In the Pipeline for Treatment of Motor Fluctuations in Parkinson’s

The most disabling symptoms of Parkinson’s are probably postural instability leading to falls as well as cognitive and psychiatric disorders. Motor fluctuations are not far behind. These are short-duration responses to oral levodopa with “on” and “off” periods which can be unpredictable and sometimes impossible to treat.

Strategies currently available are deep brain stimulation, used for many years, and, more recently, intestinal infusions of levodopa gel. These methods are “invasive” and cumbersome, if not frightening, for many patients.

There are four new approaches in the pipeline.

The first focuses on sustained release. The “Accordion Pill” slowly releases levodopa. Also in trials is a continuous subcutaneous infusion of levodopa (think insulin). Subcutaneous apomorphine has been available as a “rescue” for off periods for decades and is now in late clinical trials as a continuous infusion (also think insulin).

The second is the rapid treatment of “off states.” Subcutaneous apomorphine does this but patients usually need a caregiver to give the injection. Easier is a levodopa inhalation device which delivers the medication into the lungs (think asthma). It is also in late clinical trials.

The third and the least promising, in my opinion, is to add on a daily oral medication with a different mechanism of action than levodopa to reduce off- time. There are several available now in the US and another drug (istradefylline) is marketed in Japan and is in trials in the US. This approach is limited: “another trial, another hour” of on-time.

The last is the most promising but the least likely to succeed, specifically using “viral vectors” to insert genes directly into the brain to enhance dopamine formation.

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What Is Preclinical Multiple Sclerosis?

Because MRI is easily available, occasional patients who have imaging for, say, headaches have typical MRI findings of multiple sclerosis without recognized symptoms. This is termed “radiologically isolated syndrome.” At least 50% develop typical symptoms within several years and are then diagnosed with clinically definite MS. There is thus a preclinical phase, during which patients accumulate MRI lesions without symptoms. In fact, 90% of MRI lesions cause no symptoms because the brain can compensate by making new synapses (connections between neurons). This ability is termed brain reserve. With age, brain reserve may fail and patients may then develop “progressive” MS.

Anorexia of aging
Jack Florin – Your Neurologist in Orange County.

A new study supports the idea of preclinical MS by identifying an “MS Prodrome.” Approximately 14,000 MS cases and 67,000 controls in four Canadian provinces were included. Medical records for the five years before the first MS symptoms were reviewed. Compared to the controls, people with MS utilized more health resources, mainly for musculoskeletal, genitourinary, and psychiatric symptoms. They more commonly saw urologists and psychiatrists and higher proportions received prescriptions.

See Multiple Sclerosis, July 1, 2018. Lead author is Wijnands.

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In the Pipeline for Treatment of Motor Fluctuations in Parkinson’s

The most disabling symptoms of Parkinson’s are probably postural instability leading to falls as well as cognitive and psychiatric disorders. Motor fluctuations are not far behind. These are short-duration responses to oral levodopa with “on” and “off” periods which can be unpredictable and sometimes impossible to treat.

Strategies currently available are deep brain stimulation, used for many years, and, more recently, intestinal infusions of levodopa gel. These methods are “invasive” and cumbersome, if not frightening, for many patients.

Lifestyle Changes to Prevent Dementia
Making Exercise Easier for People with Multiple Sclerosis

There are four new approaches in the pipeline.

The first focuses on sustained release. The “Accordion Pill” slowly releases levodopa. Also in trials is a continuous subcutaneous infusion of levodopa (think insulin). Subcutaneous apomorphine has been available as a “rescue” for off periods for decades and is now in late clinical trials as a continuous infusion (also think insulin).

The second is the rapid treatment of “off states.” Subcutaneous apomorphine does this but patients usually need a caregiver to give the injection. Easier is a levodopa inhalation device which delivers the medication into the lungs (think asthma). It is also in late clinical trials.

The third and the least promising, in my opinion, is to add on a daily oral medication with a different mechanism of action than levodopa to reduce off- time. There are several available now in the US and another drug (istradefylline) is marketed in Japan and is in trials in the US. This approach is limited: “another trial, another hour” of on-time.

The last is the most promising but the least likely to succeed, specifically using “viral vectors” to insert genes directly into the brain to enhance dopamine formation.

For more information, please visit our website.

 

Why We Itch

Fullerton Neurology and Headache Center of Orange County

Consider the famous case study which formed the basis for a New Yorker magazine piece. One year after developing ophthalmic herpes zoster (shingles), affecting the skin above the right eye, a woman developed an uncontrollable itch which resisted all treatment. Her hands and scalp were bandaged. Despite all this, she was able to scratch through the scalp and, incredibly, the skull to the point that her brain protruded through a large skull defect.

