bienvenidos al blog


En el mundo actual, donde el tiempo de atención se encuentra limitado y las tecnologías intentan reemplazar la figura del médico en pos de una atención mecanizada; muchos pacientes se encuentran a la deriva, llenos de dudas y ansiedad que persiste a pesar de la gran cantidad de estudios a los que fueron sometidos.







Este blog tiene como objeto recuperar ese tiempo perdido...intentaremos responder científica y humanamente las preguntas de pacientes y, por qué no, la de médicos que quieren una segunda opinión.







La idea es encaminar a los enfermos o a sus familiares, acercándoles un abanico de posibilidades diagnósticas, en función de sus síntomas y exámenes complementarios si los tuviesen y, de ser posible, plantear estrategias de tratamiento.







A los médicos acercar información actualizada o simplemente compartir experiencias neurológicas para enriquecer nuestra actividad a partir del intercambio de ideas.







Queda asi planteado nuestro objetivo .



Muchas gracias a todos los interesados.















José Santiago Bestoso







médico neurólogo.























martes, 26 de marzo de 2013

treatment of Multiple System Atrophy Using Intravenous Immunoglobulin


treatment of Multiple System Atrophy Using Intravenous Immunoglobulin

Peter Novak, Arlene Williams, Paula Ravin, Omar Zurkiya, Amir Abduljalil, Vera Novak
Disclosures
BMC Neurol. 2012;12(131) 
 


 
Abstract and Introduction

Abstract

Background Multiple system atrophy (MSA) is a progressive neurodegenerative disorder of unknown etiology, manifesting as combination of parkinsonism, cerebellar syndrome and dysautonomia. Disease-modifying therapies are unavailable. Activation of microglia and production of toxic cytokines suggest a role of neuroinflammation in MSA pathogenesis. This pilot clinical trial evaluated safety and tolerability of intravenous immunoglobulin (IVIG) in MSA.
Methods This was a single-arm interventional, single-center, open-label pilot study. Interventions included monthly infusions of the IVIG preparation Privigen®, dose 0.4 gram/kg, for 6 months. Primary outcome measures evaluated safety and secondary outcome measures evaluated preliminary efficacy of IVIG. Unified MSA Rating Scale (UMSARS) was measured monthly. Quantitative brain imaging using 3T MRI was performed before and after treatment.
Conclusions Treatment with IVIG appears to be safe, feasible and well tolerated and may improve functionality in MSA. A larger, placebo-controlled study is needed.Results Nine subjects were enrolled, and seven (2 women and 5 men, age range 55–64 years) completed the protocol. There were no serious adverse events. Systolic blood pressure increased during IVIG infusions (p<0 .05="" 19.0="" 1="" 23.3="" 23.9="" 26.1="" 5="" 6.0="" a="" activities="" all="" and="" because="" comparing="" daily="" different="" dropped="" from="" functions="" imaging="" improved="" in="" living="" motor="" mr="" non-threatening="" not="" of="" out="" p="" participants="" post-treatment.="" post-treatment="" pre-="" pre-treatment="" rash.="" results="" significantly="" skin="" study="" subjects="" the="" to="" two="" umsars-i="" umsars-ii="" unchanged="" usmars-ii="" vs.="" was="" were="" worsened="">

Beyond Amyloid Beta: A New Alzheimer Disease Biomarker?


Beyond Amyloid Beta: A New Alzheimer Disease Biomarker?

An AAN Poster Brief

Bret Stetka, MD, Jacques Hugon, MD, PhD
DisclosuresMar 25, 2013


     
    Editor's Note: 

    This year's American Academy of Neurology Annual Meeting featured an Integrative Neuroscience Session looking at advances in, and the potential role of, biomarkers in Alzheimer disease (AD). Following the session, Medscape spoke with Jacques Hugon, MD, PhD, Professor of Neurology at Saint-Louis Lariboisière Fernand-Widal Hospital in Paris, France, about a biomarker with the potential to aid in AD diagnosis. It's not amyloid beta or tau.
    Medscape: Dr. Hugon, what can you tell us about PKR?
    Dr. Hugon: PKR is a kinase that has been shown to play a role in recognizing and signaling viral infection, but its activity has also been shown to be altered in several neurologic disorders in which it negatively modulates memory.[1] Once overactivated, PKR becomes a toxic kinase. As we have shown in our study,[2] PKR accumulates in the brain of patients with AD and can induce the death of neurons. We have seen that the PKR level in the cerebrospinal fluid (CSF) and the activity of PKR in the brain are highly elevated in patients with AD compared with non-AD patients. Our study showed that the mean level of PKR and phosphorylated PKR in the CSF was 300% higher in patients with AD. Sensitivity was 91.1% and the specificity was 94.3%.
    In addition, patients with mild cognitive impairment already have high levels of total CSF PKR and phosphorylated PKR. So, the final story is that the level of PKR in those with high levels of the kinase can predict the degree of cognitive decline. Patients with high levels of PKR in the CSF have been followed for more than 2 years in our department, and we found a clear correlation between the levels of phosphorylated PKR and cognitive decline based on repeated mini-mental state exams. The patients with high CSF levels of PKR have had a more rapid cognitive decline.
    Medscape: From your data it looks like PKR levels correlate with tau levels, What are the implications of this finding?
    Dr. Hugon: Yes, they do correlate with tau levels. PKR can indirectly induce the phosphorylation of tau, so the two may be linked. PKR can also control the production of amyloid beta.

    Dr. Hugon:
     Yes. This could definitely end up being a new biomarker. We performed CSF evaluations in my department rather frequently and now we have collected several hundreds of biomarker samples -- including PKR -- in patients with mild cognitive impairment and AD.Medscape: Amyloid beta, tau, and phosphorylated tau increasingly are being tested as biomarkers of AD, particularly in research and academic settings. Could PKR ultimately be added to the list?
    This procedure is a major part of our practice, especially in young patients. In addition, we are testing potential PKR antagonists in preclinical settings. We have shown earlier that blocking PKR can attenuate amyloid-beta-induced neuronal death in cell cultures. PKR is a possible new target to alter the course of the disease and to possibly restore memory deficits in affected patients.

