Antiglutamic Acid Decarboxylase 65 Antibody–Associated Hemiataxia

PRACTICAL IMPLICATIONS

Hemiataxia is an under-recognized manifestation of anti-GAD65 antibody–associated neurologic disease. Early diagnosis is critical to optimize immunotherapy treatment response.

Autoimmune and paraneoplastic movement disorders are increasingly recognized because of improved methods in detecting antibodies directed against intracellular, membrane, and other antigens.¹ High concentrations of antiglutamic acid decarboxylase 65 (GAD65) antibodies are associated with several neurologic syndromes including stiff-person syndrome, epilepsy, limbic encephalitis, and cerebellar ataxia.² Anti-GAD65–associated cerebellar ataxia is typically generalized with prominent gait disturbance and eye movement abnormalities.¹ Limb ataxia is present in 60%–70% of patients.³ Here, we present 2 unusual cases of hemiataxia associated with high concentrations of anti-GAD65 antibodies.

Case A is a 75-year-old woman with Hashimoto disease who developed acute onset gait ataxia at the age of 67 years. Her gait difficulty fluctuated with episodes of worsening associated with headaches and vertigo. After one such episode at the age of 69 years, she noticed acute onset left-sided incoordination. Examination revealed dysmetria and dysdiadochokinesis only in the left arm and leg and ataxic gait (video 1). MRI of the brain showed progressive generalized cerebellar atrophy (figure). Serum anti-GAD65 antibody concentration was >4,800 IU/mL. CSF anti-GAD65 was initially negative but was positive on repeat testing one year later (1.41 nmol/L). A CT scan of the chest, abdomen, and pelvis was normal. Monthly IV immunoglobulin (IVIG) infusions markedly improved left arm and gait ataxia (video 1). She later developed spasms of the paraspinal muscles and also required treatment for stiff-person syndrome. She remains ambulatory with no ataxia in the right hemibody.

Figure. MRI of the Brain From Case A.

Figure shows selected images from the MRI of the brain from the patient in case A taken 4 years from onset of symptoms. Panels (A and B) show axial T2 fluid-attenuated inversion recovery sequence demonstrating moderate generalized atrophy of the cerebellum, which is more prominent in the left hemisphere, consistent with left-sided hemiataxia.

Video 1

The patient (Case A) demonstrates marked finger-to-nose ataxia on the left and severe gait ataxia, both of which improved after a course of IVIG.Download Supplementary Video 1 ^{(9.4MB, wmv)} via http://dx.doi.org/10.1212/000939_Video_1

Case B is a 62-year-old woman with insulin-dependent diabetes mellitus and hypothyroidism who first noticed leaning to the left while walking. Two months later, she developed left-sided incoordination and action tremor in the left hand. Her examination revealed dysarthria as well as dysmetria, dysdiadochokinesis, and cerebellar outflow tremor on the left side only. MRI of the brain showed a 1.8 cm cavernoma in the left putamen and mild generalized cerebellar volume loss. Serum anti-GAD65 antibody concentration was >25,000 IU/mL. CT scan of the chest, abdomen, and pelvis was normal. She was treated with IVIG and pulse dose intravenous methylprednisolone with substantial improvement in symptoms, although proximal left sided tremor remained.

Discussion

Hemiataxia is a rare manifestation of the anti-GAD 65-associated neurologic syndromes. Our literature review found 3 similar cases (table).^4–6 All 3 had diabetes mellitus (2 were insulin-dependent) and one also had thyroiditis. All had subacute onset of hemiataxia (2 on the right and one on the left). Two were women older than 60 years old, and one was a 44-year-old man. One remained with hemiataxia after 6 years and also had generalized epilepsy.⁶ Interestingly, the patient in case A, with a longer documented course of symptoms, also displayed other symptoms of anti-GAD65 antibody-associated neurologic disease, including evidence of brain stem involvement and stiff-person syndrome.^1,7

Table.

Reported Cases of Anti-GAD65–Associated Hemiataxia

There are other autoimmune neurologic diseases with unilateral manifestations, including anti-leucine-rich glioma-inactivated 1 receptor encephalitis with its characteristic unilateral faciobrachial dystonic seizures and Rasmussen encephalitis with hemi-inflammation of the brain.⁵ The tropism for one side of the brain in these syndromes is not well understood, but it suggests that one hemisphere is more vulnerable than the other to the damaging effects of the autoantibody. Similarly, the pathogenesis of neurotoxicity of the anti-GAD65 antibody and the mechanism by which IVIG and other immunotherapies are effective are not well understood.² It is likely that multiple mechanisms are involved, which may account for the variable presentation and response to immunotherapy. Reports of immunotherapy response rates in patients with anti-GAD65 antibody-associated neurologic disease vary from as low as 17%⁴ up to 70% in carefully selected patients.² Most studies emphasize the importance of early initiation of treatment to prevent lasting cell damage and improve long-term outcomes.^1,3

Appendix. Authors

Study Funding

No targeted funding reported.

Disclosure

E.J. Hill reports no disclosures; J. Jankovic received research/training funding from AbbVie Inc., CHDI Foundation, Dystonia Coalition, Hoffmann-La Roche Ltd., Michael J. Fox Foundation for Parkinson Research, National Institutes of Health, Parkinson’s Foundation, Parkinson Study Group, Roche, and Teva Pharmaceutical Industries Ltd. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.