Editorial
By the late 17th century, as far as the nervous system was concerned, not much had changed for over two millennia since the Greeks and Romans rationalized existing ideas on the nature of disease (see The Concept of Disease, Walter Riese, 1953). But as Samuel Ludwin makes clear in ‘A tale of two books: milestones on the path to understanding multiple sclerosis’ (page 2224), medical history is not just the record of dates and details; rather, it describes the climate in which discoveries were made and mistakes perpetuated, with all the handicaps and weightings of social context. Magic medicine ignored the sick individual as a source of information. Plato (427–327 BC) believed in health as a state of harmony; disease was an excess, alteration or relocation of earth, fire, air and water (the body) and ‘soul’. Hippocrates (460–377 BC) internalized medicine, relating disease to the individual and illustrated his ideas with case histories describing the onset, duration and outcome of symptoms. For Galen (130–200 AD), disease had a locus and a pathological process, but function altered first and disordered structure followed. It was a short step to extend the concept of physiology (Francis Glisson: 1597–1677) to the pathological process (Frascatoro: 1484–1553). The work of Leonardo da Vinci (1452–1515) moved neurological attention from functions dependent on the contents of the ventricles to a real anatomy. This was much improved by Andreas Vesalius (1514–1564) who doubted that his anatomy could ever illuminate matters relating to the soul. He considered the human body to be the servant of harmony. But as for how it all worked, Kenelme Digby (1603–1665) was still advancing Platonic ideas on the nervous system; and even William Harvey (1578–1657) left the brain to the attentions of others. Beyond the experimentalists and iatrochemists who fashioned neuroscience in the 1660s, lay the concepts of natural history, detected by observation over time (Sydenham: 1624–1689; and Baglivi: 1669–1707), the anatomical seat of disease (Morgagni: 1682–1771) and the final transition from alteration in vital properties to the notion of cellular (dis)organization (Rudolph Virchow: 1821–1902). Today, we encapsulate these evolving concepts under the rubrics of aetiology, mechanisms and treatment. But not every disorder falls neatly into place. Reviewing McAlpine’s Multiple Sclerosis (4th edition) and Multiple Sclerosis as a Neuronal Disease, edited by Steven Waxman, as a distinguished neuropathologist, whose own work pioneered many ideas on axonal–glial interactions and the biology of remyelination—and an astute observer of the art, science and societal relationships of medicine—Professor Ludwin is well qualified to chart the erratic course of disease concepts and knowledge concerning multiple sclerosis, leading to our still imperfect understanding of that difficult disease, or collection of disorders, and the security or otherwise of the handles on which hang contemporary thoughts concerning its aetiology, mechanisms and treatment.Each of these books acknowledges information gathered from the use of animal models. In the present issue, Ralf Gold, Christopher Linington and Hans Lassmann critically review the 70 years of activity in experimental allergic encephalomyelitis since Thomas Rivers first described the prototypic version in monkeys—fed bananas for breakfast, bread for lunch, hot milk for supper and raw carrots or roasted peanuts as treats—acknowledging the limitations but identifying the achievements and insights yet to be realized from this model, used on an industrial scale and richly funded by hopeful sponsors for several decades (page 1935). On the same topic, Manuel Friese and co-authors from Oxford, UK, and Barcelona, Spain, take on board the low dividend for validating treatments that work in these models for the target disease, multiple sclerosis, and suggest an improved strategy based on drug evaluation in humanized mouse models (page 1940). Doron Merkler and colleagues from Munich and Göttingen, Germany, describe a new variant of experimental allergic encephalomyelitis that models an aspect currently of intense interest in multiple sclerosis—the cortical lesion—by stereotactic immunological injury of the primed rodent cortex; the lesions resolve spontaneously and by remyelination (page 1972). Katsuichi Miyamoto and investigators from the National Institute of Neuroscience, the University of Kinki and Minami-Kyoto National Hospital, Japan, add the complex activities of a new-generation cyclooxygenase-2 (COX-2) inhibitor to the list of molecules that may put a spanner in the immunological works of inflammatory brain disease, using both direct inhibition and manipulation of experimental allergic encephalomyelitis in COX-2-deficient transgenic mice (page 1984).
