Locked-in syndrome

INTRODUCTION — 

The locked-in syndrome is a severe neurologic condition consisting of near-total body paralysis with preserved consciousness. Because consciousness and higher cortical functions are spared, patients can sometimes communicate through eye movements. It is most often caused by ischemic stroke or hemorrhage of the brainstem.

The causes, clinical features, diagnosis, and management of locked-in syndrome will be reviewed here. Related conditions that involve impairment in consciousness or responsiveness, such as coma, unresponsive wakefulness syndrome, minimally conscious state, akinetic mutism, and catatonia, are discussed elsewhere.

●(See "Stupor and coma in adults".)

●(See "Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis".)

DEFINITION AND TERMINOLOGY — 

In 1966, Plum and Posner coined the term "locked-in" to describe the state of quadriplegia and anarthria (speechlessness due to severe dysarthria) with preserved consciousness [1]. Synonymous with locked-in syndrome are "de-efferented state," "pseudocoma," and "coma vigilante."

Alexandre Dumas provided one of the earliest descriptions of the locked-in syndrome in "The Count of Monte Cristo" by vividly depicting a character who was "a corpse with living eyes." Following a stroke, Monsignor Noirtier de Villefort could only communicate by raising, closing, or winking his eyes [2].

Classic locked-in syndrome — There are two defining components of the locked-in syndrome:

●Retained alertness and cognitive abilities

●Paralysis of the limbs, face, and oral structures such that the individual cannot speak or gesture with the limbs or face

Consciousness and preservation of cognitive abilities are typically identified by eye blinking or eye movements in response to questioning.

Incomplete locked-in syndrome — Patients who have additional voluntary movements beyond eye movements (eg, some movement of facial muscles or a distal limb) but are otherwise quadriparetic and have retained alertness/cognitive abilities may be described as having an incomplete or partial locked-in syndrome [3]. For some patients, classic locked-in syndrome may improve to incomplete locked-in syndrome during recovery.

Complete locked-in syndrome — Patients with brain lesions that cause paralysis of all eye movements in addition to the limb/oral structure paralysis and retained consciousness consistent with locked-in syndrome may be described as having "complete" or "total" locked-in syndrome.

Such patients who are unable to move, speak, or gesture but demonstrate purposeful brain responses on advanced diagnostic tests are described as having complete cognitive motor dissociation (CMD), or covert consciousness [4-6]. CMD is a clinical syndrome characterized by an impairment in motor responsiveness that is greater than volitional brain responsiveness. These patients may appear to be unconscious as they show no signs of language comprehension or responsiveness on bedside examination, but task-based functional magnetic resonance imaging (fMRI) or electroencephalography (EEG) shows that they follow instructions. CMD was first described in 2006 in an individual with severe traumatic brain injury who met the behavioral criteria of unresponsive wakefulness syndrome but who was found to have task-related modulations in cerebral metabolic activity on fMRI corresponding to specific instructions [7]. Subsequent studies showed that both task-based fMRI and EEG can be used to identify responsiveness to motor imagery commands in patients with CMD who are unable to communicate on the behavioral examination [8,9].

PATHOPHYSIOLOGY — 

The motor tracts that are disrupted in patients with locked-in syndrome course from the cortex toward the bulbar motor neurons and spinal cord by traveling through the brainstem. Most cases of locked-in syndrome are due to damage to the pons or midbrain. The somatotopic organization of nerve pathways in these brainstem regions accounts for the clinical features of near-complete paralysis despite preserved consciousness (figure 1).

●Damaged motor fiber tracts – Bulbar impairment and limb paralysis in locked-in syndrome are mediated by the motor tracts to the spinal cord neurons that travel in the basal and ventral portions of the brainstem; these include the cerebral peduncles in the midbrain, the base of the pons, and the medullary pyramids (image 1).

Motor function of the mouth, pharynx, and jaws is mediated by the corticobulbar fibers that travel in the dorsal portion of the midbrain and pons near the tegmental-basal junction and synapse with the motor neurons located in the ambiguous (cranial nerves IX, X, XI), trigeminal (cranial nerve V), and facial (cranial nerve VII) nuclei. Bilateral lesions involving these fibers cause a loss of voluntary mouth and tongue movement as well as loss of speech and swallowing.

