Cerebral involvement in a patient with Goodpasture's disease due to shortened induction therapy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Goodpasture's disease is a rare immunological disease with formation of pathognomonic antibodies against renal and pulmonary basement membranes. Cerebral involvement has been reported in several cases in the literature, yet the pathogenetic mechanism is not entirely clear.</p> <p>Case presentation</p> <p>A 21-year-old Caucasian man with Goodpasture's disease and end-stage renal disease presented with two generalized seizures after a period of mild cognitive disturbance. Blood pressure and routine laboratory tests did not exceed the patient's usual values, and examination of cerebrospinal fluid was unremarkable. Cerebral magnetic resonance imaging (MRI) revealed multiple cortical and subcortical lesions on fluid-attenuated inversion recovery sequences. Since antiglomerular basement membrane antibodies were found to be positive with high titers, plasmapheresis was started. In addition, cyclophosphamide pulse therapy was given on day 13. Encephalopathy and MRI lesions disappeared during this therapy, and antiglomerular basement membrane antibodies were significantly reduced. Previous immunosuppressive therapy was performed without corticosteroids and terminated early after 3 months.</p> <p>The differential diagnostic considerations were cerebral vasculitis and posterior reversible encephalopathy syndrome. Vasculitis could be seen as an extrarenal manifestation of the underlying disease. Posterior reversible encephalopathy syndrome, on the other hand, can be triggered by immunosuppressive therapy and may appear without a hypertensive crisis.</p> <p>Conclusion</p> <p>A combination of central nervous system symptoms with a positive antiglomerular basement membrane test in a patient with Goodpasture's disease should immediately be treated as an acute exacerbation of the disease with likely cross-reactivity of antibodies with the choroid plexus. In our patient, a discontinuous strategy of immunosuppressive therapy may have favored recurrence of Goodpasture's disease.</p

Unilateral optic neuropathy following subdural hematoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Unilateral optic neuropathy is commonly due to a prechiasmatic affliction of the anterior visual pathway, while losses in visual hemifields result from the damage to brain hemispheres. Here we report the unusual case of a patient who suffered from acute optic neuropathy following hemispherical subdural hematoma. Although confirmed up to now only through necropsy studies, our case strongly suggests a local, microcirculatory deficit identified through magnetic resonance imaging <it>in vivo</it>.</p> <p>Case presentation</p> <p>A 70-year-old Caucasian German who developed a massive left hemispheric subdural hematoma under oral anticoagulation presented with acute, severe visual impairment on his left eye, which was noticed after surgical decompression. Neurologic and ophthalmologic examinations indicated sinistral optic neuropathy with visual acuity reduced nearly to amaurosis. Ocular pathology such as vitreous body hemorrhage, papilledema, and central retinal artery occlusion were excluded. An orbital lesion was ruled out by means of orbital magnetic resonance imaging. However, cerebral diffusion-weighted imaging and T2 maps of magnetic resonance imaging revealed a circumscribed ischemic lesion within the edematous, slightly herniated temporomesial lobe within the immediate vicinity of the affected optic nerve. Thus, the clinical course and morphologic magnetic resonance imaging findings suggest the occurrence of pressure-induced posterior ischemic optic neuropathy due to microcirculatory compromise.</p> <p>Conclusion</p> <p>Although lesions of the second cranial nerve following subdural hematoma have been reported individually, their pathogenesis was preferentially proposed from autopsy studies. Here we discuss a dual, pressure-induced and secondarily ischemic pathomechanism on the base of <it>in vivo </it>magnetic resonance imaging diagnostics which may remain unconsidered by computed tomography.</p

Effects of physiological aging and cerebrovascular risk factors on the hemodynamic response to brain activation: a functional transcranial Doppler study

