Risks and benefits of invasive epilepsy surgery workup with implanted subdural and depth electrodes.

PURPOSE: In patients with pharmacoresistant focal-onset seizures, invasive presurgical workup can identify epilepsy surgery options when noninvasive workup has failed. Yet, the potential benefit must be balanced with procedure-related risks. This study examines risks associated with the implantation of subdural strip and grid, and intracerebral depth electrodes. Benefit of invasive monitoring is measured by seizure outcomes. Diagnostic procedures made possible by electrode implantation are described. METHODS: Retrospective evaluation of invasive workups in 242 epilepsy surgery candidates and additional 18 patients with primary brain tumors implanted for mapping only. Complications are scaled in five grades of severity. A regression analysis identifies risk factors for complications. Outcome is classified according to Engel's classification. KEY FINDINGS: Complications of any type were documented in 23% of patients, and complications requiring surgical revision in 9%. We did not find permanent morbidity or mortality. Major risk factor for complications was the implantation of grids and the implantation of electrode assemblies comprising strip and grid electrodes. Depth electrodes were significantly correlated with a lower risk. Tumors were not correlated with higher complication rates. Chronic invasive monitoring of 3-40 days allowed seizure detection in 99.2% of patients with epilepsy and additional extensive mapping procedures. Patients with epilepsy with follow-up >24 months (n = 165) had an Engel class 1a outcome in 49.7% if epilepsy surgery was performed, but only 6.3% when surgery was rejected. SIGNIFICANCE: The benefit of chronic invasive workup outweighs its risks, but complexity of implantations should be kept to a minimum.

Doxycycline improves filarial lymphedema independent of active filarial infection: a randomized controlled trial.

BACKGROUND: The aim of this study was to determine whether improvement of filarial lymphedema (LE) by doxycycline is restricted to patients with ongoing infection (positive for circulating filarial antigen [CFA]), or whether the majority of CFA-negative patients with LE would also show a reduction in LE severity. METHODS: One hundred sixty-two Ghanaian participants with LE stage 1-5 (Dreyer) were randomized blockwise into 2 groups (CFA positive or negative) and allocated to 3 treatment arms of 6 weeks: (1) amoxicillin (1000 mg/d), (2) doxycycline (200 mg/d), or (3) placebo matching doxycycline. All groups received standard hygiene morbidity management. The primary outcome was reduction of LE stages. Secondary outcomes included frequency of acute attacks and ultrasonographic assessment of skin thickness at the ankles. Parameters were assessed before treatment and after 3, 12, and 24 months. RESULTS: Doxycycline-treated patients with LE stage 2-3 showed significant reductions in LE severity after 12 and 24 months, regardless of CFA status. Improvement was observed in 43.9% of doxycycline-treated patients, compared with only 3.2% and 5.6% in the amoxicillin and placebo arms, respectively. Skin thickness was correlated with LE stage improvement. Both doxycycline and amoxicillin were able to reduce acute dermatolymphangioadenitis attacks. CONCLUSIONS: Doxycycline treatment improves mild to moderate LE independent of ongoing infection. This finding expands the benefits of doxycycline to the entire population of patients suffering from LE. Patients with LE stage 1-3 should benefit from a 6-week course of doxycycline every other year or yearly, which should be considered as an improved tool to manage morbidity in filarial LE. Clinical Trials Registration. ISRCTN 90861344.

Elevated adaptive immune responses are associated with latent infections of Wuchereria bancrofti.

In order to guarantee the fulfillment of their complex lifecycle, adult filarial nematodes release millions of microfilariae (MF), which are taken up by mosquito vectors. The current strategy to eliminate lymphatic filariasis as a public health problem focuses upon interrupting this transmission through annual mass drug administration (MDA). It remains unclear however, how many rounds of MDA are required to achieve low enough levels of MF to cease transmission. Interestingly, with the development of further diagnostic tools a relatively neglected cohort of asymptomatic (non-lymphedema) amicrofilaremic (latent) individuals has become apparent. Indeed, epidemiological studies have suggested that there are equal numbers of patent (MF(+)) and latent individuals. Since the latter represent a roadblock for transmission, we studied differences in immune responses of infected asymptomatic male individuals (n = 159) presenting either patent (n = 92 MF(+)) or latent (n = 67 MF(-)) manifestations of Wuchereria bancrofti. These individuals were selected on the basis of MF, circulating filarial antigen in plasma and detectable worm nests. Immunological profiles of either Th1/Th17, Th2, regulatory or innate responses were determined after stimulation of freshly isolated PBMCs with either filarial-specific extract or bystander stimuli. In addition, levels of total and filarial-specific antibodies, both IgG subclasses and IgE, were ascertained from plasma. Results from these individuals were compared with those from 22 healthy volunteers from the same endemic area. Interestingly, we observed that in contrast to MF(+) patients, latent infected individuals had lower numbers of worm nests and increased adaptive immune responses including antigen-specific IL-5. These data highlight the immunosuppressive status of MF(+) individuals, regardless of age or clinical hydrocele and reveal immunological profiles associated with latency and immune-mediated suppression of parasite transmission.

