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extensive serum and csf evaluations for infectious , toxic , and metabolic causes were negative .
serum contained antibodies against p / q - type vgccs ( 483.5 pmol / l ; normal range 0.024.5 pmol / l ) ( arup laboratories , salt lake city , ut ) .
contrasted ct of the chest , abdomen , and pelvis were without evidence of malignancy as were pet scans at 6 and 12 months after onset of ataxia .
the patient was treated with iv igg 2 g / kg over 3 days followed by methylprednisolone 1 g iv daily for 3 days , an oral prednisone taper beginning at 60 mg daily , and mycophenolate mofetil 500 mg twice daily .
a repeat trial of iv igg , however , was discontinued after he developed aseptic meningitis .
the patient 's ataxia and dysarthria subsequently worsened despite plasma exchange and an increase in mycophenolate dosage to 750 mg twice daily .
electrophysiologic studies at that time demonstrated low amplitude and unexpectedly variable motor response compound motor action potentials in several nerve distributions . with 10 seconds of voluntary exercise
, there was 50% to 300% facilitation in amplitude and area under the waveform curve .
the findings were thought to represent evidence of a correctable presynaptic defect in neuromuscular junction transmission consistent with lems .
the patient 's pretreatment serum was confirmed by arup laboratories to have vgcc autoantibodies , without other paraneoplastic or other antineuronal autoantibodies .
organotypic cultures of cerebellums from 24-day - old sprague - dawley rat pups were incubated with 1:400 dilutions of patient sera as previously described . at intervals from 24 to 144 hours
, cultures were coincubated for 2 hours with sytox cell viability dyes , fixed with 2% paraformaldehyde , labeled postfixation with cy5-conjugated goat anti - human igg , and analyzed by confocal microscopy .
controls were sera from neurologically normal individuals without malignancy . to confirm that the reactivity of the patient 's igg for purkinje cells represented specific binding to vgccs , normal adult rat tissue was fixed with paraformaldehyde , placed in paraffin blocks , and sectioned onto slides .
the normal tissue was treated with an antigen retrieval system before blocking for 1 hour with serial concentrations of commercially obtained rabbit anti - vgcc antibodies directed against the 1a subunit of the vgcc ( thermo pa5 - 19598 , rockford , il ) , and then was subsequently exposed to patient sera ( 1:200 ) for 24 hours .
sections were fixed and labeled with cy5-conjugated donkey anti - human igg to detect the patient 's antibodies and fluorescein isothiocyanate 
cerebellar slices exposed to the patient 's serum for 48 hours showed presence of antibody predominantly within the neuropil , with labeling of occasional purkinje cells ( figure 1 ) . by 72 hours , purkinje cells exhibited surface binding of antibody , and by 144 hours , purkinje cells also showed cytoplasmic labeling , indicating igg uptake ( figure 1 ; videos 1 and 2 at neurology.org/nn ) .
most antibody - labeled purkinje cells excluded sytox dyes , indicating that these cells were viable ( figure 1 ) . at 144 hours , however , scattered purkinje cells showed staining with sytox dyes , indicative of cell death ( figures 1 and 2 ) .
pretreatment of rat tissue with commercial anti - vgcc antibody inhibited binding of the patient 's igg to purkinje cells in a concentration - dependent manner , confirming the specificity of the patient 's antibody for vgccs ( figure e-1 ) .
immunohistologic evaluation of the patient 's serum using composite frozen sections did not detect any other characterized neuron - specific antibody patterns ( data not shown ) .
slice culture of rat cerebellum incubated with patient serum containing vgcc autoantibodies and examined at different points in time . ( a ) slice culture incubated with normal serum for 144 hours , treated with sytox dyes to detect cell death , and labeled with cy5-conjugated anti - human igg , showing absence both of neuronal antibody binding and of sytox staining indicative of cell death .
