922
Kragballe et al used betamethasone-17-valerate 0-1% (’Betnovate’) as the drug of comparison, and we believe that this provides a major difficulty in interpretation of their data. In our view, betnovate is by no means the best treatment for psoriasis. Several workers have shown that this topical corticosteroid, among others, does not fare well in comparisons with, for example, dithranol,l and that it is associated with earlier relapse than are other drugs. In addition, when corticosteroids are used to suppress psoriasis there is a real danger of pituitary adrenal suppression,2,3 skin thinning,4 and masked ringworm infection,s as well as the possibility of provoking the more serious condition of pustular psoriaiS.6 It is true that betamethasone valerate is widely used, but that is not a reason to compare its effect with other drugs. It might have been appropriate to compare calcipotriol with an identical but unmedicated vehicle control. Without this type of control it is difficult to know how much therapeutic activity is attributable to the drug and how much to the vehicle. Kragballe et al might have done better to use a preparation of dithranol, even though it would have made the double-blind design very difficult. Dithranol is acknowledged to be the most effective topical agent for psoriasis, and we would have obtained more useful information about the activity of the vitamin D3 analogue by comparison with this agent. Notwithstanding our minor criticisms of the trial design it is clear that topical vitamin D3 and its analogues have therapeutic activity, though the mechanism of action is puzzling. In our study, we did biopsies after treatment but showed only that the improvement in histological features and proliferative profile accorded with the clinical status; we cannot say from this finding if the agent has an antiproliferative effect. We hope that the arrival of a new class of topical agents for psoriasis that have a moderate suppressive activity will not inhibit more fundamental research to develop more effective remedies for this troublesome disease. Department of Dermatology, University of Wales College of Medicine,
C. C. LONG R. MARKS
Cardiff CF4 4XN, UK
1. Horwitz SN, Johnson RA, Sefton J, Frost P. Addition of a topically applied corticosteroid to a modified Goeckerman regimen for treatment for psoriasis: effect on duration of remission. J Am Acad Dermatol 1985; 13: 784-91. 2. Allenby CF, Main RA, Marsden RA, Sparkes CGG. Effect of adrenal function of topically applied clobetasol propionate (Dermovate). Br Med J1975; i: 619-21. 3. Staughton RCD, August PJ. Cushing’s syndrome and pituitary adrenal suppression due to clobetasol propionate. Br Med J 1986; ii: 419-21. 4. Dykes PJ, Marks R. An appraisal of the methods used in the assessment of atrophy from topical corticosteroids. Br J Dermatol 1979; 101: 599-606 5. Ive AF, Marks R. Tinea incognito. Br Med J 1969; iii: 149-52. 6. Baker H. Generalised pustular psoriasis. In: Roenigk HH Jr, Maibach HI, eds. Psoriasis. New York: Marcel Dekker, 15-33.
Maternal
alpha-fetoprotein congenital hypothyroidism serum
in
SIR,-Dr Ben-Neriah and colleagues (Feb 16, p 437) report two
pregnancies
with increased maternal
serum
alpha-fetoprotein
(MSAFP) concentrations (5-3 and 7-0 multiples of the median [MoM], respectively) at 17 weeks’ gestation, in which primary congenital hypothyroidism was subsequently diagnosed after birth. Based on these two cases, Ben-Neriah et al suggest an association between increased second trimester MSAFP values and congenital hypothyroidism and recommend thyroid stimulating hormone (TSH) measurements in amniotic fluid, followed by prenatal thyroxine therapy, when indicated. In 1972, one of our group identified a hypothyroid newborn baby with an increased serum AFP value.1 This finding, together with a 2 more comprehensive study on hypothyroid newborn children,2 prompted us to examine MSAFP concentrations from pregnancies where the infant was subsequently identified as having congenital hypothyroidism. Between January, 1980, and February, 1987, 31 cases of congenital hypothyroidism were identified in Maine, and 13 of these pregnancies had an MSAFP measurement at 15-20 weeks’ gestation. The median MSAFP value for the 13 pregnancies was 0-9 MoM (range 0-5-2-9 MoM) and only one of the 13 measurements was higher than the laboratory’s cut-off of 20 MoM. Our data
suggest that it is premature to recommend TSH measurements in amniotic fluid samples obtained from pregnancies with increased MSAFP values. JAMES E. HADDOW GEORGE J. KNIGHT Foundation for Blood Research, GLENN E. PALOMAKI Scarborough, Maine 04074, USA Moses H Cone Memorial Hospital, Greensboro, North Carolina
A. MYRON JOHNSON
serum level of &agr;1-fetoprotein in an infant with iatrogenic hypothyroidism. Clin Res 1972; 20: 56. 2. Larrson A, Hagenfeldt L, Blom L, Mortensson W. Serum alpha-fetoprotein: a biochemical indicator of prenatal hypothyroidism. Acta Paediatr Scand 1983; 72:
1.
