ИЗ ИСТОРИИ НЕВРОЛОГИИ
© ЛАНСКА Д.ДЖ., 2015 УДК 616.8-009.16/.18
Ланска Д.Дж.
экстрапирамидные расстройства позы и тонуса: исторический аспект вопроса до середины xx века
Медицинский центр по делам ветеранов системы здравоохранения Великих озер, неврологическое отделение, Тома, Висконсин, США
Lanska D.J.
extrapyramidal disorders of posture and tone: historical developments to the middle of the 20th century
Neurology Service, Veterans Affairs Medical Center, Great Lakes Healthcare System, Tomah, Wisconsin, USA
В историческом аспекте изучение расстройств поддержания позы и тонуса - это прежде всего развитие учения и понимание таких нозологий, как болезнь Паркинсона, некоторых «Паркинсотзм-плюс»-синдромов, наследственных торсионных дистоний и различных фокальных и сегментарных дистоний. Результаты: Классическое описание болезни Паркинсона было представлено Джеймсом Паркинсоном в 1817 г. в его монографии «Эссе о дрожательном параличе». Приблизительно в 1960 г. Жан-Мартин Шарко со своими студентами, работая над уточнением основных проявлений заболевания, начал разрабатывать клинический спектр этого заболевания, эвристический алгоритм для проведения дифференцированного диагноза c другими болезнями. В частности, именно Шарко выявил, что ригидность и брадикинезия являются основными проявлениями болезни Паркинсона, а слабость сама по себе не является симптомом заболевания. В 1888 г. Шарко описал случаи атипичного паркинсонизма, что в начале XX века позволило выделить такие нозологии, как мультисистемная атрофия, болезнь Вильсона, летаргический энцефалит. Раскрытие патофизиологии и патогенеза болезни Паркинсона и болезни Вильсона в итоге позволило разработать рациональную терапию леводопой и агонистами дофамина болезни Паркинсона и хелатами (БАЛ, пенициллинамин, тритилен тетрамин), цинком и трансплантацией печени - при болезни Вильсона. С момента первого описания дистонии в XIX - начале XX века ее неоднократно относили к психическим заболеваниям из-за вычурных поз, возникающих при произвольных движениях, наличия облегчающего (корригирующего) жеста и невозможности выявить нейропатоло-гический субстрат, в частности при генерализованной дистонии. Только лишь вXX веке была доказана органическая природа заболевания, выявлена генетическая мутация при некоторых формах наследственной дистонии, локализован патологический фокус в базальных ганглиях, контралатеральные гемидистонии. Дискуссия: клинические проявления заболеваний, сопровождающихся нарушением позы и тонуса, были описаны в конце XIX- начале XX веков. Понимание патофизиологии и патогенеза в начале XX века позволило разработать рациональную терапию, в частности при болезни Паркинсона и во второй половине XX века - болезни Вильсона.
Заключение: несмотря на развитие фармакологии и значительное облегчение состояния многих пациентов, доступная в настоящее время лекарственная терапия несет лишь временный эффект, нередко приводя к развитию серьезных побочных эффектов. За исключением болезни Вильсона, при лечении других расстройств позы и тонуса ни один препарат не воздействует непосредственно на саму причину заболевания. И лишь генетическое консультирование в некоторых редких случаях наследственных форм может предотвратить развитие болезни. Однако наука развивается в этом направлении большими шагами, а развитие новых технологий позволяет ожидать значительный прогресс в понимании и лечении этих заболеваний.
Ключевые слова: история медицины; XIX век; двигательные расстройства; диагностика; тремор; хорея; атетоз; болезнь Паркинсона; миоклония.
Для цитирования: Неврологический журнал. 2015; 20 (6): 50-61. DOI: http://dx.doi.org/10.18821/1560-9545-2015-20-6-50-61
Historical developments in our understanding of extrapyramidal disorders ofposture and tone to the middle of the 20th century emphasized Parkinson s disease, some "Parkinson-plus syndromes, hereditary torsion dystonias, and various focal or segmental dystonias. Results: The classic clinical description of Parkinson's disease was given in 1817 by James Parkinson in his monograph entitled An Essay on the Shaking Palsy. Beginning around 1860, Jean-Martin Charcot and his students worked to clarify and refine the cardinal features of the disorder, began to elaborate the clinical spectrum of this disease, and developed heuristics to distinguish Parkinson's disease from other disorders. In particular, Charcot elaborated rigidity and bradykinesia as cardinal features of Parkinson s disease, and recognized that weakness per se is not a feature of this disorder. As early as 1888, Charcot recognized and began to characterize the clinical features of atypical parkinsonism, which anticipated later descriptions of multisystem atrophy, Wilson's disease, and encephalitis lethargica in the early 20th century. Elaboration of the pathology and pathophysiology of Parkinson s disease and Wilson's disease ultimately led to the development ofrational therapeutics with levodopa and dopamine agonists for Parkinson's disease, and with chelators (BAL, penicillamine, triethylene tetramine), zinc, and liver transplantation for Wilson s disease. Since the original descriptions of dystonia in the 19th and early 20th centuries, dystonias have repeatedly been interpreted in psychological or psychiatric terms because of the bizarre contortions exacerbated by voluntary movement,
relief by certain movements or gestures (geste antagoniste), and failure to identify a neuropathological substrate, particularly for generalized dystonias. Only in the late 20th century was an organic framework established with identification of genetic mutations in some families with dystonia and with demonstration of focal pathology in the basal ganglia contralateral to hemidystonia. Discussion: The general clinical features of extrapyramidal disorders of posture and tone were elaborated during the late 19th and early 20th centuries. Progress in pathology and pathophysiology during the early 20th century led to the development of rational therapeutics, particularly for Parkinson's disease and Wilson's disease, during the second half of the 20 th century. Conclusion: While the therapies developed have produced significant benefits for many patients, available treatments generally provide only partial relief from these disabling diseases, while often causing troubling side effects. With the exception of Wilson's disease, none of the available treatments affect the underlying course of these diseases, and the only means of prevention concerns genetic counseling for the rare inherited forms of these disorders. However, the rapid pace of increasing knowledge in this area, and the recent development ofpowerful new technologies suggest strongly that further significant progress in understanding and treating these disorders can be anticipated.
