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Anti-GAD65 Related Neurological Disorder Presenting as Isolated Hemiataxia: A New Report with Review of Previously Published Patients

The National Program for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases, and Stroke (NPCDCS) has been implemented since 2010, with a focus on major risk factors such as diabetes and hypertension.[2] The efforts have recently been boosted by the initiation of a community‐based screening program for people above 30 years of age.[3] Under the National Health Mission, it is a significant achievement to bring preventive care for non‐communicable diseases (NCD) through 76000 Health and Wellness Centers across the country. Although tertiary centers and at times secondary centers are being equipped with thrombolytics under free drugs and diagnostic schemes, a “hub and spoke” model is being tested at some states for the best utilization of the “golden hour”. As the present study was conducted a decade earlier (2010–2013) when NPCDCS was in infancy, it would be a matter of great interest if recent developments in the health care delivery system have brought any change in the observations noted in the study.


Anti-GAD65 Related Neurological Disorder Presenting as Isolated Hemiataxia: A New Report with Review of Previously Published Patients
To the Editor, Gamma-aminobutyric acid (GABA) is one of the inhibitory neurotransmitters in the central nervous system. It is synthesized by the action of the enzyme glutamic acid decarboxylase (GAD) on glutamate and GAD65 is mostly confined to the nerve terminals while GAD67 is widely present in various organs and cells. [1] In some individuals, autoantibodies are formed against GAD65 that block the conversion of glutamate to GABA leading to decreased activity of inhibitory neurotransmission and increased motor activity. Anti-GAD antibody syndromes are known for their multiple forms of clinical presentation-classically the stiff person syndrome, ataxic syndrome, limbic encephalitis, and epilepsy. [1,2] Even more complex is the presentation with unilateral symptoms which usually indicate structural diseases of the brain rather than an immune phenomenon. We present one such rare case of anti-GAD antibody-mediated hemiataxia syndrome.
A 40-year-old lady presented with unsteadiness of right upper and lower limbs for the preceding one year. Her initial symptom was overshooting of the right hand past the target while rubbing soap on body. After a month, this difficulty was noted while washing plates in the kitchen and over the next few months she had to switch to eating with the left hand as her right hand would overshoot and smear food around her mouth. Two months after her hand unsteadiness, she developed a similar overshoot of her right foot while putting on a slipper. Once the slipper was worn, she could grip on to it tightly and walk. Though her right foot was unsteady, she did not have swaying of her body while walking. She had no slurring of speech. There were no twisting movements, abnormal postures, jerks, weakness, or sensory changes in the involved limbs. There was no cognitive decline, seizures, or bulbar symptoms. She followed a non-vegetarian diet, was not diabetic, had never taken alcohol or any chronic medications. There was no exposure to heavy metals or toxins and her family history was non-contributory.
On examination, she had gaze-evoked nystagmus at 30° left gaze, hypotonia of her distal right upper and lower limbs, appendicular ataxia strictly limited to her right upper and lower limbs (past pointing, intention tremor, dysdiadochokinesia, rebound phenomenon, abnormal heel shin test). Truncal ataxia was minimal; evident only on tandem walk, and there was no weakness, extrapyramidal system involvement or features of raised intracranial pressure. The patient thus had a progressive hemiataxic syndrome of 1 year duration; a structural lesion in the right neocerebellum such as a slow-growing mass or inflammatory granuloma was considered.
Investigations revealed normal hemogram, thyroid function tests, liver and renal function tests. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain revealed no structural lesion of the cerebellum or its peduncles. Anti-thyroid peroxidase antibody, anti-TTG-IgA levels, and anti-nuclear antibody were negative. Her serum anti-GAD65 antibody was strongly positive; however, other paraneoplastic antibodies such as anti-yo, Tr, Hu, and CRMP5 were negative. The cerebrospinal spinal fluid examination was normal. A thorough search for occult malignancy revealed none. A diagnosis of anti-GAD65 antibody-mediated cerebellar ataxia was made. She had partial improvement after methylprednisolone pulse treatment and monthly intravenous immunoglobulin infusions. Her post-treatment Scale for the Assessment and Rating of Ataxia (SARA) score [3] was eight (pre-treatment was 11). At 10 months follow up she continued to have unilateral limb ataxia (SARA score-6).
