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This case was presented to the Clinical Eye Movement Society at the American Neurological Association Meeting in October 2009.
The patient is a 65 year old woman who was in good health until seven weeks prior to admission.
On June 22/09 on the return flight from her daughter’s wedding in Oregon she began to feel “dizziness” which she characterized as an “inability to sense herself in space”. This progressed insidiously over the course of hours and became intense enough to cause difficulty in standing and an inability to walk unassisted off the plane on arrival. Fully upright she felt as though “there is a sensation of backwards motion, with someone trying to push me off my heels”.
She also reported difficulty with short term memory, intermittent blurring of vision, and “eyes bobbing up and down”, a prominent feature that “caused quite a stir among physicians”.
She had no impairment in her speech, or swallowing, no motor or sensory changes, and no hearing loss, tinnitus or headache.
On return home, she consulted an ENT specialist on Cape Cod who diagnosed an inner ear problem and prescribed meclizine. Her PCP diagnosed vestibular neuritis and prescribed a short course of prednisone.
Her symptoms progressed and she was admitted to the Massachusetts General Hospital.
Past Medical History:
Hypertension in both parents and both were alcoholics
Retired but working in the family business
Smoked 1 to 2 packs per day for 25 years, quit 4 years ago. Alcohol: At least 2 glasses of wine per night for many years, occasionally “the better part of a bottle of wine on weekends”.
Weight loss of ten pounds in the last three months
No GI symptoms
Alert, appropriately interactive, normal affect
Orientation: Oriented to person, states’ MEEI’ for place and ‘Cambridge’ for City
Oriented to 2009 but states ‘June’ for month (August)
Attention: WORLD backwards without error
Followed simple and complex commands
Repetition, naming, comprehension intact
Memory: 3/3 at registration and 0/3 at 5 minutes.
Normal fund of knowledge
Normal apart from ocular motility
2+ symmetric reflexes
Plantar responses flexor
Impaired vibration sense in the toes
All other modalities normal
Prominent trunkal ataxia
Ataxic gait with a tendency to fall backwards sitting
Complained of marked oscillopsia and difficulty reading.
Visual acuity: J5 with difficulty
Confrontation fields, pupil reflexes and fundoscopy normal.
Upbeat nystagmus fixing on a far target
Square wave jerks (saccadic intrusions)
Full horizontal and vertical eye movements.
Upbeat nystagmus suppressed on convergence
No nystagmus supine
Horizontal and vertical saccadic dysmetria
Saccadic pursuit in all directions
Horizontal optokinetic response impaired
Vestibular-ocular reflex appeared preserved.
Blood Studies showed:
WBC 12.1th/cmm (4.5-11.0)
Neuts 11.34 th/cmm (1.8-7.7)
Brain MRI without Gadolinium:
Non-specific white matter foci representing chronic small vessel ischemic change.
Brain MRI thin slices through the brainstem/cerebellum showed stable scattered T2/FLAIR hyperintensities in the periventricular and deep white matter that are non-specific.
A demyelinating process cannot be fully excluded.
Head and Neck MRA with 3D-reformatting:
CT scan of the chest with intravenous contrast:
Skeletal degenerative changes
No suspicious lytic or blastic lesions
Cerebrospinal fluid protein 69 mg/dl (elevated)
Sugar 60 mg/dl
Elevated IgG 22.5 mg/dl (0-8.0)
CSF albumin 33.2 mg/dl (normal)
Serum was sent to the Mayo Clinic for a paraneoplastic panel of antibodies including anti-Ma1, anti-Ma2, anti-Ri, anti-Yo, anti-Hu, anti-Zic4 anti-CV2.
Result: Anti-Hu antibody positive – Titre 1:15,360
Transabdominal and transvaginal ultrasound:
Heterogenous, thickened endometrial stripe measuring 17 mm
Endometrial tissue biopsy negative.
CT of abdomen and pelvis with intravenous contrast:
Solid appearing 3.8 x 2.9 x 3.5 cm well defined heterogeneous mass (measuring 80 Hounsfield units post contrast) arising from the tail of the pancreas. (Figure 1)
Core biopsies of the pancreatic mass were performed using CT guidance. Both normal pancreatic tissue and tumor were obtained (Figure 2A-E). The tumor cells are small, round, uniform cells in a single cell pattern without gland formation or mucin production, findings consistent with an endocrine neoplasm. (A) Immunohistochemical stains for endocrine (chromogranin (B) and synaptophysin (C)) and exocrine (trypsin (D)) differentiation confirm the diagnosis of an endocrine neoplasm.
