General Neurology
Brain death/death by neurologic criteria
Nov. 09, 2024
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Locked-in syndrome …
- Updated 05.14.2024
- Released 05.19.2004
- Expires For CME 05.14.2027
Locked-in syndrome
Introduction
Overview
“Locked-in” syndrome describes patients who are awake and conscious but selectively “de-efferented,” with no means of producing speech or moving their facial muscles or limbs. They are aware and perceive normally but are effectively locked in their own bodies, unable to communicate except possibly by blinking or eye movements. Locked-in syndrome typically results from a lesion in the brainstem, classically in the ventral pons. In this article, the author discusses the presentation, etiology, prognosis, diagnostic evaluation, and management of locked-in syndrome. Updates focus on the progress in brain-computer interfaces for communication and functionality of these patients.
Key points
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• Locked-in syndrome is a de-efferented state characterized by quadriplegia and paralysis of the lower cranial nerves. | |
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• Patients retain consciousness and can classically communicate by vertical eye movements and eye blinking. | |
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• The most common etiology is atherothrombotic occlusion of the basilar artery resulting in ischemia of the ventral pons. | |
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• Advances in technology, such as brain-computer interfaces, are allowing for improved communication for patients with locked-in syndrome. |
Historical note and terminology
In 1875, French physician Camille Darolles, an intern supervised by François Damaschino (1840-1889), gave the first accurate clinical and pathological report of a complete or total case of locked-in syndrome, which lasted only for a few hours before the patient's death (24; 32; 122). Darolles presented the case at a monthly meeting of the Société Anatomique de Paris chaired by Jean-Martin Charcot (1825-1893).
New York neurologists Fred Plum (1924-2010) and Jerome Posner (1932-) first introduced the term in 1983, and they described the syndrome as “a state in which selective supranuclear motor de-efferentation produces paralysis of all four limbs and the last cranial nerves without interfering with consciousness” (98).
The famous case of Jean-Dominique Bauby (1952-1997) provides a patient’s perspective of locked-in syndrome following a devastating brainstem stroke. Despite being locked in, Bauby “dictated” his memoir to Claude Mendibil by the laborious method of blinking when the correct letter was reached by a person slowly reciting the alphabet over and over again. The book includes vivid depictions of the insensitivity of some healthcare providers toward a severely disabled person (as well as his outspoken reactions to such treatment) (09; 66). Bauby died suddenly 2 days after publication the of his book, The Diving Bell and the Butterfly (09). The book was later adapted for a critically acclaimed film of the same name.
Clinical manifestations
Presentation and course
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• Locked-in syndrome has been categorized into three types: classic, incomplete, and total (or complete). | |
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• Classic cases have quadriplegia and anarthria with preserved consciousness, vertical eye movements, and blinking. Incomplete cases also possess some voluntary motor movements (typically in the fingers or neck). | |
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• Total or complete cases have no movements, including that of the eyes or eyelids; patients with this syndrome are particularly likely to be misdiagnosed as comatose or in a persistent vegetative state, even though they are fully conscious. | |
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• Locked-in syndrome that presents acutely is most often a result of a lesion in the ventral pons that causes bilateral interruption of the corticospinal and corticobulbar tracts. | |
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• Patients with locked-in syndrome also suffer multiple complications secondary to extended hospitalizations and bedridden states, such as pneumonia, decubiti, urinary incontinence, and urinary infection. |
Locked-in syndrome has been categorized into three types: classic, incomplete, and total (or complete) (10; 25). Classic cases have quadriplegia and anarthria with preserved consciousness, vertical eye movements, and blinking. Incomplete cases also possess some voluntary motor movements (typically in the fingers or neck). Total or complete cases have no movements, including that of the eyes or eyelids; patients with this syndrome are particularly likely to be misdiagnosed as comatose or in a persistent vegetative state, even though they are fully conscious (77; 37; 58; 59).
