Zonisamide attenuates the severity of levodopa-induced dyskinesia via modulation of the striatal serotonergic system in a rat model of Parkinson's disease.

Glutamate, GABA, acetylcholine, dopamine, and serotonin interact with each other to regulate the flow of neural information in the striatum. Serotonin type 1A receptor (5HT1A) is primarily expressed on glutamatergic nerve terminals, and 5HT1B is expressed on GABAergic medium spiny neurons (MSNs). Zonisamide (ZNS) reportedly improves the off period without worsening levodopa-induced dyskinesia (LID) in patients with advanced Parkinson's disease. In this study, LID model rats were prepared by administrating levodopa to unilaterally 6-OHDA-lesioned rats. We analyzed changes in serotonergic neurotransmission of LID model rats to elucidate the relationship between LID and the serotonergic system and pathomechanism of the anti-dyskinetic effects of ZNS. Abnormal involuntary movements (AIMs) were most severe in intermittently levodopa-treated rats but milder in rats intermittently medicated with levodopa and ZNS. Continuously levodopa-infused rats or intermittently ZNS-injected rats did not develop AIMs, and no differences in the expression of brain-derived neurotrophic factor, 5-HT transporter, 5HT1A, and 5HT1B mRNA between the lesioned striatum and normal side were observed. Expression of 5HT1B mRNA was elevated in the lesioned striatum of intermittently levodopa-treated rats, but this elevation was normalized by concomitant use of ZNS. The severity of AIMs was correlated with the ratio of 5HT1B to 5HT1A mRNA expression in the lesioned striatum, indicating that the anti-LID effect of ZNS is based on inhibition via 5HT1B receptors to direct pathway MSNs sensitized by intermittent levodopa treatment. Selectively acting serotonergic drugs, especially those that lower the 5HT1B to 5HT1A ratio, are promising new therapeutic agents to attenuate LID development.

PPARγ receptors are involved in the effects of cannabidiol on orofacial dyskinesia and cognitive dysfunction induced by typical antipsychotic in mice.

Tardive dyskinesia (TD) is a movement disorder that appears after chronic use of drugs that block dopaminergic receptors such as antipsychotics. Besides the motor symptoms, patients with TD also present cognitive deficits. Neuroinflammatory mechanisms could be involved in the development of these symptoms. A previous study showed that cannabidiol (CBD), the major non-psychotomimetic compound of Cannabis sativa plant, prevents orofacial dyskinesia induced by typical antipsychotics by activating peroxisome proliferator-activated receptors gamma (PPARγ). Here, we investigated if CBD would also reverse haloperidol-induced orofacial dyskinesia and associated cognitive deficits. We also verified if these effects depend on PPARγ receptor activation. Daily treatment with haloperidol (3 mg/kg, 21 days) increased the frequency of vacuous chewing movements (VCM) and decreased the discrimination index in the novel object recognition test in male Swiss mice. CBD (60 mg/kg/daily) administered in the last 7 days of haloperidol treatment attenuated both behavioral effects. Furthermore, haloperidol increased IL-1ß and TNF-α levels in the striatum and hippocampus while CBD reverted these effects. The striatal and hippocampal levels of proinflammatory cytokines correlated with VCM frequency and discrimination index, respectively. Pretreatment with the PPARγ antagonist GW9662 (2 mg/kg/daily) blocked the behavioral effects of CBD. In conclusion, these results indicated that CBD could attenuate haloperidol-induced orofacial dyskinesia and improve non-motor symptoms associated with TD by activating PPARγ receptors.

Movement Disorders in Chronic Kidney Disease - A Descriptive Review.

OBJECTIVES: The objective of this study is to describe the mechanism of damage to subcortical structures in chronic kidney disease (CKD) and to describe the range of movement disorders associated with CKD. MATERIALS AND METHODS: We have reviewed the Medline literature up to January of 2020 using key words movement disorders and chronic kidney disease. The reviewed articles were studied for mechanisms of subcortical damage in CKD as well as type of the reported movements, their frequency and updated treatment. RESULTS: The search revealed 183 articles most of them dealing with restless legs syndrome. The damage to basal ganglia in CKD resulted from several mechanisms including accumulation of nitro tyrosine caused by reactive oxygen species and action of uremic toxins leading to endothelial damage and dysfunction of blood-brain barrier. Involuntary movements in CKD include restless legs syndrome (RLS), myoclonus, asterixis, dystonia, chorea, tremor, and Parkinsonism. CONCLUSIONS: Chronic kidney disease can cause several abnormal involuntary movements via damaging basal ganglia and subcortical structures. The most common movement disorders in CKD are RLS, myoclonus and asterixis. Restless legs syndrome and myoclonus when severe, need and respond to treatment. Movement disorders in CKD improve with improvement of kidney function.

