Clinical diagnosis and treatment of NEUROPATHIC pain

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

13. 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 !!

15. 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

17. Secondary hyperalgesia is CENTRAL phenomenon

18. Summary

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

21. Spontaneous pain

23. ALODYNIA – innocuous stimulus produces pain

25. HYPERALGESIA Lower threshold for pain stimulation

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

27. 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

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

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

30. 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

31. 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

32. Small fiber neuropathy

33. 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“

34. 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

35. 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

36. Small x Large fiber neuropathy

37. 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

38. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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!!

48. 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

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