Novel CNS-directed drug delivery systems in Alzheimer's disease and other neurological disorders.

Increasing knowledge of the neurochemical aspects of central nervous system function raises the possibility of treating Alzheimer's disease (AD) and other neurological diseases by the appropriate manipulation of neurotransmitters, neuromodulators, neurohormones or neurotrophic factors. Clinical application of this knowledge may, however, be inhibited by long standing problems with drug delivery to the central nervous system (CNS). Novel, CNS-directed, drug delivery systems might be used to overcome many of these problems. The problems encountered in drug delivery to the brain, present experience with the clinical use of some novel drug delivery systems and the advantages and disadvantages of these systems will be discussed.

Continuous ICV infusion of scopolamine impairs sustained attention of rhesus monkeys.

Systemic administration of anticholinergic agents impairs cognitive performance in animals and man. The anticholinergic, scopolamine, has profound effects on peripheral and central cholinergic function, making interpretation of its effects on cognitive performance difficult. To circumvent this problem, scopolamine was administered directly to the central nervous system of rhesus monkeys using a subcutaneously implanted infusion pump connected to a cannulae directed toward the right lateral ventricle. Intracerebroventricular (ICV) infusion of scopolamine (0.004, 0.012, 12.5, and 40.0 micrograms/kg/h) produced a dose-dependent decrease in the number of responses on a continuous performance task. Response decrements produced by scopolamine were seen mainly during the last half of the test session and at short stimulus durations. These data suggest that scopolamine produces a deficit in sustained attention or slowing of information processing that is mediated through direct central cholinergic blockade in the rhesus monkey.

The spectrum of imaging and neuropsychological findings in Pick's disease.

To seek improved methods for the diagnosis of Pick's disease, we reviewed imaging studies of four women and two men (ages 48 to 65 years at onset) and psychometric testing of three of them with autopsy or biopsy-proved Pick's. The presence of Pick bodies was required for the diagnosis. Seven patients with biopsy-proved Alzheimer's disease served as a comparison group. In the Pick's patients, CT in five of six showed marked frontal pole or temporal pole atrophy, which clearly differed from the pattern of cerebral atrophy seen in the Alzheimer's patients. Psychometric testing showed performance patterns that tended to differ from those of the Alzheimer's patients in that recent memory was relatively preserved despite marked impairment of executive functions. The distinctive psychometric pattern in the Pick's patients was evanescent, however. Thus, there were imaging and psychometric findings of potential diagnostic value for Pick's disease, but, for different reasons, they were imperfect.

Intracerebroventricular bethanechol chloride administration in Alzheimer's disease.

In June 1983 we began evaluating intracerebroventricular (ICV) cholinergic drug infusion in patients with biopsy-documented Alzheimer's disease (AD). An initial trial in four patients showed this treatment approach to be feasible, but objective improvement in cognitive or social function was not documented. A double-blind, placebo-controlled crossover study involving a larger number of patients has since been done. The results of this study, presented here, document a statistically significant improvement in some neuropsychological test results during periods of drug infusion. However, the degree of improvement is not sufficient to justify further treatment with the presently available drug, bethanechol chloride.

Anticonvulsant activity of the glial GABA uptake inhibitor, THAO, in chemical seizures.

The antiseizure activity of the glia-selective GABA uptake inhibitor, 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepin-3-ol (THAO), was evaluated in rats in models of acute chemoconvulsion. In these experiments, intracerebroventricular administration of the drug 30 min prior to testing in doses between 100-750 micrograms provided protection against maximal pentylenetetrazol seizures and increased the latency to isonicotinic acid hydrazide seizures. Pentylenetetrazol seizure thresholds, in contrast, were not significantly elevated. The ability of THAO to suppress tonic but not generalized minor seizures suggests that it may block seizure spread.

Venous hypertension associated with a posterior fossa dural arteriovenous fistula: another cause of bithalamic lesions on MR images.

We report a case of a posterior fossa arteriovenous fistula (AVF) with bithalamic hyperintensity of MR images. The thalamic abnormality improved after surgery, suggesting reversible venous hypertension as the pathogenesis of the finding, as opposed to infarction. This manifestation of a posterior fossa AVF should be considered in the differential diagnosis of bilateral thalamic disease.

Colloid cyst of the third ventricle: sometimes more conspicuous on CT than MR.

We present two cases of surgically proved colloid cysts that were more apparent on CT scans than on MR images. These cysts, while hyperdense on CT scans, were nearly isointense with brain on multiple MR sequences. This relative lack of visibility represents a potential pitfall when imaging a patient with headache.

Arteriovenous malformations in elderly patients.