Transient Improvement after Switch to Low Doses of RimabotulinumtoxinB in Patients Resistant to AbobotulinumtoxinA.

BACKGROUND: Botulinum toxin type B (BoNT/B) has been recommended as an alternative for patients who have become resistant to botulinum toxin type A (BoNT/A). This study aimed to compare the clinical effect, within a patient, of four injections with low doses of rimabotulinumtoxinB with the effect of the preceding abobotulinumtoxinA (aboBoNT/A) injections. METHODS: In 17 patients with cervical dystonia (CD) who had become resistant to aboBoNT/A, the clinical effect of the first four rimabotulinumtoxinB (rimaBoNT/B) injections was compared to the effect of the first four aboBoNT/A injections using a global assessment scale and the TSUI score. RESULTS: After the first two BoNT/B injections, all 17 patients responded well and to a similar extent as to the first two BoNT/A injections, but with more side effects such as dry mouth and constipation. After the next BoNT/B injection, the improvement started to decline. The response to the fourth BoNT/B injection was significant (p < 0.048) lower than the fourth BoNT/A injection. Only three patients developed a complete secondary treatment failure (CSTF) and five patients a partial secondary treatment failure (PSTF) after four BoNT/B injections. In nine patients, the usual response persisted. CONCLUSION: With the use of low rimaBoNT/B doses, the induction of CSTF and PSTF to BoNT/B could not be avoided but was delayed in comparison to the use of higher doses. In contrast to aboBoNT/A injections, PSTF and CSTF occurred much earlier, although low doses of rimaBoNT/B had been applied.

Beneficial effects of the phytocannabinoid Δ9-THCV in L-DOPA-induced dyskinesia in Parkinson's disease.

The antioxidant and CB2 receptor agonist properties of Δ9-tetrahydrocannabivarin (Δ9-THCV) afforded neuroprotection in experimental Parkinson's disease (PD), whereas its CB1 receptor antagonist profile at doses lower than 5 mg/kg caused anti-hypokinetic effects. In the present study, we investigated the anti-dyskinetic potential of Δ9-THCV (administered i.p. at 2 mg/kg for two weeks), which had not been investigated before. This objective was investigated after inducing dyskinesia by repeated administration of L-DOPA (i.p. at 10 mg/kg) in a genetic model of dopaminergic deficiency, Pitx3ak mutant mice, which serves as a useful model for testing anti-dyskinetic agents. The daily treatment of these mice with L-DOPA for two weeks progressively increased the time spent in abnormal involuntary movements (AIMs) and elevated their horizontal and vertical activities (as measured in a computer-aided actimeter), signs that reflected the dyskinetic state of these mice. Interestingly, when combined with L-DOPA from the first injection, Δ9-THCV delayed the appearance of all these signs and decreased their intensity, with a reduction in the levels of FosB protein and the histone pAcH3 (measured by immunohistochemistry), which had previously been found to be elevated in the basal ganglia in L-DOPA-induced dyskinesia. In addition to the anti-dyskinetic effects of Δ9-THCV when administered at the onset of L-DOPA treatment, Δ9-THCV was also effective in attenuating the intensity of dyskinesia when administered for three consecutive days once these signs were already present (two weeks after the onset of L-DOPA treatment). In summary, our data support the anti-dyskinetic potential of Δ9-THCV, both to delay the occurrence and to attenuate the magnitude of dyskinetic signs. Although further studies are clearly required to determine the clinical significance of these data in humans, the results nevertheless situate Δ9-THCV in a promising position for developing a cannabinoid-based therapy for patients with PD.

