Category	Response	Score
Eye opening (E)	Spontaneous	4
	To speech	3
	To pain	2
	Nil	1
Speech/verbal response (V)	Appropriate and orientated	5
	Confused	4
	Inappropriate words	3
	Incomprehensible sounds	2
	Nil	1
Motor response (M)	Obeys commands appropriately	6
	Localizes to pain	5
	Withdraws to pain	4
	Flexes to pain	3
	Extends to pain	2
	Nil	1

GCS = E + V + M. Minimum score 3, maximum score 15.

Coma is a life-threatening emergency. Assessment must be swift and comprehensive, and occur in tandem with life support measures and initial investigations (Box 17.1, p. 624, and see Fig. 20.21 (p. 722)).

Box 17.1 Management of the comatose patient

This is a neurological emergency (see also Fig. 20.21). Enlist the help of an experienced nurse. The immediate priority is cardiorespiratory resuscitation.

• Secure airway; give oxygen

• Check pulse/BP and breathing. Resuscitate if necessary. Place on continuous cardiac and oximetry monitoring

• Record Glasgow Coma Score

• Perform primary survey: check head/spine for trauma; immobilize spine if necessary

• Check breath: hepatic fetor, ketones, alcohol

• Check rectal temperature with low-reading thermometer

• Secure IV access and give 50 mL of 50% glucose. In patients with suspected alcohol use, the glucose should be preceded by 250 mg thiamine IV (to prevent Wernicke’s encephalopathy)

• Check pupils: if pinpoint, give 0.4–1.2 mg naloxone IV to counteract possible opiate poisoning

• Treat seizures (lorazepam and phenytoin — see Box 17.4) and suspected bacterial meningitis (p. 54)

Initial assessment

• Assess vital signs and airway safety. Guedel airway insertion may be necessary. Is intubation/ventilation or circulatory support required?

• Capillary blood glucose and pulse oximetry

• History. Taking a history from relatives, witnesses and paramedics is crucial.

• Onset?

• How found?

• Any head/spinal injury?

• Past history of diabetes, epilepsy, opiate/alcohol use, suicide attempts?

• Any medication or prescriptions available?

• General examination. Look for clues to the cause of coma. Is there fever, purpuric rash, shock, anaemia, liver disease, melaena or renal disease, e.g. haemodialysis shunt or injection marks? Is there a MedicAlert bracelet? Is there evidence of trauma — blood or CSF in ears/nose or bruising (battle sign or ‘racoon eyes’ indicating skull fracture)? Neck stiffness can still be detected in unconscious patients and is indicative of meningeal infection or subarachnoid haemorrhage (SAH).

• Neurological examination. This is helpful to lateralize signs, to determine the level of pathology and to assess integrity of brainstem reflexes.

• Pupil size and reaction to light. These are of great diagnostic significance in coma. Unilateral fixed dilated pupil indicates 3rd nerve compression or stretch, and suggests herniation of the uncus of the temporal lobe through the tentorial hiatus (coning) or posterior communicating artery aneurysm. Bilateral fixed and dilated pupils follow as coning progresses and indicate imminent death, but can also occur in deep coma of any cause, e.g. tricyclic overdose and hypothermia. Bilateral pinpoint pupils occur in opiate overdose and pontine lesions. Small reactive pupils are usually found in toxic and metabolic coma.

• Eye position and movements. Conjugate deviation of eyes may indicate a frontal hemispheric lesion, e.g. stroke (eyes deviated towards lesion, away from hemiplegic side) or pontine lesion (eyes away from lesion). Disconjugate eye position may indicate a brainstem lesion. Roving eye movements (‘windscreen wiper eyes’) are seen in light metabolic coma or diffuse cortical injury.

• Fundoscopy. Look for papilloedema, hypertensive retinopathy and subhyaloid haemorrhage (in SAH).

• Other brainstem reflexes. Look for the corneal reflex, gag reflex (or cough reflex with suction catheter via endotracheal tube), (if spine is stable) doll’s eye movements, and assess pattern and effort of respiration.

• Limbs. Check for asymmetric spontaneous movements, response to painful stimuli and extensor plantar responses. Focal motor signs usually suggest a structural cause, e.g. stroke or space-occupying lesion. Hypoglycaemia and hepatic coma occasionally cause focal signs.

Investigations where cause of coma is unknown after initial assessment

• CT brain is the priority once the patient is stabilized and glucose checked, especially if lateralizing neurological signs are present, e.g. hemiparesis. Note that raised intracranial pressure (ICP) cannot always be excluded with imaging; specialist review of imaging may be required to look for features of raised pressure such as early cerebral oedema or effacement of chiasmatic cisterns.

• Blood for:

• FBC, U&E, creatinine, liver biochemistry, glucose, coagulation, thyroid function, cortisol

• toxicology, including alcohol, paracetamol and salicylates

• blood cultures.

• Urine toxicology, ABG, ECG and CXR

• Lumbar puncture (LP) and CSF examination should be performed only after risk assessment and if there is no CT evidence of a mass lesion or raised ICP.

N.B. Treat suspected bacterial meningitis with IV antibiotics and high-dose steroids immediately — BEFORE lumbar puncture.

• Lumbar puncture is contraindicated in meningococcal septicaemia (p. 54). If viral encephalitis is a possibility (p. 55), start IV aciclovir 10 mg/kg 3 times daily (monitor renal function).

• EEG should be done if there is suspicion of non-convulsive status epilepticus.

• MRI brain should be performed if the cause of the coma is still uncertain, and obtain a neurological opinion.

Immediate management

• Immediate management is directed at treating the underlying cause.

• Nursing care of skin (pressure areas), eyes and mouth is essential.

• If the patient cannot swallow after 12 hours, insert a naso-gastric tube.

• Ensure adequate fluid and calorific intake.

• Only catheterize if absolutely necessary.

Acute confusional state (delirium)

Delirium is characterized by abnormalities of perception and cognition, often without a decrease in the level of consciousness. Impairment in consciousness, if present, can vary and fluctuates with confusion, usually being worse at night. It is very common, especially in elderly hospitalized patients. There are a wide variety of causes, often occurring in combination, in a patient vulnerable by virtue of age or impaired cognitive reserve. Common causes include systemic infection, hypoxia, electrolyte imbalance, liver or renal failure, and drug/alcohol intoxication or withdrawal (especially anticonvulsants, anxiolytics, opiates), as well as brain injury, encephalitis/meningitis or deficiency states such as Wernicke–Korsakoff encephalopathy.

Delirium should be distinguished from dementia, aphasia and psychosis. Dementia can also predispose to the development of periods of delirium with intercurrent illnesses. In dementia there is no clouding of consciousness, the patient is alert, and there is less likely to be agitation or rapid fluctuations.

Management

• Initial management and evaluation is similar to that of the comatose patient. Review the notes, take a history and examine the patient.

• General measures include nursing in moderately lit, quiet room, repeated reassurance, and correction of metabolic imbalance. Perform appropriate investigations to determine the cause and treat underlying disease. Sedation must be used judiciously, as occasionally paradoxical worsening of confusion can result, particularly with benzodiazepines. Give haloperidol 1 mg oral twice daily if patient presents risk to themselves or others.

Delirium tremens (DTs)

This is the most serious alcohol withdrawal state and occurs 1–3 days after alcohol cessation. Patients have disorientation, agitation, tremor and visual hallucinations. For treatment, see Box 17.2.

Box 17.2 Management of delirium tremens

Specific drug treatment

• One of the following orally:

– Diazepam 10–20 mg

– Chlordiazepoxide 30–60 mg

– Repeat 1 hour after last dose, depending on response.

Fixed-schedule regimens

• Diazepam 10 mg every 6 hours for 4 doses, then 5 mg 6-hourly for 8 doses or

• Chlordiazepoxide 30 mg every 6 hours for 4 doses, then 15 mg 6-hourly for 8 doses

Provide additional benzodiazepine when symptoms and signs are not controlled.

Stroke

Stroke is characterized by the sudden onset of focal neurological symptoms caused by interruption of the vascular supply to a region of the brain (ischaemic stroke) or intracerebral haemorrhage (haemorrhagic stroke). It is a common cause of mortality and physical disability.

Paramedics and members of the public are encouraged to make the diagnosis of stroke on a history and simple examination (the ‘FAST’ test):

• face — sudden weakness of the face

• arm — sudden weakness of one or both arms

• speech — difficult speaking/slurred speech

• time — the sooner the treatment can be started, the better.

N.B. Stroke is a medical emergency and prompt treatment can improve prognosis.

• Diffusion-weighted MRI (DWI) shows changes early in infarction (Fig. 17.1B) and may distinguish between acute and chronic areas of ischaemia. It is more sensitive than CT for small infarcts and for the detection of haemorrhage. If MRI is unavailable a CT should be performed so that there is no delay in giving thrombolysis.

Fig. 17.1 Middle cerebral artery (MCA) infarction.

(A) CT performed initially shows only very subtle low-density changes in the right MCA territory.

