537
EDITORIALS
ie, attributable to change in central pathways induced by peripheral nerve or root injury. Whilst it is likely that fibres of all sizes are affected in established PHN, information from a total of seven necropsies is an inadequate basis for any secure hypothesis. Nurmikko and Bowsher have now shed more light on the mechanism of PHN with their study of sensation. Sixty-two patients were cutaneous examined in detail, at least 3 months after unilateral shingles. Of these, forty-two experienced PHN and
Postherpetic neuralgia Postherpetic neuralgia (PHN) is usually defined as pain persisting for more than a month after the date of original eruption,l although qualitatively there is little difference between this and the pain of acute herpes zoster infection. Overall, about 10% of patients with shingles will subsequently get PHN, a third of whom will still have pain a year later. The development and persistence of PHN are greatly increased in elderly patients: almost 50% of those over 70 years may be so affiicted.22 Studies of
zoster3,4 have shown that dorsal root ganglia sustain the brunt of the damage, with acute inflammation and necrosis, which is sometimes haemorrhagic. In more severe cases inflammation spreads to adjacent motor and sensory roots, and acute
exceptionally to anterior and posterior horns or posterior columns.3 Knowledge of pathological changes in PHN is sparse because of a dearth of one of the most careful necropsy studies the patient was a 67-year-old man with severe neuralgia extending over dermatomes T7 and T8.s The posterior horn was atrophic on the affected side from T4 to T8, with loss of both myelin and axons. Despite these changes, only the T8 dorsal root ganglion and nerve roots at that level were affected. Markers for unmyelinated afferents (substance P), substantia gelatinosa neurons (opiate receptors), glial cells (glial fibrillary acidic protein), and descending, spinal projections (dopamine 0 hydroxylase andl serotonin) were normal in the affected spinal cord. It; was suggested that the pain of PHN might be causedl by uninhibited activity of unmyelinated primary afferents as a result of loss of myelinated afferent fibres and perhaps the presence of hypersensitive neurons ir.L the dorsal horn. Preferential loss of large diameter neurons was alsc) reported in another study6 of four cases of PHNr affecting intercostal nerves. According to the "gat( control" theory, reduction of large fibres might allom1 increased transmission of nociceptive informatiori through the dorsal horn. In the peripheral nerves of,1 further two subjects with PHN7 there was depletion o f large fibres, probably at an early stage, witli subsequent loss of fibres of all diameters. Conversely , one might view PHN as deafferentation pain-
necropsy data. In
,
.
,
-
twenty did not; the two groups were matched for age and elapsed time from the acute phase. Perception thresholds were carefully evaluated for warmth, cold, hot pain, touch, pinprick, vibration, and two-point discrimination. Pain elicited on light touch (allodynia) was assessed by visual analogue scale, while skin temperature was measured, presumably to assess sympathetic activity. In those without PHN, sensation was normal and recovery was good; in those with PHN there were changes in all sensory thresholds compared with patients’ healthy mirror image sites, which indicated damage to fibres of every diameter. Clinically this observation could be useful: if a patient has persistent neuralgia after zoster and sensation is normal, the pain should be due to some process other than PHN. These results contrast with those of a smaller study of twelve patients with PHN,99 in which there were two groups-those with continuous pain localised to the area of sensory loss and those with mainly allodynia in whom sensation was relatively preserved. In Nurmikko and Bowsher’s study the presence of allodynia in 87% of the PHN group 8led to the suggestion that second-order sensory neurons, which would normally transmit nociception, were now being stimulated by large-fibre afferents concerned with mechanoreception-ie, a form of central sensory reorganisation. In six of their twelve patients with zoster confined to the ophthalmic division there was increased pain sensitivity in the adjacent maxillary division, which also implies central change ("somatotopic remodelling"). These researchers concluded that both large and small fibres are damaged in PHN and that central changes may contribute substantially to the unpleasantness of the disorder.
