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The term “Gilles de la Tourette syndrome”, or the more commonly used term “Tourette syndrome” (TS) refers to the association of motor and phonic tics which evolve in a context of variable but frequent psychiatric comorbidity. The syndrome is characterized by the association of several motor tics and at least one phonic tic that have no identifiable cause, are present for at least one year and appear before the age of 18. The presence of coprolalia is not necessary to establish or rule out the diagnosis, as it is present in only 10% of cases. The diagnosis of TS is purely clinical and is based on the symptoms defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). No additional tests are required to confirm the diagnosis of TS. However, to exclude certain differential diagnoses, further tests may be necessary. Very frequently, one or more psychiatric comorbidities are also present, including attention deficit hyperactivity disorder, obsessive-compulsive disorder, anxiety, explosive outbursts, self-injurious behaviors, learning disorders or autism spectrum disorder. The condition begins in childhood around 6 or 7 years of age and progresses gradually, with periods of relative waxing and waning of tics. The majority of patients experience improvement by the end of the second decade of life, but symptoms may persist into adulthood in around one-third of patients. The cause of TS is unknown, but genetic susceptibility and certain environmental factors appear to play a role. The treatment of TS and severe forms of tics is often challenging and requires a multidisciplinary approach (involving the general practitioner (GP), pediatrician, psychiatrist, neurologist, school or occupational physicians, psychologist and social workers). In mild forms, education (of young patients, parents and siblings) and psychological management are usually recommended. Medical treatments, including antipsychotics, are essential in the moderate to severe forms of the disease (i.e. when there is a functional and/or psychosocial discomfort linked to tics). Over the past decade, cognitive-behavioral therapies have been validated for the treatment of tics. For certain isolated tics, botulinum toxin injections may also be useful. Psychiatric comorbidities, when present, often require a specific treatment. For very severe forms of TS, treatment by deep brain stimulation offers real therapeutic hope. If tics are suspected and social or functional impairment is significant, specialist advice should be sought, in accordance with the patient's age (psychiatrist/child psychiatrist; neurologist/pediatric neurologist). They will determine tic severity and the presence or absence of comorbidities. The GP will take over the management and prescription of treatment: encouraging treatment compliance, assessing side effects, and combating stigmatization among family and friends. They will also play an important role in rehabilitation therapies, as well as in ensuring that accommodations are made in the patient's schooling or professional environment.

Chronic constipation is one of the most frequent non-motor symptoms in Parkinson's disease (PD), and impairs patients’ quality of life.

Parkinson's disease (PD) is a complex, age-related, neurodegenerative disease whose pathogenesis remains incompletely understood. Here, we give an overview of the progress that has been made over the past four decades in our understanding of this disorder. We review the role of mitochondria, environmental toxicants, alpha-synuclein and neuroinflammation in the development of PD. We also discuss more recent data from genetics, which strongly support the endosomal-lysosomal pathways and mitophagy as being central to PD. Finally, we discuss the emerging role of the gut-brain axis as a modulator of PD progression. This article is intended to provide a comprehensive, general and practical review of PD pathogenesis for the general neurologist.

Twenty-four Parkinson's disease (PD) patients who had planned to fast during the 2016 Ramadan were included in this observational study. Twenty patients fasted during the whole Ramadan. Six were able to abstain from drug intakes from dawn to dusk; the others needed 1 or 2 intakes of L-DOPA during the day. There were no serious side effects reported during the Ramadan period. Compared to before Ramadan, there were no significant changes after the fasting period in quality of life (PDQ 39), non-motor symptom scale or clinical impression of severity index scores.

The proven effectiveness of neuromodulation and stimulation techniques for the management of psychiatric disorders has brought strongly needed innovation in psychiatry, given the high prevalence and high costs of treatment resistance. Although evidence-based guidelines in neuromodulation have been implemented to improve the clinical efficacy, safety, and research procedures, practical suggestions on how to design a psychiatric neuromodulation unit (PNU) are not available in the scientific literature. In this contribution, we have combined the results of a literature search with the suggestions of clinical psychiatrists, managers, and bioethicists who have had firsthand experience in building a PNU. Eleven key issues concerning the implementation and management of a PNU were identified: general context, team composition, environment, basic technical equipment, clinical versus research activities, target clinical population, education and training, interdisciplinarity, ethical aspects, regulatory and reimbursement issues, fund-raising, and partnership development. Moreover, a business plan comprising pragmatic solutions and recommendations for designing an efficient PNU was laid out.