    viernes, 1 de marzo de 2013

    Coronary Calcium Predicts Stroke Risk


    Coronary Calcium Predicts Stroke Risk

    Sue Hughes
    Mar 01, 2013
     

    Coronary artery calcium (CAC) is an independent predictor of future stroke events in the general population, results of a new study show.
    In the trial, published online February 28 in Stroke, CAC predicted stroke in both men and women and was more predictive in persons younger than 65 years than in older individuals. It was also independent of the presence of atrial fibrillation and Framingham risk factors.
    It was most effective in discriminating stroke risk specifically in persons in low (<10 20="" and="" categories="" framingham="" intermediate="" investigators="" p="" report.="" risk="" to="">
    "When a patient stands in front of us we can find out about their risk factors such as diabetes, blood pressure et cetera, but we don't know much about their extent of vascular disease," lead investigator, Dirk M. Hermann, MD (University Hospital Essen, Germany), commented to Medscape Medical News. "We know that CAC is a good predictor of MI [myocardial infarction], but we wanted to know if it is a good predictor of stroke as well, and we found that it was. This study shows that the risks go together. If a patient is at risk of MI, they are also at risk for stroke. We now have a test that can tell us if a patient is at risk of 2 very common conditions."
    "That CAC, as we now have shown, is able to predict stroke events independent of established risk factors, making this marker promising for risk stratification not only in the hands of cardiologists but also in the hands of neurologists," the authors conclude.
    "This study suggests that broad CAC screening of the population may be the way forward," Dr. Hermann said. Still, he added, "We have to think carefully about whether this is feasible. We don't recommend this at the moment because of the radiation risk." However, he points out that imaging techniques are rapidly evolving and the ability to see disease processes in the body is improving "dramatically."
    "New multislice CT [computed tomography] is associated with much lower radiation, so perhaps in the future broad screening programs will be possible. Then it will be public health question as to whether it is cost-effective," he said. "Even cardiologists are not routinely doing CAC screening at the moment, but it is starting to happen in certain centers practicing preventative medicine. This is modern medicine."
    Heinz Nixdorf Recall Study
    For the current study, 4180 persons aged 45 to 75 years from the population-based Heinz Nixdorf Recall study without previous stroke, coronary heart disease, or myocardial infarction, were evaluated for stroke events over an average 94 months.
    Cox proportional hazards regressions were used to examine CAC as a stroke predictor in addition to established vascular risk factors (age, sex, systolic blood pressure, low-density lipoprotein, high-density lipoprotein, diabetes mellitus, smoking, and atrial fibrillation).
    During the follow-up period 92 incident strokes occurred (82 ischemic and 10 hemorrhagic). Patients who sustained a stroke had significantly higher CAC values at baseline (median, 104.8) than those without stroke (11.2). In a multivariable Cox regression, log10(CAC+1) was an independent stroke predictor, with a hazard ratio of 1.52.
    CAC was most predictive in patients at relatively low cardiovascular risk and in younger rather than older patients.
    "That's probably because higher-risk and older patients have many more risk factors so the CAC result will become less relevant," Dr. Hermann speculated. "Whereas in younger and lower risk patients, there's nothing else to tell you that this person is at risk so it is more useful."
    In the paper, the authors write, "These observations indicate that among cohorts without apparent risk, subjects exist that nonetheless exhibit a high stroke incidence. On the basis of our data, CAC is suitable to identify those subjects."
    Dr. Hermann has disclosed no relevant financial relationships.
    Stroke. Published online February 28, 2013. Abstract

    Eye Tests May Predict Alzheimer's Risk


    Eye Tests May Predict Alzheimer's Risk

    Deborah Brauser
    Mar 01, 2013
     
    Abnormalities in retinal vascular parameters (RVPs) may indicate increased amyloid plaque in the brain and can serve as biomarkers for preclinical Alzheimer's disease (AD), new research suggests.
    Findings from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Flagship Study of Ageing showed that participants with AD had several significantly different RVPs, including narrower veins and a significantly higher arteriole-to-venule ratio (AVR), than their peers without AD.
    In additional analysis of just the participants without an AD diagnosis, Pittsburgh compound B positron emission tomography (PiB-PET) imaging showed that participants who had high neocortical plaque burden also had some of these RVP changes, possibly representing preclinical AD.
    "This is the first study to investigate retinal blood vessel changes with respect to amyloid plaque burden in the brain," write the investigative team, led by Shaun Frost, a PhD candidate at the Commonwealth Scientific and Industrial Research Organization in Perth, Australia.
    "Models combining RVPs perform well at distinguishing diagnosed AD patients from healthy controls," they add.
    The researchers note that because PET and magnetic resonance imaging scans can be expensive to administer and are not widely available, these eye tests may represent a simpler, noninvasive option — although not as a stand-alone measure.
    "Retinal photographic analysis shows potential as an adjunct for early detection of AD or monitoring of AD-progression or response to treatments," they write.
    The study was published online February 26 in Translational Psychiatry.
    Difficult Diagnosis
    "The primary neuropathological hallmark of [AD] is the presence of cerebral amyloid deposits (plaques)," write the investigators.
    "Although post-mortem examination of the brain is required for confirmation of AD, a diagnosis of 'probable AD' can be made in patients, fulfilling the criteria set down by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association," they add.
    However, a conclusive diagnosis of probable AD only comes after neurologic damage has already occurred in these patients. Therefore, there is a great need for ways to detect the condition before irreversible damage occurs.
    Because the retina "is a developmental outgrowth of the brain," the investigators sought to assess whether pathologic retinal vascular changes could be used as a potential screening measure for AD.
    For this analysis, the investigators evaluated a cohort of the AIBL study participants, consisting of 25 with probable AD (52% women; mean age, 72.4 years) and 123 of their healthy peers (55% women; mean age, 71.6 years).
    Digital retinal color photographs for these individuals were taken, and semiautomatic software was used to evaluate for 19 RVPs, such as width and branching of retina vessels. In addition, AVR was calculated for each participant on the basis of central retinal arterial to venular equivalent thickness.
    Additional analysis of RVPs in relation to neocortical plaque burden, as shown with PiB-PET scans, was conducted for 45 of the healthy peers.
    Significant Abnormalities
    Results showed significant between-group differences in 13 of the RVPs measured.
    These included lower central retinal arteriolar and venular equivalent calibers (P = .01 and P < .001, respectively), fractal dimension of both the arteriolar and venular networks (P = .008 and P < .001, respectively), venular curvature tortuosity (P = .02), and number of first branching arterioles and venules (P = .007 and .006, respectively) for those with probable AD vs those without.
    In addition, the participants with probable AD had significantly elevated zone B arteriolar and venular standard deviations (P = .001 and .002, respectively), venular branching coefficient (P = .02), arteriolar and venular branching asymmetry factor (P = .02 and .03, respectively), and arteriolar length-to-diameter ratio (P = .03).
    In the imaging data analysis, the subgroup of healthy volunteers with high levels of amyloid plaque (as shown by PET-PiB-measured standardized uptake value ratio greater than 1.5) had higher venular branching asymmetry factor (P = .01) and arteriolar length-to-diameter ratio (P = .02) compared with those who had lower levels of amyloid plaque.
    These 2 parameters were also larger in patients with AD compared with those with high levels of amyloid plaque, "hence these results are consistent with the hypothesis that RVP changes may precede AD diagnosis," write the study authors.
    There were also significantly more APOE ε4 carriers in the AD group vs the non-AD group (P = .02) and in those with high levels of amyloid plaque vs those with lower levels (P = .04).
    An Even Better Biomarker?

