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ИЗ ИСТОРИИ НЕВРОЛОГИИ
© D.J. LANSKA, 2015
гиперкинетические двигательные расстройства: история развития вопроса до середины хх века
Д.Дж. Ланска
Медицинский центр по делам ветеранов системы здравоохранения Великих озер, неврологическое отделение, Тома, Висконсин, США
hyperkinetic disorders of movement:
historical developments to the middle of the 20th century
Lanska D.J.
Neurology Service, Veterans Affairs Medical Center, Great Lakes Healthcare System, Tomah, Wisconsin, USA
Введение. В 1912 г. С.А.К. Уилсон впервые использовал термин «экстрапирамидный» и обратил внимание на важное значение ба-зальных ганглиев в развитии тех или иных двигательных расстройств. 70 лет спустя, в 1981 г., Всемирной Федерацией неврологов экстрапирамидные расстройства были разделены на расстройства движения и расстройства поддержания позы и тонуса. В историческом аспекте среди гиперкинетических нарушений наиболее изученными были тремор и хорееформные расстройства, однако встречались и описания таких гиперкинезов, как атетоз, патологическая стартл-реакция, тик, миоклонус и баллизм. Результаты. Несмотря на то, что тремор и другие неритмичные экстрапирамидные расстройства были известны еще в средние века, лишь в конце XIX века были проведены клинические и патоморфологические исследования, которые позволили систематизировать и описать большинство экстрапирамидных расстройств. Ограниченные знания в области нейроанатомии, нейрофизиологии и патофизиологии головного мозга в сочетании с зачастую догматическим и примитивным пониманием механизма развития болезни, а также постоянное противоборство между психиатрической и неврологической парадигмой патогенеза заболеваний (как, например, при хорее, патологическом стартл-синдроме и тиках) повлияли на отсрочку в понимании патофизиологии и классификации двигательных расстройств. Обсуждение. Проведенные в XIX веке исследования не смогли пролить свет на генез гиперкинетических расстройств (таких как тремора, хореи, патологического стартл-синдромов тиков и миоклонуса) из-за сложности в установлении клинико-патоморфологических корреляций, поскольку морфологические исследования практически не проводились, даже если большинство исследователей и предполагали органическую природу заболевания. Лишь в XX веке с развитием «научной медицины» и таких методик, как выявление специфических маркеров (например, титра антистрептолизина-О), изучение заболеваний на моделях животных (например, хореи Синденгама или гемибаллизма), использование генетических методов (например, при болезни Гентингтона) значительно продвинулось понимание патогенеза некоторых заболеваний. Заключение. Необходимо дальнейшее мультидисциплинарное изучение патогенеза заболеваний с привлечением специалистов в области как практической, так и фундаментальной медицины, с использованием новых диагностических и терапевтических технологий, для достижения прогресса в профилактике и лечении этих зачастую инвалидизирующих заболеваний.
Ключевые слова: история медицины, двигательные расстройства, диагностика, тремор, хорея, атетоз, болезнь Паркинсона, миоклонус
Для цитирования: Неврологический журнал. 2015; 20 (5): 55-68.
HYPERKINETIC DISORDERS OF MOVEMENT: HISTORICAL DEVELOPMENTS TO THE MIDDLE OF THE 20th CENTURY LANSKA D.J.
Neurology Service, Veterans Affairs Medical Center, Great Lakes Healthcare System, Tomah, Wisconsin, USA
Introduction: In 1912, SAK Wilson introduced the term "extrapyramidal" into neurology and focused attention upon the importance of the basal ganglia in producing a range of movement disorders. Nearly seventy years later, in 1981, the World Federation of Neurology proposed a classification that dichotomized extrapyramidal disorders into disorders of movement and disorders of posture and tone. Historical descriptions of hyperkinetic disorders of movement to the middle of the 20th century emphasized tremors and choreiform disorders, but other hyperkinetic disorders of movement were also recognized, including athetosis, pathological startle reactions, tics, myoclonus, and ballism. Results: Although tremor was recognized in antiquity, and although the existence of arrhythmic hyperkinetic extrapyramidal movement disorders was first suggested during the Middle Ages, it was only in the late 19th century and afterwards that careful clinical and pathological studies separated and characterized the most common categories of hyperkinetic movement disorders. Limited understanding of brain organization (neuroanatomy, neurophysiology) and pathological processes, along with often dogmatically expressed but crude mechanistic explanations of disease, and in some cases a chronic tension between psychiatric and neurologic paradigms of disease pathogenesis (e.g., as occurred with chorea, pathologic startle syndromes, and tics), collectively added to delays in categorizing the different movement disorders and understanding the pathophysiology of these conditions. Discussion: Early pathological studies in the 19th century were often uninformative regarding the genesis of hyperkinetic movement disorders (e.g., tremor, chorea, pathological startle syndromes, tics, and myoclonus). It was because of such difficulties in establishing clinical-pathological correlations that many investigators initially abandoned pathological studies, considering these disorders "far beyond the reach of the microscope," even when they still believed that the disorders had an underlying organic cause. Only in the 20th century, with the advent of modern "scientific medicine," did the development of disease markers (e.g., antistreptolysin O titer), animal models (e.g., Sydenham's chorea, hemballism), and modern genetic techniques (e.g., Huntington's disease) greatly facilitate the elaboration of the underlying pathophysiology of some of these disorders. Conclusion: Careful studies, utilizing collaborative teams of clinicians and basic scientists, and employing novel diagnostic and therapeutic technologies, will undoubtedly be needed to significantly advance the prevention and treatment of these often disabling disorders.
Key words: history ofmedicine; movement disorders; diagnosis; tremor; chorea; athetosis; Parkinson's disease; myoclonus.
For citation: Nevrologicheskiy zhurnal. 2015; 20 (5): 55-68.
Fig. 1. British neurologist Samuel Alexander Kinnear Wilson (18781937) introduced the term "extrapyramidal" into neurology and in addition focused attention upon the importance of the basal ganglia in producing a range of movement disorders. Courtesy of Wikimedia Commons.
Рис. 1. Британский невролог Самюэль Александер Киннер Уил-сон (1878-1937), который ввел в неврологическую практику термин «экстрапирамидный» и обратил внимание на значимость базальных ганглиев в развитии ряда двигательных расстройств. С разрешения Викимедиа Коммонс.
Introduction: In 1912, the American-born, but European-trained, British neurologist Samuel Alexander Kinnear Wilson (1878-1937) (Fig. 1) introduced the term "extrapyramidal" into neurology and in addition focused attention upon the importance of the basal ganglia in producing a range of movement disorders [1]. Nearly seventy years later, in 1981, Dutch neurologist Johannes P.W.F. Lakke (1928-2001) and an international group of colleagues, on behalf of the Research Group on Extrapyramidal Disorders of the World Federation of Neurology, proposed a Classification and nomenclature of terms used in the clinical description of extrapyramidal disorders that dichoto-
Сведения об авторе/For correspondence:
Lanska Douglas John (Lanska D.J.) - Doctor of Medicine, Director of Continuing Medical Education, e-mail: Douglas.Lanska@gmail.com Дуглас Джон Ланска - доктор мед. наук, директор факультета непрерывного медицинского образования /факультета усовершенствования врачей/
mized extrapyramidal disorders into disorders of movement and disorders of posture and tone [2]. In the late 20th century a number of different classifications of these disorders were proposed, and these disorders are now generally simply called "movement disorders," which inter alia allows inclusion of disorders of abnormal movement that are not associated with any basal ganglia pathology, such as myoclonus and ataxia, while still implicitly excluding strictly pyramidal disorders [3].