IMPORTANCE: Brain hypometabolism is associated with the clinical consequences of the degenerative process, but little is known about regional hypermetabolism, sometimes observed in the brain of patients with clinically manifest Huntington disease (HD). Studying the role of regional hypermetabolism is needed to better understand its interaction with the motor symptoms of the disease. OBJECTIVE: To investigate the association between brain hypometabolism and hypermetabolism with motor scores of patients with early HD. DESIGN, SETTING, AND PARTICIPANTS: This study started in 2001, and analysis was completed in 2016. Sixty symptomatic patients with HD and 15 healthy age-matched control individuals underwent positron emission tomography to measure cerebral metabolism in this cross-sectional study. They also underwent the Unified Huntington’s Disease Rating Scale motor test, and 2 subscores were extracted: (1) a hyperkinetic score, combining dystonia and chorea, and (2) a hypokinetic score, combining bradykinesia and rigidity. MAIN OUTCOMES AND MEASURES: Statistical parametric mapping software (SPM5) was used to identify all hypo- and hypermetabolic regions in patients with HD relative to control individuals. Correlation analyses (P < .001, uncorrected) between motor subscores and brain metabolic values were performed for regions with significant hypometabolism and hypermetabolism. RESULTS: Among 60 patients with HD, 22 were women (36.7%), and the mean (SD) age was 44.6 (7.6) years. Of the 15 control individuals, 7 were women (46.7%), and the mean (SD) age was 42.2 (7.3) years. In statistical parametric mapping, striatal hypometabolism was significantly correlated with the severity of all motor scores. Hypermetabolism was negatively correlated only with hypokinetic scores in the cuneus (z score = 3.95, P < .001), the lingual gyrus (z score = 4.31, P < .001), and the crus I/II of the cerebellum (z score = 3.77, P < .001), a region connected to associative cortical areas. More severe motor scores were associated with higher metabolic values in the inferior parietal lobule, anterior cingulate, inferior temporal lobule, the dentate nucleus, and the cerebellar lobules IV/V, VI, and VIII bilaterally corresponding to the motor regions of the cerebellum (z score = 3.96 and 3.42 in right and left sides, respectively; P < .001). CONCLUSIONS AND RELEVANCE: Striatal hypometabolism is associated with clinical disease severity. Conversely, hypermetabolism is likely compensatory in regions where it is associated with decreasing motor scores. Hypermetabolism might be detrimental in other structures in which it is associated with more severe motor symptoms. In the cerebellum, both compensatory and detrimental contributions seem to occur. This study helps to better understand the motor clinical relevance of hypermetabolic brain regions in HD.

IMPORTANCE: Every year, Ramadan fasting is practiced by many Muslim individuals. In cases of chronic disease, religious texts allow fasting to be broken. However, many believers still want to fast even at the risk of damaging their health. To our knowledge, there are no published recommendations on the medical management of Parkinson disease (PD) during Ramadan. Effective treatments exist in PD and usually require several daily drug intakes. Apart from worsening symptoms, interrupting PD treatment might lead to a severe withdrawal syndrome. OBSERVATIONS: Although no specific studies on this topic have led to formal recommendations, we suggest some options for adapting the treatment for patients who fast during Ramadan. The general principle is based on switching the patient’s treatment to an equivalent dosage of a dopamine agonist that can be administered once daily or by transdermal patch. However, such an option is only feasible for patients who require a moderate amount of PD treatment and can tolerate dopamine agonist therapy. CONCLUSIONS AND RELEVANCE: Because many patients with PD require regular multiple daily administration of dopamine-replacement medication, the management of Ramadan fasting is not easy. Switching the patient’s treatment to an equivalent dosage of a dopamine agonist that can be administered once daily or by transdermal patch seems to be a reasonable option to consider for patients treated with a low-to-moderate amount of PD medication.

Neuroleptics are known to induce Parkinsonism, tardive dyskinesia and their long-term use was associated with increased risk of hip fractures and impaired cognitive function and even death. The primary objective of Neurodem study was to determine the IAI of patients with Alzheimer’s disease in French NH. 1022 patients were enrolled. The IAI was 24.8 %. Multivariate logistic analysis showed that having a severe form of dementia, resident without MMS evaluation the last 12 months and having a prescription for an anxiolytic drug were associated with a higher risk of having a prescription for an antipsychotic drug. The results from our study show that the percentage of patients receiving an antipsychotic drug (24.8 %) was higher than the national average (18 %). Effective educational activities about appropriate use of antipsychotic drugs in patients with Alzheimer’s disease are needed.

Le traitement dopaminergique est remarquablement efficace pour corriger l’essentiel des symptômes de la maladie de Parkinson (MP). Après quelques années de traitement, il se complique toutefois, chez un grand nombre de patients, de fluctuations d’efficacité invalidantes, à savoir par la réapparition des symptômes parkinsoniens au cours de la journée. L’identification des facteurs de risque de développement des fluctuations et l’analyse du profil de tolérabilité dopaminergique des patients permettent d’esquisser une personnalisation de la stratégie thérapeutique. De façon schématique, les patients les plus à risque de développement de fluctuations sont ceux qui présentent des formes de MP à début précoce, purement dopaminergique, akinéto-rigide et avec une symptomatologie à prédominance périphérique. Ces sujets ont pour la plupart une tolérabilité a priori satisfaisante aux divers traitements antiparkinsoniens. La stratégie thérapeutique utilise tout l’arsenal à disposition pour corriger de façon optimale et prévenir, dès le traitement initial, la survenue des fluctuations afin d’éviter le développement à terme de complications motrices invalidantes. À l’opposé, les patients qui ne présentent pas ces caractéristiques sont à moindre risque de fluctuations. Ils sont par contre souvent exposés à une tolérabilité a priori moins bonne aux traitements antiparkinsoniens. Chez ces patients la stratégie repose sur une approche pragmatique, basée surtout sur la l-dopa, pour réduire au maximum le risque d’effets indésirables des médicaments dopaminergiques.

Our knowledge of the cerebral bases of decision making has grown considerably in the past decade. The dopamine system is closely involved in many aspects of the decisional process. It is therefore not surprising that the dysfunctions that occur in Parkinson’s disease (PD) can alter some patients’ decisions. Put simply, a decision is the final step of a process in which a subject weighs up the potential benefits and costs associated with each of the different options available for a given choice. The option that appears to have the best ratio of benefits to costs is chosen. In some PD patients, dopamine agonists destabilize the balance: the benefits are given an inappropriately high weighting relative to the costs, leading patients to take decisions they would not otherwise have taken. This might be one of the explanations for impulse control disorders observed in some PD patients. Dysfunction of the subthalamic nucleus (STN) induced by dopamine replacement or by deep brain stimulation is another mechanism that can alter decision making. The STN plays an active role in the decisional process, especially by slowing down the process when the difference between the options to be considered in a given choice is small (e.g. a win-win choice). Deep brain stimulation applied to the STN may interfere with its monitoring role and lead to an impulsive choice. Attention disorders and frontal lobe dysfunction, highly prevalent in the course of PD, are other factors that may alter a patient’s decision making. Patients and caregivers need to be aware of this, since the consequences can sometimes be detrimental.

