1609
words such as "You can be sure that I will be giving you all the results as soon as I receive them and I will tell you only the truth". Truth leads to trust. Touching leads to trust. Trust is never more critical than in the optimum managment of patients who have had to be given bad news. I would also emphasise the importance of never withholding the bad news from any mentally competent adult, no matter what advice may be received from relatives or others. Alan McGuinness
Gastroenterology Unit, Sydney Hospital, Sydney, NSW 2000, Australia
JOHN R. GRAHAM
Compliance and tuberculosis treatment SIR,-Your April 6 editorial (p 823) states that "Doctors no longer have the right-if, indeed, they ever had-to expect patients to comply with their advice, whether proscriptive or prescriptive". We strongly support this tenet; however, we suggest one major exception. Tuberculosis is spread almost exclusively by human-tohuman aerogenic transmission: when a patient with pulmonary disease coughs, he generates an aerosol containing tubercle bacilli which may then be inhaled by others. We contend that doctors have not only the right but also the obligation to see that the patient adheres to the prescription (chemotherapy) or the proscription (quarantine). On the premise that the tubercular patient potentially infringes the right of a citizen to be free of disease, laws throughout the US strictly constrain public access for patients with communicable (untreated) pulmonary tuberculosis. Failure on the part of physicians to be assertive in ensuring regular administration of antituberculosis medications has dire consequences: high rates of treatment failure/relapse, continued contagion, and acquired drug resistance. With the closure of sanatoria and the abolition of most specialised tuberculosis clinics, tuberculosis treatment in North America and Europe has been "mainstreamed" into the general health care system over the past three decades. Unfortunately, during this era non-compliance has become the major impediment to the successful treatment of these patients.1 A major element in this trend has been the laisser-faire policy represented by your editorial position on the care of these patients. Medication cannot be forced upon unwilling patients by the practitioner or the state; however, aggressive, large-scale programmes of directly observed or supervised therapy should be used for those proven to be or at high risk of being non-compliant with therapy. Every effort should be made to induce adherence to treatment-and if this cannot be accomplished and the patient(s) remain contagious, public agencies should be willing to quarantine such individuals. Although this always has been a defensible proposition, it is even more compelling in an era of HIV which has seen a substantial increase in tuberculosis case rates in many regions, including epidemics of multiply resistant disease in several locations in the United States. Clinical Mycobacteriology Service, Division of Infectious Diseases, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, USA, and University of Colorado School of Medicine
MICHAEL D. ISEMAN
University of Colorado School of Medicine, Denver, Colorado
JOHN A. SBARBARO
1. Fox W
Compliance of patients and physicians: experience and lessons from tuberculosis, I. Br MedJ 1983; 287: 33-35.
Frequency of rhodopsin codon 23 mutation and retinitis pigmentosa SIR,-Although those of us with an interest in retinitis pigmentosa (RP) welcome Dr Sorscher and Dr Huang’s description (May 11, p 1115) of a rapid method to detect a particular rhodopsin mutation, we feel that they make several misleading statements that should be clarified. Firstly, they state that the frequency of autosomal dominant RP (ADRP) in the general population is "about 1 in 3500". The prevalence of all types ofRP is indeed in this region, but the ADRP subgroup represents only 19-26% of the total, which includes autosomal recessive and X-linked forms as
as a sizeable sporadic group.l Secondly, Sorscher and Huang ambiguously state that the rhodopsin codon 23 mutation was seen in 17 of 148 individuals "with the disease"-referring to a series of unrelated ADRP patients of North American origin.2 It should be noted, however, that this point mutation was not found in ninety-one unrelated European ADRP families3 and that many other rhodopsin mutations have since been found in ADRP families.’*’’* A large number of ADRP families are unlinked to this region and therefore represent mutation(s) at other remote gene(s).6,7 We welcome the ingenious methods that Sorscher and Huang present for mutation detection, but they have unintentionally inflated both the frequency of ADRP and of the rhodopsin codon 23 mutation, which is responsible for the disease in a small proportion of RP patients.
