Directional DBS increases side-effect thresholds-A prospective, double-blind trial.

OBJECTIVE: The objective of this study was to investigate whether directional deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson's disease (PD) offers increased therapeutic windows, side-effect thresholds, and clinical benefit. METHODS: In 10 patients, 20 monopolar reviews were conducted in a prospective, randomized, double-blind design to identify the best stimulation directions and compare them to conventional circular DBS regarding side-effect thresholds, motor improvement, and therapeutic window. In addition, circular and best-directional DBS were directly compared in a short-term crossover. Motor outcome was also assessed after an open-label follow-up of 3 to 6 months. RESULTS: Stimulation in the individual best direction resulted in significantly larger therapeutic windows, higher side-effect thresholds, and more improvement in hand rotation than circular DBS. Rigidity and finger tapping did not respond differentially to the stimulation conditions. There was no difference in motor efficacy or stimulation amplitudes between directional and circular DBS in the short-term crossover. Follow-up evaluations 3 to 6 months after implantation revealed improvements in motor outcome and medication reduction comparable to other DBS studies with a majority of patients remaining with a directional setting. CONCLUSION: Directional DBS can increase side-effect thresholds while achieving clinical benefit comparable to conventional DBS. Whether directional DBS improves long-term clinical outcome needs to be investigated in the future. © 2017 International Parkinson and Movement Disorder Society.

Determining the orientation angle of directional leads for deep brain stimulation using computed tomography and digital x-ray imaging: A phantom study.

PURPOSE: Orientating the angle of directional leads for deep brain stimulation (DBS) in an axial plane introduces a new degree of freedom that is indicated by embedded anisotropic directional markers. Our aim was to develop algorithms to determine lead orientation angles from computed tomography (CT) and stereotactic x-ray imaging using standard clinical protocols, and subsequently assess the accuracy of both methods. METHODS: In CT the anisotropic marker artifact was taken as a signature of the lead orientation angle and analyzed using discrete Fourier transform of circular intensity profiles. The orientation angle was determined from phase angles at a frequency 2/360° and corrected for aberrations at oblique leads. In x-ray imaging, frontal and lateral images were registered to stereotactic space and sub-images containing directional markers were extracted. These images were compared with projection images of an identically located virtual marker at different orientation angles. A similarity index was calculated and used to determine the lead orientation angle. Both methods were tested using epoxy phantoms containing directional leads (Cartesia™, Boston Scientific, Marlborough, USA) with known orientation. Anthropomorphic phantoms were used to compare both methods for DBS cases. RESULTS: Mean deviation between CT and x-ray was 1.5° ± 3.6° (range: -2.3° to 7.9°) for epoxy phantoms and 3.6° ± 7.1° (range: -5.6° to 14.6°) for anthropomorphic phantoms. After correction for imperfections in the epoxy phantoms, the mean deviation from ground truth was 0.0° ± 5.0° (range: -12° to 14°) for x-ray. For CT the results depended on the polar angle of the lead in the scanner. Mean deviation was -0.3° ± 1.9° (range: -4.6° to 6.6°) or 1.6° ± 8.9° (range: -23° to 34°) for polar angles ≤ 40° or > 40°. CONCLUSIONS: The results show that both imaging modalities can be used to determine lead orientation angles with high accuracy. CT is superior to x-ray imaging, but oblique leads (polar angle > 40°) show limited precision due to the current design of the directional marker.

Pseudohypoxic brain swelling (postoperative intracranial hypotension-associated venous congestion) after spinal surgery: report of 2 cases.

BACKGROUND AND IMPORTANCE: Pseudohypoxic brain swelling is a rare event that may occur after uneventful brain surgery when subgaleal vacuum drainage is used. To date, such cases of unexpected postoperative disturbances of consciousness associated with radiological signs of basal ganglia, thalamic, brainstem, and cerebellum damage without any signs of vessel occlusion have not been known to occur after spinal surgery. CLINICAL PRESENTATION: We report for the first time on 2 patients presenting with a clinical and radiological picture of pseudohypoxic brain swelling after spinal surgery. In the first patient, bilateral basal ganglia damage occurred after thoracic spondylodiscitis surgery, manifested by epileptic seizures and coma lasting 1 week postoperatively with subsequent recovery. The second patient suffered basal ganglia and cerebellar and brainstem infarction after lumbar spondylodiscitis surgery, resulting in death. Because intraoperative cerebrospinal fluid leakage and use of postoperative epidural suction drainage with cerebrospinal fluid loss occurred in both cases, they are highly suspected to have potentially caused the complications. CONCLUSION: Pseudohypoxic brain swelling should be considered in patients with unexpected neurological deterioration after spinal surgery. It might be a form of postoperative intracranial hypotension-associated venous congestion, which should be distinguished from common postoperative cerebral ischemic events caused by arterial or venous occlusions.

The novel chimeric anti-NCAM (neural cell adhesion molecule) antibody ch.MK1 displays antitumor activity in SCID mice but does not activate complement-dependent cytolysis (CDC).

A monoclonal chimeric antibody ch.MK1 was generated by immunizing F004 mice expressing human instead of murine IgG1/kappa immunoglobulin constant regions. The novel antibody specifically binds cell surface-expressed human neural cell adhesion molecule (NCAM) as shown by immunoprecipitation, flow cytometry and cytospins. Functional analysis revealed nearly complete absence of complement-dependent cytolysis in ch.MK1 and in all other anti-NCAM antibodies tested for reference (UJ13a, ERIC1, 123C3, ch.5A2, B159), indicating an unexpected and group-specific property of anti-NCAM antibodies. As a most plausible mechanism, posttranslational modification of NCAM by complement-inhibiting polysialic acid is discussed. The antibody ch.MK1 demonstrated significant in vivo activity against NCAM-positive neuroblastoma in SCID mice in presence of human peripheral blood mononuclear cell. In absence of human peripheral blood mononuclear cell no distinct antitumor activity of the antibody alone was observed. In ch.MK1 the cellular component of the immune system seems to be the dominant effector mechanism, whereas complement-dependent cytolysis seems not to be necessarily required for antitumor activity. These observations help us to understand immunotherapeutic mechanisms of native anti-NCAM antibodies and may additionally contribute to the understanding of results of currently ongoing clinical studies with conjugated anti-NCAM antibodies.

One step generation of fully chimeric antibodies using Cgamma1- and Ckappa mutant mice.

Humanized antibodies (Abs) are effective drugs against a variety of diseases such as cancer, autoimmune diseases, transplant rejection and others. The most powerful technology to develop humanized Abs is the use of mice that produce humanized Abs. By modifying the genetic background of F004 mice a new mouse substrain was developed for optimized "one step" generation of chimeric humanized monoclonal Abs. The new mice (F004-Jen) demonstrated improved fertility still expressing the human locus at the same level as the parental F004 mouse. The value of these mice for the generation of chimeric Abs was exemplified for a panel of chimeric Abs against the human neural cell adhesion molecule (NCAM): The fully chimeric human IgG1/kappa Ab Ch.MK1 bound to NCAM expressing cells with a K(D)=4.3-8.7 x 10(-8) M and was functionally active as demonstrated by depleting NCAM expressing cells. We also demonstrated that chimeric IgG1/kappa Abs can be induced by hybridoma class switching of IgM producing hybridoma cells, providing an alternative way to chimeric Abs. The present data highlight F004-Jen mice as an efficient tool for "one step" generation of chimeric Abs.