Patients with stroke confined to have diminished response to rehabilitation efforts

Ichiro Miyai, MD, PhD; Alan D. Blau, PhD; Michael J. Reding, MD; and Bruce T. Volpe, MD

Article abstract-Prediction of the functional outcome for patients with stroke has depended on the severity of impair- ment, location of brain injury, age, and general medical condition. This study compared admission and discharge func- tional outcome (Functional Independence Measure, FIM) and deficit severity (Fugl-Meyer, F-M) scores in a retrospective study of patients with similar neurologic impairments: homonymous hemianopia, hemisensory loss, and hemiparesis. CT-verified stroke location was the independent variable: cortical (n = ll),basal ganglia and (normal cortex and thalamus, n = 131, or combined (cortical, basal ganglia, and internal capsule, n = 22). By 3 months on average after stroke, all groups demonstrated significantly improved motor function as measured by F-M scores. Patients with cortical lesions had the least CT-imaged damage and the best outcome. Patients with combined lesions and more extensive brain injury had significantly higher FIM scores (p< 0.05) than patients with injury restricted to the basal ganglid internal capsule. Patients with basal ganglidinternal capsule injury were more likely to have hypotonia, flaccid paralysis, and persistently impaired balance and ambulation performance. While all patients had a comparable rehabilitation experience, these results suggest that patients with stroke confined to the basal ganglia and internal capsule benefited less from therapy. Isolated basal ganglia stroke may cause persistent corticothalamic-basal ganglia interactions that are dysfunctional and impede recovery. NEUROLOGY 1997;48:95-101

In several studies rehabilitative intervention has im- matter, but not the basal ganglia, corona radiata, or inter- proved the functional outcome of patients with nal capsule. The basal ganglia lesion (BG) involved the but until there is a precise definition of the caudate, , and corona radiata with or without in- severity of the impairment, lesion location, and ternal capsule damage. The combined lesion (COM) in- quantitative definition of functional outcome, the volved cortex, corona radiata, and the basal ganglia with clinical mechanisms for improvement will remain or without internal capsule damage. The thalamus was unclear. To begin to understand these mechanisms also examined in each scan, and was not damaged in any for functional improvement, this study quantified patient. In order to estimate the volume of injury, each lesion on CT was transposed to the right hemisphere of the neurologic impairment and functional outcome in pa- standardized horizontal brain template^.^ These images tients with lesions confined to the cortex, or to the were then superimposed using NIH Image Version 1.54. to basal ganglia and internal capsule, or to both loca- produce lesion density maps for each group of patients. tions: cortex, and basal ganglidinternal capsule. Reliable and valid scales were used to measure neuro- logic impairment and functional outcome; namely the Methods. We retrospectively reviewed the rehabilitation Fugl-Meyer scale (F-M),'O ambulation endurance," and the outcome of consecutively admitted patients presenting Functional Independence Measure (FIM).12 Each patient with hemiparesis, hemisensory loss, and hemianopia. All was evaluated at the time of admission and discharge. All patients admitted to the Burke Rehabilitation Hospital patients had multidisciplinary rehabilitation in the same from December 1993 to July 1995 were included. Patients stroke unit. Self-care subscore of FIM was the sum of who had had prior stroke, who were not functionally inde- scores for eating, grooming, bathing, dressing upper body, pendent prior to admission, or who had any complications dressing lower body, toileting, bladder management, and requiring transfer to an acute-care hospital were excluded. bowel management (max = 56). Ambulation subscore of These inclusion and exclusion criteria permitted a compar- FIM was the sum of scores for transfers: to bed, to toilet, to ison of the outcome of stroke rehabilitation among patients tub; and walking on level surfaces and on stairs (max = with comparable neurologic deficit^^.^ and with the same 35). Communication subscore was the sum of scores for quantity and quality of rehabilitation experience. Location comprehension and expression (max = 14). Cognition sub- of the brain lesions was classified as cortical, basal score of FIM was the sum of scores for communication, ganglidinternal capsule, or combined based on CT infor- social interaction, problem solving, and memory (max = mation obtained on average 8 2 3 days after the onset. The 35). Total FIM score then was the sum of self-care, ambu- cortical lesion (CX) involved cortical and subcortical white lation, and cognition subscores (max = 126). Total FM

