Brain-first forms of Parkinson's disease are over-represented in patients with non-responsive resting tremor.

Motor subtypes in Parkinson's Disease (PD) are unstable over time, limiting mechanistic insights and biomarker discovery. We focused on Rest Tremor (RT) as a symptom to test for phenotype stability and link it to specific circuits and disease mechanisms. Using the PPMI cohort data over 5 years we found that RT is more stable than classical Tremor-Dominant definitions, a stability also seen for RT response to therapy. At time of diagnosis, the population of therapy-resistant RT patients was enriched with a brain-first PD profile as predicted by a-Synuclein origin site and connectome (SOC) model. Resistant-RT patients have lower gastrointestinal and cardiovascular symptoms, lower prevalence of probable REM-Sleep behaviour disorder, and higher dopaminergic asymmetry compared to therapy-responsive or no tremor patients. Treating RT as a distinct phenomenon revealed a relative phenotypic stability with treatment response being linked to different patterns of disease progression.

Dopamine neuron activity encodes the length of upcoming contralateral movement sequences.

Dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement speed, and loss of these neurons leads to bradykinesia in Parkinson's disease (PD). However, other aspects of movement vigor are also affected in PD; for example, movement sequences are typically shorter. However, the relationship between the activity of DANs and the length of movement sequences is unknown. We imaged activity of SNc DANs in mice trained in a freely moving operant task, which relies on individual forelimb sequences. We uncovered a similar proportion of SNc DANs increasing their activity before either ipsilateral or contralateral sequences. However, the magnitude of this activity was higher for contralateral actions and was related to contralateral but not ipsilateral sequence length. In contrast, the activity of reward-modulated DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, sequence length. These results indicate that movement-initiation DANs encode more than a general motivation signal and invigorate aspects of contralateral movements.

Autonomic nervous system response to remote ischemic conditioning: heart rate variability assessment.

BACKGROUND: Remote ischemic conditioning (RIC) is a procedure applied in a limb for triggering endogenous protective pathways in distant organs, namely brain or heart. The underlying mechanisms of RIC are still not fully understood, and it is hypothesized they are mediated either by humoral factors, immune cells and/or the autonomic nervous system. Herein, heart rate variability (HRV) was used to evaluate the electrophysiological processes occurring in the heart during RIC and, in turn to assess the role of autonomic nervous system. METHODS: Healthy subjects were submitted to RIC protocol and electrocardiography (ECG) was used to evaluate HRV, by assessing the variability of time intervals between two consecutive heart beats. This is a pilot study based on the analysis of 18 ECG from healthy subjects submitted to RIC. HRV was characterized in three domains (time, frequency and non-linear features) that can be correlated with the autonomic nervous system function. RESULTS: RIC procedure increased significantly the non-linear parameter SD2, which is associated with long term HRV. This effect was observed in all subjects and in the senior (> 60 years-old) subset analysis. SD2 increase suggests an activation of both parasympathetic and sympathetic nervous system, namely via fast vagal response (parasympathetic) and the slow sympathetic response to the baroreceptors stimulation. CONCLUSIONS: RIC procedure modulates both parasympathetic and sympathetic autonomic nervous system. Furthermore, this modulation is more pronounced in the senior subset of subjects. Therefore, the autonomic nervous system regulation could be one of the mechanisms for RIC therapeutic effectiveness.

Cognitive complaints in Parkinson's disease patients: from subjective cognitive complaints to dementia and affective disorders.

Subjective cognitive complaints (SCC) are frequent in elderly populations. PD patients report SCC more often than healthy controls. The association between SCC, objective cognitive impairment and affective symptoms remains controversial. We assessed consecutive PD patients between March 2014 and March 2015. Presence of SCC was defined as a score ≥ 1 in the Non-Motor Symptom Assessment Scale for Parkinson's Disease (NMSS) Domain 5. MoCA was used for cognitive impairment assessment. Pill Questionnaire measured the impact in daily activities. PD with Dementia (PDD) and PD with Mild Cognitive Impairment (PDMCI) were defined as the presence of cognitive impairment with or without impact on daily activities. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scales. Significance was set at p < 0.05. From 134 patients, 128 were included. PDD was diagnosed in 21 (16.4%), PDMCI in 31 (24.2%), and 76 (59.4%) had normal cognition (PDCN). SCC were present in 85% of whole cohort and evenly distributed (p = 0.361), PDD (95.2%), PDMCI (83.9%) and PDCN (82.9%). Severity was significantly different between PDD (20.00 ± 10.81), PDMCI (6.54 ± 5.5) and PDCN (6.97 ± 6.98), p < 0.001. A score ≥ 19 had a specificity of 77.3% and a sensitivity of 78.8% for identifying PDD. In PDCN, SCC severity was found to be related to depression (OR 1.23, CI 95% 1.02-1.47, p = 0.026) more than with MoCA scores (OR: 0.86, CI 95% 0.69-1.05, p = 0.141). SCC are common in PD. Their severity can help distinguish PDD from non-demented PD patients. In PDCN, SCC should alert the clinician for an affective disorder.

