Cortical control of saccades in Parkinson disease and essential tremor.

A number of studies suggest that some features of essential tremor (ET) and Parkinson disease (PD) overlap. Besides tremor, also some cognitive features have been implicated in ET and PD. There is recent evidence that a common genetic mutation occurs in ET and PD. Saccadic eye movements could provide an easily quantifiable procedure to help in the differential diagnosis in early PD and ET. Being able to distinguish early on the two diseases may help in tailoring therapy. Cortical control of saccades and antisaccades as they pertain to the potential discrimination of PD and ET is reviewed. Imaging and electrophysiological studies are highlighted; however, there are still few studies. Hopefully this review will stimulate further research, in particular in the direction of differences and similarities in the neural circuits involved in PD and ET.

Remodeling of the fovea in Parkinson disease.

To quantify the thickness of the inner retinal layers in the foveal pit where the nerve fiber layer (NFL) is absent, and quantify changes in the ganglion cells and inner plexiform layer. Pixel-by-pixel volumetric measurements were obtained via Spectral-Domain optical coherence tomography (SD-OCT) from 50 eyes of Parkinson disease (PD) (n = 30) and 50 eyes of healthy control subjects (n = 27). Receiver operating characteristics (ROC) were used to classify individual subjects with respect to sensitivity and specificity calculations at each perifoveolar distance. Three-dimensional topographic maps of the healthy and PD foveal pit were created. The foveal pit is thinner and broader in PD. The difference becomes evident in an annular zone between 0.5 and 2 mm from the foveola and the optimal (ROC-defined) zone is from 0.75 to 1.5 mm. This zone is nearly devoid of NFL and partially overlaps the foveal avascular zone. About 78 % of PD eyes can be discriminated from HC eyes based on this zone. ROC applied to OCT pixel-by-pixel analysis helps to discriminate PD from HC retinae. Remodeling of the foveal architecture is significant because it may provide a visible and quantifiable signature of PD. The specific location of remodeling in the fovea raises a novel concept for exploring the mechanism of oxidative stress on retinal neurons in PD. OCT is a promising quantitative tool in PD research. However, larger scale studies are needed before the method can be applied to clinical follow-ups.

Visual acuity and contrast sensitivity in patients with cerebral lesions.

Spatial contrast sensitivity as a function of spatial frequency was measured in patients with cerebral lesions. In most of these patients visual acuity, as measured by the Snellen chart, was 20/30 or better, yet marked departures from normal contrast sensitivity were found. The greatest loss in contrast sensitivity occurred at high frequencies, but in one patient the loss was greatest in the midfrequency range. This finding lends support to the channel hypothesis of spatial contrast discrimination.

Visual association cortex and vision in man: pattern-evoked occipital potentials in a blind boy.

In a 6-year-old child who had been blind since the age of 2 years, occipital potentials of normal amplitude and waveform could be evoked not only by diffuse light flashes but also by alternating checkerboard ans sinusoidal grating patterns of low spatial frequency. Computerized tomography demonstrated destruction of the occipital lobes except of the primary visual projection area. Thus, in man, destruction of visual association cortices may result in loss of vision with partial preservation of pattern-evoked occipital potentials.

Visual deficits related to dopamine deficiency in experimental animals and Parkinson's disease patients.

In patients affected by Parkinson's disease, and in the monkey model of this disease, visual defects have been shown using psychophysical and electrophysiological measures of spatial and temporal contrast sensitivity. These studies imply an essential role for dopamine in primate vision. There is electrophysiological and neurochemical evidence to suggest that at least part of the problem is impaired retinal processing caused by systemic dopaminergic deficiency. Some of the deficits that have been demonstrated, consistent with physiological studies, suggest that center-surround interaction of neurons may suffer as a consequence of dopaminergic deficiency. The role of the regulation of retinal dopamine (D1 and D2) receptors in primate vision and of the balance of these receptors in presynaptic dopaminergic deficiency is not yet determined. Using sinusoidal grating stimuli in cognitively loaded tasks may increase understanding of the behavioral consequences of visual deficits seen in dopamine deficiency syndromes.

Role of the calcarine cortex (V1) in perception of visual cues for saccades.

