- Email: [email protected]
Cognitive impairments in the locked-in syndrome: A case report
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Cognitive Impairments in the Locked-In Syndrome: A Case Report Peter W. New, MBBS, M Clin Epi, FAFRM (RACP), Sonia J. Thomas, BA, MPsych ABSTRACT. New PW, Thomas SJ. Cognitive impairments in the locked-in syndrome: a case report. Arch Phys Med Rehabil 2005;86:338-43. No neuropsychologic studies have been reported that assess cognitive functioning in survivors of locked-in syndrome (LIS) due to purely pontine lesions and then document the process of recovery by serial testing over a lengthy period. A previously well man in his early thirties was admitted to the hospital with progressive stroke symptoms and signs. Investigations showed occlusion of the basilar artery and acute infarction of the pons, including basis and tegmentum. Despite thrombolysis, he had persisting clinical features of the LIS. He had minimal change during the first month but then slowly improved. Recovery continued gradually, and he was discharged home 7 months after stroke; at this time he was ambulating with a cane, was mildly dysarthric, was able to swallow foods of modified consistency, and was independent in all self-care activities. Neuropsychologic testing, done 6 months after stroke, showed noteable cognitive impairments. These included mild difficulties with attention and concentration, significant reduction in speed of processing, moderate impairment of perceptual organization skills, mild inefficiencies in new learning of verbal information, and a moderate reduction in executive skills. Pathologic laughing and crying were also noted. There was progressive improvement in most areas of physical and cognitive functioning until at least 2 years after stroke. Neuropsychologic testing in this patient suggests that the LIS may be associated with impairments of higher-level cognitive functioning. Key Words: Case report; Cerebrovascular accident; Cognition disorders; Locked-in syndrome; Pons; Recovery of function; Rehabilitation. © 2005 by American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation HE LOCKED-IN SYNDROME (LIS) is manifested by tetraplegia, lower cranial nerve palsies, and anarthria, with T preservation of vertical gaze and consciousness. It is associ1
ated with lesions of the brainstem, usually at the level of the ventral pons.2 The most common cause is vascular, usually due to ischemia from basilar artery occlusion or from pontine
From the Rehabilitation and Aged Services Program, Kingston Centre, Southern Health, Melbourne (New, Thomas); and Department of Epidemiology & Preventive Medicine, Monash University, Victoria (New), Australia. Presented in part to the Australasian Faculty of Rehabilitation Medicine 7th Annual Scientific Meeting, March 25, 1999, Adelaide, Australia. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the author(s) or on any organization with which the author(s) is/are associated. Correspondence to Peter New, MBBS, Rehabilitation and Aged Services Program, Kingston Centre, Warrigal Rd, Cheltenham, Victoria 3192, Australia, e-mail: [email protected]. Reprints are not available from the author. 0003-9993/05/8602-8585$30.00/0 doi:10.1016/j.apmr.2004.09.005
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hemorrhage.3,4 Many nonvascular causes have also been reported, including trauma,5 tumor,6 central pontine myelinolysis,7 and infection.8 The prognosis for LIS is usually extremely poor. In patients with LIS from vascular causes, a mortality rate of 67% and a recovery rate of 10% (those achieving independence in activities of daily living) have been reported.3 Only a few articles report on the functional abilities of LIS survivors,3,9,10 and many remain locked in. The time frame for recovery varies greatly. A small number of patients recover within hours11; others have delayed improvement over many months.10,12,13 Outcome has been reported to be better in sudden-onset LIS patients who undergo thrombolysis within 6 hours of onset. In gradual-onset LIS, the window for thrombolysis is believed to be longer, possibly up to 2 days.14 Detailed reviews of the LIS have been conducted.3,9,15,16 More than 20 years ago, it was observed that no systematic study of cognitive functioning of LIS survivors had been conducted.12 Since then, a number of studies have been published that examine this subject in a restricted fashion. Limited cognitive assessment in a few LIS survivors has found that language, calculations, spatial orientation, right-left discrimination,17,18 memory, and intellectual functioning19 were intact. One report9(p26) mentioned patients with “cognitive deficiencies in learning and retention”; however, no specific details were given. Cognitive problems were reported in some people with LIS in a recent survey of 44 long-term survivors.20 Attentional difficulties were reported by 11% of survivors and memory problems by 19%. There are a number of limitations, however, to that survey. No radiologic investigations were reported that would have excluded cortical or subcortical lesions that could have caused the cognitive impairment in the head injury subgroup and that might have accounted for the reported symptoms. Traumatic brain injury was the cause of the LIS in 14% of patients, and memory problems were statistically significantly more likely to be reported in this group than in the remainder of the LIS sample. The prevalence of attention and memory problems in the patients with LIS due to stroke was not reported separately. A possible confounding factor that could account for the patients’ perceived symptoms was that 13% reported that they felt depressed, and depression can be associated with impairments of attention and memory. There is also possible responder bias, because the survey was completed by a member of each patient’s family, and no formal neuropsychologic testing was conducted. A recent case series, with matched controls, of patients with small lacunar infarctions of the brainstem, including the pons, has documented cognitive impairment.21 Affected patients were noted to have slower cognitive processing speed, difficulties with concept shifting, and trouble finding the correct words on a naming task. They also came up with fewer words in a given semantic category on an idea-generation task. The researchers reported that these problems were not secondary to motor impairments but were due to cognitive disturbances. No patients in this study, however, were reported to have had an LIS stroke.
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The above reports on cognitive impairment in the LIS and brainstem infarction have limitations, as summarized. Furthermore, it remains that no neuropsychologic studies have been reported that assess cognitive functioning in survivors of LIS due to purely pontine lesions and then document the process of recovery by serial testing over a lengthy period. CASE DESCRIPTION A previously well, right-handed man in his early thirties was admitted to the hospital with 6 hours of headache, diarrhea, vomiting, and dysarthria. He continued to deteriorate, becoming tetraplegic with increased tone and anarthric with an absent gag reflex, but consciousness was preserved. Horizontal eye movements were also absent. Magnetic resonance imaging (MRI) and angiography (MRA) showed occlusion of the basilar artery above the anterior inferior cerebellar artery and acute infarction of the pons, including the basis and tegmentum. There were no abnormalities seen in the cortex or subcortical regions. Angiography showed occlusion of the left vertebral artery, and the appearance suggested underlying dissection. Clinical and radiologic findings at the time supported the diagnosis of a “classical” LIS, as described by Bauer et al.5 Thrombolysis performed 17 hours after the onset of symptoms re-established vessel patency; however, the patient showed little improvement. He required ventilation via a tracheostomy, a percutaneous enterogastrectomy feeding tube, and an indwelling catheter; he was fully dependent for all self-care. There were no clinical features or complications during his acute management to suggest a secondary hypoxic brain injury. A repeat brain MRI scan 2 weeks after stroke showed resolving changes from the infarction, with no new lesions. There was virtually no change during the first month, and the patient was transferred to a slow-stream rehabilitation hospital. There he made slow but progressive improvement. His limb power returned, recovering from distal to proximal muscles, as has been noted in LIS patients.22 He began swallowing very small amounts of pureed food and was able to vocalize a few sounds. Four months after stroke, he was transferred to a fast-stream rehabilitation program, where he received a more intensive allied health therapy program than previously, typically for 2 to 4 hours a day. Improvement continued in all areas. Cognitive difficulties were noted in therapy sessions and were confirmed by a comprehensive neuropsychologic assessment, which will be outlined in detail in the next section. Severe emotional lability was noted, and this improved by discharge. The major problem was with pathologic laughing and, to a lesser extent, pathologic crying (ie, he displayed these emotions involuntarily, often in response to inappropriate stimuli). He was discharged home 7 months after stroke, fully continent and independent in all personal activities of daily living and some light domestic tasks. His dysarthric speech was 80% intelligible, and his dietary intake was modified to a soft consistency to ensure safe swallowing. Muscle spasticity had improved and he was ambulating 50m with a stick, but he had difficulty with fine motor tasks. The patient’s disability was assessed by the rehabilitation team at admission, 4 months after stroke, and on discharge using the FIM instrument.23 The FIM is an 18-item ordinal scale, with scores for individual items ranging from 1 (total assistance) to 7 (complete independence). Two separate domains have been defined: the motor domain, consisting of 13 items, and a cognitive domain, consisting of 5 items.24 His total FIM score on admission was 65 (motor score, 41; cognitive score, 24), and this improved to 111 by discharge (motor score, 82; cognitive score, 29).
