EDITORIAL 695 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.6.697 on 1 June 2003. Downloaded from

Multiple sclerosis activated or cells ...... with in the course of axonal injury. Such cells are consistently found in close contact with degenerating Axonal injury in multiple sclerosis axons. Many of their toxic effector molecules may lead to axonal injury, H Lassmann although a direct injurious effect has so far only been shown for proteases10 and ...... reactive nitrogen species.11 In particular, Renewed interest in axonal destruction in MS nitric oxide (NO) intermediates are par- ticularly attractive candidates. At low concentration they may induce func- ultiple sclerosis (MS) is an in- in two different ways. During acute tional conduction block, thus explaining flammatory demyelinating dis- demyelination high numbers of axons clinical deficit in the absence of overt Mease, which implies that are damaged, most likely by the action of structural damage.12 At higher concen- sheaths are the primary target in the toxic inflammatory mediators. This trations, and in particular when axons destructive process. However, this pri- phase of massive axonal injury, however, are electrically active, NO derivatives mary demyelinating process is inevitably lasts only for a few days to weeks. In may lead to irreversible destruction of associated with axonal injury and de- contrast a low grade axonal degenera- axons.13 This may in part be accom- struction, which is variable in its extent tion occurs in silent inactive plaques. plished by the blockade of mitochondrial between different plaques of the same Although only few axons are destroyed function and the disturbance of energy patients and even more variable between at a given time point, such lesions may metabolism, which can be induced by persist in the CNS for years. Thus, this 14 lesions of different patients. Axonal NO radicals. In addition, they may low burning axonal injury may account pathology has been noted in the earliest interfere with synaptic conduction and more to the global axonal loss in MS pathological descriptions of the disease may even directly damage nerve cell than axonal degeneration in acute and its cause and functional conse- bodies and dendrites. As nitric oxide plaques and it may in part also explain quences have been discussed in detail in intermediates can also be involved 1 the slow progression of clinical disability the early 20th century. However, when it in demyelination and oligodendroglia in the chronic progressive phase of the became clear from experimental studies damage, these molecules seem to be par- disease. that an inflammatory demyelinating dis- ticularly attractive candidates in the So far only limited data are available ease similar to MS can be induced by pathogenesis of tissue damage in MS.11 on the mechanisms of axonal injury and autoimmunity against myelin antigens, In addition to toxins produced by T cells destruction. Not all axons are affected in the interest in axonal injury vanished. It and macrophages, specific the same way. Overall, small calliber only reappeared when recent MRI inves- may be involved in the initiation of tigations provided increasing evidence axons are more vulnerable to damage in MS plaques compared with thick fibres.6 axonal injury. In other patients or lesions for axonal and neuronal loss in MS tissue damage occurs through a hypoxia 1 When considering the molecular mecha- brains. nisms of axonal damage, two different like metabolic injury, which may be par- Detailed quantitative studies on ax- phases of axonal disintegration have to ticularly effective in augmenting NO onal injury and loss in MS appeared in 15 be distinguished: the trigger of axonal mediated axonal destruction. the late 1990s. Using amyloid precursor damage and the downstream pathways The trigger activates several down- protein (APP) as a marker for acute of axonal dissolution (see fig 1). Al- stream events, which in a cascade of axonal injury Ferguson et al showed that though the triggers of axonal injury action result in the final dissolution of

