Dopa-induced Dyskinesia Research Articles

In situ continuous Dopa supply by responsive artificial enzyme for the treatment of Parkinson’s disease

Oral dihydroxyphenylalanine (Dopa) administration to replenish neuronal dopamine remains the most effective treatment for Parkinson’s disease (PD). However, unlike the continuous and steady dopamine signaling in normal neurons, oral Dopa induces dramatic fluctuations in plasma Dopa levels, leading to Dopa-induced dyskinesia. Herein, we report a functional nucleic acid-based responsive artificial enzyme (FNA-Fe3O4) for in situ continuous Dopa production. FNA-Fe3O4 can cross the blood-brain barrier and target diseased neurons relying on transferrin receptor aptamer. Then, FNA-Fe3O4 responds to overexpressed α-synuclein mRNA in diseased neurons for antisense oligonucleotide treatment and fluorescence imaging, while converting to tyrosine aptamer-based artificial enzyme (Apt-Fe3O4) that mimics tyrosine hydroxylase for in situ continuous Dopa production. In vivo FNA-Fe3O4 treatment results in recovery of Dopa and dopamine levels and decrease of pathological overexpressed α-synuclein in PD mice model, thus ameliorating motor symptoms and memory deficits. The presented functional nucleic acid-based responsive artificial enzyme strategy provides a more neuron friendly approach for the diagnosis and treatment of PD.

Exercise decreases aberrant corticostriatal plasticity in an animal model of l-DOPA-induced dyskinesia.

Physical exercise attenuates the development of l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) in 6-hydroxydopamine-induced hemiparkinsonian mice through unknown mechanisms. We now tested if exercise normalizes the aberrant corticostriatal neuroplasticity associated with experimental murine models of LID. C57BL/6 mice received two unilateral intrastriatal injections of 6-hydroxydopamine (12 μg) and were treated after 3 wk with l-DOPA/benserazide (25/12.5 mg/kg) for 4 wk, with individualized moderate-intensity running (60%-70% V̇o2peak) or not (untrained). l-DOPA converted the pattern of plasticity in corticostriatal synapses from a long-term depression (LTD) into a long-term potentiation (LTP). Exercise reduced LID severity and decreased aberrant LTP. These results suggest that exercise attenuates abnormal corticostriatal plasticity to decrease LID.

Differential impact on speech production from chronic thalamic DBS in Essential Tremor and that from STN DBS in Parkinson's disease

Essential Tremor (ET) is the most common tremor syndrome seen in adults. The characteristic tremor in ET is postural and action tremors, with a frequency of 4–7 Hz; while in patients with Parkinson’s disease (PD), the dominant tremor is resting tremor with a typical frequency of 5 Hz. Deep brain stimulation (DBS) in the ventral intermediate nuclei (Vim) has been shown effective in treating action or intention tremors in medically resistant ET, while DBS in the subthalamic nucleus (STN) has been shown effective in treating rigidity, rest tremor and Dopa-induced dyskinesias in PD. However, chronic bilateral DBS, whether in Vim or STN, may have negative impact on speech production. We report two cases where both patients received DBS greater than one year and developed speech impairment. When the stimulation in Vim was turned off for 30 min in ET, the patient's speech returned to the baseline while turning the STN stimulation off for 30 min in PD, minimal changes were observed and 12 h with stimulation-off were required for speech to return to the non-stimulated state.Essential Tremor (ET) is the most common tremor syndrome seen in adults. The characteristic tremor in ET is postural and action tremors, with a frequency of 4–7 Hz; while in patients with Parkinson’s disease (PD), the dominant tremor is resting tremor with a typical frequency of 5 Hz. Deep brain stimulation (DBS) in the ventral intermediate nuclei (Vim) has been shown effective in treating action or intention tremors in medically resistant ET, while DBS in the subthalamic nucleus (STN) has been shown effective in treating rigidity, rest tremor and Dopa-induced dyskinesias in PD. However, chronic bilateral DBS, whether in Vim or STN, may have negative impact on speech production. We report two cases where both patients received DBS greater than one year and developed speech impairment. When the stimulation in Vim was turned off for 30 min in ET, the patient's speech returned to the baseline while turning the STN stimulation off for 30 min in PD, minimal changes were observed and 12 h with stimulation-off w...

The Outcome of Dopamine Dysregulation Syndrome in Parkinson's Disease: A Retrospective Postmortem Study.

