Gondi V, Yock TI, Mehta MP. Proton therapy for paediatric CNS tumours — improving treatment-related outcomes. Nat Rev Neurol. 2016;12(6):334–345. doi:10.1038/nrneurol.2016.70.
In this review, the authors provide an introduction to the types of pediatric CNS tumors for which proton therapy can be considered, and discuss the evidence that proton therapy limits toxicities and improves quality of life for patients. As you no doubt remember from your residency, a proton has a defined maximum penetration depth, called the Bragg peak, at which the majority of its energy is released over a few millimeters. The Bragg peak is determined by the energy of a proton, and can be shortened to match the distal edge of the target by placement of customized tissue-equivalent material in the beam path. Before reaching the Bragg peak, a proton loses only a small amount of its energy, so delivers a lower ‘entrance’ dose than does conventional X‑ray therapy. Beyond the Bragg peak, a proton has no energy, so delivers no ‘exit’ dose. The improvement in dose distribution achieved with proton therapy can meaningfully affect the risk of long-term radiotherapy effects, such as secondary malignancy, cognitive toxicity, endocrinopathy, hearing loss and vasculopathic effects. Despite its higher up front costs, proton therapy has been shown to be more cost effective than X ray therapy owing to the dramatic reduction in the excess costs of managing long-term toxicities. Keep in mind that randomized trials of proton ther¬apy versus X ray therapy are unlikely due to the rarity of the diseases involved and the ethical issues surrounding the enrollment of children into trials in which one arm is asso¬ciated with a greater likelihood of toxicity. Uncertainty about the biological effects of proton therapy on certain healthy tissue and the relative inaccessibility of proton therapy, especially in developing nations, pose important challenges to the widespread use of proton therapy for pediatric CNS tumors.
Koelman DLH, Chahin S, Mar SS, et al. Acute disseminated encephalomyelitis in 228 patients: A retrospective, multicenter US study. Neurology. 2016;86(22):2085–93. doi:10.1212/WNL.0000000000002723.
ADEM is a rare inflammatory demyelinating disorder of the CNS, first described in 1724. The diagnosis remains clinical due to the lack of a distinctive biological marker. The disease typically follows a self-limiting monophasic course, but multiphasic forms have been reported. MS may be indistinguishable from ADEM at first presentation. This was a retrospective, multicenter study in 4 US academic medical centers of all patients clinically diagnosed with ADEM. The initial presentation of pediatric and adult ADEM and monophasic and multiphasic disease were compared. Of the 228 patients (122 children, 106 males, 7 deaths), approximately one quarter experienced at least one relapse. Relapsing disease in children was more often diagnosed as multiphasic ADEM than in adults, in whom MS was diagnosed more often. Features helpful in predicting a subsequent relapsing demyelinating disease included female sex and absence of encephalopathy at presentation. Fever, ataxia, meningeal signs, and deep gray matter lesions on neuroimaging may be useful in the early prediction of relapsing disease. In contrast with most prior studies, they did not find the presence of oligoclonal bands, presence of periventricular lesions, or corpus callosum involvement on neuroimaging to be significantly associated with relapsing disease. They conclude that relapsing disease after ADEM is fairly common and associated with a few potentially predictive features at initial presentation.
Saver JL. Cryptogenic Stroke. N Engl J Med. 2016;374(21):2065–2074. doi:10.1056/NEJMcp1503946.
This “Clinical Practice” feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines. The percentage of ischemic strokes that are classified as cryptogenic has declined over time as diagnostic testing has advanced, from 40% in the 1970s to 10-15% today for highly cryptogenic stroke in advanced centers performing extensive testing. However, stroke that is cryptogenic after a standard diagnostic evaluation remains a common clinical challenge, accounting for 20 to 30% of all ischemic strokes. The most common causes of determined ischemic stroke include large-artery atherosclerosis, cardioembolism, and small vessel disease. Causes of stroke which are initially considered cryptogenic but diagnosed after more specialized testing include occult atherosclerosis (including nonstenosing but unstable plaques at intracranial and cervical sites or stenosing plaques at the thoracic origins of the common carotid and thoracic vertebral arteries); nonatherosclerotic arteriopathies, such as dissection or vasculitis; hypercoagulable states; cardioembolism from medium-grade sources, such as low-burden paroxysmal atrial fibrillation or dilated cardiomyopathy of moderate degree; and paradoxical embolism. In young adults 18 to 30 years of age, dissection is most common. In patients older than 60 years of age, occult atrial fibrillation becomes more frequent.
