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Intracerebral drug delivery in rats with lesion-induced memory deficits

Matthew A. Howard III, Alan Gross, M. Sean Grady, Robert S. Langer, Edith Mathiowitz, H. Richard Winn, and Marc R. Mayberg

✓ Pharmacological treatments directed at increasing cortical acetylcholine activity in patients with Alzheimer's disease have largely been disappointing, perhaps because denervated areas of brain may not be exposed to adequate amounts of drug. A new method has been developed to enable localized intracerebral delivery of neurotransmitter substances using a polymeric drug delivery system. Microspheres of a polyanhydride sebacic acid copolymer were impregnated with bethanechol, an acetylcholinesterase-resistant cholinomimetic. Twenty rats received bilateral fimbria-fornix lesions, producing cholinergic denervation of the hippocampus and marked impairment in spatial memory. The animals were trained for 2 weeks to run an eight-arm radial maze, after which they received bilateral intrahippocampal implants of saline (five rats), blank polymer (five rats), or bethanechol-impregnated polymer (10 rats). Following implantation, spatial memory was assessed by radial-maze performance testing for 40 days. Untreated lesioned rats showed persistently poor spatial memory, entering maze arms with near random frequency. Similarly, animals treated with saline and blank polymer did not improve after implantation. Rats treated with bethanechol-impregnated microspheres, however, displayed significant improvement within 10 days after implantation; this improvement persisted for the duration of the experiment (p < 0.05, Student's t-test). Histological analysis of regional acetylcholinesterase staining showed widespread loss of activity throughout the hippocampus bilaterally in all animals. The microsphere implants were visible within the hippocampus, with minimal reactive changes in surrounding brain. It is concluded that intracerebral polymeric drug delivery successfully reversed lesion-induced memory deficits, and has potential as a neurosurgical treatment method for Alzheimer's disease and other neurodegenerative disorders.

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Comparison of balloon angioplasty and papaverine infusion for the treatment of vasospasm following aneurysmal subarachnoid hemorrhage

J. Paul Elliott, David W. Newell, Derek J. Lam, Joseph M. Eskridge, Colleen M. Douville, Peter D. Le Roux, David H. Lewis, Marc R. Mayberg, M. Sean Grady, and H. Richard Winn

Object. The purpose of this study was to test the hypothesis that balloon angioplasty is superior to papaverine infusion for the treatment of proximal anterior circulation arterial vasospasm following subarachnoid hemorrhage (SAH). Between 1989 and 1995, 125 vasospastic distal internal carotid artery or proximal middle cerebral artery vessel segments were treated in 52 patients.

Methods. Blood flow velocities of the involved vessels were assessed by using transcranial Doppler (TCD) monitoring in relation to the day of treatment with balloon angioplasty or papaverine infusion. Balloon angioplasty and papaverine infusion cohorts were compared based on mean pre- and posttreatment velocity at 24 and 48 hours using the one-tailed, paired-samples t-test. Balloon angioplasty alone was performed in 101 vessel segments (81%) in 39 patients (75%), whereas papaverine infusion alone was used in 24 vessel segments (19%) in 13 patients (25%). Although repeated treatment after balloon angioplasty was needed in only one vessel segment, repeated treatment following papaverine infusion was required in 10 vessel segments (42%) in six patients because of recurrent vasospasm (p < 0.001). Seven vessel segments (29%) with recurrent spasm following papaverine infusion were treated with balloon angioplasty. Although vessel segments treated with papaverine demonstrated a 20% mean decrease in blood flow velocity (p < 0.009) on posttreatment Day 1, velocities were not significantly lower than pretreatment levels by posttreatment Day 2 (p = 0.133). Balloon angioplasty resulted in a 45% mean decrease in velocity to a normal level following treatment (p < 0.001), a decrease that was sustained.

Conclusions. Balloon angioplasty is superior to papaverine infusion for the permanent treatment of proximal anterior circulation vasospasm following aneurysmal SAH.

