Neurology in Practice

THE BARE ESSENTIALS Eelco F M Wijdicks

Correspondence to Comatose patients present to the neurologist in should be discouraged. It is better to note a set of Professor E F M Wijdicks, several ways, mostly first in the emergency room or key findings and make comparisons over time (eg, Consultant, Neurosciences Intensive Care Unit, St intensive care unit. Given the many causes of coma, “the patient has improved, is now able to track my Mary’s Hospital, Mayo Clinic, the central focus is a comprehensive evaluation that finger, but eyes open only to a loud voice, localise to 200 first Street SW, Rochester, starts with a detailed history, although this has to be pain, extubated and able to protect the airway”). MN 55905, USA; wijde@ mayo.edu an account—at least to begin with—from bystand- Comatose patients have several outcomes: they ers, paramedics or even the police. This is followed may lose all brain function (), remain by a neurological and general examination, gath- unconscious (persistent vegetative state) or regain ering of key findings, localisation of the involved consciousness (minimally conscious, fully con- brain structure, neuroimaging and other laboratory scious but disabled, or good recovery) (figure 1). tests. Sorting out the cause of coma is what neu- Most emerge from coma in 1–2 weeks. Survivors rologists do best—compared with other specialists. with abnormal consciousness may remain in a Of course the relatively recent availability of MRI minimally conscious state (MCS) or in a persis- has helped tremendously in understanding some tent vegetative state (PVS). Empirically, there is cases of coma but brain imaging can be normal. overlap between these states, particularly in the Indeed, unravelling the cause of coma remains in first weeks to months after the acute brain . many circumstances a clinical judgement. Some patients may have only a fraction of aware- Once treated, comatose patients can recover ness—for example, brief fixation to objects that suddenly (eg, after quick correction of hypo- is only detected by close observation over time. glycaemia) but many patients have significant These conditions are not diagnosed on the spot. structural brain injury and take days to awaken. About 25% of patients stay in a prolonged state of Persistent vegetative state (PVS) is defined as:

but even then slow awakening is ▶ No awareness of self or environment. to be expected; only a very small fraction survive ▶ No sustained reproducible, purposeful or vol- but never emerge from coma. untary behavioural response to visual, audi- tory, tactile or noxious stimuli. DEFINITIONS OF ALTERED STATES OF ▶ No language comprehension or expression. CONSCIOUSNESS ▶ Mostly intact cranial nerve reflexes. Impaired consciousness has been traditionally ▶ Roving nystagmoid eye movements. regarded as a problem with alertness, awareness ▶ Presence of sleep and wake cycles, often eyes of self, or both. open during the day.

▶ A disturbance of arousal—mainly a function ▶ Stable unsupported blood pressure and intact of the reticular formation in the brainstem— respiratory drive. leads to diminished alertness. ▶ Bowel and bladder incontinence. ▶ A disturbance involving content—a function Minimally conscious state (MCS) is defined as: of multiple cortical areas—leads to dimin- ished awareness, and failure to accurately ▶ Patients make eye contact or turn head when integrate what is perceived. being talked to. These two components are interrelated but ▶ An abulic emotionless state but with eye track- sometimes dissociated. One can be awake and ing movements. aware, awake but not aware and not awake and ▶ May mouth words, may fend off pain. not aware. ▶ Eyes following moving person. Coma is best defined as a completely unaware ▶ Some intelligible verbalisation. patient unresponsive to external stimuli with only ▶ May hold object or use object when asked. eye opening to pain with no eye tracking or fix- ation, and limb withdrawal to a noxious stimu- The frequency of these prolonged comatose lus at best (often with reflex motor movements). states is not known, nor is it clearly established Brainstem reflexes can be partly absent or absent. where the point of no return is. Patient registries The degree of coma is more difficult to define. may provide some insight into the frequency Terms such as , drowsiness, obtundation, of coma after severe traumatic brain injury or , light or deep coma are all vague and stroke but there are definitional difficulties and

