By Douglas J. Lanska

Douglas J. Lanska

In the late 1860s, on the basis of his clinical and anatomical studies, Norwegian physician Gerhard Armauer Hansen (1841-1912) concluded preliminarily that leprosy was a distinct disease with a specific cause, and not simply a degenerative condition with multiple potential etiologies. (See Figures 1 and 2.) His subsequent epidemiological studies in Norway found no association between the occurrence of leprosy in various districts and general mortality rates, provided evidence that leprosy was contagious rather than hereditary, and demonstrated that isolation of cases produced a decline in incidence.

In 1873, Hansen discovered rod-shaped bodies — Mycobacterium Leprae, sometimes called Hansen’s bacillus — in leprous nodules, although he did not clearly identify them as bacteria. He described these in a report to the Medical Society of Christiania (now Oslo) and in his main treatise in 1874, with a shorter English version in 1875:

Figure 1. Gerhard Armaner Hansen. Photograph by J.F. Lehman, Munich, 1912. Public domain. Courtesy of the U.S. National Library of Medicine.

“While leprosy may be … indirectly proved to be a specific disease by demonstrating its contagiousness, it would, of course, be the best if a direct proof could be given. I will briefly mention what seems to indicate, that such proof is, perhaps, attainable. There are to be found in every leprous tubercle extirpated from a living individual — and I have examined a great number of them — small staff-like bodies, much resembling bacteria, lying within the cells; not in all, but in many of them. Though unable to discover any difference between these bodies and true bacteria, I will not venture to declare them to be actually identical. Further, while it seems evident that these low forms of organic life [i.e., bacteria] engender some of the most acute infectious diseases, the attributing of the origin of such a chronic disease as leprosy to the apparently same matter must, of course, be attended with still greater doubts. It is worthy of notice, however, that the large brown elements found in all leprous proliferations in advanced stages … bear a striking likeness to bacteria in certain stages of development … .”

Figure 2. A 24-year-old Norwegian man with lepromatous leprosy. From Leloir H. Traité pratique et théorique de la lè
pre. Paris: A. Delahaye et Lecrosnier. 1886. This figure was later reprinted by Hansen in his monograph (1895). Public domain. Courtesy of the Bibliothè
que nationale de France.

Hansen tried unsuccessfully to stain his preparations. In 1879, when Hansen was visited by Albert Neisser (1855-1916), a young colleague from the laboratory of German physician and pioneering microbiologist Robert Koch (1843-1910) in Breslau, Hansen, encouraged him to try to stain the bacteria. (See Figure 3.) Shortly after Neisser returned to Breslau, he succeeded in staining the bacteria, and then promptly announced his findings, suggested that these bacteria were indeed the infectious agent of leprosy, and claimed priority for the discovery.

Hansen replied quickly and tried to assert his own priority, and by 1880 he had also succeeded in staining the bacteria. (See Figure 4.)

Figure 3. Albert Neisser. Public domain. Courtesy of the U.S. National Library of Medicine.

“It was not my intention to make any of my investigations on this subject public at present, but as not only Dr. Edlund to whom in the preceding year I showed preparations, and mentioned that I considered leprosy a parasitic disease, in his little work on ‘Leprosy’ speaks of its precise origin as something that he has discovered in the form of “micrococci,” by also Dr. Neisser, of Breslau, who passed some portion of this summer in Bergen has just published the result of his investigations of those preparations that he made while here, and as these results also point out that in general, the preparations are filled with ‘bacilli’ which he supposes to be peculiar to leprosy, and as its ‘contagium’— I feel myself called upon to announce what I have attained to, up to the present time, in my researches after the same ‘contagium,’ and, this, partly to assert my priority with reference to this discovery, and partly in order to advance those details in research which I omitted to announce on account of the still uncertain result in my report to the Medical Society of Christiania [Oslo], 1874, concerning my investigations into the etiology of leprosy.”

