Jens Witsch

EARLYDRAIN- outcome after early lumbar CSF-drainage in aneurysmal subarachnoid hemorrhage: study protocol for a randomized controlled trial

BackgroundAneurysmal subarachnoid hemorrhage (SAH) may be complicated by delayed cerebral ischemia, which is a major cause of unfavorable clinical outcome and death in SAH-patients. Delayed cerebral ischemia is presumably related to the development of vasospasm triggered by the presence of blood in the basal cisterns. To date, oral application of the calcium antagonist nimodipine is the only prophylactic treatment for vasospasm recognized under international guidelines.In retrospective trials lumbar drainage of cerebrospinal fluid has been shown to be a safe and feasible measure to remove the blood from the basal cisterns and decrease the incidence of delayed cerebral ischemia and vasospasm in the respective study populations. However, the efficacy of lumbar drainage has not been evaluated prospectively in a randomized controlled trial yet.Methods/DesignThis is a protocol for a 2-arm randomized controlled trial to compare an intervention group receiving early continuous lumbar CSF-drainage and standard neurointensive care to a control group receiving standard neurointensive care only. Adults suffering from a first aneurysmal subarachnoid hemorrhage whose aneurysm has been secured by means of coiling or clipping are eligible for trial participation. The effect of early CSF drainage (starting < 72 h after securing the aneurysm) will be measured in the following ways: the primary endpoint will be disability after 6 months, assessed by a blinded investigator during a personal visit or standardized telephone interview using the modified Rankin Scale. Secondary endpoints include mortality after 6 months, angiographic vasospasm, transcranial Doppler sonography (TCD) mean flow velocity in both middle cerebral arteries and rate of shunt insertion at 6 months after hospital discharge.DiscussionHere, we present the study design of a multicenter prospective randomized controlled trial to investigate whether early application of a lumbar drainage improves clinical outcome after aneurysmal subarachnoid hemorrhage.Trial registrationwww.clinicaltrials.gov Identifier: NCT01258257

Space-occupying cerebellar infarction: complications, treatment, and outcome

Space-occupying brain edema is a frequent and one of the most dreaded complications in ischemic cerebellar stroke. Because the tight posterior fossa provides little compensating space, any space-occupying lesion can lead to life-threatening complications through brainstem compression or compression of the fourth ventricle and subsequent hydrocephalus, both of which may portend transtentorial/transforaminal herniation. Patients with large cerebellar infarcts should be treated and monitored very early on in an experienced stroke unit or (neuro)intensive care unit. The general treatment of ischemic cerebellar infarction does not differ from that of supratentorial ischemic strokes. Treatment strategies for space-occupying edema include pharmacological antiedema and intracranial pressure-lowering therapies, ventricular drainage by means of an extraventricular drain, and suboccipital decompressive surgery, with or without resection of necrotic tissue. Timely escalation of treatment is crucial and should be guided by clinical and neuroradiological rationales. Patients in a coma after hydrocephalus and/or local brainstem compression may also benefit from more aggressive surgical treatment, as long as the conditions are reversible. Contrary to the general belief that outcome in survivors of space-occupying cerebellar stroke is usually good, recent studies suggest that for many of these patients, the long-term outcome is not good. In particular, advanced age and additional brainstem infarction seem to be predictors for poor outcome. Further trials are necessary to investigate these findings systematically and provide better selection criteria to help guide decisions about surgical therapies, which should always be carried out in close cooperation among neurointensive care physicians, neurologists, and neurosurgeons.

Glial Fibrillary Acidic Protein Serum Levels Distinguish between Intracerebral Hemorrhage and Cerebral Ischemia in the Early Phase of Stroke

