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The neuropathology of hereditary spastic paraparesis
S16 ~‘htzicuiNcrrrdo~gy and Neurosurgcy, 94 (SuppI.) (1992) S16 -- $18 C3 1992 Elsevier Science Publishers B.V. All rights reserved 0303~&467/92/$05.00 CNN 00109
The neuropathology
of hereditary spastic paraparesis R.P.M. Bruyn
Department of Neurology, Ouaknrijn Hospital, Utrecht (The Netherlands)
I&y words:
Hereditary spastic paraparesis; Neuropathology
Summary Hereditary spastic paraparesis or Striimpell’s disease is a genetically determined neurodegenerative disorder in which the signs and symptoms are predominant in the legs. Inheritance is usually autosomal dominant and in a minority recessive. Neuropathological study reveals a degeneration of the corticospinal tract decreasing from lower lumbar to cervical level and of posterior columns increasing from lumbar to upper cervical level as well as degeneration of the spinocerebellar tracts in approximately 50%. The nature of this nucleodistal central axonopathy and elinicopathological discrepancy for posterior columns, as well as the limits of the pathological process are poorly understood. Introduction
rosis, amyotrophic lateral sclerosis, infectious diseases, such as neurosyphilis and tropical spastic paraparesis
Strtimpell described two brothers with a bilateral pyramidal syndrome confined to the legs, resulting in the same spastic walking pattern their father exhibited [l] and what now has become known as hereditary spastic paraparesis or Strtimpell’s disease. At the turn of the century Lorrain [2] reviewed the literature, which at that time consisted of approximately 20 reports, and added 3 personal cases, so the eponymous credit is earned by Strtimpell more than Lorrain. Harding [3] made a distinction between “pure” and “complicated” forms; the “complicated” form is much more frequent and besides spastic paraparesis there are other neurological signs, such as dementia, extrapyramidal signs, skin abnormalities and skeletal changes.
(HTLV-I) .
Clinical findings The clinical signs essentially consist of a spastic paraparesis, of which the spasticity is more pronounced than the paraparesis, hyperreflexia of the legs and to a lesser degree of the arms, and Babinski signs. Sometimes, slight sensory disturbances are found, such as diminished vibration sense at the feet, and urinary urge incontinence. Differential diagnosis includes spinal cord compression, cervical myelopathy, cerebral palsy, multiple scleCorrespondence to: R.P.M. Bruyn, Department of Neurology, Oudenrijn Hospital, Van Heuven Goedhartlaan 1, 3527 CE Utrecht, The Netherlands. Tel.: (30) 953359; Fax: (30) 948356.
Genetic aspects Usually the disease is inherited as an autosomal dominant trait and comprises early and late onset types. Until an ultimate classification is found, based on modern genetic studies, which identify gene and gene-product, Harding’s [4] distinction in type I with age of onset below 35 and type II with onset over 35 years on the basis of her study of 22 families with “pure” spastic paraplegia remains useful. Type I runs a protracted course and the severity varies markedly. Type II runs a more progressive course showing more muscle weakness, urinary symptoms and sometimes sensory disturbances. Earlier, Behan and Maia [5] also distinguished two groups: one with onset in “middle life” (over 35 years) and a second group with onset in first or second decade. Strumpell[6] was the first to discern two groups on the basis of age at manifestation, one with onset in the third decade and the other group with onset between the third and sixth year. Autosomal recessive inheritance of “pure” cases has been described in only a few instances, whereas X-linked “pure” cases do not exist. Cases of “complicated” Xlinked spastic paraparesis have been sporadically mentioned [7-121. Linkage studies have been unraveling until now [13,14].
Fig. 1. Degeneration of the (crossed and uncrossed) pyramidal tracts, dorsal columns and dorsal spinocerebellar
Pathologic findings Because the patients usually die at home or in nursing homes there is an extreme paucity of detailed neuropathological reports. Schwarz [15] reviewed all pathological data and concluded that of 24 cases known at that time, only 7 could be identified as “pure” cases [6,16-211 and added a detailed neuropathological description of one patient. Subsequently, very few pathological descriptions were given by him and others [5,22-241. In all autopsied cases the pathological findings were more or less the same viz. degeneration of the lateral corticospinal tracts decreasing from lower lumbar to upper cervical level, frequent, but to a slighter degree, involvement of the uncrossed pyramidal tracts, increasing degeneration of the fasciculus gracilis from lumbar to upper cervical level without abnormalities of the posterior root fibers. The spinocerebellar tracts are involved in approximately 50%, marked neuronal loss in Clark’s column in four cases, cerebellum and basal ganglia showed loss of neurones in only one case. In four cases the number of Betz cells was diminished. There is onIy one quantitative study [22] in which the pyramids of a 57-year-old patient have been carefully examined: the pyramid measured 5.87 mm2, compared to the control values
tracts at the cervicothoracic level.