IMPORTANCE: Freezing of gait (FOG) is a common axial symptom of Parkinson disease (PD). OBJECTIVE: To determine the prevalence of FOG in a large group of PD patients, assess its relationship with quality of life and clinical and pharmacological factors, and explore its changes from the off to on conditions in patients with motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional survey of 683 patients with idiopathic PD. Scores for FOG were missing in 11 patients who were not included in the analysis. Patients were recruited from referral centers and general neurology clinics in public or private institutions in France. EXPOSURE: Patients with FOG were identified as those with a score of 1 or greater on item 14 of the Unified Parkinson’s Disease Rating Scale (UPDRS) in the on condition. Item 14 scores for FOG in the off condition were also collected in patients with fluctuating motor symptoms. MAIN OUTCOMES AND MEASURES: Quality of life (measured by the 39-item Parkinson’s Disease Questionnaire and 36-Item Short Form Health Survey), anxiety and depression (Hospital Anxiety and Depression Scale), clinical features (UPDRS), and drug consumption. RESULTS: Of 672 PD patients, 257 reported FOG during the onstate (38.2%), which was significantly related to lower quality of life scores (P < .01). Freezing of gait was also correlated with longer PD duration (odds ratio, 1.92 [95% CI, 1.28-2.86]), higher UPDRS parts II and III scores (4.67 [3.21-6.78]), the presence of apathy (UPDRS item 4) (1.94 [1.33-2.82]), a higher levodopa equivalent daily dose (1.63 [1.09-2.43]), and more frequent exposure to antimuscarinics (3.07 [1.35-6.97]) (logistic regression). The FOG score improved from the off to on states in 148 of 174 patients with motor fluctuations (85.1%) and showed no change in 13.8%. The FOG score improved by more than 50% in 43.7% of patients. Greater improvement in the on state was observed in younger patients (r = −0.25; P < .01) with lower UPDRS II and III scores (r = −0.50; P < .01) and no antimuscarinic use (r = −0.21; P < .01). CONCLUSIONS AND RELEVANCE: Freezing of gait in PD patients correlates with poor quality of life, disease severity, apathy, and exposure to antimuscarinics. Dopaminergic therapy improved FOG in most patients with motor fluctuations, especially younger ones with less severe disease and no antimuscarinic use. This finding suggests that quality of life is impaired in PD patients with FOG and that optimizing dopaminergic therapy and avoiding antimuscarinics should be considered.

The AMANDYSK trial was designed to assess long-term efficacy of chronic treatment with amantadine in patients with Parkinson disease (PD) and levodopa-induced dyskinesia (LID).

La physiopathologie de l’hydrocéphalie chronique de l’adulte (HCA) implique probablement des processus neurodégénératifs. Contrairement à la maladie d’Alzheimer (MA) l’association avec la dégénérescence lobaire frontotemporale comportementale (DLFTc) est peu décrite.

Relying on recent experimental data in 2 animal models of Parkinson disease (PD), we have tested the effects of the loop diuretic bumetanide as an add-on treatment to dopaminergic drugs in 4 volunteered patients with PD using the Unified Parkinson's Disease Rating Scale. Bumetanide is a specific antagonist of the chloride importer NKCC1 (sodium/potassium/chloride cotransporter isoform 1) that ameliorates neuronal inhibition by reducing intracellular chloride levels in a variety of pathological conditions. Bumetanide is however not labeled for use in PD. We report an improvement of PD motor symptoms in the 4 patients treated with bumetanide (5 mg/d for 2 months). Bumetanide also improved gait and freezing in 2 of these patients. Our results suggest that bumetanide is well tolerated and call for double-blind, placebo-controlled, randomized trials to confirm the therapeutic efficacy of bumetanide.

Recent studies have improved our knowledge of the factors responsible for the development of dyskinesias in Parkinson's disease and the associated pathophysiology. Deep brain stimulation has been shown to be effective to treat severe tardive dyskinesias. This review highlights some recent findings related to levodopa-induced and antipsychotic-induced dyskinesias.

Introduction. In Parkinson’s disease (PD), the quality of life of both patients and caregivers is affected. While key issues relating to quality of life may not emerge in conversations with healthcare professionals (HCPs), unguarded social media conversations can provide insight into how people with Parkinson’s disease (PwPD) and their caregivers are affected. We conducted a qualitative and quantitative netnographic study of PD conversations posted on social media sites over a 12-month period. Objective. To identify key themes and issues for PwPD. Methods. Using predefined and piloted search terms, we identified 392,962 social media posts (between March 31, 2020, and March 31, 2021, for the UK and France, and between September 30, 2019, and March 31, 2021, for Italy, Spain, and Germany). A random sample of these posts was then analyzed using natural language processing (NLP), and quantitative, qualitative,in-depth contextual analysis was also performed. Results. Key themes that emerged in the PD conversation related to the changing experience of symptoms over time are the physical, emotional, and cognitive impact of symptoms, the management and treatment of PD, disease awareness among the general public, and the caregiver burden. The emotional impact of motor symptoms on PwPD is significant, particularly when symptoms increase and PwPD lose their independence, which may exacerbate existing anxiety and depression. Nonmotor symptoms can also compound the difficulties with managing the physical impact of motor symptoms. The burden of nonmotor symptoms is felt by both PwPD and their caregivers, with the impact of nonmotor symptoms on cognitive processes particularly frustrating for caregivers. The experience of off-time was also featured in the online conversation. Some PwPD believe there is a lack of adequate management from healthcare professionals, who may not appreciate their concerns or take sufficient time to discuss their needs. Conclusion. This study identified key themes that PwPD and their caregivers discuss online. These findings help signpost issues of importance to PwPD and areas in which their care may be improved.

