Christos Krogias

["Chronic cerebrospinal venous insufficiency" and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients].

ZusammenfassungÜber die Hypothese eines möglichen ursächlichen Zusammenhangs von Störungen der zerebralen venösen Hämodynamik und der Entstehung der Multiplen Sklerose (MS) wird aktuell kontrovers diskutiert. Die neue „venöse Hypothese“ postuliert, dass Abflussstörungen des zervikalen Venensystems eine Stauung und Druckerhöhung des intrakraniellen Venensystems mit nachfolgender Entzündungsreaktion bedingen. Diese Hypothese wird unter drei Gesichtspunkten analysiert und bewertet: (1) Validität der publizierten Befunde, (2) Plausibilität im Licht derzeitig akzeptierter Pathogenesemodelle der MS und (3) Kompatibilität mit ersten eigenen Untersuchungen.Die Autoren kommen zu der Schlussfolgerung, dass die „venöse Hypothese“ als ausschließliche Ursache die MS keinesfalls erklären kann. Lediglich 20% unseres unselektierten MS-Kollektivs erfüllten zwei der neu aufgestellten neurosonologischen Kriterien einer „chronischen zerebrospinalen venösen Insuffizienz“. Die pathogenetische Relevanz dieser subtilen Veränderungen der venösen Flussverhältnisse ist derzeit völlig offen. Ebenfalls ist unklar, inwieweit diese Veränderungen Grund oder Folge der MS sind. Keinesfalls lassen sich damit nach derzeitigem Erkenntnisstand invasive „therapeutische“ Maßnahmen rechtfertigen, insbesondere nicht außerhalb kontrollierter Studienprotokolle.SummaryCurrently, the hypothesis that altered venous hemodynamics might play a causative role in the pathogenesis of multiple sclerosis (MS) is being controversially discussed. This new „venous hypothesis“ postulates that obstructions of the cervical venous system cause an increased pressure of the intracranial venous system and that in turn intracranial congestion disintegrates the blood-brain barrier initiating the inflammatory process in MS.The „venous hypothesis“ is analyzed and evaluated with regard to the following aspects: first concerning the validity of published data, second with regard to the plausibility in view of the currently approved pathogenetic model of MS, and third with regard to the compatibility with preliminary neurosonological findings in a small but unselected cohort of patients at our department.The authors conclude that the „chronic cerebrospinal venous insufficiency (CCSVI)“ cannot represent the exclusive pathogenetic factor in the pathogenesis of MS. In our cohort, only 20% of the patients fulfilled the required neurosonological features of CCSVI. So far, the pathogenetic relevance of these findings remains speculative. Thus, based on the current scientific position we cannot justify invasive „therapeutic“ approaches, especially if they are performed outside of clinical trials.

Cortical and Subcortical Grey and White Matter Atrophy in Myotonic Dystrophies Type 1 and 2 Is Associated with Cognitive Impairment, Depression and Daytime Sleepiness

Objectives Central nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2). We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM). Methods 12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes of brain, ventricles, cerebellum, brainstem, cervical cord, lesion load and VBM results of the patient groups were compared to 33 matched healthy subjects. Results Clinical symptoms were depression (more pronounced in DM2), excessive daytime sleepiness (more pronounced in DM1), reduced attention and flexibility of thinking, and deficits of short-term memory and visuo-spatial abilities in both patient groups. Both groups showed ventricular enlargement and supratentorial GM and WM atrophy, with prevalence for more GM atrophy and involvement of the motor system in DM1 and more WM reduction and affection of limbic structures in DM2. White matter was reduced in DM1 in the splenium of the corpus callosum and in left-hemispheric WM adjacent to the pre- and post-central gyrus. In DM2, the bilateral cingulate gyrus and subgyral medio-frontal and primary somato-sensory WM was affected. Significant structural-functional correlations of morphological MRI findings (global volumetry and VBM) with clinical findings were found for reduced flexibility of thinking and atrophy of the left secondary visual cortex in DM1 and of distinct subcortical brain structures in DM2. In DM2, depression was associated with brainstem atrophy, Daytime sleepiness correlated with volume decrease in the middle cerebellar peduncles, pons/midbrain and the right medio-frontal cortex. Conclusion GM and WM atrophy was significant in DM1 and DM2. Specific functional-structural associations related morphological changes to cognitive impairment, depression and daytime sleepiness, partly indicating involvement of complex neuronal networks.

