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SUDEP Risk Decreases During Long-Term VNS Treatment

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The data do not indicate which of several potential mechanisms explain the observed decline in risk.

For patients with refractory epilepsy who receive vagus nerve stimulation (VNS) therapy, the risk of sudden unexpected death in epilepsy (SUDEP) decreases significantly during long-term follow-up, according to research published online ahead of print January 16 in Epilepsia. This finding “has not been previously reported in the literature and would be of value for patients at risk of SUDEP,” said the authors.

Long-Term Data Are Lacking

Most epidemiologic studies of SUDEP have had cross-sectional designs. Consequently, neurologists have lacked information about potential changes in the rate of SUDEP over time. Cyberonics, a Houston-based company, records information about implantation of its VNS device when the implanting facilities provide this information to it. To understand the evolution of SUDEP risk over time, Philippe Ryvlin, MD, Head of the Department of Clinical Neurosciences at Vaud University Hospital in Lausanne, Switzerland, and colleagues analyzed information from the company’s database.

For their study, the authors examined patients who underwent device implantation for epilepsy between November 16, 1988, and December 31, 2012. Eligible participants were US citizens or residents at the time of implantation and had a Social Security Number and a known date of birth. To ascertain patients’ vital status and cause of death, Dr. Ryvlin and colleagues submitted data to the Centers for Disease Control and Prevention’s National Death Index (NDI). The NDI included an underlying cause and as many as 20 contributory causes for each death.

The investigators defined SUDEP according to the criteria published by Annegers in 1997. To adjudicate SUDEP, they examined NDI data and death reports that Cyberonics recorded in a subset of patients. For patients for whom a death report was unavailable, the investigators performed adjudication by extrapolation.

Rate of SUDEP Decreased by One-Fourth

According to the database, 57,551 patients underwent implantation with the VNS device during the study period. A total of 40,443 (70%) participants met the researchers’ inclusion criteria. Patients’ average age at implantation was 30.8, and 15% of patients were under age 12. Half of participants were male.

The median duration of follow-up was 7.6 years. In all, 2,864 (7%) participants underwent explantation or had their devices turned off before the cutoff date, and 3,689 (9%) patients died during the study period.

A total of 953 (25.8%) of the deaths were associated with underlying and contributory causes considered compatible with SUDEP. Adjudication per protocol resulted in 632 (66.3%) cases of definite, probable, and possible SUDEP. The consensus conclusion among investigators resulted in 638 (66.9%) SUDEP cases. Adjudication by extrapolation resulted in 667 (70.0%) SUDEP cases and 286 (30.0%) non-SUDEP cases.

The crude and age-adjusted rates of SUDEP during years 3 to 10 of follow-up (2.10/1,000 patient years and 1.68/1,000 patient years, respectively) were significantly lower than those observed during the first two years of follow-up (2.74/1,000 patient years and 2.47/1,000 patient years, respectively). The crude rate ratio of SUDEP was 0.77, and the age-adjusted rate ratio of SUDEP was 0.68.

Biomarkers of SUDEP Would Aid Research

Because the study did not include a control group, and the database did not have preimplantation baseline information or data about individual responses to VNS therapy, the analysis does not clarify the role of VNS in the rate of SUDEP. Factors such as attrition, natural evolution, aging, or changes in medications or medical practice over time could explain the study findings, said Dr. Ryvlin.

The reasons for which SUDEP risk decreases over time should be investigated further, said the authors. A three-year randomized controlled trial would require at least 28,000 patients in each arm to compare adjunctive VNS treatment and standard treatment, but this level of enrollment is not feasible. “Novel biomarkers highly predictive of SUDEP will be needed to make prospective studies of SUDEP prevention feasible in an enriched population,” said Dr. Ryvlin. “Until then, only large retrospective cohorts, such as the study presented here, can help us make progress in SUDEP prevention, an issue that one should acknowledge when weighing the limitations and value of currently available data.”

—Erik Greb

ECTRIMS and EAN Publish Recommendations for Treating MS

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The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have published a guideline to offer up-to-date, evidence-based recommendations for the treatment of adult patients with MS. The guideline is intended to fill a perceived need for a comprehensive document that includes information about recently approved MS therapies and helps clinicians and patients resolve difficulties in everyday clinical practice. It was published in the February issue of Multiple Sclerosis.

Authors Addressed 10 Questions

Xavier Montalban, MD, PhD, Chair and Director of the Department of Neurology and Neuroimmunology at Vall d’Hebron University Hospital in Barcelona, and colleagues agreed to investigate 10 questions related to treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns, and treatment of MS in pregnancy. They developed the guideline following the recommendations of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group, along with EAN recommendations for writing a neurologic management guideline. Literature searches relied upon databases such as the Cochrane Central Register of Controlled Trials, Excerpta Medica, and Medical Literature Analysis and Retrieval System Online.