In this lecture, we review the historical descriptions of hyperkinetic disorders of movement to the middle of the 20th century. Historically, the emphasis in that period was on tremors and choreiform disorders, but other hy-perkinetic disorders of movement were also recognized, including athetosis, pathological startle reactions, tics, myoclonus, and ballism. Hypokinetic-akinetic disorders were recognized initially with the description of Parkinson's disease in the early 19th century, and later with various "Parkinson-plus" syndromes in the late 19th and 20th centuries [4-6]. Hypokinetic-akinetic disorders will be discussed in an upcoming article on extrapyramidal disorders of posture and tone.
Tremor: Tremors are now defined as "a rhythmic, regular, oscillating movement of limbs, trunk, head or part thereof," and this rhythmicity distinguishes them from other hyperkinesias [2]. In the second century, Galen (130-200 AD) used the term tremor to refer to "involuntary alternating up-and-down motion of the limbs," occurring during action and resulting from partial "weakness of the force that supports and moves the body" [7-8]. Galen distinguished tremor from palpitation, an "unnatural expansion and collapse" occurring at rest [7-8]. In the early 16th century, the Swiss-German Renaissance alchemist and physician Paracelsus (1493-1541) recognized tremor as a component of mercurialism [9]. Later, in the 17th and 18th centuries, Franciscus de la Boe Sylvius (1614-1672), Gerard van Sweiten (1700-1772), and others further distinguished involuntary movements during action and at rest [8,10].
Rest tremors are present distally at rest and usually decrease with movement, whereas different types of action tremors occur with limb muscles are activated to maintain a posture (i.e., postural tremor) or during goal-directed movements (i.e., intention tremor) [2]. While postural tremors persist unchanged during movements in which the limb remains supported against gravity (e.g., reaching movements), intention tremors increase in amplitude with proximity to the target, with oscillations that occur perpendicular to the intended trajectory. These basic, but fundamental, distinctions were not suggested, though, until the late 19th century, and then only in a relatively crude form.
Physiologic tremor: Physiological tremor is a "normal" and generally asymptomatic oscillation of the limbs that results from ordinary (non-pathologic) neuro-muscular and mechanical processes. It can be manifest "at rest or in action under the influence of emotion, fatigue or physical exercise," but typically is most evident with sustained posture [2].
As early as 1610 Italian physicist and astronomer Galileo Galilei (1564-1642) recognized that cardioballistic
Fig. 2. American physician Augustus Eschner (1862-1949). Courtesy of the U.S. National Library of Medicine. Рис. 2. Американский врач Август Эшнер (1862-1949). С разрешения Национальной медицинской библиотеки США.
and respiratory movements contributed to the shaking of the magnified image in a hand-held telescope: "The instrument must be held firm, and hence it is good, to escape the shaking of the hand that arises from motion in the arteries and from breathing, to fix the tube in some stable place..." [11, p.147].
In 1897, American physician Augustus Eschner (18621949) (Fig. 2) offered several ways of demonstrating physiologic tremor in healthy individuals, including holding a glass of water and viewing the surface, or using a mechanical recording apparatus [12-13]. Eschner noted that: "[Small amplitude physiologic tremors should be expected] ... as every muscular movement is made up of a series of alternate contractions and relaxations, occurring ordinarily with such frequency as to escape detection with the unaided eye." Eschner considered uneven integration of individual muscle twitches to be the basis of physiologic tremor, but he ignored other possible components, including rhythmic bursts of discharges from central generators, oscillatory feedback systems, resonant properties of the moving parts, postural adjustments, and cardiobal-listic and respiratory movements [13].
Rest tremor: British physician James Parkinson (17551824) provided the first clear clinical description of a specific rest tremor in his treatise on the "shaking palsy" in 1817 [4, 6]. His report received limited recognition until later in the 19th century when French neurologist Jean Martin Charcot (1825-1893) labeled the condition "Parkinson's disease" [14-18]. According to Charcot, the tremor of Parkinson's disease is present both at rest and during activity (Fig. 3). Indeed, a rest tremor is, by definition, "present in the distal part of the body at rest," but in contrast to Charcot's characterization it "usually diminishes during voluntary movement" [emphasis
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Fig. 3. Diagrammatic representations of the low-frequency (4-5 Hz) tremors of multiple sclerosis and Parkinson's disease, drawn by French neurologist Jean Martin Charcot (1825-1893) [84]. The period from A to B represents the arm at rest, whereas from B to C represents the arm during a voluntary movement. The top curve represents the intention tremor of "disseminated sclerosis" [i.e., multiple sclerosis]. There is no tremor at rest, whereas with the initiation of a voluntary movement the arm demonstrates a "trembling" which increases in amplitude (with increasing proximity to the target). The next three curves illustrate how Charcot considered the tremor associated with the "shaking palsy" (Parkinson's disease). In the first variety (line 2) "the tremor stops during voluntary acts", whereas in the second variety (line 3) "the tremor continues as such for the voluntary act", and in the third variety (line 4) "the tremor amplitude increases a little during the voluntary act." Рис. 3. Графическое изображение низкочастотного (4-5 Гц) тремора при рассеянном склерозе и болезни Паркинсона, предложенное французским неврологом Жаном Мартеном Шарко (1825-1893) [84]. Отрезок от А до В представляет собой руку в покое, от В до С - руку во время произвольного движения. Верхняя кривая - ин-тенционный тремор при рассеянном склерозе. В покое тремора не наблюдается, однако в начале произвольного движения появляется «дрожание» в руке, которое увеличивается по амплитуде (при приближении к цели). Следующие три кривые иллюстрируют видение Шарко тремора при «дрожательном параличе» (болезни Паркинсона). Первый вариант (линия 2) - «тремор прекращается во время произвольного движения», второй вариант (линия 3) -амплитуда тремора сохраняется во время произвольного двигательного акта и третий вариант (линия 4) - «незначительное увеличение амплитуды тремора во время произвольного движения».
added] [2]. In 1888, British neurologist William Gowers (1845-1915) gave a vivid clinical description of the rest tremor of Parkinson's disease: "The tremor ... causes a movement of the fingers at the metacarpophalangeal joints similar to that by which Orientals beat their small drums. This movement may be chiefly in the thumb and forefinger, which may move as in the act of rolling a small object between their tips" [19].
In the late 19th century, graphical recordings using mechanical devices allowed investigators to demonstrate that the rest tremor of Parkinson's disease is a relatively low frequency tremor with a frequency of 4-8 cycles/ second, that is suppressed by action, and is generally synchronous in symmetric body parts, but varying in amplitude and frequency over time (Fig. 4) [12-13].
