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Injection of GABA-agonist into globus pallidus in patient with Parkinson's disease
RESEARCH LETTERS
Acarbose-induced hepatic injury Yoshinori Fujimoto, Motoyuki Ohhira, Naoyuki Miyokawa, Shigeru Kitamori, Yutaka Kohgo
Carrascosa and colleagues 1 described a patient with acarbose-induced hepatic injury. We report similar findings in three patients, in whom liver-biopsy samples were also taken. A 52-year-old woman with mild non-insulin-dependent diabetes mellitus (NIDDM) was given acarbose (200 mg daily) for 8 months in addition to an antihypertensive drug (cilazapril) and Chinese herbal medicine (tohki-shakuyakusan). She presented with excess wind and hepatomegaly. Her aspartate aminotransferase (AST) rose to 486 IU/L (normal range 10–30), alanine aminotransferase (ALT) to 907 IU/L (0–35), while her total bilirubin was normal at 11 mol/L (3–16). After discontinuation of acarbose and Chinese herbal medicine, AST and ALT had fallen to normal within 1 month. She was given acarbose (200 mg daily) again since systemic absorption of acarbose is limited to less than 1%2 and severe liver injury seemed unlikely with this drug. However, her serum aminotransferase activity rose again after 3 days (AST 338 IU/L, ALT 393 IU/L). Acarbose was stopped and her serum aminotransferase activity fell to within the normal range 10 days later. A 62-year-old woman with NIDDM had severe general fatigue, jaundice, and hepatomegaly with high aminotransferases (AST 1023 IU/L, ALT 1837 IU/L) and high total bilirubin (77 mol/L) after 2·5 months of acarbose (300 mg daily) administration. 1 month after
cessation of acarbose, transaminase activities all returned to normal. In addition, a 53-year-old woman with NIDDM had hepatomegaly without symptoms after 4 months of acarbose (300 mg daily). Her AST, ALT, and total bilirubin were 591 IU/L, 1189 IU/L, and 24 mol/L, respectively. 1 month later, after cessation of acarbose, AST had fallen to 56 IU/L and ALT to 123 IU/L. In all three patients serology for hepatitis B and C viruses was negative; PCR tests for hepatitis C and G viruses were negative; antibodies of immunoglobulin M class against hepatitis A virus, cytomegalovirus, and Epstein-Barr virus were negative; tests for antinuclear, antismooth muscle, and antimitochondrial antibodies were negative; serum iron and urine copper were normal; and abdominal ultrasonography showed only hepatomegaly. Liver biopsies were undertaken in the latter two patients; one sample was obtained 2 weeks after the onset of hepatomegaly (A), and the other was 1 month after the onset (B). As shown in the figure, both cases showed histological findings revealing mild infiltration of inflammatory cells, particularly lymphocytes, in all parts of the lobules and portal tracts, ceroid-containing macrophages and Councilman bodies among hepatocytes, liver-cell regeneration, and mild fibrosis in partial portal areas. It has been reported that injction of a high dose of acarbose into rats induced lysomal glycogen storage in the liver mimicking the cytological picture of Pompe’s disease. 3 However, we did not observe lysosomal glycogen accumulates. As the incidence of acarbose-induced liver injury is low and unpredictable, the category of liver injury seems to be idiosyncratic rather than intrinsic.4 Furthermore, these idiosyncratic reactions could be toxic-metabolic dependent rather than hypersensitivity-related, because the patients at the onset of liver injury had no symptoms of allergic reactions such as skin rash, fever, or arthralgia; the duration from the start of the drug therapy to the onset of the liver injury was relatively long; and liver biopsy specimens showed no granulomas and eosinophils. We suggest that serum aminotransferase activity should be regularly checked during acarbose treatment. 1 2 3
4
Carrascosa M, Pascual F, Aresti S. Acarbose-induced acute hepatotoxicity. Lancet 1997; 349: 698–99. Acarbose for diabetes mellitus. Med Lett 1996; 38: 9–10. Konishi Y, Hata Y, Fujimori K. Formation of glucogenosomes in rat liver induced by injection of acarbose, an ␣-glucosidase inhibitor. Acta Histochem Cytochem 1989; 22: 227–31. Lee MW. Drug induced hepatotoxicity. N Engl J Med 1995; 333: 1118–27.