well
MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK
DOUGLAS H. LESTER ALAN F. WRIGHT
Kaplan J, Bonneau D, Frezal J, et al. Clinical and genetic heterogeneity m retinitis pigmentosa. Hum Genet 1990; 85: 635-42. 2. Dryja TD, McGee TL, Reichel E, et al. A point mutation of the rhodopsin gene m one form of retinitis pigmentosa. Nature 1990; 343: 364-66 3. Farrar GJ, Kenna P, Redmond R, et al Autosomal dominant retinitis pigmentosa. absence of the rhodopsin proline-histidine substitution (codon 23) in pedigrees from Europe. AmJ Hum Genet 1990; 47: 941-45. 4. Dryja TD, McGee TL, Hahn LB, et al. Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. N EnglJ Med 1990; 323: 1.
1302-07
Bhattacharya S, Lester D, Keen J, et al. Retinitis pigmentosa and mutations in rhodopsin. Lancet 1991; 337: 185. 6 Lester DH, Ingleheam CF, Bashir R, et al. Linkage to D3S47 (C17) in one large autosomal dominant retinitis pigmentosa family and exclusion in another: confirmation of genetic heterogeneity. Am J Hum Genet 1990; 47: 536-41. 7. Farrar GJ, McWilliam P, Bradley DG, et al. Autosomal dominant retinitis pigmentosa: linkage to rhodopsin and evidence for genetic heterogeneity. Genomics 5
1990; 8: 35-40.
Ceftazidime-resistant Klebsiella
pneumoniae SiR,—The incidence of Enterobacteriaceae with resistance to third-generation cephalosporins due to plasmid-mediated, expanded-spectrum p-lactamases (ESBL) may be underestimated. We report here three ceftazidime-resistant Klebsiella pneumoniae strains isolated in a London hospital during 1990. Case 1 (16, F; Guillain-Barre syndrome). She had been transferred from an Athens hospital. Her urine grew K pneumoniae (serotype K69) but antibiotics were not required during her 2-month hospital stay in London. Minimum inhibitory concentrations (MICs) were estimated on ’Isosensitest’ agar with an inoculum of 101 colony-forming units and aerobic incubation for 18 h. An MIC above 2 mg/1 is taken as indicating resistance to ceftazidime.1 The MIC of ceftazidime was 64 mg/l, falling to 0-25 mg/1 on addition of 2 mg/1 clavulanic acid, which inhibits ESBL. Case 2 (28, M; quadriplegia). He was admitted with urinary retention and fever. K pneumoniae (non-typable) was isolated from both urine and blood. The MIC of ceftazidime was 512 mg/1, reduced to 4 mg/1 by clavulanic acid. The strain was also resistant to gentamicin and netilmicin. He was successfully treated with intravenous amikacin after a lack of response to 24 h of intravenous cefotaxime 2 g three times daily. He had been an inpatient in two other London hospitals in the previous 5 years, with no history of foreign travel. Case 3 (17, M; neutropenia after bone-marrow transplantation for acute myeloid leukaemia). He became febrile a week after the graft (day 1) and the fever persisted despite empirical antibiotic therapy. K pneumoniae was isolated from blood culture on days 8, 12, and 15. By day 15 the MIC of ceftazidime was 32 mg/l, reduced by clavulanic acid to 1 mg/l. Imipenem 500 mg four times a day was started on day 15, the organism being sensitive by Stokes’ method, and he became apyrexial within 24 hours. On day 21 fever returned, with profound hypotension, and K pneumoniae was again isolated from blood culture. The MIC of ceftazidime was now 512 mg/1, reduced to 4 mg/1 by clavulanic acid. Doubling the dose of imipenem resulted in a second defervescence and a slow clinical recovery. All isolates were serotype K48.