From the Department of Neurology, Cornell University Medical College, The Burke Rehabilitation Center, White Plains, Ny. Received May 17, 1996. Accepted in final form June 25, 1996. Address correspondence and reprint requests to Dr. Bruce T. Volpe, Department of Neurology, Cornell University Medical College, The Burke Rehabilitation Center, 785 Mamaroneck Ave, White Plains, NY, 10605. Copyright 0 1997 by the American Academy of Neurology 95 Figure 1. This photomontage depicts lesion density maps (A, D. G) of stroke patients with motor, sensory, and visual deficits, and examples of CT from patients with the largest (B, E, H) and smallest (C, F, I!, lesions within each group. Patients had a cortical lesion (CX, A-C) that in- volved cortical and subcortical , but not the basal ganglia, corona radiata, or internal capsule; a basal ganglia lesion (BG', D-F) that involved the caudate lznd puta- men and corona radiata uth or without internal capsule damage; or a combined lesion (COM, C-I) that involved cortex, corona radiata, and the basal ganglia with or without internal capsule damage. Each le- sion on CT was transposed to the right hemisphere of the standardized horizontal brain templates.' These images were then superimposed us- ing NIH Image Version 1.54 to pro- duce lesion density maps lor each group of patients. (A, CX; D, BG; G, COM).

score (max = 202) was the sum of scores for upper extrem- shown in table 1. Patients in the three groups demon- ity (max = 661, lower extremity (max = 34), balance strated comparable age, sex distribution, interval post- (max = 14), joint pain (max = 441, and passive motion stroke, side of stroke, type of stroke (infarction or hemor- (max = 44). Sensation subscore of F-M was omitted be- rhage), Mini-Mental State Examination score and compli- cause approximately half of the patients could not be eval- cations. uated due to aphasia. Table 2 and figure 2 display the dynamic (changes in Statistical analysis relied on an ANOVA in which lesion FIM for all groups. The first analysis attempted to test group, functional outcome scores, and age were factors.13 whether age had an effect on the change in FIM scores. A three-factor mixed ANOVA was performed with group (CX Results. Forty-six of 330 patients had hemiparesis, versus BG versus COM) and age (above and below 65) as hemisensory loss, and hemianopia. All patients had dam- between-subject factors. Time (admission versus dis- age in the cortical or subcortical region that was consistent charge) was the within-subject factor. The dependent vari- with the neurologic deficit, namely, the sensorimotor cor- able was the total FIM score. There was no main effect of tex and the subcortical sensory and motor pathways and age [F(1,40)= 0.014, ns], nor was there any significant age the optic radiations (for the BG group, posterior to the interaction with other variables. Since age had no effect on internal capsule approximately 3.1 cm dorsal to the can- the change in FIM scores over time, it was dropped from thomeatal line, for the CX and COM group, temporal and further analysis. parietal lobes). Further motor evaluation demonstrated The second analysis focused on the change of FIM that flaccidity (all the articular segments of the affected scores for each group over time. There were significant upper and lower extremities) was present in 0 of 11 pa- main effects for group [F(2,40) = 6.107, p < 0.0051, and for tients with CX, 5 of 13 patients (38%)with RG, and 4 of 22 time [F(1,40) = 75.785, p < 0.00011. All group:; improved patients (18%)with COM. CT analysis revealed that 11 significantly from admission to discharge in FIM scores patients had CX lesions, 13 patients had BG lesions, and [CX, F(1,lO) = 23.939, p < 0.001; BG: F(1,12) = 15.431, 22 patients had COM lesions. Figure 1 demonstrates the p < 0.002; COM: F(1,21) = 64.874, p < 0.00111. Impor- lesion density map for each group and examples of the tantly, there was a significant interaction between group largest and smallest injury within each group. The brain and time [F(2,40) = 4.996, p < 0.021. Post hoc analysis injury was always confined to the territory of the middle using the least significant difference test (LSD) revealed cerebral artery, but the thalamus was normal in all scans. that the CX group had a significantly higher admission Demographic features of patients in each group are total FIM score (76 2 5) than either the BG group (54 2 7, 96 NEUROLOGY 48 January 1997 Table 1 Demographic features in stroke patients with motor, sensory, and visual deficits