(B) Diffusion-weighted MRI done at the same time shows the full extent of the area of ischaemia.

(Courtesy of Dr Paul Jarman.)

Thrombolysis (Box 17.3)

N.B. Every minute counts. The benefit of thrombolysis decreases with time, even within the 4.5-hour window.

• Exclude patients with strokes due to haemorrhage, infection or other non-ischaemic pathologies (Box 17.3).

• Are there any contraindications to thrombolysis?

• Give alteplase after discussion with a senior doctor.

Box 17.3

(Amended from Adams HP, et al. 2007)

Thrombolysis in acute ischaemic stroke

Exclusion criteria

Historical

• Stroke or head trauma within the previous 3 months

• Any prior history of intracranial haemorrhage

• Major surgery within 14 days

• Gastrointestinal or genitourinary bleeding within the previous 21 days

• Myocardial infarction in the previous 3 months

• Arterial puncture at a non-compressible site within 7 days

• Lumbar puncture within 7 days

Laboratory

• Platelets ≤ 100 × 10⁹/L

• Serum glucose ≤ 2.8 mmol/L or ≥ 22.2 mmol/L

• INR ≥ 1.7 if on warfarin

• Elevated partial thromboplastin time if on heparin

Dose of IV alteplase (tissue plasminogen activator)

• Total dose 0.9 mg/kg (maximum 90 mg)

• 10% of total dose by initial IV bolus over 1 min

• Remainder infused IV over 60 mins

Thrombolysis improves long-term morbidity after an ischaemic stroke but is associated with an increased risk of acute haemorrhage. Maximal benefit of thrombolysis is achieved if it is given as soon as possible, although benefit may be derived if administered up to 4.5 hours after the start of symptoms. The short time window and need for prior MRI/CT to exclude haemorrhage or massive infarction require urgent action. Intra-arterial thrombolysis and mechanical disruption of clot are occasionally employed in specialist centres.

Further management

Subsequent management aims to reduce complications, lower the risk of further events and ensure adequate rehabilitation.

• Admit to a stroke unit. Specialist care, including nursing, physiotherapy, speech and language therapy and occupational therapy, on a dedicated stroke unit improves outcome. Maintain hydration, perform swallowing assessment for aspiration risk, and turn regularly to avoid pressure sores. Try to avoid catheterization if possible. Do not lower BP in the acute phase unless hypertensive encephalopathy or other acute complications of severe hypertension (e.g. hypertensive nephropathy, hypertensive cardiac failure/acute myocardial infarction, aortic dissection, eclampsia) are present. Hyperglycaemia is associated with poorer outcome, so maintain normoglycaemia with insulin if required. Treat infections.

• Secondary prevention

• Do not give antiplatelet drugs within 24 hours of recombinant tissue-type plasminogen activator (rt-PA). Then start clopidogrel 75 mg per day. Treatment with modified release dipyridamole (200 mg × 2 daily) in combination with aspirin (300 mg/day loading dose, then 75–150 mg/day) is now recommended only if clopidogrel is contraindicated or not tolerated (see NICE guidelines 2010).

• Modify risk factors, particularly hypertension, hypercholesterolaemia, diabetes and smoking. Sustained hypertension persisting beyond 2 weeks should be treated (target BP < 140/85 mmHg or 130/80 mmHg if diabetic). All patients should be on a statin (e.g. simvastatin 40 mg) unless cholesterol < 3.5, started 48 hours after stroke.

• Identification of embolic source

• Carotids. All patients with anterior circulation stroke who are not severely disabled by the stroke should have carotid imaging with Doppler or MRI/CT angiography to identify symptomatic carotid stenosis. Early carotid endarterectomy greatly reduces the risk of further stroke if there is 70–99% stenosis on the affected side. Benefits for 50–69% stenosis and for asymptomatic > 70% stenosis are more modest.

• Cardiac source. Perform echocardiography to identify a cardiac source of embolism if an embolic stroke is possible. Transoesophageal echocardiography (TOE) is appropriate in younger patients with cryptogenic stroke, e.g. to identify a patent foramen ovale (PFO) or if endocarditis is suspected. Twenty-four-hour ECG monitoring is used to identify paroxysmal atrial fibrillation. Anticoagulation should be initiated in atrial fibrillation or if cardiac thrombus is present — generally wait 2 weeks after the acute event before starting anticoagulation to reduce the risk of haemorrhagic transformation, unless dealing with a lacunar or small stroke.

• Thrombophilia screen. This should be performed in cases of stroke in the young.

• Treat or prevent complications. DVT prophylaxis with SC low molecular weight heparin (LMWH), e.g. enoxaparin 40 mg SC daily (N.B. not in haemorrhagic stroke). Treat complications early, e.g. depression, seizures, pneumonia. If patient deteriorates neurologically, repeat brain imaging. Intracerebral haematoma, for example, might require urgent neurosurgical intervention.

• Rehabilitation. In severe stroke refer early for multi-disciplinary rehabilitation assessment. Discharge with a full plan for rehabilitation and having liaised with the patient’s primary care physician.

Surgery in acute stroke

Decompressive craniectomy should be considered in cases of massive MCA infarction in patients under 60 years of age where there are clinical deficits compatible with MCA infarct. CT demonstrates infarction in at least 50% of the arterial territory without additional ipsilateral infarction in the anterior or posterior cerebral arterial territories. Surgery should be performed within 48 hours of symptom onset or in the event of a deteriorating clinical condition.

The National Institute of Health’s Stroke Scale Score, which is comprised of 11 items with total scores of 0–42, is a useful validating system. A score of > 15 suggests a decrease in the level of consciousness.

Transient ischaemic attacks (TIAs)

This is a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal ischaemia without acute infarction. The previous definition with its arbitrary 24-hour time scale is no longer used, as the end point is now tissue injury. Examples include anterior circulation — sudden transient loss of vision in one eye (amaurosis fugax), aphasia, hemiparesis; or posterior circulation — diplopia, ataxia, hemisensory loss, dysarthria, transient global amnesia.

• Migraine aura can be difficult to distinguish from TIA when it occurs without headache.

• TIA is not a cause of loss of consciousness.

• Examination for cause: look for atrial fibrillation, hypertension, carotid artery bruit and valvular heart disease.

• TIAs may herald the onset of stroke (one-quarter of patients developing stroke have had a TIA, usually within the previous week).

• The ABCD² score can help to stratify stroke risk in the first 2 days.

•Age > 60 years	1 point
•BP > 140 mmHg systolic and/or > 90 mmHg diastolic	1 point
•Clinical features
Unilateral weakness	2 points
Isolated speech disturbance	1 point
Other	0 points
•Duration of symptoms (mins)
> 60	2 points
10–59	1 point
< 10	0 points
•Diabetes
Present	1 point
Absent	0 points

A score of < 4 is associated with a minimal risk, whereas > 6 is high-risk for a stroke within 7 days of a TIA.

• If patients are considered to have had a high-risk TIA, i.e. ABCD² score > 4, or have had two recent TIAs, especially within the same vascular territory, then they should be admitted for investigation and commencement of secondary prevention.

• All patients should be referred to a TIA clinic and ideally seen within 24 hours. Investigation and treatment should be regarded as urgent and should be completed within 2 weeks.

Investigations

• Look for the source of the embolus — carotids (Doppler) or cardiac echo, ECG + 24-hour tape.

• CT brain in the first instance. Further (MRI) imaging of the brain and vascular system may subsequently be required where pathology or vascular territory is uncertain.

Treatment

• Antiplatelet therapy as for stroke (p. 632).

• Modification of vascular risk factors — smoking, hypertension, statins as above.

• Early endarterectomy for symptomatic 70–99% carotid artery stenosis (within 1 week if possible).

• Anticoagulation for atrial fibrillation (p. 457) (aspirin 300 mg daily for 2 weeks, then anticoagulate with heparin and warfarin or dabigatran).

Intracerebral haemorrhage

• If stroke is secondary to an intracerebral bleed, management is primarily supportive. There is a limited role for surgical evacuation of haematoma.

• Stop antiplatelet therapy and reverse anticoagulation (if the patient has a mechanical cardiac valve, consult a cardiologist).

• Hypertension should be treated but not aggressively, as it may reduce cerebral perfusion. Give antihypertensives if BP is persistently > 200 mmHg systolic (p. 457). Cerebellar haematomas may progress to brainstem compression or obstructive hydrocephalus and require prompt neurosurgical evaluation.

Subarachnoid haemorrhage (SAH)

SAH usually results from arterial bleeding into the subarachnoid space following rupture of saccular berry aneurysms on the circle of Willis (70–80%). Arteriovenous malformations account for 5–10% of SAH.