The excised distal pancreas revealed a 3.2 x 3.2 x 2.5 cm. well circumscribed, mottled tan-red heterogenous tumor mass with grossly clear resection margins (Figure 2E). Histology confirmed the diagnosis of an endocrine neoplasm. An immunohistochemical marker for proliferation (ki-67) highlighted a weak proliferation index (2%) and a marker for lymphatic endothelial cells (D2-40) did not reveal lymphatic invasion, however, malignant behavior was demonstrated by metastasis to a regional lymph node (1 of 23 nodes positive for tumor). As such this neoplasm is thus classified as a well-differentiated endocrine carcinoma.
(Courtesy of Martha Bishop Pitman, M.D.)
The patient was treated with intravenous methylpredisolone (1,000 mg/day for five days), cyclophosphamide, one dose intravenously 1100 mg (600 mg/m2 ) followed by oral 75 mg daily (1mg/kg/day), and a course of intravenous immunoglobulin (0.5g/kg/day for five days). During the initial two months in hospital, she had progressive decline in cognitive function and memory and increasing gait ataxia, becoming wheelchair bound and unable to converse intelligibly. However, six weeks post-surgery, she started to improve cognitively, becoming more attentive, conversational and oriented, developing some insight into her illness. However, she still needed assistance to walk and her upbeat nystagmus persisted; at this point her eye movements were recorded.
The recordings were made by R. John Leigh, M.D. et al Daroff-Dell’Osso Laboratory, Veterans Affairs Medical Center: Case Western Reserve University, Cleveland. A representative record of her nystagmus during far viewing and during near viewing is shown in Figure 3A-D.
Paraneoplastic upbeat nystagmus suppressed by convergence and absent in the supine position is consistent with a channelopathy affecting the central otolith pathway.
After the eye movement recordings, she started on memantine 10 mg/day increasing to 2 tablets/day and was seen several weeks later, on February 24, 2010. Her nystagmus persisted unchanged, suppressing with near viewing and abolished when supine. Her cognition was mildly improved.
At this visit, a Brain FDG PET Scan (5.0 mCi of F-18 FDG injected) was done. The acquired tomographic images were evaluated independently and co-registered with images from two comparison MRI examinations for interpretation.
The study showed:
1. Marked hypometabolism in the right and left rectus gyri, corresponding to focal volume loss that appears to have slightly progressed in the interval between the head MRI examinations of 8/13/2009 and 8/27/2009. This PET finding is of uncertain clinical significance, although the association of volume loss during a period when the patient was acutely symptomatic from her paraneoplastic syndrome suggests a possible correlation.
2. Mild hypometabolism in the left frontal lobe (outside of the gyrus rectus and oribitofrontal gyri) and in the left temporal lobe, of uncertain clinical significance, and not definitively suggestive of a specific neurodegenerative process.
3. There is otherwise essentially normal cortical metabolic activity in the right temporal lobe, the right and left parietal lobes, the right and left occipital lobes and in the deep gray matter nuclei and in the cerebellum.
This 65 year old patient with pancreatic cancer and a paraneoplastic upbeat nystagmus had
• Upbeat nystagmus fixing on a far target
• Lid nystagmus
• Square wave jerks (saccadic intrusions)
• Full horizontal and vertical eye movements.
• Normal convergence
• Upbeat nystagmus suppressed on convergence
• No nystagmus supine
• Horizontal and vertical saccadic dysmetria
• Saccadic pursuit in all directions
• Horizontal optokinetic response impaired
• Vestibular-ocular reflex appeared preserved.
Upbeat nystagmus (UBN) has not been previously described as a paraneoplastic phenomenon associated with an identified tumor. Several specific mechanisms have been proposed to account for UBN, all of which concern disturbance of central pathways conveying upward eye movement signals from the vestibular nuclei to the oculomotor nuclei.
First, interruption of brainstem pathways from the labyrinthine semicircular canals mediating upward eye movements, including the ventral tegmental tract, may cause UBN.
Second, imbalance of central otolithic projections may also cause UBN; when, as in our patient, UBN is modulated by vergence and changes in head position relative to gravity, this mechanism seems probable, since the otolith-ocular responses are strongly modulated by viewing distance. Our patient also showed marked retropulsion, consistent with a central otolithic disturbance.
