Frequency and Characterization of Movement Disorders in Anti-IgLON5 Disease.

OBJECTIVE: Anti-IgLON5 disease is a recently described neurological disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are under-reported. Here we describe the frequency and types of movement disorders in a series of consecutive patients with this disease. METHODS: In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by three experts in movement disorders. RESULTS: Seventy two patients were included. In 41 (57%) the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least one movement disorder with a median of three per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients, 72%), chorea (24, 33%), bradykinesia (20, 28%), dystonia (19, 26%), abnormal body postures or rigidity (18, 25%), and tremor (15, 21%). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients, 32%) including dystonia (13), myorhythmia (6), chorea (4) or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31(43%) of patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only seven (13%) cases. CONCLUSIONS: Movement disorders are a frequent and leading cause of initial neurological consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

Seronegative and seropositive autoimmune autonomic ganglionopathy (AAG): Same clinical picture, same response to immunotherapy.

Two patients with a syndrome of pandisautonomia with clinical criteria of AAG are provided. Both patients present a similar clinical picture and response to immunosuppressive treatment. One of them has positive antibodies against the ganglionic nicotinic acetylcholine (gAChr) and the other does not. This brief article serves to reflect the spectrum of AAG, at a clinical level, in laboratory tests and in the response to immunotherapy, independently of the presence of positive gAChr antibodies.

Long-term impact on quality of life of subthalamic nucleus stimulation in Parkinson's disease.

Long-term impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on health-related quality of life (HRQOL) and associated factors in patients with Parkinson's disease (PD) are not clear. In this prospective study, we included 69 PD patients (64 % men, mean age 61.3 ± 7.4 and disease duration 13.2 ± 5.7 years) undergoing STN-DBS. They were evaluated preoperatively (baseline), 1 and 5 years postoperatively assessing 39-item Parkinson's Disease Questionnaire (PDQ-39), Schwab and England Activities of Daily Living Scale (SEADL), Unified Parkinson's Disease Rating Scale (UPDRS) off- and on-medication, patient diaries, dopaminergic treatment, mortality and surgical complications. Five years postoperatively, off-medication, there were improvements from baseline in UPDRS-II and III total (27.2 and 26.7 %, respectively) and SEADL (18.6 % more completely independent patients) (p < 0.05) scores, while on-medication, there was a deterioration in UPDRS-III (37.8 %, mainly axial signs) (p < 0.05) and minor improvements in SEADL (3.7 %). While at 1 year PDQ-39, the summary index improved substantially (36.5 %) (p < 0.05), at 5 years patients regressed (only 8.8 %) (p < 0.05), though changes in PDQ-39 subscores remained significant, with improvements in ADL (18.8 %), emotional well-being (19.0 %), stigma (36.4 %) and discomfort (20.6 %), despite worsening in communication (47.8 %) (p < 0.05). Lower preoperative PDQ-39 summary index and greater 1-year UPDRS-III-off total score gain predicted better long-term HRQOL. STN-DBS produces long-term improvements in HRQOL in PD. Preoperative HRQOL and short-term postoperative changes in off-medication motor status may predict long-term HRQOL in PD following STN-DBS.

Autonomic involvement in Parkinsonian carriers of PARK2 gene mutations.

BACKGROUND AND OBJECTIVES: The objective of this study was to assess the presence of autonomic nervous system dysfunction in PARK2 mutation carriers. PATIENTS AND METHODS: We performed a cross-sectional analysis of 8 PARK2 carriers (age: 60.1 ± 12.8 years) and 13 individuals with idiopathic PD (iPD) (age: 59.2 ± 8.9 years). Autonomic dysfunction was measured using the SCOPA-AUT questionnaire, non-invasive autonomic tests and responses of noradrenaline and vasopressin levels to postural changes. Myocardial sympathetic denervation was assessed with metaiodobenzylguanidine (MIBG) scintigraphy. This damage was further investigated in postmortem epicardial tissue of one PARK2 carrier and three control cases (two PD patients and one subject without PD). RESULTS: The prevalence of autonomic symptoms and orthostatic hypotension (OH) was lower in PARK2 mutation carriers than in iPD patients (SCOPA OUT: 3.4 ± 4.8 vs. 14.7 ± 7.2, p < 0.001; OH: present in three iPD patients but none of the PARK2 mutation carriers). Second, sympathetic myocardial denervation was less severe in PARK2 mutation carriers compared to controls, both in MIBG scintigraphy (late H/M uptake ratio: 1.52 ± 0.35 vs. 1.32 ± 0.25 p < 0.05) and in postmortem tissue study. Interestingly, axonal alpha-synuclein deposits were absent in epicardial tissue of the PARK2 mutation carrier while they were present in the two PD patients. INTERPRETATION: Our study supports the view that autonomic nervous system dysfunction and myocardial sympathetic denervation are less pronounced in PARK2 mutation carriers than in individuals with iPD, suggesting that the involvement of small peripheral sympathetic nerve fibers is a minor pathological hallmark in PARK2 carriers.

