Radioprotective effect of a pan-caspase inhibitor in a novel model of radiation injury to the nucleus of the abducens nerve.

There is increasing evidence that neuronal cell death occurs via extrinsic (death receptors) and intrinsic (mitochondria) pathways. Radiation induces caspase activation fundamentally via the mitochondrial pathway. Caspases are the key regulators of apoptosis. Healthy male Sprague­Dawley rats were used in the present study to examine the radioprotective effect of a type of pan-caspase inhibitor, z-VAD-fmk, following radiation, to investigate the effects of caspase blockade in a model of the nucleus of the abducens nerve. z-VAD-fmk was injected intracerebroventricularly as a bolus injection (0.2 µg/h for 1 h) into rats prior to exposure to radiation. Irradiation was conducted at room temperature at a dose of radiation of 4 Gy. The present study performed immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and western blot analysis and identified no significant changes in the expression of the X-linked inhibitor of apoptosis protein (XIAP) following radiation (P>0.05). As compared with the radiation alone group, the quantification of TUNEL-positive neurons was reduced in z-VAD­fmk-treated animals following radiation (P<0.01). Inhibition of caspase induced by z-VAD­fmk reduced the expression and activation of caspase-3, -8 and -9 (P<0.01). z-VAD-fmk effectively prevented radiation-induced apoptosis and this caspase inhibitor may be a potential therapeutic target in the treatment of brain radiation injury. The nucleus of the abducens nerve may be used as a radiation injury model, providing visual information and data on the apoptotic morphology of the abducens nucleus.

Modulation of intracortical facilitatory circuits of the human primary motor cortex by digital nerve stimulation.

We investigated the effect of electrical digit stimulation on two different intracortical facilitatory phenomena. Paired-pulse transcranial magnetic stimuli (TMS) with different conditioning stimulus (CS) intensities were applied over the primary motor cortex (M1). Electromyographic (EMG) recordings were made from the relaxed right abductor digiti minimi muscle (ADM). The effect of preceding sensory stimulation applied to the ipsilateral digit V on the conditioning magnetic stimulus was examined. Changing the CS intensity affected the influence of peripheral electrical stimulation on motor evoked potential (MEP) amplitudes evoked by paired pulse TMS. Inhibition induced by ipsilateral digit stimulation was strongest with the lowest CS intensity if MEP amplitudes were evoked by a subthreshold CS followed by a suprathreshold test stimulus (TS) at an interstimulus interval (ISI) of 10 ms. In contrast, inhibition induced by digit stimulation in a paired-pulse paradigm with a suprathreshold first and a subthreshold second stimulus at ISI of 1.5 ms was strongest with the highest CS intensity. These findings suggest that appropriately timed peripheral electrical stimuli differentially modulate facilitatory interactions in the primary motor cortex. They further support the hypothesis that intracortical facilitation (ICF) and short-interval intracortical facilitation (SICF) are evoked through different mechanisms.

Modulation of corticospinal excitability by paired associative stimulation: reproducibility of effects and intraindividual reliability.

OBJECTIVE: Electrical stimulation of the median nerve followed by a magnetic pulse on the primary motor cortex (M1) is effective to cause an increase in the amplitude of motor evoked potential (MEP) registered in the target muscle with the interstimulus interval (ISI) at 25ms (paired associative stimulation, PAS). The aim of this study is to evaluate the reproducibility of PAS with ISI 25 (PAS25), assessed in two separate sessions. Intraindividual reliability of TMS measures was also evaluated. METHODS: Motor threshold of abductor pollicis brevis (APB), assessed at rest, and MEP amplitude of APB and abductor digiti minimi (ADM) were assessed before and after PAS25 in 18 healthy volunteers (nine males and nine females). RESULTS: Data showed a significant increase of MEP amplitude in the target muscle (APB) after PAS25 and a reproducibility of group effect in the two sessions, as assessed by ANOVA, but a lack of intraindividual reliability, as assessed by intraclass correlation coefficients (ICC). CONCLUSIONS: The results underline the reproducibility of mean effects and the need to be careful when comparing the same subject on different days. SIGNIFICANCE: Electrical stimulation of the median nerve followed by a magnetic pulse delivered on M1 after 25ms causes a reproducible increase in MEP amplitude, without showing an acceptable intraindividual reliability.

Three-dimensional kinematics at the level of the oculomotor plant.