Patients present with sudden onset of an explosive headache — thunderclap (< 30 secs from onset to maximal severity), often associated with vomiting. There may be loss of consciousness at the onset. Sentinel haemorrhage can cause warning headache a few days before the major bleed. Examination may reveal neck stiffness, reduced level of consciousness, focal neurological deficit, e.g. third nerve palsy (indicating ruptured posterior communicating artery aneurysm) or hemiparesis. Subhyaloid haemorrhage may be visualized on fundoscopy. Migraine and coital headache can also occasionally present with sudden onset of severe headache. In thunderclap headache always investigate for possible SAH.

Management

• Initially stabilize the patient, resuscitate, give O₂, site IV access, and place on cardiac and BP monitor (see management of coma, p. 627).

• Perform an urgent CT brain to look for subarachnoid or intraventricular haemorrhage (95% sensitivity on day 1, falling to 50% at 1 week and 30% at 2 weeks after the bleed).

• If the history is suggestive and CT is normal, perform lumbar puncture to look for blood-stained CSF and xanthochromia (bilirubin discoloration of CSF due to cell lysis). Xanthochromia may be detected from ~12 hours to 3 weeks after SAH. Visible inspection of a centrifuged sample is often sufficient to detect xanthochromia, but laboratory spectrophotometry is more sensitive.

• If SAH is confirmed, arrange for CT cerebral angiography to identify the source of bleeding.

• Definitive treatment is early endovascular coiling of the aneurysm or surgical clipping where endovascular treatment is not possible.

• Nimodipine (e.g. 60 mg orally 4-hourly for 2–3 weeks, or 1 mg/hour IV) can reduce arterial spasm and reduce further cerebral infarction.

• Avoid hypotension (it may worsen the ischaemic deficit). Treat hypertension if diastolic pressure is persistently > 130 mmHg. Aim for a very gradual decrease in BP with monitoring and frequent repeat neurological examination.

• Supportive measures include bed rest, analgesia and laxatives (avoid sudden rises in ICP or BP).

• Watch for complications, including hyponatraemia (SIADH), hydrocephalus (obstruction of cerebral aqueduct by blood) and vasospasm causing ischaemic deficits.

Subdural haemorrhage

Subdural haemorrhage is caused by venous bleeding from bridging veins between cortex and venous sinuses. The elderly, alcoholics and patients on anticoagulants or with epilepsy are particularly susceptible. Subdural haemorrhage often follows head trauma, which may be minor. The latent period between injury and symptoms can be several weeks.

Patients present with headache, drowsiness and confusion that may fluctuate, focal neurological deficits and/or personality change.

Conservative management may be appropriate in older patients without neurological deficit.

Extradural haemorrhage

Extradural haemorrhage results from arterial bleeding between bone and dura, usually at the site of skull fracture (often the middle meningeal artery). Following head injury there may be a lucid interval followed by a rapid reduction in the level of consciousness as the haematoma increases in size. Refer to a neurosurgeon.

Epilepsy

Epilepsy is a predisposition to recurrent seizures. Seizures are classified as:

• Generalized seizures. These are due to diffuse electrical discharge within the brain. They are characterized by loss of awareness (e.g. absence seizures and generalized tonic clonic seizures) or myoclonic jerks.

• Partial seizures. Seizure activity is localized to one part of the brain (also known as localization-related epilepsy (LRE)):

• simple partial (no loss of awareness, e.g. motor jerking of a body part, epigastric aura).

• complex partial (alteration of awareness, frequently associated with stereotypical behaviour and automatisms). Partial seizures may become secondarily generalized.

Diagnosis

The diagnosis of epilepsy is predominantly clinical, but determining whether an episode of apparent loss of consciousness is due to epilepsy can be difficult. The main distinction is from syncope (p. 385). Witness descriptions or video recordings of the event are invaluable. Ask the patient and the witness what happened before, during and after the event. Ask about risk factors for epilepsy (e.g. family history, birth and developmental history, febrile convulsions in childhood, previous meningitis or encephalitis, significant head injury), arrhythmias and diabetes. Also enquire about drug use and alcohol excess.

• Syncope may be associated with precipitants, e.g. prolonged standing in a hot place, micturition, a bout of coughing, or distress such as pain or the sight of blood.

• Syncopal prodrome and rapid recovery are characteristic.

• Loss of consciousness while lying down is not likely to be syncope.

• Urinary incontinence may occur in both syncope and seizures, and is a poor discriminator.

• Even in simple syncope, isolated jerks of a limb or the whole body may be seen.

Examination is often normal.

Investigations and referral

• Lying and standing BP.

• FBC, electrolytes, glucose.

• ECG (look for conduction block, arrhythmia, long QT interval).

• For a probable epileptic event, brain imaging with MRI (especially if focal onset seizure) and EEG to classify epilepsy type. EEG is usually not helpful where diagnosis (syncope vs. seizure) is uncertain.

Use of anti-epileptic drugs (AEDs) (Table 17.2)

After a first seizure, patients should be seen in a specialist neurology clinic. AEDs are indicated when there is a firm diagnosis of epilepsy and a substantial risk of recurrent seizures (usually after second seizure or after first seizure with abnormal imaging or unequivocal abnormal EEG). The aim is monotherapy with seizure freedom and no side-effects. There is no role for trial of an AED where diagnosis of epilepsy is uncertain.

• Introduce AEDs at low dose and gradually titrate upwards until the seizures are controlled or side-effects become unacceptable.

• Partial seizures or secondary generalized seizures (LRE) are often treated with carbamazepine retard, lamotrigine or levetiracetam.

• Generalized seizure types may be treated with sodium valproate, levetiracetam or lamotrigine as first-line treatment. Phenytoin is now generally only used in emergency treatment of seizures to achieve a rapid therapeutic effect.

• Acute symptomatic seizures e.g. in the context of an intercurrent infection in patients with epilepsy can be treated with clobazam 10 mg twice daily for one week, 10 mg daily for one week and then stopped.

• If seizures are not controlled with the first AED, gradually introduce a second agent and slowly withdraw the first AED once the second is established. If the patient is still not seizure-free, then combination therapy may be required. Levetiracetam is increasingly used and is licensed as first-line therapy for all seizure types.

• Epilepsy is one of the few disorders where non-generic prescribing is justified to ensure consistent drug levels.

• Routine monitoring of AED levels is not needed and should be possibly reserved for assessing compliance and toxicity.

• In refractory epilepsy reconsider diagnosis, for example, non-epileptic attack disorder. Consider combination therapy with newer AEDs, vagal nerve stimulation and, in LRE, epilepsy surgery (e.g. temporal lobectomy for temporal lobe epilepsy secondary to hippocampal sclerosis).

Table 17.2 Anti-epileptic drugs (AEDs) — indications and common side-effects

Driving and epilepsy

Rules for this vary in different countries. In the European Union, patients with epilepsy are not legally permitted to drive motor vehicles unless they have been seizure-free for 12 months (with or without medication); this can be as little as 3 months in parts of the USA. Driving may be permitted by some licensing authorities if attacks occur solely in sleep. Similarly there may be more flexibility if an isolated seizure is considered ‘provoked’. Rules are much more stringent for driving commercial vehicles and for some occupations, e.g. aircraft pilots, divers. In the UK it is an essential medical requirement to inform patients of the law. The patient should then inform the licensing authority.

Lifestyle issues

Patients should avoid known precipitants, e.g. sleep deprivation, recreational drugs or excess alcohol. Encourage full compliance with prescribed medication. Give safety advice, e.g. showers rather than baths, care when cooking, do not bathe infants alone, do not swim alone or in deep water, avoid strobe lighting in generalized epilepsies.

Women and epilepsy

Women of childbearing age should be informed of the risk of teratogenicity with AEDs (particularly high with sodium valproate and increased if multiple AEDs). Careful planning of pregnancy is essential. Enzyme-inducing AEDs increase oestrogen metabolism and reduce efficacy of the OCP (e.g. carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, topiramate; a higher dose of oestrogen is required). Give advice on contraception, including barrier methods (in combination with the OCP), intra-uterine devices or depot injections. If the patient is planning pregnancy commence folic acid 5 mg daily to reduce the risk of neural tube defects and try to reduce medication to monotherapy at the lowest effective dose. If the patient is taking valproate, switch to another AED. Advise patients to seek medical attention as soon as they know they are pregnant.

Long-term use of AEDs, particularly in women, is associated with osteoporosis. Refer peri- and post-menopausal patients for bone mineral density scans at approximately 3-yearly intervals.

Withdrawal of AEDs

AED withdrawal should only be contemplated after at least 2 years of freedom from seizures. In juvenile myoclonic epilepsy (10% of patients in epilepsy clinics) patients usually require lifelong therapy.

Ensure that the patient is actively involved in decision-making. Probability of remaining seizure-free after AED withdrawal is increased if:

• the patient is seizure-free on monotherapy

• there is no structural lesion

• there has been a long seizure-free period.

If the patient is taking multiple AEDs, withdraw only one drug at a time.

EEG prior to or during drug reduction can be helpful in predicting seizure recurrence.

Advise patients not to drive during periods of drug reduction and for 6 months after reduction/withdrawal is completed. If they have a seizure during drug alteration the Driving Licence Authority regulations will apply.

