By Gagandeep Singh, MV Padma, Pramod Pal, Jeyaraj Pandian, PN Sylaja, Suvarna Alladi, and Lalit Dandona

Gagandeep Singh

The burden of neurological diseases as measured by disability adjusted life years (DALYs) and years of life lost is an invaluable piece of information for many. Among the many are health care policy makers, academic institutions, and neurological health care providers. The India State-Level Disease Burden Initiative recently published trends of the burden of neurological diseases across the states of India from 1990 to 20191.

India is seventh largest in terms of area among all countries in the world. It has a population of nearly 1.4 billion, second highest after China, and is slated to be the most populous nation in the world by 2025. The country is geographically divided into 28 states and eight union territories. The per capita gross domestic product of India is US$ 2,100, with a ten-fold variation between the states and union territories. Arguably, therefore, considerable variation is expected in terms of socio-demographic standings, income, and cultural and ecological characteristics between the states of India. Inherent, e.g., genetic, differences are also likely to exist between different subpopulations within the country. Predictably, therefore, disease burdens including those of neurological disorders are likely to vary across the states.

The neurological diseases burden across the states of India, 1990-2019, not only underscores the geographical disparities across India but also the temporal trends in the burden of all neurological diseases combined and a range of neurological disorders1. Overall, neurological disorders accounted for nearly a tenth of DALYs for all diseases combined in India. This proportion increased somewhat between 1990 and 2019; from 8.3% to 9.9%. Remarkably, however, over the same time period, the point estimate of the contribution of non-communicable neurological disorders to DALYs from all causes increased from 4.0% to 8.2%, i.e., doubled.

As distinct from this trend, the proportion of communicable neurological disorders including meningitis, encephalitis and tetanus decreased from 4.1% to 1.1%, i.e., nearly four times. Aside from these two major subgroups of neurological disorders, the contribution of injury-related neurological disorders increased from 0.2% to 0.6%, representing a three-fold increase.

These data are testimony to the epidemiological transition taking place in the country. Over the decades since the Indian independence in 1947, it was assumed that communicable disorders, meaning thereby neurological infections, were the major predicament for Indian health care policy makers and care providers. This is changing and we need to be mindful of this evolution. The increase in injury related DALYs, likely a reflection of increasing use of vehicular transport, is also concerning as it is a largely preventable cause of enormous neurological morbidity and mortality.

The considerable variation in the neurological burden and of the incidence or prevalence and DALYs attributed thereof between the states of India is relevant as health is a state subject in India. Individual states, henceforth, need to prioritize their health care budgets, programmatic undertakings, and health care personnel training slots according to these data. The DALYs of communicable neurological disorders correlate inversely and those of injury-related neurological disorders varied directly with socio-demographic development indices of various states, while there is no such correlation in the case of non-communicable disorders. Subnational or within-country variations in the neurological burden are perhaps relevant to low- and middle-income countries and among them, for the most part to countries with large land areas with multi-ethnic populations, for instance, India and China. In China, likewise, there are remarkable socio-demographic variations between the industrialized east and the agrarian west and these may plausibly impact disease burdens and health care.

How does the neurological disease burden data from India compare with global numbers and proportions? Globally, the top five neurological disorders in terms of proportional contribution are stroke, migraine, Alzheimer’s and other dementias, meningitis, and epilepsy in that order2. Distinct from this, the order in India is as follows: stroke, migraine, epilepsy, cerebral palsy, and encephalitis (Alzheimer’s and other dementias and traumatic brain injuries closely follow encephalitis).

Encouraging to note, the incidence of, and age-standardized DALYs due to, stroke have somewhat declined between 1990 and 2019. This may reflect better preventative care implementation, leading to a reduced incidence and improved treatments in the form of specialist stroke units across the country. The age-standardized point estimates for the prevalence of epilepsies, cerebral palsy, Parkinson’s disease, multiple sclerosis and motor neuron disease have increased markedly. This probably could be attributed to a closing diagnostic gap but also, in case of epilepsies and Parkinson’s disease, increased longevity of the Indian population with time.

