10 Standout Neurological Studies from 2018

And why they matter, in the words of their investigators

Staff from Cleveland Clinic’s Neurological Institute published hundreds of articles in the peer-reviewed literature in 2018, and they presented scores of studies at major professional society meetings. Given the institute’s multidisciplinary breadth — comprising neurology, neurosurgery, psychiatry and rehabilitation — and its integration of basic research with clinical studies, that translates to a daunting range of investigations.

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Yet some studies promise to matter more than others, so leaders of the Neurological Institute looked back and identified 10 of their team’s 2018 study publications or presentations that promise to particularly resonate in the years ahead, sometimes for very different reasons. We profile those investigations here — and why they matter.

Discovery of MS neurodegeneration without white matter demyelination

(Lancet Neurol. 2018;17:870-884)

Neurodegeneration and demyelination can be independent events in multiple sclerosis (MS). That was the key revelation of this August publication by Cleveland Clinic researchers reporting their discovery of a new subtype of the disease they’ve named myelocortical MS.

Their discovery stemmed from a review of specimens from 100 cases of MS made available through Cleveland Clinic’s rapid brain donation program. They found that 12 of the brain specimens had no cerebral white matter demyelination despite showing loss of myelin in the cerebral cortex and spinal cord. Further comparative study showed no differences in MRI features between lesions in myelocortical MS versus typical MS. Histologic exam showed decreased neuronal density and the presence of swollen myelinated axons in myelocortical MS despite the absence of white matter demyelination. “This suggests that the axon itself, rather than myelin, may be the primary site of injury in MS,” says lead author Bruce Trapp, PhD, Chair of Cleveland Clinic’s Department of Neurosciences.

“These findings suggest that stopping disability progression in MS may require combining neuroprotective therapies with current anti-inflammatory therapies,” adds co-author and Cleveland Clinic neurologist Daniel Ontaneda, MD. “They also indicate that we need to develop more-sensitive strategies for diagnosing and following the disease. Correctly discerning the swollen myelinated axons in myelocortical MS from the cerebral white matter demyelination in typical MS will be critical to exploring tailored treatment strategies.” See the full Consult QD story here.

First demonstration of illusory movement perception with prostheses in amputees

(Sci Transl Med. 2018;10(432):eaao6990)

A newly developed automated neural-machine interface has for the first time allowed amputees to effortlessly perform complex motor tasks in real time using a prosthetic hand while perceiving that their missing hand is carrying out the action. The approach and results of experiments on six above-the-elbow amputees were described by a Cleveland Clinic-led research team directed by Paul Marasco, PhD, of the Department of Biomedical Engineering.

The work provides a critical new element that could lead to fully integrated and efficient prosthesis control. “Combining kinesthetic, cutaneous and motor systems could result in an integrated prosthetic limb that’s intuitively controlled and provides a natural perception of complex movement,” Dr. Marasco explains.

The system developed by his team creates an illusory perception that the amputee’s missing hand is acting by vibrating a muscle containing the nerves that would be used for natural control. Motor and sensory nerves no longer used due to amputation are surgically redirected to muscles higher in the arm or chest, where they reinnervate host muscle. Using a wearable vibration unit and a 22-sensor data glove on the remaining hand, the subject simulates what’s perceived to be occurring in the missing hand. A virtual reality prosthetic system is created from the data to integrate movement sensations into control of the hand. “Our experiments show that the brain interprets the signals from the system very effectively,” says Dr. Marasco. “This is a promising strategy to improve function and quality of life in amputees.” See the full Consult QD story here.

Phase 2 trial identifies promising therapy for progressive MS

(N Engl J Med. 2018;379:846-855)

The investigational drug ibudilast slowed progression of brain atrophy in patients with progressive multiple sclerosis (MS) by nearly half relative to placebo, according to results of the phase 2 SPRINT-MS study. The 48 percent reduction in brain atrophy over two years seen with ibudilast compares favorably with the 18 percent reduction reported in separate studies of ocrelizumab, which in 2017 became the first FDA-approved therapy for progressive MS. “The SPRINT-MS results are very encouraging,” says Cleveland Clinic neurologist Robert Fox, MD, lead author and principal investigator of the 28-center, 255-patient trial.

Ibudilast, a small-molecule compound that takes on progressive MS via novel mechanistic pathways, was found to be well-tolerated. The oral therapy has been approved in Japan since 1989 for use in asthma and cerebrovascular disorders. “Our hope is that ibudilast’s benefit in slowing brain volume loss will translate to slowed progression of physical disabilities in patients with progressive MS,” notes Dr. Fox. See the full Consult QD story here.