Status epilepticus (SE)

Isolated seizures usually terminate spontaneously within 2 mins. SE is defined as seizures or multiple seizures occurring without full recovery of consciousness over a prolonged period (> 10 mins). It is a neurological emergency with high mortality. In young women presenting with SE, consider eclampsia.

Administer oxygen. The patient may need a naso-pharyngeal airway. Early administration of benzodiazepines (e.g. lorazepam IM or IV, diazepam 20 mg rectally, buccal midazolam 10 mg) can prevent frequent seizures from progressing to SE.

Acute management

This is shown in Box 17.4.

Box 17.4 Status epilepticus management

Remember

• Accuracy of diagnosis — ensure not pseudo-status epilepticus

• Treat convulsions quickly

• Continued ICU monitoring and cardiorespiratory support

Several treatment schedules exist

• At home, give immediate benzodiazepines, e.g. diazepam (10–20 mg) orally or buccal midazolam 10 mg, and repeat once if necessary. If oral route impossible, give rectal diazepam

• Arrange immediate admission to hospital

• Administer oxygen, monitor ECG, BP, routine bloods (include alcohol level, glucose, calcium, magnesium, drug screen, anticonvulsant levels)

• Correct hypoglycaemia if found

• Give thiamine IV (250 mg) if nutrition is poor or excess alcohol use suspected. (In the UK, give vitamin B and C, high-potency ampoules, one pair IV over 10 mins). Beware anaphylaxis with IV thiamine

• Anti-epileptic drugs (AEDs):

1 Give lorazepam IV 4 mg at 2 mg/min

2 Reinstate previous AEDs. Measure levels urgently. Has the patient had phenytoin recently?

3 If status continues, IV phenytoin or fosphenytoin is used:

a) Phenytoin: give 15 mg/kg IV diluted to 10 mg/mL in 0.9% saline into a large vein at ≤ 50 mg/min

(Phenytoin 250 mg 5 mL ampoule)

b) Fosphenytoin: this is a pro-drug of phenytoin and can be given faster than phenytoin. Doses are expressed in phenytoin equivalents (PE): fosphenytoin 1.5 mg = 1 mg phenytoin

Give 15 mg/kg (PE) fosphenytoin (15 mg × 1.5 = 22.5 mg) diluted to 10 mg/mL in 0.9% saline at 50–100 mg (PE)/min

(Fosphenytoin sodium 750 mg 10 mL ampoule)

4 If status continues, give phenobarbital 10 mg/kg diluted 1 in 10 in water for injection at ≤ 100 mg/min. (Phenobarbital 200 mg/mL 1 mL vial in propylene glycol 90% with water for injection 10%.) IV clonazepam, valproate or levetiracetam are alternative AEDs that can be administered

5 If status persists, use thiopental or propofol anaesthesia with assisted ventilation and transfer patient to ICU. Alternative sedatives include lorazepam or midazolam infusions

• EEG monitoring is valuable if there is doubt about the nature of status and to monitor for burst suppression pattern

• Search for an underlying cause and treat appropriately

• Complications of status epilepticus, including acidosis, aspiration pneumonia, rhabdomyolysis and acute kidney injury also need addressing

• Patients require continuous monitoring until status epilepticus is controlled

• Remember: 25% of apparent status turns out to be pseudo-status

Movement disorders

Movement disorders may be divided into:

• hypokinetic disorders, where there is too little movement, e.g. parkinsonism.

• hyperkinetic disorders, where there are additional involuntary movements (tremor, chorea, dystonia, tics and myoclonus).

Idiopathic Parkinson’s disease (PD)

PD is a neurodegenerative disorder affecting nigrostriatal dopaminergic cells, as well as other brain cell populations.

• The diagnosis is clinical and based on the presence of distinctive motor features: tremor (resting, ‘pill-rolling’), rigidity, hypokinesia (poverty of movement — the sine qua non of Parkinsonism) and postural changes (stooped posture, shuffling gait, reduced arm swing, impaired balance).

• Patients may have hypophonia, reduced facial expression and impaired dexterity, e.g. manifesting as micrographia. Non-motor features, such as anosmia, diffuse aches and pains and rapid eye movement (REM) sleep behaviour disorder, may precede development of motor symptoms by many years. Symptoms and signs are initially unilateral, becoming bilateral as the disease progresses. Check for use of neuroleptic, antiemetic or other drugs causing Parkinsonism, e.g. valproate. In patients under the age of 50, exclude Wilson’s disease (p. 193).

• A dopamine transporter (DaT) scan may occasionally be useful to confirm nigrostriatal dopaminergic cell loss in patients with atypical tremor where diagnosis is uncertain.

Medical treatment (Table 17.3)

Dopamine replacement with a dopamine agonist or L-dopa (LD) (combined with a dopa decarboxylase inhibitor (DDI) — benserazide, co-beneldopa) is the mainstay of pharmacological therapy. There is no conclusive evidence that any of the currently available drugs is neuroprotective. Antiparkinsonian drugs should be initiated at low dose and titrated gradually to the minimum dose required for adequate symptom control.

• Initial medical treatment. Exercise and physiotherapy are useful. Initiate pharmacological treatment when there is impairment/disability resulting from symptoms. Early treatment with monoamine oxidase B (MAOB) inhibitors (selegiline or rasagiline) may delay the need for more definitive dopamine replacement therapy by several months.

• Dopamine receptor agonists (DAs) are used, particularly in younger patients (e.g. below age 70, but depends on individual patient needs). Although less efficacious in symptom control than LD and generally less well tolerated, initial DA monotherapy may be associated with fewer long-term motor complications. Start LD + DDI (co-beneldopa or co-careldopa) in older patients or those more severely affected at diagnosis.

• Non-ergot DAs (pramipexole and ropinirole oral 3 times daily, or once daily with slow-release formulations, rotigotine via transdermal patch) are used in preference to ergot-derived drugs.

• All patients with PD will eventually require treatment with LD, often in combination with a DA. A typical starting dose is 50 mg of LD (e.g. co-careldopa 62.5 mg) 3 times daily, increasing after 1 week to 100 mg 3 times daily.

• LD absorption after protein-rich meals is unpredictable and taking doses at least 40 mins prior to meals may be helpful.

• Use domperidone as an antiemetic (20 mg 3 times daily) when initiating DA therapy. Other antiemetics may exacerbate parkinsonism by blocking central dopamine receptors.

• Subsequent medical treatment. As the disease progresses, medical therapy for PD becomes more difficult. Higher doses of dopamine replacement therapy are required and response becomes more unpredictable with the development of motor fluctuations and dyskinesias. Approximately 10% of patients per year develop motor complications in the form of ‘wearing off’ (the duration of effect of individual doses of LD becomes progressively shorter), dyskinesias (involuntary choreiform movements) and, eventually, ‘on/off’ phenomenon (sudden, unpredictable transitions from mobile to immobile). Eventually, patients may alternate between the ‘on’ state with dopamine-induced dyskinesias and periods of complete immobility (‘off’).

• Motor complications. Management of the motor complications of treatment is difficult. Dose fractionation of LD, increasing dose frequency and introduction of a catechol-O-methyl transferase (COMT) inhibitor (entacapone or tolcapone) improve motor control for ‘end-of-dose deterioration’. Entacapone is also available as a combined preparation with LD and carbidopa. Controlled-release preparations of LD are generally not used during the day owing to slow onset of action and unpredictable response. However, slow-release LD is still often used in the management of overnight symptoms.

Table 17.3 Drugs used in Parkinson’s disease

Other drugs used to treat PD

• MAOB inhibitors such as selegiline and rasagiline have a mild symptomatic effect (see above).

• Amantadine 100–200 mg once or twice daily has a modest antiparkinsonian effect but may improve dyskinesias in advanced disease. Amantadine should not be taken after 2 p.m. as it may disturb sleep.

• Antimuscarinics (e.g. trihexyphenidyl up to 15 mg daily) may help tremor in particular but are now rarely used in PD except in younger patients. They often cause confusion in older patients.

• Apomorphine (SC pump 1–4 mg/hour during daytime; maximum dose 100 mg) is a potent, short-acting, DA administered subcutaneously by an auto-injector pen as intermittent ‘rescue’ injection for ‘off’ periods or by continuous infusion pump. It is used in advanced PD.

• A formulation of LD administered by continuous infusion via a jejunostomy tube is used in patients with advanced disease but availability is limited by high cost.

Surgical treatment

Deep brain stimulation (DBS), particularly bilateral insertion of electrodes into the subthalamic nucleus or globus pallidus, is increasingly used to treat advanced PD where medical treatment causes severe motor fluctuations and dyskinesias. Efficacy is equivalent to LD treatment but drug-induced complications such as dyskinesias improve after drug reduction or withdrawal.

