Pavel Hradílek

Safety and Efficacy of the Sonographic Acceleration of the Middle Cerebral Artery Recanalization: Results of the pilot Thrombotripsy Study

The aim was to demonstrate the safety and efficacy of continuous ultrasound monitoring of the artery occlusion area (sonothrombotripsy) in patients with acute middle cerebral artery (MCA) occlusion. A total of 52 consecutive patients with acute MCA occlusion were included in the thrombotripsy group. Doppler monitoring of the region of occlusion was performed for up to 45 min. The control group was created from the NAIS study database. Patients were matched for their vascular status, age, sex, artery occlusion, NIHSS at admission, rt-PA treatment and time to the first ultrasound examination. The number of recanalized arteries at 6 and 24 h after the onset of symptoms, the number of independent patients (mRS 0-2 versus 3-6) after 90 d, and the number of serious adverse events were statistically evaluated. In the thrombotripsy group, 19 patients (36.5%) had complete recanalization and 27 (51.9%) patients had partial recanalization at 1 h after the start of the TCCS monitoring. Higher recanalization rates at 6 and 24 h after stoke onset were also seen compared with controls (69.2% versus 7.7% and 92.3% versus 61.5% complete recanalizations, respectively, p < 0.05). Independence (mRS 0-2) at day 90 was achieved by 61.5% of the thrombotripsy patients and 32.7% controls, p < 0.05, odds ratio 1.88 (95% confidence interval = 1.23 - 2.90). In both groups, two symptomatic intracerebral hemorrhages and one symptomatic brain edema occurred. Sonothrombotripsy with diagnostic transcranial duplex technology is safe and may offer benefit in addition to standard of care stroke treatment.

Colour Doppler imaging evaluation of blood flow parameters in the ophthalmic artery in acute and chronic phases of optic neuritis in multiple sclerosis.

Purpose:  Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS). It is caused by the immune‐mediated inflammation of the optic nerve. Some vascular factors that may influence blood flow in the ophthalmic artery (OA) have also been suggested as factors in the pathogenesis of ON. The purpose of our study was to evaluate blood flow velocities and resistance (RI) and pulsatile (PI) indices in the OA in both orbits in patients in the acute and chronic phases of unilateral ON and to compare these with equivalent findings in healthy control subjects.

Analysis of the upper urinary tract function in multiple sclerosis patients

Aims –  The objective of this study was to analyse the upper urinary tract (UT) function in a group of consecutive multiple sclerosis (MS) patients, who had not previously been treated by urologist.

Distal enlargement of the optic nerve sheath in the hyperacute stage of intracerebral haemorrhage

Aims Optic nerve sheath diameter (ONSD) enlargement is detectable in patients with increased intracranial pressure. The aim was to detect an enlargement of the ONSD using optic nerve sonography in patients with acute intracerebral haemorrhage (ICH) within 6 h of the onset of symptoms. Methods Thirty-one acute ICH patients, 15 age-matched acute ischaemic stroke patients and 16 age-matched healthy volunteers were enrolled consecutively in this prospective bi-centre observational study. All acute stroke patients underwent brain CT, optic nerve sonography and transcranial colour-coded duplex sonography (TCCS) at admission within 6 h of stroke onset. The ONSD both 3.0 and 12.0 mm behind the globe using optic nerve sonography were recorded and statistically evaluated, as were age, sex, haemorrhage volume and midline shift measured by CT, and blood flow velocities in both middle cerebral arteries using TCCS. Results In acute ICH patients, a significant enlargement of ONSD was detected (p<0.0083). The best cut-off point to predict ICH volume >2.5 cm3 was the relative ONSD enlargement of >0.66 mm (>21 %), with 90.3% accuracy and kappa coefficient 0.760 (95% CI 0.509 to 1.000). Conclusions Sonographically measured enlargement of the ONSD may already be detectable in the hyperacute stage of increased intracranial pressure.

Transcranial Duplex Sonography and CT Angiography in Acute Stroke Patients

Acute occlusion of cervical or intracranial arteries is the most common cause of ischemic stroke (IS). The aims of the current study were to compare the occurrence of acute pathologic findings in intracranial arteries using transcranial color‐coded sonography (TCCS) and computed tomographic angiography (CTA) performed within 3 hours of IS onset and to assess the correlation between the vascular findings on admission and the patients clinical state on admission and 3 months after the IS. Forty‐five consecutive patients with an acute IS were included in the prospective study during an 18‐month period. All patients underwent CTA and TCCS within the first 3 hours of symptom onset. A high rate of pathologic findings in the intracranial circulation was found (70.9% in CTA and 77.4% in TCCS examinations). The CTA and TCCS findings with respect to the intracranial arteries were consistent in 87.1% of cases (Cohens κ, .797). The sensitivity, specificity, and positive and negative predictive values achieved with TCCS in patients with middle cerebral artery main stem occlusion were 92.3%, 94.4%, and 92.3% and 94.4%, respectively. There was no correlation between the patients clinical status on admission and 3 months after the onset of the IS and the CTA or the TCCS findings (P > .1 in all cases). A substantial agreement was found between TCCS and CTA in the detection of pathologic findings in intracranial vessels in acute stroke patients. Both methods can be used for this purpose.