●Spared ocular fibers and consciousness centers – Some ocular motor function and consciousness are preserved in patients with locked-in syndrome because pathways that control these functions are located rostral or dorsal to the lesion.

The eye movement nuclei (cranial nerves III, IV, VI) and connecting pathways that control eye movements (the medial longitudinal fasciculi [MLF] and the pontine lateral gaze center in the paramedian pontine reticular formation [PPRF]) are found in the medial tegmentum on each side of the midline. Bilateral lesions that involve these structures cause a loss of horizontal eye movements. When the lesions involve only one side, some horizontal eye movement is preserved. Voluntary blinking and vertical eye movements remain intact.

Sparing of the ascending reticular activating system and other arousal nuclei in the pontine and midbrain tegmentum allows for normal wakefulness, but sleep-wake cycles may be abnormal depending on the extent of damage to the intricate sleep pathways in the brainstem [10]. Various abnormalities have been identified in both rapid eye movement (REM) and non-REM sleep [11]. The medial and lateral reticular formation subserves consciousness and the control of respiratory, cardiac, and vasomotor functions, respectively. The portion of the reticular activating system that relates to consciousness is chiefly located in the paramedian tegmentum [12], while cardiovascular and respiratory-related structures are located more laterally in the tegmentum of the pons and medulla oblongata.

Lesions that extend to involve the bilateral medial tegmentum produce coma [13,14]. However, automatic respirations and cardiovascular functions are not affected if the brainstem tegmental lesions are paramedial and lateral tegmental structures are spared. (See "Stupor and coma in adults".)

Extrapontine causes of locked-in syndrome may occur when other brainstem or hemispheric lesions produce bilateral quadriplegia with bulbar weakness but do not impact pathways involved in cognition or alertness [15-17].

CAUSES — 

Several conditions that typically involve damage to the brainstem may lead to locked-in syndrome. The most common cause of locked-in syndrome is ischemic or hemorrhagic stroke, accounting for 38 of 44 cases in a review from France [18].

●Ischemic brainstem stroke – Ischemic infarction of the ventral pons is usually due to basilar artery embolism or thrombosis (picture 1) [19]. Infarction from vasospasm may also occur such as in the setting of cocaine use [20]. The most vulnerable territory is the paramedian base of the pons. Because the tegmentum has a generous collateral supply that courses from the lateral aspect, the lateral and medial tegmentum are often spared in ischemic stroke. Midbrain infarction or traumatic injury of the bilateral cerebral peduncles causing the locked-in syndrome has also been reported [15,21,22].

●Pontine hemorrhage – A second cause of stroke-induced locked-in syndrome is pontine hemorrhage (image 2), which is most often related to hypertension but can also result from vascular malformations [23,24].

●Other causes – Several other conditions have been reported to cause locked-in syndrome in individual reports. These include:

•Trauma [15,18]

•Malignant intracranial hypertension with brain herniation [25,26]

•Infection (eg, pontine abscess) [27,28]

•Brainstem (primary or metastatic) tumors [29,30]

•Demyelination, including central pontine myelinolysis (image 3) [31-34]

CLINICAL FEATURES

Arousal and responsiveness — Patients with locked-in syndrome may appear unresponsive but they are not. They may move or open their eyes to sound or to command. Electroencephalography (EEG) or other diagnostic testing typically shows preserved sleep-wake cycles.

Responsiveness may be variable or limited by the presence of sedating medications or concomitant conditions that produce encephalopathy. In the acute setting, edema associated with the lesion (eg, infarction) can also extend to the tegmentum of the pons on one or both sides. Bilateral lesions affecting the paramedian tegmentum can impact reticular activating pathways and result in coma in this setting. Such patients can progress from coma to locked-in syndrome, as consciousness may return as edema resolves. With unilateral pontine tegmental lesions, consciousness is typically preserved.

Careful clinical evaluation and instruction may help patients to communicate through eye blinking or purposeful eye movements. (See 'Examination' below and 'Communication' below.)

Preserved eye movements — Vertical eye movements, which are controlled in the rostral portion of the brainstem, are preserved in patients with locked-in syndrome. Horizontal eye movements may also be preserved in patients with ventral pontine lesions that do not involve the extraocular nerves and pathways. Lesions that extend to unilateral tegmental areas result in loss of horizontal eye movements.

