A Rare Presentation of Dizziness: Vestibular Testing in Paraneoplastic Cerebellar Degeneration

Abstract

Background:

Paraneoplastic cerebellar degeneration (PCD) is a rare neurological disorder caused by tumor-mediated antibodies targeting the cerebellum, often leading to irreversible cerebellar damage. The most common antibody implicated in PCD is anti-Purkinje cell cytoplasmic antibody type-1, associated with malignancies such as breast, gynecological, and lung cancers. Symptoms often include dizziness, imbalance, progressive ataxia, and other cerebellar signs/symptoms, but early presentations may mimic acute vestibular syndrome, thus complicating diagnosis.

Purpose:

To present a case of PCD and demonstrate how objective vestibular test results facilitated the management of the patient’s medical care.

Research Design:

Case report.

Case Presentation:

A 67-year-old female with a history of left breast cancer presented with acute dizziness, imbalance, and left-sided lower-extremity weakness. The patient was referred for objective vestibular testing at the request of her internal medicine doctor.

Results:

Vestibular testing revealed continuous down-beating nystagmus and abnormal video head impulse test (vHIT) findings of the posterior canals only. Findings and history raised concern for central vestibular origin. Subsequent neurological evaluations revealed progressive cerebellar dysfunction. After a long medical journey, anti-Yo antibodies were detected, confirming a diagnosis of PCD.

Conclusions:

PCD can present with early vestibular symptoms, such as vertigo and dizziness, and as a result of damage to Purkinje cells in the cerebellum. This damage extends to the central vestibular system structures, which can lead to down-beating nystagmus and impaired vestibular-ocular reflex function as evident by vHIT findings. Early vestibular testing can play a role in the diagnosis, particularly when accompanied by a detailed cancer history.

Clinical Relevance Statement:

Given the rapid disease progression of PCD, it is crucial for clinicians conducting vestibular testing to understand signs of central nervous system involvement and refer patients promptly for neurological evaluation.

INTRODUCTION

Paraneoplastic syndromes are rare debilitating neurological disorders characterized by the production of tumor-mediated antibodies in response to an underlying cancer. When these antibodies target the cerebellum specifically, this is often called paraneoplastic cerebellar degeneration (PCD). PCD is most commonly caused by anti–Purkinje cell cytoplasmic antibody type-1 (PCA-1), also known as anti-Yo, which leads to irreversible damage to the Purkinje cells in the cerebellum. This leads to progressive ataxia, coordination and motor decline, and other neurological symptoms often preceding the presentation of the underlying malignancy by several months to a year (Afzal et al., 2015). Anti-Yo is typically associated with breast and gynecological cancers, although it has also been reported in lung cancer and Hodgkin’s disease (Peterson et al., 2011; Venkatraman & Opal, 2016).

Although the onset of cerebellar dysfunction typically develops over several days to weeks, patients with PCD can often first present with symptoms more consistent with that of an acute vestibular syndrome: vertigo, dizziness, associated nausea, and vomiting. Progressive ataxia, diplopia, dysarthria, dysphagia, transient opsoclonus, and cognitive impairment often develop with disease progression. As a result, PCD can initially be confused with a peripheral vestibular disorder (Kherallah et al., 2022; Mendes et al., 2023), possibly leading to delays in medical diagnosis and oncology intervention. We present a patient diagnosed with PCD (anti-Yo) who was seen for vestibular laboratory testing as the initial diagnostic assessment, and red flags on the examination suggested a nonperipheral vestibular source for symptoms and signs.

CASE PRESENTATION

Initial Symptoms

A 67-year-old female presented for a vestibular evaluation (vestibular test battery [VTB]) at the request of her primary care doctor. She reported concerns of acute dizziness described as “spatial disorientation,” followed by gradual imbalance and left-sided lower-extremity weakness characterized as a “heaviness” sensation, which began two months before the evaluation. She had not fallen but reported a near fall after a quick lateral turn when ambulating. Significant medical history included left breast cancer status postmastectomy in 2013 and right hip replacement. There was no known family history of neurological or gait disorders. Although she had a reported prior history of alcohol use disorder, she denied any alcohol use three months prior to the evaluation or any history of recreational drug use.

