Centripetal Nystagmus, Slow Saccades, Cerebellar Ataxia, and Parkinsonism in a Patient With Anti-GAD65-Associated Stiff Person Syndrome Spectrum Disorder.

ABSTRACT: A 68-year-old woman with positional dizziness and progressive imbalance presented for vestibular evaluation. Examination was notable for spontaneous downbeat nystagmus (DBN), horizontal and vertical gaze-evoked nystagmus (GEN) with centripetal and rebound nystagmus, and positional apogeotropic nystagmus. There was also mild-moderate slowing of saccades horizontally and vertically and poor fast phases with an optokinetic stimulus. Further consultation by a movement disorder specialist uncovered asymmetric decrementing bradykinesia and rigidity, masked facies, and a wide-based stance without camptocormia. Screening serum laboratory results for metabolic, rheumatologic, infectious, heavy metal, endocrine, or vitamin abnormalities was normal. Surveillance imaging for neoplasms was unremarkable, and cerebrospinal fluid (CSF) analysis was negative for 14-3-3 and real-time quaking-induced conversion (RT-QuIC). However, her anti-glutamic acid decarboxylase-65 (GAD65) immunoglobulin G (IgG) level was markedly elevated in serum to 426,202 IU/mL (reference range 0-5 IU/mL) and in CSF to 18.1 nmol/L (reference range <0.03 nmol/L). No other autoantibodies were identified on the expanded paraneoplastic panel. The patient was referred to neuroimmunology, where torso rigidity, spasticity, and significant paravertebral muscle spasms were noted. Overall, the clinical presentation, examination findings, and extensive workup were consistent with a diagnosis of anti-GAD65-associated stiff person syndrome-plus (musculoskeletal plus cerebellar and/or brainstem involvement). She was subsequently treated with intravenous immunoglobulin (IVIg) and has been stable since commencing this therapy. In patients with centripetal nystagmus, especially in association with other cerebellar findings, an autoimmune cerebellar workup should be considered.

Brainstem Pathologies Correlate With Depression and Psychosis in Parkinson's Disease.

BACKGROUND: The pathological hallmarks of Parkinson's disease include intraneuronal Lewy bodies, neuronal loss, and gliosis. We aim to correlate Parkinson's disease neuropsychiatric symptoms, (e.g., depression, psychosis, and anxiety) with the severity of neuropathology in the substantia nigra and locus coeruleus. METHODS: The brains of 175 participants with a primary pathologic diagnosis of Parkinson's disease were analyzed semi-quantitatively to ascertain the burden of neuronal loss and gliosis and Lewy body pathology within the locus coeruleus and substantia nigra. Participants' history of anxiety, depression, and psychosis were determined using a chart-extracted medical history or record of formal psychiatric evaluation. RESULTS: Of the sample, 56% (n = 98), 50% (n = 88), and 31.25% (n = 55) of subjects had a diagnosis of psychosis, depression, and anxiety, respectively. Psychosis (χ2 = 7.1, p = 0.008, df = 1) and depression (χ2 = 7.2, p = 0.007, df = 1) were associated with severe neuronal loss and gliosis in the substantia nigra but not in the locus coeruleus. No association was observed between anxiety and neuronal loss and gliosis in either region. No neuropsychiatric symptoms were associated with Lewy body score. After controlling for disease duration and dementia, psychosis (odds ratio [OR]: 3.1, 95% confidence interval [CI]: 1.5-6.4, χ2 = 9.4, p = 0.012, df = 1) and depression (OR: 2.6, 95% CI: 1.3-5.0, χ2 = 7.9, p = 0.005, df = 1) remained associated with severe neuronal loss and gliosis in the substantia nigra. CONCLUSION: These results suggest that psychosis and depression in Parkinson's disease are associated with the underlying neurodegenerative process and demonstrate that cell loss and gliosis may be a better marker of neuropsychiatric symptoms than Lewy body pathology.

Non-staged bilateral Globus Pallidus Internus deep brain stimulation lead revision using intraoperative MRI: a case report and literature review.

BACKGROUND: Deep brain stimulation (DBS) lead revision due to suboptimal therapy is common but there is no standardised protocol. We describe a novel technique using iMRI to perform concurrent new Globus Pallidus Internus (GPi) DBS lead implantation and old lead removal in a dystonia patient.Case-description: A 60-year-old woman with medication and neurotoxin-refractory isolated cervical dystonia underwent awake bilateral GPi DBS surgery with MER-guided lead implantation. She initially had a favourable response but later reported suboptimal benefit despite reprogramming. MRI demonstrated suboptimal lead placement and MRI-guided revision surgery under general anesthesia was planned. The goal was to place new leads superior and medial to the existing leads. Using a 1.5 T iMRI and the ClearPoint® NeuroNavigation system, new leads were placed through the existing burr holes, into the new targets with radial errors < 0.08mm bilaterally without crossing the old leads. The old leads were then removed and the new leads connected to the existing pulse generator. The patient tolerated the procedure well and had improved side-effect profile at all contacts at 1-month follow-up. CONCLUSIONS: Non-staged iMRI-guided DBS revision surgery under general anesthesia is technically feasible and is an alternative strategy to a staged iMRI-guided revision surgery or an awake MER-guided revision surgery in select patients.

Suicide in Parkinson's disease.

Persons with Parkinson's disease (PwP) have many known risk factors for suicide and suicidal ideation (SI). Despite this, there is limited understanding of suicidality in this population. We conducted a systematic review to synthesise the available literature on suicidality in PwP and highlight areas for potential intervention and further research. We identified 116 articles discussing SI, suicidal behaviours, suicide attempts and/or fatal suicide in PwP. These articles describe prevalence, suicide methods, risk factors for suicide and SI and treatment of suicidality. In this review, we summarise the current literature and provide suggestions for how clinicians can identify and treat PwP who are at risk for suicide, for example, through aggressive treatment of depression and improved screening for access to lethal means.