( b , c ) slice cultures incubated for 48 and 72 hours with serum containing vgcc autoantibodies . in these images , binding of the patient 's igg is labeled red ; rare dead cells outside the purkinje cell layer are labeled green . at 48 hours
, igg can be detected throughout the neuropil with labeling of occasional purkinje cells ( arrows ) ( b ) . by 72 hours
, there is extensive binding of igg to purkinje cell membranes ( arrows ) ( c ) .
( d  f ) a slice culture incubated with patient serum for 144 hours and labeled with cy5-conjugated anti - human igg ( d ) , stained with sytox dyes to detect cell death ( e ) , and as a merged image ( f ) . in cultures at this time point , some purkinje cells continued to show surface binding of antibody panels ( g  i ) .
in other areas , however , purkinje cells showed uptake of igg with cytoplasmic and nuclear labeling ( d ) ; some igg - containing purkinje cells demonstrated staining with sytox dyes , indicating cell membrane disruption and death ( e , f ) , whereas others excluded sytox dyes , indicating antibody uptake by viable purkinje cells .
purkinje cell antibody binding and cell death at 144 hours are shown at higher power in panels g through i. arrows indicate the same cells in panels d  f and in g 
adult rat tissue was fixed , sectioned , and treated with an antigen retrieval system before blocking for 1 hour with serial concentrations of commercially obtained rabbit anti - vgcc antibodies directed against the 1a subunit of the vgcc receptor before being exposed to a 1:200 dilution of patient serum for 24 hours .
tissue was then labeled with cy5-conjugated donkey anti - human igg to detect the patient 's antibodies and fluorescein isothiocyanate 
pretreatment with commercial anti - vgcc antibody inhibited binding of the patient 's igg to purkinje cells in a dose - dependent manner , confirming the specificity of the patient 's antibody for the vgcc .
although vgcc autoantibodies are usually associated with lems , they have also been detected in 21% to 41% of patients with paraneoplastic cerebellar degeneration associated with lung cancer and in 11% of patients with cerebellar degeneration in the absence of malignancy .
the present case provides further evidence that adult patients presenting with subacute cerebellar ataxia should be tested for vgcc autoantibodies .
although vgcc autoantibodies have been shown to be pathogenic in lems , their role in paraneoplastic cerebellar injury is less well defined .
other investigators have demonstrated that a single cisternal injection of mice with igg from a vgcc - positive patient with lems and cerebellar degeneration produced temporary motor ataxia , whereas injection of igg from a patient with lems alone produced no cerebellar impairment .
these authors postulated that vgcc autoantibodies can cause cerebellar dysfunction as well as lems , but that anti - vgcc antibodies in patients with lems and acd may react against a slightly different epitope than do those in patients with lems alone .
these investigators did not detect histologic evidence of neuronal death in brains examined after 24 hours or 15 days after this single infusion .
in contrast , our studies , using more prolonged exposure of cerebellar neurons to patient anti - vgcc serum , demonstrated surface labeling of purkinje cells followed by antibody uptake and scattered purkinje cell death .
it is possible that purkinje cell death might have been due to another unidentified antibody in the patient 's serum , directed toward an unknown antigen of purkinje cells , in addition to vgccs .
however , adsorption of the patient 's serum against the 1a subunit of the vgcc antibodies effectively abolished all igg labeling by our anti - human secondary antibody , making the presence of an additional autoantibody less likely .
although the possibility also exists that purkinje cell death might have been due to some other nonantibody factor present in our patient 's serum , our prior studies using other patient paraneoplastic antisera have demonstrated that neuronal death is specifically dependent on anti - neuronal igg and not on other serum components .
our data , together with those of the investigators discussed above suggest that anti - vgcc antibodies may initially cause functional impairment of purkinje cells , but that longer exposure to vgcc autoantibodies may result in irreversible purkinje cell injury and death .
although autoimmune neurologic disorders associated with cell - surface antibodies frequently respond to immunosuppressive treatment , the condition of patients with anti - vgcc antibodies and acd has often failed to improve , even when there was improvement in accompanying lems ( table ) .
