Cerebrospinal Fluid Oligoclonal Proteins in Amyotrophic Lateral
Sclerosis
To the Editor.\p=m-\Accordingto the studies of others' and confirmed by our own technique,2 elevated levels of CSF IgG and oligoclonal banding of immunoglobulins are often found in subacute sclerosing panencephalitis, progressive rubella panencephalitis, and multiple sclerosis. In each of these illnesses, persistent viral infection and/or dysimmune mechanisms have been implicated. With the rationale that these CSF abnormalities may be markers of such mechanisms, we have examined the CSF of 11 patients with amyotrophic lateral sclerosis. IgG levels were determined using CSF immunoelectrophoresis. For protein electrophoresis, CSF was concentrated 50 times with Amicon B15 concentrators. Samples were applied to agarose gel and underwent electrophoresis at 200 V for 45 minutes.
Slides were fixed and stained with amido black. Each pattern was read by
investigators. protein values ranged from 20 to 66 mg/dl (mean, 47 mg/dl). Ten of 11 patients had normal CSF IgG levels, ranging from 6 to 11 mg/dl. In one patient, the level was 17 mg/dl (normal, up to 16 mg/dl). The CSF protein patterns were normal, no evidence of an oligoclonal band being present in any patient. These findings fail to support a role for a persistent viral infection in amyotrophic lateral sclerosis. Al¬ though they do not exclude viral etiol¬ ogy, they demonstrate that if a virus is the cause, it must be a persistent, two
demonstrating oligoclonal immunoglobulin bands. Neurolgy 27:273-277, 1977. 2. Houff SA, Schumacher GL, Leinikki PO, et al: Multiple sclerosis: Association with virus antibodies, in situ CNS IgG synthesis, and oligoclonal IgG. Neurology 27:372, 1977. 3. Richardson EP: Our evolving understanding of progressive multifocal leukoencephalopathy. Ann NY Acad Sci 230:358-364, 1974. 4. Asher OM, Gibbs CJ, Gajdusek DC: Pathogenesis of subacute spongiform encephalopa-
tems.3-4
B. T.
Adornato, MD
S. A. Houff, MD W. K. Engel, MD
J. L. Sever, MD Medical Neurol Branch and Infectious Dis Branch
NINCDS Natl Institutes of Health Bldg 10, Rm 10D118 Bethesda, MD 20014 1. Johnson KP, Arrigo SC, Nelson BJ, et al: Agarose electrophoresis of cerebrospinal fluid in multiple sclerosis: A simplified method for
Gustavo Roman, MD Dept of Neurol Univ of Vermont Burlington, VT 05401 Gabriel Toro, MD Dept of Neurol National Univ of Colombia School of Med Bogota, Colombia, SA
thies. Ann Clin Lab Sci 6:84-102, 1976.
Cerebral Malaria To the Editor.\p=m-\Iwas interested to read the article on cerebral malaria in the Archives (35:271-275, 1978). I was surprised that there was no mention of the effect of blood sludging on the brain circulation that occurs in malaria as described by Knisely et al1 that outlines some of the mechanical factors involved in brain damage with malaria. Experimental findings of Knisely et al coincide with our therapeutic findings on the beneficial effects of anticoagulant therapy in senile and presenile dementia.2 It strikes me that further research along these lines would be very useful in that from a therapeutic point of view, the use of anticoagulant therapy might prevent cerebral damage and even death resulting from malaria. Arthur C. Walsh, MD 121 University PI Pittsburgh, PA 15213
Total
unconventional infection that does not stimulate a measurable immunoglobu¬ lin response, like that in progressive multifocal leukoencephalopathy and in the transmissible spongiform encephalopathies, both of which have normal IgG levels and protein pat¬
response of the host to the parasite and that this vasculopathy is the main and potentially treatable cause of cerebral malaria. However, we agree with Dr Walsh in that further research in this area is warranted. mune
Knisely MH, Stratman-Thomas WK, Eliot monkeys: II. A first step in the separation of the mechanical pathologic circulatory factors in one sludge disease from possible specific toxic factors of that disease. Angiology 15:411-416, 1964. 2. Walsh AC, Walsh BH: Presenile dementia: Further experience with an anticoagulant\p=m-\ psychotherapy regimen. J Am Geriatr Soc 1.
TS,
et al: Knowlesi malaria in
24:467-472, 1974.
In Reply. We did mention sludging of the circulation and "plugging" of the cerebral capillaries by clumped erythrocytes among the numerous factors that have been implicated in the pathogenesis of cerebral malaria,
although inadvertently, no reference to the pioneer work of Knisely et al1-4
made. We also referred to the work of Dennis et al5-6 on the use of heparin in the treatment of malaria. Many factors related to the role of the parasitized erythrocyte have been implicated in the pathogenesis of cerebral malaria, but the point we wanted to emphasize was that the alterations of the vascular permeability and the obstruction of the circulation occur before the plugging of the vessels by the RBCs, as clearly demonstrated by Maegraith.7 We strongly believe that this early alteration of the vasculature is the result of the imwas
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/12/2015
Knisely MH, Stratman-Thomas WK, Eliot Capillary circulation in the malarial infected monkey: A cinematographic study. JAMA 1.
