Charcot and hallucinations: A study in insight and blindness.

Jean-Martin Charcot (1825-1893) showed little interest in mental disorders, the domain of nineteenth-century alienists. But hallucinations are not confined to the field of psychiatry, and Charcot, who had once tested the hallucinogenic effects of hashish in his youth, went on to describe hallucinations in the course of various neurological conditions as just another semiological element. Most of his or his disciples' writings on hallucinations can be found in his work on hysteria. Hallucinations and delusions were part of "grand hysteria" and occurred at the end of the attack (third or fourth phase). Hypnosis or chemical agents could also induce hallucinations. Charcot and his disciples did not go so far as to emphasize the importance of hallucinations when they evoked past trauma, especially sexual trauma. Charcot's materialistic orientation led him and his disciples-especially D. M. Bourneville (1840-1909), G. Gilles de la Tourette (1857-1904), and the neurologist and artist P. Richer (1849-1833)-to seek hysteria in artistic representations of "possessed women" and in the visions of nuns and mystics. Finally, Charcot recognized the importance of hallucinations in neurological semiology, by means of precise and relevant observations scattered throughout his work. Preoccupied with linking hysteria to neurology, Charcot only scratched the surface of the possible significance of hallucinations in this context, paving the way for the work of his students Pierre Janet (1859-1947) and Sigmund Freud (1856-1939).

Volumetric changes and clinical trajectories in Parkinson's disease: a prospective multicentric study.

BACKGROUND: Longitudinal measures of structural brain changes using MRI in relation to clinical features and progression patterns in PD have been assessed in previous studies, but few were conducted in well-defined and large cohorts, including prospective clinical assessments of both motor and non-motor symptoms. OBJECTIVE: We aimed to identify brain volumetric changes characterizing PD patients, and determine whether regional brain volumetric characteristics at baseline can predict motor, psycho-behavioral and cognitive evolution at one year in a prospective cohort of PD patients. METHODS: In this multicentric 1 year longitudinal study, PD patients and healthy controls from the MPI-R2* cohort were assessed for demographical, clinical and brain volumetric characteristics. Distinct subgroups of PD patients according to motor, cognitive and psycho-behavioral evolution were identified at the end of follow-up. RESULTS: One hundred and fifty PD patients and 73 control subjects were included in our analysis. Over one year, there was no significant difference in volume variations between PD and control subjects, regardless of the brain region considered. However, we observed a reduction in posterior cingulate cortex volume at baseline in PD patients with motor deterioration at one year (p = 0.017). We also observed a bilateral reduction of the volume of the amygdala (p = 0.015 and p = 0.041) and hippocampus (p = 0.015 and p = 0.053) at baseline in patients with psycho-behavioral deterioration, regardless of age, dopaminergic treatment and center. CONCLUSION: Brain volumetric characteristics at baseline may predict clinical trajectories at 1 year in PD as posterior cingulate cortex atrophy was associated with motor decline, while amygdala and hippocampus atrophy were associated with psycho-behavioral decline.

Intrasubject subcortical quantitative referencing to boost MRI sensitivity to Parkinson's disease.