In comparison, the increase in prevalence for Alzheimer’s and other dementias is relatively modest, indicating perhaps that a considerable diagnostic gap still exists for this disorder. Inconsistent with the increase in prevalence of epilepsies and Parkinson’s disease, the age-standardized DALY rates attributed to these two neurological disorders have decreased over the past three decades. These surely signal progress in terms of closing the huge treatment gap and improved awareness for the two disorders.

Taken as a whole, the burden of neurological diseases across the states of India provides new information, which is both concerning and reassuring. These data call for a different level of preparedness to respond to the neurological disease burden in India. Moreover, the data call to attention subnational variations, and hence, should be a worthwhile exercise for neurological and epidemiological experts collectively in different nations constituting the membership of the World Federation of Neurology. •

By JMS Pearce MD, FRCP

Plate VII, Book VII, Vesalius’s ‘De Fabrica’ from https://www.researchgate.net/figure/Andreas-Vesaliuss-depiction-of-the-basal-ganglia-This-reproduction-of-plate-VII-of-book_fig1_276048418

In his De Humani Corporis Fabrica (1543), anatomically Andreas Vesalius distinguished the subcortical nuclei of the corpus striatum from the cortex and white matter, but he neither named them nor suggested their possible functions.

The corpus striatum was named by Thomas Willis (1621–1675), (whose birth quatercentenary we celebrate this year) in Cerebri Anatome (1664). He believed it was the source of motor functions, a view that persisted for almost 200 years.

The German anatomist and physiologist Karl Friedrich Burdach (1776-1847) provided more anatomical detail, but he had little idea about function, believing that the basal nuclei were responsible for sensory perception and consciousness. However, he differentiated the caudate nucleus (Streifenhügel) from the putamen (Schale). He also identified the substantia nigra (schwarzgraue), and the pale inner part of the lentiform nucleus that he called globus pallidus.

Before 1870, the motor function of the corticospinal pyramidal tract and the existence of an extrapyramidal system were not understood. The brain was simply the organ of consciousness, memory, and intelligence. The cortex was not known either to control or initiate motor function, not least because anatomists had not clearly delineated the anatomy or the physiology of the several descending tracts.

Electrophysiologically, Gustav Fritsch(1838-1927) and Eduard Hitzig (1838-1907) first showed the role of the pyramidal system, i.e. the motor cortex and its efferent tracts, in 1870. David Ferrier’s (1843-1928) classical ablation/stimulation experiments extended the results of Fritsch and Hitzig. He showed that Faradic stimulation of the cerebral cortex could produce movements and fits, and that cerebral functions were localized in definable discrete areas, which he mapped as sensory and motor across several species, thus defining cerebral localization.  Carpenter in 1874 ranked Ferrier’s cerebral localization “among the greatest advances in the physiology of the nervous system made in the last 50 years.”

As a concept, the extrapyramidal system (EPS) was first conceived indirectly by Johann Prus (of Lemberg, Galicia, now Lviv, Ukraine) in 1898. He discovered that experimental lesions in the pyramidal tracts failed to control induced cortical epilepsy. He unilaterally transected the pyramidal tract in dogs at the levels of the internal capsule, midbrain, pons, and medulla, and noted:

“Bilateral epileptic seizures occurred on stimulation of the cerebral cortex, on the same as well as the side opposite the operation… To explain the results of my experiments I had to assume that there is in the dog either bilateral innervation in the cortex, and that excitation spreads to the other hemisphere by means of the commissure fibres when the pyramidal tract has been cut, or that in this case conduction of cortical epilepsy takes place by means of a so far unknown centrifugal, i.e., motor pathway (Italics by JMSP).”

He deduced the presence of an unknown centrifugal motor pathway. But it was Samuel Kinnier Alexander Wilson (1878-1937) who was first to use the term “extrapyramidal” in its modern sense. His term extrapyramidal was adopted to distinguish between the clinical effects produced by damage of the basal nuclear tracts and those caused by damage to the classic pyramidal pathway.

