• Physiology: the brain is 1% of body weight but gets over 10% of cardiac output for its high metabolic demand. It is sensitive to embolism and ischaemia and any reduction in global cerebral perfusion for more than a few seconds causes collapse. The brain is irrigated by four arteries: two internal carotid arteries anteriorly (anterior circulation) and the two vertebrals posteriorly which then join to form the basilar (posterior circulation). Vertebrals arise from ipsilateral subclavians. The branches of these arteries meet again with the circle of Willis with posterior communicating artery connecting ICA to PCA and the anterior communicating between R and L anterior cerebral arteries.
  
• Pathophysiology: the brain is contained within a bony box and so as pressure increases the largest exit is the foramen magnum. The skull contains, by volume, 80% brain, 10% blood, 10% CSF. Within the skull there are further compartments due to the falx and tentorium. These limit the scope of expansion such that any increase in intracranial volume will cause a gradual and ultimately exponential rise in ICP which leads to brainstem compression and death. ↑ICP will also reduce cerebral perfusion pressure, which is mean systemic arterial pressure (MAP) minus ICP. Normal ‘opening’ pressure is 10–25 cm CSF. Always measure opening pressure at LP. Rising ICP can result in focal signs and herniation syndromes.

Motor

• About: cell bodies for the corticospinal/nuclear tracts lie in layer V of the primary motor cortex (PMC) in the precentral gyrus. Voluntary precise motor movements are decided within centres within the frontal lobe and relayed to the PMC. There are only two cells between brain and muscle, the upper (UMN) and lower motor neurons (LMN).
  
• Upper motor neuron: myelinated motor axons exit the PMC and pass inferiorly as the corona radiata via the posterior limb of the internal capsule to form the cerebral peduncle in front of the midbrain. Corticonuclear fibres synapse with local cranial nerve motor nuclei to the eyes (III, IV, VI), face (X, VII), tongue (XII) and pharynx and larynx (IX, X). Corticospinal tracts pass to the spinal cord to innervate respiratory, trunk, arms and leg muscles. Within the brainstem the motor fibres lie ventrally. At the level of the medulla (pyramid) the motor fibres cross right to left and left to right, accounting for the contralaterality of the motor system. At the level of the foramen magnum the fibres pass laterally to form the lateral corticospinal tracts in the spinal cord. The axon descends until it reaches its corresponding nerve root level where it synapses with the anterior horn cell. Structural lesions cause a C/L UMN weakness. Structural lesions within the brainstem cause an ipsilateral cranial nerve palsy and C/L UMN weakness.
  
• Lower motor neuron: the UMN axon synapses with the corresponding LMN cell body called the anterior horn cell. This axon passes out in the spinal canal and fuses with the posterior nerve root and forms a nerve root that passes out via the spinal foramina. Motor to arms joins the brachial plexus and to legs the sacral plexus. Here the peripheral nerves form and pass to their respective muscles. Structural lesions will simply cause an ipsilateral LMN weakness and sensory loss.
  
• Neuromuscular junction: the action potential reaches the terminal bouton and releases Ach. If sufficient Ach is released there is then summation of the stimulus and the generation of an action potential that leads to muscular contraction. Ach is broken down by local cholinesterases. Weakness (myasthenia) can be caused by a lack of Ach – denervation or even excess Ach, e.g. organophosphates, or damage to the post-synaptic nicotinic acetyl choline receptor – such that an action potential cannot form.

Types of weakness

• UMN: ↑tone (spasticity), hyperreflexia, clonus, extensor plantar, upper limb flexors > extensors. Lower limb extensors > flexors.
  
• LMN: ↓tone, absent or reflexes, muscle wasting, absent plantar response.
  
• Muscle end plate: fatigability, no wasting, reflexes normal/↓, plantar normal or reduced.
  
• Myopathy: proximal weakness, ↓tone, ↓reflexes, ↓plantar response, mild wasting.

Brainstem

Contains cranial nerve nuclei and descending motor and ascending sensory tracts, the reticular formation required for sleep and wakefulness. The important clinical anatomical facts are below. The brainstem has three levels. Neuroanatomy books show the images inverted compared with CT/MRI imaging.

• Midbrain: almost V shaped on cross-sectional imaging. Corticospinal/nuclear fibres form the front of the V. At the back on either side are the nuclei for the IIIrd nerve and below the IVth nerve. The IIIrd nerve exits ventrally and lies close to the Pcomm artery. The aqueduct lies at the back of the midbrain.
  
• Pons: almost bulbous appearance on imaging. Motor fibres anteriorly. Packed with fibres passing via pons to cerebellum. Contains the V, VI, VII and VIII cranial nerves. The VII and VI lie close together. Any LMN facial weakness with an ipsilateral VI suggests an ipsilateral pontine lesion affecting both nuclei. Behind the pons lies the IVth ventricle. In front of the pons lies the basilar artery.
  
• Medulla: more of the spinal cord butterfly-like shape. Motor fibres lie anteriorly forming the pyramids and decussate. The posterolateral aspect is vulnerable to infarction due to posterior inferior cerebellar artery occlusion resulting in Horner’s syndrome due to damage to sympathetic tract, damage to nucleus ambiguus (IX, X, XI) involved in swallowing and to the vestibular nuclei and inferior cerebellar peduncle and spinal trigeminal nucleus.

Cranial nerves
(I) Olfactory: smell. Damaged by frontal meningiomas. Most often loss of smell is due to ENT issues. (II) Optic nerve: see below. (III) Oculomotor (midbrain): levator palpebrae superioris, superior, inferior and medial rectus, inferior oblique. Parasympathetic to constrict pupils for accommodation and light (Edinger–Westphal nucleus to ciliary ganglion). (IV) Trochlear (midbrain): superior oblique. Unable to look down and in. (V) Trigeminal (pons): muscles of mastication, sensory to face (ophthalmic/maxillary/mandibular divisions), dura mater, intracranial blood vessels, teeth. (VI) Abducent (pons): lateral rectus. (VII) Facial (pons): facial expression and eye closure, stapedius. Sensory external auditory meatus and taste from anterior 2/3rds of tongue. Salivary and lacrimal glands. (VIII) Vestibulocochlear (pons): balance (vestibular apparatus) and hearing (cochlea). (IX) Glossopharyngeal (medulla): sensory from pharynx, middle ear, carotid sinus and body, posterior 1/3rd tongue. Salivary glands. Stylopharyngeus (X) Vagus (medulla): sensory from pharynx, larynx, oesophagus, aortic bodies and arch. Parasympathetic to chest and abdominal organs. (XI) Spinal accessory (medulla): sternomastoid and trapezius. (XII) Hypoglossal (medulla): motor to tongue.

Cerebellum
Primary role is coordinating motor function with other parts of the brain. Lies behind the IVth ventricle. Receives sensory and motor input from the motor and premotor cortex and returns feedback to these same centres. Hemispheres deal with ipsilateral movement. Hemispheric damage causes ipsilateral cerebellar signs. Midline damage causes a truncal ataxia. Signs are past pointing, dysarthric speech, nystagmus and dysdiadochokinesia. Acute cerebellar dysfunction is a feature of acute and chronic alcohol and drug toxicities e.g. anticonvulsants and stroke disease. Structural damage lateralises, toxic issues are generalised.

Autonomic
Composed of sympathetic and parasympathetic systems both using two neurons. Sympathetic fight and flight responses increase heart rate, are inotropic, dilate pupils, bronchodilate and increase muscle blood flow and decrease cutaneous, reduce lacrimation and intestinal motility and salivation and increase sweating. They stimulate the internal urinary sphincter to prevent voiding. Parasympathetic antagonises these with bradycardia, increased lacrimal and salivary secretions and pupil constriction and bronchoconstriction and detrusor stimulation and urination and defecation. There are pre- and post-ganglionic neurons which synapse in an autonomic ganglion. The sympathetic ganglion lies in the sympathetic chain lateral to the spinal cord. Parasympathetic ganglion lies close to the target organ. Sympathetic preganglionic fibres release Ach and postganglionic fibres release noradrenaline to adrenergic receptors, except for Ach at sweat glands. Parasympathetic releases Ach at pre- and post-ganglionic neurons. Initial synapse for both is a nicotinic Ach receptor. The parasympathetic final synaptic target for Ach is a muscarinic Ach receptor. Impaired autonomic function seen long term with diabetes and amyloid, but acutely with GBS and drug toxicities. These may cause severe autonomic instability. Monitoring and support is key and the use of appropriate drugs. For example, Atropine is an anticholinergic that blocks muscarinic Ach receptors and so blocks parasympathetic activity, therefore raising heart rate, dilating pupils, drying secretions and causing urinary retention. Most pharmacological interventions in illness seek to support the circulation mimicking fight/flight responses with agents producing sympathetic activity and blocking parasympathetic. Sympathetic excess and its effects due to drugs or disease need to be managed with alpha and beta adrenergic blockers and other drugs that lower BP and heart rate.