Figure 4. Left: Hansen’s drawing (1880) of “brown elements colored with methyl violet, from a tubercle treated with osmic acid.” From Hansen (1880). Right: A photomicrograph of Mycobacterium Leprae (small red rods), taken from a leprosy skin lesion. Public domain. Courtesy of the U.S. Centers for Disease Control and Prevention, Public Health Image Library (PHIL) #2123.

Although an international consensus generally favored Hansen in this priority dispute as the discoverer of Mycobacterium Leprae, neither Hansen nor Neisser succeeded in fulfilling Henle’s postulates — the criteria to establish a causative relationship between a microbe and a disease propounded in 1840 by German physician, pathologist and anatomist Jakob Henle (1809-1885):

1. The microbe occurs in every case of the disease under circumstances that account for the pathological changes and clinical course of the disease;
2. The microbe occurs in no other disease as a nonpathogenic parasite; and
3. After being isolated and grown in pure culture in an artificial medium, it can induce the disease in an experimental host. These criteria were later augmented by Koch and subsequently known as the Henle-Koch postulates.

Neither Hansen nor Neisser demonstrated that the bacteria observed in cases of leprosy were specific to that disease, nor was Hansen able to transmit the disease to animals or humans using leprous material from patients. Hence, at the time of the Hansen-Neisser controversy, it remained unproven that leprosy is infectious, despite even an unethical attempt by Hansen to transmit leprosy to a patient without informed consent. Furthermore, to this day Mycobacterium Leprae has not been grown in pure culture in an artificial medium.

References:

1. Evans AS. Causation and Disease: The Henle-Koch Postulates Revisited. Yale J.
2. Biol Med. 1976;49(2):175-195.
3. Fite GL, Wade HW. The Contribution of Neisser to the Establishment of the Hansen Bacillus as the Etiologic Agent of Leprosy and the So-called Hansen-Neisser Controversy. Int J Lepr. 1955;23:418-428.
4. Hansen GA. Spedalskhedens Arsager (causes of leprosy). Translation by Pierre Pallamary. Intl J Leprosy 1955;23:307-309.
5. Hansen GA. On the Etiology of Leprosy. Br Foreign Medico-chirurgical Rev 1875;55:459-489.
6. Hansen A. The Bacillus of Leprosy. Q J Microscopical Sci 1880;20:92-102.
7. Hansen GA, Looft C. Leprosy: In Its Clinical & Pathological Aspects. Translated by Norman Walker. Bristol: John Wright & Co., 1895.
8. Irgens LM. The Discovery of Mycobacteriom Leprae: A Medical Achievement in the Light of Evolving Scientific Meathods. Am J Dermatopathol 1984;6(4):337-343.
9. Vogelsang TM. The Hansen-Neisser Controversy, 1879-1880. Int J Lepr. 1963;31:74-80.
10. Vogelsang TM. Gerhard Henrik Armauer Hansen: 1841-1912: The Discoverer of the Leprosy Bacillus. His Life and his Work. Int J Lepr 1978;46:257-332.
11. Peter J Koehler is the editor of this history column. He is neurologist at Atrium Medical Centre, Heerlen, The Netherlands. Visit his website at www.neurohistory.nl.

By Gallo Diop

Gallo Diop

The first Turkish-African Meeting of Headache and Pain Management was held May 2-6 in Istanbul, Turkey. It was convened by the Turkish Headache Society and organized by Prof. Hayrunnisa Bolay from Gazi University, Ankara. There was major support from the Turkish International Cooperation Agency (TIKA). It was held under the auspices of and with support from the International Headache Society (IHS). In attendence was Alan Rapoport, president; three other board members of the IHS (Hayrunnisa Bolay, Peter Goadsby, Andy Charles); Dimos Mitsikostas, president of the European Headache Federation; Zaza Katsarava, vice president of the European Headache Federation; and Aksel Siva, president of Turkish Headache Society. This scientific neuro-event was attended by almost 70 senior and young neurologists from different African countries (Botsawana, Djibouti, Egypt, Ethiopia, Kenya, Morocco, Nigeria, Senegal, Sudan), Germany, Georgia, Greece, Denmark, U.K., U.S., and the hosting country Turkey, represented by headache experts from universities of Istanbul and of Gazi (Ankara). The key highlights were:

