Erika Driver-Dunckley

Validation of the questionnaire for impulsive-compulsive disorders in Parkinson's disease.

As no comprehensive assessment instrument for impulse control disorders (ICDs) in Parkinsons disease (PD) exists, the aim of this study was to design and assess the psychometric properties of a self‐administered screening questionnaire for ICDs and other compulsive behaviors in PD. The Questionnaire for Impulsive‐Compulsive Disorders in Parkinsons Disease (QUIP) has 3 sections: Section 1 assesses four ICDs (involving gambling, sexual, buying, and eating behaviors), Section 2 other compulsive behaviors (punding, hobbyism, and walkabout), and Section 3 compulsive medication use. For validation, a convenience sample of 157 PD patients at 4 movement disorders centers first completed the QUIP, and then was administered a diagnostic interview by a trained rater blinded to the QUIP results. A shortened instrument (QUIP‐S) was then explored. The discriminant validity of the QUIP was high for each disorder or behavior (receiver operating characteristic area under the curve [ROC AUC]: gambling = 0.95, sexual behavior = 0.97, buying = 0.87, eating = 0.88, punding = 0.78, hobbyism = 0.93, walkabout = 0.79). On post hoc analysis, the QUIP‐S ICD section had similar properties (ROC AUC: gambling = 0.95, sexual behavior = 0.96, buying = 0.87, eating = 0.88). When disorders/behaviors were combined, the sensitivity of the QUIP and QUIP‐S to detect an individual with any disorder was 96 and 94%, respectively. Scores on the QUIP appear to be valid as a self‐assessment screening instrument for a range of ICDs and other compulsive behaviors that occur in PD, and a shortened version may perform as well as the full version. A positive screen should be followed by a comprehensive, clinical interview to determine the range and severity of symptoms, as well as need for clinical management.

Gambling and increased sexual desire with dopaminergic medications in restless legs syndrome

Objectives: Do patients with restless legs syndrome (RLS) report gambling or other abnormal behaviors as previously reported in Parkinson disease. Methods: This survey study was sent to 261 idiopathic RLS patients, and it included the Gambling Symptoms Assessment Scale, Altman Self-Rating Mania Scale, and questions pertaining to sexual activity and novelty-seeking behaviors. Results: Ninety-nine patients responded to the survey, and 77 were actively taking 1 or more dopaminergic medications. Of the 70 respondents who answered the gambling questions, 5 (7%) noted a change in gambling, with 4 (6%; 95% confidence interval, 2%-14%) stating that increased urges and time spent gambling occurred specifically after the use of dopaminergic medications (2 on pramipexole, 1 on ropinirole, and 1 on levodopa and pramipexole). Increased sexual desire was reported by 4 (5%) of the 77 respondents, 3 (4%; 95% confidence interval, 1%-11%) reported that this occurred specifically after the use of dopaminergic medications (1 on pramipexole, 1 on ropinirole, and 1 on levodopa). One patient reported both an increase in gambling and sexual habits. Conclusions: This exploratory survey study revealed the development of gambling and/or increased sexuality in patients with RLS. These data raise the possibility that, as in Parkinson disease, RLS patients should be cautioned about potential behaviors that may occur with the use of dopaminergic medications. Further prospective studies are needed to assess the relationship between these medications and compulsive behaviors associated with the treatment of RLS.

Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain‐only donations and currently has banked more than 1600 brains. More than 430 whole‐body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimers disease, Parkinsons disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimers Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinsons Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinsons Research. The Program has made rapid autopsy a priority, with a 3.0‐hour median post‐mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant‐funded projects.

Submandibular gland needle biopsy for the diagnosis of Parkinson disease

Objective: This study investigates salivary gland biopsies in living patients with Parkinson disease (PD). Methods: Patients with PD for ≥5 years underwent outpatient transcutaneous needle core biopsies (18-gauge or 16-gauge) of 1 submandibular gland. Minor salivary glands were removed via a small incision in the lower lip. Tissue was fixed in formalin and serial 6-µm paraffin sections were immunohistochemically stained for phosphorylated α-synuclein and reviewed for evidence of Lewy type α-synucleinopathy (LTS). Results: Fifteen patients with PD were biopsied: 9 female/6 male, mean age 68.7 years, mean PD duration 11.8 years. Twelve of the needle core biopsies had microscopically evident submandibular gland tissue to assess and 9/12 (75%) had LTS. Only 1/15 (6.7%) minor salivary gland biopsies were positive for LTS. Five patients had an adverse event; all were minor and transient. Conclusions: This study demonstrates the feasibility of performing needle core biopsies of the submandibular gland in living patients with PD to assess LTS. Although this was a small study, this tissue biopsy method may be important for tissue confirmation of PD in patients being considered for invasive procedures and in research studies of other PD biomarkers.

No evidence for cognitive dysfunction or depression in patients with mild restless legs syndrome.

Restless legs syndrome is a common disoder that may interrupt sleep and has been reported to produce daytime fatigue and/or mood changes. This study assessed whether patients with RLS have more cognitive dysfunction and depression than individuals of the same age and education who do not have RLS. The study showed that older individuals with mild RLS for at least 1 year do not have cognitive dysfunction and are not depressed compared with a control group of similar age and education.

Restless legs syndrome in Parkinson's disease patients may improve with subthalamic stimulation

We report on 6 advanced Parkinsons disease (PD) patients who underwent bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) surgery whose restless legs syndrome (RLS) improved postoperatively. Despite a mean 56% decrease in their levodopa equivalents postoperatively, their RLS scores dropped by a mean of 84% (100% in three). Our findings suggest that bilateral STN DBS surgery can improve RLS in patients with advanced PD.

Heterogeneous neuropathological findings in Parkinson's disease with mild cognitive impairment.

Parkinson’s disease (PD) patients often develop mild cognitive impairment (PD-MCI) and dementia (PDD) [5, 8]. The pathologic substrate for PDD appears to be heterogeneous and includes Lewy bodies, Alzheimer’s disease (AD) pathology, and cerebrovascular disease [6, 7, 9, 10]. Neuropathological changes in PD-MCI have not been described. We present eight PD-MCI cases clinically and neuropathologically characterized as previously described [2, 4, 5]. The cognitive battery assessed five domains (memory, frontal/executive, language, attention, and visuospatial) using previously described PD-MCI criteria [5]. Lewy bodies were staged using the Unified Lewy Body Staging System [3] while AD and cerebrovascular pathology were assessed using standardized procedures [4]. Of 356 subjects autopsied from 1987 to 2010, 80 had PD (21 PD-cognitively normal, 8 PD-MCI, 51 PDD). The 8 PD-MCI cases (2 females, 6 males) were Hoehn and Yahr stage 2–3, mean age 82.8 years (range 74–89), and mean PD duration 11.4 years (range 2–25 years) (Table 1). All were examined within 18 months of death and mean post-mortem interval was ~3 h. MCI subtypes were: amnestic MCI-memory only (n = 4), non-amnestic MCI with frontal executive dysfunction (n = 3), and non-amnestic MCI with frontal executive/visuospatial dysfunction (n = 1). Table 1 Demographics and neuropathologic findings Using our Unified Lewy Body Staging scheme three cases were brainstem-predominant (stage 2a), three were brainstem-limbic predominant (stage 3), and two were neocortical Lewy body stage (stage IV) (Table 1). Three cases had no neuritic plaques, one had sparse plaques, and four had moderate neuritic plaques present (Table 1). Braak AD staging ranged from stages II to IV (Table 1) with two meeting NIA-Reagan clinicopathologic criteria for AD (intermediate or higher), both having amnestic MCI. Cerebrovascular findings are in Table 1. The sample size was too small to correlate pathologic and clinical findings. This study revealed heterogeneous pathologic findings in eight PD-MCI patients. The Lewy body distribution varied [brainstem-predominant (IIa), brainstem-limbic (III), and neocortical (IV)], with five of the eight cases having at least limbic involvement. Therefore, whether Lewy body pathology is the cause of cognitive impairment remains unclear, although limbic involvement may be a key factor. In a much larger series we previously found that PDD was associated with increasing neocortical Lewy body staging, and more than 50% or our PDD cases met neuropathological criteria for AD [10]. Interestingly, the two PD-MCI cases that met neuropathological criteria for AD had amnestic MCI. Literature review revealed four PD cases with cognitive impairment, but not clear dementia, three with neocortical Lewy body stage and one limbic stage [1]. This group also found that none of their 18 PDD cases met neuropathological criteria for AD [1]. While not reporting on PD-MCI cases, Jellinger reported that neuritic plaque pathology was greater in PDD cases compared with non-demented cases [9]. In our series the majority of PD-MCI cases were Braak AD stages III–IV (two amnestic MCI cases being stage IV), as we found with our PDD cases [10]. These findings are similar to those found in amnestic MCI cases without PD [11]. In summary, this study provides an initial evaluation of the neuropathologic findings in PD-MCI. These preliminary data indicate that the underlying neuropathology is heterogeneous, similar to MCI without PD [11]. It seems likely that the major contributors, however, are limbic and/or neocortical Lewy body and AD histopathology and possibly cerebrovascular pathology. Further detailed clinicopathological studies will help further illuminate this issue.

Essential tremor is not associated with cerebellar Purkinje cell loss

There has been controversy as to whether there is an underlying neurodegenerative process of the cerebellum in essential tremor (ET). The aim of this study was to examine whether ET is associated with Purkinje cell (PC) loss. Prospectively categorized ET and control subjects who were longitudinally examined in the Arizona Study for Aging and Neurodegenerative Disorders and came to autopsy between 1998 and 2013 underwent standardized neuropathological assessment of the brain. PC linear density of the cerebellar hemisphere was calculated in a blinded manner. There were 56 ET cases and 62 age‐matched controls free of dementia and other neurodegenerative disorders included in the study. Mean PC linear density was 3.80 ± 0.81 cells per mm for tremor cases and 3.82 ± 0.91 cells per mm for controls (Δ 0.02; 95% confidence interval [CI]: −0.30‐0.34). PC counts were not associated with tremor duration (r = 0.06; 95% CI: −0.21‐0.32). These data demonstrate that ET is not associated with cerebellar PC loss.

Comparison of Psychogenic Movement Disorders and Psychogenic Nonepileptic Seizures: Is Phenotype Clinically Important?

BACKGROUND Psychogenic non-epileptic seizures (PNES) and psychogenic movement disorders (PMDs) are common in neurology practice, yet it is not established whether clinically relevant differences between these two groups exist. METHODS In this retrospective chart review 172 patients were identified (PNES n = 116, PMD n = 56). RESULTS The whole group was characterized by female gender (82%), abuse history (45%), chronic pain (70%), depression (42%), subjective fatigue (47%), subjective cognitive complaints (55%), and referral for psychiatric evaluation (54%). Statistically significant differences (P <. 01) were found for age, education, frequency of symptoms, altered consciousness, developmental abuse, and coexisting anxiety. Clinical practice also differed for the two groups in history-taking and referrals for neuropsychological testing and/or psychiatric evaluation. CONCLUSIONS This retrospective study revealed more similarities than differences suggesting these are manifestations of the same psychopathology, with age and co-morbid anxiety potentially being important factors in predicting the symptomatic presentation. Prospective studies are needed to confirm our results. Future studies focusing more globally on somatoform disorders, rather than each phenotypic presentation, are likely needed to improve clinical care and outcomes.

Patient versus informant reporting of ICD symptoms in Parkinson's disease using the QUIP: Validity and variability ☆

Questions exist regarding the validity of patient-reporting of psychiatric symptoms in Parkinsons disease (PD). We assessed observer variability and validity in reporting of impulse control disorder (ICD) symptoms in PD by using the Questionnaire for Impulsive-Compulsive Disorders in Parkinsons Disease (QUIP). PD patients and their informants (71 pairs) completed the QUIP to assess four ICDs (compulsive gambling, buying, sexual behavior, and eating) in patients. Trained raters then administered a diagnostic interview. Sensitivity of the QUIP for a diagnosed ICD was 100% for both patient- and informant-completed instruments, and specificity was 75% for both raters. Approximately 40% of patients without an ICD diagnosis had a positive QUIP, suggesting that many PD patients experience subsyndromal ICD symptoms that require ongoing monitoring. Agreement between patient- and informant-reporting of any ICD behaviors on the QUIP was moderate (kappa=0.408), and for individual ICDs was highest for gambling (kappa=0.550). Overall, a negative QUIP from either the patient or informant rules out the possibility of an ICD, while a positive QUIP requires a follow-up diagnostic interview and ongoing monitoring to determine if symptoms currently are, or in the future become, clinically significant.