Exploring the promise of an immunotherapy vaccine for glioblastoma

(Presented at the Society for NeuroOncology annual meeting in November)

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The immunotherapy vaccine SurVaxM is safe and appears to improve survival in patients with newly diagnosed glioblastoma compared with matched historical controls receiving standard therapy. So concludes a multicenter phase 2 trial of the vaccine led by Cleveland Clinic. SurVaxM stimulates the immune system to kill tumor cells that contain survivin, a protein that allows cancer cells to resist conventional treatments.

The single-arm trial included 63 patients with newly diagnosed glioblastoma who had undergone surgical resection, chemotherapy and radiation. Patients received four priming doses of SurVaxM with montanide and sargramostim every two weeks, after which they received adjuvant temozolomide therapy and maintenance SurVaxM every 12 weeks until progression. Progression-free survival at six months was 96.7 percent, and overall survival at 12 months was 94.2 percent.

“These results are encouraging,” says Cleveland Clinic neuro-oncologist Manmeet Ahluwalia, MD, who served as lead investigator and presented the findings. “Overall survival at 12 months with traditional treatment is about 60 to 65 percent.” Particularly notable, he adds, is that patients with poor prognostic factors — unmethylated MGMT and higher survivin levels — appeared to have better survival than would be expected. The next step is a randomized phase 2 trial. See the full Consult QD story here.

Teasing out sleep disorders’ role in neurological diseases

(Neurology. 2018;90(15 Supplement):P1.093)

One-third of neurological outpatients are at high risk for obstructive sleep apnea (OSA), and one-quarter have significant insomnia symptoms. So finds a retrospective analysis of 19,052 adults seen for initial outpatient visits at Cleveland Clinic centers for psychiatry, brain tumor, movement disorders, cerebrovascular disease and epilepsy over an 18-month period.

“These associations are of interest because there’s a vast body of literature showing that untreated sleep disorders are associated with worse disease-specific outcomes,” says Nancy Foldvary, DO, MS, Director of Cleveland Clinic’s Sleep Disorders Center. She served as senior investigator for the analysis, which was presented in April at the American Academy of Neurology’s annual meeting. The study was conducted using Cleveland Clinic’s Knowledge Program platform, which collects patient-reported health status measures at every visit for seamless integration into the electronic medical record.

Dr. Foldvary’s team is now analyzing similar outpatient data from other centers in Cleveland Clinic’s Neurological Institute. After publishing earlier findings that treating OSA with continuous positive airway pressure led to better seizure control in patients with epilepsy, Dr. Foldvary hopes to launch a study to see if similar benefits can be achieved in additional neurological populations. “Sleep impacts numerous neurological conditions, and treating sleep disorders may have trickle-down effects on the management of many of them,” she says. See the full Consult QD story here.

Amyloid reversal in mouse model boosts BACE1 inhibitors’ prospects in humans

(J Exp Med. 2018;215:927-940)

Depleting the BACE1 enzyme in middle-aged mice with a murine form of Alzheimer’s disease (AD) fully reverses formation of brain amyloid plaques and improves the animals’ cognitive function, reported researchers from Cleveland Clinic’s Department of Neurosciences. Their study found that genetic engineering to reduce BACE1 levels not only halted formation of amyloid plaques but actually reversed existing plaques. Additional AD hallmarks, such as microglial cell activation and formation of abnormal neuronal processes, also were reversed, and BACE1 reductions were associated with improved learning and memory in the mice.

The findings, which represent the first observation of a marked reversal of amyloid depletion in an AD mouse model, suggest the potential to treat AD in humans without significant toxicity. They give renewed support to the prospects of the BACE1 inhibitor class of experimental drugs for AD in humans, several of which have failed in clinical trials, perhaps because of use too late in the course of AD. “Ongoing human trials of BACE1 inhibitors address various stages of AD, including presymptomatic stages,” notes James Leverenz, MD, Director of Cleveland Clinic Lou Ruvo Center for Brain Health in Cleveland. “We’re hopeful these results in mice may translate to the human disease.” See the full Consult QD story here.

Finding a role for ultra-early thrombolysis in emergent large vessel occlusion

(Presented at the 2018 International Stroke Conference in January)

For patients with emergent large vessel occlusion (ELVO), ultra-early treatment with intravenous tissue plasminogen activator (IV tPA) increases rates of recanalization and improves clinical outcomes, according to a retrospective Cleveland Clinic study. The investigation is the first to look at ultra-early thrombolysis — within 60 minutes of symptom onset, the “golden hour” — specifically in the setting of ELVO.

