Clinical manifestations

Presentation and course

Patients with paraneoplastic cerebellar degeneration present with symptoms suggestive of a pancerebellar syndrome. They typically present with acute onset dizziness, incoordination, and gait instability and over days to weeks will develop progressive appendicular and truncal ataxia, sometimes with brainstem involvement such as oscillopsia, dysarthria, dysphagia, and dysphonia. Abnormalities of oculomotor function are common and include nystagmus (particularly downbeat nystagmus), disruption of smooth pursuit movements, ocular dysmetria, and opsoclonus. PCA1 (anti-Yo), PCA-Tr (anti-Tr or anti-delta/notch-like epidermal growth factor-related receptor [DNER]), and mGluR1 (metabotroptic glutamate receptor 1) IgG are principally associated with a cerebellar syndrome whereas the other paraneoplastic autoantibodies (such as anti-Hu [ANNA-1]) may manifest with multilevel neuroaxis involvement such as the peripheral nerve or dorsal root ganglia (56).

One large case series noted a mean age at onset of 46 years, with the majority of patients presenting with subacute (2 weeks to 3 months) disease onset. Gait ataxia, followed by limb ataxia, dizziness, dysarthria/dysphagia, nystagmus, and double vision, were the most common presenting symptoms; 28% of patients also had pyramidal signs, and 15% had radiculopathy/peripheral neuropathy. Prodromal symptoms like cough, fever, and diarrhea are also commonly reported (46).

Patients with antineuronal nuclear autoantibody type 1 (ANNA1 or anti-Hu) antibodies are more likely to have multilevel neurosis involvement such as encephalopathy, brainstem syndrome, myelopathy, sensory neuronopathy, neuropathy, and even disorders of the neuromuscular junction. In these instances, multiple antibodies indicating neurologic autoimmunity may be found concomitantly. Lambert-Eaton myasthenic syndrome and paraneoplastic cerebellar degeneration may coexist when P/Q type calcium channel (PQ VGCC) antibodies are present (59; 52). Antineuronal nuclear autoantibody type 2 (ANNA-2) may also present with paraneoplastic cerebellar degeneration in the context of other brainstem manifestations.

Particularly emphasis should be placed on the PCA1 antibodies. PCA1 antibodies are almost entirely restricted to patients with paraneoplastic cerebellar degeneration and carcinomas of the breast (importantly in both men and women), ovary, endometrium, and fallopian tubes (38; 56). There are a few reported women and men with other adenocarcinomas (53). A small percentage of patients have been identified with breast or ovarian cancer but no neurologic symptoms (17).

Antiglial nuclear antibody (AGNA) are now referred to as anti-SOX1 due to their targeting of the SOX1 protein. There is a strong link with lung cancer, Lambert-Eaton myasthenic syndrome (LEMS), and cerebellar ataxia. Although LEMS and cerebellar ataxia are the most common phenotypes, limbic encephalitis, encephalomyelitis, and gastrointestinal pseudo-obstruction have also been reported. Cell-based assays are the most sensitive diagnostic test (78). SOX1 is part of a large family of developmental transcription factors and are highly expressed in the early neuroectoderm and nervous system. It was first noted to be antigenic in LEMS in 2005 (65).

Anti-kelch-like protein 11 antibody disease manifestations include hearing disorders and cognitive changes and rarely opsoclonus-myoclonus, long spinal cord lesions, dysarthria, and seizures. Cerebellar atrophy is commonly noted on imaging, and most patients have an inflammatory CSF (45).

Neurologic symptoms often precede the diagnosis of malignancy, antedating the discovery by up to 2 years (59). In patients with PCA-Tr antibodies and Hodgkin lymphoma, initial reports demonstrated that disease onset appeared to occur after Hodgkin diagnosis, but other reports suggest up to 80% of patients may have symptoms prior to cancer diagnosis (06; 69).

