A 61-year-old woman was referred to Affiliated Zhejiang Hospital, Zhejiang University School of Medicine due to sudden vertigo with nausea and vomiting for 10 d.
History of present illness
Ten day prior to referral to our hospital, the patient suffered from vertigo. The vertigo was persistent, preventing her from opening her eyes. She felt dizzy when she opened her eyes, which was accompanied by nausea and vomiting. The vertigo became worse when her posture changed, and her symptoms were relieved when lying on her left side, while the symptoms were worse when she turned her head to the right. The patient had no palpitations, tinnitus, hearing loss, headache, limb weakness, numbness, limb convulsions, vague speech, or consciousness loss. She went to a nearby hospital and underwent a computed tomography (CT) scan of the brain, which showed no obvious abnormalities. She was treated with Betahistine, but her vertigo did not relieve.
History of past illness
She had a history of hypertension. She underwent "pancreatic tumor resection" more than 20 years ago and recovered well after surgery.
Personal and family history
There was no history of dizziness, headache, or tumor in the family.
The patient's neurological examination showed spontaneous downbeat nystagmus, gaze in all directions showed torsion with downbeat nystagmus, and nystagmus was stronger when she gazed to the right. The patient had clear speech and normal hearing. Her right finger-to-nose and heel-to-shin tests were unstable, her limb muscle strength was grade 5, her limb tendon reflex was (+), Romberg's sign could not be completed, and the bedside head impulse test was negative.
Laboratory investigation revealed hemoglobin 147 g/L, white blood cell count (WBC) 9.3 × 109/L (N 70.8, L 21.8, M 7%), platelet count 119 × 109/L, sodium 139.79 mmol/L, potassium 3.72 mmol/L, chloride 103.1 mmol/L, glucose 4.3 mmol/L, TSH 1.487 μU/mL, FT 41.41 ng/dL, FT3 2.79 pg/mL, anti-thyroglobulin < 15, anti-thyroid peroxidase < 28 IU/mL, C3 1.25 and C4 3.8 g/L, folic acid 12.39 nmol/L, and vitamin B12 284 pmol/L. However, the level of the tumor marker carbohydrate antigen 125 (CA125) was significantly increased; her CA125 level was 332.50 U/mL (the normal level of CA125 is < 35 U/mL); and the level of the tumor marker carbohydrate antigen 199 (CA199) was 21.63 U/mL (the normal level of CA199 is < 39 U/mL), which was normal. Next, we performed a lumbar puncture on this patient, and cerebrospinal fluid (CSF) analysis revealed a colourless fluid with CSF pressure 100 mmH2O, WBC 0 cells/mm3, protein 0.31 g/L, and glucose 5.0 mmol/L. Serum and CSF analysis of paratumor antibodies and autoimmune cerebellitis antibodies showed that the patient was positive for anti-Yo antibody, through the immunospot assay. The video head pulse test (vHIT) results suggested that the left semicircular canal gain, which was used to evaluate vestibulo-ocular reflex function, was slightly lower than the right gain (Figure 1).
Figure 1 Video head pulse test suggested that the left semicircular canal gain (horizontal semicircular canal, posterior semicircular canal, and anterior semicircular canal) was slightly lower than the right gain, and the left horizontal semicircular canal was accompanied by glance.
Because the patient had a history of hypertension, which is a risk factor for cerebrovascular disease, and signs of ataxia, although there was no obvious abnormality on her skull CT, central vertigo was still considered, and cerebral infarction was considered first. Therefore, the patient underwent a brain magnetic resonance imaging (MRI) examination that showed no obvious abnormalities (Figure 2). Then she underwent a brainstem magnetic resonance scan that also showed no obvious abnormalities.
Figure 2 Magnetic resonance imaging showed multiple sub-frontal and parietal cortexes, semi-oval centers, and lateral ventricles with multiple spot-like and sheet-like lesions, equal signal on diffusion-weighted imaging, slightly longer signal on T1, longer signal on T2, and partially high signal on flair.
A: Diffusion-weighted imaging; B: T1; C: T2; D: Flair.
Based on the results of the serum and CSF paratumor antibodies tests, we looked for the primary tumor. Abdominal para-aortic lymph node B-ultrasound indicated multiple sites of peritoneal lymphadenopathy. Subsequently, positron emission tomography-CT examination was performed, which revealed that the patient had increased fluorodeoxyglucose metabolism in the porta hepatis region, mesenteric roots, and back of the pancreas and multiple retroperitoneal soft tissue nodules and enlarged lymph nodes that were considered malignant. Contrast-enhanced abdominal CT examination revealed multiple enlarged lymph nodes in the retroperitoneum and porta hepatis region, which might be a metastatic tumor (Figure 3). Because of severe nausea and vomiting, the patient and her family members worried that the patient could not tolerate endoscopic retrograde cholangiopancreatography (ERCP) examination, then refused to take ERCP and magnetic resonance cholangiopancreatography (MRCP) examinations. Therefore, the patient did not receive endoscopic ultrasound, MRCP, and ERCP examinations.
Figure 3 Contrast-enhanced computed tomography scan of the whole abdomen.
