Case Report
Diagnostic approach of a patient presenting with altered consciousness in critical care


    Toeback (1), S. Depoortere (3), M. C. Kerckhoffs (1), A.J.C. Slooter (1,2,4)

    1Department of Intensive Care Medicine, 2Department of Psychiatry and UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands, 3Department of Neurology, Diakonessenhuis, Utrecht, the Netherlands, 4 Department of Neurology, UZ Brussel and Vrije Universiteit Brussel, Brussels, Belgium


    J. Toeback -
    Case Report

    Diagnostic approach of a patient presenting with altered consciousness in critical care


    Disorders of consciousness may be challenging clinical entities encountered in critical care medicine. Consciousness consists of both arousal and awareness and can be deranged by structural brain damage, infectious or inflammatory diseases, intoxications, epileptic seizures, metabolic disorders and hypothermia. Detailed story taking of patients and caregivers can guide to important diagnostic clues. Clinical neurologic assessment is crucial and may attribute to localize structural lesions. Additional technical investigations are necessary and guided by clinical assessment in order to narrow the differential diagnosis.


    Disorders of consciousness are frequently encountered problems in intensive care unit (ICU) patients. Normal consciousness implies both intact arousal (wakefulness) and intact awareness (content of consciousness).[1,2] Syndromes of altered consciousness are present when arousal and/or awareness is reduced. An important disorder of consciousness is coma. As most comatose patients are admitted to an ICU, intensivists should be able to differentiate between various disorders that present with coma. This article primarily aims to offer intensivists clinical clues in order to assess patients with disorders of consciousness more easily and confidently and does not aim to provide a complete overview on underlying causes. Reversible etiologies of coma should be detected as early as possible in order to limit long-term impairment.


    When both arousal and consciousness decline, somnolence progresses to lethargy, and a spectrum of disorders of consciousness unfolds, from delirium to finally coma.[2] Usually, coma does not persist beyond two weeks, after which it may progress to an unresponsive wakefulness syndrome or a minimally conscious state.

    Delirium and acute encephalopathy

    Delirium is defined as an acute disturbance of awareness and attention, without a severely reduced level of arousal, as in coma.[3] These patients have reduced attention spans and other cognitive deficits, are usually disorientated and may show psychomotor depression (apathy) or agitation.[3] Delirium is by definition due to other medical conditions, substance intoxication or withdrawal, and typically has a multifactorial etiology.[3] Patients with subsyndromal delirium show signs of delirium, but do not fulfill all diagnostic and statistical manual of mental disorders-5 (DSM-5) delirium criteria.[3]  Acute encephalopathy is a term to denote global brain dysfunction, which presents clinically as either coma, delirium or subsyndromal delirium.[3]

    Unresponsive wakefulness syndrome – Minimally conscious state

    An unresponsive wakefulness syndrome (UWS, former terminology: vegetative state) is characterized by a condition of wakefulness (i.e. eyes open) without arousal, whereas patients in a minimally conscious state (MCS) show minimal interaction with their environment. In MCS, it is crucial that behavior is not attributed to reflex behavior but reproducible and originating from cortical brain function.[2] For example, appropriate smiling is considered to be cortically mediated behavior, while unprovoked grimacing is not. Both UWS and MCS patients open the eyes according to a sleep-wake rhythm.[2] When functional communication recovers or objects can be used functionally, the patient is emerging from a MCS.[2] Clinicians should regard the variety of these disorders as a spectrum where one condition may gradually evolve into another after a certain period of time, even years after brain injury.