Antibodies against GAD65 result in multi-faceted neurological presentations and are all characterized by a fundamental loss of inhibitory transmission. Cerebellar ataxia is the second most common form of anti-GAD65 disease. [4] Female gender, subacute onset cerebellar dysfunction, preceding episodes of vertigo, brainstem dysfunction, coexisting features of stiff person syndrome, or systemic autoimmunity are clinical pointers towards this entity. [4,5] Anti-GAD65-associated cerebellar ataxia is typically generalized and patients predominantly present with gait disturbance and eye movement abnormalities. Asymmetric involvement of the two sides is a described feature (seen in 20 out of 34 cases in a study [5] ) but anti-GAD65 disease presenting as hemiataxia is extremely rare and only a few cases have been described in the literature.
A systematic English literature review was performed to identify previously reported cases of anti-GAD65 disease who presented with hemiataxia in the databases of Scopus, PubMed, and Google Scholar using the keywords "Anti-GAD65-associated cerebellar ataxia" and "Hemiataxia" and "Autoimmune cerebellar ataxia" and "immune-mediated cerebellar ataxia" combined with study filters for original research, case reports and case series. We reviewed the reference list of published articles to increase the sensitivity and to select more studies, which we could not retrieve from databases. Our search found four reports [6][7][8][9] describing five cases of anti-GAD65-associated hemiataxia in the literature. Including our case, there was a total of six cases for analysis [ Table 1].
All of the cases were above 40 years of age and the majority of them were female (except one). The duration of ataxia symptoms was highly variable (3 weeks to 8 years) and there was no right-left predominance. Four patients had underlying diabetes mellitus (two had insulin-dependent diabetes mellitus), three had thyroiditis and one patient each had pernicious anemia, hepatitis C infection, and primary generalized epilepsy. No associated comorbid condition was noted in one patient (index case). MRI of the brain was normal in two individuals, two patients had generalized cerebellar atrophy, one patient had asymmetric atrophy of the left cerebellar hemisphere, peduncle, and vermis and one patient showed MRI features of chronic small vessel disease. Functional neuroimaging (positron emission tomography [PET] scan) was performed in three out five previously published patients (two had abnormal and one had normal MRI) and all of them had normal PET findings. We could not perform functional neuroimaging in our patient due to nonavailability of these investigations in our institute. Solnes et al. [10] performed a retrospective analysis in 23 patients of proven antibody positive autoimmune encephalitis assessing the positivity rate of 18 F-FDG PET and MRI. Their results have shown that around 96% patients had at least one region of interest with metabolic changes and the most predominant finding was lobar hypometabolism (commonly in parietal lobe followed by occipital lobe). Overall, the PET scan was more often abnormal during the diagnostic period than MRI (in 96% versus 43% patients, respectively). They concluded that the PET scan may play an important role in the initial diagnostic evaluation of suspected autoimmune encephalitis.
All of the patients received immunotherapy predominantly with pulse methylprednisolone and monthly intravenous immunoglobulins. Two patients showed excellent response to immunomodulation, three had partial recovery, and no response was seen in one patient. Interestingly, one patient who showed an initial excellent response developed other signs of the disease during the illness (stiff-person syndrome and brain-stem dysfunction). [9] There are interesting examples of autoimmune neurological disorders which present with unilateral signs and symptoms such as Rasmussen's encephalitis, unilateral faciobrachial dystonic seizures of anti-LGI-1 receptor encephalitis, etc. [7] The neurotropism for a particular area of the brain in these autoimmune neurological disorders is intriguing; it may suggest that a particular part or hemisphere of the brain is more susceptible to the destructive effects of the autoantibodies probably due to the variable density of the targets or receptors.
