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Abstract

The locked-in syndrome (LiS) is characterized by quadriplegia with preserved vertical eye and eyelid movements and retained cognitive abilities. Subcategorization, aetiologies and the anatomical foundation of LiS are discussed. The damage of different structures in the pons, mesencephalon and thalamus are attributed to symptoms of classical, complete and incomplete LiS and the locked-in plus syndrome, which is characterized by additional impairments of consciousness, making the clinical distinction to other chronic disorders of consciousness at times difficult. Other differential diagnoses are cognitive motor dissociation (CMD) and akinetic mutism. Treatment options are reviewed and an early, interdisciplinary and aggressive approach, including the provision of psychological support and coping strategies is favoured. The establishment of communication is a main goal of rehabilitation. Finally, the quality of life of LiS patients and ethical implications are considered. While patients with LiS report a high quality of life and well-being, medical professionals and caregivers have largely pessimistic perceptions. The negative view on life with LiS must be overthought and the autonomy and dignity of LiS patients prioritized. Knowledge has to be disseminated, diagnostics accelerated and technical support system development promoted. More well-designed research but also more awareness of the needs of LiS patients and their perception as individual persons is needed to enable a life with LiS that is worth living.

Keywords

brainstem cognitive function consciousness differential diagnosis ethics lesion pons quadriplegia quality of life treatment

Introduction

The locked-in syndrome (LiS) was first described by Plum and Posner 1972 and is one of the most disabling entities. Patients are locked in their own bodies, unable to move due to quadrioplegia, except for vertical eye and eyelid movements. Although no other voluntary muscle movements are possible, cognitive abilities of the patients are not impaired.¹

In 1979, Bauer et al. introduced further subcategorizations: he distinguished the classical LiS from the complete and incomplete LiS to describe patients whose capacity of voluntary movements went below or above the classical LiS motor symptoms. In complete LiS, no voluntary movements are achievable at all, and patients lack any possibility to communicate directly, which makes further diagnostics indispensable. Incomplete LiS is a less severe form, which can also be a transitory stage of recovery, where patients are able to execute more voluntary movements than in the classical form of LiS.² For patients who additionally suffer from disturbances of consciousness, the term locked-in plus (LiPS) was introduced, by the Salzburg Coma Group.³

Nevertheless, the first literary description of LiS was written long before these modern medical ones, by Alexandre Dumas in his novel The Count of Monte Cristo in 1844. Monsieur Noirtier de Villefort, a key character, is not able to speak, ‘motionless as a corpse, he greeted his children with bright, intelligent eyes . . . ’. Dumas even showed that he understood the basic aetiology of LiS as he describes strokes and brain bleeds in his story.⁴ As a metaphor for human existence, LiS can be found throughout fictional literature.⁵ As Kondziella⁶ shows, even complete LiS was described long before the medical community became aware of it by Roald Dahl in a short story William and Mary (1959).

One of the most influencing non-fictional books on the topic is The Diving Bell and the Butterfly written by Jean-Dominique Bauby in 1997 by blinking. The author, himself suffering from LiS, gives very personal and touching insights into the life of a LiS patient and shows the pain but also beautiful moments of his existence in this autobiography.⁷

LiS is a very rare syndrome and no exact incidence or prevalence is known. In 1986, Patterson and Grabois obtained a sample of 139 cases including six own cases and cases from a literature review. They found a mean age of onset of 52 years (range: 16–90) with more males than females affected (85 to 52). A total of 89 patients were diagnosed with classical, 46 incomplete and 3 complete LiS (one unclassified); 10 patients showed transient states. Eighty-two patients suffered an infarction of the pons, other vascular and non-vascular etiologies being less common. Roughly one third of the patients had a history of hypertension. A mortality rate of 60% was reported, but no time frame given, although the majority of deaths occurred within the first 4 months after onset.⁸ A newer study reports a mortality rate of 75% in the acute phase.⁹ The most reported causes of death are pulmonary complications and further brainstem damage.^8,9 Sensory perception varied wildly in the population from normal to absent. It was also shown that substantial recovery is possible^8,10–16 and can continue over years,¹⁷ possibly by reorganization of the descending pathways.¹⁸ One survey of chronic LiS patients showed a recovery of functional movements in 72%.¹⁹ Distal motor functions are more likely to recover,²⁰ and even when large brainstem strokes are apparent in magnetic resonance imaging (MRI), substantial recovery is possible.²¹