    Coma is defined by the European Federation of Neurologic Societies as a state of profound unawareness from which a patient cannot be aroused, without a normal sleep-wake cycle. The eyes of a comatose patient are by definition closed.[2]

    Anatomy of  coma

    Anatomically, coma implies either bilateral cerebral hemispheric impairment, and/or impairment of brainstem function, more specifically involving the formatio reticularis (figure 1).[2] The formatio reticularis is an anatomically poorly defined region, more a set of nuclei located in the dorsal brainstem from the upper part of the mesencephalon to the lower part of the medulla oblongata. It takes part in an ascending pathway called the ascending reticular activating system (ARAS) and in a descending pathway to the spinal cord via the reticulospinal tract.[2]

    Figure 1. Anatomy of coma: formatio reticularis

    Coma can be due to structural brain lesions, infectious or inflammatory diseases, intoxications, epileptic seizures, metabolic disorders and hypothermia, which will be discussed in detail below. As in all patients with neurologic impairment, it is important to consider an anatomical-clinical relationship between an area of brain dysfunction and clinical signs or symptoms. In the clinical presentation of a patient with coma, normal brainstem reflexes indicate that coma is due to diffuse bilateral (sub)cortical dysfunction, without affecting the brainstem. Always keep in mind that lesions affecting only one hemisphere such as an infarction without mass effect or even a hemispherectomy can never be a sufficient cause for a disorder of consciousness. This means that if these patients present with a decreased level of consciousness, additional causes should be explored.

    Evaluation of coma

    History taking and clinical evaluation

    In patients presenting with alterations of consciousness, detailed history assessment is crucial. Importantly, patients with pre-existent brain damage, such as atrophy and patients with neurodegenerative diseases, such as Alzheimer’s disease are more vulnerable to develop a state with decreased arousal levels. Obviously, head trauma in history taking makes a structural etiology likely. In epileptic seizures, a detailed description of symptoms (semiology) can be valuable localizing information. Prodromal psychiatric signs might suggest auto-immune mediated pathology. Hyperacute onset and cardiovascular risk factors suggest cerebrovascular etiologies. Associated (thunderclap) headache is suggestive for subarachnoid hemorrhage. Prodromal general malaise and travel history might suggest an infectious cause. Detailed drug history taking, both medical and recreational is necessary.

    We recommend an ABCD-clinical assessment starting with an evaluation of possible airway (A) collapse due to an impaired level of consciousness with associated loss of airway reflexes. Corrections for airway collapse fall outside the scope of this article. Observation of possible aberrant breathing (B) patterns (Cheyne-stokes, Kussmaul respiration, neurogenic hyperventilation or apneic hypoventilation) and recognition of possible circulatory (C) disturbances (e.g. Cushing reflex) should be evaluated (figure 2). Before testing for neurological disorders (D), examiners should exclude interference of sedatives or neuromuscular blocking agents when interpreting clinical signs and symptoms. We recommend a clinical neurologic examination starting with an assessment of the level of consciousness, such as the Glasgow coma scale (GCS). In patients with minor alterations of consciousness, one should look for signs of motor lateralization. Afterwards, we recommend a top-down approach of brainstem reflexes. Finally axial and limb muscle tone should be tested and reflexes evaluated.

    Figure 2. Respiratory patterns in coma

    Assessment of the level of consciousness

    The GCS (table 1) is the most frequently used scale to characterize arousal level.[2]  Verbal and, in case of no response, noxious stimuli should first be applied centrally (e.g. sternal rub) and subsequently facially (e.g. supra-orbital pressure) or vice versa. Supra-orbital pressure on the superior-medial part of the orbita or alternatively, firm retromandibular pressure are central stimuli to the trigeminal nerve (N V). Only afterwards, stimulation of the limbs (e.g. pressure on nail bed) should be attributed. Beware of spinal reflexes, which will be discussed below. The best motor response is counting as the M-response.

    Table 1. Glasgow coma score (GCS)[1]

    The GCS has been developed to assess arousal level in the acute phase of traumatic brain injury, and is nowadays used in all ICU patients. It should however be noted that all components of the GCS may be subject to other factors than the level of consciousness: e.g. motor function is impaired in ICU acquired weakness. Also, verbal response cannot be assessed in mechanically ventilated patients, and does not reflect impaired consciousness in patients with aphasia. A more detailedscore to document the level of consciousness in ICU patients is therefore the FOUR score (table 2).[4]

    Table 2. Four-score[4]

