More MS news articles for July 2002

Series of BMJ Articles on Neurodegenerative diseases
Neurodegenerative diseases raise profound questions

BMJ 2002;324 ( 22 June )

People increasingly understand that if they don't die of heart disease or cancer then brain failure is going to get them (p 1465). Neurological and psychiatric disorders account for only 1.4% of deaths but 28% of years lived with a disability (p 1469). As populations age the burden of illness caused by neurodegenerative illness will increase. That's one reason why we have devoted this issue to neurodegenerative disease (and our sister journal Journal of Neurology, Neurosurgery, and Psychiatry is doing the same with its June issue), but another is that it's a fascinating subject that raises fundamental questions.

Defining neurodegenerative diseases is difficult, but the "core members" are the dementias, Parkinson's disease, motor neurone disease, cerebellar degenerations, Huntington's disease, and prion disease (p 1465). But should more "psychiatric" diseases be included? Mary Baker, Rajendra Kale, and Mathew Menken, the editors of this issue, mount a powerful argument for ending the division between neurology and psychiatrya division that appeared only in the 20th century (p 1468). As our understanding of the brain grows, an increasing number of mental illnesses are shown to have a biological basisand more and more mental activities can be seen with increasingly sophisticated imaging (p 1529).

Science may bring together the ragbag of conditions called neurodegenerative diseases. Lawrence Golbe describes how all seem to be characterised by the aggregation of intracellular proteins caused by abnormalities in protein folding (p 1467). Understanding these abnormalities may bring new methods of treatment and prevention as well as a more rational classification of disease.

One of the questions raised by this issue is how doctors and patients can have very different perspectives. Mary Baker, a former chief executive of the Parkinson's Disease Association, observes tongue in cheek that for doctors Parkinson's disease is all above the waist while for patients its mostly below the waist. Doctors think about basal ganglia. Patients worry about continence, sexual function, and whether they can walk. An editorial she writes with Leslie Findley describes how doctors think that the condition of a patient with Parkinson's disease will be determined by severity of disease and adequacy of drug treatments (p 1466). In fact less than a fifth of variation of quality of life is accounted for by these two factors. Mood accounted for 40%, and the quality of communication with healthcare workers another large chunk.

But should the "unravelling of memory and mind" necessarily be regarded as a disease? Andrew Moscrop reviews a book that argues that dementia is emphatically human and brings a dramatic involvement in the present (p 1528). Defining it as a disease at the beginning of the 20th century reduced the condition to "a plain horror, an utterly inhuman circumstance."


To receive Editor's choice by email each week subscribe via our website:

© BMJ 2002

Defining neurodegenerative diseases

BMJ 2002;324:1465-1466 ( 22 June )

Disorders will be named after responsible rogue proteins and their solutions

Defining neurodegenerative diseases is like defining the continent of Europe: part history, part science, part politics, and to cap it, both could have an effect on health and prosperity.

A big advantage of the term is that it is a concept that patients can relate to from parallels in everyday life. Wearing out in time of certain componentssometimes replaceable, sometimes notencompasses principles of selective neuronal death as a primary event with age as a major risk factor and good remedies patchy.

Paradoxes abound. Neurodegeneration is a major element and is often the cause of the disability in many diseases not usually classified as degenerativefor example, multiple sclerosis, epilepsy, some inborn errors of metabolism, schizophrenia, and even tumours. Conversely, inflammatory processes are activated and vascular compromise occurs in some degenerative diseases. A Napoleonic view could encompass most brain diseases under the rubric of neurodegenerative, but this would lack focus.

Few health authorities run services for neurodegenerative disease as a whole because they can cut across several subspecialties. Core members are the dementias, Parkinson's disease, motor neurone disease, cerebellar degenerations, Huntington's disease, and prion diseases. Subclassification is clearly of importance for research, management, and ultimately for more targeted treatment.

Problems exist with terminology. For example, patients whose diagnostic label changes midcourse may feel that they have been misled. Thus a patient initially labelled as having Parkinson's disease may have the diagnosis changed to a rarer label (Lewy body dementia, corticobasal degeneration, progressive supranuclear palsy, or multisystem atrophy) as additional features like dementia or a gaze palsy or autonomic failure become apparent. The case with Alzheimer's disease is similarfronto-temporal, multi-infarct, and dysphasic versions of dementia.

