High Glucosylceramides and Low Anandamide Contribute to Sensory Loss and Pain in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) causes chronic pain in two-thirds of patients, in part originating from sensory neuropathies. The aim of the present study was to describe the phenotype of PD-associated sensory neuropathy and to evaluate its associations with lipid allostasis, the latter motivated by recent genetic studies associating mutations of glucocerebrosidase with PD onset and severity. Glucocerebrosidase catalyzes the metabolism of glucosylceramides. METHODS: We used quantitative sensory tests, pain ratings, and questionnaires and analyzed plasma levels of multiple bioactive lipid species using targeted lipidomic analyses. The study comprised 2 sets of patients and healthy controls: the first 128 Israeli PD patients and 224 young German healthy controls for exploration, the second 50/50 German PD patients and matched healthy controls for deeper analyses. RESULTS: The data showed a 70% prevalence of PD pain and sensory neuropathies with a predominant phenotype of thermal sensory loss plus mechanical hypersensitivity. Multivariate analyses of lipids revealed major differences between PD patients and healthy controls, mainly originating from glucosylceramides and endocannabinoids. Glucosylceramides were increased, whereas anandamide and lysophosphatidic acid 20:4 were reduced, stronger in patients with ongoing pain and with a linear relationship with pain intensity and sensory losses, particularly for glucosylceramide 18:1 and glucosylceramide 24:1. CONCLUSIONS: Our data suggest that PD-associated sensory neuropathies and PD pain are in part caused by accumulations of glucosylceramides, raising the intriguing possibility of reducing PD pain and sensory loss by glucocerebrosidase substituting or refolding approaches. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Patient and caregiver perceptions of the social impact of advanced Parkinson's disease and dyskinesias.

Parkinson's disease (PD) exacts a physical and emotional toll on both patients and family. The aim of this study was to compare patient and caregiver perceptions of the social consequences of basic symptoms of PD and levodopa-induced dyskinesias. Forty patients with PD and dyskinesias and 35 of their caregivers completed a self-report questionnaire on the impact of PD and dyskinesias on their feelings of security and embarrassment and participation in family/social events, and indicated their preference for the "on" (with dyskinesias) or the "off" (without dyskinesias) state. The patients scored significantly higher than the caregivers did on the negative social impact of the disease in general (p = 0.002) and of the dyskinesias in particular (p = 0.03). Nevertheless, the patients expressed a significantly greater preference for the "on" state (83 %) than the caregivers (59 %) (p = 0.03). Preferences turned to be reverse in direction among spouse-caregivers who significantly preferred the "off" state (54 %) than the patients (25 %) (p = 0.04). Although patients have a worse perception of the effects of PD than their caregivers do, they prefer the more independent "on" state, whereas their caregivers prefer the "off" state.

Effect of Repeated Intravenous Amantadine Infusions in Patients with Parkinson's Disease: An Open-Label Pilot Study.

Amantadine is an antiviral drug available in oral and intravenous forms. Oral amantadine is used to treat the motor symptoms of early Parkinson's disease (PD) and to ameliorate dyskinesia in late-stage disease. However, the long-term influence of intravenous amantadine on motor symptoms and dyskinesias in PD has not been investigated. The aim of the present study was to examine the long-term effect of repeated boosts of intravenous amantadine in patients with PD with and without response fluctuations and dyskinesias. Twelve patients diagnosed with PD, six with levodopa intolerance or insufficient response to antiparkinson medications, and six with response fluctuations and dyskinesias, were treated with intravenous amantadine for 6 months: three sequential infusions over 3 days in the first month followed by five once-monthly infusions. Changes in motor function and involuntary movements were evaluated with the Unified Parkinson Disease Rating Scale (UPDRS) and Abnormal Involuntary Movement Scale (AIMS; dyskinesia group). A significant immediate improvement in motor scores was documented in both groups after amantadine infusion. However, the difference in mean UPDRS motor score from before the first infusion to after 6 months of treatment was not statistically significant. In patients with dyskinesias, there was a significant improvement in AIMS scores between the first and the last visits (6.3 ± 2.7 vs. 1.6 ± 1.3; P = 0.014). In conclusion, continuous treatment with intravenous amantadine can be useful in patients with PD for immediate relief of motor symptoms and in patients with dyskinesias for progressive reduction of involuntary movements.

Natural history of headache in patients with lymphocytic meningitis following lumbar puncture.

