Acta Neurol. Skandinav. 51, 245-248, 1975
SHORT COMMUNICATIONS
Department of Neurology, Whittington Hospital, London, England, and St. Margaret’s Hospital, Birmingham, England.
FURTHER STUDIES ON PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA
M . Direkze and G. Campbell ABSTRACT 46XY, normal male karyotype (G-banded) was noted i n each patient with progressive external ophthalmoplegia. Although vacuoles have been recognized in other conditions, their presence in significant numbers in the diseases under scrutiny suggests the possibility of a common offending agent. It is likely that vacuolation is a pathological indication of infection by slow viruses.
Progressive external ophthalmoplegia, variously associated with peripheral neuropathy, posterior column dysfunction, athetosis, incoordination, cardiac conduction defects and malabsorption, have been described. Direkze (1973), reporting three patients with similar associations, emphasized t h e lack of a clear genetic basis, commented on t h e difficulty of establishing the cause of muscle atrophy in biopsy specimens, and raised t h e possibility of infection by a slow virus to account for the progressive assault on t h e anatomy. Further studies were undertaken to determine the morphological characteristics of the chromosomes in the three patients reported by him. I t was felt t h a t scrutiny of autopsy material so f a r reported, and comparison with findings i n animal models known or presumed t o have had infections with slow viruses, may perhaps provide clues as to the aetiological basis of the disease process.
Clinical Features The three patients were males, aged 31, 61 and 29 years respectively when first seen i n the Neurology Department; they presented with bilateral ptosis and varying degrees of external ophthalmoplegia. In addition, the first had atbetosis, ataxia, wasting of sternomastoid, posterior column sensory loss i n t h e lower limbs, ‘sock’ distribution of peripheral sensory loss, areflexia and malabsorption. The second showed dysphagia, dysphonia and a marked wasting of neck muscles. The last had bilateral optic atrophy, partial palatal palsy and wasting of the facial, sternomastoid and proximal limb muscles.
246 Investigations Lymphocytes were cultured, harvested, hydrated and stained according to conventional methods. The slides wcre microscopically examined; well-stained cells were photographed; and karyotypes wcre prepared from enlarged prints. In all, 54 cells were examined, and a normal male karyotype was present in each, with the cxception of a questionable abnormality in chromosome 2, case 2. The studies were therefore repeated, with the inclusion of banding. 46XY, a normal male karyotype iG-banded), was noted i n each case.
Dl‘scussion The inquiry into the morphology of the chromosomes was initiated with a dual purpose: to determine whether a common chromosomal abnormality existed in a few patients with somewhat similar neurological signs, indicating a possible genetic basis; and to search f o r single chromosome breaks-a form of indirect evidence of a virus infection. On the basis of the above investigations, the first possibility seems remote. Single chromosome breaks wcre first noted by Hampar h Ellison (1961) in a tissue-culture system, and later hy Nichols ef al. (1962) in leucocyte cultures from patients with measles. It is of interest t h a t changes i n chromosome numbers, and chromosome pulverization (extreme fragmentation of chromatin), have been observed in in vifro systems in association with virus infection. Reports on autopsy material from patients with progressive external ophthalmoplegia are fcw. The presence in these individual reports of other conditions (such as aqueduct stenosis with dilatation of the lateral and third ventricle, with protrusion of its floor as a cystic mass the size of a walnut-Becketf h N e t s k y (1953); infiltrating spongioblastoma-polare in t h e left parietal lobe-Schwarz & Liu (1954) ; and carcinoma of the bronchus-Sfephens e f at. (1958), makes the interpretation of the changes described a difficult task. The most significant and consistent abnormality of vacuolation i n the neurones of t h e white matter, brain stern and cervical cord, was noted i n the case reports by Kearns h Sayre (1958), and Daroff e t al. (1966). The latter also recorded t h e presence of vacuolation of t h e 3rd and 4th cranial nerve nuclei and t h e median longitudinal fasciculi. I t is of interest that Rearns & S a y r e (1958) made the following observation: “An additional finding, the importance of which was obscure, was the presence of marked vacuolation of t h e central white matter of the brain and lenticular nuclei which persisted through t h e brain, the brain stem and cervical cord. Although the appearance suggested a postmortem artefact, the location of the spaces and the short interval between death and fixation by embalming of the brain, suggest t h a t some other factor was present.” Comparison of the above with a group referred to as spongiform cncephalopathies, which includes scrapie, encephalopathy of mink, and rida ( a disease affecting Icelandic sheep described by Sigurdsson (1954 b ) in association with introduction of the concept of slow virus infection), brings t o light common features, such as ataxia and clumsiness of gait, i n t h e way of clinical findings, and vacuolation a t different sites in t h e brain. There are interesting similarities between kuru and rida; they are confined to isolated groups, t h e former to a population in t h e eastern highlands of New Guinea, while the latter is enzootic i n Northern Iceland; ataxia and tremor are clinical findings in common; and spongy degeneration of t h e grey