BACKGROUND Tourette syndrome (TS) is thought to result from dysfunction of the associative-limbic territories of the basal ganglia, and patients with severe symptoms of TS respond poorly to medication. High-frequency stimulation has recently been applied to patients with TS in open studies using the centromedian-parafascicular complex (CM-Pf) of the thalamus, the internal globus pallidus (GPi), or the anterior limb of the internal capsule as the principal target. OBJECTIVE To report the effect of high-frequency stimulation of the CM-Pf and/or the GPi, 2 associative-limbic relays of the basal ganglia, in patients with TS. DESIGN Controlled, double-blind, randomized crossover study. SETTING Medical research. PATIENTS Three patients with severe and medically refractory TS. INTERVENTION Bilateral placement of stimulating electrodes in the CM-Pf (associative-limbic part of the thalamus) and the GPi (ventromedial part). MAIN OUTCOME MEASURES Effects of thalamic, pallidal, simultaneous thalamic and pallidal, and sham stimulation on neurologic, neuropsychological, and psychiatric symptoms. RESULTS A dramatic improvement on the Yale Global Tic Severity Scale was obtained with bilateral stimulation of the GPi (reduction in tic severity of 65%, 96%, and 74% in patients 1, 2, and 3, respectively). Bilateral stimulation of the CM-Pf produced a 64%, 30%, and 40% reduction in tic severity, respectively. The association of thalamic and pallidal stimulation showed no further reduction in tic severity (60%, 43%, and 76%), whereas motor symptoms recurred during the sham condition. No neuropsychological, psychiatric, or other long-term adverse effect was observed. CONCLUSIONS High-frequency stimulation of the associative-limbic relay within the basal ganglia circuitry may be an effective treatment of patients with TS, thus heightening the hypothesis of a dysfunction in these structures in the pathophysiologic mechanism of the disorder. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00139308Arch Neurol. 2008;65(7):952-957--

To clarify the clinical and neurophysiologic spectrum of myoclonus–dystonia patients with mutations of the SGCEgene.

ABSTRACTWe have identified a second resistance-nodulation-cell division (RND)-type efflux pump, AdeIJK, in clinical isolate Acinetobacter baumanniiBM4454. The adeI, adeJ, and adeKgenes encode, respectively, the membrane fusion, RND, and outer membrane components of the pump. AdeJ belongs to the AcrB protein family (57% identity with AcrB from Escherichia coli). mRNA analysis by Northern blotting and reverse transcription-PCR indicated that the genes were cotranscribed. Overexpression of the cloned adeIJKoperon was toxic in both E. coliand Acinetobacter. The adeIJKgenes were detected in all of the 60 strains of A. baumanniitested. The two latter observations suggest that the AdeIJK complex might contribute to intrinsic but not to acquired antibiotic resistance in Acinetobacter. To characterize the substrate specificity of the pump, we have constructed derivatives of BM4454 in which adeIJK(strain BM4579), adeABC(strain BM4561), or both groups of genes (strain BM4652) were inactivated by deletion-insertion. Determination of the antibiotic susceptibility of these strains and of BM4652 and BM4579, in which the adeIJKoperon was provided in trans, indicated that the AdeIJK pump contributes to resistance to β-lactams, chloramphenicol, tetracycline, erythromycin, lincosamides, fluoroquinolones, fusidic acid, novobiocin, rifampin, trimethoprim, acridine, safranin, pyronine, and sodium dodecyl sulfate. The chemical structure of these molecules suggests that amphiphilic compounds are the preferred substrates. The AdeABC and AdeIJK efflux systems contributed in a more than additive fashion to tigecycline resistance.

L’association de l’hydrocéphalie chronique de l’adulte (HCA) et de la dégénérescence lobaire fronto-temporale comportementale (DLFTc) est peu rapportée dans la littérature.

ABSTRACTThe AdeABC pump of Acinetobacter baumanniiBM4454, which confers resistance to various antibiotic classes including aminoglycosides, is composed of the AdeA, AdeB, and AdeC proteins; AdeB is a member of the RND superfamily. The adeA, adeB, and adeCgenes are contiguous and adjacent to adeSand adeR, which are transcribed in the opposite direction and which specify proteins homologous to sensors and regulators of two-component systems, respectively (S. Magnet, P. Courvalin, and T. Lambert, Antimicrob. Agents Chemother. 45:3375-3380, 2001). Analysis by Northern hybridization indicated that the three genes were cotranscribed, although mRNAs corresponding to adeABand adeCwere also present. Cotranscription of the two regulatory genes was demonstrated by reverse transcription-PCR. Inactivation of adeSled to aminoglycoside susceptibility. Transcripts corresponding to adeABwere not detected in susceptible A. baumanniiCIP 70-10 but were present in spontaneous gentamicin-resistant mutants obtained in vitro. Analysis of these mutants revealed the substitutions Thr153→Met in AdeS downstream from the putative His-149 site of autophosphorylation, which is presumably responsible for the loss of phosphorylase activity by the sensor, and Pro116→Leu in AdeR at the first residue of the α5helix of the receiver domain, which is involved in interactions that control the output domain of response regulators. These mutations led to constitutive expression of the pump and, thus, to antibiotic resistance. These data indicate that the AdeABC pump is cryptic in wild A. baumanniidue to stringent control by the AdeRS two-component system.

