Postradiation Motor Neuron Carl H.
Sadowsky, MD;
Ernest
Sachs, Jr, MD; Jos\l=e'\Ochoa, MD, PhD
\s=b\ We report an unusual case of selective lower motor neuron syndrome (MNS) complicating whole neuraxis radiation therapy. Only three well-documented similar cases have been found in a thorough review of the literature. The syndrome has a stereotyped time course and is self-$ limited. We discuss here possible pathogenetic mechanisms and their relationship to motor neuron disease. (Arch Neurol 33:786-787, 1976)
of radiation damage to cord have been recog¬ the rarest being lower motor
Four types spinal the
nized,1
neuron
syndrome (MNS), presumably
due to damage to anterior horn cells of the spinal cord. A recent example prompted review of possible pathogenetic mechanisms and their relation¬ ship to motor neuron disease (MND). REPORT OF A CASE
15-year-old girl with four-month history of frontal headache, vomiting, and diplopia was seen on June 7, 1973, as an outpatient at the Dartmouth-Hitchcock Medical Center. Findings on physical A
a
examination were as follows: bilateral 4 to 5 diopters of papilledema, vertical nystag¬ mus, left sixth nerve paresis, dysmetria and past pointing of the left hand, and ataxia of gait. Brain scan showed increased uptake in the midline inferior to the torcular. Angiography demonstrated hydrocephalus and a left cerebellar mass high under the tentorium. On June 11, a solid tumor (histologically malignant medulloblastoma) was removed from the vermis. Postoperatively, the patient was treated (June 20 to July 25, 1973) with a course of
Accepted
for publication June 15, 1976. From the Sections of Neurology and NeurosurMedical Center, gery, Dartmouth-Hitchcok Hanover, NH. Dr Sadowsky is now with the US Air Force Hospital, Wiesbaden, West Germany. Reprint requests to Division of Neurology, Dartmouth Medical School, Hanover, NH 03755
(Dr Ochoa).
Syndrome
cobalt 60 radiation to the skull (4,000 rads centrally), and a betatron-electron beam course of radiation to the spine. Using a scanning technique, a dose of 3,800 rads was delivered (July 18 to Aug 17) to the entire spine (4,763 rads at the surface) with fields 6 cm wide, scanning length 53.5 cm, and field length 3 cm. Chemotherapy was never administered. When seen 11 months after radiation she complained of progressive difficulty in walking due to weakness of leg muscles for the past three months. She denied involve¬ ment of the arms, sensory symptoms, pain, or sphincter disorder. On examination she had definite weakness and muscle wasting of the lower limbs, worse distally. Light touch, pinprick, vibration, and position sense and two-point discrimination thresh¬ olds were entirely normal. Ankle jerks were absent, but all other deep tendon reflexes were 1 +. Plantar responses were flexor. Spontaneous sweating of the feet was
present.
Electrophysiological
studies revealed normal motor conduction velocity and sural nerve action potentials, with bilateral advanced denervation of the extensor digitorum brevis, tibialis anterior, gastrocnemius, and vastus medialis muscles in order of severity. Cerebrospinal fluid cytologie findings were normal (two lymphocytes, one large mononuclear cell, and 111 RBCs per cubic millimeter); protein concentration was 200 mg/100 ml and a myelogram was normal. Other investigations included a normal blood cell count, B,, level, and sedimenta¬ tion rate. On neurological evaluation one month later the patient was just able to stand aided by a cane. Flaccid weakness and atrophy of foot intrinsics and peroneal muscles was obvious. Sensory examination gave normal findings. Ankle jerks were absent. The CSF protein level was 118 mg/ 100 ml and cytologie results were normal. Follow-up electromyography of leg muscles was unchanged, and EMG and results of nerve conduction studies in upper limbs were normal.
A right ascending lateral popliteal nerve action potential was normal one year after radiation (Aug 13, 1974). No new symptoms have developed and the patient's previous deficits have re¬ mained unchanged. She has consistently denied sensory symptoms.
