Paraneoplastic cerebellar degeneration

INTRODUCTION — Paraneoplastic neurologic syndromes are a heterogeneous group of neurologic disorders associated with systemic cancer and caused by mechanisms other than metastases, metabolic and nutritional deficits, infections, coagulopathy, or side effects of cancer treatment.

Paraneoplastic cerebellar degeneration (PCD) is an uncommon disorder that can be associated with any cancer; the most commonly associated are lung cancer (particularly small cell lung cancer [SCLC]), gynecologic and breast cancer, and lymphoma (particularly Hodgkin disease [HD]) [1]. The neurologic symptoms frequently precede or coincide with the diagnosis of cancer.

This topic discusses PCD. An overview of paraneoplastic syndromes and other paraneoplastic disorders are discussed separately. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle" and "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

PATHOGENESIS — The cerebellum is a frequent target of paraneoplastic autoimmunity. All paraneoplastic antibodies have been reported in association with PCD [2-17]. Some of these autoantibodies are associated with specific clinical settings (table 1) that may help focus the search for an underlying occult malignancy.

In addition to antibody-mediated immune responses, cytotoxic T cell responses appear to be important in the pathogenesis of PCD and are most likely the primary mediators of the pathologic damage [7,18,19].

Pathologic examination shows marked degeneration of the Purkinje cells with minimal involvement of the molecular or granular cell layers along with inflammation, depending on the stage of the disease, in the cerebellar cortex, deep cerebellar nuclei, and inferior olivary nuclei (picture 1) [1,2]. In patients who have PCD coexisting with Lambert-Eaton myasthenic syndrome (LEMS), the immunologic target of the antibodies appears to be the P/Q type voltage-gated calcium channel of the cerebellar molecular layer [3]. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis", section on 'Pathophysiology'.)

ASSOCIATED ANTIBODIES — Only three antibodies, anti-Yo, anti-Tr (or anti-Delta/Notch-like epidermal growth factor-related receptor [DNER]), and anti-metabotropic glutamate receptor 1 (mGluR1), predominantly associate with cerebellar dysfunction; the other paraneoplastic antibodies often associate with symptoms involving other areas of the nervous system, with or without cerebellar dysfunction.

Anti-Yo — The most common among the associated antibodies, anti-Yo antibodies (also called Purkinje cell cytoplasmic antibody type 1 [PCA-1]) primarily occur in patients with PCD who have breast cancer or tumors of the ovary, endometrium, and fallopian tube [4,5,20-22]. Rare cases of anti-Yo-associated PCD have been described in men with adenocarcinoma [23-27].

The target antigens of anti-Yo antibodies are the cerebellar degeneration-related (CDR) proteins that are expressed by Purkinje cells (picture 1) and ovarian and breast cancers [6,7,28,29].

Anti-Tr — DNER antibodies [30] appear to be specific for cerebellar degeneration associated with Hodgkin disease (HD) and less commonly non-Hodgkin lymphoma [8,9,31-34]. In some patients, these antibodies are detectable in the cerebrospinal fluid (CSF) but not in serum.

In contrast to other clinical settings, PCD often develops after the diagnosis of HD or when the patient's tumor is in remission [31].

Anti-mGluR1 — Antibodies to mGluR1 were initially identified in two patients with paraneoplastic cerebellar ataxia and Hodgkin lymphoma. Additional patients have since been reported, all with cerebellar ataxia and most without an associated cancer (table 1) [16,35,36].

Others — The remaining antibodies have been reported in association with a variety of neurologic syndromes, both with and without accompanying cerebellar dysfunction.

●Anti-Hu antibodies (also called antineuronal nuclear antibody, type 1 or ANNA-1) are prevalent in patients with small cell lung cancer (SCLC) and PCD. In one report of 57 such patients, 44 percent had a high titer of anti-Hu antibodies [2]. These patients are more likely to have multifocal neurologic disease and severe disability than other patient groups [37]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Anti-Hu encephalomyelitis'.)