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confounding factors; for example, sedation in the the thalamus, and monoaminergic neurons first weeks after major brain injury (physician projecting from the upper brainstem to the induced coma) may impact on time to awakening. thalamus, hypothalamus, basal forebrain and Here are some sobering facts. cortex (figure 2). ▶ Stimulation of the posterior hypothalamus ▶ Withdrawal of support is a common cause of causes arousal. death in comatose patients. ▶ Lesions of the cuneus and precuneus associa- ▶ MCS is far more common than PVS within tion cortex may be involved in the MCS. 6 months from brain injury. ▶ Lesions of the anterior cingulate gyrus result ▶ The diagnosis of PVS may not have been made in marked abulia. by a neurologist—misjudgements are more common than appreciated. ▶ Patients in PVS may be kept alive for decades NEUROLOGICAL EXAMINATION OF THE but with no prospects for improvement. COMATOSE PATIENT Finding the cause of coma requires many steps ANATOMY AND NEUROPHYSIOLOGY OF COMA and it helps to know the major categories before starting (table 1). ▶ Coma is currently understood as being caused by interruption of the ascending reticular acti- ▶ Structural injury of the cerebral hemisphere(s). vating system in the midbrain and pons pro- ▶ Intrinsic brainstem injury, or compression jecting to the thalamus and cortex. from surrounding damaged tissue such as ▶ The thalamus through its intralaminar swollen infarcted cerebellum. nuclei plays an important role in maintaining ▶ Acute metabolic or endocrine derangement arousal. (eg, hypoglycaemia, hyponatraemia, acute ▶ The thalamus and ascending reticular acti- panhypopituitarism). vating system can be damaged from shift or ▶ Diffuse physiological brain dysfunction (eg, displacement of the brainstem, as well as by seizures, intoxication or poisoning, hypother- direct destruction. mia, smoke inhalation, near drowning, heat ▶ The ascending reticular activating sys- stroke, acute catatonia, malignant neuroleptic tem contains cholinergic neurons of the syndrome). medial pontine tegmentum projecting to Every physician should be familiar with two pitfalls.

Figure 1 Categories ▶ The first is failure to recognise the locked-in of altered states of Coma syndrome which can mimic coma. (Some consciousness, from patients in this state have been inadvertently coma to its potential insufficiently sedated, intubated and phar- consequences. MCS, maceutically paralysed.) In a classic form of minimally conscious state; Brain death Conscious PVS, persistent vegetative locked-in syndrome, they have their eyes open state. and can only blink to commands or move Good PVS MCS their eyes vertically. Their motor tracts are de-­ recovery efferented by a lesion in the ventral pons spar- ing the ascending reticular activating system Disability and thus they can hear, see and feel pain. ▶ The second, psychogenic unresponsiveness, is often only considered after exclusion of other causes and requires some clinical experience to definitively demonstrate its presence and to think about it in the first place and before ordering a battery of tests, some of which may be risky. The hand drop test is a classic but not completely reliable test (one arm is lifted and held in front of the face and when let loose slides next to the patient’s face rather Figure 2 The main than on to it). Closed eyes which open with pathways connecting tickling the nose hairs is more characteristic. the ascending reticular Some patients may have forced upward or formation with the downward gaze that may suddenly change in thalamus and cortex. From The comatose patient, direction. Others have abnormal movements, Wijdicks EFM, used misinterpreted as seizures, but these generally with permission of Mayo look more like ‘fish out of water’ flopping. (To Foundation for Medical complicate matters, I have seen a psychogenic Education and Research. locked-in syndrome with blinking as the only

