Book review |
FROM NEUROSCIENCE TO NEUROLOGY: NEUROSCIENCE, MOLECULAR MEDICINE, AND THE THERAPEUTIC TRANSFORMATION OF NEUROLOGY
Edited by Stephen Waxman 2005
London: Elsevier Academic Press.
Price £77.50 $(US)125.00 ISBN: 0-12-738903-2 Neurology: the case for treatment
|
In July 2005, 30 of my colleagues and I celebrated our 60th anniversary of graduation in Medicine in 1945, from the Newcastle Medical School, then a part of King's College Newcastle, in the University of Durham. Immediately after graduation, I became House Officer to Professor F. J. Nattrass, who, though Professor of Medicine, had also made a name in neurology, his principal special interest. Indeed, he wrote a short textbook which sold well in the 1930s, entitled The Commoner Nervous Diseases; his seminal paper on recurrent polyneuritis, as it was then called, led to this condition being referred to in the French literature even today as ‘Maladie de Nattrass’.
It is interesting, even alarming, in retrospect, to note just how much of the practice of medicine, and of neurological medicine in particular, was based upon tradition and myth rather than scientific fact. Although motor neuron disease in its various forms was reasonably well recognized and characterized, any patient presenting with a spastic paraparesis was thought to be suffering from disseminated sclerosis (as it was then called) unless proven otherwise. As there was a widespread belief that lumbar puncture was harmful in patients with that condition, I was never allowed, as a house physician, to carry out that procedure even in suspected cases; goodness knows how many spinal neoplasms were consequently overlooked, especially since, in the Royal Victoria Infirmary in Newcastle, the principal teaching hospital, there were no facilities for myelography or other forms of neuroradiology; and any patient requiring such procedures had to be transferred to the care of the neurosurgeons under G. F. Rowbotham at the Newcastle General Hospital. But even in that department in 1946, there were no facilities for angiography and any patient suspected of having an intracranial tumour was subjected to air encephalography unless the intracranial pressure was thought to be substantially raised in which case ventriculography through a skull burr hole was the preferred option. Subarachnoid haemorrhage, too, was a purely clinical diagnosis and there was no certain method of distinguishing between bleeding into or over the surface of the brain. Even more curious was the fact that although syringomyelia was recognized as a distinct neurological entity, the preferred treatment was radiotherapy directed to the cervical cord. I was never able to identify the rationale underlying that procedure.
Anticonvulsant treatment for epilepsy was available and clinical distinctions were regularly made between grand mal and petit mal, but temporal lobe epilepsy or complex partial seizures were not then fully recognized and the use of EEG was in its infancy. There was limited EEG availability at the Newcastle General Hospital but in the Royal Victoria Infirmary this service was provided under Professor Alexander Kennedy in the Department of Psychiatry after he arrived in Newcastle in the 1950s. Nevertheless, treatment of epilepsy with phenobarbitone and phenytoin (known as Epanutin in the United Kingdom and Dilantin in the United States) was reasonably effective, particularly in the control of major seizures; the latter remedy was introduced on the basis of research carried out in Boston in the 1930s by James Jackson Punam and the redoubtable H. Houston Merritt.
Migraine was well-recognized, but the only remedies then available for its treatment were simple analgesics, such as aspirin (the other major benefits of that drug now so useful in the prevention of stroke, for instance, were not then recognized or even contemplated). The opiates and pethidine (known as Demeral in the United States) were available for controlling severe pain, though with the oft-repeated injunction that they must be used very sparingly because of the risk of addiction. In some painful conditions, tinct. opii, given by mouth, was preferred to injections of morphine or diamorphine (heroin) for reasons of patient convenience. Most of the conditions then regarded as progressive degenerative nervous diseases of unknown origin were considered to be untreatable. In parkinsonism, however, the standard treatment was tincture of stramonium.
When I began my post-graduate training in medicine and later in neurology, the latter was generally regarded as a diagnostic specialty with little to offer in the way of treatment. It is sad now to recognize that, when an allegedly incurable neurological disease was diagnosed, only limited supportive treatment and nursing were recommended. Thus, tuberculous meningitis, once diagnosed, was invariably fatal; patients were often shunted off into a side ward and given heavy sedation. Even more disturbingly, little was known or applied in the field of rehabilitation. When I began research into neuromuscular disease, I found that patients, once diagnosed as suffering from muscular dystrophy or other progressive disorders, were told, as were their relatives, that no treatment was available. In consequence, patients became progressively and often fatally deformed when simple supportive care, with attention to posture and to the prevention of contractures and skeletal deformity, might have transformed their lives and provided greater longevity.