When carving out bewildering classifications neurology has been slow to allow patients a vote. Practitioners may also have preferred a common stem of Parkinsonism or dementia, for example, with a subvarietywhich was underplayed until the diagnosis was definite or a change needed because the treatment or prognosis altered significantly. Time could then be concentrated on more important errorsfor example, missing Wilson's disease, mistaking essential tremor for Parkinson's disease, overlooking drug induced dementia or Parkinsonism, or mistaking conditions which respond to drug treatment, such as myasthenia or motor neuropathy, for motor neurone disease. In all these conditions, missing depression is easy enough unless it is specifically sought.

Contributions from basic science

Genes and proteins involved with these conditions are being rapidly elucidated, and naming the condition after the protein is an option.1-5 This already happens for Creutzfeld Jakob diseaseCJD/prion disease. However, until we are able to make a molecular diagnosis in life and offer specific treatment it is probably premature to use this strategy in clinical settings, even for those conditions where the molecular defect has been identified. Classifications that need postmortem data have caused enough problems in the past. Asking the diagnostician to predict the presence of a Lewy inclusion body or neuropathological changes of Alzheimer's disease when no test is available is to ask for a lot. Nevertheless we need to be aware of evolving terminology: alpha synuclein, parkin, and Parkinson's disease; amyloid and Alzheimer's; tau and fronto-temporal dementia and progressive supranuclear palsy; SODI (superoxide dismutase 1) and motor neurone disease; glutamine repeats and Huntington's disease; and the new neuroserpinopathies.6

Though causative mutations have been described in some families, both genetic and environmental risk factors play a part in the aetiology of these conditions. The ratio variesthe genetic contribution is higher in Huntington's disease, Alzheimer's disease, and cerebellar degenerations and lower in Parkinson's disease, motor neurone disease, and prion diseases. The expectation is that we will find the genes that interact with environmental factors, which may be dietary, chemical, or biological agents. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a good though rare example of an environmental agent that caused an epidemic of Parkinsonism among drug misusers.7 MPTP is a simple chemical, and a viable hypothesis is that autointoxication by similar molecules may cause sporadic diseases.8 Another example is the epidemic of a variety of degenerative diseases on Guam, where the environmental agent has not been discovered.9

A common feature of these conditions is a long run-in period until sufficient protein accumulates, followed by a cascade of symptoms over 2-20 years, with increasing disability leading to death. This provides a wide therapeutic window, especially as groups at risk are identified earlier and preclinical diagnosis becomes feasible. The increasing incidence with age can be seen as a threat (given population projections) or as an opportunitya delay in the onset of these conditions by, say, 5-10 years would dramatically reduce their incidence and therefore costs. Individuals have realised that if they are lucky enough to side step or survive cancer and vascular disease the next threat is neurodegeneration in its various guises. But have governments realised this? Secondary postponement of disability is possible10 and it is impressive and fast moving in Parkinson's disease and modest in Alzheimer's and motor neurone disease.11

The key characteristics of these conditions are that progressive degeneration occurs as a primary event long before symptoms develop and that it is selective, at least initially, for a particular neuronal pool. Other groups of neurones could joinfor example, sensory end organ failureand there is overlap with what we arbitrarily accept as ageing. In the future these diseases will be increasingly defined by the proteins involved. Improved diagnostics will hopefully change terminology and reduce the need to second guess pathology, thus increasing the accuracy of classification from the start. Eventually the mechanisms through which particular proteins cause toxicity would be elucidated, as will genetic and environmental risk factors. Primary preventive strategies could then emerge and ultimately (as in the case of polio and vaccination) these diseases will be defined by their solutions.

Adrian Williams, professor of clinical neurology.
University of Birmingham, Edgbaston, Birmingham B15 2TT

