Inflammatory complications of CGRP monoclonal antibodies: a case series.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is expressed throughout the body and is a known mediator of migraine, exerting this biological effect through activation of trigeminovascular, meningeal and associated neuronal pathways located in close proximity to the central nervous system. Monoclonal antibodies (mAb) targeting the CGRP pathway are an effective new preventive treatment for migraine, with a generally favourable adverse event profile. Pre-clinical evidence supports an anti-inflammatory/immunoregulatory role for CGRP in other organ systems, and therefore inhibition of the normal action of this peptide may promote a pro-inflammatory response. CASES: We present a case series of eight patients with new or significantly worsened inflammatory pathology in close temporal association with the commencement of CGRP mAb therapy. CONCLUSION: This case series provides novel insights on the potential molecular mechanisms and side-effects of CGRP antagonism in migraine and supports clinical vigilance in patient care going forward.

Myasthenia gravis seven years after removal of an invasive thymoma.

This report describes a 59-year-old male who developed myasthenia gravis 92 months following excision of an invasive thymoma, in the absence of tumour recurrence. This report highlights the importance of prolonged clinical surveillance in post-thymectomy patients.

Changes in axonal excitability and burst pattern behaviour in synkinesis.

Synkinesis after severe facial nerve paralysis has been related to the processes of aberrant reinnervation and increased excitability of the facial nucleus. We present the electrophysiological features of synkinesis in a 32-year-old woman who developed grouped 'myokymic-like' discharges with eye blinking in the absence of spontaneous muscle activity. With eye blinks, the interspike intervals of discharges in the orbicularis oris varied between 25-150Hz, overlapping with rates of myokymia and neuromyotonia. Analysis of the discharge patterns in the present case suggests that synkinesis reflects aberrant regeneration with effects mediated by properties of axonal excitability that determine the burst pattern characteristics.

Sway patterns in orthostatic tremor: impairment of postural control mechanisms.

Sway parameters in orthostatic tremor (OT) patients were compared with age-matched controls. The effects of vision (eyes open or closed), stance width (feet apart or together), and external support (with or without) on sway and 14-18 Hz energy were measured. Sway in OT patients decreased in the presence of each of the stabilizing factors but the extent of benefit obtained by OT patients was significantly less than controls for support for the sagittal plane (22% vs. 42% decrease; P < 0.01) and feet apart in the mediolateral plane (38% vs. 65% decrease; P < 0.01). Three patients with proprioceptive loss also had a reduced response to these factors. Energy in the 14-18 Hz range did not always change in parallel with sway levels. Vision suppresses activity at the OT frequency in patients. Postural control mechanisms in OT remain responsive to postural conditions, but patients differ significantly from normals in the degree of their responsiveness. OT appears to have disruption of the normal generation or processing of proprioceptive signals as one of its important components.

Evidence for reflex and perceptual vestibular contributions to postural control.

Vestibular signals are known to have an important role in stance under specific conditions. Potentially these effects could be modulated by vestibular reflexes or by voluntary responses to perceived vestibular signals. Our preliminary aim was to confirm that vestibulospinal reflexes change in parallel with sway under different postural conditions, and then to determine whether any relationship was present between these reflexes and body sway within fixed postural conditions. Sixteen subjects (eight male, eight female) were tested in conditions assessing the effects of vision (eyes open or closed), support surface (firm or compliant), external support (with or without) and stance width (feet apart or together). Sway (centre of pressure) in the anteroposterior (AP) and mediolateral planes was measured using a force platform. A subgroup of 11 subjects (five male, six female) underwent testing to measure short (SL) and medium latency (ML) reflexes from soleus. Bipolar, transmastoid galvanic stimulation (1 mA, 200 ms) was administered while subjects stood in the most unstable of our conditions (eyes closed, compliant surface and feet together). In the final part, to assess possible perceptual contributions to body sway, short duration AP sway levels were measured and expressed in angular terms (sway in mrad, velocity in mrad s(-1)) in the 11 subjects for both our baseline (eyes open, firm surface and feet apart) and most unstable conditions. Average sway levels increased more than seven-fold between conditions and had significant, positive correlations with reported changes in mean vestibulospinal reflexes under similar conditions (overall r = 0.75, P < 0.001). However, the SL reflex for the subgroup of 11 subjects had a significant negative correlation (r = -0.71; P = 0.014) with the degree of AP sway in the condition with maximum reliance on vestibular inputs (eyes closed, compliant surface, and feet together). Under baseline conditions, 5/125 (4%) of the short-term AP sway displacements were above the threshold previously reported for the detection of imposed sway. In the unstable condition, when sway was increased, 43/138 (31%) of the short-term AP sway movements were above the threshold for perception of imposed body sway based on vestibular signals. Our results confirm that vestibulospinal reflexes appear to be acutely facilitated as body sway increases. For the most unstable condition, when non-vestibular information was absent or attenuated, subjects with larger SL reflexes had less AP sway, suggesting that the SL reflex acted to attenuate sway. Under the same condition, short duration sway levels increased such that 31% were above the previously published threshold for detection using vestibular afferents. We conclude that both vestibular reflexes and perceptual signals appear to have a specific role in the maintenance of upright stance, under conditions in which other sources of postural information are attenuated or absent.