Intention tremor: Charcot distinguished the tremor of Parkinson's disease from the kinetic "intentional" (inten-
Fig.4. American physician Augustus Eshner used a tambour recording apparatus for some studies, including those requiring "simultaneous observations of the two sides of the body or of two or more different parts" (A) [11]. For example (B), the use of two tambours allowed simultaneous recording from both hands in a patient with Parkinson's disease (upper curve is the left hand, lower curve is the right hand, and middle line marks time in seconds); the tracings demonstrate a synchronous tremor in the two hands at about 5.5 hertz. Eschner was also able to demonstrate (C) suppression of a rest tremor with action (i.e., finger extension) in a patient with Parkinson's disease (left portion of the tracing shows a tremor at rest and the far right portion without tremor is during action). Prior to action, the tremor had a frequency of approximately 4.7 hertz. The tracings in B and C are the negatives of the originals made on smoked paper.
Рис. 4. Американский врач Август Эшнер, который в своих исследованиях использовал прибор с пишущим механизмом для «одновременной регистрации двух сторон тела или двух и более различных частей тела» (А) [11]. Например (В), использование двух приборов (тахометров) позволило одновременно записать тремор обеих рук пациента с болезнью Паркинсона (верхняя кривая - левая рука, нижняя кривая - правая рука, средняя линия обозначает время в секундах); на графике показан синхронный тремор в обеих руках с частотой 5,5 Гц. Эшнер смог также продемонстрировать (С) подавление тремора в руках при движении (например, выпрямлении пальца) у пациента с болезнью Паркинсона (левая часть кривой демонстрирует тремор покоя и правая - отсутствие тремора во время произвольного движения). Частота тремора в покое составляла приблизительно 4.7 Гц. Линии В и С - негативы, сделанные на папиросной бумаге.
tion) tremor seen in multiple sclerosis, which was later understood to be caused by disruption of the cerebellum or cerebellar connections within the brainstem [14-17]. Charcot noted that in patients with multiple sclerosis tremor is not present at rest, but only with activity, and that the tremor amplitude increases with effort and with proximity to an intended target during goal-directed movements. Although not specifically mentioned by Charcot, the direction of oscillation is perpendicular to the intended trajectory. An intention tremor is "sometimes called incorrectly action tremor" [2], or at least it is fair to say that this is imprecise and misleading, because tremors present with action include physiologic, postural, and intention tremors.
Postural tremors: A postural tremor is "most apparent when the muscles of a limb or trunk are activated to maintain a posture" [2]. In the late 19th-century, high-frequency postural tremors were noted by Charcot and others in various disorders, including alcoholism, mercurial poisoning, general paresis (neurosyphilis), and Basedow's disease (hyperthyroidism), but in general the descriptions relied mostly on frequency rather than the precipitating action (i.e., maintenance of posture).
In 1887 American neurologist Charles Dana (18521935) described a familial postural tremor [20-21]. Although Dana's description was previously accepted as an early description of hereditary essential tremor, in the family reported by Dana the condition (1) reportedly increased under the influence of alcohol; (2) did not interfere with fine manual tasks; and (3) was not likely hereditary given the large reported pedigree, with almost all individuals affected (i.e., with 41 of 42 individuals in
two successive generations affected, and with the sole exception an individual who would be an obligate carrier under an autosomal dominant mode of hereditary transmission) [21]. Although there was considerable interest in hereditary neurologic disorders in the late 19th century, especially following Friedreich's description of hereditary ataxia in 1863 and Huntington's report of hereditary chorea in 1872 [22], there was no understanding at this time of Mendelian genetics and most investigators considered any familial disorder as "hereditary." Hereditary conditions were not understood in anything resembling the modern sense until Mendel's laws were simultaneously rediscovered and promulgated in 1900. In any case, Dana acknowledged an earlier, but very cursory, report of familial tremors by Most in 1836. Multigenerational familial tremors having characteristics of autosomal dominant transmission were recognized in the early 20th century (e.g., Mitchell in 1903)[23], but clear recognition of autosomal dominant transmission of essential tremor did not occur until the middle of the 20th century [6].
Chorea: The word "chorea" is derived from the Greek word "choros," which means to dance. Chorea is now understood as "a state of excessive, spontaneous movements, irregularly timed, non-repetitive, randomly distributed, and abrupt in character" that "may vary in severity from restlessness with mild intermittent exaggeration of gesture and expression, fidgeting movements of the hands, unstable dance-like gait to a continuous flow of disabling, violent movements" [2]. However, initially the term was applied broadly to a diverse group of movements that could not be characterized as a regular oscillation (i.e.,
a tremor) [24]. Indeed, since the Middle Ages, the term chorea had been used to describe various organic and psychological disorders of motor control including tics, parkinsonism, focal dystonias, and psychogenic movement disorders [6,9,24]. The iconoclastic Swiss-German Renaissance physician Paracelsus (1493-1541) introduced the idea that chorea could result from an organic medical condition with his tri-part categorization of the causes of St. Vitus' dance: chorea imaginationis (arising from the imagination), chorea lasciva (arising from sexual desires), and chorea naturalis (organic chorea) [9]. Chorea is now recognized as either a primary disorder (e.g., with inherited forms of chorea), or as a secondary disorder (e.g., with post-infectious, cerebrovascular, traumatic, autoimmune, metabolic, and toxic etiologies).
Choreomania (chorea major, St. Vitus' dance, chorea Sancti Viti, St. John's dance): In the Middle Ages, epidemics of a psychosomatic "dancing mania" erupted in central Europe coincident with the Black Plague [6,9,25]: the term "dancing mania" was derived from "choreomania," a concatenation of choros (dance) and mania (madness). This mass psychogenic illness occurred primarily in mainland Europe between the 14th and 17th centuries, and involved groups of people dancing erratically, sometimes thousands at a time. Dancing mania was initially considered an ordeal sent by a saint, or a punishment from God for people's sins. The people
Fig. 5. English physician Thomas Sydenham (1624-1689) applied
the term Saint Vitus' dance to his description of childhood chorea in
1686. Courtesy of the U.S. National Library of Medicine.
Рис. 5. Английский врач Томас Сиденгам (1624-1689) применил
термин «Пляска Святого Витта» для описания хореи у детей в
1686 г. С разрешения Национальной медицинской библиотеки
США.
affected by this mania danced and jumped until they collapsed from exhaustion, or until they ended their processions at places dedicated to a specific saint, who through prayer was asked to intercede to end the dancing. St. Vitus and St. John the Baptist were among the various saints called upon to intercede, leading to the terms St. Vitus' dance (or chorea Sancti Viti) and St. John's dance.
Sydenham's chorea: In 1686, English physician Thomas Sydenham (1624-1689) (Fig. 5)—generally noted for emphasizing bedside observation and for providing vivid clinical descriptions of diseases—applied the term Saint Vitus' dance to his description of childhood chorea [6]. In so doing he added to the confusing nomenclature of chorea, because after Sydenham the term St. Vitus dance could mean either organic chorea (Sydenham's chorea, chorea minor, or chorea anglorum) or psychogenic chorea (chorea major or chorea germa-norum). Sydenham described childhood chorea as "a kind of convulsion, which attacks boy and girls from the 10th year to the time of puberty. ... The hand cannot be steady for a moment. It passes from one position to another by a convulsive movement, however much the patient may strive to the contrary" [26, pp. 257-8].
