Devin K. Binder

Brain-derived Neurotrophic Factor

Since the purification of BDNF in 1982, a great deal of evidence has mounted for its central roles in brain development, physiology, and pathology. Aside from its importance in neural development and cell survival, BDNF appears essential to molecular mechanisms of synaptic plasticity. Basic activity-related changes in the central nervous system are thought to depend on BDNF modification of synaptic transmission, especially in the hippocampus and neocortex. Pathologic levels of BDNF-dependent synaptic plasticity may contribute to conditions such as epilepsy and chronic pain sensitization, whereas application of the trophic properties of BDNF may lead to novel therapeutic options in neurodegenerative diseases and perhaps even in neuropsychiatric disorders.

Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels

The glial water channel aquaporin‐4 (AQP4) has been hypothesized to modulate water and potassium fluxes associated with neuronal activity. In this study, we examined the seizure phenotype of AQP4 −/− mice using in vivo electrical stimulation and electroencephalographic (EEG) recording. AQP4 −/− mice were found to have dramatically prolonged stimulation‐evoked seizures after hippocampal stimulation compared to wild‐type controls (33 ± 2 s vs. 13 ± 2 s). In addition, AQP4 −/− mice were found to have a higher seizure threshold (167 ± 17 μA vs. 114 ± 10 μA). To assess a potential effect of AQP4 on potassium kinetics, we used in vivo recording with potassium‐sensitive microelectrodes after direct cortical stimulation. Although there was no significant difference in baseline or peak [K+]o, the rise time to peak [K+]o (t1/2, 2.3 ± 0.5 s) as well as the recovery to baseline [K+]o (t1/2, 15.6 ± 1.5 s) were slowed in AQP4 −/− mice compared to WT mice (t1/2, 0.5 ± 0.1 and 6.6 ± 0.7 s, respectively). These results implicate AQP4 in the expression and termination of seizure activity and support the hypothesis that AQP4 is coupled to potassium homeostasis in vivo.

NEW INSIGHTS INTO WATER TRANSPORT AND EDEMA IN THE CENTRAL NERVOUS SYSTEM FROM PHENOTYPE ANALYSIS OF AQUAPORIN-4 NULL MICE

Aquaporin-4 (AQP4) is the major water channel in the CNS. Its expression at fluid-tissue barriers (blood-brain and brain-cerebrospinal fluid barriers) throughout the brain and spinal cord suggests a role in water transport under normal and pathological conditions. Phenotype studies of transgenic mice lacking AQP4 have provided evidence for a role of AQP4 in cerebral water balance and neural signal transduction. Primary cultures of astrocytes from AQP4-null mice have greatly reduced osmotic water permeability compared with wild-type astrocytes, indicating that AQP4 is the principal water channel in these cells. AQP4-null mice have reduced brain swelling and improved neurological outcome following water intoxication and focal cerebral ischemia, establishing a role of AQP4 in the development of cytotoxic (cellular) cerebral edema. In contrast, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema caused by freeze-injury and brain tumor, probably due to impaired AQP4-dependent brain water clearance. AQP4-null mice also have markedly reduced acoustic brainstem response potentials and significantly increased seizure threshold in response to chemical convulsants, implicating AQP4 in modulation of neural signal transduction. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the CNS associated with altered brain water balance.

Molecular mechanisms of brain tumor edema

Despite their diverse histological types, most brain tumours cause brain oedema, which is a significant cause of patient morbidity and mortality. Brain tumour oedema occurs when plasma-like fluid enters the brain extracellular space through impaired capillary endothelial tight junctions in tumours. Under-expression of the tight junction proteins occludin, claudin-1 and claudin-5 are key molecular abnormalities responsible for the increased permeability of tumour endothelial tight junctions. Recent evidence suggests that the membrane water channel protein aquaporin-4 (AQP4) also plays a role in brain tumour oedema. AQP4-deficient mice show remarkably altered brain water balance after various insults, including brain tumour implantation. AQP4 expression is strongly upregulated around malignant human brain tumours in association with reduced extracellular volume, which may restrict the flow of extracellular fluid from the tumour bed into the brain parenchyma. Elimination of excess fluid leaking into brain parenchyma requires passage across three AQP4-rich barriers: a) the glia limitans externa, b) the glia limitans interna/ependyma, and c) the blood-brain barrier. Modulation of the expression and/or function of endothelial tight junction proteins and aquaporins may provide novel therapeutic options for reducing brain tumour oedema.