In 2013, a study estimated a prevalence of 0.7/10,000 patients with classical LiS in Dutch nursing homes.²² ALIS (Association of Locked-in Syndrome) in France states on its website that more than 500 French people live in LiS in 2022.²³ Life expectancy has improved in the last decades for LiS patients,²⁴ some living for many decades in LiS.²⁵

The aim of this review is to give an up-to date overview of LiS, focusing on anatomy, pathophysiology, treatments, quality of life, ethics and new developments in the field. Not only are the structures that can be affected in LiS and the resulting symptoms discussed but also the anatomical foundations of LiPS. Moreover, differential diagnosis of LiS that have to be considered and treatment options are recapitulated. Finally, ethical considerations are presented. This review is important to inform and raise awareness about LiS and counteract prevalent misconceptions about this rare disease among medical doctors and other health care staff.

Methods

A literature search was done in MEDLINE/PubMed in 2022. An advanced search for title or mesh term ‘locked-in syndrome’ ((locked-in syndrome[MeSH Terms]) OR (locked-in syndrome[Title])) yielded 441 results (265 of them case reports) of the years 1971 until 2022. Titles and subsequently abstracts were screened for relevance. Findings that were available in English language and important for this review were included. Essential citations were pursued. Literature on special topics (e.g. the anatomy of the brainstem) was searched separately.

Causes of locked-in syndrome

The most common aetiologies of LiS are infarction and haemorrhage in the vertebrobasilar artery territory,⁸ supplying the brainstem, most importantly the ventral part of the pons. This is sometimes preceded by a pontine warning syndrome, which describes recurrent, fluctuating motor or sensory symptoms associated with a high risk of basilar infarction.^16,26–28 Further aetiologies are listed in Table 1. Moreover, LiS was reported in children^29–31 and cases of transient LiS of different aetiologies were also described.^32–42

Table 1.

Aetiologies of LiS.

Aetiologies leading to infarction/other damage of the pons	• Aneurysm^43–45/vascular malformation^{37,40,42,46,47} of the basilar artery • Artery dissection^{10,33,48–51} (e.g. due to cervical manipulation^52–55) • Basilar artery vasospasm⁵⁶ • Basilar migraine⁵⁷ • Central pontine myelinolysis^58–60 • Cocaine abuse⁶¹ • Hyperhomocysteinemia⁶² • Infection^63–65 mechanical brain herniation^66–70 • Multiple sclerosis^71–73 • Pontine abscess⁷⁴ • Primary^75,76 or metastatic^77–79 tumour • Prolonged hypoglycemia⁸⁰ • SARS-CoV-2^81,82 • Traumatic brain injury (axonal injury,^12,83–88 secondary infarction^{34,35,50,87,89–93})
Locked-in like states	• Conversion disorders⁹⁴ • Late-stage amyotrophic lateral sclerosis⁹⁵ • Severe cases of Guillain-Barré syndrome^31,96,97 (also reported as a complication of SARS-CoV-2⁹⁸) • Snake bites^99–101 • Supratentorial traumatic lesions¹³
Iatrogenic	Complications during • Coronary bypass surgery¹⁰² • Lumbar puncture¹⁰³ • Shunt procedures³⁹ • Stellate ganglion^36,104,105 or intrascalene brachial plexus block³⁸ • Adverse effects of medications^14,106 • Post-cardiopulmonary bypass inflammatory reaction¹⁰⁷ • Postoperative pneumocephalus¹⁰⁸

Although in most cases the brainstem and especially the ventral pons is the primary site of injury, recent studies have shown that other brain areas may be involved in addition. Diffuse supra- and infratentorial white matter fibre tract injuries have been reported,¹⁰⁹ as well as atrophy in cortical areas¹¹⁰ (e.g. dorsomedial prefrontal cortex¹¹¹) and changes in cortical rhythms in resting-state electroencephalography (EEG) experiments compared with healthy controls.¹¹² However, one study also showed increased fibre density and connectivity in some parts of the brain.¹¹³

Pathophysiology of motor impairment in locked-in syndrome

In the early literature, classical LiS was also called the ventral pons syndrome. Being ‘locked in’ within a body, all voluntary movements are impaired by the damage of the corticospinal and corticobulbar tracts, which both run side by side through the cerebral peduncles of the midbrain and are located in the very ventral part of the pons and the medulla oblongata.