2 Figures and 1 Table, including a nice flow diagram of escalating use of more sophisticated testing for cryptogenic stroke
Singhal AB, Topcuoglu MA, Fok JW, et al. Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Ann Neurol. 2016;79(6):882–894. doi:10.1002/ana.24652.
Accurate diagnosis and distinction between RCVS and PACNS remains challenging. Misdiagnosis often leads to unnecessary diagnostic procedures such as brain biopsy or repeated cerebral angiography, or the empiric use of immunosuppressive therapy. In this cohort study, the authors describe (1) the uniformly dramatic presentation of RCVS and the heterogeneous features of PACNS, (2) the recognizable brain lesion patterns, (3) the overlap between RCVS and PACNS in hemorrhagic vasculitis from sympathomimetic drugs, (4) the distinctive normal-becoming-abnormal evolution of brain MRI in RCVS, (5) the detailed morphology and distribution of angiographic abnormalities in both conditions, (6) the correlation between the FLAIR dot sign and PRES, and (7) the dissociation between the extent of brain lesions and vasoconstriction severity. Headache was common in both conditions, but the specifics mattered. The onset of RCVS was dramatic, with patients requiring urgent evaluation for severe (usually thunderclap-TCH) headaches. In the absence of ruptured aneurysms, recurrent TCH is virtually diagnostic for RCVS; recurrences do not occur in any other condition associated with TCH. The pattern of normal admission scans becoming abnormal within days was unique to RCVS. All PACNS patients had abnormal brain scans on admission. Except for the 4 drug-induced vasculitis cases, they did not observe PRES or brain hemorrhages in PACNS. Infarcts in RCVS were located in superficial border zone or watershed regions, but were not the usual internal or external watershed infarcts associated with large-artery stenosis or embolic events. They often spared the cortical ribbon and rarely involved the deep structures. PACNS patients had disseminated small infarcts and microangiopathic white matter changes consistent with the diffuse involvement of distal arteries. The sausage-on-a-string appearance historically associated with PACNS was significantly more common in RCVS. Patients with PACNS often had normal cerebral angiography, and if abnormal, the arteries were typically irregular and notched. Note that angiographic abnormalities in RCVS are dynamic and can develop after days, so normal angiography does not necessarily exclude RCVS. A single TCH with border zone–only infarct or vasogenic edema should be considered diagnostic for RCVS or PRES (both interrelated reversible conditions). Additionally, a single TCH with normal MRI (with or without he FLAIR dot sign- hyperintense vessels on FLAIR) should be considered diagnostic for RCVS, provided CSF shows no evidence for meningitis or SAH.
6 Tables, 3 Figures
Tu T-W, Williams RA, Lescher JD, Jikaria N, Turtzo LC, Frank JA. Radiological-pathological correlation of diffusion tensor and magnetization transfer imaging in a closed head traumatic brain injury model. Ann Neurol. 2016;79(6):907–920. doi:10.1002/ana.24641.
This study investigated the radiological–pathological correlation between diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) techniques and immunohistochemistry using a closed head rat model of TBI. Forty rats underwent a modified Marmarou weight drop closed head injury model for TBI. Another 5 animals without injury served as the controls for this study. TBI was induced by freely dropping a custom made 450g impactor guided by a brass tube from a distance of 2m from the helmet used to stop skull fractures (stainless steel disk 10mm diameter and 3mm thickness strapped on top of the shaved head by an elastic band and positioned midline between bregma and lambda). All rats survived after TBI experiments. There was no evidence of skull fracture, subdural hematoma, or hemorrhage on the acute T2*-weighted images and at time of euthanasia.
DTI axial diffusivity and fractional anisotropy (FA) were sensitive to axonal integrity, whereas radial diffusivity showed significant correlation to the myelin compactness. FA was correlated with astrogliosis in the gray matter, whereas mean diffusivity was correlated with increased cellularity. The magnetization transfer ratio at 3.5ppm demonstrated a strong correlation with both axon and myelin integrity. MTI is sensitive in reflecting the consequences of TBI in brain, but is less specific than DTI for showing DAI in white matter. Although conventional T2-weighted MRI did not detect abnormalities following TBI, DTI and MTI afforded complementary insight into the underlying pathologies reflecting varying injury states over time, and thus may substitute for histology to reveal diffusive axonal injury pathologies in vivo.
8 Figures
Turc G, Maïer B, Naggara O, et al. Clinical Scales Do Not Reliably Identify Acute Ischemic Stroke Patients With Large-Artery Occlusion. Stroke. 2016;47(6):1466–1472. doi:10.1161/STROKEAHA.116.013144.