We have performed a retrospective analysis of the frequency and relation to treatment of dopamine dysregulation syndrome (DDS) using the Queen Square Brain Bank (QSBB) database. A search of the QSBB database for consecutive cases donated between 2005 and 2016 with a pathological diagnosis of Parkinson's disease was performed. DDS was present in 8.8% of cases, was more prevalent in males, and was associated with younger age of onset, longer disease duration, and more dopa-induced dyskinesias. Treatment approaches for DDS included: reduction of levodopa, reduction/cessation of dopamine agonist (DA), and initiation of infusion therapies. DDS had completely resolved in just over half the patients. DA peak l-dopa equivalent daily dose (LEDD) was higher in patients who failed to achieve remission. This is the first study to provide data on the course of DDS until death. Treatment strategies consisted mainly of reduction of dopaminergic treatment, and, despite the majority of patients showing some improvement, half remained symptomatic. Successful treatment was associated with a lower l-dopa dosage at death.

Greater improvement in LRRK2 G2019S patients undergoing Subthalamic Nucleus Deep Brain Stimulation compared to non-mutation carriers.

BackgroundBilateral subthalamic nucleus deep brain stimulation (STN-DBS) of parkinson’s disease (PD) patients has demonstrated to improve motor performance and to reduce dopa-induced dyskinesia. An association between the occurrence of dyskinesias and LRRK2 (leucine-rich repeat kinase 2) G2019S gene mutations has recently been suggested. The aim of this study is to discover the impact of the G2019S mutation (with high incidence in the authors’ native Algeria) on the symptom response of PD in patients who underwent STN-DBS.MethodsWe carried out a comparative statistical study for the clinical evaluation and neuropsychological assessment of 27 Algerian PD STN-DBS patients, both G2019S mutation carriers (MC) and non-carriers (NC). A multiple correspondence analysis (MCA) was then conducted to compare the results with those from groups of individuals with similar modalities.ResultsThe MCA revealed that MC and NC PD patients showed two different patterns of clinical evaluations. The group of idiopathic patients showed some differences compared to the clinical evaluations, depending on gender. No association was found between the G2019S mutation and the Mini Mental State Examination scores (MMSE), and MC patients appeared more susceptible to dyskinesia than NC patients. In NC patients, we found two cases with Parkin mutations who had a different “honeymoon” period and different initial symptoms. The results showed considerable improvement of motor unified parkinson’s disease rating scale III (UPDRS-III) in a situation of stimulation without medication in the MC patients with a percentage of improvement (51.1 %) over the required 30 % compared to the NC patients (25.5 %). The same result was observed for the Schwab and England’s activities of daily living scale (S and E scale), which thus demonstrated a greater effectiveness of DBS for MC patients than for NC patients. However, the Hoehn and Yahr scale (H and Y Scale) showed the same significance in a situation of stimulation for MC and NC patients. In this later group, the best scores of UPDRS-III were observed for patients with the Parkin mutation before they underwent surgery.ConclusionsThis study shows that surgical treatment probably has a more significant impact on LRRK2 G2019S MC than on idiopathic patients.

Current treatment and future prospects of dopa-induced dyskinesias.

Levodopa-induced dyskinesias (LID) are one of the main issues in the management of Parkinson's disease (PD); once these dyskinesias are established treatment becomes difficult, so preventive strategies should be first evaluated. Although levodopa (LD) treatment has recently been related as risk factor for LID, the main strategy to delay LID is to start PD treatment with dopamine agonists, adding LD at low doses. After LID onset, approaches include reducing single LD doses, reducing or discontinuing monoamine oxidase type B/catechol O-methyltransferase (MAO-B/COMT) inhibitors and extended-release (ER) LD. Amantadine represents the best antidyskinetic tool, and ER amantadine is the most promising upcoming antidyskinetic drug. New LD formulations such as IPX-066 (able to provide continuous dopaminergic stimulation) also represent promising new approaches. The involvement of a nondopaminergic system in the pathogenesis of LID suggests that the modulation of glutamate, serotonin and adenosine could have potential as new upcoming drug targets, but the role of such drugs will still need to be confirmed in randomized controlled trials.

Gene therapy for Parkinson's disease: still a hot topic?

