Journal of Neuro-Ophthalmology, December 1986, Volume 6, Issue 4

Neuropathologic findings in idiopathic opsoclonus and myoclonus. Their similarity to those in paraneoplastic cerebellar cortical degeneration.

The neuropathologic findings in an idiopathic case of the opsoclonus/myoclonus syndrome are reported. Although neurologic dysfunction may have been more widespread, structural lesions were limited to the cerebellum and inferior olives. Severe depletion of Purkinje cells with preservation of granular cells was evident throughout the neo- and paleocerebellum; however, groups of Purkinje cells were preserved in the archicerebellum. No abnormalities were evident in the paramedian pontine reticular formation of the caudal pons. Inflammation and evidence of anoxic damage were absent. These changes are very similar to those described in paraneoplastic cerebellar cortical degeneration.

1(;) 1986 Raven Press, New York Neuropathologic Findings in Idiopathic Opsoclonus and Myoclonus Their Similarity to Those in Paraneoplastic Cerebellar Cortical Degeneration Stephen Hunter, M.D. and Carol Kooistra, M.D. The neuropathologic findings in an idiopathic case of the opsoclonus/myoclonus syndrome are reported. Al­though neurologic dysfunction may have been more widespread, structural lesions were limited to the cere­bellum and inferior olives. Severe depletion of Purkinle cells with preservation of granular cells was evident throughout the neo- and paleocerebellum; however, groups of Purkinje cells were preserved in the archicere­bellum. No abnormalities were evident in the parame­dian pontine reticular formation of the caudal pons. In­flammation and evidence of anoxic damage were ab­sent. These changes are very similar to those described in paraneoplastic cerebellar cortical degeneration. Key Words: Cerebellar degeneration-Myoclonus­Neuropathology - 0psoclonus. From tilt' Division of Neuropatholo~y and Department of Neurology, University of Florida College of Medicine, Gaines­ville, Florida. Address correspondence and reprint requests to Stephen Hunter, M.D., Dl'partment of Pathology, Box )-275 ).H.M.H.C., Gainesville, FL 32610, US-A. 236 Opsoclonus is the involuntary generation of random saccadic eye movements. Although the burst and pause cells that initiate and maintain saccadic eye movements are located in the para­median pontine reticular formation, the saccadic system is influenced by numerous other supranu­clear centers within the central nervous system. These centers include the frontal eye fields, pari­etal cortex, thalamus, superior colliculus, basal ganglia and cerebellum (1). In several neuropathO­logic studies the anatomic site responsible for the production of opsoclonus appears to be the cere­bellum; however, in other cases the brainstem or thalamus have been implicated (2,3). Usually occurring in association with myo­clonus, opsoclonus is paraneoplastic, encephalitic, or idiopathic in the large majority of cases (4,5). Several neuropathologic descriptions of paraneo­plastic (Table 1) and encephalitic (6,7) opsoclonus/ myoclonus are available; however, the neuropath­ologic findings in idiopathic cases have not pre­viously been documented. The present report concerns the neuropathologic findings in an idio­pathic case of opsoclonus/myoclonus. Structural lesions in this case were most prominent in the cerebellum and were very similar to lesions de­scribed in paraneoplastic cerebellar cortical degen­eration. CASE REPORT Approximately 3 months prior to her death, an obese 58-year-old white woman was admitted to her local hospital with a lO-week history of daily temperature spikes to 102°F. Her past medical his­tory included angina and migraine headaches. She was housebound due to severe seronegative rheu- IDIOPATHIC OPSOCLONUS AND MYOCLONUS 237 TABLE 1. Neuropathologic findings in paraneoplastic opsoclonuslmyoclonus 1 Triflamizole is an experimental anti-inflammatory agent which according to a representative of the DuPont Company, has n~t as of the present time been associated with any neuro­logic side effects. matoid arthritis. Long-term medications included Nitrodur, Procardia, Subitrate, Inderal, and Triflam­izole.! Upon admission, all medications were discontinued