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Intravenous immunoglobulin for multiple sclerosis
THE LANCET
concluded that that process is inefficacious, in part because the socalled new nodes of Ranvier, necessary for saltatory conduction, do not conform to the normal structure. It is also difficult to understand how well functional remyelination can proceed in the face of the dense gliosis that characterises the plaques. There may be another explanation for the EDSS reduction, which, incidentally, accounts for most if not all the overall statistical success if this trial. Trials of some other potential immunotherapeutic agents have also reported such changes, although none quite so dramatic. Most clinicians know that the EDSS score of MS patients may vary by more than one point, not only from day to day but also even from morning to late afternoon. Patients often mention that they have good days and they have bad days; fatigue, a frequent and very variable symptom of MS clearly influences the EDSS, as do ambient temperature, degree of humidity, barometric pressure, symptomatic treatment, the enthusiasm of the investigator(s), stress, and mild or even subclinical infections. It is remarkable that changes as small as one point on the EDSS scale have been so widely accepted as important in therapeutic trials. It is not difficult to accept the statement that the investigators were blinded, but what about the patients? MS patients all desperately want to get better. Those who have guessed from the side-effects that they are receiving the active ingredient, even if these side-effects are not severe enough to cause drop-outs, are encouraged to do well, whereas those who do not know what they are getting also want to help by doing better. For many years those of us managing large numbers of MS patients have accepted the fact that a majority of MS sufferers will improve regardless of the nature of the treatment, from megavitamins to balneotherapy. Gauging the efficacy of therapy by measuring disease activity by gadolinium-enhanced magnetic resonance imaging may prove to be a more reliable method for doing so, but spending time and money evaluating changes of the EDSS would seem to add little if anything to these exercises. Charles M Poser Department of Neurology, Beth Israel Hospital, Boston, MA 02215, USA
1
Fazekas F, Deisenhammer F, Strasser-Fuches S, et al. Randomized placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997; 349: 589–93.
1178
SIR—Why did Andersson and colleagues say in their March 1 commentary1 that the effect of intravenous immunoglobulin on sustained progression of neurological impairment remains to be determined when the primary endpoint of Fazekas and colleagues seminal paper2 was the EDSS and demonstrated a significant (p=0·008) benefit over placebo? Simon J Ellis Department of Neurology, North Staffordshire Royal Infirmary, Stoke on Trent ST4 7LN, UK
1
2
Andersson P-B, Waubant E, Goodkin DE. How should we proceed with diseasemodifying treatments for multiple sclerosis? Lancet 1997; 349: 586–87. Fazekas F, Deisenhammer F, Strasser-Fuches S, et al. Randomized placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997; 349: 589–93.
Review of diagnostic criteria of hyper-reactive malarial splenomegaly S IR —Hyper-reactive malarial splenomegaly (HMS) is a form of severe malaria, with a mortality rate that exceeds 50%,1,2 compared with a rate of 6–20% in cerebral malaria. Data on the prevalence of HMS is scant, but in areas with intense transmission of malaria, prevalence varies from 1–2% in Nigeria to 80% among certain tribes in Papua New Guinea. Although patients with HMS respond to malarial prophylaxis, the disorder is not curable; after treatment the spleen reenlarges and immunological function deteriorates. Criteria for the diagnosis of HMS were first published in 1979, 3 with minor revisions in 1981. 4 The diagnosis was based on the exclusion of other causes of splenomegaly, immunity to malaria, splenomegaly of at least 10 cm, a serum concentration of IgM at least 2 SD above the normal mean concentration for the area, and a clinical and immunological response to malaria prophylaxis. Minor diagnostic criteria included hepatic sinusoidal lymphocytosis, normal lymphocyte response to phytohaemagglutinin stimulation, and lymphocyte proliferation. Then, as now, the difficulty of differentiating between HMS and malignant lymphoproliferative disorders was well recognised. An absolute lymphocytosis in HMS occurs predominantly in west Africa. HMS has many clinical signs in common with lymphoproliferative disorders, such as a type of splenic