COMMENT
This case seems identical in its clin¬ ical manifestations and evolution to the three cases reported by Greenfield and Stark." Thus, all four cases have consisted of a selective lower motor neuron disease confined to lower limb muscles, starting three to eight months after radiation of the spinal axis. All have followed a subacute and progressive, self-limited course. A relatively large series of cases pre¬ sumed to belong to this category was reported in 1969.:; No detailed clinical information was provided; it is diffi¬
cult, therefore, to subject that report to comparison. It is unlikely that the clinical mani¬ festations in our patient might have
been the consequence of a recurrence of the medulloblastoma, with seeding of the subarachnoid space, as the picture progressed without involve¬ ment of sensory or autonomie func¬ tion, without a cellular reaction in the CSF (on two occasions), and without development of pain. Further confi¬ dence was given by a normal myelogram and by the self-limited course of the process as assessed 16 months after the peak of weakness. From clinical and electrophysiological data it seems clear that the disease process is a result of selective injury to the lower motor neuron. The possibility of subclinical damage to the central branch of primary sensory neurons or the peripheral branch of the small dorsal root ganglia cells
Downloaded From: http://archneur.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 06/10/2015
cannot be ruled out.
The primary site of injury within the lower motor neuron cannot be established with certainty. If ionizing radiation had caused the syndrome through direct damage of nerve roots, one would have expected combined motor and sensory manifestations.4 In the cases under discussion there was complete sparing of all clinical sensory modalities. Hence, primary involve¬ ment of the anterior horn cells is most likely, and not only by exclusion. Studies on the rat sciatic nerve point out that the CNS is more sensitive to ionizing radiation than the nerve trunk."1 Kristensson et al," in a patho¬ logical analysis of five cases of delayed radiation lesions in man, demonstrated well-preserved spinal roots adjacent to markedly destruc¬ tive lesions of the spinal cord. Further, there is good evidence to support susceptibility of anterior horn cells to ionizing radiation. Olkowski7 reported a decrease in uptake by motor neurons of tritiated uridine in total-body radiated rats, suggesting decreased RNA synthesis in these cells. Thus, damage to anterior horn cells follow¬ ing radiation appears to be con¬ firmed. Selective damage to lumbosacral motor neurons is unsurprising in Greenfield and Stark's patients, who received focal radiation. However, our patient received whole neuraxis radia¬ tion. We have no way of advancing into the questions of radiation field overlap vs regional selective cell
vulnerability. Another puzzle is
the
rarity of this
syndrome. At this stage one can only speculate: ionizing radiation may have activated a latent virus. This possi¬ bility can be entertained from evi¬ dence of herpes simplex virus activa¬ tion after modification of physical variables (fever, ultraviolet radiation,
surgery of the fifth cranial nerve in tic douleureux, etc). Extrapolation of an analogous mechanism for motor