538
The most effective treatment of the acute phase is acyclovir/° but it is uncertain whether this drug will prevent PHN. Because of the tendency for natural resolution of pain it is essential that treatment is evaluated by randomised double-blind placebo trial with matching for age. Of ten such trials in which acyclovir was given in the acute phase ’10-12 only twoll,12 showed reduction of PHN at 6 months and this was with high doses-800 mg five times daily for 7 or 10 days. The high cost of such treatment has to be balanced carefully against the likelihood of amelioration of PHN and savings in other painrelieving measures. Oral steroids given during the acute stage may afford protection against subsequent PHN,13 but this evidence is based on a small trial in which only fifteen of thirty-five patients received treatment, and no effect was documented in another trial in which patients receiving acyclovir were randomised to either prednisolone or placebo.14 Similar uncertainty prevails with respect to amantadine, which may be beneficial in the acute phase15 but is not so clearly advantageous for PHN when strictly defined. If PHN has developed it is important to avoid wasting time by prescription of conventional analgesics, which are uniformly ineffective. Few therapies have been stringently evaluated, but overall most evidence favours use of tricyclic antidepressants,16 from which modest relief may be gained. When there is dysaesthesia or lancinating pain, an anticonvulsant such as carbamazepine or sodium valproate can be added.Neuroaugmentation in the form of topical ethyl chloride spray is temporarily soothingp as may be transcutaneous nerve stimulation.18 Topical capsaicin (a substance P antagonist) appeared beneficial in about half those treated in two open trials19,20 but not in another that was blinded and controlled.21 Moreover, some people have to abandon the spray because of post-capsaicin burning. Capsaicin cream is still being evaluated and may yet have a place in elderly patients intolerant of oral drugs. Many surgical procedures have been suggested, all of which have uncertain effects.A possible exception is the Nashold procedure22 (dorsal root entry zone coagulation) which may diminish pain, but only in the short term. 1. Jolleys JV. Treatment of shingles and post-herpetic neuralgia. Br Med J
1989; 298: 1537-38.
RK, Duma C, Foley KM. Acute herpetic and postherpetic neuralgia: clinical review and current management. Ann Neurol 1986;
2. Portenoy
20: 651-64. 3. Head H, Campbell AW. The pathology of herpes zoster and its bearing on sensory localization. Brain 1900; 23: 353-523. 4. Juel-Jensen BE, MacCallum FO. Herpes simplex, varicella and zoster. Philadelphia: Lippincott, 1972: 127-32. 5. Watson CPN, Morshead C, Van der Kooy D, Deck J, Evans RJ. Post-herpetic neuralgia: post-mortem analysis of a case. Pain 1988; 34: 129-38. 6. Noordenbos W. Physiological correlates of clinical pain syndromes. In: Soulairac A, Cahn J, Charpentier J, eds. Pain. New York: Academic Press, 1968: 465-76. 7. Zacks SI, Langfitt TW, Elliott FA. Herpetic neuritis: a light and electron microscopic study. Neurology 1964; 14: 744-50.
8. Nurmikko T, Bowsher D. Somatosensory findings in postherpeticc neuralgia. J Neurol Neurosurg Psychiatry 1990; 53: 135-41. 9. Rowbotham MC, Fields HL. Post-herpetic neuralgia: the relation of pain complaint, sensory disturbance and skin temperature. Pain 1989; 39: 129-44. 10. O’Brien J, antiviral
Campoli-Richards DM. Acyclovir: an updated review of its activity, pharmacokinetic properties and therapeutic efficacy.
Drugs 1989; 37: 233-309. 11. Morton P, Thomson AN. Oral acyclovir in the treatment of herpes zoster in general practice. N Z Med J 1989; 102: 93-95. 12. Huff JC. Oral acyclovir therapy of acute herpes zoster: a multi-centre study. Res Clin Forum 1987; 9: 37-43. 13. Eaglstein WH, Katz R, Brown JA. The effects of early corticosteroid therapy on the skin eruption and pain of herpes zoster. JAMA 1970; 211: 1681-83. 14. Esmann V, Kroon S, Geil JP, et al. Prednisolone does not prevent post-herpetic neuralgia. Lancet 1987; ii: 126-29. 15. Galbraith AW. Prevention of post-herpetic neuralgia by amantadine hydrochloride (Symmetrel). Br J Clin Pract 1983; 37: 304-06. 16. Watson CP, Evans RJ, Reed K, et al. Amitriptyline versus placebo in postherpetic neuralgia. Neurology 1982; 32: 671-73. 17. Taverner D. Alleviation of post-herpetic neuralgia. Lancet 1960; ii: 671-73. 18. Nathan PW, Wall PD. Treatment of post-herpetic neuralgia by prolonged electrical stimulation. Br Med J 1974; ii: 645-47. 19. Watson CPN, Evans RJ, Watt VR. Postherpetic neuralgia and topical capsaicin. Pain 1988; 33: 333-40. 20. Bernstein JE, Bickers DR, Dahl MV, Roshal JY. Treatment of chronic
postherpetic neuralgia
with topical
capsaicin. J Am Acad Dermatol
1987; 17: 93-96.
