Very Early Constraint-Induced Movement during Stroke Rehabilitation (VECTORS): A single-center RCT.

BACKGROUND: Constraint-induced movement therapy (CIMT) is among the most developed training approaches for motor restoration of the upper extremity (UE). METHODS: Very Early Constraint-Induced Movement during Stroke Rehabilitation (VECTORS) was a single-blind phase II trial of CIMT during acute inpatient rehabilitation comparing traditional UE therapy with dose-matched and high-intensity CIMT protocols. Participants were adaptively randomized on rehabilitation admission, and received 2 weeks of study-related treatments. The primary endpoint was the total Action Research Arm Test (ARAT) score on the more affected side at 90 days after stroke onset. A mixed model analysis was performed. RESULTS: A total of 52 participants (mean age 63.9 +/- 14 years) were randomized 9.65 +/- 4.5 days after onset. Mean NIHSS was 5.3 +/- 1.8; mean total ARAT score was 22.5 +/- 15.6; 77% had ischemic stroke. Groups were equivalent at baseline on all randomization variables. As expected, all groups improved with time on the total ARAT score. There was a significant time x group interaction (F = 3.1, p < 0.01), such that the high intensity CIT group had significantly less improvement at day 90. No significant differences were found between the dose-matched CIMT and control groups at day 90. MRI of a subsample showed no evidence of activity-dependent lesion enlargement. CONCLUSION: Constraint-induced movement therapy (CIMT) was equally as effective but not superior to an equal dose of traditional therapy during inpatient stroke rehabilitation. Higher intensity CIMT resulted in less motor improvement at 90 days, indicating an inverse dose-response relationship. Motor intervention trials should control for dose, and higher doses of motor training cannot be assumed to be more beneficial, particularly early after stroke.

How do strength, sensation, spasticity and joint individuation relate to the reaching deficits of people with chronic hemiparesis?

Hemiparetic subjects present with movement deficits including weakness, spasticity and an inability to isolate movement to one or a few joints. Voluntary attempts to move a single joint often result in excessive motion at adjacent joints. We investigated whether the inability to individuate joint movements is associated with deficits in functional reaching. Controls and hemiparetic subjects performed two different reaching movements and three individuated arm movements, all in the parasagittal plane. The reaching movements were a sagittal 'reach up' (shoulder flexion and elbow flexion) and 'reach out' (shoulder flexion and elbow extension). Joint individuation was assessed by getting each subject to perform an isolated flexion-extension movement at each of the shoulder, elbow and wrist joints. In addition, we measured strength, muscle tone and sensation using standard clinical instruments. Hemiparetic subjects showed varying degrees of impairment when performing reaching movements and individuated joint movements. Reaching impairments (hand path curvature, velocity) were worse in the reach out versus the reach up condition. Typical joint individuation abnormalities were excessive flexion of joints that should have been held fixed during movement of the instructed joint. Hemiparetic subjects tended to produce concurrent flexion motions of shoulder and elbow joints when attempting any movement, one explanation for why they were better at the 'reach up' than the 'reach out' task. Hierarchical regression analysis showed that impaired joint individuation explained most of the variance in the reach path curvature and end point error; strength explained most of the variance in reaching velocity. Sensation also contributed significantly, but spasticity and strength were not significant in the model. We conclude that the deficit in joint individuation reflects a fundamental motor control problem that largely explains some aspects of voluntary reaching deficits of hemiparetic subjects.

Open-label dose-titration safety and efficacy study of tizanidine hydrochloride in the treatment of spasticity associated with chronic stroke.

BACKGROUND AND PURPOSE: Spasticity is a frequently observed motor impairment that develops after stroke; it can cause pain and disability in those affected. The objective of the present study was to evaluate the safety and efficacy of tizanidine, a centrally acting alpha(2)-adrenergic agonist, in the treatment of stroke-related spasticity. METHODS: Forty-seven patients, who were a minimum of 6 months poststroke and had significant spasticity, were studied at 4 centers. Tizanidine was administered in an open-label manner for 16 weeks, beginning at 2 mg/d and slowly titrated to a maximum of 36 mg/d. The Modified Ashworth Scale, muscle strength testing, functional assessments, and Pain and Functional Spasticity Questionnaires were administered at baseline and at 4, 8, 16, and 18 weeks (after 1 week off tizanidine). RESULTS: Spasticity was significantly improved between baseline and week 16, with a decrease in total upper extremity Modified Ashworth Scale score of 2.80+/-0.47 (P<0.0001). No decline in strength was noted. Treatment with tizanidine resulted in a significant improvement in pain intensity (P=0.0375), quality of life (P=0.0001), and physician assessment of disability (P=0.0001). The most frequent side effects were somnolence (62%) and dizziness (32%). No serious adverse events were considered to be drug related. Ten of 47 patients (21%) were able to reach the maximum daily dosage of 36 mg. CONCLUSIONS: Overall, the data suggest that tizanidine is safe and efficacious in the treatment of stroke-related spasticity, preserving muscle strength while reducing muscle tone and painful spasms in affected patients.