Prognosis and complications

Neurologic deficits in paraneoplastic cerebellar degeneration generally worsen over a period of several weeks to months and then stabilize frequently with disability. Only about one third of patients can walk independently, and many patients cannot sit up or feed themselves. With few exceptions, paraneoplastic cerebellar degeneration does not remit spontaneously (39). Younger patients, with less disability, and early-stage malignancy treated early and aggressively from an immunologic and oncologic perspective experience better neurologic outcomes and longer survival (06). An overall mortality of around 10% has been described (46). These somewhat favorable results in patients with malignancy, severe irreversible neurologic deficits, and poor performance status may reflect a limited duration of follow-up and attrition of patients from the study.

Survival varies antibody type and is noted to be worse in patients with ANNA1, PCA1 compared to those with ANNA2 or PCA-Tr antibodies (39), with worse outcomes in ANNA1 and PCA1 (52; 69; 39). Survival outcomes are, of course, impacted by duration of follow-up (ie, shorter study follow-up, better survival). Significant neurologic improvement after successful treatment of the associated tumor appears to be more common in patients with ANNA-2, Collapsin response mediator protein 5 (CRMP-5) antibodies, and PCA-Tr antibodies. Although exceptions exist, patients with antibodies against plasma membrane antigenic targets such as mGluR1, acetylcholine receptor antibodies, voltage gated calcium channel (VGCC) antibodies, and PCA-Tr antibodies generally appear to have better outcomes than those with autoantibodies that target nuclear or cytoplasmic antigens.

Clinical vignette

A previously healthy 57-year-old woman acutely developed vertigo, nausea and vomiting, intermittent diplopia, and unsteady gait. Over the next several weeks, the symptoms persisted, and she also developed slurred speech and incoordination of both hands. Examination 2 months later was notable for the following: coarse right-beating nystagmus in primary gaze (worse looking to the right), mild weakness of the right lower face, moderate dysarthria, exaggerated gag reflex, titubation of the head and trunk, dysmetria and intention tremor of both upper extremities, and diffuse hyperreflexia with a Babinski sign on the right. She was unable to stand without assistance and could not walk. Brain MR scan was unremarkable. CSF was notable for 60 nucleated cells, lymphocytic predominate, protein 96 mg/dl, IgG 19.3 mg/dl (upper limit 6.0), elevated IgG index, and three unique CSF oligoclonal bands. Chest x-ray was normal as was CT of the chest, abdomen, and pelvis. Serum and CSF contained high-titer anti-PCA1 ("anti-Yo") antibodies. Mammogram (which the patient never previously had) showed left-sided mass and biopsy demonstrated adenocarcinoma.

The patient was administered 5 days of intravenous methylprednisolone and 5 days of intravenous immunoglobulin 0.4 mg/kg daily with plans for repeated infusions of methylprednisolone on a weekly basis for 12 weeks. She was referred to oncology. Two axillary lymph nodes were positive for tumor, and she was begun on chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil. The cyclophosphamide served a dual purpose of treating both the immunologic disease and oncologic disease. Approximately 3 months later, the neurologic exam had stabilized. The weekly infusions were increased to twice weekly and then gradually weaned off. Plasmapheresis was offered, but she declined and was transferred to a chronic care facility. Six months later (after 4 cycles of chemotherapy), no tumor was evident. Her neurologic deficits had improved slightly but she remained nonambulatory. Repeated MRI of the brain at this time demonstrated cerebellar hemispheric and vermian atrophy.

Biological basis

Etiology and pathogenesis

Autoantibodies. Patients with paraneoplastic and nonparaneoplastic autoimmune cerebellar degeneration have one of a steadily growing number of antineuronal autoantibodies identified in serum and CSF (Table 1) (39). To date, virtually all known paraneoplastic antibodies react with cerebellar neural antigens. Antibodies targeting both intracellular and cell surface (or plasma membrane) proteins have been identified to be associated with cerebellar degeneration, with and without an associated malignancy. mGluR1 antibodies, VGCC antibodies, and PCA-Tr antibodies are directed against antigens located on the cell surface in contrast to the great majority of antineuronal antibodies whose antigenic targets are intracellular including PCA1, ANNA1, and CRMP5 antibodies. GAD65 antibodies were one of the first to be discovered and have a varied presentation, including cerebellar ataxia phenotype (43%), but overlap syndromes are common. The incidence of malignancies are rare (4%) (08).