The corticospinal tract is crucial for voluntary movements of the body and extremities, whereas corticobulbar fibres are responsible for voluntary, non-oculomotor movements of muscles innervated by caudal cranial nerves (e.g. speech, tongue movement).

Eye movements are spared as they are controlled by different centres in the brainstem. The paramedian pontine reticular formation (PPRF) is responsible for horizontal eye movements and saccades. The PPRF signals the abducens nucleus an ipsilateral horizontal eye movement whereupon the nucleus contracts the ipsilateral rectus lateralis muscle via the abducens nerve. Simultaneously, the contralateral oculomotorius nucleus signals via the MLF (medial longitudinal fasciculus) to contract the ipsilateral rectus medialis muscle. This results in a horizontal gaze movement, which has its control centre in the pons.¹¹⁴

Vertical eye movements are controlled by mesencephalic structures [the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), interstitial nucleus of Cajal, the posterior commissure, oculomotorius and trochlearis nucleus and nerve].¹¹⁵ The levator palpebrae superioris responsible for retraction of the upper eyelid and therefore blinking is also innervated by the oculomotor nerve. Therefore, damage of paramedian mesencephalic structures can cause vertical gaze paralysis and ptosis. A patient who suffered from top of the basilar artery occlusion which could be recanalized but still resulted in bilateral infarctions in the midbrain tegmentum, especially affecting the oculomotor nuclei, showed bilateral ptosis, non-reactive pupils and ophthalmoplegia.¹¹⁶

The additional involvement of riMLF and other mesencephalic structures in brainstem damage in LiS leads to the clinical presentation of complete LiS (therefore formerly also referred to as mesencephalic LiS¹¹⁷). Otherwise, the sparing of PPRF, and/or parts of the corticospinal tracts results in incomplete LiS presenting without oculomotor disturbances and/or preserved body movements. Figure 1 shows a typical MRI of a classical or incomplete LiS patient.

Figure 1.

MRI of a patient with locked-in syndrome due to basilar thrombosis showing lesions involving the ventral pons (arrow).

Involuntary movements have been reported in LiS patients by Bauer et al.¹¹⁸ who described stimulus evoked oral automatisms like sucking, chewing and swallowing, most likely apparent due to lost pyramidal control of the motor centres in the brainstem. Moreover, involuntary movements like flexor and extensor spasms,⁴⁰ pain reactions, compulsory mimic reactions, cat crying, whining, moaning, groaning, yawning, sighing and coughing were reported.¹¹⁹ Many of these motor behaviours have also been described in newborns suffering from anencephaly, which shows that the cortex is not needed for these complex movements.¹²⁰ Trismus and yawning were described in one patient.¹²¹ A possible explanation for the excessive yawning could be its role in thermoregulation as a mechanism to cool the brain.^122,123 Besides orofacial stereotypes, palatal tremor has also been observed.¹²⁴ These motor phenomena have to be kept in mind when examining a patient and distinguished from voluntary movements that can serve as communication.

Differential diagnosis

The locked-in syndrome is often misdiagnosed due to its severe symptoms. The most important differential diagnoses that have to be considered are unresponsive wakefulness syndrome (UWS), minimally conscious state (MCS), CMD) and akinetic mutism.