    Observation of ocular alignment, gaze palsy and facial symmetry

    To observe the position of the eyes, use a flashlight with both eyes open and observe the corneal reflection. Normal reflections are located on the superior-medial border of the pupil symmetrically. Asymmetry may be an important finding indicating ocular misalignment and suggestive for oculomotor, trochlear or abducens  (N III, IV or VI) nerve palsies. A tonic gaze deficit towards one side may suggest dysfunction of the frontal lobe. A general rule of thumb is that inhibiting pathology such as structural lesions cause ipsilateral eye deviation, and excitating pathology such as epilepsy, eye deviation to the contralateral side. Facial asymmetry is also an important localizing marker. Note that central facial palsy (supranuclear palsy) is considered a palsy of the lower contralateral part of the face, and that lesions of the facial nerve (or facial nucleus; N VII) cause a complete paralysis of the ipsilateral face.

    Pupils and pupillary light reflexes

    Open the eyes of the patient passively. After opening the eyes, an immediate pupillary response to light may be observed.[1] Try to darken the room in order to reduce the impact of surrounding lights. Use a flashlight, from laterally in an angle of 45° and observe any pupillary constriction.[1] In the opposite eye, indirect pupillary response can be evaluated.[1] The pupillary light reflex assesses the optical (N II, afferent), midbrain (mesencephalon) and oculomotor (N III, efferent) cranial nerve function.[1] Patients suspected of brain herniation resulting in anisocoria always have a concomitant decline in consciousness. Note also that the pupillary light reflex, given it is a motor response generated by smooth muscle, is the only brainstem reflex to be contained in deeply sedated patients receiving neuromuscular blocking agents. Pupil light reflexes may be absent due to high dose barbiturates and intoxications with e.g. bupropion, tricyclic antidepressants and baclofen.[5] Midbrain lesions cause fixed large pupils or pupils in mid position with or without pupillary irregularity, whereas pontine lesions cause pinpoint pupils with intact pupil light reflexes.[1]
    A downward and outward position of an eye with a dilated pupil, is suggestive for oculomotor nerve (N III) palsy. Note that pupillary dilatation precedes an ocular misalignment. This is due to the structure of the third cranial nerve were the parasympathetic fibers lay eccentric and are therefore more vulnerable for compression.[1]

    Corneal reflexes

    To assess corneal reflexes, swipe with a cotton wool gently over the cornea and observe reactive blinking of the ipsilateral eye.[1] It is important to perform this gently in order to avoid a corneal lesion, and to perform the test on the lateral border of the eye in order to avoid to test a menace reflex. A corneal reflex implies functioning of the trigeminal (N V, afferent) and facial (N VII; efferent) cranial nerves.[1] Sedatives may inhibit corneal reflexes and in patients wearing contact lenses they may be difficult to provoke.

    Spontaneous eye movements, oculocephalic and oculovestibular reflexes

    Try to take notice of subtle spontaneous eye movements such as nystagmus or ocular bobbing. Nystagmus is a clinical symptom in which involuntary repetitive horizontal, vertical or rotatory eye movements can be observed. It consists of a rapid saccadic and a slow phase eye movement. By convention, nystagmus is defined towards the direction of the (rapid) saccadic movement of the eye.[1] Ocular bobbing is considered as involuntary irregular vertical eye movements, and is observed typically in pontine lesions.[1]

    Vestibular testing informs clinicians on functioning of oculomotor, trochlear, abducens and vestibulocochlear (N III, IV, VI and VIII) cranial nerves. It implies oculocephalic and/or oculovestibular testing. Given the need of iced water, oculocephalic reflexes are performed more often than oculovestibular reflexes. Always confirm the absence of cervical trauma before performing oculocephalic reflexes. Briskly move the patients head laterally left and right and afterwards vertically up and down and observe any saccade (rapid movement) or pursuit (slow movement) of the eye(s) in the corresponding position.[1] If absent (i.e. pathological), the eyes remain in the neutral position (Doll’s eyes).[1] Horizontal movements origin from pontine structures whereas vertical movements origin from mesencephalic structures. Caloric testing is a more potent stimulus than oculocephalic testing. It should be performed after checking on an intact eardrum, without obstructive ear lesions in a 30° head elevation position and infusion of 50 mL of ice cooled water with an observation of minimally 60 seconds. A normal response is characterized by a tonic deviation of both eyes toward the ipsilateral ear, with horizontal nystagmus to the contralateral ear.