Johnson AM, Salter KE High
481-84.
SIR,-Dr Ben-Neriah and his colleagues report very high maternal serum a-fetoprotein (MSAFP) concentrations in two women who were subsequently delivered of infants with congenital hypothyroidism. The values were 5-3 and 7-0 multiples of the normal median (MoM) at 17 weeks’ gestation. Ben-Neriah et al conclude that amniotic fluid thyroid stimulating hormone (TSH) should be measured in unexplained cases of raised MSAFP so that
begin antenatally. investigated the possible correlation between MSAFP and congenital hypothyroidism, using information from women and newborn babies having routine screening tests at John Radcliffe Hospital, Oxford, in 1979-89. We regarded a pregnancy as affected if the baby had a raised TSH on the routine dried blood spot, confirmed by TSH and either thyroxine or free thyroxine measurement in a subsequent serum sample and by physical examination. 21 singleton and 1 twin affected pregnancies were identified in which MSAFP had been tested. None of the singletons had raised MSAFP values (range 0-59-1 ’54 MoM, median 1-06). In treatment can
We
the twin pregnancy MSAFP concentration was 2-69 MoM but values in normal twins are roughly double those in singletons. Our results indicate that pregnancies affected by neonatal hypothyroidism have normal MSAFP concentrations. Our experience provides no reason to investigate cases of raised MSAFP for the possibility of this disease. Department of Environmental and Preventive Medicine, Medical College of St Bartholomew’s London EC1M 6BQ, UK
Hospital,
Nuffield Department of Clinical Biochemistry, John Radcliffe Hospital, Oxford
Chronic
HOWARD CUCKLE NORA JONES JONATHAN KAY SUSAN STANDING
fatigue syndrome and depression
SIR,—While it is appropriate to assess the possibility of a relation between depressive disorders and chronic fatigue syndrome (CFS), Professor Kendell (Jan 19, p 160) ignores key epidemiological, psychiatric, and immunological findings. Our epidemiological study in an Australian community1 revealed that carefully defined CFS is present in at least 37 persons per 100 000, has a female to male sex ratio of 1-3/1, and occurs in children (8 of 42 cases identified were under 15). These demographic characteristics of CFS in the community do not resemble those of depression. Contrary to Kendell’s notion of a "glamorous disorder", cases of CFS in our survey came from all social classes, and the illness was associated with considerable personal losses and cost to the community. Kendell seeks to draw together similarities between CFS and depression but ignores important differences. Patients with typical primary depression are characterised by clinical features, such as anhedonia, weight loss, suicidal ideation, psychomotor retardation or agitation, and anxiety, that are notably absent in CFS.2,3 Furthermore, the severity of depression in patients with CFS is not comparable with that seen in non-melancholic depression, and the patients with CFS report lower amounts of neuroticism.3 4 Nor do they exhibit abnormal dexamethasone suppression3 or the shortened latency to rapid-eye-movement sleep5 found m depression. The rate of premorbid depressive disorders does not seem to be increased.4 Patients with CFS lack many essential
923
characteristics of patients with primary depression; their symptoms more
closely resemble those
seen
with
primary medical disorders.5 Kendell laments the "fact" that patients with CFS refuse