Prus‘s 1898 publication in the Wiener klinische Wochenschrift

In his 1912 classic paper Progressive Lenticular Degeneration (Wilson’s disease), he described the autopsy of three patients with this disease where he observed pathology outside the pyramidal system and named them extrapyramidal tracts:

“In spite of the great degree of motor weakness and helplessness, in a pure case [of hepatolenticular degeneration] the abdominal reflexes are preserved and a double flexor response is obtained.  … the problem lay outside of the pyramidal system, “ in other words, this affection, where it occurs in an uncomplicated form, is an extrapyramidal motor disease. … To distinguish these apparently motor pathways from pyramidal and pontine tracts we shall call them extrapyramidal tracts.”

Although he failed to define specific tracts anatomically, this was the first use of the term “extrapyramidal” in neurology literature. In this era, several others inferred a motor role for areas outside the pyramidal tracts. (See Table 1.) The Swiss neurologist (of Russian descent) Constantin von Monakow (1853-1930) delineated a rubrospinal tract and the Austrian neuropsychiatrist Baron Constantin von Economo (1876-1931) proposed that the substantia nigra was involved with motor control of chewing and swallowing; lesions of the substantia nigra and red nucleus of cats and monkeys induced choreoathetosis. The Russian neurologist Vladimir Bechterew (1857-1927) stimulated the substantia nigra in dogs and noted swallowing, changes in respiration, ocular and pupillary changes, and contraction of neck muscles.9

Before Wilson’s paper, the confusion about sites of pathology in the several extrapyramidal disorders is evident in James Parkinson’s (1755-1824) account of the disease he discovered in 1817; he mistakenly guessed it originated in the “medulla spinalis.” The pathology was then unknown, but in 1894 while studying paralysis agitans, Hermann Oppenheim (1858-1919), the foremost Berlin clinical neurologist, provided sufficient clinical evidence to establish the duality of motor control, and to infer the existence of both pyramidal and extrapyramidal tracts in motor function. He wrote:

“Resistance to passive motion is always present in the later stages, and often before that time. It differs from spastic rigidity [of pyramidal tract disorders] in that it is not increased by passive motion, but is constant and regular . . .”

William Alexander Hammond (1828-1900), a founder of American Neurology in A treatise on diseases of the nervous system of 1871 recognized athetosis and suggested: “One probable seat of the morbid process is the corpus striatum.” The Austrian neuropsychiatrist Gabriel Anton (1858–1933) in 1896 indicated the basal nuclei could cause a motor disorder when in childhood double athetosis he reported hypermyelinated lesions in the putamen, later named état marbré,

Wilson’s long classic paper11 pointed out that the EPS (extrapyramidal system) had a “steadying” influence on the anterior horn cells:

“the relation of the corpus striatum (basal ganglia) to the rest of the motor system is one of tone control, and of steadiness of innervation. . . . Remove its influence by disease, [then] tonic postures become overemphasized.”

His view of dual motor function, pyramidal and extrapyramidal, was quickly and widely accepted.

Extrapyramidal Disease

The term extrapyramidal disease now refers to a group of motor disorders associated with pathological alterations in the basal grey matter whose function is predominantly motor. Clinically, extrapyramidal disorders consist of one or a combination of the following phenomena:

1. abnormal involuntary movements
2. changes in tone of skeletal muscles with an increase or decrease in resistance to passive motion
3. poverty or excess of movement
4. alteration of automatic movements.

The two motor systems are linked both anatomically and functionally, with extensive feedback loops.

Anatomically, the striatal EPS is polysynaptic and consists of nuclei and fibre tracts that receives projections from the cerebral cortex and sends efferent subcortical pathways to the brainstem and cord. Extrapyramidal structures comprise the cerebellum, basal nuclei including the neostriatum — subcortical caudate nucleus and the putamen nuclei — plus the substantia nigra, red nucleus, and the subthalamic nucleus of Luys. From them arise subcortical extrapyramidal tracts that terminate in the spinal cord. The Tectospinal, rubrospinsal, reticulospinal, and vestibulospinal tracts were described within the two decades 1890-1910.