    "I think this is a good study, but I wish they had looked at another subgroup of patients," Gilbert T. Feke, PhD, senior research associate in the Department of Ophthalmology at Massachusetts Eye and Ear Infirmary in Boston, told Medscape Medical News.
    "They looked at control subjects and those with Alzheimer's, but they didn't have an in-between group."
    Dr. Feke, who was not involved with this research, presented preliminary findings from a similar study in a poster presentation at the 2011 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO).
    His investigative team examined 7 elderly participants with probable AD, 10 with mild cognitive impairment (MCI), and 17 with normal cognition.
    Results showed that the AD group had significantly narrower retinal veins than the other 2 groups, as well as decreased retinal blood flow. In addition, the MCI group had significantly lower blood flow and blood speed than those with normal cognition.
    "This interim report suggests that hemodynamic abnormalities may precede neural loss in the retina in cognitively impaired subjects," said the researchers in the presentation.
    "We found that decrease in vessel diameter doesn't happen until people actually have [AD]. Those with MCI didn't show it. Instead, they showed the reduction in blood speed and flow. So that puts a bit of a damper on relying on vessel diameter measurements to be the sole biomarker," added Dr. Feke.
    He noted that diameters in his study and in the current study were measured when the retinal blood vessels were rather large. However, the AD process "starts in the tiniest vessels. And when things happen in those vessels, that slows down blood speed."
    "There aren't a whole lot of people pursuing the idea of examining the retina in this way. But the idea itself is excellent because the retina is part of the brain," he concluded.
    The AIBL study was funded by a grant from the National Institute for Mental Health, and portions were presented at the 2011 Alzheimer's Association International Conference in Paris, France. Dr. Zeke's research, abstract 2132/poster A102 , was presented at ARVO in Fort Lauderdale, Florida, May 2, 2011. The study authors and Dr. Feke have reported no relevant financial relationships.
    Tansl Psychiatry. Published online February 26, 2013. Full article

    martes, 26 de febrero de 2013

    No Greater Risk for Aneurysm Rupture in Pregnancy, Delivery


    No Greater Risk for Aneurysm Rupture in Pregnancy, Delivery

    Pauline Anderson
    Feb 26, 2013
     

    A new study has found no increased risk for aneurysm rupture during pregnancy and delivery, suggesting that the relatively high rate of cesarean deliveries among women with an unruptured aneurysm that was also uncovered by the study may be unnecessary.
    Further, the researchers found that when an aneurysm does rupture, prompt obliteration using surgical clipping or endovascular coiling may decrease poor outcomes.
    "No one knows what the risk of rupture of a cerebral aneurysm is in a pregnant woman, or what the risk is with vaginal delivery," said study senior author, Brian Hoh, MD, the William Merz Associate Professor of Neurosurgery at the University of Florida, Gainesville. "We attempted to answer these questions using a large national hospital database."
    The study appeared in the February issue of the journalNeurosurgery.
    Clipping, Coiling
    The researchers gathered hospital discharge data involving pregnancies or deliveries from the Nationwide Inpatient Sample (NIS) for 1988 to 2009. During that time, 2,715,161 hospitalizations were related to pregnancies; of these, 193 involved unruptured aneurysms and 714, ruptured aneurysms.
    The investigators estimated the prevalence of unruptured aneurysms in the general population of women to be 3.95%, about half of that previously reported in the general population, and further estimated the rate to be 1.8% among women of child-bearing age, 45.3% as high as that among all women.
    Assuming that rate of 1.8%, the researchers estimated that 48,873 of the hospitalized women had unruptured aneurysms. The estimated risk for aneurysm rupture during pregnancy was therefore 1.4% (714 of 48,873; 95% confidence interval [CI], 1.35% - 1.57%).
    There were 17,340,466 hospitalizations involving deliveries, of which 218 involved unruptured and 172 ruptured aneurysms. Again, assuming a rate of 1.8%, 312,128 of these women had undetected unruptured aneurysms. This led to an estimated risk for an aneurysm rupture during delivery of 0.05% (172 of 312,128; 95% CI, 0.0468% - 0.0634%).
    The study showed that the probability of a woman with an aneurysm during pregnancy receiving clipping is significantly higher than that of her receiving coiling. Of the 714 hospitalized pregnant women with a ruptured aneurysm, 2.9% received coiling, 10.5% received clipping, and 86.6% received neither. Of the 172 hospitalizations involving ruptured aneurysms with delivery, 4.7% received coiling, 12.8% received clipping, and 82.5% received neither.
    The authors noted that for pregnancy, the mortality rate among patients who received no treatment was almost double that among those who received clipping or coiling (10.2% vs 5.2%).
    Cesarean Deliveries
    The researchers estimated a national cesarean delivery rate of 25.52% (95% CI, 25.50% - 25.54%). But among patients with unruptured aneurysm, the estimated rate was 70.18% (95% CI, 64.06% - 76.30%; P< .001).
    The authors noted that there are no evidence-based recommendations for obstetric management in patients with unruptured intracranial aneurysm and no evidence to suggest that maternal or fetal outcome is improved by cesarean delivery compared with closely supervised vaginal delivery.
    "Because the finding of an unruptured cerebral aneurysm in a pregnant woman is so rare, there is little evidence to guide obstetricians and neurosurgeons in the care of these patients," said Dr. Hoh.
    The method of delivery for women with intracranial unruptured aneurysm should be based on obstetric considerations, he said. "Cesarean delivery would be indicated in several circumstances, such as when the clinical state of the mother is severe," for example, coma or brainstem damage, or when the aneurysm is diagnosed at labor.
    The study was relatively small, which diminished its statistical power and limited the ability to incorporate covariates into the analysis, the authors note. Another limitation was that the diagnostic codes that were used may be incomplete.
    Numbers Questioned
    In an accompanying comment, R. Loch Macdonald, professor, surgery/neurosurgery, University of Toronto, division head, neurosurgery, St. Michael's Hospital, Toronto, Ontario, Canada, noted that the NIS is not population-based database because it includes selected patients admitted to a subset of hospitals, and that only 13% to 20% of the patients in the study who were coded as having subarachnoid hemorrhage were treated.
    "There is something wrong with this number," he writes, adding that the figure is markedly lower than the percentage treated at hospitals such as his institution, St. Michael's, where the only cases not treated are those with nonaneurysmal subarachnoid hemorrhage and patients in very poor condition who are not expected to survive.
    He also questioned the authors' estimates of pregnant women with unruptured and ruptured aneurysms. Patients with these aneurysms do tend to be female, but they're older and cigarette smokers, he said.
    "The authors try to adjust for this and derive a 1.8% incidence of unruptured aneurysms among women 16 to 44 years of age," but this could still be an overestimation.
    "Overall, this report adds to the literature, suggesting that, although intracranial hemorrhage is an important cause of obstetrical morbidity and mortality, aneurysmal cases are rare, and, if they are more likely to occur during pregnancy and the puerperium, then this increased risk is likely to be small."
    The authors have disclosed no relevant financial relationships.
    Neurosurgery. 2013;72:143-150. Abstract
     

    Dural Venous Sinus Angioplasty and Stenting for the Treatment of Idiopathic Intracranial Hypertension


    Dural Venous Sinus Angioplasty and Stenting for the Treatment of Idiopathic Intracranial Hypertension

    Jeremy D Fields, Parisa P Javedani, Julie Falardeau, Gary M Nesbit, Aclan Dogan, Erek K Helseth, Kenneth C Liu, Stanley L Barnwell, Bryan D Petersen
    Disclosures
    J NeuroIntervent Surg. 2013;5(1):62-68. 

    Abstract and Introduction

    Abstract

    Background Lumboperitoneal shunt (LPS), ventriculoperitoneal shunt (VPS) and optic nerve sheath fenestration (ONSF) are accepted surgical therapies for medically refractory idiopathic intracranial hypertension (IIH). In the subset of patients with IIH and venous sinus stenosis, dural venous sinus stenting has emerged as an alternative surgical approach.
    Methods All cases of dural stents for IIH at our institution were retrospectively reviewed. Eligibility criteria included medically refractory IIH with documented papilledema and dural venous sinus stenosis of the dominant venous outflow system (gradient ≥10 mm Hg).
    Results Fifteen cases (all women) of mean age 34 years were identified. All had failed medical therapy and six had failed surgical intervention. Technical success was achieved in all patients without major periprocedural complications. The mean preprocedural gradient across the venous stenosis was reduced from 24 mm Hg before the procedure to 4 mm Hg after the procedure. Headache resolved or improved in 10 patients. Papilledema resolved in all patients and visual acuity stabilized or improved in 14 patients. There were no instances of restenosis among the 14 patients with follow-up imaging.
    Conclusion In this small case series, dural sinus stenting for IIH was performed safely with a high degree of technical success and with excellent clinical outcomes. These results suggest that angioplasty and stenting for the treatment of medically refractory IIH in patients with dural sinus stenosis warrants further investigation as an alternative to LPS, VPS and ONSF.