OBJECTIVE: To determine the initial level at which the pathways for cue perception, saccades and antisaccades diverge. METHODS: Two procedures: single pulse transcranial magnetic stimulation (sTMS) over posterior occiput and backward masking were used. A visual cue directed saccades to the left or right, either a pro-saccade (to the side of the cue but beyond it) or an antisaccade, i.e., contraversive saccade. No visual target was presented. RESULTS: Latencies of the two types of saccades did not differ. Focal sTMS applied unilaterally over V1 suppressed both perception of a cue flashed 80-90ms earlier contralaterally (but not ipsilaterally) and the appropriate saccade. Masking at a delay of 100ms abolished the appropriate saccade and cue perception. CONCLUSIONS: V1 is essential for the perception of a flashed cue and for executing appropriate pro- and contraversive saccades. Masking may occur beyond V1, where the pathways for perception and for saccades at least to the next visual processing level start separating. SIGNIFICANCE: VI is needed for rapid, accurate perceptual and motor responses to the crudest (left versus right) cues. It is unlikely that the "where" system can have a major direct input bypassing V1.

Getting around and communicating with the environment: visual cognition and language in Parkinson's disease.

Vision in PD. In PD an impairment of dopaminergic neurons of the preganglionic retina and a defect of the retinal nerve fibers (axons of the retinal ganglion cells) has been demonstrated and a correlation of loss of spatial contrast sensitivity, with the progression of motor impairment in PD has been described. These low level visual deficits contribute but do not directly explain behavioural visual deficits in PD involving spatial cognition, internal representation, space navigation and visual categorization. Language deficits in non-demented PD patients can include impairments in comprehension, verbal fluency, and naming. Comprehension deficits become evident when patients are required to process sentences with non-canonical, irregular grammatical structures. Semantic memory deficits may result in the impairments in category fluency and confrontational naming. Selective language deficits may be due to impaired dynamics of the "phonological loop" connecting the pre-frontal cortex and the basal ganglia. A more encompassing linguistic and functional model of PD specific language impairments would be useful for evaluating language deficits in the context of motor dysfunction.

Effects of hepatic arterial yttrium-90 microsphere administration alone and combined with regional bromodeoxyuridine infusion in dogs.

Brachytherapy by embolization with radiotherapeutic microspheres following intraarterial infusion of a radiosensitizer represents an attempt to combine several selective modalities into a more potent, focused attack on regionally confined tumors. In pursuit of this goal, we examined the ability of foxhounds with surgically implanted hepatic arterial (HA) delivery systems to tolerate a clinically relevant dosage of HA yttrium-90 (Y-90) by microsphere administration either alone or preceded by a 28-day constant HA infusion of either 5-bromo-2'-deoxyuridine (BUDR) or a control solution. Five dogs received BUDR (10 mg/kg/day) and five a control buffer infusion for 28 days immediately prior to the administration of Y-90-coated 15 micron resin microspheres (equivalent of 5000 rads to the entire liver) to each dog on day 31. In all animals, blood counts, bilirubin, amylase, appetite, weight, and behavior remained unchanged. Dogs receiving the microspheres after buffer infusion alone exhibited no hepatic enzyme alanine aminotransferase or alkaline phosphatase elevation. Alanine aminotransferase and alkaline phosphatase levels both rose during the third week of BUDR infusion, and while subsequent microsphere administration further increased enzyme levels, these levels had largely normalized by necropsy on day 82. At necropsy, the type and degree of hepatic toxicity among the animals receiving radioactive microspheres was comparable to that previously described in patients receiving external beam hepatic irradiation at conventional doses (2000-3000 rads). Also noted was a radiation-induced cholecystitis (due in large part to the gallbladder's total reliance on the hepatic artery for blood supply). One resin microsphere dog exhibited a small quantity of microspheres in the lungs causing focal radiation-induced granulomas suggesting the need to assess shunting of microspheres through the liver in clinical studies. Thus, HA Y-90 microspheres with BUDR can produce acceptable, nonlethal, and tolerable toxicities in this dog model suggesting that clinical studies of this combination are not likely to be contraindicated by synergistic toxicity. Although HA BUDR did not contribute significantly to the toxicity of the Y-90 microspheres, HA BUDR by itself administered uninterrupted for 4 weeks may, like HA FUDR (clinically), cause chemical hepatitis/cholangitis. The unexpected fragmentation of the resin spheres (albeit without myelosuppression) has led us to begin studies with a recently developed nondisruptible glass microsphere (ThereSphere) in which the Y-90 is part of the glass matrix and cannot leach.(ABSTRACT TRUNCATED AT 400 WORDS)