Locked-in syndrome that presents acutely is most often a result of a lesion in the ventral pons that causes bilateral interruption of the corticospinal and corticobulbar tracts. Injury to the corticospinal tracts causes quadriplegia, whereas injury to corticobulbar tracts and exiting cranial nerve fascicles affects the lower cranial nerves, which are essential for control of the facial, pharyngeal, and tongue muscles and, in consequence, for emotional expression, verbal expression (either vocalizations or speech), and swallowing. Preservation of supranuclear oculomotor pathways, due to the sparing of the midbrain tectum, allows the patient with locked-in syndrome to open his or her eyes, blink, and produce vertical eye movements. However, horizontal eye movements may be adversely affected in large ventral pons lesions involving paramedian pontine reticular formation or the abducens nuclei or fascicles (69; 117). Sensation is preserved because of spared sensory pathways, which lie dorsal to the ventral pontine lesion.
This syndrome can also be caused by bilateral mesencephalic lesions involving the cerebral peduncles or by bilateral lesions of the internal capsule or corona radiate (10; 21; 132).
People with acute ventral pontine lesions often remain comatose for days or weeks, supported by artificial respiration before gradually waking up. Despite becoming awake and aware, they remain voiceless and paralyzed. Because of their apparent unresponsiveness, they superficially resemble patients with akinetic mutism or a vegetative state. Consequently, the correct diagnosis is likely often missed or delayed. More often than not, the family rather than a healthcare team member first recognizes the affected patient is aware (67). Even after the patient is recognized as being aware, communication remains difficult and limited, despite coded blinks or eye movements, because of fluctuating vigilance and easy fatigability and because the eye movements themselves may be inconsistent, very small, and easily exhausted (67).
Some survivors with locked-in syndrome report persisting cognitive difficulties, and diverse cognitive impairments have been documented on neuropsychological studies in affected patients (69; 83; 109; 104; 61). Reported impairments in individual cases have variously included mild or moderate difficulties with attention and concentration, processing speed, auditory recognition, verbal learning, oral comprehension of complex sentences, delayed visuospatial memory, mental calculation, problem-solving, and executive skills. In some cases, the observed neuropsychological deficits were attributable to fatigue (answering even a series of simple questions using eye movements can be exhausting for these patients), and others could be related to additional cortical or thalamic structural brain lesions other than the principal ventral pontine lesion.
Emotional lability and pathologic laughter and crying have frequently been described in patients with locked-in syndrome. Pathologic laughter and crying are unrelated to depression and do not ameliorate with pharmacologic treatment but may improve with cognitive behavioral treatment. This emotional lability does not indicate an underlying mood disorder (105).
Respiratory compromise can result from pontine injury, and some patients require ventilator assistance. Subsequent evaluation may reveal intact phrenic nerve function but asymmetric diaphragmatic movement, making these patients good candidates for diaphragmatic pacing. A prolonged wean from the ventilator to pacing may increase their autonomy, reduce complications such as pneumonia, and improve quality of life (30).
Patients with locked-in syndrome also suffer multiple complications secondary to extended hospitalizations and bedridden states, such as pneumonia, decubiti, urinary incontinence, urinary infection, and chronic pain (125; 55; 92; 13). Almost half of the paients with locked-in syndrome report experiencing pain that affects their quality of life, sleep, and cognition (13).
In a survey of attitudes concerning the ethics of life-sustaining treatment in locked-in syndrome in a cohort of medical and nonmedical Chinese participants, the study sample included 1545 respondents, including 180 family members of individuals with locked-in syndrome (130). Most participants (70%), especially neurologists, thought that life-sustaining treatment should not be stopped in individuals with locked-in syndrome. Most respondents (59%) reported wanting to be kept alive if they were in that condition, although older people thought the opposite.
Prognosis and complications
The etiology of the initial insult strongly influences the overall prognosis of the patient with locked-in syndrome, with vascular etiologies generally suffering worse overall functional recoveries and higher mortalities than those with nonvascular causes (54; 114). For example, patients with locked-in syndrome secondary to central pontine myelinolysis have a more favorable prognosis than those with vascular etiologies (47).
Most patients who do not have progressive disorders of the brainstem can ultimately regain some control of finger and toe movements. In a study of 14 patients with locked-in syndrome, significant motor recovery was observed within 3 to 6 months after initiation of early and intensive multidisciplinary rehabilitation; nevertheless, profound impairments persisted over 11 years of follow-up (18; 31). Only a few subjects progressed to the point where they could manipulate an object. None could speak in sentences, and most could not even speak a single word consistently. Although most patients with locked-in syndrome who survive suffer from severe residual impairment, early recovery of eye movements usually indicates a relatively better prognosis (131).
