Francesco Lena

Subthalamic nucleus stimulation and somatosensory temporal discrimination in Parkinson’s disease

Whereas numerous studies document the effects of dopamine medication and deep brain stimulation on motor function in patients with Parkinsons disease, few have investigated deep brain stimulation-induced changes in sensory functions. In this study of 13 patients with Parkinsons disease, we tested the effects of deep brain stimulation on the somatosensory temporal discrimination threshold. To investigate whether deep brain stimulation and dopaminergic medication induce similar changes in somatosensory discrimination, somatosensory temporal discrimination threshold values were acquired under four experimental conditions: (i) medication ON/deep brain stimulation on; (ii) medication ON/deep brain stimulation off; (iii) medication OFF/deep brain stimulation on; and (iv) medication OFF/deep brain stimulation off. Patients also underwent clinical and neuropsychological evaluations during each experimental session. Somatosensory temporal discrimination threshold values obtained in patients were compared with 13 age-matched healthy subjects. Somatosensory temporal discrimination threshold values were significantly higher in patients than in healthy subjects. In patients, somatosensory temporal discrimination threshold values were significantly lower when patients were studied in medication ON than in medication OFF conditions. Somatosensory temporal discrimination threshold values differed significantly between deep brain stimulation on and deep brain stimulation off conditions only when the patients were studied in the medication ON condition and were higher in the deep brain stimulation on/medication ON than in the deep brain stimulation off/medication ON condition. Dopamine but not subthalamic nucleus deep brain stimulation restores the altered somatosensory temporal discrimination in patients with Parkinsons disease. Deep brain stimulation degrades somatosensory temporal discrimination by modifying central somatosensory processing whereas dopamine restores the interplay between cortical and subcortical structures.

Stimulation of subthalamic nuclei restores a near normal planning strategy in Parkinson's patients.

A fundamental function of the motor system is to gather key information from the environment in order to implement behavioral strategies appropriate to the context. Although several lines of evidence indicate that Parkinson’s disease affects the ability to modify behavior according to task requirements, it is currently unknown whether deep brain stimulation (DBS) of the subthalamic nucleus (STN) affects context-related planning. To explore this issue, we asked 12 Parkinson’s patients with bilateral STN DBS and 13 healthy subjects to execute similar arm reaching movements in two different paradigms: go-only and countermanding tasks. In the former task patients had to perform speeded reaching movements to a peripheral target. In contrast, in the countermanding task participants had to perform the same reaches unless an infrequent and unpredictable stop-signal was shown during the reaction time (RT) indicating that they should withhold the ongoing action. We compared the performance of Parkinson’s patients in different DBS conditions. We found that patients with both DBS-ON behaved similarly to healthy subjects, in that RTs of no-stop trial increased while movement times (MTs) decreased with respect to those of go-only-trials. However, when both DBS were off, both RTs and MTs were longer in no-stop trials than in go-only trials. These findings indicate that bilateral DBS of STN can partially restore the appropriate motor strategy according to the given cognitive contexts.

24-Hour infusion of levodopa/carbidopa intestinal gel for nocturnal akinesia in advanced Parkinson's disease

Levodopa/carbidopa intestinal gel (LCIG) is safe and efficacious in advanced Parkinson’s disease (PD). The infusion is approved for a maximum of 16 hours/day. The role of 24-hour administration is unclear, although its use has been reported. We evaluated 8 LCIG-treated patients who consented to receive round-the-clock LCIG infusion to address severe nocturnal akinesia, unresponsive to oral therapies. Patients provided informed consent. Patients were assessed before the initiation of LCIG infusion and at the last visit, 3 6 1.9 years later. At follow-up all patients had been on a 24-hour infusion regimen for 26 6 31.6 months (range, 4-72 months). Patients underwent evaluation for motor impairment (Unified Parkinson’s Disease Rating Scale [UPDRS-III]), disability (UPDRS-II), and complications (UPDRS-IV); axial impairment (Gait and Falls Questionnaire [GFQ]); nonmotor symptoms (Non-Motor Symptom Scale (NMSS); sleep quality (PD Sleep Scale [PDSS]); overall cognitive and neuropsychiatric function (UPDRS-I, Mini-Mental State Examination [MMSE], Neuropsychiatric Inventory [NPI], and the Questionnaire for Impulsive-Compulsive Disorders in PD [QUIP]); activities of daily living (ADLs), instrumental ADLs (IADLs), and healthrelated quality of life (8-item PD Questionnaire [PDQ-8]). The primary caregiver completed the Relative Stress Scale (RSS). The Wilcoxon paired test was used to compare baseline and follow-up assessments. Eight PD patients underwent 24-hour LCIG infusion (7 men aged 65 6 6.9 years; age at PD onset, 51 6 3.9 years; disease duration, 14 6 4.7 years). Infusion rate was reduced at night (mean reduction, 27%) to prevent adverse events and limit gel consumption in all patients except one who maintained a constant rate of 4 mL/hour per day. No sign of tolerance development was observed in any patient. Total LEDD, motor severity, and motor complications did not differ when comparing baseline and follow-up assessments. There were significant improvements in fatigue and sleep quality, mood/cognition, hallucinations, and urinary function (PDSS, NMSS domains 2-4, 7; Table 1). There was no change in cognitive and psychiatric functions, except for a reduction in the frequency and severity of impulsive compulsive behaviors (ICB); 6 patients presented at least 1 ICB at baseline, and 3 patients at follow-up). However, 1 patient developed severe and refractory psychotic symptomatology associated with surreptitious self-increase in the infusion dose (dopamine dysregulation syndrome), which required hospitalization and treatment with clozapine and eventually warranted discontinuation of LCIG. TABLE 1. Clinical data at baseline and at the last follow-up (post-24-hour Duodopa)