The authors evaluated data for all disease-modifying treatments (DMTs) approved by the European Medicines Agency at the time of publication. They did not consider combination therapies, complementary or alternative medicine, or symptomatic treatment. Although focused on Europe, the guideline does not account for regulatory or organizational issues specific to any European country.

Strong Recommendations

Dr. Montalban and colleagues agreed upon 21 recommendations and consensus statements. The recommendations were categorized as strong or weak, according to the quality of evidence and the risk–benefit balance. The authors formulated consensus statements on questions for which evidence was insufficient to support a formal recommendation.

The first of the guideline’s three strong recommendations is that neurologists offer interferon or glatiramer acetate to patients with clinically isolated syndrome (CIS) and an abnormal MRI with lesions suggestive of MS who do not fulfill criteria for MS. The second is to offer early treatment with DMTs to patients with active relapsing-remitting MS, as defined by clinical relapses or MRI activity. The authors defined active lesions as contrast-enhancing lesions or new or unequivocally enlarging T2 lesions assessed at least annually. This recommendation also applies to patients with CIS who fulfill current diagnostic criteria for MS. The third strong recommendation is to offer a more efficacious drug to patients treated with interferon or glatiramer acetate who show evidence of disease activity.

Weak Recommendations

Nine of the guideline’s recommendations are categorized as weak. For example, neurologists should consider treating patients with active secondary progressive MS with interferon beta-1a or -1b, taking into account the treatments’ “dubious efficacy,” as well as their safety and tolerability, according to the authors. Neurologists should consider mitoxantrone, ocrelizumab, and cladribine for this population. The authors recommend considering ocrelizumab as a treatment for patients with primary progressive MS.

As a way of monitoring treatment response, the authors recommend that neurologists consider combining MRI with clinical measures when evaluating disease evolution in treated patients. When making treatment decisions in the event of safety concerns, neurologists should consider the possibility that disease activity may resume or rebound if treatment is stopped, particularly with natalizumab, said Dr. Montalban and colleagues. Continuation of DMT treatment should be considered for patients who are clinically stable, who have stable MRI, and who have no problems with safety or tolerability, according to the guideline.

“For women planning a pregnancy, if there is a high risk of disease reactivation, consider using interferon or glatiramer acetate until pregnancy is confirmed,” said the authors. “In some very specific (active) cases, continuing this treatment during pregnancy could also be considered.” Delaying pregnancy is advisable for women with persistent high disease activity. If such a woman decides to become pregnant or has an unplanned pregnancy, neurologists may consider treatment with natalizumab throughout pregnancy after a full discussion with the patient of the potential implications. “Treatment with alemtuzumab could be an alternative therapeutic option for planned pregnancy in very active cases, provided that a four-month interval is strictly observed from the latest infusion until conception,” said Dr. Montalban and colleagues.

Consensus Statements

Several of the guideline’s consensus statements relate to the monitoring of treatment response. For patients treated with DMTs, the authors recommend performing a standardized reference brain MRI within six months of treatment onset, and comparing it with a subsequent brain MRI performed 12 months after starting treatment. The measurement of new or unequivocally enlarging T2 lesions is the preferred MRI method of gauging treatment response, supplemented by gadolinium-enhancing lesions. To monitor treatment safety, the authors recommend performing a standardized reference brain MRI every year in patients at low risk for progressive multifocal leukoencephalopathy (PML), and every three to six months in patients at high risk for PML.

If the neurologist and patient have decided to switch therapies, they should consider the patient’s characteristics and comorbidities, drug safety profiles, and disease severity when choosing a new DMT. If treatment of a highly efficacious drug is stopped because of safety or efficacy problems, the neurologist should consider starting another highly efficacious drug, according to the guideline. Disease activity, the drug’s half-life and biologic activity, and the potential for resumed disease activity or rebound should be considered when choosing a new therapy, said Dr. Montalban and colleagues.

—Erik Greb

Nutrition Early in Life Has Long-Term Effects on Neurodevelopment

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A policy statement from the American Academy of Pediatrics emphasizes the importance of nutrition from conception to age 2 and includes 10 recommendations regarding patient care and nutrition assistance programs.

Nutrition during a child’s first 1,000 days—from conception to age 2—is pivotal for a child’s neurodevelopment and lifelong health, according to an American Academy of Pediatrics (AAP) policy statement.

“Healthy, normal neurodevelopment is a complex process involving cellular and structural changes in the brain that proceed in a specified sequence,” said Sara Jane Schwarzenberg, MD, and Michael K. Georgieff, MD, both of the University of Minnesota Masonic Children’s Hospital, Minneapolis, and the AAP Committee on Nutrition, in the statement. “Changes that are too rapid or too slow in one part of the brain may result in the failure of crucial pathway connections to other parts of the brain. Timing is crucial; once a particular developmental sequence fails, it may not be possible to retrieve all the lost function.”