[25,26] a size a little larger than the pyramid of a ‘L-yearold child. They also found a marked reduction in the total number of myelinatcd nerve fibers: an estimated 376 055 ncrvc fibers in one pyramid compared to 688 800 fibers in control cases [26]. The distribution of the nerve fibers in one pyramid was as follows: 89% were l-4 pm, 8.8% were 5-10 pm, and 2.2% were more than 11 pm in diameter, which closely approximates the control figures given by Lassek 1261. Accordingly, there was a proportional loss of nerve fibers of all sizes. No changes were found in the cerebral peduncles. We had the possibility to study the autopsy findings of one patient with “pure” spastic paraplegia and in conclusion, the pathologicai changes in our patient are virtually the same as in the other cases (Fig. 1) and seem to be compatible with a retrograde axonal dying-back process. Discussion Studying the pathologic data raises the following questions. The first one is how to explain the absence of a clinicopathological correlation as far as the dorsal column degeneration is concerned: a nucleodistal (dying-
S18
back) degeneration of the fasciculus gracilis already visible at lumbar level and being most prominent at cervical level, yet without noticeable or only slight sensory changes. Therefore, it must be concluded that either practically all of the dorsal column fibers must be degenerated before clinical symptoms manifest, or the sensory ascending stimuli travel not only through the dorsal columns, the function of which is traditionally associated with transmitting various discriminative tactile impulses, vibration and kinesthesia. Recent research changed traditional views on dorsal column function drastically [27], and it now seems that the dorsal columns subserve the detection of temporal or sequential stimuli with a spatial component, as well as the appreciation of stimuli, that need digital exploration for recognition. Finally, they seem to occupy a key position in relaying sensory input to the motor cortex in order to control certain types of complex motor acts (digital movements, phasic motor behavior). The dorsal columns are not the only ascending pathways involved in transmitting sensory stimuli, such as vibration or 2-points discrimination, but other parallel pathways in the dorsolateral fasciculus of the spinal cord (e.g. dorsal spinothalamic tract) do so as well. The second question one can ask is whether the disease is really limited to the level of the spinal cord. Loss of Betz cells was only found in four cases with hereditary spastic paraparesis, and may be interpreted as a phenomenon of retrograde degeneration, not infrequently encountered in chronic degenerative diseases of the spinal cord. Several electrophysiological reports suggest multisystem involvement as assessed by visual, brainstem and somatosensory evoked potentials and studies of saccadic eye movements, though not all of these offer unequivocal conclusions [28-321. The third and by far the most intriguing question is the nature of the disease. At first glance the degenerative process appears to be a “dying-back” phenomenon, a process of progressive breakdown of axons beginning farthest away from the trophic perikaryon and proceeding towards the cell body, which eventually dies as well. However, trans-synaptic degeneration, present in other neurodegenerative diseases such as olivopontocerebellar atrophy and Friedreich’s ataxia, does not occur in Strtimpelf’s disease, nor does the cell body show any alterna-
tions. Any theory trying to explain the pathogenesis by positing enzyme deficiency, premature ageing process or toxic factors remains purely speculative until now.