Does the application of constraint-induced movement therapy during acute rehabilitation reduce arm impairment after ischemic stroke?

BACKGROUND AND PURPOSE: Motor dysfunction after unilateral deafferentation in primates can be overcome by restraining the unaffected limb. We asked whether a constraint-induced movement (CIM) program could be implemented within 2 weeks after stroke and whether CIM is more effective than traditional upper-extremity (UE) therapies during this period. METHODS: Twenty-three persons were enrolled in a pilot randomized, controlled trial that compared CIM with traditional therapies. A blinded observer rated the primary end point, the Action Research Arm Test (ARA). Inclusion criteria were the following: ischemic stroke within 14 days, persistent hemiparesis, evidence of preserved cognitive function, and presence of a protective motor response. Differences between the groups were compared by using Student's t tests, ANCOVA, and Mann-Whitney U: tests. RESULTS: Twenty subjects completed the 14-day treatment. Two adverse outcomes, a recurrent stroke and a death, occurred in the traditional group; 1 CIM subject met rehabilitation goals and was discharged before completing 14 inpatient days. The CIM treatment group had significantly higher scores on total ARA and pinch subscale scores (P:<0.05). Differences in the mean ARA grip, grasp, and gross movement subscale scores did not reach statistical significance. UE activities of daily living performance was not significantly different between groups, and no subject withdrew because of pain or frustration. CONCLUSIONS: A clinical trial of CIM therapy during acute rehabilitation is feasible. CIM was associated with less arm impairment at the end of treatment. Long-term studies are needed to determine whether CIM early after stroke is superior to traditional therapies.

Mirror movements complicate interpretation of cerebral activation changes during recovery from subcortical infarction.

In recovered stroke patients, performance of motor tasks with the affected limb has been reported to activate cortical areas ipsilateral to the affected side. The better to determine the causal role these areas play in recovery of motor function, we assessed cerebral activation during motor activity longitudinally after hemiparesis due to cerebral infarction. A secondary goal was to ascertain the relation between mirror movements and activation ipsilateral to motor activity. Positron emission tomography with oxygen-15 water measured regional cerebral blood flow during wrist movement early and late in the course of recovery from hemiparesis. Surface electromyography recorded muscular activity, and computer-assisted video analysis quantified movement during the scans. Mirror movements, movements contralateral to the instructed movement of the hemiparetic arm, were often seen. Activation of motor areas in the hemisphere ipsilateral to the affected limb roughly correlated with presence of mirror movements. Other changes in cerebral activation were small, when the task was controlled for rate, but high-rate-specific recruitment of ipsilateral cortical areas occurred in one case. However, the common occurrence of mirror movements, particularly with effortful tasks, complicates interpretation of data regarding the role of the ipsilateral hemisphere in recovery.

Neural correlates of recovery from aphasia after damage to left inferior frontal cortex.

OBJECTIVE: To determine neural correlates of recovery from aphasia after left frontal injury. METHODS: The authors studied the verbal performance of patients with infarcts centered in the left inferior frontal gyrus (IFG), using a battery of attention-demanding lexical tasks that normally activate the left IFG and a simpler reading task that does not normally recruit the left IFG. The authors used positron emission tomography (PET) and functional MRI (fMRI) to record neural activity in the same group of patients during word-stem completion, one of the attention-demanding lexical tasks. To identify potential neural correlates of compensation/recovery, they analyzed the resulting data for the group as a whole (PET, fMRI) and also for each participant (fMRI). RESULTS: Patients with damage to the left IFG were impaired on all attention-demanding lexical tasks, but they completed the word-reading tasks normally. The imaging studies demonstrated a stronger-than-normal response in the right IFG, a region homologous to the damaged left IFG. The level of activation in the right IFG did not correlate with verbal performance, however. In addition, a perilesional response within the damaged left IFG was localized in the two patients who gave the best performance in the word-stem completion task and showed the most complete recovery from aphasia. CONCLUSIONS: Right-IFG activity may represent either the recruitment of a preexisting neural pathway through alternative behavioral strategies or an anomalous response caused by removal of the left IFG. Perilesional activity in the left IFG may represent sparing or restoration of normal function in peri-infarctual tissue that was inactive early on after injury. This activity may be of greater functional significance than right IFG activity because it was associated with more normal verbal performance.

