Paraneoplastic Opsoclonus; Downbeat Nystagmus

Downbeat Nystagmus; Paraneoplastic OpsoclonusPowerPoint Presentation: Neuroblastoma: http://library.med.utah.edu/NOVEL/Wray/PPT/Neuroblastoma.ppt Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical SchoolAtaxiaThe patient is Case 27-1995 Case Records of the Massachusetts General Hospital (New Eng. J Medicine 1995, 333:579-586). The discusser was Dr. Elizabeth Engle, Associate Professor of Neurology, Harvard Medical School. The baby girl was born after a 30 week gestation, with a birth weight of 1.25 kg. The mother was reported to have abused alcohol and other drugs, especially medications for pain, throughout gestation. After delivery the baby was transferred to the Mass General Hospital, intubated for approximately 1 week and discharged at 3 ½ months. Her early developmental milestones were delayed; her first steps were at 21 months, and she walked in a stable fashion at 24 months. Bilateral esotropia was operated on at 21 months. She received the appropriate immunizations and was treated for otitis media on two occasions. At 26 months she had an upper respiratory tract infection with a temperature of 38.9oC followed by conjunctivitis. Two weeks later she began to fall up to 5 times daily and when she attempted to take 1 or 2 steps she appeared unsteady. Eight days later she was observed to walk "like a drunk" and held onto furniture for support. Eleven days later she could not walk without assistance. In addition her head and body shook, her upper extremities trembled, especially when she was reaching for things. Her father noted the tremor was present when she was sitting. She refused to eat solid food. Initially the pediatrician suspected a diagnosis of parainfectious acute cerebellar ataxia of childhood. Her symptoms, however, progressed and she was brought to the Emergency Room and admitted. Family history was negative for neurologic disease. Her sister, 5 years old, was alive and well. Past History negative for head trauma, exposure to toxic substances, headache, nausea, vomiting, lethargy, visual symptoms or changes in voice or speech. On admission she was afebrile. Blood pressure 100/60 mm Hg. Her weight was 12.2 kg (50th percentile), height 89 cm (75th percentile), and the head circumference 49 cm (75th percentile). On neurologic examination she was alert, pointed to body parts, and sang a children's song intelligibly. Cranial-nerve function was normal apart from mild bilateral esotropia, with full extraocular movements and no nystagmus. Muscle tone was diminished, muscle strength was normal and symmetric. The deep tendon reflexes were +++ in the right upper extremity and ++ in the left, plantar responses flexor. Axial and appendicular ataxia, with dysmetria, was noted. The child was able to take one or two steps unsteadily but required support and promptly lost her balance. Sensory examination normal. Investigations: The workup was directed towards detection of a neuroblastoma. Hematological studies: A complete blood count, and chemistries for urea nitrogen, creatinine, glucose, calcium, phosphorus, magnesium, sodium and potassium were all normal. Urine tests: Negative for toxic drugs. Chest x-ray normal. Lumbar puncture showed: Clear, colorless cerebrospinal fluid with 4 red cells per cubic millimeter No white cells Negative cytology Glucose level 48 mg/dl (2.7 µmol per liter) Protein 29 mg/dl Brain MRI: Revealed a T2 weighted hyperintense signal in the forceps major regions that extended into the centrum semiovale bilaterally in the areas of the terminal myelination zones. No mass or abnormal enhancement was seen. Discharge: The child was discharged on the third hospital day. No medications were prescribed. Four weeks after discharge, she began to vomit one to five times daily and her father observed intermittent, rapid, "jiggling" movements of her eyes. Readmission to MGH at the age of 29 months. Neurological examination: She was alert and spoke only a few words unintelligibly, without dysarthria. The fundi showed normal optic discs and retinas, and the pupils were equal and constricted equally in response to light. Visual fields were full in response to a threat. The extraocular movements were intact. Vertical nystagmus was noted on upward and downward gaze. On several occasions she had rapid, irregular multidirectional saccadic eye movements diagnostic for