Paraneoplastic syndrome

By Marcello Cherchi, MD PhD

For patients

If the body’s immune system recognizes a cancer, then it may mount an immunological attack against that cancer. However, in so doing, it may mistakenly also attack some of the body’s healthy (non-cancerous) cells. This is called a paraneoplastic syndrome. When a paraneoplastic syndrome involves the brain, it often attacks a part called the cerebellum, which can result in unsteadiness, clumsiness and deficits in coordination. In order to arrive at this diagnosis, your doctor may order a variety of tests, which may include imaging studies (such as an MRI of the brain). If a cancer is discovered, then the treatment is removal of the cancer.

For clinicians

Overview

Paraneoplastic syndromes arise when the immune system’s recognition of a malignancy results in mis-directed immune-mediated damage of healthy tissues.  Although any part of the body, and any part of the nervous system, can be affected, what usually comes to the attention of an otoneurologist is a paraneoplastic cerebellar disorder (which usually presents with ataxia), sometimes with a cochleovestibular component (which can present with vertigo, hearing loss and tinnitus).  These symptoms can begin rapidly, or evolve gradually, and they may precede recognition of the cancer by months or even years.  Paraneoplastic syndromes have been described with a broad variety of malignancies and antibodies.  Physical examination usually shows signs of appendicular and/or midline cerebellar dysfunction; ocular motor abnormalities usually include spontaneous down beat nystagmus, but broad array of ocular motor abnormalities have been reported.  These ocular motor abnormalities may be more easily detected and characterized with instrumented testing.  Other vestibular tests will not confirm a paraneoplastic syndrome, but may help exclude alternative diagnoses.  Brain MRI sometimes will show cerebellar atrophy, less commonly enhancement.  The differential diagnosis includes other cerebellar diseases.  In a patient with stigmata of malignancy (e.g., weight loss, blood in stool, hemoptysis) in whom no cancer has yet been identified, it is reasonable to consider a paraneoplastic etiology of symptoms.  If an apparently paraneoplastic syndrome occurs, then a search for malignancy should be undertaken, usually with CT of the chest/abdomen/pelvis without and with oral and intravenous contrast.  If that is unrevealing, then a full-body FDG‑PET scan is reasonable.  The main treatment is removal of the cancer.  If that fails, then there are no clear guidelines about what to try next, though a variety of immunosuppressive/immunomodulatory strategies have been attempted.  Prognosis is unfavorable.

Introduction

When the immune system identifies “non-self” antigens, it may mount an immune response. “Non-self” antigens may be present on infectious agents (viruses, bacteria), and the immune system response serves the purpose of destroying the invading pathogen. Cancerous cells, which are the body’s own cells whose genes have mutated, may express surface antigens that to the immune system appear “non-self,” and the immune system response serves the purpose of destroying the cancer cells (sometimes referred to as “immune surveillance”).

In some cases the “non-self” antigens (in the infectious agent or on the cancer cell) are similar to antigens of the body’s own healthy cells — sometimes called “molecular mimicry.” This is problematic because the immune system response to the infectious agent or cancer cell will mistakenly also attack the body’s own healthy cells. When this mis-directed immune attack is triggered by an infectious agent it is called a “para-infectious” phenomenon. When this mis-directed immune attack is triggered by a cancer it is called a “paraneoplastic” phenomenon.

These immune-mediated phenomena can attack any tissue in the body, including the nervous system. They can attack any part of the peripheral or central nervous system (Dalmau and Rosenfeld 2008). Within the central nervous system, the cerebellum is often affected; when triggered by an infectious agent this is called “para-infectious cerebellitis;” when triggered by a malignancy this is called “paraneoplastic cerebellar disease.”

In this section we will focus on paraneoplastic syndromes primarily or exclusively involving the cerebellum and audio-vestibular system.

Epidemiology

The prevalence of paraneoplastic syndromes is unknown (Dalmau and Rosenfeld 2008), and estimates vary dramatically, from 1 per 100,000 cancer patients (0.01%) to 553 per 60,000 cancer patients (0.9%) — a difference of nearly two orders of magnitude. Paraneoplastic syndromes have been reported with many different types of cancers.

