Gianni Orofino

Gender differences in motor and non-motor symptoms among Sardinian patients with Parkinson's disease

BACKGROUND Parkinsons disease (PD) occurs more frequently in men than in women and a higher risk for PD development in males compared with females has been hypothesized, suggesting gender may be a significant factor in the development and progression of parkinsonism. To date, gender differences in non-motor symptoms are under-reported. OBJECTIVE To assess gender differences in motor and non-motor symptoms among Sardinian PD patients. METHODS One hundred fifty-six (91 male and 65 female) consecutive Sardinian PD outpatients were included in this analysis. Modified Hoehn and Yahr scale and UPDRS were used to assess motor symptoms, while non-motor disturbances were evaluated with the non-motor symptoms scale (NMSS). Presence of depression, anxiety and other iatrogenic behavioral disorders was also investigated. In order to determine how gender differences could be specific to PD, 132 age-matched normal controls were assessed with the NMSS. RESULTS Women were more likely than men to present with tremor as initial symptom (p<.025) and worse UPDRS instability score (p<.02). NMSS score in females was significantly higher than that in males (p<.018). A significantly higher severity in cardiovascular (p<0.002), sleep/fatigue (p<.018) and mood/apathy (p<.001) domains was observed in female PD patients, while the sexual dysfunction domain was reported with a significantly higher score in male patients (p<.017). Fatigue (p<.03), lack of motivation (p<.015) and sadness (p<.009) were observed significantly more frequent in females, while altered interest in sex was noted as more common in males (p<.001). Frequency of depression (p<.011) and anxiety (p<.001) was significantly higher in females, while male patients had increased frequency of compulsive sexual behaviors (p<.05). There was a significantly higher frequency of non-motor symptoms in eight domains in both male and female PD patients compared with controls (p<.001, for all comparisons, with the exception of urinary disturbances in females: p<.004). Only sexual dysfunctions were not significantly higher in male and female PD patients compared with controls. DISCUSSION The present study highlights the role of gender differences associated with the occurrence of motor and non-motor disorders and our findings indicate that spectrum and severity of non-motor symptoms may present with different gender distribution in PD patients, suggesting a possible sex-related effect.

Behavioral, neuropsychiatric and cognitive disorders in Parkinson's disease patients with and without motor complications.

BACKGROUND Parkinsons disease (PD), commonly defined as a hypokinetic movement disorder, is hampered by the appearance of motor complications (MC), including dyskinesias and motor fluctuations, and non-motor symptoms such as behavioral, neuropsychiatric and cognitive disorders, which, in the last years, are gaining increasing attention. The factors affecting MC and these non-motor symptoms are still largely unknown and their interactions are not yet fully evaluated. OBJECTIVE To identify the presence of behavioral, neuropsychiatric and cognitive disorders in PD patients with and without MC and to evaluate their association with MC. METHODS Consecutive PD patients received a comprehensive structured clinical evaluation including pharmacologic treatment, MC and non-motor symptoms such as reward-seeking behaviors, neuropsychiatric symptoms (depression, anxiety, psychoses and hallucinations) and dementia. RESULTS 349 patients were included in this analysis. Patient with MC showed enhanced frequency of dementia (p < 0.001), anxiety, depression and psychoses (p < 0.01). A higher frequency of impulse control disorders was detected in patients with dyskinesias (22.2% - p < 0.001) and motor complications (12.2% - p < 0.05). Dyskinesias were significantly more present in patients with hypersexuality (p < 0.05) and compulsive shopping (p < 0.001), while they were not significantly associated with pathological gambling and binge eating. Patients with dyskinesias also had significantly higher frequency of dopamine dysregulation syndrome, hallucinations and delusions (p < 0.001), with the exception of delusional jealousy. DISCUSSION We found a higher frequency of behavioral, neuropsychiatric and cognitive disorders in patients with MC. The lack of detection of dyskinesias in several PD patients with pathological gambling in our study represents a very interesting issue. While binge eating mainly seems to be related to the use of dopamine agonists, the significant lack of association between dyskinesias and delusional jealousy suggests the hypothesis of a possible underlying psychopathological predisposition rather than a mere pharmacologic effect in PD patients with these behavioral complications.

