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Central distal axonopathy syndromes Newly recognized models of naturally occurring human degenerative disease.

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HYPOTHESIS
n
Central Distal Axonopathy Syndromes:
Newly Recognized Models of Naturally
Occurring Human Degenerative Disease
1
P. K. Thomas, MD, DSc," H. H. Schaumburg, MD,? P. S. Spencer, PhD, MRCPath,t H. E. Kaeser, MD,$
C. A. Pallis, MD, FRCP,§ F. Clifford Rose, MD, FRCP," and N. H. Wadia, MDB
It is a paradox that the same toxic substances that
selectively destroy particular areas of the human nervous system following accidental exposure may prove
of benefit in advancing our understanding of the
pathogenesis of neurodegenerative disorders. A neurotoxic substance may be both an environmental hazard and a useful tool for the neuroscientist. Recent
examples include the establishment of the centralperipheral distal axonopathy of human acrylamide intoxication as a model of spinocerebellar degeneration
[15], and the use of selective neuronopathic destruction of the human substantia nigra by methylphenyltetrahydropyridine as a new approach to the study of
Parkinson's disease 191. Careful study of experimental animal models of such toxic conditions can contribute to the elucidation of the pathophysiological and
biochemical mechanisms underlying the naturally occurring human conditions.
Several novel patterns of neuropathological change
characterized by a distal axonal degeneration confined
to the central nervous system have recently been recognized. Our experience with clioquinol intoxication
[ l , 21) and lathyrism [I61 in humans suggests that
newly identified patterns of nervous system degeneration, termed the central distal axonopathy (CDA) syndrome [8}, are clinicopathological entities, as judged
on the basis of common clinical features and electrophysiological findings. CDA probably underlies several
human degenerative diseases, such as hereditary spastic
paraplegia [19}. The salient clinical features of the
CDA syndrome related to clioquinol intoxication are:
(1) subacute onset and evolution; (2) severe paresthesias and diminished sensation in the lower limbs, at
times extending onto the lower trunk but usually sparing the upper limbs; (3j spastic paraparesis, tendon hyperreflexia (but sometimes absent ankle jerks), and extensor plantar responses; and (4j visual dysfunction
ranging from mild impairment to severe optic atrophy
[12, 141.
This constellation of clinical features, seen in victims
of the epidemic of clioquinol neurotoxicity that occurred in Japan in the years preceding 1971, initially
led to the introduction of the term szrbacute myelo-optic
neuropathy to describe the symptoms E141. Necropsy
studies established the presence of a symmetrical pattern of axonal degeneration in the lateral columns of
the lumbar spinal cord (distal corticospinal tracts) and
in the gracile columns at the cervicomedullary junction
(distal projections of the dorsal root ganglion cells).
Varying degrees of axonal degeneration were also present in the optic tracts 17, 141. Although peripheral
nerve involvement was initially considered to be a cardinal feature of the syndrome, it is now recognized that
it is not an important component t17). Somatosensory
evoked potential recordings have shown that conduction in peripheral sensory axons is normal, whereas
central conduction is delayed [ 131. The combination of
distal sensory loss in the lower limbs and loss of the
ankle jerks in cases of clioquinol toxicity was one of the
considerations that led to the initial assumption that
the peripheral nerves were involved. Yet the extension
of the sensory loss and paresthesias to the whole of the
legs and the lower trunk without involvement of the
upper limbs, as is seen in more severe cases, is not typical of a peripheral neuropathy. The explanation of the
loss of the ankle jerks is still uncertain, but it has been
From the *Royal Free Hospital School of Medicine and Institute of
Neurology, the $Royal Postgraduate Medical School, and the ':Charing Cross Hospital, London, United Kingdom; the ?Institute of
Neurotoxicology, Departments of Neurology, Neuroscience and
Pathology iNeuropathology), Albert Einstein College of Medicine,
Bronx, NY; the $Universitats-Klinik, Kantonsspital, Basel, Switzerland; and the TJ. J. Group of Hospitals, Bombay, India.
Received Sept 14, 1983, and in revised form Dec 7. Accepted for
publication Dec 9, 1983.
of ~
~
Address reprint requests to profThomas, D~~~~~~~~~
ical Science, Royal Free Hospital School of Medicine, Rowland Hill
London NW3 2PF, United fingdom.
313
~
~
suggested that this finding is related to degeneration of
the intramedullary portion of the afferent fibers subserving the monosynaptic tendon reflex [I).
