The Axon Returns to Favor in Multiple Sclerosis Pathology

The Axon Returns to Favor

in Multiple Sclerosis Pathology

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Nov- Dec 99	Rank Last Period Sep- Oct 99
1	B. Fisher, et al., "Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study," J. Natl. Cancer Inst., 90(18):1371-88, 16 September 1998. [10 U.S. and Canadian institutions] *120NT	40	7
2	F.J. Palella, et al., "Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection," New Engl. J. Med., 338(13):853-60, 26 March 1998. [5 U.S. institutions] *ZD284	33	1
3	S. Hulley, et al., "Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women," JAMA-J. Amer. Med. Assoc., 280(7):605-13, 19 August 1998. [U. Calif. San Francisco; Johns Hopkins U., Baltimore, MD; Wake Forest U. Sch. Med., Winston-Salem, NC; Wyeth-Ayerst Res., Radnor, PA] *110ME	33	3
4	L. Hansson, et al., "Effects of intensive blood-pressure- lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial," The Lancet, 351(9118):1755-62, 13 June 1998. [10 institutions worldwide] *ZU444	30	4
5	F.O. Nestle, et al., "Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells," Nature Medicine, 4(3):328-32, March 1998. [U. Zurich Med. Sch., Switzerland; U. Heidelberg, Germany; U. Munstervon, Munster, Germany] *ZN163	29	8
6	J.R. Downs, et al., "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS," JAMA-J. Amer. Med. Assoc., 279(20):1615-22, 27 May 1998. [7 U.S. institutions] *ZP489	29	9
7	B.D. Trapp, et al., "Axonal transection in the lesions of multiple sclerosis," New Engl. J. Med., 338(5):278-85, 29 January 1998. [Cleveland Clinic Fdn., OH; Haukeland Hosp., Bergen, Norway] *YT963	25	†
8	D.M. Eisenberg, et al., "Trends in alternative medicine use in the United States, 1990-1997: Results of a follow-up national survey," JAMA-J. Amer. Med. Assoc., 280(18):1569-75, 11 November 1998. [Beth Israel Deaconess Med. Ctr., Boston, MA; Harvard Med. Sch., Boston] *136GX	23	†
9	I. Goldstein, et al., "Oral sildenafil in the treatment of erectile dysfunction," New Engl. J. Med., 338(20):1397-1404, 14 May 1998. [6 U.S. institutions] *ZM667	22	†
10	P. McLaughlin, et al., "Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program," J. Clin. Oncol., 16(8):2825-33, August 1998. [11 U.S. institutions] *107NT	22	†

SOURCE: ISI's Hot Papers Database. Read the full legend.

ultiple sclerosis is usually described as a demyelinating disease, a reference to damage to the protective, electrically insulating myelin sheath that surrounds the axons, the long filaments that carry impulses over long distances. Traditionally, the axons themselves were thought to be spared in this disease. Even in chronically demyelinated axons conduction can be restored by an increase in the density of sodium channels. However, if the axon degenerates (becomes transected), that is that; no action potential can reach the postsynaptic neuron, and the situation is not reversible. In therapeutic multiple-sclerosis research, much effort has been devoted to tackling the inflammation and trying to slow down the demyelination or even to restore myelin.

There have been hints before but Bruce D. Trapp and his colleagues from the Cleveland Clinic Foundation, Ohio, and the Haukeland Hospital in Bergen, Norway, have brought axonal transection center stage in multiple sclerosis (paper # 7).

This is a purely histologic study, making use of advanced staining and three-dimensional microscope techniques to look at post-mortem brain tissue from patients with multiple sclerosis. It is not typical of the papers one finds in general clinical journals such as the New England Journal of Medicine, and perhaps that fact alone testifies to its potential importance.

One of the "stains" was an antibody to non-phosphorylated neurofilament known as SMI-32. Normal axons are not positive with this antibody. All 47 of the multiple-sclerosis lesions studied by the team were positive. Eighteen lesions (from five patients) were studied quantitatively by calculating the number of terminal axonal ovoids, representing transection, in a cubic millimeter of brain. For the five active lesions this number averaged an astonishing 11,236. Fewer than 1 per c.mm. are found in white matter from control brain. Even in the inactive centers of the chronic active lesions the average was 875. A typical lesion in active multiple sclerosis would therefore contain several million transected axons.

In an accompanying editorial, Stephen G. Waxman draws a symmetry with observations in some traumatic spinal-cord injuries where surviving axons cannot function through demyelination. Maybe a rethink is needed here and in multiple sclerosis. Such a rethink may not be easy. "Chapters on ‘demyelinating’ diseases will not necessarily become shorter as a result of the reclassification of multiple sclerosis as an ‘axonal’ disorder," he says (New Engl J. Med., 338: 323-25, 1998).

In a review article published some 18 months after paper # 7, Trapp and colleagues list four avenues down which their findings point (see Curr. Opin. Neurol., 12:295-302, 1999). These include a search for surrogate markers for early axonal loss and the need for disease-modifying therapy to begin early. At the clinical level much will now depend on how successfully research on so-called neuroprotective agents proceeds.

Mr. David W. Sharp, MA (Cambridge) is Deputy Editor of The Lancet, London, U.K.