Inflammation and fatigue in early, untreated Parkinson's Disease.

OBJECTIVES: Parkinson's disease (PD)-related fatigue is a significant clinical problem, and the pathological processes that cause fatigue remain unknown. The aim of the present study was to explore the possible association of peripheral inflammation markers and fatigue in PD. MATERIALS & METHODS: We included 47 drug naïve, newly diagnosed PD patients with low (≤3.0) or high (>5.5) fatigue levels as evaluated by the Fatigue Severity Scale (FSS). Strict diagnostic criteria were applied for inclusion. Patients with possible confounding causes for fatigue were excluded. Serum concentrations of a panel of inflammatory markers (IL-8, TNF-α, MCP1, MIP-1ß, IL-6, IL-6R, p-selectin, E-selectin-1, ICAM, VCAM-1, CCL5, IL1-Ra, and TNFR1) were measured using ELISA technology in PD patients with and without fatigue to assess the potential relationships of fatigue in newly diagnosed, treatment-naïve patients. RESULTS: Fatigued PD patients had significantly higher levels of the IL-1 receptor antagonist (IL1-Ra) (1790 pg/mL (SD1007) vs 1262 pg/mL (SD379)) and of the adhesion molecule VCAM 1 (1071 ng/mL (SD276) vs 895 ng/mL (SD229)) than non-fatigued patients. A binary logistic regression model, including high or low FSS score as the dependent variable and UPDRS motor score, MADRS, MMSE, ESS, and IL1-Ra/VCAM-1 as independent variables, showed a significant effect both for IL1-Ra and VCAM-1. CONCLUSIONS: Higher serum levels of the inflammatory molecules IL1-Ra and VCAM-1 were associated with higher fatigue levels in patients with newly diagnosed, drug-naïve PD. These findings highlight an altered immune response as a potential contributor to PD-related fatigue, from the earliest clinical stages of the disease.

A double-blind comparison of galantamine hydrobromide ER and placebo in Parkinson disease.

OBJECTIVE: To study the efficacy and safety of galantamine hydrobromide ER for the enhancement of cognition in non-demented Parkinson's patients (PD). METHODS: Sixty-nine non-demented PD participants were randomised in a double-blind, placebo-controlled study of galantamine or placebo. Galantamine was administered over 16 weeks (8 mg/day for 4 weeks, a therapeutic dose of 16 mg/day for 6 weeks and a maximum dose of 24 mg/day for 6 weeks). Outcome measures were neuropsychological (attention, verbal fluency, executive, memory, visuospatial), behavioural (Frontal Systems Behavior Scale, Neuropsychiatric Inventory-Questionnaire, PDQ-39) and motor (Unified Parkinson's Disease Rating Scale motor scale). RESULTS: 26 individuals on active medication and 28 individuals on placebo were included in the outcome analyses. No significant differences were found between the active and placebo groups on cognitive, behavioural or motor outcome measures. Most common adverse events were gastrointestinal and self-reported worsening of PD symptoms. CONCLUSIONS: Contrary to our hypotheses, galantamine treatment did not improve attention/executive, memory or visuospatial performance in non-demented PD patients. Further, there was a high, statistically significant drop-out rate in the treatment group due to gastrointestinal side effects and self-reported worsening of PD symptoms. Treatment with galantamine did not enhance self-perception of mental sharpness or quality of life. No negative behavioural change such as hallucinations or apathy was found with treatment.

Sleep symptoms and their clinical correlates in Machado-Joseph disease.

OBJECTIVE: To evaluate the presence of sleep symptoms in Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3). SUBJECTS/METHODS: We used a sleep questionnaire and the Epworth Sleepiness Scale to compare 53 patients with MJD/SCA3 and 106 controls. RESULTS: Patients with MJD/SCA3 reported more symptoms of insomnia, restless leg syndrome and REM sleep behavior disorder as well as nocturnal cramps, snoring and nocturnal apnea. Insomnia was the most frequently reported sleep-related complaint in the MJD/SCA3 group. CONCLUSIONS: Our results indicate that sleep disorders are common in patients with MJD/SCA3 and probably have a multifactorial etiology, with components of a primary sleep disorder in addition to sleep-disrupting symptoms such as nocturia and cramps.