TS:
116:2430-2431, 1941. 2. Knisely MH, Stratman-Thomas WK, Eliot TS, et al: Knowlesi malaria in monkeys: I. Microscopic pathological circulatory physiology of
rhesus monkeys during acute plasmadium Knowlesi malaria in monkeys. J Nat Malaria Soc 4:285-300, 1945. 3. Knisley MH, Stratman-Thomas WK, Eliot TS, et al: Knowlesi malaria in monkeys: II. A first step in the separation of the mechanical pathologic circulatory factors in one sludge disease from possible specific toxic factors of that disease. Angiology 15:411-416, 1964. 4. Knisely MH: The settling of sludge during life: First observations, evidences, and significances: A contribution to the biophysics of disease. Acta Anat 44(suppl 41):1-64, 1961. 5. Dennis LH, Eichelberg JW, Irman MM, et al: Depletion of coagulation factors in drugresistant Plasmodium falciparum malaria. Blood 29:713-721, 1967. 6. Dennis LH, Conrad ME: Anticoagulant and antimalarial action of heparin in simian malaria. Lancet 1:769-771, 1968. 7. Maegraith B: Other pathological processes in malaria. Bull WHO 50:187-193, 1974.
Birth Risk and Left-Handedness Reconsidered
To the Editor.\p=m-\Ina note in the Archives (33:664, 1976), Leviton and Kilty presented data that they claim supported Bakan's1.2 hypothesis that left-handedness results from left\x=req-\ hemispheric brain injury associated with perinatal factors. In this letter, we shall discuss critically this issue and Leviton and Kilty's contribution to it and present data that have a direct bearing on the validity of Bakan's hypothesis. In his original study, Bakan1 found for male university students, that left-handedness is more likely to occur in the progeny of high-risk birth orders, ie, first and fourth (plus) born. In delineating the rationale for their research, Leviton and Kilty have, correctly, called attention to the fact that the studies3.4 that have failed to
replicate Bakan1
were
inadequately
conceived because they both failed to consider sex as a separate variable. In their study, Leviton and Kilty measured the relationship between the
Sclerosis
To the Editor.\p=m-\Accordingto the studies of others' and confirmed by our own technique,2 elevated levels of CSF IgG and oligoclonal banding of immunoglobulins are often found in subacute sclerosing panencephalitis, progressive rubella panencephalitis, and multiple sclerosis. In each of these illnesses, persistent viral infection and/or dysimmune mechanisms have been implicated. With the rationale that these CSF abnormalities may be markers of such mechanisms, we have examined the CSF of 11 patients with amyotrophic lateral sclerosis. IgG levels were determined using CSF immunoelectrophoresis. For protein electrophoresis, CSF was concentrated 50 times with Amicon B15 concentrators. Samples were applied to agarose gel and underwent electrophoresis at 200 V for 45 minutes.
Slides were fixed and stained with amido black. Each pattern was read by
investigators. protein values ranged from 20 to 66 mg/dl (mean, 47 mg/dl). Ten of 11 patients had normal CSF IgG levels, ranging from 6 to 11 mg/dl. In one patient, the level was 17 mg/dl (normal, up to 16 mg/dl). The CSF protein patterns were normal, no evidence of an oligoclonal band being present in any patient. These findings fail to support a role for a persistent viral infection in amyotrophic lateral sclerosis. Al¬ though they do not exclude viral etiol¬ ogy, they demonstrate that if a virus is the cause, it must be a persistent, two
demonstrating oligoclonal immunoglobulin bands. Neurolgy 27:273-277, 1977. 2. Houff SA, Schumacher GL, Leinikki PO, et al: Multiple sclerosis: Association with virus antibodies, in situ CNS IgG synthesis, and oligoclonal IgG. Neurology 27:372, 1977. 3. Richardson EP: Our evolving understanding of progressive multifocal leukoencephalopathy. Ann NY Acad Sci 230:358-364, 1974. 4. Asher OM, Gibbs CJ, Gajdusek DC: Pathogenesis of subacute spongiform encephalopa-
tems.3-4
B. T.
Adornato, MD
S. A. Houff, MD W. K. Engel, MD
J. L. Sever, MD Medical Neurol Branch and Infectious Dis Branch
NINCDS Natl Institutes of Health Bldg 10, Rm 10D118 Bethesda, MD 20014 1. Johnson KP, Arrigo SC, Nelson BJ, et al: Agarose electrophoresis of cerebrospinal fluid in multiple sclerosis: A simplified method for
Gustavo Roman, MD Dept of Neurol Univ of Vermont Burlington, VT 05401 Gabriel Toro, MD Dept of Neurol National Univ of Colombia School of Med Bogota, Colombia, SA
thies. Ann Clin Lab Sci 6:84-102, 1976.
