New Guidelines Address Alzheimer's, Tick-Borne Encephalitis

Daniel M. Keller, PhD

June 09, 2014

ISTANBUL, Turkey — Two sets of recently released European guidelines address Alzheimer's disease (AD) and tick-borne encephalitis (TBE). The guidelines are a joint effort of the European Neurological Society and the European Federation of Neurological Societies, which recently merged to form the European Neurological Association.

The AD guidelines weakly recommend concomitant use of cholinesterase inhibitors (ChEIs) with memantine for the treatment of moderate to severe AD. However, the combination garnered a strong recommendation for the treatment of patients with severe disease with behavioral symptoms.

Reviewing several studies of memantine as an adjunct to ChEI therapy, the guidelines committee used the Grades of Recommendation Assessment, Development and Evaluation (GRADES) system. The components of GRADES are the Patients, Intervention, Comparison, and the Outcome of interest (PICO); the importance of the outcome on a 9-point scale; grading the quality of evidence; study limitations; and inconsistency of the evidence, imprecision, indirectness, and publication bias.

Presenting the guidelines here at the 24th Meeting of the European Neurological Society (ENS), Reinhold Schmidt, MD, PhD, professor and vice chairman of the Department of Neurology at the Medical University of Graz, Austria, and president-elect of the Austrian Society for Neuroscience, said that "each of these components can downgrade [the strength of] the recommendations."

Using 2 rounds of voting with consensus on the second round, the panel made strong or weak recommendations based on 4 key factors: quality of the evidence, balance between desirable and undesirable effects, values and preferences, and cost.

The PICO question centered on 4 points to assess whether a combination of ChEI plus memantine rather than ChEI therapy alone should be used in patients with moderate to severe AD in general and specifically to improve the global clinical impression, cognitive functioning, behavior, and activities of daily living (ADLs). Also considered was the frequency of serious adverse effects.

The panel searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group database, using terms relevant to the disease and to its various treatments. Studies included in the analysis involved patients with moderate to severe AD; assessed at least 1 of the outcomes defined in the PICO question; and had a randomized, double-blind, parallel-group design.

The panelists unanimously but weakly recommended that the desirable consequences of combined ChEI and memantine treatment in moderate to severe AD outweigh the undesirable ones.

As part of the overall recommendation, the panel found weak evidence to suggest benefits on ADLs, cognitive functioning, and global clinical impression. The only strong recommendation for the combination was in improvement in behavioral symptoms.

"The overall strength of recommendation is weak because it is weak for global clinical impression, cognitive functioning, and ADL," said Professor Schmidt.

Following the presentation, session chairman Michael Brainin, MD, PhD, professor of clinical neurology at the Danube University in Krems, Austria, told Medscape Medical News that "to use a combination of drugs rather than a single drug against Alzheimer's dementia is a practice-changing new thing which has never been proven to be superior before anywhere in the world. We're very keen to get this published... it's very, very important."

He noted that the drugs are or soon will become generic, so the costs of 2 drugs should not be prohibitive.

However, he did have a problem with the term "weak recommendation." He said after much statistical analysis and sorting out relative strengths and weaknesses as part of the guideline development process, "you come to a colloquial conclusion."

"I'm not very happy about that because the term 'weak recommendation' sounds to health care professionals similar to 'no recommendation.'" He suggested that the GRADE system take this implication seriously "and maybe readjust their vocabulary."

He asserted that weak evidence is still evidence.

"The opposite would be there is no evidence. So weak evidence might be good evidence, might be the best evidence you get for a clinical decision, especially as far as processes are concerned."

He added that it is very difficult to get randomized studies for processes such as diagnosing or treating patients earlier vs treating later or having computed tomography on the first day vs MRI the next day.

Professor Brainin agreed with the strong recommendation for the use of combination therapy for behavioral problems, which begin to dominate care and ADLs after the disease has progressed for a couple of years. "So when these things come up, then it's probably time to combine," he said.

Tick-Borne Encephalitis Guidelines

In the same session, Pille Taba, MD, PhD, associate professor in the Department of Neurology and Neurosurgery at the University of Tartu, Estonia, presented a second set of European guidelines, addressing the diagnosis and management of TBE, which can cause significant morbidity and long-term sequelae.

TBE is a growing public health concern in Europe and Asia, with increasing endemic areas and an increasingly prolonged season. Some of the highest-risk areas are Russia, the Baltic states, Slovenia, and the Czech Republic. "It is an international problem due to travel," Professor Taba said.

These are the first such guidelines for the disease. Management recommendations have mainly addressed prevention but not treatment. She said that TBE often requires interdisciplinary treatment involving neurology, infectious disease (ID), and intensive care specialists.

The guideline development task force comprised 4 neurologists and 3 ID physicians, 2 of whom were qualified in both specialties. Development again involved PICO questions specific to the subject matter, with recommendations based on the GRADE system and 2 task force meetings to reach consensus.

PICO questions concerned populations at risk and recommended for vaccination, clinical and laboratory criteria for a case definition, the type of emergency interventions to use, recommended symptomatic treatment options, predictors for outcomes, and management aspects specific for children.

The task force used 229 references (out of 6408 retrieved) consisting of original articles, reviews, meta-analyses, and regulations derived from searches of MEDLINE, EMBASE, and the Cochrane Library using relevant key words.

Four vaccines are available against the 3 subtypes of the TBE virus, members of the Flaviviridae family. Because no data were available on Russian vaccines, they were not appropriate for recommendations.

Finding high-quality underlying evidence, the task force made "strong" recommendations for vaccination and revaccination based on patient age, disease endemicity, and travel. With low quality of evidence for postexposure prophylaxis with specific immune globulin after a tick bite, the task force made a "weak" recommendation against use of this approach.

The panel laid out the clinical course, syndromic characteristics of the disease, differential diagnosis, and clinical and laboratory tests to perform, as well as definitions of probable and confirmed TBE cases. It made the following recommendations:

  • Diagnosis: "strong" recommendation for using specific antibody detection; "weak" recommendation for using polymerase chain reaction;

  • Laboratory: "strong" recommendation for lumbar puncture and testing cerebrospinal fluid for pleocytosis in conjunction with specific serum antibodies and the clinical picture; "weak" recommendation for using brain and spinal cord MRI;

  • Emergency management: "weak" recommendation for emergency management (based on good clinical practice consensus but low-quality evidence), including (neuro) intensive care unit admission, intracranial and cerebral perfusion pressure monitoring, temperature management, and continuous electroencephalogram monitoring;

  • Symptomatic treatment: based on low-quality evidence but based on good clinical practice and consensus, "weak" recommendations for or against various symptomatic treatments;

  • Antiviral and immunomodulating treatment: "weak" recommendation against both.

The task force made a "strong" recommendation for TBE vaccination in children starting at 1 year in highly endemic areas. It also recommended vaccination for people with occupational exposures and for travelers to endemic areas if their visits will include outdoor activities.

Professor Taba showed the audience a photo of richly forested land in Estonia and told them, "Estonia is very beautiful. I advise everyone to go to the forest but to vaccinate first."

The guidelines were developed by joint committees of the European Neurological Society and the European Federation of Neurological Societies. Professor Schmidt has received honoraria for lectures from Pfizer, Merz Austria, Novartis, Ever Pharma, Janssen, and Lundbeck. Several other Alzheimer's disease guideline panel members also received honoraria or funding from pharmaceutical companies with products or research programs in the area of Alzheimer's disease. Professor Taba and Professor Brainin have disclosed no relevant financial relationships.

24th Meeting of the European Neurological Society (ENS). Presented June 1, 2014.

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