Without careful clinical investigation and EEG, LiS can be misinterpreted as a disorder of consciousness, for example, the UWS if signs of consciousness such as voluntary movements are very subtle or missing. The UWS (formerly known as vegetative state¹²⁵ or apallic syndrome¹²⁶) is the first remission stage of a coma and marked by spontaneous eye opening and mostly resumed autonomic function but a lack of conscious behaviour.¹²⁷

More recently, the MCS was proposed as an interim state in which patients show reproducible behavioural signs of minimal consciousness even though these can be very inconsistent for instance due to high vigilance fluctuations. Behaviours like following simple commands, gestural or verbal yes/no answers, intelligible verbalizations or purposeful behaviour have to be present to diagnose a patient as suffering from MCS.¹²⁸ This entity has also been subcategorized into MCS+ and MCS− based on the complexity of the behavioural responses of the patient (for example, command following versus minimal behavioural interaction).¹²⁹ Moreover, the term ‘emergence from MCS’ has been defined by a functional interactive communication or functional object use.¹²⁸

The gold standard for diagnosing these disorders of consciousness (UWS, MCS) is the Coma Recovery Scale–Revised (CRS-R). This is a standardized, behavioural scale which is able to discriminate UWS, MCS and conscious patients according to their behavioural output.¹³⁰ UWS patients show reflexive behaviours only, whereas MCS patients exhibit signs of minimal consciousness as described above. However, patients who are not able to show their consciousness behaviourally are missed by the CRS-R.

Another term that has gained more and more importance recently is CMD, also known as functional locked-in syndrome, nonbehavioural MCS or covert cognition.^131,132 This pathology describes patients who, although showing a preserved yet possibly limited capacity of rational thoughts, have no capability of creating any output to the environment due to complete paralysis. The state of these patients can only be detected by further diagnostics such as functional MRI or event-related EEG techniques.¹³³

Akinetic mutism is a clinical picture in which a patient neither moves (akinetic) nor speaks (mutism). This clinical picture was first described by Cairns in a patient with an epidermoid cyst of the third ventricle in 1941.¹³⁴ Akinetic mutism was also described in a case of paramedian thalamic infarction where the lesions included dorsomedian and intralaminar nuclei.^135,136 According to Arnts et al.,¹³⁷ akinetic mutism is the most severe form of a motivational disorder and caused by a disruption of the frontal subcortical circuit which can occur when the anterior cingulate cortex, the striatum, the internal pallidal complex or the medial thalamus are damaged.

Although the classical locked-in syndrome is not a disorder of consciousness or motivation, it nevertheless is often difficult to differentiate LiS from UWS, MCS, CMD or akinetic mutism due to quadriplegia and anarthria.¹³⁸ However, besides structured, precise and repeated bedside examination, it can be differentiated with further diagnostics, for example, imaging like MRI, as the location of the lesions differ. UWS, MCS, CMD and akinetic mutism are characterized by lesions found supratentorial, whereas the lesions of all forms of LiS are dominantly in the brainstem. In CMD for instance, the connectivity between subcortical and cortical areas is impaired,¹³⁹ in contrast to patients suffering from LiS where the main locus of the injury is the ventral pons.¹⁴⁰ However, one patient with supratentorial lesions, which caused an incomplete locked-in like syndrome, has been described,¹³ and LiS due to traumatic causes can also present with lesions outside of the typical location.⁸⁴ LiS should therefore always be considered. Moreover, a clear definition of CMD and its related terms is needed to differentiate it from complete LiS and allow a consistent nomenclature.¹³²

Nevertheless, there are patients who show lesions in the brainstem, which are typical for LiS, but no clinical signs of consciousness can be found. One possible explanation is that the patient suffers from complete LiS, where no voluntary movement is possible at all and therefore, patients seem to be in deep non-reactive coma at bedside examination. To diagnose LiS, functional magnetic resonance imaging (fMRI) and EEG-based active paradigms are mandatory.^141,142 Still, there are patients who show no or only minimal signs of consciousness even when using these diagnostic measures. One of course has to keep in mind that a negative fMRI outcome by far does not mean that the patient is not conscious as bad timing, movement artefacts or other problems can lead to an erroneous result. Moreover, many paradigms need a high level of cognitive functioning and can be tiring or too complicated for the patients. Therefore, the European Academy of Neurology suggests using not only a repeated standardized clinical assessment but also a multimodal evaluation for patients suffering from disorders of consciousness.¹⁴²

Still, there are patients in LiS who also suffer from a dysfunction of consciousness and are therefore in LiPS.³ The anatomical foundation of LiPS is discussed in the following chapter.

