In this study, the authors from Norway investigated the complexity of the course and outcomes of long-lasting locked-in syndrome (LIS) in a national cohort of patients. They examined the functional status of patients with locked-in syndrome over time. They also investigated the potential importance of different localization of lesions within and outside the brainstem on LIS outcomes.
LIS is caused by ventral pontine lesion. The most common cause of LIS is vascular (typically occurs as an ischemic stroke), while more rare causes include trauma, infection and inflammatory demyelination. The LIS is divided into three categories, based on neurologic deficits and clinical presentation. The term “classic LIS” refers to a neurological condition characterized by quadriplegia and mutism, but intact consciousness and cognitive functions. The patients communicate through eye movements, vertical gazing and/or blinking. In total LIS, patients are unable to communicate through their eyes. For incomplete LIS, various criteria were employed, including voluntary motion beyond vertical gazing and/or blinking, the ability to move any limb against gravity, or the ability to walk a few steps with assistance. However, the patients are completely dependent in activities of daily living (ADL).
About the study
The demographic, medical, and follow-up data for the time period between 2012 and 2022 were obtained from the register of the Norwegian National Unit for Rehabilitation of locked-in syndrome. The register included all patients with LIS as long as they met all the following criteria: severe communication impairment, paralysis or paresis in all 4 extremities, complete dependence in ADL, and normal or close-to-normal cognition. When one or more of the four criteria were no longer met, the patient was not in the LIS state.
A magnetic resonance imaging (MRI) and a computerized tomography (CT) scan were used to determine the localization of brain lesions. Verbal communication, motor function, and dependence in ADL were evaluated during annual follow-up visits using the modified Rankin scale and LIS motor recovery scale. The LIS motor recovery scale by Patterson et al. measures functional motor status in five categories, ranging from “no recovery” to “no neurologic deficit.” The modified Rankin’s scale measures the degree of disability or dependence in ADL.
Results
A population-based sample included 51 patients, and follow-up data were available for 43 of them. The majority of patients were men (n=36), whereas 15 were women. This is consistent with previous research. The median age at onset of LIS was 55.7 years.
The etiology of LIS was ischemic stroke in 35 patients, and hemorrhagic stroke in 14 patients. In one case, hemorrhage in the brainstem occurred after invasive treatment of an ischemic stroke, and in another case, LIS was caused by septic infarction and subsequent hemorrhage. In five cases, stroke was associated with dissection, and in three patients with ongoing infection. Hypertension was the most prevalent risk factor. Three patients had a history of drug abuse. Seven patients were unable to work due to a previous stroke or other chronic illness.
For most of the patients (n = 44), MRI reports were available, and their data were combined with CT scan reports. The findings from the MRI and CT scan revealed numerous combinations of lesions within and outside the brainstem.
Only 10% of the patients had an isolated pontine lesion. The majority of patients (80%) had various lesions outside the brainstem. 39 patients had 1 or more lesions outside the brainstem, most commonly in the cerebellum (n = 30) and occipital lobes (n = 8). 15 patients had only one lesion localized outside the brainstem, and all were localized in the cerebellum. Six patients had primary hemorrhage in the cerebellum or posterior cranial fossa, suggesting that the brainstem lesion may have occurred as a secondary lesion. Cerebellar lesions were found in all patients with dissection. The findings also revealed that LIS can be mesencephalic (n = 3) or due to an isolated injury to the medulla oblongata (n = 3) without any other brainstem lesions. 14% of patients had a primary cerebellar or posterior cranial fossa hemorrhage, which is presumably associated with a secondary injury in the brainstem. That mechanism has been called “pseudo-LIS.”
The functional outcome
Out of 51 patients, 15 died, at a median age of 3.5 years after disease onset. The median age of patients who died was 65.4 years, and they were older at the onset of LIS compared to those who survived. The cumulative survival rates at three, five, and 10-years were 87%, 79%, and 73%, respectively. Of 15 patients who died, three came out of the LIS state before death. 12 patients remained in the LIS state until they died, one patient had classic LIS and 11 had incomplete LIS.
Of the 51 patients, 23 came out of the LIS state (including three patients who came out of the LIS state before their death). 18 patients came out of the LIS state between 6 weeks and 2 years after disease onset. The prevalence of multiple lesions outside the brain stem was significantly lower in patients who came out of the LIS state than in patients who remained in the LIS state.
All but 1 patient achieved some motor improvement. Only three patients achieved complete motor recovery, while 88% of patients had a persistently high level of dependence. Three patients who achieved full motor recovery came out of the LIS state fairly quickly, between 6 weeks and 6 months. However, they had residual neurological deficit and could not return to work.
At the final follow-up, most patients (n = 27) had achieved “minimal recovery” of motor function according to the LIS motor recovery scale, and were fully dependent in ADL. Seven patients were unable to respond verbally, 12 were able to make sound, 16 exhibited dysarthric speech and 8 functional speech without dysarthria.
The authors discussed considerable variation in the literature regarding criteria for the LIS and the complex trajectories of LIS motor outcomes, dependence, and verbal communication.
In summary, this study examined an unselected population-based sample of patients with vascular LIS. Even patients who remained in the LIS state for more than 6 weeks were found to came out of it, most often within 2 years from disease onset. The authors suggested that long-lasting LIS should be considered as a chronic condition with varying courses and outcomes. Although the majority of patients remain severely disabled, even small improvements in function can significantly increase the potential for activity and participation. It seems that additional lesions outside the brainstem are common in long-lasting LIS and may be prognostic for remaining in the LIS state.
The article was published in Neurology.
Journal Reference
Nilsen HW et al. Demographic, Medical, and Clinical Characteristics of a Population-Based Sample of Patients With Long-lasting Locked-In Syndrome. Neurology Sep 2023, 101 (10) e1025-e1035. (Open Access) https://doi.org/10.1212/WNL.0000000000207577