HF, Harries AJ, Gamester RE, Justins D. Randomised doubleblind study of topical capsaicin for treatment of post-herpetic neuralgia. Pain 1990 (suppl 5): 111 (abstr). 22. Nashold BS. Current status of the DREZ operation: 1984. Neurosurgery 21. Drake
1984;
15: 942-44.
Tolerance and the fetal
graft
The
paradox of the fetal allograft was unveiled by Billingham over 25 years ago.Why does a mother not reject the semiallogeneic feto-placental graft within the uterus even when there has been repeated exposure to paternal antigens. More simply, how does the baby stay in the womb? To understand the underlying mechanisms one has to appreciate the complex relation between placenta and uterus. In human beings haemochorial placenta fetal villi interdigitate with maternal intervillous vascular spaces. The interface between mother and child is the syncytiotrophoblast membrane-this is a dialysis membrane 25 square metres in surface area that bidirectionally transports all substances entering or leaving the fetal circulation.2 An additional function is to camouflage the developing fetus from the maternal immunological effectors. The membrane is continually renewed from the villous cytotrophoblasts immediately beneath it. At the tip of each villus there is a column of cytotrophoblasts in direct contact with the maternal decidua. Extravillous cytotrophoblasts are also in direct contact with maternal tissue, migrating deeply into the myometrium as interstitial trophoblasts or within the maternal vasculature as endovascular cytotrophoblasts. Some of these cells are even transported to maternal pulmonary blood vessels, where they remain throughout pregnancy.3 Graft rejection is mainly concerned with the recognition of antigens of the major histocompatibility complex (MHC) by T cells. The products of the MHC class II antigenic loci-HLA DP, DQ, and
EDITORIALS
ie, attributable to change in central pathways induced by peripheral nerve or root injury. Whilst it is likely that fibres of all sizes are affected in established PHN, information from a total of seven necropsies is an inadequate basis for any secure hypothesis. Nurmikko and Bowsher have now shed more light on the mechanism of PHN with their study of sensation. Sixty-two patients were cutaneous examined in detail, at least 3 months after unilateral shingles. Of these, forty-two experienced PHN and
Postherpetic neuralgia Postherpetic neuralgia (PHN) is usually defined as pain persisting for more than a month after the date of original eruption,l although qualitatively there is little difference between this and the pain of acute herpes zoster infection. Overall, about 10% of patients with shingles will subsequently get PHN, a third of whom will still have pain a year later. The development and persistence of PHN are greatly increased in elderly patients: almost 50% of those over 70 years may be so affiicted.22 Studies of
zoster3,4 have shown that dorsal root ganglia sustain the brunt of the damage, with acute inflammation and necrosis, which is sometimes haemorrhagic. In more severe cases inflammation spreads to adjacent motor and sensory roots, and acute
exceptionally to anterior and posterior horns or posterior columns.3 Knowledge of pathological changes in PHN is sparse because of a dearth of one of the most careful necropsy studies the patient was a 67-year-old man with severe neuralgia extending over dermatomes T7 and T8.s The posterior horn was atrophic on the affected side from T4 to T8, with loss of both myelin and axons. Despite these changes, only the T8 dorsal root ganglion and nerve roots at that level were affected. Markers for unmyelinated afferents (substance P), substantia gelatinosa neurons (opiate receptors), glial cells (glial fibrillary acidic protein), and descending, spinal projections (dopamine 0 hydroxylase andl serotonin) were normal in the affected spinal cord. It; was suggested that the pain of PHN might be causedl by uninhibited activity of unmyelinated primary afferents as a result of loss of myelinated afferent fibres and perhaps the presence of hypersensitive neurons ir.L the dorsal horn. Preferential loss of large diameter neurons was alsc) reported in another study6 of four cases of PHNr affecting intercostal nerves. According to the "gat( control" theory, reduction of large fibres might allom1 increased transmission of nociceptive informatiori through the dorsal horn. In the peripheral nerves of,1 further two subjects with PHN7 there was depletion o f large fibres, probably at an early stage, witli subsequent loss of fibres of all diameters. Conversely , one might view PHN as deafferentation pain-
necropsy data. In
,
.
