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Novel CCM1, CCM2, and CCM3 mutations in patients with cerebral cavernous malformations: in-frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein complex.

Cerebral cavernous malformations (CCM) are prevalent cerebrovascular lesions predisposing to chronic headaches, epilepsy, and hemorrhagic stroke. Using a combination of direct sequencing and MLPA analyses, we identified 15 novel and eight previously published CCM1 (KRIT1), CCM2, and CCM3 (PDCD10) mutations. The mutation detection rate was >90% for familial cases and >60% for isolated cases with multiple malformations. Splice site mutations constituted almost 20% of all CCM mutations identified. One of these proved to be a de novo mutation of the most 3′ acceptor splice site of the CCM1 gene resulting in retention of intron 19. A further mutation affected the 3′ splice site of CCM2 intron 2 leading to cryptic splice site utilization in both CCM2 and its transcript variant lacking exon 2. With the exception of one in‐frame deletion of CCM2 exon 2, which corresponds to the naturally occurring splice variant of CCM2 on the RNA level and is predicted to result in the omission of 58 amino acids (CCM2:p.P11_K68del), all mutations lead to the introduction of premature stop codons. To gain insight into the likely mechanisms underlying the only known CCM2 in‐frame deletion, we analyzed the functional consequences of loss of CCM2 exon 2. The CCM2:p.P11_K68del protein could be expressed in cell culture and complexed with CCM3. However, its ability to interact with CCM1 and to form a CCM1/CCM2/CCM3 complex was lost. These data are in agreement with a loss‐of‐function mechanism for CCM mutations, uncover an N‐terminal CCM2 domain required for CCM1 binding, and demonstrate full‐length CCM2 as the essential core protein in the CCM1/CCM2/CCM3 complex. Hum Mutat 29(5), 709–717, 2008.

Human Intracranial High Frequency Oscillations (HFOs) Detected by Automatic Time-Frequency Analysis

Objectives High frequency oscillations (HFOs) have been proposed as a new biomarker for epileptogenic tissue. The exact characteristics of clinically relevant HFOs and their detection are still to be defined. Methods We propose a new method for HFO detection, which we have applied to six patient iEEGs. In a first stage, events of interest (EoIs) in the iEEG were defined by thresholds of energy and duration. To recognize HFOs among the EoIs, in a second stage the iEEG was Stockwell-transformed into the time-frequency domain, and the instantaneous power spectrum was parameterized. The parameters were optimized for HFO detection in patient 1 and tested in patients 2–5. Channels were ranked by HFO rate and those with rate above half maximum constituted the HFO area. The seizure onset zone (SOZ) served as gold standard. Results The detector distinguished HFOs from artifacts and other EEG activity such as interictal epileptiform spikes. Computation took few minutes. We found HFOs with relevant power at frequencies also below the 80–500 Hz band, which is conventionally associated with HFOs. The HFO area overlapped with the SOZ with good specificity > 90% for five patients and one patient was re-operated. The performance of the detector was compared to two well-known detectors. Conclusions Compared to methods detecting energy changes in filtered signals, our second stage - analysis in the time-frequency domain - discards spurious detections caused by artifacts or sharp epileptic activity and improves the detection of HFOs. The fast computation and reasonable accuracy hold promise for the diagnostic value of the detector.

Neurosurgical venous considerations for tumors of the pineal region resected using the infratentorial supracerebellar approach