Vision

• Optic nerve lesion: Mild will cause altered colour perception, reduced acuity and even loss of vision. There may be nothing to find clinically. Later optic atrophy. Classically with MS.
  
• Optic chiasm: A central lesion usually a pituitary macroadenoma +/– haemorrhage or some other tumour type can compress chiasm often causing an asymmetrical bitemporal hemianopia. Sudden acute onset with pituitary apoplexy.
  
• Cortical Vision: Left parietal, temporal and occipital cortex all contain parts of the visual pathways for vision from the right side of the midline. Damage causes a right partial or complete homonymous hemianopia. An isolated temporal lesion will cause a superior quadrantanopia and parietal an inferior quadrantanopia.

Sensory pathways (ascends to contralateral parietal lobe)

• Cortical level sensory: Left parietal cortex receives the sensory input from the right – touch, vibration and all sensation other than smell.
  
• Anatomy of ascending sensory function (3 cells and 3 synapses): sensation is a much more subtle and subjective sign. Different modalities are carried in different tracts and this can help to localize a lesion and so different modalities are tested. All perceived sensation terminates eventually in the contralateral post central gyrus of the parietal lobe.
  
• Posterior column/medial lemniscus pathway: vibration and proprioception enter via the dorsal root and pass into the ipsilateral posterior columns (lower body sensation in the medial gracile fasciculus and upper body in the lateral cuneate fasciculus). This ascends to form the medial lemniscus tract within the brainstem which then crosses at the medulla to synapse in the contralateral thalamus higher up and then passes via the internal capsule up to terminate in the primary sensory cortex on the post central gyrus of the parietal lobe.
  
• Spinothalamic: pain and temperature enter via the dorsal root and pass to opposite side close to the central canal. They then pass up the cord to synapse in the ipsilateral thalamus and pass as axons via the internal capsule on the post central gyrus of the parietal lobe.

About: wakefulness is controlled by the reticular activating system (RAS) which is a fine network of nerves within the brainstem ascending as far as the thalamus and hypothalamus bilaterally. Compression, stroke, tumours and any other pathology can cause disruption with coma. Progressive rises in ICP result in brainstem ischaemia and dysfunction and finally respiration ceases. It is important to understand the different forms of cerebral oedema which are detailed below. The RAS is closely associated with the cranial nerve nuclei for eye movement as well as the medial longitudinal fasciculus, so associated eye signs are commonly seen and help with localisation. Pupillary response is important as the IIIrd nerve lies close to the tentorium and can be subject to external pressure from above from a local aneurysm (post communicating artery). The pupillomotor constrictor fibres lie on the surface of the nerve so the ability of the eye to respond to light is impaired if the nerve is compressed resulting in a sluggish pupil response to light. With isolated pontine lesions there may be pinpoint pupils which are responsive but difficult to determine. This is an important eye sign in a comatose patient. Another important sign in the comatose patient is to look for meningism. Assuming no cervical injury then use passive neck flexion so that chin is almost touching chest. If there is any flexion of the knees then consider meningeal irritation and the need for CT/LP to exclude meningitis or SAH as a cause of coma. Structural lesions causing coma must be within the brainstem or involve both cerebral hemispheres and must be large enough to cause compression/ischaemia and impaired function of brainstem and diencephalon.

Glasgow Coma Scale

• Developed in the 1970s when the only brain imaging was a plain skull X-ray, as a clinical way to identify worsening neurological function that would necessitate neurosurgical intervention. Advice: communicate what patients can do rather than just the absolute score.
  
• Describe score as X out of 15 to ensure no misunderstanding. Changes may be more important than actual values. Difficult to deal with aphasic patients who get a reduced score of 1 out of 5 for best verbal.
  
• An aphasic alert patient has only a baseline score of 11. Possibly ignore speech and mark best eye and best motor out of 10. Coma is generally defined as a GCS of 3–8. Consciousness depends upon the brainstem reticular activating system and its cortical projections being intact and functioning.

Clinical clues

• Signs of trauma and injury: Battle’s sign, panda eyes, skull lacerations or haematomas. If so consider immobilising the spine and appropriate imaging to exclude spinal and brain injury and any other trauma-associated injuries.
  
• Asymmetry: an asymmetrical motor response to pain may suggest a lateralising structural lesion rather than toxic metabolic cause unless the lower brainstem is affected when symmetry returns.
  
• Post-ictal: headache, incontinent, known epilepsy, alcohol (DTs), bitten (usually the side) tongue may suggest seizure and post-ictal drowsiness.
  
• Dilated pupil (cocaine, IIIrd nerve) and may suggest pressure on ipsilateral IIIrd. Pupil constricting fibres lie superficially and liable to pressure. Suspect coning if sluggish to constrict or fixed and dilated. As progresses both pupils may become fixed and dilated. Rarely in a non-comatose patient Ipratropium nebuliser with mask close to eye causes dilation. TCA overdose can cause coma and fixed dilated pupils, up going plantars.
  
• Constricted pupil and usually reactive but very hard to detect (consider opiates and a test dose of Naloxone, Horner’s syndrome). Rarely an isolated pontine bleed or infarct will cause pinpoint pontine pupils which are just about reactive. Toxic conditions often also cause small symmetrical reactive pupils.
  
• Bilateral fixed dilated: massive brainstem injury. Exclude hypothermia and drug toxicity/adrenergic syndrome.
  
• Dysconjugate gaze suggests brainstem pathology. If the head can be safely turned (no spinal injury) then usually the eye moves relative to the orbit fixated at same position. If the eyes are static within the orbit this is abnormal loss of ‘doll’s eye movement’.
  
• Look for meningism: comatose patient always use passive neck flexion (unless there is a history of head trauma and possible neck injury) so that chin is almost touching chest. If there is any flexion of the knees then consider meningeal irritation and needs CT/LP to exclude meningitis or SAH.
  
• Averted gaze with the eyes looking fixedly to one side suggests a contralateral irritative lesion, e.g. a tumour causing seizure.
  
• Coma is unlikely to be stroke if patient moves all limbs symmetrically, pupils and eye movements normal, CT is normal, coma is deep, e.g. GCS 3–6, gaze is not averted to one side, there are other signs such as fever. Look for toxic metabolic causes and consider LP. Patients often too ill and unstable to MRI acutely.
  
• Jaundiced: hepatic encephalopathy, falciparum malaria, and malignancy. Check skin for petechiae – meningococcal meningitis, DIC. Pyrexia, cold sores: HSV encephalitis.
  
• Back: turn patient and check back including along spinal cord and orifices. Abdominal, chest and cardiac exam are needed.
  
• Investigations: FBC, U&E CRP: WCC, glucose, TSH/FT4 (myxoedema coma), infection. ABG: hypoxia, hypercarbia, acidosis. For metabolic acidosis calculate anion gap. Urine: blood, protein, WCC, toxicology if overdose suspected (check blood paracetamol/salicylates). LP: if no contraindications and suspected meningitis or encephalitis. MRI scan and EEG: done later. Difficult to monitor sick restless patient in MRI scanner. Treat for seizures acutely if suspected. IV anticonvulsant: (PHENYTOIN 20 mg/kg over 1 h) if persisting seizures (always consider non-convulsive status). CT head: often the most discriminating test in unexplained coma and needs to be done immediately post arrival in the emergency department. Get a neurosurgical consult if abnormal head CT and surgically amenable finding +/– mannitol or steroids – see doses below.
  