Assessment of Intrathecal Free Light Chain Synthesis: Comparison of Different Quantitative Methods with the Detection of Oligoclonal Free Light Chains by Isoelectric Focusing and Affinity-Mediated Immunoblotting.

Objectives We aimed to compare various methods for free light chain (fLC) quantitation in cerebrospinal fluid (CSF) and serum and to determine whether quantitative CSF measurements could reliably predict intrathecal fLC synthesis. In addition, we wished to determine the relationship between free kappa and free lambda light chain concentrations in CSF and serum in various disease groups. Methods We analysed 166 paired CSF and serum samples by at least one of the following methods: turbidimetry (Freelite™, SPAPLUS), nephelometry (N Latex FLC™, BN ProSpec), and two different (commercially available and in-house developed) sandwich ELISAs. The results were compared with oligoclonal fLC detected by affinity-mediated immunoblotting after isoelectric focusing. Results Although the correlations between quantitative methods were good, both proportional and systematic differences were discerned. However, no major differences were observed in the prediction of positive oligoclonal fLC test. Surprisingly, CSF free kappa/free lambda light chain ratios were lower than those in serum in about 75% of samples with negative oligoclonal fLC test. In about a half of patients with multiple sclerosis and clinically isolated syndrome, profoundly increased free kappa/free lambda light chain ratios were found in the CSF. Conclusions Our results show that using appropriate method-specific cut-offs, different methods of CSF fLC quantitation can be used for the prediction of intrathecal fLC synthesis. The reason for unexpectedly low free kappa/free lambda light chain ratios in normal CSFs remains to be elucidated. Whereas CSF free kappa light chain concentration is increased in most patients with multiple sclerosis and clinically isolated syndrome, CSF free lambda light chain values show large interindividual variability in these patients and should be investigated further for possible immunopathological and prognostic significance.

Detection of oligoclonal IgG kappa and IgG lambda bands in cerebrospinal fluid and serum with Hevylite™ antibodies. comparison with the free light chain oligoclonal pattern

BackgroundOligoclonal IgG bands in cerebrospinal fluid that are absent in serum indicate intrathecal IgG synthesis and are a sensitive marker of CNS inflammatory diseases, in particular multiple sclerosis. It may be of interest to determine whether these bands are predominantly IgGκ or IgGλ.MethodsWe have used Hevylite™ antibodies and developed a technique for detection of oligoclonal IgGκ and IgGλ bands by means of isoelectric focusing followed by immunoblotting. The same technique was used for oligoclonal free κ and free λ detection. Among several techniques tested, affinity immunoblotting appears to be the most sensitive; it can detect less than 1 ng of IgGκ or IgGλ paraprotein. We compared oligoclonal IgG profiles with those of oligoclonal IgGκ and IgGλ. There was good agreement concerning the presence or absence of intrathecal synthesis. We observed the ratios between oligoclonal IgGκ and IgGλ bands, and they did not always match the ratios between free κ and free λ bands. We were also able to detect antigen-specific CSF-restricted oligoclonal IgGκ and IgGλ bands in neuroborreliosis. It remains to be determined subsequently by a clinically-oriented prospective study, whether predominant IgGκ/IgGλ or free κ/free λ can be observed more frequently in particular diseases with oligoclonal IgG synthesis.DiscussionVery sensitive detection of oligoclonal IgGκ and IgGλ bands in cerebrospinal fluid with Hevylite antibodies is feasible; detection of antigen-specific IgGκ or IgGλ is possible as well. In particular situations, e.g. when difficulties arise in distinguishing between oligoclonal and monoclonal pattern, the test may be of considerable clinical value.