In a study of 100 locked-in patients due to pontine infarcts over 1 year of follow-up, about a quarter (24%) of those with isolated pontine infarcts (n=72) had a "good outcome" (with a score of 3 on the Modified Rankin Scale of Neurological Disability, indicating moderate disability: requiring some help, but able to walk without assistance) (61). Those with pontine infarcts plus multiple ischemic lesions did significantly worse cognitively and overall. Because many patients with locked-in syndrome can show significant improvement, aggressive supportive measures and intense physical, speech, and cognitive therapy are appropriate to facilitate interaction with others and the environment (61).
In a study of 51 patients with vascular locked-in syndrome who remained in the locked-in state for at least 6 weeks, ischemic stroke was the most common etiology (69%) (86). Among the 43 patients with follow-up, (1) 53% emerged from the locked-in state, most within 2 years after onset; (2) 98% achieved some motor improvement; (3) only 7% achieved full motor recovery; and (4) 88% had a persistently high level of dependence. The 3-year survival rate was 87%. Only 9% had an isolated pontine lesion, whereas 80% showed various lesions outside the brainstem. Individuals who emerged from the locked-in state had a significantly lower prevalence of lesions outside the brainstem than those who remained in the locked-in state.
Although the mechanisms of motor recovery in quadriplegic patients with bilateral pontine infarcts remain unclear, potential contributors include perilesional reorganization; in one patient followed with serial diffusion tensor tractography, recovery was apparently mediated by residual portions of the extreme lateral aspects of the corticospinal tracts (64).
There is a high case fatality rate in the first several months following development of locked-in syndrome. In a series of 20 patients with locked-in syndrome (19 were vascular, and one was of unknown etiology), 15 (75%) died in the acute period: five from stroke progression or cardiac arrest and 10 from pulmonary infection or sepsis (85). Intubation was required in all cases during their hospitalization; tracheostomy was required in eight (40%). Another study reported a mortality of 87% among 79 patients with locked-in syndrome during the first 4 months (91).
In contrast, patients with chronic locked-in syndrome (ie, survival for more than 1 year) can have surprisingly long survivals, with 5-, 10-, and 20-year survival rates of 83%, 83%, and 40%, respectively (31). Therefore, once a patient becomes medically stable and survives the acute injury, life expectancy increases to several decades with appropriate medical care (67).
Despite what healthcare professionals, the general public, and even caregivers may think about the quality of life of patients with locked-in syndrome, affected individuals report surprisingly good and meaningful quality of life that stays stable over time (67; 27; 101; 134). Indeed, patients with locked-in syndrome often report normal mental and personal general health despite maximal restriction in physical activities (67). Patients consistently report a higher quality-of-life than is estimated by others, including by their spouses or caregivers (73). When asked to rate their life on a quality scale ranging from the “best time in my life” to the “worst time in my life,” patients with locked-in syndrome did not vary from matched controls (15). In a study of 65 patients with locked-in syndrome, 68% reported never having a suicidal thought, and only 17% reported feelings of depression. Variables associated with unhappiness were dissatisfaction with mobility in the community, with recreational activities, and with the incapacity to deal with life events. Shorter time locked-in, anxiety, and nonrecovery of speech production were also associated with unhappiness. The highest limitations were reported in community reintegration. Quality of life scores did not differ between nonventilated and invasively ventilated patients with locked-in syndrome (102). Even those with “complete” locked-in syndrome reported no difference in quality of life compared to matched controls (103).
Biased clinicians provide less-aggressive medical treatment in patients with locked-in syndrome (73; 74). Although the prompt assessment of decisionality in these patients is challenging, it is nevertheless essential to allow them to participate in decision-making regarding their own care (74). In addition, as eloquently expressed by Laureys and colleagues:
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Biased clinicians might provide less aggressive medical treatment and influence the family in inappropriate ways. It is important to stress that only the medically stabilized, informed [locked-in syndrome] patient is competent to consent to or refuse life-sustaining treatment. Patients suffering from [locked-in syndrome] should not be denied the right to die - and to die with dignity - but also, and more importantly, they should not be denied the right to live - and to live with dignity and the best possible revalidation, and pain and symptom management (67). |
Nevertheless, complex legal, ethical, and emotional issues are involved in supporting such patients with life-sustaining treatments, such as invasive ventilation, or withdrawing such treatment (40).
