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Delays in Parkinson’s Treatment Due to Fear of Side Effects a Serious Problem, Neurologist Says

delays in treatments

A fear of the potential side effects of Parkinson’s disease treatments, dubbed “levodopa phobia,” can cause patients and their doctors to delay the use of these therapies, a neurologist says.

However, evidence suggests that starting adequate levodopa therapy early is safe, particularly for patients with increased functional disability, according to a lecture by Joseph Jankovic, MD, a professor of neurology at Baylor College of Medicine, which was presented by the Parkinson Voice Project (PVP.)

Jankovic’s lecture, “New and Emerging Treatments for Parkinson’s Disease,” was presented to patients and caregivers via Skype as part of the PVP’s Parkinson’s Lecture Series, from the Clark and Brigid Lund Parkinson’s Education Center. A video of the presentation is available online.

Disease-modifying therapies

There are no therapies currently available that slow or prevent the progression of Parkinson’s, though several are in clinical trials. A Phase 3 trial (NCT00256204), called ADAGIO, completed in 2011, suggested that early Azilect (rasagiline) treatment might be able to delay the progression of the disease. However, the study included two dosages, 1 mg and 2 mg, and while the benefits were true for the the lowest dose, they didn’t hold up for the larger dose. Because the two doses were associated with different outcomes, the results needed careful interpretation, and the U.S. Food and Drug Administration (FDA) did not approve Azilect as a disease-modifying therapy. 

Researchers are exploring several treatments with the potential to modify the disease, including inosine (which elevates urate levels), and isradipine (a calcium channel inhibitor). Both are in Phase 3 trials (NCT02642393 and NCT02168842).

However, Jankovic said, the “most important strategy in development” is reducing alpha-synuclein, the protein that doesn’t work properly and accumulates in the brains of Parkinson’s patients, leading to neuronal death.

Jankovic and his colleagues last year published a study based on a Phase 2 trial  (NCT03100149) of an antibody — prasinezumab (PRX002/RG7935) — that’s designed to clear alpha-synuclein proteins. The 80-patient, ascending-dose study showed that the treatment was safe, and reduced alpha-synuclein concentrations in the blood over the course of 52 weeks, with no serious adverse events reported. The study supported the continuation of the Phase 2 trial.

Similar antibodies currently being tested in trials include Biogen’s BIIB054 (NCT03318523), AstraZeneca’s MEDI1341 (NCT03272165) — both currently recruiting — and AbbVie’s ABBV-951 (NCT03781167), which is not yet enrolling participants.

Early symptomatic therapies

When patients first start to experience symptoms severe enough to require treatment, they and their doctors may be reluctant to start levodopa or levodopa-carbidopa — the most commonly used treatment for Parkinson’s symptoms — for fear they will develop motor complications such as dyskinesias.

Some patients may turn to natural supplements, such as bacopa extract or mucuna pruriens. Jankovic “strongly discouraged” the use of these products for “many, many reasons,” chief among them that some supplements contain levodopa at inconsistent doses.

An alternative for patients and neurologists concerned about starting levodopa too early are dopamine agonists such as Mirapex (pramipexole), Requip (ropinirole), Dostinex (cabergoline), and Permax (pergolide). Instead of helping the brain produce more of the dopamine it lacks, these treatments directly stimulate the receptors that dopamine would normally act on.

A 2009 study, which compared pramipexole with levodopa in patients who had not yet been treated with levodopa, found that 50% of those on pramipexole experienced dyskinesia, compared with 68.4% of the levodopa patients.

“There is no doubt that delaying levodopa therapy by using dopamine agonists early may delay the onset of levodopa-related motor complications,” Jankovic said.

Although levodopa has some potential for side effects in vitro (or in the laboratory), Jankovic said there is no evidence that this translates to patients. Therefore, delaying the use of the therapy, particularly for patients with increased functional disability, is not backed by currently available scientific data, he said.

However, he believes that because every patient is different, the timing, choice, and dosage of therapy must be individualized according to the needs of each particular patient.

Emerging and experimental therapeutics

Almost all patients with severe Parkinson’s who take levodopa or levodopa-carbidopa will, over time, experience motor fluctuations and dyskinesias. Thus, many emerging therapies are designed to make the treatment more effective and reduce the side effects.

There are three therapies work to extend the effectiveness of levodopa by maintaining increased dopamine concentrations in the brain. Xadago (safinamide) inhibits monoamine oxidase, an enzyme that normally breaks down dopamine. Opicapone works by preventing a different enzyme, catechol-O-methyltransferase (COMT), from breaking down dopamine. Gocovri (amandine) prevents cells from recycling dopamine.

Several new formulations of levodopa are intended to stretch the effects of a single dose, or act almost immediately to help patients recover from “off” episodes between doses.  