Fig 1. MRI brain scan 8 months after stroke. T1-weighted image with infarct location indicated by arrow.
Eight months after stroke, repeat MRI and MRA showed normal vertebral and basilar blood flow and a well-defined cavity within the lower anterior midbrain and upper anterior pons, corresponding to the previously identified area of acute infarction. As noted previously, there were no abnormalities seen in the cortex or subcortical regions (fig 1). A singlephoton emission computer tomography (SPECT) scan showed normal cerebral perfusion. Periodic reviews documented gradual improvement in all areas. By 33 months after stroke, the patient no longer required a modified diet, and speech was almost fully intelligible. He was walking independently for a kilometer and could jog for 10 to 20m, but his base of support was widened. Grade 4/5 weakness persisted around his hips and fingers. Tone was slightly increased. A reduction in the duration and frequency of the pathologic crying and, to a lesser extent, the pathologic laughing was reported. These problems continued to cause him substantial distress. He had returned to his premorbid workplace, but with some changes to his role due to persisting cognitive deficits. The changes included using structured routine, minimizing unpredictable demands, and avoiding multitasking. In addition, strategies were provided to minimize distractions and to try to compensate for the pathologic crying and laughing. The above strategies partially compensated for cognitive difficulties, according to workplace feedback. Neuropsychologic Results Neuropsychologic testing was conducted at 6, 12, and 24 months after stroke (table 1). Alternate forms are available only for the Austin maze25-27 and Rey-Osterrieth complex figure tests,28-30 and they were used on repeat testing to control for practice effects. The purpose of review assessments was to identify areas of improvement. Therefore, a subset of tests, where performance was below premorbid estimates from each previous assessment, was selected. Arch Phys Med Rehabil Vol 86, February 2005
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COGNITIVE IMPAIRMENTS IN THE LIS, New Table 1: Neuropsychologic Test Results Test
Wechsler Scales WAIS-III Digit span Vocabulary Arithmetic Comprehension Similarities Picture completion Matrix reasoning Block design Object assembly Digit symbol Verbal IQ Performance IQ Full-scale IQ Test
WMS-III Mental control Logical memory I Logical memory II Visual reproduction I Visual reproduction II Visual reproduction II recognition Verbal paired associates I Verbal paired associates II Other Tests
SDMT Rey figure: copy Rey figure: 30-min recall Austin maze WCST No. of trials Total errors Total perseverative responses Total perseverative errors TMT-A TMT-B TMT-B minus TMT-A (ie, TMT-B speed) HVOT
6-Month Percentiles (Age Scale)
12-Month Percentiles (Age Scale)
24-Month Percentiles (Age Scale)
37th (9) 75th (12) 63rd (11) 75th (12) 37th (9) 16th (7) 84th (13) 50th (10) 1st (3) 1st (3) 103 (prorated) 86 96
37th (9) NA 95th (15) 63rd (11) 63rd (11) 25th (8) 84th (13) 37th (9) 5th (5) 9th (6) 110 (prorated) 87 100
50th (10) NA NA NA 63rd (11) NA NA NA 16th (7) 9th (6) NA NA NA
Age Scale
Age Scale
Age Scale
4 15 11 11 9 10 7 9
9 15 15 13 17 12 13 13
Percentiles (Raw Score)
⬍0.1st (25) 62nd (35) 66th (22) 7th (73) 107 8th (35) 5th (20) 4th (19) 0.3rd (59s) ⬍0.1st (200s) ⬍0.1st (141s) High probability of impairment (16)
NA NA NA NA NA NA NA NA
Percentiles (Raw Score)
Percentiles (Raw Score)
0.1st (30) 50th (33) 90th (28) 42nd (43)
12th (48) 62nd (35) 79th (24) 79th (29)
79 98th (12) 99th (7) 99th (6) 0.1st (64s) 7th (100s) 88th (36s) Moderate probability of impairment (20)
NA NA NA NA 2nd (51s) 18th (84s) 90th (33s) Moderate probability of impairment (20)
NOTE. For the WAIS-III and WMS-III, borderline is 4 to 6, below average is 7, average is 8 to 12, and high average is 13 to 15. Abbreviations: HVOT, Hooper Visual Organizational Test; NA, not assessed; Rey figure, Rey-Osterrieth complex figure; SDMT, Symbol Digit Modalities Test; TMT-A, Trail-Making Test Part A; TMT-B, Trail-Making Test Part B; WAIS-III, Wechsler Adult Intelligence Scale–III; WMS-III, Wechsler Memory Scale–III; WCST, Wisconsin Card Sorting Test.