Pisa syndrome in a patient with progressive supranuclear palsy

Dear Professor Kaye, Pisa syndrome (PS) is an abnormal posture characterized by a tonic flexion of the trunk to one side accompanied by a slight rotation in the sagittal plane, originally described as the consequence of acute axial dystonia related to neuroleptic administration. Subsequently PS has been reported in patients treated with antiemetics, antidepressants, cholinesterase inhibitors and dopamine agonists. A similar picture may also occur as an idiopathic phenomenon and in neurodegenerative diseases, including parkinsonism. With regard to parkinsonism, although PS has been previously indicated as a red flag for multiple system atrophy (MSA), this abnormal posture is not infrequently observed in patients with typical Parkinson’s disease (PD) and other atypical parkinsonism disorders such as dementia with Lewy bodies (DLB). However, PS has not yet been described in patients with progressive supranuclear palsy (PSP). We describe a patient affected by PSP who developed a dystonic lateral flexion of the trunk compatible with the diagnosis of PS. The patient was a 69-year-old man who manifested postural instability with unexplained falls at 66 years of age. No history of substance abuse, head trauma, or family history of neurodegenerative disorder was noted. His past medical history was remarkable for hyperthyroidism treated with methimazole. During this time, the relatives referred to alterations of mood and behavior with apathy, loss of interest in ordinary pleasurable activities and associated anxiety. The patient was initially treated with antidepressant drugs such as mirtazapine (30 mg/day) and escitalopram (10 mg/day) with mild improvement of mood disorders. During the following two years, impairment of postural stability with frequent falls and visual disturbances were noted. He also complained of sleep disorders mainly characterized by insomnia, and mirtazapine and escitalopram were suspended. When admitted to our Movement Disorders Centre, neurological examination showed prominent postural instability with falls, symmetric akinesia and rigidity, proximal more than distal, and vertical supranuclear palsy. Mild dysphagia and dysarthia with occasional echolalia and palilalia were registered. Neuropsychological examination showed a mild/moderate cognitive deficit with a score of 23/30 on the Mini Mental State Examination, apathy, impairment in abstract thought and decreased verbal fluency. Treatment with levodopa/carbidopa up to 100/25 mg four times per day caused poor response of parkinsonism and was subsequently suspended because of severe nausea and vomiting. A brain MRI scan was normal, while a Iodine-N-omega-fluoropropyl-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane (I-FP-CIT) single photon emission CT (SPECT) scan (DatSCANTM Nycomed Amersham plc, Little Chalfont, Buckinghamshire, UK) demonstrated bilateral abnormal dopamine transporter (DAT) binding in the striatum,

Rasagiline and Pisa syndrome in Parkinson’s disease patients

We read with interest the article written by Valentino et al. [1] about the insidious onset of Pisa syndrome in a patient with Parkinson’s disease during treatment with rasagiline, an inhibitor of monoamine oxidase type B (MAO-B). Although we are in agreement with the authors that a dopaminergic impairment seems to play a major role in the development of PS [2–4], we are not undoubtedly certain that only rasagiline might be considered the unique iatrogenic factor favoring the onset of PS in this patient. To this regard, although the authors hypothesized that the drug alone was probably not sufficient to induce PS, they only considered a combination of other genetic and clinical PD characteristics as concomitant risk factors, ignoring the possible involvement of other iatrogenic agents. In fact, as suggested by the same authors, a close temporal relationship between rasagiline introduction and development of PS onset was not noted, with PS occurring nearly 1 year before the addition of rasagiline. Furthermore, it should be highlighted that, at PS onset, the patient was taking other concomitant drugs such as pramipexole and levodopa, which are well-described iatrogenic factors [2–4]. Interestingly, also in two previous studies which reported rasagiline as an iatrogenic factor favoring the onset of PS [3, 5], this drug was concomitant to pramipexole or levodopa treatment, and never in monotherapy. Moreover, in four of these five cases [5], rasagiline was introduced to manage motor worsening or wearing-off phenomena, while in the remaining case levodopa and pramipexole were added to improve motor impairment. Thus, no patient with PS has been described in monotherapy with rasagiline to date. Moreover, although the authors reported that the postural bending observed completely remitted 1-month after rasagiline withdrawal, it should be noted that the patient in Fig. 1b of [1] presented with a residual truncal deviation to the left, despite the EMG findings. Finally, because the clinical effect of rasagiline mainly relies on the MAO-B inhibition which can lead to the increase of extracellular dopamine levels in striatal synapses, we retain that PS in these patients could be determined by an unbalance between the overall dopaminergic stimulation (comprehensive of dopamine agonists and levodopa in addition to rasagiline, and not determined by the only MAO-B inhibitor) and the disease progression characterized by the presence of motor worsening or wearing-off phenomena. With this regard, a reduction of dopaminergic treatment might represent a feasible strategy in the resolution of this postural disability. In conclusion, we agree with the authors about the importance of a rapid individuation of PS in PD, before it evolves in a chronic posture with irreversible changes.