    Introduction

    Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri and benign intracranial hypertension, is a rare disorder characterized by increased intracranial pressure (ICP) without an intracranial mass. The overall prevalence in North America is approximately 0.9–1.07/100 000 but rises to 15–19/100 000 among women aged 20–44 years who are overweight (≥20% above their ideal bodyweight).[1] The most widely accepted criteria for diagnosis require: (1) symptoms and (2) signs referable only to elevated intracranial pressure; (3) cerebrospinal fluid (CSF) opening pressure >25 cm H2O measured in the lateral decubitus position; (4) normal CSF composition; and (5) no evidence for an underlying structural cause (using MRI or contrast-enhanced CT for typical patients and MRI and MR venography for all others).[2] The most common symptoms are headache, visual disturbance and tinnitus. Papilledema is present in at least 95%. Although headache may be severe, visual loss due to prolonged papilledema and secondary optic atrophy remains the most feared complication and may progress without recognition by the patients themselves.[3,4]
    Medical treatment generally consists of a combination of carbonic anhydrase inhibitors such as acetazolamide or topiramate (to decrease CSF production) and symptomatic treatment for headache. For medically refractory patients, two surgical strategies have most commonly been employed—CSF diversion with ventriculoperitoneal or lumboperitoneal shunts (VPS or LPS) and optic nerve sheath fenestration (ONSF). While progression of visual loss may be prevented by these surgical approaches, both have significant limitations. Both VPS and LPS have variable clinical response rates and significant shunt failure rates requiring subsequent surgical revision.[5] Moreover, LPS may lead to a number of adverse events including acquired Chiari syndromes, low pressure headaches and archnoiditis of the lumbosacral nerve roots.[6] Although ONSF often temporarily arrests visual loss associated with IIH, recurrence of visual symptoms is common and the procedure does not address headache, tinnitus or other symptoms associated with elevated intracranial pressure.
    The underlying pathophysiology of IIH has yet to be fully defined, but a number of recent investigations have implicated stenosis of the dural venous sinuses as a potential contributor to the syndrome of IIH in a subset of patients. Transverse sinus stenosis was demonstrated by MRI in 90% of patients with IIH,[7]although the degree to which venous sinus stenosis on MRI corresponds to trans-stenosis pressure gradients is not known. Furthermore, elevation of pressures within the dural sinuses proximal to the stenosis is common and significant pressure gradients across the venous stenoses have been demonstrated by direct manometry in patients with IIH.[8,9] Although considerable controversy exists regarding whether dural venous stenosis is a cause of IIH or an effect of elevated intracranial pressure, the results of several case series suggest that stenting of the stenotic dural venous sinus may represent a therapeutic option for medically refractory IIH.[3,10,11] In this paper we present our single-center experience with dural venous sinus stenting for IIH

    Methods

    We retrospectively reviewed all cases of patients treated with dural stents for IIH with papilledema at our institution. The study protocol was approved by our institutional review board.

    Patient Selection and Characteristics

    Patients were considered eligible for stenting based on the following criteria: (1) medically refractory IIH; (2) papilledema confirmed by an ophthalmologist; and (3) dural venous sinus stenosis of the dominant venous outflow system with a gradient of ≥10 mm Hg. This cut–off pressure was selected because a gradient of 5–6 mm Hg from the superior sagittal sinus to the internal jugular bulb is present in normal controls.[9]
    Demographic features (age, gender, body mass index (BMI)), prior treatments (medical and surgical), CSF opening pressures, neuro-ophthalmologic evaluation, procedural details and clinical outcomes were obtained by retrospective chart review. Headache intensity and the presence of tinnitus at last follow-up were assessed by a combination of chart review and telephone interview. Headache was evaluated by structured interview and was categorized as: (1) resolved (no further headache); (2) improved (residual symptoms not requiring continued intervention); (3) no change (no change in symptoms compared with before stenting procedure); (4) worsened (worse than before stenting procedure); and (5) different (change of symptoms compared with prior to the stenting procedure not otherwise meeting the criteria for categories 1–4).

    Procedure

    Prior to intervention, diagnostic angiography and venous pressure measurements were performed under moderate sedation. A full evaluation of the dural sinuses was performed by study of both internal carotid arteries and the posterior circulation. A 6F shuttle sheath (Cook Medical, Bloomington, Indiana, USA) was then placed in the dominant internal jugular vein. A 0.027 inch Renegade microcatheter (Stryker, Kalamazoo, Michigan, USA) was placed coaxially within the 6F shuttle and navigated over a 0.014 inch guidewire into the torcula. The microcatheter was then pulled back from the torcula to the internal jugular vein and simultaneous pressure measurements were obtained from the 6F sheath and microcatheter tip. These pressures were recorded to obtain pressure gradients from the torcula, transverse sinus and sigmoid sinus with respect to the internal jugular vein. After identifying a venous sinus stenosis, dural sinus venography was performed through the 0.027 inch microcatheter to define the anatomy of the stenosis and the size of the native dural sinus.
    Patients with a dural venous sinus stenosis of the dominant venous outflow system with a gradient of ≥10 mm Hg were referred for stent placement.
    All patients were pretreated with aspirin 325 mg and clopidogrel 75 mg for 5 days or loaded with aspirin 325 mg and clopidogrel 600 mg at least 4 h prior to the procedure. Intravenous heparin was given during the stent procedure to raise the activated clotting time to >250 s. Dual antiplatelet therapy was continued for 6 months and aspirin indefinitely thereafter.
    All dural sinus stent procedures were performed with the patients under general anesthesia.
    First, venous access was achieved in the jugular vein ipsilateral to the intended treatment site via the transfemoral approach. The choice of venous access sheath systems evolved as we gained experience with the procedure in order to provide adequate support for stent placement. The final venous access sheath system was a triaxial construct consisting of 12F, 9F and 7F 80–90 cm length sheaths. This system provided sufficient support for the delivery of the stent to the stenotic region of the transverse sinus.
    After placement of the venous sheaths, diagnostic angiography was performed from the ipsilateral internal carotid artery and the venous phase of this study was used as a road map for traversal and stenting of the dural sinuses. Introduced through the venous sheaths, an 0.027 inch Renegade microcatheter was again navigated across the area of stenosis and placed with the distal tip at the level of the torcula. Dual venous pressure measurements were then repeated to confirm the presence of a persistent trans-stenosis gradient. Through this microcatheter, a stiff 0.018 inch guidewire (Platinum Plus; Stryker) exchange length guidewire was placed with the distal tip into the superior sagittal sinus or contralateral transverse sinus. Over this guidewire, a Sterling 6 mm×40 mm over-the-wire balloon angioplasty catheter (Stryker) was positioned across the stenosis and then inflated fully at 8–10 atmospheres for 10 s for two inflations. Following balloon angioplasty, in most cases a Zilver 518 10 mm diameter self-expanding stent (Cook Medical) was positioned across the residual area of narrowing and deployed. The self-expanding stents ranged from 40 to 80 mm in length and were chosen to completely cover the stenosis with at least 10 mm of coverage of the adjacent non-stenotic portion of the vein on each side. A single stent was used to treat the stenotic portion of the vessel in all but one case (for which two stents were used due to inadequate coverage of the stenosis). After initial experience suggested that bilateral stenting was not necessary, unilateral stenting procedures were performed.
    Following stent placement, the 0.027 inch lumen microcatheter was then advanced through the stent to the level of the torcula and simultaneous pressure measurements were obtained to verify efficacy of the stenting procedure and elimination of the trans-stenosis pressure gradient. The arteriotomy was then closed with a StarClose device (Abbott, Chicago, Illinois, USA) and the venotomy was closed with manual pressure.

