- Email: [email protected]
Diverse CTXΦs and evolution of new pathogenic Vibrio cholerae
RESEARCH LETTERS
Temporal-lobe epilepsy associated with glutamic-acid-decarboxylase autoantibodies B Giometto, P Nicolao, M Macucci, B Tavolato, R Foxon, G F Bottazzo
A man aged 19 years, previously in good health with no history of febrile convulsions or head injury or family history of diabetes or other autoimmune disorders, suddenly developed complex partial seizures. The episodes occurred several times a day over the next 4 months. Routine blood analyses and neurological assessments were normal. Electroencephalography showed temporal and parietal spikes, and signal abnormalities were seen on magnetic-resonance images. Analysis of cerebrospinal fluid showed mild lymphocytic pleiocytosis (25/mm3), increased IgG intrathecal synthesis (IgG index 0·8; normal <0·7) and IgG oligoclonal bands, which confirmed acute encephalitis. PCR analysis for herpesvirus and antibodies, and antibodies to Epstein-Barr virus and to cytomegalovirus were negative in the serum and cerebrospinal fluid. Thoracic and abdominal computedtomography scans did not show tumours at 1 year follow-up. Multiple antiepileptic drugs were tried with no success, but transient remission (2 weeks) was obtained with methylprednisolone (1 g daily for 5 days). On 4% paraformaldehyde fixed rat cerebellum sections, the patient’s serum and cerebrospinal fluid stained typically glutamic acid decarboxylase (GAD)-rich producing neurons (titre 1:64 000 in serum; 1:1500 in the cerebrospinal fluid). Three serum samples of patients with Stiffman syndrome with GAD autoantibodies gave the same pattern. On western blot with human neuronal proteins, the serum recognised a 65 kDa-band equivalent to the molecular weight of GAD and was positive for human recombinant GAD65 by radioimmunoprecipitation (320 LH-u and 1100 LH-u in two samples taken 5 months apart). The serum samples also gave a selective staining on pancreatic islets, similar to that for sera which are positive only for GAD autoantibodies.1 The antibody-specificity index was 5·07, indicative of intrathecal synthesis of GAD autoantibodies. With the exception of antinuclear (1:1600 and 1:1280 diffuse pattern in two serum samples, respectively) and antidouble-stranded DNA (1:40) antibodies, no other islet-related, organ-specific and nonorgan-specific autoantibodies were detected. About 60% of patients with Stiffman syndrome possess GAD autoantibodies, but are at higher titre and with different GAD eiptope specificity, compared with the GAD autoantibodies of patients with type 1 diabetes.2 A proportion of patients with Stiffman syndrome with GAD autoantibodies have type 1 diabetes and other organ-specific autoimmunity. Such patients are usually females, but our patient was a male with no other islet-related or organ-specific antibodies (only antinuclear antibodies were found). GAD autoantibodies have also been described in patients with cerebellar ataxia3 and in a case with palatal myoclonus and epilepsy.4 Whether GAD autoantibodies contribute to the pathogenesis of these disorders remains to be fully substantiated, but the beneficial effects of plasmapheresis in Stiffman syndrome is notable.5 We have shown that an autoimmune temporal-lobe epilepsy could be associated with GAD autoantibodies. We recommend testing for the presence of GAD autoantibodies in patients with drug-refractory temporal-lobe epilepsy (15–20% of all epilepsy cases) to identify a potentially treatable subgroup, as in Stiffman syndrome. Further studies, including the characterisation of immunodominant epitope(s) on the GAD molecule, are needed to identify the neurological manifestations in patients with GAD autoantibodies.