Sway patterns in a case of orthostatic tremor responsive to alcohol.

We describe changes in the extent of sway in a man with orthostatic tremor (OT) who reported increased stability after alcohol. He was tested at baseline and again after 40 g (0.5 g/kg) of alcohol. These results were compared to those of 3 age-matched controls (no alcohol). The patient's baseline sway was greater than controls, larger in the lateral than the anteroposterior plane, but retained normal responsiveness to the use of external support, increasing stance width, and vision. Tremor frequency significantly decreased after alcohol, as did low- and high-frequency tremor amplitude and the extent of body sway. Despite these findings, sway remained greater than controls. OT thus may show functionally important alcohol responsiveness.

Anodal vestibular stimulation does not suppress vestibular reflexes in human subjects.

Anodal current applied to the vestibular apparatus has previously been found to inhibit discharge from irregular vestibular afferents in squirrel monkeys. We wished to investigate whether anodal currents applied over the mastoid processes of human subjects would significantly reduce ongoing vestibular activity and thereby the size of galvanic-evoked vestibulospinal reflexes, measured by soleus electromyogram. Nine subjects were tested, of whom six subjects (five females, one male) provided data for the final analysis. Tonic anodal current was applied over one mastoid at 0 (baseline), 2, 4, 6 and 8 mA. The cathode was placed at C7. Superimposed on each intensity of tonic current were separate, short anodal currents of 4 mA, duration 20 ms, presented as 128 stimuli to the same side, and used to test vestibular responsiveness. These trials were then repeated with the anode overlying the contralateral mastoid. Short latency (SL) and medium latency (ML) reflexes were measured from the right soleus muscle. All six subjects used in the final analysis had readily identifiable reflexes to all stimuli. One-way ANOVA revealed no significant difference in the magnitude of the SL ( P=0.99) or ML ( P=0.96) components of the vestibulospinal reflexes across the group. Despite surface anodal currents of up to 8 mA, there was no consistent effect on the size of galvanic-evoked vestibulospinal reflexes. As 8 mA is close to the maximum intensity tolerated by volunteer subjects, our results indicate that anodal current applied over the mastoids is unlikely to be a useful means of suppressing vestibular function in human subjects.

Galvanic and acoustic vestibular stimulation activate different populations of vestibular afferents.

OBJECTIVE: To deduce whether similar or distinct populations of vestibular afferents are activated by acoustic and galvanic vestibular stimulation by comparing the effectiveness of 'matched' stimuli in eliciting vestibulospinal reflexes. METHODS: Twelve subjects (5 men, 7 women) underwent individual 'matching' of 2 ms tone burst and galvanic stimuli, using vestibulocollic reflexes so that corrected reflex amplitudes to tone burst and galvanic stimuli were within 10% of each other. These same intensities were then administered using 20 ms durations to determine whether they were equally effective in evoking vestibulospinal responses. RESULTS: Corrected reflex amplitudes for vestibulocollic responses to tone burst and galvanic stimulation were not significantly different for the right (P=0.45) or left (P=0.68) sides. All subjects had vestibulospinal responses to galvanic stimulation (average intensity 4.0 mA for both sides). The short latency (SL) and medium latency (ML) components of the vestibulospinal reflexes were larger after galvanic compared to tone burst stimulation in 11 of 12 subjects (P<0.01). CONCLUSIONS: Despite evoking equal-sized vestibulocollic reflexes, there was a clear dissociation between the magnitude of tone burst and galvanic-induced vestibulospinal reflexes. Galvanic stimulation evoked SL and ML reflexes in all subjects. Tone burst stimuli evoked only small SL reflexes and, in most cases, no ML reflexes. Acoustically-evoked vestibulocollic reflexes are likely to be due to saccular excitation. The limited effectiveness of longer tone burst stimuli to evoke ML vestibulospinal reflexes suggests that saccular afferents have, at most, only a minor role in the production of these reflexes. We conclude that galvanic stimulation is more effective in eliciting vestibulospinal reflexes than tone burst stimulation, and that the two methods activate different populations of vestibular afferents.