Vestibular Evaluation

She completed vestibular testing, which demonstrated the following significant findings: (1) 3–6 degrees/second (d/s) continuous, pure down-beating nystagmus observed during both right and left Dix-Hallpike conditions (see Table 1); (2) video head impulse testing (vHIT) VOR gain parameter of 0.61 (less than 0.7 reference range) for left posterior semicircular canal (SCC) with evidence of overt saccades (see Figure 1). The right posterior canal VOR gain value was 0.77; however, overt saccades were also observed. All other SCCs VOR gain values were within normal reference range without evidence of corrective saccades. Bilaterally absent (no measurable responses to air or bone conduction stimuli) ocular vestibular-evoked myogenic potentials were also observed. The remaining portions of the vestibular evaluation were unremarkable: no signs of oculomotor dysfunction observed on saccade performance test or smooth pursuit test, no provoked nystagmus during eccentric gaze testing with or without fixation, no post-headshake nystagmus in the horizontal or vertical conditions, no nystagmus provoked during positional testing (head and body), symmetrical bithermal water caloric irrigations (15 percent unilateral weakness of the right ear, abnormal >25 percent based on laboratory normative values) with normal directional preponderance (<30 percent based on laboratory normative values) and fixation suppression, and bilaterally present cervical vestibular-evoked myogenic potential responses.

Table 1.

Relevant Videonystagmography Findings

Vision-denied test performed	Characteristics of down-beating nystagmus
Upward gaze	None
Downward gaze	None
Right gaze	None
Left gaze	None
Dix-Hallpike right ear down	6 d/s (brief)
Dix-Hallpike right return-to-sit	None
Dix-Hallpike left ear down	3 d/s (continuous)
Dix-Hallpike left ear return-to-sit	None
Horizontal head center supine	None
Horizontal head roll right	None
Horizontal head roll left	None

Note: Within our laboratory, >7 d/s is the criterion for clinically significant vertical nystagmus (Honaker, 2021).

Figure 1.

Abnormal posterior canal vHIT findings.

Due to vestibular test findings of down-beating nystagmus and below reference range posterior canal vHIT VOR value and overt saccades in conjunction with the patient’s symptoms of gradual imbalance, lower-extremity weakness, and history of cancer, a neurological consultation was recommended to rule out a possible central vestibular contributor. Physical therapy was not recommended at that time. Although down-beating nystagmus was observed during positional testing, the likelihood of atypical posterior SCC BPPV or anterior SCC BPPV was considered low based on the following: symptoms were not provoked during ear-down positions, the nystagmus did not follow a crescendo-decrescendo pattern, nystagmus did not fatigue with repeated positioning, no torsional component was observed, and nystagmus did not reverse upon return-to-sit.

Progressing Symptoms and Subsequent Neurological Evaluations

Approximately three weeks after the vestibular evaluation, her gait began to decline rapidly, as per assessment of managing medical providers, necessitating the use of an assistive device for ambulation. She received her first outpatient neurological evaluation with significant examination findings, including truncal ataxia, rotary lateral gaze nystagmus of the left eye, and positive Babinski. Magnetic resonance imaging (MRI) was completed at that time, which revealed “no evidence of an acute intracranial process, mass, or pathological enhancement. Mild nonspecific white matter changes, likely reflecting chronic microvascular ischemia. Otherwise, age-appropriate MRI of the brain” (see Figure 2). Electromyography and additional laboratory tests ordered were unremarkable. The managing provider’s differential diagnosis included paraneoplastic syndrome versus cervical myelopathy.

Figure 2.

The patient’s initial MRI completed at the onset of symptoms showed “no evidence of an acute intracranial process, mass, or pathological enhancement. Mild nonspecific white matter changes, likely reflecting chronic microvascular ischemia. Otherwise, age-appropriate MRI of the brain.”

With continued progression of symptoms, she was seen in the emergency department (ED) five times over the next two and a half months for gait and truncal ataxia, recurring falls, dysarthria, dysphagia, myoclonus of her left leg, and difficulties with handwriting. During the initial two hospitalizations she was found to have borderline low B12 levels, for which thiamine was initiated because of her history of alcohol use. Neurological consultations did not reveal any significant change in her bedside neurological examination. The medical team also expressed concerns for possible conversion disorder.

The patient’s gait instability, ataxia, and previously noted neurological symptoms continued to progress, with newly formed confusion and altered mental status. Additional diagnostic testing while in the ED revealed a high-titer positive anti-Yo (PCA-1) antibody, cerebrospinal (CSF) fluid analysis demonstrated inflammatory changes, including a white blood cell count of 10, positive oligoclonal bands, and an elevated immunoglobin G index. A repeat MRI demonstrated atrophy of the bilateral cerebellar hemispheres and vermis, and positron emission tomography (PET) imaging revealed diffuse hypometabolism of the cerebellum, and bilateral cerebellar and vermis atrophy (see Figures 3 and 4). After a prolonged diagnostic course, the cause for her debilitating symptoms was ultimately identified: anti-Yo PCD.