I therefore turned with keen interest and anticipation to this volume, edited by Stephen Waxman, and reviewed the chapters written by internationally recognized experts to see whether objectives defined by the editor in his preface and in the publisher's blurb have been achieved. As Waxman indicates, the book focuses on the remarkable transformation that has occurred within neurological diagnosis and management, changing situations previously regarded as impossible to treat into ones offering several therapeutic possibilities. Twenty-five years ago, computerised tomography was in its infancy and MRI not yet feasible. Many medical students were taught not to make a diagnosis of multiple sclerosis early in its course as so little could be done, and good clinicians—many of them senior—made that diagnosis and then walked away from the bedside as there was so little therapy to offer. Peripheral neuropathies were also regarded as untreatable and strokes were treated with bed rest and not much else. By contrast, we now have imaging techniques which portray the brain and spinal cord non-invasively in elegant detail. There are drugs that may favourably modify the course of multiple sclerosis; plasma exchange and intravenous immunoglobulin are routinely and effectively used to treat Guillain–Barré syndrome. Strokes are prevented by aggressive diagnosis and treatment of hypertension, and may sometimes be reversed with early thrombolytic treatment. New and more effective treatments for Parkinson's disease, migraine, spasticity and dystonia are all at hand and there is more to come. The editor claims that the goal of his book is to capture the trajectory and the creative processes underlying the neurological revolution. Accordingly, I examined the individual chapters to see how, in the course of 55 years in neurology, my personal practice had been modified, while also seeking to identify exciting future prospects.
Not surprisingly, the first section of the book is entitled Clinical Rewards from Neuroscience, Molecular Medicine and Translational Research, and begins with a clear and well illustrated chapter on the evolution of MRI as a clinical tool. I look back with some concern upon the fact that, for diagnostic purposes, I subjected many patients to the painful and distressing procedure of pneumoencephalography or to angiography, when seeking to diagnose and locate sources of intracranial bleeding. Those with raised intracranial pressure were referred to neurosurgical colleagues so that, when appropriate, ventriculography or angiography could be performed to localize intracranial neoplasms. But we also used pneumoencephalography in seeking to reach a diagnosis of Alzheimer's disease or other forms of dementia, looking for the evidence of cerebral atrophy often found in such cases. And in diagnosing spinal disease, innumerable patients were subjected to myelography, with an oily contrast medium, resulting (in some cases) in subsequent arachnoiditis. Although for a limited period, echoencephalography and scintigraphy using injected radio isotopes played a minor role, and angiography may still be required at times in investigating cerebrovascular disease (despite the success of Doppler imaging in the diagnosis of extracranial vascular lesions), the evolution of MRI and its functional variant have added much precision and accuracy to diagnosis and have saved much patient suffering and discomfort.
As a young House Officer, and subsequently as a trainee in medicine and neurology, I recognized the significant distinction between ischaemic stroke (then called cerebral thrombosis) on the one hand and haemorrhagic stroke (cerebral haemorrhage or apoplexy) on the other. But the distinction was not always easy to make and no drug therapy was accordingly attempted. The recognition of lacunar stroke through the work of C. Miller Fisher and of extracranial carotid or vertebral disease as a cause of stroke had to await the advent of angiography, finally introduced into Newcastle in the mid-1950s. In preparing my MD thesis on subarachnoid haemorrhage, based upon an analysis of 312 cases admitted over a 10-year period to the Royal Victoria Infirmary, I had to rely largely upon clinical records and the results of CSF examination. This nevertheless enabled me to identify some unusual causes of this clinical syndrome and its sequelae; of course, surgical treatment of intracranial aneurisms was not possible until angiography arrived. Now, the crucial importance of treating hypertension in stroke prevention and the role of aspirin and other agents (as first shown by Henry Barnett) in the prevention of strokes in patients with transient ischaemic attacks is well-recognized. The value of early administration of thrombolytic agents, once imaging has been carried out to distinguish ischaemic strokes from those resulting from haemorrhage is becoming clear. The role of neuro-protective agents remains speculative, but their potential is carefully considered in this volume, as are methods of preserving function in acute injury to the brain and/or spinal cord, where yet again the role of neuroprotective agents, including corticosteroids, is considered in depth.
As expected, an excellent chapter describes methods of influencing the course of multiple sclerosis, mentioning corticosteroids and immunosuppressants in some cases, but concentrating, appropriately, on the role of the interferons and glatiramer acetate. Although, as the editor and the authors clearly indicate, this is not a textbook of neurological therapeutics, the complementary place of rehabilitation techniques is reviewed alongside such pharmacological therapeutic innovations. Interestingly, too, in the treatment of the epilepsies (innumerable new anticonvulsant drugs were introduced during my professional lifetime) in all their varieties, now comprehensively classified, the place of surgery in treatment highlighted so effectively by Wilder Penfield and his colleagues in Montreal many years ago was relatively neglected for many years as the new therapeutic agents emerged; but the recent significant revival of interest in new methods of neurosurgical management are very well described by Jerome Engle.