Multiple enlarged lymph nodes in the retroperitoneum and porta hepatis region and no obvious enhancement, which suggested a metastatic tumor. A: Retroperitoneum (orange arrow); B and C: Porta hepatis region (shown by orange arrows and orange circles).
Then, we performed an ultrasound-guided lymph node puncture on this patient and biopsied the posterior peritoneal and cervical lymph nodes. Pathological results suggested metastatic cancer, and pancreaticobiliary duct origin was considered. The immunohistochemical findings were as follows: Cytokeratin (CK) 7 (+), CK19 (+), CK20 (-), caudal-related homeobox transcription factor 2 (CDX2) (-), Ki67 (+; 40%), and carcinoembryonic antigen (CEA) (-) (left cervical lymph node pathology); and CK7 (+), CK19 (+), CK20 (-), CDX2 (-), Ki67 (+; 40%), and CEA (partial +) (retroperitoneal lymph node pathology) (Figure 4).We reviewed the pathology of the "pancreatic tumor" resected from the patient more than 20 years ago. The pathological examination result was a grade II duodenal ampulla bile duct adenocarcinoma.
Figure 4 Lymph node pathology.
A: Left cervical lymph node pathology. Hematoxylin-eosin (HE) staining, × 100 magnification. The lymph nodes were infiltrated by atypical cells, and the atypical cells partly had an adenoid structure; B: Retroperitoneal lymph node pathology. HE staining, × 200 magnification. Atypical cells grew in nests, some of which had adenoid structures and infiltrating growth, with nuclear divisions visible
The sudden vertigo that presented in this patient belonged to the category of acute vestibular syndrome. The vHIT showed that the left horizontal semicircular canal, anterior semicircular canal, and posterior semicircular canal gains were lower than the right gains, and the left horizontal semicircular canal was accompanied by saccade. The patient had an acute onset, and the semicircular canal gain of the vHIT test was low, so her diagnosis was somewhat confusing, as the symptoms could also indicate peripheral vestibular system diseases such as vestibular neuritis. However, the patient had ataxia of the right limb and trunk at the same time, and the symptoms continued to progress for more than 10 d, which did not match the manifestations of vestibular neuronitis. Therefore, we believed that the cause was positioned in the central vestibular system. Because the onset of this patient was acute, and there was a history of hypertension, which is a risk factor for cerebrovascular disease, we first considered cerebrovascular disease, but cerebellar hemorrhage, infarction, and metastasis were excluded by skull CT/MRI examinations, and the thin-layer MRI scan of the brainstem that she received later also did not reveal any infarcts. Due to the central compensation mechanism, patients with cerebral infarction will improve after the acute phase (about 7 d). However, the patient's symptoms continued to develop after 10 d, which did not match the manifestations of cerebrovascular disease.
Subsequently, we found a significant increase in CA125 and positive anti-YO antibodies in serum and cerebrospinal fluid, then the patient was diagnosed with anti-YO positive PCD. Finally, through lymph node puncture, the patient’s pathology suggested adenocarcinoma of pancreaticobiliary duct origin, therefore, this patient was diagnosed as possible anti-Yo antibody-positive PCD with cholangiocarcinoma.
Anti-Yo antibody-positive PCD usually presents as symptoms of subacute cerebellar degeneration. The main clinical manifestation is cerebellar ataxia of the trunk and limbs, which lasts for weeks to months. If the patient has dysarthria, nystagmus, diplopia, and other symptoms that indicate brainstem involvement, without any intervention, symptom development will peak within 6 mo. PCD with acute onset is relatively rare[7,8], Vogrig et alreported two cases of acute stroke-like onset of PCD, similar to the onset of our patient. However, currently accurate explanations for the variability of the onset and progression of PCD are lacking. Recent studies have found that large-scale cerebellar inflammatory cytokines are produced in the PCD mouse model, and this inflammatory response can induce Purkinje cell death at an early stage.
In the early stages of PCD with anti-Yo antibody positivity, magnetic resonance examinations of the brain are usually normal, and cerebellar atrophy usually appears in the late stages of disease.The majority of patients with anti-Yo antibody-positive cerebellar ataxia are eventually diagnosed with cancer. The most common tumors are breast and ovarian cancers, followed by occasional lung cancer and Hodgkin's disease. A retrospective survey by Monstad et al and others found that the rates of anti-Yo antibody positivity in 557 ovarian cancer patients and 253 breast cancer patients were 2.3% and 1.6%, respectively, but only 12% of the anti-Yo antibody-positive patients had PCD. However, there have been relatively few reports of PCD with cholangiocarcinoma. At present, only Bruhnding et al reported the case of a male PCD patient with cholangiocarcinoma; the patient received IVIg treatment, but the ataxia did not improve, and given this poor overall prognosis, the patient declined further treatment. We reported for the first time that a female PCD patient who was probably caused by cholangiocarcinoma.
Our patient's CA125 was significantly higher. Elevated CA125 is most common in ovarian cancer, and there is also a certain positive rate in other non-ovarian malignancies. It has been shown that serum CA125 levels are elevated in patients with cholangiocarcinoma, and the specificity of elevated CA125 in diagnosing cholangiocarcinoma is 79.2%, and CA125 is barely elevated in patients with benign biliary tract diseases.