cx BG COM p Value

(n = 11) (n = 13) (n = 22) Age (years) 64 2 4 73 2 3 64 2 2 n.s.* Sex (M/F) 318 617 12/10 n.s.t Days after stroke 24 2 3 31 f 5 25 * 5 n.s.;k Side (WL) 912 914 11/11 n.s.1 Type (I/H) 11/0 10/3 2012 n.s.t MMSE 19 * 3 13 2 3 11 t 2 n.s.:b Complications Hypertension 7 (64%) 7 (54%) 15 (68%) n.s.t Ischemic heart disease 4 (36%) 3 (23%) 8 (36%) n.s.t Diabetes mellitus 4 (36%) 3 (23%)) 10 (45%) n.s:t Atrial fibrillation 3 (27%) 4 (31%) 6 (27%) n.s.t Congestive heart failure 2 (18%) 3 (23%) 6 (27%) n.s.t Hypercholesterolemia 3 (27%) 1(8%) 2 (9%) nst COPD 0 (0%) 0 (0%) 2 (9%) n.s.t Depression 2 (18%) 3 (23%) 6 (27%) nst

Data are mean 2 SEM. t Chi-square test. * ANOVA.

CX = cortical lesion; BG = basal ganglia lesion; COM = combined lesion of CX and BG; M = male; F = female; R = right; L = left; H = hemorrhage; MMSE = Mini-Mental State Examination; COPD = chronic obstructive pulmonary disease.

p < 0.01) or COM (52 2 3, p < 0.005). The BG and COM did not differ between the BG (103 rfr 5) and the COM groups had comparable FIM scores on admission. Further, groups (100 t 4), however, it was significantly better in the COM group discharge FIM score (81 2 4) was no dif- the CX group (149 t 10, p < 0.0001). Similarly, discharge ferent from that of the CX group (96 2 5)and was signifi- total F-M score did not differ between the BG (109 t 8) cantly higher than the BG group (65 ? 6, p < 0.05). Post and the COM (110 t 6) groups. It was significantly better hoc analysis of the subscores of the FIM demonstrated that in CX (160 2 9, p < 0.0001, see table 2). Thus, neurologic the differences in total FIM depended on self-care and deficit improved comparably for all groups. These results ambulation subscores ( p < 0.02, COM versus BG), but not suggest that the remarkable functional improvement in on the communication or cognition subscore (see table 2). the COM group compared with the BG group cannot be Next, an ANOVA was performed with ambulation en- dependent on change in neurologic deficit measured by durance as the dependent variable. Results demonstrated F-M score. main effects for group [F(2,40) = 8.250, p < 0.0021 and Subscore analysis of F-M revealed that the only sub- time [F(1,40)= 87.154,~< 0.00011 and a significant inter- score with significant main effects for group [F(2,41) = action between group and time [F(2,40) = 9.509, p < 8.663, p < 0.0011 and time [F(1,41) = 69.837, p < 0.0011 0.00011. These results are consistent with the observation and a significant interaction [F(2,41) = 3.584, p < 0.051 for total FIM score. Post hoc analysis showed that ambula- was the balance score of F-M. Post hoc analysis revealed tion endurance at admission was significantly better in the that the CX group had a significantly higher admission CX group (140 f 38 ft) than BG (32 2 16 ft, p < 0.02) or F-M balance score (8 2 1) than either the COM (5 2 1,p < COM (46 2 23 ft, p < 0.02). The BG and COM groups had 0.0005) or BG groups (4 2 1, p < 0.0005) without differ- comparable admission ambulation endurance. Once again, ence between COM and BG. However at the time of dis- on discharge the CX group was significantly better than charge, the COM group F-M balance score (8, 2 1) was the other two, but the COM group improved to a higher comparable to the CX group (10 2 l), and was significantly functional level than BG [discharge endurance scores (see higher than the BG group (6 5 1, p < 0.05, see table 2). table 2) CX (577 2 111 ft), BG (119 ? 27 ft), COM (320 2 Discharge disposition (home versus nursing home) did 45 ft)]. not differ among the three groups. Home/nursing home To analyze the neurologic deficit scores, a similar was 11/0 in CX, 10/3 in BG, and 19/3 in COM. Length of ANOVA with total F-M score as the dependent variable stay (LOS) was 42 2 5 days in the CX group, 54 ? 5 days was applied. Results demonstrate main effects for group in BG, and 65 ? 5 days in COM. The COM group had [F(2,34) = 19.802,~< 0.00011, and time [F(1,34) = 7.391, significantly longer LOS than CX (p < 0.01, LSD), how- p < 0.021. Also there was no interaction between group ever, there was no difference between BG and COM nor and time [F(2,34) = 0.978, ns]. Admission total F-M score between CX and BG. January 1997 NEUROLOGY 48 97 Table 2 FIM, ambulation endurance, and F-M in stroke patients with motor, sensory, and visual deficits

