Effects of Repeated Eyelid Injections with Botulinum Toxin A on Innervation of Treated Muscles in Patients with Blepharospasm.

PURPOSE: To assess changes in innervation and muscle morphology after repeated botulinum toxin A injections in subjects with benign essential blepharospasm. METHODS: Surgical waste specimens were processed for histologic examination of nerve fibers, neuromuscular junctions, fiber size, and central nucleation and compared to age matched controls and to two subjects with blepharospasm that had not received botulinum toxin A injections. RESULTS: There was a significant increase in amount of nerve fibers and numbers of neuromuscular junctions in the orbicularis oculi muscles from subjects with blepharospasm treated repetitively with botulinum toxin A. In addition there was a significant decrease in mean muscle fiber cross-sectional area and an increase in central nucleation. The specimens from the subjects with only blepharospasm had the same density of nerves but had intermediate levels of neuromuscular junctions. CONCLUSIONS: These data suggest that repeated injections of botulinum toxin A has an effect on nerve and neuromuscular junction numbers, which are partly mirrored in orbicularis oculi muscle from subjects with blepharospasm only. These studies suggest the potential for modulating these changes in order to extend the duration of effectiveness of botulinum toxin.

Loss of CXCR4/CXCL12 Signaling Causes Oculomotor Nerve Misrouting and Development of Motor Trigeminal to Oculomotor Synkinesis.

Purpose: Proper control of eye movements is critical to vision, but relatively little is known about the molecular mechanisms that regulate development and axon guidance in the ocular motor system or cause the abnormal innervation patterns (oculomotor synkinesis) seen in developmental disorders and after oculomotor nerve palsy. We developed an ex vivo slice assay that allows for live imaging and molecular manipulation of the growing oculomotor nerve, which we used to identify axon guidance cues that affect the oculomotor nerve. Methods: Ex vivo slices were generated from E10.5 IslMN-GFP embryos and grown for 24 to 72 hours. To assess for CXCR4 function, the specific inhibitor AMD3100 was added to the culture media. Cxcr4cko/cko:Isl-Cre:ISLMN-GFP and Cxcl12KO/KO:ISLMN-GFP embryos were cleared and imaged on a confocal microscope. Results: When AMD3100 was added to the slice cultures, oculomotor axons grew dorsally (away from the eye) rather than ventrally (toward the eye). Axons that had already exited the midbrain continued toward the eye. Loss of Cxcr4 or Cxcl12 in vivo caused misrouting of the oculomotor nerve dorsally and motor axons from the trigeminal motor nerve, which normally innervate the muscles of mastication, aberrantly innervated extraocular muscles in the orbit. This represents the first mouse model of trigeminal-oculomotor synkinesis. Conclusions: CXCR4/CXCL12 signaling is critical for the initial pathfinding decisions of oculomotor axons and their proper exit from the midbrain. Failure of the oculomotor nerve to innervate its extraocular muscle targets leads to aberrant innervation by other motor neurons, indicating that muscles lacking innervation may secrete cues that attract motor axons.

Sub-Tenon's anesthesia for canine cataract surgery.

OBJECTIVE: To test a sub-Tenon's anesthesia technique in dogs as an alternative to systemic neuromuscular blockade to aid in canine cataract surgery under general anesthesia. PROCEDURES: A prospective controlled clinical study was performed involving 12 dogs undergoing bilateral cataract surgery under general anesthesia. One eye was randomly assigned to have phacoemulsification and prosthetic lens implantation performed with sub-Tenon's anesthesia (STA), and the control eye had surgery performed with systemic neuromuscular blockade (NMB). Intraocular pressure (IOP) was measured immediately before and after STA administration. Globe position, globe rotation, pupillary dilation, and vitreal expansion were assessed for both STA and NMB eyes during surgery. RESULTS: Sub-Tenon's anesthesia produced a globe position suitable for cataract surgery with the degree of vitreal expansion not significantly different to control NMB eyes. STA produced greater anterior globe displacement than NMB in all cases. STA had no significant effect on IOP. CONCLUSION: Sub-Tenon's anesthesia was an effective alternative to systemic neuromuscular blockade for canine cataract surgery and may be beneficial for surgical exposure in deep orbited breeds.