Retarded Onchocerca volvulus L1 to L3 larval development in the Simulium damnosum vector after anti-wolbachial treatment of the human host.

BACKGROUND: The human parasite Onchocerca volvulus harbours Wolbachia endosymbionts essential for worm embryogenesis, larval development and adult survival. In this study, the development of Wolbachia-depleted microfilariae (first stage larvae) to infective third stage larvae (L3) in the insect vector Simulium damnosum was analysed. METHODS: Infected volunteers in Cameroon were randomly and blindly allocated into doxycycline (200 mg/day for 6 weeks) or placebo treatment groups. After treatment, blackflies were allowed to take a blood meal on the volunteers, captured and dissected for larval counting and DNA extraction for quantitative real-time PCR analysis. RESULTS: PCR results showed a clear reduction in Wolbachia DNA after doxycycline treatment in microfilariae from human skin biopsies with > 50% reduction at one month post-treatment, eventually reaching a reduction of > 80%. Larval stages recovered from the insect vector had similar levels of reduction of endosymbiotic bacteria. Larval recoveries were analysed longitudinally after treatment to follow the kinetics of larval development. Beginning at three months post-treatment, significantly fewer L3 were seen in the blackflies that had fed on doxycycline treated volunteers. Concomitant with this, the proportion of second stage larvae (L2) was significantly increased in this group. CONCLUSIONS: Doxycycline treatment and the resulting decline of Wolbachia endobacteria from the microfilaria resulted in retarded development of larvae in the insect vector. Thus, anti-wolbachial treatment could have an additive effect for interrupting transmission by reducing the number of L3 that can be transmitted by blackflies.

Macrofilaricidal Activity in Wuchereria bancrofti after 2 Weeks Treatment with a Combination of Rifampicin plus Doxycycline.

Infection with the filarial nematode Wuchereria bancrofti can lead to lymphedema, hydrocele, and elephantiasis. Since adult worms cause pathology in lymphatic filariasis (LF), it is imperative to discover macrofilaricidal drugs for the treatment of the infection. Endosymbiotic Wolbachia in filariae have emerged as a new target for antibiotics which can lead to macrofilaricidal effects. In Ghana, a pilot study was carried out with 39 LF-infected men; 12 were treated with 200 mg doxycycline/day for 4 weeks, 16 were treated with a combination of 200 mg doxycycline/day + 10 mg/kg/day rifampicin for 2 weeks, and 11 patients received placebo. Patients were monitored for Wolbachia and microfilaria loads, antigenaemia, and filarial dance sign (FDS). Both 4-week doxycycline and the 2-week combination treatment reduced Wolbachia load significantly. At 18 months posttreatment, four-week doxycycline resulted in 100% adult worm loss, and the 2-week combination treatment resulted in a 50% adult worm loss. In conclusion, this pilot study with a combination of 2-week doxycycline and rifampicin demonstrates moderate macrofilaricidal activity against W. bancrofti.

The role of ultrasonography in the differentiation of the various types of filaricele due to bancroftian filariasis.