The policy statement was published in the February issue of Pediatrics.

A Crucial Period

Research shows that the most active period of neural development is in the first 1,000 days. During this time, structures and processes develop that influence behavior and provide a basis for later-developing structures, including auditory and visual systems, myelination, and brain circuits involved in social development.

The importance of macronutrients for development was highlighted in a study of rural Guatemalan children between 1969 and 1989. Children in some villages received a high-calorie, high-protein supplement, and some children received a low-calorie supplement without protein. Both supplements contained vitamins and minerals. Children who received the high-calorie, high-protein supplements before age 2 had higher test scores, better reading and vocabulary skills, and faster information processing, compared with children who received the low-calorie supplements.

Many populations lack access to high-quality macronutrient sources, however. In the United States in 2015, 16.6% of households (6.4 million) were food insecure (ie, their access to adequate food was limited by a lack of money or other resources). In households with incomes below 185% of the poverty line, 36.8% were food insecure, according to the Department of Agriculture.

Food insecurity extends to micronutrients such as vitamins and minerals like zinc; iron; choline; folate; iodine; vitamins A, D, B6, and B12; and long-chain polyunsaturated fatty acids. A lack of any of these micronutrients in early childhood can lead to neurodevelopmental issues later in life, the authors said. An important source of micronutrients is human milk, provided by breastfeeding. Studies have shown that infants who are fed human milk have improved cognitive performance, compared with infants who consume formula.

Government-sponsored programs exist that provide nutritional support to women, infants, and young children. The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) is one of the most important programs, helping 53% of children under age 1, the authors said. The Supplemental Nutrition Assistance Program (SNAP) provides economic aid to buy food; it kept approximately 4.9 million children out of poverty in 2012, the authors said. SNAP Nutrition Education is intended to help people make healthy food choices with limited money.

10 Recommendations

The AAP policy statement includes the following 10 recommendations:

Be knowledgeable about breastfeeding, and help breastfeeding mothers. The AAP recommends exclusive breastfeeding for the first six months and continued breastfeeding with the addition of food for at least the first year.
Advocate at the local, state, and federal levels to preserve and strengthen programs focused on maternal, fetal, and neonatal nutrition.
Be familiar with food sources that supply nutrients necessary for brain development, and make appropriate dietary recommendations. Know which nutrients are at risk in the breastfed infant after six months, such as zinc, iron, and vitamin D.
Nutritional advice should convey that eating healthy is a positive choice, not just an avoidance of unhealthy foods.
Existing assistance programs should aim to improve micro- and macronutrient offerings. For example, food pantries and soup kitchens can create food packages and meals that target the needs of pregnant women, breastfeeding women, and children up to age 2.
Encourage parents to use programs that provide early childhood nutrition (eg, WIC), and advocate for the removal of barriers to enrolling or staying enrolled in these programs.
Oppose changes in eligibility or financing structures that would adversely affect programs providing early childhood nutrition.
Anticipate neurodevelopmental issues in children with early nutrient deficiency.
Work with obstetricians and family physicians to encourage improvements in maternal diet and identify clinical situations that may limit the availability of crucial micronutrients to the fetus.
Advocate to reduce hunger at the local, national, and global levels. The statement lists organizations focused on hunger, such as Feeding America, 1,000 Days, and Share Our Strength.

—Ian Lacy

Zonisamide May Improve Motor Symptoms in Patients With Dementia With Lewy Bodies

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Change in UPDRS part 3 score at week 12 was significantly greater in the zonisamide (50 mg) group, compared with the placebo group.

Zonisamide may improve parkinsonism in patients with dementia with Lewy bodies (DLB) without worsening cognitive function or psychiatric symptoms, according to a study published in the February 20 issue of Neurology.

“This study provides Class I evidence that zonisamide (adjunctive to levodopa) improves parkinsonism and is well tolerated in patients with DLB,” said Miho Murata, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues. “We found that the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 total score at week 12 was significantly improved in the zonisamide 50 mg/day group, compared with the placebo group.”

Four placebo-controlled, randomized trials have found that zonisamide—a drug used to treat seizures—improves motor symptoms in Parkinson’s disease with a low incidence of motor complications such as dyskinesia or psychiatric symptoms such as hallucinations. In another study that included three patients with DLB, zonisamide was associated with improved parkinsonism and reduced caregiver burden without worsening cognition or behavioral or psychological symptoms.

A Phase II, Placebo-Controlled, Double-Blind Study

Based on results from these studies, Dr. Murata and colleagues conducted a phase II, placebo-controlled, randomized double-blind study to examine the efficacy and safety of zonisamide as an adjunct to levodopa therapy for parkinsonism in patients with DLB.

Eligible participants were between ages 20 and 84 and had a UPDRS part 3 score of 10 or greater. The investigators excluded patients with Parkinson’s disease with dementia (ie, well-established Parkinson’s disease followed by onset of dementia), those who did not respond to levodopa therapy, and patients with epilepsy.

