- Email: [email protected]
Ciprofloxacin for treatment of malakoplakia
148
Hendry BM, Ellory JC. Effects of dialysis and transplantation on red cell Na pump function in renal failure. Nephron
3. Fervenza FC,
1989; 53: 121-28. 4. Fervenza FC, Meredith D, Ellory JC, Hendry BM. A study of the membrane transport of aminoacids in erythrocytes from patients on haemodialysis. Nephrol Dial Transplant 1990; 5: 594-99. 5. Fervenza FC. Meredith D, Ellory JC, Hendry BM. Abnormal erythrocyte choline transport in patients with chronic renal failure. Clin Sci 1991; 80: 137-41. 6. Zeisel SH, Costa K, Franklin PD, et al. Choline, an essential nutrient for humans. FASEB J 1991; 5: 2093-98. 7. Martin K. Choline transport in red cells. In: Ellory JC, Lew VL, eds. Membrane transport in red cells. London: Academic Press, 1977: 101-13. 8. Deves R, Krupka RM. The binding and translocation steps in transport as related to substrate structure: a study of the choline carrier of erythrocytes. Biochim Biophys Acta 1979; 557: 469-85. 9. Edmondson RPS, Hilton PJ, Jones NF, Patrick J, Thomas RD. Leucocyte sodium transport in uraemia. Clin Sci 1975; 49: 213-22. 10. Cotton JR, Woodard T, Carter NW, Knochel JP. Resting skeletal muscle membrane potential as an index of uremic toxicity. J Clin Invest 1979; 63: 501-06.
11. Ruiz P, Gomez F, Schreiber AD. Impaired function of macrophage Fc&ggr; receptors in end-stage renal disease. N Engl J Med 1990; 322: 717-22. 12. Cole CH, Balfe JW, Welt LG. Induction of an ouabain-sensitive ATPase defect by uremic plasma. Trans Assoc Am Phys 1968; 81: 213-20. 13. Graves SW, Brown B, Valdes R. An endogenous digitalis-like substance in patients with renal impairment. Ann Intern Med 1983; 99: 604-09. 14. Kelly RA, Canessa ML, Steinman TI, Mitch WE. Hemodialysis and red cell cation transport in uremia: role of membrane free fatty adds. Kidney Int 1989; 35: 595-603. 15. Estrada C, Bready J, Berliner J, Cancilla PA. Choline uptake by cerebral capillary endothelial cells in culture. J Neurochem 1990; 54: 1467-73. 16. Deves R, Reyes G, Krupka RM. The carrier reorientation step in erythrocyte choline transport: pH effects and the involvement of a carrier ionizing group. J Membrane Biol 1986; 93: 165-75. 17. Ancelin ML, Parant M, Thuet MJ, Philippot JR, Vial HJ. Increased permeability to choline in simian erythrocytes after Plasmodium knowlesi infection. Biochem J 1991; 273: 701-09. 18. Kirk K, Wong HY, Elford BC, Newbold CI, Ellory JC. Enhanced choline and Rb transport in human erythrocytes infected with the malaria parasite Plasmodium falciparum. Biochem J 1991; 278: 521-25.