Parkinson's disease is a synucleinopathy with widespread degeneration within the peripheral nervous system and across a variety of brains regions. The best studied and understood region of neural degeneration is the dopaminergic nigrostriatal system. Striatal dopamine insufficiency and nigral neuronal loss underlie the cardinal motor symptoms of PD. Levodopa and deep brain stimulation (DBS) are the most potent therapies for these symptoms. However, they have side effects that warrant the investigation of new therapies. One novel therapy is gene transfer (or therapy), in which, for the most part, viruses are used to deliver therapeutic molecules. Gene therapy methodologies can be divided into two general types: symptomatic and disease modifying (for review, see Kordower and Bjorklund, 2013). The first gene therapy clinical trial for PD was the delivery of aromatic amino decarboxylase (AADC) (Mittermeyer et al, 2012). This approach was aimed at symptomatic benefit. AADC is the enzyme that converts levodopa to dopamine and AADC gene delivery attempts to make the conversion of the exogenous levodopa to dopamine more efficient. In animal studies, lower doses of levodopa result in the same antiparkinsonian benefit as high doses when it is combined with gene delivery of AADC. Lower doses would also obviate or delay the emergence of dopa-induced dyskinesias. AADC gene delivery was safe and well tolerated in a Phase 1 clinical trial (Mittermeyer et al, 2012). An open-label assessment demonstrated some benefit in a small number of patients. Oxford Biomedica employed a equine lentivirus to deliver tyrosine hydroxylase, AADC, and GTP cyclohydrolase, the combination of which makes dopamine. Preclinical studies in rodents and monkeys delivering lenti-dopamine demonstrated significant antiparkinsonian benefit. A Phase 1/2 clinical trial has been completed again demonstrating safety and tolerability with some measure of efficacy as determined via open-label assessments (Palfi et al, 2014). Another series of studies models gene therapy after deep brain stimulation (DBS). In PD, the subthalamic nucleus is hyperactive and DBS blocks that hyperactivity. Glutamic acid decarboxylase (GAD) reduces cellular activity and reverses motor dysfunction in rodent and nonhuman primate models of PD. A Phase 2 randomized sham controlled trial was performed and met the primary endpoint (LeWitt et al, 2011). However, the magnitude of the effect was small and it is unclear whether this approach is going forward. Disease-modifying gene therapy strategies have focused on the glial cell family of ligands (GFLs), namely, GDNF and neurturin. Gene delivery of both of these trophic factors protects nigrostriatal circuitry and motor function in numerous rodent and nonhuman primate models of PD (Kordower and Bjorklund, 2013). A new clinical trial using gene delivery of GDNF is currently underway. Unfortunately, two Phase 2 clinical trials testing neurturin failed (Marks et al, 2010; Olanow et al, manuscript in preparation). Why is this molecule so potent in preclinical models but ineffective in patients with PD? We have postulated that the failure is due to the extensive degeneration of the nigrostriatal system at the time the patients were treated (Kordower et al, 2013). Furthermore, the few fibers that are remaining are defective in axonal transport mechanisms and thus the trophic factor fails to be efficiently transported, either retrogradely or anterogradely, to nigral perikary. Gene therapy for PD still has great promise. Multiple approaches are safe and well tolerated. However, at this time, no study has demonstrated robust clinical benefit using rigorous double-blind assessments. However, it is possible that a resolution of delivery issues, which will maximize the spread of the vector to the target area, as well as moving to a less-impaired patient population, might unlock the potential of this strategy. Additionally, as currently practiced, gene therapy for PD only addressed the cardinal motor symptoms, and other signs, including potentially disabling psychiatric symptoms, require a different gene therapy approach.

L‐dopa‐induced dyskinesias in unilateral 6‐hydroxydopamine‐lesioned rats are not modified by excitotoxic lesion of the entopeduncular nucleus and substantia nigra pars reticulata

l-Dopa-induced dyskinesias (LIDs) are a troublesome complication in Parkinson's disease after long-term therapy and a major reason for surgical treatment. LIDs are effectively eliminated by surgery. We aimed to reproduce such effect in the 6-hydroxydopamine (6-OHDA)-lesioned rat model. Single or combined lesions with quinolinic acid were caused in the entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr) on 6-hydroxydopamine (6-OHDA)-lesioned rats treated for 3 weeks with l-Dopa (6 mg/kg plus 15 mg/kg benserazide, i.p.). l-Dopa administration was continued for a further week following the lesion and abnormal involuntary movements (AIMs) scored at the end of treatment. Neither the individual lesions of the EP and SNr nor the combined lesions had any antidyskinetic effect nor decreased the total number of rotations. These results suggest that excitotoxic lesions of neurons bodies of the output nuclei of the basal ganglia, which destroy cell bodies and spare fibers of passage, do not induce a beneficial reduction of dyskinesias in contrast to thermolytic lesions in humans (which provokes a complete tissue destruction), thus supporting the possibility that other nuclei or systems might be involved in the antidyskinetic effect of pallidotomy.

Contribution of Serotonergic Transmission to the Motor and Cognitive Effects of High-Frequency Stimulation of the Subthalamic Nucleus or Levodopa in Parkinson’s Disease