antidepressant therapy. Our review of 565 patients with CFS diagnosed in our tertiary referral service revealed that 38% had received antidepressant therapy while 34% had taken some other form of psychotropic medication concurrently or alternatively. He suggests that depressive disorders "have the great merit of being eminently treatable", unlike the viral infection thought to underlie postviral fatigue syndrome. While many treated patients with depression do improve in the short-term, studies of the outcome decades show that four-fifths of patients admitted to hospital with depression can be expected to have recurrent depressive disorder.6 By contrast, the median duration of symptoms from onset to sampling in our prevalence study1 was 30 months, suggesting self-limiting natural history in many cases. Only 3 of 42 cases (7%) in this sample had symptoms for more than 20 years. Kendell makes no reference to immunological studies in CFS. He states that "depression itself may predispose to subsequent infection by an effect on immune mechanisms", a highly contentious hypothesis since immune disturbances seem to be limited to patients with severe depressive disorders who are older and often admitted for treatment.7,8Disturbances of cell-mediated immunity have been found in CFS,9,10 and these changes are not likely to be attributable to concurrent depression. Immunological therapy alone has been shown to resolve associated depressive symptoms in patients whose chronic fatigue responded to treatment.’1 We agree that patients labelled as having CFS are likely to be heterogeneous in character and that research demands more homogeneous groups, but we do not support the Centers for Disease Control definition that, by excluding patients with current or past psychological disorder, institutionalises the exact dualistic thinking of which Kendell is so critical. Manu et al12 found that 67% of patients referred with chronic fatigue did not meet CDC criteria because of concurrent psychiatric diagnoses. Further work is clearly required to categorise patients who present with both chronic fatigue and the strong conviction that they are physically ill.4 Premature and largely unwarranted assertions that patients with CFS resemble those with primary depression and will therefore respond to conventional antidepressant treatments may hinder progress towards an understanding of the pathophysiology of CFS and the development of effective therapy.
over
Mood Disorders Unit, Division of Psychiatry, Prince Henry Hospital, Little Bay, NSW 2036, Australia
Departments of Infectious Diseases and Immunology, Division of Medicine, Prince Henry Hospital
Mitochondrial inclusions and Creutzfeldt-Jakob disease
depression complicating
IAN HICKIE
ANDREW LLOYD DENIS WAKEFIELD
AR, Hickie I, Boughton CR, Spencer O, Wakefield D. The prevalence of chronic fatigue syndrome in an Australian population. Med J Aust 1990; 153: 522-28. 2 Wessely S, Powell R. Fatigue syndromes: a comparison of chronic "postviral" fatigue with neuromuscular and affective disorders. J Neurol Neurosurg Psychiatry 1989; 52: 940-48. 3. Taerk GS, Toner BB, Salit IE, et al. Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). Int J Psychiatry Med 1987; 17: 49-56. 4 Hickie I, Lloyd A, Wakefield D, Parker G. The psychiatric status of patients with chronic fatigue syndrome. Br J Psychiatry 1990; 156: 534-40. 5 Rodin G, Voshart K. Depression in the medically ill: an overview. Am J Psychiatry 1986; 143: 696-705. 6 Kiloh LG, Andrews G, Nielsen M. The long term outcome of depressive illness. Br J 1. Lloyd
SIR,-Dr Lewin and Mr Edwards (Jan 26, p 236) report the presence of an electronmicroscopic mitochondrial inclusion body in a biopsy sample from a patient with Creutzfeldt-Jakob-like dementia. They suggest that the inclusion body is the agent