Figure 3.

The patient’s repeat MRI, which was completed four months after the onset of symptoms, demonstrated bilateral cerebellar hemisphere and vermis atrophy.

Figure 4.

PET scan of the brain. Warmer colors (red/yellow) indicate regions of increased uptake, whereas cooler colors (green/blue) represent lower metabolic activity. The image represents symmetrically decreased cerebellar hypometabolism.

A comprehensive workup was conducted to identify the underlying neoplasm. An imaging study revealed a 1.0-centimeter nodule in the middle lobe of the lung; a biopsy was also completed, which supported a carcinoid tumor. The medical team hypothesized that this tumor was the underlying cause of PCD through a remote, immune-mediated paraneoplastic mechanism. In PCD, the cerebellar dysfunction does not result from direct tumor invasion or metastasis, but rather from an immune response triggered by the presence of the malignancy. Unfortunately, the patient passed away as a result of PCD approximately five months after vestibular testing and the onset of symptoms, and two months after receiving the confirmatory diagnosis.

DISCUSSION

The typical symptomatology of anti-Yo PCD reflects subacute cerebellar and/or brainstem dysfunction: ataxia of the trunk and limbs, oscillopsia, blurred vision, diplopia, nystagmus, dysarthria, tremor, and in some cases, dysphagia (Peterson et al., 2011). Nystagmus patterns and direction are dependent on cerebellar involvement. It is theorized that during the initial stages of PCD the cerebellar vermis and midline structures are most impacted (Lou et al., 2021). Damage localized to these areas, including the flocculonodular lobe or cerebellar nodulus, can manifest as horizontal (gaze evoked), multidirectional, or more commonly down-beating nystagmus. There have been several case reports in the medical literature supporting early-onset symptoms of dizziness, vertigo, and nausea before PCD diagnosis—potential early clinical manifestations, as seen in our case example. Kherallah et al. (2022) described three patients with PCD with initial presenting symptoms of acute vertigo, nausea, and vomiting. All patients demonstrated two to three d/s down-beating nystagmus during the spontaneous gaze condition when under Frenzel or video goggles. Down-beating nystagmus velocity increased with lateral gaze, and as the disease progressed, cerebellar symptoms became more pronounced over time. Kim (2022) reported on a patient with acute vertigo, seen for vestibular laboratory testing four days after symptom onset, presenting with spontaneous down-beating nystagmus in vision-denied conditions. Our patient’s vestibular test findings included the presence of continuous down-beating nystagmus (vision-denied conditions; suppressed with fixation) during bilateral Dix-Hallpike testing. The studies of PCD, which included vestibular laboratory testing, demonstrated a similar presentation of down-beating nystagmus (although elicited in different conditions) as our patient: pure down-beating nystagmus in mostly vision-denied conditions. Although vestibular laboratory findings in patients with anti-Yo PCD are limited to a few case reports, down-beating nystagmus has been consistently noted during neurological examinations. In the largest study to date, which evaluated 55 patients with anti-Yo, 20 presented with acute vertigo and 19 exhibited down-beating nystagmus upon bedside neurological evaluation (Peterson et al., 2011). This aligns with the literature, further supporting the association between early vestibular symptoms and the presence of down-beating nystagmus as two early clinical features in patients with anti-Yo PCD.

The clinical manifestations of PCD are a result of autoimmune-mediated and irreversible death of Purkinje cells of the cerebellum (Venkatraman & Opal, 2016). The presence of the tumor triggers the remote destruction of both the Purkinje cells and granular cells in the cerebellar cortex, although the exact pathomechanism underlying this process remains unclear. It is believed that the vestibular nuclei in the brainstem, which receive input from Purkinje cells in the floccular lobe, play a significant role in regulating VOR and vestibulospinal reflex functions (Shemesh & Zee, 2019). One mechanism possibly explaining the development of down-beating nystagmus is the malfunction of direction-specific Purkinje cells (located within the floccular lobe), which are important for processing downward visual motion as opposed to upward motion. When these cells are compromised because of PCD, the firing rate for neurons responsible for upward eye movements increases, leading to an upward drift of the eyes during VOR slow phase. This is followed by a fast phase of downward eye movements to correct eye position, hence the down-beating nystagmus pattern (Marti et al., 2005). Thus, dysfunction of Purkinje cells in PCD contributes to both cerebellar and vestibular abnormalities.