Stuttering in Parkinson's disease after deep brain stimulation: A note on dystonia and low-frequency stimulation.

Stuttering, a speech fluency disorder, is a rare complication of Deep Brain Stimulation (DBS) in Parkinson's Disease (PD). We report a 61 years-old patient with PD, afflicted by severe On and Off dystonia, treated with Subthalamic Nucleus DBS that developed post-DBS stuttering while on 130 Hz stimulation. Stuttering reduction was noted when frequency was changed to 80 Hz, but the previously observed dystonia improvement was lost. There are no reports in literature on patients developing stuttering with low-frequency stimulation. We question if low-frequency stimulation could have a role for managing PD's post-DBS stuttering, and notice that stuttering improvement was associated with dystonia worsening suggesting that they are distinct phenomena.

Deep brain stimulation for lesion-related tremors: A systematic review and meta-analysis.

Deep brain stimulation (DBS) is an effective treatment for essential tremor or tremor in Parkinson's disease. The effectiveness of DBS in reducing tremors that develop after a structural lesion of the central nervous system (such as Holmes' tremor - HT) has only been addressed in case reports or series. We conducted a systematic review of all published original reports of DBS in central nervous system lesion-related tremor (excluding demyelinating disorders due to their non-static nature). Where available, we extracted data regarding each patient's demographic, tremor and surgical details. Improvement was calculated as a percentage of change in any objective tremor rating scale. We identified 35 publications reporting on 82 patients. The ventral intermedius nucleus(VIM) of the thalamus was the preferred target (63.6%) and 18.2% targeted globus pallidus pars interna(GPi). Median improvement was 77.5% and 71.4% for patients with post-stroke and post-traumatic tremor respectively. Seven subjects (13.5%) had less than 50% improvement. Therapeutic effectiveness was not associated with age, tremor duration, age of onset or follow-up time. A large range of stimulation parameters were used with median voltage, pulse width and frequency values higher for GPi (4.80 V, 105 us, 170 Hz) than for thalamic stimulation (3.0 V, 90 us, 140 Hz). DBS reports for Holmes' and lesional tremors treatment are scarce and highly heterogeneous limiting a proper summary analysis and comparisons. Even facing a probable report bias, a high number of subjects with good long-term tremor control were found. These results should promote the creation of tremor registries before clinical trials.

Tetrabenazine in treatment of hyperkinetic movement disorders: an observational study.

BACKGROUND: Tetrabenazine (TBZ) is commonly used in hyperkinetic movement disorders. In this retrospective study, we aimed to assess the TBZ effectiveness and adverse events (AEs) in Huntington disease (HD), vascular chorea, tics, dystonia, tardive oromandibular (OM) dyskinesia and other tardive syndromes (TS). METHODS: Qualitative analysis of clinical response was used to estimate TBZ effectiveness. TBZ-associated AE frequency and subsequent discontinuation rate were used to estimate tolerability; the tolerability profile was measured through the TBZ minimal dose and exposure time required to elicit AEs. RESULTS: Of 108 included patients, 87% had a clinically meaningful improvement sustained over a period of 40 months. TBZ-responder rate ranged from 100% in HD to 62.5% and 77.1% in tic disorders and OM dyskinesia, respectively (p < 0.001). TBZ-associated AE frequency ranged from 40.9% in other TS and 41.7% in vascular chorea and HD, to 60% in OM dyskinesia (p < 0.001). The most common AEs were Parkinsonism (51.8%) and psychiatric disorders (25%). The 'other AEs' category (mainly somnolence) presented the shortest minimal exposure time (3 months). AE-eliciting dose differed from 18.8 mg and 25 mg in tics and tardive disorders, to 75 mg in HD (p = 0.003). Patients with AEs were tendentiously older at TBZ initiation (p = 0.022). CONCLUSIONS: TBZ proved an effective and relatively well tolerated treatment in hyperkinetic disorders, with excellent results in HD. AEs were more common in OM dyskinesia, which may be related to higher age at TBZ initiation. TBZ-associated somnolence and Parkinsonism were more frequent during the titration and maintenance periods, respectively.