Introduction: In 1912, the American-born, but European-trained, 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 [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 dichotomized 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" [3]. The classification of these disorders has continued to evolve to the present [4], now over a century after Wilson's formulation of extrapyramidal diseases.
In this lecture, we review the historical descriptions of extrapyramidal disorders of posture and tone to the middle of the 20th century, along with some related developments in pathology and therapeutics. The emphasis in this period was on Parkinson's disease and some "Parkinson-plus syndromes", including Wilson's disease (others were described more recently), as well as on hereditary torsion dystonias and various focal or segmental dystonias.
Key words: hi story of medicine-19th century; movement disorders; diagnosis; tremor; chorea; athetosis; Parkinson's disease; myoclonus.
For citation: Nevrologicheskiy zhurnal. 2015; 20 (6): 50-61.
DOI: http://dx.doi.org/10.18821/1560-9545-2015-20-6-50-61
Parkinson's Disease: Recently has it been suggested that Parkinson's disease, with all four cardinal signs (rest tremor, bradykinesia, cogwheel rigidity, and postural instability), was described as early as 1690 by Hungarian physician Ferenc Papai Pariz (1649-1716) (Fig. 1) [5]. This is a dubious attribution, because no individual case descriptions were presented. In any case, Pariz's work, published in Hungarian, had little, if any, impact on the broader field of medicine. Other claims for early descriptions of Parkinson's disease are also quite limited and none were sufficient to establish a specific clinical disease concept or framework.
The classic clinical description of Parkinson's disease was given in 1817 by British general practitioner James Parkinson (1755-1824) in his monograph entitled An Essay on the Shaking Palsy [6-8]. Parkinson gave a short account of six subjects, three of whom he had never examined, but only saw on the neighborhood streets or when making his medical rounds. According to Parkinson, the disorder was characterized fundamentally by a tremulous involuntary shaking at rest, which had an insidious and generally asymmetric onset, and a long and progressive course to debility and dependence. It was associated with a sense of weakness (or as Parkinson phrased it a "lessened muscular power"), stooped ("bowed") posture, postural instability, festinat-
Сведения об авторе/For correspondence:
Lanska Douglas John (Lanska D.J.) - Doctor of Medicine, Director of Continuing Medical Education; e-mail: [email protected]. Дуглас Джон Ланска - доктор мед. наук, директор факультета непрерывного медицинского образования /факультета усовершенствования врачей.
Fig. 1. Hungarian physician Ferenc Papai Pariz (1649-1716) described the cardinal signs of Parkinson's disease (rest tremor, bradykinesia, cogwheel rigidity, and postural instability) as early as 1690. His report in Hungarian was not recognized until recently, and had little impact on clinical medicine. Courtesy of Ец^щ Lor6nd University, Hungary. Рис. 1. Венгерский врач Ференц Папаи Париз (1649-1716) описал основные симптомы болезни Паркинсона (тремор покоя, ригидность по типу «зубчатого колеса» и постуральная неустойчивость) в 1690 г. Еще до недавнего времени его труд на венгерском языке не был известен, поэтому оказал незначительное влияние на клиническую медицину. Предоставлено с разрешения университета Eotvos Lorand, Венгрия.
Fig. 2. French neurologist Jean-Martin Charcot (1825-1893) drawn by Paul Richer (1849-1933) in 1891 [13]. Charcot used drawings by Richer to illustrate the abnormal posture of Parkinson's disease. Charcot recognized Parkinson's contribution proposed the eponym Parkinson's disease in his honor. Charcot distinguished the rest tremor of Parkinson's disease from the intention tremor of multiple sclerosis, distinguished clinical features of Parkinson's disease and atypical parkinsonism, and worked to elaborate the clinical spectrum of Parkinson's disease. Рис. 2. Французский невролог Жан-Мартен Шарко (1825-1893), портрет кисти Поля Рихтера (1849-1933), 1891 г [13]. Шарко использовал рисунки Рихтера для иллюстрации аномальной позы при болезни Паркинсона. Шарко в признательность за вклад Паркинсона предложил эпонимическое название болезни Паркинсона в его честь. Шарко отдифференцировал тремор покоя при болезни Паркинсона от интенционного тремора при рассеянном склерозе, разделил проявления болезни Паркинсона от атипичного паркинсонизма и работал над уточнением клинического спектра болезни Паркинсона.
ing gait, and, late in the course, a disturbance of speech, dysphagia, and drooling. This sense of weakness was the basis of Parkinson's terms "shaking palsy" and "paralysis agitans." Based on his observations, Parkinson provided an initial summary definition of the disorder: "Involuntary tremulous motion, with lessened muscular power, in parts not in action [i.e., at rest] and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace [ie., fes-tination]; the senses and intellects being uninjured" [6]. This is the first clear clinical definition of this disease, though it is incomplete and erroneous in several aspects. For example, Parkinson did not mention rigidity, incorrectly considered bradykinesia to be a manifestation of weakness, and incorrectly believed cognition to be uniformly spared.