The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets.

l-DOPA is the gold-standard pharmacotherapy for treatment of Parkinson's disease (PD) but can lead to the appearance of troubling dyskinesia which are attributable to 'false neurotransmitter' release of dopamine by serotonergic neurons. Reducing the activity of these neurons diminishes l-DOPA-induced dyskinesia (LID), but there are currently no clinically approved selective, high efficacy 5-HT1A receptor agonists. Here we describe the effects of NLX-112, a highly selective and efficacious 5-HT1A receptor agonist, on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets, a non-human primate model of PD. NLX-112 exhibited modest plasma half-life (~2h) and marked plasma protein binding (96%). When administered to parkinsonian marmosets with l-DOPA (7 mg/kg p.o.), NLX-112 (0.025, 0.1 and 0.4 mg/kg p.o.) reduced LID scores at early time-points after administration, whilst only minimally interfering with the l-DOPA-induced reversal of motor disability. In contrast, the prototypical 5-HT1A receptor agonist, (+)8-OH-DPAT (0.6 and 2 mg/kg p. o.), reduced LID but also abolished l-DOPA's anti-disability activity. Administered by itself, NLX-112 (0.1, 0.2 mg/kg p.o.) produced very little dyskinesia or locomotor activity, but reduced motor disability scores by about half the extent elicited by l-DOPA, suggesting that it may have motor facilitation effects of its own. Both NLX-112 and (+)8-OH-DPAT induced unusual and dose-limiting behaviors in marmoset that resembled 'serotonin behavioral syndrome' observed previously in rat. Overall, the present study showed that NLX-112 has anti-LID activity at the doses tested as well as reducing motor disability. The data suggest that additional investigation of NLX-112 is desirable to explore its potential as a treatment for PD and PD-LID.

Child Neurology: A young child with an undiagnosed case of dystonia responsive to l-dopa.

Childhood-onset dystonias are a heterogeneously diverse group. There exists a specific set of dystonias that respond profoundly well to low doses of l-dopa (dopa-responsive dystonia [DRD]). Classical DRD is caused by deficiency of GTP cyclohydrolase 1 or tyrosine hydroxylase, but other conditions can cause dystonias that are partially responsive to dopamine. The idea of a diagnostic therapeutic trial with l-dopa for children who present with dystonia has been around for decades and is frequently advocated for; however, l-dopa trials are not without risk.

Synergistic Effects of Efflux Pump Modulators on the Azole Antifungal Susceptibility of Microsporum canis.

The microbiologic and clinical resistance of dermatophytes is seldom reported, and the mechanisms associated with resistance are not well known. This study investigated the effect of efflux pump modulators (EPMs) (i.e., haloperidol HAL and promethazine PTZ) and their inhibiting activity on the minimum inhibitory concentrations of itraconazole (ITZ) and fluconazole (FLZ) against selected M. canis strains. M. canis strains with low (≤ 1 µg/ml itraconazole and < 64 µg/ml fluconazole) and high (> 1 µg/ml itraconazole and ≥ 64 µg/ml fluconazole) azole MIC values were tested using Checkerboard microdilution assay. The disk diffusion assay, the minimum fungicidal concentration and the time-kill assay were also performed in order to confirm the results of checkerboard microdilution assay. The MIC values of ITZ and FLZ of M. canis decreased in the presence of subinhibitory concentrations of HAL and PTZ, the latter being more effective with a greater increased susceptibility. Synergism was observed in all strains with high azole MICs (FICI < 0.5) and no synergism in the strains with low azole MICs. A fungicidal activity was observed after 48 h of incubation when ITZ and FLZ were tested in combination with HAL or PTZ. These results suggest that the drug efflux pumps are involved in the defense mechanisms to azole drugs in M. canis strains. The synergism might be related to an increased expression of efflux pump genes, eventually resulting in azole resistance phenomena. Complementary studies on M. canis resistance are advocated in order to investigate the molecular mechanisms of this phenomenon.

Haloperidol discontinuation in a herpes simplex encephalitis patient with atypical abnormal movements using the herbal medicine Ukgansan-gami: A case report.