Although they are effective at treating the motor impairments that are the core symptoms of Parkinson's disease, current treatments, namely L: -3,4-dihydroxyphenylalanine (L: -DOPA), the gold standard medication and high-frequency stimulation of the subthalamic nucleus (HFS-STN), can lead to cognitive and mood alterations. Many of these side effects, such as depression, anxiety and sleep disturbances, could be related to abnormal functioning of the serotonergic system, but much basic research remains to be done. Molecular studies in humans and animal models of the disease have reported diverse drastic changes to the serotonergic system. It has also been shown that the serotonergic system both plays a major role in the mechanism of action of the current therapies and is altered by the therapies. It has been reported that HFS-STN decreases serotonin release in several regions, mostly via inhibition of serotonergic neuron activity. The involvement of serotonergic neurons in L: -DOPA treatment is even more significant. First, serotonergic neurons, able to convert exogenous L: -DOPA to dopamine, are a major site to release dopamine throughout the brain. Second, the substitution of serotonin by newly synthesized dopamine in serotonin neurons leads to acute and chronic alteration of serotonin release and metabolism. Therefore, both therapeutic approaches, via distinct mechanisms, decrease serotonergic system activity and, rather than alleviating cognitive or mood disorders, tend to aggravate them. Molecular strategies targeting the serotonergic system are being developed and could be decisive in limiting L: -DOPA-induced dyskinesia, as well as mood and cognitive symptoms produced by antiparkinsonian therapies.

MRI measures predict progressive supranuclear palsy

Parkinsonism can be caused by idiopathic Parkinson disease (PD), multisystem atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other less common conditions. In the early phases of illness, clinical features may substantially overlap, making accurate diagnosis difficult. To further confound this clinical conundrum, pathologically proven PSP may manifest as 3 distinct clinical phenotypes: PSP–pure akinesia with gait freezing (PSP-PAGF), Richardson syndrome (RS), and PSP parkinsonism (PSP-P).1 Patients with PSP-PAGF have pure akinesia with gait freezing. People with RS have a classic presentation with supranuclear gaze palsy as well as falls and dementia early in the course of the disorder. Those with PSP-P, however, have asymmetric onset, tremor, and moderate initial response to levodopa that may include dopa-induced dyskinesia. Given these overlapping features it is not surprising that early stages of PSP-P can be mistaken for PD, MSA, or even CBD. Standardized clinical diagnostic criteria for PSP known as the National Institute of Neurological Disorders and Stroke (NINDS)–SPSP criteria define probable and possible PSP, with definite PSP requiring histopathology.2 Vertical supranuclear gaze palsy and falls in the first year of disease onset are consistent with probable PSP while supranuclear gaze palsy alone or falls with slowness of vertical saccades are consistent with possible PSP. …

Changes in the mRNA Levels of α2A and α2C Adrenergic Receptors in Rat Models of Parkinson’s Disease and l-DOPA-Induced Dyskinesia

The changes in the mRNA levels of α(2A) and α(2C) adrenoceptors were investigated in unilateral 6-OHDA-lesioned rat model of Parkinson's disease and L: -DOPA-induced dyskinesia using in situ hybridization. In the untreated 6-OHDA-lesioned rats, α(2A) expression was elevated in the locus coeruleus (160 ± 8% and 142 ± 8% in lesioned and unlesioned sides compared to the comparable side in sham-operated rats). Following long-term (21 days, twice daily) treatment with L: -DOPA (25 mg/kg L: -DOPA methyl ester plus benserazide 6.25 mg/kg) in 6-OHDA-lesioned rats, levels of α(2A) adrenoceptor mRNA in the locus coeruleus were decreased, compared to the 6-OHDA-lesioned rats, returning to the levels of α(2A) mRNA in the sham-operated rats. α(2A) adrenoceptor expression was not changed in other brain regions in any treatment group. There was no change in α(2C) expression in the rostral or caudal striatum in which the highest density of α(2C) mRNA is present. In conclusion, the data presented in this study demonstrate an increase in α(2A) adrenoceptor mRNA in the locus coeruleus in the 6-OHDA-lesioned rat model of Parkinson's disease. In addition, the data show that repeated treatment with L: -DOPA in 6-OHDA-lesioned rats, which induces dyskinesia, restores α(2A) mRNA levels. These changes of α(2A) mRNA expression, observed in the locus coeruleus, might be of importance to basal ganglia transmission and motor function.

Flibanserin attenuates l-DOPA-sensitized contraversive circling in the unilaterally 6-hydroxydopamine-lesioned rat model of Parkinson’s disease

A central problem in the treatment of Parkinson's disease (PD) is the development of motor disturbances like L: -DOPA-induced dyskinesia (LID) after long-term treatment. Preclinical and clinical studies demonstrated that serotonin 5-HT(1A) receptor agonists attenuate this disabling motor side effect. The aim of this study was to investigate the ability of flibanserin compared to buspirone to attenuate L: -DOPA-sensitized contraversive circling in hemiparkinsonian rats, which is an animal model of LID. Both drugs have a preferential affinity for the serotonin 5-HT(1A) receptors. Buspirone was in comparison because it was expected to have an effect in this model. Unilaterally 6-hydroxydopamine lesioned rats were treated twice daily intraperitoneally (ip) with L: -DOPA methylester (12.5mg/kg) and benserazide (3.25mg/kg) for 21days (on days 1, 3, 5, 8, 11, 14, 17 and 21). On day 24, L: -DOPA-sensitized rats were treated ip 5min prior to administration of L: -DOPA methyl ester and benserazide with either saline (controls), 2.5, 5 and 10mg/kg buspirone or flibanserin. Acute administration of both flibanserin and buspirone, dose dependently, attenuated the increased contraversive circling. An almost complete inhibition of the turning response was observed at 5mg/kg buspirone and 10mg/kg flibanserin. The current preclinical findings further implicate the 5-HT(1A) receptor as a promising therapeutic target for the reduction of LID and predict a potential efficacy of flibanserin in the treatment of LID in PD.

