Mild Parkinsonism Research Articles

Progranulin gene mutation with an unusual clinical and neuropathologic presentation

Progranulin gene (PGRN) mutations cause frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Patients usually present with a frontotemporal dementia syndrome and have prominent atrophy and neuronal loss in frontal and temporal cortices and the striatum, with neuronal intranuclear and cytoplasmic inclusions. Clinical, neuropathological, and genetic studies are reported on an individual with PGRN mutation and her family members. We describe a patient with a PGRN c.26C>A mutation who presented with progressive stuttering dysarthria, oculomotor abnormalities, choreic buccolingual movements, and mild parkinsonism. Two other family members were affected, one with a behavioral variant frontotemporal dementia syndrome, the other with a diagnosis of probable Alzheimer's disease. At autopsy there was no neuronal loss in the cortex or medial temporal lobe structures, but there was striatal gliosis. Immunohistochemistry for ubiquitin and TDP-43 revealed neuronal cytoplasmic and intranuclear inclusions as well as neurites. This study further expands the clinical and pathological spectrum of PGRN mutations, and suggests the diagnosis could be missed in some individuals with atypical presentations.

Neurological deterioration during treatment in Wilson’s disease: Question

A 32-year-old woman with Wilson’s disease and mild cirrhosis presented with mild parkinsonism. She had been non-compliant with therapy over many years. Her cranial fluid attenuated inversion recovery MRI demonstrated mild brainstem, striatal and thalamic hyperintensity, with pallidal hypointensity (Fig. 1A). Subsequently she commenced penicillamine 750 mg twice daily. Urinary copper excretion suggested good compliance.

