Brain Microvasculature Involvement in ANCA Positive Vasculitis.

OBJECTIVE: Endothelial dysfunction is associated with arterial stiffness, a factor that is increasingly recognised as an important determinant of cardiovascular risk. High-flow organs such as the brain and kidneys are particularly sensitive to excessive pressure and flow pulsatility. High, local blood flow is associated with low microvascular impedance, which facilitates the penetration of excessive pulsatile energy into the microvascular bed leading to tissue damage. Systemic endothelial dysfunction and arterial stiffness have been demonstrated in peripheral vessels in associated vasculitis (AAV). Although, the brain involvement is not infrequent in AAV, it has not been evaluated previously. Our aim is to evaluate the involvement of the brain microvasculature in AAV. METHODS: Twenty-three patients with inactive AAV were studied. Brain blood flow was assessed by transcranial Doppler (TCD) and single-photon positron emission tomography (SPECT), structural brain involvement by brain MRI and cognitive scores by Montreal Cognitive Assessment (MoCA) test. RESULTS: Lower mean flow velocity (MFV) was associated to altered SPECT perfusion, higher white matter changes (WMC), lower MoCA scores and younger age (p < 0.05). Middle cerebral artery pulsatility index (MCA-PI) was related to hypertension, diabetes, lower scores on MoCA, increased vasculitis damage index (VDI) and perfusion impairment in SPECT (p < 0.05). These data were reproduced for all intracranial arteries. Up to 88.9% of patients had WMC on MRI. A higher lesion load was associated with age, decreased MoCA and fewer MFV with higher PI. The multivariable linear regression analysis showed that the greater the lesion loads, greater the bifrontal atrophy, MCA-PI and lower MoCA scores. Up to 60.9% of patients presented a decreased MoCA score (p = 0.012). It appeared to be related to VDI (p = 0.04), WMC (p = 0.004) and altered SPECT (p = 0.05). CONCLUSIONS: The alterations in brain perfusion SPECT, the presence of white matter lesions on MRI, as well as increased PI and RI with lower MFV of the cerebral vessels in TCD suggest the presence of microangiopathy in asymptomatic AAV that could lead to cognitive impairment.

Paraneoplastic Neurological Syndromes and Glutamic Acid Decarboxylase Antibodies.

IMPORTANCE: Little is known of glutamic acid decarboxylase antibodies (GAD-abs) in the paraneoplastic context. Clinical recognition of such cases will lead to prompt tumor diagnosis and appropriate treatment. OBJECTIVE: To report the clinical and immunological features of patients with paraneoplastic neurological syndromes (PNS) and GAD-abs. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series study and immunological investigations conducted in February 2014 in a center for autoimmune neurological disorders. Fifteen cases with GAD65-abs evaluated between 1995 and 2013 who fulfilled criteria of definite or possible PNS without concomitant onconeural antibodies were included in this study. MAIN OUTCOMES AND MEASURES: Analysis of the clinical records of 15 patients and review of 19 previously reported cases. Indirect immunofluorescence with rat hippocampal neuronal cultures and cell-based assays with known neuronal cell-surface antigens were used. One hundred six patients with GAD65-abs and no cancer served as control individuals. RESULTS: Eight of the 15 patients with cancer presented as classic paraneoplastic syndromes (5 limbic encephalitis, 1 paraneoplastic encephalomyelitis, 1 paraneoplastic cerebellar degeneration, and 1 opsoclonus-myoclonus syndrome). When compared with the 106 non-PNS cases, those with PNS were older (median age, 60 years vs 48 years; P = .03), more frequently male (60% vs 13%; P < .001), and had more often coexisting neuronal cell-surface antibodies, mainly against γ-aminobutyric acid receptors (53% vs 11%; P < .001). The tumors more frequently involved were lung (n = 6) and thymic neoplasms (n = 4). The risk for an underlying tumor was higher if the presentation was a classic PNS, if it was different from stiff-person syndrome or cerebellar ataxia (odds ratio, 10.5; 95% CI, 3.2-34.5), or if the patient had coexisting neuronal cell-surface antibodies (odds ratio, 6.8; 95% CI, 1.1-40.5). Compared with the current series, the 19 previously reported cases had more frequent stiff-person syndrome (74% vs 13%; P = .001) and better responses to treatment (79% vs 27%; P = .005). Predictors of improvement in the 34 patients (current and previously reported) included presentation with stiff-person syndrome and the presence of a thymic tumor. CONCLUSIONS AND RELEVANCE: Patients with GAD-abs must be screened for an underlying cancer if they have clinical presentations different from those typically associated with this autoimmunity or develop classic PNS. The risk for cancer increases with age, male sex, and the presence of coexisting neuronal cell-surface antibodies.

Triple therapy with darbepoetin alfa, idebenone, and riboflavin in Friedreich's ataxia: an open-label trial.