THE LANCET • Vol 352 • August 8, 1998
1
2
3
4
5
Genovese S, Bonifacio E, McNally JM, et al. Distinct cytplasmic islet cell antibodies with different risks for Type I (insulin dependent) diabetes mellitus. Diabetologia 1992; 35: 385–38. Sepe V, Lai M, Shattock M, Foxon R, Collins P, Bottazzo GF. Isletrelated autoantigens and the pathogenesis of insulin-dependent diabetes mellitus: a 1996 update. In: Leslie RDG, ed. Molecular pathogenesis of diabetes mellitus. Basel: Karger 1997; 22: 68–89. Giometto B, Miotto D, Faresin F, Argentiero V, Scaravilli T, Tavolato B. Anti-GABAergic neuron autoantibodies in a patient with stiff-man syndrome and ataxia. J Neurol Sci 1996; 143: 57–59. Nemni R, Braghi S, Natali-Sora MG, et al. Autoantibodies to glutamic acid decarboxylase in palatal myoclonus and epilepsy. Ann Neurol 1994; 36: 665–67. Brashear RH, Phillips LH. Autoantibodies to GABAergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology 1991; 41: 1588–92.
Department of Neurology and Psychiatry (Second Clinic), University of Padua, Padua 35128, Italy (B Giometto); Service of Neurology, Empoli, Italy; and Department of Immunology, St Bartholomew’s and the Royal London School of Medicine and Dentistry, London, UK
Diverse CTXs and evolution of new pathogenic Vibrio cholerae Harvey H Kimsey, G Balakrish Nair, Amit Ghosh, Matthew K Waldor
Toxigenic Vibrio cholerae O139 Bengal emerged in late 1992 in southern India as the first non-O1 cause of epidemic cholera, and rapidly became the main cause of cholera on the Indian subcontinent.1 Despite the initial explosive spread of V cholerae O139, by 1994 the incidence of O139 Bengal cholera had declined and the El Tor biotype of V cholerae O1 once again became the predominant cause of cholera in this region.2 In August, 1996, after nearly 3 years, V cholerae O139 reemerged as the main cause of cholera in Calcutta.2 The genes encoding cholera toxin (ctxAB), the principal virulence factor of V cholerae, are part of a larger genetic element originally termed the CTX element.3 This element is subdivided into an RS region, which encodes a site-specific integration system, and a core region that encodes ctxAB as well as five other genes.3 The V cholerae chromosome commonly harbours tandem duplications of the RS region or of the entire CTX element.3 The re-emerged O139 strains (designated O139 Calcutta) are genetically similar to O139 Bengal,2 however, DNA hybridisation studies showed that the O139 Calcutta chromosome contains two tandemly arranged copies of a CTX element with a unique restrictionendonuclease map, as well as one copy of the El Tor-type CTX element.2 We showed that the CTX element corresponds to the genome of CTX, an integrated bacteriophage.3 Our recent experiments defining DNA sequence and functional differences between the CTX prophages found in classical and El Tor biotype V cholerae O1 strains suggested a molecular explanation for the novel restriction sites in the O139 Calcutta CTX element. We found that the DNA sequences of the classical and El Tor CTX repressors and their cognate operators are highly diverged, whereas the sequences that surround this phage immunity region are nearly identical.4 Similar to the molecular basis for heteroimmunity among lambdoid phages, the specificity of CTX immunity is based on the divergence of the sequences of repressors and their operators.4 To test whether the novel restriction sites present in the O139 Calcutta CTX element correspond to another divergent CTX immunity region, we sequenced this region from an O139 Calcutta and an O139 Bengal strain. Although the DNA sequences adjacent to the immunity region of the O139 Calcutta CTX element were nearly identical to the corresponding El Tor O1 sequences, the sequence of the O139 Calcutta immunity region differed greatly from the sequences of the El Tor and classical CTX
457
RESEARCH LETTERS 5
Waldor MK, Mekalanos JJ. Emergence of a new choldera pandemic: molecular analysis of virulence determinants in Vibrio cholerae O139 and development of a live vaccine prototype. J Infect Dis 1994; 170: 278–83.
Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, 750 Washington Street, Boston MA 02111, USA (M K Waldor); National Institute of Cholera and Enteric Disease, Calcutta, India and Institute of Microbial Technology, Chandigarah (e-mail: [email protected])
Overlooking orthostatic hypotension with routine blood-pressure equipment S E Caine, K Alsop, M Mac Mahon
Comparison of DNA sequences of RS regions of O139 Calcutta and El Tor CTX prophages A=Schematic representation of CTX prophages (long arrows) and associated RS regions (short arrows) in El Tor strain E7946,3 O139 Bengal strain, MO105 and O139 Calcutta strain AS207.2 In CTX prophages core regions are white and RS regions are grey or black. Conserved (X =XbaI, P=Pst I) and divergent (B=Bg lII, H=HindIII) restriction sites are shown. Arrowheads represent PCR primers used to amplify O139 Calcutta CTX prophage RS region. B=% DNA sequence identity of indicated regions between E7946 and AS207.
prophage immunity regions (figure). The DNA sequence of the O139 Calcutta immunity region contained all of the reported novel restriction sites in the O139 Calcutta CTX element. The DNA sequence of the O139 Bengal immunity region was identical to the El Tor O1 immunity region, suggesting, in accord with previous restriction maps,5 that this strain harbours the El Tor-type CTX prophage. Our DNA-sequence analysis showed that O139 Calcutta harbours an El-Tor-type CTX prophage (CTXImmEl Tor), as well as a unique O139 Calcutta prophage (CTXImm Calcutta) that is distinct from CTXImm El Tor, primarily because it harbours a novel immunity region. This suggests that O139 Calcutta arose either by CTXImm Calcutta infection of a non-immune O139 CTXImm El Tor lysogen, or conversely by CTXImm El Tor infection of a non-immune O139 CTXImm Calcutta lysogen. Alternatively, recombination in a toxigenic O139 strain harbouring a resident El Tor-type CTX prophage and a superinfecting (heteroimmune) non-toxigenic phage containing the Calcutta immunity region could have given rise to the newly emerged V cholerae O139 Calcutta. In either case, this DNA sequence analysis illustrates the continuing importance of phage-mediated horizontal gene transfer in the evolution of new pathogens. Diverse (heteroimmune) CTXs may establish the basis for the rapid evolution of new pathogenic variants of V cholerae. Given the striking temporal association of the novel O139 Calcutta CTX immunity region with the re-emergence of V cholerae O139, an assessment of the contribution of this new phage immunity cassette in the re-emergence of V cholerae O139 is warranted. We thank M Bennish, G Keusch, and A Camilli for reviewing this paper. This work was supported by NIH AI42347 and the Tupper Research Fund. 1
2
3 4
Cholera Working Group. Large epidemic of cholera-like disease in Bangladesh caused by Vibrio cholerae O139 synonym Bengal. Lancet 1993; 342: 387–90. Sharma C, Maiti S, Mukhopadhyay AK, et al. Unique organization of the CTX genetic element in Vibrio cholerae O139 strains which reemerged in Calcutta, India, in September 1996. J Clin Microbiol 1997; 95: 3348–50. Waldor MK, Mekalanos JJ. Lysogenic conversion by a filamentous phage encoding cholera toxin Science 1996; 272: 1910–14. Kimsey H, Waldor MK. CT immunity: application in the development of cholera vaccines. Proc Natl Acad Sci USA 1998; 95: 7035–39.