Subsequent investigators, including Bouteille (1810), Bright (1831), See (1850), and Roger (1866), suggested a relationship between childhood chorea, rheumatic arthritis, and valvular heart disease [27]. In 1887, Canadian-born physician William Osler (1849-1919) reviewed clinical and pathologic data on 410 cases of Sydenham's chorea treated at the Infirmary for Nervous Diseases in Philadelphia since 1876 [28]. In 1894 while at Johns Hopkins, Osler published a monograph based largely on his earlier studies in Philadelphia, entitled On Chorea and Choreiform Affections [29], that remains among the most widely cited 19th-century American contributions to neurology [30]. Osler classified choreiform disorders into chorea minor (Sydenham's chorea), chorea major (hysterical chorea), secondary or symptomatic chorea (e.g., post-hemiplegic and Huntington's choreas), and pseudo-chorea (e.g., tics). The bulk of Osler's treatise focused on Sydenham's chorea, which he astutely described as "an acute disease of childhood . characterized by irregular, involuntary movements, a variable amount of psychical disturbance, and associated very often with arthritis and endocarditis" [29, p. 2]. Osler carefully reviewed both the literature, and the experience of clinicians in Philadelphia, to marshal evidence that Sydenham's chorea is an "infectious disorder," which is frequently associated with endocarditis, particularly affecting the mitral valve.
As early as the 1860s, British neurologists John Hugh-lings Jackson (1835-1911) and William Henry Broad-bent (1835-1907) implicated striatal dysfunction in childhood chorea. In 1868, Jackson concluded that: "It has long seemed to me that embolism . of parts in the region of the corpus striatum gives a most satisfactory explanation of the physiology and pathology of cases of chorea" [31, p. 238]. Broadbent claimed that chorea is "a delirium of the sensori-motor ganglia" [i.e., basal ganglia], which (in agreement with Jackson) he felt is caused typically by embolism, but which in some cases
Fig.6. American general practitioner George Huntington (18501916) presented the classic description of adult-onset hereditary chorea in 1872. Courtesy of the Wellcome Library. Рис. 6. Американский врач общей практики Джордж Хантингтон (1850-1916) представил классическое описание наследственной хореи с дебютом во взрослом возрасте в 1872 г. С разрешения Библиотеки Уэллком.
may be caused by "a morbid condition of the blood" [32-33]. In the early 20th century the embolic theory was discarded because of the "diffuse nature of the encephalitis," the absence of pathology of the cardiac valves in many cases of childhood chorea, and the relative absence of chorea in cases of adult bacterial endocarditis [33]. Instead, several authorities proposed that Sydenham's chorea was a bacterial meningoencephalitis [3334]. By 1899, a diplococcus had been isolated from the cerebrospinal and pericardial fluids of a child who died with chorea and carditis, and from 1901 to 1903 English pediatrician Frederic John Poynton (1869-1943) and English pathologist Alexander Paine (1866-1933) produced irregular movements, arthritis, and carditis in rabbits intravenously injected with diplococci from affected patients [34]. However, bacteria were not consistently cultured from brain tissue or cerebrospinal fluid of affected cases, and the process by which an infection would selectively target the corpus striatum was never satisfactorily explained. Nevertheless, by the 1930s, the development of the antistreptolysin O titer as a marker of antecedent streptococcal pharyngitis provided the means to unequivocally establish that all manifestations of rheumatic fever, including Sydenham's chorea, are sequellae of group A streptococcal pharyngitis. Sydenham's chorea is now understood to be a /»osf-infectious
disorder resulting from an antibody cross-reaction to basal ganglia epitopes following infection with group A P-hemolytic streptococci [6].
Huntington's Disease: In 1872, American general practitioner George Huntington (1850-1916) (Fig. 6) presented the classic description of adult-onset hereditary chorea [6, 22, 35], even if there had been several earlier descriptions, including those by Reverend Charles Oscar Waters (1816-1892) from New York in 1841, Norwegian physician Johann Christian Lund (1830-1906) in 1860, and American physician Irving Lyon (1840-1896), in 1863 while serving as a House Surgeon at Bellevue Hospital in New York [35-37]. Huntington first encountered victims of hereditary chorea at age eight while accompanying his physician father around East Hampton at the extreme eastern end of Long Island, New York. After his own medical school graduation in 1871, George Huntington incorporated the clinical notes of cases treated previously by his father and grandfather in an essay entitled "On chorea," which was edited by his father. Huntington noted that, "[It] is spoken of by those in whose veins the seeds of the disease are known to exist, with a kind of horror, and not at all alluded to except through dire necessity, when it is mentioned as 'that disorder'" [22]. Huntington further noted the hereditary transmission, the gradual onset of chorea in adulthood, the progressive course, a tendency to insanity and suicide, and lack of response to treatment [22, 35]. Huntington's description of hereditary chorea was considered particularly important, because of his clear and concise description, and
Fig. 7. American neurologist and former U.S. Surgeon General William Hammond (1828-1900) first described "athetosis" in 1871. Courtesy of the U.S. National Library of Medicine. Рис. 7. Американский невролог Уильям Хэммонд (1828-1900) впервые описал «атетоз» в 1871 г. С разрешения Национальной медицинской библиотеки США.
Fig. 8. Hand postures of athetosis. The woodcuts were made from photographs, and were included as illustrations in the first edition of William Hammond's Text-book of Nervous Diseases in 1871 [39]. The top figure was of Hammond's own case, and the lower was from a case of a colleague, J.C. Hubbard.
Рис. 8. Положение руки при атетозе. Гравюры (деревянные клише) сделаны по фотографиям, которые были включены в качестве иллюстраций к первому учебнику по неврологии под редакцией Уильяма Хэммонда в 1871 г. [39]. Верхний рисунок - представлен клинический случай, наблюдаемый Хэммондом, нижний - случай, описанный коллегой, Дж. С. Хаббардом.
because it demonstrated that hereditary conditions could have their clinical onset in adulthood, whereas previously recognized hereditary conditions, like Friedreich's ataxia, all had their onset in [22, 35]. William Osler applauded Huntington's description and concluded that, "In the history of medicine there are few instances in which a disease has been more accurately, more graphically, or more briefly described" [38, p. 115]. By the late 1880's authors began referring to hereditary chorea as "Huntington's chorea," as did Huntington himself after about 1895 [35].
The distinct clinical profile, midlife onset, and autosomal dominant inheritance pattern made Huntington's disease ideal for investigation by genetic linkage analysis a century after Huntington's description. In the decade from 1983 to 1993, the disease was sequentially linked to an anonymous polymorphic DNA marker, as-
sociated with a mutation on the tip of the short arm of chromosome 4 (in 4p16.3), and ultimately attributed to an unstable expanded CAG trinucleotide repeat in a novel gene coding for a protein now labeled huntingtin [6].