Scintigraphic, neuroradiological and clinical comparison in two patients with primary sporadic and two with secondary Fahr’s disease

Bilateral striopallidodentate calcification, usually termed Fahr’s disease, can give rise to various clinical manifestations including hyperkinetic movement disorders or a hypokinetic Parkinsonian syndrome, behavioural and mood changes, cognitive deficits and even frank dementia. We describe four patients all of whom underwent a detailed scintigraphic, neuroradiological and clinical work-up: two had primary, sporadic Fahr’s disease and two had Fahr’s disease secondary to hypoparathyroidism. The neuroradiological and clinical studies disclosed similar anatomical and pathological changes in the four patients but variable and sometimes unexpected clinical manifestations. Both patients with primary forms had hypokinetic Parkinsonian syndrome, both patients with secondary forms had hyperkinetic movements. Dopamine autotransporter scan brain scintigraphy disclosed an unexpected unilateral putamen involvement despite substantially symmetric calcifications.

Theatre is a valid add-on therapeutic intervention for emotional rehabilitation of Parkinson's disease patients

Conventional medical treatments of Parkinsons disease (PD) are effective on motor disturbances but may have little impact on nonmotor symptoms, especially psychiatric ones. Thus, even when motor symptomatology improves, patients might experience deterioration in their quality of life. We have shown that 3 years of active theatre is a valid complementary intervention for PD as it significantly improves the well-being of patients in comparison to patients undergoing conventional physiotherapy. Our aim was to replicate these findings while improving the efficacy of the treatment. We ran a single-blinded pilot study lasting 15 months on 24 subjects with moderate idiopathic PD. 12 were assigned to a theatre program in which patients underwent “emotional” training. The other 12 underwent group physiotherapy. Patients were evaluated at the beginning and at the end of their treatments, using a battery of eight clinical and five neuropsychological scales. We found that the emotional theatre training improved the emotional well-being of patients, whereas physiotherapy did not. Interestingly, neither of the groups showed improvements in either motor symptoms or cognitive abilities tested by the neuropsychological battery. We confirmed that theatre therapy might be helpful in improving emotional well-being in PD.

Effects of postural exercises in patients with Parkinson’s disease and Pisa syndrome: A pilot study

BACKGROUND Pisa syndrome (PS) or lateral axial dystonia is often seen in patients with Parkinsons disease (PD). It is characterized by a marked and reversible lateral flexion of the trunk (LFT) more than 10°. OBJECTIVE To assess the effectiveness of a program of postural exercises and assess the effectiveness in term of pattern of muscular hyperactivity. METHODS A total of 6 patients with PD and PS enrolled in the program of 10 sessions of postural exercise (90 min/session). EMG of thoraco-lumbar paraspinal muscles was performed to detect the pattern of muscular hyperactivity. Outcomes were examined using the Unified Parkinsons Disease Rating Scale part II and part III, degree of LFT and Visual Analogues Scale for back pain. RESULTS EMG showed two patterns of muscular hyperactivity; ipsilateral to the bending side and contralateral to the bending side. The exercise improved the outcomes in both groups. Patients with muscular hyperactivity ipsilateral to the bending side gained more improvements. CONCLUSION Our results show that the exercise may be considered as a possible treatment for patients with PD and PS irrespective of the pattern of muscular activation. The effectiveness of exercise differed according to the pattern of muscular activation.

Improvement of lateral axial dystonia following prismatic correction of oculomotor control disorders in Parkinson's disease.