1610
All patients were nursed in isolation and no secondary cases occurred. The klebsiella strains showed resistance to cefotaxime and aztreonam, and up to five further classes of antibiotics. Resistance to third-generation cephalosporins was successfully transferred to Escherichia coli J62 from the K pneumoniae strains from the first two cases, consistent with these ESBLs being plasmid-mediated; and plasmids of 60 and 70 MD, respectively, were found on agarose gel
electrophoresis. illustrate the possible origins of organisms producing ESBLs-namely, international transfer with the patient, inter-hospital transfer, and selection of the resistant strain within a hospital. Nosocomial outbreaks of ESBL-producing Enterobacteriaceae with multiple resistance2 to a range of antibiotic classes have occurred in Europe3,4 and the USA. The continued use of third-generation cephalosporins exerts substantial selection pressure in favour of ESBL-producing organisms and also for the evolutionof ESBLs. This, together with the introduction of similar oral cephalosporins, such as ceflxime, into the community, should prompt laboratory surveillance for such strains. We suggest a variation of the double-disc synergy test3 on isolates showing moderate resistance to cefotaxime. Should the use of thirdgeneration cephalosporins be restricted?7 These three
cases
We thank Dr T. L. Pitt, Central Public Health Laboratory, for serotyping the isolates, and Prof J. M. T. Hamilton-Miller and Dr S. H. Gillespie for advice and comments.
London NW3 2QG, UK
A. A. MACDONALD P. A. C. MAPLE C. C. KIBBLER
Division of Hospital Infection, Central Public Health Laboratory, London NW9
R. C. GEORGE A. P. JOHNSON
Department of Medical Microbiology, Edinburgh University Medical School
S. K. DU BOIS S. G. B. AMYES
Department of Medical Microbiology, Royal Free Hospital,
Working Party. In-vitro antibiotic sensitivity testing. J Antimicrob Chemother 1988; 21: 701-10. 2. Jacoby AJ, Sutton S. Properties of plasmids responsible for production of extended-spectrum beta-lactamases. Antimicrob Agents Chemother 1991; 35: 1 BSAC
164-69. 3. Sirot J, Chanal C, Pent A, Sirot D, Labia R, Gerband G. Klebsiella pneumoniae and other enterobacteriaceae producing novel plasmid-mediated beta-lactamases markedly active against third-generation cephalosporins: epidemiologic studies. Rev Infect Dis 1988; 10: 850-59. 4. Brun-Buisson C, Legrand P, Phillipon A, Montravers P, Ansquer M, Duval J. Transferable enzymatic resistance to third generation cephalosporins during a nosocomial outbreak of Klebsiella pneumoniae. Lancet 1987; ii: 302-06. 5. Rice LB, Willey SH, Papanicolaou GA, et al. Outbreak of ceftazidime resistance caused by extended-spectrum beta-lactamases at a Massachusetts chronic-care facility. Antimicrob Agents Chemother 1991; 34: 2193-99. 6. Collatz E, Labia R, Gutmann L. Molecular evolution of ubiquitous beta-lactamases towards extended-spectrum enzymes active against newer beta-lactam antibiotics. Mol Microbiol 1990; 4: 1615-20. 7. Payne DJ, Amyes SGB. Transferable resistance to extended-spectrum beta-lactams: a major threat or a minor inconvenience? JJ Antimicrob Chemother 1991; 27: 255-61.