'Drug holidays' in the treatment of Parkinson's disease. A brief review.

"Drug holiday," the withdrawal of levodopa for a variable period of time, is a controversial method of treating patients with Parkinson's disease who have levodopa-related complications. Only four studies have been published in which patients were observed for one year or longer. Although it is extremely beneficial for some patients, this treatment provides a sustained one-year benefit for only a minority of patients.

Psychobiological heterogeneity of familial and sporadic schizophrenia.

BACKGROUND: Although schizophrenia is presumed to be heterogeneous, there has been limited success distinguishing familial from sporadic cases. We used psychobiological measures to examine heterogeneity, as they may be closer to neurobiology than symptoms. Smooth pursuit eye movement quality (SPEM) and dichotic listening (DL) tests to tones and words were used to assess hemispheric laterality asymmetry. METHODS: Forty-six research unit patients participated in assessments of family history (FH) and physiological measures. FH was categorized by three exclusive groups: FH-1 patients had a chronic schizophrenia-related psychosis in a first-degree relative, FH-2 had it in second-degree relative, and FH-3 had no family member with a reoccurrence. RESULTS: Analysis of variance showed a significant group difference for SPEM and DL tones. SPEM was significantly worse in all three schizophrenia groups than for the normal comparison subjects. Among the schizophrenia groups, the nonfamilial group (FH-3) had the worst SPEM quality, FH-2 had intermediate quality, and FH-1 had the best quality. Conversely, only the nonfamilials (FH-3) had normal right hemispheric lateralization for tones, whereas familials did not, and FH-2 again had intermediate values. The lateralization quotient for DL words did not significantly differ among the groups. CONCLUSIONS: SPEM was affected most in sporadic, not familial schizophrenia, whereas dichotic listening was most affected in familial schizophrenia. This double dissociation supports the utility of the familial/sporadic distinction and suggests that etiological factors in different forms of schizophrenia may impact principally on distinct neurobiological substrates, despite similar patient phenomenology.

Suicidal behavior in schizophrenia and its relationship to awareness of illness.

OBJECTIVE: Suicidal behavior is prevalent in individuals with schizophrenia. Although a relationship between greater awareness of illness and suicidal behavior has been posited, the question has not been systematically studied. The purpose of this study was to examine the relationship between suicidal behavior and various aspects of insight in 218 patients with schizophrenia. METHOD: Patients who were participating in the DSM-IV field trial for schizophrenia were assessed with the Scale to Assess Unawareness of Mental Disorder and an instrument that was developed for the field trial study that measured multiple aspects of psychopathology, including suicidal behavior. RESULTS: The prevalence of suicidal thoughts and behavior found in this study was consistent with previous published reports. Schizophrenia patients with recurrent suicidal thoughts and behavior were generally more aware of their negative symptoms and delusions than were nonsuicidal patients. Contrary to expectations, general awareness of having a mental disorder did not predict suicidal behavior. CONCLUSIONS: The notion that insight may be associated with greater suicidality was partially supported.

Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees.

OBJECTIVE: Schizophrenia following a traumatic brain injury could be a phenocopy of genetic schizophrenia or the consequence of a gene-environment interaction. Alternatively, traumatic brain injury and schizophrenia could be spuriously associated if those who are predisposed to develop schizophrenia have greater amounts of trauma for other reasons. The authors investigated the relationship between traumatic brain injury and psychiatric diagnoses in a large group of subjects from families with at least two biologically related first-degree relatives with schizophrenia, schizoaffective disorder, or bipolar disorder. METHOD: The Diagnostic Interview for Genetic Studies was used to determine history of traumatic brain injury and diagnosis for 1,275 members of multiplex bipolar disorder pedigrees and 565 members of multiplex schizophrenia pedigrees. RESULTS: Rates of traumatic brain injury were significantly higher for those with a diagnosis of schizophrenia, bipolar disorder, and depression than for those with no mental illness. However, multivariate analysis of within-pedigree data showed that mental illness was related to traumatic brain injury only in the schizophrenia pedigrees. Independent of diagnoses, family members of those with schizophrenia were more likely to have had traumatic brain injury than were members of the bipolar disorder pedigrees. The members of the schizophrenia pedigrees also failed to show the gender difference for traumatic brain injury (more common in men than in women) that was expected and was present in the bipolar disorder pedigrees. Subjects with a schizophrenia diagnosis who were members of the bipolar disorder pedigrees (and thus had less genetic vulnerability to schizophrenia) were less likely to have had traumatic brain injury (4.5%) than were subjects with schizophrenia who were members of the schizophrenia pedigrees (and who had greater genetic vulnerability to schizophrenia) (19.6%). CONCLUSIONS: Members of the schizophrenia pedigrees, even those without a schizophrenia diagnosis, had greater exposure to traumatic brain injury compared to members of the bipolar disorder pedigrees. Within the schizophrenia pedigrees, traumatic brain injury was associated with a greater risk of schizophrenia, consistent with synergistic effects between genetic vulnerability for schizophrenia and traumatic brain injury. Posttraumatic-brain-injury schizophrenia in multiplex schizophrenia pedigrees does not appear to be a phenocopy of the genetic disorder.