●Anti-P/Q type calcium channel antibodies were the second most commonly associated antibody (seen in 24 percent) in the above series of patients with SCLC and PCD [2]. These antibodies were present in all patients who also had Lambert-Eaton myasthenic syndrome (LEMS), as well as in some patients with cerebellar dysfunction without LEMS [3,38,39]. Antitumor treatment did not alter the course of the cerebellar degeneration, but it did improve the myasthenic symptoms. LEMS is discussed separately. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis".)

●Anti-Ri (ANNA-2) antibodies have been associated with PCD, primarily in patients with breast cancer, gynecologic cancers, and SCLC [37,40]. Multifocal disease also occurs in this group, with associated encephalitis and/or opsoclonus myoclonus occurring in more than half.

●Anti-CRMP5 (or CV2) antibodies, directed against a cytoplasmic antigen in some glial cells and against peripheral nerve antigens [10], have been associated with several syndromes, including PCD, limbic encephalitis, encephalomyelitis, chorea, peripheral neuropathy, and optic neuritis [10-12,41]. The most common tumors are SCLC and thymoma. Anti-CRMP5 antibodies often associate with thymoma and SCLC [42]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Anti-CRMP5 encephalomyelitis'.)

●Antibodies to Ma proteins, which are selectively expressed in brain, testis, and some tumors, can occur in patients with paraneoplastic brainstem and cerebellar dysfunction associated with a variety of tumors arising in the testes (germ-cell tumors), breast, colon, and parotid gland, among others [43,44]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Ma2-associated encephalitis'.)

●Antibodies to Kelch-like protein 11 (KLHL11) can be found in some patients with isolated or predominant cerebellar ataxia associated with testicular cancer [45,46]. These patients often have sensorineural hearing loss or vestibular symptoms. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Others'.)

●Antibodies to Zic4 have been described in patients with neurologic disorders including cerebellar dysfunction and SCLC. These patients often have concurrent anti-Hu or CRMP5 antibodies. Patients with isolated Zic4 antibodies are more likely to develop cerebellar dysfunction than those with concurrent immunities [13,47].

●Antibodies to protein kinase C, a protein highly expressed in the Purkinje cells of the cerebellum, have been described in two patients with PCD: one with non-SCLC and the other with papillary adenocarcinoma of hepatobiliary origin [48,49].

Other antibodies have been reported in isolated patients with cerebellar ataxia or cerebellar degeneration. However, the clinical information and number of cases reported are too limited in order to know whether they manifest as pure cerebellar syndromes.

●Antibodies against the carbonic anhydrase related protein VIII (CARP VIII) have been identified in two patients with PCD, one with melanoma [17] and the other with ovarian adenocarcinoma [50].

●Anti-inositol 1,4,5-triphosphate receptor 1 (ITPR1) antibodies have been described in four patients but only one had cancer (breast cancer) that developed 11 years after the onset of the cerebellar syndrome [51].

●Antibodies against tripartite motif-containing [TRIM] protein 9 or TRIM protein 67 were found in two patients with a subacute, progressive, severe cerebellar ataxia associated with adenocarcinoma of the lung [52].

●Antibodies against the metabotropic glutamate receptor 2 (mGluR2) have been reported in two patients with paraneoplastic cerebellar ataxia. One 78-year-old patient had a progressive syndrome and a small cell tumor of unknown origin and the other was a three-year-old child with steroid-responsive acute cerebellitis preceding the diagnosis of an alveolar rhabdomyosarcoma [53].

CLINICAL FEATURES — Patients with PCD typically present with dizziness, nausea, and vomiting, often beginning acutely, and followed several days later by gait instability, oscillopsia, diplopia, both truncal and appendicular ataxia, dysarthria, and dysphagia [20,21,37,54]. Symptoms typically continue to worsen for weeks to months before stabilizing. Severe disability with inability to walk or even sit unsupported, inability to write or feed oneself, and limited communication secondary to dysarthria are common, with some patients having a somewhat better outcome.

In some patients, PCD occurs along with other neurologic signs. As an example, when cerebellar degeneration occurs with encephalomyelitis, the underlying tumor is small cell lung cancer (SCLC) in approximately 80 percent of cases [2]. As noted above, Lambert-Eaton myasthenic syndrome (LEMS) can occur with PCD in patients with SCLC who have anti-P/Q type calcium channel antibodies. Even patients with anti-Yo antibodies and relatively isolated PCD have detectable cognitive deficits approximately 20 percent of the time [20,55].