massive axonal damage occurs during http://jnnp.bmj.com/ seem to be specific for inflammatory the . A disturbance of axoplasmic the stage of active demyelination in fresh membrane permeability and a state of 2 conditions, such as MS, the downstream lesions. Similar conclusions were mechanisms of axonal dissolution ap- relative energy failure leads to uncon- reached by Trapp et al studying axonal pear similar in a variety of different trolled ion influx into the axoplasm, in transsections in MS lesions by confocal pathological conditions of the nervous particular in those that are still electri- 3 13 laser microscopy. In addition, these system, including inflammation, cally active. Intra-axonal accumulation studies confirmed earlier observations ischemia, or trauma. of sodium ions is then counteracted by a that acute axonal injury correlated with Axonal injury can be initiated through reverse operation of the sodium/calcium the degree of infiltration in 7 direct T cell mediated cytotoxicity. Class exchanger, resulting in excess intra- on October 1, 2021 by guest. Protected copyright. the lesions and that macrophages were axonal Ca++. This activates Ca++ 2–4 I MHC restricted T lymphocytes can closely attached to damaged axons. transsect axons in vitro in an antigen dependent proteases, which may de- These basic observations were extended dependent immunological reaction,8 and grade cytoskeletal proteins and, thus, 5 in several ways by Kornek et al. In this pathological studies revealed a weak cor- impair . Voltage gated study the quantity of acute axonal injury relation between tissue infiltration with calcium channels then accumulate at was correlated with lesional stages, cytotoxic T cells and acute axonal sites of disturbed axonal transport and defined by the presence and antigenic injury.9 The attachment of highly acti- become locally integrated into the ax- composition of myelin debris in macro- vated cytotoxic T cells on demyelinated onal membrane.16 This may lead to phages. These data suggested that mas- axons is frequently encountered in par- further influx of Ca++ into the axons, sive acute axonal injury occurs during a ticular in lesions of Marburg’s type of which finally will result in complete dis- small time window of about two weeks acute MS and the cytotoxic granules of solution of the axonal cytoskeleton and after onset of demyelination. In addition, such T cells are arranged in a polarised axonal disintergration. This pathway can there is a slow burning, ongoing axonal fashion towards the contact zone be inhibited for therapeutic purposes at destruction, which can be seen even in between the lymphocyte and the axon. several levels. Thus, NO mediated axonal inactive demyelinated plaques, in which Such a constellation suggests the specific injury can be inhibited by blockade of inflammation is sparse or absent. Such interaction of the T cell with the target Na+ channels or through an inhibitor of ongoing axonal injury is lacking in axon in the sense of an “immunological Na+/Ca++ exchange17 and Na+channel remyelinated shadow plaques.5 synapse”.7 Even more important com- blockers have also been found neuropro- These data, taken together, suggest pared with direct T cell mediated cyto- tective in autoimmune encephalomyeli- that axons in MS lesions are destroyed toxicity seems to be the interaction of tis in vivo.18 In addition, blockade of

www.jnnp.com 696 EDITORIAL J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.6.697 on 1 June 2003. Downloaded from

degeneration overall is permanent. Yet the CNS has a large functional reserve capacity. Even in a tract system with clearly defined and measurable clinical function, such as the pyramidal tract, permanent clinical deficit is only seen when more than 60% of the axons in the tract system are lost.23 This implies that irreversible structural damage accumu- lates in MS brains already during the earliest stages of the disease, and perma- nent clinical deficit only appears when the functional reserve capacity of the CNS tissue is exhausted. Under these circumstances, axonoprotective therapy has to start early in the disease course in a preventive rather than a classical therapeutic strategy. Its abundance, its early appearance in disease course, and the diffuse nature of axonal damage in MS, which is not nec- essarily restricted to demyelinating lesions,26 has triggered speculations that MS is a primary neurodegenerative disease, with a secondary (super- imposed) inflammatory reaction, which may amplify the damage in the . Although such a scenario can so far not be definitely excluded, several observations argue against it. Inflamma- Figure 1 Triggers of axonal injury and axonal degeneration. tory demyelination as a consequence of a neurodegenerative disease may eventu- ally be discussed in adrenoleukodystro- N-type voltage gated Ca++ channels too Axonal destruction in demyelinated phy, but is not a feature of classical may ameliorate axonal injury. Finally, plaques results in widespread secondary destructive processes of the CNS, such as inhibition of Ca++ dependent proteases “Wallerian” degeneration throughout neurodegenerative diseases, stroke, or 19 can be used to prevent axonal injury. the CNS tissue. This is most obvious trauma. In addition, in MS patients, Interestingly, the same mechanisms of when plaques are located in a defined dying early in the course of the disease or axonal disintergration seem to operate in tract system, where secondary degenera- from fulminate Marburg’s type of the ischemic conditions or in brain tion is clearly visible distal to the plaque disease, the pathological alterations are 20–21 24 trauma. This raises hope that neuro site. Secondary degeneration may lead largely restricted to the demyelinated and axon protective strategies, having in certain locations, such as the spinal plaques and are always associated with http://jnnp.bmj.com/ been in development for brain ischemia cord to the paradox situation, that the inflammation. Similarly, the extent of for several years, may turn out to be loss of axonal profiles in a plaque is axonal injury in old inactive demyeli- equally effective in inflammatory brain similar to that in the contralateral, seem- 23 25 26 nated plaques, like that in acute lesions, diseases such as MS. ingly “unaffected” white matter. correlates with the number of activated Although in relation to myelin sheaths Thus, in the the net loss of macrophages and microglia cells.5 Fi- axons are relatively spared in MS lesions, axons in a tract system is the result of nally, diffuse white matter injury in MS the degree of axonal destruction is axonal injury in multiple demyelinated is always associated with a profound and profound. Its extent is highly variable, plaques located rostral or caudal from diffuse inflammatory reaction, mainly on October 1, 2021 by guest. Protected copyright. axonal density within plaques ranging the site of investigation. Thus, secondary composed of cytotoxic T lymphocytes 20-80% of that in the periplaque white “Wallerian” degeneration is an impor- and activated microglia cells. Thus, the matter. Within chronic established de- tant element, underlying diffuse abnor- failure of current immunomodulatory or myelinated plaques the reduction of malities and axonal loss in the so called immunosuppressive therapies to effec- axonal density is on average 60-70% normal white matter, typically found in tively block disease in the progressive compared with that in normal tissue of MS brains.26. In addition, however, there 22 phase of MS may be more related to the the same area. A similar percentage of is a diffuse inflammatory process in the poor efficacy of the anti-inflammatory axonal loss is found, when the absolute “normal” white matter of MS patients, therapies than to a non-inflammatory number of nerve fibres is counted in a which by itself is associated with blood— 23 nature of the “neurodegenerative” com- defined tract area of the spinal cord. In brain barrier disturbance, brain oedema, ponent of MS. contrast, in fresh lesions the reduction of ongoing axonal destruction, and reactive axonal density is only in the range of gliosis. These diffuse white matter J Neurol Neurosurg Psychiatry 74 30%. Two different factors seem to changes seem to be particularly promi- 2003; :695–697 contribute to the increased axonal loss in nent in patients with primary progres- chronic lesions: either the slow burning sive MS...... axonal disruption, which takes place Axonal injury and loss in MS lesions chronically in established demyelinated has major consequences for the patients. Author’s affiliation H Lassmann, plaques, or repeated demyelination and Clinical deficit, induced by inflammation Division of Neuroimmunology, Brain Research Institute, University of Vienna, remyelination within the same area of and demyelination, is principally revers- Spitalgasse 4, A-1090 Wien, Austria; the . ible, while functional loss due to axonal [email protected]

