379
We also found that when the DH rash was finally controlled with GFD alone, the IgA persisted in the skin. However, we have found that the IgA may eventually disappear. In three out of twelve patients the
IgA disappeared at seven years in
one, and at ten years in two. In addition, the IgA returned to the skin
when these patients had gluten re-introduced
to
the diet. Thus
changes in immunological responses to gluten in DH can take up to ten years to reveal themselves. A similar time, or even longer, might be necessary for intestinal immunity to become normal after gluten withdrawal. Variation in degrees of gluten sensitivity in both DH and coeliac disease may explain O’Mahoney and colleagues’ findings, rather than two separate stages in the development of both these disorders. Dermatology Department, St Mary’s Hospital, London W2 1NY, UK 1 2 3 4 5
6
7 8 9 10
LIONEL FRY JONATHAN N. LEONARD
Fry L, Seah PP, Harper PG, Hoffbrand AV, McMinn RMH The small intestine m dermatitis herpetiformis J Clin Pathol 1974; 27: 817-24. Gebhard KRL, Katz SI, Marks J, et al. HL-A antigen type and small intestinal disease in dermatitis herpetiformis. Lancet 1973; ii: 760-62 Fry L, Leonard JN, Swam AF, et al. Long term follow-up of dermatitis herpetiformis with and without dietary gluten withdrawal. Br J Dermatol 1982; 107: 631-40. Holmes GKT, Prior P, Lane MR, Pope W, Allan RN. Malignancy in coeliac disease—effect of a gluten-free diet. Gut 1989; 30: 333-38. Leonard JN, Tucker WFG, Fry JS, et al. Increased incidence of malignancy in dermatitis herpetiformis. Br Med J 1983, 286: 16-18. Fry L, McMinn RMH, Cowan JD, Hoffbrand AV Effect of a gluten-free diet on dermatological, intestinal and haematological manifestations of dermatitis herpetiformis Lancet 1968, i: 557-61 Shuster S, Watson AJ, Marks J. Coeliac syndrome in dermatitis herpetiformis. Lancet 1968; i 1101-05 Weinstein WM, Brow JR, Parker F, Rubin CE. The small intestinal mucosa in dermatitis herpetiformis. Gastroenterology 1971, 60: 362 Fry L, Seah PP, Riches DJ, Hoffbrand AV Clearance of skin leasions in dermatitis herpetiformis after gluten withdrawal Lancet 1973; i 288-91. Leonard JN, Haffenden GP, Tucker WFG, et al Gluten challenge in dermatitis herpetiformis. N Engl J Med 1983; 308: 816-19.
and abolition of physical and mental fatigue; for the first timc in 7 years the patient needed to be awakened by her parents at 0700-0800 h. This response has been sustained for 6 weeks of treatment without tolerance, and she has had no subjective side-effects apart from minor morning dryness of the eyes. Blind placebo replacement for ritanserin for one week resulted in an immediate return of insomnia. Objective sleep laboratory studies, scored blind, confirmed the improvement on ritanserin 5 mg. Total sleep time increased from 227 to 427 min on first dose and to 465 min after 4 weeks; during the same period sleep efficiency changed from 47% to 97%. The absolute duration of the rapid eye movement stage increased from 5 to 75 min and slow-wave sleep from 136 to 209 min over the 4 weeks. Morning multiple sleep latency tests remained steady at 9-11 min. Visual analogue scales showed an increase in alertness, reduced lethargy, and improved morning vigilance. Although the exact mode of action of ritanserin is uncertain these results support the many data implicating 5-HT mechanisms in sleep maintenance. University Department of Neurology, King’s College School of Medicine and Dentistry, and Institute of Psychiatry, London SE5 8AF, UK, and Clinical Pharmacology Unit, Janssen Research Foundation, Wantage
M. DAHLITZ P. WELLS
R. JAMES C. IDZIKOWSKI
J. D. PARKES
Encephalitis lethargica. its sequelae and treatment. Newman KD (trans). London Oxford University Press, 1931. 2. Lhermitte J, Tournay A. Rapport sur le sommeil normal et pathologique Rev Neurol 1 Von Economo C.