458
Sudden drops in blood pressure (BP) are responsible for many unexplained falls and drop attacks in the elderly. Treatment of neurogenic orthostatic hypotension can relieve symptoms and improve orthostatic tolerance.1 Although the sphygmomanometer and Dinamap are the most frequently used instruments to diagnose orthostatic hypotension, their validity has not been previously studied. We examined 80 consecutive patients referred with unexplained falls for orthostatic hypotension with the gold standard method (digital photoplethysmography; 2300 Finapres, Ohmeda) and compared the results with simultaneous sphygmomanometer and Dinamap (Critikon 8100) measurements. Those with atrial fibillation were excluded and the person using the sphygmomanometer and Dinamap was blinded to Finapres readings. Orthostatic hypotension was defined as a drop in systolic BP of more than 20 mm Hg within 2 min of standing up. Of the 80 patients, 45% reported synacope in the previous 6 months and 56% had been injured as a result. Orthostatic hypotension was detected in 60 (75%) with Finapres, of whom the majority were missed using other methods (table). We then examined if these methods could detect larger drops in BP and found that the sphygmomanometer and Dinamap readings were normal in 75% and 68%, respectively, of those with Finapres BP drops of more than 40 mm Hg. With a diagnostic criterion of a more than 5 mm Hg drop in BP for the sphygmomanometer and Dinamap, compared with the Finapres 20 mm Hg drop, sensitivities of both instruments improved substantially (table). Our results suggest that orthostatic hypotension is being overlooked in most patients tested with routine BP equipment. With these devices, there is usually a delay of at least 30 s before a BP reading is obtained, whilst Finapres records immediate and continuous changes in BP in response to change of posture. Routine BP equipment is not adequate to diagnose orthostatic hypotension and our results suggest that any drop in BP with these devices should raise the suspicion of orthostatic hypotension. 1
2
Low P A, Gilden JL, Freeman R, Sheng K-N, McElligott MA. Efficiacy of midodrine versus placebo in neurogenic orthostatic hypotension: randomised, double-blind multicenter study. JAMA 1997; 277: 1013–96. Imholz BPM, Wieling W, Langewouters GJ, van Montfrans GA. Continuous finger arterial pressure measurement: utility in the cardiovascular laboratory. Clin Autonom Res 1991; 1: 45–53.
Department of Medicine for the Elderly, Bristol Royal Infirmary, Bristol, BS2 8HW, UK (M Mac Mahon) Sensitivity
Specificity
More than 20 mm Hg drop in systolic BP Sphygmomanometer Dinamap
25% 37%
90% 92%
More than 5 mm Hg drop in systolic BP Sphygmomanometer Dinamap
69% 75%
64% 53%
BP measurements in diagnosis of orthostatic hypotension
THE LANCET • Vol 352 • August 8, 1998
Temporal-lobe epilepsy associated with glutamic-acid-decarboxylase autoantibodies B Giometto, P Nicolao, M Macucci, B Tavolato, R Foxon, G F Bottazzo
A man aged 19 years, previously in good health with no history of febrile convulsions or head injury or family history of diabetes or other autoimmune disorders, suddenly developed complex partial seizures. The episodes occurred several times a day over the next 4 months. Routine blood analyses and neurological assessments were normal. Electroencephalography showed temporal and parietal spikes, and signal abnormalities were seen on magnetic-resonance images. Analysis of cerebrospinal fluid showed mild lymphocytic pleiocytosis (25/mm3), increased IgG intrathecal synthesis (IgG index 0·8; normal <0·7) and IgG oligoclonal bands, which confirmed acute encephalitis. PCR analysis for herpesvirus and antibodies, and antibodies to Epstein-Barr virus and to cytomegalovirus were negative in the serum and cerebrospinal fluid. Thoracic and abdominal computedtomography scans did not show tumours at 1 year follow-up. Multiple antiepileptic drugs were tried with no success, but transient remission (2 weeks) was obtained with methylprednisolone (1 g daily for 5 days). On 4% paraformaldehyde fixed rat cerebellum sections, the patient’s serum and cerebrospinal fluid stained typically glutamic acid decarboxylase (GAD)-rich producing neurons (titre 1:64 000 in serum; 1:1500 in the cerebrospinal fluid). Three serum samples of patients with Stiffman syndrome with GAD autoantibodies gave the same pattern. On western blot with human neuronal proteins, the serum recognised a 65 kDa-band equivalent to the molecular weight of GAD and was positive for human recombinant GAD65 by radioimmunoprecipitation (320 LH-u and 1100 LH-u in two samples taken 5 months