1.  Polymeropoulous MH, Lavedan C, Leroy E, Ide SE, Dejejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997; 276: 2045-2047[Abstract/Full Text].
2.  Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura H, Monishima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392: 606-608
3.  Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 1991; 349: 704-706[Medline].
4.  Julien JP. Amytrophic lateral sclerosis. Unfolding the toxicity of the misfolded. Cell 2001; 104: 584-591.
5.  Walker LC, Levine H. The cerebal proteinopathies. Ageing Neurobiol 2000;559-61.
6.  Davis RL, Holohan PD, Shrimpton AE, Tatum AH, Daucher S, Collins GH, et al. Familial encephalopathy with neuroserpin inclusion bodies. Am J Pathol 1999; 155: 1901-1903[Abstract/Full Text].
7.  Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism in humans due to a product of meperdine-analog synthesis. Science 1983; 219: 979-980[Medline].
8.  Parsons RB, Smith ML, Williams AC, Waring RH, Ramsden DB. Expression of nicotinamide N-methyltransferase (E.C. in the parkinsonian brain. J Neuropath Exp Neurol 2002; 61: 111-124[Medline].
9.  Garruto RM, Gajdusek DC, Chen KM. Amyotrophic lateral sclerosis and parkinsonism-dementia among Filipino migrants to Guam. Ann Neurol 1981; 10: 341-350[Medline].
10.  Orr HT, Zoghbi HY. Reversing neurodegeneration: a promise unfolds. Cell 2000; 101: 1-4[Medline].
11.  Fricker-Gates RA, Dunnett SB. Rewiring the parkinsonian brain. Nature Med 2002; 8: 105-106[Medline].

© BMJ 2002

Treating neurodegenerative diseases

BMJ 2002;324:1466-1467 ( 22 June )

What patients want is not what doctors focus on

Parkinson's disease is an excellent example of the challenges of caring posed by people with neurodegenerative disorders. It is insidious in onset, inexorably progressive, of unknown cause, incurable, yet amenable to management with pharmacological and other interventions. With the ageing of the population the prevalence of Parkinson's disease and other such disorders is projected to increase in the years ahead.1 Thus all doctors must be prepared to provide diagnostic and management strategies for this growing population of patients. Medical practitioners must understand the expectations of patients and their families and introduce these perspectives within the framework of scientific understanding and evidence based practice. Conventional medical education has set a tradition of practice based on science, basic and clinical, cemented by a period of postgraduate training in the conventional apprenticeship mode. This has ensured that practices are generally competent and safe and grounded in the best available information. But is this approach consistent with the mission of professionals to build partnerships with patients by means of strategies for care consistent with the knowledge, attitudes, and values of a public most of which is educated.

Do most people believe, for example, that the quality of life of patients with neurodegenerative disorders depends primarily on the severity of disease and the effectiveness of pharmacological interventions? Without a detailed examination of evidence or a familiarity with the risks associated with treatment, patients may have an outlook that differs from that of professionals with respect to health related factors conducive to a better quality of life. Moreover, protocols for the care of patients are likely to derive more from the research interests and focus of investigators than the daily burdens of the people who have the illness.

There is a growing consensus that a lack of congruence exists between what patients and doctors value in terms of the impact of disease on quality of life and what should be done about it. In Parkinson's disease, there is robust evidence in favour of this divergence of perspective which may represent a potential barrier to the effectiveness of protocols for care, guidelines for management, and the most effective and efficient use of health resources.2 When face to face interviews with more than 1000 patients with Parkinson's disease and carers were carried out in six countries only 17.3% of the variation in perceptions of health related quality of life could be explained by the severity of disease and the effectiveness of drug treatment. Such evidence necessarily represents a wake-up call for those health providers who believe that these factors are most important for prognosis and require a large share of professional effort.3

During these interviews, patients were also given the opportunity to complete specially developed questionnaires and validated instruments to identify other domains of care of equal or greater importance which affect the quality of their life. These domains had been identified in pilot studies by the investigators. The salient responses that accounted for approximately 60% of health related quality of life were respondents' mood, satisfaction with the explanation at the time of diagnosis, and current levels of optimisminclusive of severity of disease and pharmacological interventions. Indeed the mood (depression), as measured by the Beck depression inventory, explained about 40% of variation in the perceived quality of life across this cohort of patients. 2 4 5

Apart from effecting a cure, maintenance and improvement of the health related quality of life are the objectives of any treatment programme for neurodegenerative disorders. The message for clinicians from this and other studies is that, contrary to prevailing opinion, a single minded focus on severity of disease and the effectiveness of drugs will not adequately address the changes in the health related quality of life expected from encounters between patients and doctors. Undergraduate and postgraduate medical education must provide a broader framework that includes the complexities of factors that are interwoven in their efforts to improve quality of life.