Rarer novel autoantibodies continue to be identified. One such autoantibody is plasticity-related gene 5 (PRG5) associated with squamous cell cancer of the lung and tripartite motif-containing protein 9, 46, and 67 (TRIM9/TRIM46/TRIM67) with pulmonary adenocarcinoma and carbonic anhydrase-related protein VIII and breast adenocarcinoma (79; 80; 16; 62). Metabotropic glutamate receptor 2 antibody (mGluR2-Ab) has also been described in patients presenting with various underlying cancers (64). Antibodies to glucose-regulated protein 78 (GRP78) were identified to alter and facilitate the brain uptake of autoantibodies across the blood-brain barrier, causing paraneoplastic cerebellar degeneration (70). Seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs) described in four patients presents with subacute gait ataxia and extrapyramidal syndromes (44). Another autoantibody is GTPase regulator associated with focal adhesion kinase 1/Rho GTPase activating protein 26‐immunoglobulin (GRAF1/ARHGAP26‐IgG), of which there are 27 cases reported in which the patients present with progressive cerebellar syndrome and more rarely peripheral neuropathy (60).

Another newly described autoantibody, kelch-like protein 11 (KLH11), is associated with a brainstem encephalitis and less commonly a progressive cerebellar syndrome. It is associated with testicular and less commonly extratesticular germ cell tumors and in a subset of patients only a regressed germ cell tumor is identified (49; 19).

Table 1. Common Autoantibodies in Paraneoplastic Cerebellar Degeneration

The pathogenesis of several of these autoantibodies is discussed in greater detail below.

PCA1. PCA1 antibodies were one of the first described paraneoplastic autoantibodies (38) and characteristically stain the cytoplasm and proximal dendrites of Purkinje cells in a coarsely clumped pattern by immunochemistry.

PCA1 antibodies react specifically with a 58 to 62 kd protein and (less strongly and consistently) with a 34 to 38 kd protein (12; 18; 74).

Initially, several target autoantigens for PCA1 antibodies were cloned using serum from affected patients as antibody probes to screen human cDNA expression libraries (18; 21). Three of the cloned autoantigens (PCD17, CDR62, and CDR3) share a high degree of sequence homology with one another and feature a "leucine zipper". CDR62 (or CDR2) downregulates c-Myc-dependent transcription and suppresses transcriptional activity dependent on nuclear factor-kappa B (57) and antibody reactivity to some but not all breast and ovarian cancers has been seen providing mechanistic insights (21; 68). Initially, the primary antigen was thought to be CDR2 but work has demonstrated that CDR2L is the major antigenic target for these antibodies (43; 33). Models for immune-mediated tumor regression in mice have defined the essential role of cytotoxic T lymphocytes in tumor immunity and autoimmune neuronal degeneration (02). Investigations have elucidated a potential association with several HLA class 2 alleles (34), suggesting a potential background of autoimmunity in patients with PCA1 antibodies.

PCA-Tr. PCA-Tr in association with cerebellar degeneration is the most common phenotype associated with Hodgkin lymphoma, and less commonly with non-Hodgkin lymphoma (06; 24). The antigenic target of anti-Tr antibodies has been identified as the Delta/Notch-like epidermal growth factor-related receptor (15; 30). Sera of patients with anti-Tr applied to tissue show a characteristic immunostaining pattern of punctate reactivity in the soma and large dendrites of Purkinje cells, and some neurons in the molecular layer (26). Detection of these antibodies is thought to be more often seen in the CSF than serum (06).

mGluR1. mGluR1 autoantibodies appear to cause a pancerebellar syndrome that is subacute and can be associated with the unique syndrome of dysgeusia (47). Autoantibodies were first detected in two patients in the early 2000s to these g-protein coupled cell surface receptors (71). There is a distinct Purkinje-cell body staining that is punctate and compatible with Purkinje cell spines observed in the molecular layer of the cerebellum; staining of neuron of the olfactory bulbe, tubercle, cerebral cortex, CA3 hippocampal region, thalamus, superior colliculus, and spinal trigeminal nucleus. In vitro application of patients' IgG to mouse cerebellar slices blocks mGluR1-mediated currents, and in vivo infusion of patients' IgG into mouse cerebellum causes abnormal eye movements (11).