Pharmacological characterization of MRZ-8676, a novel negative allosteric modulator of subtype 5 metabotropic glutamate receptors (mGluR5): focus on l-DOPA-induced dyskinesia

Subtype 5 metabotropic glutamate receptors (mGluR5) are abundant in the basal ganglia, amygdala, septum, hippocampus, peripheral sensory neurones and dorsal horn of the spinal cord. Thus, mGluR5 has been implicated in central processes underlying movement control, emotion, learning, and nociception. Different negative allosteric modulators (NAMs) of mGluR5 were repeatedly shown to be efficacious in models of L: -DOPA-induced dyskinesia (LID), anxiety, and some forms of pain. MRZ-8676 (6,6-dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one) is a novel proprietary, selective, orally bioavailable mGluR5 NAM. MRZ-8676 (8.33, 25 and 75mg/kg) showed a high efficacy in the rat model of LID, with the maximal effect size reaching ~80%. The antidyskinetic effects of MRZ-8676 (75mg/kg) did not show tolerance as assessed after repetitive (6days) treatment. MRZ-8676 (25 or 75mg/kg) demonstrated moderate efficacy in two rat models of anxiety-contextual fear conditioning and the elevated plus maze. MRZ-8676 (25mg/kg) was also effective in the formalin test, a rat model of persistent pain. The efficacious doses of MRZ-8676 did not produce any detrimental effects on motor performance of rats as determined by means of automated open field and rotarod. However, high doses of MRZ-8676 (75 or 150mg/kg) disrupted learning in an aversive learning paradigm of the contextual fear conditioning test. In conclusion, MRZ-8676 is a new investigational agent with an efficacy profile similar to the widely published reference mGluR5 NAMs. The drug was demonstrated to possess a superior antidyskinetic efficacy with a sufficient therapeutic window. MRZ-8676 has also therapeutic potential as an anxiolytic and analgesic drug.

Neuronal intranuclear inclusion disease: Two cases of dopa‐responsive juvenile parkinsonism with drug‐induced dyskinesia

There are very few conditions that present with dopa-responsive juvenile parkinsonism. We present two such children with neuronal intranuclear inclusion disease (NIID) who had an initial good levodopa response that was soon complicated by disabling dopa-induced dyskinesia. One child was diagnosed by rectal biopsy in life, and the other diagnosis was confirmed at postmortem. In this patient, dopamine transporter imaging showed severely decreased binding of the radiotracer in the striatum on both sides. Bilateral subthalamic deep brain stimulation in this patient produced initial improvement, but this was not sustained. Both patients died within 10 years of symptom onset. As well as levodopa responsiveness with rapid onset of dyskinesia, clues to the diagnosis of NIID in patients presenting with parkinsonism include the presence of gaze-evoked nystagmus, early onset dysarthria and dysphagia and oculogyric crises. Differential diagnosis of clinical symptoms and neuropathological findings are discussed including the approach to rectal biopsy for early diagnosis.