Predictors of acute hospital costs for treatment of ischemic stroke in an academic center.

BACKGROUND AND PURPOSE: We sought to determine predictors of acute hospital costs in patients presenting with acute ischemic stroke to an academic center using a stroke management team to coordinate care. METHODS: Demographic and clinical data were prospectively collected on 191 patients consecutively admitted with acute ischemic stroke. Patients were classified by insurance status, premorbid modified Rankin scale, stroke location, stroke severity (National Institutes of Health Stroke Scale score), and presence of comorbidities. Detailed hospital charge data were converted to cost by application of department-specific cost-to-charge ratios. Physician's fees were not included. A stepwise multiple regression analysis was computed to determine the predictors of total hospital cost. RESULTS: Median length of stay was 6 days (range, 1 to 63 days), and mortality was 3%. Median hospital cost per discharge was $4408 (range, $1199 to $59 799). Fifty percent of costs were for room charges, 19% for stroke evaluation, 21% for medical management, and 7% for acute rehabilitation therapies. Sixteen percent were admitted to an intensive care unit. Length of stay accounted for 43% of the variance in total cost. Other independent predictors of cost included stroke severity, heparin treatment, atrial fibrillation, male sex, ischemic cardiac disease, and premorbid functional status. CONCLUSIONS: We conclude that the major predictors of acute hospital costs of stroke in this environment are length of stay, stroke severity, cardiac disease, male sex, and use of heparin. Room charges accounted for the majority of costs, and attempts to reduce the cost of stroke evaluation would be of marginal value. Efforts to reduce acute costs should be monitored for potential cost shifting or a negative impact on quality of care.

Global aphasia without hemiparesis: language profiles and lesion distribution.

OBJECTIVES: Global aphasia without hemiparesis (GAWH) is an uncommon stroke syndrome involving receptive and expressive language impairment, without the hemiparesis typically manifested by patients with global aphasia after large left perisylvian lesions. A few cases of GAWH have been reported with conflicting conclusions regarding pathogenesis, lesion localisation, and recovery. The current study was conducted to attempt to clarify these issues. METHODS: Ten cases of GAWH were prospectively studied with language profiles and lesion analysis; five patients had multiple lesions, four patients had a single lesion, and one had a subarachnoid haemorrhage. Eight patients met criteria for cardioembolic ischaemic stroke. RESULTS: Cluster analysis based on acute language profiles disclosed three subtypes of patients with GAWH; these clusters persisted on follow up language assessment. Each cluster evolved into a different aphasia subtype: persistent GAWH, Wernicke's aphasia, or transcortical motor aphasia (TCM). Composite lesion analysis showed that persistent GAWH was related to lesioning of the left superior temporal gyrus. Patients with acute GAWH who evolved into TCM type aphasia had common lesioning of the left inferior frontal gyrus and adjacent subcortical white matter. Patients with acute GAWH who evolved into Wernicke's type aphasia were characterised by lesioning of the left precentral and postcentral gyri. Recovery of language was poor in all but one patient. CONCLUSIONS: Although patients with acute GAWH are similar on neurological examination, they are heterogeneous with respect to early aphasia profile, language recovery, and lesion profile.

Intractable hiccups during stroke rehabilitation.

OBJECTIVE: To study the frequency of intractable hiccups during stroke rehabilitation and the impact on rehabilitation management. DESIGN: Case series, retrospective chart review. SETTING: Inpatient stroke rehabilitation floor within a tertiary care teaching hospital. PATIENTS: Three patients admitted for stroke rehabilitation with hiccups of at least 48 hours out of 270 consecutive cases. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Response to pharmacologic treatment. RESULTS: All three subjects had pontine infarcts and required gastrostomy tube feedings and lengthy rehabilitation stays. Subjects suffered from significant complications including aspiration pneumonia, respiratory arrest, and nutritional depletion. Chlorpromazine treatment was terminated in all three subjects because of sedation that interfered with therapies. Treatment with carbamazepine was successful in only one patient; in the other two subjects, their hiccups were controlled with haloperidol or baclofen. All subjects were ultimately managed with a single agent. CONCLUSIONS: Pharmacologic interventions for intractable hiccups must be tailored to the unique circumstances of the stroke rehabilitation patient. Intractable hiccups can be associated with potentially fatal consequences, and safe management may require an inpatient rehabilitation setting and multidisciplinary team approach to optimize the feeding management of this challenging population.