References
9 10 11 12 13 14
15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
Striimpell A. Arch. Psychiat Nervenkrankh 1880; 10; 217-238. Lnrrain M. Thesis Steinheil, Paris, 1898. Harding AE. Lancet 1983; I: 1151-1155. Harding AE. J Neurol Neurosurg Psychiat 1981; 44: 871-883. Behan WMH, Maia M. J Neurol Neurosurg Psychiat 1974; 37: 8-u). Striimpelt A. Dtsch Z Nervenheilk 1904; 27: 291339. Johnston AW, McKusick VA. Am J Hum Genet 1962; 14: 83-94. Ford FR, Springfield, IL, Charles C. Thomas, 5th edn, 1973; 3.53356. Raggio JF, Thurmon TF, Anderson E. LA State Med Sot 1973; 125: 4-7. Zatz M, Penha-Serrano C, Otto PA. J Med Genet 1976;13: 217-222. Keppen LD, Leppert MF, O’Connell P et al. Am J Hum Genet 1987; 41 : 933-943. lku A, Kamsoy H, Karatepe A, Giikcay F. Acta Neurol Stand 1991; 83:4O+Q36. Boustany RMN, Fieischnick E, Alper CA et ai. Neurology 1987; 37: 910-915. Kolodny EH, Boustany RMN, Rouleau GA, Growden JH, Martin JB. Progress in Clinical and Biological Research. Vol.306. New York, Alan R Liss 1989; 205-211. Schwan GA. Arch Neurol Psychiat 1952; 68: 655-682. Striimpell A. Arch Psych Nervenkrankh 1886; 17: 217-238. Newmark L. Dtsch Z Nervenheilk 1904; 27: l-23. Newmark L. Dtsch Z Netvenheilk 1906; 31: 224-230. Newmark L. Dtsch Z Nervenheilk 1911; 42: 419-431. Jacob C. Rev Sot Med Argentine 1909; 17: 665-703. Kahlstorf A. Z Ges Neurol Psychiat 1937; 159: 774-780. Schwalz GA, Liu CN. Arch Neurol Psychiat 1956; 75: 144-162. Kramer W. Neuropathol Appl Neurobiol1977; 3: 48&489. Sack GH, Huether CA, Garg N. Johns Hopkins Med J 1978, 143: 117-121. Duncan D. Anat Ret 1940: 76: 64-65. (Abstr.) Lassek AM. J Comp Neurol1942; 76: 217-225. Davidoff RA. Neurology 1989; 39: 1377-1385. Dimitrijevic MR, Lenman JAR, Prevec T, Wheatly K. J Neurol Neurosurg Psychiat 1982; 45: 46-49. Livingstone IR, Mastaglia, Edis R, Howe JW. Arch Nemo1 1981; 38: 75-79. McLeod JG, Morgan JA, Reye C. J Neural Neurosurg Psychiat 1977; 40: 611615. Pedersen L, Trojaborg W. Electrenceph Clin Neurophysiol 1981; 51: 283-297. Tedeschi G, Allocca S, Di Costanzo A. et al. J Neural Sci 1991; 103: 55-60.
The neuropathology
of hereditary spastic paraparesis R.P.M. Bruyn
Department of Neurology, Ouaknrijn Hospital, Utrecht (The Netherlands)
I&y words:
Hereditary spastic paraparesis; Neuropathology
Summary Hereditary spastic paraparesis or Striimpell’s disease is a genetically determined neurodegenerative disorder in which the signs and symptoms are predominant in the legs. Inheritance is usually autosomal dominant and in a minority recessive. Neuropathological study reveals a degeneration of the corticospinal tract decreasing from lower lumbar to cervical level and of posterior columns increasing from lumbar to upper cervical level as well as degeneration of the spinocerebellar tracts in approximately 50%. The nature of this nucleodistal central axonopathy and elinicopathological discrepancy for posterior columns, as well as the limits of the pathological process are poorly understood. Introduction
rosis, amyotrophic lateral sclerosis, infectious diseases, such as neurosyphilis and tropical spastic paraparesis
Strtimpell described two brothers with a bilateral pyramidal syndrome confined to the legs, resulting in the same spastic walking pattern their father exhibited [l] and what now has become known as hereditary spastic paraparesis or Strtimpell’s disease. At the turn of the century Lorrain [2] reviewed the literature, which at that time consisted of approximately 20 reports, and added 3 personal cases, so the eponymous credit is earned by Strtimpell more than Lorrain. Harding [3] made a distinction between “pure” and “complicated” forms; the “complicated” form is much more frequent and besides spastic paraparesis there are other neurological signs, such as dementia, extrapyramidal signs, skin abnormalities and skeletal changes.
(HTLV-I) .
Clinical findings The clinical signs essentially consist of a spastic paraparesis, of which the spasticity is more pronounced than the paraparesis, hyperreflexia of the legs and to a lesser degree of the arms, and Babinski signs. Sometimes, slight sensory disturbances are found, such as diminished vibration sense at the feet, and urinary urge incontinence. Differential diagnosis includes spinal cord compression, cervical myelopathy, cerebral palsy, multiple scleCorrespondence to: R.P.M. Bruyn, Department of Neurology, Oudenrijn Hospital, Van Heuven Goedhartlaan 1, 3527 CE Utrecht, The Netherlands. Tel.: (30) 953359; Fax: (30) 948356.