Idiopathic Intracranial Hypertension

OBJECTIVEThe history, diagnosis, and therapy of idiopathic intracranial hypertension (IIH) (pseudotumor cerebri) are reviewed. Theories of pathogenesis are considered, the clinical presentation is described, and potential diagnostic and therapeutic challenges are explored. METHODSAn extensive literature review of IIH and related conditions (secondary pseudotumor syndromes) was performed. The history of and rationale for the diagnosis and medical and surgical approaches to treatment are reviewed. Available outcome studies are presented. RESULTSDiagnosis of IIH requires that the modified Dandy criteria be satisfied. Multiple potential contributing causes of intracranial hypertension must be identified or excluded. The clinical presentation most often includes headaches and papilledema, but many other findings have been described. The most important goal of therapy is to prevent or arrest progressive visual loss. Medical therapies include alleviation of associated systemic diseases, discontinuation of contributing medications, provision of carbonic anhydrase inhibitors, and weight loss. Surgical therapies include lumboperitoneal shunting, ventriculoperitoneal shunting, and optic nerve sheath fenestration. On the basis of the advantages and disadvantages of these treatment modalities, a suggested treatment paradigm is presented. CONCLUSIONIdiopathic intracranial hypertension is the term to be adopted instead of pseudotumor cerebri. IIH remains an enigmatic diagnosis of exclusion. However, prompt diagnosis and thorough evaluation and treatment are crucial for preventing visual loss and improving associated symptoms.

EXPRESSION OF AQUAPORIN WATER CHANNELS IN MOUSE SPINAL CORD

Aquaporins (AQPs) are membrane proteins involved in water transport in many fluid-transporting tissues. Aquaporins AQP1, AQP4, and AQP9 have been identified in brain and hypothesized to participate in brain water homeostasis. Here we use reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry to describe the expression and immunolocalization of AQPs in adult mouse spinal cord. AQP4 was expressed in glial cells, predominantly in gray matter, and in astrocytic end-feet surrounding capillaries in spinal cord white matter. AQP9 expression extensively co-localized with glial fibrillary acidic protein-immunoreactive astrocytes, located predominantly in the white matter. AQP5 was detected by RT-PCR but not by immunohistochemical analysis. Interestingly, AQP8 was detected primarily in ependymal cells lining the fluid-filled central canal. The aquaporin expression pattern in spinal cord suggests involvement in water homeostasis and diseases associated with abnormal water fluxes such as spinal cord injury and syringomyelia.

Expression of the aquaporin-1 water channel in human glial tumors

OBJECTIVE:Malignant glial tumors are associated with cerebral edema. The aquaporins (AQPs) are a family of membrane proteins that provide a major pathway for water transport in mammals. In the central nervous system, AQP1 is selectively expressed in the choroid plexus and thought to participate in cerebrospinal fluid production. Prior studies have suggested that AQP1 may be up-regulated in glial tumors, potentially contributing to tumor-associated edema. The objective of this study was to investigate the expression of AQP1 in a large series of human glial tumors. METHODS:Thirty-six human glial tumors were obtained from the University of California, San Francisco Neurosurgery Tissue Bank. AQP1 expression was evaluated by reverse transcriptase polymerase chain reaction, complementary deoxyribonucleic acid gene array, Western blot analysis, and immunohistochemical analyses. RESULTS:AQP1, normally restricted to choroid epithelia, was highly expressed in glioblastomas. Complementary deoxyribonucleic acid array, Western blot analysis, and immunohistochemical analysis revealed intense up-regulation of AQP1 expression in all glioblastomas studied. CONCLUSION:The abnormal up-regulation of AQP1 in glial tumors suggests a potential pathological role for this membrane water channel and raises the possibility that selective AQP1 inhibition might offer a new therapeutic target for treatment of tumor-associated edema.