Rytary, a capsule that can be taken orally, contains beads of carbidopa-levodopa that dissolve and release the medicine at different times. Since the treatment needs to be taken more than once a day, patients end up ingesting a higher dose of levodopa than they would otherwise. But the effects start sooner and last longer than the common formulation of carbidopa-levodopa.

Researchers have experimented with administering the treatment continuously for 24 hours using an intestinal gel, which is surgically implanted into the small intestine and programmed to consistently administer the treatment at the appropriate dose.

But choosing this surgery “cannot be taken lightly,” Jankovic said. While patients did increase their “on” time without dyskinesia (by 4.11 hours for those who used the intestinal gel compared with 2.24 hours for those who used oral levodopa), almost all of the 66 patients in a 2014 study experienced gastrointestinal side effects as a result of the device insertion.

Jankovic also described the “accordion” pill currently being tested in a Phase 3 trial (NCT02605434). The pill, developed by Intec Pharma, is a multilayer film that unfolds in the stomach and stays there for 12 hours, releasing a combination of levodopa and carbidopa.

Rather than extending the life of a dose of levodopa, some companies develop “rescue therapies” that can be taken during “off” periods, or when treatment wears off. These therapies take effect almost immediately, and help the patient make it until their next scheduled dose of levodopa. Several forms — both approved and in trials — are dopamine agonists injected under the skin.

Other companies are developing dopamine agonists they hope will be delivered through less invasive methods, such as under the tongue, in the case of APL-130277, or through inhalation, like Inbrija.

Surgical therapies are gaining more attention, with scientists testing focused ultrasound, which was approved by the FDA at the end of 2018. However, it is available in very few centers, and costs more than $4 million.

Also during 2018, researchers conducted a pilot study of five patients suggesting that spinal cord stimulation may be able to help patients improve gait.

Jankovic says it is too early to meaningfully discuss several other experimental therapies, such as gene therapies or stem cell treatments. “Ask me in 10 years,” he said.

Different agents are being investigated to treat non-motor symptoms, including Exelon (rivastigmine) and memantine (sold under the brand name Namenda, among others) for cognitive impairment, paroxetine and venlafaxine for depression, and SEP-363856 for psychosis. Nuplazid (pimavanserin) is the only therapy currently approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

In addition to all the therapies on the market, Jankovic said, he “couldn’t emphasize enough the importance of physiotherapy,” and high-intensity exercise — “something that really makes you huff and puff.”

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Parkinson’s Patients with Poorer Quality of Life May Benefit the Most from Deep Brain Stimulation, Study Finds

dbs oucome quality of life

Individuals with Parkinon’s disease who have worse quality of life due to their disease-related impairments may benefit most from treatment with deep-brain stimulation.

The study with that finding, “Quality of life predicts outcome of deep brain stimulation in early Parkinson disease,” was published by the journal Neurology.

Deep-brain stimulation (DBS) is an invasive surgical technique in which thin wires are implanted in the brain to deliver electric pulses to specific areas, such as the subthalamic nucleus (STN), to ease motor symptoms in patients for whom standard medications are not effective.

Studies have shown that DBS can effectively help manage motor symptoms and reduce the necessary daily dose of medication, improving quality of life in those with advanced or early-stage Parkinson’s.

In a previous Phase 4 clinical trial (NCT00354133) called the EARLYSTIM study, researchers evaluated the long-term impact of STN-DBS as an add-on to best medical treatment regarding quality of life in patients with Parkinson’s disease for a period of more than two years.

The study enrolled patients younger than 61 who had a good response to levodopa therapy, but who still had developed motor complications. Among the participants, 124 were treated with DBS-STN and best medical treatment, while 127 patients received the best medical treatment only.

In the most recent study researchers reviewed the trial data to understand which factors contributed to the detectable changes in disease-specific quality of life, as measured using the 39-item Parkinson’s Disease Questionnaire summary index (PDQ-39-SI). The self-reported questionnaire assesses Parkinson’s-specific health across eight quality-of-life dimensions.

The analysis revealed that quality of life over the two years of follow-up correlated with the initial value of the PDQ-39-SI in both treatment groups. Still, this association was more pronounced among patients who were treated with STN-DBS.

Patients with very mild impairment due to Parkinson’s, corresponding to PDQ-39-SI values lower than 15, were found not to benefit from STN-DBS as compared to patients treated with standard care alone. In contrast, patients treated with STN-DBS who had PDQ-39-SI sores higher than 15 (worse quality of life) at the beginning of the study experienced better quality of life changes.

“In patients with very low baseline ratings on the PDQ-39-SI, the natural progression of impairment of [quality of life] may outweigh the improvement achieved by STN-DBS,” researchers wrote. “On the other hand, some patients with very modest impairment of their [quality of life] seem to have less to gain from STN-DBS,” they added.