Functionally, the EPS maintains posture and regulates involuntary postural tone and movement. It also has a role in behaviour, learning and cognition. Medium spiny neurons are the principal neurons of the striatum. They are the efferent cells, projecting to both segments of the globus pallidus, ventral pallidum, and substantia nigra. GABAergic in function, they are of several subtypes, and contain dopamine receptors and cholinergic and GABAergic interneurons. Both pyramidal and extrapyramidal systems project in the descending white matter tracts. (See Table 1.)

The extrapyramidal motor disorders are well recognized in basal nuclear diseases. They include Parkinson disease, Huntington chorea, Sydenham chorea, multiple system atrophy, torsion dystonias, and progressive supranuclear palsy. Altered posture and tone generally accompany involuntary movements, both bradykinetic and hyperkinetic — recognizable as tics, tremors, myoclonus, ballistic movements, chorea, and athetosis. They often show clinically characteristic individual patterns.

Exhaustive classifications (ICD-10 codes G20-G26 Chapter VI): contain 38 pages that include: acute dystonic reactions, blepharospasm, neuroleptic malignant syndrome, oculogyric crises, akathisia, drug-induced Parkinsonism, and various dyskinesias. •

JMS Pearce MD, FRCP, is Emeritus Consultant Neurologist at the Department of Neurology, Hull Royal Infirmary. E-mail: jms.pearce@me.com

1. Parent A. The History of the Basal Ganglia: The Contribution of Karl Friedrich Burdach. Neuroscience & Medicine 2012;03: 374-379. 10.4236/nm.2012.34046.
2. Quatercentenary of Thomas Willis’s birth — Department of Physiology, Anatomy and Genetics (DPAG) (ox.ac.uk)
3. Burdach KF. Vom Baue und Leben des Gehirns (Of Structure and Life of the Brain);1819 -1826. cited by Parent1
4. Lanska DJ. Early Controversies over Athetosis: I. Clinical Features, Differentiation from other Movement Disorders, Associated Conditions, and Pathology. Tremor Other Hyperkinet Mov (N Y). 2013;3:tre-03-132-2918-1.
5. Pearce JMS. Sir David Ferrier MD, FRS. J Neurol Neurosurg Psychiatry. 2003 Jun;74(6):787.
6. Ferrier D. The Functions of the Brain. London: Smith, Elder, 1876, pp. 163-196. [dedicated to Hughlings Jackson.]
7. Carpenter W. On the Physiological Import of Dr. Ferrier’s Experimental Investigations into the Functions of the Brain, West Riding Lunatic Asylum Med Reports 1874; 4: 1-23.
8. Prus J. Ueber die Leitungsbahnen und Pathogenese der Rindenepilepsie [Pathways and pathogenesis of cortical epilepsy] Wiener Klinische Wochenschrift, 11 (1898), pp. 857-863 (Annotated translation by Willner & Kennard, 1948
9. Louis ED. The Origins of the Term “Extrapyramidal” within the Context of Late Nineteenth- and Early Twentieth-Century Neurology, Neurophysiology and Neuropathology. The Journal of the History of Medicine and Allied Sciences, 1993. pp. 68-79
10. Lee J, Muzio MR. Neuroanatomy, Extrapyramidal System. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2020.
11. Wilson S.A.K., Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain, 1912, 34, 296-509.
12. von Monakow C. Der rote Kern, die Haube und die Regio hypothalamica bei einigen Säugetieren und beim Menschen. Arb. Hirnanat, Inst. Zurich, 1909, 3, 49—267.
13. von Economo C J. Zur Physiologie und Anatomie des mittelhirns. Arch. Psychiat. Nervenkr 1910; 46, 275-356;
14. Schiller F. The Vicissitudes Of The Basal Ganglia (Further Landmarks in Cerebral Nomenclature). Bulletin of the History of Medicine
15. 1967;41:515-538.
16. Oppenheim H. Lehrbuch der Nervenkrankheiten. Berlin S. Karger 1894. translated 2nd edn : Textbook of Nervous Disease. New York, G. E. Steckert, 1911.
17. H. McDowdl and J. M. Cedarbaum, in Clinical Neurology, eds. A. B. Baker and R. J. Joynt (Philadelphia:]. B. Lippincott Company, 1990), pp. 1-97.
18. Goetz T, Arslan A, Wisden W, Wulff P. GABA(A) receptors: structure and function in the basal ganglia. Prog Brain Res. 2007;160:21-41.
19. Lanska DJ. Nhe history of movement disorders. Handbook Clinical Neurology. Chapter 33. 2010;95:501-46.