BACKGROUND: Analysis of cerebrospinal fluid (CSF) obtained by lumbar puncture (LP) is essential for diagnosis of meningitis. What is the impact of the procedure upon the natural history of headache and associated signs in patients with lymphocytic meningitis and what factors can have prognostic value for the future progression of symptomatology? This study was aimed at looking into these questions. METHODS: One hundred and one patients with clinical and laboratory diagnosis of aseptic meningitis answered a questionnaire intended at assessing the severity and nature of headache and meningeal irritation signs before and one, and twenty four hours after the LP. Later they were divided into three groups according to presence and type of headache after 24h. Demographic and clinical data was obtained from patients files. RESULTS: There was almost 50% improvement in headache severity and associated signs after 24hours from LP in the whole group of patients. Patients that did not have pain after 24hours had higher BMI and lower headache severity one hour after LP compared to patients in the other groups (p=0.064 and p=0.005). Patients with papilledema had higher incidence of post dural puncture headache (PDPH). CONCLUSIONS: Our study shows that patients with aseptic meningitis undergo improvement in all parameters of headache and also in signs of meningeal irritation following LP. Higher BMI and low headache intensity are positive prognostic factors for improvement of headache after 24hours while papilledema is associated with a higher incidence of PDPH.

Progression of postural changes in Parkinson's disease: quantitative assessment.

Previous studies of posture in Parkinson's disease (PD) patients focused on the pathophysiology of severe deformities, using mainly subjective estimations or goniometric measures. The aim of this study was to investigate risk factors associated with flexed posture in PD and their effects on the course of posture variations. One hundred-ninety patients with definite PD were prospectively evaluated for angles of spinal inclination in upright position, extension, and flexion using a mechanical computer-assisted, hand-held device (SpinalMouse). Patients underwent clinical examination, including background data and bone mineral density. Motor function was evaluated with the UPDRS, and back pain with the RMDQ. Physical activity data were collected by self-report. Postural measurements were repeated after 10-17 months. Angle of upright inclination correlated with age (p = 0.0004), older age at disease onset (p = 0.0085), longer disease duration (p = 0.003), higher UPDRS motor and posture score (p = 0.0005 and 0.0001), the presence of back-pain (p = 0.0097), and osteoporosis (p = 0.027). There was no correlation between upright angle of inclination and gender, disease type, or side of disease onset. Re-evaluation of posture in 124 patients at 13.77 ± 4.4 months after the initial evaluation showed significant deterioration in forward bending (p < 0.0001) and was significantly associated with disease duration (p = 0.029), worsening of the UPDRS score (p = 0.016), right-side disease onset (p = 0.032), presence of vertebral fractures (p = 0.049), and the lack of physical activity (p = 0.0327). Older age, disease severity and duration, presence of back-pain and osteoporosis are associated with postural abnormalities in PD. Physical activity might slow the worsening of postural abnormalities in PD.

Beneficial effect of levodopa therapy on stooped posture in Parkinson's disease.

OBJECTIVE: This study was designated to quantitatively evaluate the effect of levodopa on spinal posture in patients with PD using a computer-assisted handheld SpinalMouse device. METHODS: Prospective case-study involving 48 patients with definite PD. All patients were recruited between September 2011 and September 2013 and included 22 dopa-naïve, evaluated before and 3 months after initiation of treatment, and 26 patients with response fluctuations studied during the "off" and "on" states. The SpinalMouse instrument, a computer-assisted mechanical hand-held device, designed to noninvasively assess the curvature of the spine was guided along the midline of the vertebral column in upright, full flexion, and full extension positions to objectively assess spinal posture. RESULTS: In the dopa-naïve patients, spinal incline in the upright position was 12.4±1.2° before and 7.6±1.3° after treatment; p=0.002. Corresponding area-under-the-curve (AUC) values were 131.7±8.0 cm(2) and 87.1±7.3 cm(2); p<0.0001. In the response fluctuations patients, spinal incline was 13.3±1.3° in the "off" and 9.3±1.2° in the "on" period; p=0.015. Corresponding AUC values were 144.6±9.2 cm(2) and 103.1±8.2 cm(2); p<0.0001. CONCLUSIONS: This is the first study that objectively measured and quantified abnormalities of spinal posture in patients with PD. Findings suggest that levodopa does have a beneficial effect on anterior flexion of the thoracolumbar spine, and thus indicate that the disorder of stooped posture in PD is mediated, at least in part, by dopamine deficiency.

Risk factors for post lumbar puncture headache.

BACKGROUND: Lumbar puncture (LP) is complicated by headache in about one-third of patients. The aim of the study was to evaluate potential risk factors for post-LP headache. METHODS: 144 Patients undergoing diagnostic LP at a tertiary medical center completed questionnaires on fear of the procedure, pre-existing headache, and post-LP headache. Data on patient demographics, operator experience, and other procedure-related parameters were collected from hospital files. RESULTS: The post-LP headache group (n=37, 27.6%) was characterized by a significantly younger age and higher proportion of women relative to the no-headache group (n=97); body mass index was similar. Both groups had similar levels of fear of the procedure and there was no correlation between intensity of patients' anxiety to the procedure and its occurrence. Patients with high opening pressure had higher levels of post-LP headache (28.6% vs. 18% p=0.078) and a history of headaches was significantly more prevalent in the post-LP-headache group (66.6% vs. 38.1%, p=0.003). CONCLUSIONS: Fear of the procedure does not predispose to occurrence of post-LP headache while a history of headache and elevated intracranial pressure does. These findings may be related to the possible pathophysiology of the condition, namely a change in compliance and pressure gradients with resultant venous distention.