Sometimes, the eyes bob downward spontaneously or when the head is rolled from side to side in the "doll's eyes" maneuver. In such cases, the eye movement abnormality may consist of ocular skew or loss of horizontal conjugate gaze to the side of the lesion, ocular bobbing (in a downward direction), or an internuclear ophthalmoplegia (INO) manifested by abnormalities of gaze to the opposite side that are due to loss of adduction of the ipsilateral eye along with nystagmus of the abducting eye. As an example, a lesion of the left medial longitudinal fasciculus (MLF) would result in loss of rightward movement of the left eye and nystagmus of the right eye during attempted gaze to the right side. (See "Internuclear ophthalmoparesis".)

Other patients may have a "one-and-a-half" syndrome, characterized by a combination of lateral gaze and internuclear deficits. If gaze to each side is tallied as one, the only gaze remaining is abduction of one eye (ie, only one-half of the usual two movements). As an example, a lesion of the left pontine tegmentum affecting both the paramedian pontine reticular formation (PPRF) and the MLF would result in the only residual movement being abduction of the right eye on right lateral gaze.

Quadriplegia and bulbar weakness — Near-complete motor weakness is the key abnormal finding on neurologic examination of patients with locked-in syndrome. Bilateral pontine or other brainstem lesions cause a loss of voluntary limb movement accompanied by exaggerated deep tendon reflexes, limb spasticity, and extensor plantar reflexes (Babinski signs).

An inability to speak or swallow is due to the interruption of supranuclear nerve tracts or efferent fibers controlling these functions. The lips, tongue, and soft palate are all weakened, preventing coordination of voluntary vocalization or swallowing. Respiratory function is often affected when the lateral tegmentum of the pons or medulla is involved. Patients may require assistance in ventilation and clearance of pulmonary secretions.

Other findings — Many patients with incomplete locked-in syndrome retain some other voluntary movements besides vertical eye motion such as horizontal gaze, facial expression, limb, head, or tongue movements [11].

Patients with the locked-in syndrome may also experience involuntary motor phenomena including [11]:

●Crying or laughing

●Trismus or bruxism

●Oral automatisms

●Groaning

●Yawning or sighing

●Coughing

●Facial grimacing

During the acute setting, some patients have involuntary limb movements that resemble seizures, especially when they first become weak [35]. These movements may include periodic limb-stiffening, shivering, or dystonic posturing.

DIAGNOSIS — 

The diagnosis of locked-in syndrome should be considered in patients with paralysis and an inability to speak. Locked-in syndrome is diagnosed by clinical and/or diagnostic testing that identifies preserved consciousness (eg, through purposeful eye movements) in such patients. Imaging and other testing is also performed to identify an underlying cause and guide treatment.

Examination — The essential component of the neurologic examination to establish the diagnosis of the locked-in syndrome is to demonstrate preservation of consciousness, alertness, and cognitive function.

The neurologic examination should begin by determining whether the patient is awake, opens eyes to voice, blinks to command, and can move the limbs. The paralyzed patient with the locked-in syndrome will be able to respond even to complex linguistic requests with vertical eye movements and blinking but cannot move the limbs or speak.

Observation of eye movements may be assessed in some patients during bedside interaction. However, the diagnosis can easily be missed in other patients if voluntary eye movements are not examined with great care in patients who seem unresponsive [36]. Strategies to optimize the evaluation of consciousness through eye movement examination include:

●Correct metabolic, infectious, and pharmacologic factors that may cause impaired consciousness (see "Acute toxic-metabolic encephalopathy in children")

●Hold eyelids open to assess horizontal and vertical eye movements

●Ask patients to signal awareness by looking in a specific direction (eg, "look to the right") or blinking (as able) in response to questions

●Use written instructions for patients with prior or associated hearing loss

●Ensure the examination is performed in a language the patient understands

To avoid false negative results, examinations should be repeated if initial testing did not reveal evidence of consciousness through voluntary eye movements. Some investigators have noted that patients with the locked-in syndrome tire quickly when using vertical eye movements to communicate [36]. In addition, patients with the locked-in syndrome may have a severely limited attention span in the first weeks or months after onset of the locked-in syndrome [36].