This article discusses the presentation, natural history, and management of arteriovenous malformations (AVMs) in elderly patients, based on our experience at the Dartmouth-Hitchcock Medical Center. We also present a review of the literature. In our series of 50 patients with AVMs who were operated on by one surgeon, six patients were 65 years old or older at the time of presentation. All six patients presented with intracerebral hemorrhage, and one patient had developed a seizure disorder 2 months before hemorrhaging. In three patients, the clinical course was consistent with the occurrence of two hemorrhages within a 48-hour period. The patients' preoperative neurological status varied from intact to moribund. In two patients, the diagnosis of AVM was made intraoperatively. Preoperative angiography revealed the diagnosis in the remaining patients. All the patients underwent surgical excision of their AVMs. Despite concurrent medical illnesses, all patients tolerated the procedure well with no new, persistent neurological deficits. At follow-up, all patients showed sufficient neurological recovery to return to the community and four of the patients were neurologically intact. Based on this experience and a review of the literature, we conclude that AVMs in elderly patients are not benign lesions and that surgical excision should be considered among the management options for these patients.

Encephalomeningocele presenting with spontaneous cerebrospinal fluid rhinorrhea in an elderly man: case report.

The case of a patient with spontaneous cerebrospinal fluid (CSF) rhinorrhea from an intranasal encephalomeningocele is presented. The case is unusual in that the patient was entirely asymptomatic until the age of 65, when copious CSF rhinorrhea developed without trauma or operation as an inciting event. The pertinent literature is reviewed, and no identical case has been found.

Telencephalic theory of generalized epilepsy: observations in split-brain patients.

The anatomical structures involved in the origin and spread of generalized seizures in humans have not been fully elucidated. Cortical, centrencephalic, and corticoreticular theories have been proposed to explain the clinical and electroencephalographic findings in patients with primary, generalized epilepsy or secondarily generalized seizures. Our observations in patients undergoing forebrain commissurotomy for intractable, generalized seizures lead us to propose a telencephalic theory of generalized epilepsy. This theory stresses the importance of the cerebral cortex as the site of origin of seizure discharge and the function of the forebrain commissures in the rapid propagation and bilateral synchronization of such discharge. These observations plus a review of the data generated from animal models of epilepsy are presented as evidence for such a theory. Although none of our patients had classical petit mal epilepsy, our findings suggest a secondary role of the brain stem reticular formation in generalized seizures and may be cogent to the discussion of primary, generalized epilepsy.

Carotid endarterectomy with regional anesthesia.

The senior author (REH) has changed his technique for performing carotid endarterectomy from the use of general anesthesia to the use of cervical block anesthesia. Because a randomized study was not performed, it is difficult to separate effects of increased surgical experience from those caused by a change in anesthetic regimen. Nonetheless, there has been a substantial decrease in complications, length of hospital stay, and costs concomitant with the change to regional anesthesia; we think there is a causal relationship. The use of cervical block anesthesia has practically eliminated the non-stroke-related complications associated with carotid endarterectomy in our practice. The technique for performing carotid endarterectomy under cervical block anesthesia is described in detail.

Early discharge after carotid endarterectomy.

A consecutive series of 233 carotid endarterectomies performed over a 4-year period by one neurosurgeon was reviewed to analyze the number, nature, cause, and time to occurrence of complications. The time to discharge was analyzed regarding the type of anesthesia used and the time period during which surgery was performed. The records were reviewed to determine whether any complication could have been prevented by routine postoperative monitoring in an intensive care unit or by longer postoperative hospitalization. There were no perioperative deaths. The incidence of ipsilateral stroke was 1.7% and of major stroke was 0.9%. Nondisabling myocardial infarctions occurred in 1.3% of the patients. Complications occurred in a bimodal time course, less than 48 hours or greater than 1 week. The time to discharge decreased during the study period from 4.44 +/- 4.22 days for the first year of the study to 1.56 +/- 1.31 days for the last year of the study (P < 0.0001). A trend toward earlier discharge for patients who received cervical block anesthesia rather than general anesthesia did not reach statistical significance. No adverse patient outcome could be attributed to lack of intensive care unit monitoring or to early discharge. Our data demonstrate that patients who have undergone carotid endarterectomies do not routinely require intensive care unit monitoring and that discharge 24 to 48 hours after surgery is safe for the majority of patients. This regimen can result in considerable savings without compromising the quality of patient care.

Teratoma of the cavernous sinus: case report.

We report the case of an infant with a mature teratoma of the lateral wall of the cavernous sinus. A complete excision of the tumor was achieved. There was no evidence of recurrence at 1-year follow-up examination. Intracranial teratomas and the anatomy of the lateral wall of the cavernous sinus are briefly reviewed. To our knowledge, this is the first case of a teratoma confined to the cavernous sinus.

Clinical outcomes for patients at high risk who underwent carotid endarterectomy with regional anesthesia.

OBJECTIVE: To compare the clinical outcomes for patients with carotid artery stenosis with advanced age, diabetes mellitus, atherosclerotic coronary vascular disease, and contralateral internal carotid artery occlusion who underwent carotid endarterectomy (CEA), using regional anesthesia, with the outcomes for patients without these risk factors. METHODS: A prospective series of 600 CEAs performed using regional anesthesia was analyzed. All patients were surgically treated under the direction of one neurosurgeon, in an academic medical center. Clinical outcome measures were any stroke, death, or cardiac morbidity within 30 days after surgery. All patients were monitored until a clinical end point was reached and/or 6 weeks had elapsed after surgery. The incidence of adverse clinical outcomes among the suspected high-risk patients was compared with the incidence for the entire series using contingency-table analysis (chi2 and Fisher's exact tests). RESULTS: Fifteen strokes (2.5%), three cardiac complications (0.5%), and two deaths (0.3%) occurred within 30 days after CEA. None of the suspected risk factors was associated with a significantly (P < 0.05) increased risk of perioperative morbidity or death. CONCLUSION: CEA using regional anesthesia can be performed for patients with advanced age, diabetes mellitus, atherosclerotic coronary vascular disease, and contralateral internal carotid artery occlusion, with acceptably low perioperative morbidity rates.