Communication skills emerge as paramount tools that together with counselling and behavioural modification contribute substantially to the results of any treatment programme. A recent study assessing the effectiveness of specialist nurses for patients with Parkinson's disease in general practice showed that nurse specialists helped to preserve patients' sense of wellbeing even though health outcomes were unchanged.6 This study emphasises that a major role of the nurse specialist is in counselling and educating patients and carersthat is, as a facilitator of communication. Merely increasing the total number of neurological specialists may not be the best or only solution to these challenging and complex problems. Health planners need to consider the scope and character of diverse and comprehensive skills necessary for improving the quality of life for the growing number of people with neurodegenerative disorders.

Leslie J Findley, professor.
Essex Neurosciences Unit, Oldchurch Hospital, Essex RM7 0BE
Mary G Baker, president, European Parkinson's Disease Association.
Kailua, Maybourne Rise, Mayford, Woking, Surrey GU22 0SH

1.  Menken M, Munsat TL, Toole JF. The global burden of disease study. Implications for neurology. Arch Neurol 2000; 57: 418-420[Medline].
2.  Findley LJ for Global Parkinson's Disease Steering Committee. Factors impacting on quality of life in Parkinson's disease: results from an international survey. Movement Disord 2002; 17: 60-67[Medline].
3.  Janca A. A report on the WHO Working Group on Parkinson's disease. Neuroepidemiology 1999; 18: 236-240[Medline].
4.  Beck AT, Steer RA, Garvin MG. Psychometric properties of the Beck depression inventory: twenty-five years of evaluation. Clin Psychol Rev 1998; 8: 77-100.
5.  Peto V, Jenkinson C, Fiztpatrick R, Greenhall R. The development and validation of a short measure of functioning and well being for individuals with Parkinson's disease. Qual Life Res 1995; 4: 241-248[Medline].
6.  Jarman B, Hurwitz B, Cook A, Bajekal M, Lee A. Effects of community based nurses specialising in Parkinson's disease on health outcome and costs: a randomised controlled trial. BMJ 2002; 324: 1072-1075[Abstract/Full Text].

© BMJ 2002

Neurodegeneration in the age of molecular biology

BMJ 2002;324:1467-1468 ( 22 June )

Abnormal protein folding holds the key to specific treatment

Clinicians still think of neurodegenerative disorders in terms of nonspecific, 19th century style palliation. For a few disorders, we can temporarily relieve symptoms by pharmacological or surgical manipulation of the neurotransmitters emitted by the degenerating neurones. In the past decade, thinking about these disorders has been reordered by the discovery that most of them feature excessive protein misfolding and intracellular protein aggregation. This insight could permit us to interrupt the process of neuronal loss itself.

Tau, an important component of cytoskeletal physiology, is the protein that aggregates most commonly in neurodegenerative diseases, both in terms of number of disorders and numbers of patients affected. It forms the neurofibrillary tangles of Alzheimer's disease, Pick's disease, progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration, postencephalitic parkinsonism, and a handful of others.

Next most common, at least in terms of population prevalence, is -amyloid, principal component of the amyloid plaques of Alzheimer's disease. Another protein with epidemiological importance is -synuclein, which forms the aggregates of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and others. Tau and -synuclein may even interact to increase the risk of Parkinson's disease.1

The mechanisms by which protein aggregates impair cell function and survival are slowly becoming known. One advanced example is -synuclein. The normal function of this small protein, still unclear, includes protecting neurotransmitter-laden vesicles and helping to transport them from cell body to synapse. The classic pathogenetic hallmark of Parkinson's disease is the Lewy body, a layered, radially arranged fibrillary aggregate of some two dozen chemical components, chief among which, found in 1997, is -synuclein.2 It seems, however, that Lewy bodies themselves do not damage neurones. Rather, an early stage of aggregate consisting of fewer than 30 -synuclein molecules, a "protoaggregate" or "oligomer," is probably the offending species. It may exert its toxic action by creating pores in lipid membranes.3 One result is leakage of dopamine from vesicles into the cytoplasm. Free dopamine, aside from its direct oxidative toxicity, exacerbates the pathogenetic process by inhibiting the further aggregation of the protoaggregates into Lewy bodies.4 By sequestering the protoaggregates, the Lewy bodies may provide a protective function. The story for the other neurodegenerative disorders may be variations on the theme of protoaggregates producing toxicity and mature aggregates providing a means of sequestering them.

