Reply Karl Vass, MD,*t and Hans Lassmann, MD"$

The ultimate cause of neurological dysfunction in experimen- tal allergic encephalitis (EAE) is still being debated. It was one of Pender and colleagues' significant contributions to EAE research to draw our attention to demyelination as a possible cause for neurological deficit in the course of the disease [1-7]. Although we fully agree that demyelination at the central nervous system (CNS)lperipheral nervous system (PNS) interface and within the ventral and dorsal roots may significantly contribute to development of clinical signs, we think, as stated in our article {SJ, that this cannot be the only explanation. Other factors such as inflammation are of importance as well.

Pender and colleagues' studies document a coincidence of demyelination and clinical signs, but they do not prove that demyelination is the cause of neurological deficit in EAE. In particular, the minimal amount of dem yellnation leading inevitably to clinical manifestation of neurological deficit is not known. Our view that additional factors other than demy- elination significantly contribute to development of clinical signs in EAE result from studies of intrathecal injection of demvelinating EAE sera or specific antibodies. Dependent on the injected antibodies, significant demyelination is found either in the CNS, as shown in our study f81, in the PNS, or in both the CNS and the PNS 19, lo}. In all these conditions, demyelination was more pronounced than we have ever seen in active T-cell-mediated EAE, despite the complete absence of neurological deficit.

Thus, we think our observation of widespread demyelin- ation without T-cell inflammation in the dorsal and ventral root entry zones not resulting in conduction block and neuro- logical symptoms underlines the importance of inflammation. We agree, however, that demyelination of more fibers of critical functional pathways than induced by our model is also able to induce neurological signs.

*Neurological InItitute ?Department of Neurohgy University of Vienna $Research Unit for Experimental Neuropathology Austrian Academy of Sciences Vienna, Austvia

Refeveencej 1.

2.

3.

4.

5.

Pender MP. The pathophysiology of acute experimental allergic encephalomyelitis induced by whole spinal cord in the Lewis rat. J Neurol Sci 1988;84:209-222 Pender MP. Demyelination and neurological signs in experi- mental allergic encephalomyelitis. J Neuroimmunol 1987; 15:

Pender MP. Demyelination of the peripheral nervous system causes neurologic signs in myelin basic protein-induced experi- mental allergic encephalomyelitis: implications for multiple scle- rosis. Ann NY Acad Sci 1988;540:732-734 Pender MP. Conduction block due to demyelination at the ven- tral root exit zune in experimental allergic encephalomyelitis. Brain Res 1986;367:398-401 Pender MP, Nguyen KB, Willenborg DO. Demyelination and early remyelination in experimental allergic encephalomyelitis

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passively transferred with myelin basic protein-sensitized lym- phocytes in the Lewis rat. J Neuroimmunol 1989;25:125-142 Pender MP, Sears TA. Involvement of the dorsal root ganglion in acute experimental allergic encephalomyelitis in the Lewis rat. A histological and electrophysiological study. J Neurol Sci 1986;

Pender MP, Seats TA. Nerve conduction block in the periph- eral nervous system in experimental allergic encephalomyelitis. Nature 2982;296860-862 Vass K, Heininger K, Schder 3, et al. Interferon-y potentiates antibody-mediared demyelination in vivo. Ann Neurol 1392; 32:198-206 Iassmann H, Kitz K, Wisniewski HM. In vivo effect of sera from animals with chronic relapsing experimental encephalomy- elitis on central and peripheral myelin. Acta Neuropathol 198 1; 5 5:297-306 Lassmann H, Stemberger H, Kitz K, et al. In vivo demyelinating activity of sera from animals with chronic experimental allergic encephalomyelitis: antibody nature of the demyelinating factor and the role of complement. J Neurol Sci 1983;59:123-137

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Alpha-tocopherol Levels in ParkinsGnian Brains Serge Przedborski, MD, Vernice Jackson-Lewis, MS, and Uday Muthane, M D

Because of our major interest in the oxidative stress hypothe- sis in Parkinson's disease (PD) and in the use of antioxidant therapy to slow down or to prevent the progression of this disorder, we read with great interest the study on brain alpha- tocopherol levels in patients with PD published by Dexter and colleagues { 11. We offer the following comments.

First, these authors measured brain concentrations of alpha-tocopherol in patients with PD; they anticipated re- duced levels based on the free radical theory of PD. It is important to note that, thus far, low levels of alpha- tocopherol, as found in vitamin E deficiency, have not been associated with the degeneration of the nigrostriatal dopa- minergic pathway {2} so characteristic of PD. Hence, we were not surprised that the authors did not find reduced levels of alpha-tocopherol in the brains of patients with PD as compared with normal aged-matched control subjects.