Patients with no purposeful eye movements should be reexamined over time, as some may emerge from coma into a locked-in state after a delay, such as those with a lesion restricted to the ventral pons [36]. Hearing may recover before eye-opening [37]. Subtle motor responses such as a nonstereotypical grimace or brow furrowing to verbal instruction or noxious stimulation may also be seen [38]. Because of the inherent difficulty in diagnosing the locked-in syndrome in patients with severe neurologic injuries, the diagnosis is often delayed.

Neuroimaging — Neuroimaging is performed as part of the initial evaluation of patients presenting with neurologic symptoms who are subsequently found to have the locked-in syndrome, such as those with brainstem stroke. When the cause of locked-in syndrome is unknown, neuroimaging is required to identify the cause and to guide treatment.

●For patients who present with abrupt onset of symptoms, we perform computed tomography (CT) scan of the head without contrast as the initial imaging test to assess for stroke (eg, intracerebral hemorrhage).

●For most other patients, we perform brain magnetic resonance imaging (MRI), including those with uncertain cause or extent of injury on head CT.

MRI with diffusion-weighted sequences is performed without contrast to identify acute ischemic infarction. Infarction and other structural lesions of the brainstem including tumor, abscess, and demyelination are best visualized on MRI with contrast because CT of the posterior fossa may be compromised by beam-hardening artifact. However, noncontrast CT and either T2*-weighted gradient echo or susceptibility-weighted MRI sequences are sensitive for the detection of brainstem hemorrhage (image 2). CT-based imaging is also used as an alternative imaging test for patients with a contraindication to MRI.

Noninvasive vascular imaging including either CT or magnetic resonance angiography are also performed for patients with stroke to identify the location and severity of large- and medium-size vessel occlusions in the extracranial arteries of the neck and intracranial circulation. Steno-occlusive disease of short and long circumferential basilar artery branches that supply the pons is often too small to be detected on these examinations.

Additional specialized brain imaging such as task-based functional MRI (fMRI) may be performed for selected unresponsive patients who have a lesion on neuroimaging consistent with locked-in syndrome but are unresponsive on examination to help distinguish coma from cognitive motor dissociation. Task-based fMRI is available at specialized centers, but its role in management and prognosis remains uncertain.

Additional testing — Further diagnostic testing should be performed when the diagnosis is uncertain despite neuroimaging. Specific testing modalities vary by clinical features.

●Electroencephalography – Electroencephalography (EEG) is performed for patients with suspected seizures or ongoing nonconvulsive status epilepticus. The clinical features of seizures and status epilepticus are discussed in detail separately. (See "Seizures and epilepsy in older adults: Etiology, clinical presentation, and diagnosis" and "Seizures and epilepsy in children: Classification, etiology, and clinical features" and "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis".)

Nonepileptiform abnormalities on EEG may also be useful to help identify alternative causes of symptoms. The presence of alpha coma can help to distinguish diffuse cerebral injuries found in some patients with unresponsive wakefulness syndrome from focal injuries associated with locked-in syndrome.

EEG may also be used as an adjunct to the clinical examination to support the diagnosis of locked-in syndrome. Changes in rhythm with auditory or visual stimuli may show reactivity, indicative of consciousness. However, reactivity is not a reliable measure of consciousness as it may be absent in some patients with locked-in syndrome [39]. In addition, reactivity may also be seen in patients with catatonia.

●Evoked potentials – Evoked potentials assess the integrity of a specific neural pathway and can be used to localize the site or level of nervous system dysfunction. Evoked potential testing has little diagnostic utility for patients with locked-in syndrome due to the sensitivity of diagnostic imaging. They may be used in cases with nondiagnostic imaging findings, such as those who are unable to undergo brain MRI. However, brainstem auditory-evoked potentials may be normal in patients with locked-in syndrome who have brainstem lesions that do not involve auditory pathways. Somatosensory-evoked potentials have variable patterns and thus show no specific characteristics in the locked-in syndrome [39].

●Laboratory testing – Laboratory testing may be warranted for unresponsive patients with suspected coma of unknown cause. Specific testing is discussed in detail separately. (See "Stupor and coma in adults", section on 'Laboratory tests'.)