Metabolomics As a Tool for the Characterization of Drug-Resistant Epilepsy

Purpose Drug resistance is a critical issue in the treatment of epilepsy, contributing to clinical emergencies and increasing both serious social and economic burdens on the health system. The wide variety of potential drug combinations followed by often failed consecutive attempts to match drugs to an individual patient may mean that this treatment stage may last for years with suboptimal benefit to the patient. Given these challenges, it is valuable to explore the availability of new methodologies able to shorten the period of determining a rationale pharmacologic treatment. Metabolomics could provide such a tool to investigate possible markers of drug resistance in subjects with epilepsy. Methods Blood samples were collected from (1) controls (C) (n = 35), (2) patients with epilepsy “responder” (R) (n = 18), and (3) patients with epilepsy “non-responder” (NR) (n = 17) to the drug therapy. The samples were analyzed using nuclear magnetic resonance spectroscopy, followed by multivariate statistical analysis. Key findings A different metabolic profile based on metabolomics analysis of the serum was observed between C and patients with epilepsy and also between R and NR patients. It was possible to identify the discriminant metabolites for the three classes under investigation. Serum from patients with epilepsy were characterized by increased levels of 3-OH-butyrate, 2-OH-valerate, 2-OH-butyrate, acetoacetate, acetone, acetate, choline, alanine, glutamate, scyllo-inositol (C < R < NR), and decreased concentration of glucose, lactate, and citrate compared to C (C > R > NR). Significance In conclusion, metabolomics may represent an important tool for discovery of differences between subjects affected by epilepsy responding or resistant to therapies and for the study of its pathophysiology, optimizing the therapeutic resources and the quality of life of patients.

Fluctuating Cotard syndrome in a patient with advanced Parkinson disease

Introduction:Nonmotor fluctuations of psychiatric symptoms in patients suffering from Parkinson disease (PD) represent a very disabling condition, which may seriously interfere with the quality of life of patients and caregivers. In this regard, these disturbances are present with a higher frequency in advanced PD patients with associated motor complications and can appear both in “on” and in “off” period. Here we report on a case of fluctuating Cotard syndrome clearly related to “wearing-off” deterioration and responsive to levodopa treatment in a patient affected by advanced PD. Case Report:A 76-year-old woman presented with a 13-year history of PD. Her caregivers reported that, in the last 2 months, she has developed a sudden onset of nihilistic delusion (Cotard syndrome), mainly during the “wearing-off” condition and associated with end of dose dyskinesias and akathisia.As Cotard syndrome clearly improved with the administration of levodopa, the patient was successfully treated changing the levodopa schedule with the shortening of intervals between levodopa intakes in small doses. Conclusions:Both the appearance of the Cotard syndrome in this patient during the “off” state and the subsequent improvement of psychotic symptoms after levodopa administration strongly suggest an important correlation with the dopaminergic dysregulation.This finding suggests that dopaminergic deficit might play a key factor in the development of Cotard syndrome.

Focal 123I-FP-CIT SPECT Abnormality in Midbrain Vascular Parkinsonism

Cerebrovascular diseases are considered among possible causes of acute/subacute parkinsonism, representing up to 22% of secondary movement disorders. In cases of suspected vascular parkinsonism (VP), dopamine transporter SPECT has been highly recommended to exclude nigrostriatal dopaminergic degeneration. We report the case of a hemiparkinsonism related to a left midbrain infarct with focal lateralized putaminal abnormalities at 123I-FP-CIT SPECT imaging. The asymmetric uptake at dopamine transporter SPECT was different to findings commonly observed in typical PD pattern, because the ipsilateral striatum, in opposite to idiopathic PD, showed normal tracer binding. However, this selective parkinsonism after infarction of the midbrain was responsive to levodopa. In conclusion, we retain that there is a need of more functional imaging studies in VP addressed to a more consistent classification of its different clinical forms and to a better understanding of the adequate pharmacological management.

Priapism and Hypersexuality Associated With Rotigotine in an Elderly Parkinsonian Patient: A Case Report.

