Continuous CSF drainage in AD: results of a double-blind, randomized, placebo-controlled study.

BACKGROUND: Alzheimer disease (AD) has been associated with abnormal cerebral clearance of macromolecules, such as amyloid and microtubule-associated-protein tau (MAP-tau). We hypothesized that improving clearance of macromolecules from the CNS might slow the progression of dementia. OBJECTIVE: This prospective, randomized, double-blinded, placebo-controlled trial evaluated the safety and effectiveness of a surgically implanted shunt in subjects with probable AD. METHODS: A total of 215 subjects with probable AD by National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria received either a low-flow ventriculoperitoneal shunt or a sham (occluded) shunt for 9 months. Longitudinal CSF sampling was performed in both active and control subjects. Primary outcome measures were the Mattis Dementia Rating Scale and the Global Deterioration Scale. CSF Abeta((1-42)) and MAP-tau also were assayed. RESULTS: After a planned interim analysis, the study was halted for futility. Using the intent-to-treat population, no between-group differences were observed in the primary outcome measures. The surgical procedure and device were associated with 12 CNS infections, some temporally associated with CSF sampling. All were treated successfully. CONCLUSIONS: We found no benefit to low-flow CSF shunting in subjects with mild to severe Alzheimer disease. CSF infections, while treatable, occurred more frequently than expected, in some cases likely related to CSF sampling.

Assessment of low-flow CSF drainage as a treatment for AD: results of a randomized pilot study.

OBJECTIVE: This prospective, randomized, controlled study was designed to investigate the safety, feasibility, and preliminary efficacy of long-term CSF drainage via a low-flow ventriculoperitoneal shunt in subjects suffering from AD. METHODS: Twenty-nine subjects selected for probable AD (National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Dementias Association criteria) were screened to exclude normal pressure hydrocephalus or other etiologies of dementia and randomized to treatment (shunt) or no treatment groups. The study endpoint was the comparison of group performance on psychometric testing at quarterly intervals for 1 year. Shunted subjects had CSF withdrawn for MAP-tau and Abeta((1-42)) assays at the same time intervals. RESULTS: There was no mortality from the surgical procedure, and no patient sustained a subdural hematoma. Five notable postoperative adverse events, which resolved without permanent neurologic deficit, were reported in the shunt group. Group mean Mattis Dementia Rating Scale total scores showed little change over the year in the shunt-treatment group, in contrast to a decline in the control group (p = 0.06). Mini-Mental State Examination mean scores supported a trend in favor of shunt treatment (p = 0.1). There was a concomitant decrease in ventricular CSF concentrations of AD biomarkers MAP-tau and Abeta((1-42)). CONCLUSIONS: The surgical procedure and the device are reasonably safe. Adverse events were consistent with shunt procedures for hydrocephalus in this older population. The endpoint data show a trend in favor of the treated group. A larger, randomized, double-blinded, controlled, clinical trial is underway.

The effects of posteroventral pallidotomy on balance function in patients with Parkinson's disease.

Parkinson's disease is a chronic, progressive neurodegenerative disorder resulting from dopaminergic cell loss in the pars compacta of the substantia nigra. Conventional treatment of Parkinson's disease consists of pharmacological replacement of dopamine. A treatment alternative, posteroventral pallidotomy (PVP), has been used for medically intractable stages of the disease. The purpose of this study was to evaluate the effects of PVP on balance function, as measured by dynamic posturography, in patients with medically intractable Parkinson's disease. Five subjects were studied within 2 days prior to and within 6 months following PVP. Pretreatment abnormalities were found in vestibular, visual, and somatosensory processing in balance function. Posteroventral pallidotomy resulted in improvement in vestibular compensation of posture in some patients, which may be at least partially due to an improvement in latencies to respond to changes in stance. Dynamic posturography is an effective tool in the evaluation of balance and posture in patients with advanced Parkinson's disease.

The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer's type.

OBJECTIVE: To evaluate the production rate of CSF in patients with differing disease states. METHODS: The authors measured the production rate of CSF in three groups of patients: five patients with PD below age 60 (aged 51 +/- 4 years, mean +/- SD), nine with PD over age 60 (aged 69 +/- 6 years, mean +/- SD), and seven with dementia of the Alzheimer's type (AD) (aged 72 +/- 9 years, mean +/- SD). This method, based on the Masserman technique, employs ventricular rather than a lumbar access to the CSF space. Furthermore, the volume of CSF removed during the procedure is only 3 mL rather than 10 mL. RESULTS: These measurements indicate that the mean rate of CSF production in patients with PD under age 60 was 0.47 +/- 0.13 mL/minute, in patients with PD aged 60 or older the mean rate was 0.40 +/- 0.12 mL/minute, and in patients with AD the mean rate was 0.20 +/- 0.06 mL/minute. CONCLUSION: These results indicate that the rate of CSF production in patients with PD is normal, and that the rate of CSF production in patients with AD is markedly reduced.