• Coma and normal CT: treat medical, infective, toxicology, metabolic causes. Consider LP, EEG, toxicology, etc. Rare ‘stroke and normal CT’ causes of coma would be basilar artery thrombosis of artery of Percheron infarct. Look for a bright basilar artery.

Differentials for coma

• Obvious or occult head injury: was there head trauma which has been missed by emergency department? Look for injury. Blood in ear canal. Trauma review should highlight issues. Get CT head. Look for haemorrhage, oedema. Exclude cervical spine injury? Do not accept trauma patients with ‘medical’ problems medically unless a full trauma survey has been done. CT may look normal if there is diffuse neuronal injury with perhaps signs of cerebral oedema.
  
• SAH: thunderclap headache, persisting headache, N&V, low GCS. May be localising signs. Blood in subarachnoid space on CT and aneurysm/AVM may be seen. Site of blood helps locate aneurysmal site. Unilateral dilated pupil (IIIrd nerve) due to ↑ICP or PCOMM/superior cerebellar aneurysm. Urgent neurosurgical consult. CT negative suspected SAH is unlikely to cause coma or lateralising neurology. Look for hydrocephalus. Section 11.23.
  
• Haemorrhagic stroke: large haemorrhage with ↑ICP (cerebellar bleeds and possibly supratentorial superficial cortical bleeds benefit from surgery). Look for and manage secondary hydrocephalus with external ventricular drainage. Section 11.22.
  
• Subdural haematoma: may be astonishingly little to find even with marked changes if gradual onset; even a minor TIA episode. Stop anticoagulants. CT is diagnostic. Neurosurgical referral. Section 11.25.
  
• Ischaemic stroke: large infarct with oedema (consider hemicraniectomy). Assess for thrombolysis. Strokes generally do not cause coma unless ↑ICP and pressure on brainstem, e.g. malignant MCA syndrome or large cerebral, subthalamic, cerebellar haemorrhage. The very rare exception is unilateral or bilateral thalamic strokes or top of the basilar artery stroke (if suspected get MRI) and extensive brainstem strokes.
  
• Non-convulsive SE: may be few or no outward sign of on-going seizures except perhaps eye flickering. Needs EEG. Treat with anticonvulsants, e.g. PHENYTOIN 20 mg/kg IV. Section 11.16.
  
• Post cardiac arrest: often undergo urgent PCI and consider therapeutic hypothermia (cooled to 32–34°C for 12–24 h if rhythm was VF). Supportive management after PCI. May be significant hypoxic brain damage. Section 1.11.
  
• Severe renal failure: uraemia can reduce GCS. Can reduce clearance of opiates. Bloods show AKI. Section 10.4.
  
• Drug overdose: alcohol, ethylene glycol (specific antidote), benzodiazepines (flumazenil in selected cases), tricyclic antidepressants with coma and fixed dilated pupils, upgoing plantars. This list is not comprehensive.
  
• Opiates/codeine: causes miosis, respiratory depression. Opiate medications, transdermal patches NALOXONE 100–400 mcg IV stat and repeated as t1/2 short if required.
  
• CNS infections: meningitis: purpura, fever, neck stiffness. Meningism. CT/LP. Give CEFTRIAXONE 1–2 g 12 h IV. Section 11.11.
  
• Encephalitis: seizure, focal signs, fever, neck stiffness, delirium. Assume HSV and give IV ACICLOVIR. Needs CT/LP. Section 11.9.
  
• Cerebral malaria: travel in endemic area <6 months. Get blood films to lab. Urgent expert advice. QUININE IV. Section 9.3.
  
• Post-ictal/Non Convulsive status: supportive ABCs if fitting has stopped. May need anticonvulsant if SE. Should gradually awaken within 2 h – if not then start to look for causes. Sections 11.16 and 11.17.
  
• Raised ICP: space occupying lesion, e.g. abscess, tumour, haematoma will be seen on CT.
  
• Cerebral oedema: post-hypoxic brain damage or proximal MCA stroke, tumour, vasogenic oedema, diabetic ketoacidosis, high altitude, Reye’s syndrome, hypoxic injury, carbon monoxide, SIADH.
  
• Liver failure: jaundice, abnormal LFTs, signs of liver failure; recent paracetamol overdose – N-acetyl cysteine. Section 7.11.
  
• Encephalopathy: drug-induced, metabolic, liver failure. Sodium valproate can cause coma and associated with ↑blood ammonia.
  
• Endocrine: hypothyroid: hypothyroid appearance, thyroidectomy scar, ↓HR, give thyroxine +/− steroids. Section 5.7.
  
• Hypoglycaemia: check blood glucose, give 20–50 ml 50% GLUCOSE or GLUCAGON 1 mg IM. Look for cause.
  
• Hyperglycaemia: DKA/HHS with dehydration, ketones in urine/breath, ↑Na, cerebral oedema. Section 5.18.
  
• Addisonian crisis: ↓BP, pigmentation, ↑K, ↓Na. Section 5.1.
  
• Pituitary apoplexy: CT may show bleeding, visual loss Section 5.9.

Coma management: the ‘coma cocktail’

Management (G5 = 5% Glucose, NS = 0.9% Saline)

• Supportive: ABC, oxygen, physiological monitoring. Ideally HDU or ITU bed. Correct positioning, skin care, recovery position. Nasopharyngeal airway. May need intubation and ventilation if airway and breathing unsafe or GCS <9. Discuss with ITU and critical care outreach team. Escalate for consultant to consultant referral if appropriate on a case-by-case basis. Consider coma cocktail above.
  
• Initial: all patients need rapid blood glucose determination and 50 ml of 20–50% GLUCOSE IV where indicated and PABRINEX IV paired vials TDS for 1–2 days if deficiency suspected.
  
• NALOXONE 100–400 mcg IV (lower dose in chronic users) if opiate abuse/use suspected. Up to NALOXONE 2 mg may be needed.
  
• CNS infection: consider empirical treatment for meningitis + encephalitis if suspicions (get LP if not contraindicated). Give ACICLOVIR if encephalitis or CEFTRIAXONE + DEXAMETHASONE if bacterial meningitis confirmed on LP.
  
• FLUMAZENIL 0.2–0.5 mg slow IV if benzodiazepine excess and compromised and no history of epilepsy. An infusion may be needed.
  
• Differential is wide: if unclear despite history and examination and initial bloods then a CT brain will help to separate potential surgical/physical causes from medical causes. A normal CT brain has its own diagnostic differential (see below).
  
• Urinary catheters: only if essential. Patients can be padded and simple suprapubic pressure can result in reflex bladder emptying. Only if retention or close does output need monitoring.
  
• Seizures: if continuing then LORAZEPAM 2–4 mg IV and PHENYTOIN 20 mg/kg IV loading dose. Section 11.16.
  
• Hydration: can be difficult to assess. Fluid replacement 25–30 ml/kg per day in all comatose patients, initially to match normal losses. If coma persists then manage feeding and nutritional issues.
  
• Medications: these will often be stopped. If they are vital then try other routes, e.g. PR for ASPIRIN. A NG tube can be placed for vital medications. Some important medications to continue – steroids (may need to be increased) or immunosuppression, anti-Parkinsonian medications, anti-anginals, antibiotic prophylaxis, warfarin or other anticoagulants where appropriate, rate-controlling medications, e.g. DIGOXIN (give IV or NG) or beta-blockers, HAART therapies, anticonvulsants.
  
• Exposure: avoid possible hypothermia with blankets or ‘space blankets’ and warmers as needed.
  
• Stress ulcers: stress ulceration – consider PPI/H2 blocker in selected patients.
  
• Resuscitation status: determine ceiling of care, particularly in patients with poor prognosis.
  
• Management of ↑ICP: see below.

• Physiology: the brain is insensitive to pain. However, meningeal arteries, proximal portions of the cerebral arteries, dura at the base of the brain, venous sinuses and cranial nerves 5, 7, 9, and 10, and cervical nerves 1, 2, and 3 can generate pain.
  