Motor and non-motor symptoms in old-age onset Parkinson's disease patients.

Advancing age is a well-known risk factor for Parkinson's disease (PD). With population ageing it is expected that the total number of patients with PD onset at oldage increases. Information on the motor but particularly on non-motor phenotype of this late-onset population is lacking. We recruited 24 patients with PD onset at or over 75 years. Each patient was matched with 1 control patient with PD onset between the ages of 40 and 65 and matched for disease duration. Both groups were assessed with the UPDRS, the Non-motor symptoms scale (NMSS) and other scales to assess non-motor symptoms. Groups were compared with conditional logistic regression analysis. Old-age onset PD was, on average, 80 years at the time of PD onset while middle-age onset were 59. Disease duration was approximately 5 years in both groups. While no difference was observed in the total UPDRS-III scores, old-age onset PD was associated with higher axial symptoms (7.42 vs. 4.63, p = 0.011) and a higher frequency of dementia (7/24 vs. 0/24, p = 0.009). While no difference in the total number of non-motor symptoms was observed (6.79 vs. 6.22, p = 0.310), old-age onset patients had a higher prevalence of gastrointestinal symptoms (20/24 vs. 12/24, p = 0.037). For the same disease duration, older age onset is associated with worse axial motor dysfunction and dementia in PD patients. Beside gastrointestinal symptoms, non-motor symptoms are not associated with age.

Herbal Supplements Association with Reversible Cerebral Vasoconstriction Syndrome: A Case Report.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is a clinico-radiologic syndrome characterized by thunderclap headache and reversible multifocal arterial constrictions that resolves within 3 months. RCVS can be either spontaneous or related to a trigger; vasoactive drugs including over-the-counter medicine are common culprits. Nevertheless, there are sparse data on the association of herbal supplements in the genesis of unexplained RCVS. METHODS: We describe a case of RCVS with a temporal association with the consumption of a diet pill composed of green tea, L-carnitine, and conjugated linoleic acid. We reviewed the literature describing RCVS cases associated with consumption of herbal supplements or plants. RESULTS: A 50-year-old black woman presented at the emergency room with a thunderclap headache less than 1 week after beginning a new herbal supplement with weight loss purpose. Angiographic study revealed multiple arterial constriction of virtually all intracranial territories that were reversed 28 days later. The patient was discharged with minimal symptoms. From our review, we identified 5 previous reports of herbal product-related triggers. CONCLUSIONS: Different factors can trigger RCVS. Besides our case, at least 5 other nutraceutical products were described to be associated with the disorders, 3 of them in patients without any other clear cause. Clinicians should be aware of the possible role of herbal supplements in RCVS, and their use should be systematically assessed in large RCVS cohorts to clarify this association.

Steroid-responsive painful ophthalmoplegia: Tolosa-Hunt syndrome, Eales disease, or both?

Introduction Tolosa-Hunt syndrome (THS) is one of the most common 'benign' causes of painful ophthalmoplegia. Diagnosis is based on clinical and imaging findings and the exclusion of other causes because there is no specific biomarker for the syndrome. Eales disease, an idiopathic inflammatory venous disease that primarily affects the eye, can also affect the central (as stroke or myelitis) and peripheral nervous system. Case report We report the case of a 32-year-old woman with a subacute left ophthalmoplegia and evidence of a gadolinium-enhanced lesion suggesting an inflammatory granuloma that resolved within 48 hours after treatment with steroids. A diagnosis of THS was considered at this time. On a follow-up ophthalmological examination, a diagnosis of Eales disease with involvement of the left eye was made. The patient was treated successfully. Conclusion Eales disease could be a cause of painful ophthalmoplegia and may mimic THS. Long-term follow-up of patients diagnosed with THS may be necessary to exclude other diagnoses.

