Faculty Bibliography

OBJECT: Deep brain stimulation (DBS) of the thalamus is used for the treatment of patients with medically refractory essential tremor (ET). The authors evaluated patient outcomes after DBS surgery. METHODS: Clinical outcomes were evaluated in 19 patients who had undergone DBS surgery by using the Fahn-Tolosa-Marin clinical tremor rating scale. All adverse outcomes were also systematically recorded during follow-up outpatient visits. Eighteen DBS systems were implanted. The median follow-up period after surgery was 27 months (range 10-75 months). The preoperative mean Fahn-Tolosa-Marin action tremor score was 3.3 +/- 0.5, and the postoperative mean score with the DBS system activated was 0.8 +/- 0.4. The mean preoperative writing score was 2.8 +/- 0.9, and the postoperative mean writing score with the DBS system activated was 1 +/- 0.6. (Wilcoxon rank-sum test, p < 0.005). Fourteen patients were treated with bipolar stimulation, and four eventually required monopolar stimulation. Complications included lead breakage (one patient); temporary erythema of the incision through which the pulse generator had been implanted, which required oral antibiotics (one patient); electrode migration, which required surgery (one patient); and mild hand tingling during stimulation (three patients). Twelve of 18 patients with implanted systems experienced no morbid condition. CONCLUSIONS: Thalamic DBS is safe and effective for medically refractory ET. Stimulator adjustments can frequently occur in some patients, and tremor may worsen despite a readjustment in the system.

OBJECTIVE: The treatment of children with craniopharyngiomas should be individualized because of their heterogeneous clinical and radiographic characteristics. We performed this study to correlate the clinical and radiographic features at the time of presentation with the multimodality treatments the children received. METHODS: Medical records were reviewed for children with craniopharyngiomas who presented to the Children's Hospital of Pittsburgh for their initial management between 1983 and 2004. Children were treated with microsurgical tumor resections (27), intracavitary irradiation with phosphorus 32 (32P) (12), and with gamma knife stereotactic radiosurgery (GKSR) (5). CONCLUSIONS: There were no deaths in any treatment group. Gross total resections were thought to be performed in 18 patients and were confirmed by imaging in 13 of the 18 patients. The primary operative morbidities were hormonal and visual. Every child needed at least two replacement hormones and most had panhypopituitarism. Vision worsened postoperatively in 5 of 27 children. There was no operative morbidity or mortality from 32P. After 32P treatment, one child required a later cyst aspiration and one required a craniotomy for progressive cyst enlargement. There was no morbidity or mortality from GKSR, which achieved tumor stabilization or shrinkage in 4 of 5 cases. Resections, 32P, and GKSR are complimentary treatment modalities for children with craniopharyngiomas. Their indications and outcomes differ, but all should be available in the treatment armamentarium.

PURPOSE: To better analyze how whole-brain radiotherapy (WBXRT) affects long-term tumor control and toxicity from the initial stereotactic radiosurgery (SRS) for brain metastases, we studied these outcomes in patients who had survived at least 1 year from SRS. METHODS AND MATERIALS: We evaluated the results of gamma knife radiosurgery for 160 brain metastases in 110 patients who were followed for a median of 18 months (range, 12-122 months) after SRS. Eighty-two patients had a solitary brain metastasis and 28 patients had multiple metastases. Seventy patients (116 tumors) were treated with initial radiosurgery and WBXRT, whereas 40 patients (44 lesions) initially received radiosurgery alone. Median treatment volume was 1.9 cc in the entire group, 2.3 cc in the WBXRT group, and 1.6 cc in the SRS alone group. Median tumor dose was 16 Gy (range, 12-21 Gy). RESULTS: At 1, 3, and 5 years, local tumor control was 84.1% +/- 5.5%, 68.6% +/- 8.7%, and 68.6% +/- 8.7% with SRS alone compared with 93.1% +/- 2.4%, 87.7% +/- 4.9%, and 65.7% +/- 10.2%. with concurrent WBXRT and SRS (p = 0.0228, univariate). We found that WBXRT improved local control in patient subsets tumor volume > or =2 cc, peripheral dose < or =16 Gy, single metastases, nonradioresistant tumors, and lung cancer metastases (p = 0.0069, 0.0080, 0.0083, 0.0184, and 0.0348). Distal intracranial failure developed at 1, 3, and 5 years in 26.0% +/- 7.1%, 74.5% +/- 9.4%, and 74.5% +/- 9.4% with SRS alone compared with 20.7% +/- 4.9%, 49.0% +/- 8.7%, and 61.8% +/- 12.8% with concurrent WBXRT and SRS (p = 0.0657). We found a trend for improved distal intracranial control with WBXRT for only nonradioresistant tumors (p = 0.054). Postradiosurgery complications developed in 2.8% +/- 1.2% and 10.7% +/- 3.5% at 1 and 3-5 years and was unaffected by WBXRT (p = 0.7721). WBXRT did not improve survival in the entire series (p = 0.5027) or in any subsets. CONCLUSIONS: In this retrospective study of 1-year survivors of SRS for brain metastases, the addition of concurrent WBXRT to SRS was associated with an improved local control rate in patient subsets with tumor volume > or =2 cc, peripheral dose < or =16 Gy, single metastases, nonradioresistant tumors, and specifically lung cancer metastases. A trend was noted for improved distal intracranial control for patients having nonradioresistant tumors. Distant intracranial relapse >1 year posttreatment is a significant problem with or without initial WBXRT.