Patients’ cognitive status before the treatment, as determined by the Mattis Dementia Rating Scale (MDRS), was not predictive of change in quality of life in either treatment group. However, higher scores for depression and poorer mood correlated with larger improvements in quality of life among patients in the STN-DBS group.

These findings “may indicate that these patients have a potential for nonmotor improvement to gain from surgery,” researchers suggested.

Changes in quality of life during the two years of follow-up were independent of patient age, disease duration, duration of motor complications, severity of parkinsonian motor manifestation under levopoda therapy, or treatment complications.

Supported by these findings, the team believes that “baseline impairment of quality of life is (…) a reasonable aspect to consider for the decision to treat with STN-DBS.”

“The subjective individual suffering as measured with the PDQ-39-SI should be taken into account as a predictive factor for outcome when selecting patients with early motor complications for STN-DBS,” researchers concluded.

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Deep-brain Stimulation Can Reverse Mitochondria Defects Linked to PD, Study Finds

DBS mitochondria

 

Deep brain stimulation therapy can help lessen Parkinson’s symptoms, partly by increasing the number of mitochondria — cells’ powerhouses — in brain nerve cells, a study shows.

The study, “Post mortem examination of Parkinson’s disease brains suggests decline in mitochondrial biomass, reversed by deep brain stimulation of subthalamic nucleus,” was published in The FASEB Journal.

DBS is an invasive technique in which thin wires are surgically implanted into the brain to deliver electric pulses to specific brain areas and ease motor symptoms, such as tremors, in patients for whom standard medications are not effective.

Studies have shown that DBS can effectively reduce motor symptoms and the necessary daily dose of medication, improving quality of life both in patients with advanced Parkinson’s and those  with early-stage disease.

However, despite being the most commonly used surgical treatment for Parkinson’s disease, the exact mechanisms through which DBS may work to help prevent nerve cells’ degeneration remain elusive.

Now, researchers at the Imperial College London analyzed brain cells collected from individuals with Parkinson’s disease who had either received DBS (three patients) or not (four patients), as well as from three healthy individuals. All the tissue samples were collected post mortem and had been stored at the Parkinson’s UK Brain Bank, at the Imperial College London.

The team found that Parkinson’s-affected brain cells had fewer mitochondria compared to healthy ones. Also, the mitochondria were not located inside the cells where they normally are, such as the synaptic terminals.  Synapses are junctions between two nerve cells that allow them to communicate.

“These results suggest a change in the availability of mitochondria in synaptic terminals as a precursor or a result of Parkinson’s disease,” researchers said.

Samples from patients who had undergone DBS had fewer mitochondria than control samples, but slightly more than Parkinson’s patients not treated with DBS. In addition, the volume of these energy-producing organelles in DBS-treated samples was closer to that observed in healthy brain cells.

“DBS treatment seemed to have inhibited or reversed the reduction in mitochondrial volume and numbers caused by Parkinson’s disease,” researchers wrote. These results suggest “enhanced metabolic plasticity leading to neuroprotection” in the brain areas most affected by the disease as a result of DBS.

Additional studies are still warranted to better understand the effects of DBS therapy on mitochondria and overall nerve cell survival.

“This potentially opens avenues for exploring how to replicate this cell power-up with non-surgical treatments, without the need for implanting electrodes in the brain,” Kambiz Alavian, PhD, lecturer in the department of medicine at the Imperial College London and senior author of the study, said in a news release written by Kate Wighton.

Brain tissue samples are one of the most reliable sources of information on neurological disorders. However, studies using this type of sample can be challenging, as they can only be performed after an individual has died.

“We now hope to carry out larger studies to explore new treatments that may preserve brain cell mitochondria. The ultimate goal would be to keep cells powered up for longer, and Parkinson’s symptoms at bay,” he said.

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Parkinson’s Patients on DBS Aren’t More Impulsive, Study Finds

deep brain stimulation, impulsivity

Parkinson’s patients treated with deep brain stimulation (DBS) are not more impulsive than other patients or healthy people toward food or monetary rewards, according to new research.

The study, “Deep brain stimulation of the subthalamic nucleus and the temporal discounting of primary and secondary rewards,” was published in the Journal of Neurology.

Although DBS of the subthalamic nucleus (STN) — a brain region hyperactive in Parkinson’s and implicated in motor control — is an effective way to ease the disease’s hallmark motor symptoms, it may induce confusion and changes in behavior and in decision-making processes, such as those regarding food. This may lead to a tendency toward risky decision-making in gambling tasks and increased impulsivity.

Aiming to better understand impulsivity in this patient population, a research team from Italy used a task called delay discounting, in which the patients had to decide whether they preferred an immediate, smaller reward over a larger one later. A preference for the immediate reward would be expected from impulsive participants. However, studies using monetary rewards in people with Parkinson’s who underwent DBS have led to contradictory results.

