Neuropathologic Findings in a Patient With Neuroblastoma and Myoclonic Encephalopathy Fred A. Ziter, MD; Patrick F.
Bray, MD; Pasquale
\s=b\ The neuropathological basis for myoclonic encephalopathy associated with neuroblastoma has never been demonstrated. In our 6-year-old patient, the brain changes were restricted to the cerebellum and consisted of demyelination, gliosis, and loss of Purkinje's cells. (Arch Neurol 36:51, 1979)
"M" ine years ago, the association -^ between neuroblastoma and
myoclonic encephalopathy with opsoclonus was first noted" and since then has been well described.J While this neurological complication of neuro¬ blastoma is recognized as a remote effect of the neoplasm, the pathologi¬ cal basis underlying the encephalopa¬ thy has not been demonstrated. We describe the morphologic brain changes in a child with myoclonic encephalopathy who later died from metastatic neuroblastoma. REPORT OF A CASE The patient was normal until age 22 months when he developed "shakiness" of the hands, trunk, and head. During the ensuing month, he lost his motor and speech abilities and became unable to feed himself. Examination disclosed irritability, inability to walk even with assistance, marked ataxia of trunk and extremities, and titubation of his head. The ocular findings were typical of opsoclonus with
rapid "shimmering"
or
"fluttering" conju¬
movements. After six months, steady improvement of motor ability was noted, but he continued to exhibit intellec¬ tual impairment. At 5 years of age, he had a slight exacerbation of the ataxia, and ten
gate eye
months later a mediastinal mass was discovered. Exploratory thoracotomy dis¬ closed a ganglioneuroblastoma. Because of widespread métastases he was treated with cobalt 60 radiation therapy (2,957 rads), and later with cyclophosphamide (Cytoxan), vincristine, and actinomycin D. After developing widespread bony metas-
Accepted for publication Jan 9, 1978. From the Departments of Neurology, Pediatrics, and Pathology, University of Utah College of Medicine, Salt Lake City. Dr Cancilla is now with the Department of Neuropathology, University of Iowa College of Medicine, Iowa City. Reprint requests to Department of Neurology, University of Utah College of Medicine, 3E512 Medical Center, 50 N Medical Dr, Salt Lake City, UT 84112 (Dr Ziter).
A.
Cancilla,
MD
tases, he died at the age of 6 years and 9 months. The patient had received no radia¬ tion therapy to the head or neck.
Neuropathological Findings The brain weighed 1,240 g and was fixed in 10% neutral formaldehyde. The outer surface of the dura was covered with several nodules of granular and hemorrhagic tissue. A similar lesion measuring 1 cm in diameter was present on the inner aspect of the dura. The meninges were thin and glistening as they covered the convex¬ ity and base of the brain. The convolutional pattern was normal. The arteries of the circle of Willis were thin and transparent. There was no evidence of increased intra¬ cranial pressure. Coronal sections of the cerebrum showed an intact cortical ribbon, normal-appearing centrum semiovale and basal ganglia, pale substantia nigra, and normal-sized lateral ventricles. The brain stem was cut in a horizontal plane at 0.5-cm intervals and was grossly normal. The cere¬ bellum was firm and covered by thin meninges. The folia were grossly normal without evidence of atrophy. The cerebel¬ lum was sectioned in the midsagittal plane, and the exposed vermis appeared to be normal. Parasagittal sections through the cerebellar peduncles, dentate nuclei, and cerebellar folia were normal. Sections of cerebrum, basal ganglia, brain stem, cerebellar peduncles, and cere¬ bellum, including the dentate nuclei, were examined with hematoxylin-eosin, Nissl, Holzer, Weil, Bodian, and Bielschowsky stains. Microscopic abnormalities were lim¬ ited to the cerebellum. The cerebellar folia were well developed and showed no evidence of atrophy. The Purkinje's cells were distributed at the junction of the molecular and granular layers. Occasional¬ ly there was a loss of cells, and this loss was supported by the demonstration of "empty baskets" with the silver stain. This dropout of Purkinje's cells was patchy and not extensive, and it was best demonstrated by special staining procedures. The neurons in the dentate nuclei appeared normal. The myelin stain and, to a lesser extent, the silver and hematoxylin-eosin stains dis¬ closed pallor in the hilum of the dentate and perinuilear mantle. A mild increase in astrocytes, some of which had abnormal forms, was seen in the same area. Axons appeared to be slightly irregular and beaded, but otherwise were uniformly distributed. A stain for fat showed occa¬ sional foci of perivascular fat-laden cells in these areas. Histological sections from the nodular areas in the dura showed neuro¬ blastoma.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/12/2015
COMMENT
In
our
patient, who died of a neuro¬
blastoma, the neuropathological ab¬
normalities were limited to the cere¬ bellum. They consisted of demyelina¬ tion and gliosis of the white matter around and within the dentate nuclei and occasional loss of Purkinje's cells. In reviewing the literature, one finds a number of scattered case reports of patients with opsoclonus who had autopsy studies of the brain. Some of these patients, who exhibited the motor neurologic deficit, died from the associated malignancies, none of which was a neuroblastoma. These studies of patients who had tumors have shown abnormalities in the nervous system that varied some¬ what, but the most consistent findings have been loss of Purkinje's cells in the cerebellar cortex and demyelina¬ tion with gliosis.'"" Thus, one can conclude that despite differences in age and type of underlying malignancy, patients who develop opsoclonus as a remote effect of neoplasm including neuroblastoma tend to show a similar pattern of
damage—cerebellar demyelination, gliosis, and Purkinje's cell loss.