www.jnnp.com EDITORIAL COMMENTARY 697 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.6.697 on 1 June 2003. Downloaded from

REFERENCES 10 Anthony DC, Miller KM, Fearn S, et al. experimental allergic encephalomyelitis. 28 1 Kornek B, Lassmann H. Axonal pathology in Matrix metalloproteinase expression in an Neuroreport 2002; :1909–12. multiple sclerosis: a historical note. Brain experimentally-induced DTH model of multiple 19 Stys PK, Jiang Q. -dependent sclerosis in the rat CNS. J Neuroimmunol Pathol 1999;9:651–56. neurofilament breakdown in anoxic and 1998;87:62–72. 2 Ferguson B, Matyszak MK, Esiri MM, et al. ischemic rat central axons. Neurosci Lett 11 Smith KJ, Lassmann H. The role of nitric Axonal damage in acute multiple sclerosis 2002;328:150–4. oxide in multiple sclerosis. Lancet lesions. Brain 1997;120:393–9. 20 Hewitt KE, Stys PK, Lesiuk HJ. The 2002;1:232–41. 3 Trapp BD, Peterson J, Ransohoff RM, et al. use-dependent sodium channel blocker 12 Redford EJ, Kapoor R, Smith KJ. Nitric oxide mexiletine is neuroprotective against global Axonal transection in the lesions of multiple donors reversibly block axonal conduction: sclerosis. N Engl J Med 1998;338:278–85. ischemic injury. Brain Res 2001;898:281–7. demyelinated axons are especially 21 Wolf JA, Stys PK, Lusardi T, et al. Traumatic 4 Fraenkel M, Jakob A. Zur Pathologie der susceptible. Brain 1997;120:2149–57. axonal injury induces calcium influx multiplen Sklerose mit besonderer 13 Smith KJ, Kapoor R, Hall SM, et al. modulated by tetrodotoxin-sensitive sodium Berücksichtigung der akuten Formen. Z Neurol Electrically active axons degenerate when channels. J Neurosci 2001;15:1923–30. 1913;14:565–603. exposed to nitric oxide. Ann Neurol Mews I 5 Kornek B, Storch M, Weissert R, et al. 2001;49:470–9. 22 , Bergmann M, Bunkowski S, et al. Multiple sclerosis and chronic autoimmune 14 Bolanos JP, Almeida A, Stewart V, et al. and axon pathology in encephalomyelitis: A comparative quantitative Nitric oxide-mediated mitochondrial damage clinically silent multiple sclerosis lesions. study of axonal injury in active, inactive and in the brain: mechanisms and implications for Multiple Sclerosis 1998;4:55–62. remyelinated lesions. Am J Pathol neurodegenerative diseases. J Neurochem 23 Bjartmar C,KiddG,MorkS,et al. 2000;157:267–76. 1997;68:2227–40. Neurological disability correlates with spinal 6 Evangelou N, Konz D, Esiri MM, et al. 15 Aboul-Enein F, Rauschka H, Kornek B, et al. cord axonal loss and reduced N-acetyl Size-selective neuronal changes in the anterior Preferential loss of myelin-associated aspartate in chronic multiple sclerosis patients. optic pathways suggest a differential glycoprotein reflects hypoxia-like white matter Ann Neurol 2000;48:893–901. susceptibility to injury in multiple sclerosis. damage in stroke and inflammatory brain 24 Evangelou N, Konz D, Esiri MM, et al. Brain 2001;124:1813–20. diseases. J Neuropathol Exp Neurol Regional axonal loss in the corpus callosum 7 Neumann H, Medana I, Bauer J, et al. 2002;62:25–33. correlates with cerebral white matter lesion Cytotoxic T lymphocytes in autoimmune and 16 Kornek B, Storch MK, Bauer J, et al. volume and distribution in multiple sclerosis. degenerative CNS diseases. Trend Neurosci Distribution of calcium channel subunit in Brain 2000;123:1845–9. 2002;25:313–9. dystrophic axons in multiple sclerosis and 25 Lovas G, Szilagyi N, Majtenyi K, et al. 8 Medana I, Martinic MA, Wekerle H, et al. experiemntal autoimmune encephalomyelitis. Axonal changes in chronic demyelinated Transection of MHC class I-induced neurites Brain 2001;124:1114–24. cervical spinal cord plaques. Brain by cytotoxic T lymphocytes. Am J Pathol 17 Kapoor R, Davies M, Blaker PA, et al. 2000;123:308–17. 2001;159:809–15. Blockers of sodium and calcium entry protect 26 Evangelou N, Esiri MM, Smith S, et al. 9 Bitsch A, Schuchardt J, Bunkowski S, et al. axons from nitric oxide-mediated Quantitative pathological evidence for axonal Acute axonal injury in multiple sclerosis. degeneration. Ann Neurol 2003;53:174–80. loss in normal appearing white matter in Correlation with demyelination and 18 Lo AC, Black JA, Waxman SG. multiple sclerosis. Ann Neurol inflammation. Brain 2000;123:1174–83. Neuroprotection of axons with phenytoin in 2000;47:391–5.