with no apparent effect on the sub­sequent clinical course of her condition. Initially no symptoms other than fever were apparent, and no cause for fever was found. The patient was noted to be confused, and over the next week she became agitated and tremulous with myoclonus of the face and upper extremities. Subsequently, she lapsed into a rigid, bradykinetic state. Lumbar puncture and computed tomography (CT) scan disclosed no abnormalities. Diffuse symmetric slowing was present on electroencephalogram (EEG), Haldol and Benadryl were administered, and no significant therapeutic response to these medications was noted. Two months after admis­sion the patient was discharged. One week later she returned to the hospital after the abrupt onset of fever to 106°F and hypoten­sion. Neurologic examination disclosed marked Tumor type and location Adenocarcinoma of uterus (18) Uterus (19) Lung (20) Breast (11) Oat cell carcinoma of lung (21) Neuroblastoma Case 1 (17) Case 2 (22) Case 3 (23) Neuropathology Loss of Purkinje cells; peridentatal demyelination; cerebral and cerebellar gliosis. Minimal lymphocytic perivascular infiltrate of brainstem. Diffuse loss of Purkinje cells and inferior nucleus olivary neurons; gliosis in dentate cerebellar white matter, pons, inferior olives, and superior cerebellar peduncles. Complete loss of PurkinJe cells; moderate loss of cerebellar granular cells; gliosis in cerebellar molecular layer, white matter and dentate nucleus; peridentatal demyelination; lymphocytic perivascular infiltrate and microglial nodules within mesencephalon, diencephalon, and cerebellar meninges. Minimal perivascular lymphocytic infiltrates within brainstem and cerebellar meninges. No abnormalities. Mild peridentatal demyelination. Patchy loss of Purkinje cells. Peridentatal demyelination. stimulus-sensitive myoclonus of the lids, eyes, limbs, and trunk, She could not speak but was able to follow simple commands, nod to mean yes and shake her head to mean no, open and close her eyes, raise her arm, and grunt, Cranial nerve examination disclosed normal visual fields and mid-size reactive pupils. Irregular, conjugate eye movements were present in all directions of gaze and appeared to be exacerbated by attempted vol­untary gaze and oculocephalic maneuver. Occur­ring in clusters, these eye movements appeared to be continuous without visually detectable intersac­cadic intervals. Lid blinking, which at times be­came so prominent as to mimic blepharospasm, was also present. Voluntary and oculocephalic eye movements were demonstrable in all directions except upgaze. Examination of the remaining cra­nial nerves showed no other abnormalities with the exception of continuous irregular movements of the mouth, lips and tongue. Results of motor examination of the extremities were difficult to as­sess, but muscle tonus was flaccid throughout and foot drop appeared to be present on the left side. Deep tendon reflexes were symmetric and graded 1-2 +. Plantar responses were bilaterally equiv­ocal. A mild normocytic anemia was present. White blood cell count, liver function, and results of routine metabolic tests were normal. The eryth­rocyte sedimentation rate was 15. CT scan of the head and abdomen, lumbar puncture (including studies for cryptococcus and viral cultures), nu­merous blood cultures, and urine screen for lead, thallium, mercury and drugs likewise disclosed no abnormalities, Urinary copper was elevated 10- to IS-fold and urinary vanillyl-mandelic acid levels were mildly elevated at 8.0 ng/ml. Ceruloplasmin, cerebrospinal fluid (CSF) and serum Venereal Dis­ease Research Laboratories tests (VDRLs), CSF IgG, monospot, cold agglutinins, acute and com'a­lescent titers for cytomegalovirus (CMV), herpes virus (HSV), Epstein-Barr virus (EBV), and toxo­plasmosis were normal. Evaluation for neoplasia, including a chest x-ray, chest and abdominal CT scans, urinalysis, bronchoscopv, and stool guaiacs, was negative. EEG demonstrated a gener­alized slowing and brainskm auditof\' l:'\'oked re­sponses were normal. The p,ltll'l)t .., m\'th:lllI)US was partially contwlled Ill) stl'wlds, thi,1Tl1l11e, and valproic acid. She continued to I'XpCril'IKl' kmpl'rature eleva­tions without obvious