Cognitive and behavioral symptoms in Parkinson's disease patients with the G2019S and R1441G mutations of the LRRK2 gene.

OBJECTIVE: To compare the cognitive and psychiatric status of patients with Parkinson's disease related to the G2019S and the R1441G mutations of the LRRK2 gene (LRRK2-PD) and idiopathic Parkinson's disease (iPD) patients. METHODS: We examined cognition and psychiatric symptoms in 27 patients with LRRK2-PD (12 G2019S and 15 R1441G) and 27 iPD patients. RESULTS: The groups were similar in age, education, disease duration, levodopa equivalent daily dose, and Unified Parkinson's Disease Rating Scale (UPDRS) II-IV; however, the LRRK2-PD showed less impairment on UPDRS-I (2.0 ± 1.7 vs. 4.2 ± 2.8, p = 0.003). The LRRK2-PD presented less frequent subjective cognitive complaints (18.5% vs. 63.0%, p = 0.002), and mild cognitive impairment or dementia (25.9% vs. 59.2%, p = 0.027). They also showed less impairment on scales for general cognition (Mattis dementia rating scale 131.2 ± 10.9 vs. 119 ± 24.0, p = 0.022), episodic verbal memory (Rey's auditory verbal learning test, immediate recall 39.2 ± 9.5 vs. 27.6 ± 12.8 p < 0.001, delayed recall 7.2 ± 3.7 vs. 4.7 ± 4.0 p = 0.022), and the Neuropsychiatric Inventory (9.7 ± 9.2 vs. 20.5 ± 14.3, p = 0.004, significant differences for apathy and hallucinations). The LRRK2-PD subjects were less frequently treated with antipsychotic medication (0% vs. 25.9%, p = 0.010). There were no significant differences between G2019S and R1441G mutation carriers. CONCLUSIONS: Mutations of the LRRK2 gene might cause PD associated with less cognitive and neuropsychiatric impairment as compared to iPD.

Orthostatic hypotension in Parkinson disease: how much you fall or how low you go?

Orthostatic hypotension (OH) is frequent in patients with Parkinson's disease (PD) and can occur with or without symptoms. Pharmacological treatments are effective, but often exacerbate supine hypertension. Guidelines exist for the diagnosis, but not for the treatment of OH. We examined the relationship between blood pressure (BP) and symptoms in a cohort of PD patients with the goal of identifying a hemodynamic target to guide treatment. We measured BP supine and upright (tilt or active standing) and identified the presence or absence of symptomatic OH by using a validated patient-reported outcome questionnaire in 210 patients with PD. We evaluated the usefulness of the 20/10 and 30/15 mmHg diagnostic criteria (systolic/diastolic) to identify symptomatic OH. Fifty percent of the PD patient cohort met criteria for the 20/10 fall and 30% for the 30/15 BP fall. Among the patients who met either OH criteria, the percentage of those with symptoms was small (33% of those with 20/10 and 44% of those with 30/15 mmHg; 16% and 13%, respectively, overall). Symptomatic OH was associated with an upright mean BP below 75 mmHg. A mean standing BP <75 mmHg had a sensitivity of 97% and a specificity of 98% for detecting symptomatic OH. Although the prevalence of OH in PD is high, not all patients have symptoms of organ hypoperfusion. A mean standing BP below 75 mmHg appears to be a useful benchmark when deciding whether the benefits of initiating pharmacological treatment of OH outweigh the risks of exacerbating supine hypertension.