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Table 1 Classification and causes of coma form of communication in a nurse assistant for Structural brain injury a full 48 h after a marital spat.) Cerebral hemisphere Examination of the comatose patient follows Unilateral (with displacement) a set of clinical tests to locate the lesion. These Intraparenchymal haematoma findings are then integrated with neuroimaging Middle cerebral artery ischaemic stroke or electrophysiology test results. Many comatose Intracranial venous thrombosis patients do not, however, have specific findings Haemorrhagic contusion which can be problematic. Nonetheless, a routine Cerebral abscess set of clinical tests is necessary to assess the depth Brain tumour of coma, the location of the lesion and possibly Subdural or epidural haematoma the underlying cause. Bilateral Subarachnoid haemorrhage ▶ Initial neurological examination may use a Multiple traumatic brain contusions coma scale—the Glasgow Coma Scale is a uni- Penetrating traumatic brain injury versally used instrument (table 2). Anoxic–ischaemic encephalopathy ▶ Another coma scale, the FOUR score, provides Multiple cerebral infarcts far more neurological detail while incorporat- Bilateral thalamic infarcts ing the bare necessities of a coma examina- Lymphoma tion: eye response, motor response, brainstem Encephalitis reflexes and respiration (table 3). Gliomatosis The neurological examination proceeds with Acute disseminated encephalomyelitis assessment of the cranial nerves and motor Cerebral oedema response to pain. Multiple brain metastases Acute hydrocephalus ▶ Fundoscopy may reveal diagnostic findings (eg, Acute leukoencephalopathy subhyloid haemorrhage in aneurysmal sub- Posterior reversible encephalopathy syndrome arachnoid haemorrhage, acute papilloedema Air or fat embolism in increased intracranial pressure or hyperten- Brainstem sive crisis). Pontine haemorrhage ▶ Small or pinhole pupils (<2 mm) are due to a Basilar artery occlusion and brainstem infarct pontine lesion or opioids (figure 3A). Central pontine myelinolysis ▶ Midsize light fixed pupils (4–6 mm) are due to Brainstem haemorrhagic contusion a midbrain lesion (figure 3B). Cerebellum (with displacement of brainstem) ▶ Maximally dilated pupils (>8 mm) are due Cerebellar infarct to a lesion of the third cranial nerve nuclei, Cerebellar haematoma mesencephalon or compression of peripheral Cerebellar abscess fibres of the third nerve. However, drugs and Cerebellar glioma toxins can also dilate the pupils (eg, lidocaine, Acute metabolic–endocrine derangement amphetamines, cocaine). Hypoglycaemia ▶ Unilateral fixed pupil is due to a third cranial Hyperglycaemia (non-ketotic hyperosmolar) nerve lesion (compression of the midbrain Hyponatraemia Hypernatraemia Addison’s disease Table 2 Glasgow Coma Scale Acute hypothyroidism Eye opening Acute panhypopituitarism 4 = Spontaneous Acute uraemia 3 = To speech Hyperbilirubinaemia 2 = To pain 1 = None Diffuse physiological brain dysfunction Best motor response Generalised tonic–clonic seizures 6 = Obeying Poisoning, illicit drug use 5 = Localising pain 4 = Withdrawal 3 = Abnormal flexing Gas inhalation 2 = Extensor response Acute (lethal) catatonia 1 = None Malignant neuroleptic syndrome Best verbal response Psychogenic unresponsiveness 5 = Oriented Hysterical coma 4 = Confused conversation Malingering 3 = Inappropriate words Reprinted with permission from Wijdicks EFM. Catastrophic 2 = Incomprehensible sounds neurologic disorders in the emergency department. New York: Oxford 1 = None University Press, 2004.

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Table 3 The FOUR Score ▶ Cluster breathing and central neurogenic Eye response hyperventilation indicate bihemisphere or 4 = Eyelids open or opened, tracking or blinking to command pontine lesions, while ataxic breathing indi- 3 = Eyelids open but not tracking cates a lesion in the lateral tegmentum of the 2 = Eyelids closed but open to loud voice lower pons. 1 = Eyelids closed but open to pain 0 = Eyelids remain closed with pain However, recognition of these patterns is dif- Motor response ficult and cannot be observed when mechanical 4 = Thumbs-up, fist or peace sign ventilation has taken over. Moreover, their locali- 3 = Localising to pain sation is not firmly established. 2 = Flexion response to pain Motor responses are elicited with painful stim- 1 = Extension response to pain uli such as compression over the supraorbital 0 = No response to pain, or generalised myoclonus status nerve, temporomandibular joint or nailbed; flex- Brainstem reflexes ion, extension or no response at all. None of these 4 = Pupil and corneal reflexes present responses are localising and even the distinction 3 = One pupil wide and fixed between decerebrate and decorticate responses 2 = Pupil or corneal reflexes absent may not have significance for prognostication (not 1 = Pupil and corneal reflexes absent infrequently both responses can be present in the 0 = Absent pupil, corneal and cough reflex same patient). Respiration 4 = Not intubated, regular breathing pattern ▶ Decorticate responses are defined by slow 3 = Not intubated, Cheyne–Stokes breathing pattern flexion of the elbow, wrist and fingers. 2 = Not intubated, irregular breathing 1 = Breathes above ventilator rate ▶ Decerebrate responses are defined by adduc- 0 = Breathes at ventilator rate or apnoea tion and internal rotation of the shoulder, arm extension and wrist pronation with fist formation.