• About: on referral if thunderclap (peak less than 5 min) and/or worst ever at onset then SAH is the immediate concern. What is the GCS and observations? How is the patient? Symptoms/signs other than headache? Has there been a head injury? Meningism, fever, rash or malaise? Meningitis/encephalitis. Medications causing headache: nitrates, dipyridamole, beta-blockers, sildenafil, calcium channel blockers, ACEI, alcohol, analgesia headaches with opiates, triptans, NSAIDs.
  
• Discussion: most will be benign (only 7% of suspected SAH are SAH) but all need to be taken seriously. The human and medicolegal cost of missing SAH is high. Keep a low threshold to CT/LP. Note red flag signs and symptoms below of serious pathology. Caution as nearly half of secondary headaches (SAH, tumours, ↑ICP, etc.) respond to triptans.
  
• Note: When to worry: the old adage is ‘worry about the “first, worst or cursed”’. The first, in someone who doesn’t have headaches; the worst, in someone who does; or headaches “cursed” with some other significant symptoms like weakness or confusion or meningism. Further reading: Forbes, R. Acute Headache. Ulster Med J (2014); 83(1): 3–9.

Immediate assessment

• ABC, assess GCS and look for focal neurology. A reduced GCS or thunderclap headache or possible head injury or on anticoagulants requires immediate CT brain. Thunderclap encompasses headaches which proceed from nil to maximal within 4–5 min and not just those that feel like hit round the head with baseball bat. Cluster headache seen more often in middle-aged males – responds to high flow O2. Ask about recent LP or epidural with low-pressure headache. Horner’s syndrome (small pupil, partial ptosis are the main signs) – think carotid dissection or lateral medullary infarct, or lung tumour and cerebral metastases. Eye symptoms – for red eye with injected conjunctiva consider acute angle closure glaucoma especially in an older patient.
  
• Investigations: ESR/CRP/temporal artery ultrasound or biopsy: if temporal arteritis considered (age >50 y). CT head: will exclude bleeding and tumour. If CT negative and recent SAH suspected then LP may be needed; however, modern scanners very sensitive. LP risks other disabling headaches. If concerns of SAH (wait 12 h post max headache), meningitis or encephalitis and no contraindications. Measure opening pressure. CT angiogram or MR angiogram: if carotid/vertebral dissection or aneurysm or RCVS suspected.

Red flags related to headache

• Sudden onset severe (max <4 min): exclude SAH. Needs CT/LP.
  
• ↑Headache with cough or bending: MRI for posterior fossa lesion.
  
• ↑Headache in morning with nausea/vomiting (exclude SOL).
  
• ↑Severity over time: consider SOL/mass.
  
• ↑When standing: low ICP, CSF leak, colloid cyst of IIIrd ventricle.
  
• Headache + neurological symptoms/signs need investigation.
  
• Headache + visual loss age >50 y: check ESR/CRP, ?GCA.
  
• Headache + immunosuppressed, HIV, TB, meningitis, lymphoma.
  
• Headache + cancer: exclude cerebral metastases.

• About: primary headaches are so called as there is no identifiable structural pathology and the outcome is good. The paradox is that their headaches are often more severe and debilitating than those with an underlying pathology with a few exceptions, e.g. SAH. The diagnosis is clinical and often no tests needed, but in some, where there may be diagnostic uncertainty or changing symptoms or red flags or onset later in life, then imaging is indicated to exclude structural pathology.

Causes

• Migraine (no aura): aura absent but severe often pulsating, often recurring unilateral headache may last 4–72 h. Shorter with effective treatment, longer than 72 h in others. Desire to be alone, quiet, lie down and sleep. Severe attack looks ill, nauseated, grey pallor. Feels very miserable. Headache often worse than those with aura. Manage as migraine with aura.
  
• Migraine with aura: recurrent episodic headache with systemic symptoms. Comes on gradually, and there may be preceding aura such as tingling, weakness, and altered speech, word finding difficulties, flashing lights, scotomas or fortification spectra. Positive family history. Headache then comes on and lasts 4–72 h by definition but some are shorter and some longer. Patients feel awful; look grey, usual response for severe attacks is to want to lie down and sleep. First line: ASPIRIN 900 mg or IBUPROFEN 600 mg PO if not vomiting or else DICLOFENAC 100 mg PR + METOCLOPRAMIDE. Second line: triptans, e.g. SUMATRIPTAN 50 mg PO or 6 mg SC (C/I with IHD/TIA, stroke). If severe vomiting, consider IV NS.
  
• Cluster headaches (commonest of the trigeminal autonomic cephalgias). Occur in repeated attacks. Severe. Unilateral. Retro-orbital stabbing. Tearing, miosis, ptosis. Restless patient pacing floor. Give 100% O2 and SUMATRIPTAN 6 mg SC as the first choice treatment for the relief of acute attacks of cluster headache. Prevent with PREDNISOLONE or VERAPAMIL. Commoner in men.
  
• Paroxysmal hemicranias: severe, unilateral orbital, supraorbital, and/or temporal pain, always same side, lasting 2–45 min up to 5–10 times/day. With either conjunctival injection, lacrimation, nasal congestion, runny nose, ptosis, eyelid oedema. Dramatic effect of INDOMETHACIN 150 mg daily.
  
• Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome: rare, males > females in middle age. Moderate headache lasts 1 minute. Ipsilateral conjunctival injection, lacrimation. Nasal stuffiness/rhinorrhoea and increased intraocular pressure on the symptomatic side and swelling of the eyelids. Usually frontal and periocular. Intractable to medications.
  
• Medication overuse headache: must be excluded in all patients with chronic daily headache (headache >15 days per month for more than 3 m) and those using opioid-containing medications or overusing triptans are at most risk. Resembles migraine or tension type headache. Chronic analgesic ingestion especially codeine. Gradual withdrawal. Prevent with AMITRIPTYLINE or GABAPENTIN.
  
• Tension headache: usually a chronic band-like headache but many variants. Rarely truly thunderclap. Often long history of similar episodes. No associated symptoms or signs beyond headache. Give NSAID or paracetamol.
  
• Coital/post-coital headache: diagnosis once SAH excluded. May be experienced with orgasm. There is a real possibility that this could be SAH but it would be less likely if it has occurred several times before without incident. In future take NSAIDs prior to sex. Exclude SAH in all cases with LP/CT. Benign form is orgasmic cephalgia once SAH safely excluded.
  
• Exploding head syndrome: not a true headache but can be misunderstood with poor history. Auditory hallucination that occurs whilst falling asleep – sound like a gun going off in one’s head. May be unable to speak or move. Benign condition – avoid extensive investigations or treatment.

• About: identifiable structural pathology needs to be identified and managed. Primary and secondary headaches can co-exist.
  
• Subarachnoid haemorrhage: ‘red flags – worst ever headache, neck stiffness, meningism, vomited, onset with exercise’. Rupture of an aneurysm or AVM is usually catastrophic and presents with thunderclap headache and often collapse and coma. Section 11.23.
  
• Acute stroke: both ischaemic and acute haemorrhagic stroke can cause sudden headache but more common with haemorrhage. CT scan will be diagnostic. Particularly worrying is patient on anticoagulation or with any focal neurology. In those with ischaemic stroke it is often on the affected side and is a vascular headache which represents shunted blood through collaterals due to a major arterial obstruction, e.g. MCA occlusion. Needs urgent CT head. Section 11.19.
  
• Cerebral venous thrombosis: consider this within the differential of thunderclap presentation. CT head may be normal, show clot or venous infarction +/– haemorrhage. Suspect if LP shows high red cells, high opening pressure and increased lymphocytes. Diagnose formally with CT venography or MR venography, whichever available. Anticoagulate. Section 11.21.
  
• Space occupying lesion: gradually increasing size or oedema or bleed into a focal lesion, e.g. tumour or abscess.
  
• Acute infection: bacterial meningitis: look for petechiae if meningococcaemia, neck stiffness, Kernig’s sign, meningism. Acute delirium in elderly, pyrexia. Treat empirically if any suspicion. Many with fever of recent onset and headache will have a systemic illness headache. This is poorly understood. Usually self-limiting with good outcome, when the underlying infection resolves. Some, however, end up with a non-specific persistent headache for months.
  