This investigation was supported in part by training grants 2T1-NB 5503 and 5T1-NB 5309
from the National Institutes of Health, grant 3401 from the Utah State Division of Health, by the Children's Cancer Study Group A, National Cancer Institute, and by the Eleanor Roosevelt Cancer Research Foundation.
References 1. Solomon GE, Chutorian AM: Opsoclonus and occult neuroblastoma. N Engl J Med 279:475-477, 1968. 2. Senelick RC, Bray PF, Lahey ME, et al: Neuroblastoma and myoclonic encephalopathy. J Pediatr Surg 8:623-632, 1973. 3. Alessi D: Lesioni parenchimatose del cervelleto da carcinoma uterino (gliosi carcinotossica). Riv Patol Nerv Ment 55:148, 1940. 4. Ellenberger C, Campa, JF, Netsky MG: Opsoclonus and parenchymatous degeneration of the cerebellum. Neurology 18:1041-1046, 1968. 5. Brain WR, Daniel PM, Grenfield JG: Subacute cortical cerebellar degeneration and its relation to carcinoma. J Neurol Neurosurg Psychiatry 14:59-75, 1951. 6. Parker HL, Kernohan JW: Parenchymatous cortical cerebellar atrophy (chronic atrophy of Purkinje's cells). Brain 56:191-212, 1933.
Bray, MD; Pasquale
\s=b\ The neuropathological basis for myoclonic encephalopathy associated with neuroblastoma has never been demonstrated. In our 6-year-old patient, the brain changes were restricted to the cerebellum and consisted of demyelination, gliosis, and loss of Purkinje's cells. (Arch Neurol 36:51, 1979)
"M" ine years ago, the association -^ between neuroblastoma and
myoclonic encephalopathy with opsoclonus was first noted" and since then has been well described.J While this neurological complication of neuro¬ blastoma is recognized as a remote effect of the neoplasm, the pathologi¬ cal basis underlying the encephalopa¬ thy has not been demonstrated. We describe the morphologic brain changes in a child with myoclonic encephalopathy who later died from metastatic neuroblastoma. REPORT OF A CASE The patient was normal until age 22 months when he developed "shakiness" of the hands, trunk, and head. During the ensuing month, he lost his motor and speech abilities and became unable to feed himself. Examination disclosed irritability, inability to walk even with assistance, marked ataxia of trunk and extremities, and titubation of his head. The ocular findings were typical of opsoclonus with
rapid "shimmering"
or
"fluttering" conju¬
movements. After six months, steady improvement of motor ability was noted, but he continued to exhibit intellec¬ tual impairment. At 5 years of age, he had a slight exacerbation of the ataxia, and ten
gate eye
months later a mediastinal mass was discovered. Exploratory thoracotomy dis¬ closed a ganglioneuroblastoma. Because of widespread métastases he was treated with cobalt 60 radiation therapy (2,957 rads), and later with cyclophosphamide (Cytoxan), vincristine, and actinomycin D. After developing widespread bony metas-
Accepted for publication Jan 9, 1978. From the Departments of Neurology, Pediatrics, and Pathology, University of Utah College of Medicine, Salt Lake City. Dr Cancilla is now with the Department of Neuropathology, University of Iowa College of Medicine, Iowa City. Reprint requests to Department of Neurology, University of Utah College of Medicine, 3E512 Medical Center, 50 N Medical Dr, Salt Lake City, UT 84112 (Dr Ziter).
A.
Cancilla,
MD
tases, he died at the age of 6 years and 9 months. The patient had received no radia¬ tion therapy to the head or neck.