Non-motor complications

Eventually, postural instability, falls, swallowing problems and other LD-unresponsive problems may develop. Fludrocortisone may help with postural hypotension. Cognitive impairment and dementia become a significant problem in advanced disease and respond to cholinesterase inhibitors, e.g. rivastigmine (start 1.5 mg up to 3–6 mg twice daily). Treating depression (present in up to 50% of patients) with a selective serotonin reuptake inhibitor (SSRI) is one of the interventions that most improves quality of life in PD. Access to skilled physiotherapy, occupational therapy and nurse specialists is necessary throughout the course of the disease.

Hyperkinetic movement disorders

Benign essential tremor

This describes symmetrical postural tremor of hands e.g. holding a cup or cutlery; sometimes head or voice tremor occurs. There is usually a long history by the time of presentation and a family history is common. Tremor may improve with alcohol. Treatment is with a β-blocker, e.g. propranolol 80–240 mg of slow release or 40 mg 3 times daily, or primidone — start at 62.5 mg daily and gradually increase; maximum dose 750 mg daily, often poorly tolerated. Rarely, thalamic DBS is required if tremor is severe.

Chorea

Chorea is jerky, dance-like, involuntary movements that ‘flit’ from one body part to another. When chorea is mild, the patient may appear ‘fidgety’. Causes include systemic disease (thyrotoxicosis, SLE, primary polycythaemia, rheumatic fever — Sydenham’s chorea), drugs (e.g. LD and OCP), pregnancy and Huntington’s disease. Treatment involves dopamine-blocking and depleting drugs, which may reduce chorea. Tetrabenazine depletes neurones of dopamine (starting dose 12.5 mg twice daily, increasing to 12.5–25 mg 3 times daily; maximum dose 200 mg/day) but may be limited by development of depression and parkinsonism. Neuroleptic drugs such as sulpiride 200–400 mg twice daily, which block dopamine receptors, are also used.

Dystonia

Dystonia is painless muscle spasms causing twisting movements and abnormal postures. Childhood-onset dystonia is often genetic or due to a structural brain abnormality (e.g. birth asphyxia) and is more likely to become generalized. Late-onset dystonia is commoner, usually sporadic and more likely to remain localized to one body part, particularly the cranio-cervical region, e.g. blepharospasm or torticollis. Task-specific forms may occur, e.g. writer’s cramp or occupational dystonias, especially in musicians. Treatment of focal dystonia is by IM injection of botulinum toxin. Duration of effect is approximately 3 months.

• Dopa-responsive dystonia is a genetic disorder that responds dramatically to low doses of LD; a trial of treatment should be considered in cases of early-onset dystonia (< 30 years of age).

• Acute dystonic reactions (e.g. trismus, spasmodic torticollis, oculogyric crises) may occur after even a single administration of a dopamine receptor antagonist, e.g. phenothiazines, butyrophenones and metoclopramide. Treat with an IV antimuscarinic, e.g. benzatropine 1–2 mg IV or procyclidine 5–10 mg IV. Tardive dystonia may follow prolonged use of neuroleptic medications in psychiatric practice.

Myoclonus

Sudden involuntary jerks of a single muscle or a group of muscles may cause patients to drop what they are holding or fall to the floor (negative myoclonus). Myoclonus may be part of epilepsy (e.g. juvenile myoclonic epilepsy) or encephalopathies and a wide variety of neurological disorders. Drugs such as clonazepam, levetiracetam or valproate can be useful.

Headache

The history is often sufficient to differentiate between common primary headache syndromes and more sinister, but rare, secondary headache.

Acute single episode of headache

If the headache is associated with drowsiness or neck stiffness, meningitis (p. 54), encephalitis (p. 55) and subarachnoid haemorrhage (p. 634) must be excluded. Sudden-onset thunderclap headache is suggestive of SAH. The incidence of serious secondary causes of headache is higher in A&E attenders than in general practice.

• Examination should include GCS, temperature, BP, neck stiffness, a check for any focal neurological signs, and fundoscopy (papilloedema is a late sign of raised ICP).

• Investigations include ESR, CT scan and lumbar puncture, if necessary (check opening pressure; send for microscopy, protein, glucose (with matched blood glucose for ?meningitis) and xanthochromia if SAH is a possibility)

Primary headache disorders

Migraine

There is a high population prevalence (~10–15%, F > M). Migraine usually starts in the teenage or early adult years and rarely starts after age 40. The headache is typically:

• moderate or severe

• throbbing

• hemicranial or holocranial

• made worse by head movements or exertion

• associated with features such as nausea, photophobia, phonophobia and osmophobia

• lasts usually from 4 hours to 3 days.

Migraine is due to changes in the brainstem blood flow which cause release of vasoactive peptides leading to neurogenic inflammation which produces the pain. Migraine without aura is more common than migraine with aura (25%) and those who experience auras usually do not have aura before each attack. Aura occurs before the onset of the headache and should last no longer than 1 hour. Visual aura is more common than sensory aura or dysphasia. Weakness (hemiplegic migraine) is rare. Typically, aura consists of positive and negative symptoms (shimmering, bright lights, fragmented images with scotomas or other visual field defects such as hemianopia) and usually evolves, changing over minutes. Migraine aura without subsequent headache (acephalic migraine) may occur in older patients and be confused with TIA.

• Acute treatment. Paracetamol 1 g, aspirin 900 mg (dispersible formulation) or an NSAID, e.g. ibuprofen 400–600 mg, naproxen 500 mg or tolfenamic acid 200 mg rapid release, is given, as early as possible during an attack. Gastric emptying is reduced during the attack so dispersible formulations are preferred. Antiemetics (e.g. metoclopramide 10 mg or domperidone 10 mg) are also usually required, both to promote absorption of analgesics and reduce nausea. Combined tablets are available. If these measures are ineffective, use a 5-hydroxytryptamine (5HT)_1B/_1D serotonin receptor agonist (triptan). These drugs relieve both the pain and the nausea. Triptans should be avoided in patients with vascular disease or uncontrolled/severe hypertension. Triptans should not be given too early (e.g. during the aura phase), as they may be ineffective at that point. They should be given at the onset of the headache. There are several triptans available with a spectrum of efficacy, including:

• Sumatriptan 25–100 mg at onset of headache, repeat if necessary after at least 2 hours, max. 300 mg in 24 hours; SC 6 mg sumatriptan produces highest efficacy and most rapid response.

• Zolmitriptan 2.5 mg at onset, repeat if only partial response after 2 hours; 5 mg also available.

• Rizatriptan 10 mg at onset, repeat after 2 hours if only partial response.

• Naratriptan 2.5 mg at onset, repeat after 4 hours if only partial response; has placebo level side-effects but probably lower efficacy than other triptans. It is used when other triptans are not tolerated.

• Almotriptan 12.5 mg at onset, repeat after 2 hours if necessary, max. 25 g in 24 hours.

• Eletriptan 40 mg at onset, repeat after 2 hours if necessary, max. 80 g in 24 hours.

• Frovatriptan 2.5 mg at onset, repeat after 2 hours if necessary, max. 5 g in 24 hours.

• Oro-dispersible formulations exist for some triptans but absorption is slower. Nasal spray formulations also exist (but sumatriptan spray is not recommended in vomiting as absorption depends on ingestion; zolmitriptan spray is partially absorbed in the mouth).

If there is no response to an initial dose, do not persist with subsequent doses during the same attack; the drug may be effective in subsequent attacks, however. Ergotamine and derivatives are no longer recommended except in specialist headache clinics. Avoid the use of opiate-based drugs.

• Women and migraine

• Combined oral contraceptives may provoke or exacerbate migraine, necessitating withdrawal or a switch to a progesterone-only pill. The OCP may be effective in menstrual migraine.

• Women with migraine and aura should not take an oestrogen-containing OCP and should be advised not to smoke owing to increased stroke risk.

• In pregnancy migraine may improve. Paracetamol is safe as acute treatment.

• Treatment of frequent migraine and chronic migraine. Trigger factors to be avoided include stress and ‘let-down’ after a stressful period, lack (or excess) of sleep, missing meals, alcohol and bright light. Individual foods are rarely a trigger. Analgesic overuse must be stopped (see below). Migraine suppression medication is underused and should be advised if frequency of migraine is more than twice per month or one disabling attack per month.

• Propranolol LA, a β-blocker, 80 mg increasing according to response (atenolol, metoprolol and bisoprolol are also used).

• Sodium valproate 200 mg twice daily, increasing after 1 week to 400 mg twice daily. Higher doses may be required. Women must be warned about potential teratogenicity.

• Topiramate 25 mg at night, increasing by 25 mg every 2 weeks to 50 mg twice daily. Women must be warned about potential teratogenicity.

• Amitriptyline 10 mg at night, increasing by 10 mg per week to 50–70 mg.

• Serotonin antagonists: pizotifen is occasionally used but may cause weight gain.

• Methysergide is rarely used because of side-effects (retroperitoneal, heart valve and pleural fibrosis). If methysergide is initiated, this should be under the supervision of a specialist headache clinic.