responsible for the disease. Various inclusion bodies have been suggested as the agent for Creutzfeldt-Jakob disease and other scrapie-like diseases. A candidate that has been researched for many years is the synaptic inclusion body.1 A drawback to the identification of inclusion bodies in mitochondria is that these organelles are notoriously sensitive to postmortem change, especially in brain material. Even in animals whose brains have been perfused mitochondria can be abnormal. Typically they become enlarged, rounded in cross section, and their cristae are disorganised. The cristae may be largely absent and form paracrystalline structures identical to those Lewin and Edwards describe. Control material is essential. In all material from patients with degenerative diseases, whether biopsied or not, there is some degree of lysis of organelles before tissue sampling. Since an agent responsible for scrapie-like disease has never been isolated its electronmicroscopic identification poses great difficulties. Many structures thought to have pathological significance for Creutzfeldt- Jakob2 and other diseases have later proved to be artifacts or non-specific .3’4 Any suggestion that a structure of importance might be artifact has to be taken seriously. 46
Craighouse Avenue, Edinburgh EH10 5LN, UK
PETER H. GIBSON
PH, Doughty LA. An electron microscopic study of inclusion bodies in the synaptic boutons of scrapie affected animals. Acta Neuropathol 1989; 77: 420-25. 2. Liberski PP, Gibson PH. Cerebellar lamellar body in two strains of murine scrapie. J Comp Pathol 1989; 97: 491-93. 3. Gibson PH. Scrapie-associated fibrils and AIDS encephalopathy. Lancet 1985; ii: 1. Gibson
612-13. 4. Gibson PH, Tomlinson BE. Numbers of Hirano bodies in the hippocampus of normal and demented people with Alzheimer’s disease. J Neurol Sci 1977; 27: 199-206.
**Thisletter has been shown - ED.L.
to
Dr
Lewin, whose reply follows.
SIR,-We agree that artifactual changes can be seen in mitochondria, even in rapidly fixed biopsy material, and that these changes have sometimes been implicated as the underlying causal factors in some disease processes. However, artifactual changes in mitochondria are often accompanied by many other intracellular changes1 that were not noted in our case. Nuclear membranes were intact, and neighbouring mitochondria with their cristae looked normal. The mitochondrial crystalloid arrays that we observed were well organised and exhibited a repetitive pattern. Further, the mitochondria containing crystalloid inclusions had intact membranes and cristae, and did not show swelling, variation in matrix density, or disruption of membranes. We feel that the inclusions noted are not artifacts and are related to the underlying spongiform encephalopathy. However, definitive characterisation will only be possible after further histochemical, biochemical, and immunological analyses. Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8
PETER LEWIN VERN EDWARDS
BF, Ericsson JLE. The effect of the fixative solution on the ultrastructure of cells and tissue. Lab Invest 1965; 14: 1245-323.
1. Trump
Psychiatry 1988; 153: 752-57. 7. Hickie
I, Hickie C, Silove D, Wakefield D, Lloyd A. Is there significant immune dysfunction in depressive disorders? Psychol Med 1990; 20: 755-61 8. Schleifer SJ, Keller SE, Bond R, Cohen J, Stein M. Major depressive disorder and immunity. Arch Gen Psychiatry 1989; 46: 81-87 9 Lloyd A, Wakefield D, Boughton C, Dwyer J. Immunological abnormalities in the chronic fatigue syndrome. Med J Aust 1989; 151: 122-24. 10. Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 1990; 28: 1403-10. 11 Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J. High dose intravenous immunoglobulin therapy in the chronic fatigue syndrome: a double-blind, placebo-controlled trial. Am J Med 190; 89: 561-68. 12 Manu P, Lane TJ, Matthews DA. The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue. Ann Intern Med 1988; 109: 554-56.