Axial movements are relatively preserved with respect to limb movements in aphasic patients.

Apraxia is commonly manifested during the acute stage following left hemisphere cerebrovascular accident and typically co-occurs with aphasia. We examined 30 acute stroke patients with aphasia and apraxia in order to determine if such patients show evidence of preservation of selective subclasses of movements. Although Geschwind noted the preservation of axial movements to command in aphasic apraxic patients, his views were subsequently refuted. However, we found that aphasic apraxic patients of varying degrees of severity, including patients with global aphasia, showed relative preservation of axial movements to command and imitation. Theoretical interpretations and implications for acute neurologic rehabilitation are discussed.

Simultaneous bilateral thalamic hemorrhages following the administration of intravenous tissue plasminogen activator.

A patient suffered the onset of simultaneous bilateral thalamic hemorrhage several hours after the administration of intravenous tissue plasminogen activator. The patient exhibited features of the paramedian diencephalic syndrome, including executive dysfunction, anterograde amnesia, inattention, and disturbances of visual perception. During rehabilitation, she made significant gains in overlearned activities of daily living tasks, but her inability to retain new information left her severely disabled. The use of intravenous thrombolytic therapy is believed to account for this patient's unusual stroke syndrome. With recent evidence supporting the efficacy of intravenous thrombolysis in acute stroke, patients with multiple hemorrhagic strokes as a result of thrombolysis may become more common on rehabilitation services.

Expansion of a haematoma after urokinase thrombolysis of superior sagittal sinus thrombosis.

SUMMARY: Thrombosis of the superior sagittal sinus may result in significant morbidity and recently up to 20% mortality, Primary treatment has consisted of anticoagulation and methods for controlling increased intracranial pressure. The development of interventional neuroradiologic techniques has enabled infusion of thrombolytics at the clot. We describe a woman with a cerebral haemorrhage due to a thrombosed superior sagittal sinus. Her decreased level of consciousness and increasing hemiparesis prompted direct thrombolytic therapy (urokinase). Flow was restored in the occluded sinus, but an acute expansion of the haematoma an hour after conclusion of the infusion resulted in temporary worsening of her neurologic deficits. Although the ultimate outcome was satisfactory, the possibility of further intracranial bleeding must be balanced against the risk of death with conservative therapy.

Functional outcome for patients with hemiparesis, hemihypesthesia, and hemianopsia. Does lesion location matter?

BACKGROUND AND PURPOSE: Patients with hemiparesis, hemisensory loss, and hemianopsia ("HHH" deficits) due to stroke may have large cortical lesions caused by middle cerebral trunk vessel occlusion or smaller subcortical lesions due to lenticulostriate involvement. We studied the usefulness of lesion location in predicting functional recovery within this syndrome. METHODS: We reviewed our records and found 41 patients who had a single ischemic hemispheric stroke, HHH deficits, and an available CT scan performed more than 24 hours after the onset of symptoms. CT scans were read independently and blindly by the authors. Lesions were initially categorized by arterial distribution on the basis of CT templates published by Kinkel. The numerous combinations of arterial branch vessel occlusions observed did not allow for statistical analyses because of the small number of subjects within each subgroup. Lesions were therefore classified as cortical (C), subcortical (S), or mixed (M). RESULTS: There were no significant differences among the three anatomic groups for age, sex, interval after stroke, Mini-Mental Status Examination score, or admission Barthel Index score. Functional outcome measures did not differ significantly for the three groups: mean +/- SD discharge Barthel score (C, 64 +/- 31; S, 47 +/- 20; M, 57 +/- 21), length of stay ([days] C, 64 +/- 25; S, 77 +/- 24; M, 73 +/- 28), and frequency of nursing home placement (C, 4/8; S, 3/6; M, 2/16). CONCLUSIONS: For patients with HHH deficits, the anatomic location of the lesion (C versus S versus M) does not affect functional outcome.

Medical and neurological complications during inpatient stroke rehabilitation.