Results are presented as percentile scores, where possible, to facilitate comparison with expected population norms. The percentiles for the Wechsler Adult Intelligence Scale–III31 (WAIS-III) are estimates only. They have been calculated from a conversion table32 for WAIS–Revised, because no WAIS-III scaled score–percentile conversion tables are available. For other tests, results were converted to percentile ranks from a published conversion table.33 No conversion to percentiles is available for the Wechsler Memory Scale–III34 (WMS-III). The estimated level of premorbid intelligence, based on educational background and highest subtest score on the WAIS-III, was high average. On initial testing, the WAIS-III full-scale IQ was below this estimate. This was mainly due to impairments of processing speed, attention and concentration, Arch Phys Med Rehabil Vol 86, February 2005
and functioning on performance-based tests. Results at 12 months indicated that the verbal IQ had increased to approximate premorbid estimates, using a confidence interval of 95% (ie, verbal IQ score from 105 to 115 ranges from average to high average). Mild to moderate improvements in processing speed and attention at 12 months had a marginal impact on performance IQ, and full-scale IQ remained in the average range, below premorbid estimates. Initial performance on the digit symbol subtest indicated significant slowing in speed of processing. This could have been accounted for by impaired graphomotor skills. Therefore, the effects of graphomotor skills were controlled for by using the oral Symbol Digit Modalities Test35 (SDMT), which has no motor component, and the impairment persisted. At the
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12-month review, speed on both measures had increased. At 24 months, however, speed had plateaued on the digit symbol subtest but had increased on the SDMT. This suggests that improvements in graphomotor and processing speed occurred between 6 and 12 months, with processing speed continuing to improve and approximating average levels at 24 months. Graphomotor speed remained significantly below average levels. Distractibility was a major clinical feature, which corresponded to poor performance on the mental control subtest of the WMS-III and Part B of the Trail-Making Test36,37 (TMT). Concentration on the former test improved to premorbid estimates at 12 months. Divided attention on the TMT improved at 12 and 24 months, but the patient’s performance was still substantially below premorbid estimates, at approximately the 20th percentile. This interpretation must be mediated by the confounding effect of graphomotor slowing on performance. A difference score (TMT-B minus TMT-A) essentially removes the speed element from the test evaluation of TMT-B.38 This calculation indicated that, on initial testing, divided attention was significantly impaired, but on both reviews, it had returned to the premorbid estimate above the 90th percentile. On the mental arithmetic subtest, the patient had difficulty retaining the details of the questions in his mind and manipulating them. This working memory difficulty improved significantly at 12 months after stroke, commensurate with premorbid estimates. On initial testing, poor performance was displayed on the object assembly subtest of the WAIS-III. There was no corresponding poor performance on the block design subtest of the WAIS-III and no evidence of impaired planning skills on his copy of the Rey-Osterrieth complex figure. An impairment of perceptual organizational and integration skills, however, was noted from the results of the Hooper Visual Organizational Test39 (HVOT), confirming that the reduction in these skills, rather than planning skills, produced a poor performance on the object assembly subtest. Although poor motor skills may have contributed to a lower score, performance continued to improve across reviews on the object assembly subtest and the HVOT. The HVOT is not a timed test, which suggests that increased speed associated with improved motor skills was less of a contributing factor on both tests than improvement in visual organization and integration skills. A mild impairment of visual organization and integration skills persisted at 24 months after stroke. On the WMS-III, the patient’s visual and verbal memory were generally intact on initial testing. Inefficiencies in verbal learning were apparent on the verbal paired associates subtest, where performance was at a low-average level, indicating difficulties organizing the information to be learned. This improved to estimated premorbid levels at review testing 12 months after stroke. A pushbutton maze, the Austin maze test, was administered to assess executive functioning. Issues of decreased motor control did not reduce the patient’s ability to accurately press the buttons. In addition, this test was not timed; therefore, motor slowing was not a confounding factor in interpretation. On initial testing, the same errors were repeated across trials, use of error feedback was not evident, and he had difficulty slowing down responses to eliminate impulsive errors. These results suggested executive impairment, specifically mental flexibility, impulse control, and error use. Executive difficulties were also evident on initial assessment on the Wisconsin Card Sorting Test40,41 (WCST). The total number of errors, perseverative responses, perseverative errors, and the number of trials made to complete the task, indicated a
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level of functioning significantly below premorbid estimates. On review testing, executive problems improved significantly, reaching estimated premorbid levels at 24 months after stroke. In summary, neuropsychologic deficits on initial testing included the following: significant slowing of graphomotor speed; significant slowing in speed of processing information; fluctuation in sustained attention; poor divided attention; difficulties on tasks requiring visual organization and integration; inefficiencies in verbal new learning and impaired executive skills, specifically mental flexibility, impulse control, error utilization; and an inability to inhibit laughing and crying. Deficits that persisted at 24 months after stroke included slow graphomotor speed, visual integration and organization skills, and difficulties with pathologic laughing and crying. DISCUSSION Our patient made a slow but gradual recovery in function over a prolonged period of time. His final functional status was a “full recovery,” using the Patterson classification.3 This pattern of recovery of LIS is very uncommon overall, but there are other cases in the literature where this has been reported.10,12,13 Because improvement is difficult to predict and can be delayed and notable, we agree with others that aggressive supportive therapy should be considered in the early months after the onset of LIS.10,13 An interdisciplinary rehabilitation approach is essential to provide comprehensive care for these patients.3,10,42 Studies reporting normal cognitive abilities in LIS patients17-19 have been based on limited testing of discrete functions and not on detailed assessments, such as those conducted in this case. A previously mentioned report of some LIS patients having cognitive deficiencies9 did not provide any results of neuropsychologic testing. Of the 8 patients mentioned in that report, only 1 had LIS due to pontine ischemia. The remaining patients had other causes associated with cognitive impairment. Our case of LIS had an isolated lesion of the lower anterior midbrain and upper anterior pons, with no evidence of additional lesions that could explain the documented cognitive impairments. As mentioned above, serial MRI brain scans did not show any cortical or subcortical lesions that could account for the cognitive impairments. In addition, the neuropsychologic profile was not consistent with a hypoxic brain injury, in which severe memory difficulties are predominantly noted consequences. There may be a possibility that the occlusion of the left vertebral artery could have led to diffuse and widespread brain lesions not detectable in a SPECT or MRI scan, although this is unlikely. The results of our testing suggest that lesions of the pons and lower midbrain may be associated with impairment of higher-level cognitive functioning. Practice effects must be considered when interpreting neuropsychologic testing undertaken at 12 and 24 months. For the WAIS-III, test-retest data for adults 30 to 54 years, after an interval of 2 to 12 weeks, show that the mean full-scale IQ score on the second testing was 5 points higher than that on the first testing, 8 points higher for performance IQ, and 2 points higher for verbal IQ.43 For the auditory subtests used from the WMS-III, test-retest data for adults 16 to 54, after an interval of 2 to 12 weeks, indicated that the largest increase in subtest scores was only 2 points higher than on initial testing.43 Improvements on repeat testing in the current case occurred on 4 or more scale scores, which suggests more than just a practice effect. No test-retest data were available for the visual reproduction subtest. It is important to note that data related to the testing intervals used in this case (ie, 6mo, then 12mo) were not available. Arch Phys Med Rehabil Vol 86, February 2005