A Squint of Brain: A Capgras Syndrome Variant

Back to table of contents Previous article Next article LETTERFull AccessA Squint of Brain: A Capgras Syndrome VariantAntonio Carota M.D.,Nishant Mishra M.B.B.S.,Mohamed Allaoua M.D.,Joseph Ghika M.D.,Antonio Carota M.D.Search for more papers by this author,Nishant Mishra M.B.B.S.Search for more papers by this author,Mohamed Allaoua M.D.Search for more papers by this author,Joseph Ghika M.D.Search for more papers by this author,Published Online:1 Jan 2008AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Capgras Syndrome is a delusional disorder which occurs whenever the patient believes that people close to him have been replaced by duplicates. We describe a variant of Capgras Syndrome, which probably relates to dementia with Lewy bodies. Case ReportMr. W, a right-handed 83-year-old retired businessman, presented with a 3-year history of impaired memory, topographical disorientation, fluctuating vigilance, bradykinesia, and nightmares with jerky movements. He developed a unique visual hallucination of a woman physically indistinguishable from his wife and whom he called “She.” Mr. W reported that he knew “She,” his main economic adviser and friend, for many years, but that they had never been lovers or married. He wished to cuddle her, felt loved by her, and was delighted to have her around.Mr. W affirmed that “She” was real although he had never heard her voice. On several occasions, the patient was found talking to “She.” He asked her, “Where is my wife?” While entering the car, he would say “Let me find some place between you.”However, he never touched his wife, mistaking her for “She,” nor did he feel as if it were “She” touching him when his wife was doing so. Neurological examination revealed mild symmetric parkinsonism, normal visual acuity and ocular movements, and no cortico-spinal or cerebellar signs. Cognitive examination revealed severe loss of insight, bradypsychism, temporal disorientation, retrograde and anterograde memory deficits with perturbed recognition and intrusions, proper name anomia, constructive apraxia, and visual agnosia (difficult recognition of overlapped figures but not prosopagnosia). Mini-Mental State Examination (MMSE) score was 20 and no symptoms of anxiety or depression were reported. Finally, Mr. W fulfilled consensus criteria for diagnosis of probable dementia with Lewy bodies. 1 Magnetic resonance imaging (MRI) showed symmetric cortical atrophy, slightly predominant on the frontal and occipital lobes. [ 18 F]fluorodeoxyglucose positron emission tomography (PET) scan revealed bilateral hypometabolism (predominantly on the left hemisphere) of the lateral and medial temporal regions, fusiform and parahippocampal gyri, and peritemporal fronto-orbital areas. CommentThe hallucinatory experience of Mr. W has the salient attribute of the Capgras syndrome, i.e., the misidentification of a person close to him. Features unique to this report are that the delusion was strictly limited to the visual modality, it did not encroach upon the patient’s wife but upon a visual hallucination of her, and that this misperception generated a convivial reaction.Actually, Mr. W’s symptoms seem to correspond to a variant of the Capgras syndrome for which pathogenic mechanisms that are specific to dementia with Lewy bodies possibly intervene. Hence, dementia with Lewy bodies manifests with early impairment of visuo-perceptive abilities and with complex visual hallucinations, 2 which have been related to the involvement of occipital regions. 3 , 4 In healthy individuals, complex visual information binds with preset memories and stored emotional attributes to produce a unified, meaningful, stable, and real image of the world. 5 It is conceivable that, for Mr. W, cognitive deficits specific to dementia with Lewy bodies (loss of insight, impaired attention and reality-checking, control deficit over intrusive memories, and visual agnosia) uncoupled visual inputs from regular cognitive and emotional processing. As suggested by PET images, dysfunction of limbic areas could be a key mechanism of this “squint of brain.”Department of NeurologyDepartment of NeurologyDepartment of Nuclear MedicineDepartment of Neurology, University Hospital (CHUV) of Lausanne, SwitzerlandReferences1 . McKieth IG, et al. Diagnosis and management of dementia with Lewy Bodies: third report of the DLB Consortium. Neurology 2005; 65:1863–1872Google Scholar2 . Klatka LA, et al: Psychiatric features in diffuse Lewy Body disease: a clinicopathologic study using Alzheimer’s disease and Parkinson’s disease comparison groups. Neurology 1996; 47:1148–1152Google Scholar3 . Harding AJ, et al: Visual hallucinations in Lewy body disease relate to Lewy Bodies in the temporal lobe. Brain 2002; 125:391–403Google Scholar4 . Mori T, et al: Correlation of visual hallucinations with occipital rCBF changes by donepezil in DLB. Neurology 2006; 66:935–937Google Scholar5 . Treisman A: Feature binding, attention and object perception. Philos Trans R Soc Lond B Biol Sci 1998; 353:1295–1306Google Scholar FiguresReferencesCited byDetailsCited ByCapgras Syndrome Associated With Bromazepam in a Patient With Vascular Dementia15 October 2020 | Clinical Neuropharmacology, Vol. 43, No. 6 Volume 20Issue 1 Winter, 2008Pages 109-110 Metrics PDF download History Published online 1 January 2008 Published in print 1 January 2008

Clinical and Pathological Heterogeneity of Neuronal Intermediate Filament Inclusion Disease

To report new cases of neuronal intermediate filament inclusion disease (NIFID). Case report. Pathologically proved NIFID was found in 2 patients from the Universitat de Barcelona-Hospital Clínic Brain Bank. The findings of a neuropathological examination in both patients revealed intracellular inclusions that were detected with hematoxylin-eosin and stained positive for antineurofilament and alpha-internexin antibodies, variably for ubiquitin, and negatively for tau, alpha-synuclein, and TAR-DNA binding protein 43. Medical records were retrospectively reviewed. The first patient developed progressive behavioral changes characterized by apathy and indifference at the age of 37 years, and frontotemporal dementia was diagnosed. The second patient developed progressive tremor and mild speech disturbances at the age of 70 years. Her neurological examination results showed mild dysarthria, hypomimia, a mild rigid-akinetic left-predominant parkinsonism, and bilateral rest and postural tremor. The clinical impression was atypical parkinsonism. No response was obtained with levodopa, and the disease progressed rapidly, with falls and frontal-subcortical cognitive impairment. Late-onset presentation may be the clinical debut of NIFID. These 2 cases confirm the clinical and pathological heterogeneity of NIFID and suggest its inclusion in the differential diagnosis of several neurodegenerative disorders, including frontotemporal dementia and atypical parkinsonism.