Multiple sclerosis is an inflammatory demyelinating disease of the CNS associated with T cells autoreactive for myelin components. In this study, we analysed the T‐cell receptor (TCR) usage of the variable β (Vβ) chain transcriptome in the blood of multiple sclerosis patients at various stages of the disease using a global and quantitative comparison of the complementarity‐determining region 3 length distribution (CDR3‐LD) of transcripts of the 26 Vβ genes. We investigated 35 patients: 12 with a high risk of multiple sclerosis, 10 with clinically definite multiple sclerosis, 13 with a relapsing–remitting worsening and active multiple sclerosis and 13 healthy individuals. Cells bearing the TCR transcripts with altered CDR3‐LD were sorted and studied for CD4 or CD8 phenotype, cytokine transcript accumulation and response to human myelin basic protein (MBP). We show that patients from all the groups have a significantly skewed blood T‐cell repertoire. Vβ transcriptome patterns were more altered in patients from the clinically definite multiple sclerosis group and the worsening and active multiple sclerosis group than in the high risk group. The T cells sorted from Vβ families with altered CDR3‐LD concerned both CD4 and CD8 T cells, with a more pronounced skewing in the CD8 compartment. These cells displayed a significantly increased level of interferon‐γ, interleukin‐2 and tumour necrosis factor‐α transcripts compared with their counterparts from the healthy individual group. Furthermore, using interferon‐γ enzyme‐linked immunospot (ELISPOT) assays, T cells from four out of seven altered Vβ families tested from multiple sclerosis patients responded to human MBP, whereas no response was observed with human albumin or with altered Vβ families from healthy individuals. Our data support the concept of an early autoimmune component in the disease and emphasize the possible involvement of CD8‐positive T cells in multiple sclerosis.

The pathogenesis of the motor fluctuations and dyskinesias that complicate levodopa treatment for Parkinson's disease (PD) remains uncertain. To evaluate the relationship between the degree of dopamine neuron loss and the severity of dyskinesias in a rodent model of PD, Sprague-Dawley rats were lesioned unilaterally using different doses of 6-hydroxydopamine injected into the substantia nigra pars compacta (SNc). All rats received two daily oral doses of levodopa for one month. In most of the animals chronic levodopa administration induced abnormal involuntary movements (AIMs), which were in some respects similar to human dyskinesias. We found that a minimum dopamine cell loss of around 95 was required for the development of dyskinesias after one-month of levodopa treatment. Moreover, we observed a positive relationship between the percentage dopaminergic cell loss in the SNc and the severity of levodopa-induced AIMs.

Objective: To describe a reversible neurological condition resembling a crossed midbrain syndrome resulting from high frequency stimulation (HFS) in the midbrain. Methods: Postoperative evaluation of quadripolar electrodes implanted in the area of the subthalamic nucleus of 25 patients with Parkinson's disease (PD) successfully treated by HFS. Results: Four of the 25 patients experienced reversible acute diplopia, with dystonic posture and tremor in the contralateral upper limb when the white matter between the red nucleus and the substantia nigra was stimulated. The motor signs resembled those caused by lesions of the red nucleus. The ipsilateral resting eye position was "in and down" (three patients) or "in" (one patient). Enophthalmos was seen. Abduction was impaired and vertical eye movements were limited, but adduction was spared. The movements of the controlateral eye were normal. The ocular signs could be best explained by sustained hyperactivity of the extrinsic oculomotor nerve. Simultaneous tonic contraction of the superior rectus, the inferior rectus, and inferior oblique may cause the enophthalmos and partial limitation of upward and downward eye movements. Antagonist tonic contraction of the ipsilateral medial rectus severely impairs abduction. Conclusion: This crossed midbrain syndrome, possibly resulting from simultaneous activation of oculomotor nerve and lesion-like inhibition of the red nucleus suggests that high frequency stimulation has opposite effects on grey and white matter.

The biological form of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a heterodimer consisting of two polypeptides, p66 and p51, which have identical N-termini. The p51 polypeptide is generated by action of viral protease cleaving the p66 polypeptide between residues Phe440and Tyr441. Dimerization has been mostly studied using bacterially purified RT bearing amino acid changes in either subunit, but not in the context of HIV-1 particles. We introduced changes of conserved amino acid residues 430–438 into the protease-sensitive subdomain of the p66 subunit and analyzed the reverse transcriptase processing and function using purified variants and their corresponding HIV-1 recombinant clones. Our mutational analysis shows that the conserved Glu438residue is critical for proper heterodimerization and function of virion-associated RT, but not of bacterially expressed RT. In contrast, the conserved Glu430, Glu432, and Pro433residues are not important for dimerization of virion-associated RT. The network of interactions made by the Glu438carboxyl group with neighboring residues is critical to protect the Phe440–Tyr441from cleavage in the context of the p66/p51 heterodimer and may explain why the p66/p51 is not processed further to p51/p51.

An equilibrium between spliced and unspliced primary transcripts is essential for retrovirus multiplication. This equilibrium is maintained by the presence of inefficient splice sites. The A3 3′-splice site of human immunodeficiency virus type I (HIV-1) is required for Tat mRNA production. The infrequent utilization of this splice site has been attributed to the presence of a suboptimal polypyrimidine tract and an exonic splicing silencer (ESS2) intatexon 2 ∼60 nucleotides downstream of 3′-splice site A3. Here, using site-directed mutagenesis followed by analysis of splicing in vitroand in HeLa cells, we show that the 5′ extremity of tatexon 2 contains a second exonic splicing silencer (ESS2p), which acts to repress splice site A3. The inhibitory property of this exonic silencer was active when inserted downstream of another HIV-1 3′-splice site (A2). Protein hnRNP H binds to this inhibitory element, and two U-to-C substitutions within the ESS2p element cause a decreased hnRNP H affinity with a concomitant increase in splicing efficiency at 3′-splice site A3. This suggests that hnRNP H is directly involved in splicing inhibition. We propose that hnRNP H binds to the HIV-1 ESS2p element and competes with U2AF35for binding to the exon sequence flanking 3′-splice site A3. This binding results in the inhibition of splicing at 3′-splice site A3.