Athetosis and post-hemiplegic hemichorea: Atheto-sis is an extrapyramidal movement disorder that manifests as "irregular, slow, forceful, writhing movements generally of the extremities, very often characterized by finger movements" [2].
In the first American textbook of neurology, published in 1871, American neurologist and former U.S. Surgeon General William Hammond (1828-1900) (Fig. 7), first described "athetosis" (a term he derived from the Greek term athetos, "without fixed position") as a hy-perkinetic movement disorder "characterized by an inability to retain the fingers and toes in any position in which they may be placed, and by their continual motion" 6, 30, 39-40]. There were associated "pains in the spasmodically-affected muscles, and especially complex movements of the fingers and toes, with a tendency to distortion," with a slower and more sinuous quality compared with chorea, and without any associated weakness (Fig.8). Relying on English neurologist Thomas Willis' (1621-1675) 200-year-old erroneous concept that the corpus striatum is the seat of motor power, Hammond speculated that "one probable seat of the morbid process is the corpus striatum," a serendipitous supposition ultimately supported by the autopsy on the original case which was reported by his son Graeme Monroe Hammond (1858-1944) in 1890 [41]. In this case, there was a lesion involving the posterior thalamus, part of the internal capsule, and the lenticular nucleus (Fig. 9). Graeme Hammond "called attention to the fact that the motor tract was not implicated in the lesion, and claimed that this case was further evidence of his theory that athetosis
Fig. 9. Pathology of the original case of athetosis as reported by his son Graeme Monroe Hammond (1858-1944) in 1890 [41]. This confirmed the localization that had been proposed by his father, William Hammond, in 1871.
Рис. 9. Патоморфология пациента с атетозом, которого наблюдал сын Хэммонда Грем Монро (1858-1944) в 1890 г. [41]. Это исследование подтвердило локализацию патологического процесса, которую предположил еще его отец, Уильям Хэммонд в 1871 г.
Fig. 10. Hand postures in post-paralytic choreoathetosis. Post-paralytic choreoathetosis was recognized by many eminent late 19th-century neurologists, including Charcot, Gowers, and Mitchell. Athetosis was often considered as just a form of post-hemiplegic chorea, even though Hammond's original case and some others never experienced a hemiparesis. The leftmost column of illustrations from Gowers' textbook (1888) show "continuous mobile spasm (athetosis) after slight hemiparesis" in a 24-year-old syphilitic patient who developed left hemiparesis at age 23 and abnormal involuntary movements 4 months later [19]. The center column of illustrations, also from Gowers' textbook (1888), are some of the postures of the left hand of a 23-year-old male with "post-hemiplegic mobile spasm''; the abnormal movements began one year after onset at the time of some improvement in volitional movement [19]. The right-most column of illustrations were derived from those of German neurologist Adolph von Strümpell as shown in the late 19th-century multi-authored American textbook of neurology edited by Francis Dercum (1895) [85].
Рис. 10. Положение руки пациента с хореоатетозом, развившимся после паралича. Постпаралитический хореоатетоз описан многими выдающимися неврологами конца XIX столетия, в том числе Шарко, Гоуерсом и Митчеллом. Атетоз обычно рассматривался как форма постгемиплегической хореи, даже, несмотря на то, что в этом и других наблюдаемых Хэммондом случаях, гемипареза не наблюдалось. Левый столбик рисунков - «постоянный мобильный спазм (атетоз) после незначительного гемипареза», иллюстрация взята из учебника Гоуерса (1888 г.). Атетоз развился у 24-летнего пациента, страдавшего сифилисом, у которого в 23 года развился гемипарез, а спустя 4 месяца -аномальные непроизвольные движения [19]. Центральный столбик иллюстраций также взят из учебника Гоуерса (1888 г.) - некоторые позы левой руки 23-летнего мужчины с постгемиплегическим мобильным спазмом»; аномальные движения появились через год после заболевания на фоне улучшения произвольных движений [19]. Правый столбик иллюстраций представлен из книги немецкого невролога Адольфа фон Штрюмпеля согласно американскому учебнику по неврологии, составленному коллективом авторов под ред. Ф. Деркума в конце XIX века (1895 г.) [85].
was caused by irritation of the thalamus, the striatum, or the cortex, and not by a lesion of the motor tract," or, in other words, that athetosis is an extrapyramidal, rather than pyramidal, disorder of movement [41].
Despite the confirmation of a proposed clinico-path-ological association, athetosis was, and remains, controversial, being considered by many late-19th- and 20th-century neurologists as a form of post-hemiplegic chorea, i.e., a manifestation of a pyramidal disorder, or alternatively as an intermediate condition that was part of a continuum between chorea and dystonia [6, 40]. The preeminent 19th-century American neurologist Silas Weir Mitchell (1829-1914), who had been a longstanding
friend of Hammond, described similar cases under the term "post-paralytic chorea," noting that "as there is a post-choreal paralysis, so, also, is there a post-paralytic chorea... [In] adults who have had hemiple-gia and have entirely recovered power, there is often to be found a choreal disorder, sometimes of the leg and the arm, usually of the hand alone" [42, p. 343]. British neurologist William Gowers (1845-1915) similarly felt there was considerable clinical overlap between Hammond's athetosis and "post-hemi-plegic disorders of movement" and described similar patients in whom the movement disorder followed a sudden hemiplegia with some degree of recovery (Fig. 10) [18,43]. Gowers argued that athetosis is a movement disorder within the spectrum of "post-hemiplegic disorders of movement," between the irregular "quick, clonic spasm" of chorea and the "slow, cramp-like incoordination" and tonic spasms associated with "spastic contracture" [43, p. 291]. As a result, Gow-ers was willing to accept athetosis as a clinical entity with the proviso that hemiparesis could be associated with it, depending on the extent of the lesion. In contrast, French neurologist Jean-Martin Char-cot (1825-1893) dismissed Hammond's athetosis as "simply choreiform movements" [44, p. 390] or as "only a variety of post-hemiplegic hemichorea" [44, p. 394] to which Hammond retorted, "I have only to say that the distinction between the two conditions is as well marked as between chorea and disseminated cerebro-spinal sclerosis. In atheto-sis the movements are slow, apparently determinate, systematic, and uniform; in post-hemiplegic chorea they are irregular, jerking, variable, and quick. Moreover, athetosis is not by any means necessarily post-hemiple-gic" 45, p. 324]. Even modern authors have erroneously indicated that Hammond's original cases were examples of a post-hemiplegic movement disorder, but as emphasized by Hammond "In the original case there had never been hemiplegia, nor was there such a state in the second case, on which [Hammond's] description of the disease was based" 45, p. 324]. Hammond's cases both occurred after convulsions and loss of consciousness, and both were associated with some sensory loss. Hammond accepted that hemiplegia could be an antecedent in some cases, but "Where the motor tract is implicated there will
Fig. 11. American neurologist George Miller Beard (1839-1883) described abnormal startle reactions in French Canadians and lumbermen in the Moosehead Lake region of northern Maine in the period from 1878-1880. Courtesy of the U.S. National Library of Medicine. Рис. 11. Американский невролог Джордж Миллер Берд (18391883), который описал патологические стартл реакции у фран-коговорящих канадцев и лесорубов в районе озера Мусхед на севере штата Мэн в период с 1878-1880 гг. С разрешения Национальной медицинской библиотеки США.
