Locked-in Syndrome

Locked-in syndrome (LIS) is a rare neurological disorder in which patients are awake and conscious but are unable to move their limbs or speak. The disorder is a result of brain injury to the ventral aspect of the pons and caudal ventral midbrain; etiologies include brainstem stroke, tumors, intracranial bleeding, and demyelinating disorders. Consciousness and the ability to think and reason remain intact, as do the abilities to blink and move the eyes. Diagnosis is made clinically, and the initial management is supportive care for breathing and feeding. Definitive management depends upon the underlying cause and is followed by several months of rehabilitation. Prognosis is generally poor, although some patients are able to achieve significant improvement in some functions.

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Overview

Definition

Locked-in syndrome (LIS) is a rare neurological disorder in which patients are awake and conscious but are unable to move their limbs or speak due to pathology affecting the brainstem.

Classification

  • Classic form: 
    • Total immobility
    • Preserved consciousness as determined via EEG
    • Vertical eye movements intact
  • Incomplete form: classic form with some remaining voluntary movements
  • Total form:
    • Complete loss of motor function
    • Includes the loss of vertical eye movements

Epidemiology

  • Most common cause = ischemic or hemorrhagic stroke
  • Prevalence 0.7/10,000 in one Dutch study of 187 nursing homes
  • Many patients have cardiovascular comorbidities (e.g., hypertension, diabetes).

Etiology

  • Vascular causes:
    • Hemorrhagic or ischemic stroke 
    • Occlusion of the basilar artery
  • Trauma:
    • Brainstem contusion
    • Penetrating trauma
  • Space-occupying masses:
    • Astrocytoma
    • Pontine reticulum cell sarcoma
    • Metastasis from lung cancer or melanoma
  • Infection: pontine abscess
  • Toxins: heroin abuse
  • Demyelination:
    • Osmotic demyelination syndrome (previously called central pontine myelinolysis)
    • ALS
Diagram of cerebellum blood supply

Cerebellar arteries:
Blood supply to the brainstem is shown; a stroke occurring in the pons due to occlusion of the basilar artery pontine branches may result in locked-in syndrome.
SCA: superior cerebellar artery
PICA: posterior inferior cerebellar artery
AICA: anterior inferior cerebellar artery

Image: “Diagram of cerebellum blood supply” by Semiconscious. License: Public Domain

Pathophysiology

Ischemic or hemorrhagic stroke can affect the vulnerable territory at the paramedian base of the pons. The tegmentum (ventral part of the midbrain) has collateral supply that often spares the lateral and medial tegmentum.

  • Damage to the brainstem involves: 
    • Corticospinal and bulbar tracts
    • Abducens nucleus
    • Paramedian pontine reticular formation (PPRF) in the pons 
    • → Spastic quadriplegia: patient unable to move their extremities or face
  • Disruption of the cranial nerves V, VII, IX, X, XI, and XII → neurologic deficits
    • Bilateral sensory deficit to the face → bilateral peripheral facial palsy
    • Absent gag reflex
    • Weak tongue movement
    • Neck weakness
    • Horizontal eye movements impaired
  • The following are preserved/intact: 
    • Consciousness
    • Language comprehension
    • Vertical eye movements
    • Eyelid closure
    • Breathing regulation
    • Wakefulness 
    • Cognition
  • Onset of symptoms
    • Acute onset: suggests vascular or demyelinating etiologies 
    • Subacute onset: infectious etiologies
    • Chronic and recurrent presentations: autoimmune etiology
The brainstem

Anatomy involved in locked-in syndrome

Image: “The brainstem” by Blausen.com staff (2014). License: CC BY 3.0

Clinical Presentation and Diagnosis

Diagnosis of LIS requires demonstration of preserved consciousness, alertness, and cognitive function in a patient with paralysis of the limbs and mouth.

Clinical presentation

Eye movement:

  • Ask the patient to blink or make eye movements as a form of communication.
  • If the patient is fully awake and can communicate, eye movement is used as a code: 
    • Upward movement means yes.
    • Downward movement means no.

Physical exam:

  • Intact neurologic findings:
    • Vertical eye movements 
    • Blinking
    • Alertness and perception of the environment 
  • Deficits:
    • Impaired horizontal eye movement
    • Anarthria and dysphagia (bulbar palsy) → may cause aspiration pneumonia
    • Difficulty with voluntary breathing or apnea: Some patients may be intubated at the time of examination.
    • Quadriplegia
    • Bilateral sensory deficit to the face (cranial nerve V)
    • Bilateral peripheral facial palsy (cranial nerve VII)
    • Absent gag reflex (cranial nerve IX)
    • Neck weakness (cranial nerve XI)
    • Weak tongue movement (cranial nerve XII)

Diagnosis

  • Labs:
    • Electrolytes
    • CBC
    • Serum glucose
    • CSF analysis: if suspected infection
  • Neuroimaging:
    • CT/MRI: contrast to detect masses
    • CT/MRA: to diagnose a vascular cause of LIS
  • Other tests
    • EEG: documents normal sleep-wake cycles; patient is not unconscious 
    • Electrophysiologic studies: if demyelinating neuropathies are considered (e.g., ALS)

Management

Medical treatments to promote recovery from LIS are rehabilitative and supportive therapies.