From juvenile parkinsonism to encephalitis lethargica, a new phenotype of post-streptococcal disorders: Case report

We report the case of a 16-year-old boy presented with a mild akinetic-rigid parkinsonism shortly after a post-streptococcal infection. After stopping corticoids, he had a rapid neurological deterioration to a fatal encephalitis lethargica-like syndrome. Serum analysis demonstrated consistently elevated anti-streptolysin-O. This case illustrates a new severe phenotype in the spectrum of the post-streptococcal disorders. This etiology should be considered in the differential diagnosis of a movement disorder with a rapid detrimental evolution.

A Squint of Brain: A Capgras Syndrome Variant

Back to table of contents Previous article Next article LETTERFull AccessA Squint of Brain: A Capgras Syndrome VariantAntonio Carota M.D.,Nishant Mishra M.B.B.S.,Mohamed Allaoua M.D.,Joseph Ghika M.D.,Antonio Carota M.D.Search for more papers by this author,Nishant Mishra M.B.B.S.Search for more papers by this author,Mohamed Allaoua M.D.Search for more papers by this author,Joseph Ghika M.D.Search for more papers by this author,Published Online:1 Jan 2008AboutSectionsView articlePDFView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleTo the Editor: Capgras Syndrome is a delusional disorder which occurs whenever the patient believes that people close to him have been replaced by duplicates. We describe a variant of Capgras Syndrome, which probably relates to dementia with Lewy bodies. Case ReportMr. W, a right-handed 83-year-old retired businessman, presented with a 3-year history of impaired memory, topographical disorientation, fluctuating vigilance, bradykinesia, and nightmares with jerky movements. He developed a unique visual hallucination of a woman physically indistinguishable from his wife and whom he called “She.” Mr. W reported that he knew “She,” his main economic adviser and friend, for many years, but that they had never been lovers or married. He wished to cuddle her, felt loved by her, and was delighted to have her around.Mr. W affirmed that “She” was real although he had never heard her voice. On several occasions, the patient was found talking to “She.” He asked her, “Where is my wife?” While entering the car, he would say “Let me find some place between you.”However, he never touched his wife, mistaking her for “She,” nor did he feel as if it were “She” touching him when his wife was doing so. Neurological examination revealed mild symmetric parkinsonism, normal visual acuity and ocular movements, and no cortico-spinal or cerebellar signs. Cognitive examination revealed severe loss of insight, bradypsychism, temporal disorientation, retrograde and anterograde memory deficits with perturbed recognition and intrusions, proper name anomia, constructive apraxia, and visual agnosia (difficult recognition of overlapped figures but not prosopagnosia). Mini-Mental State Examination (MMSE) score was 20 and no symptoms of anxiety or depression were reported. Finally, Mr. W fulfilled consensus criteria for diagnosis of probable dementia with Lewy bodies. 1 Magnetic resonance imaging (MRI) showed symmetric cortical atrophy, slightly predominant on the frontal and occipital lobes. [ 18 F]fluorodeoxyglucose positron emission tomography (PET) scan revealed bilateral hypometabolism (predominantly on the left hemisphere) of the lateral and medial temporal regions, fusiform and parahippocampal gyri, and peritemporal fronto-orbital areas. CommentThe hallucinatory experience of Mr. W has the salient attribute of the Capgras syndrome, i.e., the misidentification of a person close to him. Features unique to this report are that the delusion was strictly limited to the visual modality, it did not encroach upon the patient’s wife but upon a visual hallucination of her, and that this misperception generated a convivial reaction.Actually, Mr. W’s symptoms seem to correspond to a variant of the Capgras syndrome for which pathogenic mechanisms that are specific to dementia with Lewy bodies possibly intervene. Hence, dementia with Lewy bodies manifests with early impairment of visuo-perceptive abilities and with complex visual hallucinations, 2 which have been related to the involvement of occipital regions. 3 , 4 In healthy individuals, complex visual information binds with preset memories and stored emotional attributes to produce a unified, meaningful, stable, and real image of the world. 5 It is conceivable that, for Mr. W, cognitive deficits specific to dementia with Lewy bodies (loss of insight, impaired attention and reality-checking, control deficit over intrusive memories, and visual agnosia) uncoupled visual inputs from regular cognitive and emotional processing. As suggested by PET images, dysfunction of limbic areas could be a key mechanism of this “squint of brain.”Department of NeurologyDepartment of NeurologyDepartment of Nuclear MedicineDepartment of Neurology, University Hospital (CHUV) of Lausanne, SwitzerlandReferences1 . McKieth IG, et al. Diagnosis and management of dementia with Lewy Bodies: third report of the DLB Consortium. Neurology 2005; 65:1863–1872Google Scholar2 . Klatka LA, et al: Psychiatric features in diffuse Lewy Body disease: a clinicopathologic study using Alzheimer’s disease and Parkinson’s disease comparison groups. Neurology 1996; 47:1148–1152Google Scholar3 . Harding AJ, et al: Visual hallucinations in Lewy body disease relate to Lewy Bodies in the temporal lobe. Brain 2002; 125:391–403Google Scholar4 . Mori T, et al: Correlation of visual hallucinations with occipital rCBF changes by donepezil in DLB. Neurology 2006; 66:935–937Google Scholar5 . Treisman A: Feature binding, attention and object perception. Philos Trans R Soc Lond B Biol Sci 1998; 353:1295–1306Google Scholar FiguresReferencesCited byDetailsCited ByCapgras Syndrome Associated With Bromazepam in a Patient With Vascular Dementia15 October 2020 | Clinical Neuropharmacology, Vol. 43, No. 6 Volume 20Issue 1 Winter, 2008Pages 109-110 Metrics PDF download History Published online 1 January 2008 Published in print 1 January 2008