Pathophysiological mechanism of disease

In a paraneoplastic syndrome, an immune response, whether humoral or cell-mediated (Dalmau and Rosenfeld 2008), erroneously attacks the body’s own healthy cells, presumably because of similarity between the epitopes of the cancer and the epitopes of healthy cells. A variety of antibodies has been identified.

Shams’ili and colleagues (Shams’ili, Grefkens et al. 2003) studied 50 patients with paraneoplastic cerebellar degeneration, and identified antibodies listed in the Table below.

Table: Antibodies and associated cancers in 50 patients with paraneoplastic cerebellar degeneration. From Shams'ili and colleagues (2003).
Table: Antibodies and associated cancers in 50 patients with paraneoplastic cerebellar degeneration. From Shams’ili and colleagues (2003).

Clinical presentation

Paraneoplastic syndromes have a wide range of tempo in symptom onset, ranging from hours to months.

The Figure below, from Hammami and colleagues (Hammami, Eggers et al. 2021), shows the chronology of cochlear and vestibular symptom development in 26 patients with paraneoplastic syndromes.

Figure: Chronology of cochlear and vestibular symptoms in 26 patients with paraneoplastic syndromes. From Hammami et al. (2021).
Figure: Chronology of cochlear and vestibular symptoms in 26 patients with paraneoplastic syndromes. From Hammami et al. (2021).

Physical examination

The neurological symptoms of patients with paraneoplastic syndromes often manifests with cerebellar symptoms such as ataxia, dysarthric speech, and abnormal eye movements.

Audiologic evaluation

While not common, paraneoplastic syndromes can cause hearing loss, and on audiometry this can be unilateral, bilateral and symmetric, or bilateral and asymmetrical.

Hammami and colleagues (Hammami, Eggers et al. 2021) studied 26 patients with “cochleovestibular” paraneoplastic manifestations, and stated that 16/26 (62%) of these patients presented with both cochlear and vestibular symptoms, 8/26 (31%) presented only with hearing loss, and 2/26 (8%) presented only with tinnitus. Of the patients with hearing loss, 13/26 (50%) had asymmetrical progression.

Kattah and colleagues (Kattah, Eggers et al. 2021) studied a 45-year-old man with a testicular seminoma whose paraneoplastic syndrome included bilateral, modestly asymmetrical, high greater than low frequency sensorineural hearing loss, as shown in the Figure below.

Figure: Audiometry in a 45-year-old male with testicular seminoma whose paraneoplastic syndrome included bilateral, modestly asymmetrical, high greater than low frequency sensorineural hearing loss. From Kattah et al. (2021).
Figure: Audiometry in a 45-year-old male with testicular seminoma whose paraneoplastic syndrome included bilateral, modestly asymmetrical, high greater than low frequency sensorineural hearing loss. From Kattah et al. (2021).

The hearing loss in paraneoplastic syndromes depends on the presence of malignancy, and thus can occur at any age. Since cancer tends to be more a disease of adults, it is unsurprising that a larger proportion of these cases occur in older age (Kearsley, Johnson et al. 1985), though it can occur in middle age (Kattah, Eggers et al. 2021) or even early childhood. For example, paraneoplastic hearing loss has been identified in a 24-month old child (by brainstem auditory evoked responses) with an anti‑Hu neuroblastoma (Fisher, Wechsler et al. 1994).

In paraneoplastic syndrome patients with cochlear and/or vestibular symptoms, the variety of antibodies and associated cancers is broad.

The Figure below, from Hammami and colleagues (Hammami, Eggers et al. 2021), shows the proportions of antibodies and associated cancers in 26 patients with paraneoplastic syndromes who had cochlear and/or vestibular symptoms.

Figure: The proportions of antibodies and associated cancers in 26 patients with paraneoplastic syndromes who had cochlear and/or vestibular symptoms. From Hammami et al. (2021).
Figure: The proportions of antibodies and associated cancers in 26 patients with paraneoplastic syndromes who had cochlear and/or vestibular symptoms. From Hammami et al. (2021).