disease has been disappoint¬ derived from on neuronal inclusions in MND,N and from unsuc¬ cessful attempts at isolating and transferring virus in such a condition, has been inconclusive.81' There are, however, fairly convincing documents on the development of a MND-like picture as a late sequel of poliovirus infection.1" Thus, even though MND (Charcot disease) may be unrelated to viral infection, it is quite possible that motor neurons may be circumstan¬ tially involved in a progressive disease process caused by a virus. As to the possible effect of ionizing radiation itself as an effective trigger for viral activation, there is the precedent of the virus-induced thymic lymphoma in mice." Following radiation this spe¬ cies develops a thymus neoplasm attributed to activation of a latent leukemia virus that can be isolated from the affected tissue. Altogether, it seems reasonable to regard virus activation as a viable hypothesis for postradiation MNS. Despite a nega¬ tive history for poliomyelitis, this virus or other viruses cannot be excluded in the case we have described here. neuron
ing. Indeed, evidence morphological studies
A second alternative to account for such rare selective degeneration of motor neurons would be some meta¬ bolic deviation, of genetic origin, leading to an aberrant response to environmental influences. In the same way that, for example, individuals with xeroderma pigmentosum1- have a
special liability
to
light
exposure,
others may be particularly liable to ionizing radiation: this is certainly true at least for mice.1 Finally, it is also conceivable that radiation has ultimately caused selec¬ tive motor neuron degeneration as a manifestation of ischemie cell dam¬ age, the one pathogenesis proposed by Greenfield and Stark.- Both the predi¬ lection of ionizing radiation injury for the vascular endothelium, and the occasional selective loss of motor neurons following ischemia, have been confirmed. Indeed, a fashionable ex¬ planation for radiation myelopathy is vascular injury.14 ' Further, patholog¬ ical and clinical studies on the effects of aortic clamping (in treatment of coarctation),1'1 cardiac arrest,17 dissect¬ ing aneurysm of the aorta, and atheromatous emboli to the spinal cord" have contributed convincing data on selective anterior horn cell degenera¬ tion following ischemia. Although we can only contribute speculation on the question of the nature of cell damage in this syn¬ drome, it seems likely that it results from damage to the motor neuron as opposed to the nerve or nerve roots. ·
Dr Marchant Tulloh gave helpful comments the radiation scheme used in this
regarding
References 1. Regan TJ, Thomas JE, Colby MY: progressive radiation myelopathy.
Chronic JAMA
203:128-132, 1968. 2. Greenfield MM, Stark FM: Post-irradiation neuropathy. Am J Roentgenol Radium Ther Nucl Med 60:617-622, 1948. 3. Maier JG, Perry RH, Saylor W, et al: Radia-
tion myelitis of the dorsolumbar spinal cord. Radiology 93:153-160, 1969. 4. Stoll BA, Andrews JT: Radiation induced peripheral neuropathy. Br Med J 1:834-837, 1966. 5. Haymaker W, Lindgren M: Nerve disturbance following exposure to ionizing radiation, in
Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North Holland Publishing Co, 1970, vol 7, chap 14. 6. Kristensson K, Molin B, Sourander P: Delayed radiation lesions of the human spinal
cord. Acta Neuropathol 9:34-44, 1967. 7. Olkowski Z: Radioautographic studies on the 3H uridine incorporation into the motor neurons of the spinal cord of X-irradiated mice. Radiat Res 51:280-292, 1972. 8. Hirano A: Progress in the pathology of motor neuron diseases, in Zimmerman HM (ed): Progress in Neuropathology. New York, Grune & Stratton Inc, 1973, vol 2, chap 7. 9. Cremer NE, Oshiro LS, Norris FH Jr, et al: Cultures of tissues from patients with amyotrophic lateral sclerosis. Arch Neurol 29:331-333, 1973. 10. Campbell AMG, Williams ER, Pearce J: Late motor neuron degeneration following poliomyelitis. Neurology 19:1101-1106, 1969. 11. Upton AC, Cosgrove GE: Radiation induced leukemia, in Rich MA (ed): Experimental Leukemia. New York, Appleton-Century-Crofts,
1968, chap 5.