To summarize, to correctly diagnose LiS and its subgroups, repeated, clinical bedside evaluation, imaging and, in case no communication can be established, fMRI or EEG-based functional examinations should be performed.

Impairment of consciousness in locked-in plus syndrome

Impairment of consciousness in LiPS patients may be caused either by (1) a lesion extending rostral through the mesencephalon into the medial thalamus, or (2) a lesion that stretches dorsal affecting the ascending reticular activating system, or (3) combinations thereof. Figure 2 displays the regions of the brainstem and thalamus that can be affected in different forms of LiS, while Figure 3 shows the MRI of a LiPS patient.

Figure 2.

Regions of the brainstem and thalamus which can be lesioned in classical LiS, complete LiS and LiPS, including the most important structures causing the symptoms and function losses.

Figure 3.

MRI of a patient with locked-in plus syndrome due to basilar artery thrombosis, the arrows showing the lesions involving the brainstem (pons and mesencephalon) and thalamus.

A study investigating the cognitive functioning of LiS patients found that lesions can occur in locations beyond the pons (e.g. the thalamus) and that these were related to a worse cognitive outcome.¹⁴³ Schnakers et al.¹⁴⁴ showed that additional lesions on top of the brainstem lesions are often related with cognitive deficits. Other studies also reported cognitive impairments in locked-in patients.^145,146 However, these studies did not investigate patients with impaired consciousness, but they show a continuum on which LiPS could represent the most extreme form.

The top of the basilar syndrome is an event that occludes the most distal part of the basilar artery usually involving damage of the thalamus.¹⁴⁷ Percheron was the first to describe the arterial supply of the thalamus including the paramedian arteries. These originate shortly after the bifurcation of the basilar artery, although there are varying patterns of origin.¹⁴⁸ The paramedian arteries supply the medial and intralaminar thalamic nuclei, which play an important role for consciousness and other cognitive functions. Their bilateral occlusion therefore can cause impairment of consciousness and even deep coma.^149–151

The central thalamus (including the intralaminar nuclei) plays a key role in awareness and consciousness.¹⁵² In an experimental study, consciousness was restored in an anesthetised macaque by stimulating the central lateral thalamus (which belongs to the intralaminar thalamic nuclei) but not any other surrounding region.¹⁵³

In addition, a study demonstrated that patients with LiS and severely impaired awareness had lesions, which extended into the midbrain and/or pontine tegmentum, whereas purely thalamic lesions alone did not severely impair consciousness.¹⁵⁴ It was also shown that a small region of the left rostral dorsolateral pontine tegmentum is significantly more often associated with coma compared with controls.¹⁵⁵

One structure of key importance involved in these cases is the ascending reticular activating system (ARAS). As Moruzzi and Magoun¹⁵⁶ proposed in 1949, the ARAS is important for arousal. Wakefulness in turn is needed for awareness and consciousness. ARAS consists of various diffuse brainstem nuclei, which are mostly located in the midline of the dorsal part of the brainstem and project inter alia to the thalamus and the cortex. A tractography study demonstrated that the intralaminar thalamic nuclei are an important connection of the ARAS.¹⁵⁷

A lesion of the ARAS or its connections to the thalamus or other structures like the hypothalamus and basal forebrain will therefore also cause an impairment of consciousness.

To summarize, the impairment of consciousness in LiPS patients can be explained by brainstem lesions, which not only involve the ventral pons but also the mesencephalon, thalamus and dorsal regions of the brainstem.

Treatment

After the acute stabilization and treatment of the underlying cause, an intensive and early rehabilitation (begun on average 1 month after onset) improves the functional outcome of LiS patients and reduces the mortality rate.¹⁵⁸ The currently available recommendations on the rehabilitation of LiS patients suggest that the treatment and management of pain, spasticity, incontinence, nutrition, tracheostomy, vision, vegetative and vestibular functions and communication are highly important.¹⁵⁹ Moreover, the benefit of early interdisciplinary therapy including physical, speech, occupational therapy and the use of assistive devices are critical.¹⁶⁰ Furthermore, based on a case report, multisensory, progressive, multimodal and technology based interventions are suggested to fill the gap in motor retraining.¹⁶¹ A multidisciplinary approach including nursing interventions is also recommended.^162,163 Although very rare, LiS in children poses special challenges especially in the areas of communication, treatment and end-of-life decisions.³⁰