1927, 1: 751-887.
Lugaresi E, Medori R, Montagna P, et al Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei N Engl J Med 1986, 315: 997-1003. 4. Jouvet M The role of monoamines and acetylcholine containing neurons in the regulation of the sleep-waking cycle Ergeb Physiol 1972; 64: 166-307. 5. Idzikowski C, Mills FJ, Glennard R. 5-Hydroxytryptamine-2 antagonist increases human slow wave sleep Brain Res 1986, 378: 164-68 3.
Treatment of insomnia with ritanserin
Cystic fibrosis genetics in southern Europe
StR,—The anatomical and pharmacological basis of sleep
StR,—About 70% of mutations in the cystic fibrosis (CF) gene in North American, British, and Dutch patients are caused by the three base pair deletion known as l1Fs08.1 In southern Europe, however, this mutation is present in only 46% of CF chromosomes; this means that direct deletion analysis will detect only 26% of CF patients and 46% of carriersDuring the past two years seven families with a 1 -in-4 risk of CF and with at least one living affected child have been typed here with probes MET, J311, KM19, and XV2C, to identify informative probes for carrier detection and prenatal diagnosis. A non-radioactive method, based on biotinylation of the probes and colorimetric detection of the hybrid DNA target/probe was used for Southern blot analysisIn all seven families a fully informative pattern was established and the carrier status of the normal siblings could be assigned. l1Fs08 deletion was detected by amplification of DNA by polymerase chain reaction followed by vertical electrophoresis in a 12% polyacrylamide minigel and ethidium bromide staining. None of the seven patients was homozygous for l1Fs08; five were compound heterozygotes and two did not have the mutation at all (table). Restriction fragment length polymorphism (RFLP) analysis was in perfect agreement with the mutation analysis
is not understood. In the encephalitis lethargica era, Von Economol established that lesions of the anterior hypothalamus led to persistent insomnia. However, lesions at other sites may have similar results.2 In the rare condition of fatal familial insomnia there is severe bilateral loss of neurons in the anterior and dorsomedial thalamic nucleiwhereas in animals lesions of the raphe nuclei, which contain serotonin (5-HT) neurons, cause profound insomnia, a fmding that may indicate involvement of 5-HT in sleep mechanisms.’ A 24-year-old woman presented with a history of severe persistent insomnia for 7 years. Subjective records kept over 3 months showed that sleep latency was prolonged (90-120 min) and sleep duration varied between 3 and 4 h per 24 h. The patient complained of very early waking, severe daytime tiredness, and physical and mental fatigue, but not of excessive daytime sleepiness. These symptoms followed the drainage, re-drainage, and radiotherapy of a cystic parapituitary tumour, involving also the floor of the third ventricle. The tumour resulted in a chiasmal field defect and hypopituitarism. Her circadian function was unremarkable as determined by a mean sleep onset time of 2400 h, with normal timing and amplitude of urinary melatonin metabolite excretion (J. Arendt, University of Surrey, personal communication). Hormonal replacement therapy was given with hydrocortisone 40 mg, thyroxin 100 pg, and desmopressin 0-2 ml maintenance in
man
daily. Over 7 years many attempts had been made to restore normal sleep-wake patterns with triazolam, temazepam, diazepam, the non-benzodiazapine hypnotic zopiclone, and melatonin. None of these had been successful. After the 5-HT2 antagonist ritanserin (Janssen Research Foundation) was reported to cause major alterations in slow-wave sleepy the patient was given daily 5 mg ritanserin orally at 0800 h. Within 2 days of starting this drug she reported an increase in sleep duration from 4 to 8 h in 24 h and a change in sleep quality rating from "extremely poor" to "totally refreshing". There was a striking improvement in waking energy