247 Table I . Vacuolation of neurones in scrapie sheep.
Serial no.
s. S.
s. s. C. C. C. C. C. C.
3 18 20 22 171 263 270 266 268 269
Total no. of vacuoles in 54 sections 1,185 1,836 1,476 2,052 3,294 5,832 4,266 1,260 3,474 1,314
Average no. of vacuoles per section 22 34 27 38 61 108 79 23 64 24
Range
per section
14-28 10-56 15-51 9-54 29-78 41-215 51-123 19-29 25-88 7-43
Table 2. Vacuolation of neurones in apparentl!l healthij sheep.
Serial no. C.
52 53 c. 5 4 c. 55 c. 97 C. 98 c. 99 c. 100 c. 101 c. 102
c.
Total no. of vacuoles in 54 sections
Average no. of vacuoles per section
per section
41 57 None
0.76 1.05 -
0-3 0-7 -
10 10
0.18 0.18 0.05 0.26
0-1
0.3
0-1
3 14 None None 16
Range
0-1 0-1 0-1
Reprinted from Zlotnik, I. (1957) : Significance of vacuolated neurones in the medulla of sheep affected with scrapie. Nature (Lond.) 180, 393-394; by kind permission of the Editor.
matter, with marked changes i n the cerebellum, has been observed in both. In kuru, neurones of the corpus striatum show vacuolation. Holman h Pattison (1943), i n a n analysis of brain tissue from 75 sheep with clinical signs of scrapie, noted that vacuoles were mainly confined to the medulla oblongata; but they detected a certain selectivity for groups of cells within it, such as reticular formation, vestibular and lateral cuneate nuclei. They added that statistical examination of t h e findings indicated t h a t vacuoles would be expected in not less than 9 4 per cent of cases. Zlotnik (1957), in an analysis of material from two groups of 10 each (one in advanced clinical natural scrapie, and the other healthy animals of comparable age), found marked vacuolation in 54 serial sections taken from the former, a t three different levels of the medulla. (See Tables 1 and 2 ) . Furthermore, by following vacuolatcd cells in serial sections, it was observed
that the vacuoles were confined to the cytoplasm, and displaced the nucleus to one side. It appears, therefore, that vacuolation is a consistent pathological finding in a group of diseases resulting from a n agent whose presence in t h e host is manifested clinically by a protracted course and progressive damage t o the anatomy. Transmission from dam to kits, from man to man (cannibalism), and from man to animal (intracerebral inoculation) is recognized as a property of some of these agents. Although a common pathological finding does not necessarily imply a common causal factor, it is likely, i n t h e context of t h e clinical picture and :autopsy findings in some patients with progressive external ophthalmoplegia, t h a t !he offending agent is a slow virus. Whether there is a genetic predisposition to invasion by these organisms remains obscure. 1 cknoudedgements
We wish to acknowledge the assistance of Dr. D. T. Hughes, Cytogenetics Unit, Institute of Child Health, London, with chromosomal studies in two of the cases. Our thanks to Miss Phyllis Jenkins and Miss Ann Duffy f o r help in the preparation of this manuscript. References: Beckett, R. S . & M. G. Netsky (1953): Familial ocular myopathy and external ophthalmoplegia. Arch. Neurol. Psychiat (Chic.) 69, 6672.--Daroff, R. B., C. B. Solitare, J. H. Pincus & G. H. (;laser (1966) : Spongiform encephalopathy with chronic progressive external ophthalmoplegia. Neurology (Minneap.) 16, 161-169.Direkze, M. (1973) : Progressive external ophthalmop1egia.-Some clinical associations. Acta neurol. scand. 49, 195-204.