Third Department of Internal Medicine (Y Fujimoto) and Department of Pathology, Asahikawa Medical College, Asahikawa 078, Japan; and Department of Internal Medicine, Obihiro City Hospital, Obihiro
Injection of GABA-agonist into globus pallidus in patient with Parkinson’s disease Richard D Penn, Jeffrey S Kroin, Andrea Reinkensmeyer, Daniel M Corcos
Histological findings of liver biopsy specimens (A and B) obtained from two patients with acarbose-induced hepatic injury Infiltration of inflammatory cells, but not granulomas or eosinophils, were observed in lobules and portal tracts. A⫻61·5, B⫻123.
340
Animal work in Parkinsonian models suggests that local inhibition produced by muscimol decreases the output of the globus pallidus to the thalamus and reduces rigidity and bradykinesias.1 After approval by the Rush Human Investigation Committee and the Food and Drug Administration, and with the patient’s informed consent, we injected muscimol into the internal portion of the globus pallidus (GPi) in a
THE LANCET • Vol 351 • January 31, 1998
RESEARCH LETTERS
Initial 0–10 s
B
Final 30–40 s
C 60
Peak amplitude (deg)
800 700 600 500 400 300 200 100 0
Peak amplitude (deg)
Peak velocity (deg/s)
A
50 40 30 20 10 0
60 50 40 30 20 10 0 st te e-
on si Le ol m ci us M
Pr
on si Le
st te e-
ol m ci us M
Pr
on si Le
st te e-
ol m ci us M
Pr
Movement speed and amplitude before and 20 min after muscimol injection, and then after a pallidotomy lesion Figure A shows an increase in velocity after muscimol injection and pallidotomy at both the first 10 s and the last 10 s of a 40 s trial. Figure B depicts amplitude changes that parallel the velocity changes. Figure C shows the increase in resting tremor amplitude with muscimol and then its ablation with pallidotomy.
54-year-old patient with Parkinson’s disease before a unilateral pallidotomy procedure. He was off medication and had bradykinesia, rigidity, and a mild rest tremor. The right GPi was localised on magnetic resonance imaging (MRI) and then mapped electrophysiologically with single-unit recording. 2,3 Then 2·5 g of muscimol in 2·5 L of normal saline was injected over 5 min into a point that was 2 mm above the lower boundary of the ventral posterior GPi. The figure shows the velocity (A) and amplitude (B) of left-side hand movements just before injection, 20 min after injection, and then after standard pallidotomy heat lesions of 75°C for 1 min in three contiguous locations over a 6 mm tract in the GPi (confirmed to be in the GPi on the postoperative scan). At baseline, the patient’s movements were slow and fatigued rapidly, and he had a mild resting tremor (C). No changes were seen until 10 min after the injection when the tremor increased and the patient felt his arm could move better. At 20 min, the patient’s movements increased in velocity and showed less fatigue. The increased tremor was still present. On examination, his rigidity and cogwheeling present at baseline had completely cleared, and the patient remarked spontaneously that he felt his arm was lighter and easier to move. After the pallidotomy, his velocity of movement improved further and fatigue was less; his tremor was abolished. Thus, two of the cardinal signs of parkinsonism can be reduced by local inhibition. Tremor increased, possibly due to the decrease in rigidity, or simply the variability that is known to occur due to stress. The pallidotomy subsequently abolished this tremor. It should be noted that the heat lesion covered a large area of the GPi and external GP and is not equivalent to the more localised pharmacological effects. Injection of muscimol may prove to be an effective way of confirming the GPi target for pallidotomy. It also points to new ways to treat neurological disease with localised parenchymal infusion of medication. Muscimol, given systemically at 5–10 g, causes sedation and other side-effects. 4 Locally in low g quantities, it produced no sedation or other central sideeffects and reduced two major symptoms of Parkinson’s disease. 1
2
3
4
Baron MS, Wichmann T, DeLong MR. Inactivation of the sensorimotor territory in the internal pallidum reverses parkinsonian signs in MPTP-treated monkeys. Soc Neurosci Abstr 1992; 18: 693. Baron MS, Vitek JL, Bakay RAE, et al. Treatment of advanced Parkinson’s disease by posterior GPi pallidotomy: 1-year results of a pilot study. Ann Neurol 1996; 40: 355–66. Shannon KM, Penn RD, Kroin JS, et al. Stereotactic pallidotomy for the treatment of Parkinson’s disease: efficacy and adverse effects at six months in 26 patients. Neurology (in press). Shoulson I, Goldblatt D, Charlton M, Joynt R. Huntingtons disease:
THE LANCET • Vol 351 • January 31, 1998
treatment with muscimol, a GABA-mimetic drug. Ann Neurol 1978; 4: 279–84. Departments of Neurosurgery (R D Penn), Occupational Therapy, and Neurological Sciences, Rush Medical College, Rush-Presbyterian-St Luke’s Medical Center, Chicago, IL 60612, USA (R D Penn); and School of Kinesiology and Department of Psychology, University of Illinois at Chicago
Chlamydia trachomatis detection and the menstrual cycle Patrick J Horner, Tessa Crowley, Jo Leece, Anthony Hughes, George Davey Smith, E Owen Caul
It has been reported that populations with a low prevalence of Chlamydia trachomatis infection contain a higher proportion of women with low infectious burdens and that such low infectious burdens will reduce the sensitivity of enzyme immunoassays (EIA) more than that of the ligase chain reaction (LCR), if used to detect C trachomatis in the community.1 We present data to suggest that this argument is potentially flawed and other considerations may be more important. We undertook a prospective study to determine whether menstrual-cycle variation influences C trachomatis detection using LCR, EIA, and direct immunofluoresence (DIF). Women were categorised into a higher or a lower prevalence group. Women with purulent cervical mucus, contact cervical bleeding, or who were contacts of men with non-gonococcal urethritis were categorised as high risk; otherwise they were defined as low risk. C trachomatis was detected with EIA (IDEIA, Dako Diagnostics Ltd) on a cervical swab; LCR (Abbott) on a cervical swab and a first catch urine (FCU) specimen, and DIF on a spun deposit from EIA cervical swab and the FCU specimen. The cold chain as specified for the LCR was maintained.2 These were undertaken blind to each other and to the clinical data. A combined gold standard “all chlamydia” was used, with a positive LCR or DIF result at either site considered positive and a patient only being considered negative if these tests were all negative. We studied women under 30 attending our department who had a regular menstrual cycle (28 [range 24–32] days). C trachomatis detection overall at the cervix (LCR and DIF) was associated with the phase of the cycle. Thus 25 of 168 (15%) were chlamydia-positive in weeks 1–3 compared with 18 of 65 (28%) in weeks 4+ (p=0·028). There were 224 women from whom both urine and cervical samples were available. 162 were in weeks 1–3 of the menstrual cycle, of whom 30 were menstruating, and 62 in weeks 4+. No significant cycle variation was observed using EIA (DIF-confirmed), 18 (11%) were positive in weeks 1–3, 11 (18%) were positive in weeks 4+ (p=0·18). For LCR of the cervix the corresponding values
341
Acarbose-induced hepatic injury Yoshinori Fujimoto, Motoyuki Ohhira, Naoyuki Miyokawa, Shigeru Kitamori, Yutaka Kohgo
Carrascosa and colleagues 1 described a patient with acarbose-induced hepatic injury. We report similar findings in three patients, in whom liver-biopsy samples were also taken. A 52-year-old woman with mild non-insulin-dependent diabetes mellitus (NIDDM) was given acarbose (200 mg daily) for 8 months in addition to an antihypertensive drug (cilazapril) and Chinese herbal medicine (tohki-shakuyakusan). She presented with excess wind and hepatomegaly. Her aspartate aminotransferase (AST) rose to 486 IU/L (normal range 10–30), alanine aminotransferase (ALT) to 907 IU/L (0–35), while her total bilirubin was normal at 11 mol/L (3–16). After discontinuation of acarbose and Chinese herbal medicine, AST and ALT had fallen to normal within 1 month. She was given acarbose (200 mg daily) again since systemic absorption of acarbose is limited to less than 1%2 and severe liver injury seemed unlikely with this drug. However, her serum aminotransferase activity rose again after 3 days (AST 338 IU/L, ALT 393 IU/L). Acarbose was stopped and her serum aminotransferase activity fell to within the normal range 10 days later. A 62-year-old woman with NIDDM had severe general fatigue, jaundice, and hepatomegaly with high aminotransferases (AST 1023 IU/L, ALT 1837 IU/L) and high total bilirubin (77 mol/L) after 2·5 months of acarbose (300 mg daily) administration. 1 month after
