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Clinical diagnosis and treatment of NEUROPATHIC pain. MUDr.Rudolf Černý, CSc Dept of Neurology 2nd School of Medicine Charles University in Prague. Definitions.

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Clinical diagnosis and treatment of NEUROPATHIC pain


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    1. Clinical diagnosis and treatment of NEUROPATHIC pain MUDr.Rudolf Černý, CSc Dept of Neurology 2nd School of Medicine Charles University in Prague

    2. Definitions • Pain definition IASP : “unpleasant sensorial and affective experience, caused by actual or potential tissue damage, ore described in terms of such a damage” • Pain is always subjective experience, psychological elaboration of : • nociceptive afference • dysfunction of the nervous system • stored experience (memory trace, learned pain behavior) • psychosocial dysfunction • Neuropathic pain = generated by the nervous system

    3. Components of chronic pain • nociceptive - tissue damage, local inflammation, activation of nociceptor endings • neuropathic - pain is generated by peripheral or central nervous system • Projected pain into the respective innervation area. Primary NS damage is not a indispensable condition • psychogenic - transformation of non painful perception, affection and cognitive processes into pain experience • social • subconscious behavior pattern in failing coping with work load or family problems • conscious purposeful behavior with the aim to receive compensation claims, rent or social benefits

    4. Criteria of NP • evidence of NS lesion • neuroanatomical correlation of the pain perception (sensory disturbance in distribution of radicular dermatome, area nervina etc…) • evidence of sensorial disturbance abnormity • chronic conditions – 3- 6 months • low efficacy of analgesics

    5. Epidemiology of NP • 25% patients in centers for Pain treatment • Populational prevalence estimated about 1 % ! • like Epilepsy • prevalence increases with age, above 70 nearly 50% reffer some symptoms of NP ! • Permanent complication in peripheral nerve injuries cca 5% • Metabolic polyneuropathy - cca 50%  diabetics elder then 60 years • NS Infections -cca 30% cases of HIV, neuroboreliosis, herpes zoster • Central NP : • syringomyelia - 75% cases • 30% in MS • 8% ischemic strokes

    6. Pathophysiology of NP • complex event – NS adaptation to chronic pain stimulation • functional adaptation – morphological restructuralization • all level of neuraxis involved • result – sensitization (periph. and central) • increased sensitivity to painful stimuli • painful perception of innocuous stimulation • spontaneous pain perception WITHOUT peripheral stimulation

    7. cause-adaptaption-mechanismus-symptomes • primary causative event • chronic nociceptor stimulation– neurogennic inflammation • NS dysfunction • idiopathic cases (erythromelalgia, SFN) • adaptation • changes in PN fibers, sympatical and thermic fibers switched to nociception • central sensitization – posterior horn, thalamus, SMA, cingulum • molecular mechanisms • Na channels, NMDA receptors, GABA receptors, microglia activation • neuronal mechanisms – expansion of receptive fields • changed activity of PH interneurons, thalamus – Thunberg grill

    8. Mechanismy NB • hyperaktivace nociceptorů a vláken C, A delta • funkční změny DRG, zadní roh, STT • molekulární, receptorové, synaptické • strukturální změny • synapse • populace interneuronů ZR • talamus • druhá vrátka, přesun k hyperaktivitě talamic relay neuron STT • porucha integrace tepelných x bolestivých vjemů v mediálním jádře - CB • cortex – nábor nových areí

    9. Peripheral sensitization • Nociceptors • recruitment of silent, mechano-insenzitive nociceptors • acid sensing ion channels • heat activated ion channels • CGRP, sbst P • against - anti-inflammatory mediators (ACh, anandamid) • Peripheral nerve fibers • expression of Na channels • high frequency firing C-fibers • ectopic source of action potentials in axon membrane

    10. Central sensitization • DRG cells : • 3 funkční stavy řízené K kanálem (tonic, plateau = amplifikace, rhytmic firing = filtrace) • remodelace • sprouting Abeta zakončení • „hyperalgesic“ neuron • spinotalamická dráha • parabrachiální – „normální“ akutní bolest • spino-retikulo-talamická – PAG – chronická bolest • Talamus • Kortex

    11. Molecular mechanisms • new channels • Na, Ca alfa2 delta • expression of new membrane receptors • sbst P, TRPV1, NK1, alfa2 adrenoreceptor • microglia activation • paradoxical effects of glycin release • macrophage activation – TNF alfa – Schwann cell – NGF expression • changes of membrane properties of HEALTHY nerve fibers ! • efferent sympatical activation

    12. Paradoxical excitation by inhibitory mediators - GABA, Glycin !! • peripheral nerve fiber lesion - chronic stimulation of lamina I PH Neurons • decrease of potassium transporter concentration KCC2 • intracellular accumulation of Cl • with increase intracellular KCL concentration GABA a glycin produce EXCITATORY PSPs !!

