locked-in syndrome

Locked in syndrome

Locked-in syndrome also known as pseudocoma, de-efferented state or cerebromedullospinal disconnection, is a rare neurological disorder in which patients who are awake and conscious but there is complete paralysis of all voluntary muscles except for the ones that control the movements of the eyes 1). Individuals with locked-in syndrome are conscious and awake, but have no ability to produce movements (outside of eye movement) or to speak (aphonia). Cognitive function is usually unaffected. Communication is possible through eye movements or blinking. Locked-in syndrome is caused by damaged to the ventral part of the pons (most frequently an ischemic pontine lesion), a part of the brainstem that contains nerve fibers that relay information to other areas of the brain 2). Additional conditions that can cause locked-in syndrome include infection in certain portions of the brain, tumous, loss of the protective insulation (myelin) that surrounds nerve cells (myelinolysis), inflammation of the nerves (polymyositis), and certain disorders such as amyotrophic lateral sclerosis (ALS) 3).

It is of vital importance to accurately test and assess the cognitive abilities of all patients in disorders of consciousness using one of the recognized batteries of evaluation such as the Coma Recovery Scale-Revised (CRS-R). Time and patience are of the utmost importance in evaluating a patient as it is extremely tiring for them to attempt to respond with, in many cases, only eye movement or blinking 4).

Locked-in syndrome was defined by Plum and Posner in 1966 as a condition in which selective supramotor de-efferentiation produces paralysis of all four limbs and the lower cranial nerves without interfering with consciousness 5). The patients are “locked” in their body, and their only possibility of communicating is to use vertical eye movements and blinking 6).

The American Congress of Rehabilitation Medicine in 1995 7) defines locked-in syndrome as a syndrome characterized by preserved awareness, relatively intact cognitive functions, and by the ability to communicate while being paralysed and voiceless. The American Congress of Rehabilitation Medicine 8) recommends neurobehavioral criteria to be used when diagnosing locked-in syndrome. The criteria are (1) eye opening well sustained, (2) basic cognitive abilities preserved (clinical examination), (3) severe hypophonia or aphonia (loss of voice) on clinical examination, (4) quadriplegia/quadriparesis on clinical examination and (5) communication primarily through eye movements or through blinking.

Locked-in syndrome can be divided into three categories depending on the extent of motor impairment 9):

  1. Classical locked-in syndrome refers to Plum and Posner’s definition of patients with total immobility except for vertical eye movements and blinking;
  2. Incomplete Locked-in syndrome refers to patients with preserved voluntary movements, other than vertical eye movements and blinking;
  3. Total Locked-in syndrome refers to patients with total immobility including all eye movements.

People with locked-in syndrome often remain comatose for some days or weeks, needing artificial respiration and then gradually wake up, but remaining paralyzed and voiceless, superficially resembling patients in a vegetative state or akinetic mutism. In acute locked-in syndrome, eye-coded communication and evaluation of cognitive and emotional functioning is very limited because vigilance is fluctuating and eye movements may be inconsistent, very small, and easily exhausted. It has been shown that more than half of the time it is the family and not the physician who first realized that the patient was aware. Distressingly, recent studies reported that the diagnosis of locked-in syndrome on average takes over 2.5 months. In some cases it took 4-6 years before aware and sensitive patients, locked in an immobile body, were recognized as being conscious. Once a locked-in syndrome patient becomes medically stable, and given appropriate medical care, life expectancy increases to several decades. Even if the chances of good motor recovery are very limited, existing eye-controlled, computer-based communication technology currently allow the patient to control his environment, use a word processor coupled to a speech synthesizer, and access the worldwide net. Healthy individuals and medical professionals sometimes assume that the quality of life of an locked-in syndrome patient is so poor that it is not worth living. On the contrary, chronic locked-in syndrome patients typically self-report meaningful quality of life and their demand for euthanasia is surprisingly infrequent. 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. In our opinion, there is an urgent need for a renewed ethical and medicolegal framework for our care of locked-in patients.

Locked-in syndrome is a rare neurological disorder that affects males and females in equal numbers. Locked-in syndrome can affect individuals of all ages including children, but most often is seen in adults who are more at risk for brain stroke and bleeding. Because cases of locked-in syndrome may go unrecognized or misdiagnosed, it is difficult to determine the actual number of individuals who have had the disorder in the general population.

The view on prognosis of locked-in syndrome has shifted a lot through the years. When locked-in syndrome first became a subject of study, the opinion was that acute mortality was high 10), with nearly no long-term survivors 11). Since then opinion has shifted, the numbers on mortality still vary between studies but the overall view on survival is more positive. If the patient medically stabilises and survives the first year, 5-year survival may be up to 81%–86% 12) and some patients survive for decades 13).

Patients with chronic locked-in syndrome often continue to have highly impaired motor function, even if some improvement is possible 14). Among other things, the impairments lead to them becoming dependent in the activities of daily living (ADL) (self-care, etc). Tetraplegia, along with impairments in breathing patterns, also means that respiratory complications are common 15). Most patients living with locked-in syndrome learn to communicate in some way 16).

Locked-in syndrome causes

Locked-in syndrome is usually secondary to a bilateral ventral pontine lesion or more rarely a mesencephalic lesion 17). The most frequent cause is vascular, either lack of blood flow (ischemia or infarct) or bleeding (hemorrhage) – less frequently it can be caused by trauma 18). An infarct can be caused by several different conditions such as a blood clot (thrombosis) or stroke. Additional conditions that can cause locked-in syndrome include infection in certain portions of the brain, tumors, loss of the protective insulation (myelin) that surrounds nerve cells (myelinolysis), inflammation of the nerves (polymyositis), and certain disorders such as amyotrophic lateral sclerosis (ALS) 19).

Neuropathological studies of autopsied cases have helped to understand the pathophysiology of the locked-in syndrome 20). Preserved consciousness depends on the sparing of specific cortical areas such as the frontoparietal network and the thalamocortical pathways 21). Disruption of corticospinal and corticobulbar tracts for the nuclei of lower cranial nerves during their course through the ventral part of the pons induces quadriplegia and paralysis of the lower cranial nerves. Lateral eye movements are generally impossible due to damage to either the lateral gaze centre (adjacent to the nucleus of the abducens nerve) or its connexions with the cortex. However, vertical eye movements are spared because the vertical gaze center is located in or just above the superior colliculi. Finally, locked-in syndrome patients usually have partially preserved cutaneous sensation. The medial lemniscus located on the dorsal side of the pyramidal tracts is usually disrupted, but the more laterally located spinothalamic tract is generally spared.

Cognitive functions in locked-in syndrome survivors have been explored by few neuropsychological studies. Very recent investigations 22) in locked-in syndrome patients have highlighted moderate and selective cognitive impairments, some of which seem to be related to supratentorial cortical involvement.

Locked-in syndrome symptoms

Individuals with locked-in syndrome classically cannot consciously or voluntarily chew, swallow, breathe, speak, or produce any movements other than those involving the eyes or eyelids. Some affected individuals can move their eyes up and down (vertically), but not side-to-side (horizontally). Affected individuals are bedridden and completely reliant on caregivers. Despite physical paralysis, cognitive function is unaffected.

Individuals with locked-in syndrome are fully alert and aware of their environment. They can hear, see and have preserved sleep-wake cycles. Affected individuals can communicate through purposeful movements of their eyes or blinking or both. They can comprehend people talking or reading to them.

Individuals with locked-in syndrome often initially are comatose before gradually regaining consciousness, but remain paralyzed and unable to speak.

Clinical forms

The locked-in syndrome may be classified in three different clinical forms, according to the traditional classification of Bauer. This classification is based on the amount of motor outputs, which are preserved in the patients. It talks about a pure form when the patient loses the control of all body movements with the exception of blinking and vertical eye movements; an incomplete form when some voluntary movements other than eye movements are preserved and a total form when a complete loss of motor function occurs. The last condition is particularly dramatic as the patients are completely unable to interact with the environment and to express their needs and thoughts.

Quality of life

Although the locked-in syndrome appears as the most dramatic form of motor disability one can imagine, some scientific reports indicate that the quality of life of patients is not so poor as expected. A recent survey investigated the self-reported quality of life of chronic patients with locked-in syndrome and concluded that many patients have a happy and meaningful life, especially when proper social services help patients to have a normal role at home as well as in the community.

Additional symptoms under investigation

Patients with locked-in syndrome are traditionally considered cognitively intact as all the cerebral structures with the exception of the ventral portion of the pons of the brain are apparently preserved. However, recent evidence suggests that the patients can develop some non-motor symptoms including motor imagery defects, pathological laughter and crying, and difficulties in the recognition of some facial expressions. The interruption of the cortico-ponto-cerebellar pathways, by means of the the same lesion causing the locked-in syndrome, may be responsible for the appearance of these clinical manifestations. However, these symptoms are not detected in all affected individuals and are currently under further investigation. The recognition of motor imagery defects deserves special attention because these symptoms, whenever present, may interfere with the success of rehabilitation strategies.

Locked-in syndrome diagnosis

A diagnosis of locked-in syndrome is usually made clinically. A variety of tests may be performed to rule out other conditions. Such tests include magnetic resonance imaging (MRI), which shows the damage to the pons, and magnetic resonance angiography, which can show the blood clot in the arteries of the brainstem. These tests can also rule out damage elsewhere in the brain.

An electroencephalogram (EEG), a test that measures the electrical activity of the brain, may reveal normal brain activity and sleep-wake cycles in individuals with locked-in syndrome.

