Intrathecal drug delivery in the era of nanomedicine.

Administration of substances directly into the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord is one approach that can circumvent the blood-brain barrier to enable drug delivery to the central nervous system (CNS). However, molecules that have been administered by intrathecal injection, which includes intraventricular, intracisternal, or lumbar locations, encounter new barriers within the subarachnoid space. These barriers include relatively high rates of turnover as CSF clears and potentially inadequate delivery to tissue or cellular targets. Nanomedicine could offer a solution. In contrast to the fate of freely administered drugs, nanomedicine systems can navigate the subarachnoid space to sustain delivery of therapeutic molecules, genes, and imaging agents within the CNS. Some evidence suggests that certain nanomedicine agents can reach the parenchyma following intrathecal administration. Here, we will address the preclinical and clinical use of intrathecal nanomedicine, including nanoparticles, microparticles, dendrimers, micelles, liposomes, polyplexes, and other colloidalal materials that function to alter the distribution of molecules in tissue. Our review forms a foundational understanding of drug delivery to the CSF that can be built upon to better engineer nanomedicine for intrathecal treatment of disease.

Fate of nanoparticles in the central nervous system after intrathecal injection in healthy mice.

Cerebrospinal fluid (CSF) is produced in the cerebral ventricles and circulates within the subarachnoid space (SAS) of the brain and spinal cord, where it exchanges with interstitial fluid of the parenchyma. The access of CSF to the entire central nervous system (CNS) makes it an attractive medium for drug delivery. However, few intrathecal (IT) therapies have reached the clinic due, in part, to limited distribution and rapid clearance. Given the success of nanoparticle (NP) carriers in prolonging circulation and improving delivery of systemically administered agents, we sought to evaluate the distribution of IT injected NPs within the CNS. We administered fluorescent, 100 nm PEGylated-NPs into the cisterna magna of healthy mice and studied their distribution along the brain and spinal cord. Our data demonstrate that NPs are capable of distributing rapidly through the SAS along the entire neuraxis with reproducible, anatomically defined patterns of delivery. NPs were well retained within the leptomeninges for over 3 weeks, showing preference for ventral surfaces and minimal penetration into the CNS parenchyma. Clearance of NPs occurred across the cribriform plate into the nasal mucosa, with a small fraction of NPs localizing with nerve roots exiting the spinal column. Larger 10 µm particles were also capable of moving through the SAS but did not achieve as widespread distribution. These studies demonstrate the ability of NPs to achieve widespread delivery along the neuraxis and highlight IT administration as a potentially significant route of administration for delivery of nanomedicine to the subarachnoid space.

Spontaneous intraparenchymal hemorrhage in full-term neonates.

OBJECTIVE: Spontaneous intraparenchymal hemorrhage is extremely rare in full-term newborns. Reports to date have been limited to descriptions of individual cases, small groups within larger studies of intracranial hemorrhage, and one series of four patients. Structural lesions are rarely identified, and the majority of patients described have been managed without surgical intervention. METHODS: Analysis of a computerized database of pediatric neurosurgical patients from January 1960 to February 2000 identified full-term newborns younger than 3 months of age with nontraumatic intraparenchymal hemorrhages. Prenatal histories, labor and delivery histories, clinical presentations, imaging studies, management, and outcomes were reviewed. RESULTS: Eleven full-term newborns with spontaneous intraparenchymal hemorrhages were identified. The majority had normal prenatal courses. Most presented within the first 2 days of life (6 of 11 patients), and the most common presenting sign was seizure (7 of 11 patients). No cause was identified in 6 of 11 patients; the remainder were attributed to coagulopathy (n = 3), ruptured intracranial aneurysm (n = 1), or hemorrhagic infarction (n = 1). Eight patients underwent surgical hematoma evacuation on the basis of radiographic evidence of significant mass effect, evidence of signs of elevated intracranial pressure, or both. Three patients did not receive surgical intervention. There were no subsequent hemorrhages or deaths during a mean follow-up period of 4.5 years (range, 1-16 yr). Four patients had normal neurological outcomes, four had motor deficits (one of whom additionally demonstrated cognitive delay), and three had delayed speech. CONCLUSION: No cause is identified in most newborns with spontaneous intraparenchymal hemorrhage. Radiographic evidence of mass effect or signs of elevated intracranial pressure may necessitate surgical hematoma evacuation. Outcome varies widely and may be normal, even in patients with sizeable intraparenchymal hemorrhages.