lymphoma typified by villous lymphocytes.5 In the past, these signs may have been misclassified as an incorrect diagnosis of an African form of chronic lymphocytic leukaemia, which presents with lymphocytosis and splenomegaly rather than lymphadenopathy. In addition, there is some geographical variation in the phenotype of HMS, which may explain some of the diagnostic difficulties. Cases of HMS without raised concentrations of IgM have been described, patients with lymphoma show some response to malarial prophylaxis, hepatic sinusoidal lymphocytosis is also associated with chronic viral infections and chronic lymphocytic leukaemia, and phytohaemagglutinin responses are imprecise. Because histological changes in HMS are not specific and ultrasonography can detect abnormalities of liver texture and vasculature, a liver biopsy is no longer appropriate to confirm a diagnosis of HMS. Current criteria for the diagnosis of HMS are not sufficiently stringent to enable the condition to be reliably distinguished from malignant lymphoproliferative disorders. With the increasing availability of cytotoxic drugs in developing countries, it is vital that this distinction be made. We therefore propose that the criteria for HMS be refined to include: splenomegaly of at least 10 cm below the costal margin; a serum concentration of IgM at least 2 SD above the normal mean concentration for the area; a sustained response to malarial prophylaxis with a reduction in the size of the spleen of at least 40%; and evidence of the polyclonal nature of the lymphocytes—eg, unrestricted use of immunoglobulin light chains or absence of a discrete rearrangement of the immunoglobulin gene. *Imelda Bates, George Bedu-Addo *Haematology Division, St George’s Hospital Medical School, London SW17 0RF, UK; and Haematology Unit, Department of Medicine, Komto Anokyu Teaching Hospital, Kumasi, Ghana
1
2
3
4
5
Hamilton P, Stuiver P, Ziegler J. Splenectomy in tropical splenomegaly syndrome—a five year follow-up. J Trop Med Hyg 1974; 74: 230–32. Crane G, Wells J, Hudson P. Tropical splenomegaly in New Guinea. 1: natural history. Trans R Soc Trop Med Hyg 1972; 66: 724–32. Greenwood B, Fakunle Y. The tropical splenomegaly syndrome. In: the role of the spleen in the immunology of parasitic disease. Basel: Schwabe, 1979: 229–51. Fakunle Y. Tropical splenomegaly. In: Luzzatto L, ed. Clinics in haematology. London: WB Saunders, 1981: 963–75. Bates I, Bedu-Addo G, Rutherford T, Bevan D. Splenic lymphoma with villous lymphocytes in tropical west Africa. Lancet 1992; 340: 575–77.
Vol 349 • April 19, 1997
concluded that that process is inefficacious, in part because the socalled new nodes of Ranvier, necessary for saltatory conduction, do not conform to the normal structure. It is also difficult to understand how well functional remyelination can proceed in the face of the dense gliosis that characterises the plaques. There may be another explanation for the EDSS reduction, which, incidentally, accounts for most if not all the overall statistical success if this trial. Trials of some other potential immunotherapeutic agents have also reported such changes, although none quite so dramatic. Most clinicians know that the EDSS score of MS patients may vary by more than one point, not only from day to day but also even from morning to late afternoon. Patients often mention that they have good days and they have bad days; fatigue, a frequent and very variable symptom of MS clearly influences the EDSS, as do ambient temperature, degree of humidity, barometric pressure, symptomatic treatment, the enthusiasm of the investigator(s), stress, and mild or even subclinical infections. It is remarkable that changes as small as one point on the EDSS scale have been so widely accepted as important in therapeutic trials. It is not difficult to accept the statement that the investigators were blinded, but what about the patients? MS patients all desperately want to get better. Those who have guessed from the side-effects that they are receiving the active ingredient, even if these side-effects are not severe enough to cause drop-outs, are encouraged to do well, whereas those who do not know what they are getting also want to help by doing better. For many years those of us managing large numbers of MS patients have accepted the fact that a majority of MS sufferers will improve regardless of the nature of the treatment, from megavitamins to balneotherapy. Gauging the efficacy of therapy by measuring disease activity by gadolinium-enhanced magnetic resonance imaging may prove to be a more reliable method for doing so, but spending time and money evaluating changes of the EDSS would seem to add little if anything to these exercises. Charles M Poser Department of Neurology, Beth Israel Hospital, Boston, MA 02215, USA
1
Fazekas F, Deisenhammer F, Strasser-Fuches S, et al. Randomized placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997; 349: 589–93.