The primary end point was change from baseline in UPDRS part 3 score at week 12. Secondary end points included changes from baseline in total UPDRS score, each UPDRS part, and each UPDRS item at each evaluation.

The study included a four-week run-in period and a 12-week treatment period. During the run-in period, patients received placebo tablets once daily under single-blind conditions to eliminate any confounding effects of other antiparkinson drugs.

Participants were randomized 1:1:1 to placebo, zonisamide (25 mg), or zonisamide (50 mg) daily. Patients visited study sites every four weeks for five visits. Dosage and administration of antidementia drugs were unchanged from 12 weeks before the run-in period throughout the treatment period. Dosage and administration of levodopa/decarboxylase inhibitor therapy and other antiparkinson, antihypertensive, CNS, cardiovascular, or gastrointestinal drugs or herbal medicine were unchanged from two weeks before the run-in period throughout the treatment period.

Zonisamide Did Not Worsen Cognitive Function or Behavior

In all, 158 patients were randomized to receive zonisamide or placebo, and 137 patients completed treatment. Zonisamide (50 mg) was associated with significantly greater improvement in UPDRS part 3 scores at week 12, compared with placebo (between group difference, –4.1). In addition, zonisamide did not worsen cognitive function, behavior or psychological symptoms of dementia, or caregiver burden.

The incidence of adverse events was higher in the zonisamide (50 mg) group than in the zonisamide (25 mg) group and placebo group (65.3%, 43.1%, and 50.0%, respectively). The incidences of common drug-related adverse events (eg, decreased weight, decreased appetite, and rash) were higher among patients who received zonisamide, compared with patients who received placebo. The rates of serious adverse events were similar between the groups.

“There is an urgent need for new treatments for DLB,” said Linda A. Hershey, MD, PhD, Professor of Neurology at the University of Oklahoma Health Sciences Center in Oklahoma City, who wrote an accompanying editorial. “The successful execution of this trial is a major accomplishment, which provides evidence that future trials are warranted.”

—Erica Tricarico

RNS May Reduce the Risk of SUDEP

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Responsive neurostimulation (RNS) appears to reduce the risk of sudden unexpected death in epilepsy (SUDEP), according to research published online ahead of print January 16 in Epilepsia. The results provide evidence that treatments that reduce seizures decrease the risk of SUDEP, according to the authors. The data also indicate that not every SUDEP follows a seizure.

Orrin Devinsky, MD, Director of the Comprehensive Epilepsy Center at New York University Langone Medical Center, and colleagues examined data for all deaths in patients with epilepsy who received RNS in clinical trials or following FDA approval through May 5, 2016, and adjudicated them for SUDEP. In all, 256 patients received treatment during trials, and 451 received treatment after FDA approval.

The investigators observed 14 deaths, including two possible, one probable, and four definite cases of SUDEP. The rate of probable or definite SUDEP was 2.0/1,000 over 2,036 patient stimulation years and 2.3/1,000 over 2,208 patient implant years. The age-adjusted standardized mortality ratio for definite and probable SUDEP was 0.75.

“The SUDEP rate of 2.0/1,000 patient stimulation years among patients undergoing treatment with RNS is favorable relative to patients [with treatment-resistant epilepsy] randomized to the placebo arm of add-on drug studies (SUDEP rate of 6.1/1,000 patient years), patients who were referred for epilepsy surgery but did not receive epilepsy surgery (SUDEP rate of 6.3/1,000 patient years), and patients with recurrent seizures after epilepsy surgery (SUDEP rate 6.3/1,000 patient years),” said the authors. “Future explorations can examine whether certain seizure patterns are particularly associated with SUDEP.”

—Erik Greb

New AEDs Have Not Increased Seizure Control

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Current therapies appear to suppress seizures rather than modify the underlying disorder.

The development of new antiepileptic drugs (AEDs) with novel mechanisms of action has not improved overall outcomes for patients with epilepsy, according to an analysis published online ahead of print December 26, 2017, in JAMA Neurology.

“A paradigm shift in treatment and research strategies is needed to improve the long-term outcomes of newly diagnosed epilepsy. Patients with drug-resistant epilepsy should be considered early for nonpharmacologic therapies, such as resective surgery and brain stimulation techniques,” said Patrick Kwan, MD, PhD, Chair of Neurology at the University of Melbourne and Head of Epilepsy at the Royal Melbourne Hospital, and colleagues.

The analysis suggests that contemporary AEDs suppress seizures, but do not affect the underlying disease. “Future research should focus on novel treatments that can modify the development or progression of epilepsy, ideally guided by biomarkers,” said the authors.

