This report demonstrates for the first time that a commercially available assay used in an NHS immunology laboratory can be reliably used to provide further evidence of a possible immune mediated pathogenesis in the context of PACA.
Using a commercial indirect immunofluorescent assay for the detection of well-characterised paraneoplastic antibodies offered by our NHS immunology laboratory, we have made the observation that sera from patients with suspected immune ataxias show positive results in 91% as opposed to 5 and 4% in patients with ataxia due to a genetic or a degenerative cause respectively. In none of the positive patients was immunoblot positive (we had excluded patients with PCD), in contrast to what is seen in those cases of PCD. This readily available commercial assay therefore provides a useful additional diagnostic aid for suspected IMCA. A positive result is particularly helpful in the context of PACA where the diagnosis relies on fulfilling recently published diagnostic criteria but without any specific single test being diagnostic.
The vast majority of positive results reported here showed an immunoreactivity mimicking what is seen in anti-Hu antibody related PCD (Fig. 1). Less common patterns seen included anti-Yo, anti-CV2, anti-amphyphysin and anti-Tr antibodies. However subsequent immunoblot was negative for any of these antibodies, eliminating the likelihood of PCD.
For patients with gluten ataxia and anti-GAD ataxia, specific diagnostic markers already exist in the form of antigliadin and/or TG6 antibodies and anti-GAD antibodies respectively. The fact that sera from patients with GA or anti-GAD ataxia demonstrate reactivity with cerebellar tissue also supports the fact that these ataxias are indeed immune-mediated. Whilst further work on characterising the specificity of antibody reactivity and pathogenicity has already been done in the context of GA and anti-GAD ataxia, this report highlights the utility of a simple immunofluorescence assay as a useful tool in raising the suspicion of immune mediated ataxias [7,8,9,10]. This is particularly helpful in the context of PACA. PACA is the term used to describe autoimmune ataxias where the antigenic trigger is not known and any associated neuronal antibodies are not well-characterized or of proven pathogenicity [3]. Whilst diagnostic criteria for PACA have recently been published, any additional serological tests such as what has been described here may be useful in increasing the diagnostic suspicion for PACA.
A previous smaller study by our group, used an in-house immunohistochemistry study and showed reactivity using rat cerebellum in 12/20 (60%) patients with idiopathic sporadic ataxia (not necessarily selected for the possibility of autoimmune pathogenesis) as opposed to 1/20 (5%) in patients with genetic ataxias [11].
The expanding spectrum of cerebellar, and in particular Purkinje cell antibodies, in the context of both PCD and other immune ataxias, has been highlighted in a series of review articles by Jarius and Wildemann in which they discus the clinical, oncological, therapeutic and pathogenic features of the 12 most common Purkinje cell antibodies [12]. Whilst very specialised immunological laboratories can offer such a service, accessibility to such testing is limited for most neurologists who encounter a patient with potentially immune mediated ataxia. Furthermore, by definition PACA is not associated with such pathogenic antibodies but is likely to represent a heterogeneous entity of immune-mediated ataxias for which, so far, no specific pathogenic antibodies have been described.
In summary we present our data based on a large cohort of patients with ataxia who were tested using a commercial immunofluorescence assay, demonstrating the presence of reactivity using monkey cerebellar tissue in those patients with IMCA. Such reactivity was rare in genetic and degenerative ataxias and as such this commercially available assay can be a useful and practical screening tool, particularly for patients suspected of having PACA where a single diagnostic marker does not exist.