The authors present a microsurgical technique for the resection of a heterogeneous group of pineal-region tumors and discuss the key points for successfully performing this surgery. Twenty-six consecutive patients with pineal-region tumors were resected by the senior author (H.B.) and analyzed retrospectively. For all 26 patients, the operation was conducted using the infratentorial supracerebellar (ITSC) approach in the sitting (23 patients) or Concorde (three patients) positions. Twenty-five patients had symptomatic obstructive hydrocephalus and were treated with ventricular drainage, a previously inserted ventriculoperitoneal shunt, or an endoscopic third ventriculostomy before undergoing resection of the pineal-region tumor. The gross total removal of the tumor was achieved in 23 patients and subtotal removal was achieved in three patients. The tumors were pathologically diagnosed mainly as pineocytomas (10), pilocytic astrocytomas (6), or pineal cysts (4). Twenty-five of the patients clinically improved after surgery, and there was no mortality. Two patients experienced transient postoperative neurological deterioration: one patient developed Parinaud syndrome, and one patient developed intermittent diplopia. Successful surgery and patient outcome when treating tumors of the pineal region using the ITSC approach requires: (i) preservation of the venous flow of the Galenic draining system; (ii) preservation of the thick bridging veins of the tentorial surface of the cerebellum, especially the hemispheric bridging veins; and (iii) minimizing retraction of the cerebellum during surgery to avoid adverse effects caused by both direct cerebellar compression and disturbance of the venous circulation.

Interleaving deep brain stimulation for a patient with both Parkinson's disease and essential tremor†‡

Parkinson’s disease (PD) and essential tremor (ET) sometimes appear in the same patient, but the nature of this coexistence is a matter of ongoing debate. Although deep brain stimulation (DBS) is effective for both disorders, the targeted brain regions differ: the subthalamic nucleus (STN) or pars interna of the globus pallidus is preferred in PD patients and the nucleus ventralis intermedius of the thalamus (Vim) for ET patients. In addition, stimulation of the caudal zona incerta has been suggested for tremor control. In 1 reported patient with ET and PD, DBS in the STN improved both disorders. We present the case of a 50-year-old man who has suffered from ET since he was 5 years old. His mother and brother also suffered from ET. The Whiget Tremor Rating Scale score was 34 points (left, 14; right, 20) and improved to 16 (8/8) points after alcohol intake. Furthermore, he showed progressive signs of PD, which started 2 years ago. Both ET and PD were more dominant on the right side. Apart from the rest tremor, PD signs responded well to levodopa (motor part of the Unified Parkinson’s Disease Rating Scale score: 32 points off, 17 points on levodopa). Pharmacological treatment was difficult; treatment for ET was either insufficient (gabapentin, topiramate, alprazolam) or not well tolerated (primidone, propranolol). Dopaminergic drugs (pramipexole, ropinirole, levodopa) caused severe sleepiness. After careful evaluation, we recommended DBS. Although at this point the patient was still more affected by ET, PD symptoms were already significantly limiting the patient’s daily activities. Based on the above-mentioned case report, we selected as a target structure the medial STN, neighboring the caudal zona incerta in T2-weighted MRI (Suppl. Fig.; mid-commissural point [MCP]–based coordinates as x/y/z in millimeters: L, 10.72/ 5.75/ 4.08; R, 10.15/ 5.0/ 4.08). However, we aimed for an electrode trajectory that allowed the most dorsal poles of the quadripolar electrodes (Medtronic model 3389) to be located as close as possible to the Vim. After 5 microelectrode recordings and intraoperative macrostimulation, and after weighing benefits versus side effects, we implanted the electrodes in the anterior (left side) and lateral (right side) trajectory passing the thalamus and ending down in the STN, but not in proximity of the zona incerta. Fusion of intraoperative stereotactic computed tomography images with preoperative MRI revealed the following MCPbased positions (Suppl. Fig.): c0, 11.18/ 2.85/ 3.50; c8, 11.21/ 2.97/ 4.24; c3, 13.17/ 0.50/1.70; c11, 14.01/ 0.70/ 0.56. Projection of the electrodes on a 3-D atlas confirmed the localization of the most ventral poles (c0/c8) in the STN and the most dorsal poles (c3/c11) in the ventrolateral anterior thalamus (Fig. 1 and Suppl. Fig.). After bilateral electrode implantation, we first stimulated the left STN to alleviate right-sided symptoms of both PD and ET. However, this did not improve ET (unipolar stimulation of the most ventral pole; amplitude up to 3.5 V; impulse width, 60 ls; frequency, 130 Hz). Conversely, unipolar stimulation of the most dorsal pole (up to 4.2 V/60 ls/ 130 Hz) only improved ET. Thereafter, we programmed simultaneous unipolar stimulation at both extreme poles (up to 4.2 V/60 ls/130 Hz), but this strategy improved neither PD nor ET. Finally, we employed an interleaving stimulation of the same extreme poles (ventral: 3.3 V, dorsal: 4.3 V, both 60 ls/125 Hz). For the first time, symptoms of both PD and ET were significantly improved (Video). In contrast to an earlier case report, stimulation of the STN alone was not beneficial for ET in this patient. And simultaneous unipolar stimulation at both extreme poles was not efficacious for any symptom. However, an interleaving stimulation strategy, that is, alternating unipolar impulses with different amplitudes for the extreme poles in the STN and the ventrolateral anterior thalamic region near the Vim was successful in improving both PD and ET. The importance of pulse timing (simultaneous vs interleaving) may be related to temporal integration in the receiving brain areas.

