Locked-in Syndrome

Etiology

Locked-in syndrome is caused by any lesion affecting the ventral pons, and midbrain; this includes vascular lesions, masses, infections, traumas, and demyelinating disorders.

Vascular

The most common cause is a vascular complication in the form of a hemorrhagic or ischemic stroke. A study by Patterson and Brabois (1986) reviewed a total of 139 cases of locked-in syndrome between 1959-1983 and divided cases into vascular and nonvascular causes.[4] In a total of 139 cases,105 cases had insults caused by vascular etiology, while 34 cases were from nonvascular events. A history of hypertension was present in 43 cases, all of whom were in the vascular group—additional medical history includes 8 cases with atherosclerotic disease and 5 cases with atrial fibrillation. A survey conducted by the Association of Locked-in Syndrome of France (ALIS), which obtained information from 44 people diagnosed with LIS, had similar results with a total of 86.4% of participants listing stroke as the causative agent of their condition.

Trauma

Traumatic brain injury has been reported as the second-largest cause of LIS after vascular etiologies.[1][5] Posttraumatic LIS has been reported from either blunt or penetrating trauma leading to either a tear or thrombotic occlusion of the vertebrobasilar artery blood supply.[6][7][8][9] Only one case reported a post-traumatic LIS with no direct physical damage to the brainstem. In this case, the patient had developed a post-traumatic ventral pontomedullary contusion after the incident resulting in a pressure impingement of the brainstem.[10]

Mass

Masses affecting the ventral pons or caudal ventral midbrain can precipitate the locked-in syndrome. Fibrillary astrocytoma, pontine reticulum cell sarcoma, metastasis from an adenocarcinoma of the lung, and metastasis from a malignant melanoma have previously been reported in the literature as precipitating causes.[4][11]

Infection

Infection is a rare cause of LIS with a limited amount of cases published in the literature. One case reports a LIS stemming from a Pseudomonas predominant pontine abscess.[12] Two reports of meningitis have been reported. One of which involved the adjacent spread from a brainstem abscess, the other involving severe meningitis causing an increase in intracranial pressure leading to transmitted pressure to brainstem structures.[13][14]

Demyelination

LIS can be caused by metabolic demyelination, most notably from central pontine myelinolysis, which is a result of the rapid correction of hyponatremia.[15] Although very rare, LIS has been reported in severe cases of demyelinating diseases such as multiple sclerosis (MS), Guillain-Barre syndrome, and amyotrophic lateral sclerosis (ALS).[16][17][18][19]

Epidemiology

The mean age of onset for all cases of the locked-in syndrome has generally ranged from 30-50 years. The condition is slightly male predominant. In the ALIS study, amongst men and women who received LIS from vascular and nonvascular agents, both groups were affected equally: 51.2% of men diagnosed vs. 48.1% of women diagnosed.[5] The age of onset in this study was between 22 and 77 years of age, with a mean age of 46.79 years. Other retrospective studies had similar results with, on average, more males being affected and mean ages ranging from 33 to 45 years for both vascular and nonvascular causes.[20][21][22] Many patients with LIS from a vascular etiology had comorbid conditions such as hypertension, atherosclerosis of major arteries, and diabetes.[4]

Pathophysiology

Locked-in syndrome is precipitated by any lesion affecting the ventral pons or the caudal ventral midbrain while the integrity of the cerebrum remains intact.

The nucleus of the 3rd cranial nerve lies ventromedial in the midbrain near the cerebral aqueduct. Tracts project anteriorly from this nucleus to innervate muscles of the eye. Pupillary reflex mediated by parasympathetic nerves that travel on the 3rd cranial nerve distally may be variably conserved in episodes of ischemia.[23] Lesions of the ventromedial midbrain will affect the nucleus of this nerve, which may cause complete locked-in syndrome.

Cranial nerves 4 and cranial nerve 6, which control downward eye movement via the superior oblique muscles and the abduction of the eyes via the lateral rectus muscles respectively, may be affected in a ventral pons lesion.

The corticobulbar tracts passing through the midbrain and pons contain upper motor neurons for cranial nerves 5, 7, 9, 10, 11, and 12. The pontine respiratory group located in the pons tegmentum could be affected in large lesions leading to signs of apnea and respiratory distress. The reticular activating system, which lies dorsally, is responsible for wakefulness and is not damaged by such ventral lesions.

The corticospinal and spinothalamic tracts mediate limb and truncal motor and sensory functions. Both of these tracts travel through the crus cerebri of the midbrain and ventral pons and will subsequently be affected by a ventral brainstem lesion.