12. Haldane JBS: A search for incomplete sex linkage in man. Ann Hum Genet 7:28-57, 1936. 13. Bacq ZM, Alexander P: Fundamentals of Radiobiology. Oxford, England, Pergamon Press, 1961, chap 14. 14. Jellinger K, Sturm KW: Delayed radiation myelopathy in man. J Neurol Sci 14:389-408, 1971. 15. Palmer JJ: Radiation myelopathy. Brain 95:109-122, 1972. 16. Dodson WE, Landau WM: Motor neuron loss due to aortic clamping in repair of coarctation. Neurology 23:539-542, 1973. 17. Gilles FH, Nag D: Vulnerability of human spinal cord in transient cardiac arrest. Neurology 21:833-839, 1971. 18. Herrick MK, Mills PE Jr: Infarction of spinal cord. Arch Neurol 24:228-241, 1971.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 06/10/2015
Sadowsky, MD;
Ernest
Sachs, Jr, MD; Jos\l=e'\Ochoa, MD, PhD
\s=b\ We report an unusual case of selective lower motor neuron syndrome (MNS) complicating whole neuraxis radiation therapy. Only three well-documented similar cases have been found in a thorough review of the literature. The syndrome has a stereotyped time course and is self-$ limited. We discuss here possible pathogenetic mechanisms and their relationship to motor neuron disease. (Arch Neurol 33:786-787, 1976)
of radiation damage to cord have been recog¬ the rarest being lower motor
Four types spinal the
nized,1
neuron
syndrome (MNS), presumably
due to damage to anterior horn cells of the spinal cord. A recent example prompted review of possible pathogenetic mechanisms and their relation¬ ship to motor neuron disease (MND). REPORT OF A CASE
15-year-old girl with four-month history of frontal headache, vomiting, and diplopia was seen on June 7, 1973, as an outpatient at the Dartmouth-Hitchcock Medical Center. Findings on physical A
a
examination were as follows: bilateral 4 to 5 diopters of papilledema, vertical nystag¬ mus, left sixth nerve paresis, dysmetria and past pointing of the left hand, and ataxia of gait. Brain scan showed increased uptake in the midline inferior to the torcular. Angiography demonstrated hydrocephalus and a left cerebellar mass high under the tentorium. On June 11, a solid tumor (histologically malignant medulloblastoma) was removed from the vermis. Postoperatively, the patient was treated (June 20 to July 25, 1973) with a course of
Accepted
for publication June 15, 1976. From the Sections of Neurology and NeurosurMedical Center, gery, Dartmouth-Hitchcok Hanover, NH. Dr Sadowsky is now with the US Air Force Hospital, Wiesbaden, West Germany. Reprint requests to Division of Neurology, Dartmouth Medical School, Hanover, NH 03755
(Dr Ochoa).
Syndrome
cobalt 60 radiation to the skull (4,000 rads centrally), and a betatron-electron beam course of radiation to the spine. Using a scanning technique, a dose of 3,800 rads was delivered (July 18 to Aug 17) to the entire spine (4,763 rads at the surface) with fields 6 cm wide, scanning length 53.5 cm, and field length 3 cm. Chemotherapy was never administered. When seen 11 months after radiation she complained of progressive difficulty in walking due to weakness of leg muscles for the past three months. She denied involve¬ ment of the arms, sensory symptoms, pain, or sphincter disorder. On examination she had definite weakness and muscle wasting of the lower limbs, worse distally. Light touch, pinprick, vibration, and position sense and two-point discrimination thresh¬ olds were entirely normal. Ankle jerks were absent, but all other deep tendon reflexes were 1 +. Plantar responses were flexor. Spontaneous sweating of the feet was
present.
Electrophysiological
studies revealed normal motor conduction velocity and sural nerve action potentials, with bilateral advanced denervation of the extensor digitorum brevis, tibialis anterior, gastrocnemius, and vastus medialis muscles in order of severity. Cerebrospinal fluid cytologie findings were normal (two lymphocytes, one large mononuclear cell, and 111 RBCs per cubic millimeter); protein concentration was 200 mg/100 ml and a myelogram was normal. Other investigations included a normal blood cell count, B,, level, and sedimenta¬ tion rate. On neurological evaluation one month later the patient was just able to stand aided by a cane. Flaccid weakness and atrophy of foot intrinsics and peroneal muscles was obvious. Sensory examination gave normal findings. Ankle jerks were absent. The CSF protein level was 118 mg/ 100 ml and cytologie results were normal. Follow-up electromyography of leg muscles was unchanged, and EMG and results of nerve conduction studies in upper limbs were normal.
A right ascending lateral popliteal nerve action potential was normal one year after radiation (Aug 13, 1974). No new symptoms have developed and the patient's previous deficits have re¬ mained unchanged. She has consistently denied sensory symptoms.