Asymptomatic lung disease caused by Mycobacterium kansasii as an opportunistic infection in a patient treated with natalizumab for relapsing–remitting multiple sclerosis

Natalizumab is approved for the treatment of highly active relapsing–remitting multiple sclerosis (RRMS). Although the efficacy of this agent is considered to be high, treatment may be associated with some potentially serious infections. Progressive multifocal leukoencephalopathy (PML) with a potentially fatal outcome is the best known. Some other opportunistic infections may also occur, although literature references are rather scarce. Italian authors describe a case of rickettsiosis in a natalizumab-treated MS patient.1 While a possible association between treatment with natalizumab and infections caused by nontuberculous mycobacteria have been reported, this was based on clinical trials performed with patients with haematological diseases.2 We did not identify any publication describing a lung disease caused by Mycobacterium kansasii in a MS patient treated with natalizumab. We discuss a case of asymptomatic Mycobacterium kansasii infection that occurred during natalizumab treatment for MS. After 43 doses of natalizumab, when the MS course was stable, a pathological lesion in the upper lobe of the left lung was found on a chest X-ray during a pre-operative exam, due to planned surgery for an inguinal hernia. A previous chest X-ray prior to natalizumab treatment was normal. The patient did not experience any respiratory or other symptoms that could lead to a diagnosis of a lung disease. Mycobacterium kansasii was found in the sputum specimen repeatedly, using the MGIT (Mycobacteria Growth Indicator Tube) technique.3 Natalizumab was discontinued and we initiated a long-term treatment with a combination of anti-tuberculosis drugs. The further course of pulmonary disease was favourable, with significant regression of the cavitation in the upper lobe of the left lung, which subsequently disappeared. Nontuberculous mycobacteria are not strictly human pathogens and are not transmissible between humans. The source of Mycobacterium kansasii is environmental.4 Treatment is long-term. Three possible risk factors for the development of the opportunistic infection could be judged in our subject:

Oligoclonal free light chains in cerebrospinal fluid as markers of intrathecal inflammation. Comparison with oligoclonal IgG

AIMS To compare the sensitivity and specificity of CSF-restricted oligoclonal IgG and free light chains as markers of multiple sclerosis and other inflammatory neurological diseases. METHODS 196 paired CSF and serum samples were examined for oligoclonal IgG and oligoclonal free light chains. The sensitivity and specificity of the tests were calculated and optimal cut-offs for the number of CSF-restricted oligoclonal bands were then determined by analysis of receiver operating characteristic curves. RESULTS Optimal cut-off values were ≥5 IgG bands for multiple sclerosis, ≥4 IgG bands for inflammatory neurological disease, ≥6 free κ, and ≥2 free λ bands for both purposes. Using these cut-off values, sensitivities and specificities for multiple sclerosis were 83.8% and 91.3% for IgG, 83.8% and 81.0% for free κ, and 67.6% and 75.4% for free λ. For inflammatory neurological disease, sensitivities and specificities were 60.8% and 95.7% for IgG, 69.6% and 92.6% for free κ, and 64.8% and 86.2% for free λ. CONCLUSIONS Although exact cut-off values may vary according to method, reporting borderline results as positive, may compromise the specificity of the test and should be avoided.. The detection of intrathecal free light chain synthesis may be of value especially when the oligoclonal IgG test is negative or borderline, even though its specificity is slightly lower.

Quantitation of free light chains in the cerebrospinal fluid reliably predicts their intrathecal synthesis.

Background The results of free light chains quantitation in the cerebrospinal fluid were recently compared with the presence of cerebrospinal fluid-restricted oligoclonal IgG, but not oligoclonal free kappa light chains and oligoclonal free lambda light chains. We therefore aimed to compare the performance of the quantitative tests with the qualitative one for the same molecule. Methods Seventy-five paired cerebrospinal fluid and serum samples were analysed for oligoclonal IgG, oligoclonal free kappa light chains and oligoclonal free lambda light chains. Cerebrospinal fluid and serum free kappa and lambda light chains were quantified using Freelite™ kits on SPA Plus analyzer. ROC curves were analysed for the prediction of intrathecal synthesis and compared for cerebrospinal fluid concentration, cerebrospinal fluid/serum quotient (QfLC) and index (QfLC/QAlbumin). The presence of cerebrospinal fluid-restricted oligoclonal free kappa light chains and oligoclonal free lambda light chains bands was used as reference. Results No statistically significant differences were observed among cerebrospinal fluid concentration, QfLC and index for the prediction of free light chain intrathecal synthesis. Each parameter was able to predict the occurrence of cerebrospinal fluid-restricted oligoclonal free light chain bands (AUCs 0.932–0.999). However, we noted elevated cerebrospinal fluid free light chain concentrations in the absence of cerebrospinal fluid-restricted oligoclonal free light chain bands in two patients with very high serum free light chain values. Conclusions Quantitation of cerebrospinal fluid free light chains reliably predicts their intrathecal synthesis. Yet, cerebrospinal fluid/serum quotient may still be preferred to correct for high serum free light chain concentrations. An appropriate formula should be sought to correct for blood–cerebrospinal fluid barrier status.