MIB-1 staining index of pediatric meningiomas.

OBJECTIVE: For adult meningiomas, the staining index (SI) for the anti-Ki-67 monoclonal antibody MIB-1 is well correlated with histological atypia and tumor recurrence. MIB-1 SIs for meningiomas in the pediatric population have not been previously reported. Meningiomas tend to be more histologically aggressive and to recur more frequently in children, compared with adults. The objectives of this study were to determine whether MIB-1 SIs are correlated with pathological atypia and recurrence among pediatric meningiomas and to compare the MIB-1 SIs of pediatric meningiomas with those of adult meningiomas. METHODS: MIB-1 SIs were assessed on paraffin-embedded sections of 14 pediatric meningiomas (patient age, 2-17 yr), 5 of which contained atypical or malignant features. For comparison with benign pediatric meningiomas, MIB-1 SIs were also assessed on paraffin-embedded sections of 14 adult meningiomas (patient age, 38-90 yr), none of which displayed atypical or malignant features or recurred within a 5-month median follow-up period. RESULTS: MIB-1 SIs of pediatric meningiomas ranged from 1.2 to 31.6% (median, 9.1%). Significant differences were observed between the MIB-1 SIs for tumors with atypical or malignant features (median, 12.3%; range, 7.0-31.6%) and those for tumors without atypia (median, 7.0%; range, 1.2-12.6%; P = 0.045). There were six recurrences after gross total resection, during a 36.5-month median follow-up period. All five of the tumors with pathological atypia recurred; one tumor without atypia recurred. Significant differences were observed between MIB-1 SIs for nonrecurrent tumors (median, 6.6%; range, 1.2-12.2%) and those for recurrent tumors (median, 12.5%; range, 7.0-31.6%; P = 0.012). The median MIB-1 SI for adult control specimens was 8.8% (range, 1.2-19.3%), which did not differ significantly from that for pediatric meningiomas without atypia (P = 0.68). CONCLUSION: For this cohort of pediatric meningiomas, pathological atypia and the tendency to recur were correlated with elevated MIB-1 SIs. The median MIB-1 SI for pediatric meningiomas without histological atypia did not differ significantly from that for adult meningiomas without atypia, suggesting that the more aggressive clinical features of meningiomas in children may be attributable to factors other than the rate of cellular proliferation.

Endoscopic biopsy for tumors of the third ventricle.

Twelve patients underwent endoscopic biopsy of a tumor involving the third ventricle. Nine patients had no significant medical history while 3 had a history of cancer. Unique characteristics of each case dictated the optimal surgical technique. Endoscopic tumor biopsy was combined with additional procedures in 9 cases; shunt insertion (3), shunt insertion with endoscopic septostomy (5), and transcallosal craniotomy (1). Diagnosis was established in 11 patients (92%); 6 primary brain tumors, 3 metastatic central nervous system tumors, 1 metastatic systemic cancer, and 1 region of post-treatment gliosis. One case was aborted due to poor visualization. Therapy was directly influenced by endoscopic biopsy in 11/12 cases (92%) and craniotomy for tumor resection was avoided in 10/12 patients (83%). Of the 5 patients who underwent endoscopic septostomy, 4 required no subsequent procedures for hydrocephalus. There were no complications, and hospital stay averaged 1.78 days for patients who underwent successful endoscopic biopsy. Tumors of the third ventricle are amenable to endoscopic biopsy with excellent diagnostic yield and low morbidity. The procedure must be tailored depending upon the tumor location within the third ventricle, the degree of ventriculomegaly, and the need to perform a septostomy. Singularly or combined with other endoscopic procedures, patients can be spared multiple and more invasive surgical procedures.