SHORT REPORTS Ciprofloxacin for treatment of malakoplakia
Treatment of malakoplakia usually aims to improve macrophage function, by means of cholinergic agonists (eg, bethanechol),3 and to eliminate bacteria with antimicrobial drugs. Cholinergic agonists raise intracellular cyclic GMP concentrations,4which in turn stimulates synthesis of
factor; the latter enhances the microbicidal macrophages (unpublished). Such regimens rarely produce a sustained response, however, and the lesions continue to progress slowly. Failure of antimicrobial therapy could be due to poor penetration of the drug into the macrophages or its low activity in the phagolysosomes of the cells.6 Cure of malakoplakia by long-term antibiotic treatment has not been reported. We have lately seen a patient with extensive malakoplakia. We thought it might be worth while to try treatment with the fluoroquinolone ciprofloxacin, which penetrates well into macrophages.7 Malakoplakia of the bladder was diagnosed in 1981 when the patient was 37 years old. She was treated intermittently with bethanechol and trimethoprim. In 1985, intravenous urography showed no abnormalities. In 1989, she had severe malaise, 12 kg weight loss, diarrhoea, fever, and haematuria. Physical examination showed a large tumour in the right lower abdomen, extending to the groin, gluteal region, and loin, and extensive infiltration of the skin. Hydronephrosis of the right kidney was shown by intravenous urography. Computerised tomographic (CT) scanning showed large tumorous masses in the region of the bladder, surrounding the uterus and adnexa, invading the right psoas muscle, surrounding the right ureter, and infiltrating the gluteal muscles and abdominal skin. Histological examination and electronmicroscopy of biopsy samples taken by laparoscopy confirmed the diagnosis of malakoplakia. The patient had anaemia (haemoglobin 9-35 g/dl [58 mmol/1]), impaired kidney function (serum creatinine 200 µmol/1), and high serum lysozyme activities (ten times normal). E coli was found on urine culture. Phagocytosis and intracellular killing of E coli (serotype 054) by monocytes was normal.8 Nephrostomy was done. The patient received 500 mg ciprofloxacin twice daily. During the next few months, her clinical condition improved, the tumour masses regressed, and the haemoglobin concentration increased. After 16
tumour necrosis
function of
The tumour-like lesions of the rare disease malakoplakia, which consist of macrophages containing undigested coliform bacteria, are often misdiagnosed as a carcinoma. Although an infectious aetiology is likely, no antimicrobial therapy has been successful in the long-term. Since ciprofloxacin penetrates well into macrophages, this drug was given to two patients with advanced malakoplakia (500 mg twice daily). After long-term treatment all granulomatous lesions disappeared. Thus, malakoplakia can be cured by antibiotic treatment.
Malakoplakia is a rare chronic inflammatory disorder characterised by the formation of granulomas in the bladder or other organs of the genitourinary tract, but other organs and tissues including testis, epididymis, lungs, bone, lymph nodes, and retroperitoneal tissue can also be affected.! Clinically, the tumour-like nodules mimic a malignant neoplasm and the diagnosis can be made only by histological examination. Light microscopy shows the accumulation of macrophages with a characteristic morphology-von Hansemann macrophages. Large calcified structures (Michaelis-Gutmann bodies) are found in the cytoplasm of these macrophages.1 An infectious cause of malakoplakia is suggested by the electronmicroscopic finding of coliform bacteria in the phagolysosomes of macrophages.2 Little is known about the pathogenesis of the disease. Defective killing and impaired digestion of phagocytosed bacteria are suggested by the characteristic intracellular abnormalities of the macrophages. Lower than normal bactericidal activity against Escherichia coli and signs oflysomal abnormalities in 3 monocytes were found in one patient.
months of treatment, the infiltrates in the skin had
149
disappeared, no tumour masses were palpable, and the CT scan showed complete regression except for some thickening in the gluteal area, probably due to fibrosis. Stenosis of the right ureter persisted, but reimplantation of was not ureter the technically feasible; a ureteroileocutaneostomy was therefore constructed. Biopsy samples taken during surgery from many sites, including the bladder, showed no histological signs of malakoplakia. Ciprofloxacin therapy was stopped. A second woman presented in 1988 (then aged 53) with recurrent urinary-tract E coli infections. Cystoscopy and histology of biopsy samples suggested chronic inflammation transitional-cell carcinoma without infiltrative Endoresection of the tumour tissue was done twice. growth. In 1990, the patient presented with signs of hydronephrosis of the right kidney and recurrent tumour around the ostium of the right ureter. Histologically, the resected tissue showed the characteristic picture of malakoplakia; re-examination of the earlier samples showed malakoplakia rather than carcinoma. The distal ureter became totally occluded and hydronephrosis ensued. A catheter was introduced via a nephrostomy and treatment with ciprofloxacin 500 mg twice daily was initiated. Since the ureter remained obstructed and the kidney did not function, nephrectomy was done after 5 months. Samples taken at surgery and cystoscopy showed no abnormalities. Ciprofloxacin therapy was continued. Malakoplakia can lead to death if vital organs are affected. Viable or undigested bacteria in the macrophages will sustain the chronic inflammatory response, resulting in the accumulation of many macrophages, which form tumourlike lesions. Since ciprofloxacin penetrates macrophages easily, it can help these cells to kill and digest the ingested bacteria. Long-term treatment with ciprofloxacin is advised because it is difficult to assess clinically or with imaging techniques whether all of the lesions have disappeared. The successful treatment of these two patients suggest that physicians should consider ciprofloxacin for treatment of this rare disorder.