●Cerebrospinal fluid analysis – A lumbar puncture for cerebrospinal fluid analysis is typically performed to identify or exclude inflammatory and infectious causes such as encephalitis if imaging and EEG do not reveal a cause of the symptoms in patients with possible locked-in syndrome.

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of locked-in syndrome includes disorders of consciousness and other neurologic disorders that present with quadriplegia and an inability to speak.

Disorders of consciousness — Several neurologic syndromes characterized by impaired consciousness may mimic locked-in syndrome. They are distinguished by clinical and/or diagnostic testing that demonstrate unresponsiveness, lack of awareness of self or surroundings, or the presence of voluntary movements of oral structures or limbs (table 1).

●Coma – Patients in a coma and those with locked-in syndrome are both immobile. However, comatose patients are unresponsive and unable to arouse. Brainstem functions such as corneal, pupillary, and oculocephalic reflexes may be elicited on examination. Motor activity may be present but is restricted to reflex posturing to stimuli and/or myoclonus in coma. (See "Stupor and coma in adults".)

●Unresponsive wakefulness syndrome – The unresponsive wakefulness syndrome (also referred to as the vegetative state) is a disorder of consciousness where patients can be awakened but are unaware of self and surroundings and are unable to interact with others. They may open their eyes, similar to patients with locked-in syndrome, but do not follow instructions.

●Minimally conscious state – The minimally conscious state is a disorder of consciousness characterized by awakening and the presence of intermittent purposeful behavior. Such patients may be able to track an object with their eyes, localize to noxious stimulus, or gesture or verbalize "yes" or "no" answers. They may follow simple instructions but are unable to follow complex instructions and are unable to reliably communicate. The extent of responsiveness may fluctuate in patients in a minimally conscious state. In addition, the extent and pace of recovery from a minimally conscious state are variable. Some patients live for prolonged periods of time in a minimally conscious state, while others progress from a minimally conscious state to full recovery of consciousness.

●Akinetic mutism – Akinetic mutism is a neurologic syndrome characterized by immobility due to the inability to initiate movements. Patients with akinetic mutism are typically awake, can follow an examiner with the eyes, and have preserved body posture and postural reflexes but do not speak or initiate movement. Neurologic injury in the prefrontal motor cortex can account for this volitional motor dysfunction. (See "Stupor and coma in adults", section on 'Akinetic mutism'.)

Advanced ALS — Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle spasticity and weakness. Weakness involves both limbs and bulbar functions. Patients with advanced ALS can be immobile, unable to speak due to severe dysarthria, and may also develop impairments in extraocular muscles, consistent with neurologic deficits of other patients with locked-in syndrome. However, many patients with even advanced ALS have other preserved motor function in addition to preserved eye movements.

Unlike other causes of locked-in syndrome, ALS causes gradual weakness and does not present acutely. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

Peripheral neuropathic disorders — Purely peripheral nerve or neuromuscular disorders that may have clinical features similar to the locked-in syndrome include severe polyneuropathies or neuromuscular disorders such as:

●Guillain-Barré syndrome (see "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis")

●Myasthenia gravis (see "Clinical manifestations of myasthenia gravis")

●Critical illness neuropathy/myopathy (see "Neuromuscular weakness related to critical illness")

While these neuromuscular disorders may cause profound diffuse limb weakness, it is rare for any of them to cause complete bulbar and limb paralysis. Either speech or some limb motion is typically spared, permitting communication or signaling. The past history and gradual development of paralysis almost always allows identification of a peripheral nerve or neuromuscular problem.

In addition, pharmacologic neuromuscular blockade produces quadriplegia due to inhibition at the neuromuscular junction. Clinical effects of these agents in the setting of concomitant kidney or liver dysfunction or interaction with other medications may be prolonged and produce clinical uncertainty about the cause of symptoms. The etiology of symptoms may be established by careful history and exclusion of structural causes of symptoms. (See "Neuromuscular weakness related to critical illness", section on 'Prolonged neuromuscular junction blockade'.)

MANAGEMENT — 

The management of locked-in syndrome involves treatment of underlying causes as well as supportive care geared toward facilitating communication, reducing the risk of morbidity, and promoting rehabilitation.