Tremor dominant parkinsonism: Clinical description and LRRK2 mutation screening

Tremor dominant parkinsonism (TDP) is characterized by initial prominent resting and action tremor, mild parkinsonism, unpredictable response to medication, and a better prognosis than idiopathic Parkinson's disease (PD). We report on clinical features and longitudinal course of 26 patients suffering from TDP. Mean disease duration was 6.5 +/- 3 years, 61.5% of patients had a positive family history of tremor, 73% did not need drug treatment, performance of 123I-Ioflupane SPECT showed reduced striatal tracer uptake in 65.4% of patients, and odor identification testing was pathologic in all the patients tested (n = 22). Co-occurrence of action and resting tremor were the most annoying and disabling symptoms in all the patients, whereas rigidity and/or bradykinesia were clinically irrelevant in most of them. We also sequenced the full coding region of the Leucine-rich repeat kinase 2 gene (LRRK2) in all patients. We found a novel Val2390Met mutation that was not found in 864 chromosomes. Our results suggest a broader clinical heterogeneity related to LRRK2 mutations and points towards TDP as a subtype within the spectrum of PD, in which disabling tremor but otherwise mild parkinsonian signs and a better prognosis are the main characteristics.

Decrease in myocardial 123I-MIBG radioactivity in REM sleep behavior disorder: Two patients with different clinical progression

Although decrease in myocardial iodine-123 metaiodobenzylguanidine ( 123I-MIBG) radioactivity has been reported in patients with rapid eye movement (REM) sleep behavior disorder (RBD), its pathophysiology has not been thoroughly disclosed. We report two RBD patients with differing clinical progression, in whom myocardial 123I-MIBG scintigraphy was performed. One 69-year-old patient had more than a 20-year history of idiopathic RBD and showed a decrease in myocardial 123I-MIBG radioactivity. The other 69-year-old patient started to manifest nocturnal behaviors at age 62, then mild parkinsonism at age 68, and showed a similar decrease in myocardial 123I-MIBG radioactivity both before and after the onset of parkinsonism. These cases suggest that RBD could develop in diverse patterns of clinical progression even if signs of underlying Lewy body pathology are uniformly indicated.

