by functional imaging studies and direct brain stimulation in humans, as well as by electrophysiology and tracing studies

in animals, show striking overlap. The studies included as examples in this figure unequivocally demonstrate the involvement of each region in both pain and pleasure processing. fMRI, functional MRI; PET, positron emission tomography.





Normal tonic dopamine level

Normal phasic dopamine signal

Increased phasic dopamine signal

Increased tonic dopamine level

Reduced phasic dopamine signal

Decreased tonic dopamine level

Impulsive behaviour

Pain and stress syndromes

that separate neuronal populations encode aversive and appetitive processing in the amygdala, the NAc and the pallidum supports the existence of two neural systems for pain and pleasure at the within-region spatial scale. A similar finding has also been reported for higher cortical regions: different subregions in the orbitofrontal cortex represent the hedonic value of reward and punishment74–77.

A common currency for hedonic experienceThe robust evidence for opioid and dopamine involvement in the processing of pain and pleasure makes these two neuro-transmitter systems the prime candidates for mediating the mutually inhibitory effects of pain and reward. Although both pleasurable and painful events are often accompanied by endogenous-opioid neurotransmission, the pleasure-enhancing and antinociceptive effects of µ-opioid agonist treatment suggest that endogenous

µ-opioid signalling truly reflects pleasurable and analgesic effects in the brain. Similarly, although dopamine firing patterns differ in response to reward prediction, uncertainty and aversive events, the mutual reinforce-ment of phasic dopamine and opioid release is consistent with the idea that dopaminer-gic motivation signalling takes place during preparation for, or consummation of, a pleasurable reward. The finding that high tonic dopamine activity is associated with both increased pain and decreased pleasure, and that tonic over-activity of the dopa-mine system is known to reduce phasic dopamine and µ-opioid release, further corroborates the idea that interactions between µ-opioids and phasic dopamine signalling mediate pleasure and analgesic effects in the brain. These two neurotrans-mitter systems are thus likely to mediate the brain’s common currency, allowing for action selection based on the comparison

between competing pleasant and aversive events. As the Motivation-Decision Model suggests, being able to ‘switch off ’ pain in order to gain a reward could increase sur-vival, if the pain–pleasure (or cost–benefit) ratio is right. Similarly, aversive cues must be able to disrupt pleasure-seeking if the potential danger outweighs the potential gain.

An important and as yet unanswered question concerns the effects of chronic pain on the ability to enjoy rewards29. Anhedonia is a major symptom of depres-sion, and several recent papers have sug-gested that it might be related to reductions in dopaminergic neurotransmission that are similar to those that are seen during abstinence of addictive drugs78,79. By contrast, positive mood and cognitive flex-ibility are thought to arise from a highly responsive phasic dopamine system80. The significant co-morbidity between chronic pain and depression suggests that these patients might also lose-out on the poten-tial analgesic effects of the rewarding every-day events that they are no longer able to savour. A lack of reward-induced analgesia has been reported in ‘anhedonic’ stressed rats81. Indeed, endogenous-opioid activity is disrupted both during sad mood82 and in chronic pain patients83.

For Jeremy Bentham, a ‘good life’ consisted of the presence of pleasures combined with the absence of pains7. As we have seen, the inability to feel pleasure is associated with negative mood and depression. By contrast, positive affect is considered the hallmark of well-being80 and might actually improve health84. Bentham’s view might nevertheless be too simplistic. As stated in the beginning, closely related to the subjective interpretation of a sensory stimulus is the concept of mean-ing. Meaning allows for many alternative paths to well-being85. Consideration of this factor might help to explain the abundance of paradoxical aversive or life-threatening human behaviours found across society that are considered ‘pleasurable’. Even suffering can be rewarding if it has meaning to the suf-ferer86. Continued study of the commonalities and differences between pain and pleasure is therefore necessary if we are to advance our understanding of human suffering and well-being.

Siri Leknes and Irene Tracey are at the Oxford Centre for Functional MRI of the Brain, Department of Clinical

Neurology, Nuffield Department of Anaesthetics, Oxford University, John Radcliffe Hospital, Oxford,

OX3 9DU, UK. Correspondence to I.T.

e-mail: [email protected]

doi:10.1038/nrn2333

Box 3 | Aristotle’s ‘Golden Mean’ and phasic dopamine signalling

To maintain homeostasis, animals must aim for the ‘Golden Mean’ — that is, the right balance between pleasure-seeking and pain-avoidance. The responsiveness of the phasic dopamine system (a system which is caused by brief bursts of neuronal firing and relates to reward motivation and prediction error) is important for the regulation of appetitive and aversive behaviours. Impulsive behaviour and schizophrenia have been linked to an excessively responsive phasic dopamine system98, whereas depression, chronic pain and anhedonia have been associated with low responsiveness to reward cues78,79.

Tonic dopamine activity refers to the level of extrasynaptic dopamine that is present at a steady-state concentration in the extracellular space45,99. The baseline dopamine concentration is thought to enable a number of behavioural processes, many of which are affected in Parkinson’s disease42. Importantly, tonic dopamine levels regulate the responsiveness of the phasic dopamine system to salient environmental cues: high tonic dopamine attenuates phasic dopamine release45,99 whereas low tonic dopamine facilitates phasic dopamine firing98. The level of tonic dopamine in the limbic striatum is in turn modulated by corticostriatal and hippocampal afferents and homeostasis98,99.

Increased tonic dopamine is known to result from prolonged stress or pain51 (see figure), a mechanism that might have evolved to ensure rest and low activity levels during injury. Unfortunately, the same mechanism is thought to cause increased pain sensitivity in certain pain syndromes through its inhibition of endogenous phasic dopamine antinociception48,51. Abstinence from addictive drugs has also been associated with hyperalgesia and increased tonic signalling. The resulting inhibition of phasic signalling is thought to underpin reduced responsiveness to pleasure (anhedonia) during abstinence, and can be reversed by re-administering the addictive drug79. At 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 with excessive pleasure-seeking and substance abuse100.




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AcknowledgementsThe authors wish to thank L. Moseley and M. Kringelbach for their helpful advice on the figures, the Wellcome Trust and the Medical Research Council (Functional Magnetic Resonance Imaging of the Brain Centre).

DATABASESentrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geneCOMT

FURTHER INFORMATIONirene tracey’s homepage: http://www.fmrib.ox.ac.uk/paininternational Association for the study of Pain: http://www.iasp-pain.org

All links Are Active in the online pdf




http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1312&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum

http://www.fmrib.ox.ac.uk/pain




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 [email protected] 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 [email protected]




Antibodies in neuropsychiatric disorders and more Angela Vincent [email protected] 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.




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.

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