Localization and imaging of radiolabeled monoclonal antibodies against colorectal carcinoma in tumor-bearing nude mice.

Four monoclonal antibodies (MoAbs) (35, 115, 17-1A, and B72.3) directed towards human carcinoma surface antigens have been studied in athymic nude mice with LS174T, CO112, or SW948 colon carcinoma xenografts or negative control melanoma (MEL-1), lymphoma (Namalwa), and breast (MCF-7) carcinoma xenografts to evaluate the effects of antigenic heterogeneity and time after administration on localization and imaging. 125I-labeled 115 showed the highest uptake of any antibody in LS174T tumors. MoAbs 35 and B72.3 showed similar but lower levels of uptake in LS174T and CO112 tumors, but B72.3 concentrated less in SW948 tumors. 17-1A showed the highest degree of accumulation in SW948 tumor xenografts. No specific uptake of the four anti-carcinoma MoAbs was observed in MEL-1, Namalwa, or MCF-7 xenografts. The specificity of the in vivo tumor localization of the four anti-carcinoma MoAbs was confirmed by the low degree of accumulation of a control MoAb against influenza virus in LS174T tumors. Imaging studies with 131I-labeled colorectal cancer MoAbs showed specific uptake and retention in LS174T tumors, with progressive clearance from the whole body. The colorectal cancer MoAbs were compared for immunohistochemical binding against biopsies from patients with colorectal cancer and adjacent normal colonic tissue. Most colorectal cancer specimens showed moderate to strong staining with the four MoAbs. The percentage of positive cells varied within and between tumors demonstrating antigenic heterogeneity. Absent to slight focal staining was seen with normal colon tissue. B72.3 showed the highest degree of staining specificity. This study indicates a difference in the immunohistochemical binding of a panel of MoAbs against biopsies of colon adenocarcinoma and a dependence of in vivo localization on the human colon cancer cell line used as target. This has important implications for future clinical diagnostic and therapeutic studies.

Steady-state nonlinear pharmacokinetics of 5-fluorouracil during hepatic arterial and intravenous infusions in cancer patients.

Hepatic arterial catheters were placed for therapy in 8 patients with primary or metastatic liver cancer. Temporary hepatic venous catheters allowed direct sampling of blood for hepatic venous drug concentrations. Patients were administered from three to six infusions at rates of 10, 30, 90, 135, 180, 210, and 270 mg/kg/day (0.053 to 1.43 microM/kg/min), given over 2 h, of 5-fluorouracil (FUra). In Method 1, FUra was infused i.v., and FUra was measured in plasma from hepatic arterial and hepatic venous blood. In Method 2, FUra was given i.v. at one time and infused into hepatic arterial blood at another time, and FUra was measured in plasma from peripheral blood at the same site in both cases. Steady-state FUra plasma concentrations were measured by a sensitive and specific high-performance liquid chromatography method. Data were computer fitted to the equations appropriate for a physiological two-compartment flow model with Michaelis-Menten elimination from the peripheral compartment and blood flow rate, Q, between the central and peripheral compartment. Methods 1 and 2 gave mean Vmax and Km values which did not differ significantly; the overall mean Vmax was 2.02 microM/kg/min, and the overall mean Km was 10.9 microM. For Method 1 the mean Q1 value was 0.0803 liters/(kg X min) or 5.26 liters/min, which is the same as cardiac output, but for Method 2 the mean Q2 value was higher, namely 0.189 liters/(kg X min) or 13.0 liters/min. Steady-state systemic and intrinsic clearances and extraction ratios decreased progressively as the dose rate increased. Intra- and inter-subject variation of both Vmax and Km were of the same order of magnitude. As a result, dose rate escalation should be conservative for dose rates above 135 mg/kg/day. The results support hepatic arterial infusion as a means of improving the therapeutic index of FUra in the treatment of cancer of the liver.