Beginning around 1860, French neurologist JeanMartin Charcot (1825-1893) (Fig. 2) and his students at the Salpêtrière hospital in Paris worked to clarify and refine the cardinal features of the disorder, began to elaborate the clinical spectrum of this disease (e.g., noting both tremorous and rigid/akinetic forms, and forme frustes), and developed heuristics to distinguish Parkinson's disease from other disorders (e.g., multiple sclerosis) [8-16]. In 1861, Charcot and French neurologist Edmé Félix Alfred Vulpian (1826-1887) first called attention to this disorder, and Charcot continued to study this disorder over several decades [9]. Charcot lauded Parkinson's clear and succinct clinical descriptions and suggested the eponym of "Parkinson's disease." However, Charcot rejected Parkinson's
designation of the disease as "paralysis agitans," correctly noting that Parkinson's disease patients are not particularly weak and do not necessarily have tremor. Charcot distinguished bradykinesia as a cardinal feature of the illness, separate from rigidity, and pointed out that Parkinson and most of his successors had overlooked rigidity as a component of the illness [10]. Charcot's concept of rigidity, though, was based on simple observation and linked to abnormalities of posture (e.g., anteflexion and contractures) (Fig. 3) [13, 15]. Rigidity is no longer assessed solely on the basis of observed postures but rather is now defined as a "constant uniform increase in resistance to passive movement, throughout the range of joint placement, while the patient attempts to relax," and is distinguished from spasticity, which is a pyramidal rather than extrapyramidal form of hypertonia that is characterized by "an initial increase in resistance to active and passive movements followed by a decrease in tone in the same muscles occurring immediately (clasp-knife phenomenon)" [2].
In 1888, British neurologist William Gowers (18451915) (Fig. 4) gave an excellent description of the clinical features of Parkinson's disease, and provided his own line drawings of the characteristic posture (Fig. 5-6) [8,17]. In addition to the rest tremor and stooped posture that were recognized by Parkinson, Gowers also emphasized the masked facies (hypomimia), slowness of movement (bradykinesia), and rigidity, although he, like Parkinson, incorrectly reported weakness as a prominent feature of the disease [8,17].
Fig. 3. A woman with Parkinson's disease, emphasizing the stooped posture (left) and the more extreme camptocormia (right), drawn by French anatomist, physiologist, and artist Paul Marie Louis Pierre Richer (18491933) in 1874 and 1879, respectively [13]. Richer was an assistant to Charcot at the Salpetriere hospital in Paris, and from 1882 to 1896 was chief of the laboratory at the Salpetriere.
Рис. 3. Женщина, страдающая болезнью Паркинсона. Обращает на себя внимание согбенная поза (слева) и более выраженная каптокор-мия (справа). Изображение французского анатома, физиолога, художника Поля Мари Луи Пьер Рихтера (1849-1933), 1874 и 1879 гг соответственно. Рихтер был ассистентом Шарко в госпитале Сальпетриер в Париже, а с 1882 по 1896 г возглавлял лабораторию в Сальпетриер.
Fig. 4. British neurologist William Gowers (1845-1915). Gowers provided an excellent early description of the clinical findings in Parkinson's disease and illustrated some of the key features in various drawings. Courtesy of Wikipedia.
Рис. 4. Английский невролог Уильям Говерс (1845-1915). Говерс описал ранние симптомы болезни Паркинсона и проиллюстрировал несколько ключевых проявлений болезни в различных рисунках. Представлено из Википедии.
Fig. 5. The characteristic stooped posture of «paralysis agitans» (Parkinson's disease) was illustrated by Gowers in his monograph, A Manual of Diseases of the Nervous System (1888) [17].
Рис. 5. Характерная согбенная поза при «дрожательном параличе» (болезни Паркинсона), изображенная Говерсом в своей монографии «Руководство по болезням нервной системы» (1888) [17].
Fig. 6. Characteristic hand postures in «paralysis agitans» (Parkinson's disease) was illustrated by Gowers in his monograph, A Manual of Diseases of the Nervous System (1888) [17]. There is typically flexion at the metacarpal-phalangeal joints that may produce contractures (left), which may prevent passive (center) or volitional extension (bottom right).
Рис. 6. Характерная поза руки при «дрожательном параличе» (болезни Паркинсона), изображенная Говерсом в его монографии «Руководство по болезням нервной системы» (1888) [17]. Характерно сгибание в метакарпально-фаланговых суставах, приводящее к контрактурам (слева), что препятствует пассивному (в центре) или произвольному (справа) разгибанию кисти.
Parkinson's disease, and other extrapyramidal disorders, may also be associated with the cogwheel phenomenon, a "regular repetitive interrupting resistance to passive movements" [2]. The cogheel phenomenon was originally described by Italian neurologist Camillo Negro (1861-1927) and physiologist Zaccaria Treves (1860-1911) in 1901 [18], and later by American neurologist Harold N. Moyer (1858-1923) in 1911, and then by Spanish neurologist Roberto NYvoa Santos (18851933) in 1921 [19]. The relatively late recognition of this phenomenon was because simple observation of patients was long emphasized over physical examination.
Fundamental aspects of the pathology of Parkinson's disease were elaborated at the end of the 19th century and the beginning of the 20th century, which ultimately led to the development of rational therapeutics with levodopa and dopamine agonists in the late 20th century [8]. In 1893, French pathologist Paul Oscar Blocq (1860-1896) and Romanian neurologist Gheorghe Marinescu (18631938), working at the Salpetriere in Paris, reported a 38-year-old woman with hemiparetic parkinonism who was found at autopsy to have a tuberculoma of the right cerebral peduncle that had destroyed the substantia nigra [20]. French pathologist Edouard Brissaud (1852-1909) relied heavily on this case when he suggested that the substantia nigra might be the site of the underlying lesion in Parkinson's disease [21]. In 1912 and 1913, German-born American neurologist Freiderich Lewy (1885-1950), who later modified his name in various ways, described serpentine or elongated eosinophilic in-tracytoplasmic inclusions in the dorsal motor nucleus of the vagus nerve and in the substantia innominata of patients with Parkinson's disease [8, 22-25]. In 1919, Russian neuropathologist Konstantin Nikolaevitch Tretia-koff (1892-1958) (Fig. 7) first described the presence of these corps de Lewy (i.e., "Lewy bodies"), as he referred
Fig. 7. Russian neuropathologist Konstantin Nikolaevitch Tretiakoff (1892-1958). In 1919, Tretiakoff first described the presence of Lewy bodies in the substantia nigra, and proposed that they represented a pathology specific to Parkinson's disease. Courtesy of Wikipedia.