Sclerosing epithelioid fibrosarcomas involving the neuraxis: report of three cases.

OBJECTIVE AND IMPORTANCE: Sclerosing epithelioid fibrosarcoma (SEF) is a rare mesenchymal neoplasm composed of rounded, vimentin-immunoreactive tumor cells disposed in nests and cords within a hyalinized collagenous matrix. Most examples arise in the deep skeletal muscles of adults. The cases recorded to date have been characterized by protracted clinical evolutions with a tendency for stubborn local recurrence, followed by late metastasis. Accordingly, SEF has been regarded as a low-grade sarcoma. A single instance of brain and vertebral metastasis has been described. We report three examples of SEF distinguished by primary involvement of the neuraxis at initial presentation. CLINICAL PRESENTATION: Two tumors had intracranial, calvarial and extracalvarial, soft-tissue components, whereas the third tumor manifested as a paraspinal mass with extension into the T12-L1 neural foramen and invasion of the T12 nerve root. INTERVENTION: All three affected patients experienced local recurrence and distant metastasis after resection of the primary site. These complications appeared early in the disease course in two cases. In no case was there a response to adjuvant chemotherapy or radiotherapy. CONCLUSION: Our experience indicates that SEFs arising along the neuraxis may demonstrate unexpectedly aggressive clinical behavior, compared with those arising in the more typical location of deep skeletal muscles.

Ommaya reservoirs for the treatment of leptomeningeal metastases.

OBJECTIVE: Ommaya reservoirs are frequently used to deliver intraventricular chemotherapy in cancer patients with leptomeningeal metastases. We review techniques of catheter placement and complication avoidance. METHODS: Between January 1995 and June 1998, Ommaya reservoirs were placed in 107 patients for the treatment or prophylaxis of leptomeningeal metastases at the Memorial Sloan-Kettering Cancer Center. Patients with slit ventricles (total, 25) underwent preoperative pneumoencephalography for ventricular dilation. Intraoperative fluoroscopic guidance was used in 77 patients to confirm the catheter tip position at the foramen of Monro. Other intraoperative aids included endoscopy in 21 patients, ultrasound in 7, and stereotaxy in 6. No aids were used in 3 patients, more than one aid was used in 9, and the technique could not be determined retrospectively in 3. RESULTS: The median survival of patients treated for leptomeningeal metastases was 9 months (Kaplan-Meier method). Eight patients developed hydrocephalus requiring conversion of the Ommaya reservoir to a ventriculoperitoneal shunt and precluding delivery of chemotherapeutic agents. An additional 11 patients referred for Ommaya reservoir placement demonstrated elevated intracranial pressure requiring an initial ventriculoperitoneal shunt. Complications of Ommaya reservoir placement occurred in 10 patients (9.3%) and included two infections, five catheter malpositions, and three intracranial hemorrhages. Two deaths occurred secondary to intracranial hemorrhage: one after postoperative anticoagulation for a mechanical heart valve, and one attributed to treatment-related thrombocytopenia. Nine patients (8.4%) had treatment-related imaging abnormalities; seven were asymptomatic and two developed symptomatic leukoencephalopathy. CONCLUSION: Complications associated with Ommaya reservoirs can be minimized by intraoperative confirmation of the catheter position with fluoroscopic guidance and/or endoscopy. We recommend postoperative computed tomographic scans before initiation of intraventricular chemotherapy. Patients with elevated intracranial pressure may require shunting procedures in lieu of Ommaya reservoir placement.

Hemifacial spasm caused by a pilocytic astrocytoma of the fourth ventricle.

An 11-year-old male in whom hemifacial spasm was the presenting sign of a pilocytic astrocytoma within the fourth ventricle is reported. The child's hemifacial spasm decreased substantially after resection of the tumor. Hemifacial spasm is largely a disease of adults and only rarely is attributed to brain tumors. In contrast, this marks the fifth case of hemifacial spasm reported in a child, three of which have been attributed to tumors of the fourth ventricle.

Endoscopic-guided proximal catheter placement in treatment of posterior fossa cysts.