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Comparison of balloon angioplasty and papaverine infusion for the treatment of vasospasm following aneurysmal subarachnoid hemorrhage

J. Paul Elliott, David W. Newell, Derek J. Lam, Joseph M. Eskridge, Colleen M. Douville, Peter D. LeRoux, David H. Lewis, Marc R. Mayberg, M. Sean Grady, and H. Richard Winn

The authors used daily transcranial Doppler (TCD) evaluation to test the hypothesis that balloon angioplasty is superior to papaverine infusion for the treatment of proximal anterior circulation arterial vasospasm following subarachnoid hemorrhage (SAH). Between 1989 and 1995, 125 vasospastic distal internal carotid artery or proximal middle cerebral artery vessel segments were treated in 52 patients. Blood flow velocities of the involved vessels were assessed using TCD monitoring in relation to the day of treatment with balloon angioplasty or papaverine infusion. Balloon angioplasty and papavarine infusion cohorts were compared based on mean pretreatment velocity and mean posttreatment velocity at 24 and 48 hours using the one-tailed, paired-samples t-test. Balloon angioplasty alone was performed in 101 vessel segments (81%) in 39 patients (75%), whereas papaverine infusion alone was used in 24 vessel segments (19%) in 13 patients (25%). Although repeated treatment following balloon angioplasty was needed in only one vessel segment, repeated treatment following papaverine infusion was required in 10 vessel segments (42%) in six patients because of recurrent vasospasm (p < 0.001). Seven vessel segments (29%) with recurrent spasm following papaverine infusion were treated with balloon angioplasty. Although vessel segments treated with papaverine demonstrated a 20% mean decrease in blood flow velocity (p < 0.009) on posttreatment Day 1, velocities were not significantly lower than pretreatment levels by posttreatment Day 2 (p = 0.133). Balloon angioplasty resulted in a 45% mean decrease in velocity to a normal level following treatment (p < 0.001), which was sustained. The authors conclude that balloon angioplasty is superior to papaverine infusion for the permanent treatment of proximal anterior circulation vasospasm following aneurysmal SAH.

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Impairment of intracerebral arteriole dilation responses after subarachnoid hemorrhage

Laboratory investigation

Ik-Seong Park, Joseph R. Meno, Cordelie E. Witt, Abhineet Chowdhary, Thien-Son Nguyen, H. Richard Winn, Al C. Ngai, and Gavin W. Britz

Object

Cerebrovascular dysfunction after subarachnoid hemorrhage (SAH) may contribute to ischemia, but little is known about the contribution of intracerebral arterioles. In this study, the authors tested the hypothesis that SAH inhibits the vascular reactivity of intracerebral arterioles and documented the time course of this dysfunction.

Methods

Subarachnoid hemorrhage was induced using an endovascular filament model in halothane-anesthetized male Sprague-Dawley rats. Penetrating intracerebral arterioles were harvested 2, 4, 7, or 14 days postinsult, cannulated using a micropipette system that allowed luminal perfusion and control of luminal pressure, and evaluated for reactivity to vasodilator agents.

Results

Spontaneous tone developed in all pressurized (60 mm Hg) intracerebral arterioles harvested in this study (from 66 rats), with similar results in the sham and SAH groups. Subarachnoid hemorrhage did not affect dilation responses to acidic pH (6.8) but led to a persistent impairment of endothelium-dependent dilation responses to adenosine triphosphate (p < 0.01), as well as a transient attenuation (p < 0.05) of vascular smooth muscle–dependent dilation responses to adenosine, sodium nitroprusside, and 8-Br-cyclic guanosine monophosphate (cGMP). Impairment of NO-mediated dilation was more sustained than adenosine- and 8-Br-cGMP–induced responses (up to 7 days postinsult compared with 2 days). All smooth muscle–dependent responses returned to sham levels by 14 days after SAH.