    Cough and vomiting reflex

    A cough and vomiting reflex implies functioning of glossopharyngeal and vagus (N IX and X) cranial nerves.[1] An appropriate evaluation is performed by endobronchial suctioning or swiping with a cotton wool on the posterior pharyngeal wall.

    Neck rigidity

    Before testing rigidity, confirm the absence of cervical trauma.[1] Try to evaluate the numbers of fingers between maximum passive neck flexion from chin to chest, as a standardized method of assessing neck rigidity. Neck rigidity may be an insensitive marker in immunocompromised patients and in the early stages of meningitis. Kernig and Brudzinski tests lack sensitivity for assessing neck rigidity.

    Muscle strength and tone

    When assessing muscle tone, passive movements of the limbs should be performed and evaluated for hypo- or hypertonia.[1] When mobilizing the limbs, observe the possibility of spontaneous movements such as myoclonus (table 3).[6-8] Lateralization of tone is an important clinical finding, suggesting a lesion in the pyramidal tract, originating in the contralateral motor cortex (upper motor neuron).

    Table 3. Hyperkinetic movements in intensive care unit patients

    Tendon reflexes

    A decreased level of consciousness may suppress tendon reflexes. Assessment of biceps, triceps, brachioradial, knee or ankle jerk reflexes is important as it may reveal upper motor neuron involvement leading to hyperreflexia (except for hyporeflexia in the acute phase), or peripheral nervous system pathology resulting in hyporeflexia.[1] Plantar reflexes should always be tested, as lateralization is an important finding. Plantar reflex in extension (Babinski sign) indicates a pyramidal lesion (i.e. a lesion of the upper motor neuron), although possible transient pathology (e.g. post seizure) may also affect tendon reflexes and plantar responses.

    Auxiliary investigations

    At admission, blood and urine tests should be taken. Glucose, electrolytes, liver enzymes, pancreatic enzymes, ammonia, urea and vitamin B1 are laboratory tests of interest. Drug of abuse test kits, often available in different combinations in local institutions, are tested at admission too. The most relevant drugs of interest are benzodiazepines, antipsychotics, opioids, sympaticomimetics, anti-depressants, anti-cholinergic and cholinergic drugs. Quantitative assessment may be necessary in case of suspicion of intoxication.

    In every patient presenting with unexplained coma, imaging studies are necessary. Plain Computed Tomography (CT)-imaging excludes significant intracranial bleeding as a possible cause of coma. Subarachnoid hemorrhage may present with a normal brain CT, but in these cases, level of consciousness is intact. Often cerebral CT angiography is necessary to exclude arterial occlusion, given its urgency and possible reversibility. Note that cerebral sinus venous thrombosis cannot be ruled out with conventional CT-angiography as this lacks a venous phase of cerebral perfusion. Detection of cerebral sinus venous thrombosis requires CT-venography or Magnetic resonance imaging (MRI).[9]

    Lumbar puncture is necessary in comatose patients presenting with fever, neck rigidity and/or raised inflammatory parameters. Assessing opening pressure in comatose patients is a crucial aspect in the context of altered consciousness. Precipitation of brain herniation is a (rare) complication of lumbar puncture. It is therefore important to perform structural imaging in comatose patients before lumbar puncture to assess risk of herniation. Routine cell count, protein and glucose levels matched to blood levels, serology and polymerase chain reactions are laboratory tests of interest on cerebrospinal fluid. Normal coagulation tests and thrombocyte levels according to local guidelines are required.

    Electroencephalography (EEG) is an important tool in the assessment of patients with altered consciousness of unknown cause. It may guide diagnosis towards an epileptic etiology, but also metabolic etiologies can present with characteristic EEG changes (e.g. triphasic waves in hepatic encephalopathy). Other electrophysiological tests such as somatosensory evoked potentials mainly have their role in neurologic prognostication after circulatory arrest.