In-vivo monitoring of neuronal loss in Creutzfeldt-Jakob disease by proton
magnetic
resonance
spectroscopy
SIR,-The advent of bovine spongiform encephalopathy has renewed interest in novel approaches to the clinical diagnosis of spongiform encephalopathies such as Creutzfetdt-Jakob disease (CJD). We have seen a case of sporadic CJD where the only magnetic resonance imaging abnormalities were mild cortical atrophy and hyperintensities in the lentiform nuclei, as noted previously.’ By contrast, proton magnetic resonance spectroscopy (MRS) demonstrated significant metabolic alterations in cortical grey matter and white matter and in striatum. Right frontal lobe biopsy, done 2 days after these scans, revealed fine vacuolation of the neuropil (spongiform change) in the deep grey-matter with a slight loss of neurons and gliosis, consistent with CJD. After a cold in August, 1990, a 53-year-old woman had difficulty sleeping and complained of dizziness. When cycling she found it hard to keep her balance. A neurologist noted trunk and gait ataxia and a tremor of her right thumb. By October she had become forgetful, had difficulty expressing herself, and her speech was
Fig 1-Localised proton MR spectra of parietal white-matter. Upper: Patient with CJD, exhibiting reduction of NAA and PCr/Crand increase in Ins. Lower control Major metabolites include N-acetylaspartate (NAA), glutamate (Glu), creatine (Cr), and phosphocreatine (PCr), choline-containing compounds (Cho), and myo-inositol (Ins). Volume of interest 12 ml
slurred. Nocturnal anxiety and paraspasticity ensued and she was admitted to hospital in November. Her ataxia worsened as did her memory. Paranoid-hallucinatory states required treatment with haloperidol for a week. In December a progressive left-sided spasticity developed. Dysarthria further impeded her speech and she became demented. CSF analysis revealed oligoclonal banding. EEGs revealed diffuse slow and a-range complexes with temporooccipital sharp wave 6 and 8-complexes. No 1-2 Hz periodic sharp wave complexes (PSWC) were seen. In February, 1991, the patient was in a coma and showed spontaneous myoclonus, predominantly in her right arm. An EEG showed PSWCs, supporting the diagnosis of CJD. In March localised proton MRS was done with 20 ms echo-time stimulated-echo sequences (2-0 T Siemens ’Magnetom’).3 Measuring times were 6-5 min with 128 accumulations and repetition times of 3 s. Fig 1 shows the proton MR spectrum of the left parietal white-matter of the patient, compared with that of a 56-year-old healthy female control. The N-acetylaspartate (NAA) peak was reduced (40%), as was the creatine/phosphocreatine ratio (10%); there was an increase in inositol (30%). Similar findings were observed contralaterally and in frontal white-matter except for slightly lower values of choline-containing compounds. Two volumes of interest in predominantly grey-matter were investigated in paramedian frontal and parietal locations; only NAA was diminished (30%) (fig 2). MRS in the hyperintense region of the striatum showed a fourfold loss of metabolites. The remaining metabolite pattern exhibited a further reduction of NAA relative to creatines and cholines.
words such as "You can be sure that I will be giving you all the results as soon as I receive them and I will tell you only the truth". Truth leads to trust. Touching leads to trust. Trust is never more critical than in the optimum managment of patients who have had to be given bad news. I would also emphasise the importance of never withholding the bad news from any mentally competent adult, no matter what advice may be received from relatives or others. Alan McGuinness
Gastroenterology Unit, Sydney Hospital, Sydney, NSW 2000, Australia
JOHN R. GRAHAM
Compliance and tuberculosis treatment SIR,-Your April 6 editorial (p 823) states that "Doctors no longer have the right-if, indeed, they ever had-to expect patients to comply with their advice, whether proscriptive or prescriptive". We strongly support this tenet; however, we suggest one major exception. Tuberculosis is spread almost exclusively by human-tohuman aerogenic transmission: when a patient with pulmonary disease coughs, he generates an aerosol containing tubercle bacilli which may then be inhaled by others. We contend that doctors have not only the right but also the obligation to see that the patient adheres to the prescription (chemotherapy) or the proscription (quarantine). On the premise that the tubercular patient potentially infringes the right of a citizen to be free of disease, laws throughout the US strictly constrain public access for patients with communicable (untreated) pulmonary tuberculosis. Failure on the part of physicians to be assertive in ensuring regular administration of antituberculosis medications has dire consequences: high rates of treatment failure/relapse, continued contagion, and acquired drug resistance. With the closure of sanatoria and the abolition of most specialised tuberculosis clinics, tuberculosis treatment in North America and Europe has been "mainstreamed" into the general health care system over the past three decades. Unfortunately, during this era non-compliance has become the major impediment to the successful treatment of these patients.1 A major element in this trend has been the laisser-faire policy represented by your editorial position on the care of these patients. Medication cannot be forced upon unwilling patients by the practitioner or the state; however, aggressive, large-scale programmes of directly observed or supervised therapy should be used for those proven to be or at high risk of being non-compliant with therapy. Every effort should be made to induce adherence to treatment-and if this cannot be accomplished and the patient(s) remain contagious, public agencies should be willing to quarantine such individuals. Although this always has been a defensible proposition, it is even more compelling in an era of HIV which has seen a substantial increase in tuberculosis case rates in many regions, including epidemics of multiply resistant disease in several locations in the United States. Clinical Mycobacteriology Service, Division of Infectious Diseases, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, USA, and University of Colorado School of Medicine
MICHAEL D. ISEMAN
University of Colorado School of Medicine, Denver, Colorado
JOHN A. SBARBARO
1. Fox W
Compliance of patients and physicians: experience and lessons from tuberculosis, I. Br MedJ 1983; 287: 33-35.
