Visual neurophysiological dysfunction in infants exposed to hydroxychloroquine in utero.

AIM: Hydroxychloroquine therapy during pregnancy is thought to be safe for foetuses. Normal visual function has been showed on clinical grounds in infants exposed in utero to hydroxychloroquine, but there are few visual neurophysiological data. Our study was designed to assess retina and visual pathways using electroretinogram and visual evoked potentials in a series of infants born to mothers treated by hydroxychloroquine for connective tissue diseases. METHODS: Twenty-one infants (3-7 months of age) were consecutively examined between June 2002 and May 2007. Full-field electroretinogram was recorded by contact lens electrodes and visual evoked potentials were recorded by occipital surface electrodes using flash stimulation in mesopic condition. Analysis was focused on the amplitudes and latencies of the a- and b-waves of electroretinogram and the latency of the P(100) component of visual evoked potentials. RESULTS: Electroretinogram abnormalities were detected in six infants, associated with delayed visual evoked potentials in four of them. CONCLUSION: Early electroretinogram and visual evoked potentials testing evidenced neurophysiological visual disturbances in a subset of infants born to mothers treated by hydroxychloroquine. Systematic clinical and neurophysiological vision testing during childhood is needed to detect possible consequences of antenatal exposure to hydroxychloroquine.

Hemispheric asymmetry in cortical control of memory-guided saccades. A transcranial magnetic stimulation study.

To study the temporal organisation of memory-guided saccade control we used single-pulse transcranial magnetic stimulation (TMS) over the left posterior parietal (PPC) and prefrontal cortex (PFC) in eight healthy subjects. TMS was applied either following presentation of a visual target, i.e. 160, 260, and 360 ms after the flashed point, or during the period of memorisation, i.e. between 700 and 1500 ms, or finally 100 ms after extinguishing of the central fixation point (i.e. 2100 ms after the target presentation). Latency of memory-guided saccades and the percentage of error in amplitude (PEA) was measured and compared with results without stimulation.TMS over the left PPC 100 ms after the extinguishing of the central fixation point significantly increased memory-guided saccade latency bilaterally. Furthermore, stimulation over the left PFC had a significant effect on the PEA of contralateral memory-guided saccades when applied during the period of memorisation, i.e. between 700 and 1500 ms.In a previous study using identical methodology [13: Müri RM, Vermersch SI, Rivaud S, Gaymard B, Pierrot-Deseilligny C. Effects of single-pulse transcranial magnetic stimulation over the prefrontal and posterior parietal cortices during memory-guided saccades in humans. Journal of Neurophysiology 1996;76:2102-2106], we found that TMS over the right PPC increased the contralateral PEA when applied 260 ms after the flash, the effects on saccade latency after right PPC stimulation or on the PEA after right PFC stimulation being similar to those observed here. Taken together, these results show that (1) a hemispheric asymmetry in the preparation of memory-guided saccade amplitude during the early phase of sensorimotor integration exists, (2) memory-guided saccade triggering is controlled by PPC on both sides, and (3) PFC on both sides are involved in spatial working memory performance.

Improvement of memory guided saccades in parkinsonian patients by high frequency subthalamic nucleus stimulation.

Recent studies in the monkey suggest that the subthalamic nucleus (STN) is involved in control of eye movement, yet its functional significance in humans is unknown. Saccadic eye movements were studied in eight parkinsonian patients treated by bilateral electrical stimulation of the STN. STN stimulation improved the accuracy of memory guided saccades but not of reflexive visually guided saccades and had no effect on the antisaccade task. This study shows that, by contrast with levodopa, STN stimulation improves memory guided saccade deficits, and illustrates for the first time in humans the role of the STN in the control of purposive saccades.

Memory guided saccade deficit after caudate nucleus lesion.

The role of the caudate nucleus in ocular motor control is not well determined in humans. Eye movements were recorded from a 45 year old man with infarctions involving bilaterally the body of the caudate nucleus, with a greater extent on the left side. The patient exhibited a pattern of eye movement abnormalities in which a delay dependent decrease of accuracy of memory guided saccades predominated. By contrast, memory guided pointing was normal. It is concluded that the body of the caudate nucleus participates in a spatial short term memory network devoted to eye movements.