Experimental studies in the dog and baboon have
established the same unusual distribution of clioquinolinduced axonal degeneration in the central nervous system as was observed in humans, and the absence of
peripheral nerve degeneration (G. Krinke, H. H.
Schaumburg, unpublished observations, 1773) [8, 181.
The selective vulnerability of the centrally directed axons of the primary sensory neurons in the CDA syndrome caused by clioquinol, with sparing of the peripherally directed axons, is particularly interesting [20].
The reason for this finding is so far obscure, but some
possibilities are apparent. The environment of the centrally directed axons differs from that of the peripherally directed processes, including the association with
oligodendrocytes rather than Schwann cells. There are
also differences in functional capacity. Wujek and
Lasek {23] have shown in the rat that axonal transport
rates for slow components a and b are approximately
twice as fast in the peripherally directed axons as in the
centrally directed primary sensory fibers. Delivery of
structural proteins to the centrally directed fibers is
therefore likely to be less efficient, perhaps explaining
their reduced regeneration rate (2.1
0.5 mm a day)
compared with the peripheral processes (4.6 & 0.9
mm a day). This difference is not related to the occurrence of regeneration through different environments
in the spinal roots than in the nerve trunks, because
regeneration rates are identical in ventral roots and
motor axons in the sciatic nerve {23}. These results
imply a fundamental difference between the central
and peripheral processes of dorsal root ganglion cells.
Neuronal degeneration of the CDA pattern underlies hereditary spastic paraplegia of the “pure” type
(Strumpell’s disease) and possibly other human degenerative disorders. Patients with hereditary spastic
paraplegia may exhibit sensory loss of posterior column
type in the legs. Peripheral sensory nerve action potentials are normal 101, but spinal somatosensory evoked
potentials are small or absent and cortical responses are
delayed 14, 11, 221. Necropsy studies reveal axonal
degeneration in the lateral and posterior columns of
the spinal cord but preservation of the dorsal roots [2].
Unlike the pattern in the clioquinol syndrome, the
optic nerves are usually uninvolved.
The neuroparalytic disease lathyrism, caused by excessive consumption of neurotoxic species of la thy^^^
peas, may represent another example of the CDA syndrome {lbf. The salient clinical features of human
lathyrism include the subacute onset of spastic
paraparesis and lower extremity hyperreflexia, sparing
of the upper extremities, and normal sensation and
autonomic function. The neuropathological characteristics are less welt known, and there have been no post-
*
314 Annals of‘ Neurology
Vol 1 5 No 4
April 1984
mortem studies of active human cases and no morphological studies of the putative animal model. The
clinical data and one postmortem report of an individual who died 30 years following an episode suggest that
the changes are largely confined to the corticospinal
fibers of the thoracolumbar spinal cord l17). CDA may
underlie other human degenerative diseases largely
confined to the upper motor neurons.
The potential for recovery is likely to be poor in the
CDA syndrome, because of the reduced capacity for
axonal regeneration in the central nervous system. This
finding may account for the high incidence of persistent
sensory symptoms in patients with subacute myelooptic neuropathy related to clioquinol neurotoxicity,
and spasticity in the lathyrism patients.
W e have described a new pattern of distal axonal
degeneration, initially recognized in clioquinol neurotoxicity, that constitutes a further type of “dyingback” disorder [31. Friedreich’s ataxia is the beststudied example of an inherited system degeneration in
humans that is characterized by a central-peripheral distal axonopathy [ 5 , 61.The neuropathological features
produced by clioquinol resemble those of certain intrinsic degenerations confined to the central nervous
system, such as hereditary spastic paraplegia, that again
are characterized by a distal axonal degeneration. The
elucidation of the reasons for these different patterns
of neuronal degeneration in experimental animal models may contribute to the understanding of human disorders with similar patterns of involvement.
Supported in part by the Friedreich’s Ataxia Group, and by Grants
NS19611, OH00851, and OH00535 from the US Public Health
Service.
The authors are grateful to Patricia Vaccelli, Gloria Warkenthien,
and l e r a n Price for assistance with the manuscript.
