- Email: [email protected]
Treatment of multiple myeloma
COMMENTARY
7 8 9
prognostic factors in patients with subungual melanoma. Ann Surg 1994; 219: 197–204. Patterson RH, Helwig EB. Subungual melanoma: a clinical pathological study. Cancer 1980; 46: 2074–87. Kopf AW, Bart RS. Malignant melanoma. J Surg Oncol 1977; 3: 49–53. Banfield CC, Redburn JC, Dawber RPR. The incidence and prognosis of nail apparatus melanoma: a retrospective study of 105 patients in four English regions. Br J Dermatol 1998; 139: 276–79.
Treatment of multiple myeloma
Pigmented streak in thumb nail Nail-matrix biopsy revealed malignant melanoma invasive to 0·55 mm
As previously mentioned, treatment has historically been unsatisfactory because of the advanced stage of tumour typically seen on presentation. Tumour thickness is the most important prognostic factor in general for melanoma, and like all melanomas, survival rate increases the thinner the NAM. In view of the relative paucity of published work on this disorder, it is difficult to make definitive statements about treatment. The mainstay of treatment is surgical, but comparisons between local excision, amputation at the nearest or a more proximal joint, and the value of elective lymph-node dissection are lacking. The series of 105 cases recently reported by C C Banfield and colleagues9 contributes to further experience and recognition of this difficult tumour. These investigators reviewed four regional cancer registries covering a population of 10·6 million people over the period 1984–93. 7585 melanomas were identified, of which 105 were nail-apparatus melanoma (1·4% of melanomas). The findings confirm many observations from smaller surveys. Of particular note was that the average Breslow depth was 4·8 mm, which confirms the advanced stage of disease typically reported at initial presentation. This series offers some therapeutic comparisons. As expected, 5-year survival was greater in the thinner lesions. Patients with thinner lesions treated by local excision (mean thickness 3·2 mm) had a significantly greater 5-year survival of 79% than did those with thicker lesions (mean thickness 6·1 mm) treated by amputation. This difference suggests that amputation may not be the only surgical option, as has been previously suggested.6 There is no effective treatment for metastatic melanoma, so early detection of thin melanomas that can be cured by excision is paramount. All physicians need to heighten their awareness of suspicious skin lesions, including those of the nail apparatus, and biopsy them.
James M Spencer Division of Dermatologic Surgery, Mount Sinai Medical Center, New York, NY 10029, USA 1 2 3
4 5 6
Finley RK, Driscoll DL, Blumenson LE, et al. Subungual melanoma: an eighteen year review. Surgery 1994; 116: 96–100. Dawber RPR, Colver GB. The spectrum of malignant melanoma of the nail apparatus. Semin Dermatol 1991; 10: 82–87. Saida T. Heterogeneity of the site of origin on malignant melanoma in ungual areas; “subungual” malignant melanoma may be a misnomer. Br J Dermatol 1992; 126: 529. Saida T, Oshima Y. Clinical and histopathologic characteristics of early lesions of subungual malignant melanoma. Cancer 1989; 63: 556. Pack GT, Oropeza R. Subungual melanoma. Surg Gynecol Obstet 1976; 124: 571–82. Heaton KM, El-Naggar A, Ensign LG, et al. Surgical management and
THE LANCET • Vol 353 • January 9, 1999
Conventional cytotoxic drug treatment of patients with multiple myeloma results in a median overall survival of less than 3 years.1 New drug combinations have not been superior to the classic melphalan-plus-prednisolone regimen.2 Allogeneic transplantation was first attempted in the early 1980s. Complete remission—disappearance of the monoclonal immunoglobulin from serum or of light chains from urine, as well as of myeloma cells from the marrow—could be induced in about 50% of the patients. In some patients long-term disease-free survival was obtained, and there were hopes that some patients were cured.3 However, allogeneic transplantation is associated with a high transplant-related mortality rate—a contrast with autologous transplantation with bone marrow or, more commonly, peripheral-blood stem cells.4 Autotransplantation was also attempted in the early 1980s and has in a randomised study proved to be superior to conventional intermittent chemotherapy with VMCP (vincristine+melphalan+cyclophosphamide +prednisone) plus VBAP (vincristine+BCNU+ doxorubicin+prednisone).5 It improves both relapse-free and overall survival. But relapse eventually occurs in all patients. Autologous transplantation has been compared with allogeneic transplantation in a case-matched analysis by the European Group for Blood and Marrow Transplantation.4 The