Paraneoplastic Ocular Flutter

The patient is a 58 year old woman with known hypertension. In 1994, two weeks prior to admission she had a dramatic change in behavior with insomnia, agitation and depression. This was accompanied by "ringing of hands and anxiety for no apparent reason". She became anorexic, lost 15 pounds in weight and developed increasing headache, dizziness, head shaking, unsteadiness walking, and a feeling of generalized weakness. She denied nausea, vomiting, lethargy or syncope. After consulting her doctor she came to the Emergency Room. She was seen by Medicine, Psychiatry and Neurology and admitted to Psychiatry with a chief complaint, "I cannot stand up". Psychiatry considered her unsteady gait was histrionic and related to depression and her perception that she was unable to walk. On examination she was extremely agitated and cooperated poorly with the examiner. She was only able to walk with the use of a walker and two nursing assistants. At that time, she also complained of difficulty focusing and an abnormality of her eye movements were noted. A neuro-ophthalmology consultation led to her transfer from Psychiatry to Neurology. Past History: Significant for a previous episode of depression treated with antidepressant medication and alcohol abuse in the past. She was a heavy smoker, smoking a pack per day for over 30 years. Family History: Significant for alcohol abuse in both parents. Social History: Eldest of six siblings, unmarried and living alone. Worked as a secretary until 10 years prior to admission when she lost her job. Neurological examination: She was oriented in time, place and person but failed to obey three-step commands She had: •Fluctuating level of alertness and attentiveness •Motor impersistance and perseveration. •Impaired short term memory A constellation of cerebellar signs: •Dysarthria •Titubation •Fine tremor of the face and chin •Ocular flutter with occasional spontaneous obtrusive saccades (no continuous opsoclonus) •Marked trunkal ataxia sitting and standing •Gait ataxia with inability to walk without support The motor system was intact. Reflexes symmetric, slightly brisk, with flexor plantar responses. Coordination intact in the limbs Sensory examination showed no abnormality The Electronystagmogram showed: 1.Spontaneous and gaze nystagmus - Intermittent ocular flutter epochs (5Hz), 1-2 cycle sinusoids in duration throughout the record. Ocular flutter occurred without any rhythmic pattern, with highest frequency on saccades to the left and on eye closure. She had normal vertical excursions and normal vertical vestibulo-ocular reflex. 2.Saccades - Normal velocity and latency. With gaze-evoked nystagmus with large saccades in either direction. 3.Pursuit (tracking) 0.2 Hertz: Sinusoidal. Ocular flutter intrusions 0.3 Hertz: Saccadic breakdown to the right and left Vertical pursuit gain was negligible. 4.Optokinetic nystagmus - Poor gain in each direction 5.Positional Testing: a.Hallpike's; eyes open in the light - Dizziness with brief burst of right beating nystagmus on the first positioning. b.Static; eyes open in the dark - No nystagmus or dizziness. c.Static; eyes closed - No nystagmus or dizziness. The study showed: •Ocular flutter epochs •Loss of vertical pursuit tracking •Lateral gaze-evoked nystagmus •Saccadic breakdown of pursuit tracking at higher frequencies •A brief burst of right beating nystagmus with accompanying dizziness upon Hallpike positioning to a head hanging right position. These findings were consistent with brainstem and cerebellar dysfunction affecting fixation and saccadic and pursuit pathways. Diagnosis: Paraneoplastic Cerebellar Syndrome Ocular Flutter. Investigations: The workup was directed towards detection of an occult neoplasm breast, ovary or lung. Serum electrolytes were abnormal; Sodium 125 mmol/L (135-145) Potassium 2.8 mmol/L (3.4 - 4.8) Osmolal 262 mosm/kgw (280-296) Hyponatremia was secondary to the syndrome of inappropriate ADH Secretion (SIADH). The diagnosis of SIADH is made by finding a concentrated urine sodium (> 20 mmol/L) in the presence