Minimal objective evidence exists regarding management of Friedreich's ataxia (FRDA). Antioxidant and recombinant human erythropoietin therapies have been considered potential treatments to slow progression of FRDA in a small number of studies. The primary objective of the current study was to test the efficacy, safety, and tolerability of triple therapy-darbepoetin alfa, idebenone, and riboflavin-in FRDA in a clinical pilot study. Patients included in this study were nine females, 16 to 45 years of age (average 28 ± 8), diagnosed with FRDA with confirmed GAA repeat expansion mutations in the FXN gene and a GAA repeat ≥400 on the shorter allele. Patients had a baseline score between 8 and 28.5 (average 20.7 ± 8.3) on the scale for the assessment and rating of ataxia and 94.3 ± 27.2 g/m(2) in left ventricular mass index (LVMI). Patients had been treated with triple therapy with 150 µg darbepoetin alfa every 2 or 3 weeks, 10-20 mg/kg/day idebenone, and 10-15 mg/kg/day riboflavin for 32 ± 19.4 months (range of 8-56 months). Triple therapy was tolerated. Although not statistically significant, improvement of ataxia was observed during the first six 4-month periods of the study. Furthermore, a small decrease in disease progression during the first 2 years of treatment was observed. Long-term statistically nonsignificant improvement of LVMI and stability of the echocardiographic parameters could be considered. Triple therapy may slow disease progression of FRDA.

Neuro-ophthalmological features of primary diffuse leptomeningeal gliomatosis.

We performed an in-depth study of the neuro-ophthalmologic signs and symptoms of a rare but fatal disease known as primary diffuse leptomeningeal gliomatosis (PDLG). Two new cases of PDLG are described, and 22 published cases reviewed. Papilledema and sixth nerve palsy are the most common neuro-ophthalmic findings. Other abnormalities include third and fourth nerve palsies, nystagmus, and vision loss. Involvement of the visual system may be part of the initial presentation of PDLG.

Rheumatoid meningitis mimicking progressive supranuclear palsy.

INTRODUCTION: Rheumatoid meningitis is an uncommon manifestation of longstanding rheumatoid arthritis and few cases have been described. The clinical presentation is extremely variable as reported in medical literature. CASE REPORT: We report a 71-year-old woman with 15 years of seropositive rheumatoid arthritis who developed neurological complications: cognitive deterioration; hypomimia; limitation on vertical gaze; and axial stiffness, resembling progressive supranuclear palsy and seizures. Brain magnetic resonance imaging showed a diffuse dural plaque on both frontal and temporal lobes exhibiting homogeneous gadolinium enhancement. There was diffuse leptomeningeal enhancement and hyperintense white matter lesions. The final diagnosis made by image-guided biopsy showed rheumatoid pachymeningitis. After the definitive diagnosis, high doses of corticosteroids and immunosuppressive treatment were started. CONCLUSIONS: We emphasize the diagnostic importance of the biopsy in cases of chronic pachymeningitis and stress that diverse entities can cause progressive supranuclear palsy-like phenotypes.

Primary diffuse leptomeningeal gliomatosis mimicking meningeal tuberculosis.

Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare condition, with only 45 cases recorded to date, characterized by infiltration of the meninges by glial cells without evidence of primary tumor in the brain or spinal cord parenchyma. Here, we describe a patient with PDLG who was managed with tuberculostatic drugs owing to multiple findings that were suggestive of tuberculous meningitis. A 19-year-old woman presented with headaches and behavioral changes. A sudden decrease in visual acuity with papilledema, bilateral sixth nerve palsies, and neck stiffness developed. Lumbar puncture showed elevated opening pressure (50 cm H2O). Cerebrospinal fluid (CSF) analysis showed glucose 30 mg/dL, protein 26.5 mg/dL, white blood cell count 150 (60% lymphocytes, 40% neutrophils). The second sample of CSF provided adenosine deaminase activity 21.9 U/L. Polymerase chain reaction for Koch's bacillus was positive in the third CSF sample. Magnetic resonance imaging revealed meningeal thickening of the quadrigeminal cistern, tentorium cerebelli, cerebral convexity, and spinal cord, with gadolinium enhancement in nodular lesions. The patient died 22 weeks after symptom onset owing to brainstem infarction. Postmortem pathologic studies revealed PDLG. This entity should be included in the differential diagnosis of tuberculous meningitis that does not respond to treatment with antituberculous drugs. Surgical biopsy should be considered in contrast-enhanced areas in magnetic resonance imaging.

Tomografía axial computarizada y resonancia magnética en el diagnóstico de la enfermedad de Whipple con afectación del sistema nervioso central / Diagnostic features of central nervous system involvement in WhippleÆs disease by magnetic resonance imaging and computed tomography

Se presenta un paciente con enfermedad de Whipple y síntomas exclusivamente neurológicos, entre los que destacaron alteraciones cognoscitivas, cuadro comicial, movimientos oculares anormales y síndrome piramidal. En las técnicas de imagen (TAC y RM) se observaron en diversas regiones cerebrales masas que, en la RM, se realzaban con gadolinio. Se identificó además importante ependimitis, así como una lesión de volumen en la médula cervical. La PCR fue negativa y el diagnóstico se confirmó con microscopía electrónica. Lo más notable de este caso fue la excelente respuesta a la antibioterapia.