Third Cranial Nerve Palsy in the Setting of Chikungunya Virus Infection.

We report the case of a 62-year-old patient who developed an acute painless isolated left third cranial nerve palsy sparing the pupil in the setting of an acute chikungunya infection. The patient had no significant medical history. Specifically, he had no vascular risk factors. Ocular involvement in chikungunya fever is uncommon. The potential virus- and infection-related mechanisms of this third cranial nerve palsy are discussed.

Transient pupillary dilation following local papaverine application in intracranial aneurysm surgery.

Isolated cases of transient pupillary changes after local intracisternal papaverine administration during aneurysm surgery have been reported. This study aimed to determine the prevalence and factors associated with this phenomenon. We assessed a total of 103 consecutive patients who underwent craniotomy for cerebral aneurysm clipping for the presence of postoperative pupillary dilation (mydriasis) after intracisternal papaverine administration. Univariate and multivariate logistic regression were conducted to evaluate the association of mydriasis with patient age, sex, duration of surgery, and aneurysm location. We observed either ipsilateral or bilateral pupillary dilation in the immediate postoperative period in nine out of 103 patients (8.7%). This phenomenon was not associated with patient age or sex. There was a trend towards positive correlation with aneurysms located at the anterior communicating artery (odds ratio 3.76, p=0.10), and a negative correlation with the duration of surgery (odds ratio 0.57, p=0.08). All pupillary dilation resolved within several hours, and the onset and resolution were consistent with the half-life of papaverine. To our knowledge, this represents the largest study of posteropative pupillary changes due to papaverine. The current findings are consistent with the small number of prior case reports of transient pupillary changes after papaverine administration and appear to reflect the local anesthetic action of papaverine on the oculomotor nerve.

Effects of acute alcohol intoxication on automated processing: evidence from the double-step paradigm.

Reflexive and voluntary levels of processing have been studied extensively with respect to possible impairments due to alcohol intoxication. This study examined alcohol effects at the 'automated' level of processing essential to many complex visual processing tasks (e.g., reading, visual search) that involve ongoing modifications or reprogramming of well-practiced routines. Data from 30 participants (16 male) were collected in two counterbalanced sessions (alcohol vs. no-alcohol control; mean breath alcohol concentration = 68 mg/dL vs. 0 mg/dL). Eye movements were recorded during a double-step task where 75% of trials involved two target stimuli in rapid succession (inter-stimulus interval [ISI]=40, 70, or 100 ms) so that they could elicit two distinct saccades or eye movements (double steps). On 25% of trials a single target appeared. Results indicated that saccade latencies were longer under alcohol. In addition, the proportion of single-step responses and the mean saccade amplitude (length) of primary saccades decreased significantly with increasing ISI. The key novel finding, however, was that the reprogramming time needed to cancel the first saccade and adjust saccade amplitude was extended significantly by alcohol. The additional time made available by prolonged latencies due to alcohol was not utilized by the saccade programming system to decrease the number of two-step responses. These results represent the first demonstration of specific alcohol-induced programming deficits at the automated level of oculomotor processing.

Effect of inactivation and disinhibition of the oculomotor vermis on saccade adaptation.

The ability to adapt a variety of motor acts to compensate for persistent natural or artificially induced errors in movement accuracy requires the cerebellum. For adaptation of the rapid shifts in the direction of gaze called saccades, the oculomotor vermis (OMV) of the cerebellum must be intact. We disrupted the neural circuitry of the OMV by manipulating gamma aminobutyric acid (GABA), the transmitter used by many neurons in the vermis. We injected either muscimol, an agonist of GABA, to inactivate the OMV or bicuculline, an antagonist, to block GABA inhibition. Our previous study showed that muscimol injections cause ipsiversive saccades to fall short of their targets, whereas bicuculline injections cause most ipsiversive saccades to overshoot. Once these dysmetrias had stabilized, we tested the monkey's ability to adapt saccade size to intra-saccadic target steps that produced a consistent saccade under-shoot (amplitude increase adaptation required) or overshoot (amplitude decrease adaptation required). Injections of muscimol abolished the amplitude increase adaptation of ipsiversive saccades, but had either no effect, or occasionally facilitated, amplitude decrease adaptation. In contrast, injections of bicuculline impaired amplitude decrease adaptation and usually facilitated amplitude increase adaptation. Neither drug produced consistent effects on the adaptation of contraversive saccades. Taken together, these data suggest that OMV activity is necessary for amplitude increase adaptation, whereas amplitude decrease adaptation may involve the inhibitory circuits within the OMV.