BACKGROUND Recent studies have suggested that glial fibrillary acidic protein (GFAP) serum concentrations distinguish between intracerebral hemorrhage (ICH) and ischemic stroke (IS) shortly after symptom onset. In this prospective multicenter trial we validated GFAP in an independent patient cohort and assessed the quantitative relationship between GFAP release, bleeding size, and localization. METHODS We included patients with a persistent neurological deficit (NIH Stroke Scale ≥4) suggestive of stroke within 6 h of symptom onset. Blood samples were drawn at hospital admission. GFAP serum concentrations were measured using an electrochemiluminometric immunoassay. Primary endpoint was the final diagnosis established at hospital discharge (ICH, IS, or stroke mimic). RESULTS 202 patients were included (45 with ICH, 146 with IS, 11 stroke mimics). GFAP concentrations were significantly higher in ICH than in IS patients [median (interquartile range) 0.16 μg/L (0.04-3.27) vs 0.01 μg/L (0.01-0.01), P <0.001]. A GFAP cutoff of 0.03 μg/L provided a sensitivity of 77.8% and a specificity of 94.2% in distinguishing ICH from IS and stroke mimics [ROC analysis area under the curve 0.872 (95% CI, 0.802-0.942), P <0.001]. GFAP serum concentrations were positively correlated with ICH volume. Lobar ICH volumes were larger and thus associated with higher GFAP concentrations as compared to deep ICH. CONCLUSIONS Serum GFAP was confirmed to be a biomarker indicating ICH in patients presenting with acute stroke symptoms. Very small ICH may be missed owing to less tissue destruction.

Intragenic deletions of the IGF1 receptor gene in five individuals with psychiatric phenotypes and developmental delay

Haploinsufficiency of the gene encoding the insulin-like growth factor 1 receptor (IGF1R), either caused by telomeric 15q26 deletions, or by heterozygous point mutations in IGF1R, segregate with short stature and various other phenotypes, including microcephaly and dysmorphic facial features. Psychomotor retardation and behavioral anomalies have been seen in some cases. Here we report small, intragenic deletions of IGF1R, identified by chromosome microarray analysis in two unrelated families affected primarily with neuropsychiatric phenotypes including developmental delay, intellectual disability and aggressive/autoaggressive behaviors. The deletions are in frame, and both wild-type and mutant mRNAs are expressed as measured by quantitative real-time PCR. While short stature is considered a phenotypic hallmark of IGF1R haploinsufficiency, the present report suggests that in frame exon deletions of IGF1R present predominantly with cognitive and neuropsychiatric phenotypes.

Large Size Hemicraniectomy Reduces Early Herniation in Malignant Middle Cerebral Artery Infarction

Background: Decompressive hemicraniectomy (DHC) reduces mortality and improves outcome after malignant middle cerebral artery infarction (MMI) but early in-hospital mortality remains high between 22 and 33%. Possibly, this circumstance is driven by cerebral herniation due to space-occupying brain swelling despite decompressive surgery. As the size of the removed bone flap may vary considerably between surgeons, a size too small could foster herniation. Here, we investigated the effect of the additional volume created by an extended DHC (eDHC) on early in-hospital mortality in patients suffering from MMI. Methods: We performed a retrospective single-center cohort study of 97 patients with MMI that were treated either with eDHC (n = 40) or standard DHC (sDHC; n = 57) between January 2006 and June 2012. The primary study end point was defined as in-hospital mortality due to transtentorial herniation. Results: In-hospital mortality due to transtentorial herniation was significantly lower after eDHC (0 vs. 11%; p = 0.04), which was paralleled by a significantly larger volume of the craniectomy (p < 0.001) and less cerebral swelling (eDHC 21% vs. sDHC 25%; p = 0.03). No statistically significant differences were found in surgical or non-surgical complications and postoperative intensive care treatment. Conclusion: Despite a more aggressive surgical approach, eDHC may reduce early in-hospital mortality and limit transtentorial herniation. Prospective studies are warranted to confirm our results and assess general safety of eDHC.