and
a
REFERENCES I, Katz SM. Malakoplakia. Pathol Annu 1981; 16: 103-26. Teplitz C. Malakoplakia: pathogenesis and ultrastructural morphogenesis. A problem of altered macrophage (phagolysosomal)
1. Damjanov 2. Lou TY,
response. Hum Pathol 1974; 5: 191-207. 3. Abdou NI, NaPombejara C, Sagawa A, et al. Malakoplakia: evidence for monocyte lysosomal abnormality correctable by cholinergic agonist in vitro and in vivo. N Engl J Med 1977; 297: 1413-19. 4. Oliver JM. Impaired microtubule function correctable by cyclic GMP and cholinergic agonists in the Chediak-Higashi syndrome. Am J Pathol 1976; 85: 395-418. 5. Renz H, Gong J-H, Schmidt A, Nain M, Gemsa D. Release of tumor necrosis factor &agr; from macrophages: enhancement and suppression are dose-dependently regulated by prostaglandin E2 and cyclic nucleotides. J Immunol 1988; 141: 2388-93. 6. van den Broek PJ. Antimicrobial drugs, micro-organisms, and phagocytes. Rev Infect Dis 1989; 11: 213-45. 7. Easmon CSF, Crane JP. Uptake of ciprofloxacin by macrophages. J Clin Pathol 1985; 38: 442-44. 8. Leijh PCJ, van den Barselaar MTh, van Furth R. Kinetics of phagocytosis and intracellular killing of Staphylococcus aureus and Escherichia coli by human monocytes. Scand J Immunol 1980; 13: 159-74.
ADDRESSES. Departments of Infectious Diseases (Prof R
van
Furth, MD, J W van’t Wout, MD) and Urology (J Zwartendijk, MD), University Hospital Leiden; and Department of Urology, Refaja Hospital, Dordrecht (P A Wertheimer, MD), Netherlands.
Correspondenceto Prof R. van Furth, Department of Infectious Diseases, University Hospital Leiden, PO Box 9600,2300 RC Leiden, Netherlands.
Idiopathic hemiparetic parkinsonism, a syndrome distinct from idiopathic parkinsonism
had a syndrome of progressive with parkinsonism ipsilateral rigidity, mild resting tremor, paresis, hyperreflexia, and an extensor plantar response. Symptoms had started 24 and 3 months after a surgical procedure in the affected limb. Neuroimaging studies were unhelpful. Both the parkinsonian features and the pyramidal tract signs responded well to dopaminergic drug treatment. We propose that the syndrome be called "idiopathic Two
women
hemiparetic parkinsonism". Parkinsonism is
syndrome characterised by tremor, and loss of postural reflexes. It may be the sole manifestation of idiopathic parkinsonism or Parkinson’s disease.12 The occurrence of pyramidal tract signs with parkinsonism should raise the suspicion of secondary parkinsonism (due to cerebral trauma, multiple cerebral infarcts, cerebral tumour, or hydrocephalus) or a parkinsonism-plus syndrome with multisystem neurodegeneration.2,3 Pyramidal tract signs in any of these disorders do not improve with dopaminergic a
clinical
bradykinesia, rigidity, resting
therapy. describe 2
with hemiparkinsonism patients accompanied by ipsilateral paresis, hyperreflexia, and an extensor plantar response and whose symptoms improved with dopaminergic therapy.