Several postmortem studies have shown iron accumulation in the substantia nigra of Parkinson's disease patients. Iron concentration can be estimated via MRI-R2∗ mapping. To assess the changes in R2∗ occurring in Parkinson's disease patients compared to controls, a multicentre transversal study was carried out on a large cohort of Parkinson's disease patients (n = 163) with matched controls (n = 82). In this study, 44 patients and 11 controls were removed due to motion artefacts, 21 patient and 6 controls to preserve matching. Thus, 98 patients and 65 age and sex-matched healthy subjects were selected with enough image quality. The study was conducted on patients with early to late stage Parkinson's disease. The images were acquired at 3Tesla in 12 clinical centres. R2∗ values were measured in subcortical regions of interest (substantia nigra, red nucleus, striatum, globus pallidus externus and globus pallidus internus) contralateral (dominant side) and ipsilateral (non dominant side) to the most clinically affected hemibody. As the observed inter-subject R2∗ variability was significantly higher than the disease effect, an original strategy (intrasubject subcortical quantitative referencing, ISQR) was developed using the measurement of R2∗ in the red nucleus as an intra-subject reference. R2∗ values significantly increased in Parkinson's disease patients when compared with controls; in the substantia nigra (SN) in the dominant side (D) and in the non dominant side (ND), respectively (PSN_D and PSN_ND < 0.0001). After stratification into four subgroups according to the disease duration, no significant R2∗ difference was found in all regions of interest when comparing Parkinson's disease subgroups. By applying our ISQR strategy, R2(ISQR)∗ values significantly increased in the substantia nigra (PSN_D and PSN_ND < 0.0001) when comparing all Parkinson's disease patients to controls. R2(ISQR)∗ values in the substantia nigra significantly increased with the disease duration (PSN_D = 0.01; PSN_ND = 0.03) as well as the severity of the disease (Hoehn & Yahr scale <2 and ≥ 2, PSN_D = 0.02). Additionally, correlations between R2(ISQR)∗ and clinical features, mainly related to the severity of the disease, were found. Our results support the use of ISQR to reduce variations not directly related to Parkinson's disease, supporting the concept that ISQR strategy is useful for the evaluation of Parkinson's disease.

Distinct functional classes of PDGFRB pathogenic variants in primary familial brain calcification.

Platelet-derived growth factor receptor beta (PDGFRB) is one of the genes associated with primary familial brain calcification (PFBC), an inherited neurological disease (OMIM:173410). Genetic analysis of patients and families revealed at least 13 PDGFRB heterozygous missense variants, including two novel ones described in the present report. Limited experimental data published on five of these variants had suggested that they decrease the receptor activity. No functional information was available on the impact of variants located within the receptor extracellular domains. Here, we performed a comprehensive molecular analysis of PDGFRB variants linked to PFBC. Mutated receptors were transfected in various cell lines to monitor receptor expression, signaling, mitogenic activity and ligand binding. Four mutants caused a complete loss of tyrosine kinase activity in multiple assays. One of the novel variants, p.Pro154Ser, decreased the receptor expression and abolished binding of platelet-derived growth factor (PDGF-BB). Others showed a partial loss of function related to reduced expression or signaling. Combining clinical, genetic and molecular data, we consider nine variants as pathogenic or likely pathogenic, three as benign or likely benign and one as a variant of unknown significance. We discuss the possible relationship between the variant residual activity, incomplete penetrance, brain calcification and neurological symptoms. In conclusion, we identified distinct molecular mechanisms whereby PDGFRB variants may result in a receptor loss of function. This work will facilitate genetic counseling in PFBC.

From Dreams to Hallucinations: Jean Lhermitte's Contribution to the Study of Peduncular Hallucinosis and the Dissociation of States.

Jean Lhermitte (1877-1959) was one of the pioneers of behavioral neurology, including the field of hallucinations. This article focuses on his work concerning the relationship between hallucinations, sleep, and dreams. From 1910, Lhermitte became interested in sleep and its disorders, particularly narcolepsy and its accompanying symptoms. He also reported on sleep disorders and hallucinations occurring in people with lesions of the diencephalic region ("infundibular syndrome"), and later encephalitis lethargica. In 1922, he described a syndrome of complex, predominantly visual hallucinations in patients with vascular damage to the midbrain, known as peduncular hallucinosis. Twelve historical cases of peduncular hallucinosis, including 10 from Lhermitte, are reviewed. He gave a precise phenomenological description of peduncular hallucinosis, and put forward the hypothesis that the lesion disrupted the anatomy and connections of a center regulating wakefulness and sleep, thus enabling a dissociation of the mechanisms of dream and waking states. Although the pathophysiology of peduncular hallucinosis remains to this day partly obscure, the model of a limited subcortical lesion acting through complex mechanisms and ultimately involving the cortex remains valid. Lhermitte was also a pioneer in characterizing what contemporary sleep specialists call dissociation of states.