(figure). In Italy therefore identification of the l1F 508 mutation has not the same impact on prenatal diagnosis of CF as it has in northern Europe or North America. In all our families the prenatal diagnosis CORRELATION OF AF508 MUTATION ACCORDING TO HAPLOTYPE FOR TIGHTLY LINKED MARKERS XV2C AND KM199
We also found that when the DH rash was finally controlled with GFD alone, the IgA persisted in the skin. However, we have found that the IgA may eventually disappear. In three out of twelve patients the
IgA disappeared at seven years in
one, and at ten years in two. In addition, the IgA returned to the skin
when these patients had gluten re-introduced
to
the diet. Thus
changes in immunological responses to gluten in DH can take up to ten years to reveal themselves. A similar time, or even longer, might be necessary for intestinal immunity to become normal after gluten withdrawal. Variation in degrees of gluten sensitivity in both DH and coeliac disease may explain O’Mahoney and colleagues’ findings, rather than two separate stages in the development of both these disorders. Dermatology Department, St Mary’s Hospital, London W2 1NY, UK 1 2 3 4 5
6
7 8 9 10
LIONEL FRY JONATHAN N. LEONARD
Fry L, Seah PP, Harper PG, Hoffbrand AV, McMinn RMH The small intestine m dermatitis herpetiformis J Clin Pathol 1974; 27: 817-24. Gebhard KRL, Katz SI, Marks J, et al. HL-A antigen type and small intestinal disease in dermatitis herpetiformis. Lancet 1973; ii: 760-62 Fry L, Leonard JN, Swam AF, et al. Long term follow-up of dermatitis herpetiformis with and without dietary gluten withdrawal. Br J Dermatol 1982; 107: 631-40. Holmes GKT, Prior P, Lane MR, Pope W, Allan RN. Malignancy in coeliac disease—effect of a gluten-free diet. Gut 1989; 30: 333-38. Leonard JN, Tucker WFG, Fry JS, et al. Increased incidence of malignancy in dermatitis herpetiformis. Br Med J 1983, 286: 16-18. Fry L, McMinn RMH, Cowan JD, Hoffbrand AV Effect of a gluten-free diet on dermatological, intestinal and haematological manifestations of dermatitis herpetiformis Lancet 1968, i: 557-61 Shuster S, Watson AJ, Marks J. Coeliac syndrome in dermatitis herpetiformis. Lancet 1968; i 1101-05 Weinstein WM, Brow JR, Parker F, Rubin CE. The small intestinal mucosa in dermatitis herpetiformis. Gastroenterology 1971, 60: 362 Fry L, Seah PP, Riches DJ, Hoffbrand AV Clearance of skin leasions in dermatitis herpetiformis after gluten withdrawal Lancet 1973; i 288-91. Leonard JN, Haffenden GP, Tucker WFG, et al Gluten challenge in dermatitis herpetiformis. N Engl J Med 1983; 308: 816-19.
and abolition of physical and mental fatigue; for the first timc in 7 years the patient needed to be awakened by her parents at 0700-0800 h. This response has been sustained for 6 weeks of treatment without tolerance, and she has had no subjective side-effects apart from minor morning dryness of the eyes. Blind placebo replacement for ritanserin for one week resulted in an immediate return of insomnia. Objective sleep laboratory studies, scored blind, confirmed the improvement on ritanserin 5 mg. Total sleep time increased from 227 to 427 min on first dose and to 465 min after 4 weeks; during the same period sleep efficiency changed from 47% to 97%. The absolute duration of the rapid eye movement stage increased from 5 to 75 min and slow-wave sleep from 136 to 209 min over the 4 weeks. Morning multiple sleep latency tests remained steady at 9-11 min. Visual analogue scales showed an increase in alertness, reduced lethargy, and improved morning vigilance. Although the exact mode of action of ritanserin is uncertain these results support the many data implicating 5-HT mechanisms in sleep maintenance. University Department of Neurology, King’s College School of Medicine and Dentistry, and Institute of Psychiatry, London SE5 8AF, UK, and Clinical Pharmacology Unit, Janssen Research Foundation, Wantage
M. DAHLITZ P. WELLS
R. JAMES C. IDZIKOWSKI
J. D. PARKES
Encephalitis lethargica. its sequelae and treatment. Newman KD (trans). London Oxford University Press, 1931. 2. Lhermitte J, Tournay A. Rapport sur le sommeil normal et pathologique Rev Neurol 1 Von Economo C.