A Familial Form of Pallidoluysionigral Degeneration and Amyotrophic Lateral Sclerosis With Divergent Clinical Presentations

We describe a family with a rapidly progressive neurodegenerative disorder characterized by amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) but with unusual neuropathologic features that include pallidoluysionigral degeneration. The proband presented with primary progressive aphasia that evolved into mutism. He subsequently developed dementia with mild disinhibition and parkinsonism and late in the disease showed evidence of motor neuron disease. Two other cases (the proband's mother and maternal uncle) had features of ALS exclusively. All 3 had a young onset (fourth decade) and rapid clinical course, with average time from onset of symptoms to death of 4 years. Postmortem neuropathologic examination of the proband and his uncle showed ALS changes and extensive pallidoluysionigral degeneration without neurofibrillary tangles, ubiquitin inclusions, or detectable abnormalities in the dentate nucleus of the cerebellum. Although this exceptional combination of neuropathologic features has been described in rare cases of sporadic ALS-FTD, no pedigrees have ever been reported. In 2 affected members of this family, we failed to identify mutations in genes associated with weakness, movement disorders, or dementia, including ALS, FTD, selected spinocerebellar ataxias, and Huntington disease. Thus, this disorder may represent a novel autosomal dominantly inherited and rapidly progressive neurodegenerative disorder with a spectrum of clinical presentations but common neuropathologic features.

The neuropathology and clinical phenotype of FTD with progranulin mutations

Mutations in the progranulin gene (PGRN), on chromosome 17q21, have recently been identified as a major cause of familial frontotemporal dementia (FTD). These cases have a characteristic pattern of neuropathology that is a distinct subtype of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), with lentiform neuronal intranuclear inclusions being a consistent feature. There is no abnormal accumulation of PGRN protein in the brain and immunohistochemical and biochemical analysis indicates that the ubiquitinated pathological protein is TDP-43. In these families, FTD is inherited in an autosomal dominant fashion with high penetrance. The clinical phenotype is usually a combination of behavioural abnormality and language disturbance that is most often a form of primary progressive aphasia. Mild parkinsonism is common but motor neuron disease is notably rare. Marked variation in the disease course and clinical features are common, not only between families with different mutations, but also within individual families. This degree of clinical variability makes it difficult to predict which cases of familial FTD will turn out to have a PGRN mutation.

Relation of cerebral small‐vessel disease and brain atrophy to mild parkinsonism in the elderly

The association between cerebral small-vessel disease, brain atrophy, and the risk and severity of mild parkinsonian signs (MPS) remains unclear. The objective of this study is to examine the effect of lacunar brain infarcts, cerebral white matter lesions (WMLs), and cortical atrophy on the risk and severity of MPS. This study is a cross-sectional community-based cohort study comprising 268 subjects, 65 to 83 years of age, residing in the Augsburg region of southern Germany, and without contraindications for magnetic resonance imaging (MRI) of the brain. Main outcome measures. Subcortical and periventricular WMLs, lacunar brain infarcts, and cortical atrophy determined using a standardized MRI protocol developed for the Rotterdam Scan Study and an established rating scale. MPS, assessed in a standardized neurological examination and based on the Unified Parkinson's Disease Rating Scale motor scale. Lacunar brain infarcts and large subcortical white matter lesions were associated with an elevated risk of resting tremor. More severe cortical atrophy was related to an increased risk of rigidity and bradykinesia. In a linear regression analysis relating each individual MRI measurement with the severity of MPS, the number of lacunar brain infarcts and the degree of brain atrophy were correlated with the severity of resting tremor, whereas the size of subcortical and periventricular WMLs was correlated with the severity of rigidity. A higher degree of brain atrophy was associated with increased severity of either cardinal sign. In our study, presence and volume of lacunar brain infarcts, cerebral WMLs, and cortical atrophy were associated with the risk as well as severity of MPS. Determining the presence of these brain changes using brain imaging might contribute to identify persons at risk for MPS.