Brain (18)F-FDG, (18)F-Florbetaben PET/CT, (123)I-FP-CIT SPECT and Cardiac (123)I-MIBG Imaging for Diagnosis of a "Cerebral Type" of Lewy Body Disease.

A 67-year-old man was referred for fluctuating neuropsychiatric symptoms, featuring depression, delirious episodes, recurrent visual hallucinations and catatonic syndrome associated with cognitive decline. No parkinsonism was found clinically even under neuroleptic treatment. (18)F-FDG PET/CT showed hypometabolism in the posterior associative cortex including the occipital cortex, suggesting Lewy body dementia, but (123)I-FP-CIT SPECT was normal and cardiac (123)I-MIBG imaging showed no signs of sympathetic denervation. Alzheimer's disease was excluded by a normal (18)F-florbetaben PET/CT. This report suggests a rare case of α-synucleinopathy without brainstem involvement, referred to as "cerebral type" of Lewy body disease.

The prevalence and characteristics of hallucinations, delusions and minor phenomena in a non-demented population sample aged 60 years and over.

OBJECTIVE: Psychotic phenomena can occur in non-clinical subjects. The goals of this study were to assess the prevalence of delusions, hallucinations and minor 'psychotic' phenomena (visual illusions, feeling of presence and passage hallucinations) and to describe the characteristics of the latter in a non-clinical older population. METHODS: Three hundred and thirteen individuals aged 60 years and older, without cognitive deficits (according to mini-mental state examination scores) or patent psychotic disease, answered a structured questionnaire focusing on delusions, hallucinations and minor phenomena that they had experienced in the previous month. The study sample was stratified by age and gender according to French demographic characteristics. RESULTS: Twenty per cent of participants reported one or more psychotic phenomena. These subjects did not differ from those without psychotic symptoms as regards their age, mini-mental state examination scores or education. Minor phenomena were the most common (13%). Hallucinations, in any sensory modality, occurred in 9% of participants. No verbal auditory hallucinations or delusions were reported. The prevalence of minor phenomena increased with age and was associated with the use of psychoactive drugs. CONCLUSION: By extending the spectrum of psychotic symptoms to minor phenomena, we found that psychotic symptoms were common in a non-clinical older population. Whether the increasing prevalence of minor phenomena with age is due to prodromal neurodegenerative disease or to other factors remains to be investigated. Copyright © 2016 John Wiley & Sons, Ltd.

Clinical routine use of dopamine transporter imaging in 516 consecutive patients.

[(123)I]-FP-CIT is a single photon emission computed tomography (SPECT) ligand showing in vivo the loss of dopaminergic terminals in the brain and is now available in the market. Despite several systematic studies in clinically inconclusive cases, the use of such imaging in clinical routine is scarcely reported. We analyzed 516 files of subjects with movement disorders who were consecutively examined using [(123)I]-FP-CIT scan and determined whether the use of imaging was appropriate and if it improved clinical diagnosis or care of the patient. In addition, we determined if appropriate use was related to subspecialties in Neurology, e.g., movement disorders' specialists vs. general neurologists, and if appropriate use was increasing over time. Among the 516 scans, 18% were in agreement with the license, 62% were classified as appropriate and 37% were considered inappropriate. A change of management was obvious in 60% of patients, but in 92% of those with an appropriate request vs. 13% of patients with an inappropriate request. Movement disorders' specialists had more appropriate requests than other practitioners. Eventually, comparing the first 100 vs. the last 100 quantified SPECT, performed more than 2.5 years apart, we found no difference for the appropriateness of the examination. The use of [(123)I]-FP-CIT imaging in clinical routine does not fit a restrictive license. An inappropriate use is seen in nearly 40% of cases, which reduces the real cost-effectiveness of the technique suggesting a need for continuing medical education on the topic.

Spinal stimulation for movement disorders.