Mutations in
amyloid precursor protein gene and disease SIR,-Dr Nieto et al (March 9, p 622) note similarities in the molecular genetics of familial amyloidotic polyneuropathy and familial prion disease. In both these conditions one of several mutations in the relevant precursor protein leads to the deposition of &bgr;-pleated sheets of amyloid fibrils. Dutch-type amyloid angiopathy has a similar molecular pathology except that only one mutation in the amyloid precursor protein has been described.’ In
Kragballe et al used betamethasone-17-valerate 0-1% (’Betnovate’) as the drug of comparison, and we believe that this provides a major difficulty in interpretation of their data. In our view, betnovate is by no means the best treatment for psoriasis. Several workers have shown that this topical corticosteroid, among others, does not fare well in comparisons with, for example, dithranol,l and that it is associated with earlier relapse than are other drugs. In addition, when corticosteroids are used to suppress psoriasis there is a real danger of pituitary adrenal suppression,2,3 skin thinning,4 and masked ringworm infection,s as well as the possibility of provoking the more serious condition of pustular psoriaiS.6 It is true that betamethasone valerate is widely used, but that is not a reason to compare its effect with other drugs. It might have been appropriate to compare calcipotriol with an identical but unmedicated vehicle control. Without this type of control it is difficult to know how much therapeutic activity is attributable to the drug and how much to the vehicle. Kragballe et al might have done better to use a preparation of dithranol, even though it would have made the double-blind design very difficult. Dithranol is acknowledged to be the most effective topical agent for psoriasis, and we would have obtained more useful information about the activity of the vitamin D3 analogue by comparison with this agent. Notwithstanding our minor criticisms of the trial design it is clear that topical vitamin D3 and its analogues have therapeutic activity, though the mechanism of action is puzzling. In our study, we did biopsies after treatment but showed only that the improvement in histological features and proliferative profile accorded with the clinical status; we cannot say from this finding if the agent has an antiproliferative effect. We hope that the arrival of a new class of topical agents for psoriasis that have a moderate suppressive activity will not inhibit more fundamental research to develop more effective remedies for this troublesome disease. Department of Dermatology, University of Wales College of Medicine,
C. C. LONG R. MARKS
Cardiff CF4 4XN, UK
1. Horwitz SN, Johnson RA, Sefton J, Frost P. Addition of a topically applied corticosteroid to a modified Goeckerman regimen for treatment for psoriasis: effect on duration of remission. J Am Acad Dermatol 1985; 13: 784-91. 2. Allenby CF, Main RA, Marsden RA, Sparkes CGG. Effect of adrenal function of topically applied clobetasol propionate (Dermovate). Br Med J1975; i: 619-21. 3. Staughton RCD, August PJ. Cushing’s syndrome and pituitary adrenal suppression due to clobetasol propionate. Br Med J 1986; ii: 419-21. 4. Dykes PJ, Marks R. An appraisal of the methods used in the assessment of atrophy from topical corticosteroids. Br J Dermatol 1979; 101: 599-606 5. Ive AF, Marks R. Tinea incognito. Br Med J 1969; iii: 149-52. 6. Baker H. Generalised pustular psoriasis. In: Roenigk HH Jr, Maibach HI, eds. Psoriasis. New York: Marcel Dekker, 15-33.
Maternal
alpha-fetoprotein congenital hypothyroidism serum
in
SIR,-Dr Ben-Neriah and colleagues (Feb 16, p 437) report two
pregnancies
with increased maternal
serum
alpha-fetoprotein
(MSAFP) concentrations (5-3 and 7-0 multiples of the median [MoM], respectively) at 17 weeks’ gestation, in which primary congenital hypothyroidism was subsequently diagnosed after birth. Based on these two cases, Ben-Neriah et al suggest an association between increased second trimester MSAFP values and congenital hypothyroidism and recommend thyroid stimulating hormone (TSH) measurements in amniotic fluid, followed by prenatal thyroxine therapy, when indicated. In 1972, one of our group identified a hypothyroid newborn baby with an increased serum AFP value.1 This finding, together with a 2 more comprehensive study on hypothyroid newborn children,2 prompted us to examine MSAFP concentrations from pregnancies where the infant was subsequently identified as having congenital hypothyroidism. Between January, 1980, and February, 1987, 31 cases of congenital hypothyroidism were identified in Maine, and 13 of these pregnancies had an MSAFP measurement at 15-20 weeks’ gestation. The median MSAFP value for the 13 pregnancies was 0-9 MoM (range 0-5-2-9 MoM) and only one of the 13 measurements was higher than the laboratory’s cut-off of 20 MoM. Our data
suggest that it is premature to recommend TSH measurements in amniotic fluid samples obtained from pregnancies with increased MSAFP values. JAMES E. HADDOW GEORGE J. KNIGHT Foundation for Blood Research, GLENN E. PALOMAKI Scarborough, Maine 04074, USA Moses H Cone Memorial Hospital, Greensboro, North Carolina
A. MYRON JOHNSON
serum level of &agr;1-fetoprotein in an infant with iatrogenic hypothyroidism. Clin Res 1972; 20: 56. 2. Larrson A, Hagenfeldt L, Blom L, Mortensson W. Serum alpha-fetoprotein: a biochemical indicator of prenatal hypothyroidism. Acta Paediatr Scand 1983; 72:
1.