Role of the prefrontal cortex in the control of express saccades. A transcranial magnetic stimulation study.

Single pulse transcranial magnet stimulation (TMS) was applied in five subjects during a saccadic gap task, i.e. with a temporal gap of 200 ms between the extinguishing of the central fixation point and the appearance of the lateral target. In all subjects, a significant increase of contralateral express saccades was found when TMS was applied over the dorsolateral prefrontal cortex (DPFC) at the end of the gap of 200 ms. Earlier stimulation over the DPFC during the gap had no significant effect. Furthermore, stimulation over the posterior parietal cortex with the same time intervals, and stimulation during a no gap task had no significant influence on express saccades. These results suggest that TMS is capable of interfering specifically with the functioning of the DPFC, probably by inhibition of this region. Possibly such stimulation of the DPFC reduces the inhibition by this region onto the superior colliculus, which results in a facilitation of express saccades.

Cortical control of saccades.

Saccadic eye movements are controlled by a cortical network composed of several oculomotor areas that are now accurately localized. Clinical and experimental studies have enabled us to understand their specific roles better. These areas are: (1) the parietal eye field (PEF) located in the intraparietal sulcus involved in visuospatial integration and in reflexive saccade triggering; (2) the frontal eye field (FEF), located in the precentral gyrus, involved in the preparation and the triggering of purposive saccades; and (3) the supplementary eye field (SEF) on the medial wall of the frontal lobe, probably involved in the temporal control of sequences of visually guided saccades and in eye-hand coordination. A putative cingulate eye field (CEF), located in the anterior cingulate cortex, would be involved in motivational modulation of voluntary saccades. Besides these motor areas, the dorsolateral prefrontal cortex (dlPFC) in the midfrontal gyrus is involved in reflexive saccade inhibition and visual short-term memory.

Effects of single-pulse transcranial magnetic stimulation over the prefrontal and posterior parietal cortices during memory-guided saccades in humans.

1. We used single-pulse transcranial magnetic stimulation (TMS) to explore the temporal organization of the cortical control of memory-guided saccades in eight humans. The posterior parietal cortex (PPC) or the dorsolateral prefrontal cortex (DPFC), which are both known to be involved in the control of such saccades, were stimulated on the right side at different time intervals after the presentation of a flashed lateral visual target. The memorization delay was 2,000 ms. Single pulses were applied at 160, 260, and 360 ms after the flashed target, during the period of 700 and 1,500 ms, and finally at 2,100 ms, i.e., 100 ms after the extinguishing of the central fixation point. The effects of TMS were evaluated by calculating the percentage of error in amplitude (PEA) and latency of memory-guided saccades. The PEA was determined for the primary saccade (motor aspect) and the final eye position, i.e., after the end saccade (mnemonic aspect). Stimulation over the occipital cortex at the same time intervals served as control experiments. 2. After PPC stimulation, a significant increase in the PEA of the primary saccade and final eye position existed for contralateral saccades, compared with the PEA without stimulation, when stimulation was applied 260 ms after target presentation, but not at other time intervals. There was no significant effect on ipsilateral saccades. Latency was significantly increased bilaterally when stimulation was performed 2,100 ms after target presentation. 3. After prefrontal stimulation, a significant increase in the PEA of the primary saccade and final eye position existed for contralateral saccades, when stimulation was applied between 700 and 1,500 ms after target presentation, but not at other time intervals. There was no significant effect on ipsilateral saccades. Latency was not affected by prefrontal TMS at any stimulation times. 4. Occipital stimulation resulted in no significant effect on the PEA and latency of ipsilateral or contralateral saccades, in particular including the application at 260 ms after target presentation or during the memorization phase. 5. From these results it may be concluded that the observed effects of TMS on saccade accuracy were specific to the stimulated region and specific to the stimulation time. The PPC seems to be involved in the preparation of saccade amplitude, during the early phase of the paradigm, i.e., the sensorimotor processing period, whereas the DPFC could play a role during the later phase of the paradigm, i.e., the memorization period. Therefore in humans these results support the experimental findings suggesting that sensorimotor integration is controlled by the PPC and spatial memory by the DPFC. Furthermore, our results suggest that the PPC, although not the DPFC, plays a role in saccade triggering.