While money is a secondary reward, food is a primary reward as it is necessary for one’s survival. In rats, stimulation of the STN increased the motivation to obtain food, but reduced motivation toward cocaine, a secondary reward.

In accordance, Parkinson’s patients undergoing DBS attributed increased value to food rewards, which was associated with weight gain, a common non-motor side effect of the surgery.

The 45 participants were divided into three groups: 15 Parkinson’s patients who underwent bilateral DBS into the STN (mean age 62.8 years, 4.4 years since the surgery), 15 patients without DBS on dopaminergic replacement therapy (mean age 69.1 years) and 15 healthy controls (mean age 67.7 years).

All patients were tested under their best medical treatment condition, which means on stimulation in DBS and on medication for dopaminergic treatment.

All participants performed three computer tasks where they had to choose a smaller reward immediately or a reward that was larger but delayed — by two days, two weeks, one month, three months, six months, or one year.

“In these tasks, the choice usually depends on the time that passes between one option and the other: if it is very short, delayed gratification is chosen and vice versa,” Marilena Aiello, the study’s lead author, said in a press release.

In the food task, the participants were asked to choose from six foods, three sweet and three salty. When using discount vouchers as rewards, they had to choose from six hobbies or activities presented through pictures — a theater trip, a restaurant visit, book purchases, gardening equipment, sewing tools, or tools to paint — for which they would like to get a discount voucher.

The results revealed no differences in food or discount voucher choice comparing the three groups, even in patients who experienced weight gain and/or eating alterations after DBS.

The data further showed greater preference for immediate rewards — greater impulsivity — in patients with fewer years since DBS, on higher doses of levodopa, and with better memory.

“Our study confirms that patients with DBS are no more impulsive in this kind of situation and they do not try to find gratifications more hastily than the others,” Aiello said.

The investigators said, “In addition, our results also extend the current literature by showing, for the first time, that this result is independent of the type of reward.”

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Having More Comorbidities Linked with Confusion After DBS in Parkinson’s Patients

deep brain stimulation, confusion

Having a higher number of comorbidities is associated with postoperative confusion in Parkinson’s patients undergoing deep brain stimulation (DBS), according to a new study in Brazilian patients.

The study, “Postoperative Confusion in Patients with Parkinson’s Disease Undergoing Deep Brain Stimulation of the Subthalamic Nucleus,” appeared in the journal World Neurosurgery.

DBS targeting the subthalamic nucleus (STN) — a brain region hyperactive in Parkinson’s patients and implicated in motor control — has been shown to ease motor symptoms, but it may be associated with side effects such as postoperative confusion. This complication may damage the surgical hardware due to agitation and require treatment with antipsychotics, many of which are contraindicated in Parkinson’s.

Postoperative confusion has been correlated with imaging and clinical factors, such as older age and longer disease duration. However, no studies explored its incidence and associated factors in Brazilian patients with Parkinson’s undergoing DBS of the STN.

Aiming to address this, researchers conducted a retrospective chart review of 49 patients (33 men, mean age 57.5 years) undergoing this procedure from January 2013 to October 2017 at Hospital de Clínicas de Porto Alegre, in Brazil. Patients with dementia, severe/untreated neuropsychiatric disorders, or spontaneous or antiparkinsonian medication-induced psychosis were excluded. All surgeries were performed under local anesthesia.

Among the analyzed imaging factors were brain atrophy, or shrinkage; lesions in the white matter — made of nerve fibers — intracranial hemorrhage after surgery, and ventricular wall transgression (breaching the walls of the brain’s ventricles, a network of interconnected cavities). Clinical factors evaluated included gender, history of depression and hallucinations, age, disease duration, comorbidities — the presence of one or more additional diseases or disorders co-occurring with Parkinson’s — length of hospital stay, and duration of surgery.

Confusion was defined as any degree of disorientation and attention and/or perception impairment, associated with cognitive dysfunction and with a sudden beginning and short duration, from the first postoperative hours until hospital discharge.

The results showed that the incidence of postoperative confusion was 26.5% (13 patients), which was higher than in prior studies, researchers noted. This may have been due to the small number of patients in their study and to technical differences in DBS, they suggested.

In comparison to patients not developing confusion, those with confusion were older (mean age 63.2 vs. 55.4 years), had longer disease duration (16.5 vs. 13.2 years), higher comorbidities, longer hospital stays after surgery and a greater width of the third ventricle, one of the four brain ventricles.

There was a trend toward more intracranial hemorrhage in patients who developed confusion, as assessed with computed tomography, although not statistically significant. No patient needed re-intervention or prolonged sedation.

A subsequent statistical analysis accounting for potential confounding factors revealed that only the association with comorbidities remained significant. The team commented that “it is well-recognized that the presence of various comorbidities is a risk factor for postoperative delirium.”