abnormal startle reactions, affected individuals were referred to as "Jumpers" or "Jumping Frenchmen." Beard's initial report was based on conversations and correspondence [48], but he subsequently investigated the cases personally [49-50]. He noted that manifestations included excessive reactivity to sounds, automatic obedience, and echolalia. The term "jumping" encompassed all of the associated abnormal startle manifestations, including "lifting the shoulders, raising the hands, striking, throwing, crying, and tumbling" [50, p. 174]. Jumpers were physically healthy and active, and clearly distinguishable from the state of nervous exhaustion which he had previously described and labeled as "neurasthenia." Cases never seemed to remit, so Beard concluded that the prognosis for recovery was poor: As he said, "once a jumper, always a jumper" [50, p. 176].
Although Beard believed that jumping likely had an organic basis, he doubted that its pathophysiology could be elaborated by available scientific methods, and so reluctantly concluded that jumping could only be practically studied by psychological means. As he noted: "Far out of the range of the aided senses, far beyond the reach of the microscope, or perhaps the spectroscope, there may be molecular changes or disturbances which manifest themselves in these jumpings and strikings and throwings as a result and correlative. But for the present, possibly for all time, we can only study this subject psychologically..." [50, p. 175].
The cause of jumping remains unknown. Beard noted that jumping was familial, and believed that jumping was therefore necessarily "hereditary"; however, jumping is rarely seen in women and no detailed pedigrees supporting Mendelian inheritance have been published. Clinical authorities who have examined jumpers have most commonly interpreted jumping to be a culturally standardized
be hemiplegia, spastic spasm, and exaggerated reflexes in addition to the athetosis" [45, p. 324].
Many preferred to incorporate athetosis into a broader conceptualization of chorea, noting that that some cases included features of both types of abnormal movement and that both could occur after hemiparesis [46], while others separated the cases on etiological and phenom-enological grounds [6].
Pathologic startle syndromes: Startle is a universal and phylogenetically ancient stereotyped reflex response to sudden, intense stimulation, which can be exaggerated in a wide variety of neuropsychiatric disorders, including various culture-bound syndromes (e.g., jumping, myriachit, and latah), hyperekplexia, startle epilepsy, benzodiazepine and alcohol withdrawal syndromes, post-traumatic stress disorder, and general anxiety disorder [47]. In the late 19th century, jumping (French Canadians in Maine, United States), myriachit (Siberia), and latah (Southeast Asia) were described, and were felt by some to overlap with hysteria or tics.
Jumping: In 1878 and 1880, American neurologist George Miller Beard (1839-1883) (Fig. 11) described abnormal startle reactions in French Canadians and lumbermen in the Moosehead Lake region of northern Maine, United States [6, 21, 30, 48-50]. Because of their
Fig. 12. Russian psychiatrist Ardalion Ardalionowicz Tokarski (Ардалион Ардалионович Токарский, 1859-1901) publisjed observations on cases of "meriatschenje" (myriachit) in Kiachty (Кяхта). Courtesy of Wikipedia.
Рис. 12. Русский психиатр Ардалион Ардалионович Токарский (1859-1901), опубликовавший описание случая меряченья (или болезни судорожных подергиваний) в Кяхту. С разрешения Википедии.
Fig. 13. French physician Jean-Marc Gaspard Itard (1775-1838) offered the first clear description of tic disorders in 1825. Courtesy of the U.S. National Library of Medicine.
Рис. 13. Французский врач Жан-Марк Гаспар Итард (1775-1838) первым представил описание тиков в 1825 r. С разрешения Национальной медицинской библиотеки США.
startle response or an operant-conditioned response [6].
French neurologist Georges Gilles de la Tourette (1857-1904) translated Beard's paper in 1881 and reported similar cases on Charcot's service in Paris [5152]. After this, jumping was largely forgotten until further cases were described in the mid-1960s and afterwards [6]. These later descriptions include a somewhat expanded clinical spectrum which includes pathologic startle reaction, automatic obedience, echolalia, and rarely echopraxia and coprolalia.
Miryachit [Miriachit, Meriatschenje, Myriatchenie]: In 1884, American neurologist and former U.S. Surgeon General William Alexander Hammond (1828-1900) noted similarities between Beard's description of "jumping" and a recently published description of Siberian "miryachit" (meaning "to act foolishly") [53]. Several U.S. Navy officers had observed an affected Siberian ship's steward while on the Ussuri River in southeastern Siberia in 1882 [54]. The steward was afflicted by echopraxia, echolalia, and excessive startle, but without reported automatic obedience or actual jumping; he was unable to resist imitating the grunts, shouts, or pounding on the bulkhead intentionally produced by the crew and passengers to provoke his behavior. Unlike Beard, who had personally examined jumpers, Hammond did not make his own personal observations of miryachit.
Russian physicians in Siberia also later described this disorder. Russian psychiatrist Ardalion Ardalionowicz Tokarski (Ардалион Ардалионович Токарский, 18591901) (Fig.12) had served as an assistant to Russian neuropsychiatrist Sergei Korsakoff (Сергей Сергеевич
Корсаков, 1854-1900) from 1886-1888, then moved to Kiachty (Кяхта), where he observed numerous cases of "meriatschenje," and ultimately published his observations on what he considered pathological imitation behavior [55-56]. Tokarski also relayed the experience of Russian military physician Nicolai Ivanowich Kashin (also Kaschin; Николай Иванович Къшин, 18251872) in 1868 around Lake Baikal where Kashin had observed a military corps that simultaneously repeated all orders that they received [56]. In 1911, Russian psychiatrist Nikolai Nikolaevich Bazhenov (also Bagenoff; Николай Николаевич Баженов, 1856-1923), chief physician at the Preobrazhenskaya psychiatric hospital in Moscow, reviewed miryachit and concluded that this was a psychoneurosis [57].
Tics: Tics are involuntary, episodic, "sudden, stereotyped, complex, repetitive [but arrhythmic], normally coordinated but inappropriate movements, which can only be suppressed for a short period by an effort of will at the expense of increasing emotional tension" [2]. Tics can be categorized as motor (e.g., brief movements) or vocal (e.g., abnormal sounds produced by moving air through the nose, mouth, or throat) [58]. Tics occur as a required diagnostic feature of Tourette syndrome, but can also occur in a wide variety of neurologic disorders.
