Vagus Nerve Stimulation a New Approach in the Treatment of Crohn's Disease (VNS)

• Clinical remission 12 months after initiation of VNS [ Time Frame: 12 months after initiation of VNS ] [ Designated as safety issue: No ]

  Clinical remission at 12 months :

  1. Patient without corticoids or a dose of 20mg without dose adjustment (stable treatment) and without anti-TNF,
  2. CDAI <150 or CDAI has dropped by at least 70 or 100 points (Δ70, Δ100) compared with the baseline CDAI
  3. Stable immunosuppressive therapy.
  
  

• Clinical remission 6 months after initiation of VNS [ Time Frame: 6 months after initiation of VNS ] [ Designated as safety issue: No ]

  Clinical remission at 6 months :

  1. Patient without corticoids or a dose of 20mg without dose adjustment (stable treatment) and without anti-TNF,
  2. CDAI <150 or CDAI has dropped by at least 70 or 100 points (Δ70, Δ100) compared with the baseline CDAI
  3. Stable immunosuppressive therapy
  
  
• VNS tolerance [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  Description and frequency of adverse events
  
  
• Assessment of VNS effectiveness with biological markers [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Assessment of VNS effectiveness with biological markers of the pro-and anti-inflammatory status
  
  
• Endoscopic and ultrasound Assessment of VNS effectiveness [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Endoscopy : CDEIS (Crohn's Disease Endoscopic Index of Severity) Ultrasound : score Migaleddu V. and al, 2009
  
  
• Assessment of the central effects of VNS [ Time Frame: At 6 weeks, at 6 months, at 12 months ] [ Designated as safety issue: No ]

  Evolution of :

  • Sleep cycle : duration of sleep stages, sleep latency, latency between the different sleep stages.
  • High-resolution Electroencephalogram (EEG): Spatiotemporal evolution of the spectral density of EEG power in the different frequency bands
  • Correlation between high-resolution EEG markers of autonomic nervous system
  
  
• Evaluation of peripheral effects of VNS on sympatho-vagal balance [ Time Frame: 6 weeks, 6 months, 12 months ] [ Designated as safety issue: No ]

  Evolution of cardiac variability markers using time and frequency analysis of electrocardiogram :

  • Frequency Analysis : LH, HF, LF/HF
  • Time analysis : RMS-SD, pNN50, NN50, average cardiac rhythmn
  
  

Inflammatory bowel diseases or IBD (Crohn's disease and ulcerative colitis) are chronic inflammatory diseases involving the digestive tract, in particular the small bowel and/or the recto-colon. IBD represent a public health problem in Gastroenterology. The etiopathogeny of IBD is multifactorial involving immunological, genetic, infectious and environmental factors. An overarching hypothesis is that an unbalance of the autonomic nervous system, represented by the sympathetic and parasympathetic nervous system (e.g. the vagus nerve) is part of the mechanisms underlying the pathophysiology of IBD. A dysautonomia has been observed in IBD patients and we have recently demonstrated that this dysautonomia was linked to psychological coping, in particular in Crohn's disease. Classically, the vagus nerve, a mixed nerve, has an anti-inflammatory role through its central afferents which secondarily stimulate the hypothalamic-pituitary adrenal axis. Recent data have shown that the anti-inflammatory properties of the vagus nerve also involve peripheral efferents via an interaction of acetylcholine with nicotinic receptors leading to an inhibition of TNF release by macrophages. Vagus nerve stimulation (VNS) is currently used for the treatment of some forms of epilepsy in Human via a stimulation of vagal afferents. We have recently validated a model of chronic VNS (3h/d for 5 days) in freely moving rats by stimulating vagal efferents and we have studied the anti-inflammatory properties of VNS in an experimental model of colitis in rats. VNS significantly decreased body weight loss due to colitis and had an anti-inflammatory effect by decreasing a multivariate index of inflammation. To date, medical treatment of IBD (e.g. 5-aminosalicylates, corticosteroids, immunosuppressives or biotherapies i.e. anti-TNF) is only suspensive. The aim of our project is to propose another type of anti-inflammatory treatment based on neurostimulation of vagal efferents. For this purpose, we aim to perform a pilot study in 10 patients with moderate to severe Crohn's disease despite a reference treatment (corticosteroids and/or immunosuppressives) using the anti-inflammatory properties of VNS as an alternative to anti-TNF therapy. Central and peripheral effect of VNS will be also evaluated by electroencephalographic and sympatho-vagal (heart rate variability) recordings. The finality, at term, is to use VNS as an alternative to the conventional anti-TNF therapy not devoid of side effects, in particular infectious, with the advantage to use an intrinsic anti-inflammatory (anti-TNF) system and to take cover of problems of adherence to treatment which are frequently observed in the medical treatment of IBD.