    Differential diagnosis of coma

    Structural brain damage

    Structural brain damage is the most common etiology of coma in emergency departments, stressing the importance of structural brain imaging at admission.[10]

    Hemorrhagic brain injury

    Subarachnoid hemorrhage (SAH) is an important cause of brain injury and a decreased level of consciousness.[1] Acute onset, clinically expressed by severe headache is a classic presentation. Other presentations include apnea, resulting in hypoxemia and circulatory arrest, acute coma and sudden death. Patients may present with nuchal rigidity. Intraparenchymal bleeding, especially with mass effect and associated herniation syndromes may present as focal neurologic deficits in combination with a decreased level of consciousness. Primary intracerebral hemorrhages (PICH) can also present with a decreased level of consciousness. SAH and PICH can be complicated by hydrocephalus, which may further impair consciousness level. A hemorrhagically transformed brain infarct is in the differential diagnosis of PICH.

    Ischemic brain injury

    Ischemic brain injury is a common etiology of coma.[1,10] Classical presentation include posterior circulation stroke in the vascular territory of the basilar artery. Focal neurologic signs and acute onset guide the diagnosis. Importantly, hemispheric stroke only leads to a decreased level of consciousness in case of a mass effect, as in young patients with middle cerebral artery stroke (‘malignant’ transformation due to edema formation in a large arterial territory in case of little atrophy). Percheron infarction is a clinical syndrome secondary to anatomically variable vascularization of posterior cerebral arteries leading to bilateral thalamic infarcts and therefore decreased level of consciousness. Early recognition of injury due to ischemia is important given the therapeutic consequences for revascularization. Focal neurologic deficits complicated with epilepsy raise suspicion for cerebral venous sinus thrombosis. A clinical presentation with inflammatory signs, with focal neurologic deficits due to multifocal ischemic lesions on brain imaging, is suggestive of endocarditis or vasculitis.

    Traumatic brain injury

    Clinical stratification in mild, moderate and severe traumatic brain injury (TBI) is used, categorized by GCS scores after resuscitation of 13-15, 9-12 and 3-8 respectively.[11] Direct impact of an external force may lead to a fracture of the skull. Important consideration is warranted for associated epidural hemorrhage, classically due to a lesion of the middle meningeal artery. Subdural, traumatic subarachnoid, intra-parenchymatous, intraventricular hemorrhage and brain contusions may be present in isolation or in different combinations. A second injury may be seen on the opposite side of the skull where initial impact is located (contrecoup lesion). High-energy trauma may lead to shear stress on vascular structures and cause diffuse axonal injury (DAI).

    Postanoxic coma

    Cardiac arrest, severe cerebral hypoperfusion and other disorders leading to global cerebral hypoxia can be complicated by disorders of consciousness. Watershed infarctions are a characteristic iconographic presentation. Postanoxic coma is an important sequel of cardiorespiratory arrest. Unlike other etiologies of coma, in case of cardiorespiratory arrest, guidelines exist for neurologic prognostication.[12] According to the Dutch guideline, a multimodal approach is advocated for predicting unfavorable outcome (death, UWS/MCS or dependency with activities of daily living) after cardiorespiratory arrest when residual effects of sedatives are deemed to be unlikely in patients with a motor score of ≤2 of GCS.[12] After at least 24 hours, indicators of poor outcome are bilateral absent pupil light reflexes, bilateral absent N20 somatosensory evoked potentials, and malignant EEG patterns.[12] In addition, indicative of poor outcome are serum neuron specific enolase (NSE) >65 μg/L after 48-72 hours, status myoclonus in the first 48 hours, and diffuse brain edema on a brain CT in the first week.[12]


    Accumulation of cerebrospinal fluid (CSF) inside the ventricles is called an internal hydrocephalus, whereas external hydrocephalus refers to accumulation outside the ventricles. Hydrocephalus can be differentiated in obstructive causes (e.g. obstruction due to a mass lesion compressing e.g. the Sylvian aqueduct) or non-obstructive causes (e.g. secondary to subarachnoid hemorrhage due to an impaired resorption of CSF).[1] Distinction is important given the risk of brain herniation in patients with obstructive causes and evacuation of CSF under the level of obstruction by repetitive lumbar punctures or external lumbar drainage. Clinical presentation of hydrocephalus with Parinaud syndrome with sunset eyes, retraction of eyelids and a supranuclear eye movement disorder might be observed. However, this presentation is rare; a more common presentation is a decreasing level of consciousness, which may be acute.