    13. PH adaptation to chronic nociceptive stimulation • STT neurons can have 3 functional states: • tonic discharge – respond by series AP to perif. stimulus • rhythmic bursting – AP firing outlast the stimulus • plateau potential – spontaneous AP firing WITHOUTstimulation – hyperalgesic neuron • less then 10% neurons is normally in state 3, after sensitization process most of them !! • transition of functional states • is regulated by ratio of metabotrope receptors: • NMDA + GABAb = antagonistic regulation of a common potassium channel of type Kir3

    14. Secondary hyperalgesia is CENTRAL phenomenon

    15. Summary

    16. Symptoms of NP • Spontaneous • pain • paresthesia, dysesthesia • Evoked • hyperalgesia • allodynia • pain

    17. Spontaneous pain

    18. ALODYNIA – innocuous stimulus produces pain

    19. HYPERALGESIA Lower threshold for pain stimulation

    20. Classification of NP • Peripheral x Central • Symmetrical x Asymmetrical NP • Etiological • Symptomatological – mechanism based

    21. Peripheral cause of NP – most frequent • Focal neuropathies • Compresive neuropathy (carpal tunel) • Discogennic radix compression • Peripheral nerve injury • Postherpetic neuralgia • Mononeuropathia multiplex • Difusse polyneuropathies : • Metabolic (diabetes, etylismus, amyloid polyneuropathy, hypotyreosis, hypovitaminosis B) • Infection (HIV, borrelióza, herpes zoster, CMV) • Toxic (arsen, thalium, isoniazid, nitrofurantoin, metronidazol, chloramfenikol, cytostatics) • Hereditary senso-motor neuropathies • Complex regional pain syndrome (RSD) • Cranial neuralgias (trigeminal, glossofaryngeal…) • Chronic vertebrogennic algic syndrome, postlaminectomic syndromes

    22. Spinal cord disorders with NP • Multiple sclerosis • Spinal cord injury • Myelopathy : • Metabolical (hypovitaminoza B12, diabetes) • Vascular • Syringomyelia • Compression

    23. Central NP • Thalamic (central) pain: • Ischemic stroke • Thalamic hemorrhage • Multiple sclerosis • Arnold Chiari malformation • Neurodegeneration • Parkinson disease • Alzheimer disease • MSA, SCA • Phantom pain

    24. Typical character of NP • Continuous spontan, chronic pain - dull • Evoked pain by external and internal stimuli - lancinating • Always hypoesthesia, pain co localized • Pain is always projective with typical distribution • Temporal summation of pain by repeated stimulation • After-sensations, Mitempfindung • Trophic changes – sympatic nerves over activity

    25. Work up of NP • Clinical exam • symptom classification • sensory examination • distribution ! • evoked symptoms of pain? • semiquantitative examination (von Frey filaments, warm, cold) • Laboratory and imaging • etiological possibilities • Electrophysiological examination • assessment of NS function • EMG – only thick, non-pain fibers evaluated !! • evoked potentials - SSEP and MEP – long tracts of spinal cord • QST, QSMAT, LEP, microneurography, R-R interval variability

    26. Small fiber neuropathy

    27. SFN • PN –80% of fibers C and A delta • routine examination cannot detect function • EMG assess only thick fibers of light touch and vibration • clinical picture: • thermic hypoesthesia • low threshold of thermic pain • causalgia – „burning feet“

    28. SFN • usually part of peripheral neuropathy symptoms: • DM, etylic, HIV • hereditary – Charcot Marie Tooth • isolated SF affection possible • SKIN BIOPSY • EMG excludes general neuropathy • LEPs abnormal

    29. 117 patients with NP in legs 44 with normal EMG but: reduction of nerve endings denzity in skin !! SKIN BIOPSY in SFN imunofluorescence – Ab against PGP 9,5