• To promote the cooperation and interactions among headache specialists from IHS, headache societies across African countries and Turkey
• Aim to educate young leaders and train clinicians to alleviate pain and increase quality of life of people with headache disorders in Pan Africa
• To learn more about the current conditions and requirements for headache in Africa
• To increase skills for and knowledge about headache and pain management
• Leading international faculty to teach about headache and pain
• Particularly useful for young neurologists, algologists, senior residents and other medical doctors who care for patients with headache and painful conditions
• Membership to IHS will be provided to participants without charge if they are from a country listed as one of the 100 poorest countries in the world.

The meeting covered a wide range of important topics related to headache and pain medicine. The first part of the event ran on the website and involved the theoretical reading of basic papers and live international webinars. The second part of the meeting brought together more than a dozen world-renowned headache and pain experts to teach and mentor the junior physicians from Africa and Turkey. Teaching lectures, interactive sessions, case-based learning and practical interventional courses took place in Istanbul during four days. Professors assistant, professors and residents from African universities took part in lectures, cases presentations and discussions.

Day 1

Day 1 was the opening with welcome statements from Bolay, trustee of IHS and convener of the meeting; Prof. Najib Kissani, neurologists at the of University of Marakesh, Morocco; Rapoport, president of International Headache Society from the University of California, Los Angeles; and Siva, president of Turkish Headache Society, from Istanbul. It was followed by lectures.

Attendees of the first Turkish African Headache and Pain Meeting with IHS staff.

Yohannes W. Woldeamanuel, trained in neurology in Ethiopia (2009-2013), is an IHS scholarship awardee and post-doctoral fellow at the Stanford Headache Program. He reported on ‘’Burden of Headache in Africa and Emerging Challenges.” Woldeamanuel emphasized that headache was the 13th cause of YLDs in 2010; migraine represents 15 percent of Africa’s DALYs. In Africa, it is noted a great number of seconday-type headaches from infectious disorders (WHO, 2011, Atlas of Headache Disorders and Resources in the World; Woldeamanuel, 2014, J. Neur. Sci., 342). He suggested collecting more population data with incidence and prevalence rates, prospective research to increase awareness about pain and headache, and more research about traditional management.

Prof. Kissani reported on ‘’Headache in Morroco.” Even if the ratio is better than many African
countries, there is still great lack of specialists for taking care of pain. Prevalence of migraine in Morocco is estimated to 13 percent. Eighteen percent of patients suffering from headache have at least visited one or many healers (Kissani et al, 2009). Results of research supported by ‘’Lifting the Burden: The Global Campaign to Reduce the Burden of Headache Worldwide” Initiative revealed that 85 percent of the 3,600 interviewed people reported more than one headache last year. About 22.5 percent of them suffered from chronic headaches: tension type (48 percent) and migraine (26 percent). Fifty percent used modern medications (55 percent paracetamol; 10 percent aspirin; cost: $22/month). (Some use of combinations also are reported). Ten percent reported consulting traditional healers.

Hellen Kariuki, professor of physiology at Nairobi University, reported on ‘’Natural Traditional Methods to Overcome Pain.” She reported about the dramatic and rapid change of Africans’ lifestyle. Plants are rich sources of pain management around the world. She described some plants that are used by local tribes as painkillers. She discussed how to benefit from these findings and local oportunities to concretely improve management of pain in developing countries.

Rachid Bezad, professor of gynecolgy (Morocco), discussed ‘’The Contribution of Morocco and Africa to Medicine” and described the health system in Morocco and the opportunities of training and cooperation offered by his country.