Behavioral motor recovery in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐lesioned squirrel monkey (Saimiri sciureus): Changes in striatal dopamine and expression of tyrosine hydroxylase and dopamine transporter proteins

The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) provides an excellent opportunity to study repair and response to injury in the basal ganglia. Administration to mammals leads to the destruction of nigrostriatal dopaminergic neurons and depletion of striatal dopamine. In the squirrel monkey (Saimiri sciureus), MPTP-lesioning results in parkinsonian motor symptoms including bradykinesia, postural instability, and rigidity. Over time animals display motor behavioral recovery. To better understand this mechanism we employed a lesioning regimen of two or six subcutaneous injections of MPTP (2.0 mg/kg, free-base) to generate mild or moderate parkinsonism. Brain tissue was harvested at 6 weeks or 9 months after the last injection and analyzed for dopamine and its metabolites by high performance liquid chromatography (HPLC), and by immunohistochemical staining and Western immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine- and cAMP-responsive protein phosphatase of 32 kDa (DARPP-32), an effector molecule enriched in striatal medium spiny neurons. Several months after MPTP-lesioning, when squirrel monkeys displayed full motor behavioral recovery, striatal dopamine levels remained low with a greater return in the ventral striatum. This finding is consistent with other reports using neurotoxicant-lesioning models of the basal ganglia in rodents and other species of nonhuman primates. Elevated dopamine turnover ratio and decreased DAT expression appeared in early behavioral recovery at the 6-week time point in both mild- and moderate-parkinsonian monkeys. Tyrosine hydroxylase and DAT expression was increased in late stage recovery even within dopamine-depleted regions and supports sprouting. Altered DARPP-32 expression suggests a role of medium spiny neurons in recovery.

Mirror movements in parkinsonism: evaluation of a new clinical sign

Background: Mirror movements (MM) are not widely appreciated in parkinsonism and no report has evaluated this clinical sign in detail. Objectives: To define the parkinsonian clinical features associated with MM...

Tai Chi and Parkinsonism

To describe the effects of an eight-week Tai Chi class on two patients: one with Parkinson's disease, the other with multiple system atrophy.Both patients demonstrated improved scores on the Activities-specific Balance Confidence Scale and the Functional Reach Test. One subject also demonstrated improved scores for the Timed Up and Go test. Both subjects reported subjective improvements in balance and balance awareness.Tai Chi may be a viable option for improving balance in patients with mild Parkinsonism.

Role of dopamine transporter imaging in routine clinical practice.

Functional imaging of the dopamine transporter (DAT) defines integrity of the dopaminergic system and has its main clinical application in patients with mild, incomplete, or uncertain parkinsonism. Imaging with specific single positron emission computerised tomography ligands for DAT (FP-CIT, beta-CIT, IPT, TRODAT) provides a marker for presynaptic neuronal degeneration. Striatal uptake correlates with disease severity, in particular bradykinesia and rigidity, and monitoring of progression assists in clinical trials of potential neuroprotective drugs. DAT imaging is abnormal in idiopathic Parkinson's disease, multiple system atrophy and progressive supranuclear palsy and does not distinguish between these disorders. Dopamine loss is seen even in the earliest clinical presentations of true parkinsonism; a normal scan suggests an alternative diagnosis such as essential tremor, vascular parkinsonism (unless there is focal basal ganglia infarction), drug-induced parkinsonism, or psychogenic parkinsonism. Congruence between working clinical diagnosis and DAT imaging increases over time in favour of baseline DAT imaging results. Additional applications are characterising dementia with parkinsonian features (abnormal results in dementia with Lewy bodies, normal in Alzheimer's disease); and differentiating juvenile-onset Parkinson's disease (abnormal DAT) from dopa-responsive dystonia (normal DAT).

Parkinsonian signs in older people: prevalence and associations with smoking and coffee.

