Abstract
We investigated five patients with a locked-in-syndrome (LIS) and reported the clinical, electrophysiologic, neuroradiologic, and neuropathologic findings. EEG reactivity was present in two and absent in three cases. Somatosensory evoked potentials (SEP) varied from unilaterally normal to bilaterally absent. We conclude that there is no specific pattern of SEP abnormality characteristic of LIS and that EEG reactivity cannot be taken as a sole measure of consciousness.
NEUROLOGY 1996;46: 1092-1101
The locked-in-syndrome (LIS) is a state of tetraplegia and lower cranial nerve palsies in which vertical eye movements and blinking are the only means of communication. [1] Consciousness is preserved, but vigilance is often fluctuating, especially in the acute stage. This makes a differentiation from other states of tetraplegia with loss of consciousness such as vegetative state [2] or akinetic mutism [3] often difficult. LIS is most frequently a sequelae of basilar artery thrombosis resulting in a ventral pontine lesion. However, other rare etiologies of LIS include hemorrhage, [4] trauma, [5] tumor, [6] MS, [7] pontine abscess, [8] postinfectious polyneuropathy, [9] Borrelia burgdorferi meningitis, [10] brainstem encephalitis, central pontine myelinolysis, and heroin abuse. [11] LIS may occur, although rarely, from lesions located rostrally of the pons, such as the mesencephalon, [12,13] or in bilateral lesions in the capsula interna. [14]
Electrophysiologic findings in LIS have been a point of debate since the early 1970s. Although most of the reports believe that a reactive alpha EEG is crucial for the diagnosis of LIS, [15-17] there is some evidence that unreactive EEGs can occur in LIS. [18] Somatosensory evoked potentials (SEP), when recorded, show considerable variation in LIS, ranging from fully normal findings [13] to unilateral or bilateral abnormality. [4,19,20]
We report the clinical, electrophysiologic, and neuroradiologic (two cases) and neuropathologic (one case) findings in five cases of LIS of different etiology. For the three surviving patients, a clinical and electrophysiologic long-term follow-up is provided.
Methods.
Conventional 16- or 21-channel EEGs were performed according to the 10-20 system. Reactivity to eye opening and to repeated external auditory (loud click) and pain (nasal septum) stimulation was assessed. It was considered present when a flattening of the tracing occurred and absent if there was no change. [21]
SEP were elicited by median nerve stimulation at the wrist (stimulus rate 3 Hz, duration 0.2 ms). Potentials were recorded from Erb's point, the second cervical vertebra, and from the contralateral frontal (F3, F4 corresponding to the 10-20 system) and parietal (2 cm posterior to the vertex and 7 cm laterally) scalp. All active electrodes were referred to linked earlobes. The filter setting was 3 to 3,000 Hz. Each examination comprised two series of 1,024 trials on each side.
Patient 1.
This 54-year-old woman suffered from a cervical whiplash injury subsequent to a car accident. She was alert initially and had a mild headache. On the following day she complained of nausea, vomited, and was found stuporous a few hours later. On admission, the patient was nonresponsive without spontaneous movements. She was breathing spontaneously. Her tendon reflexes were symmetrical and the plantar responses flexor. Oculocephalic reflexes could not be elicited. The pupils were symmetrically normal, with good reaction to bright light, and corneal reflexes were preserved. Although CT showed no abnormality, an MRI revealed a hyperintense lesion on T2-weighted images, reaching from the upper medulla to the pontomesencephalic area. The upper part of the lesion showed an enhancement on T1-weighted images, corresponding to a subacute infarction thought to be a consequence of the whiplash injury (Figure 1, a through d).
Figure 1. A 54-year-old woman with an ischemic pontomesencephalic lesion that occurred 24 hours after a whiplash injury (MRI performed 3 weeks after injury). (a and b) T2-weighted (2,500/100) axial MRI sections. The lesion extends from the upper medulla (a) (arrows) and involves almost the whole pons (b); only minor parts of the tegmentum are spared (arrows). (c and d) T1-weighted (500/15) midsagittal MRI before (c) and after (d) IV infusion of gadolinium-chelat. The upper part of the lesion in the pons is enhancing and extends up to the middle tegmentum of the mesencephalon.
Two weeks later the patient began to open her eyes on hearing her name, and 4 weeks later a communication via opening and closing of the eyes was possible. In the following 6 months, there was little improvement. The patient remained almost completely tetraplegic with just minimal motor activity in the second and third fingers of the right hand and uncoordinated tongue motility. The patient has remained in this state for 5 years. She requires full hospital care but is able to communicate with a computer using the motor activity of the second and third fingers of her right hand. Mental status examination was normal. Etiology, electrophysiologic findings, and outcome of this and the following cases are summarized in the Table 1.