overall survival was significantly better with autologous transplantation, the difference being entirely due to the higher transplant-related mortality with allogeneic transplantation, mainly among men. However, the relapse rate among patients who entered complete remission was lower among those who underwent allogeneic transplantation, which indicates that if transplant-related mortality could be reduced, allogeneic transplantation might be the method of choice for some patients with multiple myeloma. Nevertheless, allogeneic transplantation will probably be suitable only for myeloma patients younger than 55 years.6 This population of patients accounts for only about 7% of those with multiple myeloma. By contrast, the treatmentrelated mortality rate for autologous transplantation remains reasonable for patients up to the age of 65,6 and will therefore be the method of choice for a larger population of patients. Even so, relapse eventually occurs in most patients, so there is justification for new approaches to prevention of relapse after transplantation and for patients not eligible for transplantation. Bisphosphonates are valuable in preventing bone resorption and destruction. The most interesting finding, though, is that bisphosphonates may have a direct antimyeloma effect.7 Thus, bisphosphonates may be indicated not only as part of supportive care but also in attempts to prevent progression of the disease. Interferon treatment is another controversial approach. Although it has an antimyeloma effect, there is uncertainty about its ability to prolong survival, whether given as induction therapy or as maintenance treatment 85
COMMENTARY
together with conventional therapy or following autologous transplantation. Still, a meta-analysis indicates that there is a median gain in survival of about 5–6 months if interferon is given after conventional treatment,8 and there are indications that a similar effect might be obtained if it is given after autologous transplantation.9 Proliferation of multiple-myeloma cells seems to be driven by interleukin-6 (IL-6). Infection of dendritic cells by human herpesvirus 8 (HHV8) in the bone marrow of patients with multiple myeloma has been said to induce IL-6 production, thereby having a role in the aetiology and progression of the disease.10 In many studies IL-6 has been the target for treatment with drugs or with antibodies that interfere with IL-6, gp 130 (ie, the IL-6 receptor b chain), and the binding of IL-6 to the receptor. Such attempts to reduce proliferation of multiple-myeloma cells have mainly been inconclusive or have not had much effect in clinical trials.11 Another attempt to kill myeloma cells in experimental systems has been suicide gene therapy. The gene for herpes simplex virus thymidine kinase (HSVtk) can be transfected into myeloma cell lines, which can then be inoculated into laboratory animals to induce tumours. Exposure of HSVtk-transduced myeloma cells to ganciclovir will kill the myeloma cells, cause tumour regression or disappearance, and exert a bystander effect on tumours induced by non-transduced myeloma cells from the same cell lines.12 Other, as yet inconclusive, attempts to use gene therapy in the treatment of myeloma have been based on transduction of genes for granulocyte-macrophage colony-stimulating factor into myeloma cells in order to enhance immunogenicity and then to use the transduced cells for vaccination.13 Recently, the knowledge that myeloma cells express oestrogen receptors and that anti-oestrogens can downregulate IL-6 and gp 130 as well as normal B-cell lymphopoiesis has led to the use of anti-oestrogens to inhibit myeloma-cell proliferation.14 Tamoxifen, an antioestrogen substance, induced apoptosis and inhibited growth of multiple myeloma cell lines as well as of multiple myeloma cells from three of three patients, provided that the cells had the oestrogen receptor alpha. These effects were not seen in normal cells. Importantly, apoptosis was induced and myeloma-cell proliferation was inhibited at drug concentrations similar to those found in clinical trials of high doses of oral tamoxifen given in combination with cytotoxic drugs such as vinblastine and daunorubicin for other cancers. Thus anti-oestrogen therapy with tamoxifen should be investigated in clinical trials in patients with multiple myeloma, especially since so much experience with this agent has been obtained from its use with receptorpositive breast cancer. The most reasonable first trial for tamoxifen in multiple myeloma, the treatment of which is in most cases unsatisfactory, is either after autologous transplantation or in combination with conventional cytotoxic drugs for patients not eligible for transplantation.