Ocular motor examination

An impressive variety of ocular motor abnormalities has been reported in association with paraneoplastic syndromes, including:

  • Centripetal nystagmus (Cherchi and Hac 2023; Hac et al. 2023)
  • Spontaneous down beat nystagmus (Kearsley, Johnson et al. 1985, Guy and Schatz 1988, McLellan, Currie et al. 1988, Hammack, Kotanides et al. 1992, McCrystal, Anderson et al. 1995, Bussiere, Al-Khotani et al. 2008, Ogawa, Sakakibara et al. 2011, Choi, Park et al. 2014, Tsuyusaki, Sakakibara et al. 2014, Martin, Dillon et al. 2017, Kattah, Eggers et al. 2021, Kherallah, Samaha et al. 2022, Shivaram, Tallapalli et al. 2022, Khatib, Do et al. 2023)
  • Elliptical nystagmus (Mistry, Lee et al. 2016)
  • Abnormal visual fixation suppression (Kearsley, Johnson et al. 1985, Ogawa, Sakakibara et al. 2011, Kattah, Eggers et al. 2021, Kherallah, Samaha et al. 2022)
  • Gaze evoked nystagmus, both horizontal and vertical (Taylor, Mason et al. 1999, Choi, Park et al. 2014)
  • Ocular flutter (Kearsley, Johnson et al. 1985, Furman, Eidelman et al. 1988, Kruger, Yonekawa et al. 2014, Shivaram, Tallapalli et al. 2022)
  • Opsoclonus, usually in the context of opsoclonus-myoclonus (Fisher, Wechsler et al. 1994, Desai and Mitchell 2012)
  • Periodic alternating nystagmus (Ogawa, Sakakibara et al. 2011, Eggers, Pittock et al. 2012)
  • Perverted nystagmus (Inui, Saito et al. 2020)
  • Positional nystagmus (Kearsley, Johnson et al. 1985, Choi, Park et al. 2014)
  • Abnormalities on rotatory chair testing, such as low gain and phase lead (Kattah, Eggers et al. 2021), suggestive of bilateral vestibular weakness
  • Rebound nystagmus (Hac, Murphy et al. 2023)
  • Saccadic dysmetria (Wray, Dalmau et al. 2011, Wray, Martinez-Hernandez et al. 2011)
  • Saccadic intrusions (Furman, Eidelman et al. 1988, Wray, Martinez-Hernandez et al. 2011)
  • See-saw nystagmus (Rizvi, Cameron et al. 2018)
  • Skew deviation (McLellan, Currie et al. 1988, Taylor, Mason et al. 1999, Martin, Dillon et al. 2017)
  • Smooth pursuit abnormalities, usually with saccadic intrusions (Kearsley, Johnson et al. 1985, Wray, Dalmau et al. 2011, Wray, Martinez-Hernandez et al. 2011, Martin, Dillon et al. 2017, Kattah, Eggers et al. 2021, Kherallah, Samaha et al. 2022)
  • Spontaneous up beat nystagmus (Kearsley, Johnson et al. 1985, Wray, Dalmau et al. 2011, Wray, Martinez-Hernandez et al. 2011, Garcia-Reitboeck, Thompson et al. 2014, Cherchi 2015)
  • Windmill nystagmus (Lee, Kim et al. 2018)

The majority of these ocular motor abnormalities localize to the cerebellum; some localize to the brainstem.

Testing: vestibular

Instrumented ocular motor testing (such as with videonystagmography) may characterize the eye movement abnormalities better than a face-to-face examination.

Computerized dynamic posturography may show increased postural sway (Wessel, Diener et al. 1988), but this is neither sensitive nor specific for paraneoplastic cerebellar degeneration.

Other tests (such as vestibular evoked myogenic potentials, video head impulse testing) have not been studied in paraneoplastic cerebellar degeneration. Their main value is to exclude competing diagnoses.

Imaging

Brain MRI may show cerebellar atrophy in paraneoplastic cerebellar degeneration (Schlake, Husstedt et al. 1989, Akpinar, Berk et al. 1990, Emir, Kutluk et al. 2000, Scheid, Voltz et al. 2006, Fancellu, Corsini et al. 2014, Venkatraman and Opal 2016, Escudero-Fernandez, Garcia-Carpintero et al. 2020). Less commonly there may be enhancement, particularly of the cerebellar folia (Darnell and Posner 2003, Dalmau and Rosenfeld 2008).