Table 1. Clinical and electrophysiological features of the 5 patients with a LIS.
Electrophysiologic examination.
The first EEG, recorded 24 hours after admission, showed polymorphous delta slowing with intermittent alpha activity and interspersed K-complexes and sleep spindles. The reactivity to exteroceptive stimuli was preserved Figure 2A. The second and third EEG performed 5 and 10 days after admission showed a completely different pattern, consisting of predominant alpha-theta activity with almost continuous bi- and triphasic waves with a frontal predominance and no reactivity to exteroceptive stimulation Figure 2B. In repeated EEGs 4 and 6 weeks after admission, the bi- and triphasic waves were hardly present and a predominant alpha pattern without reactivity to exteroceptive stimulation appeared, strongly resembling alpha coma Figure 2C.
Figure 2. EEG of the same patient as in Figure 1. (A) Twenty-four hours after admission shows polymorphous delta slowing with preserved reactivity to external stimulation. (B) Five days after admission the predominant EEG frequency is in the alpha-theta range with bi- and triphasic waves over the frontal region without reactivity to external stimulation. (C) Four weeks after admission there is predominant alpha activity still without reactivity to external stimulation.
The first SEP recording was performed 48 hours after admission. Frontal and parietal cortical responses were absent after left median nerve stimulation, whereas after right median nerve stimulation frontal and parietal cortical responses were preserved and central conduction time (CCT) was normal Figure 3. No SEP changes were observed in the first, second, and fourth week after the accident.
Figure 3. SEP of the same patient as in Figure 1and Figure 2. Recordings over Erb's point, over the second cervical vertebra, and over the contralateral parietal (Pc) and frontal (Fc) scalp are shown. Forty-eight hours after admission, the parietal (N20) and frontal responses after right median nerve stimulation are within normal range, whereas after left median nerve stimulation, both frontal and parietal cortical responses are missing.
Patient 2.
This 45-year-old man with a history of hypertension and nicotine abuse suffered from a sudden state of agitation with a rapidly progressive tetraparesis and clouding of consciousness; he was found in deep coma a few hours later. CT and MRI revealed extensive bilateral ischemic lesions in the ventral pons, extending partially into the tegmentum and involving also parts of the cerebellum (Figure 4, a through d). Basilar artery occlusion was assumed to be the cause. During the following days, the patient gradually regained consciousness but remained completely mute and tetraplegic. Opening and closing of the eyes and vertical eye movements remained the only means of communication, typical for the LIS.
Figure 4. MRI of a 45-year-old man with a LIS performed 3 days after an ischemic lesion of the pons presumably due to a basilar artery occlusion. T2-weighted (200/909) axial MR images show a hyperintense lesion, extending from the left upper medulla (a) (asterisk) through almost the whole pons (b and c) to the mesencephalon (d). Only a minor part of the pontine tegmentum is spared (arrows). An additional lesion in the left cerebellar hemisphere can be seen.
One year later, there was almost no clinical improvement. The patient had remained completely mute and tetraplegic, but there was minimal motor activity in the right hand. Communication was possible by vertical eye movements and motor activity in the right thumb, which allowed the patient to use a specially adapted personal computer. We thus were able to perform a detailed mental state examination. The patient was fully oriented, there was no alexia or agraphia, nor were there visuospatial or agnostic disturbances; verbal and figural learning and memory as well as ``frontal lobe functions'' (such as concept identification) were intact. The patient was able to play chess. However, his concentration proved to be fluctuating.
Electrophysiologic examination.
Two EEGs, the first obtained on admission and the second 1 year later, showed a well-modulated alpha activity with preserved reactivity to eye opening and external stimulation. The initial SEP, registrated at the same time as the first EEG, showed distorted low-amplitude frontal and parietal cortical responses after right median nerve stimulation and missing cortical responses after left median nerve stimulation Figure 5. A control examination 1 year later showed no changes.
Figure 5. SEP registrated on admission (same patient as in Figure 4 show distorted low-amplitude frontal and parietal cortical responses after right median nerve stimulation and missing cortical responses after left median nerve stimulation.
Patient 3.
This 74-year-old woman with a history of arterial hypertension, coronary heart disease and a transient left-sided hemiparesis several years previously suffered from sudden vertigo and malaise without neurologic findings. A few hours later, severe vertigo was again present, followed by flaccid tetraplegia and clouding of consciousness. On admission, the patient was stuporous and showed intermittent stretching of the right upper and lower limbs; the plantar response was extensor bilaterally. A ptosis was present on the right side, and pupillary reflexes were normal. Oculocephalic reflex could be elicited only to the right side. Communication was difficult but possible by opening and closing of the eyes. One week later the patient was in a LIS, fully awake, performing vertical eye movements as well as opening and closing the eyes on demand. Detailed mental status examination was not possible, because of fluctuation in attention; however, she could read complex sentences and correctly responded to questions concerning calculation and higher level comprehension. The clinical state remained unchanged until the patient died 2 months later of bronchopneumonia due to aspiration.