Comparisons of tumor suppressor p53, p21, and p16 gene therapy effects on glioblastoma tumorigenicity in situ.

The mutation and/or deletion of tumor suppressor genes have been postulated to play a major role in the genesis and the progression of gliomas. In this study, the functional expression and efficacy in tumor suppression of 3 tumor suppressor genes (p53, p21, and p16) were tested and compared in a rat GBM cell line (RT-2) after retrovirus mediated gene delivery in vitro and in vivo. Significant reductions in tumor cell growth rate were found in p16 and p21 infected cells (60 +/- 12% vs 66 +/- 15%) compared to p53 (35 +/- 9%). In vitro colony formation assay also showed significant reductions after p16 and p21 gene delivery (98 +/- 5% vs 91 +/- 10%) compared to p53 (50 +/- 18%). In addition, the tumor suppression efficacy were investigated and compared in vivo. Retroviral mediated p16 and p21 gene deliveries in glioblastomas resulted in more than 90% reductions in tumor growth (92 +/- 26% vs 90 +/- 22%) compared to p53 (62 +/- 18%). Tumor suppressor gene insertions in situ further prolonged animal survival. Overall p16 and p21 genes showed more powerful tumor suppressor effects than p53. The results were not surprising, as p16 and p21 are more downstream in the cell cycle regulatory pathway compared to p53. Moreover, the mechanism involved in each of their suppressor effects is different. This study demonstrates the feasibility of using tumor suppressor genes in regulating the growth of glioma in vitro and in situ.

Sonic hedgehog promotes proliferation and tyrosine hydroxylase induction of postnatal sympathetic cells in vitro.

The role of Sonic hedgehog (shh) in neural crest development was initially suggested by its involvement in patterning of the neural tube. While largely implicated in cell fate determination during development, its recently discovered role in the development of neurons postnatally prompted the possibility that neural crest derivatives of the sympathoadrenal lineage may respond to Shh postnatally. In the present study, we show that Shh promotes proliferation of postnatal sympathetic cells in culture. While it has been previously found to induce tyrosine hydroxylase (TH) production in the developing midbrain, we also demonstrated that Shh is capable of promoting TH induction of mature sympathetic neurons in vitro. This duality in Shh can be inhibited by activation of protein kinase A. These findings suggest that cell response to Shh is conserved in sympathetic ganglia derived from the neural crest, and further supports the notion that Shh can function postnatally in a dose-dependent manner to mediate neuronal cell fate.

Combined assessment of tau and neuronal thread protein in Alzheimer's disease CSF.

OBJECTIVE: Comparative study of CSF levels of tau and AD7C-neuronal thread protein (NTP) in patients with AD and control subjects. BACKGROUND: AD is characterized by neurofibrillary tangles composed of the abnormally hyperphosphorylated microtubule-associated protein tau. AD7C-NTP is a proposed AD marker expressed at early stages of neurofibrillary degeneration. METHODS: Enzyme-linked immunosorbent assays specific for tau and AD7C-NTP. CSF samples were obtained from 35 demented patients (25 with antemortem clinical diagnosis of probable AD, 5 with neuropathologic diagnosis of definite AD, 5 with Lewy body pathology), 29 nondemented patients with PD, and 16 elderly healthy control subjects. Receiver operating characteristics (ROC) and multivariate discriminant analysis for AD versus controls. Correlational analysis of CSF tau and AD7C-NTP and of each marker with Mini-Mental State Examination (MMSE) scores was performed. RESULTS: Levels of both tau and AD7C-NTP were significantly elevated in the AD patients compared with control subjects. ROC analysis showed that CSF tau distinguished between patients with AD and nondemented control subjects with 63% sensitivity and 89% specificity, AD7C-NTP with 70% sensitivity and 87% specificity. Combined evaluation of both markers with discriminant analysis raised the specificity to 93% at a 63% sensitivity level. Both markers positively correlated with each other within the AD group, but not among control subjects. CSF levels of AD7C-NTP, but not of tau, showed a small but significant inverse correlation (r = -0.43) with MMSE scores of AD patients. CONCLUSIONS: CSF levels of tau and AD7C-NTP may be useful biomarkers for AD.