The Figure below, from Dalmau and colleagues (Dalmau and Rosenfeld 2008) shows contrast enhancement of the sulci of the cerebellar vermis.

Figure: Contrast enhancement in the sulci of the cerebellar vermis in a patient with a paraneoplastic cerebellar syndrome from non-Hodgkin's lymphoma with anti-Tr antibodies. From Dalmau et al. (2008).
Figure: Contrast enhancement in the sulci of the cerebellar vermis in a patient with a paraneoplastic cerebellar syndrome from non-Hodgkin’s lymphoma with anti-Tr antibodies. From Dalmau et al. (2008).

Histopathology

Paraneoplastic cerebellar degeneration characteristically shows extensive loss of Purkinje cells, as well as degeneration in the deep cerebellar nuclei and inferior olivary nuclei (Dalmau and Rosenfeld 2008).

Differential diagnosis

In a patient with neurological symptoms compatible with a paraneoplastic syndrome, in whom a cancer has already been identified, and paraneoplastic antibodies have already been detected, the diagnosis of a paraneoplastic syndrome is secure.

However, the clinical scenario is often not so straightforward; either the symptom presentation may not be “classic” for a paraneoplastic syndrome, or no malignancy has yet been identified, or no antibodies have been detected (Dalmau and Rosenfeld 2008). For this reason, diagnostic criteria have been suggested.

The Table below, from Graus and colleagues (Dalmau and Rosenfeld 2008), reviews the diagnostic criteria for definite and for possible paraneoplastic neurological syndromes.

Table: Diagnostic criteria for definite and for possible paraneoplastic neurological syndromes. From Graus et al. (2004).
Table: Diagnostic criteria for definite and for possible paraneoplastic neurological syndromes. From Graus et al. (2004).

The Figure below, from Graus and colleagues (Dalmau and Rosenfeld 2008), shows the diagnostic clinical criteria in a flow-chart format.

Figure: Flowchart of diagnostic criteria for paraneoplastic neurological syndrome. From Graus et al. (2004).
Figure: Flowchart of diagnostic criteria for paraneoplastic neurological syndrome. From Graus et al. (2004).

The differential diagnosis of a paraneoplastic cerebellar syndrome includes other cerebellar insults. Since some cases of paraneoplastic cerebellar syndromes evolve over many months, they may be mistaken for a primary neurodegenerative process, such as multiple systems atrophy or a late-onset cerebellar ataxia.

Treatment

The standard of care in paraneoplastic syndromes with an identified malignancy is to remove the cancer. After that, if symptoms persist or worsen, there are no clear guidelines on how to proceed (Darnell and Posner 2003, Dalmau and Rosenfeld 2008). A variety of immune system manipulation strategies have been attempted, including steroids such as methylprednisolone (Keime-Guibert, Graus et al. 2000), other immunosuppressants — cyclophosphamide (Keime-Guibert, Graus et al. 2000), tacrolimus (Albert, Austin et al. 2000), rituximab (Esposito, Penza et al. 2008) — plasmapheresis (Cocconi, Ceci et al. 1985), intravenous immunoglobulin (Uchuya, Graus et al. 1996, Keime-Guibert, Graus et al. 2000, Widdess-Walsh, Tavee et al. 2003, Phuphanich and Brock 2007) and others. While there are occasional reports of dramatic responses to such interventions (Croteau, Owainati et al. 2001), in most cases the outcome is not satisfactory.

For a patient with suspected paraneoplastic syndrome a search should be undertaken for malignancy. This often involves a CT of the chest, abdomen and pelvis, with and without intravenous and oral contrast. If that is unrevealing, then a full-body FDG‑PET scan is reasonable (Marchand, Graveleau et al. 2007). Some investigators advocate doing CT and FDG‑PET simultaneously (Linke, Schroeder et al. 2004, Frings, Antoch et al. 2005). If no malignancy is identified, then close follow-up is appropriate, with the idea that an occult malignancy will eventually declare itself.

Prognosis

Even when malignancy is treated and immunomodulatory therapies are attempted, prognosis is unfavorable.

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Page first published on March 15, 2023. Page last updated on November 7, 2025

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