Itch can be dermatological, such as atopic dermatitis; systemic, such as in renal failure; psychogenic, such as in schizophrenia with delusions of insect infestation; and neuropathic such as in shingles, spinal nerve root compression, or stroke. Itch can be a phantom limb syndrome after an amputation. It may be the presenting symptom of malignancies, including lymphoma. Opioids commonly cause itch.

 

Unlike pain, itch can be felt only in the skin or mucosa lining the body’s entrances. Repeated scratching from neuropathic itch can discolor the skin and lead erroneously to a search for a dermatological cause.

An interesting neuropathic itch is “notalgia paresthetica,” affecting a large area in the back around the lower shoulder blade. This is a difficult spot to reach by hand and sufferers tend to rub their backs against door frames (think bears).

Unsurprisingly, treatment for neuropathic itch is difficult. Scratching temporarily relieves the itch by augmenting sensory input and becomes self-reinforcing. Breaking this cycle is critical. Cognitive behavioral therapy or medication can help. Medications that treat epilepsy and neuropathic pain can be tried. Antihistamines can help allergic but not neuropathic itch. Occlusive patches can help.

None of this, however, helped the woman with the protruding brain.

See Lancet Neurology, Vol 17, Aug 2018. Lead author is Steinhoff.

 

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Lifestyle Changes to Prevent Dementia—Are We Wasting Our Time?

Lifestyle Changes to Prevent Dementia
Lifestyle Changes to Prevent Dementia

For years, we have been counselling our patients that cognitive decline may be attenuated by healthy living. The usual canards are to exercise and maintain cognitive and social activities. Recently, the National Institute on Aging commissioned five reviews of the available scientific literature which were published in the Annals of Internal Medicine, January 2, 2018. Here are the conclusions.

Physical Activity—16 Trials: Neither single nor multiple component activity showed benefit. This included aerobic, strength, resistance, endurance, and balance training alone or in various combinations. In one large study, “multi-domain” physical activity along with dietary changes and cognitive activity was possibly helpful.

Pharmacological Interventions—51 Trials: These included currently available medications for Alzheimer’s, hypertension, diabetes, hyperlipidemia, as well as estrogen and NSAID’s. Results were inconsistent between trials.

Supplements—38 Trials: These were omega-3 fatty acids, vitamins B, D, E, beta-carotene, soy, ginko, singly or in various combinations.

Cognitive Training—11 trials: Computer-based training improved results but only for the specific tasks involved. Other interventions did not show consistent results.

The point is not that nothing can work but rather that nothing so far has been consistently proven to work.

Victims of Terror Have a Higher Risk of Migraine

migraine headache trauma stress risk

It’s painful to recall the 2011 mass shooting in a summer camp in Sweden during which a lone gunman shot to death 69 teens. All of the 362 survivors were exposed to extreme terror trying to escape and dealing with the loss of friends. Among the survivors, 213 (60%) participated in a study to determine if they had a higher risk of developing headaches. Among the girls, 45% vs 13% of a control group had daily or at least weekly headaches. Among the boys, it was 15% vs 4% for the controls.

Many studies have shown an association between repetitive or daily stress and migraine or tension-type headaches. Early childhood trauma or neglect is a strong predictor as well. But rarely can a single event of extreme psychological trauma have the same effect.

What’s the mechanism? It has been known for many years that stress triggers biological changes in the hypothalamic-pituitary-adrenal axis such as increased cortisol production or activation of the autonomic nervous system. Neurotransmitters such as serotonin, dopamine and endorphins are affected as well. Even subtle daily stressors probably can cause maladaptive persistent changes, which include effects on certain genes and connectivity in brain networks that mediate pain. Now we know that a single horrific event can do the same.

See Neurology, Vol 90, page 59. Lead author is Stensland. The editorial comment is by Heyer, page 53-54.

 

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The FDA Should Approve Marijuana to Treat Spasticity in Multiple Sclerosis

Readers of a review article by Giacoppo and others in Multiple Sclerosis and Related Disorders, 2017, pages 22-31, will probably agree with this statement. Sativex is a branded oromucosal spray containing tetrahydrocannabinol and cannabidiol in a 1:1 ratio. It has been available for years in Canada and has been approved in several European countries since 2013. Combining the two compounds reduces unwanted cognitive effects.