1927, 1: 751-887.
Lugaresi E, Medori R, Montagna P, et al Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei N Engl J Med 1986, 315: 997-1003. 4. Jouvet M The role of monoamines and acetylcholine containing neurons in the regulation of the sleep-waking cycle Ergeb Physiol 1972; 64: 166-307. 5. Idzikowski C, Mills FJ, Glennard R. 5-Hydroxytryptamine-2 antagonist increases human slow wave sleep Brain Res 1986, 378: 164-68 3.
Treatment of insomnia with ritanserin
Cystic fibrosis genetics in southern Europe
StR,—The anatomical and pharmacological basis of sleep
StR,—About 70% of mutations in the cystic fibrosis (CF) gene in North American, British, and Dutch patients are caused by the three base pair deletion known as l1Fs08.1 In southern Europe, however, this mutation is present in only 46% of CF chromosomes; this means that direct deletion analysis will detect only 26% of CF patients and 46% of carriersDuring the past two years seven families with a 1 -in-4 risk of CF and with at least one living affected child have been typed here with probes MET, J311, KM19, and XV2C, to identify informative probes for carrier detection and prenatal diagnosis. A non-radioactive method, based on biotinylation of the probes and colorimetric detection of the hybrid DNA target/probe was used for Southern blot analysisIn all seven families a fully informative pattern was established and the carrier status of the normal siblings could be assigned. l1Fs08 deletion was detected by amplification of DNA by polymerase chain reaction followed by vertical electrophoresis in a 12% polyacrylamide minigel and ethidium bromide staining. None of the seven patients was homozygous for l1Fs08; five were compound heterozygotes and two did not have the mutation at all (table). Restriction fragment length polymorphism (RFLP) analysis was in perfect agreement with the mutation analysis
is not understood. In the encephalitis lethargica era, Von Economol established that lesions of the anterior hypothalamus led to persistent insomnia. However, lesions at other sites may have similar results.2 In the rare condition of fatal familial insomnia there is severe bilateral loss of neurons in the anterior and dorsomedial thalamic nucleiwhereas in animals lesions of the raphe nuclei, which contain serotonin (5-HT) neurons, cause profound insomnia, a fmding that may indicate involvement of 5-HT in sleep mechanisms.’ A 24-year-old woman presented with a history of severe persistent insomnia for 7 years. Subjective records kept over 3 months showed that sleep latency was prolonged (90-120 min) and sleep duration varied between 3 and 4 h per 24 h. The patient complained of very early waking, severe daytime tiredness, and physical and mental fatigue, but not of excessive daytime sleepiness. These symptoms followed the drainage, re-drainage, and radiotherapy of a cystic parapituitary tumour, involving also the floor of the third ventricle. The tumour resulted in a chiasmal field defect and hypopituitarism. Her circadian function was unremarkable as determined by a mean sleep onset time of 2400 h, with normal timing and amplitude of urinary melatonin metabolite excretion (J. Arendt, University of Surrey, personal communication). Hormonal replacement therapy was given with hydrocortisone 40 mg, thyroxin 100 pg, and desmopressin 0-2 ml maintenance in
man
daily. Over 7 years many attempts had been made to restore normal sleep-wake patterns with triazolam, temazepam, diazepam, the non-benzodiazapine hypnotic zopiclone, and melatonin. None of these had been successful. After the 5-HT2 antagonist ritanserin (Janssen Research Foundation) was reported to cause major alterations in slow-wave sleepy the patient was given daily 5 mg ritanserin orally at 0800 h. Within 2 days of starting this drug she reported an increase in sleep duration from 4 to 8 h in 24 h and a change in sleep quality rating from "extremely poor" to "totally refreshing". There was a striking improvement in waking energy
(figure). In Italy therefore identification of the l1F 508 mutation has not the same impact on prenatal diagnosis of CF as it has in northern Europe or North America. In all our families the prenatal diagnosis CORRELATION OF AF508 MUTATION ACCORDING TO HAPLOTYPE FOR TIGHTLY LINKED MARKERS XV2C AND KM199