Third, there is evidence that disturbed cerebellar influences upon otolithic projections from the vestibular labyrinth can cause UBN. Thus, patients with cerebellar disease often show modulation of downbeat nystagmus, or even reversal to UBN, with change in head position. What cellular mechanisms contribute to such modulation? In one patient whose nystagmus was upbeat when supine but downbeat when prone, the potassium channel agent 3,4-diaminopyridine suppressed the downbeat nystagmus but increased the UBN. Also pertinent is the report that, in normal subjects, nicotine induces UBN that is modulated by head position.
Thus, in our patient, for whom we have strong evidence for a paraneoplastic pathogenesis of her UBN, immune attack on either neuronal channels in the nodulus and ventral uvula, which govern otolithic responses, or on acetylcholine receptors in brainstem pathways subserving the otolithic-ocular responses might be the mechanism.
Memantine, which suppresses UBN in some patients, was chosen for our patient based on its safety profile and ability to help memory defects, but proved ineffective. Based on the several hypotheses for UBN outlined above investigators are currently considering trials of drugs with effects either on central cholinergic mechanisms or on potassium channels, such as 4-aminopyridine.
Our patient showed anti-Hu antibodies, which targets intracellular antigens. However, current concepts of paraneoplastic syndromes suggest that antibodies against surface neuronal antigens, including receptors and channels, seem more likely to account for the clinical findings. In interpreting the mechanisms by which such antibodies against neuronal surface antigens cause specific clinical manifestations, study of specific disorders of eye movement may have much to contribute, since a good deal is known about their neurobiology and pharmacology.
*Taken from Wray SH, Maheshwari A, Chen T, King S, Pitman MB, Leigh RJ. Paraneoplastic Upbeat Nystagmus: Evidence for underlying mechanisms. Submitted Annals of Neurology March 2010.
Read Ref #15
Graus et al analyzed 200 patients with anti-Hu-associated paraneoplastic encephalomyelitis (PEM). The mean age of the 200 patients was 63 years (range 28-82 years) and 75% were men. The predominant neurological syndromes were sensory neuropathy (54%), cerebellar ataxia (10%), limbic encephalitis (9%) and multifocal involvement (11%). Pathological or x-ray evidence of a tumor was obtained in 167 patients (83%) and was a small-cell lung cancer in 74% of those with histological diagnosis. PEM preceded the diagnosis of the tumor in 71% of patients (mean delay 7 months; range 0.1 to 47 months).
The location and histological diagnosis of neoplasms in 167 patients in this group included 3 patients with carcinoma of the breast, 6 with carcinoma of the prostate, 1 with carcinoma of the ovary and 2 with carcinoma of the pancreas (1 small cell).
The predominant neurological symptom of PEM in this study was a sensory neuropathy. The sensory symptoms in PEM patients are usually due to a lesion in the dorsal root ganglia rather than in the peripheral nerves, and in our patient the only finding of a sensory neuropathy was loss of vibration sense in the toes.
Previous work suggested that when a tumor other than a small cell lung carcinoma (SCLC) was discovered in PEM patients the possibility of a concomitant SCLC was high and appropriate studies should be made to rule out this tumor, as in our case.
The authors hypothesize that a positive Hu immunoreactivity by the tumor would support that the tumor was responsible for the PEM.
The prognosis of PEM remains poor in terms of survival and neurological disability. In Graus et al’s series up to 53% of patients were severely disabled at the time of diagnosis and only a minority (5%) had a benign indolent course.
Regarding therapy, although immunotherapy alone is probably not effective in the majority of patients, 4 patients in the series improved with different immunotherapies. No specific immunotherapy treatment however can be recommended and ideally, all PEM patients should be offered the possibility of inclusion in therapeutic protocols.
Dalmau and Graus et al in a clinical analysis of anti-Ma2-associated encephalitis, obtained pathological studies in 12 patients. In 11 patients the microscopic studies showed perivascular lymphocytic cuffing and interstitial infiltrates of lymphocytes with variable gliosis and neuronal degeneration. The inflammatory infiltrates were mainly composed of T-cells with a smaller number of B-cells, macrophages and microglial activation.
The autopsy of four patients showed a correlation between the clinical MRI findings and the degree of pathological involvement. The areas with major pathological abnormalities were always the most symptomatic, but all four patients had abnormal findings in areas that were clinically asymptomatic. In a patient whose symptoms appeared restricted to limbic and hypothalamic dysfunction, the autopsy showed severe involvement of the hippocampus and entorhinal cortex, and mild chronic inflammation in numerous areas including frontal and parietal cortex, midbrain, substantia nigra, pontine nuclei, dorsal grey matter of the medulla, olivary nuclei and occasional dropout of Purkinje cells with Bergmann’s gliosis.