Tissue-specific pharmacodynamics of 5-bromo-2'-deoxyuridine incorporation into DNA in VX2 tumor-bearing rabbits.

The thymidine analog 5-bromo-2'-deoxyuridine (BrdUrd) is felt to exert its cytotoxic effects primarily through incorporation into DNA. We have evaluated the incorporation of BrdUrd into the DNA of relevant normal tissues (bone marrow, gut mucosa, and liver) and tumor in rabbits with the VX2 tumor growing intrahepatically. Using constant i.v. infusions, steady state plasma drug concentrations ranging from 0.4 to 65.4 microM were maintained for 24 h and tissues were harvested and processed so that a sensitive gas chromatography/mass spectrometry (GC/MS) method could be used to analyze the thymine and 5-bromouracil content of hydrolyzed DNA. In all tissues, DNA incorporation showed saturating effects as plasma BrdUrd concentration was increased and, BrdUrd incorporation as a function of plasma concentration could be fitted to a Langmuir-like equation generating tissue-specific pharmacodynamic parameters: Imax for percentage thymine replacement at infinite plasma BrdUrd concentrations, and C50 for the arterial BrdUrd concentration generating incorporation that is Imax/2. At all plasma concentrations of BrdUrd the incorporation into DNA of bone marrow was greater than that observed in VX2 tumor. However, BrdUrd labeling index (with a BrdUrd monoclonal antibody) was greater in tumor than bone marrow. Thus, pharmacodynamic differences in incorporation do not result solely from cytokinetic differences between tissues. This model may prove useful in evaluating the pharmacodynamics of incorporation in studies using hepatic arterial infusion and biochemical modulation to improve selectivity.

Cortical activation patterns during voluntary blinks and voluntary saccades.

OBJECTIVE: To investigate the activation of frontal, parietal, and occipital areas in normal volunteers during voluntary blinks and during voluntary saccades using functional MRI (fMRI). BACKGROUND: A previous fMRI study revealed the activation of the precentral and posterior middle frontal gyrus ("frontal eye field" [FEF]), the medial part of the superior frontal gyrus ("supplementary eye field" [SEF]), and the visual cortex. The parietal cortex was not included in this study. Frontal and occipital cortical areas involved in voluntary blinking have not been shown previously using fMRI. METHODS: A 1.5-T standard clinical scanner was used for both anatomic and functional studies in 12 observers. To conduct data analyses the authors used voxel-by-voxel cross-correlation. RESULTS: Voluntary blinks led to the activation (p < 0.05) of the FEF, the SEF, the posterior parietal cortex ("parietal eye field" [PEF]), and the visual cortex. Voluntary blinking produced activity in the same cerebral structures as voluntary saccades. However, the number of activated voxels was smaller during voluntary blinking than during voluntary saccades in the visual cortex and in the FEF (p < 0.01). In contrast, the extent of activation was significantly higher (p < 0.003) in the SEF and in the PEF during voluntary blinking. CONCLUSIONS: Voluntary blinks and saccades are associated with similar loci of activation patterns; however, the quantitative distribution of activation suggests that the middle part of the frontal gyrus and posterior parietal cortex are of special significance for voluntary blinks. The results argue for the importance of considering quantitative distributional properties of parallel cortical activities associated with saccades and blinks.

Nitrous oxide: clinical and electrophysiologic investigation of neurologic complications.

Prolonged exposure to nitrous oxide produces a recognized neurologic syndrome. We report clinical and electrophysiologic studies of nervous system involvement in a 25-year-old student who abused nitrous oxide. He developed signs of a sensorimotor polyneuropathy and of myelopathy. Routine blood studies, CSF examination, and myelogram were normal. Clinical electrophysiologic studies were performed serially. Nerve conduction studies demonstrated reduced amplitude and slowed sensory potentials, and mildly prolonged late responses. Sensory evoked potentials revealed prolonged latency of scalp-evoked potentials from tibial nerve stimulation with normal median nerve values. The foveal visual evoked potential was delayed in the right eye, with normal visual acuity, funduscopic examination, and spatial contrast sensitivity. Repeat electrophysiologic studies demonstrated improvement. Nitrous oxide produces multifocal reversible dysfunction within the nervous system similar to that described in patients with vitamin B12 deficiency.