Days 2-4

Days 2-4 were dedicated to various lectures, cases presentations and practical courses (such as group learning with patients suffering from headaches and practical training in invasive analgesia techniques, peripheral nerve blocks, trigger point injection and acupuncture). Various thematic topics were developed during exciting lectures: classification and evaluation of headache; how to investigate headache patients in restructed resource-setting; choice of treatment options; migraine headache and its mechanisms and management; chronic daily headache and its neurobiology and differential diagnosis; history taking of headaches and pain by specialists; secondary headaches; headaches attributed to infections; women and headache; headache in children and adolescents; chronic pain disorders; and invasive treatment in headache and pain.

From left to right, Aksel Siva, Mustafa, Dr. Ozge, Pr Ndiaye; Alan Rapoport, Hayrunnisa Bolay, Dr. Uluduz and Gallo Diop.

The meeting was successful in all aspects: organization, scientifc program, and social and friendship environment.

This educational meeting was an excellent opportunity to learn about the diagnosis and management of headache and pain disorders, new developments in the science of headache medicine and the care of headache sufferers.

Through the meeting, everybody has learned more about the current conditions in and requirements for headache in Africa. The meeting will promote the cooperation and interactions among headache specialists from the IHS, various headache societies across African countries, Turkey and worldwide.

It was a contributive additional action for the vision of World Federation of Neurology to promote, via its Africa Initiative, training and exchanges as a leveraging opportunity for trainees and specialists continuing professional development in Africa. This meeting comes also as an additional contribution of Turkish Neurology Society in regard to this aim, because this country is already offering (over three years) two scholarships per year, for a month short-term training in neurology departments of Turkish universities for young African neurologists.

Next plans will aim to educate young leaders and increase skills for and knowledge about headache and pain management to alleviate pain and increase quality of life of people with headache disorders throughout Africa. A short- and long-term plan of action has been discussed and will increase the implication of Turkey, IHS and other specialties to fulfill training needs in Africa, in addition to their various contributions during the Regional Teaching Courses organized by European Academy of Neurology and WFN in Africa for 8 years. For more information, visit www.tahpm.org.

The medical book publishing industry is challenged nowadays to turn out products quickly and efficiently, lest the rapid dissemination of today’s scientific advances through the Internet render the content of a book out of date on arrival. The second edition of Murat Emre’s “Cognitive Impairment and Dementia in Parkinson’s Disease” has avoided this fate, in large part because of the organizational skill of the editor and his recruitment of the same authoritative thought leaders that contributed to the first edition in 2010. Hence, this continuity of authorship has allowed for a seamless update of the topics covered before.

The co-authors of each of the 22 well- written chapters have handled their assignments with balanced attention to recent discoveries and to the potential for practical application. There is also a healthy regard for the concept that all roads of investigation ultimately lead back to the patient, whose struggle to cope with the twin burdens of progressive motor and cognitive impairment in Parkinson’s disease (PD) has not been significantly helped by a true breakthrough in treatment since the introduction of levodopa in the 1960s. The failure to develop more effective symptomatic or game-changing, disease-modifying therapies has been one of the great disappointments of modern-day clinical research despite years of valiant effort.

As Dr. Emre observes in his elegant introduction, cognitive impairment as an essential feature of PD was mostly unrecognized by James Parkinson in his essay on the Shaking Palsy (1817) because lack of treatment doomed its victims to a severe physical disability and a shortened lifespan. The stark reality of cognitive impairment in advanced PD became apparent only after the remarkable benefit of levodopa enabled people with PD to function better physically and thereby live longer. Well-designed, long-term cohort studies in the early part of this century revealed not only the shocking news that 70-80 percent of people with PD would develop dementia as they aged and progressed, but also that subtle cognitive abnormalities, particularly in executive function, were prevalent in a sizeable minority at early stages of the disease.

This book thoughtfully reviews the important developments in clinical and basic research of the last two decades, and it highlights new and refined information that has emerged in the five years since the first edition was published. References are up to date as of 2013 with a sprinkling of 2014, the year of publication. Early chapters on epidemiology, natural clinical history and neuropsychological assessment are comprehensive and succinct. The differential diagnosis of dementia in the setting of parkinsonism can be difficult, but the neuropsychological profile of cognitive dysfunction in PD, showing the typical executive, visuo-spatial, attention and memory deficits of PD sets it apart generally from Alzheimer’s disease, wherein disturbances of memory and language are the classic hallmark findings.