    Angiographic Follow-up and Outcome Assessment

    Papilledema and visual assessment by an ophthalmologist was undertaken in all patients before stent placement with initial follow-up examination generally 6 weeks after intervention. Evaluations included visual acuity testing, color vision, automated perimetry (Humphrey or Octopus) and funduscopic evaluation. Angiography to evaluate stent patency and restenosis was performed at 6 months after intervention in most patients, although non-invasive imaging was used in some cases. Clinical assessment took place at the time of follow-up angiography as well on an ad hoc basis if additional concerns arose.

    Results

    A total of 15 patients (all women) of mean age 34 years (range 20–56) and mean BMI 39 kg/m2 pre-procedure and 39 kg/m2post-procedure (range 30–73 kg/m2 pre-procedure and 30–49 kg/m2 post-procedure) were treated ( Table 1 ). Only one patient had a reduction in BMI of >5% during the follow-up period (from 73 kg/m2 to 47 kg/m2). Papilledema (diagnosed by an ophthalmologist) and intractable headache were present in all patients prior to the intervention. Pulsatile tinnitus was present in 14 of the 15 patients (93%).
    All had failed medical treatment with acetazolamide; in addition, topiramate and amitriptyline for the treatment of headache were each administered to three patients (20%) and furosemide to two (13%). Surgical interventions prior to stenting had been performed in six of the patients (40%): CSF diversion (VPS, LPS or both) in four patients (27%) and ONSF in six (40%).
    Technical success was achieved in all patients with no major complications. One minor complication (7%), a femoral pseudoaneurysm, was successfully treated with ultrasound-guided compression. The procedural details are shown in Table 2 and an illustrative case is depicted in figure 1. The gradient across the stenotic dural sinus was reduced from a mean of Hg (range 1–7). 1–7). A 6 mm × 40 mm balloon was used for pre–stent angioplasty in all patients. In most cases, a 10 mm × 60 mm self–expanding stent was placed. Stenting was unilateral in 13 of the 15 patients (87%) and bilateral in two (13%).

    Figure 1.

    Illustrative case of a 26-year-old woman with idiopathic intracranial hypertension (IIH). (A, B) Left internal carotid artery injection, venous phase, anteroposterior and lateral views. The left transverse sinus system is dominant and a venous stenosis at the transverse–sigmoid sinus junction is demonstrated. (C, D) Microcatheter injection at the torcula, anteroposterior and lateral views, again demonstrating the venous stenosis at the transverse–sigmoid sinus junction. (E, F) Roadmap images, anteroposterior and lateral views, demonstrating pre-stent angioplasty with a 6×40 mm over-the-wire balloon. The stiff 0.18 inch wire is positioned in the superior sagittal sinus. (G, H) Microcatheter injection at the torcula, anteroposterior and lateral views, immediately after angioplasty followed by deployment of a 10×60 mm self-expanding stent extending from the lateral aspect of the left transverse sinus to the left sigmoid sinus across the region of stenosis. The left transverse sinus system is now widely patent with evidence of residual stenosis. (I, J) Follow-up angiography 8 months after stent placement. The right internal carotid artery injection, anteroposterior and lateral views, shows no evidence of restenosis.
    Clinical follow-up was available in all patients at a mean of 14 months (median 9 months) after stenting. Angiographic follow-up was performed in all patients (catheter angiography in 13 and MRV in 2) at a mean of 9 months (median 6 months) after stenting; the remaining patient has yet to undergo her 6-month angiogram. Stents were patent without evidence of restenosis. All patients were preloaded with aspirin and clopidogrel and these medications were continued as directed (clopidogrel for 6 months and aspirin indefinitely) in 14 patients; one patient discontinued both antiplatelet agents at 4 months without any untoward clinical effect.
    Papilledema resolved in all 15 patients (see figure 2 for representative funduscopic images). Headache resolved or improved in 67% and tinnitus was eliminated in 79% of patients reporting tinnitus prior to the intervention. Visual acuity was assessed formally by an ophthalmologist in 14 of the 15 patients. Of the 14 patients with formal visual acuity testing, 13 (93%) stabilized or improved and one (7%) worsened. The patient who worsened progressed from 20/200 vision in the left eye to ability to detect hand motion only; because papilledema had resolved, the presumed mechanism was progression of optic atrophy due to injury sustained prior to stenting. Due to persistent refractory headache, two patients (13%) underwent VPS following the stenting procedure.

    Figure 2.

    Funduscopic examination (A) prior to stenting showing optic disc edema with obscuration of the optic disc margins, elevation of the optic disc and tortuosity of retinal veins and (B) 3 weeks after stenting showing resolution of optic disc edema and improved vascular tortuosity.
    .