Possible central and vestibular signs were further demonstrated with vHIT findings in our patient. We observed vHIT VOR gain values below reference range (<0.70) for the left posterior canal with evidence of corrective saccades for both left and right posterior canals. Our patient did not exhibit nystagmus at the bedside or present with fixation, and no overt ocular abnormalities were observed. The potential for our patient’s vHIT tracings to be inaccurately skewed by superimposed ocular abnormalities is less likely. Moreover, vertical high-frequency VOR gain values in patients with down-beating nystagmus have been shown to be symmetrical and comparable with normal controls (Glasauer et al., 2004). The abnormal vHIT findings observed are likely to represent true dysfunction of high-frequency VOR pathways and are less likely due to superimposed nystagmus on vHIT tracings or other overlapping ocular abnormalities.

This pattern of impaired high-frequency VOR function has been observed in all case reports of patients with anti-Yo PCD (n = 3) who received vHIT testing: two patients had unilateral horizontal SCC vHIT gain below reference range with ipsilateral overt and covert corrective saccades, with all other SCCs spared; one patient had gain within reference range for all SCCs, with present overt and covert saccades for the right horizontal canal only (Kherallah et al., 2022; Kim, 2022; Lou et al., 2021). Due to the present down-beat nystagmus observed in all patients, in addition to other oculomotor abnormalities, impaired function of central vestibular structures (rather than peripheral) was the evident source of impaired high-frequency VOR function. As mentioned earlier, the Purkinje cells located within the flocculus and nodulus send inhibitory projections to the vestibular nuclei. The irreversible Purkinje cell death caused by anti-Yo PCD likely disrupts these neural connections. If this lesion is greater on one side over the other, this could result in asymmetrical VOR tonic activity, and thus unilateral vHIT abnormalities. This would also explain the acute vertigo and dizziness patients with PCD can experience as an initial symptom.

There are additional confirmatory markers beyond the presence of anti-Yo, including inflammatory findings in CSF and increased cancer antigen 125 levels, which aid in supporting the diagnosis. However, diagnosing PCD remains particularly challenging because neuroimaging can appear normal in the early stages, whereas cerebellar atrophy becomes evident only with significant disease progression (Venkatraman & Opal, 2016). This pattern was observed in the case presented, as well as all case reports reviewed where down-beating nystagmus and/or impaired high-frequency VOR function was identified (Kherallah et al., 2022; Kim, 2022; Lou et al., 2021). Although a detailed discussion of the diagnostic criteria for anti-Yo PCD falls outside the scope of this case report, recognizing characteristic vestibular test findings is crucial for assisting in the timely and accurate diagnosis and management of this condition. Indeed, the VTB may pick up subtle changes in central vestibular function that may not be seen structurally in the early stages of the disease.

CONCLUSIONS

Patients with PCD can receive formal vestibular laboratory testing as an initial diagnostic assessment, given symptoms of acute vertigo, dizziness, and gait instability can precede other overt central signs and symptoms. The down-beating nystagmus and abnormal vHIT findings observed in our case example, as well as several case reports, can be attributed to the fact that the vermis and other central midline cerebellar structures are often the first structures implicated in the disease. If this process occurs unilaterally or asymmetrically, this could account for dizziness and vertigo as the initial presenting symptoms. Given the rapid disease progression observed in the presented case and documented in the medical literature, it is prudent for those conducting vestibular testing to be alert when down-beating nystagmus is accompanied by acute or subacute dizziness, nausea, vomiting, and any other central nervous system symptoms. More research is needed to understand high-frequency VOR disruption as evidenced on vHIT measures given inconsistent semicircular canal dysfunction pattern in case reports. Finally, providers should also gather a detailed cancer history and promptly refer patients to neurology for timely medical evaluation and management. This case illustrates the importance of interprofessional collaboration; the audiologist’s timely referral to neurology started this patient’s journey to receiving a diagnosis.

DISCUSSION QUESTIONS

• 1.How did the patient’s symptomatology, in conjunction with the objective vestibular test findings, shape the overall clinical picture?
• 2.Given that neuroimaging can appear normal in the early stages of PCD, what role should vestibular testing have in cases of central vestibular function with normal imaging?
• 3.What strategies can be implemented in the audiological settings to improve the identification of red flag symptoms that warrant further medical/neurological attention?

Abbreviations

CSF

cerebrospinal

d/s

degrees/second

ED

emergency department

MRI

magnetic resonance imaging

PCA-1

anti–Purkinje cell cytoplasmic antibody type-1

PCD

paraneoplastic cerebellar degeneration

PET

positron emission tomography

vHIT

video head impulse test

VOR

vestibulo-ocular reflex

VTB

vestibular test battery