Sonia Mazzucchi

Mild affective symptoms in de novo Parkinson's disease patients: relationship with dopaminergic dysfunction

The investigation of the relationship between affective symptoms and dopamine transporter (DAT) density provided conflicting data in both Parkinsons disease (PD) and non‐PD patients. However, the potential interference of psychoactive as well as anti‐parkinsonian drugs on DAT density should be taken into account.

Serotonergic antidepressant drugs and L-dopa-induced dyskinesias in Parkinson's disease.

Serotonergic system is believed to play a role in levodopa‐induced‐dyskinesias pathogenesis, and serotonin transporter has been evaluated as potential target.

The relationship between motor symptom lateralization and cognitive performance in newly diagnosed drug-naïve patients with Parkinson's disease

The side of motor symptom predominance may influence cognitive performance in patients with Parkinsons disease (PD): PD patients with right-side motor symptom predominance typically present difficulties in tasks of language and verbal memory, whereas PD patients with left-side motor symptom predominance typically present difficulties in visuospatial tasks. The current study aimed at investigating the relationship between motor symptom lateralization and cognitive performance in PD patients without the possible confounding effect of dopaminergic drugs, which may enhance or impair cognition on the basis of assessed function and disease stage. From the initial sample of 137 consecutive newly diagnosed drug-naïve (de novo) PD patients, clinical follow-ups and neurological examinations identified 108 right-handed patients with a unilateral motor presentation or a clear motor asymmetry (59 right-PD: 54.6%; 49 left-PD: 45.4%). Any cognitive difference emerged between right-PD patients and left-PD patients at this disease stage. Scores of lateralized motor impairment severity correlated with some cognitive performances: Right motor impairment correlated with a measure of set shifting (Trail Making Test B–A), and left motor impairment correlated with phonemic fluency and tasks with visuospatial material (Colored Progressive Matrices of Raven, Rey–Osterrieth Complex Figure Copy and Immediate Recall). Findings of the current study supported the conclusion that the side of clinical motor predominance scarcely influences cognition in the early untreated stages of PD, suggesting that cognitive differences between subgroups of lateralized PD patients probably may appear in more advanced disease stages.

Current treatment and future prospects of dopa-induced dyskinesias.

Levodopa-induced dyskinesias (LID) are one of the main issues in the management of Parkinsons 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.

Antipsychotic drugs in Huntington’s disease

ABSTRACT Introduction: The aim of this review is to overview the pharmacological features of neuroleptics experienced in the treatment of Huntington’s disease (HD) symptoms. Despite a large number of case reports, randomized controlled trials (RCT) and drug comparison studies are lacking. Areas covered: After evaluating current guidelines and clinical unmet needs we searched PubMed for the term ‘Huntington’s disease’ cross referenced with the terms ‘Antipsychotic drugs’ ‘Neuroleptic drugs’ and single drug specific names. Expert commentary: In clinical practice antipsychotics represent the first choice in the management of chorea in the presence of psychiatric symptoms, when poor compliance is suspected or when there is an increased risk of adverse events due to tetrabenazine. Antipsychotics are considered valid strategies, with the second generation preferred to reduce extrapyramidal adverse events, however they may cause more metabolic side effects. In the future ‘dopamine stabilizers’, such as pridopidine, could replace antipsychotics modulating dopamine transmission.

Symptomatic orthostatic tremor associated with Graves’ disease

We describe the case of a 70-year-old woman complaining sense of unsteadiness and tremor in her legs mainly during standing and walking, which gradually worsened over a year. A diagnosis of OT was made and clonazepam treatment was started, without any benefit. When she came to our attention, neurological exam showed leg tremor while standing and walking, tetrahyperreflexia and inability to perform tandem gait. Her cognition and mental state were normal. She also reported intolerance of heat, excessive sweating and recent loss of weight with increased appetite, dysphagia and dysphonia. Electromyography of lower limb muscles was performed with surface electrodes, positionated on right and left vastus lateralis, gastrocnemius and tibialis anterior muscles, with a strictly symmetrical disposition. The patient was observed when supine, sitting and standing. Recordings from vastus (Fig. 1) and tibialis anterioris performed during standing showed a rhythmic contractile activity at about 8 Hz (with single burst duration of 80 ms), with an alternating pattern of agonist and antagonist muscles. After prolonged supine rest, a rhythmic contractile activity at lower amplitude re-appeared in both lower legs. Due to atypical clinical signs and both EMG activity and low frequency of tremor, a symptomatic origin was suspected. Motor-evoked potentials did not demonstrate impairment of the cortico-spinal tract. Brain and cervico-dorsal MRI were normal. A potential role of thyroid was hypothesized because of systemic signs and symptoms and lack of any other signs of extrapyramidal involvement. Her thyroid function exams revealed severe hyperthyroidism: thyroid-stimulating hormone [(TSH) \0.004 lU/ ml (0.400–4.000 lU/ml), fT3 9.25 pg/ml (1.80–4.80 pg/ ml), fT4 5.05 ng/dl (0.80–1.80 ng/dl)], increased values of thyroglobulin antibodies [451 UI/ml, (\30 UI/ml)], thyroid peroxidase antibodies [ 1.020 (\10 UI/ml) and positivity of TSH receptor antibodies (19.10 UI/L)]. A chest and neck CT scan revealed an increase in thyroid size involving the upper mediastinum and affecting the left side of the esophagus. A diagnosis of Graves’ disease was performed, and the patient was started on methimazole with dramatic improvement of tremor. S. Mazzucchi U. Bonuccelli Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