Mirtazapine-Associated Urinary Retention

Back to table of contents Previous article Next article LETTERFull AccessMirtazapine-Associated Urinary RetentionPanagiotis Oulis M.D., Ph.D.,Athanasios Leonardos M.D.,George C. Koulouris M.D.George Konstantakopoulos M.D.,Panagiotis Oulis M.D., Ph.D.Search for more papers by this author,Athanasios Leonardos M.D.Search for more papers by this author,George C. Koulouris M.D.Search for more papers by this authorGeorge Konstantakopoulos M.D.Search for more papers by this author,Published Online:1 Jul 2010https://doi.org/10.1176/jnp.2010.22.3.352.e21AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Mirtazapine, an efficacious antidepressant of dual noradrenergic and serotoninergic mechanisms of action, is deemed particularly safe and well tolerated, especially with respect to its urinary side effects, owing to its very weak muscarinic anticholinergic properties. 1 Moreover, it has been found to ameliorate l -dopa-induced dyskinesias in patients with Parkinson’s disease. 2 Its safety in this respect makes it an attractive choice for the treatment of depression in elderly male patients with normal age-related prostate hypertrophy and concomitant Parkinson’s disease, whereby the possibility of incomplete voiding cannot be excluded. 3 To the best of our knowledge there are as yet no available reports on mirtazapine’s potential to induce urinary retention in this patient population. In the following we report on such a case, whereby the administration of low-dose mirtazapine resulted in the patient’s urinary retention. Case Report This is the case of an 85-year-old man with asymptomatic age-related benign prostate hypertrophy since the age of 77 and a 3-year history of Parkinson’s disease, for which he underwent a treatment with a compound of l -dopa, carbidopa, and entacapone at the dosage of 200/50/800 mg/day, respectively, equally divided in four doses. Moreover, for the last few months, the patient exhibited symptoms of a major depressive episode of mild severity according to DSM-IV diagnostic criteria, for which he had been prescribed mirtazapine, 15 mg/day. However, within 24 hours after mirtazapine’s initiation, he suffered from acute urinary retention necessitating the insertion of a Foley catheter. Mirtazapine was immediately discontinued, and his urinary retention subsided within 24 hours. The same pattern reemerged upon a second trial of mirtazapine a week later. Afterward, the patient was prescribed citalopram, 20 mg/day, without any urinary side effects. In the course of the following year, his previously mentioned antiparkinsonian medication was progressively increased to 400/100/800 mg/day without recurrence of urinary retention. DiscussionAlthough urinary retention may occur spontaneously in patients with benign prostate hypertrophy, the repeated pattern of its conditional dependence on mirtazapine administration renders this hypothesis in our case highly unlikely. With respect to the mechanisms of mirtazapine-induced urinary retention, we should note that descending norepinephrine and 5-hydroxy-tryptamine (5-HT) pathways from the brain to the ventral horn of the sacral spinal cord, in the presence of the neurotransmitter glutamate, enhance pudendal nerve activity and thus increase smooth urethral sphincter muscle contraction. 4 Moreover, stronger norepinephrine than 5-HT reuptake inhibition may induce increased peripheral stimulation of norepinephrine receptors in the smooth urethral muscle, causing urinary hesitancy or even retention. On this score, we should be reminded of reboxetine’s—a selective norepinephrine reuptake inhibitor—potential to induce urinary hesitancy or even retention. 5 Therefore, although rare, urinary retention is a possible adverse event of antidepressant treatment with mirtazapine. Accordingly, clinicians should be aware of mirtazapine’s potential to induce urinary retention, especially in elderly male patients with asymptomatic age-related benign prostate hypertrophy. 1st Department of Psychiatry, Athens University Medical School, Eginition Hospital, Athens, GreeceUnit of Functional and Stereotactic Neurosurgery, Athens University Medical School, Department of Neurosurgery, Evangelismos Hospital, Athens, Greece1st Department of Psychiatry, Athens University Medical School, Eginition Hospital, Athens, Greece

The roles of striatal serotonin and L -amino-acid decarboxylase on L-DOPA-induced Dyskinesia in a Hemiparkinsonian rat model.

The administration of L: -DOPA is the standard treatment for Parkinson's disease (PD). However, the symptomatic relief provided by long-term administration may be compromised by L: -DOPA-induced dyskinesia (LID) that presents as adverse fluctuations in motor responsiveness and progressive loss of motor control. In the later stages of PD, raphestriatal serotonin neurons compensate for the loss of nigrostriatal dopamine (DA) neurons by converting and releasing DA derived from exogenous L: -DOPA. Since the serotonin system does not have an autoregulatory mechanism for DA, raphe-mediated striatal DA release may fluctuate dramatically and precede the development of LID. The 6-hydroxydopamine lesioned rats were treated with L: -DOPA (6 mg/kg) and benserazide (15 mg/kg) daily for 3 weeks to allow for the development of abnormal involuntary movement score (AIMs). In rats with LID, chronic treatment with L: -DOPA increased striatal DA levels compared with control rats. We also observed a relative increase in the expression of striatal L: -amino-acid decarboxylase (AADC) in LID rats, even though tyrosine hydroxylase (TH) expression did not increase. The administration of L: -DOPA also increased striatal serotonin immunoreactivity in LID rats compared to control rats. Striatal DA and 5-hydroxytryptamine (5-HT) levels were negatively correlated in L: -DOPA-treated rats. These results of this study reveal that 5-HT contributes to LID. Striatal DA positively influences LID, while 5-HT is negatively associated with LID. Finally, we suggest that by strategic modification of the serotonin system it may be possible to attenuate the adverse effects of chronic L: -DOPA therapy in PD patients.