Gamma Knife radiosurgery for brain metastases from primary breast cancer.

PURPOSE The relative roles of stereotactic radiosurgery (SRS) vs. whole brain radiotherapy (WBRT) in the treatment of patients with brain metastases from breast cancer remain undefined. In this study, we reviewed our experience with these patients. MATERIALS AND METHODS We retrospectively reviewed all patients treated between 1991 and 2005 with Gamma Knife SRS for brain metastases from breast cancer. The actuarial survival and freedom from progression endpoints were calculated using the Kaplan-Meier method. RESULTS Between 1991 and 2005, 176 patients underwent SRS for brain metastases from breast cancer. The median survival time was 16.0 months for 95 newly diagnosed patients and 11.7 months for 81 patients with recurrent brain metastases. In the newly diagnosed patients, omission of upfront WBRT did not significantly affect the MST (p = .20), brain freedom from progression (p = .75), or freedom from new brain metastases (p = .83). Longer survival was associated with age <50 years, Karnofsky performance score >or=70, primary tumor control, estrogen receptor positivity, and Her2/neu overexpression. No association was found between the number of treated brain metastases and the survival time. CONCLUSION We have described prognostic factors for breast cancer patients treated with SRS for newly diagnosed or recurrent brain metastases. Most patient subsets had a median survival time of >or=11 months. Unexpectedly, upfront WBRT did not appear to improve brain freedom from progression, and a larger number of brain metastases was not associated with a shorter survival time. Breast cancer might be distinct from other primary sites in terms of prognostic factors and the roles of WBRT and SRS for brain metastases.

Increased seizure duration in mice lacking aquaporin-4 water channels

Aquaporins are intrinsic membrane proteins involved in water transport in fluid-transporting tissues. In the brain, aquaporin-4 (AQP4) is expressed widely by glial cells, but its function is unclear. Extensive basic and clinical studies indicate that osmolarity affects seizure susceptibility, and in our previous studies we found that AQP4 -/- mice have an elevated seizure threshold in response to the chemoconvulsant pentylenetetrazol. In this study, we examined the seizure phenotype of AQP4 -/- mice in greater detail using in vivo electroencephalographic recording. AQP4 -/- mice were found to have dramatically longer stimulation-evoked seizures following hippocampal stimulation as well as a higher seizure threshold. These results implicate AQP4 in water and potassium regulation associated with neuronal activity and seizures.

Trigeminal neuralgia in a patient with a dural arteriovenous fistula in Meckel's cave: Case report

OBJECTIVE AND IMPORTANCETrigeminal neuralgia is often the result of vascular compression at the root entry zone of the trigeminal nerve. We report a case of trigeminal neuralgia in a patient with a dural arteriovenous fistula in Meckel’s cave. Endovascular closure of the fistula resulted in elimination of the patient’s pain at the gasserian ganglion level. CLINICAL PRESENTATIONA 77-year-old woman was referred for treatment of trigeminal neuralgia after failed conservative treatment, including multiple gasserian ganglion blocks. Magnetic resonance imaging of the brain suggested a vascular lesion, and cerebral angiography demonstrated a dural arteriovenous fistula in Meckel’s cave. INTERVENTIONEndovascular coil embolization was performed, with obliteration of the dural arteriovenous fistula and resolution of facial pain but with decreased sensation in the face. CONCLUSIONTrigeminal neuralgia may be associated with complex vascular lesions around the base of the brain and along the course of the trigeminal nerve. The evaluation of patients with trigeminal neuralgia should include high-quality, thin-section, magnetic resonance imaging scans, to exclude the possibility of vascular lesions and other structural lesions. In particular, patients who are being evaluated for surgical treatment of trigeminal neuralgia should undergo magnetic resonance imaging, with a focus on the course of the trigeminal nerve.