Gösta Gahrton Departments of Medicine and Haematology, Huddinge Hospital and Karolinska Institutet, SE-14186, Huddinge, Sweden 1
86
Alexanian R, Haut A, Khan AU, et al. Treatment for multiple myeloma: combination chemotherapy with different melphalan dose regimens. JAMA 1969; 208: 1680–85.
2
3
4
5
6
7
8
9
10
11 12 13
14
Samson D. Principles of chemotherapy and radiotherapy. In: Gahrton G, Durie BGM, eds. Multiple myeloma. London: Arnold, 1996: 108–29. Gahrton G, Tura S, Ljungman P, et al. Allogeneic bone marrow transplantation in multiple myeloma. N Engl J Med 1991; 325: 1267–73. Björkstrand B, Ljungman P, Svensson H, et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma—a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 1996; 88: 4711–18. Attal M, Harousseau J-L, Stoppa A-M, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996; 335: 91–97. Goldman JM, Schmitz, Niethammer D, Gratwohl A. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe in 1998. Bone Marrow Transplantation 1998; 21: 1–7. Aparicio A, Gardner A, Tu Y, Savage A, Berenson J, Lichtenstein A. In vitro cytoreductive effects on multiple myeloma cells induced by biosphosphonates. Leukemia 1998; 12: 220–29. Ludwig H, Cohen AM, Polliack A, et al. Interferon-alpha for induction and maintenance in multiple myeloma: results of two multicenter randomized trials and summary of other studies. Ann Oncol 1995; 6: 467–76. Björkstrand B, Svensson H, Ljungman P, et al. Alpha-interferon treatment after autologous stem cell transplantation in multiple myeloma—retrospective case-matched analysis. 24th Annual Meeting European Group for Blood and Marrow Transplantation. Bone Marrow Transpl 1998; 21 (suppl 1): 208S. Rettig MB, Ma HJ, Vescio RA, et al. Kaposi’s sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients. Science 1997; 276: 1851–54. Treon SP, Anderson KC. Interleukin-6 in multiple myeloma and related plasma cell dyscrasias. Curr Opin Hematol 1998; 5: 42–48. Dilber MS, Abedi MR, Björkstrand B, et al. Suicide gene therapy for plasma cell tumors. Blood 1996; 88: 2192–200. Turner JG, Tan J, Crucian BE, et al. Broadened clinical utility of gene gun-mediated, granulocyte-macrophage colony-stimulating factor cDNA-based tumor cell vaccines as demonstrated with a mouse myeloma model. Hum Gene Ther 1998; 9: 1121–30. Treon SP, Teoh G, Urashima M, et al. Anti-estrogens induce apoptosis of multiple myeloma cells. Blood 1998; 92: 1749–57.
Stiff-man syndrome and its variants Stiff-man syndrome is a rare, distressing neurological disorder first described in 1956.1 Patients have been likened to “tin soldiers” with “titanic” muscle spasms. After a review of 23 cases of the syndrome investigated at a single institution over 9 years, R A Barker and colleagues2 suggest that cases should be classified into three groups—stiff-trunk (man) syndrome, stiff-limb syndrome, and progressive encephalomyelitis with rigidity. The symptoms usually begin with tightness or stiffness of the trunk muscles, which may slowly spread to the proximal muscles of the limbs. Persistent contraction of the axial muscles leads to truncal rigidity, a characteristic lumbar hyperlordosis, and restriction of movement of the hips and spine. Superimposed on this background rigidity are painful muscle spasms that may be precipitated by sudden movement, noise, tactile stimulation, or emotional upset. No other neurological abnormalities have been reported, nor have specific histopathological changes in the central nervous system. Thus, stiff-man syndrome has been considered to be a functional rather than a structural disorder. The only neurophysiological abnormality found has been continuous motor-unit activity, especially in the paraspinal muscles. Detailed post-mortem neurochemical investigations have not been done, but neuropharmacological studies provide some evidence for an imbalance between descending catecholamine excitatory and γ-aminobutyric acid (GABA) inhibitory modulatory neurotransmitter systems in the brainstem and spinal cord.3 50–60% of patients with classic stiff-man syndrome have autoantibodies in
THE LANCET • Vol 353 • January 9, 1999
7 8 9
prognostic factors in patients with subungual melanoma. Ann Surg 1994; 219: 197–204. Patterson RH, Helwig EB. Subungual melanoma: a clinical pathological study. Cancer 1980; 46: 2074–87. Kopf AW, Bart RS. Malignant melanoma. J Surg Oncol 1977; 3: 49–53. Banfield CC, Redburn JC, Dawber RPR. The incidence and prognosis of nail apparatus melanoma: a retrospective study of 105 patients in four English regions. Br J Dermatol 1998; 139: 276–79.