Conclusions

Subarachnoid hemorrhage led to a persistent impairment of endothelium-dependent dilation and a transient attenuation of vascular smooth muscle–dependent dilation responses to adenosine. Impairment of NOmediated dilation occurred when the response to cGMP was intact, suggesting a change in cGMP levels rather than an alteration in intracellular mechanisms downstream from cGMP.

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Delayed facial palsy after resection of vestibular schwannoma

Gerald A. Grant, Robert R. Rostomily, D. Kyle Kim, Marc R. Mayberg, Donald Farrell, Anthony Avellino, Larry G. Duckert, George A. Gates, and H. Richard Winn

Object. In this study the authors investigate delayed facial palsy (DFP), which is an underreported phenomenon after surgery for vestibular schwannoma (VS). The authors identified 15 (4.8%) patients from a consecutive series of 314 who underwent surgery for VS between 1988 and 2000, and in whom DFP developed. Delayed facial palsy was defined as a deterioration of facial nerve function from House—Brackmann Grades 1 or 2 more than 3 days postoperatively.

Methods. All patients underwent intraoperative neurophysiological monitoring of facial nerve function. The average latency of DFP was 10.9 days (range 4–30 days). In six patients (40%) minor deterioration (≤ two House—Brackmann grades) had occurred at a mean of 10.2 days postsurgery, whereas in nine patients (60%) moderate deterioration (≥ three House—Brackmann grades) had occurred at a mean of 11.8 days postoperatively. Five (33%) of 15 patients recovered to Grade 1 of 2 function within 6 weeks of DFP onset. Of the 15 patients with DFP, 14 had completed 1 year of follow up at the time of this study. Twelve (80%) of these 15 patients recovered to Grade 1 or 2 function within 3 months, and 13 (93%) of 14 patients recovered within 1 year. In all cases, stimulation of the seventh cranial nerve on completion of tumor resection revealed the nerve to be intact, both anatomically and functionally, to proximal and distal stimulation at 0.1 mA. A smaller tumor diameter correlated with greater recovery of facial nerve function. There was no correlation between the latency or severity of or recovery from DFP, and the patient's age or sex, the surgical approach, frequency of neurotonic seventh nerve discharges, anatomical relationship of the facial nerve to the tumor, patient's history of tobacco use, or cardiovascular disease.

Conclusions. It appears that DFP is an uncommon consequence of surgery for VS. Although excellent recovery of facial nerve function to its original postoperative status nearly always occurs after DFP, the magnitude and time course of the disorder were not predictors for subsequent recovery of facial nerve function.

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Valproate therapy for prevention of posttraumatic seizures: a randomized trial

Nancy R. Temkin, Sureyya S. Dikmen, Gail D. Anderson, Alan J. Wilensky, Mark D. Holmes, Wendy Cohen, David W. Newell, Pamela Nelson, Asaad Awan, and H. Richard Winn

Object. Seizures frequently accompany moderate to severe traumatic brain injury. Phenytoin and carbamazepine are effective in preventing early, but not late, posttraumatic seizures. In this study the authors compare the safety and effectiveness of valproate with those of short-term phenytoin for prevention of seizures following traumatic brain injury.

Methods. The study was a randomized, double-blind, single-center, parallel-group clinical trial. Treatment began within 24 hours of injury. One hundred thirty-two patients at high risk for seizures were assigned to receive a 1-week course of phenytoin, 120 were assigned to receive a 1-month course of valproate, and 127 were assigned to receive a 6-month course of valproate. The cases were followed for up to 2 years.

