Antonella Macerollo

Spontaneous pain, pain threshold, and pain tolerance in Parkinson’s disease

The mechanisms underlying pain in Parkinson’s disease (PD) are unclear. Although a few studies have reported that PD patients may have low pain threshold and tolerance, none could accurately assess whether there was a correlation between sensory thresholds and demographic/clinical features of PD patients. Thus, tactile threshold, pain threshold, and pain tolerance to electrical stimuli in the hands and feet were assessed in 106 parkinsonian patients (of whom 66 reported chronic pain) and 51 age- and sex-matched healthy subjects. Linear regression models determined relationships between psychophysical parameters and demographic/clinical features. Female gender, severity of disease, medical disease associated with painful symptoms, and dyskinesia were more frequently observed in PD patients experiencing pain, even though dyskinesia did not reach significance. Pain threshold and pain tolerance were significantly lower in PD patients than in control subjects, whereas the tactile threshold yielded comparable values in both groups. Multivariable linear regression analyses yielded significant inverse correlations of pain threshold and pain tolerance with motor symptom severity and Beck depression inventory. Pain threshold and pain tolerance did not differ between PD patients with and without pain. In the former group, there was no relationship between pain threshold and the intensity/type of pain, and number of painful body parts. These findings suggest that pain threshold and pain tolerance tend to decrease as PD progresses, which can predispose to pain development. Female gender, dyskinesia, medical conditions associated with painful symptoms, and postural abnormalities secondary to rigidity/bradikinesia may contribute to the appearance of spontaneous pain in predisposed subjects.

Physical precipitating factors in functional movement disorders

BACKGROUND A traditional explanation for functional (psychogenic) neurological symptoms, including functional movement disorders (FMD), is that psychological stressors lead to unconsciously produced physical symptoms. However, psychological stressors can be identified in only a proportion of patients. Patients commonly reported a physical event at onset of functional symptoms. In this study, we aim to systematically describe physical events and surrounding circumstances which occur at the onset of FMD and discuss their potential role in generation of functional symptoms. METHODS We recruited 50 consecutive patients from a specialized functional movement disorders clinic. Semi-structured interviews provided a retrospective account of the circumstances in the 3 months prior to onset of the FMD. Questionnaires to assess mood disturbance and life events were also completed. RESULTS Eleven males and 39 females were recruited. Forty (80%) patients reported a physical event shortly preceding the onset of the FMD. The FMD occurred after an injury in 11 patients and after an infection in 9. Neurological disorders (n=8), pain (n=4), drug reactions (n=3), surgery (n=3) and vasovagal syncope (n=2) also preceded the onset of the functional motor symptom. 38% of patients fulfilled criteria for a panic attack in association with the physical event. CONCLUSIONS In our cohort, physical events precede the onset of functional symptoms in most patients with FMD. Although historically neglected in favour of pure psychological explanation, they may play an important role in symptoms development by providing initial sensory data, which along with psychological factors such as panic, might drive subsequent FMD.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): An Evolving Concept

Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS) originated from the observational work of Swedo and collaborators, who formalized their definition in 1998 in a set of operational criteria. The application of these criteria, which focuses on tics and obsessive-compulsive symptoms as core symptoms, has encountered difficulties, eventually leading to a high rate of misdiagnosis. In particular, the core feature represented by the association between newly diagnosed infections and neuropsychiatric symptom relapses in youths with this diagnosis could not be demonstrated by longitudinal studies. Exploratory studies aiming to identify clinical or cognitive features that could discriminate PANDAS from other pediatric obsessive-compulsive and tic disorders present methodological limitations, and therefore are not conclusive. Other behavioral features, in addition to obsessive-compulsive symptoms and tics, have been included in pediatric acute-onset neuropsychiatric syndromes (PANS) and childhood acute neuropsychiatric syndromes (CANS), two new concepts recently proposed in order to define a much broader clinical spectrum encompassing etiologically diverse entities. Given the uncertainties on the clinical definition of PANDAS, it is not surprising that evidence in support of a post-infectious, immune-mediated pathophysiology is also insufficient. Anti-dopamine receptor antibodies might be relevant to both Sydenham’s chorea (SC)—the prototypical post-streptococcal neuropsychiatric disorder—and some rare forms of encephalitis targeting the basal ganglia specifically, but studies exploring their association with children fulfilling Swedo’s criteria for PANDAS have been inconclusive. Moreover, we lack evidence in favor of the efficacy of antibiotic prophylaxis or tonsillectomy in patients fulfilling Swedo’s criteria for PANDAS, whereas a response to immune-mediated treatments like intravenous immunoglobulins has been documented by one study, but needs replication in larger trials. Overall, the available evidence does not convincingly support the concept that PANDAS are a well-defined, isolated clinical entity subdued by definite pathophysiological mechanisms; larger, prospective studies are necessary to reshape the nosography and disease mechanisms of post-streptococcal acute neuropsychiatric disorders other than SC. Research is also under way to shed further light on a possible relationship between streptococcal infections, other biological and psychosocial stressors, and the complex pathobiology of chronic tic disorders.