French physician Jean-Marc Gaspard Itard (17751838) (Fig. 13) offered the first clear description of tic disorders in 1825 [6, 59], a report later cited by Gilles de la Tourette in 1885, who included Itard's case in his larger series of 9 cases [60]. Motor and vocal tics were also recognized by French physician Armand Trousseau (1801-1867) in 1873 [24]. Itard reported the case of Madame de Dampierre (c1799-1884), later the Marquise (Countess) de Dampierre, who had vocal and motor tics; the countess's various vocalizations included coprolalia
Fig.14. French neurologist Georges Gilles de la Tourette (18571904) described the tic disorder that Charcot called "maladie des tics de Gilles de la Tourette" in 1884 and 1885. Courtesy of Bibliothèque Interuniversitaire de Santé, Paris.
Рис. 14. Французский невролог Жорж Жиль де ля Туретт (18571904), описавший тик, который Шарко назвал «болезнь тиков Жиль де ля Туретта» в 1884 и 1885 гг.
Опубликовано с разрешения Межуниверситетской библиотеки Bibliothèque Interuniversitaire de Santé, Париж.
and echolalia, and because of this she was very uncomfortable and often embarrassed in public. Itard noted that such involuntary vocalizations "present an extremely rare phenomenon, and constitute an extremely disagreeable inconvenience that deprives the person who is affected of all the sweetness of society." Tics gained wider recognition late in the 19th century after Charcot presented cases before his classroom audience [61].
Gilles de la Tourette syndrome: In 1884, Gilles de la To-urette (Fig. 14), then a house physician at the Salpetriere under Charcot, contrasted French-American jumping, Siberian miryachit, and a similar Malaysian condition called latah; he concluded that the three disorders were identical, and reported seeing similar cases on Charcot's service with hyperexcitability, motor tics, echolalia, and coprolalia [52, 62]. A year later, in 1885, Gilles de la Tourette published his classic paper entitled, A study of a neurological condition characterized by motor incoordination accompanied by echolalia and coprolalia [60, 63]. In this latter paper, written "with the help of Professor Charcot," Gilles de la Tourette reported 9 cases with tics, including Itard's case of Madame de Dampierre. The cases had a childhood onset of stereotyped and multidimensional abnormal movements, including phonic tics that were either simple (e.g., throat clearing, sniffing, or grunting) or complex (e.g., coprolalia). Charcot later called this disorder "maladie des tics de Gilles de la Tourette," and it was largely because of Charcot that the disorder became known under the eponym of Char-cot's pupil, even though both Itard (1825) and Trousseau (1873) had previously described tic disorders [24,60].
Although it has been reported that Charcot initially disagreed with Gilles de la Tourette on the identity of these various syndromes, at least by 1885 Charcot felt that jumping, miryachit, latah, and Tourette syndrome were the same [60-61, 64]. However, despite clinical overlap between "jumping" and Tourette syndrome, these entities are now recognized as distinct. In "jumping," the key feature is an abnormal startle response, the abnormal reaction is always provoked, and tics are absent; whereas, in Tourette syndrome, the key feature is spontaneous motor and vocal tics, although patients with Tourette syndrome may also have an exaggerated startle response.
Gilles de la Tourette and Charcot did not emphasize spontaneous tics as the essential feature of Tourette syndrome, in part because of their attempts to establish a close relationship between their patients and those with jumping, myriachit, and latah. Echolalia is no longer considered a major clinical feature of Tourette syndrome, and a strict concordance between vocal tics and simultaneous motor tics is no longer accepted. Nevertheless, the modern definition of Tourette syndrome incorporates all the original diagnostic criteria proposed by Gilles de la Tourette and Charcot: childhood onset, a combination of motor and vocal tics, waxing and waning of symptoms, and chronicity [2,58].
Freudian psychodynamic and psychological theories of the etiology Tourette syndrome were dominant in the early 20th century, and it was only in the late 20th century that investigators marshaled support for a biological ori-
gin for tic disorders [6]. Since the 1960s, a pathophysiologic role for dopamine has been identified in the patho-physiology of tic disorders, based on several converging lines of evidence: (1) neuroleptic medications with anti-dopaminergic properties, particularly haloperidol, are useful in treating tic disorders; (2) levodopa and do-pamine agonists can induce or exacerbate tic disorders; (3) tardive tic disorders can occur after long-term neu-roleptic treatment (suggesting facilitation by dopamine receptor hypersensitivity); and (4) cerebrospinal fluid metabolites of dopamine are selectively reduced (suggesting decreased dopamine turnover) [6].
Tourette syndrome had been recognized as familial since Gilles de la Tourette's original report [60]. However, no clear pattern of inheritance and no specific gene defect have been documented, although an autosomal-dominant pattern with incomplete penetrance and variable expression is now most widely accepted. Modern genetic studies of Tourette syndrome have been frustrating because of difficulties in defining phenotypes, and determining whether subjects with obsessive-compulsive symptoms or elements of attention deficit disorder should be considered as affected cases.
Myoclonus: Myoclonus is "characterized by sudden shock-like contractions of a muscle or group of muscles" that are triggered within the central nervous system [2]. Myoclonus "may occur at rest or during action," is not suppressible, and "may be isolated, repetitive, or rhythmic" (e.g., palatal or diaphragmatic myoclonus) [2]. By 1903, Lundborg proposed a classification system for myoclonus that remains largely in use today, with primary (essential), secondary, and epilepsy-associated categories [65]. Only since the 1950s has it been recognized that myoclonic movements can be "positive" or "negative": positive myoclonus results in the contraction of a muscle or muscles, whereas negative myoclonus (e.g., asterixis) is instead associated with a brief loss of muscle tone [6]. Unlike most other hyperkinetic movement disorders, myoclonus is not extrapyramidal.
Essential myoclonus: In 1881 Nikolaus Friedreich (1825-1882) reported a 50-year-old man with a 5-year history of multifocal muscle jerking, occurring at a rate of 10 to 50 per minute, and affecting both sides of the body, symmetrically but asynchronously. The rapid muscle jerks affected the bulk of a muscle, without marked limb or joint movement except in the most powerful contractions [66]. Freidreich called the syndrome "para-myoclonus multiplex" to indicate quick movements, distinct from epilepsy, symmetrically affecting multiple sites of the body [66]. Although Friedrich suspected the problem was caused by a spinal cord disorder, no pathology of the spinal cord was later identified at autopsy [67]. Friedreich's term was adopted in shortened form as "myoclonus" and in modern terminology his case would be classified as essential or idiopathic myoclonus. Lin-demulder later reported a family with essential myoc-lonus, which helped demonstrate that such generalized myoclonus could occur in the absence of neurodegener-ative disorders, epilepsy, or obvious metabolic derangement [68].
Fig.15. Ballistic movements in a patient with "adult chorea" (probably Huntington's disease) who was photographed by American neurologist Francis Xavier Dercum (1856-1931). Dercum utilized photography to show many neurological conditions and intentionally utilized blur to connote motion. Illustration from the first multi-authored neurology text, A Text-book on Nervous Diseases (1895), which was edited by Dercum (Dercum 1895) [85]. Рис. 15. Баллизм у пациента с «хореей взрослых» (вероятно болезнью Гентингтона).
Фотография сделана американским неврологом Фрэнсисом Ха-вьером Деркумом (1856-1931). Ф. Деркум использовал фотографию, чтобы показать различные неврологические заболевания, и намеренно использовал размытое изображение, чтобы продемонстрировать движение. Иллюстрация из учебника неврологии (A Text-book on Nervous Diseases) (1895 г.), впервые написанного коллективом авторов, под ред. Ф. Деркума.