Rituximab in c-ANCA associated vasculitic polyneuropathy complicated by local peritonitis

A 70-year-old woman presented with progressive weakness over 3 weeks and paresthesia of the lower extremities. Except for a recent history of recurrent respiratory tract infections, she had been healthy previously. Within hours after hospital admission, paresis progressed markedly, and she required intensive care. Physical examination showed sensory-motor polyneuropathy with tetraplegia and symmetrical distal sensory impairment of all extremities, no cranial nerve abnormalities nor autonomous dysregulation. Because of involvement of the diaphragm the patient was intubated and ventilated. The clinical presentation was suggestive of Guillain–Barre syndrome (GBS). CSF examination revealed 92 WBC/ll, 33,700 erythrocytes/ll, glucose 69 mg/dl, lactate 35.4 mg/dl and protein 181 mg/dl. Electrophysiology was consistent with a sensorymotor polyneuropathy with axonal affection. A cranial MRI demonstrated central nervous system involvement (Fig. 1g–i). Laboratory testings showed an elevated c-antineutrophil cytoplasmic antibodies (c-ANCA)-titer (168 U/ml) and slightly elevated creatinine. In synopsis with the patient’s history of recurrent respiratory infections, Wegener’s granulomatosis with vasculitic polyneuropathy and central nervous system involvement was suspected and confirmed by sural nerve biopsy (Fig. 1a–f), as well as skin , and nasopharyngeal mucosa biopsy (not shown). High-dose steroids, plasmapheresis, and intravenous immunoglobulins were sequentially administered without improving the patient’s symptoms. Then a severe lower gastro-intestinal bleeding, which eventually required surgical removal of the ileocecum complicated the clinical course. Histology, it revealed no signs of vasculitis, but a disseminated cryptitis of the colon. Subsequently, the patient developed a localized peritonitis due to abdominal wound healing disturbance and dehiscence, warranting multiple surgical revisions. Meanwhile, the patient’s neurological and pulmonary status remained unchanged. Because therapy-escalation seemed mandatory, administration of rituximab (dose: 375 mg/m in 4 weekly courses) was preferred to cyclophosphamide, which is described to worsen wound healing [1]. Remarkably, under rituximab, the abdominal infection did not recur and the patient’s condition improved substantially. Ten weeks after admission, the patient could be weaned off the ventilator and transferred to the general ward. Within the following weeks, muscle strength in the upper, and later on in the lower extremities, recurred and the patient was transferred to rehabilitation. The patient was able to touch her nose with the left hand and to lift up her right hand against gravity. Both legs could be elevated against gravity but she was still unable to walk. The neurological improvement was quantified using the Wegener’s J. Witsch (&) J. Braun G. Trendelenburg Department of Neurology, Charite University Medicine, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany e-mail: Jens.Witsch@charite.de

Perivascular white matter lesion pattern in a patient with steroid-responsive encephalopathy

A 22-year-old woman was referred with a 4-month history of progressive encephalopathy with reduced concentration, fragmented pursuit eye movements and gait ataxia on examination. Laboratory testing revealed elevated serum TPOantibodies (356.6 kU/l), thyroglobulin antibodies were not detected (\10 kU/l), and thyroid function parameters were normal. MRI showed symmetrical white-matter lesions with a perivascular pattern and enhanced signal after application of gadolinium (Fig. 1). When the cerebral lesions together with the encephalopathic syndrome receded after treatment with steroids, steroidresponsive encephalopathy with associated autoimmune thyroditis (SREAT) was suspected. The patient was discharged and free of symptoms during the following months. Twelve months later she was re-admitted with headache, fevers (up to 40 C), generalized arthralgia and myalgia, as well as sore throat. Furthermore, the patient described a transient rash, which had already passed at admission. Laboratory testings revealed first leucopenia and, later on, leukocytosis with a fraction of 92 % granulocytes, ferritin levels of [100,000 mg/l, and elevated liver enzymes. Tests for antinuclear antibodies and rheumatoid factor were negative. Abdominal sonography showed hepatoand splenomegaly. Repeated bone marrow biopsies did not show evidence of malignancy. Because MRI at this time was unremarkable, brain biopsy was not performed. Adult-onset Still’s disease (AOSD) was diagnosed according to the criteria by Yamaguchi et al. [1]. After another 12 months, the patient died from sepsis after macrophage activation syndrome, a rare complication of AOSD. It remained unclear whether the first episode, classified as SREAT, and the AOSD were coincidental, or whether the first episode was an early manifestation of AOSD. In both SREAT and AOSD, MRI findings are unspecific or unremarkable in the majority of cases. A similar MRI J. Witsch (&) Department of Neurology, Charité University Medicine, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany e-mail: Jens.Witsch@charite.de