Underlying this story for most neurodegenerative disorders is abnormal protein folding.5 This exposes hydrophobic regions, permitting aggregation. The cell's principal means of disposing of abnormally folded proteins is the ubiquitin-proteasome system. Protein aggregates themselves can impair the function of that system, probably by a simple clogging mechanism.6 At least one neurodegenerative disorder, autosomal recessive juvenile parkinsonism, is caused by a genetic defect in a component of that system, parkin.7

The causes of the abnormal folding are various and still poorly understood. Obvious causes are genetic defects producing a single amino acid substitution or expansion of a repeating amino acid tract, as occurs in the strongly familial forms of many neurodegenerative diseases. 8 9 However, for most neurodegenerative disorders that occur sporadically or in non-Mendelian familial fashion, other causes of abnormal folding lie at the source of the pathogenetic cascade.

For example, again in the case of non-familial Parkinson's disease, exposure to pesticides,10 certain metals,11 or oxidative stress (probably via mitochondrial defects)12 can cause abnormal -synuclein folding and subsequent aggregation. Genetically determined variation in the ability to degrade exogenous toxins enzymatically or compensate for oxidative stress may be central to susceptibility to disease and to determination of the age of onset.

Introducing the concept of protein aggregation into our thinking will also allow us to transcend the classic rubric of clinical and anatomical pathology. An excellent example is the obsolescence of the term olivopontocerebellar atrophy. The sporadic form of olivopontocerebellar atrophy has been found to harbour cytoplasmic inclusions in oligodendrocytes consisting chiefly of -synuclein. The same is true for Shy-Drager syndrome and striatonigral degeneration.13 These three entities have now been combined into a pathogenetically based rubric called multiple system atrophy. The familial form of olivopontocerebellar atrophy has been subsumed into the various forms of spinocerebellar ataxia, which are differentiated by their genetic defects and by the nature of their protein aggregates. The term olivopontocerebellar atrophy has therefore proved useless and has virtually disappeared from the literature.

As we consider the pathogenesis and classification of neurodegenerative disease, we must consider the identity of the abnormally aggregating protein, the cause of its misfolding, causes of protein aggregation other than misfolding, the causes of failure of the ubiquitin-proteasome system to dispose of the abnormally folded or aggregated protein, and the mechanism by which abnormally aggregated protein causes cellular damage. This framework will bring a more rational classification of disease and a very high probability of specific treatments or prevention.

Lawrence I Golbe, professor of neurology.
UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA

1.  Golbe LI, Lazzarini AM, Spychala JR, Johnson WG, Stenroos ES, Mark MH, et al. The tau A0 allele in Parkinson's disease. Movement Disord 2001; 16: 442-447[Medline].
2.  Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature 1997; 388: 839-840[Medline].
3.  Volles MJ, Lansbury Jr PT. Vesicle permeabilization by protofibrillar -synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 2002; 41: 4595-4602[Medline].
4.  Conway KA, Rochet J-C, Bieganski RM, Lansbury PT. Kinetic stabilization of the synuclein protofibril by a dopamine-synuclein adduct. Science 2001; 294: 1346-1349[Abstract/Full Text].
5.  Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 2002; 416: 507-511[Medline].
6.  Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science 2001; 292: 1552-1555[Abstract/Full Text].
7.  Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392: 605-608[Medline].
8.  Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC. A large kindred with autosomal dominant Parkinson's disease. Annals of Neurology 1990; 27: 276-282[Medline].
9.  Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in alpha-synuclein identified in families with Parkinson's disease. Science 1997; 276: 2045-2047[Abstract/Full Text].
10.  Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neurosci 2000; 3: 1301-1306[Medline].
11.  Uversky VN, Li J, Fink AL. Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular link between Parkinson's disease and heavy metal exposure. J Bio Chem 2001; 276: 44284-44296[Abstract/Full Text].
12.  Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, et al. Oxidative stress induces amyloid-like aggregate formation of NACP/alpha-synuclein in vitro. Neuroreport 1999; 10: 717-721[Medline].
13.  Dickson DW, Liu W-K, Hardy J, Farrer M, Mehta N, Uitti R, et al. Widespread alterations in alpha-synuclein in multiple system atrophy. Am J Pathol 1999; 155: 1241-1251[Abstract/Full Text].