The HIV-1 transcript is alternatively spliced to over 30 different mRNAs. Whether RNA secondary structure can influence HIV-1 RNA alternative splicing has not previously been examined. Here we have determined the secondary structure of the HIV-1/BRU RNA segment, containing the alternative A3, A4a, A4b, A4c and A5 3' splice sites. Site A3, required for tat mRNA production, is contained in the terminal loop of a stem-loop structure (SLS2), which is highly conserved in HIV-1 and related SIVcpz strains. The exon splicing silencer (ESS2) acting on site A3 is located in a long irregular stem-loop structure (SLS3). Two SLS3 domains were protected by nuclear components under splicing condition assays. One contains the A4c branch points and a putative SR protein binding site. The other one is adjacent to ESS2. Unexpectedly, only the 3' A residue of ESS2 was protected. The suboptimal A3 polypyrimidine tract (PPT) is base paired. Using site-directed mutagenesis and transfection of a mini-HIV-1 cDNA into HeLa cells, we found that, in a wild-type PPT context, a mutation of the A3 downstream sequence that reinforced SLS2 stability decreased site A3 utilization. This was not the case with an optimized PPT. Hence, sequence and secondary structure of the PPT may cooperate in limiting site A3 utilization.

High‐frequency thalamic stimulation alleviates tremor in Parkinson's disease (PD) and essential tremor (ET). The origin of thalamic myoclonus is unexplained and the effects of low‐frequency thalamic stimulation on movement control are still unknown. We studied the effects of stimulation at a low frequency of 15 Hz in five drug‐free patients (3 PD, 2 ET) 6 months after thalamic implantation of quadripolar electrodes (unilateral in four patients, bilateral in one patient). Clinical, electrophysiological, and videotaped assessment, using a monopolar 15 Hz frequency (3 V, 90 μs) stimulation current applied simultaneously through two adjacent contacts of the electrode, was performed. We observed myoclonus and irregular jerky tremor in the upper limb contralateral to the site of stimulation. The jerks lasted less than 200 ms, were irregular and not synchronous with stimulation, were superimposed on rest or postural tremor, and increased in response to tactile, proprioceptive, or vibratory stimuli. The fact that this complex movement disorder can be induced by low‐frequency stimulation in the ventral intermediate nucleus (Vim) of the thalamus suggests that it results, at least partly, from dysfunction of the Vim and possibly adjacent nuclei of the thalamus.

In a previous study on a consecutive series of 62 patients with PD, the authors showed that bilateral subthalamic or pallidal continuous high-frequency deep brain stimulation (DBS) affects neither memory nor executive functions 3 to 6 months after surgery.

Patients with PD can have disabling visual hallucinations associated with dopaminergic therapy. Sleep disorders, including vivid dreams and REM sleep with motor behaviors (RBD), are frequent in these patients.

Levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease are considered to result from the severity of dopaminergic denervation in the striatum, which is an irrevocable phenomenon, and sensitization induced by long-term intermittent administration of levodopa. Taking advantage of the 64% reduction of levodopa treatment allowed in 12 Parkinson's disease patients by continuous high-frequency stimulation of the subthalamic nucleus, we evaluated the severity of parkinsonian motor disability and LIDs during two levodopa challenges performed before the surgical implantation of the stimulation electrodes and after 8.8 months of continuous bilateral subthalamic nucleus stimulation that was interrupted 2 hours before the levodopa test. Motor disability during the “off” and “on” drug periods was unchanged. The severity of LIDs during the “on” period and dystonia during the “off” period decreased by 54% and 62%, respectively. The reduced severity of LIDs in the absence of subthalamic nucleus stimulation demonstrates that the sensitization phenomenon resulting from long-term intermittent levodopa administration is partially reversible. Ann Neurol 2000;47:655–658

Objective To assess the effects of high frequency stimulation of the subthalamic nucleus (STN) on axial symptoms occurring in advanced stages of Parkinson's disease (PD).Methods The efficacy of STN stimulation on total motor disability score (unified Parkinson's disease rating scale (UPDRS) part III) were evaluated in 10 patients with severe Parkinson's disease. The subscores were then studied separately for limb akinesia, rigidity, and tremor, which are known to respond to levodopa, and axial signs, including speech, neck rigidity, rising from a chair, posture, gait, and postural stability, which are known to respond less well to levodopa. Patients were clinically assessed in the "off" and "on" drug condition during a levodopa challenge test performed before surgical implantation of stimulation electrodes and repeated 6 months after surgery under continuous STN stimulation. A complementary score for axial symptoms from the "activities of daily living" (ADL)--that is, speech, swallowing, turning in bed, falling, walking, and freezing--was obtained from each patient's questionnaire (UPDRS, part II).Results Improvements in total motor disability score (62%), limb signs (62%), and axial signs (72%) obtained with STN stimulation were statistically comparable with those obtained with levodopa during the preoperative challenge (68%, 69%, and 59%, respectively). When levodopa and STN stimulation were combined there was a further improvement in total motor disability (80%) compared with preoperative levodopa administration. This consisted largely of an additional improvement in axial signs (84%) mainly for posture and postural stability, no further improvement in levodopa responsive signs being found. Axial symptoms from the ADL showed similar additional improvement when levodopa and STN stimulation were combined.Conclusion These findings suggest that bilateral STN stimulation improves most axial features of Parkinson's disease and that a synergistic effect can be obtained when stimulation is used in conjunction with levodopa treatment.