Anti-GAD65-associated cerebellar ataxia is typically generalized and patients predominantly present with gait disturbance and eye movement abnormalities. Anti-GAD65 related hemiataxia is rare and could have been missed if not specifically looked for, as a striking hemiataxia is unusual from non-structural aetiologies.

Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Letter Regarding the Article Entitled: "The Effect of Dual Tasking and Deep Brain Stimulation Frequency Parameters on Gait in Advanced Parkinson's Disease"
Dear Editor, The recent article by Tandra et al. [1] reports crucial findings focusing on an interesting issue of the impact of deep brain stimulation (DBS) frequency on gait in Parkinson's disease (PD) subjects. [1] Remarkably, contrasting with the classical data remarking on the benefit of low-frequency stimulation (STIM) on axial symptoms, [2][3][4] they found that most patients had demonstrated significant improvement in gait at a single frequency differing between patients. We think that there may be some points to be further deliberated for a better understanding of this crucial report.
In a prospective study by Khoo et al., [2] the authors demonstrated that 60 Hz STIM provided superior efficacy over 130 Hz in improving the total unified Parkinson's disease rating scale (UPDRS) motor score, axial motor signs including gait and freezing of gait (FOG). However, the optimal contacts for 60 Hz STIM were found to be situated more ventrally than those for 130 Hz STIM. Such that, they emphasized that optimizing the active contacts with respect to frequency is very important in augmenting the beneficial effect of 60 Hz STIM. However, no compelling explanation was proposed to explain their observation. [2] In another study, Ricchi et al. [4] also demonstrated a significant improvement of gait after switching the STIM frequency from 130 to 80 Hz. However, at the same time, they had adapted the voltage to maintain the same total delivered energy that might be efficient in the results. [4] Remarkably, despite the immediate improvement provided after the frequency change, the improvements were no longer detectable at follow-up evaluations 1, 5, and 15 months later. [4] The other study [3] also referred by the authors detected that FOG episodes were significantly lower at the 60 Hz "high voltage/equivalent energy" and higher at the 130 Hz/high voltage than for the period of stimulation is turned off which was substantially contrasting with the results of Tandra et al. [1] Nevertheless, in that study [3] the voltage amplitudes were also increased to maintain the same total energy delivered. To clarify this point, Phibbs et al. [5] conducted a study on 20 PD subjects with subthalamic nucleus (STN)-DBS at which they compared the efficiency of 60 and 130 Hz STIM in a blinded fashion with all other parameters held constant. In conclusion, they did not find an improvement in gait parameters at 60 Hz STIM. [5] Besides, there was also less tremor control at 60 Hz. It is remarkable to state that, Tandra et al. [1] also kept the voltage and pulse width constant and supported the results of the Phibbs et al. [5] in a larger group of patients. [1] Taken together with the results of Tandra et al., [1] we think that the improvement in the low-frequency STIM pattern that had been reported previously, [2][3][4] might rather be related to the increment in the STIM voltages or other parameters to adapt the same total energy. The observation of differing optimal contact for low-frequency STIM [2] is also an intriguing point that needs to be clarified in this regard. More complicating this issue, a recent study also demonstrated that optimal frequency varied between patients, and it was also associated with electrode contact site and severity of axial symptoms. [6] Investigating the clinical phenotypes of the patients with distinct optimal STIM frequencies in detail and comparing some specific features differing between groups may also provide interesting perspectives. Tandra et al. [1] demonstrate that patients best at 90 and 180 Hz STIM do not show difference in terms of age, disease duration, UPDRS scores, voltage amplitudes. However, we wonder if they might also include the intergroup comparisons of some clinical features such as "on" medication FOG, postural instability, speech, or other axial symptoms that are rather not responsive to DBS STIM which might also provide critical contributions.
Another point is that the effects of the STIM on axial symptoms including gait and FOG occur the latest in comparison to other motor signs such as tremor, rigidity, or bradykinesia. Such that, the onset of the effect of DBS therapy on gait may take hours to weeks. [7] Therefore, the 20 min interval between the distinct STIM frequencies may not be sufficient for the evaluation