Ilia Itin

The Gly2019Ser Mutation in LRRK2 is not Fully Penetrant in Familial Parkinson's Disease: The GenePD Study

BackgroundWe report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinsons disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.MethodsA sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.ResultsThirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.ConclusionLifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Valproate for the treatment of medication-induced impulse-control disorders in three patients with Parkinson’s disease

Impulse-control disorders (ICDs) are becoming more commonly recognized in the Parkinson disease (PD) population. To date, there are no definitive methods of treating dopamine dysregulation syndromes in PD patients. We sought to uncover an effective treatment option for future study. We report a series of 3 PD patients with ICDs who were effectively treated with valproate. Based on these encouraging preliminary observations, future controlled clinical trials investigating the efficacy of valproate for ICDs in PD are recommended.

Comprehensive, Multidisciplinary Deep Brain Stimulation Screening for Parkinson Patients: No Room for “Short Cuts”

Careful, often cumbersome, screening is a fundamental part of DBS evaluation in Parkinsons disease (PD). It often involves a brain MRI, neuropsychological testing, neurological, surgical, and psychiatric evaluation, and “ON/OFF” motor testing. Given that DBS has now been a standard treatment for advanced PD, with clinicians’ improved comfort and confidence in screening and referring patients for DBS, we wondered whether we can now streamline our lengthy evaluation process. We reviewed all PD patients evaluated for DBS at our center between 2006 and 2011 and analyzed the reasons for exclusion and for dropping out despite passing the screening process. A total of 223 PD patients who underwent DBS evaluation had complete charting. Only 131 (58.7%) patients were successfully implanted. Sixty‐one (27.3%) patients were excluded after screening because of significant cognitive decline (32.7%), early disease with room for medication adjustment (29.5%), behavioral dysfunction (21.3%), suspected secondary parkinsonism or atypical parkinsonism syndrome (13.1%), PD, but with poor levodopa response (11.4%), unrealistic goals (9.8%), PD with predominant axial symptoms (6.5%), significant comorbidities (6.5%), or abnormal brain imaging (3.2%). In addition, 31 (13.9%) patients were cleared for surgery, but either chose not have it (18 patients), were lost to follow‐up (12 patients), or were denied by medical insurance (1 patient). Through careful screening, a significant percentage of surgical candidates continue to be identified as less suitable because of a variety of reasons. This underscores the continued need for a comprehensive, multidisciplinary screening process.

Dopamine Transporter (DaT) Scan Utilization in a Movement Disorder Center

The aim of this work was to describe utilization patterns of dopamine transporter (DaT) scan and its influence on patient management at a single movement disorders center. DaT scan helps differentiate between neurodegenerative from non‐neurodegenerative parkinsonism and essential tremor (ET). It has been recently approved in the United States in 2011.

Is 6 months of neuroleptic withdrawal sufficient to distinguish drug-induced parkinsonism from Parkinson's disease?

ABSTRACT Background: Drug-induced parkinsonism (DIP) is the second commonest cause of akinetic-rigid syndrome in the western world. Differentiating DIP from Parkinsons disease (PD) may be a challenge to clinicians. One of the factors distinguishing DIP from PD is that discontinuation of the neuroleptic agent in DIP should relieve the symptoms of parkinsonism. The majority of the literature uses the 6-month timeframe between the neuroleptic withdrawal and resolution of the symptoms of parkinsonism. Methods: We report two cases of DIP wherein the symptoms of parkinsonism persisted more than 6-months from withdrawal of the dopamine receptor blocking agent (DRBA) and the results of their ioflupane iodine-123 (DaT) single-photon emission computed tomography (SPECT) scan. DaT scan is a newly approved radiopharmaceutical in the United States indicated for striatal dopamine transporter visualization to assist in the evaluation of adult patients with suspected parkinsonian syndromes. Results: The first case is a patient who developed parkinsonism from risperidone, while the second case developed parkinsonism from metoclopramide. In both cases, parkinsonism persisted 6 months after discontinuation of the DRBA, therefore DaT scan was obtained, showing normal striatal dopamine transporter uptake. Nine months after the discontinuation of the DRBA, parkinsonism was significantly improved in both patients but not completely resolved. Conclusion: Our two cases illustrate the possibility of persistent parkinsonism beyond 6–9 months from the time of neuroleptic withdrawal without evidence of presynaptic dopaminergic neuronal loss that would be suggestive of conversion to PD. We recommend that the official recommendation of the minimum time of neuroleptic withdrawal be modified to at least 1 year before entertaining the diagnosis of PD conversion in patients with exposure to DRBAs.

Three Cases of Levodopa-Resistant Parkinsonism After Radiation Therapy

Case series Patients: Male, 77 • Female, 44 • Male, 9 Final Diagnosis: Radiation induced parkinsonism Symptoms: Slowness Medication: — Clinical Procedure: — Specialty: Neurology Objective: Unusual or unexpected effect of treatment Background: Unequivocal brain radiation-induced parkinsonism has so far been reported in only in two pediatric patients. However, with the rising incidence rates for brain tumors in industrialized countries and the consequential increased exposure to cranial radiotherapy, clinicians might become more exposed to this entity. Case Report: Three patients were treated for intraparenchymal brain tumor with resection, chemotherapy, and whole brain radiation. One patient developed leukoencephalopathy and parkinsonism within one year of treatment, one developed it seven years after treatment completion, and one developed dementia, parkinsonism and cerebral infracts 40 years after whole brain radiation. Brain MRIs and a DaTscan were obtained. All patients failed a trial of carbidopa/levodopa. We suggest that the brain radiation exposure was responsible for levodopa resistant parkinsonism, cognitive decline, and diffuse leukoencephalopathy. Conclusions: Although rare, radiation therapy-induced parkinsonism might be responsible for levodopa-resistant parkinsonism.

Occupational Oromandibular Dystonia in an Opera Singer Mimicking Spasmodic Dysphonia

While occupational dystonia among singers is often described as laryngeal in nature, we describe a unique case of oromandibular (jaw closure/jaw deviation) dystonia in a professional opera singer occurring exclusively when attempting to sing in the higher registry. Occurring in the context of a high-risk profession, the patient’s tone-selective symptoms were mistaken for spasmodic dysphonia which obscured the correct diagnosis and resulted in delay of treatment. After establishing the diagnosis, significant improvement was noted with botulinum toxin injections to the mandibular muscles.

Reply to Comment on: Dopamine Transporter (DaT) Scan Utilization in a Movement Disorder Center

Thank you very much for your interest in our study. Different methods for interpreting dopamine transporter (DaT) scans have been described. Our radiologist uses visual assessment for DaT scan interpretation. Although there are reports that quantitative or semiquantitative methods have better accuracy than visual assessment, there are also several reports suggesting comparable accuracy for visual assessment and semiquantitative assessment. Our radiologist classified DaT scan results using the Benamer system (i.e., Grade 1, 2, and 3 for all abnormal scans); however, in our, study we simply combined all abnormal scans regardless of their class or grade. Morphological imaging, such as computed tomography and magnetic resonance imaging of the brain, were not routinely evaluated when reading DaT scans. However, in certain cases, when an atypical pattern of decreased uptake is noted (such as a concern for structural lesions), then morphological images were obtained and compared. Lewy body dementia (LBD) was included as a prescan clinical diagnosis of neurodegenerative parkinsonism in our study. Our center does not routinely use DaT scans to assist in the diagnosis of LBD. However, in our study, 1 patient was suspected of having idiopathic Parkinson’s disease (PD) versus LBD versus another form of dementia, such as Alzheimer’s disease or frontotemporal lobe dementia. The scan for that patient turned out to be abnormal, and the patient was started on carbidopa/levodopa. Tolosa et al. described the possibility that 3 different clinical outcomes can be encountered in patients with drug-induced parkinsonism: (1) full and long-lasting recovery of drug-induced parkinsonism with no subsequent development of PD, (2) persistence and eventual worsening of parkinsonism after discontinuation of the offending drug (drug-induced parkinsonism unmasks PD), and (3) full remission of drug-induced parkinsonism after withdrawal of the offending drug with later reappearance of parkinsonism (drug-induced parkinsonism antedates PD). Rajput et al. reported 2 patients with drug-induced parkinsonism who had completely recovered after stopping the offending drugs and had histopathology findings of Lewy bodies similar to those observed in idiopathic PD. These findings underscore the complexity of the problem. Clearly, further studies involving larger numbers of patients with clinicopathological correlation are needed to determine the sensitivity and specificity of DaT scans.