Electrophysiologic examination.
An EEG was performed 1 week after admission and showed a poorly modulated alpha-theta activity. Reactivity to painful stimulation was preserved Figure 6A. SEP showed a complete absence of parietal and frontal cortical responses after left median nerve stimulation. After right median nerve stimulation, the parietal cortical response was only hardly distinguishable with a plateau-like distortion, and the frontal response was of very low amplitude Figure 6B.
Figure 6. (A) EEG of a 74-year-old woman with a LIS 1 week after an ischemic lesion of the pons. It shows a poorly modulated alpha-theta activity with preserved reactivity to painful stimulation. (B) SEP recorded at the same time as the EEG show distorted plateau-like parietal and low-amplitude frontal responses after right median nerve stimulation, whereas after left median nerve stimulation, both frontal and parietal responses are missing.
Neuropathologic findings.
After formalin fixation, the brain weight was 1,295 g. In the supratentorial segment, there was a resorbed ischemic lesion with cystic degeneration of right-sided parieto-occipital white matter, corresponding to the left-sided hemisyndrome the patient had suffered several years previously. There was moderate arteriosclerosis of the basal arteries as well as signs of arterial hypertension (dilated perivascular spaces in the brain parenchyma).
The pons showed an extensive paramedian lesion bilaterally Figure 7, a and b. Histologically, the central parts were cystic, whereas the border zones contained macrophages and showed edema, reactive astrogliosis, and demyelination. The pyramidal tracts revealed signs of early degeneration, such as bilateral vacuolarization and a decreased myelin content. These findings are consistent with an ischemic lesion due to thrombosis of the basilar artery several weeks before death.
Figure 7. Whole-mount microscopic sections (the same patient as in Figure 6, luxol-hematoxylin and eosin stain, through the rostral pons at the level of the inferior colliculi (a) and through the caudal pons at the level of the motor nucleus of the facial nerve (b). (a) The lesion involves the corticospinal tracts, whereas the medial lemniscus (arrow) and the longitudinal medial fasciculus (asterisk) are spared at this level. (b) The involvement of the medial lemniscus (arrow) and the longitudinal medial fasciculus (asterisk) are demonstrated.
Patient 4.
This 59-year-old man with a history of arterial hypertension and a peripheral occlusive disease suffered from a cardiovascular arrest, which led to immediate intubation and resuscitation. A generalized tonic clonic seizure occurred shortly after intubation. Ten days later, communication was possible by opening and closing the eyes. Mental status examination was difficult, because he refused longer testing; however, he could read and solve simple problems. During the following weeks the patient became hemispastic on the right side with brisk tendon reflexes. All other neurologic findings remained unchanged. He suffered several generalized tonic clonic seizures and died 3 months later. Autopsy was refused.
Electrophysiologic examination.
An EEG was performed on admission and showed slow alpha activity with some interspersed theta frequencies. There was no reactivity to external stimulation Figure 8A. SEP recorded at the same time showed an absence of cortical responses bilaterally. This finding remained unchanged in a second recording 10 days later Figure 8B.
Figure 8. (A) EEG of a 59-year-old man with LIS presumed to be due to an ischemic lesion of the pons subsequent to a cardiovascular arrest. It shows an alpha-theta activity without any reactivity to external stimulation. (B) The corresponding SEP show missing cortical responses bilaterally.
Patient 5.
This 21-year-old man had a 6-day history of an upper respiratory tract infection followed by fever, headache, and progressive somnolence. On admission he was comatose. Although the reactivity to painful stimuli was initially preserved, it disappeared a few days later. Oculocephalic reflexes could not be elicited. CSF showed a mild pleocytosis (10 cells/mm3) and an increased total protein content (0.94 g/L). Virology and microbiology screening were normal. Under the suspected diagnosis of encephalitis, the patient was treated with Acyclovir and large-spectrum antibiotics. Neuroradiologic investigation, including CT and MRI, did not show any pathology. However, the clinical findings, the CSF analyses, the EEG and SEP (see below) were compatible with a brainstem encephalitis, although no infectious agent could be detected. Three weeks later, the patient opened his eyes but remained unresponsive. Six weeks after admission, he began to fixate objects, and 10 weeks after admission he was in a LIS, able to communicate via closing and opening the eyes. Six months after admission, the patient was still mute and severely tetraspastic, but there was minimal motor activity of the head and of the left hand. Mental status conducted with yes/no responses via eye opening and closing was normal.