Subthalamic deep brain stimulation versus best medical therapy for L-dopa responsive pain in Parkinson's disease.

&NA; Subthalamic deep brain stimulation is superior to best medication for improvement of Parkinson’s‐related pain. This treatment effect can be predicted by pre‐operative l‐dopa challenge tests. &NA; Pain is a frequently observed non‐motor symptom of patients with Parkinson’s disease. In some patients, Parkinson’s‐related pain responds to dopaminergic treatment. In the present study, we aimed to elucidate whether subthalamic deep brain stimulation has a similar beneficial effect on pain in Parkinson’s disease, and whether this effect can be predicted by a pre‐operative l‐dopa challenge test assessing pain severity. We prospectively analyzed 14 consecutive Parkinson’s patients with severe pain who underwent subthalamic deep brain stimulation. In 8 of these patients, pain severity decreased markedly with high doses of l‐dopa, irrespective of the type and localization of the pain symptoms. In these patients, subthalamic deep brain stimulation provided an even higher reduction of pain severity than did dopaminergic treatment, and the majority of this group was pain‐free after surgery. This effect lasted for up to 41 months. In the remaining 6 patients, pain was not improved by dopaminergic treatment nor by deep brain stimulation. Thus, we conclude that pain relief following subthalamic deep brain stimulation is superior to that following dopaminergic treatment, and that the response of pain symptoms to deep brain stimulation can be predicted by l‐dopa challenge tests assessing pain severity. This diagnostic procedure could contribute to the decision on whether or not a Parkinson’s patient with severe pain should undergo deep brain stimulation for potential pain relief.

Clinical impact of CCM mutation detection in familial cavernous angioma

Introduction and backgroundA 3-year-old Bosnian girl with a large symptomatic brainstem and multiple supratentorial cavernous angiomas, who underwent neurosurgical treatment, is presented. As multiple cavernomas are more common in familial cases, genetic analyses and neuroradiological imaging were performed in the patient and her parents to see whether there was any evidence for inheritance. This information is important for genetic counseling and provision of medical care for at-risk relatives. Currently, no recommendation is available on how to manage these cases.ResultsGenetic analyses demonstrated a novel CCM1 frameshift mutation (c.1683_1684insA; p.V562SfsX6) in the child and the asymptomatic 27-year-old mother. Sensitive gradient-echo magnetic resonance imaging of the mother revealed multiple supratentorial lesions, whereas analogous imaging of the father showed no pathological findings.ConclusionThis case exemplifies that seemingly sporadic cases with multiple lesions might well be hereditary and that presymptomatic genetic testing of family members may identify relatives for whom clinical and neuroradiological monitoring is indicated.

The impact of subthalamic deep brain stimulation on sleep-wake behavior: A prospective electrophysiological study in 50 Parkinson patients