-Hampar, B. & S. A. Ellison (1961) : Chromo>omal aberrations induced by a n animal virus. Nature (Lond.) 192, 145-147.-Holman, H.H. & I.H. Pattison (1943) : Further evidence on the significance of vacuolated nerve cells in the medulla oblongata of sheep affected with scrapie. J. comp. Path. 53, 231-236.-Kearns, T. P. & G. P. Sayre (1958): Retinitis pigmentosa, etxernal ophthalmoplegia and complete heart block. Unusual syndrome with histologic study in one of two cases. Arch. Ophthal. 60, 280-289.-Nichols, W. W., A. Levan, P. Avla & E. Norrby (1962) : Measles associated chromosome breakage. Hereditas (Lund) 48, 367-370.-Schwarz, G. A. & C. Liu (1954) : Chronic progressive external ophthalmoplegia, a clinical and neuropathologic report. Arch. Neurol. Psychiat. (Chic.) 71, 34-53.-Stephens, J., M. L. Hoover & J. Denst (1958): On familial ataxia, neural amyotrophy and their association with progressive external ophthalmoplegia. Brain 81, 556-566.-Sigurdsson, B. (1954) : Rida, a chronic encephalitis of sheep with general remarks on infections which develop slowly and some of their special characteristics. Brit. vet. J. 110, 341-354.--Zlotnik, I. (1957) : Significance of vacuolated neurones in the medulla of sheep affected with scrapie. Nature (Lond.) 180. 393-394. Received June 27, 1974.
M . Direkze, M.R.C.P. 84 Granville Road Finchley London, N12 OHT England
SHORT COMMUNICATIONS
Department of Neurology, Whittington Hospital, London, England, and St. Margaret’s Hospital, Birmingham, England.
FURTHER STUDIES ON PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA
M . Direkze and G. Campbell ABSTRACT 46XY, normal male karyotype (G-banded) was noted i n each patient with progressive external ophthalmoplegia. Although vacuoles have been recognized in other conditions, their presence in significant numbers in the diseases under scrutiny suggests the possibility of a common offending agent. It is likely that vacuolation is a pathological indication of infection by slow viruses.
Progressive external ophthalmoplegia, variously associated with peripheral neuropathy, posterior column dysfunction, athetosis, incoordination, cardiac conduction defects and malabsorption, have been described. Direkze (1973), reporting three patients with similar associations, emphasized t h e lack of a clear genetic basis, commented on t h e difficulty of establishing the cause of muscle atrophy in biopsy specimens, and raised t h e possibility of infection by a slow virus to account for the progressive assault on t h e anatomy. Further studies were undertaken to determine the morphological characteristics of the chromosomes in the three patients reported by him. I t was felt t h a t scrutiny of autopsy material so f a r reported, and comparison with findings i n animal models known or presumed t o have had infections with slow viruses, may perhaps provide clues as to the aetiological basis of the disease process.
Clinical Features The three patients were males, aged 31, 61 and 29 years respectively when first seen i n the Neurology Department; they presented with bilateral ptosis and varying degrees of external ophthalmoplegia. In addition, the first had atbetosis, ataxia, wasting of sternomastoid, posterior column sensory loss i n t h e lower limbs, ‘sock’ distribution of peripheral sensory loss, areflexia and malabsorption. The second showed dysphagia, dysphonia and a marked wasting of neck muscles. The last had bilateral optic atrophy, partial palatal palsy and wasting of the facial, sternomastoid and proximal limb muscles.