Рис. 7. Русский невропатолог Константин Николаевич Третьяков (1892-1958). В 1919 г. Третьяков впервые описал тельца Леви в черной субстанции и предположил, что их наличие является специфичным для болезни Паркинсона. Представлено из Википедии.
to them, in the substantia nigra, and proposed that they represented a pathology specific to Parkinson's disease [26-27]; Tretiakoff studied the substantia nigra in nine cases of Parkinson's disease, one case of hemiparkin-sonism, and three cases of postencephalitic parkinsonism, and found pathologic changes (i.e., depigmentation, neuronal loss, and gliosis) in the substantia nigra in all of them. Subsequently some investigators confirmed nigral
pathology in Parkinson's disease, while German neurologist and neuropathologist Oskar Vogt (1870-1959) and his wife Cécile Vogt-Mugnier (1875-1962), among others, instead emphasized pathological changes in the striatum [8, 28]. In 1938, Hassler found that some cell groups within the zona compacta of the substantia nigra were severely affected [29]. In 1953, Scottish neuropathologist Joseph Godwin Greenfield (1884-1958) and Frances D. Bosanquet (1916-2004) at the National Hospital, Queen Square, London, provided the most complete pathologic analysis of parkinson's disease, confirmed the selective loss of the ventrolateral cell groups within the zona compacta of the substantia nigra, and emphasized the nigral lesion and the Lewy body as features of Parkinson's disease [8, 30].
Atypical Parkinsonism
In addition to Parkinson's disease, a number of other neurodegenerative conditions have hypokinesia as a major clinical feature. Separation of these conditions from Parkinson's disease ultimately led to important anatomical and physiological discoveries concerning basal ganglia function [8].
As early a 1888, Charcot recognized cases of atypical parkinsonism in his clinical lessons and he contrasted the postural differences between such cases and those with typical Parkinson's disease (Fig. 8) [12]. This anticipated later descriptions of multisystem atrophy, Wilson's disease, and encephalitis lethargica in the early 20th century, and progressive supranuclear palsy, cortico-basal ganglionic degeneration, and other disorders in the late 20th century.
Multisystem atrophy (olivo-ponto-cerebellar degeneration): For decades, the overlapping clinical features and pathologies in individual cases with sporadic olivo-pontocerebellar atrophy, striatonigral degeneration, and Shy-Drager syndrome have been sources of confusion, burgeoning terminology, and competing nosologies.
These disorders are now recognized as forms of multiple system atrophy, an adult-onset sporatic neurodegenerative disease characterized clinically by varying degrees of parkinsonism, cerebellar ataxia, pyramidal signs, and autonomic dysfunction, and characterized pathologically by degeneration in the substantia nigra, putamen, olivary nucleus, pontine nuclei, and cerebellum.
The term "olivo-ponto-cerebellar atrophy" was coined by French neurologists Joseph Jules Dejerine (1849-1917) and André Thomas in 1900 in their report of a 53-year-old patient who developed progressive cerebellar ataxia, hypomimia, dysarthria, hypertonia, hyperreflexia, and urinary incontinence [31-32]. The patient died at age 55 and the autopsy showed severe degeneration of the basis pontis, inferior olivary nuclei, and cerebellar peduncles, with loss of Purkinje cells in the cerebellar hemispheres.
In the late 20th century olivo-ponto-cerebellar degeneration was redefined as multisystem atrophy and glial cytoplasmic inclusions were identified as a pathological hallmark [8]. This discovery helped to define multiple system atrophy as a clinicopathological entity and drew attention to the prominent role of oligodendrocytes in the pathogenesis of the disorder. Glial cytoplasmic inclusions were subsequently shown to be highly immu-noreactive for alpha-synuclein, which provided an unexpected molecular link between multiple system atrophy and Lewy body diseases, such as Parkinson's disease and Lewy body dementia. Collectively these disorders are now considered "synucleinopathies."
Wilson's disease: In 1911, British neurologist Kinni-er Wilson (1878-1937) of the National Hospital, Queen Square, London, presented a thesis entitled, "Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver" [8, 33]. Wilson reviewed the clinical and pathologic features of 12 cases, including four he had seen and studied himself, two from the records of the National Hospital, and six previously published. In a lengthy review in Brain in 1912, Wilson concluded:
Progressive lenticular degeneration may be defined as a disease which occurs apparently only in young people, which is often familial, but not congenital or hereditary; it is essentially and chiefly a disease of the extra-pyramidal motor sysem, and is characterized by involuntary movements, usually of the nature of tremor, dysarthria or anarthria, dysphagia, muscular weakness, spasticity or hypertonicity, and contractures, with progressive emaciation; with these may be associated emotionalism and certain symptoms of a mental nature. It is progressive and, after a longer or shorter period, fatal. Pathologically it is characterized predominantly by bilateral degeneration of the lenticular nucleus, and in addition cirrhosis of the liver is constantly found, the latter morbid condition not giving rise to symptoms during the lifetime of the patient [1].
Although he was the first to describe the condition in detail, Wilson acknowledged earlier works by German neuropsychiatrist Carl Westphal (1833-1890) and German neurologist Adolph Strumpel (1853-1925) on
"pseudosclerosis" (a 19th-century label for a clinical condition with tremor resembling that seen in multiple sclerosis but distinguished by the lack of ocular signs), and British neurologist William Gowers on familial "tetanoid chorea" [17], which was associated ultimately with cirrhosis of the liver [8, 17, 34-36].
The full clinical spectrum ofWilson's disease was not recognized for many years. Unappreciated by Wilson, in 1902 German ophthalmologist Bernhard Kayser (18691954) had described ring-like deposition of greenish pigment in a patient suffering from pseudosclerosis [37], a finding reinforced a year later by German ophthalmologist Bruno Fleischer (1874-1965), who recognized the ring as a marker for a neuropsychiatric disorder associated with cirrhosis [8, 38, 39]. By the early 1960s, it was clear that while other tissues, including kidney and bone, could also be affected [40], before puberty Wilson's disease generally presented with liver disease, whereas after puberty neurological presentations were typical [41].