© BMJ 2002

The wall between neurology and psychiatry

BMJ 2002;324:1468-1469 ( 22 June )

Advances in neuroscience indicate it's time to tear it down

For more than 2000 years in the West, neurology and psychiatry were thought to be part of a single, unified branch of medicine, which was often designated neuropsychiatry. Charcot, Freud, Jackson, Bleuler, among many others, thought in terms of a unified study of the brain and the mind, irrespective of special clinical and research interests. During the 20th century, however, a schism emerged as each of these fields went its separate way. Neurologists focused on those brain disorders with cognitive and behavioural abnormalities that also presented with somatic signsstroke, multiple sclerosis, Parkinson's, and so forthwhile psychiatrists focused on those disorders of mood and thought associated with no, or minor, physical signs found in the neurological examination of the motor and sensory systemsschizophrenia, depression, anxiety disorders, and so on. For certain disorders, conflicting theories emerged about their aetiology and pathogenesis, at times engendering negative attitudes among workers in one or the other field, including derision and incivility. In academic medical centres, separate departments were formed in neurology and psychiatry that had little interest in collaboration in research, teaching, or patient care.1 Those specialists who supported a more holistic view of these disciplines were in full retreat by midcentury.2

Clearly, recent advances in neuroscience make it untenable at this time to know precisely where to draw the line between neurological and psychiatric disorders. For example, it is well known that many patients with Parkinson's disease and stroke manifest depression and, in some, dementia. Is there a substantive difference between a toxic psychosis (psychiatry) and a metabolic encephalopathy with delirium (neurology)? We have known of these examples for several years. More recent and dramatic evidence has come largely through functional magnetic resonance imaging and positron emission tomography. Obsessive-compulsive disorder is characterised by recurrent, unwanted, intrusive ideas, images, or impulses that seem silly, weird, nasty, or horrible (obsessions) and by urges to carry out an act (compulsions) that will lessen the discomfort due to the obsessions. Increasing the levels of brain serotonin with selective reuptake inhibitors may control the symptoms and signs of this disorder. Evidence of a genetic basis in some patients, structural abnormalities of the brain on magnetic resonance imaging in others, and abnormal brain function on functional magnetic resonance imaging and positron emission tomography collectively suggest that schizophrenia is a disorder of the brain.3

Nor does all of the neuroscientific evidence linking neurology and psychiatry arise from study of patients. Learning to read by braille can enlarge the brain region responding to fingertip stimulation. Brain imaging research shows that several brain areas are larger in adult musicians than in non-musicians. The primary motor cortex and the cerebellum, which are involved in movement and coordination, are bigger in musicians than in people who don't play musical instruments, as is the corpus callosum. Discontinuing the use of braille or the violin can reverse the functional neuroanatomic connections.4

Because of the vast increase in neurobiological knowledge in recent years, and the ever increasing number of disorders (including those referred to above) once thought to be psychopathological yet now known to be neuropathological, some neurologists might cling to the view that their specialty has now emerged alone as the reigning queen of the medical sciences. If they do, we do not agree with them. The concept of mental health as much more than the mere absence of brain disease is, we suggest, indispensable for neurological and psychiatric practice and care. From our angle of vision, the fundamental alliance between mental health and brain illness (devoid of the confounding terms brain health and mental illness5) as the basis of care derives in the first instance from Aristotle's distinction between efficient causes and final causes. (An efficient cause, or mechanism, is that by means of which something happens; a final cause, or teleological cause, is that for the sake of which something happens.) Neurologists and psychiatrists must have a suitably broad perspective, for theirs is the domain of purposeful behaviour and intentionality (final causes) that is no less a brain/mind function than sense perception and movement. Clearly, the education of future generations of neurologists and psychiatrists must be grounded in neuroscience, but must equally be focused on those dimensions of professional activity that quintessentially define the work of medical doctors from the neck up.6

Mary G Baker, president, European Parkinson's Disease Association.
Kailua, Maybourne Rise, Mayford, Woking, Surrey GU22 0SH
Rajendra Kale, assistant editor.
BMJLondon WC1H 9JR
Matthew Menken, chairman, research group on medical education, World Federation of Neurology.
75 Veronica Avenue, Somerset, NJ 08873, USA

1.  Price BH, Adams RD, Coyle JT. Neurology and psychiatry: closing the great divide. Neurology 2000; 54: 8-14[Full Text].
2.  Cobb S. Foundations of neuropsychiatry. Baltimore: Williams and Wilkins, 1948.
3.  Nasrallah HA, Weinberger DR. Handbook of schizophrenia: the neurology of schizophrenia. Amsterdam: Elsevier, 1986.
4.  Zeki S. Inner vision: an exploration of art and the brain. Oxford: Oxford University Press, 1999.
5.  Baker M, Menken M. Time to abandon the term mental illness. BMJ 2001; 322: 937[Full Text].
6.  Eisenberg L. The social construction of the human brain. Am J Psychiatry 1995; 152: 1563-1575.