Saccade disturbances after bilateral lentiform nucleus lesions in humans.

OBJECTIVE: To determine the roles of the putamen and pallidum in ocular motor control. METHODS: Eye movements were recorded electro-oculographically in nine patients with bilateral focal lesions affecting the lentiform nucleus, and in 12 age matched control subjects. Reflexive visually guided saccades (gap task), antisaccades, memorised sequences of saccades, memory guided saccades (with visual input only, and with both visual and vestibular inputs), and predictive saccades (with and without gap) were studied. RESULTS: Latency and accuracy of visually guided saccades were normal. The percentage of errors in the antisaccade task and latency of correct antisaccades did not differ significantly from the results of controls. The percentage of errors in saccade sequences was significantly increased. Accuracy of the two types of memory guided saccades was impaired bilaterally. The percentage of predictive saccades was significantly decreased when a gap existed, but unchanged without a gap, compared with controls. Therefore, saccades made immediately in response to an external target (reflexive visually guided saccades and antisaccades) were performed without difficulty, whereas those requiring an internal representation of such a target (such as memory guided saccades, predictive saccades, and saccade sequences) were performed with significant disturbances. CONCLUSIONS: The lentiform nucleus influences the cortical areas involved in the control of saccades when the experimental paradigm requires the use of an internal representation of the target for correct planning and execution of the ensuing saccade.

A study of two procedures of HIV-1 isolation from whole blood cultures.

Culture techniques for isolation of HIV-1 from small amounts of whole blood (WB) treated with anticoagulant have been reported and gave results identical to those of culture of separated peripheral blood mononuclear cells. Some authors obtained much higher isolation rates when EDTA was used instead of heparin. We compared two previously described techniques for cultivation of HIV-1 from WB of adult HIV+ patients staged according to the CDC classification. In addition, we assessed the influence of the type of anticoagulant used for the collection of blood in viral replication in cell cultures from whole blood. Small volumes of WB treated with either heparin or EDTA were cocultivated with phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PHA-PBMC) from healthy donors. We used two procedures for WB culture: procedure I, based on the culture of 250 microliters of WB with 1 x 10(6) PHA-PBMC from donors; and procedure II based on the culture of 500 microliters of WB with 4 x 10(6) PHA-PBMC from donors. The cocultures were placed in 24-well plates and incubated for as long as 28 days in medium containing interleukin 2 (IL-2). Twice weekly half of the medium was replaced with fresh medium. In procedure II, one million fresh PHA-PBMC from donors was added on the 7th day of culture. The culture supernatant was assayed for the presence of HIV-1 p24 antigen in an enzyme immunoassay. The kinetics of HIV-1 replication in cultures of WB from 7 AIDS patients were similar using procedures I and II. In 8 HIV+ patients the isolation rate was higher with heparin- than with EDTA-treated samples. The isolation rate was higher in AIDS patients (n = 8) than in others with both methods. In stage IV patients without AIDS (n = 8) we failed to isolate HIV-1 in 1 patient with procedure I, whereas we succeeded with procedure II. In stage II, HIV-I was isolated in 1 of 4 patients with both methods. HIV was isolated in cultures of WB from patients receiving zidovudine or related nucleoside analogues and in cultures of WB from untreated patients. HIV-1 could not be isolated from WB of patients with more than 400 CD4+ T lymphocytes in their peripheral blood (n = 4); however, it was isolated from 14 of 16 patients with less than 400 CD4+ T lymphocytes. Our results suggest that procedure II is more sensitive than procedure I and that heparin is better than EDTA for collecting WB. We showed that the rate of HIV-1 isolation from WB increased in advanced-stage patients. Further studies are needed to define the clinical applications of WB culture.

Cortical control of saccades.