Lewy bodies It is clear that the clinical diagnosis of ...... DLB is relatively common in this popula- tion, but it may be even more prevalent given that the consensus criteria used by How common is dementia with Lewy McKeith et al have a relative low sensitiv- ity for diagnosing this disease.4 The defi- bodies? nition of dementia in this study was also based on consensus criteria together R A Barker, T Foltynie with the Mini-Mental State Examina- tion scores, but with no systematic ...... http://jnnp.bmj.com/ exclusion of other medical problems, Meeting consensus criteria for the diagnosis of DLB using imaging or blood tests. Neuro- pathological confirmation of disease would obviously be useful, however the stablishing frequency figures for to identify individuals with dementia distinction between DLB and dementia diseases for which there is no and meeting consensus criteria for the in Parkinson’s disease remains Ereliable biomarker during life is diagnosis of DLB. About a quarter of the contentious,5 and so even if this study particularly difficult. As a result, various included postmortem analysis of the

group had dementia, of which a further on October 1, 2021 by guest. Protected copyright. diagnostic criteria have been established quarter were thought to have DLB (5% of brains, issues of disease classification to improve the accuracy of clinical overall 75+ population), a figure that would remain. Indeed, the increased diagnoses for the neurodegenerative dis- was half that seen for dementia of the sensitivity to detect Lewy bodies using orders, based on the previous evidence of Alzheimer’s type (DAT), but similar to alpha-synuclein immunohistochemistry clinicopathological studies of defined (which post dates the original consensus that seen for vascular dementia. This 4 pathologies. Such consensus clinical cri- finding is higher than that reported in criteria of McKeith et al ) creates uncer- teria are invaluable for increasing the other similar studies,23but does support tainty even at postmortem. specificity and precision of diagnoses, Prevalence studies must balance the the fact that DLB is a common cause of although with increasing specificity conflict that arises between (a) assessing dementia in the elderly, after DAT. The comes an inevitable loss of sensitivity, large populations, thus enabling identifi- reason for the present study finding a such that some cases get overlooked. cation of larger numbers of affected In this issue (see pp 720–724) Rahko- markedly higher prevalence may relate patients, and (b) performing detailed nen et al have attempted to define the to the inclusion of younger individuals in evaluations or investigations of all iden- prevalence of dementia with Lewy bod- the previous studies. There is a paucity of tified individuals using qualified experts ies (DLB) in people over the age of 75 population based descriptive studies of or trained personnel. With large popula- using a population based approach, in DLB, and therefore the age specific tion denominators, detailed assessments the Finnish city of Kuopio.1 This study results from this study are welcome, and become impossible, and either screening randomly selects 700 out of 4518 people must be compared with results from tools or random sampling must be used, born before 1923, and uses a structured future studies in other populations and as has been done in the selection of the questionnaire and clinical examination age groups. 700 individuals studied in this paper.