Spontaneous generalised myoclonus may indi- ocular motor complex, traction on the third cate anoxic–ischaemic brain injury but also lith- nerve or pressure of the nerve against the ium intoxication, cephalosporin intoxication and clivus). pesticides. ▶ Spontaneous eye movement abnormalities (ping-pong, ocular dipping) localise mostly to CLUES FROM THE GENERAL PHYSICAL bihemispheric dysfunction except ocular bob- EXAMINATION bing (rapid down, slow up) which localises to Although none is very specific and they can be the pons. seen in other circumstances, signs which suggest ▶ Roving eye movements indicate that the brain- certain intoxications and metabolic abnormalities stem is intact. include the following: ▶ Skew deviation of the eyes suggests an acute ▶ Classic foul breaths are dirty toilet (uraemia), Figure 3 (A) Pinpoint brainstem injury. fruity sweat (ketoacidosis), musty or fishy pupils: well known to any ▶ Horizontal deviation of the eyes to one side (acute hepatic failure), onion (paraldehyde) inner city police officer might be a sign of non-convulsive status epi- and garlic (organophosphates). (opioid intoxication) but lepticus but also of an ipsilateral hemispheric may also indicate pontine or contralateral pontine stroke. ▶ Skin bullae may indicate barbiturate poisoning. haemorrhage. (B) Mid ▶ Dryness of skin indicates barbiturate poison- position light fixed pupils Evaluation of breathing pattern abnormalities ing or anticholinergic agents. (mesencephalic lesion) in may be useful. downward compression of ▶ Profuse sweating indicates cholinergic poi- soning, neuroleptic malignant syndrome or a the upper brainstem from a ▶ Cheyne–Stokes breathing can occur with serotonin syndrome. hemispheric mass but also any type of reduced alertness and is least often the first sign of loss ▶ localising. Hypotension may indicate deliberate overdose of all brainstem reflexes with antihypertensives. (brain death). ▶ Hypertension may indicate amphetamine intoxication, cocaine or more or less any (a) party drug. ▶ Hypothermia (<35°C) is common in alcohol intoxication, and overdose with barbiturates or tricyclic antidepressants. ▶ Hyperthermia (>40°C) can be seen with (b) cocaine, tricyclic antidepressants, phencycli- dine and salicylate intoxication. ▶ Cardiac arrhythmias are a common manifes- tation of tricyclic antidepressant, cocaine and ethylene glycol poisoning.

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The vital signs may also provide clinical clues recently been discontinued? Was hyperten- to the diagnosis: sion poorly controlled?

▶ Hypothermia (<35°C) is commonly due to The most important questions that need to be exposure to a cold environment but may also asked next are as follows: indicate decreased heat production due to hypothyroidism, Addison’s disease or hypo- ▶ Is the coma due to a destructive structural glycaemia. Hypothermia in comatose patients brain lesion or to global acute physiological may herald brain death. derangement of brain function? ▶ Hyperthermia (>40°C) indicates a fulmi- ▶ Is there any structural lesion in both cerebral nant systemic infection, endocarditis or CNS hemispheres or in the brainstem? infection. ▶ Is there any brainstem lesion inside the brain- ▶ Hypotension may indicate early sepsis or ful- stem or due to displacement of the brainstem? minant acute meningococcal meningitis. These syndromes may overlap: ▶ Hypertension may indicate that coma is due to ▷ Intrinsic brainstem lesions are recognised acute hypertensive encephalopathy; it is also by skew deviation, internuclear ophthal- part of the Cushing reflex which is common moplegia, small or unequal pupils and in catastrophic intracerebral haemorrhage, in absent oculocephalic responses; particular in the pons or cerebellum. ▷ Brainstem displacement caused by lesions above the tentorium is recognised by a wide, FINDING THE CAUSE OF COMA fixed pupil, abnormal motor responses but After the patient is medically stable, more inqui- otherwise intact brainstem reflexes; ries should follow. Remember some questions ▷ Brainstem displacement from below the may be inappropriate, others could be essential. tentorium is recognised by small pupils, Questions that might be asked of family members, absent corneal reflexes and oculocephalic paramedics, or bystanders include the following: responses in some patients. ▷ Patients with an intrinsic brainstem syn- ▶ Could this be a major anoxic–ischaemic insult drome and a normal CT scan most likely to the brain? How was the patient found? have an embolus to the basilar artery; an What did the scene look like when he or she abnormal CT scan will likely show a hae- was found? Was the patient breathing on morrhage into the brainstem, traumatic arrival of the response team? Was a cardiac brain injury to the brainstem or a brainstem arrest documented? How long did the efforts tumour or infectious mass. last before resumption of the circulation? Was ▷ Patients with a brainstem displacement there noticeable blood loss? Did the patient syndrome and an abnormal CT scan often deteriorate during transport? have a massive hemispheric ischaemic or ▶ Could this be an intoxication? What pills haemorrhagic stroke, contusional lesion, or over-the-counter drugs or herbs does the large subdural or extradural haematoma, patient have access to? Has the patient made a malignant tumour or abscess with prior suicide attempts, has there been a psy- oedema. chiatric consultation, are there problems at ▶ Is any bihemispheric syndrome due to cortical work? Has anyone complained about drug or injury, extensive white matter injury or acute drinking habits? physiological brain dysfunction? Patients with ▶ Could this be a CNS infection? Did the patient bihemispheric lesions have few localising find- use antibiotics for infection? Was there a rapid ings. Gaze preference may be seen temporar- onset of fever and headache? ily. Brainstem reflexes are usually intact. ▶ Could this be hypoglycaemia or hyperglycae- ▷ Patients with bihemispheric injury and a mia? Is the patient known to be diabetic, or normal CT scan most likely are comatose could they have undiagnosed diabetes? Has the from a toxin, status epilepticus, CNS infec- patient had prior episodes of diabetic ketoaci- tion, endocrine/metabolic derangement or dosis, and has there been a recent change in anoxic–ischaemic injury. diabetic medications? Might the patient have ▷ In patients with a bihemispheric syndrome, overdosed on hypoglycaemic drugs (their own an abnormal CT may show cortical lesions, or someone else’s)? Could they have been white matter lesions, acute hydrocepha- deliberately poisoned? lus, brain oedema, cerebral haemorrhage ▶ Might the patient be hyponatraemic? Did or posterior reversible encephalopathy they have access to fluids and is he or she on syndrome. diuretics? ▷ Myoclonic status epilepticus may due to ▶ Could this be non-convulsive status epilepti- hypoxic–ischaemic brain injury after car- cus? Is the patient a known epileptic? diopulmonary resuscitation. ▶ Could this be an embolus to the basilar artery? ▶ Brain death is recognised by absent eye open- Is the patient known to have atrial fibrilla- ing to pain, no motor response to pain, and tion or other cardiac disease and has warfarin absent pupil and corneal responses. Ocular

