Introduction
The Dr. Krishnamoorthy Srinivas 90th Birthday Memorial Lecture Webinar was delivered on 15th February, 2023 by Prof. Christopher Mathias, under the auspices of Buddhi Clinic, Chennai. Mrs. Krishnamoorthy Srinivas, Prof. ES Krishnamoorthy, Founder-Director of Buddhi Clinic and his team were present at the clinic venue. It was fitting that Ms.Aparna Rajagopal, a lawyer by training, (with over a decade of dedication to her animal sanctuary and sustainable animal farm, Beejom in Noida), opened the proceedings with old, fond memories and a daughter’s perspective of a ‘good friend’ and a doctor father. For family and close friends, it was an event to honour the life of a loved one, and to professional colleagues, Srinivas’ legacy of commitment and excellence in medical care.
Eminent senior members of the Indian Neuroscience fraternity participated in the Webinar to honour the memory of Prof. Krishnamorthy Srinivas – Prof. P. Satish Chandra, former Vice Chancellor of National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Prof. Man Mohan Mehndirattha, Former Director and Professor, Department of Neurology, Gobind Ballabh Pant Institute of Medical Education, New Delhi and Prof. AV Srinivasan, Emeritus Professor, Tamil Nadu Dr MGR Medical University. AV Srinivasan, who was one of Dr. Srinivas’ earliest DM (Neurology) students and later associated closely as a professional colleague, spoke at some length about his guru. He traced the professor’s long years of training in the UK and later in Canada, the pioneering effort in establishing Neurology as a superspecialty in India, building a small department of Neurology in the well served Community Medicine centre-Voluntary Health Services (VHS) Medical Centre, Chennai, (later a multispecialty hospital), bringing world Neurology to India through the endowment lectures and interaction with the Indian Neurology groups, medical students and the lay audience, and his distinguished national and international awards and honours. The note of appreciation summed up the professor’s legacy- Dr. Srinivas, teacher, researcher, administrator, but always a clinician; a family man, with admiration for his devoted wife Padma and the achievements of his two children- Prof. ES Krishnamoorthy and Ms. Aparna Rajagopal and their respective spouses. Prof. Krishnamoorthy Srinivas followed Prof. Christopher Mathias achievements in the UK in the field of ANS with interest and could not deny a sense of pride in his Indian origin. The prestigious lectures he has delivered worldwide include (under the ‘Srinivas umbrella’) the 3rd Prof. K Srinivas lecture, Chennai (2005); K. Gopalakrishna lecture, Chennai (2006); and TS Sinivasan Conclave Lecture, NIMHANS, Bangalore (2015), 35th TS Srinivasan Gold Medal Award and Endowment Oration, Chennai (2015).
Prof. Christopher Mathias MBBS, LRCP&S, DPhil, DSc, FRCP, FMedSci
Institute of Neurology, University College London ,
National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
Neurovascular and Autonomic Medicine, The Lindo Wing,
Imperial College NHS Healthcare Medicine at St. Mary’s Hospital, London, UK
Graduating with a record of academic excellence from St. John’s Medical College, Bangalore, India, in 1972 and receiving the State Award for Academic Distinction, Mathias set foot in the UK with a Rhodes scholarship to Oxford University. What followed was his trail-blazing career trajectory in the field of Neurovascular and Autonomic Medicine. In 1987 he was awarded the Fellowship of the Royal College of Physicians, London, in 1995 the Doctorate of Science (DSc) in the Faculty of Science at London University and In 2001 he was elected to the Academy of Medical Sciences (FMedSci). In 1991 he founded Clinical Autonomic Research, the first medical journal dedicated to clinical autonomic neuroscience. He is Senior Co-Editor, with Sir Roger Bannister, of Autonomic Failure: a Textbook of Clinical Disorders of the Autonomic Nervous System, which is in its 5th edition in 2014.