Patients with the locked-in syndrome are fully conscious and should be encouraged to participate in decisions affecting their care at all stages of treatment.

Cause-specific therapies — Specific treatment of the locked-in syndrome varies by the underlying cause identified by neuroimaging or other diagnostic testing as well as by the duration since the onset of symptoms. As examples, patients with acute brainstem ischemic stroke due to basilar artery thrombosis may be candidates for revascularization, while others with subacute brainstem ischemic stroke may warrant osmotic therapies or craniectomy to treat cerebral edema. Patients with locked-in syndrome due to brainstem infection require antimicrobial therapy, and those with inflammatory lesions are typically treated with glucocorticoids.

Specific treatment of common causes of locked-in syndrome are discussed separately.

●(See "Approach to reperfusion therapy for acute ischemic stroke".)

●(See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".)

●(See "Evaluation and management of elevated intracranial pressure in adults".)

●(See "Management of acute moderate and severe traumatic brain injury".)

●(See "Treatment and prognosis of bacterial brain abscess".)

●(See "Overview of the treatment of brain metastases" and "Management of vasogenic edema in patients with primary and metastatic brain tumors".)

●(See "Treatment of acute exacerbations of multiple sclerosis in adults".)

Communication — Patients with locked-in syndrome may be able to express their needs, preferences, and even complex ideas by training to use functioning eye movements as code for language. For basic communication, a combination of eyelid blinking and vertical eye movements can be used to establish a yes/no code. A variety of electronic devices are available to facilitate communication, including computers, printers, synthetic voice machines triggered by sensitive switches, and head or eye-gaze sensors [40,41]. Such communication devices have allowed patients to email, use the internet, read daily news, write stories, compose music, and shop online [42]. Whatever form of communication is used, the method should be positioned to be continually available to the patient.

Supportive management — Acute supportive treatment for immobile patients with clinical deficits consistent with the locked-in syndrome begins with securing and maintaining an airway, ensuring adequate oxygenation, and monitoring hemodynamic status. Subsequent supportive care focuses on preventing complications and supporting rehabilitation efforts. Vigorous medical management may allow for the formation of collateral circulation and recovery of damaged neural pathways.

●Initial aggressive treatment – We suggest initial aggressive supportive measures and delay prognostication for patients with locked-in syndrome as many can achieve some meaningful recovery with intense and sustained multimodal therapy [36]. (See 'Recovery' below.)

Unless patients themselves express wishes not to be sustained, we discourage attitudes of medical nihilism towards the locked-in syndrome [43,44].

●Respiratory support – Most patients with acute locked-in syndrome require initial respiratory support due to motor weakness and dysphagia [45]. The locked-in syndrome poses high risks for respiratory complications, and patients should be monitored closely for difficulties handling secretions or needs for ventilatory assistance. Accordingly, we favor chest physiotherapy, deep breathing exercises, and chest mobilization to facilitate the clearance of bronchial secretions [46].

●Prevention and management of medical complications – Hospitalized patients with quadriplegia are at risk for several medical complications due to immobility or the underlying cause of symptoms including venous thromboembolism, aspiration pneumonia, and gastrointestinal bleeding. These complications are common among patients with locked-in syndrome [47]. Such patients should be monitored for the development of such complications and treated promptly, should they occur [45]. These issues are discussed in detail separately. (See "Complications of stroke: An overview", section on 'Medical complications'.)

●Symptomatic management of neurologic dysfunction – Patients with structural lesions causing the locked-in syndrome may also warrant treatment for other neurologic symptoms that localize to the brainstem.

•Vestibular dysfunction is common in patients with locked-in syndrome due to extraocular motor dysfunction causing diplopia or asymmetric involvement of the vestibular nuclei or pathways [45]. Periodic eye patching or antiemetic agents such as meclizine or metoclopramide may be warranted. (See "Treatment of vertigo", section on 'Symptomatic treatment'.)

•Pseudobulbar affect (PBA), or pathologic laughing or crying due to impairment of corticobulbar fibers, is common in patients with locked-in syndrome. Recognition of this condition and symptomatic treatment with medications may be warranted. Options may include dextromethorphan-quinidine, amitriptyline, or fluvoxamine. Management of PBA is discussed in greater detail separately. (See "Symptom-based management of amyotrophic lateral sclerosis", section on 'Pseudobulbar affect'.)