COMMENT
This case seems identical in its clin¬ ical manifestations and evolution to the three cases reported by Greenfield and Stark." Thus, all four cases have consisted of a selective lower motor neuron disease confined to lower limb muscles, starting three to eight months after radiation of the spinal axis. All have followed a subacute and progressive, self-limited course. A relatively large series of cases pre¬ sumed to belong to this category was reported in 1969.:; No detailed clinical information was provided; it is diffi¬
cult, therefore, to subject that report to comparison. It is unlikely that the clinical mani¬ festations in our patient might have
been the consequence of a recurrence of the medulloblastoma, with seeding of the subarachnoid space, as the picture progressed without involve¬ ment of sensory or autonomie func¬ tion, without a cellular reaction in the CSF (on two occasions), and without development of pain. Further confi¬ dence was given by a normal myelogram and by the self-limited course of the process as assessed 16 months after the peak of weakness. From clinical and electrophysiological data it seems clear that the disease process is a result of selective injury to the lower motor neuron. The possibility of subclinical damage to the central branch of primary sensory neurons or the peripheral branch of the small dorsal root ganglia cells
Downloaded From: http://archneur.jamanetwork.com/ by a University of Arizona Health Sciences Library User on 06/10/2015
cannot be ruled out.
The primary site of injury within the lower motor neuron cannot be established with certainty. If ionizing radiation had caused the syndrome through direct damage of nerve roots, one would have expected combined motor and sensory manifestations.4 In the cases under discussion there was complete sparing of all clinical sensory modalities. Hence, primary involve¬ ment of the anterior horn cells is most likely, and not only by exclusion. Studies on the rat sciatic nerve point out that the CNS is more sensitive to ionizing radiation than the nerve trunk."1 Kristensson et al," in a patho¬ logical analysis of five cases of delayed radiation lesions in man, demonstrated well-preserved spinal roots adjacent to markedly destruc¬ tive lesions of the spinal cord. Further, there is good evidence to support susceptibility of anterior horn cells to ionizing radiation. Olkowski7 reported a decrease in uptake by motor neurons of tritiated uridine in total-body radiated rats, suggesting decreased RNA synthesis in these cells. Thus, damage to anterior horn cells follow¬ ing radiation appears to be con¬ firmed. Selective damage to lumbosacral motor neurons is unsurprising in Greenfield and Stark's patients, who received focal radiation. However, our patient received whole neuraxis radia¬ tion. We have no way of advancing into the questions of radiation field overlap vs regional selective cell
vulnerability. Another puzzle is
the
rarity of this
syndrome. At this stage one can only speculate: ionizing radiation may have activated a latent virus. This possi¬ bility can be entertained from evi¬ dence of herpes simplex virus activa¬ tion after modification of physical variables (fever, ultraviolet radiation,
surgery of the fifth cranial nerve in tic douleureux, etc). Extrapolation of an analogous mechanism for motor
disease has been disappoint¬ derived from on neuronal inclusions in MND,N and from unsuc¬ cessful attempts at isolating and transferring virus in such a condition, has been inconclusive.81' There are, however, fairly convincing documents on the development of a MND-like picture as a late sequel of poliovirus infection.1" Thus, even though MND (Charcot disease) may be unrelated to viral infection, it is quite possible that motor neurons may be circumstan¬ tially involved in a progressive disease process caused by a virus. As to the possible effect of ionizing radiation itself as an effective trigger for viral activation, there is the precedent of the virus-induced thymic lymphoma in mice." Following radiation this spe¬ cies develops a thymus neoplasm attributed to activation of a latent leukemia virus that can be isolated from the affected tissue. Altogether, it seems reasonable to regard virus activation as a viable hypothesis for postradiation MNS. Despite a nega¬ tive history for poliomyelitis, this virus or other viruses cannot be excluded in the case we have described here. neuron