Epidural spinal cord stimulation (SCS) is currently proposed to treat intractable neuropathic pain. Since the 1970s, isolated cases and small cohorts of patients suffering from dystonia, tremor, painful leg and moving toes (PLMT), or Parkinson's disease were also treated with SCS in the context of exploratory clinical studies. Despite the safety profile of SCS observed in these various types of movement disorders, the degree of improvement of abnormal movements following SCS has been heterogeneous among patients and across centers in open-label trials, stressing the need for larger, randomized, double-blind studies. This article provides a comprehensive review of both experimental and clinical studies of SCS application in movement disorders.

Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial.

BACKGROUND: Parkinson's disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinson's disease. METHODS: We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×10(7) transducing units [TU]); mid dose (4·0×10(7) TU); and high dose (1×10(8) TU). Inclusion criteria were age 48-65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439. FINDINGS: 15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on-off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline. INTERPRETATION: ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients. FUNDING: Oxford BioMedica.

Awareness of memory deficits in early stage Huntington's disease.

Patients with Huntington's disease (HD) are often described as unaware of their motor symptoms, their behavioral disorders or their cognitive deficits, including memory. Nevertheless, because patients with Parkinson's disease (PD) remain aware of their memory deficits despite striatal dysfunction, we hypothesize that early stage HD patients in whom degeneration predominates in the striatum can accurately judge their own memory disorders whereas more advanced patients cannot. In order to test our hypothesis, we compared subjective questionnaires of memory deficits (in HD patients and in their proxies) and objective measures of memory dysfunction in patients. Forty-six patients with manifest HD attending the out-patient department of the French National Reference Center for HD and thirty-three proxies were enrolled. We found that HD patients at an early stage of the disease (Stage 1) were more accurate than their proxies at evaluating their own memory deficits, independently from their depression level. The proxies were more influenced by patients' functional decline rather than by patients' memory deficits. Patients with moderate disease (Stage 2) misestimated their memory deficits compared to their proxies, whose judgment was nonetheless influenced by the severity of both functional decline and depression. Contrasting subjective memory ratings from the patients and their objective memory performance, we demonstrate that although HD patients are often reported to be unaware of their neurological, cognitive and behavioral symptoms, it is not the case for memory deficits at an early stage. Loss of awareness of memory deficits in HD is associated with the severity of the disease in terms of CAG repeats, functional decline, motor dysfunction and cognitive impairment, including memory deficits and executive dysfunction.

Can nicotine be used medicinally in Parkinson's disease?

The risk of Parkinson's disease is reduced by cigarette smoking, which raises some unanswered questions. Nicotine, a major component of tobacco smoke, could exert either nonreceptor-mediated biological effects or, more importantly, act on the different subtypes of nicotinic brain receptors, in particular those associated with the nigrostriatal dopaminergic pathway. There is now robust experimental evidence for a neuroprotective effect of nicotine upon dopaminergic neurons. By contrast, in animal models of Parkinson's disease, nicotine alone has slight or no motor effects. However, nicotine may modulate dopamine transmission and has clear motor effects when associated with L-DOPA, reducing L-DOPA-induced dyskinesias. Clinical trials have yielded inconclusive results thus far and are hampered by different designs and small cohorts. Ongoing studies address either symptomatic motor or nonmotor symptoms, or neuroprotection. There is still no agreement on the daily dosage of nicotine or the method of administration. Together, these data suggest that nicotine or nicotinic receptor drugs have therapeutic potential for Parkinson's disease, although the specific treatment regimens remain to be determined.

Depression and coping as predictors of change after deep brain stimulation in Parkinson's disease.