Expansion of the clinical spectrum associated with AARS2-related disorders.

Biallelic pathogenic variants in AARS2, a gene encoding the mitochondrial alanyl-tRNA synthetase, result in a spectrum of findings ranging from infantile cardiomyopathy to adult-onset progressive leukoencephalopathy. In this article, we present three unrelated individuals with novel compound heterozygous pathogenic AARS2 variants underlying diverse clinical presentations. Patient 1 is a 51-year-old man with adult-onset progressive cognitive, psychiatric, and motor decline and leukodystrophy. Patient 2 is a 34-year-old man with childhood-onset progressive tremor followed by the development of polyneuropathy, ataxia, and mild cognitive and psychiatric decline without leukodystrophy on imaging. Patient 3 is a 57-year-old woman with childhood-onset tremor and nystagmus which preceded dystonia, chorea, ataxia, depression, and cognitive decline marked by cerebellar atrophy and white matter disease. These cases expand the clinical heterogeneity of AARS2-related disorders, given that the first and third case represent some of the oldest known survivors of this disease, the second is adult-onset AARS2-related neurological decline without leukodystrophy, and the third is biallelic AARS2-related disorder involving a partial gene deletion.

The Prevalence of Bipolar Disorders and Association With Quality of Life in a Cohort of Patients With Multiple Sclerosis.

Clinical observations of mood instability in multiple sclerosis (MS) have led to the hypothesis that bipolar disorder (BD) may be more prevalent in persons with MS than in the general population. This cross-sectional study assesses the prevalence of BD among patients with MS using standardized psychiatric diagnostic interviews and evaluates quality of life. This study demonstrates a higher prevalence of BD in patients with MS compared with the general population. It also reveals the negative impact of BD on quality of life, raises the concern that BD can occur before the onset of neurological symptoms in MS, and suggests that, in some cases, BD may delay diagnosis of MS.

Automating the analysis of eye movement for different neurodegenerative disorders.

The clinical observation and assessment of extra-ocular movements is common practice in assessing neurodegenerative disorders but remains observer-dependent. In the present study, we propose an algorithm that can automatically identify saccades, fixation, smooth pursuit, and blinks using a non-invasive eye tracker. Subsequently, response-to-stimuli-derived interpretable features were elicited that objectively and quantitatively assess patient behaviors. The cohort analysis encompasses persons with mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), Parkinson's disease mimics (PDM), and controls (CTRL). Overall, results suggested that the AD/MCI and PD groups had significantly different saccade and pursuit characteristics compared to CTRL when the target moved faster or covered a larger visual angle during smooth pursuit. These two groups also displayed more omitted antisaccades and longer average antisaccade latency than CTRL. When reading a text passage silently, people with AD/MCI had more fixations. During visual exploration, people with PD demonstrated a more variable saccade duration than other groups. In the prosaccade task, the PD group showed a significantly smaller average hypometria gain and accuracy, with the most statistical significance and highest AUC scores of features studied. The minimum saccade gain was a PD-specific feature different from CTRL and PDM. These features, as oculographic biomarkers, can be potentially leveraged in distinguishing different types of NDs, yielding more objective and precise protocols to diagnose and monitor disease progression.

Interpretable speech features vs. DNN embeddings: What to use in the automatic assessment of Parkinson's disease in multi-lingual scenarios.

Speech-based approaches for assessing Parkinson's Disease (PD) often rely on feature extraction for automatic classification or detection. While many studies prioritize accuracy by using non-interpretable embeddings from Deep Neural Networks, this work aims to explore the predictive capabilities and language robustness of both feature types in a systematic fashion. As interpretable features, prosodic, linguistic, and cognitive descriptors were adopted, while x-vectors, Wav2Vec 2.0, HuBERT, and TRILLsson representations were used as non-interpretable features. Mono-lingual, multi-lingual, and cross-lingual machine learning experiments were conducted leveraging six data sets comprising speech recordings from various languages: American English, Castilian Spanish, Colombian Spanish, Italian, German, and Czech. For interpretable feature-based models, the mean of the best F1-scores obtained from each language was 81% in mono-lingual, 81% in multi-lingual, and 71% in cross-lingual experiments. For non-interpretable feature-based models, instead, they were 85% in mono-lingual, 88% in multi-lingual, and 79% in cross-lingual experiments. Firstly, models based on non-interpretable features outperformed interpretable ones, especially in cross-lingual experiments. Specifically, TRILLsson provided the most stable and accurate results across tasks and data sets. Conversely, the two types of features adopted showed some level of language robustness in multi-lingual and cross-lingual experiments. Overall, these results suggest that interpretable feature-based models can be used by clinicians to evaluate the deterioration of the speech of patients with PD, while non-interpretable feature-based models can be leveraged to achieve higher detection accuracy.

Perry Disease: Expanding the Genetic Basis.

Background: Perry disease (or Perry syndrome [PS]) is a hereditary neurodegenerative disorder inevitably leading to death within few years from onset. All previous cases with pathological confirmation were caused by mutations within the cytoskeleton-associated protein glycine-rich (CAP-Gly) domain of the DCTN1 gene. Objectives: This paper presents the first clinicopathological report of PS due to a novel DCTN1 mutation outside the CAP-Gly domain. Methods: Clinical and pathological features of the new variant carrier are compared with another recently deceased PS case with a well-known pathogenic DCTN1 mutation and other reported cases. Results and Conclusions: We report a novel DCTN1 mutation outside the CAP-Gly domain that we demonstrated to be pathogenic based on clinical and autopsy findings.