OBJECTIVE: (i) To determine the frequencies of urogenital pathologies in men infected with bancroftian filariasis, and (ii) to evaluate the role of ultrasonography (USG) as a diagnostic tool to differentiate between diverse pathologies with different clinical implications. To date, all types of scrotal enlargement resulting from lymphatic filariasis (LF) have been summarized under one term: "filaricele". PATIENTS AND METHODS: Data were compiled from recruitment phases for field trials in an endemic area for LF in Ghana. 1453 men aged 18 years and above underwent ultrasound examinations of the scrotum. Observation parameters were: Filaria Dance Sign (FDS), dilation of supratesticular lymphatic vessels, thickness of scrotal skin, occurrence and amount of fluid accumulation, echogenicity of the fluid between the layers of the tunica vaginalis, as well as position and homogenicity of testis, epididymis and spermatic cord. In 1132 men, blood samples were taken for parasitological analysis. RESULTS: In 56% of examined patients, fluid accumulation around the testis was detected (38% subclinical-, 18% clinical stages). Differentiation of the echogenicity of the fluid revealed echo-free hydrocele (EFH) in 47% and echo-dense hydrocele (EDH) in 9%. Patients without hydrocele and subclinical stages had a thinner scrotal skin than those in clinical stages or with lymphscrotum (P < 0.001). In the EDH group the scrotal skin was thicker than in the EFH group (P < 0.001). 1.4% had a lymphscrotum. FDS was detected in 24% of all 1453 volunteers who underwent USG. The number of worm nests correlated with microfilarial load and levels of circulating filarial antigen (P < 0.001; 20% microfilaremic, 48% antigen positive). CONCLUSION: In an unexpected high number of men (56%) fluid accumulation around the testis was detected by USG of which more than one third (38%) presented with subclinical stages. The study showed that echo-dense and echo-free fluid could be differentiated and that a considerable number of cases had EDH (9%) posing a risk to develop necrotic testis and infertility and therefore requiring immediate surgical intervention. USG thus turned out to be a useful diagnostic technique to differentiate between those cases requiring immediate surgical intervention from those that can be treated with (anti-wolbachial and hyperpermeability reducing) drugs that ameliorate or halt progression of the disease.

Macrofilaricidal activity and amelioration of lymphatic pathology in bancroftian filariasis after 3 weeks of doxycycline followed by single-dose diethylcarbamazine.

In a placebo controlled trial, the effects of 21- and 10-day doxycycline treatments (200 mg/day) followed by single dose diethylcarbamazine (administered 4 months post treatment) on depletion of Wolbachia endobacteria from Wuchereria bancrofti, filaricidal activity, and amerlioration of scrotal lymph vessel dilation were studied in 57 men from Orissa, India. The 21-day doxycycline course reduced Wolbachia in W. bancrofti by 94% before diethylcarbamazine administration. After 12 months, all patients with this treatment were amicrofilaremic and different from the 10-day doxycycline (42.9%) and placebo (37.5%) groups, and significantly fewer were positive for scrotal worm nests (6.7%) compared with 10-day doxycycline (60%) and placebo (66.7%). Average scrotal lymph vessel diameters were reduced from 0.7 cm pre-treatment to 0.02 cm in patients after 21 days of treatment, while no significant changes were seen in the other groups. This latter feature confirms the beneficial effects of doxycycline on lymphatic dilation and thus adds to the existing evidence that doxycycline, in addition to being macrofilaricidal, may be used to prevent or reverse lymphatic pathology.

Mesenteric pulsatility index analysis predicts response to azathioprine in patients with Crohn's disease.

OBJECTIVE: Mesenteric blood flow measurement has been found to predict relapse after steroid-induced remission in patients with Crohn's disease (CD) and ulcerative colitis (UC). Therefore, we assessed prospectively the possible relationship between changes in mesenteric blood flow and prognosis in chronically active patients with need of immunosuppressive therapy with azathioprine (AZA) or 6-mercaptopurine (6-MP). METHODS: Doppler ultrasound (DUS) measurements of the pulsatility index (PI) of the superior mesenteric artery (SMA) and inferior mesenteric artery (IMA) were performed in 52 patients with chronically active inflammatory bowel disease (CD 31 patients; UC 21 patients) before beginning therapy with AZA/6-MP (US1) and during clinical remission (CD activity index <150, Truelove index score I) (US2). Patients were weaned from concomitant therapy with corticosteroids as soon as possible and were followed up for 12 months. RESULTS: After 1 year, 16 patients with CD (51.6%) and 13 patients with UC (61.9%) were in remission, whereas 23 patients had recurrent disease or had undergone surgery. A decreased SMA PI at US2 predicted clinical relapse in all patients with CD [100%; P < 0.001; mean (+/-SD) 77 +/- 67 d after US1], but only 4 of 8 patients (50%; difference not significant; mean 84 +/- 75 d after US1) with UC. Conversely, an increase of SMA PI was associated with sustained remission in the majority of CD patients (12/16 patients; 75%; P < 0.002), but in only 7 of 13 patients (54%) with UC. Flow measurements in the IMA and postprandial values for both arteries were less reliable. CONCLUSION: Repeated DUS measurements of the SMA PI predict response to AZA/6-MP in patients with chronic active CD.