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In general, tests that involve a large speed component, that require an unfamiliar or infrequently practiced mode of response, that have a single solution, or that involve learning tend to show large practice effects.38 Although a patient who remembers the rules from the first testing on the WCST and uses them in the second is likely to have an improved executive performance, an alternate path on the Austin maze was used on review, and performance paralleled that on the WCST. This suggests an underlying improvement in executive functioning, over and above the potential practice effects on the WCST. Overall, we believe that our findings are robust, because alternative forms were used where available, and there was no improvement between the 6- and 12-month reviews on numerous tests and subtests. In addition, the interpretations of some assessment findings were not based on individual tests but rather on the relationship between performances on a number of tests (eg, block design, object assembly, HVOT). A recent study21 of patients with small lacunar infarctions of the brainstem found similar impairments in neuropsychologic testing to those identified in our case—slower speed and difficulty with concept shifting. Because there is no direct involvement of the pons or midbrain in cognition, it is possible that there is an indirect influence. It has been hypothesized that infarctions in this region may have indirect effects on neurologic functioning through hypometabolism or other neurochemical changes.21 It is also possible that cognitive disturbances may occur because of interruption of the neural pathways passing through the brainstem. Some evidence in the literature supports this concept. Animal studies have shown the presence of a fronto-pontine loop44 and a cerebro-cerebellar circuit that consists of afferent inputs through cortico-ponto-cerebellar pathways and efferent cerebello-thalamic-cortical pathways.45 Reviews on the pedunculopontine tegmental nucleus support its involvement in attentional and learning processes, possibly by influencing cortical function via the thalamus, basal forebrain, and basal ganglia.46 The pontine and basal forebrain cholinergic systems may be involved in visual attentional functioning, modulation of short-term spatial memory, and the ability to use response rules.47 There is increasing evidence to support a role for the cerebellum in cognitive processing, and this may be partially mediated via the above-mentioned pathways. Patients with olivoponto-cerebellar atrophy have shown visuospatial deficits and signs of a mild frontal–like syndrome.48 Evidence also suggests that cerebellar lesions may be associated with impairments in planning,49 verbal paired-associate learning tasks,50,51 error detection,51 and executive functions.52 It has been suggested that patients who have lesions of the posterior lobe of the cerebellum and vermis lesions can develop impairments of executive functioning, difficulties with spatial cognition, personality changes, and language deficits.53 These findings concur with the deficits identified in our patient. A number of researchers over the years have noted the presence of pathologic laughing3,13,15 and crying3,9,21 in LIS survivors. These observations, however, have not been discussed in detail. It has been hypothesized that these phenomena may be due to a pseudobulbar lesion resulting from damage to the corticobulbar tracts.20 A recent review54 of the neurology of laughter reports that the expression of laughter is regulated by 2 partially independent pathways. An “involuntary” system involves the amygdala, thalamic/hypothalamic and subthalamic areas, and the dorsal and tegmental brainstem, whereas a “voluntary” system originates in the premotor and frontal opercular areas and proceeds through the motor cortex and pyramidal tract to the ventral brainstem. These systems and the Arch Phys Med Rehabil Vol 86, February 2005
laughter response are regulated by a laughter-coordinating center in the dorsal upper pons.54 Lesions in LIS patients could affect these pathways. Our findings have a number of implications. First, there is a need to continue supportive therapy of LIS survivors for several months, until prognosis is more certain, because it cannot be accurately predicted in the first few days or weeks. Second, because patients with LIS may have cognitive impairments, the acute hospital, rehabilitation, and long-term care facilities that care for LIS patients will need to consider this possibility in their assessment and management plans. If further research confirms a similar cognitive profile in patients recovering from LIS to that presented here, then the following recommendations will assist with management and rehabilitation. To address the distractibility and slowed processing, the following strategies are recommended: minimizing distractions in the environment, ensuring that 1 person speaks at a time, ensuring a reduced speed of speech delivery when talking with the patient, and allowing more time waiting for a response. These strategies are likely to increase the effectiveness of communication. Inefficiencies in new learning of verbal material can be improved by ensuring that verbal information is structured and delivered in small parts. This will assist registration and recall. The impulse control issue can be addressed by teaching patients to deliberate on their response before giving it (eg, STOP-THINK-RESPOND). This may improve the reliability of intentions and decisions. The increased tendency to repeat errors indicates the importance of getting tasks correct the first time, to avoid repeating the same mistake. Further research is needed to replicate these findings, to describe the different forms of cognitive impairment that can result from pons and brainstem lesions, and to localize other related areas or pathways that affect cognition. Practical issues will need to be overcome, to enable detailed systematic studies. These include the small number of patients who are available for study and the presence of possible confounding lesions. We have studied other patients with LIS who also had cognitive impairments on neuropsychologic testing. These other patients, however, all had pathologic conditions or processes involving other areas of the brain that are associated with cognitive processing. Because of these confounding factors, they were not able to add any further information to the case presented above. Practical difficulties of conducting assessment of patients who are anarthric and tetraplegic also need to be addressed, to facilitate further study of cognitive impairments in patients with LIS. Conventional understanding of neuroanatomy does not describe the pons or brainstem as having a role in cognitive functioning. If our findings can be replicated in a larger series of patients, this would challenge current concepts of cognitive functioning in the LIS and, more generally, the relationship between higher cognitive functioning and the brainstem. CONCLUSIONS Neuropsychologic testing in this patient, who sustained an LIS, suggests that lesions of the pons may be associated with impairments of higher-level cognitive functioning. After LIS, recovery in many areas may continue for up to 2 years after stroke. References 1. Plum F, Poser J. Diagnosis of stupor and coma. Philadelphia: FA Davis; 1966. 2. Karp JS, Hurtig HI. “Locked-in” state with bilateral midbrain infarcts. Arch Neurol 1974;30:176-8. 3. Patterson JR, Grabois M. Locked-in syndrome: a review of 139 cases. Stroke 1986;17:758-64.
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4. Haig AJ, Katz RT, Sahgal V. Locked-in syndrome: a review. Curr Concepts Rehabil Med 1986;3:12-6. 5. Bauer G, Gerstenbrood E, Rump IE. Varieties of the locked-in syndrome. J Neurol 1979;221:77-91. 6. Cherington M, Stears J, Hodges J. Locked-in syndrome caused by a tumor. Neurology 1976;26:180-2. 7. Messert B, Orrison WW, Hawkins MJ, Quaglieri CE. Central pontine myelinolysis: considerations on etiology, diagnosis, and treatment. Neurology 1979;29:147-60. 8. Murphy MJ, Brenton DW, Aschenbrener CA, Van Glider JC. Locked-in syndrome caused by a solitary pontine abscess. J Neurol Neurosurg Psychiatry 1979;42:1062-5. 9. Haig AJ, Katz RT, Sahgal V. Mortality and complications of the locked-in syndrome. Arch Phys Med Rehabil 1987;68:24-7. 10. Casanova E, Lazzari RE, Lotta S, Mazzucchi A. Locked-in syndrome: improvement in the prognosis after an early intensive multidisciplinary rehabilitation. Arch Phys Med Rehabil 2003;84:862-7. 11. Buchman AS, Wichter MD. Recovery following the locked-in syndrome [letter]. Stroke 1986;17:558. 12. Khurana RK, Genut AA, Yannakakis GD. Locked-in syndrome with recovery. Ann Neurol 1979;8:439-41. 13. McCusker EA, Rudick RA, Honch GW, Griggs RC. Recovery from the locked-in syndrome. Arch Neurol 1982;39:145-7. 14. Herderschee D. Prediction of outcome in ischaemic locked-in syndrome: importance of the time of angiographic findings. Eur J Med 1992;1:367-79. 15. Dolifus P, Milos PL, Chapuis A, Real P, Orenstein M, Soutter JW. The locked-in syndrome: a review and presentation of two chronic cases. Paraplegia 1990;28:5-16. 16. León-Carrión J, Van Eeckhout P, Domínguez-Morales MdelR. The locked-in syndrome: a syndrome looking for a therapy. Brain Inj 2002;16:555-69. 17. Cappa SF, Vignolo LA. Locked-in syndrome for 12 years with preserved intelligence [letter]. Ann Neurol 1982;11:545. 18. Cappa SF, Pirovano C, Vignolo LA. Chronic ‘locked-in’ syndrome: psychological study of a case. Eur Neurol 1985;24:107-11. 19. Allain P, Joseph PA, Isambert JL, Didier LG, Emile J. Cognitive functions in chronic locked-in syndrome: a report of two cases. Cortex 1998;34:629-34. 20. León-Carrión J, Van Eeckhout P, Domínguez-Morales MdelR, Pérez-Santamaría FJ. The locked-in syndrome: a syndrome looking for a therapy. Brain Inj 2002;16:571-82. 21. Van Zandvoort M, de Haan E, Van Gun J, Jaap Kappelle L. Cognitive functioning in patients with a small infarct in the brainstem. J Int Neuropsychol Soc 2003;9:490-4. 22. Richard I, Péreon Y, Guiheneu P, Nogues B, Perrouin-Verbe B, Mathe JF. Persistence of distal motor control in the locked in syndrome. Review of 11 patients. Paraplegia 1995;33:640-6. 23. Guide for the Uniform Data Set for Medical Rehabilitation (including the FIM instrument), version 5.1. Buffalo: State Univ New York; 1997. 24. Heinemann AW, Linacre JM, Wright BD, Hamilton BB, Granger CV. Relationships between impairment and physical disability as measured by the Functional Independence Measure. Arch Phys Med Rehabil 1993;74:566-73. 25. Millner B. Visually-guided maze learning in man: effects of bilateral hippocampal, bilateral frontal and unilateral cerebral lesions. Neuropsychologia 1965;3:317-38. 26. Walsh KW. Neuropsychology: a clinical approach. Edinburgh: Churchill Livingstone; 1978. 27. Bowden SC, Dumendzic J, Clifford C, Hooper J, Tucker A, Kinsella G. Healthy adults’ performance on the Austin Maze. Clin Neuropsychol 1992;6:43-52. 28. Rey A. L’examen psychologique dans les cas d’encephalopathie traumatique. Arch Psychol 1941;28:286-340.
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29. Osterrieth PA. Le test de copie d’une figure complex: contribution a l’etude de la perception et de la memoire. Arch Psychol 1944; 30:286-356. 30. Corwin J, Byslma FW. Translations of excerpts from Andre Rey’s Psychological examination of traumatic encephalopathy and P.A. Osterrieth’s The Complex Figure Copy Test. Clin Neuropsychol 1993;7:4-21. 31. Wechsler D. Wechsler Adult Intelligence Scale–Version Three. San Antonio: Psychological Corp; 1998. 32. Sattler JM. Assessment of children. 3rd ed. San Diego: Sattler; 1988. 33. Spreen O, Strauss E. A compendium of neuropsychological tests: administrator, norms, and commentary. 2nd ed. New York: University Pr; 1998. 34. Wechsler D. Wechsler Memory Scale–Version Three. San Antonio: Psychological Corp; 1998. 35. Smith A. Symbol Digit Modalities Test (SDMT) manual revised. Los Angeles: Western Psychological Services; 1982. 36. Army individual battery manual of directions and scoring. Washington (DC): War Department, Adjutant General’s Office; 1944. 37. Partington JE, Leiter RG. Partington’s pathway test. Psychol Serv Centre Bull 1949;1:9-20. 38. Lezak MD. Neuropsychological assessment. 3rd ed. New York: University Pr; 1995. 39. Hooper HE. The Hooper Visual Organization Test. Manual. Beverly Hills: Western Psychological Services; 1958. 40. Berg EA. A simple objective treatment for measuring flexibility in thinking. J Gen Psychol 1948;39:15-22. 41. Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtis G. Wisconsin Card Sorting Test. Manual revised & expanded. Odessa: Psychological Assessment Resources; 1993. 42. Mauss-Clum N, Cole M, McCort T, Eifler D. Locked-in syndrome: a team approach. J Neurosci Nurs 1991;23:273-86. 43. The Psychological Corporation. WAIS-III/WMS-III technical manual. San Antonio: Harcourt Brace; 1997. 44. Schmahmann JD, Pandya DN. Prefrontal cortex projections to the basilar pons in rhesus monkey: implications for the cerebellar contribution to higher cognition. Neurosci Lett 1995;199:175-8. 45. Schmahmann JD. From movement to thought: anatomic substrates of the cerebellar contribution to cognitive processing. Hum Brain Mapp 1996;4:174-98. 46. Steckler T, Inglis W, Winn P, Sahgal A. The pedunculopontine tegmental nucleus: a role in cognitive processes? Brain Res Rev 1994;19:298-318. 47. Everitt BJ, Robbins TW. Central cholinergic systems and cognition. Annu Rev Psychol 1997;48:649-84. 48. Botez-Marquard T, Botez MI. Cognitive behavior in heredodegenerative ataxias. Eur Neurol 1993;35:351-7. 49. Grafman J, Litvan I, Massaquoi S, Stewart BA, Sirigu A, Hallett M. Cognitive planning deficit in patients with cerebellar atrophy. Neurology 1992;42:1493-6. 50. Bracke-Tolkmitt R, Linden A, Canavan AG, et al. The cerebellum contributes to mental skills. Behav Neurosci 1989;103:442-6. 51. Fiez JA, Petersen SE, Cheney MK, Raichle ME. Impaired nonmotor learning and error detection associated with cerebellar damage. Brain 1992;115:155-78. 52. Chafetz MD, Friedman AL, Kevorkian CG, Levy JK. The cerebellum and cognitive function: implications for rehabilitation. Arch Phys Med Rehabil 1996;77:1303-8. 53. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain 1998;121:561-79. 54. Wild B, Rodden FA, Grodd W, Ruch W. Neural correlates of laughter and humour. Brain Inj 2003;126:2121-38.
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CLINICAL NOTE
Cognitive Impairments in the Locked-In Syndrome: A Case Report Peter W. New, MBBS, M Clin Epi, FAFRM (RACP), Sonia J. Thomas, BA, MPsych ABSTRACT. New PW, Thomas SJ. Cognitive impairments in the locked-in syndrome: a case report. Arch Phys Med Rehabil 2005;86:338-43. No neuropsychologic studies have been reported that assess cognitive functioning in survivors of locked-in syndrome (LIS) due to purely pontine lesions and then document the process of recovery by serial testing over a lengthy period. A previously well man in his early thirties was admitted to the hospital with progressive stroke symptoms and signs. Investigations showed occlusion of the basilar artery and acute infarction of the pons, including basis and tegmentum. Despite thrombolysis, he had persisting clinical features of the LIS. He had minimal change during the first month but then slowly improved. Recovery continued gradually, and he was discharged home 7 months after stroke; at this time he was ambulating with a cane, was mildly dysarthric, was able to swallow foods of modified consistency, and was independent in all self-care activities. Neuropsychologic testing, done 6 months after stroke, showed noteable cognitive impairments. These included mild difficulties with attention and concentration, significant reduction in speed of processing, moderate impairment of perceptual organization skills, mild inefficiencies in new learning of verbal information, and a moderate reduction in executive skills. Pathologic laughing and crying were also noted. There was progressive improvement in most areas of physical and cognitive functioning until at least 2 years after stroke. Neuropsychologic testing in this patient suggests that the LIS may be associated with impairments of higher-level cognitive functioning. Key Words: Case report; Cerebrovascular accident; Cognition disorders; Locked-in syndrome; Pons; Recovery of function; Rehabilitation. © 2005 by American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation HE LOCKED-IN SYNDROME (LIS) is manifested by tetraplegia, lower cranial nerve palsies, and anarthria, with T preservation of vertical gaze and consciousness. It is associ1
ated with lesions of the brainstem, usually at the level of the ventral pons.2 The most common cause is vascular, usually due to ischemia from basilar artery occlusion or from pontine
From the Rehabilitation and Aged Services Program, Kingston Centre, Southern Health, Melbourne (New, Thomas); and Department of Epidemiology & Preventive Medicine, Monash University, Victoria (New), Australia. Presented in part to the Australasian Faculty of Rehabilitation Medicine 7th Annual Scientific Meeting, March 25, 1999, Adelaide, Australia. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the author(s) or on any organization with which the author(s) is/are associated. Correspondence to Peter New, MBBS, Rehabilitation and Aged Services Program, Kingston Centre, Warrigal Rd, Cheltenham, Victoria 3192, Australia, e-mail: [email protected]. Reprints are not available from the author. 0003-9993/05/8602-8585$30.00/0 doi:10.1016/j.apmr.2004.09.005
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hemorrhage.3,4 Many nonvascular causes have also been reported, including trauma,5 tumor,6 central pontine myelinolysis,7 and infection.8 The prognosis for LIS is usually extremely poor. In patients with LIS from vascular causes, a mortality rate of 67% and a recovery rate of 10% (those achieving independence in activities of daily living) have been reported.3 Only a few articles report on the functional abilities of LIS survivors,3,9,10 and many remain locked in. The time frame for recovery varies greatly. A small number of patients recover within hours11; others have delayed improvement over many months.10,12,13 Outcome has been reported to be better in sudden-onset LIS patients who undergo thrombolysis within 6 hours of onset. In gradual-onset LIS, the window for thrombolysis is believed to be longer, possibly up to 2 days.14 Detailed reviews of the LIS have been conducted.3,9,15,16 More than 20 years ago, it was observed that no systematic study of cognitive functioning of LIS survivors had been conducted.12 Since then, a number of studies have been published that examine this subject in a restricted fashion. Limited cognitive assessment in a few LIS survivors has found that language, calculations, spatial orientation, right-left discrimination,17,18 memory, and intellectual functioning19 were intact. One report9(p26) mentioned patients with “cognitive deficiencies in learning and retention”; however, no specific details were given. Cognitive problems were reported in some people with LIS in a recent survey of 44 long-term survivors.20 Attentional difficulties were reported by 11% of survivors and memory problems by 19%. There are a number of limitations, however, to that survey. No radiologic investigations were reported that would have excluded cortical or subcortical lesions that could have caused the cognitive impairment in the head injury subgroup and that might have accounted for the reported symptoms. Traumatic brain injury was the cause of the LIS in 14% of patients, and memory problems were statistically significantly more likely to be reported in this group than in the remainder of the LIS sample. The prevalence of attention and memory problems in the patients with LIS due to stroke was not reported separately. A possible confounding factor that could account for the patients’ perceived symptoms was that 13% reported that they felt depressed, and depression can be associated with impairments of attention and memory. There is also possible responder bias, because the survey was completed by a member of each patient’s family, and no formal neuropsychologic testing was conducted. A recent case series, with matched controls, of patients with small lacunar infarctions of the brainstem, including the pons, has documented cognitive impairment.21 Affected patients were noted to have slower cognitive processing speed, difficulties with concept shifting, and trouble finding the correct words on a naming task. They also came up with fewer words in a given semantic category on an idea-generation task. The researchers reported that these problems were not secondary to motor impairments but were due to cognitive disturbances. No patients in this study, however, were reported to have had an LIS stroke.
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The above reports on cognitive impairment in the LIS and brainstem infarction have limitations, as summarized. Furthermore, it remains that no neuropsychologic studies have been reported that assess cognitive functioning in survivors of LIS due to purely pontine lesions and then document the process of recovery by serial testing over a lengthy period. CASE DESCRIPTION A previously well, right-handed man in his early thirties was admitted to the hospital with 6 hours of headache, diarrhea, vomiting, and dysarthria. He continued to deteriorate, becoming tetraplegic with increased tone and anarthric with an absent gag reflex, but consciousness was preserved. Horizontal eye movements were also absent. Magnetic resonance imaging (MRI) and angiography (MRA) showed occlusion of the basilar artery above the anterior inferior cerebellar artery and acute infarction of the pons, including the basis and tegmentum. There were no abnormalities seen in the cortex or subcortical regions. Angiography showed occlusion of the left vertebral artery, and the appearance suggested underlying dissection. Clinical and radiologic findings at the time supported the diagnosis of a “classical” LIS, as described by Bauer et al.5 Thrombolysis performed 17 hours after the onset of symptoms re-established vessel patency; however, the patient showed little improvement. He required ventilation via a tracheostomy, a percutaneous enterogastrectomy feeding tube, and an indwelling catheter; he was fully dependent for all self-care. There were no clinical features or complications during his acute management to suggest a secondary hypoxic brain injury. A repeat brain MRI scan 2 weeks after stroke showed resolving changes from the infarction, with no new lesions. There was virtually no change during the first month, and the patient was transferred to a slow-stream rehabilitation hospital. There he made slow but progressive improvement. His limb power returned, recovering from distal to proximal muscles, as has been noted in LIS patients.22 He began swallowing very small amounts of pureed food and was able to vocalize a few sounds. Four months after stroke, he was transferred to a fast-stream rehabilitation program, where he received a more intensive allied health therapy program than previously, typically for 2 to 4 hours a day. Improvement continued in all areas. Cognitive difficulties were noted in therapy sessions and were confirmed by a comprehensive neuropsychologic assessment, which will be outlined in detail in the next section. Severe emotional lability was noted, and this improved by discharge. The major problem was with pathologic laughing and, to a lesser extent, pathologic crying (ie, he displayed these emotions involuntarily, often in response to inappropriate stimuli). He was discharged home 7 months after stroke, fully continent and independent in all personal activities of daily living and some light domestic tasks. His dysarthric speech was 80% intelligible, and his dietary intake was modified to a soft consistency to ensure safe swallowing. Muscle spasticity had improved and he was ambulating 50m with a stick, but he had difficulty with fine motor tasks. The patient’s disability was assessed by the rehabilitation team at admission, 4 months after stroke, and on discharge using the FIM instrument.23 The FIM is an 18-item ordinal scale, with scores for individual items ranging from 1 (total assistance) to 7 (complete independence). Two separate domains have been defined: the motor domain, consisting of 13 items, and a cognitive domain, consisting of 5 items.24 His total FIM score on admission was 65 (motor score, 41; cognitive score, 24), and this improved to 111 by discharge (motor score, 82; cognitive score, 29).
Fig 1. MRI brain scan 8 months after stroke. T1-weighted image with infarct location indicated by arrow.
Eight months after stroke, repeat MRI and MRA showed normal vertebral and basilar blood flow and a well-defined cavity within the lower anterior midbrain and upper anterior pons, corresponding to the previously identified area of acute infarction. As noted previously, there were no abnormalities seen in the cortex or subcortical regions (fig 1). A singlephoton emission computer tomography (SPECT) scan showed normal cerebral perfusion. Periodic reviews documented gradual improvement in all areas. By 33 months after stroke, the patient no longer required a modified diet, and speech was almost fully intelligible. He was walking independently for a kilometer and could jog for 10 to 20m, but his base of support was widened. Grade 4/5 weakness persisted around his hips and fingers. Tone was slightly increased. A reduction in the duration and frequency of the pathologic crying and, to a lesser extent, the pathologic laughing was reported. These problems continued to cause him substantial distress. He had returned to his premorbid workplace, but with some changes to his role due to persisting cognitive deficits. The changes included using structured routine, minimizing unpredictable demands, and avoiding multitasking. In addition, strategies were provided to minimize distractions and to try to compensate for the pathologic crying and laughing. The above strategies partially compensated for cognitive difficulties, according to workplace feedback. Neuropsychologic Results Neuropsychologic testing was conducted at 6, 12, and 24 months after stroke (table 1). Alternate forms are available only for the Austin maze25-27 and Rey-Osterrieth complex figure tests,28-30 and they were used on repeat testing to control for practice effects. The purpose of review assessments was to identify areas of improvement. Therefore, a subset of tests, where performance was below premorbid estimates from each previous assessment, was selected. Arch Phys Med Rehabil Vol 86, February 2005
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COGNITIVE IMPAIRMENTS IN THE LIS, New Table 1: Neuropsychologic Test Results Test
Wechsler Scales WAIS-III Digit span Vocabulary Arithmetic Comprehension Similarities Picture completion Matrix reasoning Block design Object assembly Digit symbol Verbal IQ Performance IQ Full-scale IQ Test
WMS-III Mental control Logical memory I Logical memory II Visual reproduction I Visual reproduction II Visual reproduction II recognition Verbal paired associates I Verbal paired associates II Other Tests
SDMT Rey figure: copy Rey figure: 30-min recall Austin maze WCST No. of trials Total errors Total perseverative responses Total perseverative errors TMT-A TMT-B TMT-B minus TMT-A (ie, TMT-B speed) HVOT
6-Month Percentiles (Age Scale)
12-Month Percentiles (Age Scale)
24-Month Percentiles (Age Scale)
37th (9) 75th (12) 63rd (11) 75th (12) 37th (9) 16th (7) 84th (13) 50th (10) 1st (3) 1st (3) 103 (prorated) 86 96
37th (9) NA 95th (15) 63rd (11) 63rd (11) 25th (8) 84th (13) 37th (9) 5th (5) 9th (6) 110 (prorated) 87 100
50th (10) NA NA NA 63rd (11) NA NA NA 16th (7) 9th (6) NA NA NA
Age Scale
Age Scale
Age Scale
4 15 11 11 9 10 7 9
9 15 15 13 17 12 13 13
Percentiles (Raw Score)
⬍0.1st (25) 62nd (35) 66th (22) 7th (73) 107 8th (35) 5th (20) 4th (19) 0.3rd (59s) ⬍0.1st (200s) ⬍0.1st (141s) High probability of impairment (16)
NA NA NA NA NA NA NA NA
Percentiles (Raw Score)
Percentiles (Raw Score)
0.1st (30) 50th (33) 90th (28) 42nd (43)
12th (48) 62nd (35) 79th (24) 79th (29)
79 98th (12) 99th (7) 99th (6) 0.1st (64s) 7th (100s) 88th (36s) Moderate probability of impairment (20)
NA NA NA NA 2nd (51s) 18th (84s) 90th (33s) Moderate probability of impairment (20)
NOTE. For the WAIS-III and WMS-III, borderline is 4 to 6, below average is 7, average is 8 to 12, and high average is 13 to 15. Abbreviations: HVOT, Hooper Visual Organizational Test; NA, not assessed; Rey figure, Rey-Osterrieth complex figure; SDMT, Symbol Digit Modalities Test; TMT-A, Trail-Making Test Part A; TMT-B, Trail-Making Test Part B; WAIS-III, Wechsler Adult Intelligence Scale–III; WMS-III, Wechsler Memory Scale–III; WCST, Wisconsin Card Sorting Test.
Results are presented as percentile scores, where possible, to facilitate comparison with expected population norms. The percentiles for the Wechsler Adult Intelligence Scale–III31 (WAIS-III) are estimates only. They have been calculated from a conversion table32 for WAIS–Revised, because no WAIS-III scaled score–percentile conversion tables are available. For other tests, results were converted to percentile ranks from a published conversion table.33 No conversion to percentiles is available for the Wechsler Memory Scale–III34 (WMS-III). The estimated level of premorbid intelligence, based on educational background and highest subtest score on the WAIS-III, was high average. On initial testing, the WAIS-III full-scale IQ was below this estimate. This was mainly due to impairments of processing speed, attention and concentration, Arch Phys Med Rehabil Vol 86, February 2005
and functioning on performance-based tests. Results at 12 months indicated that the verbal IQ had increased to approximate premorbid estimates, using a confidence interval of 95% (ie, verbal IQ score from 105 to 115 ranges from average to high average). Mild to moderate improvements in processing speed and attention at 12 months had a marginal impact on performance IQ, and full-scale IQ remained in the average range, below premorbid estimates. Initial performance on the digit symbol subtest indicated significant slowing in speed of processing. This could have been accounted for by impaired graphomotor skills. Therefore, the effects of graphomotor skills were controlled for by using the oral Symbol Digit Modalities Test35 (SDMT), which has no motor component, and the impairment persisted. At the
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12-month review, speed on both measures had increased. At 24 months, however, speed had plateaued on the digit symbol subtest but had increased on the SDMT. This suggests that improvements in graphomotor and processing speed occurred between 6 and 12 months, with processing speed continuing to improve and approximating average levels at 24 months. Graphomotor speed remained significantly below average levels. Distractibility was a major clinical feature, which corresponded to poor performance on the mental control subtest of the WMS-III and Part B of the Trail-Making Test36,37 (TMT). Concentration on the former test improved to premorbid estimates at 12 months. Divided attention on the TMT improved at 12 and 24 months, but the patient’s performance was still substantially below premorbid estimates, at approximately the 20th percentile. This interpretation must be mediated by the confounding effect of graphomotor slowing on performance. A difference score (TMT-B minus TMT-A) essentially removes the speed element from the test evaluation of TMT-B.38 This calculation indicated that, on initial testing, divided attention was significantly impaired, but on both reviews, it had returned to the premorbid estimate above the 90th percentile. On the mental arithmetic subtest, the patient had difficulty retaining the details of the questions in his mind and manipulating them. This working memory difficulty improved significantly at 12 months after stroke, commensurate with premorbid estimates. On initial testing, poor performance was displayed on the object assembly subtest of the WAIS-III. There was no corresponding poor performance on the block design subtest of the WAIS-III and no evidence of impaired planning skills on his copy of the Rey-Osterrieth complex figure. An impairment of perceptual organizational and integration skills, however, was noted from the results of the Hooper Visual Organizational Test39 (HVOT), confirming that the reduction in these skills, rather than planning skills, produced a poor performance on the object assembly subtest. Although poor motor skills may have contributed to a lower score, performance continued to improve across reviews on the object assembly subtest and the HVOT. The HVOT is not a timed test, which suggests that increased speed associated with improved motor skills was less of a contributing factor on both tests than improvement in visual organization and integration skills. A mild impairment of visual organization and integration skills persisted at 24 months after stroke. On the WMS-III, the patient’s visual and verbal memory were generally intact on initial testing. Inefficiencies in verbal learning were apparent on the verbal paired associates subtest, where performance was at a low-average level, indicating difficulties organizing the information to be learned. This improved to estimated premorbid levels at review testing 12 months after stroke. A pushbutton maze, the Austin maze test, was administered to assess executive functioning. Issues of decreased motor control did not reduce the patient’s ability to accurately press the buttons. In addition, this test was not timed; therefore, motor slowing was not a confounding factor in interpretation. On initial testing, the same errors were repeated across trials, use of error feedback was not evident, and he had difficulty slowing down responses to eliminate impulsive errors. These results suggested executive impairment, specifically mental flexibility, impulse control, and error use. Executive difficulties were also evident on initial assessment on the Wisconsin Card Sorting Test40,41 (WCST). The total number of errors, perseverative responses, perseverative errors, and the number of trials made to complete the task, indicated a
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level of functioning significantly below premorbid estimates. On review testing, executive problems improved significantly, reaching estimated premorbid levels at 24 months after stroke. In summary, neuropsychologic deficits on initial testing included the following: significant slowing of graphomotor speed; significant slowing in speed of processing information; fluctuation in sustained attention; poor divided attention; difficulties on tasks requiring visual organization and integration; inefficiencies in verbal new learning and impaired executive skills, specifically mental flexibility, impulse control, error utilization; and an inability to inhibit laughing and crying. Deficits that persisted at 24 months after stroke included slow graphomotor speed, visual integration and organization skills, and difficulties with pathologic laughing and crying. DISCUSSION Our patient made a slow but gradual recovery in function over a prolonged period of time. His final functional status was a “full recovery,” using the Patterson classification.3 This pattern of recovery of LIS is very uncommon overall, but there are other cases in the literature where this has been reported.10,12,13 Because improvement is difficult to predict and can be delayed and notable, we agree with others that aggressive supportive therapy should be considered in the early months after the onset of LIS.10,13 An interdisciplinary rehabilitation approach is essential to provide comprehensive care for these patients.3,10,42 Studies reporting normal cognitive abilities in LIS patients17-19 have been based on limited testing of discrete functions and not on detailed assessments, such as those conducted in this case. A previously mentioned report of some LIS patients having cognitive deficiencies9 did not provide any results of neuropsychologic testing. Of the 8 patients mentioned in that report, only 1 had LIS due to pontine ischemia. The remaining patients had other causes associated with cognitive impairment. Our case of LIS had an isolated lesion of the lower anterior midbrain and upper anterior pons, with no evidence of additional lesions that could explain the documented cognitive impairments. As mentioned above, serial MRI brain scans did not show any cortical or subcortical lesions that could account for the cognitive impairments. In addition, the neuropsychologic profile was not consistent with a hypoxic brain injury, in which severe memory difficulties are predominantly noted consequences. There may be a possibility that the occlusion of the left vertebral artery could have led to diffuse and widespread brain lesions not detectable in a SPECT or MRI scan, although this is unlikely. The results of our testing suggest that lesions of the pons and lower midbrain may be associated with impairment of higher-level cognitive functioning. Practice effects must be considered when interpreting neuropsychologic testing undertaken at 12 and 24 months. For the WAIS-III, test-retest data for adults 30 to 54 years, after an interval of 2 to 12 weeks, show that the mean full-scale IQ score on the second testing was 5 points higher than that on the first testing, 8 points higher for performance IQ, and 2 points higher for verbal IQ.43 For the auditory subtests used from the WMS-III, test-retest data for adults 16 to 54, after an interval of 2 to 12 weeks, indicated that the largest increase in subtest scores was only 2 points higher than on initial testing.43 Improvements on repeat testing in the current case occurred on 4 or more scale scores, which suggests more than just a practice effect. No test-retest data were available for the visual reproduction subtest. It is important to note that data related to the testing intervals used in this case (ie, 6mo, then 12mo) were not available. Arch Phys Med Rehabil Vol 86, February 2005