Trigeminal neuralgia resulting from infarction of the root entry zone of the trigeminal nerve: case report.

UNLABELLED: OBJECTIVE AND CLINICAL IMPORTANCE: We present a case of trigeminal neuralgia resulting from infarction of the root entry zone of the trigeminal nerve. This is the first reported case of an unusual cause of trigeminal neuralgia. CLINICAL PRESENTATION: A 71-year-old man presented with severe lancinating pain in the left V1 and V2 distributions. Magnetic resonance imaging of the brain demonstrated a small wedge-shaped infarct at the root entry zone of the left trigeminal nerve in the pons. INTERVENTION: Medical management with carbamazepine was initially successful, but the patient later developed refractory pain and was unable to tolerate side effects of the medication. The patient underwent subsequent percutaneous glycerol rhizotomy, which resulted in complete resolution of his pain. CONCLUSION: Infarction of the root entry zone may produce typical symptoms of trigeminal neuralgia similar to a multiple sclerosis plaque at the root entry zone. Treatment of trigeminal neuralgia must consider the underlying cause. Glycerol rhizotomy may provide relief of pain for patients in whom there is no evidence of vascular compression.

Neuropsychological and motor functioning after unilateral anatomically guided posterior ventral pallidotomy. Preoperative performance and three-month follow-up.

This study presents baseline and 3-month follow-up motor and neuropsychological data for 22 patients with Parkinson's disease (PD) who underwent anatomically guided unilateral posterior ventral pallidotomy (PVP). Postsurgical improvements were seen in psychomotor speed, fine motor accuracy, and dyskinesia, whereas grip strength decreased on the side contralateral to the surgery. No change was detected in overall level of cognitive functioning, nor were changes demonstrated in memory, language, or working memory when the entire sample of patients was evaluated. When the group was divided on the basis of side of surgery, patients with left-sided pallidotomies showed a decline in verbal fluency. Patients and caregivers reported improvement in psychosocial functioning. These initial findings of improved motor performance and largely unaffected cognitive functions are consistent with results obtained with functional PVP and provide support for the use of anatomically guided posterior ventral pallidotomy in the treatment of motor symptoms of PD.

Bilateral cavernous malformations resulting from cranial irradiation of a choroid plexus papilloma.

We report a case of multiple parietal cavernous malformations in a thirteen year old female who received cranial irradiation following incomplete resection of a choroid plexus papilloma. The cavernous malformations, which developed within the prior parietal radiation ports, were diagnosed nine years after the patients' radiation treatment when the patient presented with increasing frequency of seizures. Family history was negative for familial cavernous malformations. Due to the worsening frequency of seizures, the patient underwent resection of these two cavernous malformations with diagnosis confirmed by pathology. Post-operative, there was a significant reduction in seizure frequency. The origin and pathophysiology of cavernous malformations remains controversial. Cranial radiation treatment for tumors, particularly in children, may possibly lead to the development of these lesions, as occurred in this case. This is, to our knowledge, the first case of multiple cavernous malformations occurring within a previous radiation field following radiotherapy for a neoplasm.

Functional expression of human p21(WAF1/CIP1) gene in rat glioma cells suppresses tumor growth in vivo and induces radiosensitivity.

This study reports the successful growth suppression of a rat glioblastoma model (RT-2) both in vitro and in vivo by the insertion of p21(WAF1/CIP1), a negative cell cycle regulatory gene, into the tumor cells. Greater than 95% of the tumor cells expressed p21 protein after being infected with pCL based p21 retrovirus at 4x M.O.I. (multiplicity of infection). The p21-infected cells showed a 91% reduction in colony forming efficiency and a 66% reduction in growth rate. More prominent p21 staining was found in cells exhibiting histologic evidence of senescence. Intracranial implantation of the infected cells showed complete disappearance of the p21-infected cells at day 10 and long-term survival of the animals compared to controls. Injection of pCLp21 virus into tumor established in situ showed tumor necrosis and gene expression. In a clonogenic radiation survival assay, a 93% reduction of surviving colonies of p21-infected cells was seen in comparison to vector-infected control cells and to p53-infected cells after exposure to 8 Gy (800 rads).

Intracavitary liposome-mediated p53 gene transfer into glioblastoma with endogenous wild-type p53 in vivo results in tumor suppression and long-term survival.