• Viral meningitis: similar presentation to bacterial meningitis so investigate and treat as for bacterial meningitis until diagnosis excluded. Section 11.12.
  
• Encephalitis: fever, obtunded, seizures, focal neurology, cold sores. Needs LP and antivirals: IV ACICLOVIR if diagnosis considered. Section 11.9.
  
• Pituitary apoplexy: severe headache and IIIrd nerve palsy and visual loss as severe pressure around optic nerve from haematoma. CT/MRI may show infarction/bleeding. May have known pituitary tumour. Needs neurosurgical decompression if vision affected. Needs IV HYDROCORTISONE because acute hypopituitarism is possible. Neurosurgical consult. Section 5.9.
  
• Cervical (internal carotid or vertebral) arterial dissection: neck, retro-orbital pain or occipital pain. Associated focal neurological signs. Horner’s syndrome with ipsilateral carotid dissection. Brainstem signs with vertebral dissection and may also have a Horner’s from PICA thrombosis and lateral medullary syndrome. Section 11.21.
  
• Colloid cysts: headache, syncope. CT evidence of IIIrd ventricle cyst. May see acute hydrocephalus.
  
• Reversible cerebral vasoconstriction syndrome (RCVS): single or repeated severe, often bilateral thunderclap headaches. Seizures and focal neurological deficits, ischaemic stroke and non-aneurysmal SAH, LP – ↑blood and protein. MRA/CTA/DSA: “beads on a string” appearance of cerebral arteries which resolves at 3 months. Verapamil/Nimodipine may be given. Multiple suggested causes – idiopathic, pregnancy, vasoactive drugs, hypertensive crisis, etc. Section 11.21.
  
• Temporal (giant cell) arteritis: subacute headache in older patient. Check ESR or CRP. Temporal artery tenderness or polymyalgia symptoms or transient or persistent visual loss. Needs TAB. Section 13.4.
  
• Acute angle closure glaucoma: consider in a patient with headache associated with a red eye, halos or unilateral visual symptoms. Urgent ophthalmology referral. Section 13.1.
  
• Carbon monoxide poisoning: CO produced when gas, oil, coal or wood do not burn fully. Cold weather. More than one person affected in shared accommodation. Check ABG and COHb levels. SaO2 falsely normal. Section 14.10.
  
• Spontaneous intracranial hypotension: marked low pressure headache on standing. Can come on suddenly. Relieved by remaining supine. Post LP or spontaneous leak. Give fluids and simple caffeinated drinks. May need epidural blood patches (usually done by anaesthetist). Typical meningeal enhancement on MRI and cerebellar tonsillar descent and bilateral SDH. CSF opening pressure <10 cmH2O.

Taking referral/answering bleep: What is patient doing and how long for? How were they yesterday? Is it new? Age, why is patient in hospital? Check set of observations. AMTS.

On arrival: See notes, review observations and medication. Confusion in new admissions with poor cognitive reserve is common and may suggest some serious issues and poorer prognosis. Is this confusion on a background of milder confusion or normality? Is this confusion, psychosis or dysphasia? Is this delirium or dementia, or dementia with delirium?

The confusion assessment method (CAM)

(A) Acute onset and fluctuating course: is there evidence of an acute change in mental status from baseline? Does abnormal behaviour come and go? Fluctuate during the day? Increase/decrease in severity?

(B) Inattention: does the patient have difficulty focusing attention? Are they easily distracted? Do they have difficulty keeping track of what is said?

(C) Disorganised thinking: is the patient’s thinking disorganised, incoherent? Does the patient have rambling speech/irrelevant conversation? Unpredictable switching of subjects? Unclear or illogical flow of ideas?

(D) Altered level of consciousness: alert, vigilant, lethargic, stuporous, comatose?
Confusion assessment method: delirium = A + B + either or both C and D (Inouye et al.).

General assessment

A comprehensive clinical assessment from head to toe needed as well as drug history and try to get as much corroborating history as possible. Work through common causes, e.g. infection (chest/urine), metabolic (low Na), malignancy (high Ca), drugs, e.g. codeine. Establish baseline. Use and record answers to the mental test score (AMTS) or some standard questions in terms of cognition, recall, orientation to time and place, speech, comprehension and attention span. The abbreviated MTS can be done or the more complex mini mental state examination. Any recording of cognition is useful.

Causes of confusion/delirium

• General sepsis: examine chest and CXR, sats for pneumonia. Check urine for UTI, check lactate/WCC. U&E for sepsis. Intra-abdominal sepsis, skin sepsis. Assess temp, WCC, CRP. CXR. Check urine, stool and treat empirically.
  
• Drugs: always examine drug chart and GP drugs: illicit and prescribed drugs: cocaine, heroin, amphetamine; codeine, opiates (may be a patch), tramadol, morphine, L-dopa, alcohol, large dose steroids, anticholinergics.
  
• Hypoglycaemia: check capillary blood glucose. On hypoglycaemic diabetic meds.
  
• Occult head injury: was there head trauma which has been missed by emergency department? Is a CT needed? Look for bumps and abrasions and cuts. Blood in ear canal.
  
• CNS infections: obtunded, neck stiffness, rash. Meningitis (a very common cause in elderly), encephalitis. Consider CT to exclude SOL/abscess and urgent LP and treatment. Section 11.11.
  
• Delirium tremens: agitated delirium with acute alcohol withdrawal. PABRINEX IV paired vials TDS for 1–2 days.
  
• Wernicke’s encephalopathy: eye signs, delirium, ataxia, B1 deficiency. Often alcoholics, also hyperemesis, malnutrition. Give PABRINEX.
  
• Acute stroke: dysphasia often misinterpreted as confusion. Delirium vs. dysphasia. The dysphasic patient cannot follow simple tasks – close eyes, touch nose, touch left ear. Even the most confused patient can. Is there right sided weakness, hemianopia? Section 11.19.
  
• Acute pain: elderly person and acute urinary retention, or fractured neck of femur, or acute abdomen, or MI. Agitated. Incoherent.
  
• Cardiac: ACS/silent MI seen in elderly, diabetes. Pericarditis, fast AF and ↓BP.
  
• Hypoxia and hypercarbia: check ABG, CXR, COPD, carbon monoxide poisoning. Look for CO2 retention.
  
• Drug withdrawal: alcohol, benzodiazepines, opiates, antidepressants.
  
• Acute psychosis: schizophrenia or other mental health disorder. Hyperactive, agitated, delusions, psychotic.
  
• Metabolic: low or high Na, liver failure, renal failure, myxoedema madness, apathetic thyrotoxicosis, high Ca, Addison’s disease, pituitary failure, SIADH, porphyria.
  
• Vitamin: suspect if malnourished, alcoholic, hyperemesis, give THIAMINE. B12 deficiency with pernicious anaemia and other causes. Pellagra.
  
• Malaria: travel or endemic area send thick/thin films. Treat if real possibility. Also consider other tropical disease if recent travel. HIV conversion.
  
• Autoimmune/limbic encephalitis: autoimmune which may or may not be paraneoplastic. NMDA receptor antibody encephalitis, voltage-gated potassium channel-complex antibody-associated limbic encephalitis (VGKC-LE). MRI FLAIR shows medial temporal signal changes. Cancers – lung, breast, testis, lymphoma, teratoma, thymoma. Treatment: remove tumour and/or immune modulation with varying success.
  
• Hashimoto’s encephalopathy: females usually. Psychosis, seizures. Tremor, myoclonus. Stroke-like episodes but normal MRI. Elevated CSF protein. Positive thyroid antibodies. Responds to steroids.
  
• Structural brain pathology: abscess, stroke, SAH, encephalitis, meningitis, tumour, hydrocephalus, spongiform encephalopathy; CT scan helpful. Consider LP.
  
• Seizure/NCSE: EEG, CT/MRI/ LP. Treat and see if resolves. Sections 11.16 and 17.
  
• Malignancy: high Ca, liver metastases, brain metastases, paraneoplastic.
  
• Inflammatory disease: any acute inflammatory illness or flare up. Neurosarcoidosis, Behçet’s disease, etc.
  