Investigators Examined an Expanded Cohort

In an oft-cited study published in 2000, Dr. Kwan and Martin J. Brodie, MD, followed 470 patients with newly diagnosed epilepsy who presented to the Epilepsy Unit at the Western Infirmary in Glasgow from 1982 to 1998. They observed that seizures persisted despite AED treatment for more than one-third of patients. Participants with an inadequate response to their first or second treatment regimens were likely to develop refractory epilepsy.

To study whether newer AEDs have changed treatment outcomes, Dr. Kwan and colleagues followed 1,795 patients with newly diagnosed epilepsy who presented to the Western Infirmary between July 1, 1982, and October 31, 2012. The investigators followed patients until October 31, 2014, or until their deaths. Patients with poor adherence for reasons unrelated to drug efficacy or tolerability, those whose seizures resulted from drug use, and those with nonepileptic seizures were excluded from the analysis.

Patients visited the clinic every two to six weeks for the first six months after treatment initiation. After month six, participants had follow-up visits at least every four months. Physicians collected data routinely during standard clinical care. Patients recorded seizure descriptions and the number of seizures that occurred between visits.

Nearly Two-Thirds Became Seizure-Free

Of the 1,795 study participants, 969 (53.7%) were male. Patients’ median age at referral was 33. In all, 386 patients (21.5%) had generalized epilepsy, and 1,409 patients (78.5%) had focal epilepsy. Follow-up lasted for a median of 11 years.

As of the final follow-up visit, 1,440 patients (80.2%) were receiving AED monotherapy, and 355 (19.8%) were receiving two or more AEDs. In all, 1,144 participants (63.7%) had been seizure-free for the previous 12 months or longer, of whom 993 (55.3%) had attained this outcome by taking a single AED. The remaining 151 seizure-free patients had achieved this outcome by taking two or more AEDs.

In all, 816 participants (45.4%) achieved at least one year of seizure freedom while taking their first AED, and 212 patients (28.6%) achieved this outcome while taking the second regimen, which was either monotherapy or polytherapy. The first and second regimens together accounted for 1,028 of the 1,144 patients (89.9%) who achieved at least one year of seizure freedom. At the last follow-up, seizure freedom was more common among patients with generalized epilepsy (68.1%) than among those with focal epilepsy (62.5%).

Although the use of newer AEDs increased significantly during the study, the proportion of patients who were seizure-free at the last follow-up was similar in the three time-period subgroups that the investigators examined. The cumulative probability of one year of seizure freedom also was similar in these periods. Adjustment for patient characteristics did not alter these findings.

Number of AEDs Affected Likelihood of Seizure Freedom

For patients who did not achieve one year of seizure freedom with their first AED, the likelihood of uncontrolled epilepsy increased with each subsequent AED tried (odds ratio [OR], 1.73). Dr. Kwan and colleagues found a significant difference in the probability of seizure freedom between patients treated with the first and second AED regimens (hazard ratio [HR], 0.52). The difference in this outcome between participants treated with their second and third AED regimen was also significant (HR, 0.71). Whether epilepsy was focal or generalized did not affect these findings.

When the investigators adjusted their data for sex and epilepsy classification, they found that a high number of seizures in the year before treatment initiation, a history of smoking, a history of recreational drug use, a family history of epilepsy in first-degree relatives, previous brain injury, and psychiatric comorbidity were significantly associated with an adverse prognosis. Each increase in the number of seizures in the year before treatment was associated with a 6% decrease in the chance of seizure freedom at the last follow-up.

Is Better Seizure Control Possible?

“The observation that newer drugs have not increased the percentage of people who are rendered seizure-free is not new and should not be surprising,” said W. Allen Hauser, MD, Special Lecturer in the Gertrude H. Sergievsky Center at Columbia University in New York, in an accompanying editorial. “Even though mechanisms of action of specific drugs may differ, the same animal models have been used to predict successful suppression of seizures in preclinical studies for the last 80 years, and successful response has been the basis for clinical drug development for both old and new therapeutic agents.”

Nevertheless, the data “are sobering and somewhat disconcerting,” Dr. Hauser added. “In 1881, pioneering neurologist Sir William Gowers reported that he could not control seizures in 36% of the patients to whom he prescribed bromide compounds. It seems that we might not have improved our initial management results for a much longer period than the 30 years covered in the current study. While biologically unlikely, it is possible that a two-thirds proportion represents a ceiling for the initial control of epilepsy.”

—Erik Greb

AAN Recommends Exercise for People With MCI

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Neurologists should recommend twice-weekly exercise to patients diagnosed with mild cognitive impairment (MCI) as part of an overall approach to management, according to a practice guideline update from the American Academy of Neurology (AAN). The Level B recommendation is based on six-month studies that suggest that such exercise possibly improves cognition. The update was published online ahead of print December 27, 2017, in Neurology.

“Regular physical exercise has long been shown to have heart health benefits, and now we can say exercise also may help improve memory for people with MCI,” said Ronald Petersen, MD, PhD, Director of the Alzheimer’s Disease Research Center at the Mayo Clinic in Rochester, Minnesota, and lead author of the update. “What is good for your heart can be good for your brain.”