The rates of early seizures were low and similar when using either valproate or phenytoin (1.5% in the phenytoin treatment group and 4.5% in the valproate arms of the study; p = 0.14, relative risk [RR] = 2.9, 95% confidence interval [CI] 0.7–13.3). The rates of late seizures did not differ among treatment groups (15% in patients receiving the 1-week course of phenytoin, 16% in patients receiving the 1-month course of valproate, and 24% in those receiving the 6-month course of valproate; p = 0.19, RR = 1.4, 95% CI 0.8–2.4). The rates of mortality were not significantly different between treatment groups, but there was a trend toward a higher mortality rate in patients treated with valproate (7.2% in patients receiving phenytoin and 13.4% in those receiving valproate; p = 0.07, RR = 2.0, 95% CI 0.9–4.1). The incidence of serious adverse events, including coagulation problems and liver abnormalities, was similar in phenytoin- and valproate-treated patients.

Conclusions. Valproate therapy shows no benefit over short-term phenytoin therapy for prevention of early seizures and neither treatment prevents late seizures. There was a trend toward a higher mortality rate among valproate-treated patients. The lack of additional benefit and the potentially higher mortality rate suggest that valproate should not be routinely used for the prevention of posttraumatic seizures.

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Preoperative embolization of cerebral arteriovenous malformations with silk sutures: analysis and clinical correlation of complications revealed on computerized tomography scanning

Joon K. Song, Joseph M. Eskridge, Eun-Chul Chung, Lindsey C. Blake, J. Paul Elliott, Lisa Finch, Cyrus Niakan, Kenneth R. Maravilla, and H. Richard Winn

Object. The aim of this study was to determine the incidence and clinical significance of complications related to preoperative embolization of cerebral arteriovenous malformations (AVMs) with silk sutures as documented on postprocedure computerized tomography (CT) scans.

Methods. The CT scans were obtained within 12 to 24 hours after 221 (96%) of 230 consecutive embolizations in 70 patients. These CT scans were evaluated for the presence of ischemia, infarction, hemorrhage, or contrast agent extravasation. Adverse patient outcomes were determined after each embolization and were correlated with CT findings. New abnormalities demonstrated on CT scans were also correlated with the Spetzler—Martin AVM grade, degree of arteriovenous shunting, and location. New abnormalities, the majority of them infarcts, resulted from 29 (13%) of 221 embolization procedures. In 11 (38%) of 29 cases of new CT findings, patients were asymptomatic, including 10 with new infarcts on CT scans. New neurological deficits occurred in 20 (8.7%) of 230 total embolization procedures in 19 patients, including one death. Permanent deficits occurred in nine patients (3.9% per embolization procedure, 12.8% per patient). Of the patients with new neurological deficits, 18 (90%) of 20 embolization procedures resulted in new abnormalities on CT scans. Two patients with new transient neurological deficits had no new findings on CT scans. Spetzler—Martin grade, AVM location, degree of arteriovenous shunting, and higher numbers of procedures were not statistically associated with a higher incidence of abnormalities on CT scans or new permanent neurological deficits.

Conclusions. Silk sutures are an effective and relatively safe embolic agent. After brain AVM embolization with silk sutures, new abnormalities were found on CT scans obtained in one of eight procedures. When a new CT finding occurred, the patient had roughly equal chances of having no new symptoms, having new transient neurological deficits, or having new permanent neurological deficits.

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Cerebral autoregulation following minor head injury

Elisabeth C. Jünger, David W. Newell, Gerald A. Grant, Anthony M. Avellino, Saadi Ghatan, Colleen M. Douville, Arthur M. Lam, Rune Aaslid, and H. Richard Winn

The purpose of this study was to determine whether patients with minor head injury experience impairments in cerebral autoregulation. Twenty-nine patients with minor head injuries defined by Glasgow Coma Scale (GCS) scores of 13 to 15 underwent testing of dynamic cerebral autoregulation within 48 hours of their injury using continuous transcranial Doppler velocity recordings and blood pressure recordings. Twenty-nine age-matched normal volunteers underwent autoregulation testing in the same manner to establish comparison values. The function of the autoregulatory response was assessed by the cerebral blood flow velocity response to induced rapid brief changes in arterial blood pressure and measured as the autoregulation index (ARI).