1178
SIR—Why did Andersson and colleagues say in their March 1 commentary1 that the effect of intravenous immunoglobulin on sustained progression of neurological impairment remains to be determined when the primary endpoint of Fazekas and colleagues seminal paper2 was the EDSS and demonstrated a significant (p=0·008) benefit over placebo? Simon J Ellis Department of Neurology, North Staffordshire Royal Infirmary, Stoke on Trent ST4 7LN, UK
1
2
Andersson P-B, Waubant E, Goodkin DE. How should we proceed with diseasemodifying treatments for multiple sclerosis? Lancet 1997; 349: 586–87. Fazekas F, Deisenhammer F, Strasser-Fuches S, et al. Randomized placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997; 349: 589–93.
Review of diagnostic criteria of hyper-reactive malarial splenomegaly S IR —Hyper-reactive malarial splenomegaly (HMS) is a form of severe malaria, with a mortality rate that exceeds 50%,1,2 compared with a rate of 6–20% in cerebral malaria. Data on the prevalence of HMS is scant, but in areas with intense transmission of malaria, prevalence varies from 1–2% in Nigeria to 80% among certain tribes in Papua New Guinea. Although patients with HMS respond to malarial prophylaxis, the disorder is not curable; after treatment the spleen reenlarges and immunological function deteriorates. Criteria for the diagnosis of HMS were first published in 1979, 3 with minor revisions in 1981. 4 The diagnosis was based on the exclusion of other causes of splenomegaly, immunity to malaria, splenomegaly of at least 10 cm, a serum concentration of IgM at least 2 SD above the normal mean concentration for the area, and a clinical and immunological response to malaria prophylaxis. Minor diagnostic criteria included hepatic sinusoidal lymphocytosis, normal lymphocyte response to phytohaemagglutinin stimulation, and lymphocyte proliferation. Then, as now, the difficulty of differentiating between HMS and malignant lymphoproliferative disorders was well recognised. An absolute lymphocytosis in HMS occurs predominantly in west Africa. HMS has many clinical signs in common with lymphoproliferative disorders, such as a type of splenic
lymphoma typified by villous lymphocytes.5 In the past, these signs may have been misclassified as an incorrect diagnosis of an African form of chronic lymphocytic leukaemia, which presents with lymphocytosis and splenomegaly rather than lymphadenopathy. In addition, there is some geographical variation in the phenotype of HMS, which may explain some of the diagnostic difficulties. Cases of HMS without raised concentrations of IgM have been described, patients with lymphoma show some response to malarial prophylaxis, hepatic sinusoidal lymphocytosis is also associated with chronic viral infections and chronic lymphocytic leukaemia, and phytohaemagglutinin responses are imprecise. Because histological changes in HMS are not specific and ultrasonography can detect abnormalities of liver texture and vasculature, a liver biopsy is no longer appropriate to confirm a diagnosis of HMS. Current criteria for the diagnosis of HMS are not sufficiently stringent to enable the condition to be reliably distinguished from malignant lymphoproliferative disorders. With the increasing availability of cytotoxic drugs in developing countries, it is vital that this distinction be made. We therefore propose that the criteria for HMS be refined to include: splenomegaly of at least 10 cm below the costal margin; a serum concentration of IgM at least 2 SD above the normal mean concentration for the area; a sustained response to malarial prophylaxis with a reduction in the size of the spleen of at least 40%; and evidence of the polyclonal nature of the lymphocytes—eg, unrestricted use of immunoglobulin light chains or absence of a discrete rearrangement of the immunoglobulin gene. *Imelda Bates, George Bedu-Addo *Haematology Division, St George’s Hospital Medical School, London SW17 0RF, UK; and Haematology Unit, Department of Medicine, Komto Anokyu Teaching Hospital, Kumasi, Ghana
1
2
3
4
5
Hamilton P, Stuiver P, Ziegler J. Splenectomy in tropical splenomegaly syndrome—a five year follow-up. J Trop Med Hyg 1974; 74: 230–32. Crane G, Wells J, Hudson P. Tropical splenomegaly in New Guinea. 1: natural history. Trans R Soc Trop Med Hyg 1972; 66: 724–32. Greenwood B, Fakunle Y. The tropical splenomegaly syndrome. In: the role of the spleen in the immunology of parasitic disease. Basel: Schwabe, 1979: 229–51. Fakunle Y. Tropical splenomegaly. In: Luzzatto L, ed. Clinics in haematology. London: WB Saunders, 1981: 963–75. Bates I, Bedu-Addo G, Rutherford T, Bevan D. Splenic lymphoma with villous lymphocytes in tropical west Africa. Lancet 1992; 340: 575–77.
Vol 349 • April 19, 1997