Optimizing extended-release carbidopa/levodopa in Parkinson disease: Consensus on conversion from standard therapy.

PURPOSE OF REVIEW: To help clinicians optimize the conversion of a patient's Parkinson disease pharmacotherapy from immediate-release carbidopa/levodopa (IR CD/LD) to an extended-release formulation (ER CD/LD). RECENT FINDINGS: Eleven movement disorders specialists achieved consensus positions on the modification of trial-based conversion guidelines to suit individual patients in clinical practice. SUMMARY: Because the pharmacokinetics of ER CD/LD differ from those of IR CD/LD, modification of dosage and dosing frequency are to be expected. Initial regimens may be based on doubling the patient's preconversion levodopa daily dosage and choosing a division of doses to address the patient's motor complications, e.g., wearing-off (warranting a relatively high ER CD/LD dose, possibly at a lower frequency than for IR CD/LD) or dyskinesia (warranting a relatively low dose, perhaps at an unchanged frequency). Patients should know that the main goal of conversion is a steadier levodopa clinical response, even if dosing frequency is unchanged.

Incidental Lewy body disease: do some cases represent a preclinical stage of dementia with Lewy bodies?

Lewy pathology occurs in 8-17% of neurologically normal people age >60, termed incidental Lewy body disease (iLBD). It is often assumed to represent preclinical Parkinson disease (PD). However, some iLBD cases have diffuse pathology inconsistent with preclinical PD. We analyzed iLBD cases (α-synuclein immunohistochemistry) using the Braak PD staging scheme and determined if some had a neuropathological pattern suggestive of preclinical dementia with Lewy bodies (DLB). Of the 235 brains examined, 34 had iLBD (14.5%) and all but one could be assigned a Braak PD stage. The distribution of α-synuclein pathology in the 33 cases fell into three patterns: (1) diffuse cortical and subcortical α-synuclein pathology; (2) no cortical α-synuclein pathology, but a caudal-to-rostral ascending pattern, primarily involving brainstem; and (3) intermediate between these two categories. Also, 6/33 cases failed to follow the pattern of contiguous spread proposed by Braak. These findings suggest dichotomy in the distribution of iLBD: some cases fit the Braak ascending scheme, conceptually consistent with preclinical PD, whereas others displayed prominent cortical involvement that might represent preclinical DLB.

Comparison of risk factor profiles in incidental Lewy body disease and Parkinson disease.

OBJECTIVE: To explore whether associations of potential risk factors for incidental Lewy body disease (iLBD) are similar to those for Parkinson disease (PD). DESIGN: Brain autopsy study (1988-2004) of subjects without evidence of neurodegenerative disease or tremor who were evaluated by at least 1 physician within 1 year of death. Researchers analyzed incidental Lewy pathology blinded to clinical abstraction. SETTING: Olmsted County, Minnesota. Subjects Residents of Olmsted County and the immediate vicinity aged older than 60 years. MAIN OUTCOME MEASURES: Whether risk factors previously associated with PD in Olmsted County are also associated with iLBD. RESULTS: Of 235 subjects, 34 had iLBD (14.5%). The overall risk factor profiles for iLBD and PD were fairly similar between the 2 sets of odds ratio (OR) estimates, with 11 of 16 ORs in the same direction. Prior Olmsted County studies documented 7 risk factors with statistically significant associations with PD; for physician occupation and caffeine intake, the ORs for iLBD were in the same direction and statistically significant, whereas for education, head injury, and number of children, they were in the same direction but not significant; they were in the opposite direction but not statistically significant for depression and anxiety. Incidental Lewy body disease was not associated with various end-of-life conditions or causes of death, though these patients were slightly older and more likely cachectic. CONCLUSIONS: Based on this exploratory study, iLBD and PD appear to have similar risk factor profiles. Thus, at least some cases of iLBD could represent preclinical PD, arrested PD, or a partial syndrome due to a lesser burden of causative factors. Incidental Lewy body disease is not explained by nonspecific end-of-life brain insults.

Neuropathology of non-motor features of Parkinson disease.