An admirable analysis of the neurobiology of migraine and of the transformation of headache therapy follows, and although I was a little surprised not to find cluster headache (called, in my day, periodic migrainous neuralgia) in the index or in this chapter, the explosion of biochemical knowledge in the aetiology of migraine is clearly described. As a young trainee, I well remember that one senior colleague was still trying to prevent attacks of migraine by administering Gowers' mixture over a period of weeks or months; later still we used ergot preparations in various forms, both prophylactically and in the management of an acute attack. But, within the last few years, the role of serotonin and of 5-HT receptors and the development of specific antagonists, now classified as the tryptans, brought migraine management into a new era.
Among the most difficult conditions to recognize and to treat, in which I often felt therapeutically impotent, were movement disorders, including the dystonias, both generalized and local, spasmodic torticollis, writers' cramp, blepharospasm and many others. Various forms of drug treatment and even surgical measure were often used, usually with significant lack of efficacy, but with the introduction of botulinum toxin treatment, the situation has been transformed. I lived through an era when a standard treatment for spasticity of the lower limbs in disease, such as multiple sclerosis, was intrathecal phenol injection, but the use of botulinum toxin, injected into muscles affected by spasticity or abnormal movements, has proved to be of remarkable benefit. It is a pity that in the public mind botulinum toxin has become almost glorified as a cosmetic treatment for the removal of facial wrinkles etc., when it is an agent with a very wide range of therapeutic values. I must confess that until I read this book I was unaware that the alpha 2-adrenoceptor agonist, guanfacine, is a well-recognized current treatment for the attention deficit-hyperactivity disorder and for the Tourette syndrome. An admirable contribution by Arnsten underlines the scientific studies through which the efficacy of this remedy was discovered.
Properly, two chapters in the book are devoted to parkinsonism, one dealing with prospects for slowing the progression of the disease, and the other relating to surgical treatment, its past, present and future. After the days when tincture of stramonium was a standard treatment for Parkinson's disease, later came the introduction of the anticholinergic agents such as benzhexol, and gradually the therapeutic management of the condition improved. A historic transformation came with the introduction of levodopa, based upon the discovery that dopamine was the principal neurotransmitter in the substantia nigra and other parts of the basal ganglia, and that its deficiency contributed largely to the clinical manifestations of the disease. Attempts to give both dextrodopa and levodopa showed that the former was toxic whereas the latter had a significant therapeutic effect. The story has been well told by many, not least in Awakenings, by Oliver Sacks (1973)
. I had the privilege of chairing a subcommittee of the Medical Research Council which, in the 1960s, supervised the first trials of levodopa treatment, using imported levodopa provided for us by Roche Laboratories. Two such trials were carried out in my department, and the results were subsequently published in the British Medical Journal. In Newcastle, my close friend and associate, the neurosurgeon John Hankinson, over the years, performed several hundred stereotaxic operations in appropriate patients. The relief of rigidity and tremor following a unilateral operation was often quite striking; the operation had little effect on other manifestations such as akinesa, and unfortunately bilateral operations often resulted in a significant impairment of memory and cognition, a manifestation which was not usually immediately apparent, but became so later. On one occasion when John Hankinson and I were participating in a post-graduate course for general practitioners, I had described the drug treatment of parkinsonism, and he went on to talk about his surgical methods; a general practitioner sitting in the front row began to look increasingly astonished, and said, ‘Professor Hankinson, do you really mean to say that you put a hole in the skull, that you sink a cannula into the depths of the brain and that you then pass a freezing substance along it?’ Hank said, ‘Well, it's a living!’
Interestingly, as new forms of pharmacological treatment of parkinsonism, including dopaminergic agents, have continued to emerge, the place of surgical treatment has seemed less clear. However, as in epilepsy, there has been renewed interest in surgical treatment, not just of parkinsonism but also of hemiballismus and athetosis. As yet, there is uncertainty as to whether the drugs now available to treat parkinsonism have a long-term protective effect; hence, as Marek clearly describes in his chapter, much work is in progress on the use of neuroprotective agents of all kinds, and also on genetic research following identification of the Parkin gene and of the significance of mitochondrial dysfunction (an interesting study of coenzyme Q10 treatment producing limited improvement is yet to be confirmed). The potential of stem cell therapy and of cell transplantation into the brain of patients with parkinsonism and Huntington's disease is dealt with in the second half of the book. Plainly, there are many fruitful avenues of further study in efforts to delay the progression of the condition and to relieve its manifestations.