Q09 Valproic Acid for the treatment of aggressiveness in Huntington's disease: 1-year follow-up

Background Huntingtons disease (HD) is characterised by involuntary movements, cognitive decline and psychiatric symptoms such as aggressiveness, and depression. In most cases involuntary movements and psychiatric symptoms are controlled by antipsychotic drugs, but sometimes side effects as parkinsonism or worsening of depression and apathy can reduce the therapeutic window of these drugs. Aims To evaluate the beneficial effect of Valproic Acid on psychiatric symptoms such as agitation and aggressiveness as well as depression in HD. Methods 10 symptomatic genetically confirmed HD patients (mean CAG repeat 40±2), mean disease duration (8±2 years) on antipsychotics, all with aggressiveness defined as disabling by the patients along with the care giver, were included in an open unblinded trial. Clinical evaluation including motor (UHDRS), psychiatric (NPI) and cognitive scales (MMSE) was performed at baseline and after 6 and 12 months of Valproic Acid (from 300 up to 1000 mg die). Results In our cases we reported a reduction of 10 points of NPI score in each patient persisting 1 year after the introduction of Valproate without any side effect reported. Conclusions The beneficial effect of Valproic Acid on aggressive patients is well documented since 19971 and, to our knowledge, there are only two case reports2 3 that support this effect in such psychiatric disturbance in HD. However no systematic study was done so far in this topic. Moreover, the successful use of Valproic acid in controlling aggressiveness allowed us not to increase the daily dose of neuroleptic, so preventing motor and psychiatric side effects. References 1. Haas S, Vincent K, Holt J, et al. Divalproex: a possible treatment alternative for demented, elderly aggressive patients. Ann Clin Psychiatry 1997;9:145–7. 2. Grove VE Jr, Quintanilla J, DeVaney GT. Improvement of Huntingtons disease with olanzapine and valproate. N Engl J Med 2000;343:973–4. 3. Rask G, Anderson C. Good effect of valproate against aggression in Huntington disease. Only two cases reported earlier. Lakartidningen 2010;107:3060–1.

Head tremor as a warning symptom of rapidly progressive syringomyelia: a case report

The term syringomyelia indicates different types of spinal cord defects frequently associated to Arnold-Chiari I malformation (CM1). Natural history of the disease is unpredictable with a wide clinical spectrum, ranging from complete absence of neurological symptoms to a progressively disabling syndrome. Spontaneous radiological remission has been observed. In a minority of cases, syringomyelia can present with involuntary movements. In the largest case series in literature [1], with a 15-year follow-up period, the presence of movement disorders was reported in 22 out of 100 patients with a newly diagnosed syringomyelia. Symptoms were mainly represented by spinal myoclonus, action hand tremor (usually lateralized), torticollis, blepharospasm, and abnormal head and arm postures. Further case reports described the presence of cervical dystonia or dystonia-athetosis of the hand or of the neck in patients with syringomielia [2, 3] (Table 1). The exact mechanism underlining this association is not completely understood; however, according to the leading hypothesis, a central gray matter spinal cord lesion could predispose to spinal motor neuron hyperexcitability and in rare cases manifest with involuntary movements. A 53-year-oldwoman came to our attention complaining of negative head tremor that appeared almost 1 year before and was progressively worsening, more recently associated to left arm rest and action tremor. Her family history was positive for Parkinson’s disease; her medical history reported only arterial hypertension. The patient noticed negative relationship with emotional stress. She did not complain of associated symptoms, particularly bradykinesia or gait disturbances. The first neurological examination was normal except for negative head tremor withminimal left head shift and slight rest and postural tremor involving her left arm. Muscle tone was normal. She did not report sensory tricks or tremor worsening with headmovements both on the horizontal and on the vertical plane. Serum PTH, copper, ceruloplasmin, and thyroid function were normal. Electrophysiological recording performed with surface electrodes demonstrated a rhythmic activity (7–8 Hz) suggestive for postural head tremor, associated to rare spontaneous firing of MUPs in the sternocleidomastoid muscles particularly in the right one. Her brain and cervical MRI demonstrated CM1, with displacement of the cerebellar tonsils 15 mm below the foramen magnum associated with a notable syringomyelia involving the spinal tract fromC4 to T1–T2 (Fig. 1). No previous head or cervical traumas were reported. Radiological findings were presumed of congenital origin and not directly related to the symptoms; however, neurosurgical evaluation was recommended. The patient was started on clonazepam with moderate clinical benefit. After 6 months, she started complaining of headache and slight bilateral arm paresthesias and underwent suboccipital craniectomy followed by reconstruction of the dura mater, which is the neurosurgical procedure recommended in cases of symptomatic syringomyelia associated to CM1. The patient did not report substantial post-procedural change of sensory symptoms whereas significant reduction of head and arm tremor was noticed. Clonazepam was stopped without motor symptoms re-emergence. Spine MRI controls remained stable for few months, but almost 1 year after surgery, the patient reported a rapid and clear worsening of sensory symptoms with occasional burns, arm weakness, and burning pain involving her feet. Neurological examination demonstrated impairment of tactile and thermo-dolorific sensitivity of the limbs, more pronounced at upper limbs. Cervico-dorsal MRI showed severe radiological progression with extension of syringomyelia both upward, with the * R. Ceravolo robertoceravolo66@gmail.com