Recently, the herbal medicine Ukgansan (Yigansan in China, Yokukansan in Japan) was reported to be effective in the management of movement disorders. We report the case of a 62-year-old woman with herpes simplex encephalitis exhibiting atypical abnormal movements in the chronic stage. While controlling the abnormal movements with haloperidol, an antipsychotic agent, we prescribed Ukgansan-gami, an extract of a variant of Ukgansan, at a dose of 12 g/day to prevent the recurrence of abnormal movements and allow for the discontinuation of haloperidol. The patient was successfully treated with Ukgansan-gami, with no further recurrence of symptoms, making the use of haloperidol no longer necessary. The potential mechanism of action of Ukgansan involves the inhibition of nervous system hyperexcitability through the suppression of glutamate sodium channels, as well as attenuation of hypermotility through serotonin regulation. The present case suggests that herbal medicine therapy was likely to be an alternative to antipsychotics.

Botulinum Toxin Injection in Children with Hemiplegic Cerebral Palsy: Correction of Growth through Comparison of Treated and Unaffected Limbs.

Botulinum toxin type A (BoNT-A) injections in children with cerebral palsy (CP) may negatively affect muscle growth and strength. We injected BoNT-A into the affected limbs of 14 children (4.57 ± 2.28 years) with hemiplegic CP and exhibiting tip-toeing gait on the affected side and investigated the morphological alterations in the medial head of the gastrocnemius muscle (GCM). We assessed thickness of the GCM, fascicle length, and fascicle angle on the affected and unaffected sides at baseline at 4 and 12 weeks after BoNT-A injections. The primary outcome measure was the change (percentage) in GCM thickness in the affected side treated with BoNT-A in comparison with the unaffected side. The percentage of treated GCM thickness became significantly thinner at 4 and 12 weeks after BoNT-A injection than baseline. However, the percentage of fascicle length and angle in treated limbs showed no significant change from baseline 4 and 12 weeks after the injection. BoNT-A injections might reduce muscle thickness in children with spastic hemiplegic CP. Fascicle length and angle might not be affected by BoNT-A injections after correction of normal growth of the children.

Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia.

OBJECTIVE: To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD). METHOD: Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as 'Much Improved' or 'Very Much Improved' on the Clinical Global Impression of Change. RESULTS: A total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was -4.9 (0.4) at Week 54 (n = 146), - 6.3 (0.7) at Week 80 (n = 66) and -5.1 (2.0) at Week 106 (n = 8). CONCLUSIONS: Overall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD. TRIAL REGISTRATION NUMBER: NCT02198794.

Chorea.

PURPOSE OF REVIEW: This article provides an overview of the approach to chorea in clinical practice, beginning with a discussion of the phenomenologic features of chorea and how to differentiate it from other movement disorders. The diagnostic approach, clinical features of important acquired and genetic choreas, and therapeutic principles are also discussed. Practical clinical points and caveats are included. RECENT FINDINGS: C9orf72 disease is the most common Huntington disease phenocopy, according to studies in the European population. Anti-IgLON5 disease can present with chorea. The role of immunotherapies in Sydenham chorea has increased, and further clinical studies may be useful. Benign hereditary chorea is a syndrome or phenotype due to mutations in several genes, including NKX2-1, ADCY5, GNAO1, and PDE10A. New-generation presynaptic dopamine-depleting agents provide more options for symptomatic treatment of chorea with fewer adverse effects. Deep brain stimulation has been performed in several choreic disorders, but features other than chorea and the neurodegenerative nature should be taken into consideration. Studies on genetic interventions for Huntington disease are ongoing. SUMMARY: Clinical features remain crucial in guiding the differential diagnosis and appropriate investigations in chorea. Given the complexity of most choreic disorders, treating only the chorea is not sufficient. A comprehensive and multidisciplinary approach is required.

[Hemichorea/hemiballism a rare complication of hyperglycemia]. / Hemikorea/hemiballism ­ ovanlig komplikation till hyperglykemi - Ofrivilliga rörelser hos patient med nydebuterad diabetes.

We present a case of hemichorea/hemiballism, a rare complication of hyperglycemia. Diagnosis is made clinically by signs of unilateral involuntary movements of the extremities combined with typical neuroradiological findings in the basal ganglia. Guidelines for treatment of the condition are lacking but in many cases correction for hyperglycemia is sufficient for full symptom relief. In other cases, symptomatic treatment with haloperidol and tetrabenazine can be used.