Evoked potentials, tests that average the EEG signal in response to stimulation (pain or auditory or visual), permit a look at the damaged responses in the brainstem and the preserved responses in the brain.

Electromyography and nerve conduction study can be used to rule out damage to the muscles and nerves.

An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues such as the brain. MR angiography uses a magnetic field and radio waves to produce cross-sectional images of blood vessels inside the body.

An electromyography is a test that records electrical activity in the skeletal (voluntary) muscles at rest and during muscle contraction.
Nerve conduction study determines the ability of specific nerves to relay nerve impulses to the muscles.

Locked-in syndrome treatment

Treatment should first be aimed at the underlying cause of the locked-in syndrome. For example, reversal of a basilar artery blood clot (thrombosis) with intra-arterial thrombolytic therapy may be attempted up to six hours after symptoms onset. Tumors may be treated with intravenous steroids or radiation.

Affected individuals often need an artificial aid for breathing and will have a tracheotomy (a tube going in the airway via a small hole in the throat) in the beginning.

Feeding and drinking will not be possible via the mouth (it may cause respiratory infection by running into the lungs rather than stomach) and hence will need to be assured via a small tube inserted in the stomach called gastrostomy.

Tracheostomy, mechanical ventilation, cardiac failure, chronic obstructive pulmonary disease, uncontrolled emotional lability, improper positioning during feeding, undernutrition or dehydration are factors that may lead the healthcare team to remain cautious regarding feeding through the mouth.

It is important to establish an eye-coded communication as soon as possible. It is essential that locked-in syndrome patients play an active role in decision-making processes regarding their rehabilitation. Healthcare providers and family and friends should try to find out what is the easiest code for the affected individual and consequently all use the same code. This can be ‘look up’ for ‘yes’ and ‘look down’ for no or whatever is the easiest movement for the specific case. Communication is then limited to closed yes-no questions and can next be replaced by eye-coded letter spellers such as saying the alphabet and having the affected individual look down to choose her or his letter. There are many variations on this way of communication presenting the letters in frequency of use in the English language or using letter boards with different columns and lines for vowels and consonants for example.

Next, treatment should be aimed at the early rehabilitation of the small voluntary movements that remain or recover (often in a finger or foot or swallowing and sound production). Rehabilitation and various supportive therapies are very beneficial and should be started as early as possible even if it needs to be stressed that recovery of near-normal motor control, speaking, swallowing and walking are extremely unusual.

Devices to aid in communication and other assistive technologies have proven beneficial as well as allowing individuals to become active members of society. Infrared eye tracking devices now permit affected individuals to use a computer with artificial voice, control their environment, surf on the internet and send email. In rare cases, some individuals have recovered limited motor abilities, however, in most people such recovery does not occur. Those who recover some motor control in hand or head (as will over half of the patients) can use this to communicate with a computer and sometimes control their wheelchair.

Recent studies and articles in the medical literature have noted that despite significant motor disability affected individuals can retain a good quality of life. In addition, quality of life is unrelated to the degree of physical impairment. With advances in care and assistive technologies, individuals with locked-in syndrome can become productive members of society.

Investigational therapies

Stem cell therapy has no proven benefit for individuals with locked-in syndrome and can be harmful. It should not be proposed except in case of research protocols where participants don’t pay for the treatment.

Locked-in syndrome prognosis

According to the International Encyclopedia of Rehabilitation and researchers, recovery of horizontal eye movements prior to the first four weeks is associated with a good neurological prognosis 23). Recovery of the oral-motor area (speech and swallowing) begins later and spreads over a longer period as does recovery of movement in distal parts of limbs of individuals.

The great majority of patients are weaned from their tracheostomy during the first months with one third able to utter isolated comprehensible words after the first year (Casanova et al., 2003). During inpatient rehabilitation, more than 50% of individuals start feeding orally and their gastrostomy is removed during the first year.

Devices to aid in communication and other assistive technologies have proven beneficial as well as allowing individuals to become active members of society (see Further Information section below). Infrared eye tracking devices now permit affected individuals to use a computer with artificial voice, control their environment, surf on the internet and send email. In rare cases, some individuals have recovered limited motor abilities, however, in most cases such recovery does not occur. Those who recover some motor control in hand or head (as will over half of LiS patients) can use this to communicate with a computer and sometimes control their wheelchair.

Recent studies have noted that despite significant motor disability affected individuals can and often do retain a good quality of life.

Level of independence is directly related to motor recovery. The majority of locked-in syndrome patients can move around independently, most often in powered wheelchair. However very few reach a level of motor recovery enabling them to feed and perform activities of daily living on their own 24). Even after several years, spasticity often remains a significant problem for many. Of note, individuals with locked-in syndrome usually do not suffer from a pain syndrome during the chronic phase.

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