Post hoc tests

CX(n = 11) BG (n = 13) COM (n = 22) CX vs BG CX vs COM COM vs BG

FIM Total Admission 76 + 5 54 t 7 52 t 3 <0.01 <0.005 n.s. Discharge 96 t 5 65 + 6 81 t 4 <0.001 ns. 0.05 FIM Self-care Admission 33 t 2 25 t 3 23 t 2 <0.05 (0.01 n.s. Discharge 42 -+ 3 28 t 3 37 t 2 <0.005 n.s. (0.02 FIM Ambulation

Admission 17 t 2 10 t 1 11 t 1 =0.0001 <0.000 1 11,s. Discharge 24 + 2 15 + 1 20 t 1 <0.001 n.s. (0.02 FIM Communication Admission 10 t 1 821 751 n.s. n.s. n.s. Discharge 11 2 1 LO + 1 9?1 n.s. n.s. ns. FIM Cognition Admission 26 + 3 18 t 3 18 2 2 n.s. CO.05 n.s. Discharge 30 t 1 22 ? 3 24 f 2 n.s. ns. n.s. Ambulation (ft) Admission 140 t 38 32 -+ 16 46 f 23 C0.02 (0.02 ns. Discharge 577 t 111 119 2 27 320 + 45 <0.0005 <0.02 =0.005 F-M Total Admission 149 + 10 103 ? 5 100 t 4 ~0.0001 ~0.0001 n.s. Discharge 160 + 9 109 t 8 110 f 6 <0.0005 <0.0001 ns. F-M UE+Le Admission 56 t 9 20 -+ 4 17 + 3 ~0.0001 <0.0001 n.s. Discharge 67 % 7 30 t 3 29 t 4 <0.0005 ~0.0001 n.s. F-M UE Admission 34 ? 6 10 f 3 822 <0.0001 ~0.0001 n.s. Discharge 40 + 6 16 t 5 13 & 3 =0.001 <0.0001 ns. F-M LE Admission 21 t 3 10 + 2 10 t 2 <0.005 =0.0005 n.s. Discharge 27 + 2 14 t 3 16 t 2 <0.005 10.005 ns. F-M Balance Admission 8+1 421 5+1 <0.0005 <0.0005 ns. Discharge 10 ? 1 621 8+1 (0.005 ns. <0.05 F-M Sense" Admission 13 -+ 3 17 2 4 822 n.s. ns. ns.

Discharge 16 f 3 16 -+ 4 15 ? 2 n.s. n.s. 11,s. F-M Pain Admission 42 -+ 1 40 t 2 38 2 1 n.s. <0.05 n.s. Discharge 41 t 1 36 + 1 34 f 2 n.s. co.01 ns. F-M ROM Admission 42 ? 1 41 + 1 39 t 1 ns. n.s. ns.

Discharge 41 t 1 38 t 1 37 + 1 n.s. 11,s. 11,s.

Data are mean f SEM.

.h For F-M Sense, n = 9 in CX, n = 6 in BG, n = 8 in COM.