●Rehabilitation – After the acute hospitalization, care should be centralized and coordinated in a specialized rehabilitation center experienced in the locked-in syndrome. Care should include identifying and treating pain and preventing immobility, contractures, corneal abrasions, and decubitus ulcers.

Multimodal therapy with physical, occupational, and speech therapy as well as assistive devices to facilitate interaction may improve outcomes. Supportive and preventive measures are of paramount importance for patients with the locked-in syndrome.

Planning and coordinating with family and friends is necessary to design optimal long-term care.

●Psychologic support – Depression is common but not universal among patients with chronic locked-in syndrome. Mental health screening and treatment of depression should be offered to patients to support rehabilitation and well-being. (See 'Chronic locked-in syndrome' below.)

PROGNOSIS — 

Although early reports suggested that the locked-in syndrome was an irreversible condition leading to death shortly after onset [3], accumulating evidence suggests that a substantial proportion regain some function over time, and a minority have a good functional recovery. However, most survivors of the locked-in syndrome remain chronically locked-in or severely impaired.

Mortality — In the largest review of 139 cases of patients with locked-in syndrome, the mortality rate was 60 percent, and most (87 percent) occurred within the first four months [11]. The most common causes of death were pneumonia, pulmonary embolism, extension of brainstem lesions, and sepsis. Mortality rates were lower for patients with the locked-in syndrome due to trauma and other nonvascular etiologies.

Recovery — Although data are limited, several case reports and series suggest many patients with locked-in syndrome who survive beyond the acute period improve to some degree with time and rehabilitation [46,48,49]. Support for aggressive rehabilitation therapy comes from a case series that evaluated the recovery patterns among 14 patients with the locked-in syndrome who underwent intensive, multidisciplinary rehabilitation [46]. Verbal communication recovered in four patients (28 percent), and the ability to use a device by hand, finger, or head movement was achieved by six (43 percent). Partial or full independence in activities of daily living within three to six months of onset was achieved by three patients (21 percent), and all but four patients eventually returned home. In another review of 51 patients who had locked-in syndrome from stroke persisting for at least six weeks, moderate recovery indicated by a modified Rankin Scale (mRS) score of ≤4 (table 2) at a median of 7.3 years after onset was achieved by 15 of the 43 patients (35 percent) with follow-up data [17]. Only three patients (7 percent) achieved good recovery (mRS ≤2).

The time course and extent of clinical improvement in locked-in syndrome depends on the extent and location of the underlying brain injury. One report described four patients with the locked-in syndrome due to presumed basilar artery occlusion who made substantial functional gains over several months while receiving supportive therapy and rehabilitation [48]. These patients recovered to independence in at least some activities of daily living; they regained bowel and bladder control, could eat by mouth, and regained functional, although dysarthric, speech.

Recovery may vary depending on the underlying cause. Prognostic information based largely on patients with locked-in syndrome due to ischemic stroke or intracerebral hemorrhage may not fully apply to patients with potentially reversible or treatable causes such as demyelination or infection. Near complete recovery has been reported in some patients with locked-in syndrome due to brainstem demyelination [50-52].

Chronic locked-in syndrome — The most extensive longitudinal evidence of patients with chronic locked-in syndrome comes from a cohort of 29 patients with the locked-in syndrome who were locked-in for at least one year [47,53]. The mean survival in this cohort was 4.9 years and ranged from 1.2 to 18 years by study completion. More than half of the patients regained minor movements, and 10 could trigger a switch, point, or type. Seven patients could use an electric wheelchair. Most patients achieved bowel and bladder continence. All except for seven ate food by mouth. Sixteen patients recovered the ability to speak words and sentences. All except for three patients communicated with gestures, limb movements, a letter board, or electronic equipment.

A telephone survey published in 2003 found that from the original cohort of 29 patients identified in 1985, 16 had died in the interim. Overall survival rates at 10 and 20 years were 83 and 40 percent, respectively [54]. Most patients were at home, while some lived in nursing facilities or acute care hospitals.