An understanding that Wilson's disease involves deposition of copper in tissues developed over several decades in the early 20th century. In 1913 German physician Alfred Rumpel reported excess hepatic copper in a patient dying of Westphal-Strbmpel pseudosclerosis (i.e., Wilson's disease) [42], and in 1922 German neuropsychiatrist Ernst Siemerling (1857-1931) and Hans Oloff described the association of corneal pigmentation ("Kayser-Fleischer rings") with sunflower cataracts and noted the similarity of the cataracts to those developing with a copper-containing foreign body in the eye [43], but unfortunately these findings were also initially overlooked [44]. Later, beginning in the late 1920s, various investigators reported excess copper in the brain or liver of patients dying of Wilson's disease. In 1948, in an influential paper, British neuropathologist John Cumings (1905-1974) demonstrated excess of total body copper, and particularly an excess of copper in both the brain and the liver, of patients with Wilson's disease [45]. That same year, British psychiatrist Bertram Maurice Mandelbrote (1923-2011), then a Rhodes scholar at Oxford, along with several colleagues noted that a patient with Wilson's disease excreted an increased quantity of copper in the urine [46]. Also, in the late 1940s, Carl G. Holmberg and Carl-Bertil Laurell (1919-2001), Swedish chemists at the University of Lund, purified and characterized a blue, copper-containing, plasma glyco-protein they called 'coeruloplasmin' (later spelled cae-ruloplasmin or as is now preferred, ceruloplasmin; from the Latin caeruleus, sky blue), which was demonstrated to have reduced plasma concentrations in patients with Wilson's disease in the early 1950s [8].
A genetic basis for Wilson's disease was suggested in 1916 by Wilson's former mentor, Sir Byrom Bramwell (1847-1931) [47], and similarly in 1921 by Hans Hall (1884-1922), who also coined the term "hepatolenticular degeneration" [48], but it was not until 1960 that American geneticist Alexander (Alick) Bearn (1923-2009) unequivocally established the autosomal recessive mode of transmission [40]. Incidentally, in 1902, after qualifying in medicine, Wilson had worked at the Royal Edinburgh Infirmary under Bramwell, and it was Bramwell who in-
spired him to pursue a career in neurology. Wilson, in fact, recognized that hepatolenticular degeneration was familial, but curiously he did believe that it is a hereditary disorder [1]. The gene responsible for Wilson's disease was subsequently identified as the ATP7B gene on the long arm of chromosome 13 (13q14.3), which codes for a 140-kD copper-transporting ATPase. Loss of function of the Wilson's disease gene product results in excessive intracellular deposition of copper in hepatocytes, with consequent hepatic cellular necrosis, and leakage of copper into the plasma, from whence it is transported to and deposited in other tissues, including brain.
In 1948, John Cumings (1905-1974), Professor of Clinical Biochemistry at the National Hospital, Queen Square, London, suggested that British anti-lewisite (BAL) might be of value in removing copper from the body and thereby in improving the prognosis ofWilson's disease [45]. BAL is a chelating agent designed during World War II as an antidote to the arsenical vesicant gas "lewisite," which had been developed during World War I [44, 47]. By 1951, Cumings and Boston neurologists Derek Denny Brown (1901-1981) and Huntington Porter reported clinical benefit from BAL in patients with Wilson's disease, even though the treatment required repeated painful intramuscular injections and was highly toxic [50, 51].
several therapies superceded BAL in the treatment of Wilson's disease. In 1956, British neurologist John Walshe suggested that penicillamine could be an effective orally administered chelator for copper [52], a suggestion confirmed by 1960 [8]. Penicillamine rapidly replaced BAL, but within a decade penicillamine was also found to produce several significant immunolog-ically-induced side effects, which led to continued efforts to find safer alternatives. In his MD thesis in 1961, Dutch neurologist Gerrit Schouwink (1926-1999) demonstrated that orally-administered zinc could significantly reduce the absorption of copper from the gut [53], a finding which was unpublished and initially largely unknown. Zinc was later shown to be helpful in the long-term management of Wilson's disease patients, although it may not be adequate for initial therapy. Zinc induces the synthesis of intestinal metallothionein, a metal-binding protein in the intestinal mucosa, which effectively binds copper in a complex that cannot be systemically absorbed, and is ultimately excreted in the stool with desquamated intestinal epithelial cells. Subsequently developed therapies for Wilson's disease include trieth-ylene tetramine (Trientine) as a substitute chelator for patients intolerant of penicillamine, and liver transplantation for patients with hepatic failure [8].
Encephalitis lethargica: von Economo's encephalitis: In 1917, neuropsychiatrist Constantin Freiherr von Economo (1876-1931) (Fig. 9), an Austrian nobleman, described the clinical and pathological findings of 13 cases with an unusual encephalitic condition that had occurred during the winter of 1916-1917, often with profound lethargy or stupor that Economo characterized as "sleeping sickness" [54]. Economo named the condition "encephalitis lethargica" and identified three over-
Fig. 9. Austrian neuropsychiatrist Constantin Freiherr von Economo (1876-1931) around 1920. Courtesy of the U.S. National Library of Medicine.
Рис. 9. Австрийский нейропсихиатр Константин фон Экономо (1876-1931), приблизительно 1920 г. Предоставлено Национальной медицинской библиотекой США.
lapping clinical subsets of the acute illness: somnolent-ophthalmoplegic, hyperkinetic, and amyostatic-akinetic. He documented the highly variable acute manifestations which included sleep disturbances, lethargy, neuropsy-chiatric disorders (e.g., catatonia, obsessive-compulsive disorder), oculomotor abnormalities, and various associated hypo- and hyper-kinetic movement disorders, including rigidity, akinesia, chorea, myoclonus, dystonia, opisthotonus, akathisia, and variably superimposed oculogyric crises. The ocuogyric crises were a form of dystonic reaction with ocular deviation, usually a sustained upward or lateral deviation of the eyes; associated manifestations included a fixed stare, ocular pain, backwards and lateral flexion of the neck, widely opened mouth (oromandibular dystonia), intensely painful jaw spasm (trismus), and tongue protrusion. Economo subsequently studied the evolution, natural history and sequelae of encephalitis lethargica over several years: he noted that post-encephalitic parkinsonism could develop early with the amyostatic form, or up to several years after apparently complete recovery from other forms of acute encephalitis lethargica [55]. In addition, he emphasized the neuropathological features, including microscopic inflammatory changes, particularly in the grey matter of the midbrain tegmentum and the basal ganglia.