Cigarette smoking and coffee consumption may reduce the risk of PD. Parkinsonian signs (tremor, rigidity, bradykinesia) occur in 30 to 40% of the elderly. To determine whether there was an association between cigarette smoking, coffee consumption, and parkinsonian signs in a community population of older people. Data on smoking were collected and a neurologic examination performed on 1,339 residents > or = 65 years of age in the Washington Heights-Inwood community in northern Manhattan, NY. Parkinsonian signs were rated with an abbreviated Unified Parkinson's Disease Rating Scale, resulting in a parkinsonian sign score. Coffee consumption was assessed with a semiquantitative food-frequency questionnaire, and caffeine consumption was determined. Analyses were cross-sectional. Mean age was 76.6 years. Parkinsonian signs were present in 537 (40.1%). The odds for presence of parkinsonian signs was lower in smokers than nonsmokers (odds ratio [OR] = 0.58, 95% CI = 0.47 to 0.73). Smokers had a lower mean parkinsonian sign score than nonsmokers (p < 0.001). Coffee drinking and caffeine consumption were not associated with the presence of parkinsonian signs. The odds for presence of parkinsonian signs remained lower in smokers (OR = 0.75, 95% CI = 0.57 to 0.99) after adjusting for age, gender, ethnicity, years of education, adjusted daily caffeine consumption, and dementia. The reduced risk of parkinsonian signs in cigarette smokers could reflect a protective effect of smoking on age-related parkinsonian signs in the elderly or an aversion to smoking in elderly persons with mild parkinsonism.

Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients

Objective: To describe the treatment response with melatonin for rapid eye movement (REM) sleep behavior disorder (RBD) associated with other neurologic disorders. Background: Clonazepam has been considered the treatment of choice for RBD. However, an alternative treatment is desirable for those with RBD refractory to clonazepam, for those who experience intolerable side-effects with clonazepam, and for those in whom clonazepam precipitates or aggravates obstructive sleep apnea (OSA). To date, there is minimal published data and limited follow-up regarding the use of melatonin for patients with RBD associated with other neurologic syndromes and disorders. Design/methods: The response to melatonin treatment for RBD was reviewed on consecutive patients the investigators treated with this agent at Mayo Clinic Rochester from January 2000 to June 2001. The coexisting neurologic disorders, reasons for using melatonin, effective doses, side-effects, and duration of follow-up were also reviewed on all patients. Results: Fourteen patients were commenced on melatonin over the specified time period (13 male, median RBD onset age 56 years, range 20–77 years). The coexisting neurologic findings/disorders were dementia with Lewy bodies ( n=7), mild cognitive impairment with mild parkinsonism ( n=2), multiple system atrophy ( n=2), narcolepsy ( n=2), and Parkinson's disease ( n=1). The reasons for using melatonin in these cases were incomplete response of RBD to clonazepam in six patients, existing cognitive impairment in five, intolerable side-effects with clonazepam in two, and presence of severe obstructive sleep apnea and narcolepsy in one. With seven patients continuing to use clonazepam at 0.5–1.0 mg/night, RBD was controlled in six patients, significantly improved in four, and initially improved but subsequently returned in two; no improvement occurred in one patient and increased RBD frequency/severity occurred in one patient. The effective melatonin doses were 3 mg in two cases, 6 mg in seven cases, 9 mg in one case, and 12 mg in two cases. Five patients reported side-effects, which included morning headaches (2), morning sleepiness (2), and delusions/hallucinations (1); these symptoms resolved with decreased dosage. The mean duration of follow-up was 14 months (range 9–25 months), with eight patients experiencing continued benefit with melatonin beyond 12 months of therapy. Conclusions: In this series, persistent benefit with melatonin beyond 1 year of therapy occurred in most but not all patients. Melatonin can be considered as a possible sole or add-on therapy in select patients with RBD. Prospective, long-term, controlled trials with melatonin are warranted in a larger number of patients with RBD associated with a variety of neurologic symptoms and disorders.

Treatment for delirium with risperidone: results of a prospective open trial with 10 patients

Delirium is a common psychiatric illness among medically compromised patients. There is an increasing opportunity to use atypical antipsychotics to treat delirium. The effects of these drugs on delirium, however, the most appropriate way to use them, and the associated adverse effects remain unclear. To clarify these points, a prospective open trial on risperidone was carried out in 10 patients with delirium. At a low dose of 1.7 mg/d, on average, risperidone was effective in 80% of patients, and the effect appeared within a few days. There were no serious adverse effects. However, sleepiness (30%) and mild drug-induced parkinsonism (10%) were observed; the symptom of sleepiness was a reason for not increasing the dose. One patient responded to a dose as low as 0.5 mg/d, so it is recommended that treatment start at a low dose, which may then be increased gradually. This trial is a preliminary open study with a small sample size, and further controlled studies will be necessary.