Relation of familial schizophrenia to negative symptoms but not to the deficit syndrome.

OBJECTIVE: Although a family history of schizophrenia has been associated with negative symptoms, family history is inconsistently related to the presence of the deficit syndrome. METHOD: The authors assessed family history and the deficit syndrome in 99 patients with DSM-III-R-diagnosed schizophrenia who were assessed during clinical treatment. Of these 99 patients, 45 were assessed both while antipsychotic free and during antipsychotic treatment to index their treatment response. RESULTS: Patients with (N=39) and without (N=60) a family history of schizophrenia had similar proportions of the deficit syndrome. Yet family history and deficit syndrome categorizations identified a group with greater negative symptoms on the Positive and Negative Syndrome Scale. Those with a family history had greater emotional withdrawal, poor rapport, and lack of spontaneity. Groups with and without the deficit syndrome similarly differed in these symptoms but also in affective blunting, motor retardation, and passive or apathetic social withdrawal. The study involving antipsychotic-free and antipsychotic treatment phases showed main medication effects explaining positive, psychopathology, depression, and activation symptoms but not negative symptoms. Only patients without a family history had improved negative symptoms with antipsychotic treatment. CONCLUSIONS: Patients with a family history of schizophrenia had greater and more treatment-resistant negative symptoms than those without a family history. They were not more likely to have the deficit syndrome. The group with a family history had more pathology only in negative symptoms related to psychosocial function. The stable negative symptoms specifically related to the genetic vulnerability to inherit schizophrenia might be those associated with psychosocial functioning.

Spinal cord infarction. Report of 8 cases and review of the literature.

While the incidence of spinal cord ischemia is not known, it is generally considered to be rare. Diagnosis of presumed spinal cord ischemia requires the appropriate clinical picture and exclusion of other possible etiologies. Definitive diagnosis usually requires postmortem examination. During a 52-month period, 8 patients with presumed spinal cord infarction were evaluated at a 238-bed community hospital. These cases accounted for 1.2% of all admissions for stroke. Infarction of the spinal cord was confirmed on postmortem examination in 2 cases. All 6 surviving patients regained substantial motor function. Bowel and/or bladder dysfunction returned to normal in 3 patients. The literature is reviewed, and the cases are discussed in relation to the pertinent anatomic, pathogenic, and clinical aspects of spinal cord infarction.

Hypotension due to glossopharyngeal neuralgia.

We studied two cases of glossopharyngeal neuralgia with hypotension and syncope. A patient undergoing carotid angiography suffered glossopharyngeal neuralgia, bradycardia, and hypotension due to a hematoma from a subintimal injection of dye. The second patient developed glossopharyngeal neuralgia with hypotension in the absence of bradycardia due to a metastatic head and neck tumor. This patient's hypotension was refractory to the administration of atropine sulfate and occurred in the presence of sinus tachycardia, suggesting that baroreceptor vasodepressor activity was selectively elevated.

Syndrome of diffuse encephalopathy due to nondominant thalamic infarction.

A 69-year-old woman suddenly became comatose. Within 24 hours, she became lethargic, with a diffuse encephalopathy and no focal neurologic abnormalities. CT revealed a large, nondominant thalamic infarct.

Limb dystonia in progressive supranuclear palsy.