Autonomic dysfunction in parkinsonian LRRK2 mutation carriers.

INTRODUCTION: The aim of this study was to compare autonomic function in PD symptomatic carriers of the LRRK2 mutations and idiopathic Parkinson's disease (iPD) patients. MATERIAL AND METHODS: We studied 25 PD patients: 12 with the LRRK2 mutation (6 G2019S and 6 R1441G), and 13 with iPD. All patients underwent blood pressure and heart rate monitoring during head up tilt, Valsalva maneuver and deep breathing, along with recording of sympathetic skin response (SSR) and cardiac MIBG scintigraphy. RESULTS: Three of the patients with iPD and one of the LRRK2 carriers had orthostatic hypotension. Arterial pressure "overshoot" during phase IV of Valsalva maneuver was less pronounced in patients with iPD. During passive tilt, LRRK2 carries had higher increase of blood pressure than iPD patients MIBG late myocardial/mediastinal uptake ratios were higher in LRRK2 mutation carriers (1.51 ± 0.28 vs 1.32 ± 0.25; p < 0.05). DISCUSSION: Carriers of the LRRK2 mutation had less autonomic impairment than those with iPD as shown by higher cardiac MIBG uptake and a tendency to less impairment of autonomic non-invasive tests. It is important to carry out larger studies comparing the clinical, functional and pathological characteristics of these patients.

Nocturnal hypertension and dysautonomia in patients with Parkinson's disease: are they related?

Orthostatic hypotension and supine hypertension frequently coexist in Parkinson's disease (PD) patients, leading to visceral damage and increased mortality rates. The aim of this paper is to analyze the frequency and association of both conditions in a sample of outpatients with PD. A total of 111 patients, diagnosed with PD, were studied. Disease duration, treatment, cardiovascular risk factors, UPDRS I-IV and Scopa Aut scale scores were reported. Subjects underwent 24-h ambulatory blood pressure (BP) monitoring and were assessed for orthostatic hypotension. We compared our results with those published in 17,219 patients using the same protocol and the same type of device. Overall, 71.1 % had no proper circadian rhythm. This frequency was significantly higher than that of the control population (48 %). The prevalence of the nondipper or riser patterns was higher in patients with orthostatic hypotension (77.8 vs. 66.7 %). There was a correlation between nightly increases in diastolic blood pressure and changes in BP during the orthostatic test. Patients taking higher doses of treatment had less decreases in SBP (cc:-0.25; p = 0.007) and DBP (cc:-0.33; p < 0.001) at night, however there was no relation with drug type. The majority of patients with Parkinson's disease show an altered circadian rhythm of blood pressure. Patients with a non-dipper or riser pattern on 24 h ABPM exhibited a higher prevalence of autonomic disorders (orthostatic hypotension) and received higher doses of dopaminergic treatment. A day-night variation in diastolic blood pressure was the most important marker of these findings.

Cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K mutation in the α synuclein gene.

OBJECTIVE: The aim of this study was to analyze autonomic function and cardiac sympathetic innervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene (SNCA) mutation. PATIENTS AND METHODS: Autonomic function tests were performed in six patients, four of whom were symptomatic carriers (ages: 46, 59, 52 and 28-years) and two who were asymptomatic carriers (ages: 52 and 29 years). Autopsy studies were performed on an additional two symptomatic carriers not eligible for autonomic testing. Patients completed the SCOPA autonomic questionnaire, and underwent the head-up tilt test accompanied by measurements of plasma norepinephrine. Valsalva maneuver and deep breathing tests, along with recording of sympathetic skin response (SSR) and cardiac MIBG scintigraphy were carried out. Myocardial tissue sections removed from the two autopsied cases were subjected to routine histological staining and immunohistochemical processing with monoclonal antibodies against tyrosine hydroxylase and alpha-synuclein. RESULTS: Both the four symptomatic and the older asymptomatic carriers reported abnormalities in the SCOPA questionnaire and had markedly diminished cardiac MIBG uptake. Plasma norepinephrine in the supine and tilted positions was normal in all subjects. Only one patient had significant orthostatic hypotension. There was a complete absence of tyrosine hydroxylase immunostaining in the myocardium of the two autopsied cases. INTERPRETATION: We have found imaging and histological evidence of cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene mutation. The sympathetic denervation appears to be organ-specific, with selective affectation of the heart given that plasma norepinephrine levels and blood pressure were normal.

