A 32-year-old woman presents with common symptoms that made up a rare diagnosis never seen by the neurologist in a decades-long career.
A 32-year-old woman is referred to a neurologist for
loss of balance
over the course of 3 months. On several occasions, she has dropped things, prompting her to stop carrying breakable items. She reports that her energy level is normal and that she has not had any changes in mood, has not had weight gain or weight loss, and has not had any difficulty concentrating. Her menstrual periods have been irregular for the past 6 months; home pregnancy tests have all been negative. She has been married for 3 years and has no children, although she has tried to become pregnant for the past year, without success. She smoked about half a pack of cigarettes daily for 4 years in her early 20s. When she was 24, she completely quit smoking and hasn’t smoked again. Her parents and 3 siblings are all in good health. When they were in their early 40s, her mother and one of her sisters had a diagnosis of breast cancer, which was treated successfully with surgery and chemotherapy. Her paternal grandfather had a meningioma that was removed in his mid 50s, with a full recovery.
A brain MRI, ordered by her primary care doctor, was normal.
The patient is in no acute distress, and her mental status is normal. Her cardiac, respiratory, and abdominal examinations are also normal.
On neurological examination, strength was 5/5 in all 4 extremities and sensory exam was normal to all modalities. She had dysmetria on finger to nose testing bilaterally, and the right side is worse than the left. Her cranial nerve examination is normal with the exception of bilateral nystagmus, which is worse when looking to the right.
She reports that she has adopted a wide-based gait to compensate for her loss of balance. She is completely unable to do a Romberg test or walk heel to toe due to poor balance.
Her complete blood count (CBC) and electrolyte laboratory studies are normal. Her neurologist orders a Western blot study to test for the presence of 3 antineuronal nuclear autoantibodies (ANNA, aka anti-Hu; anti-Ri; and anti-Yo). The anti-Yo test is positive, the anti-Hu and anti-Ri tests are negative. A chest CT and an abdominal and pelvic CT are normal.
Diagnosis: Paraneoplastic cerebellar ataxia
After a gynecology consultation is obtained, the gynecologist consults a leading gynecological oncologist who has seen one case of paraneoplastic cerebellar degeneration in his 40-year career (incidentally, the neurologist had never seen a case in 20 years of practice). The option of removal of her ovaries versus an ovarian biopsy is discussed. A biopsy of her left ovary shows a malignancy. After removal of the ovary, her symptoms and neurological examination improve within one week. Anti-Yo testing 3 months later is negative.
Paraneoplastic cerebellar ataxia is a rare subtype of the paraneoplastic syndromes. As a group, these conditions manifest with signs and symptoms affecting the nervous system, the skin, or the endocrine system. Paraneoplastic cerebella ataxia is most commonly associated with ovarian and uterine tumors, but cases of breast cancer and Hodgkin lymphoma have been reported as well.
The symptoms of paraneoplastic cerebellar degeneration can include ataxia, dysarthria, dysphasia, myoclonus, and gait disturbance. The symptoms initially develop slowly, and then rapidly progress, prompting evaluation and diagnosis.
Dramatic symptoms in the absence of correlating findings on a brain MRI usually raise the suspicion, at which point blood tests are ordered to look for antineuronal nuclear autoantibodies. The antibodies often correlate with the symptoms. Anti-Hu is usually associated with neuropathy, while anti-Ri and anti-Yo are more often associated with ataxia. However, it is not unusual for neurologists to order all of them because there are times when the positive test does not match with the presenting symptoms.
The recommended treatment is removal of the tumor. Often, identification of the malignancy and surgical removal is complicated by the fact that paraneoplastic symptoms begin before the tumor can be identified in imaging studies. In this instance, the imaging study was normal, and the patient herself expressed a desire to try to get pregnant.
This is why the physicians involved tried to save one of theovaries. Other treatments, such as anti-inflammatory medication, are not effective in treating the symptoms or the cause of paraneoplastic cerebellar ataxia.
The prognosis of paraneoplastic syndromes is dependent on the presence of a tumor and the identified autoantibody.1 Patients with anti-Yo antibody tend to have a poor prognosis, as do patients who have a diagnosis of cancer, even after surgical removal of the tumor. Often, the paraneoplastic symptoms are disabling, although in some instances, recurrent tumors can be a problem as well.2 Given that this patient had anti-Yo antibody and had one of her ovaries left, her clinical course of recovery is not typical, and her short-term outcome is much better than expected.
It is well recognized that antineuronal nuclear autoantibodies form in less than 1% of cancer patients but the reason for this is not clear. Generally, the antibodies specifically target certain cells, such as the peripheral nerve cells, the cerebral cells, or cells of the cerebellum. The paraneoplastic symptoms are a very early manifestation of these tumors, and often, the autoantibodies do not decrease, even when the primary tumor is removed.
Take home points
1. Aydin Ã, Ãelik ÅY, Ä°Ã§Ã¶z S, et al. Prognostic factors in anti-neuronal antibody positive patients. Noro Psikiyatr Ars. 2018;55:189-194.
2. Venkatraman A, Opal P. Paraneoplastic cerebellar degeneration with anti-Yo antibodies: a review. Ann Clin Transl Neurol. 2016;3:655-663.