The spinal cord was spared but the dorsal root ganglia showed several small aggregates of reactive lymphocytes.
Paraneoplastic Upbeat Nystagmus; Pancreatic Endocrine Carcinoma; View Paraneoplastic Upbeat Nystagmus to see the figures.
The approach to treatment in PEM is:
1. Appropriate therapy for the cancer
• Chemotherapy and/or Radiation
2. Immune modulation
• Intravenous methylprednisolone
• Intravenous immunoglobulin
• Immunoadsorption therapy
3. Symptomatic treatment for vertigo/oscillopsia
1. Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, Saiz A, Meneses P, Rosenfeld MR. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004;127:1831-1844. http://www.ncbi.nlm.nih.gov/pubmed/15215214
2. DeAngelis LM, Posner JB. Neurological complications of cancer. New York: Oxford University Press, 2009.
3. Graus F, Keime-Guibert F, Rene R, Benyahia B, Fibalta T, Ascaso C, Escaramis G, Delattre JY. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138-1148. http://www.ncbi.nlm.nih.gov/pubmed/11353730
4. Graus F, Saiz A, Dalmau J. Antibodies and neuronal autoimmune disorders of the CNS. J Neurol. 2009 Dec 25. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/20035430
5. Helmchen C, Sprenger A, Rambold H, Sander T, Kömpf D, Straumann D. Effect of 3,4-diaminopyridine on the gravity dependence of ocular drift in downbeat nystagmus. Neurology 2004; 63:752-753. http://www.ncbi.nlm.nih.gov/pubmed/15326263
6. Kim JI, Somers JT, Stahl JS, Bhidayasiri R, Leigh RJ. Vertical nystagmus in normal subjects: effects of head position, nicotine and scopolamine. J Vestib Res. 2000; 10: 291-300. http://www.ncbi.nlm.nih.gov/pubmed/11455110
7. Ko MW, Dalmau J, Galetta SL. Neuro-ophthalmologic manifestations of paraneoplastic syndromes. J Neuro-ophthalmol 2008; 28:58-68. http://www.ncbi.nlm.nih.gov/pubmed/18347462
8. Kurian M, Lalive PH, Dalmau JO, Horvath J. Opsoclonus-myoclonus syndrome in anti-N-methyl-D-aspartate receptor encephalitis. Arch Neurol. 2010 Jan;67(1):118-21. http://www.ncbi.nlm.nih.gov/pubmed/20065141
9. Leigh RJ, Zee DS. The Neurology of Eye Movements. 4th Edition. New York, Oxford University Press, 2006.
10. Liao K, Walker MF, Joshi A, Reschke M, Leigh RJ. Vestibulo-ocular responses to vertical translation in normal human subjects. Exp Brain Res. 2008; 185: 553-62. http://www.ncbi.nlm.nih.gov/pubmed/17989972
11. Marti S, Palla A, Straumann D. Gravity dependence of ocular drift in patients with cerebellar downbeat nystagmus. Ann Neurol 2002; 52:712-721. http://www.ncbi.nlm.nih.gov/pubmed/12447924
12. Pierrot-Deseilligny, C. & D. Milea. Vertical nystagmus: clinical facts and hypotheses. Brain 2005;128:1237-1246. http://www.ncbi.nlm.nih.gov/pubmed/15872015
13. Shaikh AG, Ramat S, Optican LM, Miura K, Leigh RJ, Zee DS. Saccadic burst cell membrane dysfunction is responsible for saccadic oscillations. J Neuroophthalmol. 2008; 28: 329-36. http://www.ncbi.nlm.nih.gov/pubmed/19145136
14. Thurtell MJ, Joshi AC, Leone AC, Tomsak RL, Kosmorsky GS, Stahl JS, Leigh RJ. Cross-over trial of gabapentin and memantine as treatment for acquired nystagmus. Ann Neurology (in press), 2010. http://www.ncbi.nlm.nih.gov/pubmed/20437565
15. Wray SH, Maheshwari A, Chen T, King S, Pitman MB, Leigh RJ. Paraneoplastic Upbeat Nystagmus: Evidence for underlying mechanisms. Submitted Annals of Neurology March 2010. http://www.ncbi.nlm.nih.gov/pubmed/21813784
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