References
1. Baumgartner G , Gawel MJ, Kaeser HE, et al: Neurotoxicity of
halogenated hydroxyquinolines: clinical analysis of cases reported outside Japan. J Neurol Nrurosurg Psychiatry 42- 107 31083, 1979
2. Behan WMH, Maia M: Strumpell’s familial spastic paraplegia:
genetics and neuropdthology. J Neurol Neurosurg Psychiatry
37:8-20, 1974
3. Cavanagh JB: The significance of the “dying-back” process in
experimental and human neurological disease. lnt Rev Exp Biol
3219-267, 1964
4. Dimitrijevic MR, Lenman JAR, Prevec T, Wheatly K: A study
of posterior column function in familial spastic pardplegia. J
Neurol Neurosurg Psychiatry 45:46-43, 1‘982
5. Dyck PJ, Ohta M: Neuronal atrophy and degeneration predomib
nantly affecting peripheral sensory neurons. In Dyck PJ, Thomas
PK, Lambert EH (eds): Peripheral Neuropathy. Philadelphia,
Saunders, 1975, pp 791-824
6. Greenfield JG: The Spino-Cerebellar Degenerations. Oxford,
Blackwell, 1954
7. Korio R: A review of SMON srudies in Japan. In Gent M,
Shigematsu I (eds): Epidemiological Issues in Reported DrugInduced Illnesses: SMON and Other Examples. Hamilton, Ontario, McMaster University Library Press, 1978, p 121
8. Krinke G , Schaumburg H H , Spencer PS, et al: Clioquinol and
2,5-hexanedione produce different types of distal axonopathy: a
comparative experimental study in the dog. Acta Neuropathol
(Berl) 47:213-221, 1979
9. Langston JW, Ballard P, Tetrud JW, Irwin I: Chronic parkinsonism in humans due to a product of meperidine-analog synthesis.
Science 219979-980, 1983
10. McLeod JG, Morgan JA, Reye C: Electrophysiological studies in
familial spastic paraplegia. J Neurol Neurosurg Psychiatry
40:661-665, 1977
11. Pedersen L, Trojaborg W: Visual, auditory and somatosensory
involvement in hereditary cerebellar ataxia, Friedreich’s ataxia
and familial spastic paraplegia. Electroencephalogr Clin
Neurophysiol 52:283-297, 1981
12. Schaumburg HH, Spencer PS: Clioquinol. In Spencer PS,
Schaumburg HH (eds): Experimental and Clinical Neurotoxicology. Baltimore, Williams & Wilkins, 1980, pp 395-407
13. Shibasaki H, Kagigi R, Ohnishi A, Kuroiwa Y : Peripheral and
central nerve conduction in subacute myelo-optic-neuropathy.
Neurology (NY) 32:1186-1188, 1982
14. Sobue I, Ando K, Mitsuo I, et al: Myeloneuropathy with abdominal disorders in Japan: a study of 752 cases. Neurology (Minneap) 21:168-173, 1971
15. Spencer PS, Schaumburg HH: Central-peripheral distal axonopathy: the pathology of dying-back polyneuropathies. In
Zimmerman H M (ed): Progress in Neuropathology, Vol 3. New
York, Grune & Stratton, 1976, pp 253-299
16. Spencer PS, Schaumburg H H , Cohn DF, Seth PK: Lathyrism: a
useful model of primary lateral sclerosis. In Clifford Rose F (ed):
Progress in Motor Neurone Disease. London, Pitman Medlcal
(in press)
17. Streifler M, Cohn DF, Hirano A, Shujman E: The central nervous system in neurolathyrism. Neurology (Minneap) 27: 1 176,
1977
18. Tateishi J, Ikeda H, Saito A, et d:Myeloneuropathy in dogs
induced by iodoxyquinoline. Neurology (Minneap) 22:702709, 1972
19. Tateishi J, Ohta N, Ohnishi A, et al: Discrepancy in pathological
changes in the peripheral sensory system of Goll’s tract in the
cervical cord of beagle dogs intoxicated with Chinoform.
Specific Diseases Research Commission, SMON Research
Group Reporrs, March 18-19, 1979
20. Thomas PK: Selective vulnerability of the centrifugal and centripetal axons of primary sensory neurons. Muscle Nerve
5:s117-S12 1, 1982
2 1. Thomas PK: Neurotoxicity of halogenated hydroxyquinolines:
non-Japanese cases. Acta Neurol Scand (in press)
22. Thomas PK, Jefferys JGR, Smith IS, Loulakakis D: Spinal
somatosensory evoked potentials in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry 44:243-246, 1981
23. Wulek JR, Lasek RJ: Correlation of axonal regeneration and
slow component B in two branches of a single axon. J Neurosci
31243-251, 1983
Thomas et al: CDA Syndromes
315
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central, model, syndrome, occurring, degeneration, naturally, recognize, newly, axonopathy, disease, distal, human
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