A clinical follow-up 1 year later showed further improvement of the tetraparesis. The patient was able to walk; however, his gate was severely spastic and ataxic. A horizontal and a partial upper vertical gaze palsy as well as a dysarthria, dysphonia, and dysphagia were still present.
Electrophysiologic examination.
The first EEG was performed 12 hours after admission and showed a monomorphous delta activity with superposed theta-alpha activity and intermittent suppression with preserved reactivity to acoustic and painful stimuli. Three days later, a repeated EEG showed an increase in theta and alpha frequencies. A reaction to acoustic stimulation could no longer be elicited, whereas the reaction to painful stimuli was still preserved. EEGs 2, 4, 8, 10, 12, and 16 weeks after admission showed a slow alpha-theta activity of 6.5 to 7.5 Hz without reactivity to acoustic or painful stimulation. Seven months after admission, a partial desynchronization after eye opening reappeared.
The first SEP were performed 4 days after admission and showed missing parietal N20 and frontal P22 potentials bilaterally, whereas the far field potentials P15 and N18 could be elicited Figure 9A. These findings were interpreted as a complete interruption of the somatosensory pathways at the upper brainstem level. Repeated recordings 3 and 6 weeks after admission remained unchanged. In a further recording 6 months after admission, the parietal N20 and the frontal P22 reappeared, consistent with the clinical improvement, but the central conduction time was prolonged bilaterally Figure 9B. Seven months after admission, CCT was normal after left median nerve stimulation and only slightly prolonged after right median nerve stimulation.
Figure 9. (A) SEP of a 21-year-old man with a brainstem encephalitis. SEP recorded 4 days after admission show missing frontal and parietal cortical responses bilaterally. (B) Six months after admission, the parietal N20 and the frontal P22 reappeared bilaterally; however, CCT was prolonged on both sides (7.6 ms after right and 7.1 ms after left median nerve stimulation).
Discussion.
The value of electrophysiologic measures, frequently used as an additional method in clinical states such as LIS, vegetative state, or akinetic mutism, is rather controversial. Most studies report a preserved EEG reactivity in LIS [15-17] and emphasize that it is a cardinal feature for this condition. Bassetti et al. [17] considered preserved reactivity not only typical for LIS but also appropriate to ascertain preserved consciousness. Contrary to these reports, Jacome and Morilla-Pastor [18] described an alpha pattern unreactive to acoustic or painful stimulation in three cases of LIS and cautioned against diagnosing vegetative states based only on the report of an EEG describing unreactive alpha.
The dissociation between preserved consciousness and the lack of EEG reactivity in three of our patients (patients 1, 4, and 5) supports the contention that preserved reactivity is not necessary for the diagnosis of LIS but demonstrates that EEG reactivity cannot be taken as a sole measure of consciousness. Chase et al. [22] studied 20 patients with pontine lesions and found, based on their clinical, electrophysiologic, and neuropathologic findings, that bilaterally represented structures in the rostral pontine tegmentum must be essential for the preservation of alert behavior and for the EEG arousal response. However, the lack of EEG desynchronization despite preserved consciousness demonstrates that the anatomic structures mediating alpha desynchronization and those mediating conscious behavior are not identical.
SEP are a valuable diagnostic tool in the evaluation of brainstem lesions. In cerebral trauma they are even of considerable prognostic value. [23-27] In LIS, alterations of SEP have been reported; poorly formed low-amplitude waveforms with prolonged latencies or even unilaterally absent responses have been described. [19,28] Portenoy et al. [4] reported a case with LIS due to brainstem hemorrhage with absent SEP unilaterally and low-amplitude poorly defined response on the other side. Contrary to their patient, whose SEP remained unchanged despite clinical improvement, in all our five cases, follow-up SEP corresponded well with the clinical course. They remained unchanged in the four vascular cases and they improved in the case of brainstem encephalitis, thus confirming that LIS of vascular origin has a poorer prognosis than LIS of inflammatory etiology. [11]
We found no specific SEP constellation for the clinical condition of LIS, as SEP were absent bilaterally in one (patient 4) and unilaterally in three (patients 1, 2 and 3) patients, the other side varying from completely normal to severely distorted low amplitude waveforms. In one patient (5), SEP were initially absent but reappeared later with a bilaterally prolonged CCT.
These findings suggest that contrary to posttraumatic coma where EEG reactivity and SEP are of great prognostic importance, [21,26,27] in LIS these electrophysiologic measures have some, although limited, diagnostic but no prognostic value. Moreover, the dissociation between EEG reactivity and consciousness as well as between EEG reactivity and SEP demonstrates that alpha desynchronization must be mediated by brainstem structures different from those responsible for consciousness and alpha desynchronization is independent of somatosensory pathways.
- Copyright 1996 by Advanstar Communications Inc.
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