opsoclonus. The remaining cranial nerves were intact. She also had: • Gross axial hypotonia with slightly increased tone in the lower extremities • An intention tremor in both upper extremities • Appendicular and trunkal ataxia with titubation. • Muscle strength was intact with deep tendon reflexes +++ in the lower extremities with 2 beats of ankle clonus and ++ in the upper extremities. The plantar responses were equivocal. Ataxia was, however, the primary symptom. The child could only sit unsupported in the tripod position for two to three seconds before losing her balance. With both hands held she could pull herself up, stand, and take a few steps but was very unsteady. A repeat brain MRI showed no change. On the second hospital day the abnormal eye movements became more pronounced and brief twitching movements of the fingers were observed and interpreted as myoclonus. Dr. Elizabeth Engle noted that the child's developmental delay was unrelated to the present illness since the topographic pattern of the white matter changes on MRI was characteristic of periventricular leukomalacia, which is commonly seen in premature children. Differential Diagnosis: 1. Acute cerebellar ataxia of childhood 2. Acute disseminated encephalomyelitis 3. Opsoclonus-myoclonus-ataxia syndrome Acute cerebellar ataxia is the most common parainfectious syndrome in children with a peak frequency in the third year of life. The syndrome is one of a spectrum of disorders assumed to be an immune-mediated reaction to viral infections outside the nervous system. Twenty-six percent of cases are associated with chickenpox, 52% with other presumably viral illnesses and 3% with immunizations. Pleocytosis is reported in 50% of cases. The onset of ataxia is rapid in these cases, developing over a period of hours, and becoming maximum within a day or two. Recovery usually begins within days after the onset. Three quarters of the patients have a full recovery within 8 months. Acute disseminated encephalomyelitis is a rare parainfectious syndrome with, typically, a more diffuse encephalitis with meningism, altered mental status and on MRI large asymmetric scattered foci of demyelination is present in the subcortical white matter. The opsoclonus-myoclonus-ataxia syndrome may be parainfectious or paraneoplastic and every child who presents with a prodromal illness and pleocytosis requires a thorough search for a neuroblastoma. In children with the parainfectious etiology, the child is usually over 3 years of age and appears systemically ill on presentation with pleocytosis and occasional fever. Opsoclonus develops over a period of hours reaching a peak within several days and, in most cases, the syndrome completely resolves. The paraneoplastic opsoclonus-myoclonus-ataxia syndrome occurs in approximately 2 to 3% of children with neuroblastoma. There is only one report of the syndrome occurring in a child with a hepatoblastoma. Investigations: Abdominal ultrasound: The initial diagnostic procedure in this child was an abdominal ultrasound study which showed a heterogeneous mass just above the left kidney. (Figure1) Abdominal CT: CT scan confirmed the presence of a left adrenal mass, 3.5 cm. in diameter. (Figure 2) Diagnosis: Neuroblastoma. Surgery: Surgical exploration disclosed an encapsulated left adrenal mass. A left adrenalectomy was performed, and the left para-aortic tissue was excised, although no lymphadenopathy was evident in it. A frozen section revealed a ganglioneuroblastoma. Bone marrow biopsy: Under the same anesthesia, Hematology/Oncology performed a bone marrow biopsy which was negative. Urine studies: Pre-operative screening tests for vanilmandelic and homovanillic acid levels were negative. Paraneoplastic markers: No anti-Ri antibodies were detected in the serum. Treatment: The administration of corticotropin was delayed post-operatively in this child in order to determine the possibility of spontaneous regression of the neurologic syndrome. There was, however, no amelioration of the ataxia and two months after surgery she was started on corticotropin intramuscularly with improvement within 6 weeks. Ten weeks after the start of corticotropin therapy she was walking independently and ataxia and opsoclonus had subsided. She was still impaired cognitively, speaking only single words. Prognosis: Despite her response to therapy, the child's long term prognosis was