Prof. Mathias was Clinical Service and Research Director of two leading NHS and academic departments in London, the Pickering (Neurovascular Medicine) Unit at St. Mary’s Hospital, and the Autonomic Unit at the National Hospital for Neurology and Neurosurgery, Queen Square. The centers were amalgamated in 2014, and are now based at Queen Square. He is Emeritus Professor of the Institute of Neurology since 2014. In 2014 he founded the Autonomic & Neurovascular Medicine Centre at the Hospital of St. John & St. Elizabeth, incorporating the latest techniques and with experienced autonomic personnel.
Prof. Mathias has served on many national and international committees. He was a founding member of the Clinical Autonomic Research Society of Great Britain (Secretary, 1982-1986, Chairman, 1987-1990). He was Foundation President of the European Federation of Autonomic Societies (1998 to 2004). He has served on international task forces (EFNS, American Spinal Injuries Association) and on consensus groups (such as the American Autonomic Society 1996 and American Academy of Neurology, Boston 2007). He was a Trustee of Stoke Mandeville in the Spinal Research (2017-2019).He has been Chair of the Autonomic Group of the Ehlers-Danlos International Consortium, the Ehlers-Danlos Society from 2018.
In the Dr Krishnamoorthy 90th Birthday Memorial Lecture, Prof. Christopher Mathias recollected the warm welcome he had received from Prof. Srinivas when he visited India and discussions on the luminaries Srinivas trained with while in the UK.
Prof. Christopher Mathias traced the history of the development in the field of ANS in the UK, much of which he had witnessed in a key central position as clinician-researcher with the most eminent pioneers in this then somewhat neglected field (Prof. Sir John Spalding, Prof. Stanley Peart and Prof Roger Bannister, to name a few) and in the best UK centres with focus on ANS studies. He took the audience through his professional journey, with fascinating historical references interwoven with the scientific details of his 5 decade long contribution in the ANS field.
Falling Humans, Failing Neurons: Meeting the Challenge of Autonomic Dysfunction
“Faints, falls, fits, flutter, funny turns” was the intriguing list presented by Prof. Christopher Mathias at the outset of his lecture, indicating clinical presentations of autonomic dysfunction with its challenge of falling humans, often pointing to failing neurons. Central to the lecture was the neurovascular and neurohormonal aspects of ANS, stretching from basic knowledge to ‘new millennium disorders’ in this burgeoning field.
Mathias referred to the sympathetic and parasympathetic components of the Autonomic Nervous System (ANS) and the wide range of involuntary control exerted by these components on visceral body functions, often working in opposite directions in their role of homeostatic regulation. Signs and symptoms of autonomic involvement may be related to impairment of cardiovascular, gastrointestinal, urogenital, thermo-regulatory, sudomotor, and pupillomotor autonomic functions.
Postural hypotension or orthostatic hypotension (OH) ranging from ‘dizziness’ to syncope , may have multiple causes which may be related to the heart, brain or ANS. It may be fixed, as in autonomic failure, or intermittent, as in autonomic-mediated syncope or postural tachycardia syndrome (PoTS). Autonomic –mediated syncope may occur in even superfit persons, such as in vaso-vagal syncope which is the ‘more common form’ of fainting episodes.
OH cuts across several neurovascular ANS conditions. In the normal upright position adopted by the human, the cardiovascular system comes under the influence of gravitational forces, with a fall in pressure above heart level. This exposes the brain to impaired perfusion if adequate adaptive mechanisms are not in place. The heart is unable to achieve adequate perfusion pressure independently and that is where the ANS come to the aid, by monitoring the BP and heart rate. Afferents from the heart, lungs, large vessels and baroreceptors feed information to the brain. The parasympathetic regulation of heart rate (HR) is through the vagus to the heart. There is a parallel sympathetic outflow. Sympathetic output also stimulates release of noradrenaline, which hormone constricts the blood vessels. OH occurs when mechanisms for the regulation of orthostatic (standing) BP control fails. Standing, in normal subjects, results in a fall in blood pressure and this fall is sensed by baroreceptors. The initial fall in BP is corrected by an increase in heart rate and total systemic resistance with noradrenaline release causing vasoconstriction. Regulation by baroreceptors is also dependent on normal blood volume, and defenses against excessive venous pooling.