    Discussion

    For medically refractory patients with IIH, particularly those with visual loss and intractable headache, surgical options may be considered but, unfortunately, the available surgical interventions for IIH (ie, VPS, LPS and ONSF) have significant limitations. Response rates to CSF diversion vary considerably depending on the series. Stabilization or improvement in vision has been reported to occur in as few as 62% of patients undergoing VPS or LPS and headaches to improve or resolve in as few as 45%, with frequent recurrences over time. Shunt revisions are necessary in 38–63% of patients. Furthermore, although rare, serious complications (including a 0.5% risk of in-hospital death) have been reported.[12] Similarly, ONSF is associated with substantial treatment failure rates (worsening in vision after a period of stabilization in 34% of patients at 1 year and 45% at 3 years) and failure to improve headache in one-third to one-half.[12]
    Given the problems inherent in the traditional surgical treatments for IIH, our results suggest that venous sinus stenting may be a reasonable alternative treatment in the subset of patients with venous sinus stenosis associated with a significant pressure gradient and, indeed, may treat the underlying etiology of the disease. Of the 15 patients treated, six had previously failed treatment with LPS, VPS or ONSF, including two patients who had undergone all three treatments. Visual acuity stabilized or improved in 93% of patients and papilledema resolved in all patients treated. Headaches improved or resolved in 67%. On follow-up imaging, all stents remained patent with no instances of in-stent thrombosis or restenosis.
    Our results are consistent with those reported in previous case series. A systematic review of all published case series was recently performed, encompassing a total of 40 patients (37 undergoing unilateral stents and three bilateral). Among the 40 patients described in these studies, headache resolved or improved in 33 (83%), papilledema resolved or improved in 30 (75%) and optic atrophy occurred in eight (20%).[11] Since the publication of this review, two relatively large single-center case series have been reported. In one series of 18 patients (with clinical follow-up in 15), 80% of patients had improvement or resolution of headache after stenting.[13] The results of ophthalmologic examination were not reported in this study. Most recently, in a series of 52 patients, papilledema was eliminated in all patients and headache in 44. Among the eight patients without resolution of headache, six were found to have restenosis adjacent to the stent, resulting in an overall rate of restenosis of 12%.[14]
    Several technical considerations contribute to successful stenting and to symptom resolution. Venous sinuses require relatively large stents; we used 10 mm self-expanding stents in most cases and did not observe any instances of in-stent stenosis or restenosis of the adjacent dural sinus. The use of stents 10 mm in diameter may account for the absence of restenosis or stenosis of the adjacent dura observed in our study compared with the 12% rate of restenosis seen in the aforementioned case series. Due to the tortuosity inherent in the sigmoid sinus/transverse sinus system and the stiffness of the stent, a robust support system is required for adequate access. After evaluating several different configurations, we found a triaxial 12F/9F/7F shuttle system placed within the internal jugular vein provided adequate support to ensure stent delivery. Moderate oversizing of the stent diameter with respect to the dural sinus assures adequate apposition of the stent to the venous wall, theoretically decreasing clot formation and increasing patency. In addition, short-term restenosis may result from inadequate coverage or progression of the lesion and therefore relatively long stents were employed.[15]
    The pathophysiologic relationship between IIH and venous sinus stenosis remains controversial. Undoubtedly, dural venous sinus stenosis is much more common in patients with IIH than controls.[7,16]Nonetheless, it remains unclear whether elevations in intracranial pressure are responsible for transverse sinus stenosis or transverse sinus stenosis causes elevations in intracranial pressure.[16]Regardless, the high response rates to transverse sinus stenting seen in our patients as well as those from previous investigations strongly suggests that preserving the patency of the stenotic transverse sinus frequently ameliorates the pathophysiologic mechanism that ultimately leads to IIH, either by addressing the underlying venous stenosis or by preventing venous sinus collapse in the face of elevated intracranial pressure.
    This study has a number of limitations. Invasive procedures are frequently associated with a high placebo response rate and the clinical course of IIH inherently fluctuates. Therefore, in the absence of a control group, the overall improvement in subjective symptoms such as headache and tinnitus could result from a placebo effect or the natural history of the disease rather than from the stenting procedure per se. On the other hand, papilledema was evaluated by ophthalmologists and was found to have resolved in all patients—an objective finding unlikely to result from either placebo or natural history.

    Conclusions

    We retrospectively reviewed the results of venous sinus stenting for IIH in 15 consecutive patients treated at a single institution. Patients were selected if they had IIH, with papilledema and a venous sinus stenosis with a gradient ≥10 mm Hg across the stenosis. Technical success and resolution of papilledema was achieved in all patients without any significant procedural complications. Headache improved or completely resolved in 67%. These results provide additional support for venous stenting as a surgical alternative in a properly selected subset of patients with IIH. Moreover, the high rate of clinical improvement following stenting provides additional evidence for the hypothesis that dural venous sinus stenosis contributes to the underlying etiology of IIH in a subset of patients.

    martes, 19 de febrero de 2013

    New Criteria for Alzheimer Disease and Mild Cognitive Impairment


    New Criteria for Alzheimer Disease and Mild Cognitive Impairment

    Implications for the Practicing Clinician

    Andrew E. Budson, MD, Paul R. Solomon, PhD
    Disclosures
    Neurologist. 2012;18(6):356-363. 
     

    Abstract

    Background: In most research studies and clinical trials, Alzheimer disease (AD) has been diagnosed using the criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association work group in 1984. Developments over the last 27 years have lead to the need for new diagnostic criteria.
    Review Summary: Four articles in the journal Alzheimer's & Dementia in 2011 describe new criteria for AD dementia and mild cognitive impairment (MCI) due to the AD pathophysiological process (MCI due to AD) and the underlying rationale for them. These new criteria emphasize that the AD pathophysiological process starts years and perhaps decades before clinical symptoms, and that biomarkers can be used to detect amyloid β deposition and the effects of neurodegeneration in the brain.
    Conclusions: These new criteria are immediately helpful to the practicing clinician, providing more accurate and specific guidelines for the diagnosis of AD dementia and MCI due to AD. As new diagnostic tools and new treatments for AD become available, diagnosis using these criteria will enable patients with this disorder to receive the best possible care

    Rationale for New Criteria

    Updating the prior criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and theAlzheimer's Disease and Related Disorders Association work group in 1984, new clinical criteria have recently been published for Alzheimer disease (AD) and mild cognitive impairment (MCI) due to the AD pathophysiological process (MCI due to AD). Four articles in the journal Alzheimer's & Dementia in 2011 describe these criteria and the underlying rationale for them. The first is an introduction that provides the background of why new criteria are needed.[1] The second details the hypothesis that the AD pathophysiological process starts years and perhaps decades before the onset of clinical symptoms and dementia. It also discusses the concept of "preclinical" AD.[2] The third considers both clinical and research criteria for MCI due to AD.[3] Finally, the fourth describes new clinical and research criteria for AD.[4] We will focus on new clinical criteria, the area that will be of greatest use to practicing clinicians, and briefly touch on the research criteria and theoretical issues.
    As discussed in these articles, the new criteria were developed because of the recognition of a number of important factors that have changed since 1984:
    1. It is now believed that the AD pathophysiological process starts years before detectable cognitive changes and perhaps decades prior the onset of clinical dementia (Fig. 1). The concept of the "AD pathophysiological process" is thus separated from "AD dementia."
    2. There are many patients whose cognition is not normal for age but also do not meet criteria for dementia.
    3. Other causes of dementia such as frontotemporal dementia, vascular dementia, and dementia with Lewy bodies are now understood to be more likely mistaken for AD than are thyroid disorders and vitamin B12 deficiency.
    4. The genetics of AD are now better understood.
    5. Putative biomarkers of AD are now available in some centers.
    6. New criteria are needed for clinical trials and other research.
    7. New treatments are being developed that are specific for the AD pathophysiological process, making it more important that patients truly have that process before the initiation of this type of specific treatment.
    Figure 1.
    Postulated temporal lag between the deposition of amyloid β in amyloid plaques from an autopsy series and the development of clinical Alzheimer disease (AD) dementia based upon 3 epidemiological studies (from Sperling et al2).
    The overall purpose of these changes to the criteria are to help the clinician identify and treat the disease as early as possible—ultimately before the onset of decline with the goal of enabling individuals to live long and productive lives free of the dementia caused by AD. Recent data from an Alzheimer's Association report suggest that a delay in the onset of symptoms of AD dementia by 5 years would result in a 45% reduction in the number of people with the disorder by the year 2050 and reduce projected Medicare costs of disease from 627 to 344 billion dollars.[5]
    In general, the new criteria differ from the original criteria along 2 important dimensions that have both immediate and future implications for the practicing clinician. One is the recognition of 3 stages of AD progression, with the first (preclinical AD) occurring before changes in cognition and everyday activities are detected, the second (MCI due to AD) occurring when cognitive symptoms emerge but function is still relatively unimpaired, and the third (AD dementia) diagnosed when day-to-day function is impaired. By contrast, the original guidelines only diagnosed AD dementia. Another is the incorporation of biomarkers into the diagnosis, whereas the original criteria were based primarily on clinical judgment.
    The 3 stages of AD discussed are:
    • Preclinical AD: Preceding any clinical changes, this stage is defined by measureable changes in biomarkers and poor performance on challenging cognitive tests. The biomarkers may be detectable by brain imaging or by molecular changes in cerebrospinal fluid (CSF). There are currently no clinical criteria to make the diagnosis of preclinical AD. The primary purpose of the designation of preclinical AD is to provide a framework for researchers to better define this stage of AD.
    • MCI due to AD: This stage is characterized by the first clinical changes. Mild changes in memory and other cognitive abilities that are noticeable to patients and families and can be detected through careful evaluation, but are not sufficient to interfere with day-to-day activities.
    • Dementia due to AD: This stage is characterized by changes in 2 or more aspects of cognition and behavior that interfere with the ability to function in everyday life.