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vestibular reflexes are absent and there is no ▶ Recognise metabolic acidosis and any anion evidence of spontaneous breathing. gap due to methanol, ethanol, paraldehyde or salicylates. Calculate anion gap from the serum electrolytes. Anion gap = [Na+] − [Cl−] − INVESTIGATIONS − [HCO3 ]. A gap of 11–13 mEq/l is normally pre- Acute metabolic derangements (table 4) should sent but may increase with toxins. be considered, such as hypoglycaemia, hypercal- ▶ The osmol gap is calculated using the equa- caemia, hyponatraemia or hypernatraemia, acute tion: 2 × Na + glucose/18 + blood urea uraemia or acute liver failure; panhypopituitarism nitrogen/2.8. The calculated osmolality is and myxoedema coma are rare. normally less than the measured osmolal- ▶ Essential initial laboratory tests include hae- ity but should be no more than 10 mosmol/l. matocrit, full blood count, platelet count and Atypical alcohols such as methanol, ethyl- blood smear for schistocytes; electrolytes; ene glycol (antifreeze) and isopropyl glycol glucose; urea; creatinine; liver function; increase the osmol gap. osmolality; arterial blood gases; and thyroid CT and MRI of the brain are exceedingly function. important in the workup of a comatose patient— ▶ If intoxication is suspected, urine and blood without them the cause of coma may remain a screening is needed. Drug screens are how- wild guess (table 5). ever limited in scope and may not detect the toxin. ▶ Imaging defines the existence of any mass, its ▶ Blood cultures in patients with fever and sus- remote effect and any oedema, and may hint picion of CNS infection. at the cause—for example, brain tumour, sub- dural haematoma, abscess. ▶ CT will also detect fresh intracranial haemor- rhage and contusions. Table 4 Laboratory values compatible with coma ▶ CT in traumatic brain injury is only a snap- in patients with acute metabolic and endocrine shot; in some cases repeat CT will show fur- derangements* ther abnormalities (figure 4). Derangement Serum ▶ MRI may show cortical injury, laminar necro- Hyponatraemia <110 mmol/l sis, white matter disease and white matter Hypernatraemia >160 mmol/l oedema; it may be normal early after cardio- Hypercalcaemia >3.4 mmol/l pulmonary resuscitation. Hypercapnia >9 kPa ▶ MRI/MR angiography is the preferred test in Hypoglycaemia <2.2 mmol/l patients with suspected acute basilar artery Hyperglycaemia >50 mmol/l occlusion but many centres may more easily Reprinted with permission from Wijdicks EFM. Catastrophic obtain a CT angiogram or go directly to cath- neurologic disorders in the emergency department. New York: Oxford University Press, 2004. eter angiogram for possible neuroradiological *Sudden decline in value is obligatory. intervention.