Clinical vignette
A 56-year-old, right-handed Caucasian man presented with progressive quadriparesis over a 3-week period. Prior medical history was unremarkable except for the removal of a pigmented skin lesion 6 weeks earlier, although no pathological diagnosis was obtained. On examination, he was breathing independently, his eyes were open, his fundi were without papilledema, and his pupils were equally responsive to light. He did not speak or vocalize. He did not visually track objects but did follow commands to blink or to raise or lower the eyes. Furthermore, he responded appropriately to questions using either vertical eye movements or eye blinking in a binary code. He could not move the mouth or limbs, and examination disclosed spastic quadriplegia with diffuse hyperreflexia. Sleep-wake cycles were linked to a circadian rhythm. Cranial MRI revealed a pontine mass. Emergent posterior fossa excision was performed. Histological diagnosis of the mass was malignant melanoma. In this case, a rapidly expanding pontine mass disrupted motor pathways at the level of the pons with preservation of cortical function, resulting in locked-in syndrome.
Biological basis
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• Locked-in syndrome can potentially be caused by profound bilateral dysfunction of upper or lower motor neuron pathways or the neuromuscular junction. | |
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• Classically, locked-in syndrome is due to vascular disorders of the basis pontis, usually ischemic but occasionally hemorrhagic (eg, basilar artery thrombosis, hypertensive pontine hemorrhage, etc.). | |
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• Locked-in syndrome can result from lower motor neuron pathway or neuromuscular junction dysfunction. |
Etiology and pathogenesis
Locked-in syndrome can potentially be caused by profound bilateral dysfunction of upper or lower motor neuron pathways or the neuromuscular junction.
Classically, locked-in syndrome is due to vascular disorders of the basis pontis, usually ischemic but occasionally hemorrhagic (eg, basilar artery thrombosis, hypertensive pontine hemorrhage). Damage to the same structures can be caused by demyelinating disorders (eg, central pontine myelinolysis), trauma, structural lesions (eg, abscess, malignancy), transtentorial herniation, and rare other causes (eg, hyperhomocysteinemia due to severe folate deficiency, meningovascular syphilis) (51; 119; 53; 133; 01). Most of these patients have some preserved ability to blink and make vertical eye movements. In some patients with more rostral lesions involving the midbrain, there may be complete bilateral ptosis and external ophthalmoplegia, greatly impeding or obviating the clinical differentiation from coma.
What is often unrecognized is that locked-in syndrome can result from dysfunction of lower motor neuron pathways or the neuromuscular junction. Demyelinating neuropathies (eg, Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, and toxic demyelinating neuropathies) can occasionally present fulminantly with the locked-in syndrome (06; 100; 79; 29; 46; 45). Motor neuron disease in the late stage, if supported on a ventilator, progresses into a locked-in state. Amyotrophic lateral sclerosis represents an “overlap” condition in that it results from bilateral dysfunction of both upper and lower motor neuron pathways. Disruption at the neuromuscular junction also can produce a locked-in state (though not often labeled as such); examples include (1) rare instances with myasthenia gravis and (2) toxins that cause either presynaptic (eg, botulinum toxin) or postsynaptic (eg, curare) blockade.
Epidemiology
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• Limited information is available on the epidemiology of locked-in syndrome. |
Given the broad spectrum of disease entities that may result in the presentation of locked-in syndrome, limited information is available on the epidemiology of this syndrome.
Prevention
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• Rarely is prevention feasible for locked-in syndrome. |
Multiple different conditions can cause locked-in syndrome, but rarely is prevention feasible. Prevention is possible, for example, with iatrogenic etiologies (eg, stellate ganglion blocks) and potentially with posterior circulation transient ischemic attacks (“pontine warning syndrome”) and acute basilar artery thrombosis (ie, with thrombolytic therapy within 3 hours of the ischemic injury) (39).
Differential diagnosis
Confusing conditions
Locked-in syndrome versus disorders of consciousness. Confusion of locked-in syndrome with other neurologic disorders that impair consciousness is not infrequent and can lead to mismanagement of afflicted individuals. Therefore, ensuring that patients are given the appropriate diagnosis is critical. One factor that appears to result in misdiagnosis is the confusion in terminology used to describe patients. The terms "apallic syndrome," "akinetic mutism," "coma vigil," "alpha coma," and "neocortical death" should not be used to depict individuals with locked-in syndrome. In addition, the neurologic conditions of coma, persistent vegetative state, and brain death are not synonymous with locked-in syndrome (52).