The ventral pons is supplied by the basilar artery, which is fed by two vertebral arteries. Any abnormalities of these arteries can present with signs of locked-in syndrome. The presentation may vary on a case-to-case basis due to the nature of the causative agent, which makes a correct initial diagnosis difficult.

History and Physical

Locked-in syndrome may have a variety of presenting symptoms. The three-tier categorization of the forms of LIS (classical, incomplete, and total immobility) made by Bauer (1979) presents a basic framework in elucidating patient presentation given the severity of the condition. Many common symptoms of the locked-in syndrome are a function of  the disruption of the neuronal tracts that pass through the ventral brainstem:  

• Functions lost
• Paralysis of the voluntary muscles of the limbs and torso
• Bulbar palsy including anarthria and dysphagia
• Difficulty with voluntary breathing, apnea, ataxia, hyperpnea[4] 
• Dizziness
• Vertigo
• Functions retained 
• Retention of consciousness, language comprehension, orientation
• Retention of hearing
• Vertical eye movement and blinking ability

History

Providers should be steadfast in obtaining interviews from surrounding family members. It is imperative to evaluate the symptom onset and whether there have been fluctuations or progress of symptoms over time. Acute symptom onset should suggest a rapidly progressing etiology, such as in the case of strokes, trauma, or metabolic demyelination.[4] Subacute symptom onset will be consistent with infectious etiologies, pontine contusions, or Guillain-Barre syndrome if the loss of motor function follows an ascending pattern with concurrent functional respiratory failure.[4][18] Chronic recurrent symptoms, especially in those with relapsing sensorineural deficits, will be consistent with an autoimmune demyelinating condition.[16][17][19] Prodromal and current symptoms consistent with an infectious etiology such as fevers, chills, malaise, headache, neck stiffness, and photophobia should be evaluated in cases of suspected meningitis or abscess. History of violent accidents such as motor vehicle accidents should be probed to be able to rule in or rule out trauma and promptly stabilize the patient and mitigate ongoing damage.

Physical Exam

Patients with the locked-in syndrome may either have a causative agent that primarily affects the brainstem or diffusely affects the CNS.

The physical and neurologic examination of cranial nerves can show impairment of the horizontal eye movement and sparing of the vertical eye movements. There is also the involvement of cranial nerves 5, 7, 9, 10, 11, and 12, which presents as a bilateral sensory deficit to the face, bilateral peripheral facial palsy, absent gag reflex, weak tongue movement, and neck weakness. Hearing is often preserved in LIS; however, patients often do not have the means to communicate due to the paralysis. In this case, hearing and the integrity of the cranial nerve 8 may be tested by a patient's response to verbal communication with vertical eye motions in the form of  "yes and no" responses. Both the pupillary reflex and the vestibulocochlear reflex may be preserved in LIS.[23][24]

Testing of motor strength, sensory deficits, and reflexes should all be done to localize the site of the lesion as well as to monitor for progress or improvement. Locked-in syndrome presents with bilateral weakness and sensory deficits that may be variable. Complete quadriplegia is reported in almost all patients, while proprioception, light touch, temperature, pain sensation is greatly decreased if not completely diminished. Examination of the reflexes can point to an upper motor neuron involvement like in hyperreflexia or of lower motor neuron involvement in hyporeflexia or areflexia. A positive Babinski reflex indicates corticospinal damage, usually located in ventral structures of the brainstem.

It is important to note that patients suffering from a brainstem stroke or large brainstem lesions may initially fall into a comatose state. From here, it may take weeks before the patient transitions into a locked-in state, or a member of the practicing team successfully identifies intact cognition and sudden movement. According to León-Carrión et al. (2002), the average time to diagnosis was two months after the onset of the inciting event.[5] The diagnosis is often confused with other similar conditions such as akinetic mutism and persistent vegetative states.

The early recognition of the symptoms of LIS may mitigate the considerable lag time between injury onset and the time of formal diagnosis. Serial monitoring of patients should be standard, assessment of alertness by eye movement, spontaneous or voluntary limb movements, withdrawal to noxious stimuli, and reflexes.[25] Patients who are emerging from a comatose state require special attention, daily assessment of visual tracking, eye movements, and eye blinking in response to the caregiver is especially important. León-Carrión et al. (2002) demonstrated that in over half of the cases examined in his review, the first individual to indicate that the patient could generate spontaneous voluntary movement was a family member.[5] Providers should, therefore, attempt to retrieve any bedside information from family to make sure minor improvements are not missed.