Table 5 Frequent abnormalities on brain imaging in coma Finding Suggested disorders CT Mass lesion Haematoma, haemorrhagic contusion, middle cerebral artery infarct Haemorrhage in basal cisterns Aneurysmal subarachnoid haemorrhage, cocaine abuse Intraventricular haemorrhage Arteriovenous malformation Multiple haemorrhagic infarcts Cerebral venous thrombosis Multiple cerebral infarcts Endocarditis, coagulopathy, vasculitis, thrombotic thrombocytopenic purpura Diffuse cerebral oedema Cardiac arrest, fulminant meningitis, acute hepatic necrosis, encephalitis Acute hydrocephalus Aqueduct obstruction, colloid cyst, pineal region tumour Pontine or cerebellar haemorrhage Hypertension, arteriovenous malformation, cavernous malformation Shear lesions in the white matter Traumatic brain injury MRI Bilateral caudate and putaminal lesions Carbon monoxide poisoning, methanol Hyperdense signal along sagittal, straight or Intracranial venous thrombosis transverse sinuses Lesions in corpus callosum, white matter Severe traumatic brain injury Diffuse confluent hyperintense lesions in Acute disseminated encephalomyelitis, posterior reversible encephalopathy syndrome, white matter, basal ganglia immunosuppressive or chemotherapeutic agent toxicity, metabolic leukodystrophies Pontine trident-shaped lesion Central pontine myelinolysis Thalamus, occipital, brainstem lesions Acute basilar artery occlusion Temporal, frontal lobe hyperintensities Herpes simplex encephalitis Reprinted with permission from Wijdicks EFM. Catastrophic neurologic disorders in the emergency department. Oxford: Oxford University Press, 2004.

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(a) (b) above 130 mm Hg) with intravenous labetalol (10 mg IV), hydralazine (10 mg IV) or nicar- dipine (5 mg/h). ▶ Correct hypothermia with warming blan- kets. However, consider induced hypothermia (33–34°C) treatment in patients who have been successfully resuscitated from cardiac arrest. ▶ Correct hyperthermia with cooling blankets, icepacks and ice water lavage. ▶ No harm is done if a patient with a high like- lihood of hypoglycaemia is immediately given 50 ml of 50% glucose, even before the blood sugar is known (with coadministration of 100 mg thiamine intravenously). Figure 4 Rapidly ▶ No harm is done administering naloxone evolving lesions on CT, (0.4–2 mg every 3 min intravenously) if opioid pointing out the common In patients with a normal CT scan and no expla- intoxication is suspected. requirement for repeat nation for coma, a lumbar puncture must be done CT after traumatic ▶ No harm is done administering flumazenil to rule out infection. This should include: brain injury. (A) Right (slow intravenous administration of 0.2 mg/ min up to max dose of 5 mg) which effectively subdural haematoma and ▶ opening pressure; contusional haemorrhages. reverses any benzodiazepine toxicity; this ▶ description of the CSF appearance (cloudy, yel- (B) New contralateral extra however is contraindicated in patients with a low, bloody, etc); dural haematoma. seizure disorder and in whom concomitant tri- ▶ analysis for protein, cells and glucose; cyclic antidepressant intoxication is suspected ▶ CSF culture; (may provoke seizures). ▶ india ink stain and cryptococcal antigen; ▶ Treat severe hyponatraemia with 3% hyper- ▶ viral titres and PCRs in CSF. tonic saline and furosemide after placing cen- tral venous catheter. EEG has lost some of its diagnostic value in the ▶ evaluation of coma but is able to document non- Treat hypercalcaemia with saline rehydration convulsive status epilepticus in otherwise unex- infusion followed by parenteral bisphospho- plained cases. Diffuse slowing and even the time nate pamidronate. honoured triphasic waves may be seen in patients ▶ Consider elimination of any toxin by haemo- with a structural cause of coma. EEG can be help- dialysis or haemoperfusion. ful in early herpes simplex encephalitis but MRI The priorities when faced with a patient is much more specific in documenting the extent with an acute structural cause of coma are as of the tissue destruction. follows:

MANAGEMENT OF COMA IN THE FIRST HOUR ▶ If any hydrocephalus, ventriculostomy to The initial management of a comatose patient reduce raised intracranial pressure. is to correct abnormal vital signs and laboratory ▶ Consider evacuation of any mass to relieve abnormalities. increased intracranial pressure. ▶ If a large mass cannot be removed, consider ▶ Improve oxygenation (face mask 40% oxy- decompressive craniectomy; swollen brain gen aiming at a pulse oximeter saturation of will move out and decompress the mass effect >95%). on the deeper diencephalic structures. ▶ Intubate if patient cannot protect the airway ▶ Attempt to reduce suspected increased intra- (ie, increased work of breathing, pooling secre- cranial pressure with osmotic agents; manni- tions, gurgling sounds). tol, initial dose 1–2 g/kg intravenously, often ▶ Intubate any comatose patient with irreg- with two repeated doses 30–40 min apart. ular ineffective respiratory drive and poor oxygenation. Then: ▶ Intubate any comatose patient with major facial ▶ If CNS infection is even a remote possibility, injury or consider emergency tracheostomy. start full coverage with cephotaxime (2 g every ▶ Correct hypotension by placing patient in the 6 h intravenously), vancomyocin (20 mg/kg Trendelenburg position and add crystalloids intravenously every 12 h) and ampicillin (12 g (rapid infusion of 500–1000 ml normal saline daily, divided dose every 4 h intravenously) followed by 150 ml/h) and if no response, start in combination with antiviral coverage with vasopressors (use phenylephrine intravenous intravenous aciclovir (10 mg/kg every 8 h). bolus of 100 μg). Strongly consider intravenous dexametha- ▶ Correct extreme hypertension (systolic sone 0.6 mg/kg daily before administration of above 250 mm Hg or mean arterial pressure antibiotics, and continue for 4 days.

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LONG TERM MANAGEMENT OF COMA ▷ absent motor responses at 3 days; ▶ If necessary, tracheostomy, percutaneous ▷ absent sensory evoked potential cortical gastrostomy, bladder and bowel care, infec- responses; tion surveillance and deep venous thrombosis ▷ increased serum neuron specific enolase at prophylaxis. any time. ▶ Patients may be weaned from the ventilator ▶ Outcome after traumatic brain injury is very and tracheostomy removed later if secretions difficult to predict. Many young patients make are controlled. a good recovery despite severe CT scan abnor- ▶ Methicillin resistant Staphylococcus aureus malities and slow progress. and vancomycin resistant Enterococci can be ▶ Outcome after aneurysmal intracranial hae- reduced by less overcrowding, strict iso- morrhage is determined by initial clinical lation and avoidance of multiple antibiot- grade; 50% recover to a better grade and some ics along with meticulous hand hygiene by patients may fully recover. staff. ▶ Surgery is no better than medical manage- ▶ Contractures can be reduced but not prevented ment in deep ganglionic haemorrhage but by physical therapy. evacuation of cerebellar haematoma can result ▶ Decubitus skin breaks and ulcers can be pre- in dramatic improvement. Deteriorating vented by special beds and monitoring of pres- patients with an expanding lobar haematoma sure sites along with superb nursing care. may benefit from evacuation but the degree of benefit is uncertain. ▶ Neurostimulation is of no use in PVS and (as yet) unproven in MCS. ▶ Outcome in CNS infections is affected by time to administration of antibiotic or antivi- ▶ Dopaminergic agents (eg, bromocriptine), zolpidem and lamotrigine are commonly used ral drugs (and corticosteroids). but unproven stimulant drugs in MCS. ▶ MCS may seem a better outcome for the fam- ily than PVS but may be a worse outcome for OUTCOME PREDICTION OF COMATOSE the patient who is then aware of the devastat- ing injury. SURVIVORS The outcome is determined by the underlying cause ▶ Patients in MCS may further recover but no of coma. Outcome can also be subject to physician predictors are known. expectations; for example, if the situation is judged ▶ Patients in PVS for less than 3 years may rarely by a pessimistic neurologist as hopeless and care is partially recover, and when they do it is mostly withdrawn leading to death, this can be perceived after traumatic brain injury. Nonetheless, all as a self-fulfilling prophesy. Withdrawal of sup- patients remain severely disabled. Patients in port or no aggressive care of complications in sick PVS for 3 years or more do not recover; they elderly patients may be more common than in prior have remarkable generalised brain atrophy on healthy young patients. These clinical decisions CT scan (figure 5). may impact on the utility of prognostic models.

▶ There are five prognostic indicators for poor BRAIN DEATH DETERMINATION outcome after anoxic–ischaemic brain injury: ▶ Brain death is declared when brainstem ▷ myoclonic status epilepticus at any time; reflexes, motor responses and respiratory ▷ absent corneal or pupil reflexes at 3 days; drive are absent in a normothermic, non- drugged comatose patient with an irreversible widespread brain lesion of known cause and no contributing metabolic derangements. ▶ In adults, brain death is a clinical diagnosis and confirmatory tests are not needed in the USA, UK and many other EU countries. One neurological examination should suffice but some hospital protocols may require two inde- pendent examinations and a certain period of observation. In children, confirmatory tests are required, and a longer time of observation. ▶ Brain death means the patient has died and Figure 5 CT brain organ donation is allowed after consent of scan showing marked family members. atrophy in a 26-year-old in persistent vegetative Prerequisites for brain death diagnosis (figure 6) state after refractory include the following. status epilepticus (the CT appearance corresponds to ▶ Identification of cause and irreversible the brain of a 100-year-old coma, absent major confounding reversible person). medical illness and no lingering effect of

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Figure 6 Stepwise determination of brain death.