The update also states that clinicians may recommend cognitive training for people with MCI (Level C). The evidence, however, is insufficient “to support or refute the use of any individual cognitive intervention strategy,” according to the guideline. “When various cognitive interventions are considered as a group, for patients with MCI, cognitive interventions may improve select measures of cognitive function.”

Document Updates 2001 Practice Parameter

The current practice guideline update revises the AAN’s 2001 practice parameter that provided recommendations for the diagnosis and treatment of MCI. Dr. Petersen and colleagues based the update on a systematic review of articles about MCI prevalence, prognosis, and treatment. They classified evidence according to AAN criteria and based recommendations on modified Delphi consensus.

The authors found that the prevalence of MCI is 6.7% for people between ages 60 and 64, 8.4% for people between ages 65 and 69, 10.1% for people between ages 70 and 74, 14.8% for people between ages 75 and 79, and 25.2% for people between ages 80 and 84. Approximately 15% of people with MCI who are older than 65 develop dementia during two years of follow-up.

No Evidence for Pharmacologic Treatment

Evidence does not support a symptomatic cognitive benefit in MCI for any pharmacologic or dietary agents, according to the authors. The FDA has not approved any medication for treating MCI. If clinicians offer cholinesterase inhibitors to their patients with MCI, they must first discuss the fact that the treatment is off label and not backed by empirical evidence, according to the update. Gastrointestinal symptoms and cardiac concerns are common side effects of cholinesterase inhibitors.

Assessment for MCI is appropriate for patients who complain of impaired memory or cognition, as well as those who present for a Medicare Annual Wellness Visit, according to the update. Clinicians should evaluate patients with MCI for risk factors that are potentially modifiable. Patients with MCI also should undergo serial assessments over time so that clinicians can monitor them for changes in cognitive status.

—Erik Greb

Low Serum Caffeine Level Could Indicate Early Parkinson’s Disease

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Data do not reveal an association between serum caffeine metabolite levels and levodopa equivalent doses.

Low serum caffeine and caffeine metabolite levels after an overnight fast may be a sensitive way to detect Parkinson’s disease, according to the results of a case–control study published online ahead of print January 3 in Neurology.

In the study, levels of caffeine and its metabolites were lower in patients with Parkinson’s disease and motor dysfunction, compared with those without motor dysfunction. The investigators detected no differences in serum levels of caffeine metabolites between patients with mild Parkinson’s disease and those with severe Parkinson’s disease, said Motoki Fujimaki, MD, of Juntendo University School of Medicine in Tokyo, and colleagues.

A Single-Center Study

Previous research had shown that people drinking four or more cups of coffee per day had a greater than fivefold reduction in the risk of developing Parkinson’s disease. Mouse models of Parkinson’s disease showed that caffeine and two of its metabolites have a neuroprotective effect. Those results suggested that serum caffeine might be useful as a blood marker for Parkinson’s disease.

To test that idea, Dr. Fujimaki and associates recruited 31 healthy controls (18 women) and 108 patients with Parkinson’s disease but no dementia (50 women). The control group’s mean caffeine intake of 115.81 mg/day was similar to that of patients with Parkinson’s disease (107.50 mg/day).

Serum caffeine levels measured after an overnight fast showed that a cutoff of 33.04 pmol/10 µL identified Parkinson’s disease with an area under the curve (AUC) of 0.78 (sensitivity, 76.9%; specificity, 74.2%). Inclusion of the primary caffeine metabolites theophylline, theobromine, and paraxanthine increased the AUC to 0.87. When the researchers included all 11 measurable metabolites, the AUC increased further to 0.98.

Genetic analyses revealed no significant differences in the frequencies of caffeine metabolism–associated genetic variants between patients and controls.

The study was limited by the fact that it was conducted at a single university hospital, and the patient population did not include many severe cases. The association should also be studied in other Parkinson’s disease patient populations, according to the authors.

Did Treatment Effects Influence the Findings?

A key question that the study raises is what caused the decrease in serum concentration found in patients with Parkinson’s disease, said David G. Munoz, MD, of the Department of Laboratory Medicine and Pathobiology at the University of Toronto, and Shinsuke Fujioka, MD, of the Department of Neurology at Fukuoka University in Japan, in an accompanying editorial. Almost all of the patients were receiving treatment, which could have affected serum levels, they added. The researchers looked for, but did not find, an association between serum caffeine metabolite levels and levodopa equivalent doses.

“The validity of the study depends on whether caffeine metabolism may be affected by treatment,” said Drs. Munoz and Fujioka. “To demonstrate the utility of caffeine metabolites unequivocally, a future study will have to reproduce these results in patients with untreated Parkinson’s disease or subjects at high risk of Parkinson’s disease, such as those with prodromal signs of Parkinson’s disease.”