The histopathology of PD is the focus of several chapters, which emphasize the near unanimity of opinion that misfolded alpha-synuclein is the key molecular abnormality and the main component of the signature intracytoplasmic inclusion Lewy body. The clinical and pathological continuum of Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) is also effectively explained, including elements of the debate over the contribution of the plaques and tangles of Alzheimer disease (AD) as a minority component of PDD/DLB pathology. Current evidence suggests (without being close to consensus) that DLB, which is defined arbitrarily as dementia occurring within a year of the onset of parkinsonism, has a pathological substrate of alpha-synuclein and Alzheimer plaque (sans tangles), whereas the substrate for PDD — dementia beginning more than a year after the onset of parkinsonism — is more likely to be alpha-synclein alone. Another chapter covers the neurochemistry of PD and PDD and the central relevance of the well-known deficiencies of dopamine and acetylcholine as they relate to the evolution of dementia.

The ferment in biomarker research — a relatively new phenomenon with great promise for predicting cognitive outcomes in the preclinical and early clinical stages of PD and for identifying subgroups for targeting in clinical trials of new therapies — is included in several chapters. Also since the first edition, official criteria for Parkinson dementia and mild cognitive impairment (MCI) in PD have been established under the auspices of the International Parkinson and Movement Disorder Society, using the model of the Petersen criteria for pre-Alzheimer MCI. Several chapters on recent findings in brain imaging are well executed, although it could be argued that all imaging should have been condensed into a single chapter. One of the hottest areas of research in the basic science of PD is the rapidly expanding field of Parkinson genetics. The chapter on the genetic basis of PDD is excellent and comprehensive.

Ian McKieth and Murat Emre join forces in the pentultimate chapter to discuss management of PDD and DLB, and the result is a masterful presentation of a humane message about the time-honored clinical fundamentals of taking a good history, listening empathically and caring long term for the patient and family.

Finally, the closing brief chapter by John Hardy is a sobering statement of how far we still must go before truly meaningful treatment comes into view. He acknowledges the substantial “incremental” progress in molecular biology and genetics of the last decade. The identification of numerous potentially causative somatic and mitochondrial genetic loci in some patients clears some of the fog around pathogenesis, although these advances apply only to a small fraction of the much larger universe of patients with PD, for whom genetic markers are nowhere to be found. Moreover, it is far from clear which pathogenetic pathways are influenced by alterations in the genome or, perhaps more important, how the growing number of these changes interact to produce disease and which ones are the most critical in the pathogenetic cascade. In short, the goal of a cure is “still beyond the near horizon.”

“Cognitive Impairment and Dementia in Parkinson’s Disease” is a solid achievement. The authors have created an informative and useful compendium of the universally accepted wisdom as well as the latest more controversial advances in the field. It is easy for an armchair reviewer to find fault with even the best publications, but there are a few minor shortcomings here. First, the list of contributors should have included the specific disciplines of each person in addition to their institutional affiliations. Second, some of the references at the end of each chapter were duplicated or unrelated to the citations in the text. Third, redundancy across chapters was generally appropriate for emphasis of the most important concepts and facts, but more careful editing could have minimized useless redundancy. Fourth, the importance of impaired olfaction in preclinical PD and the voluminous body of research devoted to it was all but ignored; olfaction received only a brief paragraph in one of the early chapters and no attention was paid in the chapter on biomarkers. And fifth, there was no mention of the so-called “prion hypothesis” that has been invoked in the last several years to explain how alpha-synuclein pathology spreads rostro-caudally throughout the brain as the disease progresses and leads to the development of dementia. These small quibbles hardly detract from the many assets of this fine contribution to the growing shelf of literature on one of the most pressing problems in clinical neurology.