COMA

Cause identified and coma irreversible No major confounding reversible medical illness Core temperature at least 32°C No confounding pharmaceutical agents

No poisoning

No motor response to pain applied to face and limbs Any movement attributed to spinal cord response Absent pupil response

Absent cold caloric occulovestibular response Absent cornea response Absent cough to bronchial suctioning

Apnea with PaCO2 60 mm Hg or 20 mm Hg increase from pretest baseline

Neonates Children Children Adults (7 days-2 months) (2-12 months) (12 months-18 years) (>18 years)

2 neurological 2 neurological 2 neurological 1 neurological examinations examinations examinations examination 2 EEGs 2 EEGs 12 hours apart** 2 days apart 1 day apart

BRAIN DEATH

pharmaceutical agents such as sedative drugs ▶ Ask the following seven questions. Could or neuromuscular blocking agents. this be a major anoxic–ischaemic insult to the ▶ Core temperature ≥36.5°C, systolic blood pres- brain? Could this be an intoxication? Could sure ≥100 mm Hg. this be a CNS infection? Could this be a major ▶ Euvolaemia, eucapnia, normoxaemia, metabolic derangement or endocrine crisis? normotension. Could this be nonconvulsive status epilepti- cus? Could this be an embolus to the basilar ▶ Absent brainstem reflexes. artery? Could it be psychogenic? ▶ Apnoea (no trigger of ventilator). ▶ CT (and CTA) MRI of the brain are important Apnoea needs confirmation. The apnoea test is and may provide the answer (but not always). performed using the oxygen diffusion method. The ▶ The initial management is to correct abnormal vital signs and laboratory abnormalities. patient is preoxygenated with 100% O2 followed by disconnection of the ventilator while deliver- ▶ The first priority with an acute structural cause of coma is treatment of increased intra- ing 100% O2 6 l/min through a suction catheter close to the level of the carina (approximately 1 cm cranial pressure. beyond the end of the endotracheal tube). The test ▶ The first priorities with a possible CNS infec- is positive, meaning no breathing effort, when the tion are broad antibiotic and antiviral coverage

arterial PCO2 is ≥60 mm Hg (8 kPa) or if there is an and corticosteroids.

increase of 20 mm Hg (3 kPa) in PCO2 above a nor- ▶ Tracheostomy, percutaneous gastrostomy, mal baseline value. bladder and bowel care, infection surveillance and deep venous thrombosis prophylaxis are Conclusions key components of longer term care. ▶ Sorting out the cause and degree of coma remains ▶ Outcome prediction in acutely comatose in many circumstances a clinical judgment. patients is determined by the underlying

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cause and may also be influenced by physician Further reading expectation. ▶ To ensure that the cessation of brain function is irreversible, physicians must determine the ▶ Giacino JT, Ashwal S, Childs N, et al. The minimally conscious state: definition cause of coma, exclude mimicking medical and diagnostic criteria. Neurology 2002;58:349–53. conditions, and perform a standardised series ▶ Jennett B. The vegetative state: medical facts, ethical and legal dilemmas. of tests. New York: Cambridge University Press, 2002. ▶ Jennett B, Plum F. Persistent vegetative state after brain damage. A syndrome Acknowledgements: This article was reviewed by Robin Howard, in search of a name. Lancet 1972;1:734–7. London, UK, and some of the specialist neurology registrars in ▶ Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative Edinburgh, UK. state. Parts I and II. N Engl J Med 1994;330:1499–508, 1572–9. Competing interests: None ▶ Posner JB, Saper CB, Schiff ND, Plum F. Plum and Posner’s diagnosis of Provenance and peer review: Commissioned; externally peer stupor and coma, 4th Ed. New York: Oxford University Press, 2007. reviewed. ▶ Rabinstein AA, Wijdicks EFM. Coma: raised intracranial pressure and hydrocephalus. In: Warlow C, ed. The Lancet handbook of treatment in neurology. London: Elsevier Ltd, 2006:179–200. ▶ Wijdicks EFM. The diagnosis of brain death. N Engl J Med 2001;344:1215–21. ▶ Wijdicks EFM. The Glasgow coma scale in historical context and the new FOUR score. Rev Neurol Dis 2006;3:109–17. ▶ Wijdicks EFM. The comatose patient. New York: Oxford University Press, 2008.

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