Therapeutic brain irradiation can cause progressive decline in cognitive function, particularly in children, but the reason for this effect is unclear. The study explored whether age-related differences in apoptotic sensitivity might contribute to the increased vulnerability of the young brain to radiation. Postnatal day 1 (P1) to P30 mice were treated with 0-16 Gy whole-body X-irradiation. Apoptotic cells were identified and quantified up to 48 h later using the TdT-UTP nick end-labelling method (TUNEL) and immunohistochemistry for activated caspase-3. The number of neuron-specific nuclear protein (NeuN)-positive and -negative cells were also counted to measure neuronal and non-neuronal cell loss. Significantly greater TUNEL labelling occurred in the cortex of irradiated P1 animals relative to the other age groups, but there was no difference among the P7, P14 and P30 groups. Irradiation decreased the %NeuN-positive cells in the mice irradiated on P1, whereas in P14 animals, irradiation led to an increase in the %NeuN-positive cells. These data demonstrate that neocortical neurons of very young mice are more susceptible to radiation-induced apoptosis. However, this sensitivity decreases rapidly after birth. By P14, acute cell loss due to radiation occurs primarily in non-neuronal populations.

OBJECT: No definitive treatment exists to restore lost brain function following a stroke. Transplantation of cultured neuronal cells has been shown to be safe and effective in animal models of stroke and safe in a Phase 1 human trial. In the present study the authors tested the usefulness of human neuron transplantation followed by participation in a 2-month stroke rehabilitation program compared with rehabilitation alone in patients with substantial fixed motor deficits associated with a basal ganglia stroke. METHODS: Human neuronal cells (LBS-Neurons; Layton BioScience, Inc.) were delivered frozen and then thawed and formulated on the morning of surgery. The entry criteria in this randomized, observer-blinded trial of 18 patients included age between 18 and 75 years, completed stroke duration of 1 to 6 years, presence of a fixed motor deficit that was stable for at least 2 months, and no contraindications to stereotactic surgery. Patients were randomized at two centers to receive either 5 or 10 million implanted cells in 25 sites (seven patients per group) followed by participation in a stroke rehabilitation program, or to serve as a nonsurgical control group (rehabilitation only; four patients). The surgical techniques used were the same at both centers. All patients underwent extensive pre- and postoperative motor testing and imaging. Patients received cyclosporine A for 1 week before and 6 months after surgery. The primary efficacy measure was a change in the European Stroke Scale (ESS) motor score at 6 months. Secondary outcomes included Fugl-Meyer, Action Research Arm Test, and Stroke Impact Scale scores, as well as the results of other motor tests. Nine strokes were ischemic in origin and nine were hemorrhagic. All 14 patients who underwent surgery (ages 40-70 years) underwent uncomplicated surgeries. Serial evaluations (maximum duration 24 months) demonstrated no cell-related adverse serological or imaging-defined effects. One patient suffered a single seizure, another had a syncopal event, and in another there was burr-hole drainage of an asymptomatic chronic subdural hematoma. Four of seven patients who received 5 million cells (mean improvement 6.9 points) and two of seven who received 10 million cells had improved ESS scores at 6 months; however, there was no significant change in the ESS motor score in patients who received cell implants (p = 0.756) compared with control or baseline values (p = 0.06). Compared with baseline, wrist movement and hand movement scores recorded on the Fugl-Meyer Stroke Assessment instrument were not improved (p = 0.06). The Action Research Arm Test gross hand-movement scores improved compared with control (p = 0.017) and baseline (p = 0.001) values. On the Stroke Impact Scale, the 6-month daily activities score changed compared with baseline (p = 0.045) but not control (p = 0.056) scores, and the Everyday Memory test score improved in comparison with baseline (p = 0.004) values. CONCLUSIONS: Human neuronal cells can be produced in culture and implanted stereotactically into the brains of patients with motor deficits due to stroke. Although a measurable improvement was noted in some patients and this translated into improved activities of daily living in some patients as well, this study did not find evidence of a significant benefit in motor function as determined by the primary outcome measure. This experimental trial indicates the safety and feasibility of neuron transplantation for patients with motor stroke.