—Jim Kling

C7 Nerve Transfer May Reduce Spastic Arm Paralysis

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The diversity of the patient population may preclude general conclusions about the study results.

Patients with spastic arm paralysis who receive a contralateral C7 nerve graft from their nonparalyzed side to their paralyzed side may have greater improvement in arm function and reduction in spasticity after a year, compared with patients who undergo rehabilitation alone, according to research published January 4 in the New England Journal of Medicine.

The researchers randomly assigned 36 patients who had had unilateral arm paralysis for at least five years to either surgical C7 nerve transfer plus rehabilitation or rehabilitation alone. Participants in the surgery group had an average increase of 17.7 points on the Fugl-Meyer score, while those in the rehabilitation-only group had an average increase of 2.6 points.

To evaluate spasticity, the researchers used the Modified Ashworth Scale, which is scored from 0 to 5. A higher score indicates greater spasticity. Patients who received surgery had improvement from baseline in all five areas measured, and none worsened. The smallest difference between the two groups was in thumb extension. On this measure, 15 surgery patients had a one- or two-unit improvement and three had no change, while seven controls had a one- or two-unit improvement, seven had no improvement, and four had a one-unit worsening. At one year, 16 (89%) patients in the surgery group were able to accomplish three or more of the functional tasks that researchers gave them, whereas none of the controls could do so.

“The majority of clinical improvements coincided with physiologic evidence of connectivity between the hemisphere on the side of the donor nerve and the paralyzed arm,” said lead author Mou-Xiong Zheng, MD, PhD, a hand surgeon at Huashan Hospital at Fudan University in Shanghai, and colleagues.

A Modification to a Previous Surgical Method

Damage to the contralateral cerebral hemisphere after stroke arises from interruption of the inhibitory activity of upper motor neurons. This interruption causes spasticity, along with hand weakness and loss of fractionated fine motor control. In previous studies, researchers have observed activity in the cerebral hemisphere on the same side of paralysis during stroke recovery, but Dr. Zheng and coauthors asserted that connections between the hand and that part of the brain are “sparse,” thus limiting the body’s ability to compensate for spasticity and functional loss.

The latest findings are consistent with those of earlier studies, including one by Dr. Zheng’s coauthors that suggested that the paralyzed hand could be connected to the unaffected hemisphere by transferring a cervical spine nerve from the nonparalyzed side. Researchers previously found this treatment effective for injuries of the brachial plexus. Of the five nerves of the brachial plexus, Dr. Zheng and coauthors chose the C7 nerve because it accounts for about 20% of the nerve fibers in the brachial bundle. Severing the nerve typically results in transient weakness and numbness in the arm or leg on the same side. When they evaluated the hand on the side of the donor graft, the researchers found no significant changes in power, tactile threshold, or two-point discrimination as a result of surgery.

The authors’ surgical approach was a modification of the C7 nerve transfer method that Dr. Zheng and coauthors had previously reported. The operation involved making an incision at the superior aspect of the sternum, mobilizing the donor C7 nerve on the nonparalyzed side, and routing it between the spinal column and esophagus. Then, an anastomosis was performed directly with the C7 nerve on the paralyzed side.

Rehabilitation therapy for the surgery group and controls was identical. Rehabilitation sessions took place four times weekly for 12 months at a single facility, although surgery patients wore an immobilizing cast after their operations.

The nature of the study population (ie, men of various ages with various causes of the underlying cerebral lesions) makes it difficult to draw general conclusions from the findings, Dr. Zheng and coauthors noted. “A larger cohort, followed for a longer period, would be necessary to determine whether cervical nerve transfer results in safe, consistent, and long-term improvements in the function of an arm that is chronically paralyzed as a result of a cerebral lesion,” the authors concluded.

Results Need Clarification

The results that Dr. Zheng and coauthors reported “are exciting, but need clarification and confirmation,” said Robert J. Spinner, MD, Chair of the Department of Neurologic Surgery; Alexander Y. Shin, MD, Consultant in the Department of Orthopedic Surgery; and Allen T. Bishop, MD, Consultant in the Department of Orthopedic Surgery; all at the Mayo Clinic in Rochester, Minnesota, in an accompanying editorial.

Among the questions Dr. Spinner and coauthors raised about the study are whether distal muscles can functionally reinnervate in a year, and whether C7 neurotomy on the paralyzed side led to improvements in spasticity and function. “The C7 neurotomy itself, associated with an immediate reduction in spasticity, represents a major advance for some patients with brain injury who have poor function and spasticity,” they noted. Improvement of the damaged motor cortex, which ongoing physical therapy may enhance, may also contribute to a reduction in spasticity.

Dr. Spinner and coauthors also cited a previous trial by some of Dr. Zheng’s colleagues in which 49% of patients with brachial plexus injury had motor recovery within seven years. “The presence of physiological connectivity observed in the trials does not necessarily equate with functional recovery,” the authors stated.