Mathias arrived at Worcester College in 1972 with a Rhodes scholarship from Oxford, and as graduate awardee, was offered work on animals in basic sciences. But he had hoped to be engaged in human studies, and preferably in Cardiology. When he showed his disappointment, John Walker, the college tutor suggested that he approach Prof. John Spalding in the Department of Neurology at Churchill Hospital, who was engaged in research on humans on cardiovascular control linked with ANS.
Prof John Spalding took Dr. Mathias on as supervisor in 1973 at Churchill Hospital Prof. Spalding was an active member of the Oxford team in the early 1950s that developed the East Radcliffe ventilator following a visit to Copenhagen at the epicentre of one of the world’s most devastating polio epidemics. He was convinced that in the acute phase of severe polio, other than the respiratory distress, the autonomic dysfunction was serious and called for urgent attention. Prof. Spalding wished to expand the scope of understanding the ANS role with similar studies on tetanus on the ventilator. Dr. John Corbett, after being awarded his doctorate, was on the verge of leaving for Ibadan and Lagos, Nigeria for this study. As there were not many cases available in the UK, Mathias hoped to get the required cohort for the study by joining the team. Marked autonomic instability with violent autonomic disturbances, severe hypertension and tachycardia, alternating with hypotension and bradycardia was the clinical picture in severe tetanus. Though “it was an amazing experience, it was difficult to record results in an organized manner” said Mathias. Back in the UK, he got Prof. Spalding’s nod to continue similar ANS studies in tetraplegics and quadriplegics. Prof. Hans Frankel had taken over from Prof. Ludwig Guttmann as Director, National Spinal Injuries Centre, Stoke Mandeville Hospital, Aylesbury. Dr. Mathias worked alongside with Prof. Frankel on several significant studies with the crucial clinical approach, taking into account the site and completeness of the spinal lesion.
In his lecture Mathias touched on Sir Ludwig Guttmann’s committed pioneering work at Stoke Mandeville from 1944, with several war casualties with spinal injuries being admitted. He had converted Stoke Mandeville into a centre for comprehensive care in spinal injury patients, and to this day it is run as a national centre of unmatched excellence. Today’s world Paralympics Games (which follows the Olympics in the same arena since 1960), had its humble beginnings as ‘Stoke Mandeville Games’ for Guttmann’s patients and he was the initiator of this and saw it reach such heights of recognition.
In one of the studies at Stoke Mandeville, in head up tilt on control subjects, the upright position produced a normal response. However, in high spinal cord lesion patients, (with no sympathetic outflow) the BP fell markedly, as there was no noradrenaline release. There was a rise in the HR as the vagus was intact, but did not succeed in bringing up the BP. Were there other substances involved in BP control was the question that researchers faced – perhaps prostaglandins, acetylcholine or renin-angiotensin. Prof. Stanley Peart was the expert on the renin-angiotensin-aldosterone system, from its clinical role to laboratory isolation and purification of angiotensin. Mathias approached him and through Christiansen (in a specialized Denmark laboratory), levels of a range of relevant substances was measured. Renin levels went up and rolled back, and aldosterone a little later, as it is dependent on angiotensin II. This suggested that the sympathetic nervous system was not the sole factor in BP control. Renin release and other mechanisms were involved, perhaps with the kidney as the source. Suprapubic tap resulted in BP rise and renin release. The conclusion drawn was that in tetraplegic patients, renin release during head-up tilt may occur independently of sympathetic nervous activity and is probably largely dependent on activation of renal vascular receptors. The renin-angiotensin-aldosterone system plays an important role in regulating blood volume and systemic vascular resistance, which together influence cardiac output and arterial pressure. For the first time this saw linking of the pathophydsiological lesion with the substances involved.
In a subsequent study, noradrenaline was infused through an intrarterial line in the arm or lower limb, an invasive procedure, to make it possible to monitor BP and HR continuously. Circulating noradrenaline during infusion did not significantly differ between the tetraplegics and the controls. However, over a wide range of doses by infusion, the blood pressure rose much more in the tetraplegics than in the controls. The findings indicate that tetraplegic subjects have an enhanced pressor response, as seen in the supersensitivity to the infused noradrenaline.