Treatment of multiple myeloma
Pigmented streak in thumb nail Nail-matrix biopsy revealed malignant melanoma invasive to 0·55 mm
As previously mentioned, treatment has historically been unsatisfactory because of the advanced stage of tumour typically seen on presentation. Tumour thickness is the most important prognostic factor in general for melanoma, and like all melanomas, survival rate increases the thinner the NAM. In view of the relative paucity of published work on this disorder, it is difficult to make definitive statements about treatment. The mainstay of treatment is surgical, but comparisons between local excision, amputation at the nearest or a more proximal joint, and the value of elective lymph-node dissection are lacking. The series of 105 cases recently reported by C C Banfield and colleagues9 contributes to further experience and recognition of this difficult tumour. These investigators reviewed four regional cancer registries covering a population of 10·6 million people over the period 1984–93. 7585 melanomas were identified, of which 105 were nail-apparatus melanoma (1·4% of melanomas). The findings confirm many observations from smaller surveys. Of particular note was that the average Breslow depth was 4·8 mm, which confirms the advanced stage of disease typically reported at initial presentation. This series offers some therapeutic comparisons. As expected, 5-year survival was greater in the thinner lesions. Patients with thinner lesions treated by local excision (mean thickness 3·2 mm) had a significantly greater 5-year survival of 79% than did those with thicker lesions (mean thickness 6·1 mm) treated by amputation. This difference suggests that amputation may not be the only surgical option, as has been previously suggested.6 There is no effective treatment for metastatic melanoma, so early detection of thin melanomas that can be cured by excision is paramount. All physicians need to heighten their awareness of suspicious skin lesions, including those of the nail apparatus, and biopsy them.
James M Spencer Division of Dermatologic Surgery, Mount Sinai Medical Center, New York, NY 10029, USA 1 2 3
4 5 6
Finley RK, Driscoll DL, Blumenson LE, et al. Subungual melanoma: an eighteen year review. Surgery 1994; 116: 96–100. Dawber RPR, Colver GB. The spectrum of malignant melanoma of the nail apparatus. Semin Dermatol 1991; 10: 82–87. Saida T. Heterogeneity of the site of origin on malignant melanoma in ungual areas; “subungual” malignant melanoma may be a misnomer. Br J Dermatol 1992; 126: 529. Saida T, Oshima Y. Clinical and histopathologic characteristics of early lesions of subungual malignant melanoma. Cancer 1989; 63: 556. Pack GT, Oropeza R. Subungual melanoma. Surg Gynecol Obstet 1976; 124: 571–82. Heaton KM, El-Naggar A, Ensign LG, et al. Surgical management and
THE LANCET • Vol 353 • January 9, 1999
Conventional cytotoxic drug treatment of patients with multiple myeloma results in a median overall survival of less than 3 years.1 New drug combinations have not been superior to the classic melphalan-plus-prednisolone regimen.2 Allogeneic transplantation was first attempted in the early 1980s. Complete remission—disappearance of the monoclonal immunoglobulin from serum or of light chains from urine, as well as of myeloma cells from the marrow—could be induced in about 50% of the patients. In some patients long-term disease-free survival was obtained, and there were hopes that some patients were cured.3 However, allogeneic transplantation is associated with a high transplant-related mortality rate—a contrast with autologous transplantation with bone marrow or, more commonly, peripheral-blood stem cells.4 Autotransplantation was also attempted in the early 1980s and has in a randomised study proved to be superior to conventional intermittent chemotherapy with VMCP (vincristine+melphalan+cyclophosphamide +prednisone) plus VBAP (vincristine+BCNU+ doxorubicin+prednisone).5 It improves both relapse-free and overall survival. But relapse eventually occurs in all patients. Autologous transplantation has been compared with allogeneic transplantation in a case-matched analysis by the European Group for Blood and Marrow Transplantation.4 The overall survival was significantly better with autologous transplantation, the difference being entirely due to the higher transplant-related mortality with allogeneic transplantation, mainly among men. However, the relapse rate among patients who entered