Unlike individuals who suffer from disorders of consciousness, "locked-in" patients are conscious but cannot communicate (98; 70). Loss of motor control of their facial musculature and extremities prevents these individuals from speaking and interacting with their surroundings. At times, even ocular movements may be lost. Usually, these patients are not aphasic and so can comprehend spoken speech.
The vegetative state is a chronic condition that preserves the ability to maintain blood pressure, respiration, and cardiac function, but not cognitive function. Specifically, the individual has no consciousness of self or the environment. The patient does not possess language function and, therefore, cannot communicate. Voluntary behavior or movements are absent. Facial expressions such as smiling, frowning, and crying can occur. These are not linked to any external stimulus. Sleep-wake cycles are present but do not necessarily reflect a specific circadian rhythm and are not associated with the environment. Although medullary brainstem functions remain intact to support cardiorespiratory functions, the presence of midbrain or pontine reflexes may be variable. Spinal reflex activity also may be present, but bowel and bladder functions are absent.
Coma is a state of unresponsiveness in which the patient remains with eyes closed and is unarousable (98). The patient is not conscious of self or the environment. Blood pressure and respiratory function may be intact, but the patient lacks sleep-wake cycles. The presence of flaccidity and areflexia indicate severe brainstem depression, and this is frequently found in terminal coma or severe sedative intoxication.
Brain death is declared when there is loss of function of the entire cortex and brainstem. A brain-dead individual has no response to noxious stimulation. The pupils are fixed to light stimulation. Corneal blink reflex, doll's eyes, and cold water caloric responses are not present. Brainstem reflexes are absent, with loss of spontaneous respiration. The documentation of apnea is vital to the determination of brain death. The diagnosis of brain death requires the death of the brainstem, whereas the persistent vegetative state preserves brainstem function (135).
Associated or underlying disorders
Etiologies of locked-in syndrome. The most frequent cause of locked-in syndrome in both adults and children is atherothrombotic occlusion of the basilar artery or, less frequently, brainstem hemorrhage.
A few of the most important other causes of locked-in syndrome are trauma, possibly causing basilar artery dissection (most common in younger individuals), transtentorial herniation, primary or secondary malignant infiltration of the basis pontis, and central pontine myelinolysis (85; 51). Although most cases are pathogenic, some cases are from iatrogenic influences such as chiropractic spinal and head manipulations, use of drugs with thrombogenic properties, intrathecal injections of chemotherapeutic agents, regional anesthetic nerve blocks with inadvertent intra-arterial injection of anesthetic agents, and basilar artery dissection as a complication of posterior fossa epidermoid cyst resection (126; 16; 57; 96). Other less common causes of locked-in syndrome include brainstem encephalitis, meningitis with brainstem abscess, polyneuritis (eg, Guillain-Barre syndrome, poliomyelitis, myasthenia gravis, pneumococcal meningitis, Epstein-Barr virus infection, and West Nile viral infection) (33; 76; 62). More unusual cases also exist, including ectatic elongated basilar artery (03), complication of cervical manipulation by a chiropractor (89), unstable atlantooccipital dissociation (28), complication of acute otitis media with inflammatory changes compressing the basilar artery (44), rapidly progressing polymyositis with elevated anti-acetylcholine receptor antibody activity, snake bite (129; 63), medullary infarction following lumbar puncture in a patient with basilar invagination (20), acute thrombosis and subsequent infarction of the basilar artery as a complication of cocaine abuse (02), and acute polyradiculoneuritis in a patient with COVID-19 (94).