Depression in patients with Huntington disease correlates with alterations of the brain stem raphe depicted by transcranial sonography

BACKGROUND Transcranial sonography (TCS) has become a new diagnostic tool in the evaluation of extrapyramidal disorders. Studies of TCS report alterations of the mesencephalic raphe in patients with depression. The aim of this study was to evaluate TCS findings in patients with Huntington disease in correlation with their neurologic and psychiatric status. METHODS We recruited patients with genetically confirmed Huntington disease. The neurological and psychiatric status of participants was assessed by independent physicians. Echogenicities were investigated according to examination protocol for extrapyramidal disorders using a Siemens Sonoline Elegra system. The sonography examiner was blinded for clinical data. RESULTS We included 39 patients in our study; 21 patients (53.8%) showed symptoms of depression at the time of evaluation and, of those, 15 (71.4%) had hypoechogenic raphe structures. Thirty patients (76.9%) had a history of depressive episodes, 19 (63.3%) of them with hypoechogenic raphe structures. All 9 patients without a history of depressive episodes showed normal echogenicity of raphe structures (sensitivity 63.3%, specificity 100%). Twelve (70.6%) of the 17 patients with Huntington disease who showed psychiatric disturbances prior to the occurrence of motor symptoms exhibited pathological raphe echogenicity (sensitivity 70.6%, specificity 68.2%). LIMITATIONS Most of the patients were taking antichoreatic medication, which particularly influences neurologic status. Thus, a meaningful interpretation of the correlation between TCS findings and neurologic features was limited. CONCLUSION As a novel finding, a relation between mesencephalic raphe echogenicity and depressive state could be identified in patients with Huntington disease. An alteration of the serotonergic brain stem raphe might be involved in the pathogenesis of depression in these patients.

Detection of cerebral perfusion abnormalities in acute stroke using phase inversion harmonic imaging (PIHI): preliminary results

Phase inversion harmonic imaging (PIHI) with newer contrast agents can display parameters of cerebral perfusion either using the established ipsilateral approach, or the novel bilateral approach in which both hemispheres are assessed in one examination. The aim of this study was to evaluate the potential of PIHI in detecting pathological perfusion in acute stroke, using the bilateral approach. Patients with a hemispheric syndrome presenting within 12 hours after symptom onset were examined with PIHI (SonoVue®; bolus kinetics, fitted model function) using the bilateral approach if possible. Semi-quantitative perfusion related parameters (time to peak intensity (TPI) and peak width (PW)) were evaluated, and results correlated to follow up cerebral computed tomography (CCT) scans. In these four preliminary cases (one ipsilateral, three bilateral), PIHI was able to identify the ischaemic region because the function could not be fitted to the data. In one case, there was a difference between a core region where no perfusion was seen, and a surrounding region where hypoperfusion was detected (prolonged TPI and reduced PW). PIHI was able to predict the localisation and size of the eventual infarction even if no early CCT signs were seen. Furthermore, in one case, a surrounding hypoperfused region was identified, where tissue survived after recanalisation of the initially occluded middle cerebral artery. Using the bilateral approach, two advantages in comparison with the ipsilateral approach were obvious: cortical structures could be evaluated, and only one examination was needed to compare unaffected (ipsilateral) with affected (contralateral) tissue. These results should be confirmed by more cases, and should also be correlated to acute perfusion/diffusion weighted MRI data.