Non-Motor symptoms in Portuguese Parkinson's Disease patients: correlation and impact on Quality of Life and Activities of Daily Living.

The prevalence of non-motor symptoms (NMS) in Parkinson's Disease (PD) has varied between studies. Their interrelation isn't totally understood. Also, the relative importance of each symptom, regarding its impact on activities of daily living (ADL) and health related quality of life (HRQL), remains debatable. We assessed all PD patients attending a Portuguese tertiary movement disorders center during one year (n = 134), with ADL, HRQL and other clinical scales approved for identifying the most relevant NMS in PD. All patients had at least one NMS. Sleep/fatigue, affect/cognition, attention/memory were the most frequent complaints, and their prevalence, above 80%, was higher than in most studies. There were significantly correlations between: sleepiness, psychosis and cognition; gastrointestinal, cardiovascular symptoms and pain; depression and apathy; anxiety and insomnia; olfaction, weight and hyperhidrosis. Depression/apathy exerted the strongest influence on HRQL and non-tremor motor dysfunction on ADL. Compared to studies in other countries, we found a higher prevalence of NMS, which could be specific of this population. The interrelation between NMS could be related to degeneration of different brain structures. NMS exert a stronger influence than MS in HRQL, which should be taken in account regarding treatment options.

Post-malaria neurological syndrome or viral encephalitis?

We present a case of a 60-year-old Caucasian man recently returned from Angola, where he had been successfully treated for a severe (non-cerebral) falciparum malaria infection. He was presented to the emergency room, with a subacute onset encephalopathy, ataxia and a generalised tonic-clonic seizure. Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis (123 cells/µL) and hyperproteinorrhachia (188 mg/dL). Brain MRI and EEG were unremarkable. CSF PCR testing for neurotropic viruses was negative as were CSF and blood cultures. The patient was treated with ceftriaxone and acyclovir, with full recovery on the second day of treatment. We believe post-malaria neurological syndrome, a rare self-limited encephalopathy, should be considered in the differential diagnosis. Nevertheless, the presentation, lack of changes on brain MRI and EEG, along with possible false-negative CSF viral PCR, could still represent a viral encephalitis, which brings to question the treatment approach to adopt (conservative vs wide spectrum antiviral plus antibiotics).

From Subjective Cognitive Complaints to Dementia: Who is at Risk?: A Systematic Review.

Subjective cognitive complaints (SCCs) are frequent in the elderly population. The majority of individuals with subjective complaints never progress to significant cognitive decline, but some of them have a higher risk of progression to objective cognitive impairment than persons with no cognitive concerns. We performed a systematic review of community-based studies that focused on the progression risk associated with SCC and on the complainers' characteristics associated with progression. Seventeen studies were included. As a group, SCCs are associated with a significantly higher risk of progression to dementia. Worried complainers, persons who refer an impact of their complaints on activities of daily living, and those whose complaints are also noticed by an informant have the highest risk of progression. Taking into account the fluctuating course of SCC and their frequent reversion, care should be taken to not overvaluate them. Further studies are necessary to better define risk features.

Association of depressive symptoms with allodynia in patients with migraine: A cross-sectional study.

Aims Migraine and depression have a strong association. We aimed to determine whether this relationship was particularly evident in migraineurs with allodynia. Methods A cross-sectional study was carried out of 98 consecutive patients with episodic migraine presenting for their first evaluation in an outpatient clinic. The participants completed a demographic questionnaire, the Allodynia Symptom Checklist and the Hospital Anxiety and Depression Scale (HADS). Results Among the migraineurs, 75 (77%) reported allodynia. Allodynia was associated with higher median HADS-Anxiety (9 vs. 6, p = 0.038) and HADS-Depression (6 vs. 4, p = 0.014) scores. In a multiple regression model, the HADS-Depression scores were independently associated with allodynia (odds ratio 1.236, 95% confidence interval 1.046-1.461). An increased severity of allodynia correlated with higher depression scores ( r = 0.224; p = 0.027). Conclusion Anxious and depressive symptoms are more common in migraineurs with allodynia than in those without allodynia. Further studies are necessary to clarify the relationship between depressive symptoms and allodynia, as well as its therapeutic implications in migraine.