In neuromuscular disease, one major research interest throughout my career, a significant development was the introduction of steroid therapy for the treatment of autoimmune neuropathies and for inflammatory disorders of muscle, including polymyositis and dermatomyositis. Although many forms of peripheral neuropathy are still not responsive to any therapeutic agents, the autoimmune varieties have been modified substantially by steroids, which plainly work best in subacute inflammatory demyelinating polyneuropathy. These drugs do not, however, produce significant benefit in the acute Guillain–Barré syndrome, in most cases of which plasma exchange is usually effective; although some neurologists recommend intravenous immunoglobulin, many others feel that plasma exchange is to be preferred.
Every neurologist in clinical practice will inevitably encounter patients suffering from anxiety or depression. My late colleague, Dr Henry Miller, to the chagrin of his colleagues in psychiatry, used to refer to psychiatry as ‘neurology wiwithout physical signs’. That there is a degree of truth in this assertion has clearly emerged from basic scientific studies relating to the molecular and cellular theory of depression and the role of the neuro-immune pathway, as well as of serotonin and its analogues. These issues are fully considered in a comprehensive chapter by Heninger, which I believe all psychiatrists would do well to read.
If, in this review, I have concentrated almost exclusively on the first half of this admirable volume, I have done so deliberately because of my interest in the evolution of neurological therapeutics throughout my professional lifetime. The second half of the volume, however, deals with evolving themes and technologies as they move towards the clinic, and embraces a series of chapters which clearly demonstrate the truth of my oft-used comment that today's discovery in basic laboratory science brings tomorrow's practical development in patient care. These chapters, dealing with subjects, such as genomics and proteomics, exciting developments in neuroprotection, prospects for gene therapy for CNS disease and therapeutic developments in hereditary neurological diseases, are outstanding, as are contributions on new molecular targets for the treatment of neuropathic pain, the prospects for effective nerve fibre regeneration in the brain and spinal cord, cellular plasticity of the adult brain, the role of endogenous stem cells and CNS repair, and new work on neuropathies and on Alzheimer's disease—to mention just a few. I have not yet referred to two interesting chapters on channelopathies, since this is a term which meant nothing to me until about 25 years ago. It was in the 1990s that it was discovered that several inherited CNS diseases, mainly characterised by paroxysmal movement disorders and epilepsy, were caused by mutations in ion channels. The number of channelopathies recognized affecting nicotinic, GABA and glycine receptors continues to increase year by year. Even more astonishing is the fact that more than 250 distinct mutations that contribute to congenital muscle disorders have been identified in seven different muscle ion channels. Among the conditions known to result from muscle channelopathies are the periodic paralyses, myotonia, congenital myasthenia, malignant hyperthermia and central core disease. Years ago we tried to distinguish between the hypokalaemic and hyperkalaemic varieties of periodic paralysis. One patient of mine had attacks of hyperkalaemic paralyis which were relieved by treatment with chlorothiazide, but he came back a few weeks later complaining that his attacks had returned, and I discovered that his general practitioner, who felt that it was old-fashioned to give just chlorothiazide, had given the patient chlorothiazide-K (with added potassium).
Not surprisingly, this splendid volume, beginning with a chapter on the transformation of neurological diagnosis and therapeutics arising out of new imaging techniques, ends with another on functional brain imaging and what it will mean for neurology, highlighting, as it does, the use of structural and functional images as surrogate markers of disease progression, and techniques of serial measurement of atrophy in degenerative brain disease. A final therapeutic hint emerges in the closing chapter on the use of transcranial magnetic stimulation to disturb function and to restore it.
This exciting volume almost (but not quite) makes me wish that I were starting again in the practice of neurology, armed with the therapeutic armamentarium it outlines, being attractively printed and well illustrated throughout the text, with coloured plates grouped together at the end.
Do I have any criticisms? If I have one, it is that the field of mitochondrial disease is moving so fast in relation to disorders of brain, nerve and muscle, that a chapter on this topic might have been included. On the whole, however, the volume paints an intriguing picture of the ways in which neurological diagnosis and management have been transformed during the last 50 years; as a witness to these developments, I cannot but congratulate the editor and his collaborators not least for the perspicacious glimpses they give us of what further transformations will arise in the near future.
Lord Walton of Detchant, Detchant, Northumberland
Reference
Sacks OW. Awakenings. London: Duckworth; 1973.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||