The investigators said that studies with larger groups of patients are needed to identify which variables are more relevant in the development of confusion in Parkinson’s patients undergoing this surgery.

 

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Study Highlights Importance of Personalized Parkinson’s Treatment

DBS IJLI Apokyn comparative study

Invasive treatment approaches for advanced Parkinson’s disease have differential effects on disease-associated motor and non-motor symptoms, a real-life observational study shows.

These findings suggest that selection of a treatment should be based on each patient’s particular clinical profile, researchers say.

The study, “EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson’s disease,” was published in Movement Disorders.

Parkinson’s is a progressive neurological disease mostly recognized for its motor symptoms, such as tremor, bradykinesia (impaired body movement control), and muscular rigidity. In advanced cases, oral therapies may not be sufficient to control these motor symptoms and patients often require device-aided therapies.

There are three well-established, safe, and effective treatments to improve quality of life and alleviate motor and non-motor symptoms of Parkinson’s disease: deep brain stimulation, intrajejunal levodopa infusion (IJLI), and Apokyn (apomorphine) infusion (APO).

In deep brain stimulation, electrodes are surgically implanted in certain areas of a patient’s brain. Through electrical signals received from a small device, the electrodes will stimulate these brain areas to produce dopamine — the chemical compound (neurotransmitter) lacking in Parkinson’s disease.

IJLI is one of the most influential therapies used in patients with moderate to late-stage Parkinson’s disease, shown to have positive effects on both motor and non-motor symptoms and quality of life. This approach uses a portable infusion pump that continuously dispenses levodopa gel through a tube inserted into the intestine.

Apokyn is an engineered therapy that mimics dopamine’s ability to stimulate nerve cells. Unlike other dopamine agonist agents, Apokyn is administrated by injection or continuous infusion using a pump.

Despite the demonstrated efficacy of these therapies, there is little information comparing their impact.

An international group of researchers, on behalf of the EUROPAR and the Non-motor Parkinson’s Disease Study Group of the International Parkinson’s Disease and Movement Disorders Society, compared the differential effects of DBS applied to the subthalamic nucleus (STN), IJLI, and APO in patients with advanced Parkinson’s disease.

The study included 101 Parkinson’s patients who underwent bilateral STN-DBS, 33 who received IJLI, and 39 patients who received APO treatment. Patients had a mean age of 62.3 years and had been diagnosed with the disease for a mean of 12.1 years.

Six months after receiving the treatment, patients were evaluated to determine changes in Parkinson’s symptoms.

Significant improvements concerning non-motor symptoms and motor-related complications were noted in the three groups of patients six months after receiving the treatment, as determined by the Nonmotor Symptom Scale (NMSS) and Unified Parkinson’s Disease Rating Scale-motor complications (UPDRS-IV), respectively.

Significant changes in quality of life, as assessed by the Parkinson’s Disease Questionnaire-8 Summary Index (PDQ-8 SI), were also reported by all treatment groups during follow-up.

IJLI and APO treatments were found to effectively prevent disease worsening during the follow-up period, according to Hoehn and Yahr scores, which rate severity of symptoms in Parkinson’s disease.

STN-DBS treatment reduced the amount of daily levodopa use by approximately 52%. As expected, levodopa equivalent daily dose remained stable in infusion therapies.

The three treatment approaches were found to have similar effects on dyskinesia (involuntary movements)/motor fluctuation ratios. In contrast, they had different effects on patients’ non-motor symptoms.

A more detailed analysis showed that STN-DBS had a significant positive effect on sleep and fatigue, mood and cognition, perceptual problems and hallucinations, urinary symptoms, and sexual function.

IJLI had a positive effect on sleep, mood, and cognition, and gastrointestinal symptoms, while APO therapy significantly improved patients’ mood and cognition, lessened occurrence of perceptual problems and hallucinations, as well as improved attention and memory.

In general, STN-DBS and IJLI seemed to improve non-motor symptom burden, and APO therapy was favorable for neuropsychological and neuropsychiatric symptoms and improved quality of life.

Patients who underwent IJLI treatment had more frequent non-serious adverse events (abdominal pain and gastrointestinal symptoms) immediately after the procedure, compared to those in the other two groups.

“Distinct effect profiles were identified for each treatment option,” researchers said. “This study highlights the importance of holistic assessments of motor as well as non-motor aspects of Parkinson’s that could provide a means to personalize treatment options to patients’ individual disease profiles.”

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Deep Brain Stimulation May Increase Dementia Risk in Some Parkinson’s Patients, Study Suggests

deep brain stimulation

Parkinson’s disease patients with mild cognitive impairment who undergo deep brain stimulation are at a higher risk of cognitive decline and dementia, a long term “real-life”study suggests.