Johnson AM, Salter KE High
481-84.
SIR,-Dr Ben-Neriah and his colleagues report very high maternal serum a-fetoprotein (MSAFP) concentrations in two women who were subsequently delivered of infants with congenital hypothyroidism. The values were 5-3 and 7-0 multiples of the normal median (MoM) at 17 weeks’ gestation. Ben-Neriah et al conclude that amniotic fluid thyroid stimulating hormone (TSH) should be measured in unexplained cases of raised MSAFP so that
begin antenatally. investigated the possible correlation between MSAFP and congenital hypothyroidism, using information from women and newborn babies having routine screening tests at John Radcliffe Hospital, Oxford, in 1979-89. We regarded a pregnancy as affected if the baby had a raised TSH on the routine dried blood spot, confirmed by TSH and either thyroxine or free thyroxine measurement in a subsequent serum sample and by physical examination. 21 singleton and 1 twin affected pregnancies were identified in which MSAFP had been tested. None of the singletons had raised MSAFP values (range 0-59-1 ’54 MoM, median 1-06). In treatment can
We
the twin pregnancy MSAFP concentration was 2-69 MoM but values in normal twins are roughly double those in singletons. Our results indicate that pregnancies affected by neonatal hypothyroidism have normal MSAFP concentrations. Our experience provides no reason to investigate cases of raised MSAFP for the possibility of this disease. Department of Environmental and Preventive Medicine, Medical College of St Bartholomew’s London EC1M 6BQ, UK
Hospital,
Nuffield Department of Clinical Biochemistry, John Radcliffe Hospital, Oxford
Chronic
HOWARD CUCKLE NORA JONES JONATHAN KAY SUSAN STANDING
fatigue syndrome and depression
SIR,—While it is appropriate to assess the possibility of a relation between depressive disorders and chronic fatigue syndrome (CFS), Professor Kendell (Jan 19, p 160) ignores key epidemiological, psychiatric, and immunological findings. Our epidemiological study in an Australian community1 revealed that carefully defined CFS is present in at least 37 persons per 100 000, has a female to male sex ratio of 1-3/1, and occurs in children (8 of 42 cases identified were under 15). These demographic characteristics of CFS in the community do not resemble those of depression. Contrary to Kendell’s notion of a "glamorous disorder", cases of CFS in our survey came from all social classes, and the illness was associated with considerable personal losses and cost to the community. Kendell seeks to draw together similarities between CFS and depression but ignores important differences. Patients with typical primary depression are characterised by clinical features, such as anhedonia, weight loss, suicidal ideation, psychomotor retardation or agitation, and anxiety, that are notably absent in CFS.2,3 Furthermore, the severity of depression in patients with CFS is not comparable with that seen in non-melancholic depression, and the patients with CFS report lower amounts of neuroticism.3 4 Nor do they exhibit abnormal dexamethasone suppression3 or the shortened latency to rapid-eye-movement sleep5 found m depression. The rate of premorbid depressive disorders does not seem to be increased.4 Patients with CFS lack many essential
923
characteristics of patients with primary depression; their symptoms more
closely resemble those
seen
with
primary medical disorders.5 Kendell laments the "fact" that patients with CFS refuse