Transient locked-in syndrome has been reported in various clinical circumstances, including the following:
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• Guillain-Barre syndrome (62) | |
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• Perioperative transient ischemic attack associated with cessation of warfarin (68) | |
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• Ischemic brainstem stroke without (38; 14) or with basilar artery thrombosis (95; 37) | |
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• Basilar artery vasospasm (65) | |
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• Posterior fossa subdural hematoma (111) | |
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• Silent aortic dissection (81) | |
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• Closed head injury (19; 17) | |
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• Following uncal herniation (128) | |
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• Central pontine and extrapontine myelinolysis (123) | |
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• Postoperative brainstem tension pneumocephalus (11) | |
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• Following repeated shunt procedures for idiopathic aqueductal stenosis (78) | |
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• Inadvertent intravertebral artery injection of local anesthetics during stellate ganglion block (34; 126) | |
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• Snake envenomation (04; 80) |
The reversible cases of locked-in syndrome associated with brainstem ischemia represent the fortuitous end of a spectrum of outcomes that depend on the balance of hemodynamic factors and collateralization at the time of the event. Vascular etiologies, head injury, and iatrogenic circumstances seem to be major considerations in cases of transient locked-in syndrome.
Diagnostic workup
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• It is essential to determine whether an unresponsive patient is conscious (ie, to delineate locked-in syndrome from other unresponsive syndromes that affect level of consciousness, such as coma or persistent vegetative state). | |
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• A discordance between the ability to follow commands to look up or down and the lack of other spontaneous movements or movements to command should immediately suggest the diagnosis of locked-in syndrome. | |
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• CT or MRI can assist in determining the etiology of locked-in syndrome. | |
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• EEG findings of well-defined alpha waves and distinct reactivity to sensory stimulation have been used to imply the preservation of cortical function, but such EEG reactivity is inconsistently present in such patients. |
First and foremost, it is essential to determine whether an unresponsive patient is conscious—that is, to delineate locked-in syndrome from other unresponsive syndromes that affect level of consciousness, such as coma or persistent vegetative state. Sadly, diagnosis is often long delayed; indeed, diagnosis of locked-in syndrome takes over 2.5 months on average and, in some reported cases, up to 6 years (67).
Careful neurologic examination by an experienced clinician with a high index of suspicion for the possibility of locked-in syndrome is necessary. The examiner should specifically ask the patient to blink and look up and down. A discordance between the performance of these actions, and the lack of other spontaneous movements or movements to command, should immediately suggest the diagnosis of locked-in syndrome. Note, though, that rare cases of total mesencephalic locked-in syndrome may have bilateral ptosis and complete ophthalmoplegia (77; 37). By categorizing cases as affecting upper or lower motor neurons (or both) or the neuromuscular junction and then considering any inciting events, the course (acute, subacute, or chronic), and any associated clinical findings, the differential diagnosis can be rapidly and reliably narrowed.
Many routine clinical tools are not applicable (and, worse, are potentially very misleading) in the setting of locked-in syndrome. For example, although the Glasgow Coma Scale is the “gold standard” for routine assessment of consciousness in acutely unresponsive patients, it relies exclusively on behavioral responses and provides an erroneous measure of consciousness in locked-in patients. Similarly, the Disability Rating Scale also involves basic behavioral functions like eye-opening, communication, and motor response, which cannot be applied to patients with locked-in syndrome.
CT or MRI can assist in determining the etiology of locked-in syndrome. These studies can differentiate between an ischemic infarct, an intracerebral hemorrhage, and a mass lesion involving the brainstem. A CT without contrast is helpful in suspected cases of cerebral hemorrhage. CT within the first 72 hours of onset of intracerebral hemorrhage usually provides greater resolution than MRI. CT angiography or MR angiography can be used to visualize the cerebral vasculature following the exclusion of a cerebral hemorrhage.
None of the other approaches using advanced diagnostic technologies provides a consistently clear and definitive answer to the question of whether an individual patient is locked in.
In the assessment of patients with locked-in syndrome, EEG findings of well-defined alpha waves and distinct reactivity to sensory stimulation have been used to imply the preservation of cortical function (127; 60), but such EEG reactivity is inconsistently present in such patients (43). EEG studies have demonstrated various abnormalities in locked-in syndrome patients, including slowing in the frontal or temporal leads, diffuse slowing, or cortical resting state rhythms, which are thought to imply functional impairment of cortical neuronal synchronization mechanisms in the resting state condition (08; 05). None of these findings are of particular diagnostic or prognostic utility. Transcranial magnetic stimulation has been used in conjunction with EEG to detect the presence of consciousness in states of coma, but although these studies show promise, this is still a research approach (42; 106).
