Clinical correlates of "pure" essential tremor: the TITAN study.

Background: To date, there are no large studies delineating the clinical correlates of "pure" essential tremor (ET) according to its new definition. Methods: From the ITAlian tremor Network (TITAN) database, we extracted data from patients with a diagnosis of "pure" ET and excluded those with other tremor classifications, including ET-plus, focal, and task-specific tremor, which were formerly considered parts of the ET spectrum. Results: Out of 653 subjects recruited in the TITAN study by January 2022, the data of 208 (31.8%) "pure" ET patients (86M/122F) were analyzed. The distribution of age at onset was found to be bimodal. The proportion of familial cases by the age-at-onset class of 20 years showed significant differences, with sporadic cases representing the large majority of the class with an age at onset above 60 years. Patients with a positive family history of tremor had a younger onset and were more likely to have leg involvement than sporadic patients despite a similar disease duration. Early-onset and late-onset cases were different in terms of tremor distribution at onset and tremor severity, likely as a function of longer disease duration, yet without differences in terms of quality of life, which suggests a relatively benign progression. Treatment patterns and outcomes revealed that up to 40% of the sample was unsatisfied with the current pharmacological options. Discussion: The findings reported in the study provide new insights, especially with regard to a possible inversed sex distribution, and to the genetic backgrounds of "pure" ET, given that familial cases were evenly distributed across age-at-onset classes of 20 years. Deep clinical profiling of "pure" ET, for instance, according to age at onset, might increase the clinical value of this syndrome in identifying pathogenetic hypotheses and therapeutic strategies.

The Italian tremor Network (TITAN): rationale, design and preliminary findings.

INTRODUCTION: The recently released classification has revised the nosology of tremor, defining essential tremor (ET) as a syndrome and fueling an enlightened debate about some newly conceptualized entities such as ET-plus. As a result, precise information of demographics, clinical features, and about the natural history of these conditions are lacking. METHODS: The ITAlian tremor Network (TITAN) is a multicenter data collection platform, the aim of which is to prospectively assess, according to a standardized protocol, the phenomenology and natural history of tremor syndromes. RESULTS: In the first year of activity, 679 patients have been recruited. The frequency of tremor syndromes varied from 32% of ET and 41% of ET-plus to less than 3% of rare forms, including focal tremors (2.30%), task-specific tremors (1.38%), isolated rest tremor (0.61%), and orthostatic tremor (0.61%). Patients with ET-plus were older and had a higher age at onset than ET, but a shorter disease duration, which might suggest that ET-plus is not a disease stage of ET. Familial aggregation of tremor and movement disorders was present in up to 60% of ET cases and in about 40% of patients with tremor combined with dystonia. The body site of tremor onset was different between tremor syndromes, with head tremor being most commonly, but not uniquely, associated with dystonia. CONCLUSIONS: The TITAN study is anticipated to provide clinically relevant prospective information about the clinical correlates of different tremor syndromes and their specific outcomes and might serve as a basis for future etiological, pathophysiological, and therapeutic research.

Movement disorders in emergency settings: a prospective study.

INTRODUCTION: Acute movement disorders (MD) are etiologically heterogeneous entities. Since studies on the relative frequency of different MD and their underlying diseases are limited, we performed a prospective study to investigate the spectrum of various MD and their causes in patients presenting with acute MD in an emergency room (ER) setting. OBJECTIVE: To describe the spectrum and outcomes of acute MD in a prospective cohort and to guide its management. METHODS: We investigated acute MD in 96 consecutive patients admitted to ERs between 2013 and 2017. Time of disease onset, type of MD according to published criteria, diagnostic workup, and outcome were collected. RESULTS: 73.9% of patients had hyperkinetic MD. Tremor was the most common symptom (19.8%), followed by myoclonus (17.7%), dystonia (15.6%), and chorea (11.4%). Other hyperkinetic MD (9.4%) included were gait disorders (imbalance due to involuntary movement), dyskinesia, akathisia, hemiballism, and oculogyric crisis. Hypokinetic MD included acute parkinsonism (15.6%), off-state (4%), akinesia (3%), and rigidity (3%). Co-occurrence of more than one MD was seen in 19.7% of patients. Time delay to medical consultation was between < 24 h and 28 days. Five etiological groups were recognized: drug-induced (29.2%), functional (19.8%), neurodegenerative diseases (15.6%), structural brain damage (11.5%), others (24.0%, metabolic, inflammatory, infective, undetermined). Outcome was better for neurodegenerative diseases and for drug-induced MD. Functional movement disorders (FMD) showed less favorable outcome. CONCLUSIONS: Acute MD is a distinct cause of ER admission, and a variety of treatable diseases may be the underlying cause of this symptom. Uncertain course is more probable in FMD and in structural brain lesions.