www.jnnp.com 698 EDITORIAL COMMENTARY J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.6.697 on 1 June 2003. Downloaded from

There is always some concern that both incidence and prevalence figures. Correspondence to: R A Barker; patients who refuse participation in Clinic based series have inevitable biases [email protected] descriptive studies may have differing in patient ascertainment, with ill defined REFERENCES rates of disease from those who do population denominators and no means 1 Rahkonen T, Eloniemi-Sulkava U, Rissanen S, participate, which may result in less pre- of quantifying missing cases. It is et al. Dementia with Lewy bodies according to cise prevalence estimates being made. the consensus criteria in a general population now important that other investigators aged 75 years or older. J Neurol Neurosurg Unfortunately it seems that other delineate age specific community based Psychiatry 2003;74:720–4. sources of clinical data regarding pa- figures for this condition in their popula- 2 Stevens T, Livingston G, Kitchen G, et al. Islington study of dementia subtypes in the tients refusing participation are absent tions. community. Br J Psychiatry 2002;180:270–6. in this study, thus preventing any form 3 Yamada T, Hattori H, Miura A, et al. J Neurol Neurosurg Psychiatry of sensitivity analysis. Prevalence of Alzheimer’s disease, vascular 2003;74:697–698 dementia and dementia with Lewy bodies in a Nevertheless, this study does high- Japanese population. Psychiatry Clin Neurosci light the advantage of targeting specific 2001;55:21–5...... populations of people at highest risk of 4 McKeith IG, Ballard CG, Perry RH, et al. Authors’ affiliations Prospective validation of consensus criteria for disease from which to estimate disease the diagnosis of dementia with Lewy bodies. R A Barker, T Foltynie, frequency. Using community based sam- Cambridge Centre for Neurology 2000;54:1050–8. Brain Repair and Department of Neurology, 5 Sulkava R. Differential diagnosis between ples with a defined population denomi- Forvie Site, Robinson Way, Cambridge early Parkinson’s disease and dementia with nator allows accurate identification of CB2 2PY, UK Lewy bodies. Adv Neurol 2003;91:411–3.

NEUROLOGICAL STAMP...... Félix Guyon 1831–1920

uyon was a native of the Island of Réunion. He emigrated to France, Gstudied medicine in Paris, and became a surgeon at Hôpital Necker and professor of genitourinary surgery in Paris. Guyon was an outstanding urolo- gist and a pioneer in prostatectomy and cystoscopy. In 1861 Guyon presented a paper on the hand to the Anatomical Society in Paris. This was published in the bulletin of the society, entitled “A note of an ana- http://jnnp.bmj.com/ tomical arrangement specific to the ante- rior aspect of the wrist not previously described”1 Given the date of the publi- cation and the initial of the author, one can only conclude that this was Félix Guyon of urological fame. In his paper Guyon describes “une petite loge intra- aponévrotique”. The groove or tunnel on October 1, 2021 by guest. Protected copyright. formed between the pisiform and the hamate and ligaments is now epony- mously known as Guyon’s canal and the findings associated with ulnar nerve entrapment at this site Guyon’s syn- drome. In 1979 Guyon was honoured on a stamp issued by France on the occasion of the 18th Congress of Inter- national Society of Urologists, in Paris. He is portrayed with catheters (Stanley Gibbons no 2323, Scott no 1652.) Réun- ion also issued his stamp, but it was never sold. Reference 1 Guyon F. Note sur une disposition anatomique propre g la face anterieure de la region du poignet et non encore, decrite. Bulletins da la Societe Anatomique de Paris, 2nd Series 1861;6:184–6. L F Haas

www.jnnp.com