Second, we would like to emphasize that the reported absence of reduced levels of alpha-tocopherol in P D brains should not undermine the usefulness of high-dose vitamin E administration to patients with PD, as was advocated by Fahn E31. Indeed, normal levels of vitamin E do not necessarily indicate that administration of vitamin E (to increase its con- centration in the brain 143) would be of no benefit in patients with PD. For example, although no vitamin C deficiency is found in Chediak-Higashi syndrome, high-dose supplemen- tation of vitamin C significantly improves the patient neutro- phi1 function [ 5 ] .

Third, the authors mention the growing body of evidence supporting impaired mitochondrial function in the brains of patients with P D {b}. Because mitochondria are a major site of free radical production and because both mitochondrial

560 Annals of Neurology Vol 33 No 5 May 1993

outer and inner membranes contain high amounts of alpha- tocopherol [7}, it may have been relevant to assess alpha- tocopherol levels in the brain mitochondria as well.

The Movement Disorder Group Department of Neurolou Columbia University New York, NY 10032

Refeerences 1. Dexter DT, Ward RJ, Wells FR, et al. a-Tocopherol levels in

brain are not altered in Parkinson’s disease. Ann Neurol 1992;

2. Nelson JS, Fitch CD, Fische W, et al. Progressive neuropatho- logic lesions in vitamin E deficient Rhesus monkeys. J Neuropa- tho1 E x p Neurol 1981;40:166-186

3. Fahn S. A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parlunson’s disease. Ann Neurol 1992;32:S1284132

4. Vatassery GT, Brin MF, Fahn S , et al. Effect of high doses of dietary vitamin E on the concentration of vitamin E in several brain regions, plasma, liver, and adipose tissue of rats. J Neuro- chem 1988;5 1:62 1-623

5. Boxer LA, Watanabe AM, Ester M, et al. Correction of leuko- cyte function in Chediak-Higashi syndrome by ascorbate. N Engl J Med 1976;295:1041-1045

6. Schapira AHV, Cooper JM, Dexter DT, et al. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 1990;

7. Thomas SM, Gebicki JM, Dean RT. Radical initiated alpha- tocopherol depletion and lipid peroxidation in mitochondrial membranes. Biochim Biophys Acra 1989;1002;189-197

32:591-593

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Reply D. T. Dexter, PhD,’ P. Jenner, DSc,’ and C. D. Marsden, FRSt

We thank Przedborski and colleagues for their comments on our recent article on alpha-tocopherol levels in parkinsonian brains 111. We agree that the normal alpha-tocopherol levels in the substantia nigra and other brain areas in Parkinson’s disease do not preclude the possible value of high-dose vita- min E administration to patients with PD. As we pointed out in the Discussion of our results, vitamin C and glutathione can regenerate alpha-tocopherol; therefore, its levels may be preserved at the expense of other antioxidants. There is a range of evidence to indicate ongoing oxidative stress in the substantia nigra in Parkinson’s disease [Z], so antioxidant therapy may be beneficial.

W e also agree that it would be interesting to measure alpha-tocopherol levels in mitochondrial fractions from brain; however, there are practical difficulties, because the substan- tia nigra is a small structure yielding only a few milligrams of tissue. With regard to the effect of vitamin E deficiency on the nigrostriatal dopaminergic pathway, Von Voigtlander and associates 131 demonstrated reduced striatal dopamine levels in vitamin E deficient rats. In addition, we have found a reduction of 3H-mazindol binding in the striaturn in rats ren- dered vitamin E deficient for 1 year, suggesting nigrostriatal dopaminergic dysfunction (in unpublished observations). Furthermore, positron emission tomography in 2 patients with life-long vitamin E deficiency associated with abetalipo- protanemia revealed a significant reduction of 18F-dopa up- take (unpublished observations). Accordingly, there is evi- dence that vitamin E deficiency can damage the nigrostriatal system.

‘Parkinson’s Disease Society Experimental Research Laboratories Phannacology Group Biomedical Sciences Division King’s College London f University Department of Clinical Neurology Institute of Neurology National Hospital far Neurology and Neurosuvge y London, UK

References 1. Dexter DT, Ward RJ, Wells FK, et al. a-Tocopherof levels in

brain are not altered in Parkinson’s disease. Ann Neurol 1992;

2. Jenner P, Dexter DT, Sian J, et al. Oxidative stress as a cause of nigral cell death in Parkinson’s disease and incidental Lewy body disease. Ann Neurol 1992;32:S82-S87

3. Von Voigtlander PF, Burian MA, Althaus JS, Williams LR. Ef- fects of chronic haloperidol on vitamin E levels and monoamine metabolism in rats fed normal and vitamin E deficient diets. Res Commun Chem Pathol Pharmacol 1990;68:343-352

32:591-593

Correction The terms maternal gene and paternal gene were inadver- tently transposed in Dr Lewis P. Rowlands’s reply to Dr Andrew J. Kornberg’s letter (Ann Neurol 1993;33:325) regarding molecular genetics in neu- rology.

Annals of Neurology Vol 33 No 5 May 1993 561