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In general, tests that involve a large speed component, that require an unfamiliar or infrequently practiced mode of response, that have a single solution, or that involve learning tend to show large practice effects.38 Although a patient who remembers the rules from the first testing on the WCST and uses them in the second is likely to have an improved executive performance, an alternate path on the Austin maze was used on review, and performance paralleled that on the WCST. This suggests an underlying improvement in executive functioning, over and above the potential practice effects on the WCST. Overall, we believe that our findings are robust, because alternative forms were used where available, and there was no improvement between the 6- and 12-month reviews on numerous tests and subtests. In addition, the interpretations of some assessment findings were not based on individual tests but rather on the relationship between performances on a number of tests (eg, block design, object assembly, HVOT). A recent study21 of patients with small lacunar infarctions of the brainstem found similar impairments in neuropsychologic testing to those identified in our case—slower speed and difficulty with concept shifting. Because there is no direct involvement of the pons or midbrain in cognition, it is possible that there is an indirect influence. It has been hypothesized that infarctions in this region may have indirect effects on neurologic functioning through hypometabolism or other neurochemical changes.21 It is also possible that cognitive disturbances may occur because of interruption of the neural pathways passing through the brainstem. Some evidence in the literature supports this concept. Animal studies have shown the presence of a fronto-pontine loop44 and a cerebro-cerebellar circuit that consists of afferent inputs through cortico-ponto-cerebellar pathways and efferent cerebello-thalamic-cortical pathways.45 Reviews on the pedunculopontine tegmental nucleus support its involvement in attentional and learning processes, possibly by influencing cortical function via the thalamus, basal forebrain, and basal ganglia.46 The pontine and basal forebrain cholinergic systems may be involved in visual attentional functioning, modulation of short-term spatial memory, and the ability to use response rules.47 There is increasing evidence to support a role for the cerebellum in cognitive processing, and this may be partially mediated via the above-mentioned pathways. Patients with olivoponto-cerebellar atrophy have shown visuospatial deficits and signs of a mild frontal–like syndrome.48 Evidence also suggests that cerebellar lesions may be associated with impairments in planning,49 verbal paired-associate learning tasks,50,51 error detection,51 and executive functions.52 It has been suggested that patients who have lesions of the posterior lobe of the cerebellum and vermis lesions can develop impairments of executive functioning, difficulties with spatial cognition, personality changes, and language deficits.53 These findings concur with the deficits identified in our patient. A number of researchers over the years have noted the presence of pathologic laughing3,13,15 and crying3,9,21 in LIS survivors. These observations, however, have not been discussed in detail. It has been hypothesized that these phenomena may be due to a pseudobulbar lesion resulting from damage to the corticobulbar tracts.20 A recent review54 of the neurology of laughter reports that the expression of laughter is regulated by 2 partially independent pathways. An “involuntary” system involves the amygdala, thalamic/hypothalamic and subthalamic areas, and the dorsal and tegmental brainstem, whereas a “voluntary” system originates in the premotor and frontal opercular areas and proceeds through the motor cortex and pyramidal tract to the ventral brainstem. These systems and the Arch Phys Med Rehabil Vol 86, February 2005
laughter response are regulated by a laughter-coordinating center in the dorsal upper pons.54 Lesions in LIS patients could affect these pathways. Our findings have a number of implications. First, there is a need to continue supportive therapy of LIS survivors for several months, until prognosis is more certain, because it cannot be accurately predicted in the first few days or weeks. Second, because patients with LIS may have cognitive impairments, the acute hospital, rehabilitation, and long-term care facilities that care for LIS patients will need to consider this possibility in their assessment and management plans. If further research confirms a similar cognitive profile in patients recovering from LIS to that presented here, then the following recommendations will assist with management and rehabilitation. To address the distractibility and slowed processing, the following strategies are recommended: minimizing distractions in the environment, ensuring that 1 person speaks at a time, ensuring a reduced speed of speech delivery when talking with the patient, and allowing more time waiting for a response. These strategies are likely to increase the effectiveness of communication. Inefficiencies in new learning of verbal material can be improved by ensuring that verbal information is structured and delivered in small parts. This will assist registration and recall. The impulse control issue can be addressed by teaching patients to deliberate on their response before giving it (eg, STOP-THINK-RESPOND). This may improve the reliability of intentions and decisions. The increased tendency to repeat errors indicates the importance of getting tasks correct the first time, to avoid repeating the same mistake. Further research is needed to replicate these findings, to describe the different forms of cognitive impairment that can result from pons and brainstem lesions, and to localize other related areas or pathways that affect cognition. Practical issues will need to be overcome, to enable detailed systematic studies. These include the small number of patients who are available for study and the presence of possible confounding lesions. We have studied other patients with LIS who also had cognitive impairments on neuropsychologic testing. These other patients, however, all had pathologic conditions or processes involving other areas of the brain that are associated with cognitive processing. Because of these confounding factors, they were not able to add any further information to the case presented above. Practical difficulties of conducting assessment of patients who are anarthric and tetraplegic also need to be addressed, to facilitate further study of cognitive impairments in patients with LIS. Conventional understanding of neuroanatomy does not describe the pons or brainstem as having a role in cognitive functioning. If our findings can be replicated in a larger series of patients, this would challenge current concepts of cognitive functioning in the LIS and, more generally, the relationship between higher cognitive functioning and the brainstem. CONCLUSIONS Neuropsychologic testing in this patient, who sustained an LIS, suggests that lesions of the pons may be associated with impairments of higher-level cognitive functioning. After LIS, recovery in many areas may continue for up to 2 years after stroke. References 1. Plum F, Poser J. Diagnosis of stupor and coma. Philadelphia: FA Davis; 1966. 2. Karp JS, Hurtig HI. “Locked-in” state with bilateral midbrain infarcts. Arch Neurol 1974;30:176-8. 3. Patterson JR, Grabois M. Locked-in syndrome: a review of 139 cases. Stroke 1986;17:758-64.
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