Pain processing in functional and idiopathic dystonia: An exploratory study.

BACKGROUND: Pain is often experienced by patients with functional dystonia and idiopathic cervical dystonia and is likely to be determined by different neural mechanisms. OBJECTIVE: In this exploratory study, we tested the sensory-discriminative and cognitive-emotional component of pain in patients with functional and idiopathic dystonia. METHODS: Ten patients with idiopathic cervical dystonia, 12 patients with functional dystonia, and 16 age- and sex-matched healthy controls underwent psychophysical testing of tactile and pain thresholds and pain tolerance. We delivered electrical pulses of increasing intensity to the index finger of each hand and the halluces of each foot. Pain threshold and pain tolerance were respectively defined as the (1) intensity at which sensation changed from unpainful to faintly painful and (2) intensity at which painful sensation was intolerable. RESULTS: No differences were found between the three groups for tactile and pain thresholds assessed in hands and feet. Pain tolerance was significantly increased in all body regions only in functional dystonia. Patients with continuous functional dystonia had higher pain tolerance compared to subjects with paroxysmal functional dystonia and idiopathic cervical dystonia. There was no correlation between pain tolerance and pain scores, depression, anxiety, disease duration, and motor disability in both groups. CONCLUSIONS: Patients with functional dystonia have a dissociation between the sensory-discriminative and cognitive-emotional components of pain, as revealed by normal pain thresholds and increased pain tolerance. Abnormal connectivity between the motor and limbic systems might account for abnormal pain processing in functional dystonia. © 2018 International Parkinson and Movement Disorder Society.

Changes in laser-evoked potentials during hypnotic analgesia for chronic pain: a pilot study.

BACKGROUND: Hypnotic analgesia is one of the most effective nonpharmacological methods for pain control. Hypnosis and distraction of attention from pain might share similar mechanisms by which brain responses to painful stimulation could be similarly reduced in both states. There is ample evidence for the efficacy of clinical hypnosis as a psychological intervention in the treatment of acute or chronic pain. Results are conflicting, however, with some studies showing an increase, others a reduction, and others still no change in the amplitude of event-related brain potentials during hypnosis as compared to control conditions. Here we compared the effects of clinical hypnosis to simple distraction of attention during recording of laser-evoked potentials (LEPs) in patients with chronic pain. METHODS: The dominant hand in ten patients with chronic pain was tested with LEPs during: (I) resting state; (II) clinical hypnosis, and (III) distraction of attention. Nociceptive responses elicited by LEPs were graded on a numerical rating scale (NRS), and the change in N2-P2 complex amplitude during the three experimental conditions was analyzed. RESULTS: N2-P2 amplitudes were significantly decreased during the hypnotic state as compared to the resting state and distraction of attention. CONCLUSIONS: Hypnosis is a modified state of consciousness that may differ from mental relaxation or distraction of attention from pain. A reduction in N2-P2 amplitude may result from the modulation of diverse brain networks, particularly the frontolimbic pathways, which could modify noxious stimuli input processing during hypnotic analgesia. Our findings indicate that several different brain mechanisms may act together in hypnosis and distraction of attention during pain processing and that clinical hypnosis may provide a useful non-invasive pain relief therapy.

Impulse control disorders in advanced Parkinson's disease with dyskinesia: The ALTHEA study.