The study, “Longterm outcome of cognition, affective state, and quality of life following subthalamic deep brain stimulation in Parkinson’s disease,” was published in the Journal of Neural Transmission.

Subthalamic nucleus-deep brain stimulation (STN-DBS) is a surgical treatment for Parkinson’s motor symptoms where a device that generates electrical impulses is implanted into specific regions of the patient’s brain.

Increasing evidence suggests that STN-DBS significantly improves motor symptoms as well as some non-motor symptoms, such as sensory issues and sleep disturbances. However, some reports point to a potential decline in cognition in Parkinson’s patients following STN-DBS.

Researchers here investigated the cognitive status of 104 Parkinson’s patients who received STN-DBS for nine years, from 1997 and 2006, at a single center in Germany.

Neuropsychological data from before the surgery were available for 79 of the patients, of whom 37, diagnosed with Parkinson’s for more than 11 years, were followed long term for a median of 6.3 years after surgery. During this time, they underwent several neuropsychological and motor tests.

In the remaining 42 patients, no follow-up was possible due to patients’ death (21 of the cases), loss of contact (nine patients) and patients’ refusal to undergo follow-up (12 patients).

Researchers measured patients’ dementia rate (using the Mattis dementia rating scale) and cognitive status, focusing on five domains — memory, executive function, language, attention, and working memory — mood (depression and anxiety), and quality of life using the Parkinson’s Disease Questionnaire and the 36-item Short-Form Health Survey.

Motor function was assessed using several motor tests, including the Unified Parkinson Disease Rating Scale motor subscore (UPDRSm) and Hoehn and Yahr Stage, a widely used clinical rating scale, with broad categories of motor function in Parkinson’s.

Prior to the surgery, 28 patients (75.7%) had mild cognitive impairment, while nine patients (24.3%) had normal cognitive function. Moreover, no patients showed signs of Parkinson’s-related dementia.

Patients in the two groups — with and without mild cognitive impairment — showed no differences in age, disease duration, response to treatment, and dosage with levopoda, motor function, and education. Mood and quality of life were also similar.

Patients’ verbal intelligence, measured by a multiple choice word test, and memory were lower in the mild cognitive impairment group.

After undergoing STN-DBS, 18.9%, or seven, of the patients had no cognitive impairment, while the remaining patients (41%) were diagnosed with either mild cognitive impairment (15 patients) or dementia (15 patients).

Mild cognitive impairment has been previously identified as a risk factor for dementia in Parkinson’s patients. Twenty-eight patients categorized as having mild cognitive impairment before STN-DBS developed dementia within 6.3 years after surgery.

Researchers observed a trend, although not statistically significant, between mild cognitive impairment before STN-DBS and progression to dementia according to the patients’ age, sex, and education at the beginning of the study.

Compared with non-demented Parkinson’s patients, those with dementia had longer disease duration (15 years versus 20.2 years, respectively) and more severe motor impairments (UPDRSm score of 23.7 versus 36.1), with demented patients showing a faster progression of several typical Parkinson’s symptoms — bradykinesia (slowness of movement), rigidity, impaired speech, posture, gait, and postural stability.

In general, researchers observed a decline in cognition, including memory and language, in all STN-DBS-treated patients in the 6.3 years after surgery. However, partial working memory (also referred to as short-term memory) was preserved and slightly improved in some cases.

Disease duration, but not age, at the time of DBS surgery had a significant relation to the risk of developing dementia.

“This observational, ‘real-life’ study provides long-term results of cognitive decline in STN-DBS-treated patients with presurgical [mild cognitive impairment] possibly predicting the conversion to dementia,” the researchers wrote.

“Although, the present data is lacking a control group of medically treated PD [Parkinson’s disease] patients, comparison with other studies on cognition and PD do not support a disease-modifying effect of STN-DBS on cognitive domains,” they concluded.

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Deep Brain Stimulation Technique Lessens Parkinson’s Dyskinesia, Study Finds

deep brain stimulation, dyskinesia

Using a parameter called interleaving stimulation (ILS) in deep brain stimulation (DBS) eased dyskinesia — involuntary, jerky movements — in patients with Parkinson’s, according to a new study.

In contrast, the benefits in people with tremor or dystonia — abnormal muscle tone — or in mitigating DBS-induced adverse side effects were not as evident.

The study, “Interleaving Stimulation in Parkinson’s Disease, Tremor, and Dystonia,” was published in the journal Stereotactic and Functional Neurosurgery.

DBS is a surgical treatment for Parkinson’s motor symptoms that involves implanting a device to stimulate specific brain regions using electrical impulses generated by a battery-operated neurostimulator.

ILS is a variant of DBS that enables alternating stimulation with two contacts on different brain regions set with specific measures — amplitude, or wave height, and pulse width. ILS may be applied to lessen stimulation-induced adverse side effects and to simultaneously target different brain regions to ease specific symptoms.