Outcome After Thrombectomy and Intravenous Thrombolysis in Patients With Acute Ischemic Stroke A Prospective Observational Study

Background and Purpose— In patients with ischemic stroke, randomized trials showed a better functional outcome after endovascular therapy with new-generation thrombectomy devices compared with medical treatment, including intravenous thrombolysis. However, effects on mortality and the generalizability of results to routine clinical practice are uncertain. Methods— In a prospective observational register-based study patients with ischemic stroke treated either with thrombectomy, intravenous thrombolysis, or their combination were included. Primary outcome was the modified Rankin scale score (0 [no symptoms] to 6 [death]) at 3 months. Ordinal logistic regression was used to estimate the common odds ratio as treatment effects (shift analysis). Propensity score matching was applied to compare patients treated either with intravenous thrombolysis alone or with intravenous thrombolysis plus thrombectomy. Results— Among 2650 recruited patients, 1543 received intravenous thrombolysis, 504 underwent thrombectomy, and 603 received intravenous thrombolysis in combination with thrombectomy. Later time-to-treatment was associated with worse outcomes among patients treated with thrombectomy plus thrombolysis. In 241 pairs of propensity score–matched patients with a proximal intracranial occlusion, thrombectomy plus thrombolysis was associated with improved functional outcome (common odds ratio, 1.84; 95% confidence interval, 1.32–2.57), and reduced mortality (15% versus 33%; P<0.0001) compared with intravenous thrombolysis alone. Results were similar in various sensitivity analyses accounting for missing outcome data and different analytic methods. Conclusions— Results from this large prospective registry show that also in routine clinical care thrombectomy plus thrombolysis compared with thrombolysis alone improved functional outcome and reduced mortality in patients with ischemic stroke. Earlier treatment was associated with better outcomes.

Statin pretreatment is associated with better outcomes in large artery atherosclerotic stroke

Objective: Even though statin pretreatment is associated with better functional outcomes and lower risk of mortality in acute ischemic stroke, there are limited data evaluating this association in acute ischemic stroke due to large artery atherosclerosis (LAA), which carries the highest risk of early stroke recurrence. Methods: Consecutive patients with acute LAA were prospectively evaluated from 7 tertiary-care stroke centers during a 3-year period. Statin pretreatment, demographics, vascular risk factors, and admission and discharge stroke severity were recorded. The outcome events of interest were neurologic improvement during hospitalization (quantified as the relative decrease in NIH Stroke Scale score at discharge in comparison to hospital admission), favorable functional outcome (FFO) (defined as modified Rankin Scale score of 0–1), recurrent stroke, and death at 1 month. Statistical analyses were performed using univariable and multivariable Cox regression models adjusting for potential confounders. All analyses were repeated following propensity score matching. Results: Statin pretreatment was documented in 192 (37.2%) of 516 consecutive patients with LAA (mean age: 65 ± 13 years; 60.8% men; median NIH Stroke Scale score: 9 points, interquartile range: 5–18). Statin pretreatment was associated with greater neurologic improvement during hospitalization and higher rates of 30-day FFO in unmatched and matched (odds ratio for FFO: 2.44; 95% confidence interval [CI]: 1.07–5.53) analyses. It was also related to lower risk of 1-month mortality and stroke recurrence in unmatched and matched analyses (hazard ratio for recurrent stroke: 0.11, 95% CI: 0.02–0.46; hazard ratio for death: 0.24, 95% CI: 0.08–0.75). Conclusion: Statin pretreatment in patients with acute LAA appears to be associated with better early outcomes regarding neurologic improvement, disability, survival, and stroke recurrence.

Safety of early endarterectomy in patients with symptomatic carotid artery stenosis: an international multicenter study

Although the latest recommendations suggest that carotid endarterectomy (CEA) should be performed in symptomatic carotid artery stenosis (sCAS) patients within 2 weeks of the index event, only a minority of patients undergo surgery within the recommended time‐frame. The aim of this international multicenter study was to prospectively evaluate the safety of early CEA in patients with sCAS in everyday clinical practice settings.