Frequency of rhodopsin codon 23 mutation and retinitis pigmentosa SIR,-Although those of us with an interest in retinitis pigmentosa (RP) welcome Dr Sorscher and Dr Huang’s description (May 11, p 1115) of a rapid method to detect a particular rhodopsin mutation, we feel that they make several misleading statements that should be clarified. Firstly, they state that the frequency of autosomal dominant RP (ADRP) in the general population is "about 1 in 3500". The prevalence of all types ofRP is indeed in this region, but the ADRP subgroup represents only 19-26% of the total, which includes autosomal recessive and X-linked forms as
as a sizeable sporadic group.l Secondly, Sorscher and Huang ambiguously state that the rhodopsin codon 23 mutation was seen in 17 of 148 individuals "with the disease"-referring to a series of unrelated ADRP patients of North American origin.2 It should be noted, however, that this point mutation was not found in ninety-one unrelated European ADRP families3 and that many other rhodopsin mutations have since been found in ADRP families.’*’’* A large number of ADRP families are unlinked to this region and therefore represent mutation(s) at other remote gene(s).6,7 We welcome the ingenious methods that Sorscher and Huang present for mutation detection, but they have unintentionally inflated both the frequency of ADRP and of the rhodopsin codon 23 mutation, which is responsible for the disease in a small proportion of RP patients.
well
MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK
DOUGLAS H. LESTER ALAN F. WRIGHT
Kaplan J, Bonneau D, Frezal J, et al. Clinical and genetic heterogeneity m retinitis pigmentosa. Hum Genet 1990; 85: 635-42. 2. Dryja TD, McGee TL, Reichel E, et al. A point mutation of the rhodopsin gene m one form of retinitis pigmentosa. Nature 1990; 343: 364-66 3. Farrar GJ, Kenna P, Redmond R, et al Autosomal dominant retinitis pigmentosa. absence of the rhodopsin proline-histidine substitution (codon 23) in pedigrees from Europe. AmJ Hum Genet 1990; 47: 941-45. 4. Dryja TD, McGee TL, Hahn LB, et al. Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. N EnglJ Med 1990; 323: 1.
1302-07
Bhattacharya S, Lester D, Keen J, et al. Retinitis pigmentosa and mutations in rhodopsin. Lancet 1991; 337: 185. 6 Lester DH, Ingleheam CF, Bashir R, et al. Linkage to D3S47 (C17) in one large autosomal dominant retinitis pigmentosa family and exclusion in another: confirmation of genetic heterogeneity. Am J Hum Genet 1990; 47: 536-41. 7. Farrar GJ, McWilliam P, Bradley DG, et al. Autosomal dominant retinitis pigmentosa: linkage to rhodopsin and evidence for genetic heterogeneity. Genomics 5
1990; 8: 35-40.