Evoked potentials can provide limited information concerning the functional state of the cerebral cortex and brainstem if communication with the patient is limited or absent, but the findings in patients with locked-in syndrome are highly variable and not particularly critical, either diagnostically or prognostically. Indeed, no pattern of evoked potential abnormality is specific to the locked-in syndrome, with either somatosensory evoked potentials or brainstem auditory evoked potentials (110; 127; 124; 43).
The P300 (P3) event-related potential (ERP) can be recorded in most patients with locked-in syndrome using visual or auditory stimuli under various cognitive “oddball” paradigms (88). In an oddball paradigm, sequences of repetitive stimuli are infrequently interrupted by a deviant stimulus, and the subject’s reaction to this "oddball" stimulus is recorded. Although other electrophysiological techniques can demonstrate normal or abnormal afference of sensory pathways or can suggest indirectly that the cerebral cortex is operative to some degree, early studies suggested that ERPs can provide direct evidence of ongoing cognitive activity (88). A later study recorded the auditory evoked potentials to the patient's own name and to seven other equiprobable first names in 15 brain-damaged patients and found a P3 component in response to the patient’s name in all patients with locked-in syndrome (93). However, they also found this ERP in all minimally conscious patients and in three of five patients in a behaviorally well-documented vegetative state. The authors concluded that a P3 response does not necessarily reflect conscious perception, so its utility in evaluating suspected locked-in syndrome is questionable.
PET and SPECT can assess remaining cortical and brainstem function. Blood flow and metabolic studies can also be used as a diagnostic aid in differentiating individuals in the vegetative state from patients with locked-in syndrome (70) as patients with locked-in syndrome do not usually suffer from significantly depressed cerebral blood flow or metabolism.
Transcranial Doppler can be used to distinguish between locked-in syndrome, persistent vegetative state, and brain death using differences in flow velocities in the middle cerebral and basilar arteries (113).
Functional magnetic resonance imaging has been used to assess consciousness by examining activation differences between blocks of normal speech and reversed speech, making it possible to isolate regions involved in higher-level auditory processing (107; 121).
The development of diffusion tensor imaging has provided a structural evaluation of patients with unresponsive wakefulness and helped to distinguish between patients with locked-in syndrome and minimally conscious patients based on anatomy (12).
Management
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• Decisions for care should focus on the utility of available treatment and management modalities, quality of life, and possible resource constraints. | |
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• Even if the motor recovery remains very limited, existing eye-controlled, computer-based communication technologies allow affected patients to control aspects of their environment, use a word processor coupled to a speech synthesizer, and access the internet. |
Management of locked-in syndrome should be consistent with the desires of the patient. Decisions for care should focus on the utility of available treatment and management modalities, quality of life, and possible resource constraints.
The therapeutic modalities considered for the patient with locked-in syndrome should be directed to resolving the underlying inciting injury whenever possible. For example, thrombolytics or mechanical revascularization may be employed when basilar thrombosis is suspected. Once this has been addressed, intensive and early rehabilitation should be initiated. Particular attention should be directed to maintaining airway function because this may be compromised in quadriplegic patients (108). Intensive nursing care, nutritional support, and an early rehabilitation program that includes physiotherapy, respiratory exercises, and speech training can improve functional recovery in some patients (18).
Management challenges for individuals with locked-in syndrome include blood pressure management and orthostasis, feeding (eg, timing and appropriateness of reinstating oral feeding), ventilation (eg, ventilatory support, decannulation after tracheostomy), bowel and bladder management, eye care, communication, mobility, and independence and autonomy (36). Facilitating mobility required targeted rehabilitation of head, neck, and trunk stability to improve function and proper fit in an appropriate wheelchair (36). Rehabilitation interventions should include a focus on distal motor control (to the extent feasible if not totally locked in) and upright tolerance training. In addition, special consideration should be given to developing workable communication methods through use of augmentative systems to call for help and express needs. Communication systems promote connectivity to family and friends through social media and the internet. Communication, mobility, and connectivity are essential for promoting independence and autonomy and improving quality of life.
Comfort is of the utmost importance, and close attention should be paid to a patient’s pain levels. Even the immobility itself results in considerable discomfort. Patients tend to prefer lying with their arms beside their body rather than in a crucifix position, which was previously advocated (99). Spasticity from injury to the corticospinal tracts can cause pain and discomfort, and it may be ameliorated by oral antispasticity agents or, when necessary, by intrathecal baclofen (97).