246 Investigations Lymphocytes were cultured, harvested, hydrated and stained according to conventional methods. The slides wcre microscopically examined; well-stained cells were photographed; and karyotypes wcre prepared from enlarged prints. In all, 54 cells were examined, and a normal male karyotype was present in each, with the cxception of a questionable abnormality in chromosome 2, case 2. The studies were therefore repeated, with the inclusion of banding. 46XY, a normal male karyotype iG-banded), was noted i n each case.
Dl‘scussion The inquiry into the morphology of the chromosomes was initiated with a dual purpose: to determine whether a common chromosomal abnormality existed in a few patients with somewhat similar neurological signs, indicating a possible genetic basis; and to search f o r single chromosome breaks-a form of indirect evidence of a virus infection. On the basis of the above investigations, the first possibility seems remote. Single chromosome breaks wcre first noted by Hampar h Ellison (1961) in a tissue-culture system, and later hy Nichols ef al. (1962) in leucocyte cultures from patients with measles. It is of interest t h a t changes i n chromosome numbers, and chromosome pulverization (extreme fragmentation of chromatin), have been observed in in vifro systems in association with virus infection. Reports on autopsy material from patients with progressive external ophthalmoplegia are fcw. The presence in these individual reports of other conditions (such as aqueduct stenosis with dilatation of the lateral and third ventricle, with protrusion of its floor as a cystic mass the size of a walnut-Becketf h N e t s k y (1953); infiltrating spongioblastoma-polare in t h e left parietal lobe-Schwarz & Liu (1954) ; and carcinoma of the bronchus-Sfephens e f at. (1958), makes the interpretation of the changes described a difficult task. The most significant and consistent abnormality of vacuolation i n the neurones of t h e white matter, brain stern and cervical cord, was noted i n the case reports by Kearns h Sayre (1958), and Daroff e t al. (1966). The latter also recorded t h e presence of vacuolation of t h e 3rd and 4th cranial nerve nuclei and t h e median longitudinal fasciculi. I t is of interest that Rearns & S a y r e (1958) made the following observation: “An additional finding, the importance of which was obscure, was the presence of marked vacuolation of t h e central white matter of the brain and lenticular nuclei which persisted through t h e brain, the brain stem and cervical cord. Although the appearance suggested a postmortem artefact, the location of the spaces and the short interval between death and fixation by embalming of the brain, suggest t h a t some other factor was present.” Comparison of the above with a group referred to as spongiform cncephalopathies, which includes scrapie, encephalopathy of mink, and rida ( a disease affecting Icelandic sheep described by Sigurdsson (1954 b ) in association with introduction of the concept of slow virus infection), brings t o light common features, such as ataxia and clumsiness of gait, i n t h e way of clinical findings, and vacuolation a t different sites in t h e brain. There are interesting similarities between kuru and rida; they are confined to isolated groups, t h e former to a population in t h e eastern highlands of New Guinea, while the latter is enzootic i n Northern Iceland; ataxia and tremor are clinical findings in common; and spongy degeneration of t h e grey
247 Table I . Vacuolation of neurones in scrapie sheep.
Serial no.
s. S.
s. s. C. C. C. C. C. C.
3 18 20 22 171 263 270 266 268 269
Total no. of vacuoles in 54 sections 1,185 1,836 1,476 2,052 3,294 5,832 4,266 1,260 3,474 1,314
Average no. of vacuoles per section 22 34 27 38 61 108 79 23 64 24
Range
per section
14-28 10-56 15-51 9-54 29-78 41-215 51-123 19-29 25-88 7-43
Table 2. Vacuolation of neurones in apparentl!l healthij sheep.
Serial no. C.
52 53 c. 5 4 c. 55 c. 97 C. 98 c. 99 c. 100 c. 101 c. 102
c.