Subsequently, we performed a lumbar puncture on the patient and found specific onconeural anti-Yo antibody positivity through serum and cerebrospinal fluid tests. Finally, biopsy of the lymph node was consistent with a pancreaticobiliary duct tumor. However, as mentioned above, PCD often occurs in patients with breast or ovarian cancer. In this case, there is no evidence of breast cancer or ovarian cancer. Follow-up still needs to monitor whether there are related cancers.
PCD mainly involves the vermis and midline structures of the cerebellum in the early stage, and under physiological conditions, the midline structure of the cerebellum mainly participates in the integration of otolith and semicircular canal signals, controls the otolith-ocular reflex, and participates in the regulation of the semicircular canal-ocular reflex. When the midline structure of the cerebellum is dysfunctional, the integration of otolith and semicircular canal signals becomes dysfunctional. The imbalance in the integration of otolith and semicircular canal signals may lead to differences in the regulation of semicircular canal function on both sides, which may be the reason for the higher asymmetry of semicircular canal gains in this patient seen by the vHIT.
The exact mechanism of Purkinje cell death in anti-Yo antibody-positive PCD is unknown and may be related to the activation of CD8+ T cells. Early pathological changes in anti-Yo antibody-positive PCD include infiltration of lymphocytes around the blood vessels, activation of microglia, and infiltration of CD8+ T lymphocytes into the cerebellar Purkinje cell layer[17,18]. With disease progression, the pathological manifestation of PCD is mainly large and rapid loss of noninflammatory Purkinje cells[19,20]. An autopsy study on two Yo antibody-positive PCD patients found that both patients had extensive loss of Purkinje cells, activated microglia, and CD8+ T cells infiltration in all parts of the cerebellum, and it was found that despite the long disease duration, there were still surviving Purkinje cells.
In terms of treatment, as PCD cases are rare and it is difficult to design randomized controlled trials, the currently reported treatments for PCD also lack a foundation in evidence-based medicine. In addition, currently, research on anti-Yo antibody-positive PCD has not found promising and consistent treatments. Immunotherapy is currently controversial. Vernino reported no clinical benefit in 23 patients receiving immunosuppressive therapy, such as corticosteroids, plasma exchange (PLEX), and IVIg. However, there are reports that immunotherapy at the beginning of symptoms can control the development of the disease. Rojas et al reported that one of the 22 patients treated with PLEX showed a moderate clinical benefit. One of the 17 patients treated with high doses of steroids experienced a slight, transient improvement, while Shams'ili et al reported improvement in 2 out of 6 patients receiving immunosuppressive therapy. In our patient, the symptoms of vertigo, vomiting, and ataxia of the trunk were moderately relieved after IVIg and methylprednisolone treatment, and she was able to stand and walk with help. Immunotherapy had a moderate benefit in her, and clinical benefit may be due to the removal of pathological antibodies that had not been found to date through immunotherapy. In addition, guidelines from the Agency for Healthcare Research and Quality recommend early antitumor therapy, in addition to immunotherapy, as the approach that offers the greatest chance for PNS stabilization. According to the research of Shams'ili et al, antitumor therapy combined with immunotherapy improved and sustained the condition of 2 out of 6 patients with PCD, but other studies have shown that antitumor treatment has no clear effects[24,26]. According to our pathological results, our patient, who received a targeted drug (anlotinib hydrochloride), exhibited symptom improvement, and she sustained the good state (walk with help) for 2 mo. The patient was not treated with immune checkpoint inhibitor, because it could exacerbate PNS[27,28].
However, unlike other paraneoplastic syndromes, anti-Yo antibody-associated PCD is unlikely to respond significantly to the removal of the occult tumor. Disability progression of anti-Yo antibody-positive PCD results in < 10% of patients being able to walk unassisted for a long period of time, and most patients end up being bedridden. Anti-Yo antibody-positive patients have a median survival time of 13 mo, which is higher than that for anti-Hu syndrome patients[6,25]. In addition, some studies have shown that the prognosis of breast cancer combined with anti-Yo antibody-positive PCD is better than that of ovarian cancer. The former has a survival time of 100 mo, while the latter has a survival time of only 22 mo[24,29]. Early treatment is important to improve the prognosis of disease. Widdess-Walsh et al reviewed 15 cases of anti-Yo antibody-positive PCD patients treated with IVIg and found that the best prognosis was achieved when treatment was administered within 1 mo of the onset of symptoms. In this case, the patient was given IVIg and methylprednisolone half a month after symptom onset. After treatment, she was able to stand and walk with help, and she was alive at 16 mo after the onset of the disease, but was bedridden. The patient's improvement may be due to immunotherapy before extensive Purkinje cell loss; as a result of intervention, cerebellar Purkinje cells are preserved, and neurological deficit symptoms are improved. However, cholangiocarcinoma itself is highly malignant, and there is currently no prognostic study of cholangiocarcinoma combined with anti-Yo antibody-positive PCD, so the long-term efficacy of treatment still needs to be evaluated over an extended follow-up period.