Recent studies in the monkey suggest that the subthalamic nucleus (STN) is involved in control of eye movement, yet its functional significance in humans is unknown. Saccadic eye movements were studied in eight parkinsonian patients treated by bilateral electrical stimulation of the STN. STN stimulation improved the accuracy of memory guided saccades but not of reflexive visually guided saccades and had no effect on the antisaccade task. This study shows that, by contrast with levodopa, STN stimulation improves memory guided saccade deficits, and illustrates for the first time in humans the role of the STN in the control of purposive saccades.

Parkinson's disease is characterized by a progressive degeneration of dopaminergic neurons in the midbrain, yet the cause of this neuronal loss is still unknown. It has been hypothesized that Parkinson's disease could be the consequence of accelerated ageing. In order to reveal a possible common process during ageing and Parkinson's disease neurodegeneration, catecholaminergic neurons of five anatomical regions of the brainstem (substantia nigra, central grey substance, ventral tegmental area, peri- and retrorubral area, and locus coeruleus) have been quantified using immunohistochemical staining for tyrosine hydroxylase (TH) on regularly spaced sections, between the rostral and caudal poles of the mesencephalon and in the rostral pole of the pons, in post-mortem samples of 21 control subjects who died at ages 44–110 years. No statistically significant loss of TH positive neurons was observed in the older subjects, either in the substantia nigra or in the other midbrain regions that are known to degenerate to a lesser degree in Parkinson's disease. Furthermore, in the later regions no neuronal loss was observed from age 44 to 80 years, indicating that this result is not dependent on the inclusion of `supernormal' very old people. These results suggest that from age 44 to 110 years, ageing in control adults is not, or is scarcely, accompanied by catecholaminergic cell loss in the midbrain and hence Parkinson's disease is probably not caused by an acceleration of a degenerative process during ageing.

To achieve accuracy in studying the patterns of loss of midbrain dopamine-containing neurons in Parkinson's disease, we used compartmental patterns of calbindin D28K immunostaining to subdivide the substantia nigra with landmarks independent of the degenerative process. Within the substantia nigra pars compacta, we identified dopamine-containing neurons in the calbindin-rich regions (`matrix') and in five calbindin-poor pockets (`nigrosomes') defined by analysis of the three-dimensional networks formed by the calbindin-poor zones. These zones were recognizable in all of the brains, despite severe loss of dopamine-containing neurons. The degree of loss of dopamine-containing neurons in the substantia nigra pars compacta was related to the duration of the disease, and the cell loss followed a strict order. The degree of neuronal loss was significantly higher in the nigrosomes than in the matrix. Depletion was maximum (98%) in the main pocket (nigrosome 1), located in the caudal and mediolateral part of the substantia nigra pars compacta. Progressively less cell loss was detectable in more medial and more rostral nigrosomes, following the stereotyped order of nigrosome 1 > nigrosome 2 > nigrosome 4 > nigrosome 3 > nigrosome 5. A parallel, but lesser, caudorostral gradient of cell loss was observed for dopamine-containing neurons included in the matrix. This pattern of neuronal loss was consistent from one parkinsonian substantia nigra pars compacta to another. The spatiotemporal progression of neuronal loss related to disease duration can thus be drawn in the substantia nigra pars compacta for each Parkinson's disease patient: depletion begins in the main pocket (nigrosome 1) and then spreads to other nigrosomes and the matrix along rostral, medial and dorsal axes of progression.

There is a renewal of interest in surgical approaches including lesions and deep brain stimulation directed at motor subcorticofrontal loops. Bilateral lesioning presents a far greater risk of adverse effects, especially cognitive impairment. Furthermore, the main advantages of the stimulation procedure over lesioning are adaptability and reversibility of effects. The aim of this study was to assess the influence of bilateral stimulation of the subthalamic nucleus or internal globus pallidus on memory and executive functions in Parkinson's disease. Sixty-two patients were assessed before and after 3 to 6 months of chronic bilateral stimulation of the subthalamic nucleus (n = 49) or internal globus pallidus (n = 13). The neuropsychological tests used were the Mattis Dementia Rating Scale, the Grober and Buschke Verbal Learning Test, the Wisconsin Card Sorting Test, category and literal fluency, graphic and motor series, the Stroop Test, and the Trail Making Test. Mood was evaluated by the Beck Depression Inventory. Only 4 of 25 cognitive variables were affected by deep brain stimulation. Under stimulation, performance improved for Parts A and B of the Trail Making Test, but there was a deterioration in literal and total lexical fluency. There was also a mild but significant improvement in mood. It may therefore be concluded that stimulation of the subthalamic nucleus or internal globus pallidus does not change the overall cognitive performance in Parkinson's disease and does not greatly affect the functioning of subcorticofrontal loops involved in cognition in humans. This relative absence of cognitive impairment in bilateral deep brain stimulation is likely because of the accurate positioning of the electrodes, allowing the effects of stimulation to be confined to sensorimotor circuits. Ann Neurol 1999;46:217–223