antidepressant therapy. Our review of 565 patients with CFS diagnosed in our tertiary referral service revealed that 38% had received antidepressant therapy while 34% had taken some other form of psychotropic medication concurrently or alternatively. He suggests that depressive disorders "have the great merit of being eminently treatable", unlike the viral infection thought to underlie postviral fatigue syndrome. While many treated patients with depression do improve in the short-term, studies of the outcome decades show that four-fifths of patients admitted to hospital with depression can be expected to have recurrent depressive disorder.6 By contrast, the median duration of symptoms from onset to sampling in our prevalence study1 was 30 months, suggesting self-limiting natural history in many cases. Only 3 of 42 cases (7%) in this sample had symptoms for more than 20 years. Kendell makes no reference to immunological studies in CFS. He states that "depression itself may predispose to subsequent infection by an effect on immune mechanisms", a highly contentious hypothesis since immune disturbances seem to be limited to patients with severe depressive disorders who are older and often admitted for treatment.7,8Disturbances of cell-mediated immunity have been found in CFS,9,10 and these changes are not likely to be attributable to concurrent depression. Immunological therapy alone has been shown to resolve associated depressive symptoms in patients whose chronic fatigue responded to treatment.’1 We agree that patients labelled as having CFS are likely to be heterogeneous in character and that research demands more homogeneous groups, but we do not support the Centers for Disease Control definition that, by excluding patients with current or past psychological disorder, institutionalises the exact dualistic thinking of which Kendell is so critical. Manu et al12 found that 67% of patients referred with chronic fatigue did not meet CDC criteria because of concurrent psychiatric diagnoses. Further work is clearly required to categorise patients who present with both chronic fatigue and the strong conviction that they are physically ill.4 Premature and largely unwarranted assertions that patients with CFS resemble those with primary depression and will therefore respond to conventional antidepressant treatments may hinder progress towards an understanding of the pathophysiology of CFS and the development of effective therapy.
over
Mood Disorders Unit, Division of Psychiatry, Prince Henry Hospital, Little Bay, NSW 2036, Australia
Departments of Infectious Diseases and Immunology, Division of Medicine, Prince Henry Hospital
Mitochondrial inclusions and Creutzfeldt-Jakob disease
depression complicating
IAN HICKIE
ANDREW LLOYD DENIS WAKEFIELD
AR, Hickie I, Boughton CR, Spencer O, Wakefield D. The prevalence of chronic fatigue syndrome in an Australian population. Med J Aust 1990; 153: 522-28. 2 Wessely S, Powell R. Fatigue syndromes: a comparison of chronic "postviral" fatigue with neuromuscular and affective disorders. J Neurol Neurosurg Psychiatry 1989; 52: 940-48. 3. Taerk GS, Toner BB, Salit IE, et al. Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). Int J Psychiatry Med 1987; 17: 49-56. 4 Hickie I, Lloyd A, Wakefield D, Parker G. The psychiatric status of patients with chronic fatigue syndrome. Br J Psychiatry 1990; 156: 534-40. 5 Rodin G, Voshart K. Depression in the medically ill: an overview. Am J Psychiatry 1986; 143: 696-705. 6 Kiloh LG, Andrews G, Nielsen M. The long term outcome of depressive illness. Br J 1. Lloyd
SIR,-Dr Lewin and Mr Edwards (Jan 26, p 236) report the presence of an electronmicroscopic mitochondrial inclusion body in a biopsy sample from a patient with Creutzfeldt-Jakob-like dementia. They suggest that the inclusion body is the agent