Myoclonic epilepsy: Throughout the 19th century, myoclonic jerks in association with epilepsy were recognized by various authors, including as part of what would now be called infantile spasms [69]. In 1891, Un-verricht reviewed the literature on myoclonus, dismissed the majority of cases reported to that point as incorrectly designated, and also described patients with progressive multifocal myoclonus and epilepsy [70]. In 1903, Lundborg described additional patients with familial progressive myoclonic epilepsy, distinct from "paramyoclonus multiplex" or essential myoclonus. In the 1990s, progressive myoclonic epilepsy of Unverricht-Lundborg was linked to mutations in the cystatin B gene on chromosome 21q.22, which codes for a small protein in the superfamily of cysteine protease inhibitors. Other forms of progressive myoclonic epilepsy were also recognized, including lysosomal storage diseases (e.g., neuronal ceroid lipofuscinosis), mitochondrial disorders (e.g., myoclonic epilepsy with ragged red fibers or MERRF), and glycogen storage diseases (e.g., Lafora's disease).
Secondary or symptomatic myoclonus: In the 1920s
and 1930s, multifocal myoclonus was recognized as a feature of encephalitis lethargica [71-72], CreutzfeldtJakob disease [73-74], and subacute sclerosing panencephalitis [75]. Secondary myoclonus is now recognized in a wide variety of disorders, including infections, metabolic derangements, hypoxia, and neurodegenerative diseases.
Ballism and the Subthalamic Nucleus (Nucleus Luysii): Ballistic movements are "proximal, violent and flinging in character," usually resulting from a lesion is in or near the subthalamic nucleus [2,6,76] (Fig. 15). Primary ballism is a hereditary bilateral condition, while secondary ballism is usually unilateral, i.e., hemiballis-mus (e.g., due to space-occupying lesions, cerebrovas-cular disease, trauma, infection, etc).
In 1865, Jules Luys (1828-1897) named the subthalamic nucleus the "accessory band of the superior olives" (bandelette accessoire des olives supérieures), terminology which was anatomically incorrect as noted by Auguste Forel (1848-1931), who instead proposed to rename it Luy's body (or corpus Luysii) [77-80]. Several authors in the late nineteenth century and early twentieth century reported cases of hemiballismus—characterized by continuous, nonpatterned, vigorous or even violent, large amplitude, proximally generated, involuntary limb movements—but none of these early authors clearly established the subthalamic nucleus as the locus of pathology in hemiballismus. For example, in 1884 American neurologists Ralph M. Canfield and James Jackson Putnam (1846-1918) reported a 59-year-old man with "acute hemiplegic chorea": "The right arm and leg were found to be in violent and constant motion of a distinctly choreic type, but involving the muscles of the larger joints - hip, shoulder, etc. - even more than those of the smaller" [81, p. 220]. In describing the location of areas of infarcted brain at autopsy, Canfield and Putnam noted somewhat ambiguously that "The only ganglionic matter involved besides the substantia nigra was (probably) the so-called ganglion of Luys" [81, p. 222]. The clinical-pathological relationship between hemiballism and an underlying lesion of the subthalamic nucleus was convincingly demonstrated by Martin in 1927 [82]. In 1949, Whittier and Mettler provided experimental proof of this relationship by lesioning the subthalamic nucleus in monkeys and producing hemiballismus [83]. Throughout the first half of the twentieth century, hemiballismus was generally thought to have a poor prognosis, often with progression to death within weeks or months [83], but more recent studies have shown that hemiballismus can have a relatively benign course with spontaneous recovery [6].
Discussion: Although tremor was recognized in antiquity, and although the existence of arrhythmic hy-perkinetic extrapyramidal movement disorders was first suggested during the Middle Ages, it was only in the late 19th century and afterwards that careful clinical and pathological studies separated and characterized the most common categories of hyperkinetic movement disorders. Before these disorders were recognized as distinct, it was impossible to make substantial progress toward elaborating the causes and potential treatments for these conditions. In many cases, imprecise reporting of
clinical features by different clinician investigators, and variable disease presentations across cases, produced decades, or even centuries, of clinical confusion over the boundaries of these disorders. Even when a condition was fairly well established, and the clinical features well reported, clinicians often used existing nomenclature to label new cases, even when the movements of these new cases were clearly distinct from existing disease formulations. Limited understanding of brain organization (neuroanatomy, neurophysiology) and pathological processes, along with often dogmatically expressed but crude mechanistic explanations of disease, and in some cases a chronic tension between psychiatric and neurologic paradigms of disease pathogenesis (e.g., as occurred with chorea, pathologic startle syndromes, and tics), collectively added to delays in categorizing the different movement disorders and understanding the pathophysiology of these conditions.
Major progress in elucidating causal factors often had to await the development of newer technologies, but even here failures were common and often inexplicable. Early pathological studies in the 19th century were often uninformative regarding the genesis of hyperkinetic movement disorders (e.g., tremor, chorea, pathological startle syndromes, tics, and myoclonus). It was because of such difficulties in establishing clinical-pathological correlations that many investigators initially abandoned pathological studies, considering these disorders "far beyond the reach of the microscope," even when they still believed that the disorders had an underlying organic cause (e.g., as with George Miller Beard and the jumping Frenchmen of Maine). Even when gross pathology was evident (e.g., with hemi-athetosis), the clinical-pathologic correlations were tenuous and often controversial, and the seemingly validated predictions of disease loci were serendipitous and based on erroneous concepts of brain organization. Similarly, although various familial movement disorders were initially attributed to hereditary factors, many of these were inconsistent with Mendelian genetics, and were instead presumably due to shared exposures within families to environmental etio-logic agents, or possibly to biased reporting or observation, as they were statistically impossible (and not just improbable) by any form of Mendelian transmission. Such issues complicated early studies of many familial movement disorders (e.g., postural tremor, pathologic startle, Gilles de la Tourette syndrome). Even with the autosomal-dominant transmission pattern of Huntington's disease, the hereditary aspects of this disorder were only recognized in an imprecise way until Mendelian genetics were rediscovered almost three decades after George Huntington's description of hereditary chorea. It was still nearly a century more before the underling genetic defect of Huntington's disease was identified. Only in the 20th century, with the advent of modern "scientific medicine," did the development of disease markers (e.g., anti-streptolysin O titer), animal models (e.g., Sydenham's chorea, hemballism), and modern genetic techniques (e.g., Huntington's disease) greatly facilitate the elaboration of the underlying pathophysiology of some of these disorders.
Conclusion: While we can rejoice and take pride in the progress achieved in the evaluation and management of hyperkinetic movement disorders, it is remarkable, and indeed a bit sobering, to realize how little we understand even now about many of these disorders. Careful studies, utilizing collaborative teams of clinicians and basic scientists, and employing novel diagnostic and therapeutic technologies, will undoubtedly be needed to significantly advance the prevention and treatment of these often disabling disorders.
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