A scheme for the cortical control of saccadic eye movements is proposed based partly on defects revealed by specific test paradigms in humans with discrete lesions. Three different cortical areas are capable of triggering saccades. The frontal eye field disengages fixation, and triggers intentional saccades to visible targets, to remembered target locations, or to the location where it is predicted that the target will reappear (i.e., saccades concerned with intentional exploration of the visual environment). The parietal eye field triggers saccades made reflexively on the sudden appearance of visual targets (i.e., saccades concerned with reflexive exploration of the visual environment). The supplementary eye field is important for triggering sequences of saccades and in controlling saccades made during head or body movement (i.e., saccades concerned with complex motor programming). Three other areas contribute to the preparation of certain types of saccades. The prefrontal cortex (area 46 of Brodmann) plays a crucial role for planning saccades to remembered target locations. The inferior parietal lobule is involved in the visuospatial integration used for calculating saccade amplitude. The hippocampus appears to control the temporal working memory required for memorization of the chronological order of sequences of saccades.

Effects of transcranial magnetic stimulation over the region of the supplementary motor area during sequences of memory-guided saccades.

Transcranial magnetic stimulation (TMS) over the region of the supplementary motor area (SMA) was used to study the cortical control of sequences of memory-guided saccades. In ten healthy subjects, TMS was applied during (a) the target presentation (learning) phase, (b) the memorization phase, and (c) the execution phase of such saccade sequences. Stimulation during the presentation phase resulted in a significant increase in errors, compared to the results without stimulation. In contrast, stimulation during the memorization or execution phases had no significant influence on the performance of these sequences. The effect of TMS during the presentation phase seems to be specific for an interaction with the SMA function, since, in a control experiment with TMS of the occipital cortex during the same phase, the results were similar to those without stimulation. It is hypothesized that different cortical areas are involved in the learning, memorization and execution of sequences of memory-guided saccades. The SMA action could be crucial during the learning phase, but not during the memorization and execution phases of such sequences.

Sequences of memory-guided saccades in Parkinson's disease.

Sequences of ocular saccades were studied in 8 patients with Parkinson's disease, with (i.e., "on") and without (i.e., "off") levodopa treatment. The amplitude of single saccades was decreased and not improved by treatment. The chronology of saccades during sequences was impaired in patients in the "off" state, but significantly improved during the "on" period. These results are compatible with a decreased activation of the supplementary motor area, which can be reversed by levodopa.

[Pancreatic-portal fistula. A rare complication of chronic pancreatitis]. / La fistule pancréatico-portale. Une complication rare de la pancréatite chronique.

We report a 40-year-old patient with complication of chronic pancreatitis as a pancreatico-portal fistula. The patient had subcutaneous nodular fat necrosis of the lower limbs resembling Weber-Christian syndrome, and amylasic ascitis. The diagnosis was established with retrograde endoscopic cholangio-pancreatography which found three pancreatic pseudocysts and a communication with the portal venous system. A portal thrombosis with cavernum was studied with color echo-Doppler and arteriography. The echo-endoscopy was performed for the first time in this complication and its significance estimated. The evolution was quickly and spontaneously favourable. That is a very rare complication of chronic pancreatitis and an expectant conservative management can be adopted.

Eye movement disorders after frontal eye field lesions in humans.

Eye movements were recorded electro-oculographically in three patients with a small ischemic lesion affecting the left frontal eye field (FEF) and in 12 control subjects. Reflexive visually guided saccades (gap and overlap tasks), antisaccades, predictive saccades, memory-guided saccades, smooth pursuit and optokinetic nystagmus (OKN) were studied in the three patients. Staircase saccades and double step saccades were also studied in one of the three patients. For both leftward and rightward saccades, latency in the overlap task (but not in the gap task) and that of correct antisaccades and of memory-guided saccades was significantly increased, compared with the results of controls. There was a significant decrease in the amplitude gain of all rightward saccades programmed using retinotopic coordinates (gap and overlap tasks, predictive and memory-guided saccades), whereas the amplitude gain of corresponding leftward saccades was preserved. Such an asymmetry between leftward and rightward saccades was significant. In the staircase paradigm as well as for the first saccade in the double step paradigm (with the use of retinotopic coordinates in both cases), the amplitude gain of rightward saccades was also significantly lower than that of leftward saccades. Moreover, in the double step paradigm, the amplitude gain of the first rightward saccade was significantly lower than that of the second rightward saccade (programmed using extraretinal signals), which was preserved. The percentage of errors in the antisaccade task did not differ significantly from that of normal subjects. In the predictive saccade paradigm, the percentage of predictive rightward saccades was significantly decreased. The left smooth pursuit gain for all tested velocities, the right smooth pursuit gain for higher velocities, and the left OKN gain were significantly decreased. The results show, for the first time in humans, that the FEF plays an important role in (1) the disengagement from central fixation, (2) the control of contralateral saccades programmed using retinotopic coordinates, (3) saccade prediction and (4) the control of smooth pursuit and OKN, mainly ipsilaterally. In contrast, the left FEF did not appear to be crucial for the control of the only type of saccades programmed using extraretinal signals studied here.