    Other structural lesions

    Other structural lesions that might lead to disorders of consciousness include gliomatous lesions, carcinomatous meningitis, lymphoma, brain abscesses, metastasis, chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids. Each of these disorders may present with coma and/or focal neurologic deficits, but is (very) rare among ICU patients. In these disorders, clinical presentation is more insidious, but deterioration might occur, especially if hydrocephalus occurs.

    Infectious / inflammatory diseases


    A clinical presentation with the triad of fever, nuchal rigidity, and headache should raise suspicion for meningeal disease, but most cases of meningitis do not have all these three signs. When seizures or behavioral disorders are present, an encephalitis or meningo-encephalitis should be considered. Early antibiotic therapy is crucial and lumbar puncture should not delay antibiotic treatment. In immunocompromised patients and patients older than 60 years old presenting with cerebellar and/or brain stem deficits a rhombencephalitis should be included in the differential diagnosis.

    Auto-immune encephalitis is a less frequent cause of coma. Myelin oligodendrocyte antibody (MOG) mediated disease, neuromyelitis optica with aquaporin-4 antibodies, acute disseminated encephalomyelitis (ADEM), Bickerstaff encephalitis, voltage gated kalium channel (VGKC) mediated encephalitis, N-methyl-D-aspartate receptor (NMDA) mediated encephalitis or gamma-Aminobutyric acid B (GABA B) mediated encephalitis are non-limitative examples of possible coma etiologies. Some present with seizures, others with focal neurologic deficits. Especially new onset refractory status epilepticus (NORSE), defined as a clinical presentation of status epilepticus in a patient not known with epilepsy, should be a trigger for a thorough investigation including collection of CSF, antibody testing and expert consultation.


    Both recreational and iatrogenic intoxication are prevalent causes of coma in the ICU. In delayed awakening, measurement of the used sedatives and its metabolites can be performed, but serum levels of sedatives correlate poorly with sedation levels. Pupil sizes, bowel sounds, diaphoresis and body temperature are important clinical signs to differentiate between toxidromes (table 4). Malignant neuroleptic syndrome and serotonergic syndromes are other diagnoses to consider, even after low dose or single dose exposure, therefore medication history is crucial. Hyperthermia, raised creatin kinase (CK) and diaphoresis can be shared signs. Muscle rigidity may suggest malignant neuroleptic syndrome, whereas hyperreflexia and clonus are more typical for a serotonergic syndrome. Immunotherapy (e.g. tacrolimus, rituximab, cyclosporine, tyrosine kinase inhibitors) may give rise to a posterior reversible encephalopathy syndrome (PRES), which is characterized by headache, confusion, seizures and/or cortical visual field deficits.[1]

    Table 4. Toxidromes

    Epileptic disorders

    Seizures are considered to be symptoms of cortical dysfunction and are therefore an important clinical sign in patients with disorders of consciousness. Status epilepticus can be a life-threatening medical emergency, particularly in case of generalized convulsive status epilepticus. Recurring episodes without recuperation of consciousness are also considered as a presentation of status epilepticus. Ictal epileptic signs are generally positive clinical signs such as clonic movements, myoclonus and tonic muscle activation (table 3). Early interruption with benzodiazepines is crucial, if unsuccessful early escalation to anti-epileptic regimen is advised. New onset refractory status epilepticus may be a presentation of auto-immune pathology and lumbar puncture should be part of the diagnostic work-up. Non-convulsive status epilepticus (NCSE) is reported as a complication of convulsive status epilepticus in up to 50 percent of cases, and is reported in up to 30 percent of neurological patients admitted at an ICU in general.[13] Subtle NCSE can be is associated with blinking, eye twitching, nystagmus or automatisms. NCSE is an electrophysiological, not a clinical diagnosis; therefore, EEG is crucial.[14]