apart). The serum samples also gave a selective staining on pancreatic islets, similar to that for sera which are positive only for GAD autoantibodies.1 The antibody-specificity index was 5·07, indicative of intrathecal synthesis of GAD autoantibodies. With the exception of antinuclear (1:1600 and 1:1280 diffuse pattern in two serum samples, respectively) and antidouble-stranded DNA (1:40) antibodies, no other islet-related, organ-specific and nonorgan-specific autoantibodies were detected. About 60% of patients with Stiffman syndrome possess GAD autoantibodies, but are at higher titre and with different GAD eiptope specificity, compared with the GAD autoantibodies of patients with type 1 diabetes.2 A proportion of patients with Stiffman syndrome with GAD autoantibodies have type 1 diabetes and other organ-specific autoimmunity. Such patients are usually females, but our patient was a male with no other islet-related or organ-specific antibodies (only antinuclear antibodies were found). GAD autoantibodies have also been described in patients with cerebellar ataxia3 and in a case with palatal myoclonus and epilepsy.4 Whether GAD autoantibodies contribute to the pathogenesis of these disorders remains to be fully substantiated, but the beneficial effects of plasmapheresis in Stiffman syndrome is notable.5 We have shown that an autoimmune temporal-lobe epilepsy could be associated with GAD autoantibodies. We recommend testing for the presence of GAD autoantibodies in patients with drug-refractory temporal-lobe epilepsy (15–20% of all epilepsy cases) to identify a potentially treatable subgroup, as in Stiffman syndrome. Further studies, including the characterisation of immunodominant epitope(s) on the GAD molecule, are needed to identify the neurological manifestations in patients with GAD autoantibodies.
THE LANCET • Vol 352 • August 8, 1998
1
2
3
4
5
Genovese S, Bonifacio E, McNally JM, et al. Distinct cytplasmic islet cell antibodies with different risks for Type I (insulin dependent) diabetes mellitus. Diabetologia 1992; 35: 385–38. Sepe V, Lai M, Shattock M, Foxon R, Collins P, Bottazzo GF. Isletrelated autoantigens and the pathogenesis of insulin-dependent diabetes mellitus: a 1996 update. In: Leslie RDG, ed. Molecular pathogenesis of diabetes mellitus. Basel: Karger 1997; 22: 68–89. Giometto B, Miotto D, Faresin F, Argentiero V, Scaravilli T, Tavolato B. Anti-GABAergic neuron autoantibodies in a patient with stiff-man syndrome and ataxia. J Neurol Sci 1996; 143: 57–59. Nemni R, Braghi S, Natali-Sora MG, et al. Autoantibodies to glutamic acid decarboxylase in palatal myoclonus and epilepsy. Ann Neurol 1994; 36: 665–67. Brashear RH, Phillips LH. Autoantibodies to GABAergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology 1991; 41: 1588–92.
Department of Neurology and Psychiatry (Second Clinic), University of Padua, Padua 35128, Italy (B Giometto); Service of Neurology, Empoli, Italy; and Department of Immunology, St Bartholomew’s and the Royal London School of Medicine and Dentistry, London, UK
Diverse CTXs and evolution of new pathogenic Vibrio cholerae Harvey H Kimsey, G Balakrish Nair, Amit Ghosh, Matthew K Waldor
Toxigenic Vibrio cholerae O139 Bengal emerged in late 1992 in southern India as the first non-O1 cause of epidemic cholera, and rapidly became the main cause of cholera on the Indian subcontinent.1 Despite the initial explosive spread of V cholerae O139, by 1994 the incidence of O139 Bengal cholera had declined and the El Tor biotype of V cholerae O1 once again became the predominant cause of cholera in this region.2 In August, 1996, after nearly 3 years, V cholerae O139 reemerged as the main cause of cholera in Calcutta.2 The genes encoding cholera toxin (ctxAB), the principal virulence factor of V cholerae, are part of a larger genetic element originally termed the CTX element.3 This element is subdivided into an RS region, which encodes a site-specific integration system, and a core region that encodes ctxAB as well as five other genes.3 The V cholerae chromosome commonly harbours tandem duplications of the RS region or of the entire CTX element.3 The re-emerged O139 strains (designated O139 Calcutta) are genetically similar to O139 Bengal,2 however, DNA hybridisation studies showed that the O139 Calcutta chromosome contains two tandemly arranged copies of a CTX element with a unique restrictionendonuclease map, as well as one copy of the El Tor-type CTX element.2 We showed that the CTX element corresponds to the genome of CTX, an integrated bacteriophage.3 Our recent experiments defining DNA sequence and functional differences between the