Most patients (60 to 70 percent) with PCD do not have a cancer diagnosis at the onset of their neurologic symptoms [20,21,37].

DIAGNOSIS — The diagnostic approach to patients with PCD includes ruling out other diagnoses, confirming and characterizing the paraneoplastic syndrome, and identifying the underlying neoplasm, if this is not previously known.

Differential diagnosis — The differential diagnosis of cerebellar ataxia includes cerebellar and brainstem metastases, toxic and metabolic causes, and neurodegenerative causes [55]. Alcoholism, vitamin deficiency (thiamine, vitamin E, cobalamin), hypothyroidism, cerebrovascular disease, demyelination, infectious or postinfectious cerebellitis, Miller-Fisher syndrome, antiglutamic acid decarboxylase (GAD)-associated cerebellar ataxia, Creutzfeldt-Jakob disease (CJD), human immunodeficiency virus (HIV), and celiac disease should be specifically considered. Medication lists should also be reviewed for possible contributors. (See "Approach to abnormal gait in adults", section on 'Cerebellar ataxia'.)

Testing — Diagnostic evaluation typically begins with neuroimaging and laboratory testing to exclude other conditions.

Magnetic resonance imaging (MRI) is usually not helpful for positive diagnosis of PCD but is important to exclude metastatic and cerebrovascular disease. In rare instances of PCD, contrast enhancement in the cerebellar folia can be found in acute phases of the disease, and positron emission tomography (PET) may reveal hypermetabolism [56]. Diffuse cerebellar atrophy develops subsequently but is not sensitive early in the course of symptoms [20,41,57].

Laboratory testing may include thyroid function tests, vitamin levels, and other testing (anti-gliadin, anti-GAD antibodies, HIV serology) in the appropriate clinical setting.

As with other paraneoplastic syndromes involving the nervous system, cerebrospinal fluid (CSF) examination can show inflammatory changes, at least in the early stages of the illness [20]. A mild pleocytosis (10 to 50 lymphocytes) and a mild elevation of protein are characteristic. Some patients with PCD or extensive encephalitis have the 14-3-3 protein characteristic of CJD in the CSF [58]. This might create some diagnostic confusion if a tumor is not evident because of symptom overlap between paraneoplastic disease and CJD. It is likely that the 14-3-3 protein in this setting reflects extensive central nervous system (CNS) damage rather than CJD. Immunoblotting reveals the 14-3-3 protein as a double band (similar to other false-positive results) rather than the single band in CJD. (See "Creutzfeldt-Jakob disease".)

Paraneoplastic biomarkers should be sought in the patient's CSF and serum (table 1). Not all biomarkers have commercially available testing, and some antigens remain to be characterized. Thus, negative results do not exclude a paraneoplastic or autoimmune disorder. A sample of a patient's CSF and serum should be sent to a research laboratory for examination in these cases. Other caveats regarding antibody screening are discussed separately. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Antibody screening'.)

If the patient does not have a known cancer diagnosis, evaluation for occult malignancy should also ensue. The presence of paraneoplastic biomarkers may help direct further evaluation if initial screening is negative (table 1). Tumors may be small; in some cases 18-F fluorodeoxyglucose PET (FDG-PET) or exploratory laparotomy were the only means of identifying the underlying lesion [20,59]. In a minority of patients with PCD, no tumor is identified despite vigorous investigations [20,21,37]. In such cases, serial investigations are advised. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Search for occult malignancy'.)

TREATMENT AND PROGNOSIS — Neurologic outcome for classic PCD is often poor; most patients (75 to 80 percent) become and remain nonambulatory [37]. Treatment of the underlying tumor is considered essential for neurologic stabilization; clinical improvement is less likely but can occur [1,2,20,37].

