GAD65 Antibody–Associated Neurologic Disease Presenting With Hemiparkinsonism at Onset

PRACTICAL IMPLICATIONS

In the correct context, GAD65 antibody-associated neurologic disease should be included in the differential diagnosis for parkinsonism, even hemiparkinsonism, especially in the setting of an acute-to-subacute presentation and the emergence of more prototypic features such as appendicular and truncal muscle stiffness and cerebellar ataxia. Prompt recognition of the condition is critical because early immunotherapy may confer a better prognosis.

Case

A 60-year-old previously healthy left-handed man presented to clinic with 6 months of progressive slowness and stiffness on the left side. He described loss of dexterity in the left hand and feeling of “heaviness” in the left leg. On examination, he exhibited mild bradyphrenia and hypophonia, moderate left arm and leg bradykinesia and rigidity, and left leg hesitations and reduced left-arm swing on walking (Video 1). Previous month, he had undergone MRIs of the brain and cervical spine with and without gadolinium that were unremarkable. Initial serum testing including complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, ceruloplasmin, and vitamin B12 levels were all unremarkable. The differential diagnosis at presentation included the spectrum of parkinsonian disorders with Parkinson disease being the most likely given his age group and asymmetric parkinsonism. He was diagnosed with suspected Parkinson disease, and levodopa therapy was initiated because he felt that his symptoms were functionally limiting.

Video 1

Patient's examination during first visit demonstrated slow and hypophonic speech and moderate left-sided bradykinesia. With walking, he had global bradykinesia, left leg hesitations, reduced left-arm swing, and mild truncal instability on standing and with turning. Tandem gait was tentative but preserved, and postural reflexes were preserved with the pull-test.Download Supplementary Video 1 ^{(23.2MB, mp4)} via http://dx.doi.org/10.1212/000996_Video_1

At follow-up visit 6 months later, the patient reported lack of response to levodopa and new sense of disequilibrium, speech changes, and back stiffness. His examination continued to demonstrate left hemiparkinsonism, but he had over 6 months developed an ataxic dysarthria, dysmetria of the left arm and leg, truncal stiffness and instability, and a broad-based ataxic gait on examination (Video 2). In addition, there was new lordosis of the lower back with hypertrophic lumbar paraspinal muscles. There was no myoclonus or hyperekplexia. The subacute development of a cerebellar ataxia prompted additional diagnostic testing. Serum vitamin E level was normal, and celiac antibodies were negative. Serum glutamic acid decarboxylase-65 (GAD65) antibody was >250 IU/mL (enzyme-linked immunosorbent assay, ref <5 IU/mL), which raised suspicion for GAD65 antibody-associated neurologic disease. The patient was admitted for expedited evaluation where CSF analysis confirmed an elevated GAD65 antibody titer at 56.8 nmol/L (radioimmunoassay, ref<0.02 nmol/L) and positive oligoclonal bands. CSF otherwise had 1 leukocyte/mL, 7 erythrocytes/mL, glucose 56 mg/dL, protein 25 mg/dL, negative infectious probes, and a negative Mayo paraneoplastic antibody panel. CT scan of the chest, abdomen, and pelvis with contrast and testicular ultrasound did not reveal an underlying gross malignancy. Of note, the patient did not have history or serum evidence of endocrinopathies or autoimmune disease.

Video 2

Patient's examination 6 months after initial presentation. He had ataxic dysarthria and left much greater than right appendicular dysmetria, and he continued to have bradykinesia on the left side. He also had leg stiffness, truncal instability, wide-based gait, and an inability to walk in tandem.Download Supplementary Video 2 ^{(55.1MB, mp4)} via http://dx.doi.org/10.1212/000996_Video_2

The patient was initiated on immunotherapy for a CNS GAD65 antibody-associated neurologic disease with IV immunoglobulins (IVIGs). He initially experienced mild improvement in gait ataxia and subsequently achieved stabilization without further deterioration after 6 months of monthly IVIG therapy; future plan is to continue maintenance IVIG at longer intervals of every 6 weeks. Oral diazepam helped with muscle spasms.

Discussion

GAD65 autoimmunity is associated with a spectrum of neurologic syndromes most commonly including stiff-person syndrome (SPS), cerebellar ataxia, progressive encephalomyelitis with rigidity and myoclonus, epilepsy, and limbic encephalitis typically nonparaneoplastic in origin.¹ Parkinsonism is an uncommon clinical phenotype, observed in less than 3% of GAD65-antibody seropositive subjects in 3 different cohorts.^2–4 We present a case in which hemiparkinsonism was the earliest manifestation, prompting an initial clinical misdiagnosis of the Parkinson disease. His parkinsonism was not levodopa responsive, and he subsequently developed a more typical GAD65 antibody-associated phenotype reminiscent of SPS and cerebellar ataxia. We cannot be sure that the initial examination was not actually representative of a “stiff-limb,” a limited but recognized form of SPS, but the hemiparkinsonism that was appreciated placed the localization more central.¹ Dopamine transporter scan may have been helpful in confirming a presynaptic dopamine deficit, but it was not obtained because it was deemed that this would not change clinical management. Similarly, neurophysiologic features could have differentiated SPS by demonstration of continuous muscle activity in truncal and proximal muscles and enhanced cutaneomuscular reflexes, but these investigations were not obtained in our case.⁵ Finally, we acknowledge that his speech changes, which were initially interpreted as hypophonia, likely had cerebellar qualities on initial presentation, which evolved into marked cerebellar dysarthria in follow-up. One previous case report described a complex movement disorder characterized by hemiparkinsonism and hemidystonia, but also signs of cerebellar ataxia and vertical gaze palsy within a year of symptom onset.⁶ Taken together, these cases suggest that basal ganglia involvement may be seen in GAD65 autoimmunity.

The CNS gamma-amino-butyric acid (GABA)-ergic system is believed to be targeted in GAD65 antibody-associated neurologic disease, although the precise pathologic mechanisms are unclear. This accounts for the symptomatic response to GABAergic medications, as seen in our patient. It is important to screen for malignancy and coexisting autoimmune conditions in patients with GAD65 autoimmunity, although neoplastic association is uncommon as in this case.¹ In patients with SPS phenotype, 85% have intrathecal synthesis of anti-GAD65 antibody⁷ and more than 90% have high antibody titers in serum,⁸ with radioimmunoassay offering highest sensitivity and specificity with a detection rate of 98% in one cohort of SPS.⁹

Parkinsonism can be seen rarely in GAD65 antibody-associated neurologic disease, and our case demonstrates that hemiparkinsonism can be an early manifestation of the prototypic syndromes or potentially even a novel phenotype signifying pathogenicity at the level of the basal ganglia. Subacute development of ataxia and muscle stiffness and lack of response to levodopa were red flags in this case that prompted further swift investigation into GAD65 autoimmunity. It is important in some cases to include GAD65 antibody-associated neurologic disease in the differential diagnosis for parkinsonism or even atypical parkinsonism alongside multiple systems atrophy, corticobasal degeneration, or progressive supranuclear palsy. Prompt recognition is critical because early immunotherapy may confer a better prognosis.^10,11

Appendix. Authors

Study Funding

No targeted funding reported.

Disclosure

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