Encephalitis lethargica became a global pandemic affecting more than one million people between approximately 1916 and 1926. As the epidemic of acute encephalitis waned in the mid-1920s, numerous cases of post-encephalitic parkinsonism were identified, typi-
cally with bradyphrenia, generalized rigidity, bent posture, and unsteady gait, but usually without a pill-rolling tremor. Post-encephalitic parkinsonism cases were identified even into the 1930s, but by that time the nosologic distinction between idiopathic Parkinson's disease and post-encephalitic parkinsonism had become confused. There have been no further epidemics of encephalitis lethargica, although rare sporadic cases continue to be reported.
Although encephalitis lethargica and influenza both occurred in epidemics between 1918 and 1923, the timing and extent of the outbreaks were dissimilar [56]. Furthermore, recent studies failed to identify influenza RNA in archived encephalitis lethargica brain specimens, and suggested that the 1918 influenza virus was genetically incapable of producing neurotropic disease [56, 57]. Despite considerable effort, no neurotropic virus has yet been implicated in the etiology of encephalitis lethar-gica and some have instead suggested that encephalitis lethargica was a post-infectious autoimmune disorder similar to Sydenham's chorea [58].
Dystonias: Dystonias are characterized by "abnormal postures produced by slow sustained muscle contractions which distort limbs, trunk, neck, face or mouth into characteristic postures" [2]. Current classification schemes categorize dystonias by age of onset, parts of the body affected (focal, segmental, multifocal, or generalized), temporal patterns, associated features, occurrence of other neurological or systemic manifestations, and etiology (a categorization of inherited/acquired/ idiopathic is now preferred over the earlier primary/ secondary categorization) [2, 4, 59]. Dystonias include hereditary early-onset generalized isolated dystonias, dystonias associated with other hereditary neurological syndromes (e.g., Huntington's chorea and Wilson's disease), acquired dystonias due to known specific causes (e.g., dystonic cerebral palsy, encephalitic lethargica, neuroleptic-induced dystonia, and manganese toxicity), and sporadic idiopathic dystonias. In contrast to hereditary generalized dystonias, sporadic dystonias are often focal dystonias; these include blepharospasm, oro-mandibular dystonia, torticollis, and writer's cramp.
Since the original descriptions in the 19th and early 20th centuries, dystonias have repeatedly been interpreted in psychological or psychiatric terms because of the bizarre contortions exacerbated by voluntary movement, the relief by certain movements or gestures (geste antagoniste), and failure to identify a neuropathologi-cal substrate, particularly for generalized dystonias [8]. Only in the late 20th century was an organic framework established with identification of genetic mutations in some families with dystonia (Lanska 2010) and with demonstration that the putamen, caudate, and posterior ventral thalamus were often damaged contralateral to hemidystonia [8].
Writer's cramp and other occupational dystonias: Several authors described writer's cramp in the 1830s, including Scottish neuroanatomist and surgeon Charles Bell (1774-1842) and German physician Johann Hein-
rich Kopp (1777-1858) [60, 61], and these are often cited as the earliest reports, although reports as early as the mid-18th century have also been recognized [8,62]. In 1864 and 1865, British surgeon Samuel Solly (18051871) presented a series of clinical lectures on "scrivener's palsy, or the paralysis of writers" that has been credited with increasing medical recognition of this condition [63].
Writer's cramp became a fairly common disabling problem in the 19th century, in part because of the large amount of writing performed, and in part because the available writing instruments required greater force to move across the page (Fig. 10) [17]. Case series of writer's cramp in the 19th century were often very large, including many dozens or even hundreds of patients [64]. In 1864, Solly noted that "the greatest part of the middle classes of London get their bread [i.e., earn their income] by the use of the pen, either as the exponent of their own thoughts or the thoughts of others, or in recording the sum gained, lost, or spent in this great emporium of commerce - this vast Babylon [i.e., London]" [63]. As noted by Sheehy and Marsden: "The frequency of the disorder in [the] late Victorian era must stand as a tribute to the success of the British Empire, the enormous office staff required to run it, and the difficulties of manipulating the quill pen" [65, p. 462].
There was a general recognition in the late 19th century that writer's cramp was analogous to other conditions that would later be recognized as forms of focal dystonia, including other occupational dystonias and torticollis [8, 62, 63, 66, 67]. For example, Solly noted that "Scriveners' palsy is not the only instance of a set of muscles being cramped and paralyzed [sic] by long-continued exertion. There is, as has been observed by [German pathologist Rudolph] Virchow [1821-1902], shoemakers' cramp, milking cramp, the musicians' cramp, compositors' and the sempstresses [seamstress's] cramp" [63, p. 709]. Similarly, American neurologists George Miller Beard (1839-1883) and Alphonso Rock-
Fig. 10. Hand posture in writer's cramp, drawn by Gowers (1888) [17, p. 662]. Writer's cramp or «scrivener's palsy» was prevalent in the 19th century, before the advent of typewriters or writing instruments (e.g., ballpoint pens) that moved smoothly across the paper. The figure illustrates the «cramped method of holding pen, habitual to a patient who suffered from writer's cramp».