Evidence supports the role of hyperoxidation phenomena in the mechanism of nerve cell death in Parkinson's disease (PD). The oxidative degradation of dopamine, catalyzed by monoamine oxidase type B (MAO-B), produces free radicals and thus could be implicated in the degenerative process. For this reason, we investigated by immunohistochemistry the distribution of MAO-B-containing cells in the midbrain of five patients with PD and five matched control subjects. MAO-B-like immunoreactivity was detected in glial cells, fibers, and neurons. Although most of the MAO-B-positive neurons probably belonged to the raphe dorsalis, we demonstrated by double-labeling immunohisto-chemistry that some of them were also dopaminergic. MAO-B-positive dopaminergic neurons were present in all dopa-minergic groups of the control midbrain. Within the substantia nigra pars compacta, most dopaminergic neurons were located in the dorsal part of the structure. MAO-B-positive dopaminergic neurons were still detected in PD midbrains. Compared with control subjects, the loss of dopaminergic neurons containing MAO-B (−45) was no higher than that of MAO-B-negative dopaminergic neurons (−59). The density of MAO-B-positive glial cells varied in the control midbrains: high in the least affected dopaminergic group (the central gray substance) and low in the most affected region (the substantia nigra pars compacta). The density of MAO-B-positive glial cells within dopaminergic cell subgroups in control midbrains were negatively correlated (r = −0.94; p<0.02) to the estimated neuronal loss in PD. We conclude that the presence of MAO-B in dopamine-containing neurons does not contribute to vulnerability in PD. Moreover, its presence in some glial cells might have a protective effect against oxidative stress induced by dopamine metabolism.

The data reviewed here show that, in Parkinson's disease (PD), some dopaminergic neurons are more vulnerable than others to the pathologic process. The glial cells surrounding dopaminergic neurons may be involved in this selective vulnerability. One subpopulation of glial cells, in particular, may play a neuroprotective role by metabolizing dopamine and scavenging oxygen free radicals that are associated with dopamine metabolism. Another subpopulation of glial cells may be deleterious to dopaminergic neurons. This effect may be mediated by the production of nitric oxide and cytokines, which may in turn account for the oxidative stress observed in the substantia nigra of patients with PD. Finally, this inflammatory reaction may result in the induction of apoptosis.

The degeneration of nigral dopaminergic neurons in Parkinson disease is believed to be associated with oxidative stress. Since iron levels are increased in the substantia nigra of parkinsonian patients and this metal catalyzes the formation of free radicals, it may be involved in the mechanisms of nerve cell death. The cause of nigral iron increase is not understood. Iron acquisition by neurons may occur from iron-transferrin complexes with a direct interaction with specific membrane receptors, but recent results have shown a low density of transferrin receptors in the substantia nigra. To investigate whether neuronal death in Parkinson disease may be associated with changes in a pathway supplementary to that of transferrin, lactoferrin (lactotransferrin) receptor expression was studied in the mesencephalon. In this report we present evidence from immunohistochemical staining of postmortem human brain tissue that lactoferrin receptors are localized on neurons (perikarya, dendrites, axons), cerebral microvasculature, and, in some cases, glial cells. In parkinsonian patients, lactoferrin receptor immunoreactivity on neurons and microvessels was increased and more pronounced in those regions of the mesencephalon where the loss of dopaminergic neurons is severe. Moreover, in the substantia nigra, the intensity of immunoreactivity on neurons and microvessels was higher for patients with higher nigral dopaminergic loss. These data suggest that lactoferrin receptors on vulnerable neurons may increase intraneuronal iron levels and contribute to the degeneration of nigral dopaminergic neurons in Parkinson disease.

There has been renewed interest in functional surgery as treatment for Parkinson's disease (PD). Although pallidotomy and chronic pallidal stimulation are highly effective in suppressing levodopa-induced dyskinesia(LID), both methods also seem to be effective in reducing parkinsonian disability. However, the simultaneous improvement of LID and motor signs is hard to explain with the classic model of basal ganglia circuitry. Taking advantage of the fact that deep brain stimulation is reversible and that implanted electrodes contain four discrete stimulation sites, we investigated the effect of stimulation on different sites of the globus pallidus (GP) in five PD patients. Stimulation in the dorsal GP (upper contact) significantly improved gait, akinesia, and rigidity and could induce dyskinesia when patients were in the "off" state. In contrast, stimulation in the posteroventral GP (lower contact) significantly worsened gait and akinesia, although the reduction in rigidity remained. For patients in the "on" state, stimulation in the posteroventral GP dramatically reduced LID but, as in the"off" state, worsened gait and akinesia, thus canceling out the antiparkinsonian effect of levodopa. Our results indicate that stimulation had a striking different effect on parkinsonism and dyskinesia when applied at two different loci of the GP and that stimulation applied in the posteroventral GP produced opposite effects on rigidity and on akinesia. We conclude that parkinsonian signs and LID are a reflection of at least two different anatomofunctional systems within the GP and that this functional organization of the GP needs to be considered when determining the optimal target for surgical treatment of PD.

Usingin vitrosplicing assays with HeLa cell nuclear extracts, we showed that the HIV-1 pairs of splice sites D1-A2 and D2-A2 are efficiently usedin vitro,as compared to the control D1-A2 pair of sites from the E3 transcription unit of human adenovirus-2. The strong efficiency of the two HIV-1 pairs of sites is surprising, as we also showed by primer extension analysis that the branch-site sequence used at the HIV-1 acceptor site A2 is UAGCAGA, with a dominant utilization of the ultimate G as the branched residue. No significant increase of the splicing efficiency was observed upon replacement of the wild-type branch-site sequence by a canonical sequence, in spite of the utilization of an A residue as the branched nucleotide. Results are discussed taking into account the present knowledge on branch-site selection.

High-frequency stimulation of the subthalamic nucleus (STN) was used to investigate the relationship of sleep disorders with motor handicap in PD. In 10 insomniac patients with PD, stimulation reduced nighttime akinesia by 60 and completely suppressed axial and early morning dystonia, but did not alleviate periodic leg movements (n 3) or REM sleep behavior disorders (n 5). Total sleep time increased by 47; wakefulness after sleep onset decreased by 51 minutes. Insomnia in patients with PD may predominantly result from nighttime motor disability.