A cavitary glioblastoma model was created by injection of RT-2 cells, which express endogenous wild type p53, into the peritoneal cavity of nude mice. This model developed multiple layers of tumor cells invading the peritoneal surface and was used to mimic the postoperative surgical cavity remaining after glioblastoma (GBM) excision in patients. Rhodamine labeled DMRIE/DOPE + DNA complexes were found to penetrate at least 20 tumor cell layers. Injection of p53 gene/liposome complexes into the intraperitoneal cavity after the tumor was established resulted in massive tumor necrosis. Prominent staining of human p53 protein using the DO-1 antibody was found in tumor cells near the necrotic lesions. Tumor explants expressed human p53 protein and showed a 54% growth reduction in an in vitro growth assay. Further, DMRIE/DOPE mediated p53 gene transfection significantly increased the mean survival time of tumor bearing mice compared to vector control. These results demonstrate the efficiency of using exogenous wild type p53 to suppress glioblastoma cell with endogenous wild type p53 in vivo through liposome mediated transfection method.

Pleomorphic granular cell astrocytoma of the pineal gland.

BACKGROUND: Primary neoplasms of the pineal gland are uncommon. Two patients with unusual primary pineal tumors that had similar distinctive histologic features are reported. METHODS: The surgically resected neoplastic pineal tissue from these patients were examined by light microscopy, immunohistochemistry, and electron microscopy and correlated with the patients' clinical course. RESULTS: These pineal tumors consisted of a mixture of spindle-shaped cells with fibrillated cell processes and many large lipidized and/or granular pleomorphic cells, some of which were multinucleated. These two tumors superficially resembled pleomorphic xanthoastrocytoma and granular cell tumors of the central nervous system. The pleomorphic tumor cells expressed glial fibrillary acidic protein and some also produced retinal S-antigen, a marker for retinal photoreceptor cells. Long-term follow-up (8 years) on one of these patients suggested a relatively "benign" clinical course. CONCLUSIONS: It is possible that this newly described tumor may be a distinct subset of pineal gland neoplasias with a favorable biologic behavior despite the histologic features that would suggest otherwise.

Stereotactic, angiography-guided clipping of a distal, mycotic intracranial aneurysm using the Cosman-Roberts-Wells system: technical note.

We describe the use of stereotactic, angiographic guidance for localization and clipping of a small, distal intracranial bacterial aneurysm. The technique uses the commercially available Suetens-Gybels-Vandermeulen angiographic localizer with the widely used Cosman-Roberts-Wells stereotactic system. This method is simple and easy to use and significantly decreased the operative time. It may be quite useful for surgically treating mycotic and other peripheral aneurysms.

Neural and metabolic control of arteriolar diameter.

During sympathetic nerve activity, sympathetic transmitter causes depolarizations which trigger voltage dependent Ca++ entry. The ability of arteriolar membranes to sum together successive e.j.ps is changed as a consequence of cellular activity, i.e. increased [K+]o. Furthermore, the ability of arteriolar membrane to permit voltage dependent Ca++ entry is modified by a second consequence of cellular activity, i.e. changes in external pH.

Charged-particle radiosurgery for intracranial vascular malformations.

Heavy charged-particle radiation has unique physical characteristics that offer several advantages over photons and protons for stereotactic radiosurgery of intracranial AVMs. These include improved dose distributions with depth in tissue, small angle of lateral scattering, and sharp distal fall-off of dose in the Bragg ionization peak. Under multi-institutionally approved clinical trials, we have used stereotactic helium-ion Bragg peak radiosurgery to treat approximately 400 patients with symptomatic, surgically inaccessible vascular malformations at the UCB-LBL 184-in synchrocyclotron and bevatron. Treatment planning for stereotactic heavy charged-particle radiosurgery for intracranial vascular disorders integrates anatomic and physical information from the stereotactic cerebral angiogram and stereotactic CT and MR imaging scans for each patient, using computerized treatment-planning calculations for optimal isodose contour distribution. The shape of an intracranial AVM is associated strongly with its treatability and potential clinical outcome. In this respect, heavy charged-particle radiosurgery has distinct advantages over other radiosurgical methods; the unique physical properties allow the shaping of individual beams to encompass the contours of large and complexly shaped AVMs, while sparing important adjacent neural structures. We have had a long-term dose-searching clinical protocol in collaboration with SUMC and UCSF and have followed up over 300 patients for more than 2 years. Initially, treatment doses ranged from 45 GyE to 35 GyE. Currently, total doses up to 25 GyE are delivered to treatment volumes ranging from 0.1 cm3 to 70 cm3. This represents a relatively homogeneous dose distribution, with the 90% isodose surface contoured to the periphery of the lesion; there is considerable protection of normal adjacent brain tissues, and most of the brain receives no radiation exposure. Dose selection depends on the volume, shape, and location of the AVM and several other factors, including the volume of normal brain that must be traversed by the plateau portion of the charged-particle beam. The first 230 patients have been evaluated clinically to the end of 1989. Using the clinical grading of Drake, about 90% of the patients had an excellent or good neurologic grade, about 5% had a poor grade, and about 5% had progression of disease and died, or died as a result of unrelated intercurrent illness. Neuroradiologic follow-up to the end of 1989 indicated the following rates of complete angiographic obliteration 3 years after treatment: 90% to 95% for AVM treatment volumes less than 4 cm3, 90% to 95% for volumes 4 to 14 cm3, and 60% to 70% for volumes greater than 14 cm3.(ABSTRACT TRUNCATED AT 400 WORDS)