Future studies of surgical C7 nerve transfer in patients with one-sided arm paralysis should include patients who have C7 neurotomy without nerve transfer, said Dr. Spinner and colleagues. They also noted that because Dr. Zheng and colleagues perform a relatively high volume of these operations, their results might not be easy to reproduce elsewhere.

“Factors other than technical ones, including differences in BMI and limb length across different populations, may lead to different surgical outcomes,” said Dr. Spinner and coauthors. Future research should focus on ways to enhance or speed up nerve regeneration, improve plasticity, and maximize rehabilitation, they added.

—Richard Mark Kirkner

Midlife Triglyceride Levels Predict Later Risk of Amyloid and Tau Pathology

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Data may indicate a modifiable risk factor for Alzheimer’s disease pathology that is easily measured.

High fasting triglyceride levels in midlife are associated with increased risk of amyloid β and tau pathology in the brain 20 years later, according to research published in the January 2 issue of Neurology. Increased levels of medium and large low-density lipoprotein (LDL) subfractions also may be risk factors for amyloid β pathology, said the researchers.

“Even though our results were not robust regarding all amyloid β measures, our findings, together with previous studies, may indicate that triglycerides are associated with early amyloid β accumulation and [that] cholesterol is associated with later stages of the predementia phase of Alzheimer’s disease,” said Katarina Nägga, MD, PhD, Associate Professor of Clinical Memory Research at Lund University in Sweden, and colleagues.

Patients Were Recruited From a Longitudinal Study

In 2016, researchers conducting a cross-sectional study in healthy elderly participants found an association between higher triglyceride levels and amyloid β PET. The following year, two longitudinal studies suggested that an increased number of midlife vascular risk factors and midlife dyslipidemia were associated with brain amyloid deposition, as measured with PET.

Dr. Nägga and colleagues sought to examine the association between midlife lipid levels and brain amyloid 20 years later in people who were asymptomatic at baseline and cognitively normal at follow-up. They also aimed to determine whether lipoprotein subfractions are associated with Alzheimer’s disease pathology.

In 2009, the investigators recruited participants from the longitudinal, population-based Malmö Diet and Cancer Study (MDCS) cardiovascular cohort. In that study, baseline examinations, including fasted triglyceride, cholesterol, and high-density lipoprotein (HDL) measurements, occurred between 1991 and 1994. LDL was calculated using the Friedewald formula. Follow-up took place between 2007 and 2012.

Participants who were eligible for Dr. Nägga’s study were older than 60, had a Mini-Mental State Examination score of 27 points or greater, and were without subjective cognitive impairment. People with a history of transient ischemic attack or stroke, severe neurologic or psychiatric disease, dementia, or mild cognitive impairment were excluded.

The investigators enrolled 361 patients into their study. Participants underwent cognitive testing, brain MRI, and lumbar puncture between 2010 and 2015. Dr. Nägga and colleagues measured brain amyloid β using [¹⁸F] flutemetamol PET in 134 patients. They also examined308 participants for white matter lesions using 3T MRI.

Large HDL Had a Protective Effect

In all, 318 participants were included in the analysis. Mean age was 54 at baseline and 73 at entry into Dr. Nägga’s study. Approximately 60% of participants were women. At follow-up, 23% of the population had an abnormal CSF amyloid β level, and 16% had amyloid and tau pathology.

After adjustments for age, sex, APOE ε4, education, and vascular risk factors, the odds ratio (OR) of abnormal CSF amyloid β was 1.34 among participants with high triglyceride levels at midlife. The OR of an abnormal ratio of amyloid β to phosphorylated tau was 1.46 among participants with high triglyceride levels at midlife.

Furthermore, triglycerides were associated with abnormal amyloid β PET measurements in multivariable regression models, but the association was attenuated in the fully adjusted model. Lipid levels were not associated with white matter lesion volume.

Medium and large LDL were associated with an approximately doubled risk of abnormal amyloid β PET in multivariable regression models. Large HDL decreased the risk of amyloid β pathology by about 75%. Small HDL and very small LDL were not associated with increased risk in the fully adjusted model.

A Possible Basis for Intervention Trials

One potential limitation of the current study is that its participants were healthier than the majority of participants who presented for reexamination in MDCS, said the authors. This difference introduced possible selection bias and might have caused an underestimation of the associations identified. Nevertheless, the sample size of the present study was larger than those of previous studies examining lipids and brain amyloid β.

“If our finding that increased triglyceride levels in midlife lead to an increase in abnormal amyloid β accumulation can be reproduced in larger cohorts, it would be of great interest to initiate intervention trials with triglyceride-lowering therapies in midlife and study potential long-term reductions in amyloid β as the main outcome,” said Dr. Nägga and colleagues. “If such treatments can decrease the risk of developing Alzheimer’s disease pathology, this could lead to significant health improvements for millions of people.”

—Erik Greb