Рис. 10. Поза кисти при писчем спазме в изображении Говерса (1888) [17, p. 662]. Писчий спазм или писчая судорога преобладал в XIX веке, до изобретения пишущей машинки или других пишущих приспособлений (например, шариковой ручки), движущихся гладко по поверхности бумаги. Представлена «манера держания ручки, привычная для пациента с писчим спазмом».
Fig. 11. Mechanical aids developed in the late 19th century for patients with writer's cramp [68]. Shown are various aids distributed by George Tiemann & Company of New York [68]. All of the instruments serve to redirect the type of hand and finger muscle contractions used to grip or move the writing instrument. The top row shows various loop attachments for the fingers (to minimize the need to pinch the writing instrument), the second row shows grip devices (with a similar intent), and the bottom rows show devices that allow a sliding motion along the writing surface (in some cases resembling a modern "mouse" for a personal computer). Рис. 11. Механическое приспособление, изобретенное в конце XIX века в помощь пациентам с писчим спазмом [68]. Представлено несколько разновидностей приспособлений, производимых компанией «Джордж Тиманн и компания» в Нью-Йорке [68]. Все приспособления служат для перераспределения нагрузки на кисть и уменьшения контрактуры мышц пальцев, используя рукоятку или гладкое скольжение пишущего инструмента. В верхнем ряду представлены различные петлевые приспособления для пальцев (чтобы минимизировать необходимость в сжатии пишущего инструмента), во втором ряду представлены различные рукоятки/держатели (для тех же целей), в нижнем ряду показаны приспособления, позволяющие совершать гладкие, скользящие движения по поверхности (в некоторых случаях напоминают современную «мышку» для персональных компьютеров).
well (1840-1933) noted in 1871 that writer's cramp "seems to differ but little from certain other spasmodic conditions, such as wry neck [torticollis] and histrionic spasm" [66].
Instruments used in the treatment of writer's cramp evolved over time, and most were ultimately abandoned when the development of better writing instruments and alternative means of written communications (e.g., the typewriter) decreased the frequency of and disability associated with writer's cramp. Patients initially devised a number of simple but cumbersome methods of minimizing the muscle contractions associated with writing, including enlarging the dimensions of their pens (e.g., with a piece of cork, potato, or apple). A large number of simple mechanical writing aids were subsequently devised and reported in the 19th-century medical literature [68]. Most of these instruments limited thumb and finger flexion, and instead utilized unaffected finger extensors
or more proximal muscles moving the wrist, elbow, or shoulder (Fig. 11). Nevertheless, many authorities considered any benefit of such aids to be limited, temporary, and in no way curative, and some argued that use of such instruments ultimately resulted in clinical involvement of the entire arm and even greater disability. With improvements in writing instruments there was "no temptation to exert pressure" while writing [69]; these changes followed replacement of quills and dip pens with workable stylographic pens in the 1870s and fountain pens after c1883. After the development of the typewriter in the late 19th century, use of such mechanical aids decreased markedly [17, 70].
Nineteenth-century authorities on writer's cramp also frequently advocated varying degrees of rest [17], and sometimes applied splints or slings to ensure that the limb would not be used: e.g., some physicians enforced rest by fastening the hand upon a splint [71], while others similarly ordered the "arm to be carried in a sling for a week or so, to remind the patient that all writing is to be shunned" [72].
Generalized dystonia: Early-onset generalized isolated dystonias were initially mislabeled as other types of abnormal movement [8, 73]. In 1897, Spanish neurologist Lluis Barraquer i Roviralta (1855-1928) described a patient with generalized dystonia, although he misla-beled it as "athetosis" [74, 75]. In 1908, Philadelphia neurologist and neuropathologist William Spiller (18631940) described a 12-year-old boy as having progressive spasticity and generalized "athetosis," but provided clinical data that contradicted both of these findings; in
Fig. 12. In 1908, Philadelphia neurologist William Gibson Spiller (18631940) described a 12-year-old boy as having progressive spasticity and generalized «athetosis», but provided clinical data that contradicted both of these findings (Spiller 1908). This was likely a generalized dystonia, and probably a case of dystonia musculorum deformans or torsion dysto-nia, three years before the disorder was described by German neurologist Hermann Oppenheim.
Рис. 12. В 1908 г. невролог из Филадельфии Уильям Гибсон Спил-лер (1863-1940) описал 12-летнего мальчика с прогрессирующей спастичностью и генерализованным «атетозом», однако представил клинические данные, которые противоречат обоим этим заболеваниям (Спиллер, 1908). Похоже, это была генерализованная дистония и, возможно, случай деформирующей мышечной дистонии, или торсионная дистония. Данный случай был описан за три года до описания, представленного немецким неврологом Германом Оппенгеймом.
Fig. 13. German anatomist Gustav Schwalbe (1844-1911). In 1908, Schwalbe, under the tutelage of German neuropsychiatrist Georg Theodore Ziehen (1862-1950), presented his thesis on dystonic spasms in three siblings. Scwalbe attributed these spasms to a combination of hysteria and a variety of tics, a conclusion that was apparently influenced by Ziehen, who later called this «torsion neurosis». Courtesy of the U.S. National Library of Medicine.
Рис.13. Немецкий анатом Густав Швальбе (1844-1911). В 1908 г. Швальбе под руководством немецкого нейропсихиатра Георга Теодора Циена (1862-1950) представил свою диссертацию о дистони-ческом спазме у трех сибсов. Швальбе отнес этот спазм к комбинации истерии и разновидности тиков. Данное заключение, очевидно, сделано под влиянием Циена, который позже назвал его «торсионным неврозом». Предоставлено Национальной медицинской библиотекой США.
retrospect, this was clearly a case of dystonia musculorum deformans [73, 76] (Fig. 12).