cessation of acarbose, transaminase activities all returned to normal. In addition, a 53-year-old woman with NIDDM had hepatomegaly without symptoms after 4 months of acarbose (300 mg daily). Her AST, ALT, and total bilirubin were 591 IU/L, 1189 IU/L, and 24 mol/L, respectively. 1 month later, after cessation of acarbose, AST had fallen to 56 IU/L and ALT to 123 IU/L. In all three patients serology for hepatitis B and C viruses was negative; PCR tests for hepatitis C and G viruses were negative; antibodies of immunoglobulin M class against hepatitis A virus, cytomegalovirus, and Epstein-Barr virus were negative; tests for antinuclear, antismooth muscle, and antimitochondrial antibodies were negative; serum iron and urine copper were normal; and abdominal ultrasonography showed only hepatomegaly. Liver biopsies were undertaken in the latter two patients; one sample was obtained 2 weeks after the onset of hepatomegaly (A), and the other was 1 month after the onset (B). As shown in the figure, both cases showed histological findings revealing mild infiltration of inflammatory cells, particularly lymphocytes, in all parts of the lobules and portal tracts, ceroid-containing macrophages and Councilman bodies among hepatocytes, liver-cell regeneration, and mild fibrosis in partial portal areas. It has been reported that injction of a high dose of acarbose into rats induced lysomal glycogen storage in the liver mimicking the cytological picture of Pompe’s disease. 3 However, we did not observe lysosomal glycogen accumulates. As the incidence of acarbose-induced liver injury is low and unpredictable, the category of liver injury seems to be idiosyncratic rather than intrinsic.4 Furthermore, these idiosyncratic reactions could be toxic-metabolic dependent rather than hypersensitivity-related, because the patients at the onset of liver injury had no symptoms of allergic reactions such as skin rash, fever, or arthralgia; the duration from the start of the drug therapy to the onset of the liver injury was relatively long; and liver biopsy specimens showed no granulomas and eosinophils. We suggest that serum aminotransferase activity should be regularly checked during acarbose treatment. 1 2 3
4
Carrascosa M, Pascual F, Aresti S. Acarbose-induced acute hepatotoxicity. Lancet 1997; 349: 698–99. Acarbose for diabetes mellitus. Med Lett 1996; 38: 9–10. Konishi Y, Hata Y, Fujimori K. Formation of glucogenosomes in rat liver induced by injection of acarbose, an ␣-glucosidase inhibitor. Acta Histochem Cytochem 1989; 22: 227–31. Lee MW. Drug induced hepatotoxicity. N Engl J Med 1995; 333: 1118–27.
Third Department of Internal Medicine (Y Fujimoto) and Department of Pathology, Asahikawa Medical College, Asahikawa 078, Japan; and Department of Internal Medicine, Obihiro City Hospital, Obihiro
Injection of GABA-agonist into globus pallidus in patient with Parkinson’s disease Richard D Penn, Jeffrey S Kroin, Andrea Reinkensmeyer, Daniel M Corcos
Histological findings of liver biopsy specimens (A and B) obtained from two patients with acarbose-induced hepatic injury Infiltration of inflammatory cells, but not granulomas or eosinophils, were observed in lobules and portal tracts. A⫻61·5, B⫻123.
340
Animal work in Parkinsonian models suggests that local inhibition produced by muscimol decreases the output of the globus pallidus to the thalamus and reduces rigidity and bradykinesias.1 After approval by the Rush Human Investigation Committee and the Food and Drug Administration, and with the patient’s informed consent, we injected muscimol into the internal portion of the globus pallidus (GPi) in a
THE LANCET • Vol 351 • January 31, 1998
RESEARCH LETTERS
Initial 0–10 s
B
Final 30–40 s
C 60
Peak amplitude (deg)
800 700 600 500 400 300 200 100 0
Peak amplitude (deg)
Peak velocity (deg/s)
A
50 40 30 20 10 0
60 50 40 30 20 10 0 st te e-
on si Le ol m ci us M
Pr
on si Le
st te e-
ol m ci us M
Pr
on si Le
st te e-
ol m ci us M
Pr
Movement speed and amplitude before and 20 min after muscimol injection, and then after a pallidotomy lesion Figure A shows an increase in velocity after muscimol injection and pallidotomy at both the first 10 s and the last 10 s of a 40 s trial. Figure B depicts amplitude changes that parallel the velocity changes. Figure C shows the increase in resting tremor amplitude with muscimol and then its ablation with pallidotomy.
