Relationship between fatigue, cognitive dysfunction and small fiber neuropathy Elske Hoitsma Typical patient • 45 year old male, • Runs his own busy company, married, 4 young kids. Has always been very energetic and busy. • Cough and dyspnoe • 2 episodes of high fever • Chest radiography and histology consistent with sarcoidosis • 6 months prednison, chest radiography, pulmonary function resolved; • Severe fatigue, pain and concentration problems persist… • Not capable for work Pain Nociceptive pain caused by tissue damage Neuropathic pain Mixed pain caused by damage or dysfunction of the nervous system Pain and small fiber neuropathy • PainBurning/shooting character, paraesthesias, hypersensitivity of the skin, sheet intolerance • • • • • • • • Sicca syndrome Flushes Blurry vision Hyperhidrosis / hypohidrosis Micturation disturbances Diarrhea / Constipation Sexual dysfunction Orthostatic intolerance Central nervous system Brain+spinal cord Peripheral nervous system Large (Aβ) nerve fibers Small (Aδ/C) nerve fibers Motor function Sensory function Sensory function Autonomic function muscle control position and movement sensation pain and temp. sensation basal physiology Large fiber neuropathy “Polyneuropathy” Small fiber neuropathy (SFN) 2002 Evidence of small fiber neuropathy in sarcoidosis • Fatigue • Cognitive impairment: “foggy brain” • Pain hypersensitivity of skin Sweating Tachycardia Infection/inflamm ation Proinflammatory cytokins Acute sickness respons: Fever, pain, fatigue, cognitive decline, depressive mood Fatigue and cognitive impairment Fatigue causes concentration and attention deficits cognitive impairment Mood and the autonomic nervous system The autonomic nervous system and cognition/mood Changes in autonomic nervous system hormones (e.g. cortisol elevation) correlates with fatigue, depression and cognitive impairment* Mood states in young healthy subjects can be estimated from heartrate variability ** Etc etc etc association studies *Thornton, Health psychol 2010; 29: 333-7 **Park , Auton Res 2011; 21: 103-10 pain/ small nerve fiber Persisting? dysfunction inflammation Chicken/ egg? fatigue Remission? Mood disturbances, cognitive impairment Acute sickness respons: Fever, pain, fatigue, cognitive decline, depressive mood Monofasic GBS, Lyme, virus sarcoidosis Recovery Persisting fatigue cluster Ongoing MS, sarcoidosis With fatigue Without fatigue cluster cluster Not unique sarcoidosis • Lyme disease • Post-cancer: “the pain, depression, fatigue cluster (PDF)” • Multiple Sclerosis (MS) • Sjögren’s syndrome • Systemic Lupus Erythematodes (SLE) • Inflammatory Bowel disease • Guillain Barre syndrome • etc Inflammation and cytokines The discovery of by prof Cerami Cerami, J Intern Med 2011; 269: 8-15 A crucial role for TNF-α? • Neuropathic pain/autonomic dysfunction • Fatigue • Cognition and depression Continuing TNF release in fatigued sarcoid patients in clinical remission? Anti-TNF therapy relieves only a subset of the patients? Crucial role for damaged small (autonomic) nerve fibers? inflammation SFN Hormonal dysbalance Depression, pain, fatigue, Cogn Impairm. Viral/bacterial infection particles Anti-TNF therapy Inflammation genetics Dysbalance immune system ARA290 Pain Fatigue Mood cognitio n SFN/damage autonomic nerve fibers genetics Hormonal dysbalance Anti-TNF, IvIG, ARA290 genetics Physical activity exercise Psychological factors fear Cognitive behavior therapy explain Stress Relaxation therapy Summary • Pain-Depressed cognition-fatigue (PDF) cluster • Associations • Role for TNF-alpha / autonomic nerve damage / HPA-axis hormones “Psycho-neuroimmunology” • Treatment options: * symptomatic * treat/ prevent SFN: ARA290, IvIG, anti-TNF