Paraneoplastic syndromes within the central nervous system (CNS) refer to non-metastatic involvement of the brain and/or spinal cord, most likely occurring as a result of an immune reaction to cancer cells generating antibodies which cross-react with CNS antigens [
47]. They occur rarely, but of the described CNS paraneoplastic syndromes, paraneoplastic cerebellar degeneration (PCD) is the commonest.
Paraneoplastic cerebellar degeneration
Fifty to 60% of patients with paraneoplastic cerebellar degeneration (PCD) have identifiable antibodies in serum and/or CSF, of which anti-Yo (alternatively referred to as anti-Purkinje cell cytoplasmic antibody-1; PCA-1) is the commonest, representing approximately 50% of antibody-positive PCD [
48]. PCD typically presents with sub-acute onset of ataxia which, often rapidly, progresses to pan-cerebellar failure. Often, cerebellar features plateau after a period of time. PCD may occur as an isolated cerebellar syndrome usually associated with breast or ovarian cancer and anti-Yo antibodies, or with Hodgkin’s lymphoma and Tr/DNER antibodies [
49]. Alternatively, PCD presents in association with other neurological features such as encephalomyelitis (small cell lung cancer and anti-Hu antibodies) [
50] or eye movement abnormalities (typically, opsoclonus with breast or ovarian cancer and anti-Ri antibodies) [
51]. The repertoire of antibodies associated with PCD is increasing, now including antibodies against the Purkinje cell protein carbonic anhydrase-related protein VIII (CARP) [
52] and protein kinase Cγ (PKCγ) [
53]. It seems likely that further antibodies will be discovered identifying a cause in antibody-negative PCD cases.
In general, PCD responds poorly to treatment. The rarity of the condition, coupled to the multiple antibodies that may cause the phenotype, has meant that randomised controlled trials of PCD therapies are lacking. In addition, the rather rapid disease onset followed by plateau renders determination of treatment efficacy challenging.
Treatment or removal of the underlying tumour, if possible, is important, although even if successful, often, the symptoms of PCD do not improve and the majority of patients with PCD will remain severely disabled [
50,
54]. Prognosis is poor and median survival in a study of 34 anti-Yo PCD cases was 22 months [
54]. Studies have suggested that prognosis may be slightly better in PCD associated with antibodies other than anti-Yo [
55]. Indeed, improvement in PCD associated with anti-Tr antibodies and Hodgkin’s lymphoma has been reported following treatment of the cancer [
56].
Studies have assessed the utility of additional immunotherapy in PCD. The outcomes are generally disappointing although some small case series have reported benefit (class IV evidence). Immunotherapies such as corticosteroids, IVIg and PEx have been most studied. PEx has been reported to cause improvement in some cases, although the majority of reported cases do not appear to improve [
57]. Similarly, IVIg has been reported to be effective in single cases, although a study of 22 patients with anti-neuronal antibody-associated paraneoplastic neurological syndromes (including 4 with PCD) did not reveal any effect on disability using IVIg (median 5.8 cycles) [
58‐
62]. The most commonly reported alternative immunosuppressant is cyclophosphamide, but, again, evidence is limited only to single cases [
63,
64]. Aggressive combination immunosuppressive regimes have been reported [
65]. A follow-up study of 17 patients with anti-Yo and anti-Hu paraneoplastic encephalomyelitis, sensory neuropathy or PCD receiving cycles of IVIg, cyclophosphamide and methyl prednisolone reported clinical stabilisation (evaluated by the modified Rankin scale) in those patients who were not severely disabled at time of treatment onset, but no effect in severely disabled PCD patients [
66]. It remains unclear whether early administration of immunosuppression in PCD improves prognosis.
Newer therapies including tacrolimus and rituximab have been studied in case reports or small case series in PCD. Rituximab has been reported to induce partial remission in individual cases [
67‐
69]. Tacrolimus, a potent T cell inhibitor, has been studied in a series of patients with paraneoplastic neurological disease (including PCD) [
70]. Although, the trial was not designed to quantify neurological outcome, there were anecdotal reports in some patients of improvement in function. More studies are required to determine the influence of immunosuppressive regimes on PCD.