,
-
twenty did not; the two groups were matched for age and elapsed time from the acute phase. Perception thresholds were carefully evaluated for warmth, cold, hot pain, touch, pinprick, vibration, and two-point discrimination. Pain elicited on light touch (allodynia) was assessed by visual analogue scale, while skin temperature was measured, presumably to assess sympathetic activity. In those without PHN, sensation was normal and recovery was good; in those with PHN there were changes in all sensory thresholds compared with patients’ healthy mirror image sites, which indicated damage to fibres of every diameter. Clinically this observation could be useful: if a patient has persistent neuralgia after zoster and sensation is normal, the pain should be due to some process other than PHN. These results contrast with those of a smaller study of twelve patients with PHN,99 in which there were two groups-those with continuous pain localised to the area of sensory loss and those with mainly allodynia in whom sensation was relatively preserved. In Nurmikko and Bowsher’s study the presence of allodynia in 87% of the PHN group 8led to the suggestion that second-order sensory neurons, which would normally transmit nociception, were now being stimulated by large-fibre afferents concerned with mechanoreception-ie, a form of central sensory reorganisation. In six of their twelve patients with zoster confined to the ophthalmic division there was increased pain sensitivity in the adjacent maxillary division, which also implies central change ("somatotopic remodelling"). These researchers concluded that both large and small fibres are damaged in PHN and that central changes may contribute substantially to the unpleasantness of the disorder.
538
The most effective treatment of the acute phase is acyclovir/° but it is uncertain whether this drug will prevent PHN. Because of the tendency for natural resolution of pain it is essential that treatment is evaluated by randomised double-blind placebo trial with matching for age. Of ten such trials in which acyclovir was given in the acute phase ’10-12 only twoll,12 showed reduction of PHN at 6 months and this was with high doses-800 mg five times daily for 7 or 10 days. The high cost of such treatment has to be balanced carefully against the likelihood of amelioration of PHN and savings in other painrelieving measures. Oral steroids given during the acute stage may afford protection against subsequent PHN,13 but this evidence is based on a small trial in which only fifteen of thirty-five patients received treatment, and no effect was documented in another trial in which patients receiving acyclovir were randomised to either prednisolone or placebo.14 Similar uncertainty prevails with respect to amantadine, which may be beneficial in the acute phase15 but is not so clearly advantageous for PHN when strictly defined. If PHN has developed it is important to avoid wasting time by prescription of conventional analgesics, which are uniformly ineffective. Few therapies have been stringently evaluated, but overall most evidence favours use of tricyclic antidepressants,16 from which modest relief may be gained. When there is dysaesthesia or lancinating pain, an anticonvulsant such as carbamazepine or sodium valproate can be added.Neuroaugmentation in the form of topical ethyl chloride spray is temporarily soothingp as may be transcutaneous nerve stimulation.18 Topical capsaicin (a substance P antagonist) appeared beneficial in about half those treated in two open trials19,20 but not in another that was blinded and controlled.21 Moreover, some people have to abandon the spray because of post-capsaicin burning. Capsaicin cream is still being evaluated and may yet have a place in elderly patients intolerant of oral drugs. Many surgical procedures have been suggested, all of which have uncertain effects.A possible exception is the Nashold procedure22 (dorsal root entry zone coagulation) which may diminish pain, but only in the short term. 1. Jolleys JV. Treatment of shingles and post-herpetic neuralgia. Br Med J
1989; 298: 1537-38.
RK, Duma C, Foley KM. Acute herpetic and postherpetic neuralgia: clinical review and current management. Ann Neurol 1986;
2. Portenoy
20: 651-64. 3. Head H, Campbell AW. The pathology of herpes zoster and its bearing on sensory localization. Brain 1900; 23: 353-523. 4. Juel-Jensen BE, MacCallum FO. Herpes simplex, varicella and zoster. Philadelphia: Lippincott, 1972: 127-32. 5. Watson CPN, Morshead C, Van der Kooy D, Deck J, Evans RJ. Post-herpetic neuralgia: post-mortem analysis of a case. Pain 1988; 34: 129-38. 6. Noordenbos W. Physiological correlates of clinical pain syndromes. In: Soulairac A, Cahn J, Charpentier J, eds. Pain. New York: Academic Press, 1968: 465-76. 7. Zacks SI, Langfitt TW, Elliott FA. Herpetic neuritis: a light and electron microscopic study. Neurology 1964; 14: 744-50.