BACKGROUND: Impulse control disorders and dyskinesia are common and disabling complications of dopaminergic treatment in Parkinson's disease. They may coexist and are possibly related. The objectives of this study were to assess the frequency and severity of impulse control disorders in Parkinson's disease patients with dyskinesia. METHODS: The ALTHEA study enrolled 251 Parkinson's disease patients with various degrees of dyskinesia severity from 11 movement disorders centers in Italy. Each patient underwent a comprehensive assessment including Unified Dyskinesia Rating Scale and the Questionnaire for Impulsive Compulsive Disorders in Parkinson Disease-Rating Scale. RESULTS: There was an overall 55% frequency of impulse control disorder and related behaviors (36% were clinically significant). The positive patients were younger at disease diagnosis and onset and had higher Unified Dyskinesia Rating Scale historical and total score (P = 0.001 and P = 0.02, respectively, vs negative). There was an increased frequency of clinically significant impulse control disorders in patients with severe dyskinesia (P = 0.013), a positive correlation between the questionnaire total score and dopamine agonist dose (P = 0.018), and a trend with levodopa dose. CONCLUSIONS: More than half of Parkinson's disease patients with dyskinesia have impulse control disorders and related behaviors, which are frequently clinically significant. Dopaminergic therapy total dose is associated with their severity. Clinicians should carefully assess patients with maladaptive behaviors and dyskinesia because they do not properly evaluate their motor and nonmotor status. © 2017 International Parkinson and Movement Disorder Society.

Neurological complications of HIV infection in pre-HAART and HAART era: a retrospective study.

The introduction of highly active anti-retroviral therapy (HAART) led to a radical change in the natural history of HIV infection and of the associated neurological opportunistic infections. However, the mortality of central nervous system (CNS) complications and opportunistic infections is still high in untreated HIV-infected individuals or in patients unaware of their HIV infection. We describe the outcome of HIV-infected patients followed at a single center for AIDS-related neurological syndromes in the 16 years following the introduction of HAART, and compare the findings with those in patients admitted up to 1996. We have conducted a retrospective study of patients with HIV infection or AIDS (based on WHO criteria and classified according to the 1993 CDC criteria) admitted during 20 years (January 1992 to March 2012) to the Infectious Diseases Unit of the University of Verona for the presence of focal or widespread CNS lesion on neuroimaging. Clinical history, CD4 cell count, HIV-RNA level, neurological examination, imaging, cerebrospinal fluid examination and eventual cerebral biopsy results were reviewed as well as the final neurological diagnosis and the treatment. The survival time from the clinical onset of the neurologic syndrome to death was calculated for each patient who died. A statistical analysis was performed comparing data collected up to and after 1996, i.e., before and after HAART introduction. Among 1043 patients with HIV infection or AIDS admitted to the Infectious Diseases Unit of the University of Verona between January 1992 and March 2012, 114 had a CNS lesion. The following diseases were observed: neurotoxoplasmosis (NT), progressive multifocal leukoencephalopathy), primary central nervous system lymphoma (PCNSL), the severe form of HIV-associated neurocognitive disorder, cryptococcal encephalitis (CE) and lesions of undetermined origin. The follow-up period was 4 weeks to 72 months both in the pre-HAART and HAART era. Cerebral lesions were detected in 53/243 patients (21.8%) in the pre-HAART era and in 61/801 patients (7.6%) in the HAART era (p < 0.001). Most patients who developed a neurological complication in the HAART period (40/59, 67.8%) were untreated or did not know to be HIV-infected; in particular, 27.9% of patients with a CNS lesion in the HAART era were unaware of their HIV infection vs 13.2% in the pre-HAART era (p < 0.05). Some patients were not virologically suppressed (14/59, 23.7%) or were immunological non-responders (undetectable viral load, with CD4 count <200 cells/µL; 4/59, 6.8%). Other statistically significant data were the mean age at the onset of neurological complications (32.6 ± 5.4 years in the pre-HAART, 40.3 ± 9.5 in the HAART group, p < 0.001) and the mean CD4 cell count at the onset of illness (median of 38 cells/µL (2-215) in the pre-HAART, 77 cells/µL (2-752) in the HAART group; p < 0.001). In the HAART era a reduction of PCNSL and NT was observed. Our results, while confirming a decrease in the incidence of opportunistic infections of the CNS in the HAART era, show that late presentation of patients with HIV infection remains an important issue in our catchment area.

Late-onset multiple sclerosis presenting with cognitive dysfunction and severe cortical/infratentorial atrophy.