The influence of the vascular system on the coupling of cerebral blood flow (CBF) to focal brain activation during aging is incompletely understood. Using functional transcranial Doppler sonography and a hypercapnic challenge as a marker of intact cerebral vasoreactivity, we determined CBF velocity (CBFV) changes in response to a language and arithmetic task in a group of 43 healthy young subjects (mean age 32 +/- 8.6 years), 18 healthy old subjects (mean age 64 +/- 9.8 years) and 29 old subjects with risk factors for an atherosclerosis (mean age 69 +/- 8.4 years). Despite a similar performance during the cognitive tasks the CBFV changes were significantly lower in the group of old subjects with vascular risk factors compared with the healthy young and old subjects. Similarly, the CBFV changes during hypercapnia were significantly lower in the group of old subjects with vascular risk factors compared with the healthy young and old subjects. In contrast, both cognitive tasks and hypercapnia produced comparable CBFV changes in the group of healthy young and old subjects. These results suggest that the hemodynamic response to neuronal activation is unaffected by aging alone, whereas the presence of cardiovascular risk factors significantly diminishes the capability of cerebral vessels to react to vasodilating stimuli

Evaluation of 5-Fluorouracil Pharmacokinetics in Cancer Patients with a c.1905+1G > A Mutation in DPYD by Means of a Bayesian Limited Sampling Strategy

Background and Objective: Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5FU) and DPD deficiency is an important pharmacogenetic syndrome. So far, only very limited information is available regarding the pharmacokinetics of 5FU in patients with a (partial) DPD deficiency and no limited sampling models have been developed taking into account the non-linear pharmacokinetic behaviour of 5FU. The aim of this study was to evaluate the pharmacokinetics of 5FU and to develop a limited sampling strategy to detect decreased 5FU elimination in patients with a c.1905+1G>A-related DPD deficiency. Methods: Thirty patients, heterozygous for the c.1905+1G>A mutation in DPYD, and 18 control patients received a dose of 5FU 300 mg/m(2) and/or 5FU 450 mg/m(2), followed by pharmacokinetic analysis of the 5FU plasma levels. A population pharmacokinetic analysis was performed in order to develop a compartmental pharmacokinetic model suitable for a limited sampling strategy. Clinical aspects of treating DPD-deficient patients with 5FU-based chemotherapy were assessed from the retrospectively collected clinical data. Results: In a two-compartment model with Michaelis-Menten elimination, the mean maximum enzymatic conversion capacity (V-max) value was 40% lower in DPD-deficient patients compared with controls (p <0.001). Using a limited sampling strategy, with V-max values calculated from 5FU concentrations at 30 or 60 minutes, significant differences were observed between DPD-deficient patients and controls at both dose levels (p <0.001). The positive predictive value and negative predictive value for V-max, calculated from 5FU levels at 60 minutes, were 96% and 88%, respectively, in patients treated with a single dose of 5FU 300 mg/m(2). All seven DPD-deficient patients (two males and five females) who had been genotyped prior to initiation of standard 5FU-containing chemotherapy developed grade 3-4 toxicity, with one case of lethal toxicity in a female patient. No grade 4 toxicity or lethal outcome was observed in 13 DPD-deficient patients treated with reduced doses of 5FU. The average dose of 5FU in DPD-deficient patients with mild toxicity (grade <= 2) was 61 +/- 16% of the normal 5FU dose (n=10). Conclusions: Profound differences in the elimination of 5FU could be detected between DPD-deficient patients and control patients. Pharmacokinetic 5FU profiling, using a single 5FU concentration at 60 minutes, may be useful for identification of DPD-deficient patients in order to reduce severe toxicity. Furthermore, treatment of DPD-deficient patients with standard 5FU-containing chemotherapy was associated with severe (lethal) toxicit

Anticoagulant Reversal, Blood Pressure Levels, and Anticoagulant Resumption in Patients With Anticoagulation-Related Intracerebral Hemorrhage

Importance Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH).Objective To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption.Design, Setting, and Participants Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption.Exposures Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment.Main Outcomes and Measures Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome.Results Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%).Conclusions and Relevance Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies