Alan Freeman

Cognitive impairments in advanced PD without dementia

Objective: To determine the nature and frequency of cognitive impairments in nondemented patients with advanced PD and their relationship to other variables potentially predictive of neuropsychological performance. Methods: The neuropsychological performance of nondemented, nondepressed patients with idiopathic PD (n = 61) was quantified with respect to clinically available normative data. The relationship of neuropsychological measures to motor symptoms, age, years of education, disease duration, age at disease onset, disease deterioration rate, and dopaminergic therapy was assessed. Results: Impairment was most frequent on measures sensitive to frontal lobe function (67% on Wisconsin Card Sorting Test number of categories, 30% on letter fluency, 30% on verbal learning). Poorer performance on multiple neuropsychological measures was related to greater overall motor abnormality (total Unified Parkinson’s Disease Rating Scale score), increased bradykinesia on medication, older age, longer disease duration, and reduced education. Conclusions: Even in the absence of dementia or depression, patients with advanced PD are likely to show clinically significant impairments on neuropsychological measures sensitive to changes in dorsolateral prefrontal regions participating in cognitive basal ganglia-thalamocortical circuits.

Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson's disease families.

Mutations in the leucine‐rich repeat kinase‐2 gene (LRRK2) are responsible for some forms of familial as well as sporadic Parkinsons disease (PD). The purpose of this study was to examine the frequency of a single pathogenic mutation (6055G>A) in the kinase domain of this gene in United States and Tunisian familial PD and to compare clinical characteristics between patients with and without the mutation. Standardized case report forms were used for clinical and demographic data collection. We investigated the frequency of the most common substitution of LRRK2 (G2019S, 6055G>A) and its impact on epidemiological and phenotypic features. The frequency of mutations in Tunisian families was 42% (38/91) and in U.S. families 2.6% (1/39), with the unique opportunity to compare homozygous (n = 23) and heterozygous (n = 109) Tunisian carriers of G2019S substitutions. Individuals with G2019S substitutions had an older age at onset but few other differences compared with families negative for the substitution. Patients with LRRK2 mutations had typical clinical features of PD. Comparisons between individuals with heterozygous and homozygous LRRK2 mutations suggested that gene dosage was not correlated with phenotypic differences; however, the estimated penetrance was greater in homozygotes across all age groups.

Clozapine is beneficial for psychosis in Parkinson's disease

CRAO, vision in the right eye deteriorated to less than 20/800 before ocular massage and 20/200 after, and right retinal blood flow slowed markedly. Nitroglycerin, 0.15 mg, was administered sublingually; within 1 minute, retinal blood flow increased dramatically and sludging resolved. One-half inch of Nitro1 paste was applied immediately and renewed every 3 hours. Visual acuity (before ocular massage) improved to 20/100 OD and 20/50 0s after 3 hours, and 20/15 OD and 20/20 0s after 48 hours. Intravenous dextran 40 was started 3 hours after nitroglycerin, and ocular massage was discontinued 9 hours later. Acetazolamide was stopped after 2 days, dextran after 4 days, and dipyridamole, aspirin, and nitroglycerin after 3 weeks. She was discharged on prednisone, 55 mg daily, with a very slow taper thereafter. Her ESR and hematocrit returned to normal within 4 weeks, cotton-wool spots resolved over 7 weeks (figure, B), and vision remained normal for a t least 2 years. Discussion. GCA was the most likely diagnosis in this elderly patient with bitemporal headache, temporal artery inflammation and tenderness, abrupt visual loss, polymyalgia rheumatica, jaw claudication, malaise, anorexia, fever, anemia, and elevated ESR.1 The diagnosis was not confmed pathologically because Doppler studies suggested that the left temporal artery supplied her already compromised left retinal circulation, and we were unwilling to trust the normal Doppler findings on the right. The funduscopic examination, which revealed cotton-wool spots, arteriolar narrowing, segmentation of blood flow, and normal optic disks, is characteristic of partial CRAO.2 The classic foveolar cherry-red spot and retinal opacification, were absent, probably because retinal ischemia never progressed to complete infarction. The normal appearance of the disk makes anterior ischemic optic neuropathy unlikely, although concomitant retrobulbar involvement cannot be excluded. In general, the overwhelming majority of patients with GCA lose vision from ischemic optic neuropathy rather than from CRA0.I In our patient, CRAO worsened despite 2 days of corticosteroid therapy. Attempts at dilating the retinal arteries with CO,, preventing further thrombosis with aspirin and dipyridamole, and reducing intraocular pressure and arterial afterload with acetazolamide, all standard treatments for CRAO,5 had little effect. Repeated ocular massage transiently reduced intraocular pressure, increased retinal blood flow, and improved vision; however, after 48 hours this too became ineffective, and rapid visual loss ensued. Intraocular pressure was sufficiently lowered by ocular massage to make paracentesis unnecessary, and retrobulbar injections with sympathetic blockers5 or vascular surgery were not attempted. The most dramatic and enduring response began within 1 minute of nitroglycerin treatment. An immediate, easily observable increase in retinal blood flow was followed within hours by a rapid recovery from near-blindness to normal vision. While we cannot rule out a sudden, delayed effect of other medications, drug interactions, or spontaneous recanalization of the central retinal artery, it seems likely that nitroglycerin was most responsible for her improvement. Others have described retinal vasodilation with organic nitrates. Cardell and Hanley3 obtained transient improvement with ocular massage and inhalation of amyl nitrite in a man with GCA and CRAO. KuritzkyG successfully treated two patients with nonarteritic central retinal artery branch occlusion using sublingual nitroglycerin. Wizemann et a17 induced recanalization with nitroglycerin in an experimental model of retinal vessel occlusion. Nitroglycerin is a safe, widely used medication whose side effects (systemic hypotension and headache) are rapidly reversible. Our experience and that of 0thers3,~J suggests that nitroglycerin may be efficacious in the treatment of CRAO complicating GCA. Bloodpressure should be monitored carefully during the administration of nitroglycerin, since marked systemic hypotension could reduce retinal artery perfusion, thereby abolishing the benefits of local vasodilation.5

Neuropsychological and psychiatric sequelae of pallidotomy for PD: Clinical trial findings

ObjectiveTo evaluate the neuropsychological and psychiatric sequelae of unilateral posterior pallidotomy for treatment of PD. MethodsPatients with idiopathic PD completed baseline and 3- and 6-month assessments after random assignment to an immediate surgery (n = 17) or medical management (n = 16) group. ResultsCompared with the medical management group, the immediate surgery group with single lesions centered on the posterior internal pallidum showed superior naming and response inhibition, better verbal recall at 6 months, but greater distractibility, a tendency toward lower phonemic fluency, and a transient (3 months’ only) semantic fluency deficit. The group with left lesions had more neuropsychological deficits than the group with right lesions or the medical management group, although these occurred mainly at 3 (but not 6) months. At 6 months, the patients with left lesions showed better verbal memory retention than the patients with right lesions. On most measures, the pattern of individual clinical change did not differ as a function of surgery or lesion laterality, with the exception of a higher frequency of decline in phonemic fluency in the patients with left lesions at 6 months. Although psychiatric status did not change overall, a history of depression tended to increase the risk of a depressive episode following surgery. ConclusionsWell-targeted, uncomplicated, unilateral pallidotomy does not produce overall neuropsychological or psychiatric change, although there are subtle changes on specific measures sensitive to frontal lobe function.

Lingual protrusion dystonia: Frequency, etiology and botulinum toxin therapy☆

The purpose of this study was to examine lingual protrusion dystonia (LPD); its frequency, etiology and response to botulinum toxin therapy. Previous literature suggests that LPD is more frequently the result of heredodegenerative disease and that the use of botulinum toxin therapy in LPD is associated with significant adverse effects. This is a retrospective database and record review from a movement disorder clinic. Of 421 dystonia patients, we identified 17 with LPD (4%). Of these cases, the diagnoses were: primary cranial dystonia (5), primary generalized dystonia (2), tardive dystonia (7), heredodegenerative disease (1), multifactorial (1) and post-infectious (1). All primary cases had concomitant oromandibular dystonia. In some secondary cases the LPD was the only cranial feature. Nine received botulinum toxin injections and 55.6% sustained moderate or marked improvement. Of 89 total botulinum toxin sessions, 66.3% had an excellent response, and 92.1% had some response. 97.8% of the sessions resulted in no significant adverse effects. On one occasion one patient developed severe dysphagia requiring placement of a percutaneous gastrostomy (PEG) tube. We conclude that LPD is rare, most commonly the result of tardive and primary dystonia. Botulinum toxin therapy may be very effective but needs to be utilized with care because of the possibility for the development of dysphagia.

Treatment of imbalance with varenicline (Chantix®): report of a patient with fragile X tremor/ataxia syndrome

We describe the case of a man with Fragile X tremor/ataxia syndrome, whose ataxia and imbalance improved with the use of varenicline (Chantix®) and reverted to baseline 10 days after varenicline was discontinued. Varenicline was started as part of a smoking cessation program.

Daytime Alertness in Parkinson’s Disease: Potentially Dose-Dependent, Divergent Effects by Drug Class

Many patients with idiopathic Parkinsons disease experience difficulties maintaining daytime alertness. Controversy exists regarding whether this reflects effects of antiparkinsonian medications, the disease itself, or other factors such as nocturnal sleep disturbances. In this study we examined the phenomenon by evaluating medicated and unmedicated Parkinsons patients with objective polysomnographic measurements of nocturnal sleep and daytime alertness. Patients (n = 63) underwent a 48‐hour laboratory‐based study incorporating 2 consecutive nights of overnight polysomnography and 2 days of Maintenance of Wakefulness Testing. We examined correlates of individual differences in alertness, including demographics, clinical features, nocturnal sleep variables, and class and dosage of anti‐Parkinsons medications. Results indicated that, first, relative to unmediated patients, all classes of dopaminergic medications were associated with reduced daytime alertness, and this effect was not mediated by disease duration or disease severity. Second, the results showed that increasing dosages of dopamine agonists were associated with less daytime alertness, whereas higher levels of levodopa were associated with higher levels of alertness. Variables unrelated to the Maintenance of Wakefulness Test defined daytime alertness including age, sex, years with diagnosis, motor impairment score, and most nocturnal sleep variables. Deficits in objectively assessed daytime alertness in Parkinsons disease appear to be a function of both the disease and the medications and their doses used. The apparent divergent dose‐dependent effects of drug class in Parkinsons disease are anticipated by basic science studies of the sleep/wake cycle under different pharmacological agents.

Cognitive correlates of hallucinations and delusions in Parkinson's disease

BACKGROUND Hallucinations and delusions that complicate Parkinsons disease (PD) could lead to nursing home placement and are linked to increased mortality. Cognitive impairments are typically associated with the presence of hallucinations but there are no data regarding whether such a relationship exists with delusions. OBJECTIVE We hypothesized that hallucinations would be associated with executive and visuospatial disturbance. An exploratory examination of cognitive correlates of delusions was also completed to address the question of whether they differ from hallucinations. METHODS 144 PD subjects completed a neuropsychological battery to assess cognition and the SAPS to examine psychosis. Correlational analyses assessed associations between hallucinations and delusions with cognitive domains. RESULTS 48 subjects (33%) reported psychotic symptoms: 25 (17%) experienced hallucinations without delusions, 23 (16%) had symptoms dominated by delusions. Severity and/or number of hallucination subtypes were significantly correlated with lower scores in language, memory, attention, executive functioning, and visuospatial ability. Correlations with delusions were non-significant. Tests of differences in the size of the correlations between groups revealed a significant relationship between language and visuospatial performance with hallucinations. CONCLUSIONS Cognitive correlates of hallucinations and delusions appear to be different in PD, suggesting distinct pathogenic mechanisms and possibly anatomical substrates. Hence, delusions may not share the same associations with dementia as hallucinations. Since this is a new finding, further studies will be needed to confirm our results.

Sleep and impulsivity in Parkinson's disease

BACKGROUND Impulsive behavior and poor sleep are important non-motor features of Parkinsons disease (PD) that negatively impact the quality of life of patients and their families. Previous research suggests a higher level of sleep complaints in PD patients who demonstrate impulsive behaviors, but the nature of the sleep disturbances has yet to be comprehensively tested. METHODS Consecutive idiopathic PD patients (N = 143) completed the Minnesota Impulse Disorder Interview and a sleep questionnaire that assessed sleep efficiency, excessive daytime sleepiness, restless legs symptoms, snoring, dreams/nightmares, and nocturia. Patients were also given a Unified Parkinsons Disease Rating Scale motor examination and they completed cognitive testing. RESULTS Impulsive PD patients endorsed more sleep complaints than non-impulsive PD patients. The group difference was primarily attributable to poor sleep efficiency (e.g., greater nocturnal awakenings), p < .01, and greater daytime sleepiness, p < .01, in the impulsive PD patients. Interestingly, restless legs symptoms were also greater in the impulsive PD patients, p < .05. The results could not be explained by medications or disease severity. CONCLUSIONS Poor sleep efficiency, restless legs symptoms, and increased daytime sleepiness are associated with impulsivity in PD. Longitudinal studies are needed to determine whether sleep disturbances precede impulsivity in PD.

Adult-onset dystonia.

Dystonia is defined as involuntary sustained muscle contractions producing twisting or squeezing movements and abnormal postures. The movements can be stereotyped and repetitive and they may vary in speed from rapid to slow; sustained contractions can result in fixed postures. Dystonic disorders are classified into primary and secondary forms. Several types of adult-onset primary dystonia have been identified but all share the characteristic that dystonia (including tremor) is the sole neurologic feature. The forms most commonly seen in neurological practice include cranial dystonia (blepharospasm, oromandibular and lingual dystonia and spasmodic dysphonia), cervical dystonia (also known as spasmodic torticollis) and writers cramp. These are the disorders that benefit most from botulinum toxin injections. A general characteristic of dystonia is that the movements or postures may occur in relation to specific voluntary actions by the involved muscle groups (such as in writers cramp). Dystonic contractions may occur in one body segment with movement of another (overflow dystonia). With progression, dystonia often becomes present at rest. Dystonic movements typically worsen with anxiety, heightened emotions, and fatigue, decrease with relaxation, and disappear during sleep. There may be diurnal fluctuations in the dystonia, which manifest as little or no involuntary movement in the morning followed by severe disabling dystonia in the afternoon and evening. Morning improvement (or honeymoon) is seen with several types of dystonia. Patients often discover maneuvers that reduce the dystonia and which involve sensory stimuli such as touching the chin lightly in cervical dystonia. These maneuvers are known as sensory tricks, or gestes antagonistes. This chapter focuses on adult-onset focal dystonias including cranial dystonia, cervical dystonia, and writers cramp. The chapter begins with a review of the epidemiology of focal dystonias, followed by discussions of each major type of focal dystonia, covering clinical phenomenology, differential genetics, and diagnosis. The chapter concludes with discussions of the pathophysiology, the few pathological cases published of adult-onset focal dystonia and management options, and a a brief look at the future.