We
Patient 1 was a 43-year-old right-handed woman who at age 41 noted dragging of the left leg, followed by progressive stiffness of the left arm and, in the past few months, micrographia. The only history of note was stripping of the varicose veins in the left leg at age 39. She was intelligent and in good general health, had a monotonous, hurried speech, poverty of facial expression, cogwheel rigidity in the left extremities, and a slight intermittent resting tremor of the left hand. When she walked her left arm remained rigid and flexed and her left leg was held stiffly in extension, which suggested a spastic hemiparesis. There was a mild left lower facial weakness, and a drift of the left outstretched arm. On the left side of her body there was weakness (grade 4/5 on the Medical Research Council scale) of arm extensors and leg flexors, hyperreflexia, and a Babinski sign. Plasma ceruloplasmin concentration, electroencephalograms (EEG), and computed tomography (CT) scans of the brain were normal. Treatment with levodopa/benserazide up to 200/50 mg three times a day greatly improved her parkinsonism and restored muscle strength, tendon reflexes, and plantar response to normal. When she was admitted at age 45 for a "drug holiday" for re-evaluation of her clinical condition, she showed general slowing, deterioration of her speech, left-sided hypertonic hemiparesis with circumduction of the leg, hyperreflexia, an extensor plantar response, cogwheel rigidity, and mild intermittent resting tremor of the hand. There was no postural instability and no evidence of autonomic dysfunction. A CT scan of the brain was normal. Reintroduction of levodopa/benserazide resulted in a striking improvement, with complete disappearance of the pyramidal tract
signs. Over the next 7 years she had attacks of depression and dystonia of the left foot. Bromocriptine was added because of progressive bradykinesia. Rigidity and a mild intermittent parkinsonian tremor remained confined to the left limbs.
Hendry BM, Ellory JC. Effects of dialysis and transplantation on red cell Na pump function in renal failure. Nephron
3. Fervenza FC,
1989; 53: 121-28. 4. Fervenza FC, Meredith D, Ellory JC, Hendry BM. A study of the membrane transport of aminoacids in erythrocytes from patients on haemodialysis. Nephrol Dial Transplant 1990; 5: 594-99. 5. Fervenza FC. Meredith D, Ellory JC, Hendry BM. Abnormal erythrocyte choline transport in patients with chronic renal failure. Clin Sci 1991; 80: 137-41. 6. Zeisel SH, Costa K, Franklin PD, et al. Choline, an essential nutrient for humans. FASEB J 1991; 5: 2093-98. 7. Martin K. Choline transport in red cells. In: Ellory JC, Lew VL, eds. Membrane transport in red cells. London: Academic Press, 1977: 101-13. 8. Deves R, Krupka RM. The binding and translocation steps in transport as related to substrate structure: a study of the choline carrier of erythrocytes. Biochim Biophys Acta 1979; 557: 469-85. 9. Edmondson RPS, Hilton PJ, Jones NF, Patrick J, Thomas RD. Leucocyte sodium transport in uraemia. Clin Sci 1975; 49: 213-22. 10. Cotton JR, Woodard T, Carter NW, Knochel JP. Resting skeletal muscle membrane potential as an index of uremic toxicity. J Clin Invest 1979; 63: 501-06.