UE = upper extremity; LE = lower extremity; ROM = range of motion; FIM = Functional Independence Measure; F-M = Fugl-Meyer score; CX = cortical lesion; BG = basal ganglia lesion; COM = combined lesion. 98 NEUROLOGY 48 January 1997 the worse outcome of the BG group. Put differently, the improvements in balance and ambulation ap- 110- peared to account for the greater improvements in 100 - T functional outcome in the COM group. The BG and COM groups performed comparably on admission 90 - - cx with respect to F-M evaluation of the upper extrem- 80 - BG ity, lower extremity, sensory, range of motion, and 70 - - pain subscores. Disequilibrium in elderly people may $ 60- - COM be associated with diffuse subcortical white matter lesions and with poor functional outcome.26 Other 50 - investigators have also reported that balance as 40 - measured by F-M scores and ambulation perfor- 30 - mance on the FIM correlate better with functional 20 - performance and activities of daily living than the standard F-M scores of raw motor po~er.~~.~~Along 10 - these lines, investigators have reported that damage " I I to the basal ganglia and internal capsule, particu- larly the lentiform nucleus (putamen and globus pal- lid~~)~~or the ,so was associated with hypo- tonia and muscle flaccidity. Pantano et al.29reported Figure 2. Dynamic changes of FIM total score for each further that functional outcome was poorest in pa- group. CX group had a significantly higher admission to- tients with these lesions. Similarly, our data demon- tal FIM score than either BG group (p < 0.01) or COM strate a higher proportion of patients with hypotonia (p < 0.005). COM group discharge FIM score was no dif- and flaccidity in the BG group (38%)compared with ferent from that of the CX group and significantly higher the COM group (18%) and CTX group (0%). Taken than the BG group (p < 0.05). See Results and table 2 for together these data suggest that when the basal gan- details. glia and internal capsule are damaged decreased muscle tone is likely, and may be associated with persistent imbalance and poor ambulation. Yet corti- Discussion. Patients with comparable neurologic cal damage alone more often causes increased mus- deficit (as measured by neurologic examination and cle tone, and this factor may have contributed to the F-M deficit scores) 3 months after stroke have func- best functional outcome in the CX group. tional outcome dependent on CT localization. Age The unusual improved outcome in the COM group was not a factor in our study, as has been with more damage than the BG group prompts a rep~rted.'~-'~Patients with only cortical lesions had detailed inspection of the anatomic injury (see figure the least damage and the best outcome. However, 1).The CX group had normal internal capsular anat- the comparison of the combined cortex, basal gan- omy. This lack of damage to the internal capsule glia, and internal capsule (COM) group with the almost certainly contributes to the best FIM and basal ganglia and internal capsule (BG) group dem- F-M measures, and the best functional outcome in onstrates improved functional outcome for the COM the CX group. However, patients with COM and BG group. These findings show that larger lesions do not lesions had comparable damage to the anterior and necessarily predict worse functional outcome. A de- to the posterior limb of the internal capsule. In sup- tailed examination of the differences among these port of this structural analysis is the functional mea- groups demonstrates that the BG group had persis- sure, namely, the F-M demonstrated comparable tently impaired balance, ambulation, and persistellt neurologic deficit at admission and discharge for hypotonia. There is precedent for these findings. these two groups. Differential damage to the internal Dromerick and RedingZOsuggested that discharge capsule cannot account for the difference of func- Barthel Index scores were superior in a group with tional outcome between the combined and subcorti- combined damage compared with a group with in- cal group. In fact, the only difference on CT between jury confined to the basal ganglia. The nonsignifi- the COM and BG groups was the larger region of cant differences they observed may have been due to damage in the overlying cortex in the COM group. the use of the Barthel Scale instead of more sensitive Since both the BG and COM groups had similar measures of functional outcome and neurologic defi- basal ganglia damage, the difference in functional cit, namely the FIM and the F-M scales."ST2 Another outcome among the groups might be attributed to precedent is found in studies that have demon- altered basal ganglia modulation of the cortex and strated poor functional outcome in patients with thalamus.31r3ZOur clinical data show that residual damage in the posterior limb of the internal capsule cortex impedes recovery, and suggests that cortex and either the basal ganglia or the thalam~s.~~-~~disconnected from the basal ganglia may cause per- A closer analysis of the FIM and F-M subscales sistent hemispheric dysfunction. supports the contention that persistent imbalance Clinical and experimental evidence suggest that and ambulation impairment contributed strongly to direct damage to the basal ganglia-nigral network or January 1997 NEUROLOGY 48 99 to the corticothalamic network initiates additional with hemiparesis, hemihypesthesia, and hemianopia. 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Continuous bromocriptine therapy in menstrual migraine Andrew G. Herzog, MD, MSc