Neuropathological Findings The brain weighed 1,240 g and was fixed in 10% neutral formaldehyde. The outer surface of the dura was covered with several nodules of granular and hemorrhagic tissue. A similar lesion measuring 1 cm in diameter was present on the inner aspect of the dura. The meninges were thin and glistening as they covered the convex¬ ity and base of the brain. The convolutional pattern was normal. The arteries of the circle of Willis were thin and transparent. There was no evidence of increased intra¬ cranial pressure. Coronal sections of the cerebrum showed an intact cortical ribbon, normal-appearing centrum semiovale and basal ganglia, pale substantia nigra, and normal-sized lateral ventricles. The brain stem was cut in a horizontal plane at 0.5-cm intervals and was grossly normal. The cere¬ bellum was firm and covered by thin meninges. The folia were grossly normal without evidence of atrophy. The cerebel¬ lum was sectioned in the midsagittal plane, and the exposed vermis appeared to be normal. Parasagittal sections through the cerebellar peduncles, dentate nuclei, and cerebellar folia were normal. Sections of cerebrum, basal ganglia, brain stem, cerebellar peduncles, and cere¬ bellum, including the dentate nuclei, were examined with hematoxylin-eosin, Nissl, Holzer, Weil, Bodian, and Bielschowsky stains. Microscopic abnormalities were lim¬ ited to the cerebellum. The cerebellar folia were well developed and showed no evidence of atrophy. The Purkinje's cells were distributed at the junction of the molecular and granular layers. Occasional¬ ly there was a loss of cells, and this loss was supported by the demonstration of "empty baskets" with the silver stain. This dropout of Purkinje's cells was patchy and not extensive, and it was best demonstrated by special staining procedures. The neurons in the dentate nuclei appeared normal. The myelin stain and, to a lesser extent, the silver and hematoxylin-eosin stains dis¬ closed pallor in the hilum of the dentate and perinuilear mantle. A mild increase in astrocytes, some of which had abnormal forms, was seen in the same area. Axons appeared to be slightly irregular and beaded, but otherwise were uniformly distributed. A stain for fat showed occa¬ sional foci of perivascular fat-laden cells in these areas. Histological sections from the nodular areas in the dura showed neuro¬ blastoma.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/12/2015
COMMENT
In
our
patient, who died of a neuro¬
blastoma, the neuropathological ab¬
normalities were limited to the cere¬ bellum. They consisted of demyelina¬ tion and gliosis of the white matter around and within the dentate nuclei and occasional loss of Purkinje's cells. In reviewing the literature, one finds a number of scattered case reports of patients with opsoclonus who had autopsy studies of the brain. Some of these patients, who exhibited the motor neurologic deficit, died from the associated malignancies, none of which was a neuroblastoma. These studies of patients who had tumors have shown abnormalities in the nervous system that varied some¬ what, but the most consistent findings have been loss of Purkinje's cells in the cerebellar cortex and demyelina¬ tion with gliosis.'"" Thus, one can conclude that despite differences in age and type of underlying malignancy, patients who develop opsoclonus as a remote effect of neoplasm including neuroblastoma tend to show a similar pattern of
damage—cerebellar demyelination, gliosis, and Purkinje's cell loss.
This investigation was supported in part by training grants 2T1-NB 5503 and 5T1-NB 5309
from the National Institutes of Health, grant 3401 from the Utah State Division of Health, by the Children's Cancer Study Group A, National Cancer Institute, and by the Eleanor Roosevelt Cancer Research Foundation.
References 1. Solomon GE, Chutorian AM: Opsoclonus and occult neuroblastoma. N Engl J Med 279:475-477, 1968. 2. Senelick RC, Bray PF, Lahey ME, et al: Neuroblastoma and myoclonic encephalopathy. J Pediatr Surg 8:623-632, 1973. 3. Alessi D: Lesioni parenchimatose del cervelleto da carcinoma uterino (gliosi carcinotossica). Riv Patol Nerv Ment 55:148, 1940. 4. Ellenberger C, Campa, JF, Netsky MG: Opsoclonus and parenchymatous degeneration of the cerebellum. Neurology 18:1041-1046, 1968. 5. Brain WR, Daniel PM, Grenfield JG: Subacute cortical cerebellar degeneration and its relation to carcinoma. J Neurol Neurosurg Psychiatry 14:59-75, 1951. 6. Parker HL, Kernohan JW: Parenchymatous cortical cerebellar atrophy (chronic atrophy of Purkinje's cells). Brain 56:191-212, 1933.