complete remission was lower among those who underwent allogeneic transplantation, which indicates that if transplant-related mortality could be reduced, allogeneic transplantation might be the method of choice for some patients with multiple myeloma. Nevertheless, allogeneic transplantation will probably be suitable only for myeloma patients younger than 55 years.6 This population of patients accounts for only about 7% of those with multiple myeloma. By contrast, the treatmentrelated mortality rate for autologous transplantation remains reasonable for patients up to the age of 65,6 and will therefore be the method of choice for a larger population of patients. Even so, relapse eventually occurs in most patients, so there is justification for new approaches to prevention of relapse after transplantation and for patients not eligible for transplantation. Bisphosphonates are valuable in preventing bone resorption and destruction. The most interesting finding, though, is that bisphosphonates may have a direct antimyeloma effect.7 Thus, bisphosphonates may be indicated not only as part of supportive care but also in attempts to prevent progression of the disease. Interferon treatment is another controversial approach. Although it has an antimyeloma effect, there is uncertainty about its ability to prolong survival, whether given as induction therapy or as maintenance treatment 85
COMMENTARY
together with conventional therapy or following autologous transplantation. Still, a meta-analysis indicates that there is a median gain in survival of about 5–6 months if interferon is given after conventional treatment,8 and there are indications that a similar effect might be obtained if it is given after autologous transplantation.9 Proliferation of multiple-myeloma cells seems to be driven by interleukin-6 (IL-6). Infection of dendritic cells by human herpesvirus 8 (HHV8) in the bone marrow of patients with multiple myeloma has been said to induce IL-6 production, thereby having a role in the aetiology and progression of the disease.10 In many studies IL-6 has been the target for treatment with drugs or with antibodies that interfere with IL-6, gp 130 (ie, the IL-6 receptor b chain), and the binding of IL-6 to the receptor. Such attempts to reduce proliferation of multiple-myeloma cells have mainly been inconclusive or have not had much effect in clinical trials.11 Another attempt to kill myeloma cells in experimental systems has been suicide gene therapy. The gene for herpes simplex virus thymidine kinase (HSVtk) can be transfected into myeloma cell lines, which can then be inoculated into laboratory animals to induce tumours. Exposure of HSVtk-transduced myeloma cells to ganciclovir will kill the myeloma cells, cause tumour regression or disappearance, and exert a bystander effect on tumours induced by non-transduced myeloma cells from the same cell lines.12 Other, as yet inconclusive, attempts to use gene therapy in the treatment of myeloma have been based on transduction of genes for granulocyte-macrophage colony-stimulating factor into myeloma cells in order to enhance immunogenicity and then to use the transduced cells for vaccination.13 Recently, the knowledge that myeloma cells express oestrogen receptors and that anti-oestrogens can downregulate IL-6 and gp 130 as well as normal B-cell lymphopoiesis has led to the use of anti-oestrogens to inhibit myeloma-cell proliferation.14 Tamoxifen, an antioestrogen substance, induced apoptosis and inhibited growth of multiple myeloma cell lines as well as of multiple myeloma cells from three of three patients, provided that the cells had the oestrogen receptor alpha. These effects were not seen in normal cells. Importantly, apoptosis was induced and myeloma-cell proliferation was inhibited at drug concentrations similar to those found in clinical trials of high doses of oral tamoxifen given in combination with cytotoxic drugs such as vinblastine and daunorubicin for other cancers. Thus anti-oestrogen therapy with tamoxifen should be investigated in clinical trials in patients with multiple myeloma, especially since so much experience with this agent has been obtained from its use with receptorpositive breast cancer. The most reasonable first trial for tamoxifen in multiple myeloma, the treatment of which is in most cases unsatisfactory, is either after autologous transplantation or in combination with conventional cytotoxic drugs for patients not eligible for transplantation.