OBJECTIVE: Although cognitive dysfunction is a relevant aspect of multiple sclerosis (MS) from the earliest disease phase, cognitive onset is unusual thus jeopardizing early and accurate diagnosis. Here we describe 12 patients presenting with cognitive dysfunction as primary manifestation of MS with either mild or no impairment in non-cognitive neurological domains. METHODS: Twelve patients with cognitive onset who were subsequently diagnosed with MS (CI-MS) were included in this retrospective study. Twelve cognitively normal MS patients (CN-MS), 12 healthy controls and four patients having progressive supranuclear palsy (PSP) served as the reference population. RESULTS: Ten CI-MS patients had progressive clinical course and all patients had late disease onset (median age = 49 years; range = 40-58 years). Among cognitive functions, frontal domains were the most involved. Compared to CN-MS and healthy controls, significant cortical and infratentorial atrophy characterized CI-MS patients. Selective atrophy of midbrain tegmentum with relative sparing of pons, known as "The Hummingbird sign," was observed in eight CI-MS and in three PSP patients. DISCUSSION: Our observation suggests that MS diagnosis should be taken into consideration in case of cognitive dysfunction, particularly when associated with slowly progressive disease course and severe cortical, cerebellar and brainstem atrophy even in the absence of other major neurological symptoms and signs.

Imaging of the dopamine transporter predicts pattern of disease progression and response to levodopa in patients with schizophrenia and parkinsonism: a 2-year follow-up multicenter study.

Similarly to subjects with degenerative parkinsonism, (123)I-FP-CIT SPECT has been reported either normal or abnormal in patients with drug-induced parkinsonism (DIP), challenging the notion that parkinsonism might be entirely due to post-synaptic D2-receptors blockade by antipsychotic drugs. In a previous multicenter cross-sectional study conducted on a large sample of patients with schizophrenia, we identified 97 patients who developed parkinsonism with a similar bi-modal distribution of DAT-SPECT. In this longitudinal study, we reported clinical and imaging features associated with progression of motor disability over 2-year follow-up in 60 out of those 97 patients with schizophrenia and parkinsonism who underwent (123)I-FP-CIT SPECT at baseline evaluation (normal SPECT=33; abnormal SPECT=27). As second end-point, chronic response to levodopa over a 3-month period was tested in a subgroup of subjects. Motor Unified Parkinson's Disease Rating Scale (UPDRS) at follow-up significantly increased in patients with abnormal SPECT. Specifically, a 6-point worsening was demonstrated in 18.5% of the subjects with abnormal SPECT and in none of the subjects with normal SPECT. Levodopa treatment improved motor UPDRS only in the group with abnormal SPECT. After adjustment for possible confounders, linear regression analysis demonstrated that abnormal SPECT findings at baseline were the only predictor of motor disability progression and of better outcome of levodopa treatment. Our results support the notion that a degenerative disease might underlie parkinsonism in a minority of schizophrenic patients chronically exposed to antipsychotics. Functional imaging of the dopamine transporter can be helpful to select this patient sub-group that might benefit from levodopa therapy.

[¹²³I]FP-CIT single photon emission computed tomography findings in drug-induced Parkinsonism.

Drug-induced parkinsonism (DIP) in patients treated with antipsychotic drugs is considered a form of post-synaptic parkinsonism, caused by D2-receptor blockade. Recent studies, however, carried out on small and heterogeneous patient samples, have shown that DIP may be associated with [(123)I]FP-CIT single photon emission computed tomography (SPECT) abnormalities, which are markers of dopamine nigrostriatal terminal defect. In the present study, outpatients fulfilling the DSM-IV criteria for schizophrenia and treated with antipsychotics for at least 6 months, were enrolled in order to estimate the prevalence of DIP and, among patients with DIP, the prevalence of [(123)I]FP-CIT SPECT abnormalities. Socio-demographic and clinical variables associated with the presence of DIP and SPECT abnormalities were also assessed. DIP was diagnosed in 149 out of 448 patients with schizophrenia (33%). Age, use of long-acting antipsychotics and a positive family history of parkinsonism were the only demographic variables significantly associated with the development of DIP. Neuroimaging abnormalities were found in 41 of 97 patients who agreed to undergo [(123)I]FP-CIT SPECT (42%). Only age differentiated this group of patients from those with normal imaging. These preliminary findings suggest that D2-receptor blockade may coexist with a dopamine nigrostriatal terminal defect, as assessed by [(123)I]FP-CIT SPECT abnormalities, in a relevant proportion of DIP patients. Longitudinal studies should be designed with the aim of improving our understanding of the mechanisms of pre-synaptic abnormalities in DIP patients and identifying specific treatment strategies.