Bortezomib Treatment for Patients With Anti-N-Methyl-d-Aspartate Receptor Encephalitis

Bortezomib Treatment for Patients With Anti-N-Methyl-D-Aspartate Receptor Encephalitis Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, an autoimmune disease associated with ovarian teratoma, predominantly affects young females.1 Because antibodies against subunits of the NMDAR contribute to the pathogenesis, methods targeting humoral immunity are therapeutically efficacious.2 However, some patients have an unsatisfactory outcome after high-dose corticosteroids, apheresis therapies, or CD20-targeted B-cell depletion with rituximab.2 We describe 2 patients with severe anti-NMDAR encephalitis who received the proteasome inhibitor bortezomib (Velcade), which was well tolerated and followed by marked remission.

Successful Treatment of Anti-Caspr2 Syndrome by Interleukin 6 Receptor BlockadeThrough Tocilizumab

IMPORTANCE A patient with a Caspr2 autoantibodies-associated syndrome had an unusual clinical triad and an excellent response to B-cell-anergizing therapy using the humanized monoclonal antibody tocilizumab directed against the interleukin 6 (IL-6) receptor. OBSERVATIONS A 55-year-old man had an atypical clinical triad of epilepsy, dysarthria, and paroxysmal kinesigenic dystonia, and a high titer of Caspr2 antibodies was detected in his serum and cerebrospinal fluid. Screening for underlying neoplasias was negative. With initial methylprednisolone sodium succinate and alternate treatment using plasma exchange and immunoabsorption as well as subsequent IL-6 receptor blockade through tocilizumab, a complete and stable remission of symptoms has been achieved throughout the follow-up period of 7 months. CONCLUSIONS AND RELEVANCE In our patient, the implementation of a B-cell-anergizing therapy using tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, has shown an excellent response. Larger case series or even controlled studies are needed to confirm the efficacy of tocilizumab in autoimmune synaptic or presynaptic diseases.

Clopidogrel Load for Emboli Reduction in Patients With Symptomatic Carotid Stenosis Undergoing Urgent Carotid Endarterectomy

Background and Purpose— Microembolic signals (MES) on transcranial Doppler are an independent risk factor for recurrent stroke in patients with extracranial symptomatic/asymptomatic carotid artery stenosis (CARAS). Clopidogrel load (300 mg) combined with dual antiplatelet therapy has been shown to reduce MES in patients with symptomatic CARAS. We sought to determine feasibility of clopidogrel load in decreasing asymptomatic embolization in patients with symptomatic CARAS undergoing urgent carotid endarterectomy within the first 2 weeks from the index event. Subjects and Methods— Consecutive patients with symptomatic CARAS (70%–99%) and presence of MES on 1-hour baseline (<24 hours from the index event) transcranial Doppler monitoring of ipsilateral middle cerebral artery were treated with clopidogrel load followed by clopidogrel (75 mg)±aspirin (100 mg) during the elapsed time period between hospital admission and urgent carotid endarterectomy at 3 tertiary-care stroke centers. Repeat 1-hour transcranial Doppler monitoring was performed the day before surgery. Bleeding complications during surgery and recurrent strokes or transient ischemic attacks during the first month of ictus were prospectively recorded. Results— A total of 11 symptomatic CARAS patients (mean age, 66±7 years; 73% men; 64% acute ischemic strokes) were treated with clopidogrel load followed by dual (67%) or single (33%) antiplatelet therapy. MES count was significantly reduced between baseline (median count, 8 MES/h; interquartile range, 6–19) and repeat transcranial Doppler monitoring (0 MES/h; interquartile range, 0–3; P=0.003). No bleeding complications, recurrent strokes, or transient ischemic attacks were documented. Conclusions— Our pilot observational study provides preliminary nonrandomized data regarding the potential efficacy of clopidogrel load to reduce asymptomatic embolization in patients with symptomatic CARAS before urgent carotid endarterectomy.