of hyponatremia or low plasma osmolality (<260 mmol/kg). The causes of SIADH include malignancy such as small cell carcinoma of the lung as in this patient. Electroencephalogram normal. Lumbar puncture showed normal cerebrospinal fluid (CSF) with 4 WBC, negative cytology and no oligoclonal bands Mammogram normal. Abdominal and pelvic CT normal. Bone scan negative for metastases Brain MRI focal non-enhancing periventricularT1 hypointensity and T2 hyperintensity noted adjacent to the left lateral ventricle. Differential diagnosis: Non-specific demyelination versus gliosis. Chest x-ray revealed a well circumcised 6 cm mass consistent with adenocarcinoma of the lung without significant hilar lymphadenopathy. Chest CT : In the region of the superior segment and basilar segments of left lower lung a large well rounded and smooth homogeneously soft tissue dense non-calcified mass was found approximately 5 x 3 x 5 cm with a single pleural tag. (Figures 1 and 2) Diagnosis: Primary bronchogenic carcinoma. Surgery: The patient had a left lower lobe lobectomy and excision of a number of hilar lymph nodes. Pathology: Small Cell Undifferentiated Carcinoma of the Lung with metastatic carcinoma in 2/5 hilar lymph nodes. (Figure 3-4) Paraneoplastic markers: A fresh frozen segment of the lung tumor and a sample of CSF and 3 samples of serum were sent to Dr. Posner at the Memorial Sloane Kettering Cancer Center for antibody studies (Anti-Ri, Anti-Yo, Anti-Hu). No antibodies were detected. Yo Autoantibody Test - Negative Antibodies to the Yo antigen are the most common paraneoplastic antibodies to Purkinje cells. A negative result for the Yo autoantibody test proved that the cause of the disease was not due to this paraneoplastic antibody but did not rule out paraneoplastic cerebellar degeneration as the cause of the symptoms (1,2). 1. Hammack J. et al. Neurology 1992;42:1938-1943. 2. Clouston PD et al. Neurology 1992;42:1944-1950. Ri Autoantibody Test - Negative Anti-Ri is a highly specific antineuronal antibody that reacts with nuclei of neurons in the central nervous system. The presence of anti-Ri antibody identifies the subset of patients with paraneoplastic ataxia and opsoclonus who suffer from breast or other gynecological cancer. The antibody when present is a useful marker for this type of underlying malignancy. The relative amount of anti-Ri was found to be always higher in CSF than in serum. 1.Anderson NE et al. Ann Neurol 1988;24:559-567 2.Budde-Steffen C. et al. Ann Neurol 1988;23:528-531. 3.Luque A. et al. Ann Neurol 1989;26:178 (Abstract) Protein-A Immunoadsorption: Inspite of the absence of known paraneoplastic antibodies, the patient was treated twice weekly for three weeks with Protein-A immunoadsorption, in which 250 ml of plasma was passed through a disposable column of staphylococcal Protein-A covalently bound to a silica matrix that bound both the Fc portion of IgG molecules and immune complexes. The plasma was then returned to the patient. The first treatment was given in hospital because of the possible risk of cutaneous immune complex vasculitis. In addition she received Prednisone 80 mg daily and Haldol 2.5 mg. p.o. q.hs, to minimize the risk of steroid psychosis. The mechanism of action of the immunoadsorption therapy is not clear, but it may have removed small quantities of immune complexes or antineuronal antibodies or facilitated the formation of anti-idiotype antibodies. Oncology: She had a Limited Stage Small Cell Lung Cancer, Stage T2, N1, MO of the left lower lobe initially treated with a left lower lobectomy, six cycles of post-operative chemotherapy and then subsequent radiation to the chest (50.4 Gy in 28 fractions). Prognosis: She made a full recovery on completion of all the treatments. She has had no reoccurrence of ocular flutter. The patient has been followed up for over ten years. When last seen in 2006, she was under treatment for chronic obstructive pulmonary disease and anxiety. She was still smoking one pack of cigarettes per day. See also: http://content.lib.utah.edu/cdm/ref/collection/ehsl-shw/id/40