The applause sign and neuropsychological profile in progressive supranuclear palsy and Parkinson's disease.

BACKGROUND: The applause sign has been associated with various neurodegenerative diseases. We investigate its validity in the differential diagnosis of progressive supranuclear palsy and Parkinson's disease, and its relationship with neuropsychological tests. PATIENTS AND METHODS: 23 patients with progressive supranuclear palsy and 106 patients with Parkinson's disease were included and administered the following scales: progressive supranuclear palsy rating scale, unified Parkinson's disease rating scale (UPDRS), mini-mental state examination (MMSE), frontal assessment battery (FAB), neuropsychiatric inventory and three-clap test. RESULTS: 73.9% with progressive supranuclear palsy and 21.7% with Parkinson's disease showed a positive applause sign. Only a positive applause sign, UPDRS II score and disease duration were found to be predictors of progressive supranuclear palsy. Both patient-groups showed statistically significant correlations between the applause sign and neuropsychological tests: in progressive supranuclear palsy patients MMSE correlation coefficient: 0.62 (p: 0.002) and FAB correlation coefficient: 0.48 (p: 0.02), and in Parkinson's disease patients MMSE correlation coefficient: 0.47 (p<0.001) and FAB correlation coefficient: 0.43 (p<0.001). Verbal fluency and inhibitory control (FAB) and writing and orientation in time (MMSE) discriminated between patients with normal and positive applause sign. CONCLUSIONS: A positive applause sign is not specific to progressive supranuclear palsy and may also be observed in Parkinson's disease patients with altered cognition, and it's related to cortical frontal abnormalities such as language disorders and inhibitory control.

SCOPA-AUT scale in different parkinsonisms and its correlation with (123) I-MIBG cardiac scintigraphy.

INTRODUCTION: Our objective was to assess the usefulness of the Scales for Outcomes in Parkinson's disease - Autonomic (SCOPA-AUT) in the differential diagnosis of Parkinsonisms and clarify its relation with 123-I-MIBG cardiac scintigraphy. METHODS: A total of 112 patients with Parkinson's disease (PD), 12 with multiple system atrophy parkinsonian variant (MSA-P) and 20 with progressive supranuclear palsy (PSP) participated in the study. The following variables were collected: age, sex, age at onset, length of illness, type and dose of anti-Parkinson medication, and score on the Unified Parkinson's Disease Rating Scale. The Unified Multiple System Atrophy Rating Scale was administered to patients with MSA and the Progressive Supranuclear Palsy Rating Scale to those with PSP. Finally, the SCOPA-AUT was administered to all the patients. Cardiac 123I-MIBG SPECT scans were performed on a subset of patients (25 with PD and 5 with MSA-P). RESULTS: Statistically significant differences were observed (p < 0.01) in the SCOPA-AUT scores between patients with PD (14.75+/-8.09) and those with MSA (21.07+/-5.56), the latter having higher scores on the bowel function (20.07+/-13.40 vs 34.92+/-14.91) and urinary domains (30.21+/-21.55 vs 49.26+/-21.40) (p < 0.01). No correlation was found between the SCOPA-AUT score and anti-Parkinson's medication and heart:mediastinum (H/M) MIBG uptake ratio in the cardiac SPECT (at 4 h). DISCUSSION: Severity of dysautonomia as measured by the SCOPA-AUT was not correlated with clinical severity, time since onset or the H/M ratio. In the patients with PD, the only variable associated with the H/M ratio was age at onset of the disease.

Tako-tsubo cardiomyopathy in a patient with bilateral lesions in the dorsal medulla.

Tako-tsubo-like cardiomyopathy (TTC) is much more common than originally thought. The exact pathophysiology of TTC is unclear. The most accepted theory proposes myocardial stunning of neurogenic origin, supported by the frequent antecedent of emotional or physical stress, suggesting a catecholamine-mediated mechanism. We present a patient with this syndrome and bilateral damage of the dorsal medulla oblongata likely affecting both solitary tract nuclei. Our case points to a link between baroreflex failure and TTC, highlighting the important role of sympathetic discharge in the pathophysiology of TTC.