Use of implantable pumps for central nervous system drug infusions to treat neurological disease.

Increasing knowledge of the neurochemical aspects of central nervous system function raises the possibility of treating neurological disease by the appropriate manipulation of neurotransmitters, neuromodulators, and neurohormones. Clinical application of this knowledge has been inhibited, however, by long-standing problems with drug delivery to the central nervous system (CNS). The availability of implantable drug infusion pumps and stereotactic catheter placement techniques may overcome many of these problems. The problems of drug delivery to the brain and the present and potential uses of implantable drug pumps for neurological disease are discussed. In addition, the relationship between CNS drug infusion and neural tissue transplantation is briefly reviewed.

Pediatric cerebellar infarction: case report and review of the literature.

Infarction in the vertebrobasilar system is uncommon in children. Cerebellar infarction presenting as a posterior fossa mass lesion is distinctly rare. We recently treated a 13-year-old boy with such a lesion as a complication of basilar artery migraine. A review of the literature on vertebrobasilar infarction in children is presented and the therapeutic alternatives in cerebellar infarction are discussed.

Preliminary report: intracranial cholinergic drug infusion in patients with Alzheimer's disease.

After toxicity studies in dogs, a preliminary feasibility trial of the continuous intracranial infusion of a muscarinic agonist was begun in four patients with biopsy-documented Alzheimer's disease. During the last 8 months, a totally implantable infusion system has been used to deliver bethanechol chloride into the cerebrospinal fluid of these patients at doses of 0.05 to 0.7 mg/day. Complications have been few and resolved spontaneously or were easily reversible. The subjective response to this treatment has been encouraging, with reports of improved cognitive and social function during drug infusion and a return to base line function with single-blind saline placebo infusions. Obviously, further evaluation will be necessary to demonstrate the efficacy of this treatment, and a double-blind placebo-controlled crossover trial is now being done. However, we think the preliminary results are encouraging and warrant the consideration of this approach as a potential treatment in patients with Alzheimer's disease.

Three-dimensional computed tomographic angiography in the preoperative evaluation of cerebrovascular lesions.

Although three-dimensional computed tomographic angiography was developed as a screening tool for use in patients with suspected cerebrovascular disease, this imaging modality has also proven to be of value in surgical planning for patients with large or unusual vascular lesions of the brain. The three-dimensional images generated by this technique yield valuable information regarding the size and configuration of intracranial aneurysms and vascular malformations, the presence and extent of intra-aneurysmal thrombus, the relationship of the vascular lesion to other cerebrovascular or skeletal structures, aneurysm wall thickness, and the presence and orientation of an aneurysm neck. The use of three-dimensional computed tomographic angiography in representative cases of patients with large or unusual cerebrovascular lesions is presented. It has been our experience that this imaging modality displays anatomical information that is not readily available from standard, intra-arterial angiography, provides better detail for surgical planning than magnetic resonance angiography, and is less expensive than either of these other imaging modalities.

Anticonvulsant activity of intracerebroventricularly administered glial GABA uptake inhibitors and other GABAmimetics in chemical seizure models.

The antiseizure activities of glial or neuronal GABA uptake inhibitors and GABA agonists were compared following intracerebroventricular administration in 2 acute models of chemoconvulsion in rats. The glia-selective GABA uptake inhibitor, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO), given at doses of 100-750 micrograms, i.c.v., protected against maximal pentylenetetrazol (PTZ) seizures and increased the latency to isonicotinic acid hydrazide (INH) seizures for at least 1 h following central administration. THPO failed to increase PTZ seizure thresholds. In contrast, the more potent partly glia-selective GABA uptake inhibitor, cis-4-hydroxynipecotic acid (30-300 micrograms), which is also a substrate for neuronal and glial transport systems, protected only 33% of rats against PTZ-induced tonic extension and had no effect on INH seizure latency. The neuron-selective uptake inhibitor L-2,4-diaminobutyric acid (DABA) at 1500 micrograms exhibited anti-PTZ activity initially and then, after a delay, produced proconvulsant behavior and spontaneous myoclonus in some animals. Intracerebroventricular injection of the GABA receptor agonist, muscimol, at toxic doses, gave rise to mixed anticonvulsant (INH seizures) and proconvulsant (PTZ seizure thresholds) effects. The results suggest that THPO, of the 4 compounds tested, possesses significant anticonvulsant activity. Its ability to suppress tonic but not generalized minor seizures suggests that it may block seizure spread.