54-year-old patient with Parkinson’s disease before a unilateral pallidotomy procedure. He was off medication and had bradykinesia, rigidity, and a mild rest tremor. The right GPi was localised on magnetic resonance imaging (MRI) and then mapped electrophysiologically with single-unit recording. 2,3 Then 2·5 g of muscimol in 2·5 L of normal saline was injected over 5 min into a point that was 2 mm above the lower boundary of the ventral posterior GPi. The figure shows the velocity (A) and amplitude (B) of left-side hand movements just before injection, 20 min after injection, and then after standard pallidotomy heat lesions of 75°C for 1 min in three contiguous locations over a 6 mm tract in the GPi (confirmed to be in the GPi on the postoperative scan). At baseline, the patient’s movements were slow and fatigued rapidly, and he had a mild resting tremor (C). No changes were seen until 10 min after the injection when the tremor increased and the patient felt his arm could move better. At 20 min, the patient’s movements increased in velocity and showed less fatigue. The increased tremor was still present. On examination, his rigidity and cogwheeling present at baseline had completely cleared, and the patient remarked spontaneously that he felt his arm was lighter and easier to move. After the pallidotomy, his velocity of movement improved further and fatigue was less; his tremor was abolished. Thus, two of the cardinal signs of parkinsonism can be reduced by local inhibition. Tremor increased, possibly due to the decrease in rigidity, or simply the variability that is known to occur due to stress. The pallidotomy subsequently abolished this tremor. It should be noted that the heat lesion covered a large area of the GPi and external GP and is not equivalent to the more localised pharmacological effects. Injection of muscimol may prove to be an effective way of confirming the GPi target for pallidotomy. It also points to new ways to treat neurological disease with localised parenchymal infusion of medication. Muscimol, given systemically at 5–10 g, causes sedation and other side-effects. 4 Locally in low g quantities, it produced no sedation or other central sideeffects and reduced two major symptoms of Parkinson’s disease. 1
2
3
4
Baron MS, Wichmann T, DeLong MR. Inactivation of the sensorimotor territory in the internal pallidum reverses parkinsonian signs in MPTP-treated monkeys. Soc Neurosci Abstr 1992; 18: 693. Baron MS, Vitek JL, Bakay RAE, et al. Treatment of advanced Parkinson’s disease by posterior GPi pallidotomy: 1-year results of a pilot study. Ann Neurol 1996; 40: 355–66. Shannon KM, Penn RD, Kroin JS, et al. Stereotactic pallidotomy for the treatment of Parkinson’s disease: efficacy and adverse effects at six months in 26 patients. Neurology (in press). Shoulson I, Goldblatt D, Charlton M, Joynt R. Huntingtons disease:
THE LANCET • Vol 351 • January 31, 1998
treatment with muscimol, a GABA-mimetic drug. Ann Neurol 1978; 4: 279–84. Departments of Neurosurgery (R D Penn), Occupational Therapy, and Neurological Sciences, Rush Medical College, Rush-Presbyterian-St Luke’s Medical Center, Chicago, IL 60612, USA (R D Penn); and School of Kinesiology and Department of Psychology, University of Illinois at Chicago
Chlamydia trachomatis detection and the menstrual cycle Patrick J Horner, Tessa Crowley, Jo Leece, Anthony Hughes, George Davey Smith, E Owen Caul
It has been reported that populations with a low prevalence of Chlamydia trachomatis infection contain a higher proportion of women with low infectious burdens and that such low infectious burdens will reduce the sensitivity of enzyme immunoassays (EIA) more than that of the ligase chain reaction (LCR), if used to detect C trachomatis in the community.1 We present data to suggest that this argument is potentially flawed and other considerations may be more important. We undertook a prospective study to determine whether menstrual-cycle variation influences C trachomatis detection using LCR, EIA, and direct immunofluoresence (DIF). Women were categorised into a higher or a lower prevalence group. Women with purulent cervical mucus, contact cervical bleeding, or who were contacts of men with non-gonococcal urethritis were categorised as high risk; otherwise they were defined as low risk. C trachomatis was detected with EIA (IDEIA, Dako Diagnostics Ltd) on a cervical swab; LCR (Abbott) on a cervical swab and a first catch urine (FCU) specimen, and DIF on a spun deposit from EIA cervical swab and the FCU specimen. The cold chain as specified for the LCR was maintained.2 These were undertaken blind to each other and to the clinical data. A combined gold standard “all chlamydia” was used, with a positive LCR or DIF result at either site considered positive and a patient only being considered negative if these tests were all negative. We studied women under 30 attending our department who had a regular menstrual cycle (28 [range 24–32] days). C trachomatis detection overall at the cervix (LCR and DIF) was associated with the phase of the cycle. Thus 25 of 168 (15%) were chlamydia-positive in weeks 1–3 compared with 18 of 65 (28%) in weeks 4+ (p=0·028). There were 224 women from whom both urine and cervical samples were available. 162 were in weeks 1–3 of the menstrual cycle, of whom 30 were menstruating, and 62 in weeks 4+. No significant cycle variation was observed using EIA (DIF-confirmed), 18 (11%) were positive in weeks 1–3, 11 (18%) were positive in weeks 4+ (p=0·18). For LCR of the cervix the corresponding values
341