Impact of psychiatric symptoms and sleep disorders on the quality of life of patients with Parkinson's disease.

The objective of this study is to assess how the non-motor symptoms of Parkinson's disease (PD), such as depression, cognitive deterioration, neuropsychiatric and sleep disorders, affect the quality of life, and to compare them with the motor symptoms in order to determine their real impact. A cross-sectional study was designed including 99 patients (mean age 68.5 ± 9.9 years, duration of disease 8.7 ± 6.2 years). Demographic data, onset of PD, years on treatment with levodopa (LD), class of dopaminergic drug prescribed, and dosages were obtained. The following scales were used: quality of life (PDQ-39), Unified Parkinson's Disease Rating Scale (UPDRS I-IV), Parkinson Disease Sleep Scale (PDSS) and daytime sleepiness (Epworth), Mini-Mental State Examination, depression (HAM-D), and the neuropsychiatric inventory (NPI-10). The PDQ-39 summary index (PDQ-39 SI) was 24.7 ± 13.2. A linear regression model including all variables showed that four independent variables accounted for 67.2% of the variance in the PDQ-39 SI (F = 33,277; p < 0.001): NPI, PDSS, UPDRS IV, and UPDRS I. When sub-items of the NPI, PDSS and UPDRS IV scales are analyzed, significant correlations (p < 0.001) are found between the PDQ-39 SI and depression, agitation, apathy, anxiety, hallucinations, delusions, incontinence of urine, morning painful posturing, restlessness in bed, morning fatigue, duration of off periods, unpredictable and predictable off periods, early morning dystonia, and sudden off periods. Neuropsychiatric symptoms, especially depression, nighttime sleep disorders such as urinary incontinence, nighttime restlessness, morning fatigue and somnolence, off-period dystonia and motor fluctuations are the variables that most affect the quality of life of patients with PD.

Factors influencing the symmetry of Parkinson's disease symptoms.

INTRODUCTION: The presence of asymmetry in symptoms and clinical signs favours the diagnosis of Parkinson's disease (PD). The aim of this study is to analyse this symptom asymmetry as a function of different variables and compare it with other parkinsonisms. MATERIALS AND METHODS: 201 Patients with PD were studied. The sample was supplemented with 29 patients diagnosed with MSA-P (according to the criteria established by the American Academy of Neurology) and 17 with PSP (according to the criteria established by the NINDS-SPSP International Workshop). The symmetry was evaluated, based on items 20-23, 25 and 26 of the Unified Parkinson's Disease Rating Scale, by subtracting the motor score for the left side from that for the right side. Those patients with a difference of one point or more were designated as being asymmetric. RESULTS: Around 16.4% of patients presented symmetrical clinical symptoms. There were no differences between those patients with or without family history of the disease. Those patients with symmetric symptoms were found to have longer symptomatic disease duration (10.8 vs. 7.9 years), a worse mental state (UPDRS I: 3.9 vs. 3.2), a higher incidence of complications (UPDRS IV: 4.5 vs. 3.2) and had their activities of daily living (ADL) affected to a greater degree (UPDRS II: 13.0 vs. 11.0). Around 48.3% of the MSA-P patients and 52.9% of the PSP patients showed symmetric symptoms. CONCLUSIONS: The degree of symmetry is not useful in differentiating between sporadic and familial PD. However, the observation of highly symmetrical symptoms in a patient with short evolution time indicates that an atypical parkinsonism should be suspected.

Orthostatic hypotension associated with an epidermoid tumor of the IV ventricle.

We report the case of a 32-year-old man with an epidermoid tumor of the fourth ventricle. About 14 years later, he showed a tumor recurrence which was removed. After this procedure the patient complained of presyncopal and syncopal crisis while attempting to stand or walk. On examination, severe orthostatic hypotension was confirmed and autonomic tests were abnormal. The brain MRI showed a tetraventricular hydrocephalus predominating in the fourth ventricle. A ventriculo-peritoneal shunt was performed, and after surgery the orthostatic intolerance improved. We believe that hydrocephalus has probably been a contributory factor to orthostatic hypotension, and suggest expanding testing for dysautonomia in patients with hydrocephalus.