• Encephalitis: infectious – usually HSV infection, also HIV, Murray Valley and Japanese encephalitis can be seen in epidemics. Take expert advice. Send CSF and viral and PCR. Section 11.9.
  
• Creutzfeldt–Jakob: can quickly deteriorate over weeks. Myoclonus is a helpful clue. CSF elevated protein 14-3-3. Sporadic – rapid, older, myoclonus. Variant – younger, slower, ataxia.

Reversible and non-reversible dementias

• Progressive dementias: Alzheimer’s, vascular, Lewy body, frontotemporal, alcoholic, Huntington’s disease, CJD, Pick’s disease, Parkinson’s disease, HIV, SSPE, PML.
  
• Reversible ‘pseudodementias’: B12/folate/thiamine/thyroxine deficiency, SDH, normal pressure hydrocephalus (NPH), operable tumour (e.g. meningioma), depression.

Investigations

• Blood: glucose, FBC, ESR, U&E. Calcium, B12 and folate. TFTs. Urinalysis. ABG: hypoxia, hypercarbia, CO-Hb level.
  
• CXR: tumour, infection, hypoxia. ECG: silent MI. ABG: hypoxia, hypercarbia.
  
• CT head: can be difficult but looking for major pathology, e.g. SDH, haemorrhage, tumour, oedema, etc.
  
• Lumbar puncture: meningitis/encephalitis/SAH. CSF removed in NPH done to see if improvement in walking but controversial.
  
• EEG: focal seizure or non-convulsive status or encephalopathy.
  
• Infections: HIV test, malaria thin and thick films, LP.
  
• Rare: thyroid antibodies, NMDA receptor antibody, VGKC-LE.
  
• Measure ammonia: high with hepatic encephalopathy, drugs such as valproate and some chemotherapy can cause an ammonia encephalopathy.
  
• MRI: can help if encephalitis or inflammation or stroke or malignancy or other structural lesions are suspected.

Management

• Supportive: manage anxiety, keep lights on, calm, friendly reassurance, and involve familiar people or family members. Work through potential causes as listed above. May need mild sedation or even full sedation and airway management for a CT brain.
  
• Sedation: appropriate when patient at risk of harm and not used just for convenience. Go slow. LORAZEPAM 1–4 mg PO/IM/IV can be tried or HALOPERIDOL 0.5–2 mg PO/IV/IM/SC (low doses 0.5–2 mg in elderly) are useful but avoid if at risk of seizure. Get help if risk of over-sedation and airway management. Very low threshold for a CT head is needed. Avoid haloperidol in Lewy body dementia.
  
• Antibiotics/Aciclovir: treat if suspicion for bacterial meningitis and HSV encephalitis (treat both). Get LP if possible.
  
• Give PABRINEX IV paired vials TDS for 1–2 days prior to IV GLUCOSE. Look and treat hypoglycaemia quickly.
  
• Stop opiates. Remove any transdermal opiate pain patch and give NALOXONE 100–400 mcg IV.
  
• Give PHENYTOIN 20 mg/kg IV or LORAZEPAM 1 mg IM if non-convulsive status on EEG.

Reference: Inouye et al. (1990) Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med, 113:941.

• About: high mortality. Most commonly due to Herpes simplex 1 (HSV-1).
  
• Aetiology: acute inflammation of brain parenchyma +/− spinal cord in adults.
  
• General: headache, fever, pyrexia, ↓GCS, hemiparesis, altered speech, psychosis/delirium, brainstem signs.
  
• Travel: enquire about recent exposure to ticks or travel to areas with endemic viral encephalitides.

Causes of encephalitis

• Herpes simplex virus 1: ‘general’ + cold sores, high fever. Favours temporal lobes, frontal and limbic system. Can show haemorrhagic necrosis. Rarely HSV encephalitis (HSE) may later be complicated by an autoimmune encephalitis. Increased risk of HSV if deficient in toll-like receptor 3. Younger. IV ACICLOVIR dramatically reduces mortality and morbidity.
  
• Herpes simplex virus 2 is more likely to cause a relapsing meningitis or meningoencephalitis in adults.
  
• Varicella zoster virus: ‘general’ + widespread vesicular rash. All ages.
  
• West Nile virus (WNV): arbovirus mosquito. Erythematous rash. Age >50. 10% fatality. Epidemic in the USA. Often a brainstem encephalitis with coma.
  
• Japanese encephalitis: arbovirus. ‘General’ + movement disorder. Epidemics.
  
• Enterovirus: Coxsackie/Echo virus. Seen in summer/autumn. General symptoms.
  
• Others: measles, mumps, rubella, rabies, EBV, HIV JC virus.
  
• Immunocompromised: toxoplasmosis, CMV, TB, cryptococcus, primary CNS lymphoma, PML.
  
• Non-infectious: post viral autoimmune.

Investigations

• Bloods: FBC: ↑WCC, ↑CRP. U&E: may see hyponatraemia.
  
• Imaging: urgent CT: to exclude abscess and to show asymmetric lesions in the temporal lobes with HSV. May be necrosis and haemorrhage. MRI: DWI is most sensitive. T2 changes in mesial temporal lobe/inferofrontal and insular cortex with oedema/necrosis with HSV (similar with autoimmune and HHV6). Thalamic changes with WNV.
  
• Lumbar puncture: if no C/I. CSF: ↑lymphocytes and protein. Polymorphs may be seen with WNV and CMV. Measure opening pressures. PCR for HSV and WNV virus if suspected. Bloody CSF can result in a falsely negative PCR.
  
• EEG: periodic high voltage sharp waves and slow wave complexes at 2–3 s intervals in temporal leads.
  
• Stereotactic brain biopsy: rarely needed. HSV shows neuronal inclusion bodies called Cowdry Type A, found in the neuronal nucleus.
  
• Poor prognostic indicators for HSV: age >30. Coma, Bilateral EEG abnormalities. ↑CNS viral load, treatment delayed (4 days), abnormal CT.
  
• Differential: autoimmune encephalitis (limbic with antibodies to VGKC, Hashimoto’s with thyroid disease, antibodies to NMDA receptors), ADEM.

Management

• ABC, O2 as per BTS guidelines. Arrange imaging, LP and CSF to confirm diagnosis. Monitor renal function. ITU involvement if low GCS. Specialist advice. Any suspicion of the diagnosis give ACICLOVIR 10 mg/kg 8 h IV × 14–21 days. Untreated HSV is a tragedy with disability and death. Treatment reduces mortality from 54% to 28%. Check CSF is free of HSV before ending treatment by later repeating LP and PCR. Suspected CMV infection: GANCICLOVIR. Ensure hydration and NG feeding as required. Often initially managed in HDU setting. Of those who survive there is a high risk of on-going neurological deficits. There is no evidence base for steroids.
  
• HSE survivors may deteriorate and should be investigated for recurrent HSV infection and for antibodies to NMDA-receptor and other synaptic proteins which can be a late complication. MRI may help. CSF and serum NMDA receptor antibodies checked. Immunotherapy may be indicated.

• About: causes a fatal encephalitis. Found worldwide. Lyssavirus of rhabdovirus family. Disease may be delayed 1–3 months after contact.
  
• Aetiology: from dog or other animal bite. Saliva from dog, bat, fox, skunk or other animal comes into contact with a person’s mouth, eyes, nose, or a fresh wound. Infectious phase 1–3 months. Less if wound is head and neck.
  
• Clinical: acute syndrome post bite. Fever, hydrophobia due to laryngospasm, agitation or coma, tremor, muscle spasms. Paralytic with ascending flaccid quadriparesis similar to GBS or polio with associated encephalitis.
  
• Investigations: saliva, CSF <100/mm3 lymphocytes. Protein mildly elevated. MRI – brain stem T2 changes. Immunology may be negative so use PCR for virus. Negri bodies in cytoplasm of brain biopsy of dog if available.
  
• Management: no effective treatment. ITU care. Supportive. Post-exposure prophylaxis (PEP) with rabies Ig and vaccination can be tried. The experimental Milwaukee protocol may be tried.