our patient 's ataxia improved during igg therapy but subsequently worsened after iv igg could no longer be administered .
another group described a similar case of acd with vgcc antibodies , without an underlying malignancy ; this patient also improved significantly following treatment with iv igg . in both cases ,
iv igg was administered relatively early in the course of disease , suggesting that prompt intervention may be essential and that early administration of iv igg may be an effective means of treatment .
previously reported cases of acd in patients with vgcc autoantibodies , showing initial presentation , presence or absence of lems and/or malignancy , treatment used , and treatment response paraneoplastic neurologic symptoms may antedate tumor diagnosis by as long as 5 years in as many as 70% of patients .
for this reason , follow - up screening for malignancy is essential in these patients if initial studies are negative .
as many as 6% to 20% of patients with vgcc autoantibodies and acd may develop lems . because manifestations of lems may be masked by severe cerebellar symptoms , electrophysiologic testing
vgcc autoantibodies may be associated with acd as well as lems , and patients presenting with cerebellar signs and symptoms should be tested for vgcc autoantibodies as part of a comprehensive evaluation for neuronal antibodies , including the use of screening immunofluorescence to detect potentially unclassified antibodies .
although early treatment of acd in patients with vgcc autoantibodies may result in clinical improvement , vgcc autoantibodies may cause purkinje cell death over time .
patients with acd and anti - vgcc antibodies should undergo electrophysiologic evaluation for lems , even if lems is not clinically evident , and should also undergo malignancy screening , with subsequent repeat evaluation if initial studies do not detect neoplasia .
stacey l. clardy : data collection , analysis , writing or editing assistance , review of manuscript .
john e. greenlee : data collection , analysis , writing or editing assistance , review of manuscript .
n. carlson received research support from biogen , astrazeneca , department of veterans affairs merit review .
m. bromberg serves on the scientific advisory board for accordant health care , baxter bioscience , received travel funding and speaker honoraria from walgreens infusion , grifols biotherapeutics , baxter bioscience , is an assistant editor for muscle & nerve , clinical neurophysiology , journal of clinical neuromuscular disease , receives royalties from taylor & francis , cambridge , is on the speakers bureau for walgreens infusion , grifols biotherapeutics , baxter bioscience , genzyme .
greenlee is a senior associate editor for medlink , an associate editor for clinical neurology and neurosurgery , receives publishing royalties from medlink , receives compensation for editing and reviewing chapters for medlink and the merck manual , received research support from united states department of veterans affairs .
objectives : to describe response to treatment in a patient with autoantibodies against voltage - gated calcium channels ( vgccs ) who presented with autoimmune cerebellar degeneration and subsequently developed lambert - eaton myasthenic syndrome ( lems ) , and to study the effect of the patient 's autoantibodies on purkinje cells in rat cerebellar slice cultures.methods:case report and study of rat cerebellar slice cultures incubated with patient vgcc autoantibodies.results:a 53-year - old man developed progressive incoordination with ataxic speech . 
 laboratory evaluation revealed vgcc autoantibodies without other antineuronal autoantibodies . 
 whole - body pet scans 6 and 12 months after presentation detected no malignancy . 
 the patient improved significantly with iv immunoglobulin g ( igg ) , prednisone , and mycophenolate mofetil , but worsened after iv igg was halted secondary to aseptic meningitis . 
 he subsequently developed weakness with electrodiagnostic evidence of lems . 
 the patient 's igg bound to purkinje cells in rat cerebellar slice cultures , followed by neuronal death . 
 reactivity of the patient 's autoantibodies with vgccs was confirmed by blocking studies with defined vgcc antibodies.conclusions:autoimmune cerebellar degeneration associated with vgcc autoantibodies may precede onset of lems and may improve with immunosuppressive treatment . 
 binding of anti - vgcc antibodies to purkinje cells in cerebellar slice cultures may be followed by cell death . 
 patients with anti - vgcc autoantibodies may be at risk of irreversible neurologic injury over time , and treatment should be initiated early .