The phenomenology of the geste antagoniste in primary blepharospasm and cervical dystonia

The geste antagoniste (GA), a relatively common feature of adult‐onset primary dystonia, has been systematically evaluated only in cervical dystonia, but it is still unclear whether its frequency and phenomenology differ among the various forms of focal dystonia. We analysed the frequency, phenomenology, effectiveness, and relationship of the GA with demographic/clinical features of dystonia in a representative clinical series of patients with the two most common forms of adult‐onset primary dystonia, blepharospasm (BSP) and cervical dystonia (CD). Clinical data were gathered using a standardized questionnaire, which showed substantial test‐retest reliability (κ = 0.79, P < 0.00001). The frequency of GA was similar among patients with BSP (42/59, 71.2%) and patients with CD (27/32, 84.4%), and in both groups GA showed similar effectiveness in reducing dystonia. The repertoire of GA was heterogenous in both BSP and CD patients, in whom seven BSP‐related and five CD‐related types of GA were recorded, and a “forcible” type of GA was present in 69% of BSP patients and in 48.1% of CD patients. In our whole patient population, age at dystonia onset was significantly lower among patients reporting a GA compared to those without GA (P = 0.01). GA features shared by BSP and CD predominate over differences, suggesting common mechanisms underlying this phenomenon in the two forms of primary adult‐onset dystonia.

Cortical gray matter changes in primary blepharospasm: A voxel-based morphometry study†‡§

Previous voxel‐based morphometry studies of patients with primary blepharospasm documented gray matter volumetric differences of the striatum, cerebellum, thalamus, and parietal lobe areas. However, these results were inconsistent across studies, which recruited relatively small samples and did not always provide detailed clinical information on patients with blepharospasm. The objective of this study was to analyze whole‐brain gray matter volume in a larger sample of patients with blepharospasm and to expand on previous works by evaluating whether clinical features of blepharospasm correlate to whole‐brain gray matter changes. Voxel‐based morphometry was performed on 25 patients with primary adult‐onset blepharospasm and 24 healthy subjects (controls) matched for age, sex, and handedness. Clinical data were collected through a standardized interview. Severity of blepharospasm was measured using the Jankovic Rating Scale. Patients with blepharospasm had greater gray matter volume than controls in the right middle frontal gyrus, whereas patients with blepharospasm had smaller gray matter volume than controls in the left postcentral gyrus and left superior temporal gyrus. Spearman correlation analysis with Bonferroni correction failed to show significant correlations between gray matter volume and the explored clinical variables, comprising age at onset, disease duration, blepharospasm severity, presence of an effective geste antagoniste, and dose and duration of botulinum toxin treatment. Patients with blepharospasm exhibited gray matter volume differences exclusively in cortical regions highly relevant to sensory processing and cognitive modulation of motor behavior. Gray matter changes in the primary sensory cortex may represent a common trait of primary dystonias, including blepharospasm.

Environmental risk factors and clinical phenotype in familial and sporadic primary blepharospasm

Background: Although environmental and genetic factors may contribute to the etiology of blepharospasm, their relative contribution in causing familial and sporadic blepharospasm is unknown. Methods: First-degree relatives of 122 patients with primary blepharospasm were examined with a validated 2-step diagnostic procedure, including a screening questionnaire and examination of some relatives. Examiners were blinded to the questionnaire data for family history of probands. Data for demographic and clinical features, prior ophthalmologic complaints, and nondecaffeinated coffee intake were collected from probands before family investigation. Results: Dystonia was diagnosed in 27 relatives from 23 families (20% rate of family history for dystonia). No significant differences were found between familial and sporadic cases in the frequency of coffee drinking and eye diseases or in sex, age at onset, or tendency to spread. Multivariable conditional logistic analysis testing of 67 case patients and 127 family-matched unaffected siblings yielded a significant positive association between blepharospasm and prior eye diseases (adjusted odds ratio [OR] 2.5; 95% confidence interval [CI] 1.1–6.1; p = 0.03) and a significant inverse association between case status and ever coffee drinking (adjusted OR 0.23; 95% CI 0.1–0.8; p = 0.02). Conclusions: The new information from this large family-based study on primary blepharospasm strongly supports eye diseases and coffee as risk factors for blepharospasm. The finding that the 2 environmental exposures exerted a similar influence on familial and sporadic blepharospasm, together with the convergent phenotypic expression in familial and sporadic cases, implies that familial and sporadic blepharospasm probably share a common etiologic background.