Article abstract-This investigation assessed the effects of an open, prospective trial of adjunctive continuous bromocrip- tine therapy on the frequency of refractory, disabling menstrual migraine. It compared continuous bromocriptine with previously optimal baseline therapy and cyclic perimenstrual bromocriptine use. The subjects were 24 women with disabling migraines that occurred exclusively or at least 50% of the time within 3 days before or after the onset of menstruation despite treatment. We added bromocriptine 2.5 mg three times a day to their existing regimen and compared menstrual migraine frequency during the first year with the year prior to bromocriptine. Eighteen of the 24 women experienced a 25% or greater decline in migraine frequency. Migraine frequency declined by 72% overall (p< 0.01). Three women did not tolerate bromocriptine, and three did not benefit. None of the women had a 10% or greater increase in headaches. Continuous bromocriptine therapy was also significantly more effective than intermittent bro- mocriptine use ( p < 0.05). Continuous bromocriptine therapy appears to benefit menstrual migraine. NEUROLOGY 1997;48:101-102

Migraine commonly occurs in women with a cyclic menstruation. Menstrual migraines were intractable de- catamenial pattern of exacerbation.' It occurs with spite prophylactic trials of beta blockers, antidepressants, menstruation in more than 60% of cases and exclu- and calcium channel blockers, alone or in combination. sively at that time in 14%.2 Menstrual migraine is They also failed to respond adequately to acute therapy often refractory to treatment1Z2 and can cause with ergotamine and, in some cases, sumatriptan. Disabil- monthly visits to the emergency room. Various ergot ity referred to an inability to pursue activities that were derivatives, such as methysergide and lisuride, show ordinarily carried out at work or at home. efficacy in migraine prophylaxis without particular The 24 women were placed on bromocriptine 2.5 mg tid benefit for menstrual mig~-aine.~.~Cyclic, intermit- in addition to their previously optimal existing treatment. tent bromocriptine use benefits some features of pre- The number of migraine episodes during the first year was menstrual syndrome, but has little effect on men- compared with the year prior to bromocriptine using the strual Continuous-use bromocriptine in Wilcoxon matched-pairs signed rank test. seven women with regularly occurring menstrual mi- Eight of the women were also tried on cyclic use of graine, however, was associated with only one epi- bromocriptine prior to continuous use, starting on day 21 sode during a total of 12 cycles of observation.s This of each menstrual cycle until day 3 of the next cycle for investigation assessed the effects of an open, pro- four consecutive cycles. spective trial of adjunctive, continuous bromocriptine therapy on the frequency of refractory, disabling Results. Eighteen of the 24 women (75%)experienced a menstrual migraine. We compared continuous bro- mocriptine with previously optimal baseline therapy 25% or greater decline in disabling migraine on continuous bromocriptine therapy. Fifteen of the women (62.5%)had a and cyclic perimenstrual bromocriptine use. reduction of over 50%; seven (29%) experienced complete resolution. Three did not tolerate bromocriptine because of Methods. The subjects were 24 women between the ages light-headedness or nausea. Headache frequency among of 20 and 45 years who had refractory, disabling migraine,9 the 21 who remained on therapy declined by 72%, from a with or without auras, occurring exclusively, or at least on total of 330 during the baseline year to 93 during the year 50% of occasions, within 3 days before or after the onset of of bromocriptine therapy [p< 0.01). Three did not benefit

From the Neuroendocrine Unit, Charles A. Dana Research Institute, Beth Israel Hospital, and the Department of Neurology, Harvard Medical School, Boston, MA. Presented in part at the 47th annual meeting of the American Academy of Neurology, Seattle, WA, May 1995. Received March 1, 1996. Accepted in final form June 12, 1996. Address correspondence and reprint requests to Dr. Andrew G. Herzog, Neuroendocrine Unit, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215. Copyright 0 1997 by the American Academy of Neurology 101