© BMJ 2002

Demystifying neurology

BMJ 2002;324:1469-1470 ( 22 June )

Phenomenology can help

Muhammad Ali, Dudley Moore, Ronald Reagan, and Christopher Reeve have in common that they suffered from degenerative and traumatic disorders of the nervous system, the prevalence of which will increase greatly during the next 20 years.1 Although neurological and psychiatric disorders account for only 1.4% of all deaths, they account for a remarkable 28% of all years of life lived with a disability. Thus all doctors must be prepared to meet the needs of patients with such disorders and refer appropriately for specialised care and investigations, bearing in mind that neurologists often function as consultants for other physicians. Yet do medical students and house officers believe they are being adequately prepared for independent practice, and do general doctors have confidence in their ability to diagnose and treat patients with disorders of the nervous system?

Apparently not. Schon et al recently surveyed medical students, senior house officers, and general practitioners about such matters, and the results merit serious attention.2 Compared with their knowledge of other organ systems, their knowledge of disorders of the nervous system was said to be poorest. Moreover, basic neuroscience and clinical neurology ranked at the top of the list for difficulty in learning and complexity. Practising doctors likewise averred that they had less confidence in practical clinical situations in neurology than in other system disorders. When respondents to the survey were asked to identify the causes of their difficulties in neurological education, they cited insufficient, poor, irrelevant, or poorly coordinated teaching, and intimidation by neurology's reputation as a tough grind, among other considerations. Although the survey was carried out in the United Kingdom, few neurologists and educators elsewhere would doubt the universality of these disturbing findings, which were in fact identified in the United States and Canada a generation ago. 3 4

Many groups, including the World Federation for Medical Education, the Royal College of Physicians of London, and the American Academy of Neurology, have weighed in with proposals and remedies. 5 6 Everyone agrees that the teaching of basic neuroscience and clinical neurology must be more effectively integrated, that sufficient time for neurology must be allotted in an already overburdened curriculum, and that every practising doctor must be prepared to handle common neurological disorders and emergencies. Neurologists are also discovering that there are reciprocal benefits for teaching and patient care from collaboration with other groups. For example, advances in neuroscience research have now made it untenable to draw a sharp demarcation line between the twin educational domains of neurology and psychiatry, and the Department of Mental Health and Substance Dependence of the World Health Organization has inaugurated a collaboration to grapple with these and related issues. In the United States, neurological teachers have also joined forces with their counterparts in primary care to develop and implement a family practice curriculum in neurology, intended to enlarge the range of settings in which educational programmes are carried out (CD Rom available from the American Academy of Neurology,

About 50 years ago, Morris B Bender rightly concluded that the bottom up pathway in neurological educationfrom basic science to clinical problemswas becoming dysfunctional and instituted a top down approach starting with clinical signs instead, by means of phenomenology seminars. In origin, as described by philosopher Edmund Husserl, phenomenology is the intuitive appreciation of phenomena as they are immediately perceived, without reference to scientific theory or prior learning.7 Teaching phenomenology in neurology rivets the attention of learners to an arm that shakes, an incomprehensible word, or a person lost in the world. Explanations and interpretations "to save the phenomena" follow, but do not precede or coincide with, awareness. Clearly, phenomenology is an approach that starts with the patient's perspective (illness) and only later shifts to the doctor's perspective (disease). Such teaching shifts emphasis from the passive methods so widespread in medical education to more active, self directed, and independent study.5

The a priori method of phenomenology represents a radical departure from the prevailing educational paradigm of the 20th century. This general approach, with neurology as an example, is possibly applicable in other clinical fields. As there are fewer born teachers than born poets, however, success hinges upon the availability of adequate resources to promote and sustain a cadre of seminar leaders who are both content experts and teachers trained as educators.5