Amongst three papers on involuntary movements and hyperactivity, Stephan Bohlhalter and colleagues from the National Institute of Neurological Disorders and Stroke, USA (including our Associate Editor, Mark Hallett) identify a brain network based on the paralimbic system that precedes the onset but then switches to a sensorimotor circuit involving the superior parietal lobule and cerebellum immediately before the appearance of motor and vocal tics in Tourette’s syndrome (page 2029)—as previously implicated for irritating sensations such as pain and itch. Happily, Brain receives many high quality papers in the field of neurogenetics. In the present issue, we include the reports of two new disorders: Martine Tétreault and a team from Montreal and Saguenay, Québec, Canada, describe a form of recessive congenital muscular dystrophy that maps to 3p23-21, introduced by a founder into the French–Canadian population (page 2077); and Giuliano Tomelleri and collaborators from Verona and Vicenza, Italy, describe four (sporadic and familial) cases of myopathy associated with sarcoplasmic or endoplasmic reticulum calcium 1 ATPase having calsequestrin inclusions, representing a new surplus protein myopathy (page 2085). On page 2061, Clarke Slater and investigators from Newcastle, Oxford and Bath (UK) describe, in meticulous electrophysiological and histological detail, a series of cases having limb girdle myasthenia. In his commentary on this paper, Andrew Engel concludes with the need to identify the molecular defect responsible for this variant of impaired neuromuscular transmission. We understand informally from the authors that this is now achieved and await publication of their findings—complementing the definitive account of this phenotype appearing in our current issue—with interest. Papers on peripheral nerve disorders (two also of genetics interest) include an analysis of Ross syndrome from which tonic pupil and areflexia occur together with segmental anhidrosis: Maria Nolano and colleagues from Telese Terme, Naples and Bologna, Italy, suggest that its rarity is more apparent than real, and they identify clinical and histological features that distinguish Ross syndrome for the disorder described by (Sir) Gordon Holmes and WJ Adie, and other segmental disorders of sweating (page 2119). Five papers describe aspects of stroke. We publish a normative study from Joel Feekes and Martin Cassell (Iowa City, USA) correlating functional compartments and microvascular territories in the human striatum—not altogether a new subject for study (see From the Archives, Brain 2006: 128; 2219–2221)—in which sensorimotor, associative and limbic zones map to the lateral lenticulostriate, medial lenticulostriate and recurrent artery of Huebner vascular territories, respectively (page 2189 and see cover); the high frequency of non-anastomic vessels in the matrisome renders this structure especially vulnerable to symptomatic lacunar infarctions. Ahmed Al’Qteishat and investigators from the new combined University of Manchester, and the University of Liverpool (United Kingdom) and the University of Bellvitge, Barcelona (Spain), suggest that angiogenesis may re-vascularize the penumbra and reduce tissue damage in stroke; they identify systemic and local production of hyaluronan (an extracellular matrix molecule that regulates new vessel formation by acting on receptors found on a variety of cell types in the vicinity of ischaemic injury), its metabolites and catabolites as correlates of ischaemic injury that participate in the complex interplay of inflammation and remodelling that constitutes the response to injury and tissue repair (page 2158).
At a time when the admission of experiences that defy conventional wisdom risked accusations of possession by the devil, and invited social retributions of ultimate severity (in medieval times, many thousands of women were burned at the stake on this logic), to declare form, position and voluntary movement of a missing limb must have been a risky business. Little wonder that (apart from a brief mention by Ambrose Paré) the literature on phantom limbs and body shape remained relatively silent until recent times even though the phenomenon(a) ‘must be as old as survival from amputation itself ... Admiral Lord Nelson believed that the phantom fingers of his amputated arm provided a direct proof of the existence of the soul’. These quotes are from the Presidential Address given by Dr George Riddoch to the Neurological Section of the Royal Society of Medicine (London) in 1941. On pages 2211 and 2202, Karen Reilly and Catherine Mercier with colleagues from Lyon (France), Rochester, New York (USA), Rio de Janeiro (Brasil) and Hamel, Québec (Canada) explore the ambiguity, whereby, following amputation, cortical representation of the missing part shrinks but the perceptual apparatus supporting sensory and motor qualities does not. In the first paper, transcranial magnetic stimulation is used to map cortical representation of the surviving stump muscles and the phantom movements; to show that the substrates for hand movement survive in the reorganized cortex post-amputation; and that even though these cannot necessarily be accessed, they are activated during the phantom experience. Their second paper moves this story to the periphery and records electrical activity from the stump muscles during phantom movements, demonstrating patterns that differ from those observed in corresponding muscles from the intact limb; manipulation of the peripheral neuronal apparatus by ischaemia perturbs these events, allowing the authors to conclude that phantom movements depend on the activation of surviving cortical hand motor commands that now re-target the stump so as to instruct those muscles to mimic their erstwhile role, as if limb movements were still happening. In From the Archives, we review George Riddoch’s Presidential Address (Phantom limbs and body shape. By George Riddoch. Brain 1941: 64; 197–222).
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Related articles in Brain:
- From the Archives
- Alastair Compston
Brain 2005 128: 2219-2221.[Extract] [FREE Full Text]
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