Ramiro Alvarez

The Onset of Nonmotor Symptoms in Parkinson's disease (The ONSET PD Study)

Nonmotor symptoms (NMS) in Parkinsons disease (PD) can precede onset of motor symptoms. Relationship between premotor symptoms onset and motor features is limited. Our aim is to describe the presence and perceived onset of NMS in PD as well as their possible association with motor phenotype. Presence and onset of NMS were assessed by a custom‐made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls from 11 Spanish and Austrian centers. Seventeen of thirty‐one NMS were more common in patients than controls (P < 0.05). They were usually mild and frequently reported to occur at different time‐spans before motor symptoms. Anhedonia, apathy, memory complaints, and inattention occurred more frequently during the 2‐year premotor period. Those reported more frequently in the 2‐ to 10‐year premotor period were smell loss, mood disturbances, taste loss, excessive sweating, fatigue, and pain. Constipation, dream‐enacting behavior, excessive daytime sleepiness, and postprandial fullness were frequently perceived more than 10 years before motor symptoms. No correlation between NMS burden and motor severity, age, or gender was observed. NMS associated in four clusters: rapid eye movement sleep behavior disorder symptoms‐constipation, cognition‐related, mood‐related, and sensory clusters. No cluster was associated with a specific motor phenotype or severity. NMS are common in early unmedicated PD and frequently reported to occur in the premotor period. They are generally mild, but a patient subgroup showed high NMS burden mainly resulting from cognition‐related symptoms. Certain NMS when present at the time of assessment or in the premotor stage, either alone or in combination, allowed discriminating PD from controls.

Posture-related changes of soleus H-reflex excitability

We investigated whether the modulatory effects of segmental and descending inputs on the soleus H reflex are modified by postural conditions. Fourteen healthy volunteers received a transcranial magnetic stimulus (TMS) or percutaneous electrical stimulation of the posterior tibial nerve (PTN), preceding by 0 to 400 ms the elicitation of the soleus H reflex in supine, sitting, and standing positions. In all positions, TMS induced an early period of facilitation at interstimulus intervals (ISIs) ranging between 5 and 35 ms. In supine and sitting positions, there was a second period of facilitation at ISIs between 60 and 90 ms, which was absent or significantly reduced in the standing position. PTN induced a strong inhibition of the H reflex in all positions up to 125 ms. In supine and sitting positions, inhibition continued up to 400 ms, whereas it was significantly reduced or completely absent beyond 125 ms in the standing position. These results demonstrate posture‐related differences in the modulatory effects of descending and segmental inputs on the excitability of the H‐reflex circuit.

Brain stem reflexes in patients with Wallenberg's syndrome: Correlation with clinical and magnetic resonance imaging (MRI) findings

In spite of the general clinical uniformity of Wallenbergs syndrome (WS), individual patients present with a slightly different clinical picture, and detailed studies with magnetic resonance imaging (MRI) show differences in the topography of the brain stem lesion. Neurophysiological characterization of the lesion in WS has been known for a long time, but there are no studies on the possible correlation between lesion topography and neurophysiological deficit. Assuming that afferents from the three branches of the trigeminal nerve reach different parts of the trigeminal nuclei, we examined the possible correlation between the lesion topography assessed by the MRI and the neurophysiological deficit, assessed by studying the brain stem reflexes in patients with WS within 2 weeks after stroke. Neurophysiological abnormalities were always located in the afferent branch of the reflexes examined, but not all patients exhibited abnormalities in all responses. The ophthalmic branch was involved in 92.8% of patients, and the mandibular branch in 57.1% of patients. The patients with MRI lesions located in the lower medulla had normal responses with infraorbital or mental nerve stimulation. The results of this neurophysiological study confirm the heterogeneity of WS. Whether the neurophysiological identification of different subgroups of patients is relevant for clinical outcome needs further studies.

Vibration-induced presynaptic inhibition of the soleus H reflex is temporarily reduced by cortical magnetic stimulation in human subjects

We have examined the effects of a transcranial magnetic stimulus (TMS) on the H reflex of the soleus muscle during vibration-induced presynaptic inhibition of the reflex, in seven normal volunteers. Without vibration, the H reflex was facilitated at interstimulus time intervals of > or = 5 ms after TMS. With vibration, the H reflex was markedly reduced or completely inhibited in control trials, but facilitation by TMS was noticed at intervals as short as -2.5 ms. These findings indicate an effect of TMS on the spinal interneurons mediating presynaptic vibratory inhibition of the H reflex.

Responses of the soleus muscle to transcranial magnetic stimulation

Soleus muscle responses are difficult to elicit by cortical stimulation in normal humans at rest. We have studied in normal volunteers the behavior of the soleus and tibialis anterior muscle responses to maximal intensity transcranial magnetic stimulation (TMS) in the following experimental conditions: lying in supine position, active ankle dorsal flexion, active plantar flexion, standing on the soles, standing on the toes, and standing on the heels. At rest, consistent responses were recorded in the soleus to 61% of the stimuli, only. Maximal facilitation of the response in the soleus occurred when standing on the toes. In this condition, responses were recorded to 100% of the stimuli, at a latency that was, on average, 5.2 msec shorter than the latency of the responses at rest, and similar to the latency of the responses recorded in the tibialis anterior muscle when standing on the heels. Central motor conduction time, calculated in conditions of maximal facilitation, was not different for soleus or tibialis anterior muscles. We conclude that the soleus muscle receives short latency excitatory inputs from cortico-spinal axons activated by TMS, with a conduction time similar to that for the tibialis anterior. Such short latency cortico-spinal connections to the soleus muscle may become functionally effective only during maximum enhancement of motoneuronal excitability by muscle contraction.