      Preclinical AD and Biomarkers

      As described by Sperling et al,[2] one commonly used model of AD is that many factors including age, genetics, the environment, and others combine to lead to the accumulation of amyloid β (Aβ) in the brain, which in turn produces synaptic dysfunction, neurofibrillary tangle formation, and neuronal death, all of which ultimately lead to cognitive decline (Fig. 2). Given that the events in this pathologic cascade sequence likely take years or decades from the accumulation of Aβ to the development of dementia or even MCI, there must be a prior "preclinical" stage of AD (Fig. 3).
      Figure 2.
      Hypothetical model of Alzheimer disease (AD) pathophysiological cascade sequence (from Sperling et al2).
      Figure 3.
      Model of the clinical course of Alzheimer disease (from Sperling et al2). MCI indicates mild cognitive impairment.
      The concept of a preclinical phase of a disease should not be new to practicing clinicians, nor should the concept of diagnosing a disease in the absence of symptoms. Cancer is routinely detected at the stage of "carcinoma in situ" and atherosclerosis may cause detectable narrowing of the arteries before myocardial infarct. Similarly, many diseases including Type II diabetes, osteoporosis, and hypertension are routinely detected and treated before symptoms emerge. The goal is to move AD to a similar status.
      These guidelines are primarily aimed at helping researchers determine which signature biological changes (ie, biomarkers) occur years before the onset of clinical symptoms. Currently AD biomarkers have minimal impact on clinical practice, although it is likely that these biomarkers will be important to the clinician in the near future.
      Table 1 presents several biomarkers of Aβ deposition or neurodegeneration that are currently in use. Markers of Aβ deposition include low CSF Aβ42 and positive PET amyloid imaging. Markers of neurodegeneration include elevated CSF tau [both total and hyperphosphorylated tau (p-tau)], decreased metabolism in temporal and parietal cortex on 18flurodeoxyglucose (FDG) PET, and atrophy on magnetic resonance imaging (MRI) in temporal (medial, basal, and lateral) and medial parietal cortex. Although it makes the most sense scientifically to divide the biomarkers into those measuring either Aβ deposition or neurodegeneration, in clinical practice one tends to divide the biomarkers by how they are obtained: structural MRI, PET, and CSF studies.
      Structural MRI, when analyzed using a quantitative protocol, can provide whole brain volume and volume in anatomically distinct areas of the brain. Patients in whom the AD pathophysiological process has caused neurodegeneration should have less brain tissue in temporal (medial, basal, and lateral) and medial parietal cortex—and they should lose tissue faster—than healthy individuals.[6] Volumetric MRI is currently being used in a number of ongoing clinical trials to evaluate the efficacy of disease-modifying drugs in AD. In addition, the Alzheimer's Disease Neuroimaging Initiative also includes serial volumetric MRIs in AD and MCI patients and healthy controls.[7] The Alzheimer's Disease Neuroimaging Initiative data should ultimately provide a normative database that would be an important step in allowing volumetric MRI to be used clinically. Volumetric MRI analyses are not routinely available, although we encourage all clinicians to look for qualitative patterns of atrophy in temporal (medial, basal, and lateral) and medial parietal cortex, and progressive atrophy when serial scans are available.
      There are 2 types of PET biomarkers: those that show amyloid deposition, and those that show neurodegeneration. Brain neurodegeneration can be identified by measuring glucose metabolism in the brain with FDG PET. These scans show which areas of the brain are and are not functioning well. Decreased metabolism is observed in temporal and parietal cortex when the AD pathophysiological process has caused neurodegeneration.[8] FDG PET scans are available to the clinician now, and are covered by Medicare. We do not, however, recommend using these scans routinely when the history, physical examination, cognitive testing, and structural imaging are all consistent with AD—it simply is not necessary.[8] In situations, however, in which one suspects an atypical neurodegenerative disease, an FDG PET scan can help distinguish AD from another disorder (such as dementia with Lewy bodies or frontotemporal dementia). Another reason to obtain an FDG PET scan is if one is suspecting AD in a patient younger than 66 years of age. At such a young age the prevalence of AD is similar to that of many other etiologies (such as frontotemporal dementia),[9] making it more critical to be sure that the diagnosis is AD before treatment is initiated.
      Several compounds that can identify AB deposition using PET are currently being used for research and/or are under commercial development. The 2 most widely used are the Pittsburgh compound B and florbetapir. Both have been shown to bind to brain AB.[10,11] Because amyloid accumulation is thought to be present years before the onset of clinical symptoms, PET identification of AB raises the possibility of identifying and treating patients with AD years before symptoms emerge—once a drug has been proven to be disease modifying. Amyloid PET imaging is currently being used in several clinical trials both to help identify individuals with preclinical AD and to measure the effects of antiamyloid treatments. Moreover, florbetapir has recently been submitted to the FDA for approval in clinical practice. Detection of β-amyloid by PET could be available to clinicians soon.
      Standard CSF biomarkers for AD are Aβ42, total tau, and p-tau. Studies have shown that when all 3 markers are combined, the accuracy of the diagnosis is highest, with sensitivity and specificity of 85% to 90%.[12] Although CSF analysis is already commercially available (www.athenadiagnostics.com) and used by some clinicians to aid in diagnosis, we view this test as highly promising but not yet ready for routine clinical practice.[8]
      Based upon the current scientific model regarding when different events occur in the AD pathophysiological process (Fig. 4), Sperling et al[2] discussed 3 stages of preclinical AD to be considered for research, based upon biomarkers and cognitive change. Stage 1 is asymptomatic cerebral amyloidosis, which could be determined by the presence of a biomarker sensitive to Aβ, in the absence of any marker of neurodegeneration or evidence of subtle cognitive change. Stage 2 is asymptomatic cerebral amyloidosis plus neurodegeneration in the absence of subtle cognitive change. Finally, stage 3 is amyloidosis plus neurodegeneration plus subtle cognitive or behavioral decline. Guided by these theoretical underpinnings, the new clinical and research criteria are next presented for MCI due to AD and AD dementia.
      Figure 4.
      Model of how the different stages of Alzheimer disease may be detected by changes in various biological, cognitive, and clinical markers (from Sperling et al2). CSF indicates cerebrospinal fluid; FDG, 18flurodeoxyglucose; MCI, mild cognitive impairment; MRI, magnetic resonance imaging.
     
    .