Among 158 patients who received IV tPA for ELVO strokes at Cleveland Clinic, several key outcomes were significantly improved in those who received IV thrombolysis within 60 minutes versus those who received it later: rates of recanalization (28 percent vs. 7 percent), early neurological improvement (seen in 72 percent vs. 41 percent) and good neurological outcomes at 90 days (achieved by 52 percent vs. 26 percent).

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“Our data suggest that if we’re really quick in getting these patients to medical attention and giving tPA, treatment can be highly effective,” says senior investigator M. Shazam Hussain, MD, Director of Cleveland Clinic’s Cerebrovascular Center. “Initiating treatment within the first hour is difficult, but we’ve seen that new approaches, like the use of our mobile stroke treatment unit, can enable treatment of a much larger number of patients during that golden hour.” See the full Consult QD story (with video) here.

Established cancer drug extends survival tenfold in preclinical glioblastoma study

(Sci Transl Med. 2018;10(443):eaah6816)

A preclinical investigation by a Cleveland Clinic-led research team suggests that ibrutinib, a small-molecule drug approved by the FDA to treat lymphoma and leukemia, may also be effective against glioblastoma. The NIH-funded study offers hope that ibrutinib may ultimately help improve glioblastoma outcomes and survival, which are exceptionally poor.

The researchers found that ibrutinib suppressed tumor growth and increased survival in a mouse model of glioblastoma. It was significantly more effective in slowing tumor growth than the current standard-of-care chemotherapy for glioblastoma, temozolomide, and extended average survival by more than tenfold. Ibrutinib, which is given orally, works by inhibiting glioma stem cells, whose aggressiveness makes them a therapeutic target of great interest. Further research is needed to explore the agent’s effects in humans with glioblastoma, but lead investigator Shideng Bao, PhD, of Cleveland Clinic Lerner Research Institute, notes that since ibrutinib is already FDA-approved for use in humans, clinical trials of its use for glioblastoma — alone or in combination with current therapies — are already getting underway, as detailed in this Consult QD story.

EXPAND shows slowing of disability in secondary progressive MS

(Lancet. 2018;391:1263-1273)

For the first time, a disease-modifying therapy for secondary progressive multiple sclerosis (MS) has shown superiority over placebo in slowing patients’ disability progression in a large randomized trial. The trial was the multicenter phase 3 EXPAND study, whose results were published in March, and the therapy is siponimod, an investigational oral sphingosine-1-phosphate receptor modulator believed to act by decreasing inflammation and preventing synaptic neurodegeneration and/or promoting remyelination in the CNS.

The study randomized 1,651 patients to siponimod 2 mg once daily or placebo for up to three years or until their disability had progressed after six months. Siponimod yielded a relative risk reduction of 21 percent in the primary end point, confirmed disability progression at three months.

“This is an important finding, because no drug has yet consistently slowed disability progression in patients with the secondary progressive form of MS,” says coinvestigator and co-author Robert Fox, MD, of Cleveland Clinic. “Although the 21 percent relative risk reduction may seem modest, even numerically small changes in the Expanded Disability Status Scale score can correspond to substantial changes in neurological function and daily activities for patients with this disease. These results suggest siponimod may be a useful treatment for secondary progressive MS, though longer-term follow-up and regulatory approval are needed.” See the full Consult QD story here.

Finding success with biopsychosocial strategies for chronic back pain

(Presented at the American Academy of Pain Medicine annual meeting in May)

A novel rehabilitation program for chronic low back pain combining physical therapy (PT) with cognitive behavioral therapy (CBT) and pain neuroscience education significantly improves participants’ quality of life across multiple metrics. So reported Cleveland Clinic psychologist Sarah Rispinto, PhD, in a study presentation. The population health program, known as Back on TREK, yielded clinically significant changes in validated measures of social role satisfaction, pain interference in daily life, perceived disability, fatigue and overall physical health. It also improved depression and anxiety in nearly half of the retrospective study’s 116 participants, all of whom had chronic low back pain for at least three months.

Patients attend the 12-week program for at least three hours a week for a mix of individual and group PT sessions plus behavioral medicine group sessions involving instruction on pain neuroscience and CBT techniques. “Participants generally come to understand that pain is a biopsychosocial phenomenon and they can learn ways to self-manage it,” says Dr. Rispinto. “We hope to raise the profile of biopsychosocial approaches like this as first-line interventions for chronic back pain.” Ongoing research is comparing the program’s effectiveness to that of standard PT care and gauging its effect on opioid use and healthcare utilization over the long term. See the full Consult QD story here.