    Metabolic disturbances

    Several metabolic disorders have the potency to lead to metabolic encephalopathy presenting as a disorder of consciousness. They are reported to be the most prevalent causes of coma in patients initially diagnosed as coma of unknown origin.[1] Presence of positive and negative myoclonus might coincide.[1] Myoclonus is characterized as an involuntary brief and jerky contraction of a muscle or a group of muscles. A negative myoclonus is most known in patients with a hepatic encephalopathy in which tone of a muscle or a group of muscles is suddenly relieved in a brisk or jerky pattern, which is called asterixis in this setting. Various other toxic-metabolic disturbances leading to decreased levels of consciousness however may evoke a similar movement.
    Biochemical disturbances such as hyper- and hyponatremia, hyperuremia, hypercarbia, hypoxemia, hyperammonemia, hypo- and hypercalcemia, liver dysfunction, hypo- and hypernatremia, thyroid dysfunction, acid-base dysfunction and infectious diseases are possible contributors. Usually, etiology is multifactorial. Hypo- or hyperkalemia for example are common electrolyte disturbances that although potentially fatal, do not primary lead to alterations of consciousness. Rare inherited metabolic diseases might also lead to coma, such as mitochondrial encephalopathy with lactate acidosis and stroke (MELAS), and porphyria.

    Wernicke encephalopathy

    Wernicke encephalopathy due to profound deprivation of vitamin B1 is a cause of coma that is encountered in alcoholic disease or other causes of malnutrition. Clinical presentation is characterized by ocular movement disorders (nystagmus and/or ophthalmoplegia), delirium or impaired consciousness and ataxia. However, clinical symptoms are variable. MRI may reveal characteristic atrophy of mammillary bodies, but should not be awaited to start suppletion with high dose thiamine.[15]


    Pupillary responses can be absent in deep hypothermia (core temperature below 28 degrees Celsius). Tendon reflexes may be diminished or absent with hypothermia as well. Therefore, temperature measurement is crucial in evaluation of patients with unexplained coma.

    Neurodegenerative diseases

    Some end-stage neurodegenerative diseases (e.g. dementia with Lewy bodies, Creutzfeldt-Jacob disease) evolve towards a clinical presentation affecting consciousness. As admission to the ICU is often considered disproportional care, these entities fall outside the scope of this article.

    Mimics of coma

    Besides classical disorders of consciousness, a clinician should recognize it’s mimics.

    Locked-in syndrome

    Lesions involving the ventral pons, such as basilar artery stroke, may produce a quadriparesis with intact consciousness, sleep-wake rhythm and classically sparing of vertical eye movements and blinking; the ‘locked-in syndrome’.[2] These patients are aware and awake, but communication by vertical eye movements may be impaired due to drowsiness or emotionality. Incomplete lesions due to aberrant vascularization exist. Awareness for this clinical syndrome remains important as communication with these patients can be installed by yes/no questions by determining a code of communication (looking up means yes / looking down means no, or vice versa). Therefore, all presumably comatose patients should be tested for vertical eye movements on request.

    Psychiatric conditions

    Other important mimics of disorders of consciousness are some psychiatric conditions. Patients presenting with a conversion disorder, psychogenic coma, psychogenic non-epileptic seizures (PNEA) and catatonia should be differentiated from patients without.[18-18] Medical history is important, and hetero-anamnesis should be obtained. For conversion disorder and psychogenic coma, clinical neurologic evaluation with motor inconsistencies guide to a diagnosis. Forced eye closing, eye gaze sign (patients watching the floor when turned to one side) and avoidance of the head with arm drop are considered to be useful clinical signs to assess.[18,19] A history of PNEA, eyes closed during attacks and sensitivity for suggestion may be valuable diagnostic clues.[18] Note that the absence of movement to noxious stimuli is not mentioned and should be used with care.[16-18] In catatonia, a thorough neuropsychiatric evaluation is necessary. Catatonia is a behavioral disturbance that may include rigid muscle tone and mutism, which is associated with hyperexcitement or decreased arousal.[1] Administration of benzodiazepines may decrease the severity of catatonia.[19] Generally, EEG and brain imaging are necessary to exclude with certainty underlying pathology in these psychiatric presentations.