Functional MRI mapping of occipital and frontal cortical activity during voluntary and imagined saccades.

We investigated the activation of frontal and occipital cortical areas in 14 normal volunteers during voluntary saccades in light or dark and during imagined saccades using functional magnetic resonance imaging (FMRI) with electro-oculogram monitoring. Voluntary saccades in light or dark and imagined saccades led to a significant activation (p < 0.005) of the precentral and posterior medial frontal gyrus (frontal eye field). The medial part of the superior frontal gyrus (supplementary eye field) also showed significant activity during voluntary saccades in all subjects, but only in four subjects during imagined saccades. In addition to frontal activity we found an activated primary visual cortex during voluntary saccades, both in light and in dark. In contrast to executed saccades, imagined eye movements revealed to occipital response under either condition. Our FMRI study supports the concept of frontal eye fields during voluntary saccades and demonstrates that occipital areas are associated with the generation of voluntary eye movements. However, the primary visual cortex is not active when eye movement is only imagined.

Treatment of cancers involving the liver and porta hepatis with external beam irradiation and intraarterial hepatic fluorodeoxyuridine.

A Phase I/II clinical trial was designed for patients with malignancies of the liver and porta hepatis. This protocol employed three concepts: a) boost treatment to gross tumor within the liver for selected patients, determined by the dose-volume histogram (DVH) of the normal liver that would be irradiated by boost treatment; b) concurrent use of intraarterial hepatic 5-fluorodeoxyuridine (FdUrd) as a radiosensitizer; and c) hyperfractionation (1.5 Gy fractions given bid greater than 4 hr apart). This report describes the results of treatment of the first 33 patients entered onto this study, with a minimum follow-up of 1 year. Twenty patients received only whole liver irradiation (33 Gy). Thirteen patients were treated with whole liver irradiation (30 Gy) plus a 15 Gy (6 patients) or 30 Gy (7 patients) boost (total 45 Gy and 60 Gy to the tumor, respectively). Forty-eight percent of the evaluable patients (14/29) had an objective response, based on CT scan. The median duration of response was 8 months. The chief toxicities were fatigue, nausea, gastritis, and diarrhea, which were less than or equal to grade 2 in severity. Two patients developed mild radiation hepatitis which was treated successfully with diuretics. These data suggest that the treatment of intrahepatic malignancies can be guided by the concept of DVH analysis of the normal liver to allow the safe administration of doses of radiation that are potentially tumoricidal and are well above those that would be predicted to be tolerable for the whole liver.

VEPs in humans reveal high and low spatial contrast mechanisms.

The effect of contrast on visual evoked potential (VEP) amplitude was examined in nine observers. A 6.0 cycles/deg (cpd) grating was modulated in an "on-off" mode at 7.5 Hz. The VEP response contains significant first and second harmonic components: their growth with contrast is parallel, each function consisting of two limbs. The data are consistent with the hypothesis that the pattern VEP obtained with "on-off" presentation may reflect the contributions of "low" and "high" contrast neuronal populations demonstrated in physiological studies of the primate.

Visual evoked potentials in macular disease.

Although a delayed visual evoked potential is considered to be the hallmark of optic nerve disease, relatively little has been published about VEP delays in macular disease. In this study, 20 patients with either acquired unilateral maculopathy or bilateral maculopathy in which one eye was more affected than the other were evaluated. VEP amplitudes and peak latencies were compared between eyes when recordable. Nine patients (45%) exhibited significant interocular delays in the affected or more affected eye while only four patients (20%) exhibited significant interocular attenuations in amplitude. In the nine patients exhibiting delays, three patients had a visual acuity of 20/30 or better in the affected eye or more affected eye. In the patients exhibiting amplitude attenuations, no patient had a visual acuity better than 20/50 in the affected or more affected eye. Although the mechanism of VEP delays in maculopathy is not clear, a VEP delay, in isolation of other tests, should not be used in the differential diagnosis of macular vs optic nerve disease. The clinician should specifically rule out macular disease in any patient with a delayed VEP before presuming the presence of a visual pathway dysfunction.