11. Ruiz P, Gomez F, Schreiber AD. Impaired function of macrophage Fc&ggr; receptors in end-stage renal disease. N Engl J Med 1990; 322: 717-22. 12. Cole CH, Balfe JW, Welt LG. Induction of an ouabain-sensitive ATPase defect by uremic plasma. Trans Assoc Am Phys 1968; 81: 213-20. 13. Graves SW, Brown B, Valdes R. An endogenous digitalis-like substance in patients with renal impairment. Ann Intern Med 1983; 99: 604-09. 14. Kelly RA, Canessa ML, Steinman TI, Mitch WE. Hemodialysis and red cell cation transport in uremia: role of membrane free fatty adds. Kidney Int 1989; 35: 595-603. 15. Estrada C, Bready J, Berliner J, Cancilla PA. Choline uptake by cerebral capillary endothelial cells in culture. J Neurochem 1990; 54: 1467-73. 16. Deves R, Reyes G, Krupka RM. The carrier reorientation step in erythrocyte choline transport: pH effects and the involvement of a carrier ionizing group. J Membrane Biol 1986; 93: 165-75. 17. Ancelin ML, Parant M, Thuet MJ, Philippot JR, Vial HJ. Increased permeability to choline in simian erythrocytes after Plasmodium knowlesi infection. Biochem J 1991; 273: 701-09. 18. Kirk K, Wong HY, Elford BC, Newbold CI, Ellory JC. Enhanced choline and Rb transport in human erythrocytes infected with the malaria parasite Plasmodium falciparum. Biochem J 1991; 278: 521-25.
SHORT REPORTS Ciprofloxacin for treatment of malakoplakia
Treatment of malakoplakia usually aims to improve macrophage function, by means of cholinergic agonists (eg, bethanechol),3 and to eliminate bacteria with antimicrobial drugs. Cholinergic agonists raise intracellular cyclic GMP concentrations,4which in turn stimulates synthesis of
factor; the latter enhances the microbicidal macrophages (unpublished). Such regimens rarely produce a sustained response, however, and the lesions continue to progress slowly. Failure of antimicrobial therapy could be due to poor penetration of the drug into the macrophages or its low activity in the phagolysosomes of the cells.6 Cure of malakoplakia by long-term antibiotic treatment has not been reported. We have lately seen a patient with extensive malakoplakia. We thought it might be worth while to try treatment with the fluoroquinolone ciprofloxacin, which penetrates well into macrophages.7 Malakoplakia of the bladder was diagnosed in 1981 when the patient was 37 years old. She was treated intermittently with bethanechol and trimethoprim. In 1985, intravenous urography showed no abnormalities. In 1989, she had severe malaise, 12 kg weight loss, diarrhoea, fever, and haematuria. Physical examination showed a large tumour in the right lower abdomen, extending to the groin, gluteal region, and loin, and extensive infiltration of the skin. Hydronephrosis of the right kidney was shown by intravenous urography. Computerised tomographic (CT) scanning showed large tumorous masses in the region of the bladder, surrounding the uterus and adnexa, invading the right psoas muscle, surrounding the right ureter, and infiltrating the gluteal muscles and abdominal skin. Histological examination and electronmicroscopy of biopsy samples taken by laparoscopy confirmed the diagnosis of malakoplakia. The patient had anaemia (haemoglobin 9-35 g/dl [58 mmol/1]), impaired kidney function (serum creatinine 200 µmol/1), and high serum lysozyme activities (ten times normal). E coli was found on urine culture. Phagocytosis and intracellular killing of E coli (serotype 054) by monocytes was normal.8 Nephrostomy was done. The patient received 500 mg ciprofloxacin twice daily. During the next few months, her clinical condition improved, the tumour masses regressed, and the haemoglobin concentration increased. After 16
tumour necrosis
function of
The tumour-like lesions of the rare disease malakoplakia, which consist of macrophages containing undigested coliform bacteria, are often misdiagnosed as a carcinoma. Although an infectious aetiology is likely, no antimicrobial therapy has been successful in the long-term. Since ciprofloxacin penetrates well into macrophages, this drug was given to two patients with advanced malakoplakia (500 mg twice daily). After long-term treatment all granulomatous lesions disappeared. Thus, malakoplakia can be cured by antibiotic treatment.