PURPOSE: Treatment of posterior fossa cysts by cystoperitoneal shunting may be complicated by a malpositioned proximal catheter located within the brainstem or cerebellum causing acute shunt malfunction or neurological deficits. We propose that proximal catheter placement from a posterior fossa approach aided by a malleable endoscope may prevent malposition and its complications. METHODS: We present 4 procedures we performed on 3 patients with posterior fossa cysts using a posterior fossa approach. In each case, the proximal catheter was molded along with a malleable endoscope to place the catheter parallel to the long axis of the fourth ventricle. Direct visualization during catheter placement insured an intracavitary position. RESULTS: Ultimately, the procedure was successful in all 3 patients as judged by intracavitary catheter position and decrease in cyst size on postoperative imaging. In 1 patient, revision using the same technique was required based upon suboptimal catheter position within one of numerous cystic compartments within the posterior fossa. There were no complications related to direct or indirect brainstem injury. CONCLUSIONS: Many posterior fossa cysts can be treated effectively and safely via a posterior fossa approach with the aid of a malleable endoscope. Direct visualization facilitates intracavitary catheter placement and orientation of the catheter in the long axis of the cyst, thereby decreasing the risk of injury to surrounding structures.

Symptomatic spinal epidural lipomatosis after local epidural corticosteroid injections: case report.

OBJECTIVE AND IMPORTANCE: Spinal epidural lipomatosis, which causes symptomatic compression of neural elements, is a well known but uncommon complication of Cushing's syndrome. Spinal epidural lipomatosis has been reported frequently in association with chronic systemic corticosteroid therapy, but thus far only one case has been attributed to local epidural corticosteroid injections. CLINICAL PRESENTATION: We report another case of symptomatic spinal epidural lipomatosis after epidural corticosteroid injections. This is the first such case documented by magnetic resonance imaging and confirmed with surgical exploration. INTERVENTION: The patient's symptoms of neurogenic claudication resolved after lumbar laminectomy in the region of previous corticosteroid injections and the removal of epidural fat, which was compressing the thecal sac. CONCLUSION: This case should alert clinicians that epidural lipomatosis, which causes symptomatic thecal sac compression, is a possible complication, not only of systemic glucocorticoid therapy, but also of local epidural corticosteroid injections.

IL-12-Independent costimulation pathways for interferon-gamma production in familial disseminated Mycobacterium avium complex infection.

We have described previously a family with an apparent genetic susceptibility to disseminated Mycobacterium avium complex infection and an underlying defect in IL-12 regulation leading to abnormally low interferon-gamma production. Their T cells appear to act normally when in the presence of normal accessory cells. Cell-to-cell contact was necessary for normal monocytes to complement the familial patient monocyte defect, suggesting the familial defect in interferon-gamma costimulation involves pathways requiring cell surface molecule interactions. In an effort to better characterize the abnormality in these patients, we examined the role of known costimulatory molecules in residual costimulation by patient PBMC compared to normals. Whereas normals utilized CD40/CD40L interactions and IL-12 production for optimal interferon-gamma costimulation in PHA-stimulated cocultures, familial patient interferon-gamma production was low and unaffected by their blockade. CD86 blockade caused a greater than 50% reduction in both normal and familial patient interferon-gamma production, implying that a majority of residual familial patient costimulation required this pathway. Furthermore, selected myelomonocytic cell lines (K562 and THP1) acted as potent accessory cells for interferon-gamma production by familial patient and normal T cells, largely independent of IL-12 production. However, CD86 blockade of K562 cell/familial cell cocultures resulted in less than a 20% reduction in interferon-gamma production, indicating that familial patient cells respond to IL-12- and CD86-independent costimulatory signals for interferon-gamma as well. Thus, we demonstrate that the familial defect also involves interferon-gamma costimulation pathways requiring both CD40/CD40L interaction and IL-12 production, while residual pathways remain that allow low-level interferon-gamma production. Familial Mycobacterium avium patient monocytes and certain myelomonocytic cell lines can be exploited to investigate IL-12-independent costimulation for interferon-gamma production.