Marijuana use for Multiple Sclerosis patients
40% of MS patients have used cannabis

This review was a literature search extending back ten years. Spasticity affects 80% of MS patients, responds poorly to currently available medications and worsens disability and quality of life. 83% of MS-Sativex treated patients had reduction of spasticity. 65% were considered responders in the first month. There was no evidence that other MS symptoms worsened. 60% continued treatment long term. Those who stopped cited lack of efficacy or side effects. 83% thought they benefited.

10%, and usually only for in the first month, had side effects, such as dizziness, fatigue, and dry mouth. Less than 1% had psychiatric side effects, including paranoia, hallucinations, panic, suicidal ideation and cognitive decline. These generally cleared with lowering the dose or stopping treatment. There was no evidence of tolerance, abuse, diversion or addiction.

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Mood Disorders in Multiple Sclerosis Can Be Caused By Neuro-inflammation

Fatigue in Multiple Sclerosis is often linked to inflammation in certain areas of the brain rather being a consequence of lifestyle factors.

Now, a study concludes that anxiety and depression in MS may be driven mainly by uncontrolled neuro-inflammation rather than by the uncertainty of living with an unpredictable disorder or the feeling of loss that comes with disability.

Subclinical inflammation is defined as new or worsening MRI activity without recognized relapses or increased physical disability.

The main finding of the study was that new MRI lesions alone were associated with increased depression and anxiety. This concerned only “state” anxiety, often a temporary condition, and not “trait” anxiety, which is persistent and reflects one’s personality or temperament.

Steroids, used for relapses, often, though only temporarily, improve mood, perhaps because they reduce inflammation in the brain.

Atrophy of the hippocampus is linked to mood disorders in patients without MS. Similarly, inflammation is detectable in the cerebrospinal fluid and in measuring cytokines in about half of patients with affective and schizophrenic disorders.

Fatigue in Multiple Sclerosis often improves when patients switch to a more effective disease-modifying drug. This may also be true for mood disorders, although this has not been studied. Could anti-anxiety or anti-depressant drugs alone help the course of MS? In support of this idea, stress management therapy was found to reduce new active MRI lesions over the course of 24 months.

See Neurology, Volume 89, September 26, 2017, pages 1338-47.

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Your Neurologist in Orange County.
Your Neurologist in Orange County.

Serotonin Syndrome – Much ado about nothing

It seems that every week a pharmacist reminds me that prescribing a triptan (such as Imitrex) with an SSRI/SNRI ( antidepressants such as Prozac) puts my patient at risk for the dreaded “serotonin syndrome.” I can imagine the incredulous patient at the counter as the pharmacist says, “Dr Florin, are you sure want me to fill both?”

This is one of a number of drug-induced syndromes that can be life-threatening. But does taking a triptan and an SSRI really increase this risk? The FDA thinks so and issued an Advisory in 2006 based on a handful of poorly documented cases.

A previous study identified 624,000 patients using both without a single case identified. This was used to support the American Headache Society’s petition to the FDA to remove the warning. But it went nowhere. Now, a new smaller study confirms that the incidence is extremely low, if it exists at all.

This dilemma is relevant because depression is common in migraine patients and the combination of a triptan and an antidepressant is often helpful.

Please visit our center’s website for more information.

Your Neurologist in Orange County.
Your Neurologist in Orange County.

The Stigma of Migraine

The Stigma of Migraine
The Stigma of Migraine

Only half of people with migraine are diagnosed as such, and an even smaller number treated appropriately with triptans and still fewer are placed on preventatives.

Why should this be so? Perhaps the reason is that people with migraine believe that they do not have a real disease and may be embarrassed to seek care. They are often “stigmatized” and this leads to psychological distress, low self-esteem, and poorer social and health outcomes.

In a presentation at the 27th Annual Headache Cooperative of New England symposium, Robert E. Shapiro MD, reported on a survey of 765 people. They were given vignettes of 4 conditions that may not respond well to treatment: migraine, epilepsy, panic attacks and asthma. The respondents attributed less stigma to asthma than to the other three. No differences in the level of stigma were attached to migraine or panic disorder compared to epilepsy. This seemed surprising in that epilepsy at one point was thought to be caused by demonic possession.

Another opinion by those who completed the survey was that people with epilepsy try harder and are less likely to be malingers compared to those with migraine. Further, migraineurs who missed more work were thought to be less likely to try hard, more likely to be a malingering, less trustworthy and less likely to be interviewed for a job. There are many reasons for this stigma. Migraine is often considered to be a “women’s disease,” caused by “hormones” leading to annoyance rather than severe disability.

For more information, please visit our center’s website.