8. Nurmikko T, Bowsher D. Somatosensory findings in postherpeticc neuralgia. J Neurol Neurosurg Psychiatry 1990; 53: 135-41. 9. Rowbotham MC, Fields HL. Post-herpetic neuralgia: the relation of pain complaint, sensory disturbance and skin temperature. Pain 1989; 39: 129-44. 10. O’Brien J, antiviral
Campoli-Richards DM. Acyclovir: an updated review of its activity, pharmacokinetic properties and therapeutic efficacy.
Drugs 1989; 37: 233-309. 11. Morton P, Thomson AN. Oral acyclovir in the treatment of herpes zoster in general practice. N Z Med J 1989; 102: 93-95. 12. Huff JC. Oral acyclovir therapy of acute herpes zoster: a multi-centre study. Res Clin Forum 1987; 9: 37-43. 13. Eaglstein WH, Katz R, Brown JA. The effects of early corticosteroid therapy on the skin eruption and pain of herpes zoster. JAMA 1970; 211: 1681-83. 14. Esmann V, Kroon S, Geil JP, et al. Prednisolone does not prevent post-herpetic neuralgia. Lancet 1987; ii: 126-29. 15. Galbraith AW. Prevention of post-herpetic neuralgia by amantadine hydrochloride (Symmetrel). Br J Clin Pract 1983; 37: 304-06. 16. Watson CP, Evans RJ, Reed K, et al. Amitriptyline versus placebo in postherpetic neuralgia. Neurology 1982; 32: 671-73. 17. Taverner D. Alleviation of post-herpetic neuralgia. Lancet 1960; ii: 671-73. 18. Nathan PW, Wall PD. Treatment of post-herpetic neuralgia by prolonged electrical stimulation. Br Med J 1974; ii: 645-47. 19. Watson CPN, Evans RJ, Watt VR. Postherpetic neuralgia and topical capsaicin. Pain 1988; 33: 333-40. 20. Bernstein JE, Bickers DR, Dahl MV, Roshal JY. Treatment of chronic
postherpetic neuralgia
with topical
capsaicin. J Am Acad Dermatol
1987; 17: 93-96.
HF, Harries AJ, Gamester RE, Justins D. Randomised doubleblind study of topical capsaicin for treatment of post-herpetic neuralgia. Pain 1990 (suppl 5): 111 (abstr). 22. Nashold BS. Current status of the DREZ operation: 1984. Neurosurgery 21. Drake
1984;
15: 942-44.
Tolerance and the fetal
graft
The
paradox of the fetal allograft was unveiled by Billingham over 25 years ago.Why does a mother not reject the semiallogeneic feto-placental graft within the uterus even when there has been repeated exposure to paternal antigens. More simply, how does the baby stay in the womb? To understand the underlying mechanisms one has to appreciate the complex relation between placenta and uterus. In human beings haemochorial placenta fetal villi interdigitate with maternal intervillous vascular spaces. The interface between mother and child is the syncytiotrophoblast membrane-this is a dialysis membrane 25 square metres in surface area that bidirectionally transports all substances entering or leaving the fetal circulation.2 An additional function is to camouflage the developing fetus from the maternal immunological effectors. The membrane is continually renewed from the villous cytotrophoblasts immediately beneath it. At the tip of each villus there is a column of cytotrophoblasts in direct contact with the maternal decidua. Extravillous cytotrophoblasts are also in direct contact with maternal tissue, migrating deeply into the myometrium as interstitial trophoblasts or within the maternal vasculature as endovascular cytotrophoblasts. Some of these cells are even transported to maternal pulmonary blood vessels, where they remain throughout pregnancy.3 Graft rejection is mainly concerned with the recognition of antigens of the major histocompatibility complex (MHC) by T cells. The products of the MHC class II antigenic loci-HLA DP, DQ, and