Mathias did a stint in General Medicine between 1976 to 1979 at London and Portsmouth, paving the way to his MRCP, which was awarded in 1978. Following this period, Prof. Sir Stanley Peart suggested that Mathias continue in the ANS field. In 1978 he was awarded the Wellcome Trust Senior Clinical Research Fellowship. He had the honorary post as clinical assistant to work with Sir Stanley Peart at St. Mary’s Hospital and Medical School, University of London near Paddington, (the hospital where Sir Alexander Fleming discovered penicillin).
The Medical Unit at St. Mary’s was the hub of activity then, and a major study that Mathias was involved in, was ‘Neurogenic and renovascular hypertension-central and peripheral mechanisms in renal artery stenosis’ The underlying mechanism in renovascular hypertension involves decreased perfusion to the kidney and activation of the renin-angiotensin-aldosterone (RAAS) pathways to elevate blood pressure by direct peripheral effects ( from increased afferent renal nerve activity) and probably through stimulation of sympathetic activity, which may result from the central effects of angiotensin-II. The chronic ischemia produced by the obstruction of renal blood flow leads to changes in the kidney and secretion of renin, the renin angiotensin –aldosterone system playing a role. Angiotensin is responsible for vasoconstriction and release of aldosterone which causes sodium and water retention, thus resulting in secondary hypertension or renovascular hypertension as demonstrated experimentally in patients with renal artery stenosis. The neurogenic components maintaining hypertension in renal artery stenosis are largely dependent on renal ischaemia, as revascularization by surgery, ameliorates or cures the hypertension in the majority of the patients studied. Denervation of the peripheral blood vessels by ablation demonstrated marked reductions in blood pressure in patients with resistant hypertension and elevated renal sympathetic nerve activity.
In 1984 Mathias was awarded a Wellcome Trust Senior Lectureship in Medicine, held jointly between St. Mary’s and the Institute of Neurology, working with Professor Sir Stanley Peart and Sir Roger Bannister till 1992. The collaborative study was on disorders with progressive autonomic failure –Parkinson’s disease, Multiple System Atrophy and Lewy Body disease, with cohorts for each one of these conditions. Pure autonomic failure (PAF) which often presents with orthostatic hypotension, reduced heart rate variability, anhydrosis, erectile dysfunction, and constipation, without motor or cognitive impairment, was also studied.
In 1987 Prof. Mathias was awarded the Fellowship of the Royal College of Physicians, London (FRCP). Interdisciplinary studies in nocturnal polyuria, post prandial hypotension, exercise-induced hypotension and Dopamine beta hydroxylase deficiency were the studies that followed.
In May 1991 the University of London conferred on Prof. Mathias the title of Professor of Neurovascular Medicine, held between St. Mary’s Hospital Medical School and the Institute of Neurology, British Postgraduate Medical Federation, London. He was Clinical Service and Research Director of two leading NHS and academic departments in London, the Pickering (Neurovascular Medicine) Unit at St. Mary’s Hospital, and the Autonomic Unit at the National Hospital for Neurology and Neurosurgery, Queen Square. These were tertiary referral centres serving the entire United Kingdom, also with international referrals. He pioneered the creation of clinical autonomic scientists, developments in laboratory autonomic testing, and with autonomic nurses, developed and streamlined autonomic diagnosis, investigation and treatment of many autonomic conditions.
That same year, Prof. Mathias founded the first medical journal dedicated to clinical autonomic neuroscience and served as editor till 1995, and continued as co-editor till 2013. Another important publication in Dec. 2001 was, of Autonomic Failure: a Textbook of Clinical Disorders of the Autonomic Nervous System, as Senior Editor, with Sir Roger Bannister.