Social Cognition and Oxytocin in Huntington’s Disease: New Insights

This study is aimed at relating social cognition in Huntington’s Disease (HD) to plasma levels of the social hormone oxytocin (OT). Indeed, HD patients commonly display reduced social skills and OT is involved in bonding behavior and improved recognition of facial emotions. Twelve mild-symptomatic HD patients (stage II Shoulson & Fahn) and 11 gender/age matched controls (healthy controls, HC), without concurrent psychiatric disorders, were investigated at baseline (T0) for OT plasma levels and social cognition through an extensive battery of neuropsychological tests. Social cognition was also re-examined after two years (T1) in 8 of the 12 patients. Results showed a trend for reduced T0-OT levels in HD vs. HC, mean ± stardard deviation: 6.5 ± 2.4 vs. 9.9 ± 7.2 pg/mL, without reaching statistical significance. At T0, patients showed significantly lower performances than controls at the “Faux-Pas” and “Strange Stories” tests (p < 0.05; p < 0.01); a reduced perception of visual emotions (p < 0.01) and verbal stimuli (p < 0.01) was also reported, involving anger, fear, and sadness (p < 0.05; p < 0.01). Additionally, in the HD population, OT concentrations positively correlated with T1-performances at Neutral\Faux-Pas test (p < 0.05), whereas the cognitive Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE) scores positively correlated with psychosocial perception at the “Strange Stories” and Karolinska Directed Emotional Faces (KDEF) tests (p < 0.05). This study, despite its limitations, supports correlations between OT and HD social cognition, suggesting a possible therapeutic use of this hormone. More subjects and additional body tissues/fluids, such as cerebrospinal fluid, should be investigated to confirm this hypothesis.

D5 Oxytocin plasma levels as predictor of social cognition in huntington’s disease

Background The role of Oxytocin (OT) as social hormone is supported by the improvement of recognition of the expression of the faces after administration of intranasal OT. Impaired social behaviour, partly related to altered perception of emotions, is commonly reported in Huntington’s disease (HD). Aims To evaluate OT plasma level as possible predictor of social cognition performances in a population of symptomatic HD patients. Methods 12 patients with symptomatic HD (stage II S&F) without cognitive impairment were evaluated at the baseline and after 2 years follow up (8 pt) for social cognition through an extensive battery of neuropsychological tests (Faux Pas test, Bush vignettes test, emotion recognition from both faces expression and verbal stimuli, Strange stories test). Plasma OT levels at the baseline were analysed in the whole cohort of subjects and the relationship between the levels of OT and social cognition at the baseline and at the follow up was analysed. OT plasma levels were also compared to that of a population of healthy controls matched for age. Results OT levels did not differ in the two populations, however with a trend for lower values in HD group (average 9.9 ± 7.2 controls, 6.5 ± 2.4 HD). At the baseline OT blood levels did show any significative correlation with social cognition and cognitive tests. The follow up analysis showed that higher OT levels correlated with better performances at the Neutral\Faux Pas score (p < 0.05) and with higher ability of recognising happiness from verbal stimuli (p < 0.05). Conclusions Even though not statistically significant patients showed lower OT circulating levels compared to controls; moreover the follow-up analysis pointed out a possible role of OT in predicting the progression of social cognition in HD. The present data, limited by the sample size and by the biological tissue studied, need to be confirmed in a larger population analysis even by correlating with cerebrospinal fluid measurement.