Oscillations as the Cause of Both Hyper- and Hypokinetic Symptoms of Movement Disorders

Back to table of contents Previous article Next article LETTERFull Accessβ Oscillations as the Cause of Both Hyper- and Hypokinetic Symptoms of Movement DisordersAlireza Akbari M.D.Shahriar Gharibzadeh M.D., Ph.D.,Alireza Akbari M.D.Search for more papers by this authorShahriar Gharibzadeh M.D., Ph.D.Search for more papers by this author,Published Online:1 Jul 2009https://doi.org/10.1176/jnp.2009.21.3.352AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Clinical manifestations of extrapyramidal movement disorders are usually divided into two main categories: hyperkinetic (i.e., tremor, athetosis, chorea, and ballism) and hypokinetic (i.e., akinesia, bradykinesia, and rigidity) symptoms. Despite the different pathological bases of these symptoms, simultaneous emersion of both kinds of symptoms in a single case (like coincidence of rigidity and tremor in a patient with Parkinson`s disease) and changing the general appearance of disease from hypo- or hyperkinesia to another group of symptoms suggests a similar origin for both groups of symptoms. With regard to the antikinetic effect of β band oscillatory activity, 1 all pathological procedures involving the basal ganglia can represent hypokinetic features if they persuade the basal ganglia network to oscillate at β band. Aggravation of hypokinesia caused by stimulation of subthalamic nucleus at 15 Hz through deep brain stimulation electrodes also supports the theory. 2 Simultaneous reduction of β band power and intensity of tremor during voluntary movements, 2 finding a roughly linear relationship between the amount of high frequency (at β band) synchronized activity and the patient’s tremor, and the fact that tremor cells are usually localized in the regions that also contain cells with a high frequency oscillatory component provide strong support for the role of β frequency in producing hyperkinetic symptoms. 3 Oscillation at β frequency is persistent and synchronized among large populations of neurons and caused by the alteration in network structure. Conversely, activity at tremor frequency is transient, synchronized just in small neuronal populations, and caused by the intrinsic membrane properties of neurons. 4 Therefore the tremor site will vary according to the site of the small neuronal assembly, which temporarily synchronizes at β frequency. Analyzing frequencies other than β band generated at some stage in movement disorders will help us improve our knowledge about how basal ganglia oscillatory activity transforms into hyperkinetic movements. We cannot discuss the oscillatory activities causing hyperkinesias in ballism and Huntington’s disease because chorea usually disappears with the induction of anesthesia; however, dystonia in L -dopa-induced dyskinesias is a hyperkinetic symptom that appears even under anesthesia and can be considered independent of cortical activity. Replacing the 4 Hz–7 Hz oscillatory activity seen in Parkinson’s disease with the 7 Hz–10 Hz seen in L -dopa-induced dyskinesias can change the hyperkinetic manifestation of disease from tremor to dystonia and offers a relationship between output frequencies of basal ganglia and hyperkinetic manifestations of disease. Although the peak at β band disappears in the power spectral density of subthalamic nucleus neurons affected by dopamine in L -dopa-induced dyskinesias, it is still present and can be recorded in the contralateral cortex. 5According to these observations we can conclude that neuronal synchronization at β band directly leads to the production of hypokinesia and creates a necessary background for hyperkinesia to emerge. Transient appearance of oscillatory activities in other frequencies can result in hyperkinetic movements only when they coincide with β band activity. Since the topography of motor cortex is preserved in the skeletomotor circuit, different sites of involuntary movements can be explained by different sites of oscillations in the basal ganglia.Neuromuscular Systems Laboratory, Amirkabir University of Technology, Tehran, Iran

β Oscillations as the Cause of Both Hyper- and Hypokinetic Symptoms of Movement Disorders