Non-motor manifestations of Parkinson disease (PD) are common and some may actually antedate motor dysfunction. Extrapyramidal signs in PD are tightly linked to striatonigral dopaminergic denervation associated with neuronal loss and Lewy bodies in the residual neurons of the substantia nigra. Lewy bodies composed of abnormal alpha-synuclein are the histologic hallmark of PD, and their presence beyond midbrain dopaminergic neurons is considered to be the pathologic substrate of many, if not all, of the non-motor manifestations of PD. We review the pathologic correlates of autonomic dysfunction (cardiac and gastrointestinal), hyposmia, depression, rapid eye movement behavior disorder and dementia in PD For each non-motor clinical feature there is strong evidence to suggest a role for alpha-synuclein pathology, lending further support for the notion that PD is a multisystem alpha-synucleinopathy.

Incidental Lewy body disease and preclinical Parkinson disease.

BACKGROUND: The significance of Lewy bodies detected at autopsy in the brains of clinically normal individuals is uncertain but may represent preclinical Parkinson disease (PD). OBJECTIVE: To determine whether diminished striatal dopaminergic innervation and nigral cell loss are present in incidental Lewy body disease (iLBD), as one might expect if it is a forerunner of PD. DESIGN: Case-control study. SETTING: Medical records and archival brain tissue were obtained from a tertiary medical center for further study. PARTICIPANTS: Brains from clinically healthy individuals older than 60 years with alpha-synuclein-immunoreactive Lewy bodies (iLBD; n = 12) were compared with those from clinically healthy individuals with no alpha-synuclein pathologic findings (n = 31) and patients with PD (n = 25). MAIN OUTCOME MEASURES: Striatal dopaminergic integrity assessed in sections of putamen by immunofluorescence for tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2), neuronal loss score in the substantia nigra, and distribution of Lewy bodies according to PD stage. RESULTS: Among the participants with iLBD, decreased striatal dopaminergic immunoreactivity was documented for both TH (33%) and VMAT2 (42%), compared with the pathologically normal subjects; as expected, the reductions were even greater in PD (73% decrease for TH and 96% decrease for VMAT2). Substantia nigra neuronal loss inversely correlated with both striatal TH (r = -0.84) and VMAT2 (r = -0.77). In addition, PD stage inversely correlated with both striatal VMAT2 (r = -0.85) and TH (r = -0.85). CONCLUSIONS: The results indicate that iLBD has nigrostriatal pathological features that are intermediate between those in pathologically normal persons and those with PD. The findings suggest that iLBD probably represents presymptomatic PD, rather than nonspecific, age-related alpha-synuclein pathological changes.

Cardiac sympathetic denervation correlates with clinical and pathologic stages of Parkinson's disease.

Attention has been drawn to cardiac sympathetic denervation in Parkinson's disease (PD) based on clinical studies using [123I] metaiodobenzylguanidine scintigraphy; however, the histologic correlates and time course of cardiac sympathetic denervation are poorly understood. To address these issues, we used tyrosine hydroxylase (TH) immunohistochemistry to detect cardiac sympathetic nerve fibers in the epicardium of 4 normal controls, 11 cases with incidental Lewy bodies (iLBs), and 14 cases of PD. Cardiac sympathetic innervation was significantly less in PD than in normal controls and cases with iLBs (P < 0.05). There was also a decrease in TH-immunoreactive fibers in iLB cases compared to normal controls (P < 0.01). TH-immunoreactive fibers correlated with the PD stage (r = -0.75, P < 0.001), as well as with Hoehn & Yahr clinical stage (r = -0.61, P < 0.001), and disease duration (r = -0.63, P < 0.001). Immunohistochemistry for alpha-synuclein showed neurites in epicardium in PD and iLB cases, but not in normal controls. The density of alpha-synuclein neurites correlated with Braak PD stage (r = 0.38, P < 0.05), Hoehn & Yahr clinical stage (r = 0.44, P < 0.05), and disease duration (r = 0.42, P < 0.05). This study demonstrates that cardiac sympathetic degeneration and alpha-synuclein pathology is present in presymptomatic phase of PD, and that both increase with disease duration and severity.