Total no. of vacuoles in 54 sections
Average no. of vacuoles per section
per section
41 57 None
0.76 1.05 -
0-3 0-7 -
10 10
0.18 0.18 0.05 0.26
0-1
0.3
0-1
3 14 None None 16
Range
0-1 0-1 0-1
Reprinted from Zlotnik, I. (1957) : Significance of vacuolated neurones in the medulla of sheep affected with scrapie. Nature (Lond.) 180, 393-394; by kind permission of the Editor.
matter, with marked changes i n the cerebellum, has been observed in both. In kuru, neurones of the corpus striatum show vacuolation. Holman h Pattison (1943), i n a n analysis of brain tissue from 75 sheep with clinical signs of scrapie, noted that vacuoles were mainly confined to the medulla oblongata; but they detected a certain selectivity for groups of cells within it, such as reticular formation, vestibular and lateral cuneate nuclei. They added that statistical examination of t h e findings indicated t h a t vacuoles would be expected in not less than 9 4 per cent of cases. Zlotnik (1957), in an analysis of material from two groups of 10 each (one in advanced clinical natural scrapie, and the other healthy animals of comparable age), found marked vacuolation in 54 serial sections taken from the former, a t three different levels of the medulla. (See Tables 1 and 2 ) . Furthermore, by following vacuolatcd cells in serial sections, it was observed
that the vacuoles were confined to the cytoplasm, and displaced the nucleus to one side. It appears, therefore, that vacuolation is a consistent pathological finding in a group of diseases resulting from a n agent whose presence in t h e host is manifested clinically by a protracted course and progressive damage t o the anatomy. Transmission from dam to kits, from man to man (cannibalism), and from man to animal (intracerebral inoculation) is recognized as a property of some of these agents. Although a common pathological finding does not necessarily imply a common causal factor, it is likely, i n t h e context of t h e clinical picture and :autopsy findings in some patients with progressive external ophthalmoplegia, t h a t !he offending agent is a slow virus. Whether there is a genetic predisposition to invasion by these organisms remains obscure. 1 cknoudedgements
We wish to acknowledge the assistance of Dr. D. T. Hughes, Cytogenetics Unit, Institute of Child Health, London, with chromosomal studies in two of the cases. Our thanks to Miss Phyllis Jenkins and Miss Ann Duffy f o r help in the preparation of this manuscript. References: Beckett, R. S . & M. G. Netsky (1953): Familial ocular myopathy and external ophthalmoplegia. Arch. Neurol. Psychiat (Chic.) 69, 6672.--Daroff, R. B., C. B. Solitare, J. H. Pincus & G. H. (;laser (1966) : Spongiform encephalopathy with chronic progressive external ophthalmoplegia. Neurology (Minneap.) 16, 161-169.Direkze, M. (1973) : Progressive external ophthalmop1egia.-Some clinical associations. Acta neurol. scand. 49, 195-204.-Hampar, B. & S. A. Ellison (1961) : Chromo>omal aberrations induced by a n animal virus. Nature (Lond.) 192, 145-147.-Holman, H.H. & I.H. Pattison (1943) : Further evidence on the significance of vacuolated nerve cells in the medulla oblongata of sheep affected with scrapie. J. comp. Path. 53, 231-236.-Kearns, T. P. & G. P. Sayre (1958): Retinitis pigmentosa, etxernal ophthalmoplegia and complete heart block. Unusual syndrome with histologic study in one of two cases. Arch. Ophthal. 60, 280-289.-Nichols, W. W., A. Levan, P. Avla & E. Norrby (1962) : Measles associated chromosome breakage. Hereditas (Lund) 48, 367-370.-Schwarz, G. A. & C. Liu (1954) : Chronic progressive external ophthalmoplegia, a clinical and neuropathologic report. Arch. Neurol. Psychiat. (Chic.) 71, 34-53.-Stephens, J., M. L. Hoover & J. Denst (1958): On familial ataxia, neural amyotrophy and their association with progressive external ophthalmoplegia. Brain 81, 556-566.-Sigurdsson, B. (1954) : Rida, a chronic encephalitis of sheep with general remarks on infections which develop slowly and some of their special characteristics. Brit. vet. J. 110, 341-354.--Zlotnik, I. (1957) : Significance of vacuolated neurones in the medulla of sheep affected with scrapie. Nature (Lond.) 180. 393-394. Received June 27, 1974.
M . Direkze, M.R.C.P. 84 Granville Road Finchley London, N12 OHT England