Cerebral Malaria To the Editor.\p=m-\Iwas interested to read the article on cerebral malaria in the Archives (35:271-275, 1978). I was surprised that there was no mention of the effect of blood sludging on the brain circulation that occurs in malaria as described by Knisely et al1 that outlines some of the mechanical factors involved in brain damage with malaria. Experimental findings of Knisely et al coincide with our therapeutic findings on the beneficial effects of anticoagulant therapy in senile and presenile dementia.2 It strikes me that further research along these lines would be very useful in that from a therapeutic point of view, the use of anticoagulant therapy might prevent cerebral damage and even death resulting from malaria. Arthur C. Walsh, MD 121 University PI Pittsburgh, PA 15213
Total
unconventional infection that does not stimulate a measurable immunoglobu¬ lin response, like that in progressive multifocal leukoencephalopathy and in the transmissible spongiform encephalopathies, both of which have normal IgG levels and protein pat¬
response of the host to the parasite and that this vasculopathy is the main and potentially treatable cause of cerebral malaria. However, we agree with Dr Walsh in that further research in this area is warranted. mune
Knisely MH, Stratman-Thomas WK, Eliot monkeys: II. A first step in the separation of the mechanical pathologic circulatory factors in one sludge disease from possible specific toxic factors of that disease. Angiology 15:411-416, 1964. 2. Walsh AC, Walsh BH: Presenile dementia: Further experience with an anticoagulant\p=m-\ psychotherapy regimen. J Am Geriatr Soc 1.
TS,
et al: Knowlesi malaria in
24:467-472, 1974.
In Reply. We did mention sludging of the circulation and "plugging" of the cerebral capillaries by clumped erythrocytes among the numerous factors that have been implicated in the pathogenesis of cerebral malaria,
although inadvertently, no reference to the pioneer work of Knisely et al1-4
made. We also referred to the work of Dennis et al5-6 on the use of heparin in the treatment of malaria. Many factors related to the role of the parasitized erythrocyte have been implicated in the pathogenesis of cerebral malaria, but the point we wanted to emphasize was that the alterations of the vascular permeability and the obstruction of the circulation occur before the plugging of the vessels by the RBCs, as clearly demonstrated by Maegraith.7 We strongly believe that this early alteration of the vasculature is the result of the imwas
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/12/2015
Knisely MH, Stratman-Thomas WK, Eliot Capillary circulation in the malarial infected monkey: A cinematographic study. JAMA 1.
TS:
116:2430-2431, 1941. 2. Knisely MH, Stratman-Thomas WK, Eliot TS, et al: Knowlesi malaria in monkeys: I. Microscopic pathological circulatory physiology of
rhesus monkeys during acute plasmadium Knowlesi malaria in monkeys. J Nat Malaria Soc 4:285-300, 1945. 3. Knisley MH, Stratman-Thomas WK, Eliot TS, et al: Knowlesi malaria in monkeys: II. A first step in the separation of the mechanical pathologic circulatory factors in one sludge disease from possible specific toxic factors of that disease. Angiology 15:411-416, 1964. 4. Knisely MH: The settling of sludge during life: First observations, evidences, and significances: A contribution to the biophysics of disease. Acta Anat 44(suppl 41):1-64, 1961. 5. Dennis LH, Eichelberg JW, Irman MM, et al: Depletion of coagulation factors in drugresistant Plasmodium falciparum malaria. Blood 29:713-721, 1967. 6. Dennis LH, Conrad ME: Anticoagulant and antimalarial action of heparin in simian malaria. Lancet 1:769-771, 1968. 7. Maegraith B: Other pathological processes in malaria. Bull WHO 50:187-193, 1974.
Birth Risk and Left-Handedness Reconsidered
To the Editor.\p=m-\Ina note in the Archives (33:664, 1976), Leviton and Kilty presented data that they claim supported Bakan's1.2 hypothesis that left-handedness results from left\x=req-\ hemispheric brain injury associated with perinatal factors. In this letter, we shall discuss critically this issue and Leviton and Kilty's contribution to it and present data that have a direct bearing on the validity of Bakan's hypothesis. In his original study, Bakan1 found for male university students, that left-handedness is more likely to occur in the progeny of high-risk birth orders, ie, first and fourth (plus) born. In delineating the rationale for their research, Leviton and Kilty have, correctly, called attention to the fact that the studies3.4 that have failed to
replicate Bakan1
were
inadequately
conceived because they both failed to consider sex as a separate variable. In their study, Leviton and Kilty measured the relationship between the