Beyond speed: Gait changes after botulinum toxin injections in chronic stroke survivors (a systematic review).

BACKGROUND: The mechanisms by which spasticity reductions after botulinum toxin A (BoNT) affect gait in stroke are not well understood. We systematically reviewed the effects of BoNT on spatiotemporal, kinematic, kinetic and electromyographic (EMG) measures during gait. QUESTION: What are the effects of botulinum toxin on gait mechanics in stroke patients? METHODS: Systematic search using PubMed and Web of Science. We considered all studies that reported laboratory-based and instrumented gait measures as primary or secondary outcomes to determine the effects of BoNT on walking performance in stroke populations only. Selected studies were classified and analysed based on the injection sites. RESULTS: A total of 240 articles were identified of which 22 were selected for analysis. Overall, 91% of the studies reported spatiotemporal, 64% kinematics, 23% kinetics, 32% EMG and 23% other gait measures. All but one study found significant effects of BoNT on gait measures using instrumented assessments even when clinical measures (i.e. speed) did not significantly improve. However, the majority of the studies had a high risk of bias. Overall, BoNT improved: a) dorsiflexion during stance, propulsive forces and timing and activity of more proximal musculature with injections in the plantarflexors; b) hip, knee and ankle angles and velocities, coordination and energetic cost with injections in the rectus femoris; c) segmental coordination and energetic cost when several lower limb muscles were injected; and, d) elbow and trunk angles when upper limb muscles were injected. CONCLUSION: Instrumented and laboratory measures of gait improve after BoNT injections in different muscle groups even in the absence of clinical changes.

Chorea-ballism as a dominant clinical manifestation in heteroplasmic mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome with A3251G mutation in mitochondrial genome: a case report.

BACKGROUND: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, the most common maternally inherited mitochondrial disease, can present with a wide range of neurological manifestations including both central and peripheral nervous system involvement. The most frequent genetic mutation reported in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome is A3243G in MT-TL1 gene. Stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature constitute the known presentations in this syndrome. Among the abnormal involuntary movements in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome, myoclonus is the commonest. Other movement disorders, including chorea, are rarely reported in this disorder. CASE PRESENTATION: A 14-year-old South Asian boy from rural Bengal (India), born of a second degree consanguineous marriage, with normal birth and development history, presented with abnormal brief jerky movements involving his trunk and limbs, with recurrent falls for 10 months. We present here a case of heteroplasmic mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome with A3251G mutation, in which the clinical picture was dominated by a host of involuntary abnormal movements including chorea-ballism, myoclonus, and oromandibular dystonia in a backdrop of cognitive decline, seizure, and stroke-like episode. A final diagnosis was established by muscle biopsy and genetic study. Haloperidol was administered to control the involuntary movements along with introduction of co-enzyme Q, besides symptomatic management for his focal seizures. Six months into follow-up his seizures and abnormal movements were controlled significantly with slight improvement of cognitive abilities. CONCLUSION: The dominance of hyperkinetic movements in the clinical scenario and the finding of a point mutation A3251G in MT-TL1 gene make this a rare presentation.

Botulinum toxin-B injection into the lacrimal gland and posterior cricoarytenoid muscle for the treatment of epiphora and abductor spasmodic dysphonia secondary to Parkinson's disease.

In ophthalmology, there have been few reports of botulinum toxin type-A (BTX-A) injection into the lacrimal gland to treat epiphora. In ENT, adductor and abductor (ABSD) spasmodic dysphonia are often treated with BTX-A injections into the respective overacting vocal cord muscles. We describe a 53-year old male with Parkinson's disease who did not respond to BTX-A injections to either the lacrimal gland, for epiphora secondary to Parkinsonian-related blink lagophthalmos, or posterior cricoarytenoid (PCA) muscles for ABSD. Subsequent BTX type-B (BTX-B) injections into the lacrimal gland remarkably improved his epiphora. BTX-B injections into the PCA muscle also greatly improved his dysphonia. We describe the first reported case of (1) BTX-B injection into the lacrimal gland for epiphora, (2) use of Botox in treating epiphora due to blink lagophthalmos/reduced blink frequency secondary to Parkinson's disease, (3) BTX-B use in treating ABSD, and (4) association between ABSD and Parkinson's disease.