    Hypersomnia is a clinical state describing normal appearing but excessive sleep from which arousal is eminent. [1]

    Akinetic Mutism

    Akinetic mutism is a medical term describing a decrease in goal-directed behavior and emotions with an appearing intact level of consciousness and profound apathy, that may be reversible.[20] Patients with akinetic-mutism do not move spontaneously (akinetic) and remain silent (mutism), seemingly indifferent to pain, thirst, or hunger.[20] These patients have sleep-wake cycles and resemble patients with UWS or MCS. Akinetic mutism may be due to a variety of conditions, including bilateral frontal lobe damage and damage to the mesencephalon and diencephalon.[20]

    Brain Death

    In order to fulfill diagnostic criteria for brain death according to Dutch law, there should be coma due to a known and irreversible brain disease. Further, there should not be hypothermia lower than 32 °C, hypotension < 80 mmHg systolic blood pressure, shortly preceding cardiopulmonary reanimation, intoxication, usage of neuromuscular blocking agents, severe biochemical or metabolic disturbances.[21] Unfortunately, the severity of biochemical or metabolic disturbances is not defined by law. In case of brain death the coma should be maximal (GCS 3), with absence of any normal brainstem reflexes (minimally assessing pupillary reflexes to light, corneal reflexes, oculovestibular reflexes and cough reflex) and the absence of spontaneous breathing.[21] When EEG, cerebral CT angiography or transcranial Doppler imaging meets criteria for absence of brain activity or perfusion, an apnea test after 10 minutes pre-oxygenation with 100 percent oxygen supply is performed.[21] An apnea test is defined conclusive if partial pressure of carbon dioxide rises from initially 40 mmHg to 50 mmHg and no respiratory movements are witnessed.[21]

    Any clinician confronted with the diagnosis of brain death should be aware of the possibility of spontaneous and reflex movements in patients eligible for diagnosis of brain death.[22] Most reported movements are an undulating toe flexion response and a triple reflex on tactile or noxious plantar stimuli.[22] An undulating toe sign is characterized as slow and repetitive flexion and extension movements of the toes, whereas a triple reflex involves flexion of thigh, leg and foot.[22] More impressive and rare is Lazarus sign, where after head flexion or painful stimuli to the sternum patients might initiate complex movements of bilateral arm flexion, shoulder adduction and hand raising towards the chest with or without dystonic posturing of fingers.[22] Sweating, blushing and tachycardia  may occur in brain death.[22] However, movements that are incompatible with a diagnosis of brain death are epileptic seizures, posturing motor responses (defined as a tonic flexion or extension of axial or proximal limb muscles) on noxious stimuli compatible with decortication or decerebration, any movement of the limbs after noxious stimuli to the trigeminal distribution area, or any facial movement after noxious stimuli to the limbs.[22]


    Evaluation of patients presenting with altered consciousness may be challenging. Consciousness is a complex neurologic concept concerning wakefulness and awareness. Disorders affecting both hemispheres, and/or the brainstem are associated with altered consciousness. The importance of clinical assessment cannot be overlooked. Additionally, detailed history taking and auxiliary investigations are necessary to narrow differential diagnosis.

    Take home messages

    • Consciousness consists of awareness and arousal.
    • Consciousness can be impaired if both hemispheres and/or brainstem are involved in a pathological process.
    • Clinical neurologic evaluation is a necessary tool to distinguish causes affecting bilateral hemispheres (usually with intact brainstem reflexes) from brainstem lesions (mostly aberrant brainstem reflexes).
    • Syndromes of altered consciousness can be life-threatening but reversible. Some etiologies require immediate additional technical investigations and initiation of treatment (e.g., meningitis, stroke, status epilepticus).


    All authors declare no conflict of interest. No funding or financial support was received.



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