Researchers assessed the applications and outcomes of ILS in clinical practice for patients with Parkinson’s, tremor, and dystonia. The team conducted a review through June 2015, by searching the electronic database at Toronto Western Hospital for all patients receiving DBS and ILS.

ILS was preformed in 50 patients — 27 with Parkinson’s (19 men), seven with tremor (three men), and 16 with dystonia (three men). Mean age at diagnosis was 48 for patients with Parkinson’s, 48.6 for people with tremor, and 23.8 for those with dystonia. Age at surgery was 58, 57.8 and 37.8, respectively.

Pre- and post-operative assessments (at six months) were performed with validated scales, including the Unified Parkinson’s Disease Rating Scale part III (motor section), the Fahn-Tolosa-Marin Tremor Rating Scale for patients with tremor, and the Toronto Western Spasmodic Torti-collis Rating Scale and the Burke-Fahn-Marsden Dystonia Rating Scale specifically for those with dystonia.

Twenty-nine patients underwent ILS to manage stimulation-induced adverse effects, mainly to reduce the volume of activated tissue (the amount of brain tissue that is stimulated by electrical activity in DBS). Nineteen participants — 14 with Parkinson’s, two with tremor and three with dystonia — experienced a reduction of symptoms, while 10 (seven with Parkinson’s, one with tremor and two with dystonia) saw no change.

Overall, the benefit of using ILS was predominantly noted in the lessening of dyskinesia — the involuntary, jerky movements — in patients with Parkinson’s disease, and occurred soon after the switch. The average duration of ILS in the six Parkinson’s patients who continued on this approach was 206 days.

Six additional patients also experienced easing of dyskinesia but discontinued the therapy due to worsened pain or mood, temporary benefit, and worsened motor function.

Of the nine Parkinson’s patients receiving ILS for other stimulation-induced adverse effects, only one who tried ILS for dysarthria (slurred or slow speech) continued the treatment with further improvement in parkinsonism.

Three patients with tremor and five with dystonia were receiving ILS for stimulation-induced adverse events. Among these, the approach had mixed results, with only three participants with dystonia showing improvements.

A total of 21 participants tried ILS to improve DBS clinical effectiveness (six Parkinson’s; four tremor; 11 dystonia). Of these, all six Parkinson’s patients and three with dystonia demonstrated benefits. Of the patients with Parkinson’s (mean ILS duration 420 days), four had ILS to reduce tremor, one to lower bradykinesia (slowness of movement), and one to lessen freezing of gait. ILS was not effective in people with tremor and only two patients with dystonia continued with the treatment.

“We identified 2 reasons for attempting ILS: to mitigate adverse effects and to improve disease signs and symptoms,” researchers wrote. “The most impressive finding was improvement of dyskinesias with ILS …  In tremor and dystonia, marginal effects in terms of mitigation of adverse effects and improvement of clinical outcomes were evident,” they added.

“Overall, ILS appears to have limited benefits in the treatment of other stimulation-induced adverse effects potentially due to minimal adjustment of the VAT [volume of activated tissue] and would unlikely be effective to salvage a misplaced electrode,” they concluded.

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Wireless Pacemaker-like Device May Offer Real-time Treatment for Parkinson’s, Study Reports

neuromodulator for Parkinson's

A new neuromodulator — a wireless pacemaker-like device — may provide real-time treatment to patients with diseases such as Parkinson’s by monitoring abnormalities and delivering corrective electrical signals to the brain.

The device was described in the study, “A wireless and artefact-free 128-channel neuromodulation device for closed-loop stimulation and recording in non-human primates,” published in the journal Nature Biomedical Engineering.

Recent studies have shown that closed-loop neuromodulation systems could improve deep brain stimulation for treating Parkinson’s disease and other motor disorders. These systems deliver and adjust therapeutic electrical stimulation in response to a patient’s neural state in real time.

Up to this point, it has been difficult, both medically and economically, to apply closed-loop neuromodulation systems in patients with movement disorders, and it hasn’t been clear how to implement strategies for these treatments. Previous attempts were short term, using systems that were not fully implantable.

“In order to deliver closed-loop stimulation-based therapies, which is a big goal for people treating Parkinson’s and epilepsy and a variety of neurological disorders, it is very important to both perform neural recordings and stimulation simultaneously, which currently no single commercial device does,” study author Samantha Santacruz, PhD, now an assistant professor at the University of Texas, said in a press release.

To enable advanced research in closed-loop neuromodulation, “there is a need for a flexible research platform, for testing and implementing these various closed-loop paradigms, that is also wireless, compact, robust and safe,” the researchers wrote in the study.