BACKGROUND AND PURPOSE: We sought to assess the type, frequency, and clinical predictors of neuromedical complications occurring during inpatient rehabilitation after stroke. METHODS: One hundred consecutive patient records were reviewed. All medical and neurological complications requiring a physician's order for further evaluation or treatment were recorded. RESULTS: Complications were urinary tract infection (44 cases), depression (33), musculoskeletal pain (31), urinary retention (25), falls (25), fungal dermatitis (24), hypotension (19), diabetes mellitus (16), hypertension (15), and other neuromedical problem (194). The mean +/- SD numbers of medical and neurological complications per patient were 3.6 +/- 2 and 0.6 +/- 0.8, respectively. Complications were independently related to both the severity of functional disability as judged by Barthel score (r = -.42, P < .001) and length of rehabilitation hospital stay (r = .54, P < .001). Cardiac complications were predicted by New York Heart Association class 3 or 4 symptomatology on admission (P < .05). The age, sex, interval from stroke to rehabilitation hospital admission, and ischemic versus hemorrhagic etiology of the stroke were unrelated to the number of complications observed. Thirteen patients required transfer back to an acute-care hospital, one of whom died within 24 hours of transfer. There were no deaths on the rehabilitation unit. CONCLUSIONS: We have defined the type and frequency of neuromedical complications during inpatient rehabilitation after stroke. Their frequency varies with the severity of stroke, cardiovascular comorbidity, and length of stay.

The regulatory component of adenylate cyclase. Purification and properties of the turkey erythrocyte protein.

The regulatory component (G/F) of adenylate cyclase has been purified from turkey erythrocyte plasma membranes by adaptation of procedures developed for purification of the rabbit liver protein. The major modifications entail inclusion of high concentrations of NaCl to facilitate extraction and reconstitution of the protein. A typical preparation yields 200 micrograms of protein with a reconstitutive specific activity of 3-4 mumol . min-1 mg-1. Turkey erythrocyte G/F contains two putative subunits of 35,000 and 45,000 daltons. The 52,000-dalton polypeptide that appears to be a component of rabbit liver G/F is lacking. In solution, G/F behaves as a particle with Mr = 81,000. This value is reduced to 50,000 in the presence of activating ligands, suggesting dissociation of subunits. Activation of G/F by guanine nucleotide analogs is markedly accelerated in the presence of high concentrations of Mg2+. Reconstitutive and physical properties of the protein are also affected by fluoride. Cyc- S49 lymphoma membranes reconstituted with turkey erythrocyte G/F acquire properties that are characteristic of the turkey adenylate cyclase system; at least certain differing characteristics of adenylate cyclase systems are thus dictated by the nature of their G/F.

Response of guanosine 5'-triphosphate concentration to nutritional changes and its significance for Bacillus subtilis sporulation.

We have investigated the changes in the guanosine 5'-triphosphate (GTP) and P-ribosyl-PP pools in stringent and relaxed strains of Bacillus subtilis under conditions frequently used to initiate sporulation. After a shift-down from a Casamino Acids-glutamate to a glutamate medium (Sterlini-Mandelstam shift-down), the pools of adenosine 5'-triphosphate and P-ribosyl-PP increased in both strains; in the stringent strain, ppGpp and pppGpp increased and GTP decreased rapidly, whereas in the relaxed strain, ppGpp and pppGpp increased only slightly and GTP decreased only slowly and less extensively. The stringent strain sporulated well, whereas the relaxed strain sporulated late and poorly. Addition of decoyinine, an inhibitor of guanosine 5'-monophosphate synthetase, caused a further decrease of GTP and initiated good sporulation of the relaxed strain. After a shift-down from a glucose-lactate to a lactate medium (Ramaley-Burden shift-down) the pool of P-ribosyl-PP (and GTP) decreased in both strains, indicating a shortage of purine precursors. This shift-down also caused a stringent response which prevented the consumption of nucleotides, as shown by the maintenance of adenosine 5'-triphosphate at a high concentration in the stringent strain but not in the relaxed strain. After a delay, the relaxed strain, in which GTP decreased as fast as in the stringent strain, sporulated also as efficiently. In nutrient sporulation medium the stringent strain and, less effectively, the relaxed strain accumulated ppGpp and pppGpp transiently towards the end of exponential growth. Eventually, the P-ribosyl-PP pool decreased drastically in both strains. In all cases the initiation of sporulation was correlated with a significant decrease of GTP. Granaticin, an antibiotic which prevents the charging of leucyl-transfer ribonucleic acid, was used to show that the stringent response inhibited the formation of xanthosine monophosphate from inosine monophosphate. It prevented the accumulation of xanthosine monophosphate in decoyinine-treated cultures of the stringent strain but not in those of the relaxed strain.