Malakoplakia is a rare chronic inflammatory disorder characterised by the formation of granulomas in the bladder or other organs of the genitourinary tract, but other organs and tissues including testis, epididymis, lungs, bone, lymph nodes, and retroperitoneal tissue can also be affected.! Clinically, the tumour-like nodules mimic a malignant neoplasm and the diagnosis can be made only by histological examination. Light microscopy shows the accumulation of macrophages with a characteristic morphology-von Hansemann macrophages. Large calcified structures (Michaelis-Gutmann bodies) are found in the cytoplasm of these macrophages.1 An infectious cause of malakoplakia is suggested by the electronmicroscopic finding of coliform bacteria in the phagolysosomes of macrophages.2 Little is known about the pathogenesis of the disease. Defective killing and impaired digestion of phagocytosed bacteria are suggested by the characteristic intracellular abnormalities of the macrophages. Lower than normal bactericidal activity against Escherichia coli and signs oflysomal abnormalities in 3 monocytes were found in one patient.
months of treatment, the infiltrates in the skin had
149
disappeared, no tumour masses were palpable, and the CT scan showed complete regression except for some thickening in the gluteal area, probably due to fibrosis. Stenosis of the right ureter persisted, but reimplantation of was not ureter the technically feasible; a ureteroileocutaneostomy was therefore constructed. Biopsy samples taken during surgery from many sites, including the bladder, showed no histological signs of malakoplakia. Ciprofloxacin therapy was stopped. A second woman presented in 1988 (then aged 53) with recurrent urinary-tract E coli infections. Cystoscopy and histology of biopsy samples suggested chronic inflammation transitional-cell carcinoma without infiltrative Endoresection of the tumour tissue was done twice. growth. In 1990, the patient presented with signs of hydronephrosis of the right kidney and recurrent tumour around the ostium of the right ureter. Histologically, the resected tissue showed the characteristic picture of malakoplakia; re-examination of the earlier samples showed malakoplakia rather than carcinoma. The distal ureter became totally occluded and hydronephrosis ensued. A catheter was introduced via a nephrostomy and treatment with ciprofloxacin 500 mg twice daily was initiated. Since the ureter remained obstructed and the kidney did not function, nephrectomy was done after 5 months. Samples taken at surgery and cystoscopy showed no abnormalities. Ciprofloxacin therapy was continued. Malakoplakia can lead to death if vital organs are affected. Viable or undigested bacteria in the macrophages will sustain the chronic inflammatory response, resulting in the accumulation of many macrophages, which form tumourlike lesions. Since ciprofloxacin penetrates macrophages easily, it can help these cells to kill and digest the ingested bacteria. Long-term treatment with ciprofloxacin is advised because it is difficult to assess clinically or with imaging techniques whether all of the lesions have disappeared. The successful treatment of these two patients suggest that physicians should consider ciprofloxacin for treatment of this rare disorder.
and
a
REFERENCES I, Katz SM. Malakoplakia. Pathol Annu 1981; 16: 103-26. Teplitz C. Malakoplakia: pathogenesis and ultrastructural morphogenesis. A problem of altered macrophage (phagolysosomal)
1. Damjanov 2. Lou TY,
response. Hum Pathol 1974; 5: 191-207. 3. Abdou NI, NaPombejara C, Sagawa A, et al. Malakoplakia: evidence for monocyte lysosomal abnormality correctable by cholinergic agonist in vitro and in vivo. N Engl J Med 1977; 297: 1413-19. 4. Oliver JM. Impaired microtubule function correctable by cyclic GMP and cholinergic agonists in the Chediak-Higashi syndrome. Am J Pathol 1976; 85: 395-418. 5. Renz H, Gong J-H, Schmidt A, Nain M, Gemsa D. Release of tumor necrosis factor &agr; from macrophages: enhancement and suppression are dose-dependently regulated by prostaglandin E2 and cyclic nucleotides. J Immunol 1988; 141: 2388-93. 6. van den Broek PJ. Antimicrobial drugs, micro-organisms, and phagocytes. Rev Infect Dis 1989; 11: 213-45. 7. Easmon CSF, Crane JP. Uptake of ciprofloxacin by macrophages. J Clin Pathol 1985; 38: 442-44. 8. Leijh PCJ, van den Barselaar MTh, van Furth R. Kinetics of phagocytosis and intracellular killing of Staphylococcus aureus and Escherichia coli by human monocytes. Scand J Immunol 1980; 13: 159-74.
