Koldo Berganzo

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

Orthostatic hypotension (OH) is frequent in patients with Parkinsons 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.

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.

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.

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 Parkinsons 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 Parkinsons 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 Parkinsons 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-Parkinsons 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.

Factors influencing the symmetry of Parkinson's disease symptoms

INTRODUCTION The presence of asymmetry in symptoms and clinical signs favours the diagnosis of Parkinsons 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 Parkinsons 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.

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 Parkinsons disease, and its relationship with neuropsychological tests. PATIENTS AND METHODS 23 patients with progressive supranuclear palsy and 106 patients with Parkinsons disease were included and administered the following scales: progressive supranuclear palsy rating scale, unified Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons disease patients with altered cognition, and its related to cortical frontal abnormalities such as language disorders and inhibitory control.

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.

Trastorno de conducta del sueño REM y fallo autonómico ¿puro? A propósito de 2 casos

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Anti-IgLON5 disease responsive to immunotherapy: a case report with an abnormal MRI: Supporting immunopathogenicity of anti-IgLON5

A 65-year-old man presented with a 3-month history of gait disturbance, generalized chorea, and painful intermittent cervical dystonia. He also reported sleep disruption, mood changes, and irritability. He had a medical history of hypertension and polymyalgia rheumatica. There was no family history. Neurological examination evidenced moderate generalized chorea, dystonia of the neck, mild unsteady gait, and subtle dysarthria. There were no signs of parkinsonism or limitation of eye movements. Also, no Kayser-Fleischer ring, xanthomas, or signs of neuropathy were observed. A neuropsychiatric assessment evidenced emotional lability with no neurocognitive impairment. A blood test showed normal iron profile, cholestanol, phytanic acid levels, vitamin E, copper, ceruloplasmin, creatine kinase, chitotriosidase activity, hypercoagulability, systemic autoimmunity assays, and peripheral blood smear examination. HIV and bacterial serologies were negative. Genetic testing excluded both Huntington’s disease and the main Huntington’s disease-like spinocerebellar ataxia 17. A brain MRI showed paramagnetic deposits in the basal ganglia, substantia nigra, and red nucleus (Fig. 1A,D). A normal CT of the brain (Fig. 1C,F) ruled out calcification. A video-polysomnography showed fragmented sleep, motor restlessness, vocalizations, the absence of REM-sleep, and an apnea-hypopnea index of 57 (severe sleep apnea). Symptomatic treatment with tetrabenazine, quetiapine, trazodone, and CPAP was started. Nine months later, the patient’s clinical state was suddenly impaired by an exacerbation with bulbar dysfunction (severe dysarthria, dysphagia, and aspiration pneumonia) and severe gait instability. Due to this impairment, the patient was admitted to our hospital. A lumbar puncture showed CSF pleocytosis (9 cells per mm, 100% lymphocytes). Oligoclonal bands were negative. An autoimmune etiology of the disorder was suspected. After intravenous methylprednisolone pulses (250 mg per day for three days), the patient improved to his baseline. A total body CT was normal. At this time, a control MRI revealed an increase of paramagnetic deposits (Fig. 1B,E). AntiGAD, antiIA2, and a panel of antibodies against neuronal cell-surface antigens (NMDAR, AMPAR, CASPR2, LGI1, DPPX, and GABAB) were negative in serum and CSF. Anti-IgLON5 antibodies were specifically assessed, obtaining a positive result in serum and CSF (Fig. 2). HLA-DQB1*0501 and HLA-DRB1*10:01 alleles were present. Anti-IgLON5 encephalopathy was diagnosed. In addition to symptomatic treatment, rituximab was started as maintenance immunosuppressive therapy. At present, four years after disease onset, the patient remains stable (slight dysarthria and mild chorea persist) with no new exacerbation.

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.