Lateral axial dystonia (LAD), or Pisa syndrome, is traditionally treated with botulinum toxin (BTX) injections in the paraspinal muscle, but with inconsistent results [1, 2]. Very recently the quadratum lumborum (QL) muscle has been shown as a possible new therapeutic target for important lateral deviations [3]. We report improvement of LAD following correction through prismatic lenses in two PD patients with minimal oculomotor control disorders, specifically convergence deficit and reduction of the fusional amplitudes. No radiological evidence of skeletal deformity or fracture was found. Patients were evaluated with the following before and after prismatic correction: electromyography (EMG) of the psoas major muscle in the standing position, back pain scale (BPS), grading of the trunk dystonia as per goniometer measurement, and extensive orthoptic examination. Concomitant treatments remained stable during the observation period. Results of evaluations are listed in Table 1. A 49-year-old female patient, with a 5-year history of PD, presented with progressive painful lateral flexion of the trunk toward the left side for at least 1 year, despite treatment optimization. UPDRS III score at baseline was 7. The orthoptic examination revealed exophoria, convergence deficit, mild reduction of fusional amplitudes (\10 prism diopters), so prismatic correction was prescribed (three diopters, base-out). At 1-month follow up patient referred improvement of balance and pain and this improvement remained stable at 6-month follow up. A 59-year-old male with 3-year history of PD presented with progressive painful lateral flexion of the trunk toward the right side, despite drugs adaptation (rotigotine withdrawal). His UPDRS III score was four at baseline. The orthoptic evaluation revealed exophoria and convergence deficit, thus prismatic lenses were prescribed (five diopters, base-out). At 1-month follow up patient reported consistent improvement in posture and reduction of pain, which remained stable at 3-month follow up. Several pathophysiological mechanisms have been proposed to explain LAD in PD, all of them involving dystonia in paraspinal or cervical muscles [4]. We reported subjective and objective amelioration of LAD following correction of convergence insufficiency, which is one of the alterations in the oculomotor control commonly seen in PD patients [5]. Ambient visual process allows individuals to be aware of their position in the space and provides general information to monitor balance, movement, coordination and posture. It is well known, indeed, the relationship between normal vision and normal posture [6, 7]. Prisms are wedge shaped lenses that are thicker in one side than in the other. They deviate the images and modify the ocular motor vergence angle. Patients in our study always presented slight horizontal heterophoria and we used prisms always in horizontal orientation. Of note, in patient 2, who showed more pronounced trunk deviation, we used higher diopter correction. & Sara Varanese sara.varanese@gmail.com

Motor follow-up of parkinsonian patients after deep-brain stimulation

The numerous published studies addressing parkinsonian patients’ motor follow-up after surgery for deep-brain stimulation of the subthalamic nucleus bring to the fore several methodological problems that we consider of major importance. Assessing motor function in these patients is a complex task. They must be preoperatively assessed with and without oral medication, and postoperatively assessed with and without oral medication and with the stimulators turned on and turned off, hence under four conditions MED OFF/STIM OFF, MED ON/STIM OFF, MED OFF/STIM ON, and MED ON/STIM ON. The four conditions combined in various ways offer scope for numerous comparisons yielding a wealth of information. At the same time, there are several problems in clinical practice, which suggest the need to reappraise the existing patient assessment protocols. The Core Assessment Program for Surgical Interventional Therapies in Parkinson’s disease (CAPSIT-PD) recommendations define MED ON as the motor state assessed after the patient takes the usual morning levodopa dose [1]. Because morning doses often vary from patient to patient, this definition introduces inherent interpatient variability that is hard to eliminate. The frequent changes in a patient’s morning dose after the intervention also lead to intrapatient variability. The variability in the morning dose makes it difficult to compare the motor benefits achieved by preoperative oral therapy and postoperative oral therapy and stimulation (MED ON vs. MED ON-STIM ON), a core comparison in the postoperative follow-up of parkinsonian patients after deep-brain stimulation. One way to render this comparison fully homogeneous would be to maintain oral therapy quantitatively unchanged. For example, a patient taking 100 mg of levodopa preoperatively would be assessed postoperatively while taking 100 mg even if they actually require a lower dose. This solution might nevertheless be only partly applicable given that parkinsonian patients in advanced stage of disease often take levodopa in large amounts, the preoperative morning dose often reaching 200 mg, an amount inducing supramaximal post-synaptic dopaminergic receptor stimulation. Using the same levodopa dose preoperatively and postoperatively under these conditions would obviously be meaningless insofar as the dopamine-receptor stimulation induced by a supramaximal levodopa dose could bring no further meaningful motor benefit. The difficulties encountered in clinical practice also reflect differences in patient assessment. Whereas some studies assess patients after they receive their usual morning dose [2, 3], others define MED ON as the motor state reached after patients take 150% of the usual morning dose [4–6]. Yet other studies refer to the best ON medication motor state [7]. Difficulties arise also in assessing patients in the OFF medication motor state. According to the CAPSIT-PD recommendations, patients reach the OFF medication motor state 12 h after dopaminergic withdrawal [1]. Although most studies follow this recommendation, some variability exists given that the time elapsing after withdrawing therapy ranges from 8 to 12 h [5], 10 to 12 h [2], to at least 12 h or exactly 12 h [4, 6, 7]. A 12-h interval seems an acceptable compromise that in patients with advanced disease who are fully G. Caranci (&) F. Lena N. Modugno S. Ruggieri P. Romanelli M. Manfredi Centre for Parkinson’s Disease, IRCCS Neuromed Institute, via Atinense 18, 86077 Pozzilli, Isernia, Italy e-mail: giovannicaranci@tiscali.it