Validation of "laboratory-supported" criteria for functional (psychogenic) tremor

In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity.

Neuroendocrine Aspects of Tourette Syndrome

There is sparse evidence suggesting the participation of neuroendocrine mechanisms, mainly involving sex and stress steroid hormones, to the pathophysiology of neurodevelopmental disorders such as Tourette syndrome (TS) and obsessive-compulsive disorder (OCD). Patients with TS exhibit a sex-specific variability in gender distribution (male/female ratio=3-4/1) and in its natural history, with a severity peak in the period around puberty. The administration of exogenous androgens may worsen tics in males with TS, whereas drugs counteracting the action of testosterone might show some antitic efficacy. This suggests a higher susceptibility of patients with TS to androgen steroids. There are insufficient data on the regulation of the hypothalamic-pituitary-gonadal (HPG) axis in TS. However, preliminary evidence suggests that a subgroup of women with TS might be more sensitive to the premenstrual trough of estrogen levels. Patients with TS exhibit differences in a number of behavioral, cognitive, and anatomical traits that appear to be sex related. There is a body of evidence supporting, albeit indirectly, the hypothesis of an increased exposure to androgenic steroids during the very early phases of neural development. Animal models in rodents suggest a complex role of gonadal hormones upon the modulation of anxiety-related and stereotyped behaviors during adult life. Patients with TS exhibit an enhanced reactivity of the hypothalamic-pituitary-adrenal axis to external stressors, despite a preserved diurnal cortisol rhythm and a normal restoration of the baseline activity of the axis following the acute stress response. Preliminary evidence suggests the possible implication of oxytocin (OT) in disorders related to the TS spectrum, especially non-tic-related OCD. The injection of OT in the amygdala of rodents was shown to be able to induce hypergrooming, suggesting the possible involvement of this neuropeptide in the pathophysiology of complex, stereotyped behaviors. In contrast, there is anecdotal clinical evidence that tics improve following periods of affectionate touch and sexual intercourse.

Sensory Attenuation Assessed by Sensory Evoked Potentials in Functional Movement Disorders

Background Functional (psychogenic) movement disorders (FMD) have features associated with voluntary movement (e.g. distractibility) but patients report movements to be out of their control. One explanation for this phenomenon is that sense of agency for movement is impaired. The phenomenon of reduction in the intensity of sensory experience when movement is self-generated and a reduction in sensory evoked potentials (SEPs) amplitude at the onset of self-paced movement (sensory attenuation) have been linked to sense of agency for movement. Methods We compared amplitude of SEPs from median nerve stimulation at rest and at the onset of a self-paced movement of the thumb in 17 patients with FMD and 17 healthy controls. Results Patients showed lack of attenuation of SEPs at the onset of movement compared to reduction in amplitude of SEPs in controls. FMD patients had significantly different ratios of movement onset to rest SEPs than did healthy controls at each electrode: 0.79 in healthy controls and 1.35 in patients at F3 (t = -4.22, p<0.001), 0.78 in healthy controls and 1.12 at patients C3 (t = -3.15, p = 0.004) and 0.77 in healthy controls and 1.05 at patients P3 (t = -2.88, p = 0.007). Conclusions Patients with FMD have reduced sensory attenuation as measured by SEPs at onset of self-paced movement. This finding can be plausibly linked to impairment of sense of agency for movement in these patients.

Is increased blinking a form of blepharospasm

Objective: The aim of this study was to investigate whether increased blink rate (BR) is part of the clinical spectrum of primary blepharospasm (BSP). Methods: We enrolled 40 patients (16 patients with an increased BR but without typical orbicularis oculi [OO] spasms, and 24 patients with typical involuntary OO spasms) and 18 healthy subjects. The BR, blink reflex recovery cycle, and somatosensory temporal discrimination threshold (STDT) were tested in patients and controls. Results: Patients who had typical OO spasms had an altered R2 recovery cycle whereas those who had an increased BR alone had a normal blink reflex recovery cycle. STDT values were higher in patients than in healthy subjects and no difference was found in the STDT abnormalities in the 2 groups of patients. Conclusions: Our study shows that, despite the similar STDT abnormalities, the different changes in the R2 recovery cycle in patients with BSP and those with increased BR alone suggest that these disorders arise from different pathologic mechanisms.