• About: bacterial infection in the subarachnoid space. Notifiable disease. Delayed treatment increases mortality and morbidity. Difficulty is those with an atypical and subacute presentation. Treat on clinical suspicion alone. Consider meningitis or meningococcal sepsis if ANY of the following are present: headache, fever, altered consciousness, neck stiffness, rash, seizures, shock.
  
• NB. Empirical therapy does not cover Listeria species. Suspect in older, diabetic or immunocompromised patients.
  
• Aetiology: pneumococcus/meningococcus/HiB all capsulated. They colonise nasopharynx and secrete IgA protease.
  
• Pathology: purulent exudate in the subarachnoid space. Loss of cerebral autoregulation. Localised thrombophlebitis and vasogenic oedema. Arterial/venous thrombosis and infarction. ↑Protein levels.

Infectious agents causing meningitis

• Streptococcus pneumonia: main adult cause. Related to pneumococcal pneumonia, sinusitis, otitis media. Commoner in alcoholics. Diabetes, post-splenectomy, complement deficiency, basal skull fractures and CSF rhinorrhoea. Can cause CVT, hemiplegia, hydrocephalus, ventriculitis with 20–40% mortality. Prevent with pneumococcal vaccination. Increasing penicillin resistance. Give BENZYLPENICILLIN if sensitive. CEFTRIAXONE or CEFOTAXIME IV. VANCOMYCIN IV may be added. 2 week course. Give steroids.
  
• Neisseria meningitidis: Gram –ve diplococcus. Serotype B commonest (75%). Others A and C (reducing due to vaccination) commonest in developing world and W135. Affects children and adolescents. Petechial (non-blanching) rashes or purpura are vital to early diagnosis. Complement deficiencies, e.g. properdin, increase risk. Septicaemia – Waterhouse–Friderichsen syndrome with adrenal haemorrhage causing shock. DIC. Haemorrhagic rash. Diagnose with blood/CSF Gram stain and culture and PCR. BENZYLPENICILLIN if sensitive. CEFTRIAXONE or CEFOTAXIME IV.
  
• Haemophilus influenzae: small Gram –ve. Children. Capsulated type B strains. Reduced due to HiB vaccination. Related to ENT infection in some. Develop deafness, CVST, SIADH, subdural collections. CEFTRIAXONE or CEFOTAXIME IV. Give steroids.
  
• Other Gram negatives: seen in debilitated, diabetics and cirrhotics often with head injuries and post-craniotomy. CEFTRIAXONE or CEFOTAXIME IV. 3 week course.
  
• Group B streptococci: traditionally a neonatal infection. Now being seen in all ages including elderly. BENZYLPENICILLIN or AMPICILLIN.
  
• Listeria monocytogenes: elderly, pregnant and immunocompromised. Food-borne – soft cheese, patés, coleslaw and undercooked meats. Needs IV AMPICILLIN or GENTAMICIN. Listeria resistant to cephalosporin and so not covered by empirical treatment. May cause brainstem signs. Listeriosis, Section 9.17.
  
• Staphylococcus aureus: post neurosurgery, penetrating trauma, shunt-associated meningitis post invasive procedure with coagulase negative Staph.
  
• Viral meningitis: HSV, VZV, EBV, CMV, mumps, HIV. Others are echo/enterovirus and coxsackie. Usually benign. Suspected HSV meningitis consider ACICLOVIR if severe. Any neurology beyond headache and meningism consider encephalitis.
  
• Cryptococcal (fungal): seen in immunosuppression, HIV/AIDS (Section 9.33), steroids, lymphoma. AMPHOTERICIN B IV.
  
• Tuberculosis: insidious, cranial nerve palsies. Raised lymphocytes and protein, low glucose. Give steroids. TB, Section 9.32.

Clinical

• Look for meningism. Neck stiffness (unable chin to chest), meningeal irritation, resists passive neck flexion; Kernig’s sign: patient supine with thigh flexed back to abdomen and knee flexed. Pain elicited on straightening the knee; Brudzinski’s sign: supine and flexing neck causes flexion of hips and knees.
  
• Signs may be muted in the young and elderly or immunocompromised. Chest infection, craniotomy, rhinorrhoea, petechiae (non-blanching), hands and feet and conjunctiva. Atypical presentation with delirium, stroke-like episodes, falls. Unexplained fever, N&V, photophobia, seizures, with progression, VI nerve palsy, papilloedema.
  
• Reduced level of consciousness, decerebrate posturing, falling heart rate, ↑BP.
  
• Complications: seizures, stroke from arterial/venous thrombosis, low Na. ↑ICP, hydrocephalus, cerebral abscess/empyema, and cerebral herniation.
  
• Differentials: viral meningitis due to enterovirus, mumps or HSV. Lymphocytes in CSF <300/mm3. Normal glucose and mild elevated protein. TB meningitis: lymphocytes 100–500/mm3 and ↑protein and low glucose. Fungal meningitis: e.g. cryptococcus on India ink stain.

Investigations

• FBC, U&E, ↑CRP, blood cultures immediately and antibiotics commenced.
  
• CT scan and LP: imaging not needed if fully conscious, no lateralising signs, no seizures and no HIV infection. In a fully conscious patient, a CT scan delays treatment and delays the LP. An early LP directs appropriate antibiotic treatment. It can aid diagnosis of aseptic meningitis, which avoids unnecessary antibiotics. Most cases of headache and fever of recent onset will have a systemic illness headache. If LP delayed then antibiotics should be given. LP can be delayed if severe sepsis, rapidly evolving rash or severe cardiorespiratory compromise or coagulopathy. Blood cultures should be sent.
  
• CSF: check glucose (with concurrent blood glucose), protein, microscopy and culture, lactate, meningococcal and pneumococcal PCR, enteroviral, herpes simplex and varicella zoster PCR. Consider investigations for TB meningitis. Look for ↑WCC (neutrophils) >5–2000/mm3 (note the huge range). Normal CSF has 0–5 cells/mm3. ↑protein, ↓glucose and ↑CSF pressure. PCR for bacterial DNA. Latex agglutination to pneumococcus, meningococcus, influenzae, E. coli and Group B streptococci. Very high protein and low glucose are bad prognostic predictors. ↑CSF lactate >3.5 mmol/L suggests bacterial meningitis. ↑WCC and negative Gram stain may be due to previous antibiotic treatment or viral meningitis. Mumps virus can lower CSF glucose. CSF: Indian ink stain or Gram stain for cryptococcus. Cryptococcal antigen in CSF or blood.
  
• Skin biopsy of petechial skin lesions can reveal organisms.
  
• Differential: viral meningitis, HSV encephalitis, Rocky Mountain spotted fever in USA. SAH, acute disseminated encephalomyelitis, cerebral abscess, cerebral malaria. HIV/AIDS.

Management (antibiotics + steroids)

• Supportive: ABCs, O2 as per BTS guidance. Discuss with microbiology to optimise antibiotics and expedite samples. Following require urgent senior review +/– critical care input: rapidly progressive rash, poor peripheral perfusion, capillary refill time >4 s, oliguria or SBP <90 mmHg, respiratory rate <8 or >30 /min, pulse rate <40 or >140 /min, acidosis (pH <7.3) or base excess worse than –5, WBC <4 × 109/L, lactate >4 mmol/L, GCS <12 or a drop of 2 points, poor response to initial fluid resuscitation.
  
• Antibiotics: treat on suspicion. CSF: penetration of antibiotics depends on meningeal inflammation. Try to get blood cultures, LP and CSF before antibiotics. CEFTRIAXONE or CEFOTAXIME IV immediately as empirical therapy. Duration 7 days meningococcus, 14 days pneumococcal. CSF/blood cultures will guide therapy as will patient’s age. This therapy does not cover Listeria so if considered (age >55, pregnant, immunocompromised) then add AMPICILLIN or AMOXICILLIN for 21 days and some may add GENTAMICIN 5 mg/kg/d for 10 days. If meningitis post-head injury/neurosurgery/brain abscess: MEROPENEM IV. If you suspect penicillin-resistant pneumococcus, then add VANCOMYCIN. Suspect pseudomonas then add VANCOMYCIN + CEFTRIAXONE.
  