Pathogenesis. The most striking and consistent neuropathologic finding in paraneoplastic cerebellar degeneration is a severe, diffuse loss of Purkinje cells throughout the cerebellar cortex. In extreme cases, an almost complete disappearance of Purkinje cells takes place. The remaining Purkinje cells often show nonspecific degenerative changes and are surrounded by a reactive proliferation of Bergmann astroglial cells (82; 52; 73). There may also be some neuronal loss in the granular cell layer and deep cerebellar nuclei. Some patients have perivascular cuffing and mononuclear cell infiltrates in the cerebellum and overlying leptomeninges. Up to one half of autopsied patients with predominant cerebellar signs and symptoms have a multifocal encephalomyelitis, with patchy neuronal loss and inflammatory infiltrates scattered through the cerebral hemispheres, brainstem, and spinal cord (56).

The central theory of autoimmune or paraneoplastic neurologic disorders is that an individual's tumor cells express antigenically identical or related to molecules normally expressed by neurons. In rare instances, an autoimmune response initially arising against "onconeural" antigens expressed by tumor cells subsequently attacks neurons expressing the same or related antigens (13). Clear pathogenicity of most autoantibodies has not been established but is instead considered biomarkers of neurologic autoimmunity.

Intraventricular injection of patients' PCA1 sera into rodents results in uptake of human IgG into the cytoplasm of Purkinje cells and other cerebellar neurons, without causing any notable clinical effects or neuropathologic changes (27; 75). In a study, patient PCA1 antibodies applied to cerebellar slice cultures were taken up by Purkinje cells and were associated with Purkinje cell death (31). Mice immunized with recombinant PCD17 protein produce high-titer anti-Yo antibodies but do not develop the clinical or pathological features of cerebellar degeneration (67; 75). Injection of peripheral mononuclear cells from patients with paraneoplastic cerebellar degeneration into mice with severe combined immunodeficiency results in the production of low titers of anti-Purkinje cell antibodies, but with no clinical or neuropathologic changes (75). Similarly, animals actively immunized with recombinant Hu proteins (72) or with HuD DNA vaccination (09) produce anti-Hu antibodies but do not develop clinical disease. By contrast, intrathecal injection of sera from patients with cell surface protein targeting voltage-gated calcium channel IgG into mice causes reversible ataxia (51).

Cytotoxic T cell responses have been thought to be critical to the development of neurologic disease (02; 01). It is postulated that onconeural antigens released by apoptotic tumor cells are presented to T lymphocytes in draining peripheral lymph nodes, initiating a Th1 helper response that eventually gains access to the CNS and attacks neurons expressing the antigens but mechanisms for these are largely unknown. Patients with paraneoplastic cerebellar degeneration and PCA1 antibodies have activated T lymphocytes in the cerebrospinal fluid (01). At autopsy, some patients with PCA1 antibodies have parenchymal and perivascular infiltration of CD8+ T-lymphocytes in the cerebellum and other areas of the brain (56). Some studies identified circulating CD8+ cytotoxic T lymphocytes reacting with HuD protein (76; 63).

Epidemiology

Paraneoplastic cerebellar degeneration may be the most common paraneoplastic syndrome affecting the CNS, but it is still a rare complication of cancer. Due to the severity of the symptoms, it is likely that patients will come to medical attention. Epidemiologic data from Italy suggests that the incidence of paraneoplastic neurologic syndromes is approximately 0.89/100,000 person-years, increasing likely due to increased recognition. Twenty-eight percent of the patients identified had paraneoplastic cerebellar degeneration and PCA1 was identified 30% of the time (83). It is possible that this may reflect a reporting bias.

Paraneoplastic cerebellar degeneration occurs in association with a wide variety of neoplasms, but 90% of published cases have small cell lung carcinoma, Hodgkin lymphoma, or carcinomas of the breast or gynecologic malignancies (59; 52; 69; 56; 20; 24).