    30. Small x Large fiber neuropathy

    31. Erythromelalgia - example of SFN • primary x secondary (DM, myeloproliferative dis.) • atacks: • red, hot, burning feet • VAS 4-10/10 • pain increase by warm • mikrovascular a-v shunts in skin • termoregulatory hyperperfusion • nutritive hypoperfusion, hyperkinetic hypoxy • small fiber neuropathy • increased sweating, EMG normal or • in 1/3 axonal neuropathy

    32. Primary Erythromelalgia • AD inheritance • painfull peripheral neuropathy • zvýšenou citlivost na námahu a tepelné podněty • peripheral cyanosis • manifesting form childhood • point mutation of Na1,7 channel • chromozom 2q31-32 (gen SCN9A v r. 2004) • memmbrane hyperexcitability of peripheral nerve fibers

    33. Sympatically maintained pain • not a disease but pathophysiologal mechanism • part of NP symptoms • no specific parameter from clinic or laboratory! • typical symptoms • cold pressure testu • burning, badly localized pain • trophical changes • vasoparalysis

    34. Sympatically maintained pain • S. hyperactivity in peripheral nerve lesions: • expression of adrenoreceptor in nerve membrane • synapses of S. efferent with peripheral fibers • Diagnosis • ANS exam - HRV, Ewing test • gold standard – effect of S. blockade • Therapy – alfa blockers (prazosin, klonidin, tizanidin), S. ganglia blocking

    35. Postherpetic neuralgia • DR ganglionitis – VZV • acute pain at least 20%, 9-15% after 1 month, 2-5% after 1 year • age > 60-70 year prevalence 50-75% ! • risks for PHN: • female gender • age over 50 • trigeminus- sacral roots • intensity of rash, hemorrhagic pustulas • all types of NP – contin. bunirng, attacks of lancinating pain • typical dynamic mechanical allodynia • secondary hyperalgesia exceeding the original exanthema ! • Therapy – resistant! • acute phase = acyclovir + carbamazepin + opioids • chronic phase – anticonvulsives + local – capsaicin + opioids

    36. Central Pain • 1906 Déjerine-Roussy – thalamic syndrome • incomplete lesions, 1,5 - 8% strokes • Etiology : • lacunar infarction, aart. thalamogeniculatae • other = hemorrhage, MS plaque, gliosis • rare = tumor, trauma, abscess

    37. Topic of CP • everywhere in STT • parietal pseudothalamic syndrome • POSTEROLATERAL THALAMUS • posterior arm of capsula interna • dorsolateral medulla • spinal cord, particularly cervical and CC region

    38. Pathogenesis of CP • disinhibition of thalamic relay neurons of STTs • posterolateral (VPL) Th nucleus and insula • denervation hypersensitivity, increased NMDA activity and NA channels expression • deaferentation cortical pain • somatosensoric cortex reorganisation • expansion of receptive fields (PET, SPECT) • disturbance of central inhibition • abnorm LEP x normal SSEP • Thunberg gril

    39. Character of CP • dull (sharp) • deep (superficial) • burning (icy) • paroxysms of lancinating pain • spontaneous • provoked • typical is combination of several pain types • intensity > 50%VAS • provocation of pain : • peripheral stimulation • physical and psychogenic stressors

    40. Character of CP • pain intensityDOES NOT CORRELATE with topical deficit ! • pain evolves within weeks or months foll. stroke • hemiparesis usually regressed at this time • CP can be „healed“ by subsequent stroke • very unpleasant – suffering, strong affective component • depressions, suicidium not rare!!

    41. Sensory disturbance in CP • always present hemi – quadrant distribution • can be small part - ulnar ridge of the arm, cheiro-oral syndrome • protopatic character (termoalgic, propriocepce) • epicritical sensations spared (2 points,light toMuch, grafestesia, stereognosia) • paresthesia, dysestesia • hyperalgesia, alodynia • atypical sensations: after sensations, Mitempfindung • syringomyelie disociated thermoalgic anestesia with normal touch

    42. Wallenberg syndrome • PICA ischemia • dorsolateral infarction • ipsilateral face hypoesthesia, crossed body hypoesthesia • ipsilateral bulbar palsy • ipsilateral cerebellar ataxia • peripheral vestibular failure • NO hemiparesis !