Genetic aspects Usually the disease is inherited as an autosomal dominant trait and comprises early and late onset types. Until an ultimate classification is found, based on modern genetic studies, which identify gene and gene-product, Harding’s [4] distinction in type I with age of onset below 35 and type II with onset over 35 years on the basis of her study of 22 families with “pure” spastic paraplegia remains useful. Type I runs a protracted course and the severity varies markedly. Type II runs a more progressive course showing more muscle weakness, urinary symptoms and sometimes sensory disturbances. Earlier, Behan and Maia [5] also distinguished two groups: one with onset in “middle life” (over 35 years) and a second group with onset in first or second decade. Strumpell[6] was the first to discern two groups on the basis of age at manifestation, one with onset in the third decade and the other group with onset between the third and sixth year. Autosomal recessive inheritance of “pure” cases has been described in only a few instances, whereas X-linked “pure” cases do not exist. Cases of “complicated” Xlinked spastic paraparesis have been sporadically mentioned [7-121. Linkage studies have been unraveling until now [13,14].
Fig. 1. Degeneration of the (crossed and uncrossed) pyramidal tracts, dorsal columns and dorsal spinocerebellar
Pathologic findings Because the patients usually die at home or in nursing homes there is an extreme paucity of detailed neuropathological reports. Schwarz [15] reviewed all pathological data and concluded that of 24 cases known at that time, only 7 could be identified as “pure” cases [6,16-211 and added a detailed neuropathological description of one patient. Subsequently, very few pathological descriptions were given by him and others [5,22-241. In all autopsied cases the pathological findings were more or less the same viz. degeneration of the lateral corticospinal tracts decreasing from lower lumbar to upper cervical level, frequent, but to a slighter degree, involvement of the uncrossed pyramidal tracts, increasing degeneration of the fasciculus gracilis from lumbar to upper cervical level without abnormalities of the posterior root fibers. The spinocerebellar tracts are involved in approximately 50%, marked neuronal loss in Clark’s column in four cases, cerebellum and basal ganglia showed loss of neurones in only one case. In four cases the number of Betz cells was diminished. There is onIy one quantitative study [22] in which the pyramids of a 57-year-old patient have been carefully examined: the pyramid measured 5.87 mm2, compared to the control values
tracts at the cervicothoracic level.
[25,26] a size a little larger than the pyramid of a ‘L-yearold child. They also found a marked reduction in the total number of myelinatcd nerve fibers: an estimated 376 055 ncrvc fibers in one pyramid compared to 688 800 fibers in control cases [26]. The distribution of the nerve fibers in one pyramid was as follows: 89% were l-4 pm, 8.8% were 5-10 pm, and 2.2% were more than 11 pm in diameter, which closely approximates the control figures given by Lassek 1261. Accordingly, there was a proportional loss of nerve fibers of all sizes. No changes were found in the cerebral peduncles. We had the possibility to study the autopsy findings of one patient with “pure” spastic paraplegia and in conclusion, the pathologicai changes in our patient are virtually the same as in the other cases (Fig. 1) and seem to be compatible with a retrograde axonal dying-back process. Discussion Studying the pathologic data raises the following questions. The first one is how to explain the absence of a clinicopathological correlation as far as the dorsal column degeneration is concerned: a nucleodistal (dying-
S18
back) degeneration of the fasciculus gracilis already visible at lumbar level and being most prominent at cervical level, yet without noticeable or only slight sensory changes. Therefore, it must be concluded that either practically all of the dorsal column fibers must be degenerated before clinical symptoms manifest, or the sensory ascending stimuli travel not only through the dorsal columns, the function of which is traditionally associated with transmitting various discriminative tactile impulses, vibration and kinesthesia. Recent research changed traditional views on dorsal column function drastically [27], and it now seems that the dorsal columns subserve the detection of temporal or sequential stimuli with a spatial component, as well as the appreciation of stimuli, that need digital exploration for recognition. Finally, they seem to occupy a key position in relaying sensory input to the motor cortex in order to control certain types of complex motor acts (digital movements, phasic motor behavior). The dorsal columns are not the only ascending pathways involved in transmitting sensory stimuli, such as vibration or 2-points discrimination, but other parallel pathways in the dorsolateral fasciculus of the spinal cord (e.g. dorsal spinothalamic tract) do so as well. The second question one can ask is whether the disease is really limited to the level of the spinal cord. Loss of Betz cells was only found in four cases with hereditary spastic paraparesis, and may be interpreted as a phenomenon of retrograde degeneration, not infrequently encountered in chronic degenerative diseases of the spinal cord. Several electrophysiological reports suggest multisystem involvement as assessed by visual, brainstem and somatosensory evoked potentials and studies of saccadic eye movements, though not all of these offer unequivocal conclusions [28-321. The third and by far the most intriguing question is the nature of the disease. At first glance the degenerative process appears to be a “dying-back” phenomenon, a process of progressive breakdown of axons beginning farthest away from the trophic perikaryon and proceeding towards the cell body, which eventually dies as well. However, trans-synaptic degeneration, present in other neurodegenerative diseases such as olivopontocerebellar atrophy and Friedreich’s ataxia, does not occur in Strtimpelf’s disease, nor does the cell body show any alterna-
tions. Any theory trying to explain the pathogenesis by positing enzyme deficiency, premature ageing process or toxic factors remains purely speculative until now.