Gösta Gahrton Departments of Medicine and Haematology, Huddinge Hospital and Karolinska Institutet, SE-14186, Huddinge, Sweden 1
86
Alexanian R, Haut A, Khan AU, et al. Treatment for multiple myeloma: combination chemotherapy with different melphalan dose regimens. JAMA 1969; 208: 1680–85.
2
3
4
5
6
7
8
9
10
11 12 13
14
Samson D. Principles of chemotherapy and radiotherapy. In: Gahrton G, Durie BGM, eds. Multiple myeloma. London: Arnold, 1996: 108–29. Gahrton G, Tura S, Ljungman P, et al. Allogeneic bone marrow transplantation in multiple myeloma. N Engl J Med 1991; 325: 1267–73. Björkstrand B, Ljungman P, Svensson H, et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma—a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 1996; 88: 4711–18. Attal M, Harousseau J-L, Stoppa A-M, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996; 335: 91–97. Goldman JM, Schmitz, Niethammer D, Gratwohl A. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe in 1998. Bone Marrow Transplantation 1998; 21: 1–7. Aparicio A, Gardner A, Tu Y, Savage A, Berenson J, Lichtenstein A. In vitro cytoreductive effects on multiple myeloma cells induced by biosphosphonates. Leukemia 1998; 12: 220–29. Ludwig H, Cohen AM, Polliack A, et al. Interferon-alpha for induction and maintenance in multiple myeloma: results of two multicenter randomized trials and summary of other studies. Ann Oncol 1995; 6: 467–76. Björkstrand B, Svensson H, Ljungman P, et al. Alpha-interferon treatment after autologous stem cell transplantation in multiple myeloma—retrospective case-matched analysis. 24th Annual Meeting European Group for Blood and Marrow Transplantation. Bone Marrow Transpl 1998; 21 (suppl 1): 208S. Rettig MB, Ma HJ, Vescio RA, et al. Kaposi’s sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients. Science 1997; 276: 1851–54. Treon SP, Anderson KC. Interleukin-6 in multiple myeloma and related plasma cell dyscrasias. Curr Opin Hematol 1998; 5: 42–48. Dilber MS, Abedi MR, Björkstrand B, et al. Suicide gene therapy for plasma cell tumors. Blood 1996; 88: 2192–200. Turner JG, Tan J, Crucian BE, et al. Broadened clinical utility of gene gun-mediated, granulocyte-macrophage colony-stimulating factor cDNA-based tumor cell vaccines as demonstrated with a mouse myeloma model. Hum Gene Ther 1998; 9: 1121–30. Treon SP, Teoh G, Urashima M, et al. Anti-estrogens induce apoptosis of multiple myeloma cells. Blood 1998; 92: 1749–57.
Stiff-man syndrome and its variants Stiff-man syndrome is a rare, distressing neurological disorder first described in 1956.1 Patients have been likened to “tin soldiers” with “titanic” muscle spasms. After a review of 23 cases of the syndrome investigated at a single institution over 9 years, R A Barker and colleagues2 suggest that cases should be classified into three groups—stiff-trunk (man) syndrome, stiff-limb syndrome, and progressive encephalomyelitis with rigidity. The symptoms usually begin with tightness or stiffness of the trunk muscles, which may slowly spread to the proximal muscles of the limbs. Persistent contraction of the axial muscles leads to truncal rigidity, a characteristic lumbar hyperlordosis, and restriction of movement of the hips and spine. Superimposed on this background rigidity are painful muscle spasms that may be precipitated by sudden movement, noise, tactile stimulation, or emotional upset. No other neurological abnormalities have been reported, nor have specific histopathological changes in the central nervous system. Thus, stiff-man syndrome has been considered to be a functional rather than a structural disorder. The only neurophysiological abnormality found has been continuous motor-unit activity, especially in the paraspinal muscles. Detailed post-mortem neurochemical investigations have not been done, but neuropharmacological studies provide some evidence for an imbalance between descending catecholamine excitatory and γ-aminobutyric acid (GABA) inhibitory modulatory neurotransmitter systems in the brainstem and spinal cord.3 50–60% of patients with classic stiff-man syndrome have autoantibodies in
THE LANCET • Vol 353 • January 9, 1999