C1USC ,1nd \\'ilhout response to either antibiotics llrl\il'Jllll I !":,,,I'I1'']',ll l11l'd ical condition deterillrakd ,1nd shl' d 'c'd ,'p~",. mately 1 month after tIlL' sccond "dllllsslon 238 S. HUNTER AND C. KOOISTRA NECROPSY FINDINGS Postmortem, ,1 carl'ful search of the systemic organs failed to disclose eitlwr a malignant neo­plasm or evidl'nCl' llf infection. ;\ benign 4-cm serous cvstadenllm,l of the Il'ft llvary and 80'j" atheroscierotic stenosis of the ll'ft anterior de­scending coronary artery were the only notable ,1bnormalities. The central nervous system appeared normal on gross examination. Microscopically, pathologic changes were limited to the cerebellum and In­ferior olives. Severe depletion of Purkinje cells was accompanied by increased numbers of Berg­mann's astroglia in 12 sections taken from all major regions of the cerebellum. In most areas, in­cluding the lateral hemispheres and anterior vermis, surviving Purkinje cells were rare and oc­curred singly (Fig. 1). In the dorsal vermis a few small groups of Purkinje cells remained. Only in the floccular and nodular lobes were considerable numbers of Purkinje cells present, and in these areas surviving Purkinje cells tended to occur in groups (Fig. 2). The granular cell layer disclosed no definite abnormalities in any of the sections ex­amined. Glial nuclei were more numerous in the dentate nucleus, possibly in reaction to degener­ating terminal axons of Purkinje cells; however, dentate neurons were not significantly decreased in number. Numerous sections of other areas of the central nervous system disclosed only moder­ately severe neuronal loss and acute neuronal death in the inferior olivary nuclei. The parame­dian pontine reticular formation, at the level of the nucleus of cranial nerve IV, was somewhat spongy and possibly slightly hypercellular but disclosed no definite structural abnormalities. Although pos­sibly significant, mild sponginess occurring in s~v­eral brainstem regions was interpreted as bemg consistent with artifact. Inflammatory infiltration was absent in all regions of the central nervous system. Postmortem assays of cerebellum, basal ganglia, cerebral cortex and liver disclosed mod­erate elevations of tissue zinc but normal copper levels. Tissue fixed for electron microscopy was not available. DISCUSSION The syndrome of opsoclonus/myoclonus has been ass'ociated with a wide variety of clinical con- . '. /'" ..... ;; I • • " • If., .. I Clill Nellro-0l'hthallllol, Vol. b, No.4, 1986 .,. -... ,.. ~ . ). ;'" . • I • ' ,- IDIOPATHIC OPSOCLONUS AND MYOCLONUS .. 239 ditions (Table 2). In the present case, however, none of these disorders could be implicated by ei­ther clinical or postmortem investigation. The medications taken by this patient have not been previously associated with the opsoclonus/myoc­lonus syndrome, and assays for heavy metals, drugs, and toxins were negative. Neither encepha­litis nor diffuse cerebral anoxia were present on neuropathological examination; and chronic al­cohol abuse is not supported by historical or histo­logical evidence. Finally, an extensive search for neoplasia revealed only a small benign serous cystadenoma of the ovary. This last finding is of some interest in view of the association between malignant ovarian tumors and subacute cerebellar degeneration (8,9); however, a link between be­nign tumors and para neoplastic degeneration of the central nervous system has not been estab­lished. In spite of the absence of malignancy, the neu­ropathologic findings in this case were very sim­ilar to findings that have been described in either paraneoplastic cerebellar cortical degeneration (10) or in some cases of the paraneoplastic opso­clonus/ myoclonus syndrome (11,20). As was true in the present case, the predominate change in these syndromes is a selective Purkinje cell loss, of variable severity, with relative or complete sparing of the granular cell layer. In contrast to alcoholic cerebellar degeneration, the neocerebellum and paleocerebellum are diffusely and approximately equally affected. The inferior olives and dentate nuclei may disclose variable and less severe patho­logic abnormalities. Encephalitic changes, i.e., perivascular lymphocytic