Matthew Menken, chairman, research group on medical education, World Federation of Neurology.
75 Veronica Avenue, Somerset, NJ 08873, USA

1.  Menken M, Munsat TL, Toole JF. The global burden of disease study: Implications for neurology. Arch Neurol 2000; 57: 418-420[Medline].
2.  Schon F, Hart P, Fernandez C. Is clinical neurology really so difficult? J Neurol Neurosurg Psychiatry 2002; 72: 557-559[Full Text].
3.  Menken M, Sheps CG. Undergraduate education in the medical specialities: the case of neurology. N Engl J Med 1984; 311: 1045-1048[Medline].
4.  Murray TJ. Relevance in undergraduate neurologic teaching. Can J Neurol Sci 1977; 4: 131-137[Medline].
5.  Menken M, Hopkins A, Walton H. Statement on medical education in neurology. Med Educ 1994; 28: 271-274[Medline].
6.  Charles PD, Scherokman B, Jozefowicz RF. How much neurology should a medical student learn? Acad Med 1999; 74: 23-26[Abstract].
7.  Smith B, Smith DW, eds. The Cambridge companion to Husserl. Cambridge: Cambridge University Press, 1995:8-14.

© BMJ 2002


BMJ 2002;324:1529 ( 22 June )

The internet makes a powerful case against those who believe the mind and brain are separate

The philosopher René Descartes (1596-1650) was unfortunate. He did not have access to websites or to information from research in neuroscience, particularly neuroimaging, which we have. So one cannot blame him for thinking that the mind was distinct from the body, for initiating dualism. We have such access and need to think differently from the way he did when we look at the mind-brain problem.

The brain in action: examples from fMRI presentations online

I decided to take Descartes to visit some brain websites. We saw some images of the brain at the laboratory of neuroimaging at UCLA ( Descartes appeared interested but wasn't wowed. He wanted to read about the brain in action not just see the structure. So we went on to which gave us all the basics he needed to know about functional magnetic resonance imaging (fMRI) of the brain. However, he wanted to know more about what this exciting technology could be used for. So we saw some of the presentations from the FMRI Conference 2002 at and the website of the Society for Neuroscience ( and, which I knew to be well worth wandering about.

Descartes got totally absorbed. We read that a new brain imaging study by Daniel Langleben shows that there may be an objective difference between lying and telling the truth that can be measured in the brain. fMRI detected a difference in brain activity during intentionally deceptive and truthful statements. The researchers asked 18 healthy participants to deny having an object hidden in their pocket when shown a picture of that object among many pictures of similar objects. Pictures were presented one by one while participants' brains were scanned by fMRI, which can detect brief changes in brain activity. The way questions about the objects were asked closely followed a method commonly used in deception research. The researchers found that the anterior cingulate gyrus and the left prefrontal and premotor cortex were significantly more active when participants lied than when they told the truth.

"René, what do you think?" I asked him.

"If lying and telling the truth isn't about the mind, then what is?" Descartes asked.

We further found that scientists have compiled studies that show serotonin is implicated in aggressive acts. One example involves mice who lack one type of receptor that responds to serotonin. These defective mice attack intruders faster and more intensely. Other researchers examined the spinal fluid of murderers in Finland. Their results indicate that these individuals have abnormally low levels of serotonin.

"Yes, René?"

"If aggression isn't about the mind, what is?"

We appreciated better what music does after visiting the website, for music training beefs up brain circuitry. For example, the primary motor cortex and the cerebellum are bigger in adult musicians than in people who do not play musical instruments, as is the corpus callosum. Moreover, musically trained adults perform better on word memory tests than other adults. In addition, rats exposed to Mozart completed a maze more rapidly and with fewer errors than other rats.

"Appreciating music is certainly about the mind," mused Descartes.

We spent a few moments reading that young female mice who spent several months in an environment filled with tunnels, toys, and running wheels developed more neurones and performed a learning and memory task better than did isolated mice.

"This experiment is about fun, about toys. And fun is in the mind," said Descartes.

"There is something about memory too," added Descartes. "Did you know . . .?"

"What do you think René?"

"Of course, the mind is a function of the brain. I would have said that had I known all this stuff about the brain!"

"But we have psychiatrists and neurologists who think that the two are different. They are dualists!" (see p 1468)

"Silly chaps, dualists!" said Descartes concluding his visit.

Rajendra Kale.

© BMJ 2002