In1995 Prof. Mathias was awarded the Doctorate of Science (DSc) in the Faculty of Science at London University. In2001 he was elected to the Academy of Medical Sciences (FMedSci). It was in recognition of Prof. Mathias’ contribution to ‘information of enormous value to both physiology and medicine in his work on supposedly rare disorders’.
In Feb. 2001, the analysis of 641 patients between 1992-1998, with recurrent syncope and presyncope, after cardiac, neurological, and metabolic causes were excluded, was published. Autonomic aetiology was diagnosed in 310 cases on the basis of clinical features and screening autonomic tests. Orthostatic hypotension and confirmed chronic autonomic failure was the diagnosis in 31 (4·8%) patients; neurally-mediated syncope was diagnosed in 279 (43·5%). Most of this group had vasovagal syncope (227 [35%]); other causes including carotid sinus hypersensitivity (37 [5·8%]), and a group of 15 (2·3%) were associated with rarer causes such as micturition syncope. 331 cases were of a miscellaneous, non autonomic group, rare cardiovascular causes like systemic hypotension, arrhythmias, or drugs, contributing to syncope in 53 cases; vestibular dysfunction in 32 and epilepsy in 11 cases of non-autonomic neurological causes. In 56 a psychiatric cause was thought to be contributory and in 179, the syncope was of unknown cause.
Progressively, there was an exponential rise in clinical referrals to the Neurovascular and Autonomic unit from 500 cases earlier to about 5000 cases and the various factors responsible for this increase was analysed. The above study brought to focus the significant role of autonomic testing in syncope and presyncope for evidence-based diagnosis, and management. Autonomic testing equipment and specialised laboratory tests had progressively improved and expanded their scope. Aside from this, the journal Clinical Autonomic Research, started in 1991, had gained in recognition and had established itself as the official international journal of the American Autonomic Society, the Clinical Autonomic Research Society of Great Britain, and the European Federation of Autonomic Societies and this led to referrals from outside the country as well. ‘New millennium autonomic disorders’, like PoTS required specialty diagnosis and management and new innovative approaches were employed. Prof. Stanley Peart’s leadership and expertise,- “His uncanny prescience about new millennium autonomic disorders” as Prof. Mathias put it, contributed immensely to the progress in the field.
PoTS, a rare clinical syndrome characterized by an increase in heart rate of at least 30 beats per minute on standing, and orthostatic intolerance, In PoTS, standing brings on symptoms such as palpitations, lightheadedness, brain fogging, and fatigue. It is a major cause of orthostatic intolerance especially in the young. 13-40 years, with greater prevalence in the female sex. Symptoms are often exacerbated after food ingestion, exertion and heat. The onset of PoTS often is linked to a triggering stressful event, followed by a long period of bed rest. Patients with PoTS are trained to live with the condition and avoid precipitating factors. The most common associated condition is the joint hypermobile form of Ehlers-Danlos syndrome.
Prof. Mathias was involved in functional autonomic brain imaging studies with Prof. Hugo Critchley at the Wellcome Neuroimaging Lab at Queen Square from 2002. Dr Critchley’s research focused primarily on mind-body-brain interactions and he had published widely on emotion, autonomic psychophysiology, and interoception. Many autistic and ADHD individuals struggle with awareness and response to interoceptive signalling of the state of the inside body and the ability to identify, understand and respond to them, which is so crucial to survival.
The coupling of cognitive and emotional behaviour with sympathetic arousal was studied. with Prof. Criitley. One such .fMRI study to examine regional brain activity associated with autonomic cardiovascular control was during performance of effortful cognitive and motor tasks (which involves stress). 3 patients with focal damage of the anterior cingulate cortex (ACC), while they performed these tasks, had abnormal autonomic cardiovascular responses and blunted autonomic arousal to the mental stress, unlike in the 147 normal subjects tested in identical fashion, where the ACC supports generation of associated autonomic states of cardiovascular arousal.
Prof. Christopher Mathias is Emeritus Professor of the Institute of Neurology since 2014. He founded the Autonomic & Neurovascular Medicine Centre at the Hospital of St. John & St. Elizabeth incorporating the latest techniques and with experienced autonomic personnel.