The researchers, from the University of California, Berkeley and Cortera Neurotechnologies, introduce a new device in this study that allows simultaneous recording and stimulation of the brain. The WAND — wireless artifact-free neuromodulation device — is a miniaturized, autonomous neural interface capable of closed-loop sensing and stimulation while fully canceling stimulation artifacts — recorded electrical signals coming from the device. With this WAND, electrodes are surgically implanted inside the brain, with chips contained in a chassis attached to the outside of the head.

Existing devices can detect neural biomarkers electrical signatures indicative of abnormal brain processes and stimulate the brain in a closed-loop neuromodulation system, but they contain a low number of recording and stimulating channels. WAND improves on these limitations by incorporating a large number of recording and stimulation channels and a wireless data rate to support a large number of streaming channels. The technology also automatically adjusts stimulation parameters.

“The process of finding the right therapy for a patient is extremely costly and can take years. Significant reduction in both cost and duration can potentially lead to greatly improved outcomes and accessibility,” said Rikky Muller, PhD, an assistant professor of electrical engineering at University of California, Berkeley. “We want to enable the device to figure out what is the best way to stimulate for a given patient to give the best outcomes. And you can only do that by listening and recording the neural signatures.”

In a study of non-human primates, WAND enabled long-term recordings of local brain activity and the real-time cancellation of stimulation artifacts. The researchers proved that the closed-loop system device was causing changes in brain activity by using stimulation to create a functional change in the primates’ behavior during a routine task. To this end, the device enables neuroscientific discovery and preclinical investigations of stimulation-based therapeutic interventions.

“While delaying reaction time is something that has been demonstrated before, this is, to our knowledge, the first time that it has been demonstrated in a closed-loop system based on a neurological recording only,” Muller said. “In the future, we aim to incorporate learning into our closed-loop platform to build intelligent devices that can figure out how to best treat you, and remove the doctor from having to constantly intervene in this process.”

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Focused-ultrasound Lesion Surgery Can Treat Tremors and Improve Life Quality, Study Says

tremors and surgery

Treating tremor in Parkinson’s patients using non-invasive and focused-ultrasound lesion surgery is associated with better quality of life when compared to deep brain stimulation, although both approaches are equally effective in easing this disease symptom, a review study reports.

The study, “Outcomes in Lesion Surgery versus Deep Brain Stimulation in Patients with Tremor: A Systematic Review and Meta-analysis,” was published in the journal World Neurosurgery.

At least 50 percent of people with Parkinson’s, essential tremor (ET) or multiple sclerosis (MS) given oral medications as a first-line treatment for tremor — defined as an involuntary, uncontrollable muscle contraction; most commonly in the hands — do not tolerate these medications over the long term.

Current alternatives include deep brain stimulation (DBS) and lesion surgery (LS), which induces lesions on targeted areas using a heated electrode or focused ultrasound. Prior comparisons have shown that while the two techniques are equally effective in suppressing tremor, DBS led to a greater improvement in function.

But LS with focused ultrasound is gaining in popularity, and one study suggested that it may significantly improve tremor and quality of life.

Researchers at Harvard Medical School conduced a systematic review and a meta-analysis — a type of statistical study that combines the results of various studies — to determine which strategy is most effective in diminishing tremor severity and improving life quality and function in people with Parkinson’s, ET, or MS.

Three online databases were searched for results of randomized clinical trials published up to Jan. 1, 2018, and that included adults treated with either LS or DBS, or serving as controls. Both DBS and LS studies targeted unilateral or bilateral thalamus, pallidum or subthalamic nucleus, all of which are implicated in motor function.

Thirteen Parkinson’s trials were among the 15 included in this study, and the primary outcome for all but one was change in upper limb tremor severity, as assessed with the unified Parkinson’s disease rating scale (UPDRS) part III. Changes in quality of life, cognitive function and neuropsychiatric function were also assessed with variable measures.

A total of 1, 508 patients (mean age range, 48.4 to 70.8) were included, and in addition to the 13 studies involving only Parkinson’s patients, one study looked at people with Parkinson’s, ET and MS, while the remaining study was in people with severe ET.

Four of the 15 trials — involving 125 patients — directly compared DBS to LS. The others compared either LS or DBS with controls.

Results showed that DBS and LS were not significantly different across all analyzed outcomes, which is in line with current guidelines, the researchers noted. All but one trial showed both these types of surgery eased tremor severity. Quality of life findings showed variability in outcomes, which was driven by disease duration. Specifically, longer disease duration correlated with a greater likelihood of surgery and better quality of life.

A subgroup analysis that looked specifically at LS using focused ultrasound revealed that this approach was associated with a significant improvement in quality of life compared to DNS, although changes in tremor severity were similar.

“Policy makers, healthcare providers, and patients could therefore consider focused-ultrasound [LS] as a potential choice for tremor control, based on currently available evidence,” the researchers wrote.

However, results from more studies directly comparing DBS with focused-ultrasound LS are needed, they advised.

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