guarded. She continued on ACTH-Prednisone and cytoxan and was followed by Dr. David Ebb. Dr Ebb's comments on her case were reported in the New Eng. J Medicine. (1)This baby was observed to have intermittent multidirectional back-to-back saccadic eye movements without a saccadic interval characteristic of opsoclonus. At the time the video was made, the child had continuous primary position downbeat nystagmus. Her eye movements were full in all directions of gaze. Downbeat nystagmus is caused by a central vestibular imbalance due to lesions of the vestibulocerebellum, especially the flocculus and paraflocculus and brainstem pathways. The Purkinje cells of the flocculus preferentially discharge for downward movements and it has been suggested that there is an underlying upward eye velocity bias in the central vestibular or pursuit system or in the peripheral vestibular system which is normally inhibited by the cerebellum. With lesions of the vestibulocerebellum, cerebellar inhibition is disrupted and the upward bias uncovered, resulting in spontaneous downbeat nystagmus. Downbeat nystagmus in cerebellar cases may be modified by a number of factors, including orbital position, head position and movement, head shaking and caloric stimulation. (See Table 10-1 for other causes of downbeat nystagmus. pg 482 (9)). Downbeat nystagmus may be suppressed, or converted to upbeat nystagmus, by potassium channel blockers such as 3,4-diaminopyridine and 4-aminopyridine. Opsoclonus, according to Leigh and Zee, may be due to abnormal inputs from as far away as the superior colliculus or the cerebellum, to either the pause cells or burst neurons in the paramedian pontine reticular formation and mesencephalic reticular centers that control saccadic eye movements. (9)MRI normal studies.Neuroblastoma is the most common extracranial solid tumor in children. It arises from the pluripotent neural-crest cells found in association with the adrenal gland or sympathetic ganglia. Neuroblastomas, ganglioneuroblastomas and ganglioneuromas reflect the increasing maturation of the tumor. In this child, the sectioned left adrenal gland showed the tumor surrounded by a thin yellow rim of adrenocortical tissue. The center of the mass was composed of dense, firm, dark tissue containing scattered lighter areas (Figure 3). Microscopical examination revealed dense fibrotic tissue with numerous large lymphoid follicles and nodules of neuroblastoma (Figure 4 and 5), some of which were partially calcified. The nodules had a fine fibrillary background typical of neuroblastomas (Figure 6). In some areas the cells differentiated toward ganglion cells (Figure 7). In one autopsy case of a 22 month old child with paraneoplastic opsoclonus and neuroblastoma, the brain showed microscopic abnormalities limited to the cerebellum with mild loss of Purkinje cells and demyelination and gliosis of the white matter around the dentate nucleus.The opsoclonus-myoclonus-ataxia syndrome in association with a neuroblastoma is probably immune-mediated. As Posner proposed, an epitope shared by the tumor and the nervous system may elicit an immune response directed against the tumor, leading to a more indolent course, but also directed against the nervous system, leading to neurologic symptoms. Indirect evidence of an immunologic basis for the opsoclonus-myoclonus-ataxia syndrome includes: • Uncommonly large numbers of inflammatory cells in resected ganglioneuroblastomas and neuroblastomas • Elevated cerebrospinal fluid levels of immunoglobulins and plasmocytes and • Responsiveness to corticosteroids. Paraneoplastic markers The anti-Ri antibody, present in patients with occult carcinoma of the breast and opsoclonus, has not been detected in children with neuroblastoma and opsoclonus. Anti neurofilament antibodies have however been detected in serum from two affected children with neuroblastoma but have also been found in normal subjects. Serum from one child showed cerebellum specific immuno-activity with a 62 kd protein. One child with a neuroblastoma and the opsoclonus-myoclonus-ataxia syndrome was found to have anti neuronal anti-Hu antibody in serum and cerebrospinal fluid.Complete resection of stage 1 tumors is considered definitive treatment. 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Arch Neurol Psychiat (Chicago) 1979;36:51-53. http://www.ncbi.nlm.nih.gov/pubmed/420608MTtitubatio