Orbicularis oculi responses to stimulation of nerve afferents from upper and lower limbs in normal humans.

A brief mechanical or electrical stimulus to peripheral nerve afferents from the upper and lower limbs elicited a small and inconsistent EMG response of the orbicularis oculi muscles. This response was facilitated when the stimuli were delivered at fixed leading time intervals, of 45-300 ms, with respect to a supraorbital nerve electrical stimulus. Also, the peripheral nerve stimulus modified the conventional blink reflex responses, inducing facilitation of R1 and inhibition of R2. These results suggest a complex processing of sensory inputs from the face and the limbs at the brainstem, where they are probably integrated in a network of interneurons influencing the excitability of facial motoneurons.

Clinical and imaging markers in premotor LRRK2 G2019S mutation carriers.

BACKGROUND Substantia nigra hyperechogenicity (SN+) has been proposed as a risk marker of Parkinsons disease (PD). Asymptomatic LRRK2 mutation carriers (aLRRK2+), at high risk for developing PD, provide an opportunity for the study of preclinical biomarkers. OBJECTIVE To assess SN echogenicity and other echographic features in LRRK2 G2019S carriers and their clinical and imaging correlates. METHODS Transcranial sonography was performed in 26 LRRK2 G2019S PD patients, 50 first-degree relatives, 31 idiopathic PD (IPD) patients and 26 controls. SN echogenicity and other echographic features were assessed in all study subjects. Dopamine transporter imaging (DAT-SPECT) was performed in 29 first-degree relatives. RESULTS 75% of the LRRK2-PD and 87.5% of the IPD showed SN+ (p = 0.087). aLRRK2+ had a higher frequency of SN+ than non carriers (58.3% vs. 25%, p = 0.039) and controls (58.3% vs. 12.5%; p = 0.002) and had a larger area of SN echogenicity than non carriers (p = 0.030) and controls (p < 0.001). The width of the third ventricle was significantly lower in LRRK2-PD than in IPD (1.9 mm [1.38; 2.75] vs. 3.0 mm [2.3; 5.3]; p = 0.003). Four out of 5 (80%) of the aLRRK2+ with an abnormal DAT-SPECT and four of the 5 (80%) of those with REM sleep behaviour disorder (RBD) had SN+. CONCLUSIONS SN+ is very frequent in LRRK2-PD and aLRRK2+. Most aLRRK2 with possible surrogate markers of PD such as abnormal DAT-SPECT or RBD, also had SN+, which supports that this echofeature might be a marker of PD in these asymptomatic population.

Transdermal Rotigotine Improves Sleep Fragmentation in Parkinson’s Disease: Results of the Multicenter, Prospective SLEEP-FRAM Study

Sleep disturbances occur frequently in patients with Parkinsons disease (PD). The aim of this study was to investigate the effects of rotigotine on sleep fluctuations in a sample of PD patients with self-reported complaints of nocturnal awakenings. This prospective, open-label, observational, and multicenter study enrolled consecutive outpatients with PD and administered rotigotine (mean dose 8.9 mg/day) for 3 months. The primary endpoint was the change from baseline in sleep fragmentation, assessed using the sleep maintenance subscale score of the Parkinsons Disease Sleep Scale (PDSS). The newly designed Parkinsons Disease Sleep Fragmentation Questionnaire (PD-SFQ) was used to measure other sleep parameters. A total of 62 patients were enrolled (mean age 70.2 years; 66% male). At 3 months, rotigotine significantly improved sleep fragmentation from baseline on the PDSS-2 sleep maintenance subscale (from 3.4 ± 0.9 to 1.9 ± 1.4; P < 0.0001). Rotigotine also significantly improved nocturnal motor symptoms (P < 0.0001), restless legs-like symptoms (P < 0.005), and nocturia (P = 0.004). Rotigotine significantly improved self-reported complaints of sleep fragmentation in PD patients and could be a useful treatment to improve this specific sleep problem in PD. However, these results are based on a small and clinically heterogeneous sample so they must be taken cautiously.

GBA Mutations Are Associated With Earlier Onset and Male Sex in Dementia With Lewy Bodies

Parkinsons disease (PD) and dementia with Lewy bodies (DLB) are Lewy body diseases characterized by similar pathological features. Several studies have shown a relation between alterations in the glucocerebrosidase gene (GBA) and the development of LB diseases. Here, we explored the role of GBA mutations in Spanish DLB patients.

Muscle activity changes in spasmodic torticollis after botulinum toxin treatment.

We assessed electromyographic (EMG) activity in neck muscles before and after botulinum toxin injections in 28 patients with spasmodic torticollis (ST) to investigate possible changes in muscle activation after treatment. A six‐channel EMG with surface electrodes was used to record activity of sternocleiodomastoid, trapezius and splenius capitis bilaterally. Objective benefit (>25% reduction in Tsuis score) occurred in 22 patients (78%). Of the 168 muscles studied before botulinum toxin injections, 90 presented EMG activity. Sixty‐eight of these muscles were injected and a decrease in EMG activity occurred in 44 (65%) of them. A decrease in EMG activity was also detected in 15 (68%) of those which were not injected. On the other hand, 70 of the 78 muscles without pre‐botulinum toxin EMG activity were not injected. However, after treatment, EMG activity increased in 37 (52%) of these muscles. These changes involved 18 patients and occurred without concomitant change in the main direction of head deviation despite the improvement observed in most cases. These results suggest that in ST head turning results from an abnormal central motor program which results in non‐specific neck muscle activation.