Additionally, with the use of immune checkpoint inhibitor therapy for malignancy, there is an increasing number of antibody negative and positive cases of subacute cerebellar syndromes and cerebellitis after administration of antiprogrammed cell death protein 1 (PD1) and/or anticytotoxic T-lymphocyte antigen 4 (CTLA4) therapies (81). Neurologic autoimmunity is recognized with continued use of these therapies and can cause significant morbidity (40; 86; 85).

Prevention

Tobacco abuse increases risk due to its association with small cell lung cancer. Additional preventative measures include attention to regular guideline mandated oncologic screening including colonoscopy, mammography, gynecologic examinations and pap smear, and PSA when appropriate.

Differential diagnosis

Paraneoplastic cerebellar degeneration should be considered in any adult presenting with subacute pancerebellar dysfunction (25). Often, it can be distinguished from degenerative conditions by its abrupt onset and rapid progression to severe disability over several weeks to months, but this is not always the case. The differential diagnosis of diffuse cerebellar dysfunction in adults includes inherited or sporadic neurodegenerative disorders such as the olivopontocerebellar atrophies, spinocerebellar degeneration, or multiple system atrophy (42). Rarer diseases including prion disorders such as Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker can present with primarily a cerebellar degeneration. Toxic or metabolic conditions that cause cerebellar syndromes include medication use, heavy metal poisoning, thyroid dysfunction, vitamin deficiency or alcoholism, HIV, and gluten-related or celiac disease. Therapy with phenytoin, 5-fluorouracil, and/or high-dose intravenous cytarabine treatment can present with cerebellar dysfunction; the incidence of these toxicities often increases with cumulative dose of the drug and increasing patient's age.

Demyelinating disease, cerebrovascular disease, neoplasm, infectious or postinfectious cerebellitis, or Miller-Fisher variant of Guillain-Barre syndrome can also occur.

Several autoantibodies, particularly those targeted against plasma-membrane proteins, are associated with autoimmune ataxia but without an underlying malignancy. Some may still be classified as paraneoplastic given their high predictive value for specific cancers, for example, PCA-Tr and Hodgkin lymphoma.

Several autoantibodies targeting GAD65, PCA-Tr, P/Q type VGCC, CASPR2, GABA-B, and mGLUR1 occur without an identified neoplastic association (37). GAD65 ataxia is notable in that it is associated with intracellular GAD65 autoantibodies but is not commonly associated with malignancy except thymoma in 10% of cases (66; 50; 05). Syndromically, it may occur with other forms of nonneurologic autoimmunity such as type 1 diabetes, autoimmune thyroiditis, and pernicious anemia.

Confusing conditions

The differential diagnosis of paraneoplastic cerebellar degeneration includes structural lesions such as brain metastasis, neurodegenerative conditions (multiple system atrophy, Creutzfeldt-Jakob disease), and toxic-metabolic derangements (medication related or iatrogenic, vitamin deficiencies, hypothyroidism, alcoholism, HIV, celiac disease). Demyelinating disease, cerebrovascular disease, and peri- or post-infectious causes can also be considered.

Diagnostic workup

Laboratory testing for alternative causes of cerebellar ataxia should be pursued and careful family history should be taken. Testing may include basic chemistry panels, thyroid function, antinuclear antibodies and celiac testing, and HIV and GAD antibodies.

Brain MRI may be normal-appearing initially. It can be used to exclude alternative etiologies. Rarely, in the acute phases, MRI may show cerebellar T2 signal abnormalities or contrast enhancement of the cerebellar folia (14; 23). Fluorodeoxyglucose-PET brain scanning may show diffuse cerebellar hypermetabolism in the acute phase as well (10). In chronic stages diffuse cerebellar atrophy can be seen (59).

Basic cerebrospinal fluid studies can be relatively nonspecific or normal but in approximately one half of patients with paraneoplastic cerebellar degeneration shows slightly elevated protein or a mild lymphocytic pleocytosis (10-50 lymphocytic cells), elevated IgG index, and CSF specific oligoclonal bands (59).