Elevated serum levels of soluble interleukin-2 receptor: a marker of disease activity in the hypereosinophilic syndrome.

We report here the presence of very high serum levels of the soluble interleukin-2 receptor (sIL-2R) in patients with blood hypereosinophilia with or without detectable markers of malignancy or signs of visceral involvement. The highest sIL-2R levels were observed in 16 eosinophilic patients with T-cell lymphoma (3,440 to 79,500 U/mL). Elevated levels of sIL-2R were also present (1,330 to 22,500 U/mL) in sera from 38 patients with the hypereosinophilic syndrome (HES) without detectable T-cell lymphoma. In this group of patients, the highest levels were noted in the patients with the malignant form of HES. Significantly lower levels were measured in sera of patients with hypereosinophilia associated with parasitic diseases, allergic disorders, or other miscellaneous diseases. Elevated serum sIL-2R levels were not closely paralleled by changes in the number of CD25-positive peripheral blood mononuclear cells as assessed by flow cytometric analysis. However, expression of IL-2R messenger RNA was detected in blood mononuclear cells collected from HES patients. In eight eosinophilic patients with T-cell lymphoma, the serum sIL-2R levels were significantly correlated with the eosinophil counts, and with the total number of blood hypodense eosinophils. alpha-Interferon (alpha-IFN) therapy resulted in both a dramatic clinical improvement and a rapid decrease in sIL-2R levels and blood hypereosinophilia. Similar beneficial effects of alpha-IFN were noted in patients with malignant HES who lacked a detectable T-cell lymphoma. Our data indicate that HES is associated with elevated serum IL-2R levels. The highest levels were observed in the most severe forms of HES with hematologic markers of malignancy or evident visceral involvement. Serum levels of sIL-2R might represent a useful indicator for the management of HES patients. In addition, the respective changes of sIL-2R and blood eosinophilia might reflect distinct processes of mononuclear cell activation affecting the eosinophil lineage.

Type 2 diabetes in the elderly: an assessment of metformin (metformin in the elderly).

Metformin efficacy and safety in type 2 diabetes has not been studied in the elderly patient under conditions pertaining to clinical practice. We have therefore, studied prospectively over two months 24 patients aged between 70-88 years with 115% mean ideal body wt and glycemic control greater than 10 mol.l-1 fasting and/or greater than 14 mol.l-1 postprandial, and/or an HbA1 value greater than 10%. At entry into the study, patients were on metformin + sulfonylurea (n = 15), sulfonylurea (n = 3), metformin (n = 2), insulin (n = 1) or diet alone (n = 3). They received metformin as the sole therapy when possible (sulfonylureas were discontinued in 9 cases) at a dosage of either 850 mg or 1,700 mg/day dependent on creatinine clearance values of 30-60 ml.min-1 (n = 11) and greater than 60 ml.min-1 (n = 13), respectively. Compared to pretreatment values, glycemic control at 1 and 2 months were unchanged, with metformin blood levels remaining within expected values for both dosage groups. Blood lactate levels remained unchanged in the high dosage group but were reduced (p less than 0.05) on 850 mg/day probably because of the reduction of metformin dosage in patients already treated prior to the study. It is concluded that provided the dosage is adjusted to renal function, the metabolic tolerance of metformin therapy is satisfactory in the elderly type 2 diabetic patient. With regard to efficacy, longer observations are needed to know whether this therapy may offer on a long-term basis equivalent glycemic control compared to other treatment modalities.