The classic descriptions of hereditary torsion dystonia were published in the early 20th century, almost a century after the description of dystonic writer's cramp. In 1908, German anatomist Gustav Schwalbe (1844-1911) (Fig. 13), under the tutelage of German neuropsychiatrist Georg Theodore Ziehen (1862-1950), presented his thesis on dystonic spasms in three siblings with onset between ages 12 to 14 years. He attributed these spasms to a combination of hysteria and a variety of tics, hence his label "tonic cramps with hysterical symptoms" [77, 78], a designation which was apparently influenced by Ziehen, who later called this "torsion neurosis" [79]. Schwalbe noted the "chronic course, characterized predominantly with tonic, not painful, asymmetrical cramps of variable intensity and duration spreading over the muscles of the whole body" [78, p. 657]. In his 1911 treatise, German neurologist Hermann Oppenheim (1858-1919) (Fig. 14) described four Jewish children with a progressive form of generalized dystonia, which he termed "dystonia musculorum deformans" [8, 80, 81]. oppenheim insisted that dystonia was an organic disease and therefore rejected Ziehen's term "torsion neurosis." Oppenheim introduced the term "dystonia" to reflect his conclusion that the disorder was associated with a generalized abnormality of tone with coexistent hypotonia and hypertonia: "in addition to an increased
Fig. 14. German neurologist Hermann Oppenheim (1858-1919) [85]. In his 1911 treatise, Oppenheim described four Jewish children with a progressive form of generalized dystonia, which he termed «dystonia musculorum deformans». Oppenheim insisted that dystonia was an organic disease and therefore rejected Ziehen's term «torsion neurosis» Oppenheim introduced the term «dystonia» to reflect his conclusion that the disorder was associated with a generalized abnormality of tone. Рис. 14. Немецкий невролог Герман Оппенгейм (1858-1919) [85]. В своем трактате в 1911 г. Оппенгейм описал четырех еврейских детей с прогрессирующей формой генерализованной дистонии, которую он назвал «деформирующая мышечная дистония». Оппенгейм настаивал, что дистония является органическим заболеванием и, следовательно, отверг термин, предложенный Циеном, - «торсионный невроз». Оппенгейм предложил термин «дистония». Это отражает то обстоятельство, что заболевание обусловлено генерализованным нарушением мышечного тонуса.
tonus of some muscles, one finds hypotonia of most of the others" [82, p. 682]. Oppenheim also suggested an alternative name, "dysbasia lordotica progressive," emphasizing the associated progressive postural abnormalities and the bizarre gait, which he termed "monkey gait" or "dromedary [camel] gait."
In 1911, Polish neurologist Edward Flatau (18681932) and Polish neuropsychiatrist Wladyslaw Sterling (1877-1943) instead emphasized torsion spasms as the major clinical feature [82]: "Since the nature of the disease is still unknown to us we should retain its most outstanding characteristic in the designation. In our opinion this consists in the drawing, twisting spasm which is progressive in these affected children, so we select the designation 'progressive torsion spasm'" [83, p. 683]. Flatau had studied in Moscow, where he was greatly influenced by the Russian psychiatrist Sergei Sergeievich Korsakoff (1854-1900) and the neurologist and psychiatrist Alexis Jakovlevich Kozhevnikof (1836-1902).
In 1944, American neurologist Ernst Herz (19001965) provided detailed cinematographic and electro-myographic analyses of 15 cases of generalized dys-tonia, as well as an extensive review of more than 100 literature cases, and concluded that dystonic movements were best described as slow, sustained, powerful, non-patterned contortions of the axial and appendicular muscles with simultaneous contractions of agonist and antagonist muscles [84]. Because this condition is not a
primary disease of muscles, and because not all patients develop fixed postural deformities, the terms "dystonia" and "torsion dystonia" are now generally preferred over previous designations [59].
Discussion: The field of movement disorders as a sub-discipline of neurology still relies heavily on patient observation. To be successful in managing patients with extrapyramidal movement disorders, clinicians must be able to recognize and distinguish the essential features of a range of abnormal movements. While clinical observation can be augmented by various recording and measuring technologies, these technologies cannot replace clinical observation as the fundamental mode of diagnosis of these disorders. The general clinical features of these disorders were elaborated for the most part during the late 19th and early 20th centuries by clinicians who were astute observers. The original descriptions were in some cases refined and corrected in a relatively short period following the classic original descriptions (e.g., as in Charcot's elaboration of rigidity and bradykinesia as cardinal features of Parkinson's disease, and his similar recognition that weakness per se is not a feature of this disorder) after which the clinical phenomenology underwent relatively little revision.
During the first half of the 20th century, there were major developments in understanding the pathophysiology of several of these extrapyramidal movement disorders of posture and tone, which led to the development of rational therapeutics for these particular disorders during the second half of the 20th century. This was true, for example, with Parkinson's disease and also with Wilson's disease. While the therapies developed have produced significant benefits for many patients, available treatments generally provide only partial relief from these disabling diseases, while often causing troubling side effects. With the exception of Wilson's disease, none of the available treatments affect the underlying course of these diseases, and the only means of prevention concerns genetic counseling for the rare inherited forms of the extrapyramidal diseases of posture and tone, which represent only a small subset of these disorders.
Conclusion: At the beginning of the 21st century, clinicians and neuroscientists can look with some satisfaction at the progress made in the field of movement disorders, particularly in the second half of the 20th century - for example, improved understanding of how the basal ganglia modulate cortical motor function, improved understanding of the pathophysiology of several diseases (e.g., parkinsonism, Wilson's disease, and Huntington's disease), development of effective therapies (e.g., for Parkinson's disease and Wilson's disease), and effective prevention (e.g., for rheumatic fever and its effects, including Sydenham's chorea), development of useful animal models (e.g., the MPTP model of Parkinson's disease, and transgenic mouse, fly, worm, and cellular models of Huntington's disease), and identification of genes for several disorders (e.g., Huntington's disease, Wilson's disease, some familial forms of torsion dystonia, essential tremor, and Parkinson's disease). Still, much more work remains to be done to understand these disorders and treat them effectively. The rapid pace of
increasing knowledge in this area, and the recent development of powerful new technologies (e.g., in the fields of neuroimaging, genetics, molecular biology, among others), suggest strongly that further significant progress can be anticipated.
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