To avoid pulmonary complications, which are the main cause of death, chest physiotherapy like deep breathing exercises, frequent position changes, postural drainage and suctioning is recommended.¹⁶⁴ Diaphragmatic pacing, which is established for spinal cord injured patients, is also an option that showed benefits for a LiS patient already.¹⁶⁵

Although a systematic review found insufficient evidence for the benefits of physical exercise in physical recovery of LiS patients, a positive trend was seen for muscle strength, tone, walking ability and activities in daily living and the need for well-designed studies was stated.¹⁶⁶ As in stroke patients, repetitive sensorimotor training could be beneficial for LiS patients.¹⁶⁷ Sildenafil citrate is hypothesized to support recovery.¹⁶⁸ To raise the chances for a LiS patient to return home, the involvement of relatives in rehabilitation should be considered.²⁴

Furthermore, psychological and psychiatric support and treatment is essential. Although the depression rate among LiS patients is lower than many would expect, if present, it must be treated adequately.¹⁶⁹ Offering coping strategies to patients who have difficulties in adapting to the new situation are essential.¹⁶⁹ Hallucinations and delusions are another most likely underreported symptom of LiS patients, which often improves when the patient is repeatedly informed about the illusory nature.¹¹⁰

The rehabilitation of LiS patients with cognitive impairments is still a complex problem,¹⁴³ and also patients who suffer from the LiPS syndrome need special treatment adapted to their level of functioning. Assessing cognitive functions is important to improve communication,¹⁴⁴ evaluate the possible usage of different communication devices¹⁷⁰ and to assess the patients decision-making capacity.¹⁷¹ Tasks like complex sentence comprehension, mental calculation and problem solving are often impaired.¹⁷² Motor imagery^173,174 and the recognition of negative facial expressions¹⁷⁵ can also be disturbed in LiS patients. Specific rehabilitation can benefit selected patients with cognitive deficits.¹⁷⁶ Complicating factors like central deafness also have to be considered when evaluating a patient to avoid underestimating the patient’s capacity.¹⁷⁷ Nevertheless, even after years in LiS, patients can show preserved cognitive abilities.^178–180

An ophthalmologic examination is recommended as visual function is frequently impaired in LiS patients, and appropriate treatment can improve comfort and communication.¹⁸¹ If a patient suffers from opsoclonus-myoclonus syndrome, gabapentin can ameliorate the symptoms and enable communication through eye movements.^182,183 In cases of corneal ulceration due to impaired eye closure, lateral tarsorrhaphy or botulinum therapy is indicated.¹⁶⁴ Pathological laughing and crying, which are not symptoms of a mood disorder, do not respond to pharmacological treatment and should be treated with a cognitive-behaviour approach.¹⁸⁴ Intrathecal baclofen is used frequently to treat spasticity in LiS patients and has also the potential to increase the motor recovery.^185,186 Other specific interventions that were proposed were occupational therapy in combination with new technologies, treadmill therapy and repetitive sensor motor training.^164,187 The improvement of feeding motivation and oral intake in one LiS patient treated with transcranial direct current stimulation of the prefrontal area suggests the usefulness of this application.¹⁸⁸ Moreover, spinal cord stimulation was also suggested for LiS patients.¹⁸⁹ Bispectral monitoring was used to assess postoperative analgesia in a LiS patient.¹⁹⁰

