Factors Contributing to the Severity and Laterality of Pisa Syndrome in Parkinson’s Disease

Objective: Pisa syndrome (PS) is a disabling postural deformity in Parkinson’s disease (PD). We aimed to elucidate clinical factors determining the severity and laterality of PS in PD.Methods: In 54 PD patients with PS, we measured the clinical factors that are previously known to contribute to the occurrence of PS as follows: asymmetry of motor symptoms for the evaluation of asymmetric basal ganglia dysfunction, the degree and direction of subjective visual vertical (SVV) tilt for the misperception of body verticality, the canal paresis for unilateral peripheral vestibulopathy, and the tonic electromyographic (EMG) hyperactivity of paraspinal muscles for dystonia. Multivariable linear and logistic regression analyses were conducted to identify the clinical factors associated with the degree of truncal tilt, for the quantification of the severity of PS, and PS tilting to the less affected side, respectively.Results: The multivariable linear regression analyses revealed that the larger degree of SVV tilt (β = 0.29, SE = 0.10, p = 0.005), right-sided SVV tilt (β = 2.32, SE = 0.82, p = 0.007), and higher Hoehn and Yahr (HY) stage (β = 4.01, SE = 1.29, p = 0.003) significantly increased the severity of PS. In the multivariable logistic regression analyses, greater asymmetry of motor symptoms [odds ratio (OR) = 2.01, 95% CI = 1.34–3.49] was significantly associated with PS tilting to the less affected side, while right-sided SVV tilt (OR = 0.02, 95% CI = 0.001–0.21), unilateral canal paresis (OR = 0.06, 95% CI = 0.003–0.79), and higher HY stage (OR = 0.04, 95% CI = 0.002–0.46) were associated with PS tilting to the more affected side.Conclusion: Misperception of verticality, asymmetric basal ganglia dysfunction, unilateral peripheral vestibulopathy, and motor disability are the clinical factors associated with the severity and laterality of PS in patients with PD.

Sensorimotor Rehabilitation Promotes Vestibular Compensation in a Rodent Model of Acute Peripheral Vestibulopathy by Promoting Microgliogenesis in the Deafferented Vestibular Nuclei

Acute peripheral vestibulopathy leads to a cascade of symptoms involving balance and gait disorders that are particularly disabling for vestibular patients. Vestibular rehabilitation protocols have proven to be effective in improving vestibular compensation in clinical practice. Yet, the underlying neurobiological correlates remain unknown. The aim of this study was to highlight the behavioural and cellular consequences of a vestibular rehabilitation protocol adapted to a rat model of unilateral vestibular neurectomy. We developed a progressive sensory-motor rehabilitation task, and the behavioural consequences were quantified using a weight-distribution device. This analysis method provides a precise and ecological analysis of posturolocomotor vestibular deficits. At the cellular level, we focused on the analysis of plasticity mechanisms expressed in the vestibular nuclei. The results obtained show that vestibular rehabilitation induces a faster recovery of posturolocomotor deficits during vestibular compensation associated with a decrease in neurogenesis and an increase in microgliogenesis in the deafferented medial vestibular nucleus. This study reveals for the first time a part of the underlying adaptative neuroplasticity mechanisms of vestibular rehabilitation. These original data incite further investigation of the impact of rehabilitation on animal models of vestibulopathy. This new line of research should improve the management of vestibular patients.

SK Channels Modulation Accelerates Equilibrium Recovery in Unilateral Vestibular Neurectomized Rats

We have previously reported in a feline model of acute peripheral vestibulopathy (APV) that the sudden, unilateral, and irreversible loss of vestibular inputs induces selective overexpression of small conductance calcium-activated potassium (SK) channels in the brain stem vestibular nuclei. Pharmacological blockade of these ion channels by the selective antagonist apamin significantly alleviated the evoked vestibular syndrome and accelerated vestibular compensation. In this follow-up study, we aimed at testing, using a behavioral approach, whether the antivertigo (AV) effect resulting from the antagonization of SK channels was species-dependent or whether it could be reproduced in a rodent APV model, whether other SK channel antagonists reproduced similar functional effects on the vestibular syndrome expression, and whether administration of SK agonist could also alter the vestibular syndrome. We also compared the AV effects of apamin and acetyl-DL-leucine, a reference AV compound used in human clinic. We demonstrate that the AV effect of apamin is also found in a rodent model of APV. Other SK antagonists also produce a trend of AV effect when administrated during the acute phase of the vertigo syndrome. Conversely, the vertigo syndrome is worsened upon administration of SK channel agonist. It is noteworthy that the AV effect of apamin is superior to that of acetyl-DL-leucine. Taken together, these data reinforce SK channels as a pharmacological target for modulating the manifestation of the vertigo syndrome during APV.

Breaking a Dogma: Acute Anti-Inflammatory Treatment Alters Both Post-Lesional Functional Recovery and Endogenous Adaptive Plasticity Mechanisms in a Rodent Model of Acute Peripheral Vestibulopathy.