We recommend autoantibody testing in both CSF and serum in patients in whom there is a strong clinical suspicion of neurologic autoimmunity. Not all antibodies are commercially available or well characterized and so if clinical suspicion is present, testing on a research basis may be warranted. Due to these limitations, an autoantibody may not be identified in a case of autoimmune or paraneoplastic cerebellar degeneration (20).

Some notes should be made regarding antibody associations and titers. No clear association exists between antibody titers and tumor development (06; 69; 15). Some patients with breast, ovarian, and small cell lung cancers have been found to have low titers of antineuronal antibodies without neurologic autoimmunity (17; 04). Additionally, when GAD65 or acetylcholine receptor antibodies are detected in serum, lower titers may have no clear association with malignancy or neurologic autoimmunity.

Investigation for occult malignancy should ensue in patients without a cancer diagnosis. The level of suspicion for specific malignancy diagnosis should be determined based on patient age, gender, tobacco abuse history, family history, and importantly, the paraneoplastic autoantibody specificity. We generally recommend patients undergo a CT of the chest abdomen and pelvis and/or PET scan of the body, particularly when the associated autoantibody has a high pretest probability of cancer (32; 55; 54). Mammogram and pelvic ultrasound should be considered in women if not recently performed (77). Empirical chemotherapy or other antitumor treatment without histologic proof of cancer is not recommended. In women with PCA1 antibodies, if mammogram and pelvic ultrasound are unrevealing, further testing such as breast MRI or CA125 testing with interval screening may be warranted due to the high association with these malignancies in these patients.

Comments regarding specific autoantibodies and their association with small cell lung cancer should be made. ANNA1 and CRMP5 autoantibodies are the most well recognized syndrome associations. Additionally, patients with small cell lung cancer and paraneoplastic cerebellar degeneration (or other neurologic syndrome) may have more than one type of circulating antineuronal antibody, often at lower titers (04; 61; 35; 36). The co-occurrence of antibodies may also indicate neurologic involvement at multiple levels of the nervous system. Autoantibodies to SOX1 or VGCC predict small cell lung cancer in patients with cerebellar degeneration or Lambert-Eaton myasthenic syndrome (48).

Management

Systematic analysis of immunologic and oncologic treatment in the management of these patients has been hampered by the rarity of the disease and recommendations are primarily derived from retrospective literature. Oncologic therapy is generally accepted to be necessary for disease stabilization or improvement and should be pursued expeditiously.

Immunotherapy is often utilized but it remains unclear to what degree (and in what direction---favorable or unfavorable) it impacts disease course. Historically, outcomes for patients with paraneoplastic cerebellar degeneration have been poor despite immunologic or oncologic therapy and the majority remaining nonambulatory at last follow-up. However, some anecdotal reports and retrospective series have reported improvements with plasma exchange, intravenous immunoglobulin, corticosteroids, and longer term immunosuppressants such as cyclophosphamide and rituximab. As compared to those with nonparaneoplastic (autoimmune) ataxias, immunotherapy responsiveness differs and improvement to ambulatory status is only seen in approximately 30% of patients (39).

The poor clinical response to corticosteroids or plasma exchange does not necessarily refute an autoimmune pathogenesis, as it is likely that by the time paraneoplastic cerebellar degeneration is diagnosed, many patients have already suffered irreversible neuronal damage or loss (22).

Given the disabling nature of these syndromes and uncertainty of the diagnosis at initial encounters, it is reasonable to attempt an early and aggressive immunotherapy trial, with objective measures taken pre- and post-treatment to assess for improvement. Prior literature has suggested that early immunotherapy may be associated with better outcomes (84; 39). Acute immunotherapies such as intravenous steroids, plasmapheresis, and intravenous immunoglobulin can be considered and can be continued on a weekly basis for up 6 to 12 weeks to provide ample time to assess adequate response. Longer term, aggressive immunotherapy such as rituximab or oral or intravenous cyclophosphamide can be considered (41; 28; 69; 56; 39).