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 7 weeks prior to admission.
On June 22, 2009, on the return flight from her daughter's wedding in Oregon, she began to feel "dizziness" that 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 referred to the Massachusetts Eye and Ear Infirmary and then admitted to the Massachusetts General Hospital.
Past Medical History:
Hypertension and alcoholism in both parents
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 10 pounds in the last 3 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 min.
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 tendency to sway backwards
Patient complained of marked oscillopsia and difficulty reading.
Visual acuity: 20/60 with difficulty
Confrontation fields, pupil reflexes, and fundoscopy normal.
Upbeat nystagmus in primary position
Full horizontal and vertical eye movements
Upbeat nystagmus suppressed on convergence
Horizontal and vertical saccadic dysmetria
Saccadic pursuit in all directions
Horizontal optokinetic nystagmus (OKN) present
Absent vertical OKN
Horizontal and vertical oculocephalic reflex normal
No skew deviation
WBC 12,100/mm3 (4.5–11.0)
Neuts 11,340/mm3 (1.8–7.7)
Serum electrolytes normal
Brain MRI without Gadolinium:
Nonspecific white matter foci representing chronic small vessel ischemic change
Brain MRI Thin Slices through the Brainstem/Cerebellum:
Stable scattered T2/FLAIR hyperintensities in the periventricular and deep white matter that are nonspecific.
A demyelinating process cannot be fully excluded.
Head and Neck MRI with 3D Reformatting:
CT Scan of the Chest with IV 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—titer 1:15,360
Transabdominal and Transvaginal Ultrasound:
Heterogeneous, thickened endometrial stripe measuring 17 mm
Endometrial tissue biopsy negative
CT of Abdomen and Pelvis with IV Contrast:
Solid-appearing 3.8 × 2.9 × 3.5 cm well-defined heterogeneous mass (measuring 80 Hounsfield units post-contrast) arising from the tail of the pancreas
Pancreatic mass core biopsy positive for pancreatic endocrine carcinoma
The tumor was relatively well circumscribed but extended focally into the peripancreatic soft tissue and focally involved the edge of the specimen at its inferior aspect (confirmed by synaptophysin stain). The proximal resection margin was free of tumor.
Immunohistochemical study revealed that ki-67 proliferative index was <2%, and no lymphovascular invasion was identified on D2-40-stained sections.
Based on its size and the presence of lymph node metastasis
(1 of 23 lymph nodes) the lesion was best classified into well-differentiated endocrine carcinoma.
The diagnosis was confirmed with histochemical stains that showed strong tumor cell positivity for cytokeratin cocktail, chromogranin, and synaptophysin, and no significant tumor cell staining with trypsin.
Anti-Hu–associated paraneoplastic encephalomyelitis with limbic encephalitis
Brainstem encephalitis causing upbeat nystagmus
Distal pancreatectomy with splenic preservation.
A 3.2 × 3.2 × 2.5 cm heterogeneous mass was palpable in the tail of the pancreas.
1. Appropriate therapy for carcinoma
- Distal pancreatectomy
- Chemotherapy with cyclophosphamide (one dose of 600 mg/m2 IV)
2. Immune modulation
- IV methylprednisolone (total 5 g)
- IV immunoglobulin for 5 days
3. Symptomatic treatment for oscillopsia
4. Other medication
The patient became very anxious. Impairment in cognition progressed rapidly, leading so severe confusion and inability to hold a conversation and answer questions.
There was no significant response to IV IgG.
She was discharged to rehab on 9/14/09.
The progressive deterioration in her mental function and gait ataxia stabilized and in fact improved 5 days prior to her follow-up visit on 9/28/09: 6 weeks after IV steroid therapy, 5 weeks post–tumor resection, and 3 weeks following IV IgG/ cyclophosphamide.
On examination, although she still had significant memory impairment, trunkal ataxia, opsoclonus and upbeat nystagmus, she was more attentive, oriented ×3, and conversational. She asked specific questions and had considerable insight into her illness. She was able to walk with a walker.
Serum for repeat anti-Hu antibody titer
Pathologic paraffin sections of the pancreatic tumor and serum samples were sent to Dr. Dalmau, Dept of Neurology, University of Pennsylvania, Philadelphia, PA, who kindly agreed to study Hu immunoreactivity.
I also consulted Dr. Dalmau regarding long-term therapy.
- "I usually treat my patients with metronomic doses of cytoxan (1mg/kg per day) for a very long time (months). They usually tolerate the treatment very well. The treatment should focus on the cytotoxic T cell immune response, not the antibodies. The antibodies often remain detectable for several years. Rituximab may help, not because of antibody reduction, but because of B cell depletion. (B cells are very good antigen presenters to the T cells.) I have not personally used both rituximab and cytoxan for this disorder, although I used it in other disorders and they were usually well tolerated."