Background : Due to their anti-inflammatory action, corticosteroids are the reference treatment for brain injuries and many inflammatory diseases. However, the benefits of acute corticotherapy are now being questioned, particularly in the case of acute peripheral vestibulopathies (APV), characterized by a vestibular syndrome composed of sustained spinning vertigo, spontaneous ocular nystagmus and oscillopsia, perceptual-cognitive, posturo-locomotor, and vegetative disorders. We assessed the effectiveness of acute corticotherapy, and the functional role of acute inflammation observed after sudden unilateral vestibular loss. Methods : We used the rodent model of unilateral vestibular neurectomy, mimicking the syndrome observed in patients with APV. We treated the animals during the acute phase of the vestibular syndrome, either with placebo or methylprednisolone, an anti-inflammatory corticosteroid. We used both cellular and behavioral approaches with 2-way ANOVA statistical analysis to evaluate the consequences of an acute anti-inflammatory treatment on post-lesional plasticity and functional recovery. Results : We show here, for the first time, that acute anti-inflammatory treatment alters the expression of the adaptive plasticity mechanisms in the deafferented vestibular nuclei and generates enhanced and prolonged vestibular and postural deficits. Conclusions : These results strongly suggest a beneficial role for acute endogenous neuroinflammation in vestibular compensation. They open the way to a change in dogma for the treatment and therapeutic management of vestibular patients.

L-Thyroxine improves vestibular compensation in a rat model of acute peripheral vestibulopathy

Unilateral vestibular lesions induce a vestibular syndrome, which recovers over time due to vestibular compensation. The therapeutic effect of L-Thyroxine (L-T4) on vestibular compensation was investigated by behavioral testing and immunohistochemical analysis in a rat model of unilateral vestibular neurectomy (UVN). We demonstrated that an acute L-T4 treatment reduced the vestibular syndrome and significantly promoted vestibular compensation. Thyroid hormone receptors (TRα and TRβ) and type II iodothyronine deiodinase (DIO2) were present in the vestibular nuclei (VN), supporting a local action of L-T4. We confirmed the T4-induced metabolic effects by demonstrating an increase in the number of cytochrome oxidase-labelled neurons in the VN three days after the lesion. L-T4 treatment modulated glial reaction by decreasing both microglia and oligodendrocytes in the deafferented VN three days after UVN and increased cell proliferation. The survival of newly generated cells was not affected, but neuronal differentiation was altered by the L-T4 treatment.

Vestibular rehabilitation in multiple sclerosis: study protocol for a randomised controlled trial and cost-effectiveness analysis comparing customised with booklet based vestibular rehabilitation for vestibulopathy and a 12 month observational cohort study of the symptom reduction and recurrence rate following treatment for benign paroxysmal positional vertigo

Background Symptoms arising from vestibular system dysfunction are observed in 49–59% of people with Multiple Sclerosis (MS). Symptoms may include vertigo, dizziness and/or imbalance. These impact on functional ability, contribute to falls and significant health and social care costs. In people with MS, vestibular dysfunction can be due to peripheral pathology that may include Benign Paroxysmal Positional Vertigo (BPPV), as well as central or combined pathology. Vestibular symptoms may be treated with vestibular rehabilitation (VR), and with repositioning manoeuvres in the case of BPPV. However, there is a paucity of evidence about the rate and degree of symptom recovery with VR for people with MS and vestibulopathy. In addition, given the multiplicity of symptoms and underpinning vestibular pathologies often seen in people with MS, a customised VR approach may be more clinically appropriate and cost effective than generic booklet-based approaches. Likewise, BPPV should be identified and treated appropriately. Methods/ design People with MS and symptoms of vertigo, dizziness and/or imbalance will be screened for central and/or peripheral vestibulopathy and/or BPPV. Following consent, people with BPPV will be treated with re-positioning manoeuvres over 1–3 sessions and followed up at 6 and 12 months to assess for any re-occurrence of BPPV. People with central and/or peripheral vestibulopathy will be entered into a randomised controlled trial (RCT). Trial participants will be randomly allocated (1:1) to either a 12-week generic booklet-based home programme with telephone support or a 12-week VR programme consisting of customised treatment including 12 face-to-face sessions and a home exercise programme. Customised or booklet-based interventions will start 2 weeks after randomisation and all trial participants will be followed up 14 and 26 weeks from randomisation. The primary clinical outcome is the Dizziness Handicap Inventory at 26 weeks and the primary economic endpoint is quality-adjusted life-years. A range of secondary outcomes associated with vestibular function will be used. Discussion If customised VR is demonstrated to be clinically and cost-effective compared to generic booklet-based VR this will inform practice guidelines and the development of training packages for therapists in the diagnosis and treatment of vestibulopathy in people with MS. Trial registration ISRCTN Number: 27374299 Date of Registration 24/09/2018 Protocol Version 15 25/09/2019