Study Objectives This prospective observational study was designed to systematically examine the effect of subthalamic deep brain stimulation (DBS) on subjective and objective sleep-wake parameters in Parkinson patients. Methods In 50 consecutive Parkinson patients undergoing subthalamic DBS, we assessed motor symptoms, medication, the position of DBS electrodes within the subthalamic nucleus (STN), subjective sleep-wake parameters, 2-week actigraphy, video-polysomnography studies, and sleep electroencepahalogram frequency and dynamics analyses before and 6 months after surgery. Results Subthalamic DBS improved not only motor symptoms and reduced daily intake of dopaminergic agents but also enhanced subjective sleep quality and reduced sleepiness (Epworth Sleepiness Scale: -2.1 ± 3.8, p < .001). Actigraphy recordings revealed longer bedtimes (+1:06 ± 0:51 hours, p < .001) without shifting of circadian timing. Upon polysomnography, we observed an increase in sleep efficiency (+5.2 ± 17.6%, p = .005) and deep sleep (+11.2 ± 32.2 min, p = .017) and increased accumulation of slow-wave activity over the night (+41.0 ± 80.0%, p = .005). Rapid eye movement sleep features were refractory to subthalamic DBS, and the dynamics of sleep as assessed by state space analyses did not normalize. Increased sleep efficiency was associated with active electrode contact localization more distant from the ventral margin of the left subthalamic nucleus. Conclusion Subthalamic DBS deepens and consolidates nocturnal sleep and improves daytime wakefulness in Parkinson patients, but several outcomes suggest that it does not normalize sleep. It remains elusive whether modulated activity in the STN directly contributes to changes in sleep-wake behavior, but dorsal positioning of electrodes within the STN is linked to improved sleep-wake outcomes.

A critical reflection on the technological development of deep brain stimulation (DBS)

Since the translational research findings of Benabid and colleagues which partly led to their seminal paper regarding the treatment of mainly tremor-dominant Parkinson patients through thalamic high-frequency-stimulation (HFS) in 1987, we still struggle with identifying a satisfactory mechanistic explanation of the underlying principles of deep brain stimulation (DBS). Furthermore, the technological advance of DBS devices (electrodes and implantable pulse generators, IPG’s) has shown a distinct lack of dynamic progression. In light of this we argue that it is time to leave the paleolithic age and enter hellenistic times: the device-manufacturing industry and the medical community together should put more emphasis on advancing the technology rather than resting on their laurels.

Dorsolateral Approach to the Craniocervical Junction

The region of the craniocervical junction is the site of various pathological lesions. Due to the complex topographical anatomy, performing surgery within this area requires great experience and knowledge in both spinal and skull-base anatomy. The most frequent tumors located within the craniocervical junction area are meningiomas. These lesions may occur in a great variety of appearances in terms of histological type, size, extension, insertion, vascularity, invasiveness, involvement of the vertebral artery, and growth pattern. Accordingly, the surgical removal of such tumors must be adequately adapted to all these variations. Apart from meningiomas, we have also treated a number of other lesions within this area such as neurinomas, ependymomas, hemangioblastomas, etc.

Neue CCM1-Mutation bei einem 2-Jährigen

ZusammenfassungFamiliäre und multiple Kavernome beruhen häufig auf autosomal-dominant vererbten Mutationen, die sich mit einer Penetranz von etwa 60% klinisch manifestieren. Wir berichten über einen 2-jährigen Patienten mit angeborener vaskulärer Hautmalformation des Oberschenkels. Bei der zerebralen Bildgebung wurde ein eingeblutetes Kavernom diagnostiziert und anschließend mikrochirurgisch reseziert. Die Familienanamnese war positiv, und beim Indexpatienten wurde eine neue CCM1-Mutation (c.1780_1783delinsTACCTGTTACCAAA) gefunden, sodass eine präsymptomatische genetische Diagnostik im Rahmen einer genetischen Beratung in dieser Familie möglich ist.AbstractFamilial and multiple cerebral cavernous malformations are frequently caused by autosomal dominant mutations, which are clinically manifested with a penetration of approximately 60%. We report on a 2-year-old boy who presented with a cutaneous vascular malformation of the right thigh, which prompted cranial MRI. After detection of a right parietal cavernoma with signs of previous hemorrhaging, microsurgical excision was undertaken. Cerebral cavernomas were also diagnosed in a further nine relatives of the patient. Genetic analysis revealed a novel CCM1 mutation (c.1780_1783delinsTACCTGTTACCAAA), thus enabling presymptomatic testing in further relatives. We suggest genetic counseling and testing in patients with a positive family history and/or multiple lesions due to the possible clinical impact.