Immunotherapy is often used, but does not clearly affect neurologic outcome. In one larger case series, immunotherapy was not significantly associated with recovery [37]. However, there are anecdotal reports of neurologic improvement in patients tried on various immunologic therapies, including plasma exchange, intravenous immune globulin (IVIG), corticosteroids, azathioprine, cyclophosphamide, and rituximab, given individually or in combination [9,31,37,60-70]. One literature review of 15 cases found that treatment with IVIG was more likely to be associated with a good outcome if it was administered within three months of symptom onset [71]. There are also rare reports of spontaneous improvement. In contrast to classic PCD, some patients with paraneoplastic cerebellar ataxia can have responses to immunotherapy and cancer treatment [16,52].

Given the overall poor prognosis of PCD with substantial neurologic disability, a trial of immunotherapy seems reasonable. As most antibodies are directed against intracellular proteins, which implies cytotoxic T cell mechanisms, it is reasonable to focus the treatment on (1) controlling the cancer, and (2) controlling the cytotoxic T cell response. Towards this goal, we favor the use of cyclophosphamide over plasma exchange or IVIG. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Treatment and prognosis'.)

The type of antibody appears to affect neurologic prognosis. Patients with PCD associated with anti-Hu or anti-Yo antibodies are less likely to recover, while those with anti-Tr, anti-Ri, anti-metabotropic glutamate receptor 1 (mGluR1), or anti-CRMP5 antibodies may have a somewhat better chance of neurologic improvement [2,12,33,72]. In some reports, younger age and less severe disability at diagnosis and intervention appear to favorably affect prognosis.

Survival also varies with the type of associated antibody as well as the underlying neoplasm. In one series, survival was worse in patients with anti-Hu antibodies (median 7 months) and those with anti-Yo antibodies (median 13 months) compared with patients who had anti-Tr or anti-Ri antibodies (median survival 113 and 69 months, respectively) [37]. In another series, median survival was 11 months in patients with anti-Hu antibodies compared with 48 months in those with anti-CV2 antibodies [73]. Advanced age has a negative impact on survival. While some reports find that neurologic morbidity contributes most substantively to mortality [20,37], others have found that cancer progression was more important [21,60].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Paraneoplastic neurologic disorders".)

SUMMARY AND RECOMMENDATIONS

●Associated cancers – Paraneoplastic cerebellar degeneration (PCD) is an uncommon disorder that can be associated with any cancer; the most commonly associated are lung cancer (particularly small cell lung cancer [SCLC]), gynecologic and breast cancer, and lymphoma (particularly Hodgkin disease [HD]). (See 'Introduction' above.)

●Associated antibodies – A number of autoantibodies associated with PCD have been characterized. Individual autoantibodies are often linked to specific cancer types and/or clinical syndromes (table 1). As an example, patients with PCD and anti-Yo antibodies typically have breast or gynecologic cancer and isolated cerebellar deficits and pathology. Other antibodies along with their associated tumors and characteristic clinical features are outlined. (See 'Pathogenesis' above and 'Associated antibodies' above.)

●Clinical features – Patients with PCD typically present with dizziness, nausea, and vomiting, often beginning acutely and followed several days later by gait instability and other cerebellar signs. Many patients with PCD develop cerebellar dysfunction along with other paraneoplastic neurologic disorders such as Lambert-Eaton myasthenic syndrome (LEMS) and encephalomyelitis. (See 'Clinical features' above.)

●Diagnosis – Neuroimaging and cerebrospinal fluid (CSF) analysis are important to exclude other conditions; findings in PCD may be normal or nonspecifically abnormal. Paraneoplastic biomarkers provide supporting evidence for the diagnosis. If the patient does not have a known cancer diagnosis, evaluation for occult malignancy should ensue. (See 'Diagnosis' above.)

●Treatment – As most antibodies are directed against intracellular proteins, which implies cytotoxic T cell mechanisms, we favor the use of cyclophosphamide over plasma exchange or intravenous immune globulin (IVIG). By contrast, paraneoplastic cerebellar ataxia in some patients can be treatment responsive. (See 'Treatment and prognosis' above.)

●Prognosis – Depending on the type of underlying antibody and associated neoplasm, the neurologic symptoms of patients with PCD may stabilize or rarely improve with antitumor treatment and/or immunotherapy. (See 'Treatment and prognosis' above.)