infiltration and micro­glial nodules, are usually present but may be ab­sent. When present, intlammation is not limited to the cerebellum. Although clinically distinct, paraneoplastic op­soclonus/ myoclonus and paraneoplastic cerebeIlar cortical degeneration are very similar pathologi­cally (10,11) and share virtually all of the morpho­logic features listed above. The presence of these featurl's in the opsoclonus/myoclonus syndrome, however, appears to be variable. Individual cases of this syndrome reportedly lack anyone, or even all, of these neuropathologic changes (Table 1). Although usuaIly paraneoplastic, both of these syndromes may also occur in the absence of neoplasia. This occurrence is well described in cerebellar cortical degeneration (10) and is documented here in the opsoclonus/myoclonus f U," N,,"ft>·(ll'lttlla'1/I0'. Vol. 6. No.4. 1986 NO ~. ffUNTU, AND C. KOOISTRA TABLE 2. Etiologic categories of the opsoclonus/myoclonus syndrome syndrome. Interestingly, anti-Purkinje cell anti­bodies have been detected in some cases of cere­bellar cortical degeneration (12,13) and in a single case of idiopathic opsoclonus/myoclonus (14). The only possible morphologic difference be­tween our case and cases of cerebellar cortical de­generation consisted of relative sparing of groups of Purkinje cells in the floccular and nodular lobes, a cerebellar region which is intimately involved in the control of saccadic eye movements. In contrast to what occurred in the present case, the floccular nodular lobe in subacute cerebellar degeneration may be involved equally with the neo- and paleo­cerebellum (15). This finding raises the possibility that clinical differences between the syndromes of opsoclonus/myoclonus and subacute cerebellar degeneration may be related, at least in some cases, to selective (possibly antibody-mediated) destruction of functionally distinct subsets of Pur­kinje cells, Unfortunately, the floccular nodular lobe has not been described in previous neuro­pathologic investigations of 0psoclonus/myoc­lonus. Alternatively, the opsoclonus/myoclonus syn­drome may be caused by functional disturbances that are not associated with structural abnormali­ties (16). This occurrence is well known in para­neoplastic syndromes. In the Eaton- Lambert syn­drome, for example, antibody-mediated lesions of the pre-synaptic neuromuscular junction are not Idiopathlc:parainfectlous Paraneoplastic Encephalitis Drug toxicity Vascular accidents Degenerative diseases Other Oat cell (21,24), adenocarcinoma (9,11,18), poorly differentiated carcinoma (20), squamous cell carcinoma (25), neuroblastoma (17,22,23,26) Agent unknown (27,29), viral (4,5,28,30-32), bacterial (32­35) Amitriptylene (35), Lithium­Haldol (36), Chlordecone (37), Thallium (38), Toluene (39), DDT (40) Thalamic hemorrhage (2), vertebral basilar insufficiency (41) Friedrich's ataxia (6), LaFora body disease (42), Hallervorden-Spatz disease (43) Primary brain tumor (3), multiple sclerosis (44,45), normal neonates (46), congenital anomalies (47), hydrocephalus (48), hyperosmolar coma (49) visible by ordinary light-microscopic techniques, In the opsoclonus/myoclonus syndrome, this lack of structural abnormality is supported by the re­port of a case associated with neuroblastoma in which no neuropathologic abnormalities were found at autopsy (17), In this case and in the other cases listed in Table 1, however, it should be noted that systematic investigation of various sub­regions within the cerebellum and of other areas involved in the control of saccadic eye movements was not performed, In the present case, pathologic changes were found throughout the cerebellum but were absent in other brain regions involved in the control of saccadic eye movements, Although a patchy brainstem spongy change might prove to be sig­nificant if identified in future cases, no definite structural abnormalities could be identified in the paramedian pontine reticular formation, The neuropathologic study presented here, together with other published case reports, strongly sup­ports the possibility that the cerebellum plays a primary role in at least some cases of the opso­clonus/ myoclonus syndrome. 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