CTX prophages found in classical and El Tor biotype V cholerae O1 strains suggested a molecular explanation for the novel restriction sites in the O139 Calcutta CTX element. We found that the DNA sequences of the classical and El Tor CTX repressors and their cognate operators are highly diverged, whereas the sequences that surround this phage immunity region are nearly identical.4 Similar to the molecular basis for heteroimmunity among lambdoid phages, the specificity of CTX immunity is based on the divergence of the sequences of repressors and their operators.4 To test whether the novel restriction sites present in the O139 Calcutta CTX element correspond to another divergent CTX immunity region, we sequenced this region from an O139 Calcutta and an O139 Bengal strain. Although the DNA sequences adjacent to the immunity region of the O139 Calcutta CTX element were nearly identical to the corresponding El Tor O1 sequences, the sequence of the O139 Calcutta immunity region differed greatly from the sequences of the El Tor and classical CTX
457
RESEARCH LETTERS 5
Waldor MK, Mekalanos JJ. Emergence of a new choldera pandemic: molecular analysis of virulence determinants in Vibrio cholerae O139 and development of a live vaccine prototype. J Infect Dis 1994; 170: 278–83.
Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, 750 Washington Street, Boston MA 02111, USA (M K Waldor); National Institute of Cholera and Enteric Disease, Calcutta, India and Institute of Microbial Technology, Chandigarah (e-mail: [email protected])
Overlooking orthostatic hypotension with routine blood-pressure equipment S E Caine, K Alsop, M Mac Mahon
Comparison of DNA sequences of RS regions of O139 Calcutta and El Tor CTX prophages A=Schematic representation of CTX prophages (long arrows) and associated RS regions (short arrows) in El Tor strain E7946,3 O139 Bengal strain, MO105 and O139 Calcutta strain AS207.2 In CTX prophages core regions are white and RS regions are grey or black. Conserved (X =XbaI, P=Pst I) and divergent (B=Bg lII, H=HindIII) restriction sites are shown. Arrowheads represent PCR primers used to amplify O139 Calcutta CTX prophage RS region. B=% DNA sequence identity of indicated regions between E7946 and AS207.
prophage immunity regions (figure). The DNA sequence of the O139 Calcutta immunity region contained all of the reported novel restriction sites in the O139 Calcutta CTX element. The DNA sequence of the O139 Bengal immunity region was identical to the El Tor O1 immunity region, suggesting, in accord with previous restriction maps,5 that this strain harbours the El Tor-type CTX prophage. Our DNA-sequence analysis showed that O139 Calcutta harbours an El-Tor-type CTX prophage (CTXImmEl Tor), as well as a unique O139 Calcutta prophage (CTXImm Calcutta) that is distinct from CTXImm El Tor, primarily because it harbours a novel immunity region. This suggests that O139 Calcutta arose either by CTXImm Calcutta infection of a non-immune O139 CTXImm El Tor lysogen, or conversely by CTXImm El Tor infection of a non-immune O139 CTXImm Calcutta lysogen. Alternatively, recombination in a toxigenic O139 strain harbouring a resident El Tor-type CTX prophage and a superinfecting (heteroimmune) non-toxigenic phage containing the Calcutta immunity region could have given rise to the newly emerged V cholerae O139 Calcutta. In either case, this DNA sequence analysis illustrates the continuing importance of phage-mediated horizontal gene transfer in the evolution of new pathogens. Diverse (heteroimmune) CTXs may establish the basis for the rapid evolution of new pathogenic variants of V cholerae. Given the striking temporal association of the novel O139 Calcutta CTX immunity region with the re-emergence of V cholerae O139, an assessment of the contribution of this new phage immunity cassette in the re-emergence of V cholerae O139 is warranted. We thank M Bennish, G Keusch, and A Camilli for reviewing this paper. This work was supported by NIH AI42347 and the Tupper Research Fund. 1
2
3 4
Cholera Working Group. Large epidemic of cholera-like disease in Bangladesh caused by Vibrio cholerae O139 synonym Bengal. Lancet 1993; 342: 387–90. Sharma C, Maiti S, Mukhopadhyay AK, et al. Unique organization of the CTX genetic element in Vibrio cholerae O139 strains which reemerged in Calcutta, India, in September 1996. J Clin Microbiol 1997; 95: 3348–50. Waldor MK, Mekalanos JJ. Lysogenic conversion by a filamentous phage encoding cholera toxin Science 1996; 272: 1910–14. Kimsey H, Waldor MK. CT immunity: application in the development of cholera vaccines. Proc Natl Acad Sci USA 1998; 95: 7035–39.