Flicker threshold and pattern VEP latency in ocular hypertension and glaucoma.

Latency of the pattern visual-evoked potential (PVEP) was measured in 24 ocular hypertensive (OHT) patients, eight open-angle glaucoma (OAG) patients, and 37 control subjects. The PVEP stimulus was a 2.3 cycle/degree sinusoidal grating, counterphase-modulated at 1 Hz. Field size was 9 degrees and mean luminance 1.7 log ft-lamberts. For 22 of the 32 patients, a psycholphysical measure of dynamic contrast sensitivity at 8 Hz (DRC) was obtained with a 4 degrees diameter stimulus, by determining the mean value for the contrast sensitivities to a homogeneous flickering field and to a 1.2 cycle/degree counterphase-flickering grating. Patient DRC values were compared with previously published control data from 21 subjects. Mean PVEP latencies of both the OHT and the OAG patients were greater than normal (P less than 0.001), with the OAG value larger than the OHT value (P less than 0.001). Mean DRCs were lower than normal (P less than 0.002) for both patient groups, with the OAG value lower than the OHT value (P less than 0.025). DRC correlated with PVEP latency for these patients (r = -0.66, P less than 0.001).

Flash and pattern electroretinograms in normal and laser-induced glaucomatous primate eyes.

Experimental glaucoma was produced in one eye of five cynomolgus monkeys with the argon laser delivering 100-200 50-mu spots at 1200-1500 mW power and 0.5 sec to 360 degrees of the mid-trabecular meshwork. Monocular electroretinograms (ERGs) were recorded prior to and 2, 3, and 4 mo following the laser treatment. In the laser-treated (glaucoma) eyes, normal flash ERGs were observed using 1-Hz stimulation; however, pattern ERGs (PERGs) elicited using steady-state counterphase modulation of a 0.51 cpd square wave grating showed statistically significant reductions of amplitude. Only small reductions of PERG amplitude were seen with a 1.25 cpd grating. In three animals, abnormalities of the PERG occurred prior to clinically significant cupping of the optic nervehead. Moreover, reductions of PERG amplitude were progressive and associated with the magnitude of cupping of the optic nervehead and elevation of intraocular pressure. PERG amplitude did not change following acute reductions in intraocular pressure in the glaucoma eyes. Several control experiments were conducted to insure that results were not due to alterations in pupil size, refractive state, or accommodation in the glaucoma eyes. The authors believe they now have a monkey model for the electrophysiologic study of glaucoma.

Floxuridine-associated sclerosing cholangitis. A dog model.

The authors developed a dog model for the biliary sclerosis that occurs as a severe complication of protracted hepatic arterial floxuridine (FUDR) infusions (using implanted drug delivery systems) in patients with hepatic cancers. Infusaid pumps attached to hepatic arterial catheters were used for protracted infusions in ten mixed breed hounds. To allow repeated cholangiograms, the animals' gallbladders were removed and catheters connected to subcutaneous infusion ports were positioned in the cystic ducts. Five treated dogs received FUDR 0.3 mg/kg/day through the pump for a total of 30 days. Five control dogs received only saline through the pump. Cholangiograms were obtained before and after treatment in all animals. In the control group, serum liver function test results and the cholangiographic appearance of the biliary tree remained within normal limits. By contrast, in the FUDR-treated group, serum glutamic-pyruvic transaminase and alkaline phosphatase progressively rose above normal, starting 2-3 weeks into FUDR infusion, followed by hyperbilirubinemia (7-28 mg/dl peak levels) beginning 4 to 6 weeks after initiation of the drug infusion. Cholangiograms revealed focal strictures involving the central bile ducts (five dogs) and diffuse attenuation of the intrahepatic ducts (four dogs). Thus, the liver function abnormalities and the cholangiographic findings in this dog model mimic the hepatobiliary toxicity in sensitive patients receiving similar treatment.