Background The phenotype of Parkinson disease (PD) patients with and without LRRK2 G2019S mutations is reported to be similar; however large uniformly evaluated series are lacking. Objective To characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. Methods We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). GBA mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the geriatric depression scale (GDS) and the non-motor symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. Results LRRK2 G2019S carriers (n=97) and non-carriers (n=391) were similar in age and age-at-onset of PD. Carriers had longer disease duration (8.6years versus 6.1years, p<0.001), were more likely to be women (51.5% versus 37.9%, p=0.015) and more often reported first symptoms in lower extremities (40.0% versus 19.2%, p<0.001). In logistic models adjusted for age, disease duration, gender, education, and site, carriers were more likely to have lower extremity onset (p<0.001), postural instability gait difficulty (PIGD, p=0.043) and persistent levodopa response for>5 years (p=0.042). Performance on UPDRS, MoCA, GDS and NMS did not differ by mutation status. Conclusion PD in AJ-LRRK2 G2019S mutation carriers is similar to idiopathic PD, but characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

Essential tremor is one of the most common movement disorders in adults and can affect both children and adults. An updated consensus statement in 2018 redefined essential tremor as an isolated action tremor present in bilateral upper extremities for at least three years. Tremor may also be present in other locations, commonly the neck or the vocal cords. Patients with additional neurologic symptoms are now categorized as “essential tremor plus.” Additional clinical features associated with the condition include but are not limited to cognitive impairment, psychiatric disorders, and hearing loss. When treatment is needed, propranolol and primidone are considered first line treatments. Patients who are severely affected are often offered deep brain stimulation. Although the ventral intermediate nucleus of the thalamus is the traditional surgical target, the caudal zona incerta is also being studied as a possible superior alternative. Magnetic resonance imaging guided high intensity focused ultrasound is a newer surgical alternative that may be ideal for patients with substantial medical comorbidities. Current research explores novel oral treatments, chemodenervation, and noninvasive neuromodulation for treatment of essential tremor.

The DYT6 gene for primary torsion dystonia (PTD) was mapped to chromosome 8p21-q22 in two Amish-Mennonite families who shared a haplotype of marker alleles across a 40 cM linked region. The objective of this study was to narrow the DYT6 region, clinically characterize DYT6 dystonia in a larger cohort, and to determine whether DYT6 is associated with dystonia in newly ascertained multiplex families. We systematically examined familial Amish-Mennonite dystonia cases, identifying five additional members from the original families, as well as three other multiplex Amish-Mennonite families, and evaluated the known DYT6 haplotype and recombination events. One of the three new families carried the shared haplotype, whereas the region was excluded in the two other families, suggesting genetic heterogeneity for PTD in the Amish-Mennonites. Clinical features in the five newly identified DYT6 carriers were similar to those initially described. In contrast, affected individuals from the excluded families had a later age of onset (46.9 years vs. 16.1 years in the DYT6), and the dystonia was both more likely to be of focal distribution and begin in the cervical muscles. Typing of additional markers in the DYT6-linked families revealed recombinations that now place the gene in a 23 cM region surrounding the centromere. In summary, the DYT6 gene is in a 23 cM region on chromosome 8q21-22 and does not account for all familial PTD in Amish-Mennonites.

Background: Olfactory dysfunction is an established nonmotor feature of idiopathic Parkinson

Leucine rich repeat kinase (LRRK2) G2019S mutations are presumed to cause PD through a toxic gain of function of the protein kinase. Small molecule kinase inhibitors have been developed for the treatment of certain cancers, and some antioncogenic agents such as sunitinib, may nonspecifically inhibit LRRK2. Few studies, however, have assessed cancer risk in LRRK2 mutation carriers. To explore this risk, we evaluated records of Ashkenazi Jewish (AJ) PD patients participating in genetic research. Charts were reviewed for 163 unrelated AJ PD patients, 31 of whom harbored the G2019S mutation. History of cancer was queried at baseline intake using a form reviewing medical conditions, and charts were reviewed for all follow-up visits. 9/31 LRRK2 G2019S mutation carriers had non-skin cancers, whereas 15/132 without mutations had non-skin cancers, representing an almost three-fold increased risk in this group (HR 2.9, 95% CI 1.3-6.6). Age at first non-skin cancer was younger in the LRRK2 carriers (56.0 years) than the non-carriers (62.0 years), but was not significant. 67% of the LRRK2 carriers had their cancer before the onset of PD, whereas only 40% of non-carriers developed their first non-skin cancer before onset of PD. While further evaluation is warranted, our findings indicate an increased risk of non-skin cancers in LRRK2 G2019S mutation carriers, which may be related to toxic gain of function of mutated LRRK2.

Objective This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN‐DBS) in Parkinson disease. Methods Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS‐), and noncarriers with or without DBS (GBA‐DBS+, GBA‐DBS‐). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. Results Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS‐, 98 GBA‐DBS+, and 128 GBA‐DBS‐ subjects), who were longitudinally followed (range = 36–60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA‐DBS‐ subjects (95% confidence interval [CI] = −2.35 to −1.69), 1.71 points/yr more than GBA+DBS‐ subjects (95% CI = −2.14 to −1.28), and 1.49 points/yr more than GBA‐DBS+ subjects (95% CI = −1.80 to −1.18). Interpretation Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN‐DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision‐making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN‐DBS so that alternative options may be considered. ANN NEUROL 2022;91:424–435

Summary:Purpose: To examine the relation between specific EEG features and clinical outcome, determine whether a predictable sequence of EEG patterns exists during status epilepticus (SE), and examine the relation between periodic epileptiform discharges (PEDs) and SE.Methods: EEG records of 50 patients with SE admitted to Graduate Hospital between January 1990 and July 1995 were reviewed. Ictal EEGs were available in 72%; 28% had only postictal EEGs. Poor outcome was defined as death or persistent vegetative state, and good outcome as all others. Fisher's Exact test, xz. and t tests were performed for data analysis.Results: Of 50 patients, 72% had a good outcome and 28%, a poor outcome. If PEDs were present at any time during or after SE, outcome tended to be worse (p = 0.053). With PEDs, eight (44%) of 18 had a poor outcome; without PEDs, six (19%) of 32 had a poor outcome. Etiologies for SE did not substantially differ in patients with or without PEDs, and structural abnormalities were not more associated with the presence of PEDs. PEDs were seen both early and late, during and after SE. Other EEG characteristics (lateralized vs. bilateral symmetric ictal EEG, discrete vs. continuous ictal activity, and postictal focal slowing) did not relate to outcome. No predictable sequence of EEG changes was found during SE.Conclusions: PEDs are the only EEG feature related to outcome in SE and are associated with poor outcome independent of etiology. Key Words: Status epilepticus-Periodic epileptiform discharge-PLEDs-Prognosis-EEG.Status epilepticus (SE) is a common medical emergency associated with significant morbidity and mortality. Recent estimates of the incidence of SE in the United States range from 50,000 (1) to 152,000 cases per year (1,2). Mortality in SE ranges from 2 to 27% and is higher in some subgroups (1,(3)(4)(5)(6).The EEG is an important tool in both diagnosing and managing patients with SE. Many types of EEG abnormalities can be seen during SE (7,8 nosis than the early stages of SE and that PEDs represent a late stage of SE. However, there is considerable controversy regarding the relation of PEDs to SE. PEDs, especially when lateralized, occur in the absence of seizures and have been associated with the presence of underlying structural lesions, including acute cerebral infarctions, tumors, and inflammatory conditions (8,ll). In contrast, some other studies found a close relation between seizures and PEDs (1 2,13). Although specific stages of SE have been described in an experimental model, human studies have not demonstrated any reliable EEG sequence during SE (4,14).The goals of this study were to determine whether any EEG features predict prognosis in human SE, to determine whether a predictable sequence of EEG patterns exists during SE, and to examine the relation between PEDs and SE. It is important to define which patients are at risk for poor outcome, so that new therapeutic measures can be developed on appropriate populations.

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