Unusual and benign course of idiopathic facial diplegia.

Bilateral facial nerve palsy or facial diplegia is a rare condition that occurs mainly in the context of Guillain-Barré syndrome. Its natural history has never been studied. We report four patients with isolated idiopathic bilateral facial nerve palsy with meningitis, no evidence of Guillain-Barré syndrome and rapid and complete recovery. Our report aims to draw attention to an unusual variant of bilateral facial palsy.

Nocturnal carbon dioxide monitoring in patients with idiopathic intracranial hypertension.

BACKGROUND: Idiopathic intracranial hypertension may be associated with sleep apnea. This study evaluated the incidence of sleep breathing disorders in patients with idiopathic intracranial hypertension. MATERIALS AND METHODS: Overnight respiratory monitoring was performed in 22 untreated patients with idiopathic intracranial pressure diagnosed at a tertiary medical center over a two-year period and 12 sex- and age-matched control subjects. Breathing measures included heart rate, respiratory rate,oxygen saturation, and continuous end-tidal capnography. Sleep quality and daily fatigue were assessed by self-report questionnaires. RESULTS: Mean age of the study group was 32.6±12.2 years and of the control group, 37.0±12.9 years. Neither group had significant findings of hypoxia or hypercarbia during sleep, and there were no between-group differences in mean carbon dioxide level (patients, 35.8±4.41 mmHg; controls, 37.6±4.38 mmHg; p>0.02) or minimal oxygen saturation (96.35±1.99% and 5.69±1.71%, respectively; p>0.02). The study group had significantly more events of apnea (CO2) per hour of sleep than the control group (1.21±1.38 and 0.92±0.56, respectively; p=0.02), although values were still within normal range (<5/hr). CONCLUSION: Idiopathic intracranial hypertension is not associated with a clinically significant nocturnal breathing abnormality, and hypercarbia is apparently not involved in the pathogenesis. However, it is possible that a subtle increase in paroxysmal sleep apnea (CO2) events might be sufficient to cause vasodilatation of the cerebral blood vessels, thereby increasing intracranial pressure. Screening for sleep apnea may be appropriate in idiopathic intracranial hypertension patients, and further studies are needed to clarify this issue.

Perspective: Identification of genetic variants associated with dopaminergic compensatory mechanisms in early Parkinson's disease.

Parkinson's disease (PD) is slowly progressive, and heterogeneity of its severity among individuals may be due to endogenous mechanisms that counterbalance the striatal dopamine loss. In this perspective paper, we introduce a neuroimaging-genetic approach to identify genetic variants, which may contribute to this compensation. First, we briefly review current known potential compensatory mechanisms for premotor and early disease PD, located in the striatum and other brain regions. Then, we claim that a mismatch between mild symptomatic disease, manifested by low motor score on the Unified PD Rating Scale (UPDRS), and extensive Nigro-Striatal (NS) degeneration, manifested by reduced uptake of [(123)I]FP-CIT, is indicative of compensatory processes. If genetic variants are associated with the severity of motor symptoms, while the level of striatal terminals degeneration measured by ligand uptake is taken into account and controlled in the analysis, then these variants may be involved in functional compensatory mechanisms for striatal dopamine deficit. To demonstrate feasibility of this approach, we performed a small "proof of concept" study (candidate gene design) in a sample of 28 Jewish PD patients, and preliminary results are presented.

Primary brain T-cell lymphoma in an HTLV-1 serologically positive male.

Primary central nervous system lymphoma (PCNSL) is a subgroup of extranodal non-Hodgkin lymphoma usually due to B-cells. The incidence of T-cell PCNSL is 1-4% in Western countries. Human T-lymphotropic virus (HTLV-1) causes tropical spastic paraparesis/myelopathy and adult T-cell leukemia/lymphoma. We describe the extremely rare occurrence of T-cell PCNSL in a 29 year old HTLV-1 carrier. Additional unusual features of the case included the patient's young age and normal cerebrospinal fluid cytological findings, without leptomeningeal spread. Given the long latency between HTLV-1 infection and disease manifestation, more such cases may be diagnosed in the future. We recommend that every patient with T-cell PCNSL be screened for HTLV-1.