Evaluation

Imaging Studies

Brain imaging by CT or MRI is the most valuable modality used in the diagnosis of locked-in syndrome. The addition of CT or MR angiography can show vascular lesions causing the syndrome in cases of stroke or arterial dissection. The addition of contrast medium can delineate masses like tumors or abscesses and even active demyelinating lesions.

Laboratory Examinations

The cerebrospinal fluid examination (CSF) is usually necessary if no mass or vascular lesion is present on imaging. Results of the CSF analysis may reveal an infectious or autoimmune cause of the symptoms. The CSF should be sent for differential cell count, protein, glucose, staining, cultures, and CSF protein electrophoresis (IgG oligoclonal bands for MS).[26]

Electrophysiologic Studies

Diagnosis of other demyelinating neuropathies such as ALS or GBS may be made via electromyography and nerve conduction studies, in conjunction with the physical examination.[27]

Additionally, an EEG may be used in patients to evaluate brain activity, sleep-wake cycles, and attention.[3] Language comprehension and orientation may be assessed through infrared eye movement sensors in cases of classical and complete LIS or computer modulated voice prosthetics in cases of incomplete LIS.[20] 

Blood Tests

A metabolic panel should be ordered to evaluate any aberration in the sodium level, which may indicate a potential pontine myelinolysis. A history of rapid sodium correction may point to the cause of demyelination.

Hyponatremia, hypophosphatemia, and hypomagnesemia may cause comas similar to a locked-in state, so such electrolytes should be closely examined.[28] Glucose should be monitored to rule out a hypoglycemic coma.[29] A complete blood count should be done to rule out sepsis as a cause of coma.

Treatment / Management

The removal or reversal of the causative agent primarily treats locked-in syndrome. Initially, acute management of locked-in syndrome should be focused on securing a patent airway, maintaining adequate oxygen saturation levels, and ensuring the patient is stable from a cardiac standpoint using heart rate, blood pressure, and occasionally orthostatic hypotension as predictive markers.

Care is then addressed at treating the precipitating agent. In the event of an ischemic or hemorrhagic stroke, the stroke protocol should be swiftly employed. Prompt thrombolytic therapy has been shown in one case to expedite the recovery process to nearly full recovery in ischemia related to LIS.[30]  

Removal of any precipitating mass should be done in cases of tumors and other mass lesions. Meningitis and abscesses may be treated with broad-spectrum antibiotics.[12][13][14]  (B3)

Treatments for demyelinating diseases are variable. The treatment of LIS from central pontine myelinolysis is focused on supportive measures: gradual correction of sodium abnormalities and close monitoring of respiratory status is imperative. [31] Inflammatory neuropathies may be treated in a somewhat similar fashion. Guillain-Barre syndrome may be treated with IVIG, plasmapheresis, and monitored airway ventilation.[32] Exacerbations of multiple sclerosis may be treated with high-dose glucocorticoids acutely with relapses treated with disease-modifying agents and humanized monoclonal antibodies.[33] ALS may be treated with supportive measures in conjunction with long-term agents riluzole or edaravone to prolong survival.[34]

Subacute and chronic therapy aims at improving the patient's motor functionality months after the onset of the insult. Management at this stage should be based primarily on physical, respiratory, and speech therapy.[21][25] Chest physiotherapy, breathing exercises, positional changes may also be incorporated to maintain adequate cardiovascular and respiratory function.[35] Assisted technology such as infrared eye movement sensors or computer modulated voice prosthetics may be used for speech therapy to improve communication gradually.[20] Communication books outlining thoughts and activities can be beneficial in tracking cognitive recovery as well.[25]

Differential Diagnosis

The diagnosis of locked-in syndrome can often be difficult since the condition shares many features with other mute conditions.

Medical states such as coma, persistent vegetative state, akinetic mutism, and catatonic states are the main confounding conditions.