Brain computer interfaces (BCIs) and other technical support systems are also highly important in the care of LiS patients.¹⁶⁴ EEG is the most commonly used method in BCIs, and the control signals are either evoked, spontaneous or hybrid.¹⁹¹ Especially patients with less residual movements possibilities consider the use of BCIs, the most important application being direct personal communication.¹⁹² In one survey, 63% of patients used high-tech assistive devices as their main way of communication.¹⁹ Personalized BCIs¹⁹³ and even controlling a humanoid robot¹⁹⁴ or exoskeleton¹⁹⁵ with BCI are investigated. However, BCIs have some usability challenges as a lot of time is needed for training, the usage can be very fatiguing and restricted to special settings.¹⁹¹ Moreover, motor impairments were associated with difficulties in motor imagery, which could cause problems with some BCI applications,¹⁹⁶ and even in healthy individuals, motor imagery caused significant power changes in EEG only in half of the sample.¹⁹⁷ It was shown in spinal cord injury patients that brain activity can change after injury which might interfere with BCI application designed for healthy brains and not the individually altered brains.¹⁹⁸ Nevertheless, progress in BCI technology is rapidly advancing and promises advantages for many patients.^199,200

Follow-ups and re-assessments should be done periodically as new technologies are constantly emerging and to adapt and improve the current treatment and care of a LiS patient.¹⁷⁰ As one study stated, nearly half of the patients included did not receive any kind of treatment,²⁰¹ which indicates that the full potential of recovery might often be missed. Studies found that areas of unfulfilled needs especially concerned the fields of information, respect and specialized technical aids.^202,203 Finally, treatment must not be withhold, but should be as vigorous as for other patients.¹⁴⁰

Quality of life, ethical considerations and future perspectives

Respect for inherent dignity, individual autonomy; non-discrimination; full and effective participation and inclusion in society; respect for difference and acceptance of persons with disabilities; right to life²⁰⁴

These are core principles of the United Nations Convention on the Rights of Persons with Disabilities. However, LiS patients often find these rights violated, for instance, when being considered ‘a vegetable’ by people surrounding them, including health care professionals.²⁰⁵ As Johansson explains, LiS patients must not be defined by their impairments but instead seen as individuals.²⁰⁵

A survey in chronic LiS patients showed that 72% reported happiness and 28% unhappiness. The wish for euthanasia was only expressed by 7% and a longer time in LiS was associated with happiness.²⁰⁶ One evaluation found no significant difference in quality of life in LiS patients versus healthy controls, although LiS patients experienced depressive symptoms more frequently.²⁰⁷ Interviews with LiS patients suffering from late-stage amyotrophic lateral sclerosis showed positive quality of life in the majority of cases and no regret choosing life-sustaining techniques. Moreover, caregivers underestimate the well-being of patients.⁹⁵ After over a decade living with LiS, seven patients expressed satisfaction with life and five patients reported being depressed occasionally.²⁰⁸ Many studies report a satisfactory and stable quality of life in most LiS patients.^203,209 A study including patients suffering from Parkinson’s disease came to the conclusion that life satisfaction is possible when the diagnosis and disability is accepted and an adaption to the new life situation takes place as then, patients focus more on their abilities and possibilities than on their limitations.²¹⁰ In terminally ill patients, time and certainty about prognosis helped to adapt and accept the disease which improved those patient’s lives.²¹¹ In epilepsy patients, a significant contribution of acceptance of disability to quality of live was determined.²¹² People without disability, even medical professionals, may underestimate the ability of patients of finding contentment in their new live situation. In 1987, Pearce described LiS as ‘conscious hell’.²¹³ It is important to dismantle the negative view most people have on life with LiS as not only advanced directives are influenced by them, but also treatments and advice given by medical professionals.²⁰⁵ A European survey showed that 24% of medical professionals including physicians thought that treatment can be withdrawn in LiS patients, and only 42% wanted to be kept alive if in a LiS themselves.²¹⁴ Moreover, over 90% of German neurologists would consider limiting life-sustaining treatment for LiS patients under certain circumstances in one survey.²¹⁵ A Chinese survey on the other hand showed a much greater proportion of people who would want to be kept alive in LiS, most likely because stopping life-sustaining treatment is less accepted and the topic of death mostly avoided in eastern cultures.²¹⁶ In any case it is important to allow the patient and family enough time to adjust and understand the situation before end-of-life discussions are deepened.²¹⁷