Patients with locked-in syndrome often rate their quality of life higher than caregivers and clinicians [55]. However, there is limited information on the quality of life or emotional state of patients with the locked-in syndrome. In a retrospective survey involving 13 long-term patients with the locked-in syndrome or their caregivers, seven patients reported being satisfied with life, occasional depression was reported by five patients, euthanasia was considered but refused by six, and a wish-to-die was expressed by one patient [54]. A subsequent case-control study compared 19 patients with the locked-in syndrome and 20 age-matched healthy control subjects [56]. Scores on rating scales assessing overall quality of life and mental health were similar between locked-in syndrome group and healthy controls. However, the locked-in syndrome group had significantly lower scores on measures of physical function, as expected. In addition, the locked-in syndrome group had a higher frequency of intermittent depressive symptoms.

SUMMARY AND RECOMMENDATIONS

●Definition – The locked-in syndrome is a neurologic condition consisting of near total body paralysis with preserved consciousness. Because consciousness and higher cortical functions are spared, patients can sometimes communicate through eye movements. (See 'Definition and terminology' above.)

●Pathophysiology and causes – Bulbar impairment and limb paralysis in locked-in syndrome are mediated by the motor tracts to the spinal cord neurons that travel in the basal and ventral portions of the brainstem. Ocular function and consciousness are preserved because pathways that control these functions are located rostral or dorsal to the lesion (figure 1 and image 1). (See 'Pathophysiology' above.)

The most common cause of locked-in syndrome is ischemic or hemorrhagic brainstem stroke. Other causes include trauma, intracranial hypertension with herniation, cerebral abscess, tumor, or demyelination. (See 'Causes' above.)

●Clinical features – Quadriplegia and inability to speak or swallow with retained cognition are the hallmarks of the locked-in syndrome. Respiration is often affected. Because the supranuclear ocular motor pathways are spared, patients can move their eyes and blink. (See 'Clinical features' above.)

In addition, some patients with the locked-in syndrome may have involuntary ocular, oral, or limb movements.

●Diagnosis – Locked-in syndrome is diagnosed by clinical and/or diagnostic testing that identifies preserved consciousness (eg, through purposeful eye movements) in patients who are quadriplegic and cannot speak. Imaging and other testing is also performed to identify an underlying cause and guide treatment. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of locked-in syndrome includes disorders of consciousness and other neurologic disorders that present with quadriplegia and an inability to speak. These include (see 'Differential diagnosis' above):

•Disorders of consciousness (eg, coma, unresponsive wakefulness syndrome, minimally conscious states, akinetic mutism) (table 1)

•Advanced amyotrophic lateral sclerosis (ALS)

•Severe peripheral neuropathic disorders (eg, Guillain-Barré syndrome, myasthenia gravis, critical illness neuro-/myopathy)

●Management – The management of locked-in syndrome involves treatment of underlying causes as well as supportive care geared toward facilitating communication, reducing the risk of morbidity, and promoting rehabilitation. (See 'Management' above.)

•For basic communication, a combination of eyelid blinking and vertical eye movements can be used to establish a yes/no code. A variety of electronic devices are available to facilitate communication, including computers, printers, synthetic voice machines triggered by sensitive switches, and head or eye-gaze sensors. (See 'Communication' above.)

•We suggest initial aggressive supportive measures and delay prognostication for patients with locked-in syndrome as many can achieve some meaningful recovery with intense and sustained multimodal therapy. Supportive measures include (see 'Supportive management' above):

-Respiratory support with mechanical ventilation as needed along with chest physiotherapy, deep breathing exercises, and chest mobilization to facilitate bronchial secretions.

-Monitoring to prevent and/or treatment of medical complications such as venous thromboembolism, aspiration pneumonia, and gastrointestinal bleeding.

-Symptomatic treatment of associated neurologic symptoms such as vertigo and pseudobulbar affect (PBA).

-Mental health screening and treatment of depression to support rehabilitation and well-being.

●Prognosis – Locked-in syndrome is a severe neurologic syndrome with mortality rates up to 60 percent, with most deaths occurring within the first four months. Most survivors of the locked-in syndrome remain chronically locked-in or severely impaired. However, many regain some motor function over time, and up to 25 percent of patients have a good functional recovery. (See 'Prognosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Sean Savitz, MD, who contributed to an earlier version of this topic review.