The authors assessed the performance of 13 clinical scores to predict large-artery occlusion in 1004 consecutive patients with acute ischemic stroke undergoing clinical examination and magnetic resonance or computed tomographic angiography ≤ 6 hours of symptom onset. When no cutoff was published, they used the cutoff maximizing the sum of sensitivity and specificity in the cohort. Magnetic resonance imaging has been systematically implemented in their center as first-line diagnostic imaging in candidates for reperfusion therapies. The MR protocol, remained unchanged throughout the study period and included at least 3-dimensional time-of-flight intracranial MRA and T2*-weighted gradient echo imaging, performed on a 1.5-T GE Healthcare MR scanner. Patients in whom magnetic resonance imaging was contraindicated underwent CT and, whenever feasible, neck and intracranial CTA. 328 (32.7%) had an occlusion of the internal carotid artery, M1 segment of the middle cerebral artery, or basilar artery. The highest accuracy (79%) was observed for National Institute of Health Stroke Scale score ≥ 11 and Rapid Arterial Occlusion Evaluation Scale score ≥ 5. However, these cutoffs were associated with false-negative rates >25%. Using published cutoffs for triage would result in a loss of opportunity for ≥ 20% of patients with large-artery occlusion who would be inappropriately sent to a center lacking neurointerventional facilities. Their findings call into question the usefulness of a clinical score to identify the best candidates for thrombectomy. They recommend that intracranial arterial imaging should be performed in all patients with acute ischemic stroke presenting within 6 hours of symptom onset.
3 Tables
Watson CG, Dehaes M, Gagoski BA, Grant PE, Rivkin MJ. Arterial Spin Labeling Perfusion Magnetic Resonance Imaging Performed in Acute Perinatal Stroke Reveals Hyperperfusion Associated with Ischemic Injury. Stroke. 2016;47(6):1514–15191. doi:10.1161/STROKEAHA.115.011936.
Twenty-five neonates with clinical features of acute stroke underwent magnetic resonance imaging. Perfusion data were obtained using pseudocontinuous arterial spin labeling (PCASL). Strokes were classified as arterial, venous, or both. 8 of 11 (73%) with arterial ischemic stroke demonstrated hyperperfusion, 1 of 9 (11%) with venous stroke, and 4 of 5 (80%) with both. Hypoperfusion was observed in 3 of 9 (33%) with venous and none with arterial ischemic stroke. The authors have demonstrated the feasibility of obtaining brain perfusion data using a PCASL sequence in neonates with acute stroke. They confirm that neonates often demonstrate hyperperfusion relative to the unaffected hemisphere within the region of decreased ADC and little evidence of hypoperfusion beyond it, in contrast to the core and penumbral hypoperfusion seen in adults with stroke. The majority of cases with hyperperfusion were arterial ischemic strokes, whereas most cases with hypoperfusion occurred in venous stroke.
3 Figures, 2 Tables
Vasung L, Hamard M, Soto MCA, et al. Radiological signs of the syndrome of the trephined. Neuroradiology. 2016;58(6):557–568. doi:10.1007/s00234-016-1651-8.
Sinking skin flap syndrome (SSFS), or syndrome of the trephined (ST), is characterized by the development of new neurological symptoms following decompressive craniectomy (e.g. severe headache, tinnitus, dizziness, undue fatigability or vague discomfort at the site of the bone defect, a feeling of apprehension and insecurity, mental depression or intolerance to vibration, sensorimotor or autonomic deficits, and cognitive impairments). These symptoms are aggravated during the Valsalva maneuver and are relieved after cranioplasty. Of the 143 patients the authors evaluated, only 9 % had ST. ST appeared, most frequently, during the second postcraniectomy month. Severity of the paradoxical deviation of midline structures was not significantly different between groups. The number of patients that had paradoxical herniation was not significantly higher in the ST group when compared to controls. The mean volume of the 3rd ventricle was significantly lower in the ST group compared to the control group. Therefore, their results suggest that the sunken skin flap sign and a direct effect of atmospheric pressure are not requisites for ST, that is, not all patients with sunken skin flap will develop ST. The authors note that a large number of case reports corroborate the association of sunken skin flap and ST, so their results directly conflict with the findings of multiple previous authors. They also note that there are reports on selected individuals that occasionally do not have true ST (i.e. symptoms that are relieved after cranioplasty). In addition, a variety of smaller studies indicate the uncertainty of this link and suggest that true ST also appears in the absence of a sinking skin flap sign. In conclusion, ST is an infrequent and delayed post-craniectomy complication. The most frequently reported radiological findings, such as paradoxical herniation, deviation of midline structures, sunken skin flap, and sulcal narrowing, might not be specific for ST.
