A Rare Case of Cerebellar Ataxia Due to Voltage-Gated Calcium Channel and Glutamic Acid Decarboxylase Autoantibodies

Background

Cerebellar ataxia can be antibody mediated, and this can occur in the setting of paraneoplastic syndrome or in the absence of an ongoing malignancy. Interestingly, the detection of specific types of autoantibodies has been found to be statistically linked to different etiologies. In a recent study, anti-Yo, -Zic, -CARPVIII, -Tr, -Ri, -Hu, -Ma, -CRMP-5, -ANNA-3, -PCA-2, -VGCC, and -mGluR antibodies were more commonly associated with paraneoplastic processes, while anti-GAD, -thyroid, and -gliadin were usually non-paraneoplastic [1]. We present a case of ataxia due to both voltage-gated calcium channel (VGCC) and anti-glutamic acid decarboxylase (GAD) antibodies not associated with malignancy. There are only a few similar cases reported in literature so far.

Case Report

A 55-year-old African-American woman presented to the office complaining of gradual onset of unsteadiness and recurrent falls for the past three years resulting in multiple emergency department visits. She reported difficulties coordinating routine daily activities, such as buttoning a shirt or feeding herself. She visited multiple medical offices and reported that multiple imaging studies ordered in the past were inconclusive. Her past medical history included hypertension and history of morbid obesity and uncontrolled diabetes status post gastric bypass four years prior to the visit (both significantly improved, with a body mass index of 25.9 and hemoglobin A1c of 5.9% at the time of the clinical encounter). Her family history was remarkable for a brother diagnosed with multiple sclerosis at age 25, who died at the age of 40. Her social history was relevant for active cigarette smoking and remote history of heroin abuse (last use eight years prior to the visit). She denied alcohol use. Her list of medications included methadone, enalapril, multivitamin, and cholecalciferol supplementation.

Upon neurologic examination, she was fully oriented to person, place, and time and appeared in no distress. Her cranial nerves function was intact, except for a moderate dysarthria. Her sensory reaction was intact to all four extremities to light touch and pinprick. There was no motor weakness. Her gait was ataxic and wide based with bilateral dysmetria on finger to nose test. Romberg test was positive. The bicipital, tricipital, and patellar reflexes were three+ bilaterally, with plantar responses in flexion bilaterally. Routine laboratory test results were only remarkable for a mild elevation of the erythrocyte sedimentation rate. Infectious diseases or vitamin/mineral deficiencies in the differential diagnosis, which in this specific setting would be highly considered, were ruled out (see Table 1, Section A). The brain MRI, done with contrast, only showed minimal scattered nonspecific white matter changes (see Figure 1). She subsequently underwent lumbar puncture, which showed an opening pressure of 18 cm H2O and was negative for oligoclonal bands (see Table 1, Section B).

A workup for less common causes of ataxia was then started, and the presence of serum anti-VGCC and anti-GAD antibodies was demonstrated (see Table 1, Section C). The patient subsequently underwent extensive imaging workup to rule out an occult malignancy, and all the studies failed to show evidence of cancer. A treatment cycle of three days of intravenous immunoglobulins was then instituted. Within two weeks from their administration, her coordination and gait improved significantly: she showed ability to walk unassisted without tendency to fall, and the Romberg test became negative.

Discussion

Cerebellar ataxia can be potentially treatable, and a complete understanding of the etiology must be achieved in order to establish an effective management plan. This is especially important because it is usually a disabling condition, and treating it can substantially improve the quality of life of a patient, when possible. The search for a potentially treatable cause should include a broad spectrum of different disorders, and genetic evaluation should be considered only when other etiologies can be ruled out. Disorders commonly encountered in clinical practice such as vitamin B12 deficiency and hypothyroidism can occasionally cause ataxia and in rare cases present with it [2,3]. Adverse reactions to drugs (especially certain antiepileptic and chemotherapeutic agents), systemic autoimmune diseases (such as sarcoidosis, systemic lupus erythematous and Sjogren syndrome) [4–6], deficiencies of vitamin E and B1 (thiamine) as well as mineral deficiencies (such as copper or zinc) have all been occasionally linked with neurological symptoms, including ataxia [7–9]. Antibody-mediated ataxia is another potentially treatable etiology that should be considered. Multiple autoantibodies have been associated with cerebellar ataxia [10], and it has been demonstrated that anti-VGCC and anti-GAD antibodies can directly cause ataxia in experimental models in vivo [11]. Anti-VGCC and anti-GAD antibodies have been shown to cause cerebellar synaptic dysfunction in vitro as well [1]. In a study of 67 patients with late onset cerebellar ataxia of unknown cause, immunohistochemical and immunoblotting techniques were able to detect the presence of VGCC antibodies in eight patients (11.1%) [12]. Hence, it can be hypothesized that autoimmune cerebellar ataxia may be an underdiagnosed entity in clinical practice [13]. Possible contributing factors could be the lack of specific imaging findings diagnostic of antibody-mediated ataxia [14] and the lack of awareness arising from the paucity of data available in literature. In our case, after ruling out other possible etiologies, evidence of both anti-VGCC and anti-GAD antibodies was found in the serum. Remarkably, the latter antibody has been associated with type 1 diabetes mellitus and latent autoimmune diabetes of adulthood and could have at least contributed to our patient’s history of diabetes as well. The response to the intravenous immunoglobulins confirmed the role played by these antibodies in the pathogenesis of the symptoms, and a plan for periodic infusions was established leading to sustained clinical improvement.

Besides being potentially treatable, antibody-mediated cerebellar ataxia should also prompt a complete cancer work-up, since it has been associated with a large number of malignancies and occasionally reported as the presenting sign of an otherwise asymptomatic malignancy [15–17]. The cerebellar ataxia secondary to anti-Yo antibodies has been reported as the most common variant of paraneoplastic cerebellar degeneration [18], however, the VGCC antibody has been frequently associated with a paraneoplastic process as well. In a study of 236 patients with positive VGCC antibody evaluated for paraneoplastic syndromes, 50 (21%) had at least one malignancy [19]. Human immunodeficiency virus (HIV) has also been linked to autoimmune antibody-mediated cerebellar ataxia without evidence of HIV encephalopathy or malignancy [20]. While rare, autoimmune antibody-mediated cerebellar ataxia should be considered in the differential diagnosis in cases where a clear etiology cannot be found. If an immune-mediated process is indeed demonstrated, a complete workup to rule out an occult malignancy should be instituted before immunosuppressive treatment can be safely started. Studies have shown that treatment of immune-mediated ataxia can make the difference in improving symptoms and quality of life, and favorable responses were noted to be more common among patients with non-paraneoplastic ataxia and those with exclusively ion channel antibodies [10,21,22].

Conclusions

Ataxia can be caused by a wide spectrum of possible etiologies, and understanding the pathogenesis is a critical step needed in order to treat it correctly. Clinicians should be aware of the possible association with specific autoantibodies and the necessity to rule out an occult malignancy in such cases.