ADDRESSES. Departments of Infectious Diseases (Prof R
van
Furth, MD, J W van’t Wout, MD) and Urology (J Zwartendijk, MD), University Hospital Leiden; and Department of Urology, Refaja Hospital, Dordrecht (P A Wertheimer, MD), Netherlands.
Correspondenceto Prof R. van Furth, Department of Infectious Diseases, University Hospital Leiden, PO Box 9600,2300 RC Leiden, Netherlands.
Idiopathic hemiparetic parkinsonism, a syndrome distinct from idiopathic parkinsonism
had a syndrome of progressive with parkinsonism ipsilateral rigidity, mild resting tremor, paresis, hyperreflexia, and an extensor plantar response. Symptoms had started 24 and 3 months after a surgical procedure in the affected limb. Neuroimaging studies were unhelpful. Both the parkinsonian features and the pyramidal tract signs responded well to dopaminergic drug treatment. We propose that the syndrome be called "idiopathic Two
women
hemiparetic parkinsonism". Parkinsonism is
syndrome characterised by tremor, and loss of postural reflexes. It may be the sole manifestation of idiopathic parkinsonism or Parkinson’s disease.12 The occurrence of pyramidal tract signs with parkinsonism should raise the suspicion of secondary parkinsonism (due to cerebral trauma, multiple cerebral infarcts, cerebral tumour, or hydrocephalus) or a parkinsonism-plus syndrome with multisystem neurodegeneration.2,3 Pyramidal tract signs in any of these disorders do not improve with dopaminergic a
clinical
bradykinesia, rigidity, resting
therapy. describe 2
with hemiparkinsonism patients accompanied by ipsilateral paresis, hyperreflexia, and an extensor plantar response and whose symptoms improved with dopaminergic therapy.
We
Patient 1 was a 43-year-old right-handed woman who at age 41 noted dragging of the left leg, followed by progressive stiffness of the left arm and, in the past few months, micrographia. The only history of note was stripping of the varicose veins in the left leg at age 39. She was intelligent and in good general health, had a monotonous, hurried speech, poverty of facial expression, cogwheel rigidity in the left extremities, and a slight intermittent resting tremor of the left hand. When she walked her left arm remained rigid and flexed and her left leg was held stiffly in extension, which suggested a spastic hemiparesis. There was a mild left lower facial weakness, and a drift of the left outstretched arm. On the left side of her body there was weakness (grade 4/5 on the Medical Research Council scale) of arm extensors and leg flexors, hyperreflexia, and a Babinski sign. Plasma ceruloplasmin concentration, electroencephalograms (EEG), and computed tomography (CT) scans of the brain were normal. Treatment with levodopa/benserazide up to 200/50 mg three times a day greatly improved her parkinsonism and restored muscle strength, tendon reflexes, and plantar response to normal. When she was admitted at age 45 for a "drug holiday" for re-evaluation of her clinical condition, she showed general slowing, deterioration of her speech, left-sided hypertonic hemiparesis with circumduction of the leg, hyperreflexia, an extensor plantar response, cogwheel rigidity, and mild intermittent resting tremor of the hand. There was no postural instability and no evidence of autonomic dysfunction. A CT scan of the brain was normal. Reintroduction of levodopa/benserazide resulted in a striking improvement, with complete disappearance of the pyramidal tract
signs. Over the next 7 years she had attacks of depression and dystonia of the left foot. Bromocriptine was added because of progressive bradykinesia. Rigidity and a mild intermittent parkinsonian tremor remained confined to the left limbs.