Ceftazidime-resistant Klebsiella
pneumoniae SiR,—The incidence of Enterobacteriaceae with resistance to third-generation cephalosporins due to plasmid-mediated, expanded-spectrum p-lactamases (ESBL) may be underestimated. We report here three ceftazidime-resistant Klebsiella pneumoniae strains isolated in a London hospital during 1990. Case 1 (16, F; Guillain-Barre syndrome). She had been transferred from an Athens hospital. Her urine grew K pneumoniae (serotype K69) but antibiotics were not required during her 2-month hospital stay in London. Minimum inhibitory concentrations (MICs) were estimated on ’Isosensitest’ agar with an inoculum of 101 colony-forming units and aerobic incubation for 18 h. An MIC above 2 mg/1 is taken as indicating resistance to ceftazidime.1 The MIC of ceftazidime was 64 mg/l, falling to 0-25 mg/1 on addition of 2 mg/1 clavulanic acid, which inhibits ESBL. Case 2 (28, M; quadriplegia). He was admitted with urinary retention and fever. K pneumoniae (non-typable) was isolated from both urine and blood. The MIC of ceftazidime was 512 mg/1, reduced to 4 mg/1 by clavulanic acid. The strain was also resistant to gentamicin and netilmicin. He was successfully treated with intravenous amikacin after a lack of response to 24 h of intravenous cefotaxime 2 g three times daily. He had been an inpatient in two other London hospitals in the previous 5 years, with no history of foreign travel. Case 3 (17, M; neutropenia after bone-marrow transplantation for acute myeloid leukaemia). He became febrile a week after the graft (day 1) and the fever persisted despite empirical antibiotic therapy. K pneumoniae was isolated from blood culture on days 8, 12, and 15. By day 15 the MIC of ceftazidime was 32 mg/l, reduced by clavulanic acid to 1 mg/l. Imipenem 500 mg four times a day was started on day 15, the organism being sensitive by Stokes’ method, and he became apyrexial within 24 hours. On day 21 fever returned, with profound hypotension, and K pneumoniae was again isolated from blood culture. The MIC of ceftazidime was now 512 mg/1, reduced to 4 mg/1 by clavulanic acid. Doubling the dose of imipenem resulted in a second defervescence and a slow clinical recovery. All isolates were serotype K48.
1610
All patients were nursed in isolation and no secondary cases occurred. The klebsiella strains showed resistance to cefotaxime and aztreonam, and up to five further classes of antibiotics. Resistance to third-generation cephalosporins was successfully transferred to Escherichia coli J62 from the K pneumoniae strains from the first two cases, consistent with these ESBLs being plasmid-mediated; and plasmids of 60 and 70 MD, respectively, were found on agarose gel
electrophoresis. illustrate the possible origins of organisms producing ESBLs-namely, international transfer with the patient, inter-hospital transfer, and selection of the resistant strain within a hospital. Nosocomial outbreaks of ESBL-producing Enterobacteriaceae with multiple resistance2 to a range of antibiotic classes have occurred in Europe3,4 and the USA. The continued use of third-generation cephalosporins exerts substantial selection pressure in favour of ESBL-producing organisms and also for the evolutionof ESBLs. This, together with the introduction of similar oral cephalosporins, such as ceflxime, into the community, should prompt laboratory surveillance for such strains. We suggest a variation of the double-disc synergy test3 on isolates showing moderate resistance to cefotaxime. Should the use of thirdgeneration cephalosporins be restricted?7 These three
cases
We thank Dr T. L. Pitt, Central Public Health Laboratory, for serotyping the isolates, and Prof J. M. T. Hamilton-Miller and Dr S. H. Gillespie for advice and comments.
London NW3 2QG, UK
A. A. MACDONALD P. A. C. MAPLE C. C. KIBBLER
Division of Hospital Infection, Central Public Health Laboratory, London NW9
R. C. GEORGE A. P. JOHNSON
Department of Medical Microbiology, Edinburgh University Medical School
S. K. DU BOIS S. G. B. AMYES
Department of Medical Microbiology, Royal Free Hospital,
Working Party. In-vitro antibiotic sensitivity testing. J Antimicrob Chemother 1988; 21: 701-10. 2. Jacoby AJ, Sutton S. Properties of plasmids responsible for production of extended-spectrum beta-lactamases. Antimicrob Agents Chemother 1991; 35: 1 BSAC
164-69. 3. Sirot J, Chanal C, Pent A, Sirot D, Labia R, Gerband G. Klebsiella pneumoniae and other enterobacteriaceae producing novel plasmid-mediated beta-lactamases markedly active against third-generation cephalosporins: epidemiologic studies. Rev Infect Dis 1988; 10: 850-59. 4. Brun-Buisson C, Legrand P, Phillipon A, Montravers P, Ansquer M, Duval J. Transferable enzymatic resistance to third generation cephalosporins during a nosocomial outbreak of Klebsiella pneumoniae. Lancet 1987; ii: 302-06. 5. Rice LB, Willey SH, Papanicolaou GA, et al. Outbreak of ceftazidime resistance caused by extended-spectrum beta-lactamases at a Massachusetts chronic-care facility. Antimicrob Agents Chemother 1991; 34: 2193-99. 6. Collatz E, Labia R, Gutmann L. Molecular evolution of ubiquitous beta-lactamases towards extended-spectrum enzymes active against newer beta-lactam antibiotics. Mol Microbiol 1990; 4: 1615-20. 7. Payne DJ, Amyes SGB. Transferable resistance to extended-spectrum beta-lactams: a major threat or a minor inconvenience? JJ Antimicrob Chemother 1991; 27: 255-61.