Initial management

  • Mechanical ventilation, if needed
  • Tracheostomy, if needed
  • Wean off ventilation, if possible.

Supportive management

  • Prevent systemic complications of immobilization:
    • Pressure ulcers
    • Deep vein thrombosis (DVT)
  • Nutritional care
  • PT to prevent limb contractures
  • Emotional support

Rehabilitation

  • PT and speech therapy
  • May require multimodal therapy for months to years 
  • Functional neuromuscular stimulation: 
    • May activate some paralyzed muscles
    • Devices to help communication are available.

Complications

  • Residual complete or partial paralysis
  • Nosocomial infections: ventilator-associated pneumonia (most common)

Prognosis

  • Case studies: recovery from 30 minutes to several weeks after onset (depending on the cause)
  • 60% mortality rate in the first 4 months
  • In nonvascular cases: Intensive rehabilitation measures can help significantly.
  • Most survivors of LIS remain chronically locked in or severely impaired.

Differential Diagnosis

  • Coma/disorders of consciousness: a deep state of unresponsiveness characterized by a score of 3 on the GCS, indicating a lack of response to verbal, tactile, and painful stimuli. The areas of the brain involved are the bifrontal deep gray matter and upper brainstem. As with LIS, patients show minimal responsiveness, but with LIS there is extreme motor entrapment despite preserved awareness. Accurate diagnosis requires neuroimaging to prevent misdiagnosis and appropriate rehabilitative opportunities. Management is based on the underlying cause.
  • Akinetic mutism: a rare neurological condition characterized by severe loss of movement and speech, caused by injury to the prefrontal or premotor cortex, and that has been seen in children with meningitis or brain tumors. Diagnosis is by neuroimaging to detect lesions to the prefrontal or premotor areas. Management includes treating the underlying cause, and medications such as methylphenidate and atomoxetine have been used to increase levels of dopamine and norepinephrine.
  • Guillain-Barré syndrome (GBS): an immune-mediated neuropathy that may occur after bacterial or viral infections. Guillain-Barré syndrome is characterized by acute neuromuscular paralysis that is symmetric and ascending in nature. The syndrome can progress into respiratory failure, which requires prolonged hospitalization. Diagnosis is by history and clinical exam. Management is mostly supportive and may require either plasma exchange or IV immunoglobulin. 
  • Persistent vegetative state: also called “unresponsive wakefulness” and formerly known as “apallic syndrome.” The brainstem and the spinal cord maintain vegetative functions, but higher mental processes are no longer present. Visual fixation is not possible, nor is communication. The cause is traumatic brain injury, surgical brain injury, viral infection, or ischemic stroke leading to diffuse cerebral hemisphere damage. Diagnosis is by exam, lab testing, and imaging. Management is supportive.
  • Catatonia: a psychiatric behavioral syndrome in which patients are unable to move despite having the physical capacity to do so. The underlying psychopathology may be depression, psychosis, or autism spectrum disorder (ASD). Patients are unresponsive to verbal stimuli but are able to maintain body posture. There are no CNS abnormalities found on imaging. Diagnosis can be made in 80% of patients after IV administration of lorazepam. Treatment of the underlying disorder with medications may make the condition worse.

References

  1. Das, JM, Anosike, K, & Asuncion, RMD. (2021). Locked-in syndrome. StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved August 16, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK559026/ 
  2. Caplan, LR. (2020) Locked-in syndrome. UpToDate. Retrieved August 16, 2021, from https://www.uptodate.com/contents/locked-in-syndrome
  3. Genetic and Rare Diseases Information Center (GARD). (2017). Locked-in syndrome. Retrieved August 16, 2021, from https://rarediseases.info.nih.gov/diseases/6919/locked-in-syndrome
  4. Hocker, S, & Wijdicks, EFM. (2015). Recovery from locked-in syndrome. JAMA Neurol. 2015;72(7):832-833. https://pubmed.ncbi.nlm.nih.gov/26167898/
  5. Arnts, H, et al. (2020). On the pathophysiology and treatment of akinetic mutism. Neuroscience and biobehavioral reviews, 112, 270–8. https://doi.org/10.1016/j.neubiorev.2020.02.006
  6. Kohnen, RF, Lavrijsen, JC, Bor, JH, & Koopmans, RT. (2013). The prevalence and characteristics of patients with classic locked-in syndrome in Dutch nursing homes. Journal of neurology, 260(6), 1527–34. https://link.springer.com/article/10.1007%2Fs00415-012-6821-y

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