BACKGROUND: This study examined changes in motor function and quality of life (QoL) after subthalamic nuclei deep brain stimulation (STN-DBS) in patients with Parkinson disease (PD) and the role of psychosocial predictors on individual changes. METHODS: Forty-one patients with advanced PD (29 men and 12 women; mean age: 62.0 ± 8.0; disease duration: 14.5 ± 5.7) completed self-report questionnaires before surgery and at 6 and 12 months after surgery. Psychosocial measures assessed coping strategies (Ways of Coping Checklist-Revised), symptoms of depression (Beck Depression Inventory version II), anxiety (State-Trait Anxiety Inventory), and QoL (Parkinson Disease Questionnaire 39 Items, Medical Outcomes Study 36-Item Short-Form Health Survey). RESULTS: After surgery, motor function (Unified Parkinson Disease Rating Scale III and IV), global QoL (Parkinson Disease Questionnaire 39 Items) and Physical Component Summary of the Medical Outcome Study Short Form 36-items Health Survey improved, whereas the Mental Component Summary tended to deteriorate. Depression and anxiety were stable. Improvements in motor function and QoL were associated with younger age, shorter duration of illness, higher baseline distress (depression and anxiety), and changes in problem-focused coping. Improvements in mental QoL were associated with a less frequent use of coping focused on seeking social support. CONCLUSIONS: STN-DBS is associated with major positive changes in PD affecting motor function and QoL. These changes are related to psychological variables, including emotional distress and coping. A better focus on these individual characteristics is necessary to improve care of patients with PD who undertake STN-DBS.

Feeling of presence in Parkinson's disease.

BACKGROUND: A feeling of presence (FP), that is, the vivid sensation that somebody (distinct from oneself) is present nearby, is commonly reported by patients with Parkinson's disease (PD), but its phenomenology has not been described precisely. The objective of this study was to provide a detailed description of FP in PD and to discuss its possible mechanisms. PATIENTS AND METHODS: The authors studied 52 non-demented PD patients reporting FP in the preceding month (38 consecutive outpatients and 14 inpatients). FP characteristics were recorded with a structured questionnaire. The outpatients with FP were compared with 78 consecutive outpatients without FP. RESULTS: About half the patients said they recognised the 'identity' of the presence. More than 75% of patients said the FP were not distressing, were short-lasting, were felt beside and/or behind the patient, and occurred while indoors; most patients checked for a real presence, but their insight was generally preserved. In 31% of cases, the patients had an unformed visual hallucination simultaneously with the FP. A higher daily levodopa-equivalent dose and the presence of visual illusions or hallucinations were independently associated with FP. DISCUSSION: Although FP is not a sensory perception, projection of the sensation into the extrapersonal space, along with the frequent co-occurrence of elementary visual hallucinations and the strong association with visual hallucinations or illusions, supports its hallucinatory nature. FP may be viewed as a 'social' hallucination, involving an area or network specifically activated when a living being is present, independently of any perceptual clue.

A reappraisal of long-latency abdominal muscle reflexes in patients with propriospinal myoclonus.

BACKGROUND: We report 3 patients with typical clinical and electrophysiological characteristics of propriospinal myoclonus propagating from a thoracic spine generator. METHODS: In these patients, the pattern of recruitment of long-latency electromyographic reflexes in abdominal muscles was studied in response to various stimuli. RESULTS: Abdominal reflex latency varied from 60 to 140 ms depending on stimulus location. Latency increased from magnetic stimulation of the thoracic spine to electrical stimulation of the supraorbital nerve, electrical stimulation of the median nerve, and magnetic stimulation of the motor cortex. CONCLUSIONS: Long-latency abdominal reflex jerks are probably controlled by the brain stem to propriospinal system projections in patients with propriospinal myoclonus. The stereotyped pattern of recruitment of these reflexes could be of clinical utility to differentiate organic propriospinal myoclonus from psychogenic or mimicked jerks.

Disruption of cigarette smoking addiction after posterior cingulate damage.

The authors describe the case of a 35-year-old woman with a history of an addiction to cigarette smoking who presented with an intracerebral hemorrhage from a ruptured arteriovenous malformation. The patient reported an immediate and complete disruption of her addiction to cigarette smoking following her stroke. Structural MR imaging revealed a lesion of the posterior cingulate cortex. Neuropsychological tests showed intact cognitive functioning. This observation suggests that the posterior cingulate cortex may play a role in the addiction to cigarette smoking.