Medication overuse headache

Regular use of analgesics, especially codeine-containing combinations, on two or more days per week over several months will lead to chronic headache. This occurs particularly in those with a primary headache disorder such as migraine. It is a common problem in clinical practice and complete withdrawal from analgesics is needed for prophylactic drugs to be effective. Patients should be warned that their headache will worsen for 2–3 weeks after cessation of medication, before starting to improve.

Giant cell arteritis

See p. 319.

Cluster headache

• There is severe, strictly unilateral pain centred around one eye.

• It is more common in men.

• Associated autonomic features include lacrimation, red eye, rhinorrhoea and ptosis.

• Patients are restless and agitated, tending to walk around with the pain (in contrast to migraine).

• Attacks last 15 mins to 3 hours and occur several times in 24 hours, typically at night (‘alarm clock headache’). Attacks occur in clusters lasting weeks with long periods (up to years) of complete remission between.

• Analgesics are rarely helpful. Abortive treatment with SC sumatriptan or 100% oxygen at 7–12 L/min can be effective. A short course of high-dose steroids may also be tried at the start of a cluster. Prevention of the cluster is with verapamil/lithium carbonate. Patients should have an ECG prior to starting verapamil and with each dose increase. Very high doses of verapamil may be required. Avoid alcohol during clusters.

• Paroxysmal hemicrania is a rare form of headache with shorter, more frequent, but also very severe bouts of headache and is a differential for cluster headache. It is more common in women. Unlike cluster headache, paroxysmal hemicrania is indometacin-responsive (25 mg 3 times daily, increased up to a maximum of 75 mg 3 times daily).

Idiopathic stabbing headache

There are paroxysms of sharp, well-localized, momentary pain. It may move from place to place or be localized to one spot. Idiopathic stabbing headache is common in migraineurs. Treatment is usually not required but responds to indometacin.

Idiopathic intracranial hypertension

This mainly affects young, overweight women who present with high-pressure headache (worse on lying flat) and visual obscurations or visual field deficits. Examination may reveal reduced acuity, visual field constriction and papilloedema on fundoscopy. Investigations include MRI/MR venography to exclude a mass lesion and venous sinus thrombosis. If lumbar puncture confirms high opening pressure (> 25 cmH₂O) with normal CSF constituents, then treat as idiopathic intracranial hypertension. Treatment is to advise weight loss and initiate acetazolamide 250 mg twice daily (may increase up to 500 mg twice daily). Bendroflumethazide 2.5 mg is an alternative. Repeated lumbar puncture is also used. If, despite these measures, visual acuity worsens, then refer for surgical intervention (e.g. ventriculo-peritoneal shunt, lumbo-peritoneal shunt, optic nerve fenestration).

Low-pressure headache

• The postural nature, with resolution immediately after lying flat, is the characteristic feature.

• Gadolinium-enhanced MRI may show meningeal enhancement; CSF radionuclide tracer studies may be needed to identify a leak.

• IV caffeine may be tried; an autologous epidural blood patch close to the site of the spinal leak can be helpful.

• Patients presenting with spontaneous low-pressure headache should be screened for autoimmune rheumatic disorders.

Facial pain

Trigeminal neuralgia

• Trigeminal neuralgia is usually primary but can be secondary to demyelination (MS) or other posterior fossa inflammatory/structural disorders.

• There are intense stabs of lancinating pain in the distribution of one or more branches of the trigeminal nerve. A facial trigger point is often present.

• Carbamazepine 100–400 mg/8 h or oxcarbazepine 300 mg twice daily (for more rapid titration) can be effective in reducing the frequency and severity of attacks. Gabapentin, lamotrigine and phenytoin are also used.

• MRI scanning with dedicated sequences to look for neurovascular compromise is useful.

• Surgery (trigeminal ganglion destructive procedures or posterior fossa microvascular decompression) is the treatment of choice if response to medication is inadequate or not maintained.

Benign paroxysmal positional vertigo

’Dizziness’ means different things to different people. True vertigo indicates an illusion of movement, typically spinning. The commonest cause is benign paroxysmal positional vertigo, which may follow head injury or ear infection. The Hallpike test is diagnostic, with torsional nystagmus seen. The Epley particle repositioning manœuvre may be curative. Cawthorne–Cooksey exercises/vestibular rehabilitation are preferred to vestibular sedatives (http://www.dizziness-and-balance.com/disorders/bppv/bppv.html; www.dizziness-and-balance.com/treatment/rehab/caw thorne.html).

Traumatic brain injury

Head injury is common. Most cases are mild, but severe injuries carry a high morbidity and mortality.

Severe head injury

Immediate management

• Initially, ensure that the patient is resuscitated (see coma, p. 627). Site IV access. Immobilize the neck in a stiff collar. Avoid nasal intubation if there are facial fractures. Emergency tracheostomy may be needed. Avoid hypoventilation and hypotension, as these can worsen cerebral perfusion.

• Examination must include a search for penetrating injuries and wounds. CSF otorrhoea/rhinorrhoea suggests a base of skull fracture.

• Document GCS (Table 17.1) and any neurological deficits. Perform serial examinations to detect signs of deterioration early.

• Indications for immediate intubation include:

• GCS < 8/15

• loss of protective laryngeal reflexes

• PaO₂ < 9 kPa on air; PaCO₂ > 6 kPa

• spontaneous hyperventilation resulting in PaCO₂ < 3.5 kPa.

CT scanning is also required if the patient is > 65 years old or on anticoagulants, or if there was a dangerous mechanism of injury. Head injury is often associated with trauma to the cervical spine. Imaging of the cervical spine is essential to exclude fracture or dislocation.

Further management

Most patients with severe head injury and/or, for example, contusion, intracranial haematoma, cervical or skull fracture, penetrating injury (do not remove the foreign object), focal neurological deficit, persisting coma (GCS < 8), unexplained confusion > 4 hours, seizure without full recovery or CSF leak require prompt neurosurgical consultation and subsequent neurosurgical management.

• The aim is to maintain the patient with a well-perfused and well-oxygenated brain. Maintain cerebral perfusion pressure (mean arterial pressure minus intracranial pressure; estimate ICP at 30 mmHg if unknown) > 70 mmHg using ionotropes if necessary. Nurse the patient head up at a 10–15° angle. Keep PaO₂ > 15 kPa and PaCO₂ < 4.5 kPa if possible.

• Duration of post–traumatic amnesia (PTA) is one of the most useful indicators of severity of brain injury and long-term prognosis. It presents as a confusional state and agitation following head injury and lasts until the patient is able to make and retain new memories. Nursing a confused patient in PTA is often difficult.

Late complications

Late complications following significant traumatic brain injury include incomplete recovery (hemiparesis, cognitive impairment), post-traumatic epilepsy, depression, benign paroxysmal positional vertigo, chronic subdural haematoma (p. 635), hydrocephalus and chronic traumatic encephalopathy. Patients with persisting deficits may require specialist rehabilitation on a dedicated rehabilitation unit.

Less severe head injury

Management

Some patients are discharged from A&E into the care of a responsible adult. These patients should have a GCS of 15 at time of discharge and give no cause for clinical concern. They should only be discharged when it is certain that there is someone to supervise them. The carer must be given written documentation on how to observe the patient and in which circumstances to return to the hospital.

Admission to hospital is indicated in patients with new, significant abnormalities on imaging, GCS < 15 after imaging, ongoing vomiting, severe headache or other concerns (e.g. drug or alcohol intoxication, meningism, CSF leak), or if the patient warrants CT imaging but this cannot be performed promptly.

Patients who are alert and awake with no neurological deficit are monitored in hospital for 24 hours. Observations should be recorded every 30 mins until GCS = 15 and then half-hourly for 2 hours, hourly for 4 hours and 2-hourly thereafter. Any neurological deterioration after head injury warrants further brain imaging to look for haemorrhage or expanding haematoma. MRI is more sensitive than CT and will better allow for detection of shallow intrinsic and extra-axial blood collections, as well as diffuse axonal injury.

Diseases of the spinal cord

The spinal cord extends from C1 to the lower border of L1. Below L1 the spinal canal is occupied by the cauda equina and compressive lesions cause a radiculopathy (lower motor neurone syndrome). Paraparesis (weakness of both legs) is usually due to a spinal cord lesion (occasionally a parasagittal tumour). Quadriparesis (weakness of arms and legs) is often due to a cervical cord lesion.

Spinal cord syndromes

Presentation is with motor and sensory involvement below the level of the lesion. Compression causes weakness of both legs and the sphincters may be involved. Look for motor and sensory level; the lesion may be several segments above the sensory level. Pain and spinal tenderness (abscess or vertebral collapse) often occur at the level of the lesion and radicular pain may radiate bilaterally at the level of lesion. Acute lesions (trauma, infarction) cause initial spinal shock with flaccid paraparesis and areflexia. Spasticity and hyperreflexia take weeks to develop.

Acute cord syndrome presenting as an emergency

• Stabilize the neck and move the patient with extreme caution after trauma, until spinal instability is excluded.