Progressive limb dystonia contributed to disability in 8 of 30 patients with progressive supranuclear palsy (PSP). In five, it was present when the patients were on no medication. In four, it had been present before the distinctive ophthalmoplegia permitted a correct diagnosis. The severity of limb dystonia did not correlate with the severity of either ophthalmoplegia or neck dystonia. The importance of dystonia in the pathophysiology of PSP is emphasized, with regard to both the branchial dystonia that underlies several cardinal features of the disease, and to the frequent occurrence of limb dystonia as an early sign.

Progressive parkinsonism associated with Rosenthal fibers: senile-onset Alexander's disease?

Rosenthal fibers are present in several neurologic disorders. Their occurrence in widespread subependymal, subpial, and perivascular locations is thought to be diagnostic of Alexander's disease, but they have also been reported in rare adult cases. Some of these patients were neurologically intact with severe systemic illnesses. In symptomatic cases, the neurologic disorder has simulated multiple sclerosis. We report an elderly woman with progressive parkinsonism, dementia, and hallucinations whose brain showed severe Rosenthal fiber proliferation.

Clozapine in the treatment of psychosis in Parkinson's disease.

Clozapine is an antipsychotic medication that is virtually free of extrapyramidal side effects. We report our successful treatment of 6 patients with idiopathic Parkinson's disease and various psychoses using clozapine on a chronic basis along with carbidopa/L-dopa.

Idiopathic hypoparathyroidism with extensive brain calcification and persistent neurologic dysfunction.

Idiopathic hypoparathyroidism is an uncommon cause of movement disorders. The following case illustrates the persistence of a parkinsonian gait 2 years after the restoration of normal serum calcium levels. The extensive calcifications in the brain presumably account for this as well as for the persistent mild dementia. The importance of identifying hypoparathyroidism early in the course is graphically illustrated.

The course of tardive dyskinesia and parkinsonism in psychiatric inpatients: 14-year follow-up.

Tardive dyskinesia and parkinsonism were assessed in 53 patients residing in a state psychiatric hospital in 1984 and 1998. A 4.0-point decrease in the mean Abnormal Involuntary Movement Scale score (6.0 versus 2.0; p < 0.001) and a 3.5-point increase in the Rating Scale for Extrapyramidal Signs score (2.8 versus 6.3; p < 0.001) were noted between 1984 and 1998. Over a 14-year period, tardive dyskinesia improved and parkinsonism worsened in patients who continued to receive neuroleptic drugs.

Bilateral facial palsy associated with Stevens-Johnson syndrome.

A 22-year-old man developed acute bilateral peripheral facial paralysis in association with Stevens-Johnson syndrome, probably as a result of ampicillin allergy. All symptoms cleared except the facial paralysis. He is the first patient in whom acute facial palsy and Stevens-Johnson syndrome have occurred simultaneously.

Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. The Pramipexole Study Group.

A total of 335 patients with early Parkinson's disease (PD) were enrolled in a multicenter, randomized, double-blind trial designed to assess the efficacy and safety of pramipexole. Entry was restricted to patients with idiopathic PD who were not receiving levodopa. Pramipexole was administered according to an ascending dose schedule up to 4.5 mg/d. During the 7-week dose-escalation phase, each subject was titrated to his or her maximally tolerated dose of study medication. This was followed by a 24-week period of maintenance therapy. The mean daily dose during the maintenance period was 3.8 mg. Pramipexole significantly reduced the severity of PD symptoms and signs compared with placebo, as measured by decreases in parts II (Activities of Daily Living) and III (Motor Examination) of the Unified Parkinson's Disease Rating Scale at week 24 compared with baseline (p < or = 0.0001). Differences between the active drug and placebo groups emerged at week 3 (1.5 mg/d) in the ascending-dose interval and persisted throughout the maintenance phase (p < or = 0.0001). The majority of patients completed the study (pramipexole 83%, placebo 80%). In the assessment of adverse events, nausea, insomnia, constipation, somnolence, and visual hallucinations occurred more frequently in the pramipexole treatment group compared with placebo patients. No clinically significant changes were noted in blood pressure or pulse rate. Overall, these results indicate that pramipexole is safe and effective in the treatment of early PD.