In-vivo monitoring of neuronal loss in Creutzfeldt-Jakob disease by proton
magnetic
resonance
spectroscopy
SIR,-The advent of bovine spongiform encephalopathy has renewed interest in novel approaches to the clinical diagnosis of spongiform encephalopathies such as Creutzfetdt-Jakob disease (CJD). We have seen a case of sporadic CJD where the only magnetic resonance imaging abnormalities were mild cortical atrophy and hyperintensities in the lentiform nuclei, as noted previously.’ By contrast, proton magnetic resonance spectroscopy (MRS) demonstrated significant metabolic alterations in cortical grey matter and white matter and in striatum. Right frontal lobe biopsy, done 2 days after these scans, revealed fine vacuolation of the neuropil (spongiform change) in the deep grey-matter with a slight loss of neurons and gliosis, consistent with CJD. After a cold in August, 1990, a 53-year-old woman had difficulty sleeping and complained of dizziness. When cycling she found it hard to keep her balance. A neurologist noted trunk and gait ataxia and a tremor of her right thumb. By October she had become forgetful, had difficulty expressing herself, and her speech was
Fig 1-Localised proton MR spectra of parietal white-matter. Upper: Patient with CJD, exhibiting reduction of NAA and PCr/Crand increase in Ins. Lower control Major metabolites include N-acetylaspartate (NAA), glutamate (Glu), creatine (Cr), and phosphocreatine (PCr), choline-containing compounds (Cho), and myo-inositol (Ins). Volume of interest 12 ml
slurred. Nocturnal anxiety and paraspasticity ensued and she was admitted to hospital in November. Her ataxia worsened as did her memory. Paranoid-hallucinatory states required treatment with haloperidol for a week. In December a progressive left-sided spasticity developed. Dysarthria further impeded her speech and she became demented. CSF analysis revealed oligoclonal banding. EEGs revealed diffuse slow and a-range complexes with temporooccipital sharp wave 6 and 8-complexes. No 1-2 Hz periodic sharp wave complexes (PSWC) were seen. In February, 1991, the patient was in a coma and showed spontaneous myoclonus, predominantly in her right arm. An EEG showed PSWCs, supporting the diagnosis of CJD. In March localised proton MRS was done with 20 ms echo-time stimulated-echo sequences (2-0 T Siemens ’Magnetom’).3 Measuring times were 6-5 min with 128 accumulations and repetition times of 3 s. Fig 1 shows the proton MR spectrum of the left parietal white-matter of the patient, compared with that of a 56-year-old healthy female control. The N-acetylaspartate (NAA) peak was reduced (40%), as was the creatine/phosphocreatine ratio (10%); there was an increase in inositol (30%). Similar findings were observed contralaterally and in frontal white-matter except for slightly lower values of choline-containing compounds. Two volumes of interest in predominantly grey-matter were investigated in paramedian frontal and parietal locations; only NAA was diminished (30%) (fig 2). MRS in the hyperintense region of the striatum showed a fourfold loss of metabolites. The remaining metabolite pattern exhibited a further reduction of NAA relative to creatines and cholines.