Aaron Berkowitz, MD, PhD
María Jimena Alemán

Over this past year, we have all come to wonder what we can do to make a difference in the face of problems that seem so overwhelming. When we think about the scope of the pandemic and other global health issues, the devastating numbers are heart breaking, and it’s easy to lose sight of the individual people and stories behind the statistics. In Aaron Berkowitz’s new book, “One by One by One,” he shares with us the lessons he learned as he tried to make a small difference by helping one individual at a time amid suffering measured in billions.

As a young neurologist, Berkowitz travels with the NGO Partners in Health to Haiti. After the earthquake in 2010, Partners in Health had built the largest solar-powered hospital in a low-income country anywhere in the world as part of their mission to “bring the benefits of modern medical science to those most in need of them and to serve as an antidote to despair.”1

Aspiring to live up to these words, Berkowitz is eager to help his colleagues in Haiti, who inspire him with their incredible devotion to caring for their patients under the most challenging circumstances. Through the book, we learn about the dire consequences of life and medical care in Haiti. Although Berkowitz was one of 100 neurologists at the Brigham and Women’s Hospital in Boston, in Haiti, there was one neurologist for more than 10 million citizens.

There, he meets Janel, a 23-year-old man with the largest brain tumor he had ever seen. Working against impossible odds, Berkowitz tries to save Janel’s life by arranging for him to have brain surgery back in Boston. As new challenges and unexpected events arise, we learn not only about Janel’s journey, but also about Berkowitz’s struggle to find the courage to do what is right despite many adversities.

María Jimena Alemán

“One by One by One” is a story of juxtapositions. Big problems and bigger ideals. Poverty and abundance. Naivete and hope. Triumphs and failures. Through a humble and honest view of global health inequities, Berkowitz takes us onto the front lines of working in global neurology from the field’s life changing possibilities to its complex challenges. While he provides more questions than answers, his insightful and thought-provoking reflections on ethical dilemmas will widen your view of the world.

This story is set to become a favorite for readers who admire the work of Atul Gawande and Oliver Sacks. Filled with inspiring and humorous passages, it is a book that is as enjoyable as educational.

Written with moving and powerful Haitian Creole proverbs, such as men anpil chay pa lou (many hands make the burden lighter) and tout moun se moun (every person is a person), this story’s teachings will undoubtedly resonate with you long after you’ve put the book down. •

María Jimena Alemán is currently a medical student at Universidad Francisco Marroquín in Guatemala. She is interested in global neurology and health equity.

Wolfgang Grisold

Wolfgang Grisold

In this issue, we will introduce the Constitution & Bylaws Committee, chaired by Anna Hege Aamodt (Norway). This committee ensures that the constitution and bylaws are correct and updated. Conversely, the trustees, often as requested by members, consider to implement changes, which are first scrutinized by this committee for feasibility and practicalities before they are up for voting.

From the WFN Speciality groups, Prof. Kurt Niederkorn will report on the activities of the Neurosonology Specialty Group.

Anne Hege Aamodt is the chief physician at the Headache Clinic and senior consultant at the Stroke Unit at Oslo University Hospital, Norway. She has a broad interest in cerebrovascular and headache research and is the coordinating investigator of several international and national trials. She has organizational leadership, experience in national and international scientific organizations, and was the president of the Norwegian Neurological Association from 2014-2021.