Back to table of contents Previous article Next article LETTERFull Accessβ Oscillations as the Cause of Both Hyper- and Hypokinetic Symptoms of Movement DisordersAlireza Akbari M.D.Shahriar Gharibzadeh M.D., Ph.D.,Alireza Akbari M.D.Search for more papers by this authorShahriar Gharibzadeh M.D., Ph.D.Search for more papers by this author,Published Online:1 Jul 2009https://doi.org/10.1176/jnp.2009.21.3.352AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Clinical manifestations of extrapyramidal movement disorders are usually divided into two main categories: hyperkinetic (i.e., tremor, athetosis, chorea, and ballism) and hypokinetic (i.e., akinesia, bradykinesia, and rigidity) symptoms. Despite the different pathological bases of these symptoms, simultaneous emersion of both kinds of symptoms in a single case (like coincidence of rigidity and tremor in a patient with Parkinson`s disease) and changing the general appearance of disease from hypo- or hyperkinesia to another group of symptoms suggests a similar origin for both groups of symptoms. With regard to the antikinetic effect of β band oscillatory activity, 1 all pathological procedures involving the basal ganglia can represent hypokinetic features if they persuade the basal ganglia network to oscillate at β band. Aggravation of hypokinesia caused by stimulation of subthalamic nucleus at 15 Hz through deep brain stimulation electrodes also supports the theory. 2 Simultaneous reduction of β band power and intensity of tremor during voluntary movements, 2 finding a roughly linear relationship between the amount of high frequency (at β band) synchronized activity and the patient’s tremor, and the fact that tremor cells are usually localized in the regions that also contain cells with a high frequency oscillatory component provide strong support for the role of β frequency in producing hyperkinetic symptoms. 3 Oscillation at β frequency is persistent and synchronized among large populations of neurons and caused by the alteration in network structure. Conversely, activity at tremor frequency is transient, synchronized just in small neuronal populations, and caused by the intrinsic membrane properties of neurons. 4 Therefore the tremor site will vary according to the site of the small neuronal assembly, which temporarily synchronizes at β frequency. Analyzing frequencies other than β band generated at some stage in movement disorders will help us improve our knowledge about how basal ganglia oscillatory activity transforms into hyperkinetic movements. We cannot discuss the oscillatory activities causing hyperkinesias in ballism and Huntington’s disease because chorea usually disappears with the induction of anesthesia; however, dystonia in L -dopa-induced dyskinesias is a hyperkinetic symptom that appears even under anesthesia and can be considered independent of cortical activity. Replacing the 4 Hz–7 Hz oscillatory activity seen in Parkinson’s disease with the 7 Hz–10 Hz seen in L -dopa-induced dyskinesias can change the hyperkinetic manifestation of disease from tremor to dystonia and offers a relationship between output frequencies of basal ganglia and hyperkinetic manifestations of disease. Although the peak at β band disappears in the power spectral density of subthalamic nucleus neurons affected by dopamine in L -dopa-induced dyskinesias, it is still present and can be recorded in the contralateral cortex. 5According to these observations we can conclude that neuronal synchronization at β band directly leads to the production of hypokinesia and creates a necessary background for hyperkinesia to emerge. Transient appearance of oscillatory activities in other frequencies can result in hyperkinetic movements only when they coincide with β band activity. Since the topography of motor cortex is preserved in the skeletomotor circuit, different sites of involuntary movements can be explained by different sites of oscillations in the basal ganglia.Neuromuscular Systems Laboratory, Amirkabir University of Technology, Tehran, Iran

Parkinson’s Disease with and without REM Sleep Behaviour Disorder: Are There Any Clinical Differences?

Rapid eye movement sleep behaviour disorder (RBD) may serve as a useful indicator to approach Parkinson’s disease (PD); however, PD patients do not always exhibit RBD. We wondered whether the presence of RBD would be reflected in the expansion of PD lesions and represent the same PD entity. We examined the clinical differences between PD with and without RBD and studied the frequency of RBD-like symptoms (RBD-s) and clinical differences in 150 PD patients, including 81 patients (54.0%) who satisfied the International Classification of Sleep Disorders, Revised, minimum clinical criteria for RBD. RBD-s preceding the appearance of parkinsonism were found in 44.4% of patients. Statistically, the presence of RBD-s was associated with ages above 65 years, male gender, constipation, dopa-induced dyskinesia and ‘sleep attack’, with odds ratios of 3.709, 2.469, 2.184, 5.046 and 6.562, respectively. No differences were found between the 2 groups with regard to symptoms at PD onset, disease duration, Hoehn-Yahr stage, hallucination, dementia, wearing-off, orthostatic hypotension, cerebral blood flow and antiparkinsonism drugs. In the early stage, RBD and autonomic system dysfunction are important factors in the progression of PD.

Five-year follow-up of unilateral posteroventral pallidotomy in Parkinson's disease

Background Neurocognitive outcome research of individuals with Parkinson's disease after unilateral pallidotomy is inconsistent. Although some studies reported few cognitive changes, other investigations have more consistently shown both transient and long-term cognitive decline postoperatively. Methods We report the long-term motor and neurocognitive outcome 5 years post surgery for 18 patients with Parkinson's disease (12 men and 6 woman; all right-handed) who underwent right or left unilateral posteroventral pallidotomy. Results Pallidotomy patients revealed long-term motor benefits from the surgery in their “off” state and control of dopa-induced dyskinesias in their “on” state, which is consistent with previous research. We found mild declines in oral and visuomotor information processing speed, verbal recognition memory, and mental status 5 years after surgery, which differs from previous literature regarding the long-term neurocognitive outcome after pallidotomy. Differences between the right and left pallidotomy patients for both motor and cognitive skills were not found. Conclusion Although deep brain stimulation is presently the treatment of choice, pallidotomy continues to be performed around the world. Consequently, although unilateral pallidotomy should be considered a treatment option for patients with Parkinson's disease who suffer from severe unilateral disabling motor symptoms or dyskinesias, the long-term neurocognitive outcome should also be considered in treatment decisions.