Another topic that has to be addressed is the diagnostic delay and misdiagnosis. On average, it takes more than 2 months to diagnose LiS and only in a quarter of cases the physician is the first to realize that the patient is conscious.²⁰¹ Although the study was conducted in 2002 and diagnostics and awareness may have improved since then, the importance cannot be overestimated, as the isolation resulting from misdiagnosis is devastating. Extreme cases where patients are misdiagnosed over many years have been reported.²¹⁸ One review comes to the conclusion that good interprofessional coordination and a patient-centred approach can reduce the diagnostic delay and improve a patient’s outcome.²¹⁹ A standardized diagnostic procedure was also proposed which should include at least some functional tests which involve active instructions.²²⁰ Especially in patients where typical LiS imaging findings may be missing (e.g. traumatic cases), continuous evaluation including neurophysiological tests should be performed.²²¹ New diagnostic tools are currently developed.²²²

Lack of knowledge is another factor, which can aggravate the life of LiS patients. In a European survey, 9% of medical professionals denied that LiS patients are able to feel pain.²¹⁴ In another survey among German neurologists even 14% denied pain perception in LiS patients and 30% thought LiS patients have no capability to express desires.²¹⁵ These misconceptions can have major impact on the treatment and care LiS patients receive. In a French survey, half of all participating LiS patients reported experiencing pain, most often in the lower limbs and half of them did not communicate the pain to others.²²³

Furthermore, Johansson argues that we have a moral obligation to invest in research on BCIs (and other communication devices) as for many LiS patients those are the only way to communicate and exercise their basic human rights.²⁰⁵ Different methods and improvements are investigated, especially for complete LiS patients.^224–242 However, it is important to follow a user-centred design approach as the opinions on which mental strategies to use differed between patients and researchers.²⁴³ Moreover, one study suggests that semantic processing can change in complete LiS patients, which could affect brain computer interface performance.²⁴⁴ Access to the technologies is another unsolved problem.²⁴¹

The ability to communicate not only improves the quality of life of the patient, but also their caregivers’ life.²⁴⁵ Caregivers of LiS patients rate the need for information, including information on possibilities for communication, as the most important; they often experience feelings of anxiety and depression, and the need for emotional support is frequently not met.²⁴⁶

The importance of respecting the patients’ autonomy, supporting their right to live and allowing the patient to participate in treatment decisions (and therefore determining his or her decision-making capacity) have to be stressed.¹⁷¹ Cases of requested euthanasia²⁴⁷ or withdrawal of invasive ventilation²⁴⁸ in LiS patients have been reported, a subject of controversial discussion.²⁴⁹ Decisions and wishes of LiS patients need to be taken seriously, but better information about their options without prejudices or bias and coping strategies if they fail to adapt need to be provided.¹⁶⁹ LiS patients themselves report being talked to as if they were small children,²⁵⁰ experiencing others talking about their treatment, prognosis and end-of-life decisions without being involved and how extremely negative most doctors and specialists are.²⁵¹ All participants of another study report experiencing disrespectful treatment and people talking over their heads.²⁰²

As Laureys et al.¹⁴⁰ conclude,

Patients suffering from LIS 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.

Conclusion

LiS is a very rare condition, and research papers on the topic are sparse. Most literature that does exist are case reviews, and well-designed, high-quality papers are needed. Moreover, this review has several limitations as only one database was used for the literature search, non-English literature was excluded and no systematic review was conducted. Nevertheless, it is clear that life with LiS can be worth living, meaningful and even happy and therefore should be supported. Knowledge about differential diagnostics and the different types of LiS is essential to provide the right treatment. Treatment should be early, interdisciplinary and rigorous, and psychological support and coping strategies must be provided. Negative views about life in LiS have to be revised; communication with the patient and his or her wishes and needs should be the top priority. New technological and research advances start to enable LiS patients a life that is not locked-in but involves participation in society, being included and live with dignity. Nevertheless, a lot of research still needs to be done and must be pursued to improve the quality of life of LiS patients.

Footnotes

Acknowledgements

Not applicable.

Declarations

ORCID iD

Laura Schnetzer

References

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Locked-in syndrome revisited

Abstract

Keywords

Introduction

Methods

Causes of locked-in syndrome

Pathophysiology of motor impairment in locked-in syndrome

Differential diagnosis

Impairment of consciousness in locked-in plus syndrome

Treatment

Quality of life, ethical considerations and future perspectives

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References