responsible for the disease. Various inclusion bodies have been suggested as the agent for Creutzfeldt-Jakob disease and other scrapie-like diseases. A candidate that has been researched for many years is the synaptic inclusion body.1 A drawback to the identification of inclusion bodies in mitochondria is that these organelles are notoriously sensitive to postmortem change, especially in brain material. Even in animals whose brains have been perfused mitochondria can be abnormal. Typically they become enlarged, rounded in cross section, and their cristae are disorganised. The cristae may be largely absent and form paracrystalline structures identical to those Lewin and Edwards describe. Control material is essential. In all material from patients with degenerative diseases, whether biopsied or not, there is some degree of lysis of organelles before tissue sampling. Since an agent responsible for scrapie-like disease has never been isolated its electronmicroscopic identification poses great difficulties. Many structures thought to have pathological significance for Creutzfeldt- Jakob2 and other diseases have later proved to be artifacts or non-specific .3’4 Any suggestion that a structure of importance might be artifact has to be taken seriously. 46
Craighouse Avenue, Edinburgh EH10 5LN, UK
PETER H. GIBSON
PH, Doughty LA. An electron microscopic study of inclusion bodies in the synaptic boutons of scrapie affected animals. Acta Neuropathol 1989; 77: 420-25. 2. Liberski PP, Gibson PH. Cerebellar lamellar body in two strains of murine scrapie. J Comp Pathol 1989; 97: 491-93. 3. Gibson PH. Scrapie-associated fibrils and AIDS encephalopathy. Lancet 1985; ii: 1. Gibson
612-13. 4. Gibson PH, Tomlinson BE. Numbers of Hirano bodies in the hippocampus of normal and demented people with Alzheimer’s disease. J Neurol Sci 1977; 27: 199-206.
**Thisletter has been shown - ED.L.
to
Dr
Lewin, whose reply follows.
SIR,-We agree that artifactual changes can be seen in mitochondria, even in rapidly fixed biopsy material, and that these changes have sometimes been implicated as the underlying causal factors in some disease processes. However, artifactual changes in mitochondria are often accompanied by many other intracellular changes1 that were not noted in our case. Nuclear membranes were intact, and neighbouring mitochondria with their cristae looked normal. The mitochondrial crystalloid arrays that we observed were well organised and exhibited a repetitive pattern. Further, the mitochondria containing crystalloid inclusions had intact membranes and cristae, and did not show swelling, variation in matrix density, or disruption of membranes. We feel that the inclusions noted are not artifacts and are related to the underlying spongiform encephalopathy. However, definitive characterisation will only be possible after further histochemical, biochemical, and immunological analyses. Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8
PETER LEWIN VERN EDWARDS
BF, Ericsson JLE. The effect of the fixative solution on the ultrastructure of cells and tissue. Lab Invest 1965; 14: 1245-323.
1. Trump
Psychiatry 1988; 153: 752-57. 7. Hickie
I, Hickie C, Silove D, Wakefield D, Lloyd A. Is there significant immune dysfunction in depressive disorders? Psychol Med 1990; 20: 755-61 8. Schleifer SJ, Keller SE, Bond R, Cohen J, Stein M. Major depressive disorder and immunity. Arch Gen Psychiatry 1989; 46: 81-87 9 Lloyd A, Wakefield D, Boughton C, Dwyer J. Immunological abnormalities in the chronic fatigue syndrome. Med J Aust 1989; 151: 122-24. 10. Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 1990; 28: 1403-10. 11 Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J. High dose intravenous immunoglobulin therapy in the chronic fatigue syndrome: a double-blind, placebo-controlled trial. Am J Med 190; 89: 561-68. 12 Manu P, Lane TJ, Matthews DA. The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue. Ann Intern Med 1988; 109: 554-56.
Mutations in
amyloid precursor protein gene and disease SIR,-Dr Nieto et al (March 9, p 622) note similarities in the molecular genetics of familial amyloidotic polyneuropathy and familial prion disease. In both these conditions one of several mutations in the relevant precursor protein leads to the deposition of &bgr;-pleated sheets of amyloid fibrils. Dutch-type amyloid angiopathy has a similar molecular pathology except that only one mutation in the amyloid precursor protein has been described.’ In