The differential diagnosis of locked-in syndrome includes:[36][37][38][39]

• Persistent Vegetative State: where patients have preserved eye-opening but no awareness of the self and surroundings, the language comprehension is not intact, there is no voluntary facial or body movements, but respiration is intact.
• Akinetic mutism: there is preserved consciousness, with a decreased motor response (without paralysis), and intact brainstem reflexes. The eye movements are intact; there is the slowness of speech, and greatly diminished ability to produce spontaneous speech.
• Coma: there is impaired consciousness, with no voluntary motor movements. There is a variable ability to maintain respiration and also variably preserved brainstem reflexes.
• Brain death: there is impaired consciousness, with no voluntary motor movements, inability to maintain respiration, and absent brainstem reflexes.
• Catatonia: is often associated with a previous psychogenic history. There is preserved consciousness and brainstem reflexes accompanied by rigidity, mutism, echolalia, and posturing.
• Cervical spinal cord injury: there is a variable to complete quadriplegia (with upper motor neuron signs of hyperreflexia, hypertonicity). The motor functionality to the face is retained, eye movements are intact, as well as consciousness, orientation, and language. The respiration may be variably intact.

Radiography and early physical exams should be used to localize the structures damaged. Loss of facial expressions, dysphagia, lack of neck movement and tone, and lack of the gag reflex indicates a corticobulbar lesion at the ventral structures of the midbrain or pons.

Surdyke et al. (2017) published a case in which a small algorithmic model was used to rule out other related causative agents.[24] First, consciousness, alertness, and ability to communicate were assessed. If this was present, the assessment of cervical cord injury was done via observation of respiration, and assessment of supraspinal muscles. Lastly, an evaluation to rule out akinetic mutism was done. If all three are negative, the suspicion for LIS is high.

Additionally, in a condition as complex as LIS, care should be taken to obtain a thorough history to exclude a potential intoxication. A detailed drug history should examine depressive drugs, anesthetics, and poisons that may temporarily mimic a locked-in state. Curare, a reversible nicotinic acetylcholine receptor inhibitor, has been described as a drug that may cause complete quadriplegia and respiratory failure mimicking a variable form of locked-in syndrome.[40] Prompt stabilization of the patient and a thorough history will help exclude less common causes of the locked-in syndrome to aid in quicker management.

Prognosis

Mortality and recovery are highly variable depending on the underlying cause of the locked-in syndrome. Locked-in syndrome generally has a high mortality rate in the acute setting. Retrospective studies and analysis models have estimated the 5-year and 10-year mortality rates of 84% and 31%, respectively.[20][41] The review by Patterson and Grabios on 139 cases of LIS revealed an overall mortality rate of 60%. Mortality rates for vascular causes of the condition were 67% (70 of 105 patients) versus 41% (14 of 34 patients) for nonvascular cases.[4] Many survivors in this study remained in a state where motor functionality had minimally progressed.

Patterson and Grabois categorized patients into five different groups based on recovery a few months after the onset of their condition:   

• No recovery: patients who exhibited no return of motor function
• Minimum recovery: patients who displayed some voluntary motor return but was fully dependent on others for care
• Moderate recovery: patients who have a noticeable return of motor function, giving them the ability to complete some but not all activates of daily living
• Full recovery: patients who regained the ability to perform all activities of daily living with slight neurological deficits
• No neurological deficit: patients who reported no neurologic deficits

The study demonstrated that more nonvascular cases had moderate to full recovery. A total of 18 out of the 34 patients who suffered from a nonvascular exhibited some return of motor function. Additionally, 12 of the 18 recovery cases experienced a full recovery during the first six months.

In contrast, only 29 of the 105 total vascular patients had developed some form of recovery after the onset of their condition. Of the patients who survived after the initial four months, 13 of 16 showed evidence of moderate to full functional recovery, with only 2 cases experiencing a full recovery.

Complications

Locked-in syndrome has debilitating complications after initial stabilization has been achieved. Aside from the high mortality rate, numerous cases report complete or partial paralysis among survivors.[4][42] One study reports 18 of the 29 cases followed in the review survived, with eleven of the survivors residing in their homes, the others living permanent hospital residents, and in nursing homes. Even for the patients who were sent home, the majority required assistance in activities of daily living. A minority was able to live independently and even take part-time jobs. The same report demonstrated that communication never improved to a high functional level, with many survivors requiring a communication device or computer.[42]

Due to the extended hospital stay of many patients suffering from LIS and frequent inpatient procedures, many patients get multiple nosocomial infections. Long-term intubation has led to the development of pneumonia, and catheterization has lead to the development of urinary tract infections in patients with LIS.[43] Deep vein thrombosis and bedsores are common complications due to the patient's bed-bound state. In one report, only 42% of recovered patients experienced a complete improvement in swallowing, and 50% of recovered patients had difficulty with normal breathing.[21] Both bladder and bowel incontinence have been reported as well in many of these patients in the long term.[21]