ing. Indeed, evidence morphological studies
A second alternative to account for such rare selective degeneration of motor neurons would be some meta¬ bolic deviation, of genetic origin, leading to an aberrant response to environmental influences. In the same way that, for example, individuals with xeroderma pigmentosum1- have a
special liability
to
light
exposure,
others may be particularly liable to ionizing radiation: this is certainly true at least for mice.1 Finally, it is also conceivable that radiation has ultimately caused selec¬ tive motor neuron degeneration as a manifestation of ischemie cell dam¬ age, the one pathogenesis proposed by Greenfield and Stark.- Both the predi¬ lection of ionizing radiation injury for the vascular endothelium, and the occasional selective loss of motor neurons following ischemia, have been confirmed. Indeed, a fashionable ex¬ planation for radiation myelopathy is vascular injury.14 ' Further, patholog¬ ical and clinical studies on the effects of aortic clamping (in treatment of coarctation),1'1 cardiac arrest,17 dissect¬ ing aneurysm of the aorta, and atheromatous emboli to the spinal cord" have contributed convincing data on selective anterior horn cell degenera¬ tion following ischemia. Although we can only contribute speculation on the question of the nature of cell damage in this syn¬ drome, it seems likely that it results from damage to the motor neuron as opposed to the nerve or nerve roots. ·
Dr Marchant Tulloh gave helpful comments the radiation scheme used in this
regarding
References 1. Regan TJ, Thomas JE, Colby MY: progressive radiation myelopathy.
Chronic JAMA
203:128-132, 1968. 2. Greenfield MM, Stark FM: Post-irradiation neuropathy. Am J Roentgenol Radium Ther Nucl Med 60:617-622, 1948. 3. Maier JG, Perry RH, Saylor W, et al: Radia-
tion myelitis of the dorsolumbar spinal cord. Radiology 93:153-160, 1969. 4. Stoll BA, Andrews JT: Radiation induced peripheral neuropathy. Br Med J 1:834-837, 1966. 5. Haymaker W, Lindgren M: Nerve disturbance following exposure to ionizing radiation, in
Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North Holland Publishing Co, 1970, vol 7, chap 14. 6. Kristensson K, Molin B, Sourander P: Delayed radiation lesions of the human spinal
cord. Acta Neuropathol 9:34-44, 1967. 7. Olkowski Z: Radioautographic studies on the 3H uridine incorporation into the motor neurons of the spinal cord of X-irradiated mice. Radiat Res 51:280-292, 1972. 8. Hirano A: Progress in the pathology of motor neuron diseases, in Zimmerman HM (ed): Progress in Neuropathology. New York, Grune & Stratton Inc, 1973, vol 2, chap 7. 9. Cremer NE, Oshiro LS, Norris FH Jr, et al: Cultures of tissues from patients with amyotrophic lateral sclerosis. Arch Neurol 29:331-333, 1973. 10. Campbell AMG, Williams ER, Pearce J: Late motor neuron degeneration following poliomyelitis. Neurology 19:1101-1106, 1969. 11. Upton AC, Cosgrove GE: Radiation induced leukemia, in Rich MA (ed): Experimental Leukemia. New York, Appleton-Century-Crofts,
1968, chap 5.
12. Haldane JBS: A search for incomplete sex linkage in man. Ann Hum Genet 7:28-57, 1936. 13. Bacq ZM, Alexander P: Fundamentals of Radiobiology. Oxford, England, Pergamon Press, 1961, chap 14. 14. Jellinger K, Sturm KW: Delayed radiation myelopathy in man. J Neurol Sci 14:389-408, 1971. 15. Palmer JJ: Radiation myelopathy. Brain 95:109-122, 1972. 16. Dodson WE, Landau WM: Motor neuron loss due to aortic clamping in repair of coarctation. Neurology 23:539-542, 1973. 17. Gilles FH, Nag D: Vulnerability of human spinal cord in transient cardiac arrest. Neurology 21:833-839, 1971. 18. Herrick MK, Mills PE Jr: Infarction of spinal cord. Arch Neurol 24:228-241, 1971.
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