• Steroids: adults with suspected pneumococcal or H. influenzae bacterial meningitis give DEXAMETHASONE 10 mg stat IV and then 0.15 mg/kg every 6 h for 2–4 days. Improves overall outcome with H. influenzae, tuberculous, and pneumococcal meningitis.
  
• Antifungals: cryptococcal meningitis needs LIPOSOMAL AMPHOTERICIN B 3 mg/kg IV/day and FLUCYTOSINE and then FLUCONAZOLE 400 mg OD. Discuss with infectious diseases experts.
  
• Antivirals: consider ACICLOVIR 10 mg/kg 8 h IV if HSV meningoencephalitis is within the differential. Have a low threshold for treatment whilst awaiting CSF PCR.
  
• Notifiable disease. Inform local public health. Consider prophylaxis for close adult contacts. Take local advice. RIFAMPICIN 600 mg BD for 2 days has been used. Take microbiological advice if unsure. Staff do not need prophylaxis unless they gave mouth to mouth resuscitation.

Reference: Cochrane Review (2016) Corticosteroids for acute bacterial meningitis. British Infection Society, Early Management of Suspected Meningitis and Meningococcal Sepsis in Immunocompetent Adults. 3rd Edition.

• About: meningeal inflammation but a more benign and self-limited illness than bacterial meningitis. There may be a microencephalitis.
  
• Causes: enteroviruses 80%, mumps, HSV-2, CMV, measles, influenza, HH6.
  
• Clinical: nausea, vomiting, irritability, delirium, headache, neck stiffness, photophobia, malaise. No focal neurology or seizures, etc.
  
• Investigations: FBC, WCC and CRP may show inflammatory response. HIV test advised. CT/MRI usually normal. Severe cases T1-weighted MRI may show diffuse enhancement of the meninges. LP and CSF: elevated lymphocytes. Virology: PCR to HSV, CMV, HIV. Toxoplasma serology if needed. Send blood, faeces, throat swabs for viral serology and cultures.
  
• Differential: partially treated bacterial meningitis so ask about prior antibiotic usage, other inflammatory and granulomatous or malignant conditions.
  
• Management: supportive usually recovery in 7–10 days with excellent prognosis. Manage headache and fever with analgesics and paracetamol. Ensure hydrated. Usually benign and self-limited and self-caring can be managed at home. Consider treating those with immunodeficiency. HSV meningitis treatment with ACICLOVIR should be only for those with evidence of associated encephalitis. Take advice if unsure. CMV meningitis: use Ganciclovir/Foscarnet in immunocompromised hosts.

• Types: differentiate intracerebral and subdural pus collections. An abscess has pus in the parenchyma and the other pus in subdural space (empyema).
  
• Risk factors: alcoholism, immunosuppression, e.g. post-transplant, skull fracture, associated mastoiditis or localised infection. Dental abscess, bronchiectasis, TB, AIDS, bacterial endocarditis. All commoner in men.
  
• Aetiology: local spread, e.g. Staph. aureus from penetrating skull trauma. From sinus ENT infections. Pseudomonas from ears, anaerobes and streptococci from oral cavity. Systemic blood spread from lung abscess, bronchiectasis, congenital cyanotic heart disease (Fallot’s), PFO, pulmonary AV fistula, endocarditis. Immunocompromised/HIV – toxoplasma and nocardia and fungal infections.
  
• Pathology: early cerebritis (local infection and infiltration) → late cerebritis (central necrosis) → collagen capsule formation with central necrosis takes 2 weeks. Steroids slow time course. The capsule can impede antibiotic penetration.
  
• Clinical: focal symptoms of space-occupying lesion. Headache, focal seizure. Delirium. ↑ICP – general malaise, drowsiness, progressive coma, hemianopia with temporal lobe abscess, movement disorder. Neurological signs, poor dentition. Evidence of neglect/alcoholism. Look for clubbing, murmurs, dental abscess, jaundice (look in ears). Patients can appear well if pus is well walled off.
  
• Differential: malignant glioma (also has ring enhancement but does not show DWI changes on MRI). Needle aspiration (may be only way to differentiate), metastatic tumour (look for primary), toxoplasmosis (HIV, positive serology, response to treatment), nocardia (brain biopsy, treat).
  
• Investigations: bloods: ↑ESR/CRP, ↑WCC may be normal. Blood cultures, HIV serology. Echocardiogram: endocarditis. CXR: bronchiectasis, exclude lung tumour. CT brain with contrast/MRI brain with gadolinium: shows ring-enhancing lesion with extensive surrounding oedema. Necrotic centre in early stages can show restricted diffusion on DWI. Look for hydrocephalus and signs of ↑ICP or signs of local sepsis, CT sinuses for sinusitis, mastoiditis. There may be a subdural collection. LP avoided if raised ICP and imminent herniation syndrome – take advice. A brainstem abscess should raise concerns over Listeria but there is no capsule and antibiotics should be given.
  
• Management: take neurosurgical advice. Stereotactic biopsy and culture to confirm diagnosis and identify organism to direct antibiotic therapy. Drainage may be by needle aspiration or excision and drainage if superficial and non-eloquent area. Multiple small abscesses managed medically. A short course of steroids (Dexamethasone 16–24 mg/day) may have a role if significant oedema until definitive drainage. Antibiotics: empirical IV CEFTRIAXONE 2 g 12 h + IV METRONIDAZOLE 500 mg 8 h for 6–8 weeks and review. A capsule can prevent antibiotic penetration with low levels in the core. Take microbiology advice. Anticonvulsants may be needed for seizures. Occasionally abscess can rupture causing a ventriculitis with very poor prognosis. Neurorehabilitation.

• About: sinuses have no valves so retrograde infection from central face can spread. Cavernous sinuses lie on either side of pituitary fossa and include the internal carotid artery and III, IV and VI nerve on way to the orbit. Cavernous sinus thrombosis may at times be purely due to a procoagulant state.
  
• Microbiology: Staph. aureus 70%, others are streptococci, pneumococci, Gram negatives, spread usually from facial cellulitis or sinus infection of sphenoid and ethmoid sinuses.
  
• Clinical: fever, periorbital oedema, headache, photophobia, proptosis, ptosis, III/IV/VI nerve palsy, diplopia, papilloedema, retinal haemorrhage, visual loss. Spread can be rapid over 1–2 days with spread to deep veins and venous infarction and coma.
  
• Investigations: FBC, WCC, CRP, CT brain to exclude other diagnosis. MR/CT venography is definitive for diagnosis.
  
• Differential: orbital cellulitis: periorbital swelling, proptosis, chemosis, ophthalmoplegia, fever, decreased vision, and pain. Usually unilateral. CSF normal. Preseptal cellulitis: no proptosis or ophthalmoplegia. Orbital apex syndrome: infection in the posterior orbit causes visual loss and ophthalmoplegia out of proportion to proptosis and periorbital oedema which may be minimal. Also local malignancy and inflammatory diseases.
  
• Management: IV antibiotics with anti-staphylococcal cover. Surgery is rare other than to drain co-terminous sinus infections. Anticoagulation may be considered to prevent extension of venous thrombosis.

• About: often seen in obese young females with a high opening pressure headache. Can result in visual loss. Not benign as sight may be permanently compromised.
  
• Precipitants: weight gain, tetracycline, steroids, amiodarone, Tamoxifen, Minocycline, Isotretinoin, all-trans-retinoic acid (ATRA) for APML, Ciclosporin.
  
• Clinical: classically but not always obese young females. Rapid weight gain. Chronic high pressure headache worse in morning, coughing, straining. Papilloedema and enlarged blind spot. Diplopia (VIth nerve). Pulsatile tinnitus.
  
• Investigations: FBC, U&E, ESR. CT at least initially to exclude SOL before LP. LP shows high opening pressures. Remove 20 ml helps headache/vision. CSF normal. Also consider CT/MR venography to exclude cerebral venous sinus thrombosis. Visual fields assessment.
  
• Management: stop any causative drugs, lose weight. Start ACETAZOLAMIDE. Monitor with neurology follow up. Optic nerve sheath fenestration or CSF shunting.

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