To the Editor: P riapism is an uncommon condition defined as prolonged (greater than 4 hours) penile erection not initiated by sexual stimulation. There are many different causes of priapism including hematologic disorders, trauma, metabolic conditions, and medications. Several classes of medication are involved: antihypertensives, anticoagulants, α-blockers, antidepressants, psychoactive substances. In particular, about 50% of drug-induced priapism is due to typical and atypical antipsychotics, such as chlorpromazine, zuclopenthixol, clozapine, risperidone, olanzapine, quetiapine, ziprasidone,21 aripiprazole, and iloperidone. To date, there is only 1 case report on the association between priapism and cabergoline. Cabergoline is an ergotderived dopamine agonist with high affinity for the dopamine D2 receptor, but also possesses low affinity for dopamine D1, α1and α2-adrenergic, and 5-HT1and 5-HT2serotonin receptors. Herein we present the first detailed case of rotigotine-induced priapism and hypersexuality in a patient with Parkinson disease (PD). P.P. is a 79-year-old man, with a 10-year history of an idiopathic PD with resting tremor and rigidity more marked on the left side, bradykinesia, and camptocormia. Neuropsychological testing revealed subtle executive dysfunction and mild cognitive impairment. At the beginning, tremor, rigidity, and bradykinesia were well controlled under a treatment of a combination of levodopa/ carbidopa (400 mg/daily) and pramipexole extended release (1.05 mg/daily). Six years later, he experienced significant and unpredictable levodopa-induced motor fluctuations. At the time of our first observation, the patient showed the symptoms of an advanced and complicated PD with signs of fluctuating mood, sleep disturbances, such as excessive daytime sleepiness and falling asleep suddenly for short periods of time, similar to narcolepsy. Considering that the major cause of sleepiness was drug induced, we decided to reduce and then

Pisa-Like Syndrome Under Baclofen in a Patient With Spastic Hemiparesis due to Ischemic Stroke

In its original description, Pisa syndrome was reported as an iatrogenic dystonia of the trunk caused by neuroleptic drugs. However, sometimes, not dystonic lateral flexion of the trunk is described as Pisa syndrome. These observations support the possibility of a drug-induced lateral flexion of the trunk with clinical presentation similar to Pisa syndrome, although with a different etiology and pathophysiology. Here, we describe the case of a male patient, with a previous ischemic stroke and residual spastic hemiparesis to the right side, who subacutely developed a dramatic lateral flexion of trunk (approximately 45° to the right) a few days after the introduction of Baclofen (5 mg 3 times per day). After the discontinuation of baclofen, a full recovery of the correct posture was obtained. In this respect, our case is paradigmatic: it is drug-induced but not clearly dystonic in its manifestation. Baclofen reduces the spasticity depressing the monosinaptic and polisinaptic reflex in the spinal cord by stimulating Gamma-aminobutyric acid B (GABA-B) receptors, which inhibit the release of excitatory amino acids, glutamate and aspartate. We believe that the definition of Pisa syndrome for these forms, not clearly dystonic, might be not completely appropriate, but they should be defined more correctly as Pisa-like syndromes.

An unusual delusion of duplication in a patient affected by Dementia with Lewy bodies

BackgroundDementia with Lewy bodies (DLB) is the second most frequent diagnosis of progressive degenerative dementia in older people. Delusions are common features in DLB and, among them, Capgras syndrome represents the most frequent disturbance, characterized by the recurrent and transient belief that a familiar person, often a close family member or caregiver, has been replaced by an identical-looking imposter. However, other delusional conditions near to misidentification syndromes can occur in DLB patients and may represent a major psychiatric disorder, although rarely studied systematically.Case presentationWe reported on a female patient affected by DLB who presented with an unusual delusion of duplication. Referring to the female professional caregiver engaged by her relatives for her care, the patient constantly described the presence of two different female persons, with a disorder framed in the context of a delusion of duplication.A brain 99Tc-hexamethylpropyleneamineoxime SPECT was performed showing moderate hypoperfusion in both occipital lobes, and associated with marked decreased perfusion in parieto-fronto-temporal lobes bilaterally.ConclusionsAn occipital hypoperfusion was identified, although in association with a marked global decrease of perfusion in the remaining lobes. The role of posterior lobes is certainly important in all misidentification syndromes where a natural dissociation between recognition and identification is present. Moreover, the concomitant presence of severe attentional and executive deficits evocative for a frontal syndrome and the marked global decrease of perfusion in the remaining lobes at the SPECT scan also suggest a possible dysfunction in an abnormal connectivity between anterior and posterior areas.