Eye movements and abducens motoneuron behavior after cholinergic activation of the nucleus reticularis pontis caudalis.

STUDY OBJECTIVES: the aim of this work was to characterize eye movements and abducens (ABD) motoneuron behavior after cholinergic activation of the nucleus reticularis pontis caudalis (NRPC). METHODS: six female adult cats were prepared for chronic recording of eye movements (using the scleral search-coil technique), electroencephalography, electromyography, ponto-geniculo-occipital (PGO) waves in the lateral geniculate nucleus, and ABD motoneuron activities after microinjections of the cholinergic agonist carbachol into the NRPC. RESULTS: unilateral microinjections of carbachol in the NRPC induced tonic and phasic phenomena in the oculomotor system. Tonic effects consisted of ipsiversive rotation to the injected side, convergence, and downward rotation of the eyes. Phasic effects consisted of bursts of rhythmic rapid eye movements directed contralaterally to the injected side along with PGO-like waves in the lateral geniculate and ABD nuclei. Although tonic effects were dependent on the level of drowsiness, phasic effects were always present and appeared along with normal saccades when the animal was vigilant. ABD motoneurons showed phasic activities associated with ABD PGO-like waves during bursts of rapid eye movements, and tonic and phasic activities related to eye position and velocity during alertness. CONCLUSION: the cholinergic activation of the NRPC induces oculomotor phenomena that are somewhat similar to those described during REM sleep. A precise comparison of the dynamics and timing of the eye movements further suggests that a temporal organization of both NRPCs is needed to reproduce the complexity of the oculomotor behavior during REM sleep.

Postnatal development enhances the effects of cholinergic inputs on recruitment threshold and firing rate of rat oculomotor nucleus motoneurons.

Changes in the electrophysiological and morphological characteristics of motoneurons (Mns) of the oculomotor nucleus during postnatal development have been reported, however synaptic modifications that take place concurrently with postnatal development in these Mns are yet to be elucidated. We investigated whether cholinergic inputs exert different effects on the recruitment threshold and firing rate of Mns during postnatal development. Rat oculomotor nucleus Mns were intracellularly recorded in brain slice preparations and separated in neonatal (4-7 postnatal days) and adult (20-30 postnatal days) age groups. Stimulation of the medial longitudinal fasciculus evoked a monosynaptic excitatory potential in Mns that was attenuated with atropine (1.5 µM, a muscarinic antagonist). Mns were silent at their resting membrane potential, and bath application of carbachol (10 µM, a cholinergic agonist) induced depolarization of the membrane potential and a sustained firing rate that were more pronounced in adult Mns. Pharmacological and immunohistochemical assays showed that these responses were attributable to muscarinic receptors located in the membrane of Mns. In addition, compared to control Mns, carbachol-exposed Mns exhibited a higher firing rate in response to the injection of the same amount of current, and a decrease in the current threshold required to achieve sustained firing. These latter effects were more pronounced in adult than in neonatal Mns. In conclusion, our findings suggest that cholinergic synaptic inputs are already present in neonatal Mns, and that the electrophysiological effects of such inputs on recruitment threshold and firing rate are enhanced with the postnatal development in oculomotor nucleus Mns. We propose that cholinergic input maturation could provide a greater dynamic range in adult Mns to encode the output necessary for graded muscle contraction.

17ß-estradiol attenuates injury-induced microglia activation in the oculomotor nucleus.