Stereotactic helium ion Bragg peak radiosurgery for intracranial arteriovenous malformations. Detailed clinical and neuroradiologic outcome.

89 patients with angiographically documented arteriovenous malformations were treated with helium ion Bragg peak radiation. The rate of complete angiographic obliteration 2 years after radiation was 94% in those lesions smaller than 4 cm3 (2.0 cm in diameter), 75% for those 4-25 cm3 and 39% for those larger than 25 cm3 (3.7 cm in diameter); at 3 years after radiation, the corresponding obliteration rates were 100, 95 and 70%. Major clinical complications occurred in 10 patients (8 permanent, 2 transient) between 3 and 21 months after treatment; all were in the initial stage of the protocol (higher radiation doses). 10 patients bled from residual malformation between 4 and 34 months after treatment. Seizures were improved in 63% and headaches in 68% of patients. Excellent or good clinical outcome was achieved in 94% of patients. Compared to the natural history and risks of surgery for these difficult malformations, we consider these results encouraging. Heavy-charged-particle radiation is a valuable therapy for surgically inaccessible symptomatic cerebral arteriovenous malformations. The current procedure has two disadvantages: the prolonged latent period before complete obliteration and the small risk of serious neurological complications.

Heavy-charged-particle radiosurgery for intracranial arteriovenous malformations.

We have treated over 400 patients with symptomatic inoperable intracranial arteriovenous malformations (AVMs) with stereotactic heavy-charged-particle Bragg peak radiosurgery at the University of California at Berkeley in a collaborative program with Stanford University Medical Center and the University of California Medical Center, San Francisco. A long-term dose-searching clinical trial protocol has been developed and we have followed more than 250 patients for more than 2 years. Initially, radiation doses ranged from 45 to 35 GyE, and now doses of 25, 20, 15 and, under special circumstances, 10 GyE, depending on a number of factors, are being evaluated. The characteristics of charged-particle beams provide a relatively homogeneous dose distribution with the 90% isodose contour to the periphery of the lesion. When the entire arterial phase of the AVM core is included in the treatment field, the rates for complete obliteration 3 years after treatment are: 90-95% for volumes less than or equal to 4 cm3; 90-95% for volumes greater than 4 and less than or equal to 14 cm3; and 60-70% for volumes greater than 14 cm3. The total obliteration rate for all volumes up to 70 cm3 is approximately 80-85%. For complete radiation-induced obliteration there is a relationship of dose and volume primarily, and location secondarily. Results on relationships between dose, AVM obliteration, and complications and sequelae of the radiosurgical procedure are presented and discussed.

Occult vascular malformations of the optic chiasm: magnetic resonance imaging diagnosis and surgical laser resection.

Angiographically occult vascular malformations of the optic nerve and chiasm are extremely rare. Before the advent of magnetic resonance imaging (MRI), it was difficult to diagnose these lesions preoperatively. We report MRI scan findings of optic chiasm cavernous angiomas in two patients with chiasmal syndrome. MRI was useful in localizing the vascular malformation and delineating its characteristics, especially chronic hemorrhage. One patient underwent biopsy of the lesion. The other patient underwent complete microsurgical resection of the malformation with the carbon dioxide laser with preservation of vision. Occult vascular malformations of the optic nerve and chiasm may be a more common cause of visual deterioration than previously recognized. The MRI scan is the imaging modality of choice for diagnosing and following these lesions. In certain patients, these vascular malformations may be amenable to complete surgical removal with stabilization or improvement of visual function.