    Criteria for Mild Cognitive Impairment Due to the AD Pathophysiological Process

    Based upon guidelines currently in use at memory centers and in research studies, Albert et al[3] presented the criteria for MCI due to AD. These criteria, aimed both at clinicians and researchers, refer to the symptomatic phase of the AD pathophysiological process but before the individual develops the functional impairment that defines dementia. Clinicians are increasingly making a diagnosis of MCI and the new diagnostic guidelines will formalize this process. The guidelines recognize that everyone who eventually develops AD will go through a transitional period of mild but detectable cognitive impairment. Importantly, however, not everyone who is diagnosed with MCI will go on to develop AD. MCI can be due to a variety of disorders including, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and others. Both core clinical criteria for the diagnosis of MCI due to AD and clinical research criteria are presented. As the authors start their discussion on the core clinical criteria they point out that, in addition to these criteria, clinical judgment must be used to distinguish between normal cognition and MCI, and between MCI and dementia.
    The new guidelines specify the criteria for making a diagnosis of MCI due to AD. The criteria include:
    • Excluding patients who have other causes of MCI including extensive vascular disease, frontotemporal dementia, and dementia with Lewy bodies. These exclusions will likely be accomplished through a combination of the clinical evaluation and imaging studies.
    • Including patients who show increasing cognitive decline over time. This decline could be detected historically or via serial evaluations over time.
    • Including patients who have the very rare mutations associated with early-onset familial AD (amyloid precursor protein, presenilin 1, or presenilin 2). These mutations can be identified via commercially available genotyping (http://www.athenadiagnostics.com).
    Because patients with MCI due to AD may actually be considered very early AD patients, it will be important for practicing clinicians to identify this condition. There may be at least as many patients with MCI due to AD as there are with dementia due to AD.[13,14] Although there is not substantial evidence that current treatments with FDA approved medications improve patients with MCI due to AD (there is ongoing research aimed at answering this question), patients with this condition may benefit from referrals to centers conducting studies with potential disease modifying treatments such as vaccines that are aimed at slowing the loss of neurons and thus the progression of the disease. It is becoming increasingly clear that disease-modifying drugs will be most beneficial in the earliest stages of the disease. There are now several ongoing studies with hypothesized disease modifying agents (eg, vaccines) for patients with MCI due to AD, and other studies are being planned.
    The clinical criteria are divided into 2 parts (Table 2). First, criteria are presented for the clinical and cognitive syndrome of MCI, and second, criteria are presented regarding the etiology of the MCI syndrome being consistent with AD.
    Research criteria for MCI due to AD incorporating biomarkers are next presented. The biomarkers discussed include those in Table 1. Two valuable reasons to add biomarkers is that they may help determine (1) the underlying etiology of the MCI and (2) the likelihood and time course of an individual with MCI becoming more impaired or demented. An important point discussed is that biomarkers that detect Aβ protein deposition are most useful in determining underlying etiology, whereas biomarkers that detect neuronal degeneration and injury are most useful in determining prognosis and progression. Adding each of these categories of biomarkers to the core clinical diagnosis of MCI due to AD leads to the following probabilities: If 1 of these 2 biomarker categories is positive, the "biomarker probability of AD etiology" rises to "intermediate," and both categories must be positive for the "highest" probability. The "lowest" probability is present if both categories are negative.

    Criteria for All-cause Dementia and AD

    The new criteria for AD clarify existing guidelines and are appropriate for use today by practicing physicians. The new guidelines propose 4 possible classifications of dementia caused by AD: (1) probable AD dementia, (2) probable AD dementia with increased level of certainty, (3) possible AD dementia, and (4) probable or possible AD dementia with evidence of AD pathophysiological process. The last criteria propose a system for providing additional diagnostic evidence through the use of biomarkers, and are currently intended for research purposes only, although it is likely that it will be increasingly used in future clinical practice. The hope is that the use of these new clinical criteria coupled with the judicious addition of biomarkers will eventually improve diagnostic accuracy and help make accurate diagnoses earlier in the disease process when intervention can be most beneficial. The new guidelines do not suggest any additional diagnostic procedures for patients already diagnosed with AD.
    The new criteria suggest a 4-step approach to diagnosis of dementia due to AD (Table 3). Step 1 determines that dementia is present, step 2 determines that the dementia is due to AD, step 3 provides an increased level of certainty to the diagnosis, and step 4 evaluates the biomarker probability of AD etiology.
    The next idea that is introduced is that of research criteria for "probable AD dementia with evidence of the AD pathophysiological process." These research criteria increase the certainty that the patient's clinical dementia is due to the AD pathophysiological process by adding biomarker evidence to the probable AD dementia criteria. The biomarkers fall into 2 categories, markers of Aβ protein deposition in the brain and markers of downstream neurodegeneration, (Table 1).
    If 1 of these 2 biomarker categories is positive, the "biomarker probability of AD etiology" rises to "intermediate," and if both categories are positive the probability becomes "high." The authors are specific that they do not advocate obtaining AD biomarkers for routine clinical purposes at the present time, although they do note that they may be used when they are available and deemed appropriate by the clinician.
    The clinical criteria for possible AD dementia can be found in Table 4. The term "possible" is used instead of "probable" in 2 scenarios. One is if the cognitive deficits look like AD but there is an atypical course of the disease: either sudden onset or no definite decline. The second is if there is evidence for a mixed etiology of the dementia, such that the patient meets criteria for probable AD dementia but there is also evidence of significant vascular disease, features of dementia with Lewy bodies, or other disease or condition that could be contributing to the patient's dementia.
    Pathophysiologically proven AD is next discussed, consisting simply of the unchanged criteria of patients meeting both the clinical and neuropathologic criteria for AD. Finally the criteria for dementia unlikely to be due to AD is discussed (Table 5).

    Implications for the Practicing Clinician

    These new guidelines do not suggest a fundamental difference in the way clinicians will diagnose AD dementia or MCI due to AD. For now, diagnosis of these disorders will continue to be primarily clinical. The new guidelines also do not recommend any specific treatment strategies. Implicitly or explicitly, however, they do encourage clinicians to:
    • Recognize that AD is the end of a long process, spanning years or perhaps decades, leading to death of brain cells, cognitive loss, and ultimately dementia.
    • Diagnose (and perhaps treat) AD at the earliest possible stage. At present this would be the MCI due to AD stage, but eventually will include preclinical AD.
    • Begin to consider using biomarkers in the diagnosis of all stages of AD. For now, most biomarkers will only be used in research studies (both for diagnostic purposes and to evaluate the efficacy of disease modifying treatments), but some either are available to clinicians now (eg, FDG PET scans, CSF Aβ42, and tau) or will be in the near future (eg, quantitative MRI, amyloid PET scans).
    • Evaluate patients with dementia to determine the cause of the dementia with special attention paid to amnestic and nonamnestic presentations of AD.
    • Remember that they will soon see a significant increase in patients in their practices with AD. There are currently 5.4 million patients in the United States with AD dementia and perhaps an equal amount with MCI. Because of the aging population, these numbers could triple in the next 50 years.

    Conclusions

    Today, these new criteria allow the practicing clinician to diagnose AD dementia and MCI due to AD with more clarity, providing greater certainty of the diagnosis for patients and families. In the future, these criteria will provide practitioners with the tools they need to know which patients are appropriate for the disease-modifying medications which are being developed to slow or even stop the AD pathophysiological process.