References
9 10 11 12 13 14
15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
Striimpell A. Arch. Psychiat Nervenkrankh 1880; 10; 217-238. Lnrrain M. Thesis Steinheil, Paris, 1898. Harding AE. Lancet 1983; I: 1151-1155. Harding AE. J Neurol Neurosurg Psychiat 1981; 44: 871-883. Behan WMH, Maia M. J Neurol Neurosurg Psychiat 1974; 37: 8-u). Striimpelt A. Dtsch Z Nervenheilk 1904; 27: 291339. Johnston AW, McKusick VA. Am J Hum Genet 1962; 14: 83-94. Ford FR, Springfield, IL, Charles C. Thomas, 5th edn, 1973; 3.53356. Raggio JF, Thurmon TF, Anderson E. LA State Med Sot 1973; 125: 4-7. Zatz M, Penha-Serrano C, Otto PA. J Med Genet 1976;13: 217-222. Keppen LD, Leppert MF, O’Connell P et al. Am J Hum Genet 1987; 41 : 933-943. lku A, Kamsoy H, Karatepe A, Giikcay F. Acta Neurol Stand 1991; 83:4O+Q36. Boustany RMN, Fieischnick E, Alper CA et ai. Neurology 1987; 37: 910-915. Kolodny EH, Boustany RMN, Rouleau GA, Growden JH, Martin JB. Progress in Clinical and Biological Research. Vol.306. New York, Alan R Liss 1989; 205-211. Schwan GA. Arch Neurol Psychiat 1952; 68: 655-682. Striimpell A. Arch Psych Nervenkrankh 1886; 17: 217-238. Newmark L. Dtsch Z Nervenheilk 1904; 27: l-23. Newmark L. Dtsch Z Netvenheilk 1906; 31: 224-230. Newmark L. Dtsch Z Nervenheilk 1911; 42: 419-431. Jacob C. Rev Sot Med Argentine 1909; 17: 665-703. Kahlstorf A. Z Ges Neurol Psychiat 1937; 159: 774-780. Schwalz GA, Liu CN. Arch Neurol Psychiat 1956; 75: 144-162. Kramer W. Neuropathol Appl Neurobiol1977; 3: 48&489. Sack GH, Huether CA, Garg N. Johns Hopkins Med J 1978, 143: 117-121. Duncan D. Anat Ret 1940: 76: 64-65. (Abstr.) Lassek AM. J Comp Neurol1942; 76: 217-225. Davidoff RA. Neurology 1989; 39: 1377-1385. Dimitrijevic MR, Lenman JAR, Prevec T, Wheatly K. J Neurol Neurosurg Psychiat 1982; 45: 46-49. Livingstone IR, Mastaglia, Edis R, Howe JW. Arch Nemo1 1981; 38: 75-79. McLeod JG, Morgan JA, Reye C. J Neural Neurosurg Psychiat 1977; 40: 611615. Pedersen L, Trojaborg W. Electrenceph Clin Neurophysiol 1981; 51: 283-297. Tedeschi G, Allocca S, Di Costanzo A. et al. J Neural Sci 1991; 103: 55-60.