Motor systems often require that superfluous degrees of freedom be constrained. For the oculomotor system, a redundancy in the degrees of freedom occurs during visually guided eye movements and is solved by implementing Listing's law and the half-angle rule, kinematic constraints that limit the range of eye positions and angular velocities used by the eyes. These constraints have been attributed either to neurally generated commands or to the physical mechanics of the eye and its surrounding muscles and tissues (i.e., the ocular plant). To directly test whether the ocular plant implements the half-angle rule, critical to the maintenance of Listing's law, we microstimulated the abducens nerve with the eye at different initial vertical eye positions. We report that the electrically evoked eye velocity exhibits the same eye position dependence as seen in visually guided smooth-pursuit eye movements. These results support an important role for the ocular plant in providing a solution to the degrees-of-freedom problem during eye movements.

Ocular neuromyotonia--an unusual ocular motility complication after radiation therapy for nasopharyngeal carcinoma.

The incidence of nasopharyngeal carcinoma is high amongst the Chinese population in Singapore. Abnormal ocular motility, like abducens nerve palsy, is often a presenting feature. Ocular motility problems can also arise as a complication from the treatment or tumour recurrence. This is a case report of a patient who had been treated for nasopharyngeal carcinoma with radiotherapy 13 years ago. She presented with paroxysmal diplopia and the clinical findings were consistent with ocular neuromyotonia. She responded favourably to oral carbamazepine. Ocular neuromyotonia is uncommon and it has never been reported in the local literature. Recognition of the condition is of both diagnostic and therapeutic significance.

Gaze-induced strabismus.

A 20-year-old woman with a past history of a sinonasal undifferentiated carcinoma involving the skull base and cavernous sinus, previously treated with surgery and radiation therapy, presented with intermittent horizontal diplopia induced by gaze to the right side. The gaze in the direction of the action of the right VI nerve produced sustained contraction of the right lateral rectus and an exodeviation increasing on left gaze. Ocular neuromyotonia involving the right VI nerve was believed to be secondary to the patient's previous radiation therapy. The discussants review the prior literature regarding ocular neuromyotonia involving the III, IV and VI cranial nerves, its relationship to prior radiation therapy, and possible modes of therapy including the use of Carbamazepine.

Tolerance of cranial nerves of the cavernous sinus to radiosurgery.

PURPOSE: Stereotactic radiosurgery is becoming a more accepted treatment option for benign, deep seated intracranial lesions. However, little is known about the effects of large single fractions of radiation on cranial nerves. This study was undertaken to assess the effect of radiosurgery on the cranial nerves of the cavernous sinus. METHODS AND MATERIALS: We examined the tolerance of cranial nerves (II-VI) following radiosurgery for 62 patients (42/62 with meningiomas) treated for lesions within or near the cavernous sinus. Twenty-nine patients were treated with a modified 6 MV linear accelerator (Joint Center for Radiation Therapy) and 33 were treated with the Gamma Knife (University of Pittsburgh). Three-dimensional treatment plans were retrospectively reviewed and maximum doses were calculated for the cavernous sinus and the optic nerve and chiasm. RESULTS: Median follow-up was 19 months (range 3-49). New cranial neuropathies developed in 12 patients from 3-41 months following radiosurgery. Four of these complications involved injury to the optic system and 8 (3/8 transient) were the result of injury to the sensory or motor nerves of the cavernous sinus. There was no clear relationship between the maximum dose to the cavernous sinus and the development of complications for cranial nerves III-VI over the dose range used (1000-4000 cGy). For the optic apparatus, there was a significantly increased incidence of complications with dose. Four of 17 patients (24%) receiving greater than 800 cGy to any part of the optic apparatus developed visual complications compared with 0/35 who received less than 800 cGy (p = 0.009). CONCLUSION: Radiosurgery using tumor-controlling doses of up to 4000 cGy appears to be a relatively safe technique in treating lesions within or near the sensory and motor nerves (III-VI) of the cavernous sinus. The dose to the optic apparatus should be limited to under 800 cGy.

Episodic exotropia from lateral rectus neuromyotonia--appearance and remission after radiation therapy for a thalamic glioma.

Sixteen months after radiation therapy for a moderately anaplastic astrocytoma of the thalamus, a 7-year-old boy developed spontaneous episodic contractions in his left lateral rectus muscle. During these episodes, lasting 10 to 30 seconds and occurring 20 or more times a day, he had exotropia, limitation of adduction, and retraction of the left globe. This phenomenon peaked in duration and frequency at 14 months and gradually disappeared after 22 months. As this case confirms, radiation injury to the abducens nerve can cause ocular neuromyotonia, resulting in episodic strabismus. Our case also illustrates that this condition can disappear completely after many months.