Evidence that incidental Lewy body disease is pre-symptomatic Parkinson's disease.

Lewy bodies, the histologic hallmark of Parkinson's disease (PD), are detected in the brains of about 10% of clinically normal people over the age of 60 years. When Lewy bodies are found in normal individuals, the process is sometimes referred to as incidental Lewy body disease (iLBD). The distribution of Lewy bodies in iLBD is similar to the distribution in PD, but neuronal populations vulnerable to Lewy bodies do not show significant neuronal loss in iLBD. It remains unknown if Lewy bodies in this setting represent pre-symptomatic PD or an age-related change unrelated to PD. To address this question we identified cases of iLBD and used a marker for dopaminergic and noradrenergic neurons, tyrosine hydroxylase (TH), to determine if there were changes similar to those found in PD. TH immunoreactivity in the striatum and the epicardial nerve fibers was decreased in iLBD compared to normal controls, but not to the same extent as in PD. The findings suggest that iLBD is preclinical PD and that the lack of symptoms is due to subthreshold pathology.

Unusual compulsive behaviors primarily related to dopamine agonist therapy in Parkinson's disease and multiple system atrophy.

Unusual compulsive behaviors (weighing, card and video game playing, fishing, gardening, intense interest in established hobbies, locking and unlocking doors, repetitive dressing and undressing) occurred in relation to dopamine agonist therapy (six patients) and levodopa therapy (one patient) in seven patients with parkinsonism (seven Parkinson's disease, one multiple system atrophy). These behaviors occurred in tandem with pathological gambling, hypersexuality, compulsive eating, compulsive shopping or punding in six of the seven cases. Obsessive thoughts were present in one patient, with no prior history of obsessive-compulsive disorder. The simultaneous occurrence of these phenomenologically distinct behaviors in this group of patients suggests that a broad spectrum of psychopathology may occur in this context and should be monitored for in routine neurological practice.

Early-onset familial parkinsonism due to POLG mutations.

OBJECTIVE: To define the molecular etiology of early-onset parkinsonism and peripheral neuropathy. METHODS: Two sisters had early-onset parkinsonism (dystonic toe curling, action tremor, masked face, bradykinesia, stooped posture, and rigidity), together with clinical and electrophysiological signs of sensorimotor axonal peripheral neuropathy. RESULTS: No mutations were found in the genes for parkin or PINK1. Muscle biopsies showed ragged-red and cytochrome c oxidase-negative fibers, and biochemistry showed decreased activities of respiratory chain complexes containing mitochondrial DNA-encoded subunits. Multiple mitochondrial DNA deletions were seen by long polymerase chain reaction, and sequencing of the POLG gene showed that the patients were compound heterozygous for two patogenic mutations. INTERPRETATION: POLG mutations can cause early-onset parkinsonism in the absence of progressive external ophthalmoplegia.

Neurologic spectrum of chronic liver failure and basal ganglia T1 hyperintensity on magnetic resonance imaging: probable manganese neurotoxicity.

BACKGROUND: An atypical form of parkinsonism has been described in patients with chronic liver disease, associated with increased T1 signal in the basal ganglia on magnetic resonance imaging. The magnetic resonance imaging signal changes are characteristic of manganese accumulation, which has been neuropathologically confirmed. Manganese neurotoxicity may result in additional neurologic findings besides parkinsonism. OBJECTIVE: To fully characterize patients with chronic central nervous system symptoms and chronic liver failure associated with basal ganglia T1 hyperintensity. DESIGN: Prospective and retrospective case study. SETTING: Mayo Clinic, Rochester, Minn. PARTICIPANTS: Eight patients referred for neurologic evaluation and studied prospectively, and 7 additional retrospectively identified patients who had been examined by Mayo Clinic neurologists. MAIN OUTCOME MEASURES: Neurologic syndromes identified. RESULTS: Three syndromes were recognized in these 15 patients with liver failure and basal ganglia T1 hyperintensity on magnetic resonance imaging: (1) isolated parkinsonism, (2) gait ataxia plus other neurologic findings (ataxia-plus), and (3) cognitive impairment with psychiatric features. All but 1 patient had elevated blood manganese levels. Ammonia levels were normal in most, and the neurologic syndromes did not appear to reflect the well-known toxic-metabolic encephalopathy of liver disease. CONCLUSIONS: Chronic liver failure may result in heterogeneous neurologic syndromes that cut across a variety of liver diseases. We selected cases on the basis of evidence of brain manganese accumulation, and this may be a crucial component of these syndromes. Further studies are necessary to explore this issue.

Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson's disease and multiple system atrophy.

Pathological hypersexuality developed in 13 patients with PD and two patients ultimately diagnosed clinically with MSA. Hypersexuality began within 8 months after starting dopamine agonist therapy in 14 of 15 cases, including four on agonist monotherapy. It resolved in the four cases where the agonist was stopped, despite continued levodopa therapy. This was not an isolated behavioral problem in most, with additional compulsive or addictive behaviors coinciding in nine patients (60%). A systematic literature review of pathological hypersexuality in PD revealed similar medication histories; combining these cases with our series, 26 of 29 patients (90%) were on adjuvant dopamine agonists.

Alpha-synuclein immunohistochemistry in two cases of co-occurring idiopathic Parkinson's disease and motor neuron disease.

We report on two cases of sporadic idiopathic Parkinson's disease with motor neuron disease co-occurring in the same individuals. Pathological analysis revealed the presence of Lewy bodies in brainstem nuclei and basal forebrain consistent with Lewy body disease (LBD), as well as motor neuron degeneration and argyrophilic grain disease. We compared our two cases to all previously published pathological cases of combined LBD and motor neuron degeneration.

Pathological gambling caused by drugs used to treat Parkinson disease.

BACKGROUND: Pathological gambling is a rare potential complication related to treatment of Parkinson disease (PD). However, the etiology of this behavior is poorly understood. OBJECTIVE: To examine the relationship between medical therapy for PD and pathological gambling. METHODS: In our routine movement disorders practice (2002-2004), we encountered 11 patients with idiopathic PD who had recently developed pathological gambling. We assessed the relationship to their medical therapy and compared them with cases identified by systematic review of the existing literature on pathological gambling and PD. RESULTS: All 11 patients with PD and pathological gambling were taking therapeutic doses of a dopamine agonist; 3 of these patients were not treated with levodopa. In 7 patients, pathological gambling developed within 3 months of starting to take or escalating the dose of the agonist; in the other 4 with a longer latency, gambling resolved after the agonist use was discontinued. Pramipexole dihydrochloride was the agonist in 9 of 11 cases in our series and 10 of 17 in the literature (68% in total). CONCLUSIONS: Dopamine agonist therapy was associated with potentially reversible pathological gambling, and pramipexole was the medication predominantly implicated. This may relate to disproportionate stimulation of dopamine D(3) receptors, which are primarily localized to the limbic system.

Brain metastases.

BACKGROUND: Systemic cancer is the second most common cause of death for adults in the United States. Twenty percent of these patients develop neurologic symptoms sometime during their illness. An apparent increase in the incidence of both systemic cancers and resulting brain metastases are posing an increasing challenge to health care providers. Neurologic complications lead to significant morbidity and mortality in these patients. Therefore, it is important to understand the current concepts of diagnosis and treatment of patients with brain metastases. REVIEW SUMMARY: This review summarizes the epidemiology, clinical features, pathophysiology, and diagnostic evaluation of brain metastases. The section on current treatments is presented from the perspective of the three most common primary tumor locations along with the treatment approach to other metastatic tumors. This review includes a thorough evaluation of the literature, highlights controversies over treatment options, and provides insight into novel approaches currently under investigation. Clinical studies needed for further study are also discussed. CONCLUSIONS: A clearer understanding of the pathophysiology of metastatic tumors and advances in diagnostic technology have paved the road to a better approach to treatment of brain metastases. Although no curative treatments are available to date, significant improvement in a patient's quality of life and life expectancy can be achieved with the available therapy. A better understanding of different primary cancers leading to brain metastases leads to a more effective treatment. More studies are needed to critically analyze the clear benefit of these treatment options in selected patients.