Recent studies provide increasing data indicating the prominent role of estrogens in protecting the nervous system against the noxious consequences of nerve injury. It is also clear that in the process of nerve injury and recovery not only the neurons, but the glial cells are also involved and they are important components of the protective mechanisms. In the present article the effect of 17ß-estradiol on injury-induced microglia activation was studied in an animal model. Peripheral axotomy of the oculomotor neurons was achieved by the removal of the right eyeball including the extraocular muscles of ovariectomized adult mice. The time course and the extent of microglia activation was followed by the unbiased morphometric analysis of CD11b immunoreactive structures within the oculomotor nucleus. The first sign of microglia activation appeared after 24 h following injury, the maximal effect was found on the fourth day. In ovariectomized females hormone treatment (daily injection of 17ß-estradiol, 5 µg/100 g b.w.) decreased significantly the microglia reaction at postoperative day 4. Our results show that microglia response to nerve injury is affected by estradiol, that is these cells may mediate some of the hormonal effects and may contribute to protective mechanisms resulting in the structural and functional recovery of the nervous system.

Resolution of third nerve palsy following treatment of prolactinoma with cabergoline.

This report describes a case of prolactinoma that presented acutely with a third nerve palsy without evidence of apoplexy. The third nerve palsy resolved within 48 h on medical therapy. This is an atypical clinical presentation that highlights a successful and novel medical approach to treatment.

Transient loss of power of accommodation in 1 eye following inferior alveolar nerve block: report of 2 cases.

Unintended intravascular injection from inferior alveolar nerve blocks can result in frustrating distant complications affecting such structures as the middle ear and eyes. Possible complications affecting the eyes include blurring of vision, diplopia, mydriasis, palpebral ptosis and amaurosis (temporary or permanent). In this article, we present a complication that has been reported only rarely. Two patients developed transient loss of power of accommodation of the eye resulting in blurred vision after routine inferior alveolar nerve blocks on the ipsilateral side. Clear vision returned within 10-15 minutes after completion of the blocks. The possible explanation for this phenomenon is accidental injection into the neurovascular bundle of local anesthetic agents, which were carried via the blood to the orbital region. This resulted in paralysis of a branch of cranial nerve III, the short ciliary nerves that innervate the ciliary muscle, which controls accommodation.

Adverse effects of risperidone on spatial working memory in first-episode schizophrenia.

CONTEXT: Working memory impairments are a central neurocognitive feature of schizophrenia. The nature of these impairments early in the course of illness and the impact of antipsychotic drug treatment on these deficits are not well understood. The oculomotor delayed response task is a translational spatial working memory paradigm used to characterize the neurophysiologic and neurochemical aspects of working memory in the primate brain. OBJECTIVE: To examine oculomotor delayed response task performance in patients with first-episode schizophrenia before and after antipsychotic drug treatment. DESIGN, SETTING, AND PARTICIPANTS: Twenty-five antipsychotic drug-naive, acutely ill patients with first-episode schizophrenia performed an oculomotor delayed response task at baseline before any drug treatment and again after 6 weeks of risperidone treatment. Twenty-five matched healthy controls were studied in parallel. MAIN OUTCOME MEASURE: Accuracy for remembered spatial locations on an oculomotor delayed response task. RESULTS: Before treatment, patients demonstrated baseline impairment in the ability to maintain spatial location information in working memory at longer delay-period durations (8 seconds), when maintenance demands on working memory were greatest. After 6 weeks of risperidone treatment and significant clinical improvement, this pretreatment impairment worsened such that patients were uniformly impaired across all delay period durations (1-8 seconds). This occurred in the absence of any generalized adverse effect on oculomotor systems or significant extrapyramidal adverse effects. CONCLUSIONS: Deficits in the maintenance of spatial information in working memory are present early in the course of illness. Risperidone treatment exacerbated these deficits, perhaps by impairing the encoding of information into working memory. Studies with nonhuman primates performing oculomotor delayed response tasks suggest that the apparent adverse effect of risperidone might result from treatment-related changes in modulatory functions of prefrontal D1 receptor systems.

Upward gaze-evoked nystagmus with organoarsenic poisoning.

The authors report assessment of abnormal ocular movements in three patients after organoarsenic poisoning from diphenylarsinic acid. The characteristic and principal sign is upward gaze-evoked nystagmus. Moreover, vertical gaze holding impairment was shown by electronystagmography on direct current recording.