WORLD FEDERATION OF NEUROLOGY, Constitution and Bylaws Committee

Anne Hege Aamodt

The Constitution and By-Laws Committee has members representing all regions. Anne Hege Aamodt is the chair of the committee, representing Europe and Norway. Akram Al-Mahdawi (Iraq) and Hani Aref Pan Arab (Egypt) represent the Pan Arab region, Gagandeep Singh (India) represents Asia-Oceania, Terrence Cascino from USA is represents North America, Fernando Gracia (Panama) represents Latin America, and Thérèse Sonan from Ivory Coast represent Africa.

With the representatives from the different regions, the bylaws committee is well-prepared to work with its main tasks helping the Trustees with the evaluation of proposals for the revision and improvement of the bylaws. The committee aims at providing adaptation and improvement to improve the structure and the function of the Federation. Changes in the bylaws have to be carefully considered by the committee, before voted on by the Council of Delegates after discussion of a resolution presented by the Trustees.

Kurt Niederkorn

The other task of the committee is to review and discuss any inquiry into matters pertaining to the organisation and functioning of the Federation, to help the Trustees with decisions in such matters.

The committee has been supporting the president with advice regarding the electronic voting. Electronic voting was planned before the pandemics to aid the number of people involved in making important decisions when it is not possible to meet physically.

Other points were the discussion of changing the Articles of Association to include a role for the immediate past president to ensure continuity and the length of time this would be required for. The conclusion of the committee was that this statutory position is not needed. Furthermore, the appointment of a non-executive trustee to comply with the rules of the charity commission has been discussed, such as including  people from other fields and to increase the breadth of knowledge and opinion. For instance, a lawyer, an economist, or a patient advocate has been discussed. Adding board members puts an additional strain on the WFN finances. However, we recommend that additional board member(s) advisors could be brought in as and when necessary.

For the time being, the committee is working on Standard Operating Procedures that outline areas of responsibly with updated charges, aims, and a protocol.

WFN Neurosonology Specialty Group

For the WFN Specialty groups, Prof. Niederkorn was so kind summarize the impressive activities of the WFN Neurosonology Specialty Group.

Prof. Kurt Niederkorn has been the Chairman of the Neurosonology Specialty Group/WFN since 2019. He has a long experience with neuro ultrasound, and has organized national (Austria) and international courses. He was the secretary of the Neurosonology Research Group/WFN 1993-2001. He works at Graz University, is a professor of Neurology since 1996 and was the vice chair until 2013 of the Dept. of Neurology Graz, Austria. From 2001-2019 he was the head of the Stroke Unit and Stroke Outpatient Service and Neurosonology Lab at the university clinic in Graz

The Specialty Group has a large membership, which can be found on the WCN website.

The Specialty Group was founded in 1977 and endorsed by the WFN in 1981. It is chaired by Kurt Niederkorn and its purpose is the promotion of science and research as well as education and training in the field of ultrasonic techniques (brain vessels and parenchyma and muscle, nerve). This has been a growing and expanding field and modern diagnostics of stroke need ultrasoound equipment. In addition, the group also fosters the development of nerve and muscle ultrasound.

The Specialty Group organizes biannual meetings (2011 Beijing, 2013 Sofia, 2015 Chile, 4/2019 Linz/Austria- Joint meeting with ESNCH, around 300 participants); for 11/2022 a meeting is planned in Korea.

The Specialty Group organizes and co-sponsors international teaching courses and workshops (2014 Lima, 2015 Georgia, 2019 Kazakhstan).

The International Certification in Neurosonology (GM v Reutern/E.Bartels/S Horner, in cooperation with ESNCH) worldwide has been successfully passed by 180 applicants.

Presently, it has 415 members from 50 countries who contribute Euro 25/year for the society. The Specialty Group is constituted from different Chapters: Asia, Latin America, Bulgaria and Georgia.

It has a homepage at https://www.nsrg.net (Content: meetings information and links, guidelines and recommendations). Applications for membership can be made to : alexander.razumovsky@specialtycare.net.

Both the Committees and the Specialty Groups contribute to the vital functions of the WFN.

For each issue of World Neurology, we will continue to introduce a WFN Committee and a Specialty Group. •

Wolfgang Grisold is Secretary-General of the WFN.