Dopa-responsive dystonia and Tourette syndrome in a large Danish family.

Guanosine triphosphate cyclohydrolase I (GTPCH) catalyzes the first step in the synthesis of tetrahydrobiopterin (BH4). Autosomal dominantly inherited defects in the GTPCH gene (GCH1) cause a form of dystonia that is responsive to treatment with levodopa (dopa-responsive dystonia [DRD]). To investigate molecular and clinical aspects of DRD in a large Danish family. For analysis of the GCH1 gene, a mutation-scanning method based on denaturing gradient gel electrophoresis (DGGE) was used. A novel mutation, X251R, was identified in the GCH1 gene of 2 distantly related Danish patients with DRD, one of whom also had Tourette syndrome (TS). Thirty-five additional family members were investigated for this mutation, and 16 of them underwent clinical neurological examination. A total of 18 patients were heterozygous for the X251R allele, 16 of whom had neurological complaints spanning from very mild parkinsonism to severe invalidism due to dystonia. Of 13 symptomatic heterozygotes who had been neurologically examined, 10 had signs of dystonia or parkinsonism. Sixteen of the heterozygotes were treated with levodopa, and 13 reported a treatment benefit. Three of the symptomatic heterozygotes had signs of TS. This study confirms the large variability in DRD symptoms and emphasizes the usefulness of molecular analysis for diagnosis and treatment of DRD. The presence of TS is suggested to be coincidental, though the development of TS-like symptoms due to mutations in GCH1 cannot be excluded.

Overlesioned hemiparkinsonian non human primate model: correlation between clinical, neurochemical and histochemical changes.

Monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have been widely used as animal models of Parkinson's disease (PD). Depending on the method of administration different PD models can be developed. Systemic (iv, sc.) MPTP administration can induce an advanced parkinsonian syndrome. However, systemic administration may require intensive animal care after neurotoxin administration, as well as repeated high doses of MPTP to avoid spontaneous recovery. Unilateral intracarotid artery (ICA) MPTP administration induces a stable hemiparkinsonian syndrome, with the advantage of allowing the animal to groom and feed itself and having a control side in the same animal. However, this unilateral syndrome lacks the bilateral characteristics of advanced PD. Bilateral ICA administration can induce a reliable bilateral syndrome but inherent is the risk of severely impairing the animals and leaving them unable to maintain themselves. This report analyzed the PD model induced by administration of unilateral ICA and subsequent intravenous injections of MPTP in rhesus monkeys. The combined method of MPTP administration induces an advanced stable parkinsonian syndrome, in which the ICA injection of MPTP initiates the parkinsonian syndrome primarily in one hemisphere and the subsequent iv. doses (administered as needed) further deplete the dopamine (DA) system to induce a bilateral lesion in a shorter period of time, with fewer side effects. We studied the relationships between the behavioral, biochemical and histochemical changes related to the combined MPTP treatments to further characterize this model. The monkeys were categorized as presenting mild (stage 2) or moderate (stage 3) parkinsonism based on a parkinsonian rating scale. Postmortem biochemical analysis showed massive DA reduction equally in the caudate nucleus and putamen ipsilateral to ICA MPTP infusion, with varying degrees of DA preservation in the contralateral striatum. Differences between stage 2 and stage 3 were attributed to DA concentrations in the caudate nucleus and putamen of the contralateral hemisphere. Tyrosine hydroxylase immunohistochemistry revealed that the midbrain DA neurons of the group A8, A9, and A10 showed differential vulnerability for MPTP. This finding was similar to that observed in idiopathic PD with significant relationships between the clinical stages and cell losses in the group A9 (substantia nigra pars compacta). Positron emission tomography (PET) using [18F] 6-fluoro-L-m- tyrosine (FMT) showed that uptake (Ki) values correlated well with the biochemical data and are good predictors of DA levels in the contralateral striatal regions. Consistent with the immunohistochemical analysis, PET data also showed significant correlations with all groups of the DA cells. Here we describe an animal model that can play an important role in understanding the symptoms and therapeutic basis of PD since different severities of parkinsonian symptoms can be mimicked.