Eight (28%) of the 29 patients with minor head injury demonstrated poorly functioning or absent cerebral autoregulation versus none of the controls, and this difference was highly significant (p = 0.008). A significant correlation between lower blood pressure and worse autoregulation was found by regression analysis in head-injured patients (r = 0.6, p < 0.001); however, lower blood pressure did not account for the autoregulatory impairment in all patients. Within this group of head-injured patients there was no correlation between ARI and initial GCS or 1-month Glasgow Outcome Scale scores. This study indicates that a significant number of patients with minor head injury may have impaired cerebral autoregulation and may be at increased risk for secondary ischemic neuronal damage.

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Application of magnetic resonance neurography in the evaluation of patients with peripheral nerve pathology

Aaron G. Filler, Michel Kliot, Franklyn A. Howe, Cecil E. Hayes, Dawn E. Saunders, Robert Goodkin, B. Anthony Bell, H. Richard Winn, John R. Griffiths, and Jay S. Tsuruda

✓ Currently, diagnosis and management of disorders involving nerves are generally undertaken without images of the nerves themselves. The authors evaluated whether direct nerve images obtained using the new technique of magnetic resonance (MR) neurography could be used to make clinically important diagnostic distinctions that cannot be readily accomplished using existing methods.

The authors obtained T2-weighted fast spin—echo fat-suppressed (chemical shift selection or inversion recovery) and T1-weighted images with planes parallel or transverse to the long axis of nerves using standard or phased-array coils in healthy volunteers and referred patients in 242 sessions.

Longitudinal and cross-sectional fascicular images readily distinguished perineural from intraneural masses, thus predicting both resectability and requirement for intraoperative electrophysiological monitoring. Fascicle pattern and longitudinal anatomy firmly identified nerves and thus improved the safety of image-guided procedures. In severe trauma, MR neurography identified nerve discontinuity at the fascicular level preoperatively, thus verifying the need for surgical repair. Direct images readily demonstrated increased diameter in injured nerves and showed the linear extent and time course of image hyperintensity associated with nerve injury. These findings confirm and precisely localize focal nerve compressions, thus avoiding some exploratory surgery and allowing for smaller targeted exposures when surgery is indicated.

Direct nerve imaging can demonstrate nerve continuity, distinguish intraneural from perineural masses, and localize nerve compressions prior to surgical exploration. Magnetic resonance neurography can add clinically useful diagnostic information in many situations in which physical examinations, electrodiagnostic tests, and existing image techniques are inconclusive.

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Cerebral autoregulation following minor head injury

Elisabeth C. Jünger, David W. Newell, Gerald A. Grant, Anthony M. Avellino, Saadi Ghatan, Colleen M. Douville, Arthur M. Lam, Rune Aaslid, and H. Richard Winn

✓ The purpose of this study was to determine whether patients with minor head injury experience impairments in cerebral autoregulation. Twenty-nine patients with minor head injuries defined by Glasgow Coma Scale (GCS) scores of 13 to 15 underwent testing of dynamic cerebral autoregulation within 48 hours of their injury using continuous transcranial Doppler velocity recordings and blood pressure recordings. Twenty-nine age-matched normal volunteers underwent autoregulation testing in the same manner to establish comparison values. The function of the autoregulatory response was assessed by the cerebral blood flow velocity response to induced rapid brief changes in arterial blood pressure and measured as the autoregulation index (ARI).

Eight (28%) of the 29 patients with minor head injury demonstrated poorly functioning or absent cerebral autoregulation versus none of the controls, and this difference was highly significant (p = 0.008). A significant correlation between lower blood pressure and worse autoregulation was found by regression analysis in head-injured patients (r = 0.6, p < 0.001); however, lower blood pressure did not account for the autoregulatory impairment in all patients. Within this group of head-injured patients there was no correlation between ARI and initial GCS or 1-month Glasgow Outcome Scale scores. This study indicates that a significant number of patients with minor head injury may have impaired cerebral autoregulation and may be at increased risk for secondary ischemic neuronal damage.