458
Sudden drops in blood pressure (BP) are responsible for many unexplained falls and drop attacks in the elderly. Treatment of neurogenic orthostatic hypotension can relieve symptoms and improve orthostatic tolerance.1 Although the sphygmomanometer and Dinamap are the most frequently used instruments to diagnose orthostatic hypotension, their validity has not been previously studied. We examined 80 consecutive patients referred with unexplained falls for orthostatic hypotension with the gold standard method (digital photoplethysmography; 2300 Finapres, Ohmeda) and compared the results with simultaneous sphygmomanometer and Dinamap (Critikon 8100) measurements. Those with atrial fibillation were excluded and the person using the sphygmomanometer and Dinamap was blinded to Finapres readings. Orthostatic hypotension was defined as a drop in systolic BP of more than 20 mm Hg within 2 min of standing up. Of the 80 patients, 45% reported synacope in the previous 6 months and 56% had been injured as a result. Orthostatic hypotension was detected in 60 (75%) with Finapres, of whom the majority were missed using other methods (table). We then examined if these methods could detect larger drops in BP and found that the sphygmomanometer and Dinamap readings were normal in 75% and 68%, respectively, of those with Finapres BP drops of more than 40 mm Hg. With a diagnostic criterion of a more than 5 mm Hg drop in BP for the sphygmomanometer and Dinamap, compared with the Finapres 20 mm Hg drop, sensitivities of both instruments improved substantially (table). Our results suggest that orthostatic hypotension is being overlooked in most patients tested with routine BP equipment. With these devices, there is usually a delay of at least 30 s before a BP reading is obtained, whilst Finapres records immediate and continuous changes in BP in response to change of posture. Routine BP equipment is not adequate to diagnose orthostatic hypotension and our results suggest that any drop in BP with these devices should raise the suspicion of orthostatic hypotension. 1
2
Low P A, Gilden JL, Freeman R, Sheng K-N, McElligott MA. Efficiacy of midodrine versus placebo in neurogenic orthostatic hypotension: randomised, double-blind multicenter study. JAMA 1997; 277: 1013–96. Imholz BPM, Wieling W, Langewouters GJ, van Montfrans GA. Continuous finger arterial pressure measurement: utility in the cardiovascular laboratory. Clin Autonom Res 1991; 1: 45–53.
Department of Medicine for the Elderly, Bristol Royal Infirmary, Bristol, BS2 8HW, UK (M Mac Mahon) Sensitivity
Specificity
More than 20 mm Hg drop in systolic BP Sphygmomanometer Dinamap
25% 37%
90% 92%
More than 5 mm Hg drop in systolic BP Sphygmomanometer Dinamap
69% 75%
64% 53%
BP measurements in diagnosis of orthostatic hypotension
THE LANCET • Vol 352 • August 8, 1998