Methods of improving communication with patients with locked-in syndrome have had some initial success, and refinements are in development (71). Improved communication improves social inclusion and quality of life for such patients (73; 49; 23).
Even if motor recovery remains limited, existing eye-controlled, computer-based communication technologies allow affected patients to control aspects of their environment, use a word processor coupled to a speech synthesizer, and access the internet (67). Gaze tracking systems are available that move a cursor on a computer screen or perform other motor tasks as directed by the patient’s eye movements. Such systems utilize video-oculography to monitor gaze direction, which is determined by monitoring the “pupil center corneal reflection” using either passive light or active light (infrared light) (115; 41; 82). This approach is used not infrequently in patients with locked-in syndrome and late-stage amyotrophic lateral sclerosis, and training can begin before this technology is absolutely required. Unfortunately, existing eye-writing systems have suffered from slow input rates because they require a pause between input characters to simplify the automatic recognition process. A continuous eye-writing recognition system is in development that achieves a rapid input rate because it accepts characters eye-written continuously without pauses (35).
Brain-computer interfaces have also been developed to allow patients to show nonmotor-dependent signs of awareness and enable communication. Brain-computer interfaces can potentially be utilized for communication and interaction with the environment if voluntary muscle activity is lost or impaired. However, to date, brain-computer interfaces have primarily been used for communication in laboratory research settings (48), with only limited (though promising) application in clinical settings (49). Critical issues must be addressed for brain-computer interfaces to become clinically useful alternative communications systems (48; 84). In a meta-analysis of brain-computer interfaces in amyotrophic lateral sclerosis, the authors concluded, “After 15 years of studies, it is as yet not possible to reliably establish the effectiveness of brain-computer interfaces” (75).
A brain-computer interface provides subjects with a virtual keyboard or mouse, whose keys or cursor are directed by the modulation of brain activity (87). The noninvasive recording of EEG is the most frequently and feasibly used method in brain-computer interface research; invasive recording techniques are also available, though not widely used. Modern brain-computer interfaces determine the intent of the user from a variety of different electrophysiological signals. These signals include slow cortical potentials, P3 potentials, steady-state evoked potentials (SSVEPs), functional near-infrared spectroscopy, and mu or beta rhythms (112). A specific algorithm translates the extracted features into commands representing the user’s intent. These commands can control effectors to select items such as ‘‘yes-no’’ choices or word spelling devices for communication. Visual P3 evoked potentials have been the most robust BCI, enabling accuracy close to 100% in healthy subjects, and P3 paradigms also allow for high accuracy in patients with severe motor paralysis (72). Hybrid models using more than one of these techniques have been developed seeking greater ease and accuracy. Visual, auditory, and tactile brain-computer interfaces are available based on an individual’s functionality (116). There has been more recent promising research on tactile models, suggesting these may be superior to visual and auditory brain-computer interfaces (56; 90). fMRI can also be used to reduce pretraining and does not require external behavior such as eye or finger movements (120). However, functional MRI protocols may fall short in patients with cognitive impairment or dysfunction as they rely on mental imagery, working memory, and sustained attention (26).
Intracortical brain-computer interfaces can decode intended movement from neural activity, transmit to signal processing hardware and software, and not only function as means of communication but also provide a mechanism for which motor function can be imitated. Notable accomplishments include moving a 3-dimensional brain-computer interface-driven robotic arm nonhuman primates and paralyzed humans (22; 50).
Outcomes
Treatment outcomes depend on the etiology of the locked-in syndrome. With acute basilar occlusion, the most common etiology of locked-in syndrome, revascularization reduces mortality from 87% to 39% among those with successful recanalization (118). Age and duration of occlusion are significant factors modifying outcome. Though vessel rupture and fatal bleeding complications are potential risks of treatment, the near-total mortality rate in the absence of intervention most often favors treatment.
Special considerations
Anesthesia
Anesthesia in locked-in patients is complicated by their limited means of communication; the healthcare team may need to quickly learn their communication method during the perioperative period (07).
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Douglas J Lanska MD MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
See Profile
Former Authors
- Kenneth Maiese MD
- Nicole Reams MD
Patient Profile
- Age range of presentation
-
- 0 month to 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- none
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Other specified paralytic syndromes: G83.8
- ICD-11
-
- Locked-in syndrome: 8E45
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