• Urgent MRI of the whole spinal cord is necessary.

• Contact the neurosurgeons to forewarn them about a possible need for decompression.

• If cord compression is confirmed, start high-dose steroids pre-operatively, e.g. dexamethasone 10 mg IV, followed by 4 mg IV 4 times daily. If MRI is normal or suggests myelitis, proceed to lumbar puncture to look for inflammatory cells and elevated protein.

Patients need regular turning and skin care to prevent pressure sores. Urinary catheterization is usually required. Physiotherapy may help prevent contractures. In the chronic stage, spasticity may respond to baclofen 5 mg 3 times daily or tizanidine 2 mg daily (max. 36 mg).

Cauda equina syndrome

Cauda equina syndrome is a neurosurgical emergency. Central prolapse of a lumbar disc into the lumbar canal is the usual cause, but a chronic form may result from degenerative lumbar canal stenosis or benign tumours.

• Bilateral radicular pain radiating into both legs with severe low back pain is a ‘red flag’ symptom for cauda equina compression from disc prolapse, as is impairment of sphincter or sexual function in the context of back pain.

• Examination reveals bilateral foot weakness with weakness of hip extension and knee flexion, reflex loss in ankles and/or knees, saddle anaesthesia and a palpable bladder.

• Urgent (immediate) MRI of the lumbar spine and surgical decompression are required.

Multiple sclerosis

Multiple sclerosis (MS), an autoimmune disorder causing T- and B-cell dysfunction, is characterized by episodes of demyelination that are disseminated in time and space throughout the CNS. Patients usually present with discrete episodes (relapsing–remitting type) and after many years may develop gradually progressive disability without relapses (secondary progressive). Clinical features of a relapse depend on the site affected but often consist of a combination of positive and negative sensory symptoms, weakness, ataxia, myelitis or episodes of optic neuritis, usually evolving over days and resolving fully or partially over weeks. Optic neuritis is inflammation of the nerve with disc swelling and causes visual loss. Retrobulbar neuritis refers to inflammation behind the disc causing visual loss but with no ophthalmoscopic signs.

Investigations

• MRI is very sensitive for the presence of demyelinating plaques in brain or spinal cord, most of which are clinically silent. Distinguishing white matter lesions on MRI from other pathologies e.g. ischaemic lesions, is occasionally difficult. In patients presenting with a clinically isolated syndrome suggestive of demyelination with no relevant previous neurological history, the presence of asymptomatic white matter lesions on brain MRI predicts the subsequent development of MS.

• Visual evoked potentials can be useful to detect subclinical optic nerve involvement.

• CSF analysis is seldom necessary. Mononuclear cells are raised. Oligoclonal IgG bands are present in 80% due to intrathecal synthesis.

Symptomatic treatment

Treat acute relapses with high-dose steroids (1 g methylprednisolone IV daily for 3 days with proton pump inhibitor (PPI) cover). Symptomatic treatment includes:

• baclofen 5 mg 3 times daily (max. 100 mg/day) or tizanidine 2 mg daily (max. 36 mg/day; monitor LFTs) for severe spasticity

• treatment of neuropathic pain, e.g. gabapentin

• antimuscarinics (e.g. oxybutinin or tolterodine 2 mg twice daily) for detrusor instability

• intermittent self-catheterization for incomplete bladder emptying.

Physiotherapy, occupational therapy and social worker input are necessary, as is education about the condition, often by nurse specialists.

Disease-modifying treatments

• Interferon-β or glatiramer acetate by injection (SC or IM) reduces relapse rate by one-third (severe relapses by half) but the effect on progression of disability is uncertain. Patients with relapsing–remitting MS who can still walk at least 100 metres unaided and who have had at least two clinically significant relapses in the previous 2 years should be referred to a specialist multiple sclerosis clinic for consideration of disease modifying drugs (DMD). Treatment with DMD after a clinically isolated syndrome delays time to second relapse but is not routine practice.

• Natalizumab is a monoclonal antibody that inhibits migration of leucocytes into the CNS via inhibitory α4 integrins on the surface of lymphocytes and monocytes. It is used in severe relapsing–remitting MS. There is an increased risk of progressive multifocal leucoencephalopathy with this treatment.

• Alemtuzumab, an anti-CD52 monoclonal antibody that destroys T- and B-cells, reduces disease activity.

• Mitoxantrone may be used in primary progressive MS in specialist centres. It is potentially cardiotoxic and myelosuppressive.

• New oral DMDs, e.g. fingolimod, a sphingosine-1-phosphate receptor modulator, and cladribine, an immunomodulator of lymphocytes, have shown benefit in ongoing trials.

Disorders of the neuromuscular junction

Myasthenia gravis (MG)

MG is an acquired autoimmune disease involving antibody-mediated disruption of post-synaptic nicotinic acetylcholine receptors at the neuromuscular junction. Weakness principally affects extra-ocular, bulbar and limb muscles. The hallmark is fatigability (e.g. difficulty with prolonged upgaze, voice becomes weaker on counting to 50). It may be limited to ptosis and diplopia (ocular MG) or generalized, affecting limb and respiratory/bulbar muscles.

Diagnostic investigations

• Anti-acetylcholine receptor antibodies are found in up to 90% of cases with generalized MG (only 30% in pure ocular MG); anti-MuSK antibodies (antibodies against muscle-specific tyrosine kinase) are found in up to 50% of patients that are anti-acetylcholine receptor antibody negative.

• Neurophysiology studies show decrement in compound muscle action potential after repetitive motor nerve stimulation and jitter and block on single-fibre EMG.

• CT thorax is required to exclude thymoma.

• Tensilon test has a high incidence of false positives and is no longer used. Edrophonium is not available in many countries.

Treatment

• Plasmapheresis or IV immunoglobulin 0.4 g/kg for 5 days is used for immediate control of myasthenic crisis.

• Acetylcholinesterase inhibitors have a modest symptomatic effect. Pyridostigmine initiated at 30–60 mg × 4 daily can be gradually increased up to 1.2 g daily, although doses of > 450 mg/day may be associated with acetylcholine receptor down-regulation. Co-administration of propantheline 15 mg may be required to reduce muscarinic side-effects such as colic, diarrhoea and excess salivation.

• Immunosuppression is required in most cases of generalized MG. Owing to a dip in function shortly after commencement of steroids, initiation of steroids should generally be carried out with the patient admitted to hospital. Start steroids slowly, as rapid titration may also paradoxically exacerbate weakness. In generalized MG start prednisolone at 10 mg on alternate days, increasing 10 mg every alternate day to a ceiling dose of 1–2 mg/kg on alternate days. Once the patient enters remission (often after 2–6 months), wean prednisolone to the minimum therapeutic dose (usually 10–40 mg on alternate days). Steroids may be combined with acetylcholinesterase inhibitors. Initiate PPI and osteoporosis prophylaxis with steroid therapy (p. 324). Azathioprine (titrate up to 2–2.5 mg/kg/day) is a steroid-sparing immunosuppressive agent that takes up to 6 months for full effect. Measure thiopurine S-methyltransferase (TPMT) assay for susceptibility to toxicity before therapy. Monitor FBC and liver biochemistry (every week for 8 weeks, then every 3 months while on azathioprine). In refractory patients ciclosporin, methotrexate or mycophenolate are used.

• Thymectomy is required in patients < 60 years old and with moderate–severe disease once in remission. If thymoma is found on CT, always proceed to thymectomy; in these cases, however, thymectomy does not induce remission, as it does in patients with thymic hyperplasia.

Myasthenic crisis

Respiratory infection or other stressors, e.g. surgery, can precipitate crisis. Monitor respiratory function closely with lying and sitting FVC. Alert the ICU and ventilate if the FVC is < 15 mL/kg. If ventilation is required, withdraw anticholinesterases temporarily (this removes the uncertainty of a possible overdosage leading to cholinergic crisis and depolarizing block). If the patient is ventilated, it is possible to start steroids at high dose (start at 1.5 mg/kg/day; max. 100 mg daily). Plasmapheresis or IVIG is usually also required.

Botulism

Toxin produced by Clostridium botulinum leads to cranial nerve palsies, weakness and autonomic symptoms, e.g. dry mouth, due to parasympathetic block. Botulism may mimic MG. Food-borne botulism is now rare but wound botulism in IV drug users is on the increase due to ‘skin popping’ (injection of heroin contaminated with C. botulinum spores into anaerobic skin abscesses). Neutralize toxin by administration of the botulism antitoxin and debride abscesses.

Dementia

Dementia is defined as progressive impairment of intellect, affecting more than one cognitive domain (usually including memory) and sufficient to impair day-to-day functioning. It is necessary to exclude clouding of consciousness, indicating delirium. The prevalence increases sharply with age, 25% of the over-80s being affected. Alzheimer’s disease (AD) is by far the most common cause, followed by multi-infarct dementia.

Clinical assessment

This is directed at determining whether the patient has significant cognitive impairment, identifying treatable causes and attempting to make a clinico-pathological diagnosis to guide treatment and indicate prognosis.

A definitive diagnosis can only be made by pathological examination of brain tissue, which is not usually necessary.

Clinical diagnosis is based on history (particularly a corollary history from a family member, as patients may be unaware of their difficulties), examination (especially cognitive testing, including the mini-mental state examination (MMSE) or the more comprehensive Addenbrookes Cognitive Estimate) and investigations.

• History. Ask about temporal gradient in episodic memory (‘forgets what happened yesterday but remembers what happened 40 years ago’), personality change (possible fronto-temporal dementia), language function, calculation, visuo-spatial function (e.g. ‘do you get lost?’), praxis (e.g. dressing dyspraxia), visual hallucinations (dementia with Lewy bodies), effect on functioning, tempo of progression and family history.

• Quantitative psychometric testing by a psychologist is invaluable in identifying the cognitive domains affected and providing a baseline against which to measure future progression in mild cognitive impairment.

Treatable causes for dementia are rare. Investigate all patients (see below). Additional tests may be required in younger patients and those with rapid progression. Depression can present as ‘pseudo-dementia’ and is treatable.

Investigations

• All patients

• Bloods: perform FBC, ESR, U&E, liver biochemistry, glucose, calcium, thyroid function tests, syphilis serology, B₁₂ and folate.

• Brain imaging: CT is sufficient to reveal hydrocephalus, diffuse cerebrovascular disease or a structural lesion, e.g. meningioma, but MRI may reveal a pattern of lobar or hippocampal (AD) atrophy.

Management

Counselling, provision of social support to patient and carers, respite care and use of Enduring Power of Attorney may be required. Treat depression. Avoid the use of neuroleptics for agitation and behavioural disturbance if possible, and use atypical neuroleptics (e.g. risperidone or quetiapine) sparingly if needed. In multi-infarct dementia modify risk factors.

Cholinesterase inhibitors (e.g. donepezil 5–10 mg daily, rivastigmine 1.5–6 mg twice daily, galantamine 8–12 mg twice daily) provide modest benefits in improving cognition and behaviour in AD and fronto-temporal dementia and slow progression slightly. Memantine, an NMDA antagonist, is also used for treatment of moderate to severe AD (5–20 mg per day). Drugs should be introduced at low dose and titrated up gradually according to tolerance. The MMSE should be > 12 to initiate therapy, and should be monitored at least every 6 months and treatment stopped if there is no benefit or if there is marked progression.

Motor neurone disease

Motor neurone disease (also called amyotrophic lateral sclerosis/Lou Gehrig disease in the USA) is caused by relentless destruction of the upper motor neurones and anterior horn cells in the brain and spinal cord. There is no involvement of the sensory system or motor nerves to the eyes and sphincters. The three main disease patterns are progressive muscular atrophy (mainly anterior horn cell), amyotrophic lateral sclerosis (mixed upper and lower motor neurone) and progressive bulbar/pseudobulbar palsy. There can be a mixture of upper and lower motor neurone signs. Needle EMG characteristically shows extensive muscle denervation (including bulbar muscles, and abdominal or paraspinal muscles) with preserved motor conduction velocity.

Treatment should be in the context of a multi-disciplinary team, including nurse specialist and therapists.

• Symptomatic relief includes treatment of spasticity, saliva management, gastrostomy for dysphagia, and non-invasive ventilation for respiratory failure.

• Riluzole 50 mg twice daily is used to extend life or time to ventilation.

• FBC and liver biochemistry require checking prior to initiation of therapy and every 8 weeks thereafter.

Peripheral nerve disease

This affects a single nerve (mononeuropathy) to several individual nerves (multiple mononeuropathy/mononeuritis multiplex), or causes a distal symmetrical polyneuropathy that may be due to either direct axonal damage or, less often, demyelinating disease (see Guillain–Barré, p. 659). Neuropathy usually involves both motor and sensory modalities, but occasionally only motor or only sensory nerves are affected. Since peripheral nerves have long axons, they are metabolically vulnerable and there are therefore many possible causes of neuropathy, especially axonal neuropathy. Many drugs cause a neuropathy (Table 17.4).

Table 17.4 Drug-related neuropathies

Drug	Neuropathy	Mode/site of action
Amiodarone	S, M	D, A
Anti-retroviral drugs	S > M	A
Chloramphenicol	S, M	A
Chloroquine	S, M	A, D
Cisplatin	S	A
Dapsone	M	A
Disulfiram	S, M	A
Isoniazid	S, S/M	A
Metronidazole	S, S/M	A
Nitrofurantoin	S/M	A
Paclitaxel	S > M	A
Phenytoin	M	A
Suramin	M > S	D, A
Vincristine	S > M	A

A, axonal; D, demyelinating; M, motor; S, sensory.

Axonal distal polyneuropathy

This typically produces length-dependent nerve involvement, the longest nerves (to the toes) being affected first with gradual proximal progression. A sock distribution of sensory loss, followed by eventual glove and stocking sensory loss, results. Reflexes are usually absent and distal weakness and wasting may be seen. Proprioception, vibration sensation and cutaneous sensation (e.g. pinprick, light touch) are tested, starting distally in the limbs and moving proximally.

Investigations

Investigations are directed at delineating the underlying cause. Nerve conduction studies (NCS) are useful to confirm neuropathy and to distinguish between demyelinating and axonal neuropathy. Approximately 50% will remain idiopathic after investigation.

• Initial investigations

• All patients: FBC, ESR, B₁₂, folate, U&E, LFTs, γ-glutamyl transpepidase, glucose, immunoglobulins, protein electrophoresis, urine for Bence Jones proteins, serum ACE, rheumatoid factor, ANA and CXR.

• Selected patients: Hepatitis B and C, HIV, ANCA, ENAs (extractable nuclear antigens) antineuronal antibodies, cryoglobulins, antiganglioside antibodies, heavy metal screen, homocysteine, methylmalonate, vitamin E and genetic testing (chromosome 17p duplication/deletion for CMT1a/HNLPP (Charcot–Marie–Tooth/hereditary neuropathy with liability to pressure palsies). Connexin 32, transthyretin for familial amyloid polyneuropathy and mitofusin-2 are checked in selected cases. Lumbar puncture is often performed in cases of demyelinating neuropathy. Nerve biopsy (usually sural nerve) may be necessary, particularly if vasculitis, amyloid or chronic inflammatory demyelinating polyneuropathy is suspected.

Management

• Treat the underlying cause. Ensure good glycaemic control in diabetics and thiamine/multi-vitamin replacement in alcoholic-dependent patients.

• Offer appropriate therapeutic aids (e.g. ankle–foot orthoses for foot drop) and emphasize foot care.

• For neuropathic pain, give amitriptyline (e.g. start at 10 mg at night and increase weekly in steps of 10 mg to an initial ceiling dose of 60–70 mg). Gabapentin and pregabalin are also widely used.

• In immune-mediated neuropathy, e.g. chronic inflammatory demyelinating polyneuropathy (CIDP), IV immunoglobulin or immunosuppression is sometimes required.

Guillain–Barré syndrome (GBS)

Typically, a mild antecedent infection (e.g. Campylobacter jejuni-associated diarrhoea, Epstein–Barr virus, cytomegalovirus) is followed, after a latent period of several days, by an acute progressive, demyelinating, mainly motor polyradiculoneuropathy. It is usually demyelinating but axonal GBS is also seen. Unlike in other peripheral polyneuropathies, proximal weakness is prominent. Cranial nerves (especially VII) may be affected. Patients may complain of back pain and sensory symptoms. Areflexia is usually found on examination.

• Lumbar puncture typically demonstrates an acellular CSF with a high protein content. Early in the disease CSF may be normal.

• NCS are useful in confirming the diagnosis but may also be normal early in the disease. Generally there is a demyelinating pattern. Axonal GBS is associated with a poorer prognosis.

• Specific antibody tests include antiganglioside antibodies and anti-GQ1b (in Miller Fisher variant), as well as Campylobacter serology.

• Check FVC at least every 4–6 hours and have a low threshold for transfer to ICU with a view to ventilating (if FVC < 15 mL/kg).

• Monitor BP (prone to hypotension — give IV fluids) and ECG (arrhythmias — bradycardias or tachycardias due to autonomic involvement).

Treatment

Treatment is primarily supportive, with attention to nutrition, exposure keratitis, pressure areas, and physiotherapy of chest and limbs. DVT prophylaxis with LMWH is given. IV immunoglobulin 0.4 g/kg/day for 5 days is the standard treatment in patients who have significant impairment (e.g. unable to walk, respiratory compromise) or who deteriorate rapidly. Corticosteroids are not indicated.

Autonomic features, e.g. hypotension and tachyarrhythmias, require treatment (p. 403). Hyponatraemia occurs secondary to SIADH. Neuropathic pain may require neuromodulatory agents, e.g. gabapentin. Avoid amitriptyline in GBS, as it is potentially arrhythmogenic.